Subiculum

Only primates have temporal lobes, which are largest in man, accommodating 17% of the cerebral cortex and including areas with auditory, olfactory, vestibular, visual and linguistic functions. Association fibres connect all parts of the cerebral cortex with the parahippocampal gyrus and subiculum, which in turn project to the dentate gyrus. The largest efferent projection of the subiculum and hippocampus is through the fornix to the hypothalamus. http://www.ncbi.nlm.nih.gov/pubmed/22934160

Whole-brain voxel based morphometric analysis found that higher total Lifetime Experiences Questionnaire scores are linked with increased grey matter volume in the medial temporal lobe, especially in the hippocampus. Through a series of more specific analyses, we found that supervisory and managerial experience in midlife was the dominant contributor to this effect. The rate of hippocampal atrophy in late-life in those with high level supervisory experience in midlife was five-times slower than those with no midlife supervisory experience. For the first time, we reveal that managerial and supervisory experience during our working life is connected to hippocampal integrity after retirement, some 20-30 years later. http://www.ncbi.nlm.nih.gov/pubmed/22902920

The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). http://www.ncbi.nlm.nih.gov/pubmed/15217334

The presubiculum, but not parasubiculum, was strongly reactive for glycogen phosphorylase. These patterns confirm earlier evidence that glycogenolytic demand in Layers I and III of rat entorhinal cortex is organized in a modular fashion and show that such demand can be modified by brief exposure to a novel holeboard. http://www.ncbi.nlm.nih.gov/pubmed/16229987

The anterior thalamic nuclei consist of the anterodorsal (AD), anteroventral, and anteromedial nuclei, each of which are highly differentiated and may contribute to different aspects of various cognitive and memory functions. The data show that the AD provides strong projections to layers I and IV of area 30 and to layers I, III, IV, and VI of area 29 in the retrosplenial cortex, and to layers I and III-VI of the presubiculum. The projections to the presubiculum are not organized topographically. Other minor projections were also observed in the parasubiculum and part of the medial entorhinal area. These results indicate that the AD provides strong projections to the retrosplenial cortex and presubiculum, suggesting that these projections constitute essential pathways to these cortical regions for transmitting mnemonic information, such as a novel conditioning stimulus during the initial stage of avoidance learning. http://www.ncbi.nlm.nih.gov/pubmed/22314639

These findings indicate selective early involvement of the CA1 and subiculum regions of the hippocampus and provide new information on early anterior pole involvement in the entorhinal cortex in incipient AD. http://www.ncbi.nlm.nih.gov/pubmed/22289801

The dorsal presubiculum (also known as the postsubiculum) is critically important for the direct transfer of visual landmark information to spatial signals within the limbic system. http://www.ncbi.nlm.nih.gov/pubmed/21982585

Interestingly, maltreatment was associated with 4.2% and 4.3% reductions in the left presubiculum and subiculum, respectively. http://www.ncbi.nlm.nih.gov/pubmed/22331913

The medial temporal lobe (MTL) encompasses a network of interconnected cortical areas that is considered the neural substrate for some types of memory, such as spatial, episodic, recognition, and associative memory. Within the MTL, the subiculum has been well characterized in terms of its connectivity and structure. However, the dorsal subiculum (DS) is also reciprocally connected to the perirhinal and postrhinal cortices, which are critically involved in recognition memory. This connectivity pattern suggests that DS might encode not only spatial signals but also recognition signals. Theta power was significantly higher in DS when mice explored novel objects as compared to familiar objects and that this theta modulation was absent in CA1. We also detected DS units that were responsive specifically to novel object exploration, indicating that a subset of DS neurons were tuned to novelty during the NOR task. http://www.ncbi.nlm.nih.gov/pubmed/22833721

Synaptic glutamate signaling in brain is highly complex and includes multiple interacting receptors, modulating cotransmitters and distinct regional dynamics. Hippocampal imaging studies in schizophrenia have identified 2 alterations in MTL - increases in baseline blood perfusion and decreases in task-related activation. These observations along with converging postsynaptic hippocampal protein changes suggest that homeostatic plasticity mechanisms might be altered in schizophrenia hippocampus. If hippocampal pattern separation is diminished due to partial dentate gyrus failure (resulting in "spurious associations") and also if pattern completion is accelerated and increasingly inaccurate due to increased CA3 associational activity, then it is conceivable that associations could be false and, especially if driven by anxiety or stress, could generate psychotic content, with the mistaken associations being laid down in memory, despite their psychotic content, especially delusions and thought disorder. http://www.ncbi.nlm.nih.gov/pubmed/22532703

ERPs were recorded in epilepsy patients from multicontact depth electrodes, implanted along the longitudinal axis of MTL. Patients had to respond to rare visual target stimuli by a button press. Target detection resulted in large MTL-P300 potentials in the hippocampus and subiculum. Their latencies did not differ. The hippocampal P300 amplitude increased linearly from anterior to posterior hippocampal body (HB). In contrast, an inverse gradient with larger mean amplitudes in anterior parts was observed for the subiculum. Our results indicate two separate generators of the MTL-P300, one in the anterior subiculum and one in the posterior HB. Since latencies did not differ, a parallel activation via the entorhinal cortex might have initiated the simultaneous MTL-P300. Hippocampus and subiculum are essential parts of the MTL-memory system. Their function within target detection might be to maintain a template of previous stimuli for a comparison with incoming sensory stimuli. http://www.ncbi.nlm.nih.gov/pubmed/19437422

The firing pattern of the ensemble of MTL neurons showed robust temporal autocorrelation over macroscopic periods of time during performance of the memory task. The gradually-changing part of the ensemble state was causally affected by the visual stimulus being presented. Critically, repetition of a stimulus caused the ensemble to elicit a pattern of activity that resembled the pattern of activity present before the initial presentation of the stimulus. These findings confirm a direct prediction of this class of temporal context models and may be a signature of the mechanism that underlies the experience of episodic memory as mental time travel. http://www.ncbi.nlm.nih.gov/pubmed/22488671

Objective perceptual identity correlated with activity in the left MTL, while subjective memory experience correlated with activity in the right MTL for both types of material. http://www.ncbi.nlm.nih.gov/pubmed/22230115

When a subject judged the word as "old," a second judgment was made concerning the physical similarity of the two pictures. Repetition related changes in MTL activation varied depending on whether or not subjects could correctly state that pictures were different. Moreover, psychophysiological interactions analyses showed that accuracy in recalling whether the two pictures were different was predicted by repetition-related changes in the functional connectivity of MTL with frontal regions. Specifically, correct recollection was predicted by increased connectivity between the left posterior hippocampus and the right inferior frontal gyrus, and also by decreased connectivity between the left posterior hippocampus and the left precentral gyrus on the second stimulus presentation. http://www.ncbi.nlm.nih.gov/pubmed/22807169

The role of the subiculum within the behavioural inhibition system. It receives information about available goals from areas that plan motor action. This is filtered by earlier elements of the essentially unidirectional hippocampal circuit that essentially block familiar and unimportant information while passing to the subiculum important information. The function of the subiculum is to compare and integrate this goal information and produce output when conflict between incompatible goals is detected. This output prevents execution of the responses that would address the conflicting goals, increases the valence of affectively negative stimuli and associations and releases external exploration and internal rumination intended to resolve the conflict. These subicular outputs are held to be computationally simple but to have complex consequences both because of the complexity of the target areas and because, in many cases, processing is recursive. It can involve multiple passages of essentially the same information round loops such as the circuit of Papez--each pass refining the solution to the original problem of conflicting goals. http://www.ncbi.nlm.nih.gov/pubmed/16887202

The most prominent cortical projections from the dorsal CA1 and the dorsal parts of the subicular complex are to the retrosplenial and anterior cingulated cortices in rats and monkeys — two cortical regions involved primarily in the cognitive processing of visuospatial information and memory processing  and environmental exploration (spatial navigation) in rats, monkeys, and humans. Meanwhile, the dorsal (but not ventral) parts of this subicular complex send massive parallel projections through the postcommissural fornix to the medial and lateral mammillary nuclei and the anterior thalamic complex — two structures containing the most navigation-related neurons . In turn, these subcortical structures send their projections back to the DH and retrosplennial cortex . It is apparent that this neural network, composed of the dorsal CA1-dorsal subicular complex-mammillary body—anterior thalamic nuclei, provides the most important interface to register a cognitive map for the navigation/direction system, thus, enabling animals to properly orient and execute behaviors in a learned environment. Additionally, the dorsal CA1 and dorsal CA3 project rather selectively to the caudal part (LSc) and tiny dorsal region of the medial zone of the rostral part (LSr.m.d) of the lateral septal nucleus, which in turn projects to the medial septal complex and supramammillary nucleus — two structures that generate and control the hippocampal theta rhythm activated during voluntary locomotion. Furthermore, the dorsal subiculum and lateral band of the lateral and medial entorhinal cortex send massive projections to the rostrolateral part of the nucleus accumbens and rostral caudoputamen, both of which send descending projections either directly, or indirectly via the substantia innominata (ventral pallidum) or globus pallidus (dorsal pallidum), to innervate the ventral tegmental area and/or reticular part of the substantial nigra (SNr). The ventral tegmental area plays a critical role in locomotion, while the SNr mediates in orienting movements of the eyes, head, neck and even upper limbs, via its massive projection to the deeper layers of the superior colliculus. Additionally, the ventral CA1/subiculum and these amygdalar nuclei also share intimate bi-directional connectivity with the infralimbic, prelimbic and agranular insular cortices. These ventral hippocampal/subicular-amygdalar-medial prefrontal cortical structures form a series of parallel, segregated descending projections, either directly or indirectly through the lateral septum (rostral and ventral parts), the medial and central amygdalar nuclei, and bed nuclei of the stria terminalis (BST), to innervate the periventricular and medial zones of the hypothalamus — the primary structure involved in the control of neuroendocrine, autonomic, and somatic motor activities associated with three basic classes of motivated behaviors having strong emotional components: ingestion (feeding and drinking), reproduction (sexual and parental), and defense. It is worth noting that the ventral CA1, along with the ventral subiculum and medial band of the lateral and medial entorhinal cortical areas, also gives rise to direct projections to the caudomedial (shell) nucleus accumbens (but not the rostral and lateral parts), which plays a critical role in reward processing and motivation of feeding behavior. Finally, axonal terminals of the ventral CA1 and ventral subiculum overlap with the circadian-rhythm related inputs from the suprachiasmatic nucleus of the hypothalamic subparaventricular zone and dorsomedial hypothalamic nucleus — two brain structures recently shown to control the sleep-wake circadian circle. The latter two structures may provide a critical interface for the hippocampal inputs to influence general behavioral states and affect. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822727/

The impairing effects of chronic WIN on short-term memory in the water maze and the object recognition tasks as well as long-term potentiation (LTP) in the ventral subiculum (vSub)-nucleus accumbens (NAc) pathway were temporary as they lasted only 24 h or 10 d after withdrawal. http://www.ncbi.nlm.nih.gov/pubmed/22348124

In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval. In the ventral subiculum (vSub), WIN impaired fear retrieval. In the neutral social discrimination task, WIN into the vSub impaired both acquisition/consolidation and retrieval, whereas in the medial amygdala WIN impaired acquisition. http://www.ncbi.nlm.nih.gov/pubmed/21447623

In adults, TRPC4 expression was high throughout the frontal cortex, lateral septum (LS), pyramidal cell layer of the hippocampus (HIP), dentate gyrus (DG), and ventral subiculum (vSUB). Patch-clamp recording indicated a strong metabotropic glutamate-activated cation current-mediated depolarization that was dependent on intracellular Ca(2+)and inhibited by protein kinase C in brain regions associated with dense TRPC4. http://www.ncbi.nlm.nih.gov/pubmed/17593972

Cells that moderately express alpha2 mRNA were localized to the cerebral cortex layers V and VI, the subiculum, the oriens layer of CA1, the medial septum, the diagonal band complex, the substantia innominata, and the amygdala of both animals. http://www.ncbi.nlm.nih.gov/pubmed/16255031

Small islands of alpha7 immunoreactive cells were present in the outer presubiculum. alpha4 and beta2, and alpha3, alpha4 and beta2 immunoreactive fibre tracts were present in the stratum radiatum and subiculum, respectively, suggesting nAChRs may play a role in modulating inputs to the hippocampus via Schaffer collaterals and along the perforant pathway. Some astrocytes were immunoreactive for alpha3, alpha7 and beta4 subunits. Immunoreactivity to all subunits was noted in association with blood vessels. http://www.ncbi.nlm.nih.gov/pubmed/12663058

When the area of myelination was expressed relative to brain weight, there was a twofold increase between the first and second decades. The increased staining of myelin during the first and second decades principally occurred in the subicular region and adjacent portions of the presubiculum. http://www.ncbi.nlm.nih.gov/pubmed/8192550

We observed a reduction in the numerical density of parvalbumin- and somatostatin-positive interneurons in the caudal EC and parasubiculum in BPD-I and SZ, but no change in the subiculum. http://www.ncbi.nlm.nih.gov/pubmed/21968533

We found that thickness in the entorhinal (ERC) and subicular (Sub) cortices of mild cognitive impairment subjects at initial assessment correlated to change in memory encoding over two years in early stages of neurodegeneration in AD. http://www.ncbi.nlm.nih.gov/pubmed/21559183

We demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis. http://www.ncbi.nlm.nih.gov/pubmed/17258906

The left hippocampal volume was significantly smaller in e4-carriers than non-carriers, the effect of APOE4 mapping to the subicular/CA1 region. http://www.ncbi.nlm.nih.gov/pubmed/21224004

Our primary thesis is that the encoding of short-term memories into new, long-term memories represents the collective set of nonlinearities induced by the three or four principal subsystems of the hippocampus, i.e., entorhinal cortex-to-dentate gyrus, dentate gyrus-to-CA3 pyramidal cell region, CA3-to-CA1 pyramidal cell region, and CA1-to-subicular cortex. http://www.ncbi.nlm.nih.gov/pubmed/20700470

Higher visual medial temporal atrophy rating scale scores were associated with progressive atrophy of the subiculum and the CA1-3 subregions. http://www.ncbi.nlm.nih.gov/pubmed/20143386

A local map of the animal's surroundings is stored in CA1 and subicular regions, where matching of fragment positions and attributes takes place. http://www.ncbi.nlm.nih.gov/pubmed/1308181

The present results highlight the susceptibility of subicular plasticity to acute stress and provide evidence that GR activation is necessary but not sufficient for mediating these alterations. http://www.ncbi.nlm.nih.gov/pubmed/22918985

Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum. Remarkably, despite the disparate firing rate properties of subicular neurons, we found that neurons at all proximal-distal locations exhibit robust theta phase precession, with similar spiking oscillation frequencies as neurons in area CA1. http://www.ncbi.nlm.nih.gov/pubmed/22915100

Subjects with amnestic mild cognitive impairment exhibited significant hippocampal volume reductions in the presubiculum, subiculum and cornu ammonis 2-3 areas compared with healthy subjects. http://www.ncbi.nlm.nih.gov/pubmed/22759884

According to their spiking pattern, pyramidal cells in the subiculum were classified as bursting cells and non-bursting cells. In the present study, we demonstrate that subicular bursting cells show input-specific forms of long-term potentiation (LTP). At CA1-Sub synapses, bursting cells have been shown to express a presynaptic NMDA receptor-dependent LTP that depends on the activation of a cAMP-PKA cascade (Wozny et al., Journal of Physiology 2008). In contrast, at EC-Sub synapses the induction of LTP in bursting cells shows a high induction-threshold and relies on the activation of postsynaptic NMDA receptors, postsynaptic depolarization and postsynaptic Ca(2+) influx. Each form of LTP is input-specific and fails to induce heterosynaptic plasticity. http://www.ncbi.nlm.nih.gov/pubmed/22104348

Here we show using a complete rat hippocampal preparation in vitro that the subiculum intrinsically and independently generates spontaneous slow (25-50 Hz) and fast (100-150 Hz) gamma rhythms during the rising phase and peak of persistent subicular theta rhythms. These two gamma frequencies are phase modulated by theta rhythms without any form of afferent input from the entorhinal cortex or CA1. Fast GABAergic inhibition is required for the generation of fast gamma, whereas slow gamma is generated by excitatory and inhibitory mechanisms. In addition, the transverse subicular axis exhibits gamma rhythm topography with faster gamma coupling arising in the distal subiculum region. These results suggest the subiculum is a third spontaneous gamma generator in the hippocampal formation (in addition to CA3 and the entorhinal cortex). http://www.ncbi.nlm.nih.gov/pubmed/21865453

We used single and paired intracellular patch clamp recordings from post-hoc-identified cells in acute rat hippocampal slices and identified a subpopulation of molecular layer interneurons that expressed immunocytochemical markers present in members of the neurogliaform cell (NGFC) class. Single NGFCs displayed small dendritic trees, and their characteristically dense axonal arborizations covered significant portions of the outer and middle one-thirds of the molecular layer, with frequent axonal projections across the fissure into the CA1 and subicular regions. http://www.ncbi.nlm.nih.gov/pubmed/21452204

Ventral subicular lesioning impaired the spatial task performances in rats and produced considerable degree of dendritic atrophy of the hippocampal pyramidal neuron. http://www.ncbi.nlm.nih.gov/pubmed/21074573

Using high-resolution fMRI (1.6 mm × 1.6-mm in-plane), we found that activity within the right CA23DG increased during encoding compared to retrieval. Conversely, right subicular activity increased during retrieval compared to encoding of spatial associations. http://www.ncbi.nlm.nih.gov/pubmed/20882543

Apoptotic neurons were detected in the subicular region of both suicide and Addison victims, and it is statistically significant in both right and left between the cases. The present study confirms the vulnerability of the subicular neurons to apoptosis, possibly due to corticosteroids in both ends of spectrum. http://www.ncbi.nlm.nih.gov/pubmed/20048453

In contrast to CA1 pyramidal cells, bursting pyramidal cells in the subiculum showed a Na(+) spike-evoked medium afterhyperpolarizations that was reduced by apamin, indicating cell-type-dependent differences in mAHP mechanisms. http://www.ncbi.nlm.nih.gov/pubmed/18684909

With antibodies raised against the N-terminal mouse EAAT4 sequence, the highest protein expression levels were observed in the substantia nigra pars compacta, ventral tegmental area, paranigral nucleus, habenulo-interpeduncular system, supraoptic nucleus, lateral posterior thalamic nucleus, subiculum, and superficial layers of the superior colliculus. http://www.ncbi.nlm.nih.gov/pubmed/18770868

Ventral subiculum (vSUB) lesions enhance corticosterone responses to psychogenic stressors via trans-synaptic influences on paraventricular nucleus (PVN) neurons. Synaptic relays likely occur in GABA-rich regions interconnecting the vSUB and PVN. Exposure to novelty stress increased c-fos mRNA expression in the PVN to a greater degree in vSUB lesion relative to shams, consistent with an inhibitory role for the vSUB in the HPA stress response.  vSUB lesions increased GAD65 or GAD67 mRNA levels in several efferent targets, including anterior and posterior subnuclei of the bed nucleus of the stria terminalis and lateral septum. Lesions did not effect stress-induced increases in GAD65 expression in principal output nuclei of the amygdala. The current data suggest that loss of vSUB innervations produces a compensatory increase in GAD expression in subcortical targets; however, this up-regulation is insufficient to block lesion-induced stress hyperresponsiveness, perhaps driven by amygdalar disinhibition of the PVN. http://www.ncbi.nlm.nih.gov/pubmed/16979601

The ventral subiculum (vSUB) is an interface between the hippocampal formation and structures in the brain reward circuitry, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). The vSUB powerfully activates the dopamine system, particularly in response to novelty. This activity is both necessary and sufficient to elevate nucleus accumbens dopamine levels triggered by a novel stimulus. Direct stimulation of the vSUB increases the population of active dopamine neurons in the ventral tegmental area and dopamine levels in the accumbens via a multisynaptic route relayed through the nucleus accumbens. Furthermore, activity in the vSUB is correlated with drug-seeking behaviour such that vSUB inhibition attenuates cocaine-primed reinstatement of drug-seeking, while brief vSUB activation triggers reinstatement cocaine-seeking.  We report that acute cocaine alters vSUB pyramidal neuron activity by inducing a frequency-dependent output mode transition from bursting to single-spiking. We suggest that under normal conditions bursting and output mode switching (bursting to single-spiking) may be needed for proper routing of information in and out of the vSUB. We propose that psychostimulants disrupt bursting and output mode switching leading to inappropriate dopamine/novelty signaling that is necessary to set motivational states and direct attention and ultimately, behaviour. http://www.ncbi.nlm.nih.gov/pubmed/16870273

Increased excitability enhances the flow of hippocampal output through the subiculum resulting in support for frontal lobe function and the action mode. Decreased excitability, on the other hand, reduces this output and that support, leading to a disconnection between frontal lobes and hippocampus. At the same time, correlated cholinergic activity enhances receptive mode processes, indicated by the occurrence of the hippocampal theta rhythm. It is suggested that the hypothesis provides a conceptual framework for considering various phenomena including REM sleep, schizophrenia, and hypnosis. In REM sleep the receptive mode remains dominant as cholinergic activity supports the hippocampal integration of experience into a composite view of reality. In schizophrenia, the action and receptive modes are not properly coordinated because of a dysfunction in anterior hippocampal output. http://www.ncbi.nlm.nih.gov/pubmed/16824701

In addition, inactivating the vSub with TTX attenuates the ability of the BLA to drive spike firing in the NAc. Thus, the vSub is required for activation of the NAc by the BLA. http://www.ncbi.nlm.nih.gov/pubmed/21211108

The ventral subiculum (vSUB), a hippocampal efferent target implicated in learning and stress coping, receives cholinergic input and sends glutamatergic output to the bed nucleus of the stria terminalis (BNST). Results of the 1-day retention tests showed that intra-vSUB infusion of oxotremorine (0.01 microg) or scopolamine (0.3 or 3.0 microg) enhanced or impaired retention, respectively. These data suggest that in an inhibitory avoidance task muscarinic activation of the vSUB modulated memory formation by interacting with the BNST glutamatergic and noradrenergic functions. http://www.ncbi.nlm.nih.gov/pubmed/19041726

The ventral subiculum (vSub) of the hippocampus, in particular, is proposed to gate information flow within the NAc, a factor that is disrupted in models of schizophrenia. Using in vivo extracellular recordings in anesthetized rats, we examined the response of NAc neurons to vSub stimulation and how this is modulated by the mPFC. We found that inactivation of mPFC by tetrodotoxin attenuates the ability of the vSub to drive spike firing in the NAc. Thus, a contribution of the mPFC is required for the activation of NAc by the vSub. However, when long-term potentiation is induced in the vSub-NAc pathway, the vSub is now capable of driving the NAc without the participation of the mPFC. Moreover, this interaction is dependent on activation of dopaminergic D(2) receptors in the NAc. This work demonstrates the critical role of the mPFC in the ability of vSub to drive NAc neurons in normal anesthetized animals. One model of schizophrenia posits that vSub hyperactivity may underlie both the hyperdopaminergic state and disruption of information flow in this circuit in schizophrenia. Therefore, inactivation of the mPFC, as would occur with mPFC leukotomy in schizophrenia, may prevent the abnormal vSub drive of the NAc. http://www.ncbi.nlm.nih.gov/pubmed/18815264

D1 receptor antagonism (3.0 nmol/0.5 microl SCH-23390 bilaterally) in the vSUB impaired instrumental learning and performance, reduced break point in progressive ratio (PR) tests, and produced an intrasession decline in responding during test sessions, but had no effect on spontaneous motor or food-directed behavior. D1 activation in the vSUB may be a critical component of motivational arousal associated with learned contextual cues. http://www.ncbi.nlm.nih.gov/pubmed/16768606

In the hippocampal formation (dentate gyrus, hippocampus proper and subiculum) and entorhinal cortex, the colocalization of the 5-HT2Ar with the inhibitory transmitter ?-aminobutyric acid (GABA) was studied using double immunofluorescence confocal microscopy. http://www.ncbi.nlm.nih.gov/pubmed/22119732

Subjects with late life depression exhibited significant hippocampal volume reductions in the total hippocampus, subiculum, and Cornu Ammonis (CA) 2-3 areas compared with healthy subjects. http://www.ncbi.nlm.nih.gov/pubmed/22840623

In hippocampal formation of control subjects, H3 receptor radioligand binding was prominent in dentate gyrus, subiculum, entorhinal cortex and parasubiculum. Decreased H3 binding was found in the CA4 area of bipolar subjects. Decreased H3 binding in CA2 and presubiculum of medication-free bipolar subjects was also seen. http://www.ncbi.nlm.nih.gov/pubmed/19413576

High levels of GalR2 mRNA and protein expression were observed in the presubiculum, subiculum, cingulate cortex, retrosplenial granular and agranular cortices, subregions of prefrontal cortex, and the olfactory bulb, regions which are directly or indirectly implicated in depression-like behavior. http://www.ncbi.nlm.nih.gov/pubmed/21672612

SNAP-25 levels were reduced significantly in stratum oriens of bipolar patients compared with controls (p < 0.05); they were also reduced significantly in st. oriens (p < 0.01 vs schizophrenia), in alveous (p < 0.01 vs schizophrenia) and in presubiculum (p < 0.05 vs depressed). Depressed SNAP-25 levels increased in st. moleculare (p < 0.01 vs schizophrenics) and presubiculum (p < 0.05 vs controls and bipolars; p < 0.01 vs schizophrenics). http://www.ncbi.nlm.nih.gov/pubmed/11711867

The findings also suggest further functional differences within retrosplenial subregions as area 29 received the large majority of efferents from the subiculum. http://www.ncbi.nlm.nih.gov/pubmed/22522494

Somatostatin messenger RNA (mRNA) is rapidly but transiently expressed de novo in pyramidal neurons of the subiculum and entorhinal cortex 24 hours after KA. Surviving somatostatin interneurons display increased mRNA levels at late intervals (3 months) after KA and increased labeling of their terminals in the outer molecular layer of the subiculum; the labeling correlates with the number of spontaneous seizures, suggesting that the seizures may trigger somatostatin expression. In contrast, neuropeptide Y mRNA is consistently expressed in principal neurons of the proximal subiculum and the lateral entorhinal cortex and labeling for the peptide persistently increased in virtually all major excitatory pathways of the hippocampal formation. The pronounced plastic changes differentially involving both neuropeptide systems indicate marked rearrangement of parahippocampal areas, presumably aiming at endogenous seizure protection. http://www.ncbi.nlm.nih.gov/pubmed/22437342

We conclude that the deep layer cells of the presubiculum and parasubiculum are richly interconnected with excitatory synapses. These interconnections can generate giant excitatory synaptic potentials that support the bursting behaviour exhibited by these neurons. Any of the excitatory inputs to deep layer cells can trigger the population bursts and specific inputs from entorhinal cortex produce the after-discharges. http://www.ncbi.nlm.nih.gov/pubmed/9192310

We found that subicular projections to each area were composed of a mixture of regular-spiking and bursting neurons. Neurons projecting to amygdala, lateral entorhinal cortex, nucleus accumbens, and medial/ventral orbitofrontal cortex were located primarily in the proximal subiculum and consisted mostly of regular-spiking neurons (~80%). By contrast, neurons projecting to medial EC, presubiculum, retrosplenial cortex, and ventromedial hypothalamus were located primarily in the distal subiculum and consisted mostly of bursting neurons (~80%). Neurons projecting to a thalamic nucleus were located in the middle portion of subiculum, and their probability of bursting was close to 50%. http://www.ncbi.nlm.nih.gov/pubmed/21538658

This, possibly novel, TTX-I sodium current could contribute to the coding functions of presubicular neurons, specifically the maintained firing associated with signalling of a stable head position. http://www.ncbi.nlm.nih.gov/pubmed/19596892

Saturation binding and displacement experiments showed that [(125)I]YVP and [(125)I]EYF bound selectively with a very high affinity, K(D)=0.18 nM and 0.06 nM, to NPFF(1) and NPFF(2) receptors respectively.The highest densities of [(125)I]EYF binding sites were seen in the most external layers of the dorsal horn of the spinal cord, the parafascicular thalamic nucleus, laterodorsal thalamic nucleus and presubiculum of hippocampus. http://www.ncbi.nlm.nih.gov/pubmed/12421602

Vesicular glutamate transporter 1 (VGluT1) is one of the best markers for glutamatergic neurons, because it accumulates transmitter glutamate into synaptic vesicles. Differentiation-associated Na(+)-dependent inorganic phosphate cotransporter (DNPI) shows 82% amino acid identity to VGluT1, and is another candidate for vesicular glutamate transporters. Both DNPI and VGluT1 immunoreactivities were found mostly in neuropil, presumably in axon terminals, throughout the brain. In the telencephalic regions, intense DNPI immunoreactivity was observed in the glomeruli of the olfactory bulb, layer IV of the neocortex, granular layer of the dentate gyrus, presubiculum, and postsubiculum. In contrast, VGluT1 immunoreactivity was intense in the olfactory tubercle, layers I-III of the neocortex, piriform cortex, entorhinal cortex, hippocampus, dentate gyrus, and subiculum. http://www.ncbi.nlm.nih.gov/pubmed/11835181

The regions of highest V1a receptor density included the prefrontal, cingulate, pyriform, and entorhinal cortex, as well as the presubiculum and mamillary bodies. http://www.ncbi.nlm.nih.gov/pubmed/10223283

The parasubiculum and the external principal lamina of the presubiculum may be the structures most vulnerable to early lesions in the parahippocampal gyrus in CJD. http://www.ncbi.nlm.nih.gov/pubmed/9988133

Social Fodder

As we get more toxic from industrial body burdens compounding psychological stress, this harm prevention networking becomes impossible, or improbable without the youth like us, resilient to the damages enough to be competent to the causes. The chance for community rejuvenation lies in the youth, specifically the youth predisposed to store less toxins from having less genes to store fat. The social qualities of these individuals will be a critical precursor. If we ever manage anything beyond personal gain or moral support, it will have to be a corporate involvement with home infrastructure to reduce reliance on all but the community. Every home built with independence. Producing your own fuel. Indoor green-housing can be tailored into the construct of the houses (rain capturing, angles of sunlight, rooms designated for filtration). One family growing sprouts and nuts can barely support one family for cell protection and locomotion if at all. Everyone together can scale the size up to account for one another through labor and barter. Step 1. Socialize the concepts into existence. Step 2. Implement the infrastructure from businesses. Step 3. Amplify efficiency to a state of permanent unity. Address body burdens by condition; predictable causes targeted with predictable solutions, prioritized for extent of care. Old people are not naturally useless, and can be brought back for the sake of the young. Youth should receive as much attention as we do, but not the way it is now. It may be a pipe dream to bring capitalist precedence to it's knees, but it would sure prevent unnecessary arguments. It's not as if 'our' culture is so unique that it has to willfully ignore health care from other cultures. Big Pharma and Big Agro are banking on their zombie masses being separate in will and information so thoroughly to complacently accept oppression. The oppression is excused as latent or necessary; whereas it is an active and cruel project to turn consumerist fodder into useful coroners reports.

Synopsis

Subsequent Responses And Toward And Untoward Error Perception From Other's Perspectives On A Synopsis Of Modern Human: societal phylogenetics for consumer goods, resisting tire at night and relationship to chronoastrobiology of self-organized and group-organized experimental glycolipid phylogenetic biophysics and the mind-mitochondrial-gonad axes and it's relationship to predicted random walk based on methylation status of conserved brain genes and copy number variants and the correlation with interactive waves and particles and their intensities, electronics and industrial pollutants in consumer goods, hinging on time spent in atmospheric particle density sites and contact with the grounds of these hotspots with absorbtive cells and the biophysics of the absorbtive cells in the process, functional gains and losses, thermodynamics, reactive hemodynamics and neurology referring to cannabinoids and tao and their organizations towards neurological interactions in neural cytoarchitecture based on endogenous retroviral transcript and regional laterality shifting and the mitochondrias viral transcripts mechanistic regulation yet mutualist relation with the demanded biophysics and how the mitochondria genome adapts to this independently and its relationship to people who would be enabled to discuss such an order and event and their physics of articulation and language display and response to themselves and the known confines of human organized emotional relationship and their sequences and superimposition implications in the context, social entropy and negentropy from individual self-experience and empirical observation leading to agreement and its relationship to mitochondria, being signaled by the phosphate-related molecules similarly in the active epigenetic reprogramming events of present moments cyclic adenosine monophosphate, adenosine monophosphate kinase and relationship to fatty acid synthase, fatty acid amide hydrolase and monoacylglycerol lipase and organ integrity in biophysics of neurology and accidental, arbitrary, and pro-active sought durations of things on minds consequential to information field development, glycolipid bioelectromagnetics and consciousness of the rise of self-awareness in binary confines produced as a result of the self-perception such as good and bad in the good and bad centers of the brain dominated by the hippocampus, then brainstem for pains, language centers, and self-centers in pre-frontal densities and the ability to seek to regulate the good pro-actively in the confined parameters of capacity, and coordination with psychic and physical pain and pleasure and it's augmentation of information field development in self and others as a function of the chronoastrobiology and total system thermodynamics including glaciological and volcanological in meteorological control over food chain base abundances and qualities in regulation of the retroviral transcripts in present moments and up-chain risks in microwave food biotechnology in disorganization of horizontal gene transfer, DNA information processing capacities, and chromophores and chromatin in context to success of chromosomes and complexification of quantum chromodynamics and it's relationship to electron-phonon-photon coupling and alterations of effects on sequences of hereditary infuenced biological relationship to local geophysics, anxiety, fear, migratory phenotype, and pineal hydrodynamics at the moments the self realizes indefinitely the concerns involved and precedents and expectations for biotic and abiotic stress, terrorism, and internal tensional and intentional integrity decline and effects on seeking of variables acting as resonances for resilience.

May-OCT11

BMC Gastroenterol. 2011 Feb 23;11:14.
The actin-bundling protein fascin is overexpressed in inflammatory bowel disease and may be important in tissue repair.
Qualtrough D, Smallwood K, Littlejohns D, Pignatelli M.
Source

School of Cellular and Molecular Medicine, University of Bristol, UK. david.qualtrough@bristol.ac.uk
Abstract
BACKGROUND:

Fascin is associated with increased cell motility in colorectal tumours but is absent from the normal colonic epithelium. We examined the expression of fascin in inflammatory bowel disease (IBD) and its location at regions undergoing restitution and regeneration. Tissue repair is essential for disease remission and we sought to determine the effects of therapeutic modalities on fascin expression and function using an in vitro model.
METHODS:

Immunohistochemistry was performed on colonic tissue from IBD patients to determine changes in fascin expression and distribution. A human colorectal epithelial cell line was treated with 5-aminosalicylate (a common treatment for IBD), or sodium butyrate to determine the effect on fascin expression and cell motility.
RESULTS:

Fascin overexpression was observed in both ulcerative colitis and Crohn's colitis and expression correlated with disease severity. Immunoreactivity was more intense and widespread in Crohn's compared to ulcerative colitis. Interestingly, highly expressing foci were consistently observed at the edges of ulcers where flattened, motile epithelial cells are actively involved in restitution, and also in areas of mucosal regeneration.5-aminosalicylate reduced fascin expression in colorectal epithelial cells and inhibited their motility. Conversely, sodium butyrate increased fascin expression and stimulated cell motility in the same cells.
CONCLUSIONS:

Our data shows that fascin is overexpressed in inflammatory bowel disease and its location is indicative of a role in tissue repair. Our in vitro studies show that different therapeutic modalities may have converse effects on fascin expression and may have significant consequences for disease remission and the clinical management of IBD.

PMID:
    21345224

Dig Dis Sci. 2000 May;45(5):976-81.
Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double-blind, placebo-controlled pilot study.
Vernia P, Monteleone G, Grandinetti G, Villotti G, Di Giulio E, Frieri G, Marcheggiano A, Pallone F, Caprilli R, Torsoli A.
Source

Cattedra di Gastroenterologia 1, Università La Sapienza, Roma, Italy.
Abstract

Butyrate represents the main source of energy for colonic epithelial cells; however, its availability/utilization is impaired in ulcerative colitis (UC). In the present randomized, double-blind, placebo-controlled pilot study, the safety and efficacy of colonic targeted oral sodium butyrate tablets, coated with a pH-dependent soluble polymer, have been evaluated in ulcerative colitis. Thirty patients with mild to moderate colitis underwent a six-week course of oral sodium butyrate (4 g/day) plus oral mesalazine (2.4 g/day), (Group A) or of oral mesalazine plus placebo (Group B). Clinical, endoscopic, and histologic data were collected at the beginning and the end of the study. Twenty-five patients completed the study (12 in group A, 13 in group B). No untoward side effects were reported. In group A, seven patients underwent remission and four improved; in Group B the numbers were 5 and 5, respectively. After treatment, all clinical parameters had significantly improved in both treatment arms compared to pretreatment findings. The UC disease activity index (UCDAI) score decreased from 7.27 +/- 2.02 to 2.58 +/- 2.19 (P < 0.05) in the combined treatment group and from 6.07 +/-1.60 to 3.46 +/- 1.98 (P < 0.05) in group B. The endoscopic and histologic scores also significantly improved after treatment in both groups (P < 0.05). The difference between the two treatment arms was not significant, but a significantly better improvement vs baseline values (P < 0.05) was observed in the combined treatment group vs the mesalazine group, when considering both the clinical index (delta9.58 +/- 4.19 vs 5.92 +/- 3.48) and the UCDAI score (delta4.67 +/- 2.19 vs 2.54 +/- 2.18). A more favorable trend, although not significant, was observed for all individual parameters in group A. In conclusion, results of the present pilot study indicate that oral butyrate is safe and well tolerated. These data also suggest that oral butyrate may improve the efficacy of oral mesalazine in active ulcerative colitis and prompt the need of a large scale investigation to confirm the present findings.

PMID:
    10795763

Cancer Lett. 2000 Sep 29;158(1):61-4.
Serum alpha-N-acetylgalactosaminidase is associated with diagnosis/prognosis of patients with squamous cell carcinoma of the uterine cervix.
Reddi AL, Sankaranarayanan K, Arulraj HS, Devaraj N, Devaraj H.
Source

Unit of Biochemistry, Department of Zoology, University of Madras, Guindy Campus, 600 025, Chennai, India. vkmalr@hotmail.com
Abstract

Serum alpha-N-acetylgalactosaminidase (NaGalase) is responsible for the deglycosylation of vitamin D(3)-binding protein (Gc protein). The deglycosylated Gc protein cannot be converted into major macrophage-activating factor (MAF), leading to immunosuppression. NaGalase is universally detected in a variety of cancer patients, but not in healthy individuals (Cancer Res. 56 (1997) 2827-2831). However, the diagnostic/prognostic utility of NaGalase in squamous cell carcinoma (SCC) of the uterine cervix is not known. To address this issue, the serum NaGalase was quantitatively determined in 210 patients with different stages of SCC of the uterine cervix. NaGalase levels were increased with the progression of the cancer. After radiotherapy, the increased levels returned toward or to normal levels in early stages (FIGO stage I-IIB) but not in advanced stages (FIGO stage III-IV). The present study revealed that the amount of NaGalase in the patient's bloodstream reflects the tumor burden and aggressiveness of the disease. We conclude that NaGalase is an independent predictor of diagnosis/prognosis in SCC of the uterine cervix, and therefore suggest that quantitative NaGalase alteration may reflect important differences in the immunological functions of these neoplasms.

PMID:
    10940510

Proc Biol Sci. 2010 Feb 7;277(1680):345-51. Epub 2009 Oct 21.
Reelin and apolipoprotein E receptor 2 in the embryonic and mature brain: effects of an evolutionary change in the apoER2 gene.
Myant NB.
Source

MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, , London W12 0NN, UK. audreymyant@hotmail.com
Abstract

In the mature cerebral cortex of higher vertebrates, neurons are arranged in layers, each layer containing neurons of the same functional class. The cortical layering pattern is laid down during development by migration of young post-mitotic neurons along glial fibres to their correct positions in the cortical plate. The mechanics of whole-cell movement are well understood, but there is still uncertainty as to how a migrating neuron is instructed to leave its glial support when it reaches its destination. An intraneuronal signalling pathway initiated by reelin and containing apolipoprotein E receptor 2 (apoER2) is essential for normal cortical layering, and there is strong evidence that detachment of a migrating neuron is brought about by reelin-dependent downregulation of alpha3 integrin. But there remains the problem of how the reelin signal is switched on at a position in the cortex appropriate for each class of neuron. ApoER2 of placental mammals contains an amino acid sequence that is encoded in a separate exon in the apoER2 gene and is required for normal memory and spatial learning. The separate exon is not present in marsupials, birds or reptiles. The addition of this exon to the evolving apoER2 gene may have contributed to the success of placental mammals.

PMID:
    19846452

Neuroscience. 2010 Mar 17;166(2):625-32. Epub 2009 Dec 24.
Insulin-like growth factor-1 stimulation of hypothalamic KiSS-1 gene expression is mediated by Akt: effect of alcohol.
Hiney JK, Srivastava VK, Les Dees W.
Source

Department of Integrative Biosciences, College of Veterinary Medicine, Texas A and M University College Station, TX 77843-4458, USA. jhiney@cvm.tamu.edu
Abstract

Kisspeptin, as well as insulin-like growth factor-1 (IGF-1), act centrally to stimulate luteinizing hormone-releasing hormone (LHRH) secretion at puberty. IGF-1 can induce KiSS-1 gene expression as an early pubertal event; however, the signaling pathway mediating this effect is not known. Since alcohol (ALC) blocks IGF-1 induced LHRH release acutely, we assessed whether this drug could affect IGF-1 stimulated prepubertal KiSS-1 gene expression following a binge type of exposure. Immature female rats were administered either ALC (3 g/kg) or water via gastric gavage at 07.30 h. At 09.00 h the ALC and control groups were subdivided where half received either saline or IGF-1 (200 ng) into the third ventricle. A second dose of ALC (1.5, 2 and 3 g/kg) or water was administered at 11.30 h. These regimens produced moderate blood alcohol concentrations of 77, 89 and 117 mg/dl, respectively, over the time course of the experiment. Rats were sacrificed 6 h after the IGF-1 injection and tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were collected. IGF-1 stimulated (P<0.01) KiSS-1 gene expression in the AVPV nucleus at 6 h, but did not affect expression of the kisspeptin receptor, GPR54. While ALC did not alter basal expression of either gene, its dose dependently blocked IGF-1-induced KiSS-1 gene expression in the AVPV nucleus. No changes were observed in the ARC nucleus. Assessment of IGF-1 signaling indicated that the acute administration of IGF-1, ALC, or both did not alter the basal expression of IGF-1 receptor protein. However, IGF-1 stimulated (P<0.05) phosphorylated Akt protein over basal levels, an action blocked by ALC. Our results indicate that the IGF-1 induction of KiSS-1 gene expression is mediated by Akt activation, and that ALC alters this important prepubertal action of IGF-1.

Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

PMID:
    20034543

Int J Neuropsychopharmacol. 2011 May 4:1-11. [Epub ahead of print]
Cerebroside-A provides potent neuroprotection after cerebral ischaemia through reducing glutamate release and Ca2+ influx of NMDA receptors.
Li L, Yang R, Sun K, Bai Y, Zhang Z, Zhou L, Qi Z, Qi J, Chen L.
Source

Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Abstract

Excessive presynaptic glutamate release after cerebral ischaemia leads to neuronal death mainly through excessive calcium entry of N-methyl-d-aspartate receptors (NMDARs). Our recent study reported that cerebroside can open large-conductance Ca2+-activated K+ (BKCa) channels. The present study evaluated the effects of cerebroside-A (CS-A), a single molecule isolated from an edible mushroom, on brain injury after focal or global ischaemia in adult male mice and rats. We herein report that treatment with CS-A after 60-min middle cerebral artery occlusion dose-dependently reduced the cerebral infarction with at least a 6-h efficacious time-window, which was partially blocked by the BKCa channel blocker charybdotoxin (CTX). Treatment with CS-A after 20 min global cerebral ischaemia (four-vessel occlusion) significantly attenuated the death of pyramidal cells in hippocampal CA1 area, which was also sensitive to CTX. CS-A, by opening the BKCa channel, could prevent excessive glutamate release after oxygen-glucose deprivation (OGD). In addition, CS-A could inhibit NMDAR Ca2+ influx, which did not require the activation of the BKCa channel. Furthermore, CS-A blocked the OGD-induced NMDAR-dependent long-term potentiation in hippocampal CA1 region. These findings indicate that treatment with CS-A after stroke exerts potent neuroprotection through prevention of excessive glutamate release and reduction of Ca2+ influx through NMDARs.

PMID:
    21557879

Morfologiia. 2010;137(2):38-43.
[Changes in duodenal lymphoid structures in rats with various behavioral activity, caused by delta sleep-inducing peptide and following acute emotional stress].
[Article in Russian]
Ivanova EA, Koplik EV.
Abstract

The effect of delta sleep-inducing peptide (DSIP) on the lymphoid structures of small intestine, was investigated. Studies were conducted on 42 male Wistar rats, which were previously assessed in an "open field" test. According to the results of the test, rats were divided into behaviorally active animals (prognostically resistant to stress) and passive ones (resistant to the effects of stress). As a stress, immobilization of the animals in pens with an electrical stimulation of their back for 1 hour, was used. Intraperitoneal injection of DSIP resulted in a reduction of eosinophil number in rats of all the experimental groups. After DSIP injection to the active rats of the control group, the increase in small and medium lymphocyte numbers was detected that was more expressed than in the passive rats. After an acute exposure of behaviorally active rats to stress, the number of the cells of lymphoid series was increased,mainly due to the increase in small and medium lymphocytes. In the group of passive rats, stress exposure and DSIP injection resulted in the increase of plasma cell number in all the duodenal mucosa structures studied.

PMID:
    20572393

Metallomics. 2011 May 1;3(5):513-20. Epub 2011 Feb 18.
Identification in human urine and blood of a novel selenium metabolite, Se-methylselenoneine, a potential biomarker of metabolization in mammals of the naturally occurring selenoneine, by HPLC coupled to electrospray hybrid linear ion trap-orbital ion trap MS.
Klein M, Ouerdane L, Bueno M, Pannier F.
Source

Laboratoire de Chimie Analytique Bio Inorganique et Environnement, IPREM, Université de Pau et des Pays de l'Adour / CNRS UMR 5254, Hélioparc, Avenue du Pr. Angot, Pau, France.
Abstract

Speciation analysis of selenium in human urine allowed for the first time the identification of a novel selenium metabolite, Se-methylselenoneine. Despite a concentration at low ppb level, its characterization was achieved after sample purification by solid phase extraction (SPE) followed by the parallel coupling of the bidimensional RP/HILIC chromatography with ICP-MS and ESI-LTQ Orbitrap MS detection. To confirm its biological significance with regards to selenoneine, the recently discovered analog of ergothioneine, and to discard the possibility of sample preparation artifacts, a new method was developed to monitor its actual presence, as well as the occurrence of its sulfur and/or non-methylated analogs, in non-preconcentrated urine and blood samples of non-supplemented humans. It consisted in a HILIC ESI-MS(3) method in high resolution mode (resolution 30?000 at m/z 400) with large isolation width windows for precursor ions. These two particular settings allowed respectively to keep observing the specific mass defect of selenium- and sulfur-containing molecules and to maintain the characteristic selenium pattern in product ions created through MS(n) fragmentations. As a result, all four metabolites were detected in blood and three of them in urine. Moreover, different ratios "methylated/non-methylated" were observed between urine and blood samples, which seemed to indicate their active metabolization. The analytical tool developed here will be of a great importance to further study the occurrence and the potential metabolic role in mammalian organelles, cells and fluids of these very particular and promising redox metabolites.

PMID:
    21331438

J Med Entomol. 2006 Sep;43(5):889-95.
Fumigant and repellent properties of essential oils and component compounds against permethrin-resistant Pediculus humanus capitis (Anoplura: Pediculidae) from Argentina.
Toloza AC, Zygadlo J, Cueto GM, Biurrun F, Zerba E, Picollo MI.
Source

Centro de Investigaciones en Plagas e Insecticidas (CITEFA-CONICET), Juan Bautista De La Salle 4397 (B1603ALO) Villa Martelli, Provincia de Buenos Aires, Argentina.
Abstract

The repeated use of permethrin and other insecticides for the control of head lice, Pediculus humanus capitis De Geer (Anoplura: Pediculidae), during past decades has resulted in the development of marked levels of resistance. Thus, new alternative insecticides are needed for the control of head lice. We studied the fumigant and repellent properties of essential oils from 16 native and exotic plants in Argentina, and 21 chemical components against permethrin-resistant head lice from Argentina. With a direct vapor-exposure bioassay, the most effective oil was from the native Myrcianthes cisplatensis Cambess (Myrtaceae) with a time to 50% knockdown (KT50) of 1.3 min, followed by exotic species, Eucalyptus cinerea F.V. Muell., Eucalyptus viminalis Labill., and Eucalyptus saligna Smith. with KT50 values of 12.0, 14.9, and 17.4 min, respectively. The most effective components were 1,8-cineole and anisole, with KT50 values of 11.1 and 12.7 min, respectively. Regression analysis of KT50 values and vapor pressures and water-partition coefficients for the essential oil components revealed that the most effective fumigants were among the more volatile components. Repellency assays indicated that the essential oil from Mentha pulegium L. and its benzyl alcohol component were the most effective repellents, having repellency indices of 75.5 and 57.8%, respectively. Thus, some Argentinean plants contain essential oils and components that function as fumigants or as repellents and thereby show potential for development of new control products for head lice.

PMID:
    17017225

Int J Ayurveda Res. 2010 Apr;1(2):112-21.
Tinospora cordifolia (Willd.) Hook. f. and Thoms. (Guduchi) - validation of the Ayurvedic pharmacology through experimental and clinical studies.
Upadhyay AK, Kumar K, Kumar A, Mishra HS.
Source

Department of Ayurved Research and Development, Patanjali Yogpeeth, Haridwar, India.
Abstract

T. cordifolia (Guduchi) is a large, glabrous, perennial, deciduous, climbing shrub of weak and fleshy stem found throughout India. It is a widely used plant in folk and Ayurvedic systems of medicine. The chemical constituents reported from this shrub belong to different classes, such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics, aliphatic compounds and polysaccharides. Various properties of T. cordifolia, described in ancient texts of Ayurveda, like Rasayana, Sangrahi, Balya, Agnideepana, Tridoshshamaka, Dahnashaka, Mehnashaka, Kasa-swasahara, Pandunashaka, Kamla-Kushta-Vataraktanashaka, Jwarhara, Krimihara, Prameha, Arshnashaka, Kricch-Hridroganashak, etc., are acquiring scientific validity through modern research adopting "reverse pharmacological" approach. Potential medicinal properties reported by scientific research include anti-diabetic, antipyretic, antispasmodic, anti-inflammatory, anti-arthritic, antioxidant, anti-allergic, anti-stress, anti-leprotic, antimalarial, hepato-protective, immuno-modulatory and anti-neoplastic activities. This review brings together various properties and medicinal uses of T. cordifolia described in Ayurveda, along with phytochemical and pharmacological reports.

PMID:
    20814526

J Altern Complement Med. 2006 Dec;12(10):971-80.
Trial of Essiac to ascertain its effect in women with breast cancer (TEA-BC).
Zick SM, Sen A, Feng Y, Green J, Olatunde S, Boon H.
Source

Integrative Medicine, University of Michigan, Ann Arbor, MI 48104-1555, USA. szick@umich.edu
Abstract
BACKGROUND:

Breast cancer is a major cause of morbidity, mortality, and medical expenditures among women in Canada. Essiac (Resperin Canada Limited, Waterloo, Ontario, Canada), a blend of at least four herbs (burdock root [Arctium lappa], Indian rhubarb [Rheum palmatum], sheep sorrel [Rumex acetosella], and the inner bark of slippery elm [Ulmus fulva or U. rubra]), has become one of the more popular herbal remedies for breast-cancer treatment, secondary prevention, improving quality of life, and controlling negative side-effects of conventional breast-cancer treatment.
OBJECTIVES:

Our primary objective was to determine the difference in health-related quality of life (HR-QOL), as assessed by the Functional Assessment of Cancer Therapy Breast Cancer Version, between women who are new Essiac users (since breast cancer diagnosis) and those who have never used Essiac. Secondary endpoints included differences in depression, anxiety, fatigue, rate of adverse events, and prevalence of complications or benefits associated with Essiac during standard breast-cancer treatment. Additionally, we described the pattern of use of Essiac in this cohort of women.
METHODS:

We performed a retrospective cohort study in 510 women, randomly chosen from the Ontario Cancer Tumour Registry, with a diagnosis of primary breast cancer in 2003.
RESULTS:

With the exception changes in a Physical well-being subscale and a relationship with doctor subscale, Essiac did not have a significant effect on HR-QOL or mood states. Even for Physical well-being and relationship with doctor, Essiac seemed to have a negative effect, with Essiac users doing worse than the non-Essiac users. This might be attributed to the fact that the group of users comprised younger women with more advanced stages of breast cancer, and both of these subgroups of patients have been shown to be at a significantly increased risk for negative mood states and/or a decreased sense of well-being. The women were taking low doses (total daily dose 43.6 +/- 30.8 mL) of Essiac that corresponded to the label directions found on most Essiac products. Friends were the most common source of information, and most women were taking Essiac to boost their immune systems or increase their chances of survival. Only 2 women reported minor adverse events, whereas numerous women reported beneficial effects of Essiac.
CONCLUSIONS:

Essiac does not appear to improve HR-QOL or mood states. Future studies are needed to determine whether other clinical outcomes, such as cancer reoccurrence, are affected by Essiac.

PMID:
    17212569

Vaccine. 2011 Mar 21;29(14):2530-6. Epub 2011 Feb 2.
Effects of Taishan Pinus massoniana pollen polysaccharide on immune response of rabbit haemorrhagic disease tissue inactivated vaccine and on production performance of Rex rabbits.
Wei K, Sun Z, Yan Z, Tan Y, Wang H, Zhu X, Wang X, Sheng P, Zhu R.
Source

College of Animal Science and Technology, Shandong Agricultural University, Taian, Shandong 271018, PR China.
Abstract

Varied doses of Taishan Pinus massoniana pollen polysaccharide (TPPPS) and Astragalus polysaccharide (APS) extracted by hot water extraction and ethanol precipitation method were added to the vaccine in order to prepare polysaccharide-rabbit haemorrhagic disease (RHD) tissue inactivated vaccine. The purpose was to study effects of TPPPS on immune response of RHD tissue inactivated vaccine and on production performance of Rex rabbits. Results showed that each index in groups I, II, III and IV was higher than that in group V, especially groups I, II and IV, the difference between which and group V was much more significant (P<0.05); each index in group I was extremely higher than that in group V (P<0.01); each index in group I was significantly higher than that in groups II, III (P<0.05), and generally no significant difference was observed between groups II and III. The overall level in group IV was slightly lower than that in group I. Each index in the polysaccharide groups reached its peak value later than that in the non-polysaccharide groups did. Results suggested that any dose of TPPPS can enhance immunologic function and production performance of rabbits, and the amount of 400mg per rabbit has the most obvious efficacy. Furthermore, it can extend the immune peak period of RHD tissue inactivated vaccine and the growing peak period of Rex rabbits. TPPPS has generally higher efficiency than APS.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
    21295100

Food Chem Toxicol. 2010 Jun;48(6):1644-53. Epub 2010 Mar 27.
Protective effects of silica hydride against carbon tetrachloride-induced hepatotoxicity in mice.
Hsu YW, Tsai CF, Chuang WC, Chen WK, Ho YC, Lu FJ.
Source

Department of Applied Chemistry, Chung Shan Medical University, Taichung City, Taiwan.
Abstract

The protective effects of MegaHydrate silica hydride against liver damage were evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male ICR mice were orally treated with silica hydride (104, 208 and 520 mg/kg) or silymarin (200 mg/kg) daily, with administration of CCl(4) (1 mL/kg, 20% CCl4 in olive oil) twice a week for eight weeks. The results showed that oral administration of silica hydride significantly reduced the elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride (TG), and cholesterol and the level of malondialdehyde (MDA) in the liver that were induced by CCl(4) in mice. Moreover, the silica-hydride treatment was also found to significantly increase the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px), as well as increase the GSH content, in the liver. Liver histopathology also showed that silica hydride reduced the incidence of liver lesions induced by CCl(4). The results suggest that silica hydride exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely due to both the increase of antioxidant-defense system activity and the inhibition of lipid peroxidation.

Copyright 2010 Elsevier Ltd. All rights reserved.

PMID:
    20350579

J Biol Regul Homeost Agents. 2011 Apr-Jun;25(2):187-94.
Beneficial nutraceutical modulation of cerebral erythropoietin expression and oxidative stress: an experimental study.
Sedriep S, Xia X, Marotta F, Zhou L, Yadav H, Yang H, Soresi V, Catanzaro R, Zhong K, Polimeni A, Chui DH.
Source

Bio-Cell Unit Lab and Analysis Center, Miyazaki, Japan.
Abstract

The main object of this study is to examine the effect of Klamin®, a nutraceutical containing phenylethylamine, phycocyanins, mycosporine-like aminoacids and aphanizomenon flos aquae-phytochrome on the learning and memory ability, the oxidative status and cerebral erythropoietin and its receptor EPO/EPOR system in prematurely senescent (PS) mice. A total of 28 PS mice, selected according to a prior T-maze test, and 26 non-prematurely senescent mice (NPS) mice were chosen. PS animals were divided into 3 groups and followed for 4 weeks: A) normal chow diet; B) added with Klamin® at 20 mg/kg/day (low dose); C) added with Klamin® at 100mg/kg/day (high dose). A further group of NPS mice given either normal food (group D) or high dose Klamin® (group E) was also considered. The behavioral procedures of spatial learning ability (Morris test) showed that PS mice had significantly longer learning time as compared to their NPS counterpart (p<0.01), but this effect was prevented especially in mice supplemented with high-dose Klamin® (p<0.05) which improved performances in NPS mice (p<0.05). High-dose Klamin® supplementation restored the depleted total thiol concentration in the brain observed in PS mice while normalizing their increased malonildialdehyde level (p<0.05). Moreover, the high-dosage only caused a significant upregulation of EPO/EPOR system both in PS and in NPS animals (p<0.05). Taken together, these data suggest that this specific alga Klamath extract has considerable antioxidant and adaptogenic properties, also through a stimulatory effect of cerebral EPO/EPO system.

PMID:
    21880207

Brain. 2011 Apr;134(Pt 4):1061-76. Epub 2011 Mar 7.
Unawareness of deficits in Alzheimer's disease: role of the cingulate cortex.
Amanzio M, Torta DM, Sacco K, Cauda F, D'Agata F, Duca S, Leotta D, Palermo S, Geminiani GC.
Source

Department of Psychology, University of Turin, Via Verdi 10, 10123 Turin, Italy. martina.amanzio@unito.it
Abstract

Unawareness of deficits is a symptom of Alzheimer's disease that can be observed even in the early stages of the disease. The frontal hypoperfusion associated with reduced awareness of deficits has led to suggestions of the existence of a hypofunctioning prefrontal pathway involving the right dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate gyri and limbic structures. Since this network plays an important role in response inhibition competence and patients with Alzheimer's disease who are unaware of their deficits exhibit impaired performance in response inhibition tasks, we predicted a relationship between unawareness of deficits and cingulate hypofunctionality. We tested this hypothesis in a sample of 29 patients with Alzheimer's disease (15 aware and 14 unaware of their disturbances), rating unawareness according to the Awareness of Deficit Questionnaire-Dementia scale. The cognitive domain was investigated by means of a wide battery including tests on executive functioning, memory and language. Neuropsychiatric aspects were investigated using batteries on behavioural mood changes, such as apathy and disinhibition. Cingulate functionality was assessed with functional magnetic resonance imaging, while patients performed a go/no-go task. In accordance with our hypotheses, unaware patients showed reduced task-sensitive activity in the right anterior cingulate area (Brodmann area 24) and in the rostral prefrontal cortex (Brodmann area 10). Unaware patients also showed reduced activity in the right post-central gyrus (Brodmann area 2), in the associative cortical areas such as the right parietotemporal-occipital junction (Brodmann area 39) and the left temporal gyrus (Brodmann areas 21 and 38), in the striatum and in the cerebellum. These findings suggest that the unawareness of deficits in early Alzheimer's disease is associated with reduced functional recruitment of the cingulofrontal and parietotemporal regions. Furthermore, in line with previous findings, we also found apathy and disinhibition to be prominent features of the first behavioural changes in unaware patients.

PMID:
    21385751

Panminerva Med. 2006 Mar;48(1):19-26.
Peptide hormones and lung cancer.
Moody TW.
Source

Department of Health and Human Services, National Cancer Institute, Center for Cancer Research, Office of the Director, Bethesda, MD 20892, USA. moodyt@mail.nih.gov
Abstract

Several peptide hormones have been identified which alter the proliferation of lung cancer. Small cell lung cancer (SCLC), which is a neuroendocrine cancer, produces and secretes gastrin releasing peptide (GRP), neurotensin (NT) and adrenomedullin (AM) as autocrine growth factors. GRP, NT and AM bind to G-protein coupled receptors causing phosphatidylinositol turnover or elevated cAMP in SCLC cells. Addition of GRP, NT or AM to SCLC cells causes altered expression of nuclear oncogenes, such as c-fos, and stimulation of growth. Antagonists have been developed for GRP, NT and AM receptors which function as cytostatic agents and inhibit SCLC growth. Growth factor antagonists, such as the NT1 receptor antagonist SR48692, facilitate the ability of chemotherapeutic drugs to kill lung cancer cells. It remains to be determined if GRP, NT and AM receptors will served as molecular targets, for development of new therapies for the treatment of SCLC patients. Non-small cell lung cancer (NSCLC) cells also have a high density of GRP, NT, AM and epidermal growth factor (EGF) receptors. Several NSCLC patients with EGF receptor mutations respond to gefitinib, a tyrosine kinase inhibitor. Gefitinib relieves NSCLC symptoms, maintaining stable disease in patients who are not eligible for systemic chemotherapy. It is important to develop new therapeutic approaches using translational research techniques for the treatment of lung cancer patients.

PMID:
    16633328

Spectrochim Acta A Mol Biomol Spectrosc. 2011 Oct 15;81(1):184-98. Epub 2011 Jun 21.
Antioxidant, electrochemical, thermal, antimicrobial and alkane oxidation properties of tridentate Schiff base ligands and their metal complexes.
Ceyhan G, Celik C, Urus S, Demirtas I, Elmastas M, Tümer M.
Source

Kahramanmaras Sütçü Imam University, Chemistry Department, 46100 K.Maras, Turkey.
Abstract

In this study, two Schiff base ligands (HL(1) and HL(2)) and their Cu(II), Co(II), Ni(II), Pd(II) and Ru(III) metal complexes were synthesized and characterized by the analytical and spectroscopic methods. Alkane oxidation activities of the metal complexes were studied on cyclohexane as substrate. The ligands and their metal complexes were evaluated for their antimicrobial activity against Corynebacterium xerosis, Bacillus brevis, Bacillus megaterium, Bacillus cereus, Mycobacterium smegmatis, Staphylococcus aureus, Micrococcus luteus and Enterococcus faecalis (as Gram-positive bacteria) and Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Yersinia enterocolitica, Klebsiella fragilis, Saccharomyces cerevisiae, and Candida albicans (as Gram-negative bacteria). The antioxidant properties of the Schiff base ligands were evaluated in a series of in vitro tests: 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and reducing power activity of superoxide anion radical generated non-enzymatic systems. Electrochemical and thermal properties of the compounds were investigated.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:
    21752697

Neurosci Lett. 2011 Feb 11;489(3):168-71. Epub 2010 Dec 13.
Nicotine modulates expression of dynamin 1 in rat brain and SH-SY5Y cells.
Xu Q, Li MD.
Source

Institute of Biological Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China.
Abstract

Our previous genetic and proteomic studies demonstrated that dynamin 1 is significantly associated with nicotine dependence (ND) in human smokers and its expression is highly modulated by nicotine in the brains of animals. To provide further molecular evidence for the involvement of dynamin 1 in the etiology of ND, we investigated the regulatory effect of nicotine on the expression of dynamin 1 using both in vivo and in vitro approaches. With quantitative real-time RT-PCR, we found that dynamin 1 mRNA was significantly downregulated, by 30%, 31%, and 38%, in the striatum, hippocampus, and medial basal hypothalamus (MBH), respectively, of nicotine-treated rats (P<0.01 for all three regions). Further, dynamin 1 protein was downregulated by nicotine in the ventral tegmental area (VTA: 39.5%; P<0.01), hippocampus (13.4%, P<0.05), MBH (24.6%, P<0.01), and amygdala (15.7%, P<0.05). We also determined the effect of nicotine on human SH-SY5Y cells and found that dynamin 1 mRNA was significantly down-regulated by nicotine after treatment (51.4%; P<0.01), and a consistent decrease in the amount of the protein was also observed (36.6%; P<0.05). Taken together, our findings provide further molecular evidence for the involvement of dynamin 1 in the etiology of ND.

© 2010 Elsevier Ireland Ltd. All rights reserved.

PMID:
    21159320

J Biol Chem. 2011 Jun 17;286(24):21865-75. Epub 2011 Apr 22.
Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3.
Mailloux RJ, Seifert EL, Bouillaud F, Aguer C, Collins S, Harper ME.
Source

Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M5.
Abstract

The mitochondrial uncoupling proteins 2 and 3 (UCP2 and -3) are known to curtail oxidative stress and participate in a wide array of cellular functions, including insulin secretion and the regulation of satiety. However, the molecular control mechanism(s) governing these proteins remains elusive. Here we reveal that UCP2 and UCP3 contain reactive cysteine residues that can be conjugated to glutathione. We further demonstrate that this modification controls UCP2 and UCP3 function. Both reactive oxygen species and glutathionylation were found to activate and deactivate UCP3-dependent increases in non-phosphorylating respiration. We identified both Cys(25) and Cys(259) as the major glutathionylation sites on UCP3. Additional experiments in thymocytes from wild-type and UCP2 null mice demonstrated that glutathionylation similarly diminishes non-phosphorylating respiration. Our results illustrate that UCP2- and UCP3-mediated state 4 respiration is controlled by reversible glutathionylation. Altogether, these findings advance our understanding of the roles UCP2 and UCP3 play in modulating metabolic efficiency, cell signaling, and oxidative stress processes.

PMID:
    21515686

Glycobiology. 2004 Jun;14(6):501-10. Epub 2004 Jan 22.
Chemical and biological characterization of a polysaccharide biological response modifier from Aloe vera L. var. chinensis (Haw.) Berg.
Leung MY, Liu C, Zhu LF, Hui YZ, Yu B, Fung KP.
Source

Institute of Chinese Medicine, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, People's Republic of China.
Abstract

Three purified polysaccharide fractions designated as PAC-I, PAC-II, and PAC-III were prepared from Aloe vera L. var. chinensis (Haw.) Berg. by membrane fractionation and gel filtration HPLC. The polysaccharide fractions had molecular weights of 10,000 kDa, 1300 kDa, and 470 kDa, respectively. The major sugar residue in the polysaccharide fractions is mannose, which was found to be 91.5% in PAC-I, 87.9% in PAC-II, and 53.7% in PAC-III. The protein contents in the polysaccharide fractions was undetectable. NMR study of PAC-I and PAC-II demonstrated the polysaccharides shared the same structure. The main skeletons of PAC-I and PAC-II are beta-(1-->4)-D linked mannose with acetylation at C-6 of manopyranosyl. The polysaccharide fractions stimulated peritoneal macrophages, splenic T and B cell proliferation, and activated these cells to secrete TNF-alpha, IL-1 beta, INF-gamma, IL-2, and IL-6. The polysaccharides were nontoxic and exhibited potent indirect antitumor response in murine model. PAC-I, which had the highest mannose content and molecular weight, was found to be the most potent biological response modifier of the three fractions. Our results suggested that the potency of aloe polysaccharide fraction increases as mannose content and molecular weight of the polysaccharide fraction increase.

PMID:
    14739149

Curr Med Chem. 2000 Jul;7(7):715-29.
Immunomodulation and anti-cancer activity of polysaccharide-protein complexes.
Ooi VE, Liu F.
Source

Department of Biology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.
Abstract

In the last three decades, numerous polysaccharides and polysaccharide-protein complexes have been isolated from mushrooms and used as a source of therapeutic agents. The most promising biopharmacological activities of these biopolymers are their immunomodulation and anti-cancer effects. They are mainly present as glucans with different types of glycosidic linkages such as (1-->3), (1-->6)-beta-glucans and (1-->3)-alpha-glucans, and as true herteroglycans, while others mostly bind to protein residues as polysaccharide-protein complexes. Three antitumor mushroom polysaccharides, i.e. lentinan, schizophyllan and protein-bound polysaccharide (PSK, Krestin), isolated respectively, from Lentinus edodes, Schizophyllum commune and Coriolus versicolor, have become large market items in Japan. Lentinan and schizophyllan are pure beta-glucans, whereas PSK is a protein-bound beta-glucan. A polysaccharide peptide (PSP), isolated from a strain of Coriolus versicolor in China, has also been widely used as an anti-cancer and immunomodulatory agent. Although the mechansim of their antitumor action is still not completely clear, these polysaccharides and polysaccharide-protein complexes are suggested to enhance cell-mediated immune responses in vivo and in vitro and act as biological response modifiers. Potentiation of the host defense system may result in the activation of many kinds of immune cells that are vitally important for the maintenance of homeostasis. Polysaccharides or polysaccharide-protein complexes are considered as multi-cytokine inducers that are able to induce gene expression of vaious immunomodulatory cytokines and cytokine receptors. Some interesting studies focus on investigation of the relationship between their structure and antitumor activity, elucidation of their antitumor mechanism at the molecular level, and improvement of their various biological activities by chemical modifications.

PMID:
    10702635

Cytotechnology. 2000 Jul;33(1-3):247-51.
Mannosylerythritol lipid increases levels of galactoceramide in and neurite outgrowth from PC12 pheochromocytoma cells.
Shibahara M, Zhao X, Wakamatsu Y, Nomura N, Nakahara T, Jin C, Nagaso H, Murata T, Yokoyama KK.
Source

Tsukuba Life Science Center, RIKEN (The Institute of Physical and Chemical Research), 3-1-1 Koyadai, Tsukuba, Ibaraki, 305-0074, Japan.
Abstract

We report here that a microbial extracellular glycolipid,mannosylerythritol lipid (MEL), induces the outgrowth ofneurites from and enhances the activity of acetylcholinesterase(AChE) in PC12 pheochromocytoma cells. Furthermore, treatment ofPC12 cells with MEL increased levels of galactosylceramide(Galbeta1-1'Cer; GalCer). Exposure of PC12 cells to exogenous GalCer caused the dose-dependent outgrowth ofneurites. By contrast, treatment of PC12 cells with nerve growthfactor (NGF) did not increase the level of GalCer in the cells. The neurite-related morphological changes induced by GalCerdifferend from those induced by NGF, indicating differencesbetween the signal transduction pathways triggered by NGF and by GalCer.

PMID:
    19002832

J Biochem. 2003 Apr;133(4):541-52.
Molecular action mode of Hippospongic acid A, an inhibitor of gastrulation of starfish embryos.
Mizushina Y, Murakami C, Takikawa H, Kasai N, Xu X, Mori K, Oshige M, Yamaguchi T, Saneyoshi M, Shimazaki N, Koiwai O, Yoshida H, Sugawara F, Sakaguchi K.
Source

Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180. mizushin@nutr.kobegakuin.ac.jp
Abstract

Hippospongic acid A (HA-A) is a novel natural triterpene metabolite that exhibits inhibitory activity against the gastrulation of starfish embryos isolated from a marine sponge, Hippospongia sp. We succeeded in chemically synthesizing the natural enantiomer and the racemate HA-A. In this study, we examined its action mode in vitro. HA-A was a rare compound that could selectively but uniformly inhibit the activities of all the vertebrate DNA polymerases tested such as alpha, beta, delta, epsilon, eta, kappa, and lambda, in the IC(50) range of 5.9-17.6 microM, and interestingly also those of human DNA topoisomerases I and II (IC(50) = 15-25 microM). HA-A exhibited no inhibitory effect on DNA polymerases from insects, plants and prokaryotes, or on many other DNA metabolic enzymes. HA-A was an inhibitor specific to DNA polymerases and DNA topoisomerases from vertebrates, but not selective as to a subclass species among the enzymes. Since DNA polymerase beta is the smallest, we used it to analyze the biochemical relationship with HA-A. Biochemical, BIAcore and computer modeling analyses demonstrated that HA-A bound selectively to the N-terminal 8 kDa DNA template-binding domain of DNA polymerase beta, and HA-A inhibited the ssDNA binding activity. HA-A could prevent the growth of NUGC-3 cancer cells at both the G1 and G2/M phases, and induce apoptosis in the cells. The LD(50) value was 9.5 microM, i.e. in the same range as for the enzyme inhibition. Therefore, we concluded that one molecular basis of the gastrulation of starfish embryos is a process that requires DNA polymerases and DNA topoisomerases, and subsequently the gastrulation was inhibited by HA-A. We also discussed the in vivo role of HA-A.

PMID:
    12761303

Curr Med Chem. 2007;14(9):955-67.
Inhibitory effect on replicative DNA polymerases, human cancer cell proliferation, and in vivo anti-tumor activity by glycolipids from spinach.
Maeda N, Hada T, Yoshida H, Mizushina Y.
Source

Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, 518 Arise, Ikawadanicho, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Abstract

We succeeded in purifying a major glycolipids fraction (i.e., Fraction-II) in the class of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG) from spinach using hydrophobic column chromatography. Fraction-II inhibited the activities of replicative DNA polymerases (pols) such as alpha, delta and epsilon, and mitochondrial pol gamma with IC(50) values of 43-79 microg/ml, but had no influence on the activity of repair-related pols beta and lambda. MGDG, DGDG, SQDG were purified from Fraction-II of spinach using silica gel column chromatography, and SQDG was the strongest inhibitor of mammalian pols in the three glycolipids. Therefore, SQDG and its related compounds were chemically synthesized, and the sulfate group and fatty acid moiety of the compound were suggested to be important for pol inhibition. These glycolipids showed no effect even on the activities of plant pols, prokaryotic pols and other DNA metabolic enzymes such as T4 polynucleotide kinase, T7 RNA polymerase and deoxyribonuclease I. Fraction-II also inhibited the proliferation of human cervix carcinoma (HeLa) cells with LD(50) values of 57 microg/ml, and could halt the cell cycle at the G1-phase, and subsequently induced severe apoptosis. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, Fraction-II was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that tumor necrosis with hemorrhage was significantly enhanced with Fraction-II in vivo. The spinach Fraction-II containing SQDG might be a potent anti-tumor compound, and may be a healthy food substance with anti-tumor activity.

PMID:
    17439396

J Biochem Mol Biol Biophys. 2002 Oct;6(5):341-5.
Pleurotus Eous mushroom lectin (PEL) with mixed carbohydrate inhibition and antiproliferative activity on tumor cell lines.
Mahajan RG, Patil SI, Mohan DR, Shastry P.
Source

Division of Biochemical Sciences, National Chemical Laboratory, Pune 411 008, India. padmashastry@hotmail.com
Abstract

A novel Pleurotus eous mushroom lectin (PEL) having mixed binding specificity was purified to homogeneity from the fruitbodies of P. eous. The lectin showed monomer weight of 16 kDa and was a glycoprotein having a 9% neutral sugar content. The antiproliferative activity of PEL was tested on four human tumor cell lines. A 50% inhibition of proliferation was demonstrated in MCF-7, K562 and Hep2 cell lines at the lowest concentration (2 microg/ml) of lectin tested. SK-N-MC cell line showed 50% inhibition at 50 microg/ml of PEL. The inhibitory activity of PEL was not associated with toxicity to cell lines.

PMID:
    12385970

Blood. 2011 Aug 26. [Epub ahead of print]
Hepcidin regulation by innate immune and infectious stimuli.
Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA, Ho LP, Townsend AR, Drakesmith H.
Source

Molecular Immunology Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
Abstract

Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6-independent hepcidin upregulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin upregulation that was augmented by TGF-ß1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6-dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6-independent, but partially TGF-ß-dependent. In a murine acute systemic candidiasis model, Candida albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was upregulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.

PMID:
    21873546

J Rheumatol. 2011 Oct;38(10):2153-9. Epub 2011 Sep 1.
Serum hepcidin: a direct link between anemia of inflammation and coronary artery atherosclerosis in patients with rheumatoid arthritis.
Abdel-Khalek MA, El-Barbary AM, Essa SA, Ghobashi AS.
Source

Tanta Faculty of Medicine, Rheumatology and Rehabilitation Department, Elgesh Street, Tanta, Gharbeia, Egypt. ml_barbary@yahoo.com.
Abstract
OBJECTIVE:

To investigate the role of hepcidin as an inducer of anemia of inflammation in patients with rheumatoid arthritis (RA), and its correlation to coronary artery atherosclerosis.
METHODS:

Our study included 60 patients with RA and 20 healthy controls. Anemic RA patients with serum transferrin receptors/log ferritin (sTfR-F) index value < 1.5 were classified as having pure anemia of chronic disease (ACD), and patients with sTfR-F index value > 1.5 were classified as having anemia of chronic disease with coexistent iron deficiency anemia (ACD+IDA). Measurements were taken for Disease Activity Score for 28 joints (DAS28), Modified Health Assessment Questionnaire (MHAQ), erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hsCRP), rheumatoid factor (RF), lipid profile, serum interleukin 6 (IL-6), tumor necrosis factor-a, iron studies, and serum hepcidin. Coronary calcium score (CCS) was measured using multislice spiral computed tomography as a marker of atherosclerosis.
RESULTS:

Serum hepcidin was found to be higher in anemic patients with RA than in controls (p < 0.001), and higher in the pure ACD subgroup than in the ACD+IDA subgroup (p < 0.001). Hepcidin concentration was positively correlated with disease duration, ESR, hsCRP, RF, DAS28, MHAQ, serum ferritin, IL-6, and mean CCS and inversely correlated with hemoglobin, sTfR, and the sTfR-F index.
CONCLUSION:

Hepcidin can be considered a key inducer of anemia of inflammation in patients with RA. This inflammation was proved to be directly linked to coronary artery atherosclerosis. The correlations between serum hepcidin with disease activity and IL-6 raise the possibility of using it as a surrogate marker for disease activity.

PMID:
    21885483

Blood. 2011 Aug 26. [Epub ahead of print]
TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals.
Nai A, Pagani A, Silvestri L, Campostrini N, Corbella M, Girelli D, Traglia M, Toniolo D, Camaschella C.
Source

Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy;
Abstract

The iron hormone hepcidin is inhibited by matriptase-2, a liver serine-protease encoded by TMPRSS6 gene. Cleaving the BMP-coreceptor hemojuvelin, matriptase-2 impairs the BMP/SMAD signaling pathway, downregulates hepcidin and facilitates iron absorption. TMPRSS6 inactivation causes iron-deficiency-anemia refractory to iron administration both in humans and mice. Genome wide association studies have shown that the SNP rs855791, which causes the matriptase-2 V736A amino acid substitution, is associated with variations of serum iron, transferrin saturation, hemoglobin and erythrocyte traits. Here we show that in vitro matriptase-2 736(A) inhibits hepcidin more efficiently than 736(V). Moreover, in a genotyped population, after exclusion of samples with iron deficiency and inflammation, hepcidin, hepcidin/transferrin saturation and hepcidin/ferritin ratios were significantly lower and iron parameters were consistently higher in homozygotes 736(A) than in 736(V). Our results indicate that rs855791 is a TMPRSS6 functional variant and strengthen that even a partial inability to modulate hepcidin influences iron parameters and indirectly erythropoiesis.

PMID:
    21873547

Gene. 2008 May 31;415(1-2):40-8. Epub 2008 Feb 26.
Molecular evolution and characterization of hepcidin gene products in vertebrates.
Hilton KB, Lambert LA.
Source

Department of Biology, Chatham University, Woodland Road, Pittsburgh, PA 15232, United States.
Abstract

Antimicrobial peptides (AMPs) include a diverse group of gene-encoded molecules that play a role in innate defense in many organisms. Evolutionary analyses of the AMP genes can be challenging because of gene duplication and diversification. Recently discovered, hepcidins are small, cysteine-rich antimicrobial peptides that also function as hormonal regulators of iron homeostasis. In this paper we investigated the organization, expression and molecular evolution of hepcidin. From searches of the literature and public genomic databases we collected 68 different hepcidin gene products from 51 different species, all among the vertebrates. Although some species have multiple hepcidin homologues, we suggest that each contains only one copy that functions as an iron regulator. Despite the recent report of hepcidin sequences in the pigeon (Fu, Y.M., Li, S.P., Wu, Y.F., Chang, Y.Z., 2007. Identification and expression analysis of hepcidin-like cDNAs from pigeon (Columba livia). Mol. Cell. Biochem. 305, 191-197.), searches of the chicken genomic, EST, and HTGS databases did not reveal any evidence of the presence of this gene in birds. This, along with the absence of reported avian transferrin receptor 2 and hemojuvelin sequences, suggests that iron homeostasis in birds may be regulated by an alternative mechanism.

PMID:
    18395368

Carbohydr Res. 2011 Oct 18;346(14):2255-9. Epub 2011 Jul 24.
A comparative study of antioxidative activities of cell-wall polysaccharides.
Pristov JB, Mitrovic A, Spasojevic I.
Source

Institute for Multidisciplinary Research, University of Belgrade, Belgrade, Serbia.
Abstract

Oxidative burst in plants is elicited by biotic and abiotic stressors. Analogously to some monosaccharides which act as intracellular antioxidants, cell-wall polysaccharides may be in charge of buffering free-radical production in the extracellular compartment under pronounced prooxidative settings. Although a wide range of plant polysaccharides have been examined for their antioxidative properties, this usually has not been done in a coherent and comparative manner and against biologically relevant reactive species. Here we show that different cell-wall polysaccharides, cellulose, pectin, d-galacto-d-mannan, arabinogalactan, and xylan, exhibit distinctive antioxidative activities against the hydroxyl radical (()OH)-generating Fenton reaction and superoxide. We found, using an EPR spin-trapping method, that the main carriers of 'anti-Fenton' activity in the plant cell wall are pectin and xylan. They most likely act by binding metal ions in such a manner to allow the Fenton reaction, after which they scavenge ()OH. Such a mode of action is preferred by cells resulting in a safe degradation of H(2)O(2). On the other hand, the polysaccharides examined showed similar superoxide scavenging capacities. We propose that plants may employ different antioxidative characteristics of polysaccharides to regulate their redox status by modifying the composition of the cell wall.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
    21880306

J Endocrinol. 2011 Sep 8. [Epub ahead of print]
5{alpha}-REDUCED GLUCOCORTICOIDS - A STORY OF NATURAL SELECTION.
Nixon M, Upreti R, Andrew R.
Source

M Nixon, Endocrinology, Queen's Medical Research Institute, University of Edinburgh,, Edinburgh , United Kingdom.
Abstract

5a-Reduced glucocorticoids are formed when one of the two isozymes of 5a-reductase reduce the ?4-5 double bond in the A-ring of glucocorticoids. These steroids are largely viewed inert, despite acceptance that other 5a-dihydro steroids, eg 5a-dihydrotestosterone, retain or have increased activity at their cognate receptors. However recent findings suggest that 5a-reduced metabolites of corticosterone have dissociated actions at glucocorticoid receptors in vivo and in vitro and thus are potential candidates for safer anti-inflammatory steroids.5a-Dihydro- and 5a-tetrahydro-corticosterone can bind with glucocorticoid receptors but interest in these compounds had been limited, since they only weakly activated metabolic gene transcription. However a greater understanding of the signalling mechanisms has revealed that transactivation represents only one mode of signalling via the glucocorticoid receptor and recently the abilities of 5a-reduced glucocorticoids to suppress inflammation have been demonstrated in vitro and in vivo.Thus the balance of parent glucocorticoid and its 5a-reduced metabolite may critically affect the profile of glucocorticoid receptor signalling. 5a-Reduction of glucocorticoids is up-regulated in liver in metabolic disease and may represent a pathway which both protects from glucocorticoid induced fuel dyshomeostasis and the concomitant inflammatory insult. Therefore 5a-reduced steroids provide hope for drug development, but also may act as biomarkers of the inflammatory status of the liver in metabolic disease. With these proposals in mind, careful attention must be paid to the possible adverse metabolic effects of 5a-reductase inhibitors, drugs which are commonly administered long-term for the treatment of benign prostatic hyperplasia.

PMID:
    21903862

Neurobiol Aging. 2006 Jul;27(7):1010-9. Epub 2005 Jun 23.
Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice.
Poon HF, Vaishnav RA, Getchell TV, Getchell ML, Butterfield DA.
Source

Department of Chemistry, Center of Mambrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
Abstract

The brain is susceptible to oxidative stress, which is associated with age-related brain dysfunction, because of its high content of peroxidizable unsaturated fatty acids, high oxygen consumption per unit weight, high content of key components for oxidative damage, and the relative scarcity of antioxidant defense systems. Protein oxidation, which results in functional disruption, is not random but appears to be associated with increased oxidation in specific proteins. By using a proteomics approach, we have compared the protein levels and specific protein carbonyl levels, an index of oxidative damage in the brains of old mice, to these parameters in the brains of young mice and have identified specific proteins that are altered as a function of aging. We show here that the expression levels of dihydropyrimidinase-like 2 (DRP2), alpha-enolase (ENO1), dynamin-1 (DNM1), and lactate dehydrogenase 2 (LDH2) were significantly increased in the brains of old versus young mice; the expression levels of three unidentified proteins were significantly decreased. The specific carbonyl levels of beta-actin (ACTB), glutamine synthase (GS), and neurofilament 66 (NF-66) as well as a novel protein were significantly increased, indicating protein oxidation, in the brains of old versus young mice. These results were validated by immunochemistry. In addition, enzyme activity assays demonstrated that oxidation was associated with decreased GS activity, while the activity of lactate dehydrogenase was unchanged in spite of an up-regulation of LDH2 levels. Several of the up-regulated and oxidized proteins in the brains of old mice identified in this report are known to be oxidized in neurodegenerative diseases as well, suggesting that these proteins may be particularly susceptible to processes associated with neurodegeneration. Our results establish an initial basis for understanding protein alterations that may lead to age-related cellular dysfunction in the brain.

PMID:
    15979213

Cell Mol Neurobiol. 2010 Nov;30(8):1351-7.
Dynamin and myosin regulate differential exocytosis from mouse adrenal chromaffin cells.
Chan SA, Doreian B, Smith C.
Source

Case Western Reserve University, 2109 Adelbert Road, Cleveland, OH 44106-4970, USA. shyue-an.chan@case.edu
Abstract

Neuroendocrine chromaffin cells of the adrenal medulla represent a primary output for the sympathetic nervous system. Chromaffin cells release catecholamine as well as vaso- and neuro-active peptide transmitters into the circulation through exocytic fusion of large dense-core secretory granules. Under basal sympathetic activity, chromaffin cells selectively release modest levels of catecholamines, helping to set the "rest and digest" status of energy storage. Under stress activation, elevated sympathetic firing leads to increased catecholamine as well as peptide transmitter release to set the "fight or flight" status of energy expenditure. While the mechanism for catecholamine release has been widely investigated, relatively little is known of how peptide transmitter release is regulated to occur selectively under elevated stimulation. Recent studies have shown selective catecholamine release under basal stimulation is accomplished through a transient, restricted exocytic fusion pore between granule and plasma membrane, releasing a soluble fraction of the small, diffusible molecules. Elevated cell firing leads to the active dilation of the fusion pore, leading to the release of both catecholamine and the less diffusible peptide transmitters. Here we propose a molecular mechanism regulating the activity-dependent dilation of the fusion pore. We review the immediate literature and provide new data to formulate a working mechanistic hypothesis whereby calcium-mediated dephosphorylation of dynamin I at Ser-774 leads to the recruitment of the molecular motor myosin II to actively dilate the fusion pore to facilitate release of peptide transmitters. Thus, activity-dependent dephosphorylation of dynamin is hypothesized to represent a key molecular step in the sympatho-adrenal stress response.

PMID:
    21061163

BMC Complement Altern Med. 2011 Jul 25;11:58.
Polysaccharides from Agaricus bisporus and Agaricus brasiliensis show similarities in their structures and their immunomodulatory effects on human monocytic THP-1 cells.
Smiderle FR, Ruthes AC, van Arkel J, Chanput W, Iacomini M, Wichers HJ, Van Griensven LJ.
Source

Plant Research International, Wageningen University and Research, Bornsesteeg 1, 6708 PD Wageningen, The Netherlands.
Abstract
BACKGROUND:

Mushroom polysaccharides have traditionally been used for the prevention and treatment of a multitude of disorders like infectious illnesses, cancers and various autoimmune diseases. Crude mushroom extracts have been tested without detailed chemical analyses of its polysaccharide content. For the present study we decided to chemically determine the carbohydrate composition of semi-purified extracts from 2 closely related and well known basidiomycete species, i.e. Agaricus bisporus and A. brasiliensis and to study their effects on the innate immune system, in particular on the in vitro induction of pro-inflammatory cytokines, using THP-1 cells.
METHODS:

Mushroom polysaccharide extracts were prepared by hot water extraction and precipitation with ethanol. Their composition was analyzed by GC-MS and NMR spectroscopy. PMA activated THP-1 cells were treated with the extracts under different conditions and the production of pro-inflammatory cytokines was evaluated by qPCR.
RESULTS:

Semi-purified polysaccharide extracts of A. bisporus and A. brasiliensis (= blazei) were found to contain (1?6),(1?4)-linked a-glucan, (1?6)-linked ß-glucan, and mannogalactan. Their proportions were determined by integration of 1H-NMR signs, and were considerably different for the two species. A. brasiliensis showed a higher content of ß-glucan, while A. bisporus presented mannogalactan as its main polysaccharide. The extracts induced a comparable increase of transcription of the pro-inflammatory cytokine genes IL-1ß and TNF-a as well as of COX-2 in PMA differentiated THP-1 cells. Pro-inflammatory effects of bacterial LPS in this assay could be reduced significantly by the simultaneous addition of A. brasiliensis extract.
CONCLUSIONS:

The polysaccharide preparations from the closely related species A. bisporus and A. brasiliensis show major differences in composition: A. bisporus shows high mannogalactan content whereas A. brasiliensis has mostly ß-glucan. Semi-purified polysaccharide extracts from both Agaricus species stimulated the production of pro-inflammatory cytokines and enzymes, while the polysaccharide extract of A. brasiliensis reduced synthesis of these cytokines induced by LPS, suggesting programmable immunomodulation.

PMID:
    21787425

FASEB J. 2008 Mar;22(3):703-12. Epub 2007 Oct 10.
Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways.
Atamna H, Nguyen A, Schultz C, Boyle K, Newberry J, Kato H, Ames BN.
Source

Nutrition & Metabolism Center, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA. hatamna@chori.org
Abstract

Methylene blue (MB) has been used clinically for about a century to treat numerous ailments. We show that MB and other diaminophenothiazines extend the life span of human IMR90 fibroblasts in tissue culture by >20 population doubling (PDLs). MB delays senescence at nM levels in IMR90 by enhancing mitochondrial function. MB increases mitochondrial complex IV by 30%, enhances cellular oxygen consumption by 37-70%, increases heme synthesis, and reverses premature senescence caused by H2O2 or cadmium. MB also induces phase-2 antioxidant enzymes in hepG2 cells. Flavin-dependent enzymes are known to use NAD(P)H to reduce MB to leucomethylene blue (MBH2), whereas cytochrome c reoxidizes MBH2 to MB. Experiments on lysates from rat liver mitochondria suggest the ratio MB/cytochrome c is important for the protective actions of MB. We propose that the cellular senescence delay caused by MB is due to cycling between MB and MBH2 in mitochondria, which may partly explain the increase in specific mitochondrial activities. Cycling of MB between oxidized and reduced forms may block oxidant production by mitochondria. Mitochondrial dysfunction and oxidative stress are thought to be key aberrations that lead to cellular senescence and aging. MB may be useful to delay mitochondrial dysfunction with aging and the decrease in complex IV in Alzheimer disease.

PMID:
    17928358

Antioxid Redox Signal. 2009 May;11(5):949-62.
Fragrant unsaturated aldehydes elicit activation of the Keap1/Nrf2 system leading to the upregulation of thioredoxin expression and protection against oxidative stress.
Masutani H, Otsuki R, Yamaguchi Y, Takenaka M, Kanoh N, Takatera K, Kunimoto Y, Yodoi J.
Source

Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan. hmasutan@virus.kyoto-u.ac.jp
Abstract

Thioredoxin, a key molecule in redox regulation, and many redox enzymes are regulated through the antioxidant responsive element (ARE). To search for antioxidative constituents, we screened extracts from vegetables and found that the extracts of Perilla frutescens and Artemisia princeps have potent thioredoxin-inducing activities. By activity-guided purification of Perilla frutescens extracts, we identified perillaldehyde as a novel thioredoxin inducer. Fragrant unsaturated aldehydes, such as trans-cinnamaldehyde, safranal, 2,4-octadienal, citral, trans-2, cis-6-nonadienal, and trans-2-hexenal showed the ability to activate ARE. Perillaldehyde-induced activation through the ARE was suppressed by the overexpression of wild-type Keap1, whereas sulforaphane-induced activation seemed to be partially suppressed. Mutant Keap1 (R272A/K287A or C273A/C288A) did not suppress this activation. Pretreatment with perillaldehyde reduced the H(2)O(2)-induced cytotoxicity. Thus, we show that fragrant unsaturated aldehydes from edible plants are novel thioredoxin inducers and ARE activators and may be beneficial for protection against oxidative stress-induced cellular damage. These results also suggest that perillaldehyde activates the Nrf2-Keap1 system and that the lysine and arginine residues juxtaposed to the critical cysteine residues of Keap1 are required for signal sensing.

PMID:
    19123792

J Food Sci. 2011 Mar;76(2):C250-6. doi: 10.1111/j.1750-3841.2010.02010.x. Epub 2011 Feb 3.
Neuroprotective effect of caffeoylquinic acids from Artemisia princeps Pampanini against oxidative stress-induced toxicity in PC-12 cells.
Lee SG, Lee H, Nam TG, Eom SH, Heo HJ, Lee CY, Kim DO.
Source

Dept of Food Science and Technology, Inst of Life Sciences and Resources, Kyung Hee Univ, Yongin, Gyeonggi 446-701, Republic of Korea.
Abstract

Phenolics in dry Artemisia princeps Pampanini, an herbal plant traditionally consumed as food ingredients in Korea was extracted, fractionated, and quantified as well as evaluated for its neuroprotection for PC-12 cells. Whole extract had 5,852 mg gallic acid equivalents/100 g of total phenolics and 6,274 mg and 9,698 mg vitamin C equivalents/100 g of antioxidant capacities assayed by DPPH and ABTS radicals, respectively. The fraction extracted with n-butanol had the highest levels of total phenolics and antioxidant capacity than the other fractions (n-hexane, chloroform, ethyl acetate, and water). Using a reversed-phase HPLC system, caffeoylquinic acid (CQA) and its derivatives such as 3-CQA, 4-CQA, 5-CQA, 1,5-diCQA, 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA were isolated and quantified. The whole extract and its n-butanol fraction yielded 3,5-diCQA with the highest amount, which consisted of approximately 36.8% and 33.5%, respectively. The whole extract, the n-butanol fraction, and 3,5-diCQA showed neuroprotective effect on PC-12 cells under the insult of amyloid ß peptide in a dose-dependent manner. Treatments of the whole extract and the n-butanol fraction for PC-12 cells under oxidative stress increased approximately 1.6 and 2.4 times higher cell viability, compared with the control without treatments. For PC-12 cells treated with 3,5-diCQA, intracellular oxidative stress decreased by 51.3% and cell viability increased up to 2.8 times compared to the control with oxidative insult of amyloid ß peptide only. These results indicate that phenolics from A. princeps Pampanini alleviated the oxidative stress and enhanced the viability of PC-12 cells, suggesting that it may be applied as a dietary antineurodegenerative agent in functional foods.

PMID:
    21535743

Food Funct. 2011 Sep 7. [Epub ahead of print]
Dietary chromones as antioxidant agents-the structural variable.
Dias MM, Machado NF, Marques MP.
Source

Research Unit "Molecular Physical Chemistry", University of Coimbra, Portugal.
Abstract

This study reports an evaluation of the free radical scavenging ability of a series of chromone derivatives, in the light of their structural features and conformational behaviour. The 2,2-diphenyl-1-picrylhydrazyl radical (DPPH?) test for the assessment of radical scavenging properties was applied, and the interpretation of the experimental results was assisted by ab initio theoretical approaches that allowed relevant parameters, such as the enthalpy of formation of the radical species, to be predicted. From the eighteen tested compounds, three-fisetin, luteolin and quercetin-are shown to act as effective antiradicals. Consistent structure-activity relationships (SARs) were established regarding the antioxidant role of this type of chromone-based system.

PMID:
    21897966

PLoS One. 2011;6(5):e19859. Epub 2011 May 31.
Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum.
Miyata S, Koyama Y, Takemoto K, Yoshikawa K, Ishikawa T, Taniguchi M, Inoue K, Aoki M, Hori O, Katayama T, Tohyama M.
Source

Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. smiyata@anat2.med.osaka-u.ac.jp
Abstract

Repeated stressful events are known to be associated with onset of depression. Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels. However, little is known about the related downstream molecular pathway. In this study, by using repeated water-immersion and restraint stress (WIRS) as a stressor for mice, we attempted to elucidate the molecular pathway induced by elevated plasma corticosterone levels. We observed the following effects both, in vivo and in vitro: (1) repeated exposure to WIRS activates the 3-phosphoinositide-dependent protein kinase (PDK1)-serum glucocorticoid regulated kinase (SGK1)-N-myc downstream-regulated gene 1 (NDRG1)-adhesion molecule (i.e., N-cadherin, a-catenin, and ß-catenin) stabilization pathway via an increase in plasma corticosterone levels; (2) the activation of this signaling pathway induces morphological changes in oligodendrocytes; and (3) after recovery from chronic stress, the abnormal arborization of oligodendrocytes and depression-like symptoms return to the control levels. Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms.

PMID:
    21655274

Appl Environ Microbiol. 2001 Aug;67(8):3440-4.
Laboratory-scale evidence for lightning-mediated gene transfer in soil.
Demanèche S, Bertolla F, Buret F, Nalin R, Sailland A, Auriol P, Vogel TM, Simonet P.
Source

Laboratoire d'Ecologie Microbienne, UMR CNRS 5557, Université Lyon I, France.
Abstract

Electrical fields and current can permeabilize bacterial membranes, allowing for the penetration of naked DNA. Given that the environment is subjected to regular thunderstorms and lightning discharges that induce enormous electrical perturbations, the possibility of natural electrotransformation of bacteria was investigated. We demonstrated with soil microcosm experiments that the transformation of added bacteria could be increased locally via lightning-mediated current injection. The incorporation of three genes coding for antibiotic resistance (plasmid pBR328) into the Escherichia coli strain DH10B recipient previously added to soil was observed only after the soil had been subjected to laboratory-scale lightning. Laboratory-scale lightning had an electrical field gradient (700 versus 600 kV m(-1)) and current density (2.5 versus 12.6 kA m(-2)) similar to those of full-scale lightning. Controls handled identically except for not being subjected to lightning produced no detectable antibiotic-resistant clones. In addition, simulated storm cloud electrical fields (in the absence of current) did not produce detectable clones (transformation detection limit, 10(-9)). Natural electrotransformation might be a mechanism involved in bacterial evolution.

PMID:
    11472916

J Mol Biol. 2008 Dec 19;384(3):564-76. Epub 2008 Oct 2.
Thioredoxin-1 and its natural inhibitor, vitamin D3 up-regulated protein 1, are differentially regulated by PPARalpha in human macrophages.
Billiet L, Furman C, Cuaz-Pérolin C, Paumelle R, Raymondjean M, Simmet T, Rouis M.
Source

UMR-7079, Université Pierre et Marie Curie/CNRS, Bâtiment A, 5ème étage/Case courrier 256, 7, Quai St-Bernard, 75252 Paris Cedex 5, France.
Abstract

Macrophage-derived reactive oxygen species contribute to the initiation and development of atherosclerosis. The cellular balance between oxidative and reductive states depends on the endogenous antioxidant capacity, with the thioredoxin-1 (Trx-1) system playing a major role. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is expressed by human macrophages and exhibits anti-inflammatory properties. Here we show that the selective PPARalpha activator GW647 significantly increased the Trx-1 mRNA and protein expression in human macrophages as determined by quantitative polymerase chain reaction and Western immunoblotting. Consistently, the Trx-1 activity was significantly increased by PPARalpha activation. By contrast, PPARalpha activation led to the down-regulation of vitamin D(3) up-regulated protein 1 (VDUP-1), the physiological inhibitor of Trx-1. Analysis of the Trx-1 and VDUP-1 promoters with gene reporter assays, mutational analysis, gel shift assays and chromatin immunoprecipitation analyses revealed the presence of a functional response element specific for PPARalpha in the Trx-1 promoter and the presence of a functional activator protein 1 (AP-1) site in the VDUP-1 promoter. The interference of PPARalpha/retinoid X receptor alpha with the AP-1 transcription factor elements c-Jun/c-Fos resulted in the inhibition of AP-1 binding and down-regulation of the VDUP-1 gene expression. Finally, PPARalpha activation reduced the lidocaine-induced caspase-3 activity and apoptosis, which might be due to the VDUP-1-mediated regulation of the Bax/Bcl-2 ratio. Together these data indicate that stimulation of PPARalpha in human macrophages might reduce arterial inflammation through differential regulation of the Trx-1 and VDUP-1 gene expression.

PMID:
    18848838

Br J Pharmacol. 2007 Nov;152(5):734-43. Epub 2007 Oct 1.
Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism.
Sun Y, Alexander SP, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall DA, Bennett AJ.
Source

School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK.
Abstract
BACKGROUND AND PURPOSE:

Although CB(1) receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPAR alpha and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection.
EXPERIMENTAL APPROACH:

Assays of PPAR alpha occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPAR alpha activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPAR alpha gene-disrupted mice.
KEY RESULTS:

The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPAR alpha ligand binding domain and to increase PPAR alpha-driven transcriptional activity. The high affinity synthetic CB(1/2) cannabinoid agonist WIN 55212-2 bound to PPAR alpha equipotently with the PPARalpha agonist fenofibrate, and stimulated PPARalpha-mediated gene transcription. The phytocannabinoid delta 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPAR alpha-null mice. OEA treatment also led to increased expression of the NFkappa B-inhibitory protein, Ikappa B, in mouse cerebral cortex, while expression of the NFkappa B-regulated protein COX-2 was inhibited. Conclusions and implications:These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPAR alpha and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

PMID:
    17906680

Neuron. 2000 Feb;25(2):331-43.
Identification of a novel family of oligodendrocyte lineage-specific basic helix-loop-helix transcription factors.
Zhou Q, Wang S, Anderson DJ.
Source

Division of Biology, California Institute of Technology, Pasadena 91125, USA.
Abstract

Basic helix-loop-helix (bHLH) transcription factors have been identified for neurons and their precursors but not for glial cells. We have identified two bHLH factors, Oligo1 and Oligo2, that are specifically expressed in zones of neuroepithelium from which oligodendrocyte precursors emerge, as well as in the precursors themselves. Expression of Oligo2 in the spinal cord precedes that of platelet-derived growth factor receptor alpha (PDGFRalpha), the earliest known marker of oligodendrocyte precursors, by several days. Ectopic expression of Oligo2 in vivo causes ectopic expression of Sox10, an HMG-box transcription factor expressed in oligodendrocyte and other glial precursors. These data identify Oligo genes as the earliest known markers of oligodendrocyte lineage determination and suggest they play a causal role in this process.

PMID:
    10719889

Vet Microbiol. 2011 Jan 27;147(3-4):445-9. Epub 2010 Jul 16.
Serodiagnosis of sporotrichosis infection in cats by enzyme-linked immunosorbent assay using a specific antigen, SsCBF, and crude exoantigens.
Fernandes GF, Lopes-Bezerra LM, Bernardes-Engemann AR, Schubach TM, Dias MA, Pereira SA, de Camargo ZP.
Source

Universidade Federal de São Paulo, Disciplina de Biologia Celular, São Paulo, Brazil.
Abstract

The main objective of this study is to standardize an ELISA for the diagnosis of feline sporotrichosis. Sporothrix schenckii is the etiological agent of human and animal sporotrichosis. Cats may act as reservoirs for S. schenckii and can transmit the infection to humans by a bite or scratch. There are few methods for the serological diagnosis of fungal diseases in animals. In this paper, an ELISA test for the diagnosis of cat sporotrichosis is proposed, which detects S. schenckii-specific antibodies in feline sera. Two different kinds of antigens were used: "SsCBF", a specific molecule from S. schenckii that consists of a Con A-binding fraction derived from a peptido-rhamnomannan component of the cell wall, and a S. schenckii crude exoantigen preparation. The ELISA was developed, optimized, and evaluated using sera from 30 cats with proven sporotrichosis (by culture isolation); 22 sera from healthy feral cats from a zoonosis center were used as negative controls. SsCBF showed 90% sensitivity and 96% specificity in ELISA; while crude exoantigens demonstrated 96% sensitivity and 98% specificity. The ELISA assay described here would be a valuable screening tool for the detection of specific S. schenckii antibodies in cats with sporotrichosis. The assay is inexpensive, quick to perform, easy to interpret, and permits the diagnosis of feline sporotrichosis.

Copyright © 2010 Elsevier B.V. All rights reserved.

PMID:
    20708355

Pharm Biol. 2011 Sep;49(9):907-19. Epub 2011 May 19.
Subcutaneous antifungal screening of Latin American plant extracts against Sporothrix schenckii and Fonsecaea pedrosoi.
Gaitán I, Paz AM, Zacchino SA, Tamayo G, Giménez A, Pinzón R, Cáceres A, Gupta MP.
Source

Facultad de CCQQ y Farmacia, Universidad de San Carlos, Guatemala, Guatemala.
Abstract
CONTEXT:

Subcutaneous mycoses are chronic infections caused by slow growing environmental fungi. Latin American plants are used in folk medicine to treat these afflictions. Moreover, the potential of the rich Latin American biodiversity for this purpose has not been fully explored.
OBJECTIVES:

The aim of the study was to screen Latin American plant extracts against two species of subcutaneous fungi: Sporothrix schenckii and Fonsecaea pedrosoi.
MATERIALS AND METHODS:

One hundred ninety-five organic extracts from 151 Latin American plants were screened against two subcutaneous fungi by the agar dilution method at a concentration of 100 µg/mL, and minimum inhibitory concentrations (MICs) of active extracts were determined. Positive (amphothericin B) and negative (50% ethanol) controls were used.
RESULTS AND DISCUSSION:

Twenty eight extracts showed activity at =100 µg/mL. Of these, four extracts from Gnaphalium gaudichaudianum DC (Asteraceae), Plumeria rubra L (Apocynaceae), Tecoma stans (L.) Juss. ex Kunth. (Bignoniaceae), and Trichostigma octandum (L.), H. Walter showed activity against F. pedrosoi at MIC 12.5 µg/mL; and, four extracts from Bourreria huanita (Lex.) Hemsl. (Boraginaceae), Phytolacca bogotensis Kunth (Phytolaccaceae), Monnina xalapensis Kunth (Polygalaceae) and Crataegus pubescens (C. Presl) C. Presl (Rosaceae) against S. schenckii. This is the first report on antifungal activity of the Latin American plants against these two subcutaneous fungi.
CONCLUSION:

S. schenkii and F. pedrosoi were inhibited by B. huanita (MIC: 12.5 and 25 µg/mL), G. gaudichaudianum (MIC: 50 and 12.5 µg/mL) and T. triflora (MIC: 25 µg/mL).

PMID:
    21592008

Dement Geriatr Cogn Disord. 2011 Aug 26;32(2):79-93. [Epub ahead of print]
A Systematic Literature Review of Cerebrospinal Fluid Biomarkers in Delirium.
Hall RJ, Shenkin SD, Maclullich AM.
Source

Edinburgh Delirium Research Group, Geriatric Medicine, Division of Health Sciences, School of Clinical Sciences and Community Health, Edinburgh, UK.
Abstract

Background: Cerebrospinal fluid (CSF) analysis has great potential to advance understanding of delirium pathophysiology. Methods: A systematic literature review of CSF studies of DSM or ICD delirium was performed. Results: In 8 studies of 235 patients, delirium was associated with: elevated serotonin metabolites, interleukin-8, cortisol, lactate and protein, and reduced somatostatin, ß-endorphin and neuron-specific enolase. Elevated acetylcholinesterase predicted poor outcome after delirium and higher dopamine metabolites were associated with psychotic features. Conclusions: No clear conclusions emerged, but the current literature suggests multiple areas for further investigation with more detailed studies.

Copyright © 2011 S. Karger AG, Basel.

PMID:
    21876357

Int J Food Sci Nutr. 2009;60 Suppl 4:155-62.
Preliminary assessment of nutritional value of plant-based diets in relation to human nutrients.
Aberoumand A.
Source

Department of Food Science, Behbahan University, Behbehan City, Khuzestan Province, Iran. Aberoumand38@yahoo.com
Abstract

In this research, we present preliminary nutritional data for traditional vegetables and fruits including their content of mineral elements (calcium, potassium, sodium, zinc, and iron) and antioxidant phenolic compounds levels. Eight vegetables and vegetables were studied. Plant foods Asparagus officinalis DC, Chlorophytum comosum Linn., Cordia myxa Roxb., Portulaca oleracia Linn. and Solanum indicum Linn. were collected in Behbehan, south Iran, and also Alocacia indica Sch., Eulophia ocherata Lindl. and Momordica dioica Roxb. were collected from the south of India. Nutrients were measured with food analytical standard methods. The results of this study provide evidence that these local traditional vegetables, which do not require formal cultivation, could be important contributors to improving the nutritional content of Pune and Behbehan people. Results indicate that 50% of the vegetables have significant energy values ranging from 281.4 to 303.9 kcal/100 g. From this study, it was determined that five vegetables, namely A. officinalis, C. comosum, E. ocherata, P. oleracia and S. indicum, provide mineral concentrations exceeding 2% of the plant dry weight and are much higher than typical mineral concentrations in conventional edible vegetables; they are thus recommended for future commercial cultivation. High levels of antioxidant compounds were noticed in P. oleracia and S. indicum. The three plants S. indicum, A. officinalis and P. oleracia are suitable for high-temperature food processes.

PMID:
    19274594

Indian J Pharmacol. 2011 Jul;43(4):424-8.
Influence of Momordica charantia on oxidative stress-induced perturbations in brain monoamines and plasma corticosterone in albino rats.
Kavitha N, Babu SM, Rao ME.
Source

Department of Pharmacology, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India.
Abstract
OBJECTIVES:

The objective of this study was to evaluate the antistress activity of Momordica charantia (MC) fruit extract on stress-induced changes in albino rats and also to explore attenuating effects of MC on in vitro lipid peroxidation in rat brain.
MATERIALS AND METHODS:

In this study, Wistar albino rats (180-200 g) were used. Plasma corticosterone and monoamines-5-hydroxy tryptamine (5-HT), norepinephrine (NE), epinephrine (E) and dopamine (DA) in cortex, hypothalamus and hippocampus regions of brain were determined in animals under different stressful conditions. Ethanolic fruit extract of MC, at doses of 200 and 400 mg/kg, was used. The oxidative stress paradigms used in in vivo models were acute stress (AS) and chronic unpredictable stress (CUS). Panax quinquefolium (PQ) was used as a standard in in vivo models and ascorbic acid was used as a reference standard in the in vitro method.
RESULTS:

Subjecting the animals to AS (immobilization for 150 min once only) resulted in significant elevation of plasma corticosterone levels and brain monoamine levels. Pretreatment with MC at doses of 200 and 400 mg/kg p.o. significantly countered AS-induced changes and a similar effect was exhibited by PQ at 100 mg/kg p.o. In the CUS regimen (different stressors for 7 days), plasma corticosterone levels were significantly elevated whereas the levels of 5-HT, NE, E, and DA were depleted significantly. Pretreatment with MC (200 and 400 mg/kg) attenuated the CUS-induced changes in the levels of above monoamines in cortex, hypothalamus, and hippocampus regions of brain and plasma corticosterone in a dose-dependent manner. Furthermore, MC extract (1000-5000 µg/mL) exhibited a significant quenching effect on in vitro lipid peroxidation indicating its strong antioxidant activity which was compared with ascorbic acid.
CONCLUSIONS:

This study reveals the antistress activity of MC as it significantly reverted the stress-induced changes, and the activity might be attributed to its antioxidant activity since stress is known to involve several oxidative mechanisms.

PMID:
    21844998

Methods Mol Biol. 2009;532:163-79.
Horizontal gene transfer and the evolution of methanogenic pathways.
Fournier G.
Source

Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA.
Abstract

Horizontal gene transfer (HGT) is a driving force in the evolution of metabolic pathways, allowing novel enzymatic functions that provide a selective advantage to be rapidly incorporated into an organism's physiology. Here, the role of two HGT events in the evolution of methanogenesis is described. First, the acetoclastic sub-pathway of methanogenesis is shown to have evolved via a transfer of the ackA and pta genes from a cellulolytic clostridia to a family of methanogenic archaea. Second, the system for encoding the amino acid pyrrolysine, used for the synthesis of enzymes for methanogenesis from methylamines, is shown to likely have evolved via transfer from an ancient, unknown, deeply branching organismal lineage.

PMID:
    19271184

Neurosci Lett. 2011 Jan 25;488(3):225-8. Epub 2010 Oct 12.
The effects of acupuncture (PC6) on chronic mild stress-induced memory loss.
Kim H, Park HJ, Shim HS, Han SM, Hahm DH, Lee H, Shim I.
Source

Division of Brain Disease, Center for Biomedical Science, National Institute of Health, 194 Tongillo, Eunpyeong-gu, Seoul, 122-701, Korea.
Abstract

A previous study reported that the PC6 acupuncture point can alleviate chronic mild stress (CMS)-induced anxiety [17]. Following the previous study, this study examined the effects of the PC6 acupuncture point on CMS-induced memory loss. The memory storage and acetylcholinesterase (AchE) activity in the hippocampus were measured, respectively, using a passive avoidance test (PAT) and AchE immunohistochemistry. In the PAT (retention test), the CMS group showed a markedly lower latency time than the control (post (72h): P<0.01, post (96h): P<0.05, post (120h): P<0.001). However, acupuncture at PC6 significantly recovered the impairment of memory compared to the CMS group (post (120h): P<0.001). Exposure to CMS also significantly decreased the AchE activity in the hippocampus compared to the control rats. Acupuncture stimulation at the PC6 point on the pericardium channels (3min), but not at other points (TE5), produced memory improvements and an increase in AchE reactivity in the hippocampus compared to the CMS group. These results show that the acupuncture point is effective in restoring the CMS-related biochemical and behavioral impairments, such as learning and memory.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

PMID:
    20946936

Chin Med J (Engl). 2011 Apr;124(8):1229-34.
Differential temporal neural responses of pain-related regions by acupuncture at acupoint ST36: a magnetoencephalography study.
Cheng H, Zhang XT, Yan H, Bai LJ, Ai L, Wang FB, You YB, Chen P, Wang BG.
Source

Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Abstract
BACKGROUND:

Previous neuroimaging studies primarily focused on the spatial distribution of acupuncture needling stimulation. However, a salient feature of acupuncture was its long-lasting effect. This study attempted to detect the spatial-temporal neural responses evoked by acupuncture at an analgesia acupoint ST36 by using magnetoencephalography. To further verify its functional specificity, we also adopted acupuncture at Pericardium 6 and nonacupoint as separated controls.
METHODS:

Forty-two college students, all right-handed and acupuncture naïve, participated in this study. Every participant received only one acupoint stimulation, resulting in 14 subjects in one group. Both magnetoencephalography data (151-channel whole-head system) and structural functional magnetic resonance imaging data (3D sequence with a voxel size of 1 mm(3) for anatomical localization) were collected for each subject. All processing procedures were performed in BrainStorm Toolbox.
RESULTS:

Acupuncture at ST36 showed a significantly time-varied brain activities with different onset time. Our results presented that acupuncture at different acupoints (or comparing with nonacupoint) can specifically induce neural responses in different brain areas-acupuncture at ST36 can specifically induce the neural responses of pain-inhibition areas, while acupuncture at PC6 can specifically induce the activities of the insula and amygdala.
CONCLUSIONS:

In the present study, we attempted to detect the temporal neural responses underlying the functional specificity of acupuncture at ST36, using acupoint belonging to different meridians and non-acupoint with efficacy-irreverent as separate controls. The specific neural substrates involving acupuncture at different acupoints may be related to its functional specificity in clinical settings.

PMID:
    21543002

Evid Based Complement Alternat Med. 2012;2012:692621. Epub 2011 Jul 25.
Traditional chinese medicine for senile dementia.
Lin Z, Gu J, Xiu J, Mi T, Dong J, Tiwari JK.
Source

Naturals and Bioscience, Unilever R&D Shanghai, Shanghai 200233, China.
Abstract

Traditional Chinese Medicine (TCM) has a 3000 years' history of human use. A literature survey addressing traditional evidence from human studies was done, with key result that top 10 TCM herb ingredients including Poria cocos, Radix polygalae, Radix glycyrrhizae, Radix angelica sinensis, and Radix rehmanniae were prioritized for highest potential benefit to dementia intervention, related to the highest frequency of use in 236 formulae collected from 29 ancient Pharmacopoeias, ancient formula books, or historical archives on ancient renowned TCM doctors, over the past 10 centuries. Based on the history of use, there was strong clinical support that Radix polygalae is memory improving. Pharmacological investigation also indicated that all the five ingredients mentioned above can elicit memory-improving effects in vivo and in vitro via multiple mechanisms of action, covering estrogen-like, cholinergic, antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aß activities. Furthermore, 11 active principles were identified, including sinapic acid, tenuifolin, isoliquiritigenin, liquiritigenin, glabridin, ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate and 11-angeloylsenkyunolide F, and catalpol. It can be concluded that TCM has a potential for complementary and alternative role in treating senile dementia. The scientific evidence is being continuously mined to back up the traditional medical wisdom.

PMID:
    21808655

Neurosci Lett. 2011 Jun 15;497(1):22-6. Epub 2011 Apr 16.
Protective effects of catalpol on oligodendrocyte death and myelin breakdown in a rat model of chronic cerebral hypoperfusion.
Cai QY, Chen XS, Zhan XL, Yao ZX.
Source

Department of Histology and Embryology, College of Basic Medicine, The Third Military Medical University, Chongqing 400038, China.
Abstract

Chronic cerebral hypoperfusion is thought to induce white matter lesions (WMLs) with oligodendrocyte (OLG) death and myelin breakdown. Although apoptosis is believed to be involved in the pathologic process of WMLs, effective therapies for such remain lacking. In the present study, we investigated whether catalpol, an iridoid glycoside, could act on oligodendrocytes (OLGs) and myelin sheaths in a rat chronic hypoperfusion model, and whether transcription factor cAMP-responsive element binding protein (CREB) phosphorylation is involved in the resulting neuroprotection. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. On the 30th day after hypoperfusion, OLG loss and myelin disruption in the ischemic white matter were more severe and evident than in the sham control. Spatial memory was also more seriously impaired in rats after hypoperfusion. Treatment with catalpol significantly suppressed diminished OLGs and myelin breakdown, and promoted the recovery of cognitive decline. The expression of Bcl-2 and phosphorylated CREB (p-CREB) was also significantly increased by catalpol treatment. In conclusion, catalpol could protect against hypoperfusion-induced WMLs and cognitive impairment through the p-CREB signaling pathway leading to downstream upregulation of Bcl-2. Our results suggest that catalpol may be a useful approach for treating cerebrovascular WMLs.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID:
    21524686

Zhonghua Zhong Liu Za Zhi. 2011 Apr;33(4):291-4.
[Safety and effectiveness of large dose compound Sophora flavescens Ait injection in the treatment of advanced malignant tumors].
[Article in Chinese]
Li DR, Lin HS.
Source

The Guanganmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China. lidaorui@sina.com
Abstract
OBJECTIVE:

To evaluate the effectiveness and safety of large dose compound Sophora flavescens Ait injection in the treatment of advanced malignant tumors.
METHODS:

A non-randomized case control trial was conducted. Ninety six patients with pathologically confirmed advanced non-small-cell lung cancer, gastric cancer and colorectal cancer were divided into traditional Chinese medicine group and chemotherapy group, 48 cases each. Patients of the traditional Chinese medicine group received treatment with large dose of compound Sophora flavescens Ait injection (20 ml/d), and 21 days as a cycle.
RESULTS:

Forty-seven patients of the traditional Chinese medicine group and 46 patients of the chemotherapy group completed their treatment, respectively. The clinical benefit rate (CBR) in the traditional Chinese medicine group was 83.0%, significantly higher than that in the chemotherapy group (69.6%) (P < 0.01). The Karnofsky performance status and weight improvement in the traditional Chinese medicine group was superior to that in the chemotherapy group (P < 0.05). Except the skin irritation in one patient in the traditional Chinese medicine group, there were no other clinical adverse effects related with the large dose compound Sophora flavescens Ait injection.
CONCLUSIONS:

Large dose compound Sophora flavescens Ait injection in the treatment of advanced malignant tumors is safe and effective. The recommended dose is 20 ml/d.

PMID:
    21575502

Scand J Med Sci Sports. 2011 Apr 21. doi: 10.1111/j.1600-0838.2011.01314.x. [Epub ahead of print]
Mitochondrial nutrients stimulate performance and mitochondrial biogenesis in exhaustively exercised rats.
Sun M, Qian F, Shen W, Tian C, Hao J, Sun L, Liu J.
Source

Key Laboratory of General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai, China State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Vascular Biology, Department of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China Institute for Nutritional Science, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China College of Sports and Health, East China Normal University, Shanghai, China The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Mitochondrial Biology and Medicine, Xi'an Jiaotong University School of Life Science and Technology, Xi'an, China.
Abstract

The aim of this study was to investigate the effects of a combination of nutrients on physical performance, oxidative stress and mitochondrial biogenesis in rats subjected to exhaustive exercise. Rats were divided into sedentary control (SC), exhaustive exercise (EC) and exhaustive exercise with nutrient supplementation (EN). The nutrients include (mg/kg/day): R-a-lipoic acid 50, acetyl-l-carnitine 100, biotin 0.1, nicotinamide 15, riboflavin 6, pyridoxine 6, creatine 50, CoQ10 5, resveratrol 5 and taurine 100. Examination of running distances over the 4-week period revealed that EN rats ran significantly longer throughout the entire duration of the exhaustive exercise period compared with the EC rats. Nutrient supplementation significantly inhibited the increase in activities of alanine transaminase, lactate dehydrogenase and creatine kinase, reversed increases in malondialdehyde, inhibited decreases in glutathione S-transferase and total antioxidant capacity in plasma, and suppressed the elevation of reactive oxygen species and apoptosis in splenic lymphocytes. Nutrient supplementation increased the protein expression of mitochondrial complexes I, II and III, mtDNA number and transcription factors involved in mitochondrial biogenesis and fusion in skeletal muscle. These findings suggest that mitochondrial nutrient supplementation can reduce exhaustive exercise-induced oxidative damage and mitochondrial dysfunction, thus leading to enhancement of physical performance and of fatigue recovery.

© 2011 John Wiley & Sons A/S.

PMID:
    21507065

J Agric Food Chem. 2011 Sep 14;59(17):9194-200. Epub 2011 Aug 5.
Konjac Glucomannan and Inulin Systematically Modulate Antioxidant Defense in Rats Fed a High-Fat Fiber-free Diet.
Wu WT, Chen HL.
Source

School of Nutrition, Chung Shan Medical University , Taichung, Taiwan.
Abstract

The aim of this study was to investigate the effects of konjac glucomannan (KGM) and inulin on the balance between pro-oxidative status and antioxidative defense systems in the colon, liver, and plasma of rats fed a high-fat fiber-free diet. Male Sprague-Dawley rats (n = 8 animals per group) were fed a high-fat (25% corn oil, w/w) fiber-free diet or that supplemented with KGM or inulin fiber (5%, w/w) for 4 weeks. The index of pro-oxidative status, malondialdehyde (MDA), and blood lymphocyte DNA damage; the antioxidative defense, that is, antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase) in the colonic mucosa and liver; and the plasma antioxidant levels were determined. The fermentation of fiber was shown in fecal short-chain fatty acids. Incorporation of KGM and inulin into the high-fat fiber-free diet beneficially reduced the MDA levels of the colon and liver and DNA damage in blood lymphocytes. On the other hand, both fibers enhanced the antioxidative defense systems by up-regulating the gene expressions of glutathione peroxidase and catalase in the colonic mucosa and of superoxide dismutase and catalase in the liver. Furthermore, KGM and inulin promoted antioxidative status in the blood by elevating the a-tocopherol level. KGM and inulin were well-fermented in rats and increased the concentration and daily excretion of fecal short-chain fatty acids, especially acetate and butyrate. These results suggest that in vivo utilization of KGM and inulin stimulated both local and systemic antioxidative defense systems in rats.

PMID:
    21800874

J Agric Food Chem. 2011 Feb 9;59(3):989-94. Epub 2011 Jan 5.
Effects of konjac glucomannan on putative risk factors for colon carcinogenesis in rats fed a high-fat diet.
Wu WT, Chen HL.
Source

School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Abstract

The aim of this study was to determine effects of konjac glucomannan (KGM) in a high fat corn oil diet on risk factors of colon carcinogenesis, that is, fecal ß-glucuronidase, mucinase, and bile acids, and on preventive factors, that is, fecal microflora and cecal short-chain fatty acids (SCFAs). Sprague-Dawley rats (n = 8 animals per group) were fed a normal-fat fiber-free (5% corn oil, w/w) or high-fat (25% corn oil, w/w) diet containing no fiber, KGM (5%, w/w), or inulin (5%, w/w, as a prebiotic control) for 4 weeks. Results indicated that the high-fat fiber-free diet significantly elevated the fecal ß-glucuronidase and mucinase activities and total bile acid concentration and decreased cecal SCFA contents, as compared with its normal-fat counterpart. The incorporation of KGM, as well as inulin, into the high-fat fiber-free diet beneficially reduced the fecal ß-glucuronidase and mucinase activities and lithocholic acid (secondary bile acid) concentration. Although KGM elevated the daily fecal total bile acid excretion, the change was due to the primary, instead of the secondary, bile acids. In addition, KGM beneficially promoted the daily fecal excretion of bifidobacteria and lactobacilli and cecal SCFA contents, as compared with the high-fat fiber-free diet. Therefore, the present study suggests that KGM potentially attenuated the high fat-induced risk in colon carcinogenesis.

PMID:
    21208006

Phytomedicine. 2008 Jan;15(1-2):92-7. Epub 2007 Aug 6.
Inhibitory effect of Erigeron breviscapus extract and its flavonoid components on GABA shunt enzymes.
Tao YH, Jiang DY, Xu HB, Yang XL.
Source

Institute of Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, China.
Abstract

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, is metabolized by the successive action of GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). Inhibition of both enzymes in brain tissues increases the GABA level and may have therapeutic applications in neurological diseases. Erigeron breviscapus ethanol extract was evaluated for their effect on both enzymes. This extract, its ethyl acetate fraction and aqueous fraction, significantly inhibited them at >100 microg/ml. Flavonoid components of E. breviscapus potently and noncompetitively inhibited both enzymes, and the different structure-activity relations were observed with respect to inhibition of both enzymes. Baicalein was the most potent inhibitor for GABA-T with an IC50 value of 12.8+/-1.2 microM, and scutellarein exhibited the best inhibitory effect on SSADH with an IC50 value of 7.20+/-0.9 microM. The present results may imply new pharmacological actions of E. breviscapus and contribute partially to the beneficial effect of the herb and flavonoids on the central nervous system.

PMID:
    17689232

Phytomedicine. 2011 Oct 15;18(13):1126-9. Epub 2011 May 10.
Effect of honokiol on activity of GAD(65) and GAD(67) in the cortex and hippocampus of mice.
Ku TH, Lee YJ, Wang SJ, Fan CH, Tien LT.
Source

Department of Anesthesiology, Changhua Christian Hospital, Changhua County 500, Taiwan.
Abstract

Honokiol, an active agent extracted from magnolia bark, has been reported that induces anxiolytic action in a mouse elevated plus-maze test. However, the mechanism of anxiolytic action induced by honokiol remains unclear. This study was to investigate the change in two forms of glutamic acid decarboxylase (GABA synthesized enzymes) GAD(65) and GAD(67) in the cortex and hippocampus areas while the anxiolytic actions induced by chronic administration of honokiol in mice. Mice treated with 7 daily injection of honokiol (1mg/kg, p.o.) caused anxiolytic action which was similar to that was induced by 7 daily injection of diazepam (2mg/kg, p.o.) in the elevated plus-maze test. In addition, the activity of hippocampal GAD(65) of honokiol treated mice was significantly increased than that of the vehicle or diazepam treated groups. These data suggest that honokiol causes diazepam-like anxiolytic action, which may be mediated by altering the synthesis of GABA in the brain of mice.

Copyright © 2011 Elsevier GmbH. All rights reserved.

PMID:
    21561750

Zhongguo Zhong Yao Za Zhi. 2008 Jul;33(14):1681-3.
[HPLC determination of four active components in dengzhanxixin injection].
[Article in Chinese]
Wang XM, Wang YF, Pan GX, Yang J.
Source

The Traditional Chinese Medicine Research Centre of Tianjin University of Traditional Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin 300193, China.
Abstract
OBJECTIVE:

To establish a method for determination of chlorogenic acid, caffeic acid, caffeoylquinic acid and ScuteIlarin in Dengzhan Xixin injection.
METHOD:

The HPLC method was carried out on Agilent Zorbax SB-C18 column (150 mm x 4. 6 mm, 5 pim) evaluated with acetonitrile-0.1% formic acid as mobile phase, gradient elution; the flow rate was 1.0 mL x min(-1); the temperatue of column was at 35 degrees C; the detection wavelength was at 335 nm for UV detection.
RESULT:

The calibration curves were linear in the range of 0.025 to 0.800 microg (r = 0.9990) for chlorogenic acid, 0.027 to 0.850 microg (r = 0.9999) for caffeic acid, 0.062 to 1.978 microg (r = 0.9997) for caffeoylquinic acid and 0.118 to 3.770 microg (r = 0.9999) for scutellarin,respectilely. The average recoveries were 97.19% with RSD 1.16%; 100.45% with RSD 1.16%; 97.32% with RSD 1.43% and 103.81% with RSD 0.70%, respectively.
CONCLUSION:

The assay demonstrated that the method was simple, it had adequate accuracy and selectivity to quantify the four active components in Dengzhan Xixin injection.

PMID:
    18841764

Zhongguo Zhong Yao Za Zhi. 2009 Jan;34(2):208-11.
[Effects of Dengzhan Xixin on blood-brain barrier permeability and metabolites after cerebral ischemia-reperfusion injuries].
[Article in Chinese]
Liu H, Liao W, Wei L, Lei H.
Source

Department of Rehabilitation Medicine, Zhongnan Hospital Wuhan University, Wuhan 430071, China.
Abstract
OBJECTIVE:

The investigated the effects of Dengzhan Xixin on brain water content, blood-brain barrier (BBB) permeability, T2-weighted imaging (T2WI), metabolites and the lesion ratio after cerebral ischemia-reperfusion injuries (IRI).
METHOD:

The 65 rats were randomly individed into three groups, the sham-operated group, the ischemia-reperfusion group and the Dengzhan Xixin treatment group. The models of ischemia-reperfusion of middle cerebral artery in rats were established by placing an intraluminal suture. The Dengzhan Xixin treatment group were injected 10% Dengzhan Xixin injection 22.5 mg kg(-1) after ischemia 1.5 h. The sh am-operated group (n=5) were sacrificed on 1 to measure brain water content and BBB permeability. The rats of the ischemia-reperfusion group (n=30) and the Dengzhan Xixin treatment group (n=30) were sacrificed at reperfusion for 6 h, 12 h, 1 d, 2 d, 4 d, 7 d, respectively, after ischemia 1.5 h. The additional 35 rats were individed into the same three groups. The changes of T2WI and metabolites in the brain were observed, and rats were sacrificed at reperfusion for 1 d, 2 d, 4 d after ischemia 1.5 h to determine the lesion ratio by TTC.
RESULT:

In the ischemia-reperfusion group, brain water content(77.93+/-0.68)% and BBB permeability (3.77+/-0.28) increased after reperfusion for 6 h. The peak time of brain water content was at 4 d (83.82+/-0.49)% and BBB permeability was at 2 d (5.51+/-0.24)%. In the ischemia-reperfusion group and the Dengzhan Xixin treatment group, there were hyperintense signals in the injury region of T2WI. In the ischemia-reperfusion group after reperfusion for 1 d, the ratio of NAA/Cr decreased and Cho/Cr increased. In the Dengzhan Xixin treatment group, the ratio of NAA/Cr increased and Cho/Cr decreased. In the treatment group, the lesion ratio decreased by TTC was 16.78+/-1.45 and in the ischemia-reperfusion group was 21.27+/-1.73 at 2 d.
CONCLUSION:

Dengzhan Xixin may relieve cerebral ischemia-reperfusion injury by influencing the metabolites of brain, stabilizing BBB and decreasing brain edema.

PMID:
    19385188

J Biol Chem. 2000 Sep 29;275(39):30677-82.
Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different consequences in potassium channel function.
Pabon A, Chan KW, Sui JL, Wu X, Logothetis DE, Thornhill WB.
Source

Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract

GIRK (G protein-gated inward rectifier K(+) channel) proteins play critical functional roles in heart and brain physiology. Using antibodies directed to either GIRK1 or GIRK4, site-directed mutagenesis, and specific glycosidases, we have investigated the effects of glycosylation in the biosynthesis and heteromerization of these proteins expressed in oocytes. Both GIRK1 and GIRK4 have one extracellular consensus N-glycosylation site. Using chimeras between GIRK1 and GIRK4 as well as a GIRK1 N-glycosylation mutant, we report that GIRK1 was glycosylated at Asn(119), whereas GIRK4 was not glycosylated at Asn(132). GIRK1 membrane-spanning domain 1 was required for optimal glycosylation at Asn(119) because a chimera that contained GIRK4 membrane-spanning domain 1 significantly reduced the addition of a carbohydrate structure at this site. This finding may partly account for the reason that GIRK4 is not glycosylated at Asn(132), either as a homomer or when coexpressed with GIRK1. When the GIRK1(N119Q) mutant was coexpressed with GIRK4, the biophysical properties of the heteromeric channel and the magnitude of the agonist-induced currents were similar to those of controls. Thus, N-glycosylation of GIRK1 at Asn(119) does not appear to affect its physical association with GIRK4, the routing of the heteromer to the cell surface, or heteromeric channel function, unlike the dramatic functional effects of N-glycosylation of ROMK1 at Asn(117) (Schwalbe, R. A., Wang, Z., Wible, B. A., and Brown, A. M. (1995) J. Biol. Chem. 270, 15336-15340).

PMID:
    10889209

Eur J Pharmacol. 2011 Oct 1;668(1-2):133-9. Epub 2011 Jul 13.
Evaluation of the antioxidant, anti-inflammatory and hepatoprotective properties of vanillin in carbon tetrachloride-treated rats.
Makni M, Chtourou Y, Fetoui H, Garoui el M, Boudawara T, Zeghal N.
Source

; Food Processing Department, ISET, BP 377, 9100 Sidi Bouzid, Tunisia. mohamed.makni@gmail.com
Abstract

The antioxidant and anti-inflammatory effects of vanillin are considered as important forces in the protection against liver injury and fibrosis. This study investigated the protective effects of vanillin against carbon tetrachoride (CCl(4))-induced hepatotoxicity in rat. Pretreatment with vanillin prior the administration of CCl(4) significantly prevented the decrease of protein synthesis and the increase in plasma alanine (ALT) and aspartate (AST) aminotransferases. Furthermore, it inhibited hepatic lipid peroxidation (MDA) and protein carbonyl (PCO) formation and attenuated the (CCl(4))-mediated depletion of antioxidant enzyme catalase and superoxide dismutase (SOD) activities and glutathione level (GSH) in the liver. In addition, vanillin markedly attenuated the expression levels of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) and prevented CCl(4)-induced hepatic cell alteration and necrosis, as indicated by liver histopathology. These findings suggest that the antioxidant and anti-inflammatory effects of vanillin against CCl(4)-induced acute liver injury may involve its ability to block CCl(4)-generated free radicals.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:
    21777577

Eur J Neurosci. 2011 Sep 21. doi: 10.1111/j.1460-9568.2011.07864.x. [Epub ahead of print]
Pyruvate's blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke.
Boyko M, Zlotnik A, Gruenbaum BF, Gruenbaum SE, Ohayon S, Kuts R, Melamed I, Regev A, Shapira Y, Teichberg VI.
Source

Division of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, 36 Hanoch Albek Str., Beer-Sheva, Israel 84833 Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA Department of Neurosurgery, Soroka Medical Center, Beer-Sheva, Israel Clinical Research Center, Soroka Medical Center, Beer-Sheva, Israel Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Abstract

In previous studies, we have shown that by increasing the brain-to-blood glutamate efflux upon scavenging blood glutamate with either oxaloacetate or pyruvate, one achieves highly significant neuroprotection particularly in the context of traumatic brain injury. The current study examines, for the first time, how the blood glutamate scavenging properties of glutamate-pyruvate transaminase (GPT), alone or in combination with pyruvate, may contribute to the spectrum of its neuroprotective mechanisms and improve the outcome of rats exposed to brain ischemia, as they do after head trauma. Rats that were exposed to permanent middle cerebral artery occlusion (MCAO) and treated with intravenous 250 mg/kg pyruvate had a smaller volume of infarction and reduced brain edema, resulting in an improved neurological outcome and reduced mortality compared to control rats treated with saline. Intravenous pyruvate at the low dose of 31.3 mg/kg did not demonstrate any neuroprotection. However, when combined with 0.6 mg/kg of GPT there was a similar neuroprotection observed as seen with pyruvate at 250 mg/kg. Animals treated with 1.69 g/kg glutamate had a worse neurological outcome and a larger extent of brain edema. The decrease in mortality, infarcted brain volume and edema, as well as the improved neurological outcome following MCAO, was correlated with a decrease in blood glutamate levels. We therefore suggest that the blood glutamate scavenging activity of GPT and pyruvate contributes to the spectrum of their neuroprotective mechanisms and may serve as a new neuroprotective strategy for the treatment of ischemic stroke.

© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

PMID:
    21936878

Prostaglandins Other Lipid Mediat. 2011 Jul 23. [Epub ahead of print]
A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development.
Kim HY, Spector AA, Xiong ZM.
Source

Laboratory of Molecular Signaling, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9410, United States.
Abstract

Docosahexaenoic acid (DHA), the n-3 essential fatty acid that is highly enriched in the brain, increases neurite growth and synaptogenesis in cultured mouse fetal hippocampal neurons. These cellular effects may underlie the DHA-induced enhancement of hippocampus-dependent learning and memory functions. We found that N-docsahexaenoylethanolamide (DEA), an ethanolamide derivative of DHA, is a potent mediator for these actions. This is supported by the observation that DHA is converted to DEA by fetal mouse hippocampal neuron cultures and a hippocampal homogenate, and DEA is present endogenously in the mouse hippocampus. Furthermore, DEA stimulates neurite growth and synaptogenesis at substantially lower concentrations than DHA, and it enhances glutamatergic synaptic activities with concomitant increases in synapsin and glutamate receptor subunit expression in the hippocampal neurons. These findings suggest that DEA, an ethanolamide derivative of DHA, is a synaptogenic factor, and therefore we suggest utilizing the term 'synaptamide'. This brief review summarizes the neuronal production and actions of synaptamide and describes other N-docosahexaenoyl amides that are present in the brain.

Published by Elsevier Inc.

PMID:
    21810478

J Neurotrauma. 2011 Oct 4. [Epub ahead of print]
The Salutary Effects of DHA Dietary Supplementation on Cognition, Neuroplasticity, and Membrane Homeostasis after Brain Trauma.
Wu A, Ying Z, Gomez-Pinilla F.
Source

1 Department of Integrative Biology and Physiology, University of California at Los Angeles (UCLA) , Los Angeles, California.
Abstract

Abstract The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.

PMID:
    21851229

Biol Trace Elem Res. 2011 Sep 20. [Epub ahead of print]
Effects of Subchronic Aluminum Exposure on the Reproductive Function in Female Rats.
Wang N, She Y, Zhu Y, Zhao H, Shao B, Sun H, Hu C, Li Y.
Source

College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
Abstract

The aim of this study was to investigate the effects of aluminum (Al) exposure on the reproductive function in female rats. Forty female Wistar (5 weeks old) rats, weighing 110-120 g, were divided randomly into four groups. They were orally administrated with 0, 64.18, 128.36, and 256.72 mg aluminum chloride (AlCl(3)) per kilogram body weight in drinking water for 120 days. Levels of Al, estrogen (E(2)), progestogen (P), testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in serum were measured at the end of experiment. The results showed that levels of E(2), P, FSH, and LH were significantly lower and Al concentration was significantly higher in all three Al-treated groups than those in the control group (GC). The level of T was significantly higher in the low- and medium-dose groups (GL and GM) (P?<?0.05) but not in high-dose group (GH) compared with GC. The results suggest that the reproductive function of female rats is inhibited under long-term Al exposure in an Al dose-dependent manner.

PMID:
    21932046

Neuron. 2002 Nov 14;36(4):661-74.
Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD.
Lee SH, Liu L, Wang YT, Sheng M.
Source

Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Abstract

Proteins that bind to the cytoplasmic tails of AMPA receptors control receptor trafficking and thus the strength of postsynaptic responses. Here we show that AP2, a clathrin adaptor complex important for endocytosis, associates with a region of GluR2 that overlaps the NSF binding site. Peptides used previously to interfere with NSF binding also antagonize GluR2-AP2 interaction. Using GluR2 mutants and peptide variants that dissociate NSF and AP2 interaction, we find that AP2 is involved specifically in NMDA receptor-induced (but not ligand-dependent) internalization of AMPA receptors, and is essential for hippocampal long-term depression (LTD). NSF function, on the other hand, is needed to maintain synaptic AMPA receptor responses, but is not directly required for NMDA receptor-mediated internalization and LTD.

PMID:
    12441055

Exp Neurol. 2007 Jul;206(1):114-25. Epub 2007 Apr 24.
Time course of changes in pyridoxal 5'-phosphate (vitamin B6 active form) and its neuroprotection in experimental ischemic damage.
Hwang IK, Yoo KY, Kim do H, Lee BH, Kwon YG, Won MH.
Source

Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 200-702, South Korea.
Abstract

In the present study, we investigated ischemia-induced changes of pyridoxal 5'-phosphate synthesizing enzyme and degrading enzyme and neuroprotective effects and roles of pyridoxal 5'-phosphate against ischemic damage in the gerbil hippocampal CA1 region. Pyridoxal 5'-phosphate oxidase and pyridoxal phosphate phosphatase immunoreactivities were changed in neurons up to 2 days after ischemia, while 4 days after ischemia their immunoreactivities were expressed in astrocytes. Pyridoxal 5'-phosphate oxidase immunoreactivity and its protein level were highest 12 h after ischemia, while those in pyridoxal phosphate phosphatase were highest 2 days after ischemia. Total activities of these enzymes were changed after ischemia, but specific activities of the enzymes were not altered. Treatment with pyridoxal 5'-phosphate into brains (4 microg/5 microl, i.c.v.) at 30 min before transient ischemia protected about 80% of CA1 pyramidal cells 4 days after ischemia and induced elevation of glutamic acid decarboxylase 67 immunoreactivity in the CA1 region. However, pyridoxal 5'-phosphate treatment into ischemic brains decreased GABA transaminase immunoreactivity in the CA1 region after ischemia. These results indicate that pyridoxal 5'-phosphate may be associated with the inhibitory discharge of GABA in the hippocampal CA1 neurons, and the increased level of GABA may protect hippocampal CA1 pyramidal cells from ischemic damage.

PMID:
    17531224

J Agric Food Chem. 2008 May 28;56(10):3532-7. Epub 2008 Apr 30.
Phytoecdysteroids increase protein synthesis in skeletal muscle cells.
Gorelick-Feldman J, Maclean D, Ilic N, Poulev A, Lila MA, Cheng D, Raskin I.
Source

Biotech Center, Cook College, Rutgers University, 59 Dudley Road, New Brunswick, New Jersey 08901, USA. jongf@eden.rutgers.edu
Abstract

Phytoecdysteroids, which are structurally similar or identical to insect molting hormones, produce a range of effects in mammals, including increasing growth and physical performance. To study the mechanism of action of phytoecdysteroids in mammalian tissue, an in vitro cellular assay of protein synthesis was developed. In C2C12 murine myotubes and human primary myotubes, phytoecdysteroids increased protein synthesis by up to 20%. In vivo, ecdysteroids increased rat grip strength. Ecdysteroid-containing plant extracts produced similar results. The effect was inhibited by a phosphoinositide kinase-3 inhibitor, which suggests a PI3K-mediated mechanism.

PMID:
    18444661

Ukr Biokhim Zh. 1992 Jul-Aug;64(4):61-7.
[Effect of phytoecdysteroids and nerobol on parameters of carbohydrate and lipid metabolism and phospholipid spectrum of liver mitochondrial membrane in experimental diabetes mellitus of rats].
[Article in Russian]
Syrov VN, Tashmukhamedova MA, Khushbaktova ZA, Mirtalipov DT, Mamatkhanov AU.
Abstract

Phytoecdysteroids: ecdysterone and turkesterone, introduced orally to male rats with the body mass 180-120 g in a dose of 5 mg/l kg of mass and nerobol in a dose of 10 mg per 1 kg of the mass for 15 days against a background of the developed alloxan diabetes cause a considerable decrease in the content of free fatty acids of the blood serum, sharply increased after the subcutaneous injection of alloxan to the animals (150 mg per 1 kg of the mass). The content of glycogen, malonic dialdehyde, pyruvic acid and calcium transporting function of the liver mitochondria are also normalized. These changes are closely interrelated (and may be mutually conditioned) with the preparation-induced reduction of phospholipid spectrum of the liver mitochondrial membranes pathologically changed owing to insulin insufficiency. In this case phytoecdysteroids in the first turn normalize the fractions of phospholipids which play the structural role in the mitochondrial membranes, and nerobol normalizes the level of minor and monoacylic phospholipids.

PMID:
    1448876

J Sep Sci. 2008 May;31(8):1387-92.
Supercritical fluid extraction of cynaropicrin and 20-hydroxyecdysone from Leuzea carthamoides DC.
Sovová H, Opletal L, Sajfrtová M, Bártlová M.
Source

Institute of Chemical Process Fundamentals, Academy ofSciences CR, Prague, Czech Republic. sovova@icpf.cas.cz
Abstract

Leuzea carthamoides is an adaptogenic plant containing biologically active compounds as ecdysteroids and guaianolide-type sesquiterpene lactones, conventionally extracted from the plant with ethanol. It may be a potential source of the mentioned natural compounds. Ethanol-modified near-critical CO(2) was used as selective solvent with the aim to increase the level of 20-hydroxyecdysone in the extract from L. carthamoides roots and to remove selectively cynaropicrin, a sesquiterpene lactone of bitter taste, from the leaves. The extraction conditions were varied (pressure 20-28 MPa, temperature 40-60 degrees C, ethanol concentration in the solvent 0-7.1%) and the extraction yield and extract composition were compared with the results of ethanolic extraction. The supercritical fluid extraction (SFE) from finely powdered plant was controlled by phase equilibrium. Cynaropicrin was quantitatively removed from the leaves where 89% of 20-hydroxyecdysone was retained. The extraction yield of 20-hydroxyecdysone from roots with ethanol-modified CO(2 )was lower by 30% than with ethanol but its concentration in the extract was higher by 67%.

PMID:
    18383243

J Ethnopharmacol. 2007 Jun 13;112(2):368-74. Epub 2007 Mar 19.
The selective effect of N-feruloylserotonins isolated from Leuzea carthamoides on nociception and anxiety in rats.
Yamamotová A, Pometlová M, Harmatha J, Rasková H, Rokyta R.
Source

Charles University, 3rd Faculty of Medicine, Department of Normal, Pathological and Clinical Physiology, Ke Karlovu 4, 120 00 Prague, Czech Republic. yamamoto@lf3.cuni.cz
Abstract

The effects of N-feruloylserotonins, substances isolated from the seeds of Leuzea carthamoides (WILLD.) DC., on nociception and anxiety were studied in Wistar rats. Nociceptive responses were measured using the plantar and tail-flick tests which were administered before and after swimming stress (3 min, water temperature 32 degrees C). Anxiety was evaluated using an elevated plus maze. In Experiment I, neither basal nociception nor stress-induced analgesia was influenced significantly. Separating the animals into groups based on their basal nociceptive sensitivity, either high- or low-pain threshold revealed that N-feruloylserotonins have selective effects, especially on rats with high-pain thresholds. In these animals, N-feruloylserotonins reduced the stress-induced analgesia that followed swimming stress. In Experiment II, basal nociceptive sensitivity correlated with indicators of anxiety; high-pain threshold rats were more anxious in the elevated plus maze, with less frequent visits to open arms. The opposite effect was seen in low-pain threshold rats. N-feruloylserotonins did not influence anxiety in low-pain threshold rats, although it reduced anxiety in the high-pain threshold rats as indicated by the increased ratio of open arm visit frequency compared to closed arm visit frequency in the elevated plus maze. From these results we concluded that N-feruloylserotonins have selective stress-reducing effects in stress-sensitive animals.

PMID:
    17442511

Reprod Domest Anim. 2011 Aug;46(4):573-8. doi: 10.1111/j.1439-0531.2010.01703.x. Epub 2010 Nov 23.
Effects of herbal preparation on libido and semen quality in boars.
Frydrychová S, Opletal L, Macáková K, Lustyková A, Rozkot M, Lipenský J.
Source

Department of Pig Breeding, Institute of Animal Science, Prague-Uhríneves, Workplace Kostelec nad Orlicí, Kostelec nad Orlicí, Czech Republic. vuzvkostelec@seznam.cz
Abstract

The objective of this study was to investigate the effects of a preparation from herbal extracts (PHE) on libido and semen quality in breeding artificial insemination boars. Ten fertile boars were divided into control and experimental groups according to significant difference of libido. There were no differences in semen quality between groups. Animals were fed a commercial feeding mixture for boars. The feeding mixture for the experimental group was enriched with PHE, which was prepared from Eurycoma longifolia, Tribulus terrestris and Leuzea carthamoides. Duration of the experiment was 10 weeks. Samples of ejaculate were collected weekly. Libido was evaluated according to a scale of 0-5 points. Semen volume, sperm motility, percentage of viable spermatozoa, sperm concentration, morphologically abnormal spermatozoa, daily sperm production and sperm survival were assessed. Amounts of mineral components and free amino acids were analysed in seminal plasma. Significant differences were found in these parameters: libido (4.05 ± 0.22 vs 3.48 ± 0.78; p < 0.001), semen volume (331.75 ± 61.91 vs 263.13 ± 87.17 g; p < 0.001), sperm concentration (386.25 ± 107.95 vs 487.25 ± 165.50 × 10(3) /mm(3); p < 0.01), morphologically abnormal spermatozoa (15.94 ± 11.08 vs 20.88 ± 9.19%; p < 0.001) and Mg concentration (28.36 ± 11.59 vs 20.27 ± 13.93 mm; p < 0.05). The experimental group's libido was increased by 20% in comparison with the beginning of the experiment. Results of this study showed positive effect of PHE on libido and some parameters of boar semen quality.

© 2010 Blackwell Verlag GmbH.

PMID:
    21092065

Genes Cells. 2001 Oct;6(10):857-68.
Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription.
Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M.
Source

Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Japan.
Abstract
BACKGROUND:

Nrf2 belongs to the Cap-N-Collar (CNC) transcription factor family and is essential for the antioxidant responsive element (ARE)-mediated expression of a group of detoxifying and antioxidant genes. The forced expression of Nrf2 in mammalian cells activates the expression of target genes through the ARE, with Nrf2 showing the highest transactivation activity among the CNC family of transcription factors. To elucidate the molecular mechanisms generating this potent transactivation activity, we examined the functions of the domains within Nrf2.
RESULT:

We found that Nrf2 contains two transcription activation domains, Neh4 and Neh5, which act synergistically to attain maximum a activation of reporter gene expression. Neh4 and Neh5 both individually and cooperatively bind to CBP (CREB (cAMP Responsive Element Binding protein) Binding Protein). In fact, the specific inhibitor of CBP, adenovirus E1A protein, significantly reduced Nrf2 activity. Importantly, the CBP-binding activity of Nrf2 deletion mutants positively correlated with their transactivation activity. Neh5 contains a motif which is commonly conserved among the CNC factors, whereas Neh4 contains the novel CBP-interacting motif recently identified in p53 and E2F.
CONCLUSIONS:

Our results indicate that Nrf2 exploits the cooperative binding of two independent transactivation domains to CBP in the acquisition of a potent transactivation activity.

PMID:
    11683914

Biochem J. 2007 Jun 15;404(3):459-66.
Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes.
Zhang J, Hosoya T, Maruyama A, Nishikawa K, Maher JM, Ohta T, Motohashi H, Fukamizu A, Shibahara S, Itoh K, Yamamoto M.
Source

Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Abstract

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) contains two transcription activation domains, Neh4 (Nrf2 ECH homology 4) and Neh5, which co-ordinately regulate transactivation of cytoprotective genes. In the present study we aimed to clarify the role of the Neh5 domain in Nrf2-mediated gene regulation. Deletion of the complete Neh5 domain reduces expression of endogenous Nrf2 target genes, such as HO-1 (haem oxygenase 1), NQO1 [NAD(P)H:quinone oxidoreductase 1] and GCLM (glutamate cysteine ligase modulatory subunit), in human kidney epithelial cells. Furthermore, the deletion of Neh5 markedly repressed CBP [CREB (cAMP-response-element-binding protein)-binding protein] and BRG1 (Brahma-related gene 1) from associating with Nrf2, diminishing their co-operative enhancement of HO-1 promoter activity. Mutational analysis of the Neh5 domain revealed a motif that shares significant homology with beta-actin and ARP1 (actin-related protein 1). Mutagenesis of this motif selectively decreased HO-1, but not NQO1 and GCLM, expression. Taken together, these results indicate that the Neh5 domain has the ability to regulate Nrf2 target gene transcription, yet the role of the Neh5 domain in transcription varies from gene to gene.

PMID:
    17313370

J Biochem Mol Toxicol. 2008 Feb;22(1):63-76.
Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells.
Apopa PL, He X, Ma Q.
Source

Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505, USA.
Abstract

The antioxidant-activated transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the induction of cytoprotective genes against chemical toxicity and oxidative injuries. The role of phosphorylation in Nrf2 activation has been suggested but remains elusive. We report that phenolic antioxidant/pro-oxidant tert-butylhydroquinone (tBHQ) induced two forms of the Nrf2 protein in neuroblastoma cells (IMR-32), which migrated as distinctive bands on SDS-PAGE. In vitro treatment with lambda phosphatase eliminated the slower migrating form and increased the amount of the faster migrating form of Nrf2. In vivo (32)Pi-phosphorylation resulted in (32)Pi-labeling of the Nrf2 protein in the presence of tBHQ that can be dephosphorylated by lambda phosphotase, indicating that the slower migrating form is a phosphorylated Nrf2 protein and the faster form an unphosphorylated Nrf2. Unphosphorylated Nrf2 predominated in the cytoplasm, whereas the phosphorylated form preferentially localized in the nucleus. Nuclear Nrf2 can be dephosphorylated by lambda phosphotase in vitro and be converted to the faster migrating form, implicating phosphorylation of Nrf2 in the cytoplasmic-nuclear translocation of the protein. Deletional analyses from both the carboxyl- and amino-ends revealed the transcription activation (TA) domains Neh4 (Nrf2-ECH homology 4) and Neh5 (Nrf2-ECH homology 5) as a major region necessary for the phosphorylation. The TA domains are characterized by the presence of multiple phosphorylation sites of casein kinase 2 (CK2). Moreover, CK2 phosphorylated the TA domains in vitro. Treatment with CK2 inhibitor 2-dimethylamino-4,5,6,7,-tetrabromo-1H-benzimidazole (DMAT) blocked the induction of endogenous target genes of Nrf2 in cells and inhibited the TA activities of both the full length and the TA domains of Nrf2 to a large extent. Finally, phosphorylation of the TA domains correlated with the nuclear translocation of Nrf2 that was inhibited by DMAT in a concentration-dependent manner. The findings demonstrated that phosphorylation of Nrf2 at the TA domains by CK2 is an integral component of Nrf2 activation necessary for the nuclear localization and transcription activation function of Nrf2 in neuroblastoma cells.

(c) 2008 Wiley Periodicals, Inc.

PMID:
    18273910

Mol Cell Biol. 2005 May;25(10):4150-65.
Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression.
Ki SH, Cho IJ, Choi DW, Kim SG.
Source

College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-gu, Seoul 151-742, South Korea.
Abstract

The expression of the glutathione S-transferase gene (GST), whose induction accounts for cancer chemoprevention, is regulated by activation of CCAAT/enhancer binding protein beta (C/EBPbeta) and NF-E2-related factor 2 (Nrf2). The present study investigated the repressing effects of activating glucocorticoid receptor (GR) on C/EBPbeta- and Nrf2-mediated GSTA2 gene induction and the mechanism. Dexamethasone that activates GR inhibited constitutive and oltipraz- or tert-butylhydroquinone (t-BHQ)-inducible GSTA2 expression in H4IIE cells. Also, dexamethasone repressed GSTA2 promoter-luciferase gene activity. Dexamethasone-GR activation did not inhibit nuclear translocation of C/EBPbeta or Nrf2 nor their DNA binding activities induced by oltipraz or t-BHQ. Deletion of the glucocorticoid response element (GRE) in the GSTA2 promoter abolished dexamethasone inhibition of the gene induction. Immunoprecipitation-immunoblotting, chromatin immunoprecipitation, and GST pull-down assays revealed that silencing mediator for retinoid and thyroid hormone receptors (SMRT), a corepressor recruited to steroid-GR complex for histone deacetylation, bound to TAD domain of C/EBPbeta and Neh4/5 domain of Nrf2. The GSTA2 promoter-luciferase activities were decreased by SMRT but not by truncated SMRTs. The small interference RNA (siRNA) against SMRT abolished SMRT repression of the gene induction by C/EBPbeta or Nrf2. The plasmid transfection and siRNA experiments directly evidenced the functional role of SMRT in GSTA2 repression. In conclusion, dexamethasone antagonizes C/EBPbeta- and Nrf2-mediated GSTA2 gene induction via ligand-GR binding to the GRE, and steroid-mediated GSTA2 repression involves inactivation of C/EBPbeta and Nrf2 by SMRT recruited to steroid-GR complex.

PMID:
    15870285

Antioxid Redox Signal. 2011 Apr 15;14(8):1425-36. Epub 2011 Feb 20.
Neuronal activity controls the antagonistic balance between peroxisome proliferator-activated receptor-? coactivator-1a and silencing mediator of retinoic acid and thyroid hormone receptors in regulating antioxidant defenses.
Soriano FX, Léveillé F, Papadia S, Bell KF, Puddifoot C, Hardingham GE.
Source

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Abstract

Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-? coactivator (PGC)-1a is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1a strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1a-mediated antioxidant effects. The antagonistic balance between PGC-1a and SMRT is upset in favor of PGC-1a by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concomitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1a in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1a transcription. Activity-dependent targeting of PGC-1a results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1a and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1a-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1a and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivator-corepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability.

PMID:
    20849372

PLoS One. 2011;6(6):e21056. Epub 2011 Jun 9.
In cortical neurons HDAC3 activity suppresses RD4-dependent SMRT export.
Soriano FX, Hardingham GE.
Source

Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Abstract

The transcriptional corepressor SMRT controls neuronal responsiveness of several transcription factors and can regulate neuroprotective and neurogenic pathways. SMRT is a multi-domain protein that complexes with HDAC3 as well as being capable of interactions with HDACs 1, 4, 5 and 7. We previously showed that in rat cortical neurons, nuclear localisation of SMRT requires histone deacetylase activity: Inhibition of class I/II HDACs by treatment with trichostatin A (TSA) causes redistribution of SMRT to the cytoplasm, and potentiates the activation of SMRT-repressed nuclear receptors. Here we have sought to identify the HDAC(s) and region(s) of SMRT responsible for anchoring it in the nucleus under normal circumstances and for mediating nuclear export following HDAC inhibition. We show that in rat cortical neurons SMRT export can be triggered by treatment with the class I-preferring HDAC inhibitor valproate and the HDAC2/3-selective inhibitor apicidin, and by HDAC3 knockdown, implicating HDAC3 activity as being required to maintain SMRT in the nucleus. HDAC3 interaction with SMRT's deacetylation activation domain (DAD) is known to be important for activation of HDAC3 deacetylase function. Consistent with a role for HDAC3 activity in promoting SMRT nuclear localization, we found that inactivation of SMRT's DAD by deletion or point mutation triggered partial redistribution of SMRT to the cytoplasm. We also investigated whether other regions of SMRT were involved in mediating nuclear export following HDAC inhibition. TSA- and valproate-induced SMRT export was strongly impaired by deletion of its repression domain-4 (RD4). Furthermore, over-expression of a region of SMRT containing the RD4 region suppressed TSA-induced export of full-length SMRT. Collectively these data support a model whereby SMRT's RD4 region can recruit factors capable of mediating nuclear export of SMRT, but whose function and/or recruitment is suppressed by HDAC3 activity. Furthermore, they underline the fact that HDAC inhibitors can cause reorganization and redistribution of corepressor complexes.

PMID:
    21695276

Mol Cell Biol. 2001 Sep;21(18):6091-101.
The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3.
Guenther MG, Barak O, Lazar MA.
Source

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Abstract

Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymatically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.

PMID:
    11509652

FASEB J. 2011 May;25(5):1758-66. Epub 2011 Feb 1.
Cholesterol regulation of receptor-interacting protein 140 via microRNA-33 in inflammatory cytokine production.
Ho PC, Chang KC, Chuang YS, Wei LN.
Source

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota, 55455-0217, USA.
Abstract

Receptor interacting protein 140 (RIP140) is a nuclear receptor coregulator that affects a wide spectrum of biological processes. It is unclear whether and how the expression level of RIP140 can be modulated and whether RIP140 is involved in inflammatory diseases. Here, we examine how intracellular cholesterol regulates RIP140 expression, and we evaluate the effect of RIP140 expression on macrophage proinflammatory potential. Macrophages treated with modified low-density lipoprotein express higher RIP140 mRNA and protein levels. Consistently, simvastatin reduces RIP140 levels, which can be reversed by mevalonate. Moreover, a high-fat diet elevates RIP140 but lowers miR-33 levels in peritoneal macrophages, and increases the production of IL-1ß and TNF-a in macrophages. Mechanistically, miR-33 targets RIP140 mRNA by recognizing its target located in a highly conserved sequence of the 3'-untranslated region (3'-UTR) of RIP140 mRNA. Consequentially, miR-33 reduces RIP140 coactivator activity for NF-?B, which is supported by the reduction in NF-?B reporter activity and the inflammatory potential in macrophages. This study uncovers a cholesterol-miR-33-RIP140 regulatory pathway that modulates the proinflammatory potential in macrophages in response to an alteration in the intracellular cholesterol status, and identifies RIP140 as a direct target of miR-33 that mediates simvastatin-triggered anti-inflammation.

PMID:
    21285396

Genes Dev. 2009 Mar 15;23(6):681-93.
Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways.
Ghisletti S, Huang W, Jepsen K, Benner C, Hardiman G, Rosenfeld MG, Glass CK.
Source

Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA.
Abstract

Innate immune responses to bacterial or viral infection require rapid transition of large cohorts of inflammatory response genes from poised/repressed to actively transcribed states, but the underlying repression/derepression mechanisms remain poorly understood. Here, we report that, while the nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors establish repression checkpoints on broad sets of inflammatory response genes in macrophages and are required for nearly all of the transrepression activities of liver X receptors (LXRs), they can be selectively recruited via c-Jun or the Ets repressor Tel, respectively, establishing NCoR-specific, SMRT-specific, and NCoR/SMRT-dependent promoters. Unexpectedly, the binding of NCoR and SMRT to NCoR/SMRT-dependent promoters is frequently mutually dependent, establishing a requirement for both proteins for LXR transrepression and enabling inflammatory signaling pathways that selectively target NCoR or SMRT to also derepress/activate NCoR/SMRT-dependent genes. These findings reveal a combinatorial, corepressor-based strategy for integration of inflammatory and anti-inflammatory signals that play essential roles in immunity and homeostasis.

PMID:
    19299558

Nucleic Acids Res. 1998 Jun 15;26(12):2899-907.
The corepressor N-CoR and its variants RIP13a and RIP13Delta1 directly interact with the basal transcription factors TFIIB, TAFII32 and TAFII70.
Muscat GE, Burke LJ, Downes M.
Source

University of Queensland, Centre for Molecular and Cellular Biology, Ritchie Research Laboratories, B402A, St Lucia 4072, Queensland, Australia. g.guscat@cmcb.uq.edu.au
Abstract

Repression of transcription by the classical nuclear receptors (e.g. TR, RAR), the orphan nuclear receptors (e.g. Rev-erbAalpha/beta), Mxi-1 and Mad bHLH-zip proteins and the oncoproteins PLZF and LAZ3/BCL6 is mediated by the corepressors N-CoR and SMRT. The interaction of the corepressors with the components involved in chromatin remodelling, such as the recruiting proteins Sin3A/B and the histone deacteylases HDAc-1 and RPD3, has been analysed in detail. The N-CoR/Sin3/HDAc complexes have a key role in the regulation of cellular proliferation and differentiation. However, the interaction of these corepressors with the basal transcriptional machinery has remained obscure. In this study we demonstrated that the N-terminalrepression domains and the receptor interactiondomains (RID) of N-CoR and its splice variants, RIP13a and RIP13Delta1, directly interact with TAFII32 in vivo and in vitro . We show that interaction domain II within the N-CoR and RIP13a RID is required for the interaction with TAFII32. We also observed that N-CoR directly interacts with each of the basal factors, TFIIB and TAFII70, and can simultaneously interact with all three basal factors in a non-competitive manner. Furthermore, we provide evidence that suggests the RVR/Rev-erbbeta-corepressor complex also interacts with the general transcriptional machinery, and that the physicalassociation of TFIIB with N-CoR also occurs in the presence of Sin3B and HDAc-1. Interestingly, we observed that N-CoR expression ablated the functional interaction between TFIIB and TAFII32 that is critical to the initiation of transcription. In conclusion, this study demonstrates that the N-terminal repressor region and the C-terminal RIDs are part of the corepressor contact interface that mediates the interaction with the general transcription factors, and demonstrates that TAFs can also directly interact with corepressors to mediate signals from repressors to the basal machinery. We also suggest that N-CoR interacts with the central components of the transcriptional initiation process (TFIIB, TAFs) and locks them into a non-functional complex or conformation that is not conducive to transcription.

PMID:
    9611234

Biochem Soc Trans. 2000;28(4):386-9.
Modulation of thyroid hormone receptor silencing function by co-repressors and a synergizing transcription factor.
Lutz M, Baniahmad A, Renkawitz R.
Source

Genetisches Institut, Justus-Liebig-Universität, D-35392 Giessen, Germany.
Abstract

We have found that the thyroid hormone receptor (T3R) functionally synergizes with the CCCTC-binding factor (CTCF). CTCF is a highly conserved zinc-finger protein that has been connected with multiple functions in gene regulation including chromatin insulator activity, transcriptional enhancement and silencing as well as tumour suppression. A specific property of CTCF is that some of the binding sites are found in the vicinity of T3R-binding sites. Interestingly, both factors synergize in repression as well as in activation. T3R-mediated repression has been shown to involve co-repressors such as the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), N-CoR or Alien. These co-repressors in turn have been found to interact with Sin3A. Until now, the mechanisms by which CTCF synergizes with T3R in transcriptional repression has not been determined. Here we show that CTCF comprises autonomous silencing domains that mediate transcriptional repression when tethered to a promoter sequence. At least one of these domains, the zinc-finger region of CTCF, binds Sin3A without binding to SMRT or N-CoR and recruits histone deacetylation activity. For Sin3A we identified two different domains interacting independently with the CTCF zinc-finger cluster. The ability of regions of CTCF to retain deacetylase activity is correlated with the ability to bind to Sin3A and to repress transcription. Taking these results together, the synergy in repression mediated by T3R and CTCF might be achieved by the binding of multiple molecules of Sin3A to the T3R/CTCF-DNA complex, thus providing a large platform for the recruitment of histone deacetylases.

PMID:
    10961925

J Biol Chem. 2009 Jan 30;284(5):3195-210. Epub 2008 Dec 1.
The Nrf3 transcription factor is a membrane-bound glycoprotein targeted to the endoplasmic reticulum through its N-terminal homology box 1 sequence.
Zhang Y, Kobayashi A, Yamamoto M, Hayes JD.
Source

Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK. y.z.zhang@dundee.ac.uk
Abstract

Transcription factor Nrf3 (NF-E2 p45-related factor 3) is targeted to the endoplasmic reticulum (ER). Mouse Nrf3 is subject to proteolysis, Asn glycosylation, and deglycosylation reactions. It is synthesized as a approximately 96-kDa protein that is subsequently converted into isoforms of approximately 90, 80, and 70 kDa. In the ER, the approximately 90-kDa glycoprotein is predominant and gives rise to approximately 80- and approximately 70-kDa isoforms. The approximately 90- and approximately 80-kDa polypeptides were observed in the nuclear envelope, whereas the approximately 70-kDa isoform was detected primarily in the nucleoplasm. Our experiments showed the N-terminal homology box 1 (NHB1, residues 12-31) is part of a tripartite signal peptide sequence, comprising n, h, and c regions. The h region (residues 12-23) was demonstrated to target Nrf3 to the ER and is necessary for its Asn glycosylation. The n region (residues 1-11) controlled the abundance of the approximately 90-kDa glycoprotein. The c region (residues 24-39) was found to contain a signal peptidase cleavage site that is responsible for production of the approximately 90-kDa mature Nrf3 glycoprotein from a approximately 96-kDa precursor. We have found that Nrf3 is activated by the ER stressors tunicamycin and brefeldin A, and that NHB1 is required for this response. Amino acids between the c region and NHB2 (residues 76-100) controlled the proteolytic processing of mouse Nrf3 into cleavage products of approximately 80-kDa (glycated) and approximately 70-kDa (non-glycated); by contrast, human Nrf3 lacked a signal peptidase cleavage site between its c region and NHB2. Lastly, data are presented suggesting that the NHB2 sequence in mouse Nrf3 may regulate the topology of the transcription factor within the ER membrane.

PMID:
    19047052

Free Radic Biol Med. 2009 Jan 15;46(2):146-53. Epub 2008 Oct 9.
Oxidant stress stimulates expression of the human peroxiredoxin 6 gene by a transcriptional mechanism involving an antioxidant response element.
Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, Feinstein SI.
Source

Institute for Environmental Medicine, University of Pennsylvania School of Medicine, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA.
Abstract

Peroxiredoxin 6 (Prdx6) is a unique antioxidant enzyme that can reduce phospholipid and other hydroperoxides. A549 cells, a human lung-derived cell line, express both Prdx6 and Nrf2, a transcription factor that binds to antioxidant-response elements (AREs) and promotes expression of antioxidant genes. Treatment of A549 cells with 500 microM H(2)O(2) increased Prdx6 mRNA levels 2.5-fold, whereas treatment with 400 microM H(2)O(2) or 200 microM tert-butylhydroquinone (t-BHQ) triggered a corresponding 2.5-fold increase in reporter gene activity in A549 cells transfected with the pSEAP2:Basic vector (BD Bioscience), containing 1524 nucleotides of the human Prdx6 promoter region. Deletion of a consensus ARE sequence present between positions 357 and 349 before the start of transcription led to a striking decrease in both basal and H(2)O(2)- or t-BHQ-induced activation in A549 cells and H(2)O(2)-induced activation in primary rat alveolar type II cells. Cotransfection with Nrf2 stimulated the Prdx6 promoter in an ARE-dependent manner, whereas it was negatively regulated by Nrf3. siRNA targeting Nrf2 down-regulated reporter gene expression, whereas siRNA targeting the Nrf2 repressor, Keap1, up-regulated it. Binding of Nrf2 to the ARE sequence in chromatin was confirmed by PCR after chromatin immunoprecipitation. These data demonstrate that the ARE within the Prdx6 promoter is a key regulator of basal transcription of the Prdx6 gene and of its inducibility under conditions of oxidative stress.

PMID:
    18973804

J Biol Chem. 2004 Dec 3;279(49):50810-7. Epub 2004 Sep 22.
Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene.
Sankaranarayanan K, Jaiswal AK.
Source

Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract

Antioxidant-response element (ARE) and nuclear factor Nrf2-mediated expression and coordinated induction of genes encoding chemopreventive proteins, including NQO1, are critical mechanisms in chemoprotection. Recently, Nrf3, a new member of the Nrf family with substantial homology to Nrf2, was identified and cloned. In this report, we have investigated the role of Nrf3 in ARE-mediated gene expression and induction of NQO1 in response to antioxidants. Overexpression of Nrf3 in Hep-G2 cells led to a concentration-dependent decrease in transfected and endogenous NQO1 gene expression and induction in response to antioxidant tert-butylhydroquinone (t-BHQ). Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3. Bandshift and supershift assays with in vitro transcribed and translated proteins and nuclear extracts from Hep-G2 cells treated with Me2SO and t-BHQ and immunoprecipitation assays demonstrated that Nrf3 associates with small Maf proteins to bind to the ARE. RNA interference specific to Nrf3 reduced intracellular Nrf3 leading to increased expression and induction of transfected and endogenous NQO1 gene expression in response to t-BHQ. These results combined suggest that Nrf3 is a negative regulator of ARE-mediated gene expression.

PMID:
    15385560

Biochem J. 2011 Aug 3. [Epub ahead of print]
Novel insights into the regulation of the antioxidant response element mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by NRF2.
Jyrkkänen HK, Kuosmanen SM, Heinäniemi M, Laitinen H, Kansanen E, Mella-Aho E, Leinonen H, Ylä-Herttuala S, Levonen AL.
Abstract

A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the Antioxidant Response Element (ARE), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different basic-region leucine zipper (bZIP) transcription factors, most notably NF-E2 related factor-2 (Nrf2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. While the ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE mediated signalling is downregulated is poorly known. Transcription factor BACH1 (BTB and CNC homology 1) binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes thus antagonizing the activator function of Nrf2. Herein, we demonstrate that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2 activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene, and that induction of BACH1 by Nrf2 may serve as a feedback inhibitory mechanism for ARE-mediated gene regulation.

PMID:
    21812759

J Biol Chem. 2011 Jul 1;286(26):23521-32. Epub 2011 May 9.
The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle.
Warnatz HJ, Schmidt D, Manke T, Piccini I, Sultan M, Borodina T, Balzereit D, Wruck W, Soldatov A, Vingron M, Lehrach H, Yaspo ML.
Source

Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Abstract

The regulation of gene expression in response to environmental signals and metabolic imbalances is a key step in maintaining cellular homeostasis. BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAF recognition elements, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation sequencing analysis of BACH1 target genes in HEK 293 cells with knockdown of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by chromatin immunoprecipitation sequencing were found highly enriched in genes showing expression changes after BACH1 knockdown, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, and SLC48A1) and redox regulation (GCLC, GCLM, and SLC7A11), we also discovered BACH1 target genes affecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, and MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, and vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis.

PMID:
    21555518

Haematologica. 2010 Aug;95(8):1261-8. Epub 2010 Feb 23.
Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter.
Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, Muckenthaler MU.
Source

Department of Pediatric Oncology, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany.
Abstract
BACKGROUND:

Macrophages of the reticuloendothelial system play a key role in recycling iron from hemoglobin of senescent or damaged erythrocytes. Heme oxygenase 1 degrades the heme moiety and releases inorganic iron that is stored in ferritin or exported to the plasma via the iron export protein ferroportin. In the plasma, iron binds to transferrin and is made available for de novo red cell synthesis. The aim of this study was to gain insight into the regulatory mechanisms that control the transcriptional response of iron export protein ferroportin to hemoglobin in macrophages.
DESIGN AND METHODS:

Iron export protein ferroportin mRNA expression was analyzed in RAW264.7 mouse macrophages in response to hemoglobin, heme, ferric ammonium citrate or protoporphyrin treatment or to siRNA mediated knockdown or overexpression of Btb And Cnc Homology 1 or nuclear accumulation of Nuclear Factor Erythroid 2-like. Iron export protein ferroportin promoter activity was analyzed using reporter constructs that contain specific truncations of the iron export protein ferroportin promoter or mutations in a newly identified MARE/ARE element.
RESULTS:

We show that iron export protein ferroportin is transcriptionally co-regulated with heme oxygenase 1 by heme, a degradation product of hemoglobin. The protoporphyrin ring of heme is sufficient to increase iron export protein ferroportin transcriptional activity while the iron released from the heme moiety controls iron export protein ferroportin translation involving the IRE in the 5'untranslated region. Transcription of iron export protein ferroportin is inhibited by Btb and Cnc Homology 1 and activated by Nuclear Factor Erythroid 2-like involving a MARE/ARE element located at position -7007/-7016 of the iron export protein ferroportin promoter.
CONCLUSIONS:

This finding suggests that heme controls a macrophage iron recycling regulon involving Btb and Cnc Homology 1 and Nuclear Factor Erythroid 2-like to assure the coordinated degradation of heme by heme oxygenase 1, iron storage and detoxification by ferritin, and iron export by iron export protein ferroportin.
Comment in

    * Haematologica. 2010 Aug;95(8):1233-6.

PMID:
    20179090

FEBS Lett. 2009 Nov 3;583(21):3508-18. Epub 2009 Oct 12.
Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK.
Goven D, Boutten A, Leçon-Malas V, Boczkowski J, Bonay M.
Source

Inserm U700, Université Paris 7, Faculté de Médecine Denis Diderot-site Bichat, Paris, France.
Abstract

Tobacco may be involved in the decreased macrophage heme oxygenase-1 (HO-1) expression described in smoking-induced severe emphysema, via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-BTB and CNC homology 1, basic leucine zipper transcription factor 1 (Bach1) pathway. We assessed in vitro effects of cigarette smoke condensate (CS) in the human monocyte/macrophage cell line (THP-1). CS exposure led to increased HO-1 and nuclear Nrf2 expression (6 h) followed by decreased HO-1 expression concomitantly with nuclear Nrf2/Bach1 ratio decrease (72h). CS-induced mitogen-activated protein kinase (MAPK) phosphorylation. Extracellular-signal-regulated kinase(1/2) (ERK(1/2)) and c-Jun NH2-terminal kinase (JNK) inhibition completely abrogated CS effects on HO-1 expression and nuclear Nrf2/Bach1 translocation. These results suggest that ERK(1/2) and JNK are involved in CS-induced biphasic HO-1 expression by a specific regulation of Nrf2/Keap1-Bach1.

PMID:
    19822148

Nat Struct Mol Biol. 2008 Dec;15(12):1246-54. Epub 2008 Nov 16.
Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin.
Dohi Y, Ikura T, Hoshikawa Y, Katoh Y, Ota K, Nakanome A, Muto A, Omura S, Ohta T, Ito A, Yoshida M, Noda T, Igarashi K.
Source

Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan.
Abstract

Cellular senescence is one of the key strategies to suppress expansion of cells with mutations. Senescence is induced in response to genotoxic and oxidative stress. Here we show that the transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress-induced cellular senescence. Bach1-deficient murine embryonic fibroblasts showed a propensity to undergo more rapid and profound p53-dependent premature senescence than control wild-type cells in response to oxidative stress. Bach1 formed a complex that contained p53, histone deacetylase 1 and nuclear co-repressor N-coR. Bach1 was recruited to a subset of p53 target genes and contributed to impeding p53 action by promoting histone deacetylation. Because Bach1 is regulated by oxidative stress and heme, our data show that Bach1 connects oxygen metabolism and cellular senescence as a negative regulator of p53.

PMID:
    19011633

Mol Cell Biol. 1996 Nov;16(11):6083-95.
Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site.
Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K.
Source

Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan.
Abstract

Members of the small Maf family (MafK, MafF, and MafG) are basic region leucine zipper (bZip) proteins that can function as transcriptional activators or repressors. The dimer compositions of their DNA binding forms determine whether the small Maf family proteins activate or repress transcription. Using a yeast two-hybrid screen with a GAL4-MafK fusion protein, we have identified two novel bZip transcription factors, Bach1 and Bach2, as heterodimerization partners of MafK. In addition to a Cap'n'collar-type bZip domain, these Bach proteins possess a BTB domain which is a protein interaction motif; Bach1 and Bach2 show significant similarity to each other in these regions but are otherwise divergent. Whereas expression of Bach1 appears ubiquitous, that of Bach2 is restricted to monocytes and neuronal cells. Bach proteins bind in vitro to NF-E2 binding sites, recognition elements for the hematopoietic transcription factor NF-E2, by forming heterodimers with MafK. Furthermore, a DNA binding complex that contained MafK as well as Bach2 or a protein related closely to Bach2 was found to be present in mouse brain cells. Bach1 and Bach2 function as transcription repressors in transfection assays using fibroblast cells, but they function as a transcriptional activator and repressor, respectively, in cultured erythroid cells. The results suggest that members of the Bach family play important roles in coordinating transcription activation and repression by MafK.

PMID:
    8887638

Am J Respir Crit Care Med. 2011 Jul 28. [Epub ahead of print]
Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects Against Sepsis.
Kong X, Thimmulappa R, Craciun F, Harvey C, Singh A, Kombairaju P, Reddy SP, Remick D, Biswal S.
Source

Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States.
Abstract
RATIONALE:

Sepsis syndrome is characterized by inappropriate amplified systemic inflammatory response and bacteremia that promote multiorgan failure and mortality. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates a pleiotropic cytoprotective defense program including antioxidants and protect against several inflammatory disorders by inhibiting oxidative tissue injuries. However, the role of enhanced Nrf2 activity in modulating innate immune responses to microbial infection and pathogenesis of sepsis is unclear.
OBJECTIVES:

To determine whether Nrf2 in myeloid leukocytes alter inflammatory response and protects against sepsis.
MEASUREMENTS:

Mice with deletion of Nrf2 or Keap1 in myeloid leukocyte cells and respective floxed controls were subjected to cecal ligation and puncture (CLP)-induced sepsis and were assessed for survival, organ injury, systemic inflammation and bacteremia. Using lipopolysaccharide (LPS) stimulated peritoneal macrophages, TLR4 surface trafficking and downstream signaling events were analyzed.
MAIN RESULTS:

Mortality, organ injury, circulating levels of inflammatory mediators, and bacteremia were markedly reduced in LysM-Keap1(-/-) compared to respective floxed controls (Keap1(f/f) or Nrf2(f/f)) and significantly elevated in LysM-Nrf2(-/-) mice following CLP. Peritoneal macrophages from septic LysM-Keap1(-/-) mice showed a greater bacterial phagocytic activity compared to LysM-Nrf2(-/-) and floxed controls. LPS stimulation resulted in greater reactive oxygen species-induced cell surface transport of TLR4 from trans-Golgi network and subsequent TLR4 downstream signaling (recruitment of MYD88 and TRIF, phosphorylation of IkB and IRF3, and cytokine expression) in macrophages of LysM-Nrf2(-/-) compared to LysM-Keap1(-/-) mice and floxed controls.
CONCLUSIONS:

Our study shows that Nrf2 acts as a critical immuno-modulator in leukocytes, controls host inflammatory response to bacterial infection, and protects against sepsis.

PMID:
    21799073

J Immunol. 2010 Jul 1;185(1):569-77. Epub 2010 May 28.
NADPH oxidase-dependent reactive oxygen species mediate amplified TLR4 signaling and sepsis-induced mortality in Nrf2-deficient mice.
Kong X, Thimmulappa R, Kombairaju P, Biswal S.
Source

Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
Abstract

Sepsis syndrome is characterized by a dysregulated inflammatory response to infection. NADPH oxidase-dependent reactive oxygen species (ROS) play significant roles in the pathophysiology of sepsis. We previously showed that disruption of Nrf2, a master regulator of antioxidant defenses, caused a dysregulation of innate immune response that resulted in greater mortality in a polymicrobial sepsis and LPS shock model; however, the underlying mechanisms are unclear. In the current study, compared with wild-type (Nrf2(+/+)) macrophages, we observed greater protein kinase C-induced NADPH oxidase-dependent ROS generation in Nrf2-disrupted (Nrf2(-/-)) macrophages that was modulated by glutathione levels. To address the NADPH oxidase-mediated hyperinflammatory response and sepsis-induced lung injury and mortality in Nrf2(-/-) mice, we used double knockout mice lacking Nrf2 and NADPH oxidase subunit, gp91(phox) (Nrf2(-/-)//gp91(phox-/-)). Compared with Nrf2(+/+) macrophages, LPS induced greater activation of TLR4 as evident by TLR4 surface trafficking and downstream recruitment of MyD88 and Toll/IL-1R domain-containing adaptor in Nrf2(-/-) macrophages that was diminished by ablation of gp91(phox). Similarly, phosphorylation of IkappaB and IFN regulatory factor 3 as well as cytokine expression was markedly higher in Nrf2(-/-) macrophages; whereas, it was similar in Nrf2(+/+) and Nrf2(-/-)//gp91(phox-/-). In vivo studies showed greater LPS-induced pulmonary inflammation in Nrf2(-/-) mice that was significantly reduced by ablation of gp91(phox). Furthermore, LPS shock and polymicrobial sepsis induced early and greater mortality in Nrf2(-/-) mice; whereas, Nrf2(-/-)//gp91(phox-/-) showed prolonged survival. Together, these results demonstrate that Nrf2 is essential for the regulation of NADPH oxidase-dependent ROS-mediated TLR4 activation and lethal innate immune response in sepsis.

PMID:
    20511556

Am J Physiol Lung Cell Mol Physiol. 2010 Aug;299(2):L192-203. Epub 2010 May 14.
Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of I{kappa}B kinases in mice: impact on histone acetylation.
Chung S, Sundar IK, Yao H, Ho YS, Rahman I.
Source

Dept. of Environmental Medicine, Univ. of Rochester Medical Center, Rochester, NY 14642, USA.
Abstract

Glutaredoxin 1 (Glrx1) is a small dithiol protein that regulates the cellular redox state and redox-dependent signaling pathways via modulation of protein glutathionylation. IkappaB kinase (IKK), an essential enzyme for NF-kappaB activation, can be subjected to S-glutathionylation leading to alteration of its activity. However, the role of Glrx1 in cigarette smoke (CS)-induced lung inflammation and chromatin modifications are not known. We hypothesized that Glrx1 regulates the CS-induced lung inflammation and chromatin modifications via differential regulation of IKKs by S-glutathionylation in mouse lung. Glrx1 knockout (KO) and wild-type (WT) mice were exposed to CS for 3 days and determined the role of Glrx1 in regulation of proinflammatory response in the lung. Neutrophil influx in bronchoalveolar lavage fluid and proinflammatory cytokine release in lung were increased in Glrx1 KO mice compared with WT mice exposed to CS, which was associated with augmented nuclear translocation of RelA/p65 and its phospho-acetylation. Interestingly, phosphorylated and total levels of IKKalpha, but not total and phosphorylated IKKbeta levels, were increased in lungs of Glrx1 KO mice compared with WT mice exposed to CS. Ablation of Glrx1 leads to increased CS-induced IKKbeta glutathionylation rendering it inactive, whereas IKKalpha was activated resulting in increased phospho-acetylation of histone H3 in mouse lung. Thus, targeted disruption of Glrx1 regulates the lung proinflammatory response via histone acetylation specifically by activation of IKKalpha in response to CS exposure. Overall, our study suggests that S-glutathionylation and phosphorylation of IKKalpha plays an important role in histone acetylation on proinflammatory gene promoters and NF-kappaB-mediated abnormal and sustained lung inflammation in pathogenesis of chronic inflammatory lung diseases.

PMID:
    20472709

Biochem Pharmacol. 2011 Aug 19. [Epub ahead of print]
Importance of PIKKs in NF-?B activation by genotoxic stress.
Sabatel H, Pirlot C, Piette J, Habraken Y.
Source

Laboratory of Immunology and Virology, GIGA-R, Building B34, Unit of Signal Transduction, University de Liège, 1 Allée de l'Hôpital, B-4000, Liège, Belgium.
Abstract

Alteration of the genome integrity leads to the activation of a vast network of cellular responses named "DNA damage response". Three kinases from the phosphoinositide 3-kinase-like protein kinase family regulate this network; ATM and DNA-PK both activated by DNA double-strand breaks and ATR activated by replication blocks. "DNA damage response" pathway coordinates cell cycle arrest, DNA repair, and the activation of transcription factors such as p53 and NF-?B. It controls senescence/apoptosis/survival of the damaged cells. Cell death or survival result from a tightly regulated balance between antagonist pro- and anti-apoptotic signals. NF-?B is a key transcription factor involved in immunity, inflammation and cell transformation. When activated by DNA double-strand breaks, NF-?B has most often a pro-survival effect and thereof interferes with chemotherapy treatments that often rely on DNA damage to induce tumor cell death (i.e. topoisomerase inhibitors and ionizing radiation). NF-?B is thus an important pharmaceutical target. Agents leading to replication stress induce a pro-apoptotic NF-?B. The molecular mechanisms initiated by DNA lesions leading to NF-?B nuclear translocation have been extensively studied these last years. In this review, we will focus on ATM, ATR and DNA-PK functions both in the IKKa/IKKß/NEMO-dependent or -independent signaling pathways and on the regulation they can exercise at the promoter level of NF-?B regulated genes.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
    21872579

Mol Cell. 2002 Feb;9(2):401-10.
TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90.
Chen G, Cao P, Goeddel DV.
Source

Tularik, Incorporated, Two Corporate Drive, South San Francisco, CA 94080, USA.
Abstract

The IKK complex, containing two catalytic subunits IKKalpha and IKKbeta and a regulatory subunit NEMO, plays central roles in signal-dependent activation of NF-kappaB. We identify Cdc37 and Hsp90 as two additional components of the IKK complex. IKKalpha/IKKbeta/NEMO and Cdc37/Hsp90 form an approximately 900 kDa heterocomplex, which is assembled via direct interactions of Cdc37 with Hsp90 and with the kinase domain of IKKalpha/IKKbeta. Geldanamycin (GA), an antitumor agent that disrupts the formation of this heterocomplex, prevents TNF-induced activation of IKK and NF-kappaB. GA treatment reduces the size of the IKK complex and abolishes TNF-dependent recruitment of the IKK complex to TNF receptor 1 (TNF-R1). Therefore, heterocomplex formation with Cdc37/Hsp90 is a prerequisite for TNF-induced activation and trafficking of IKK from the cytoplasm to the membrane.

PMID:
    11864612

PLoS One. 2011;6(8):e23488. Epub 2011 Aug 24.
NF-?B Inducing Kinase, NIK Mediates Cigarette Smoke/TNFa-Induced Histone Acetylation and Inflammation through Differential Activation of IKKs.
Chung S, Sundar IK, Hwang JW, Yull FE, Blackwell TS, Kinnula VL, Bulger M, Yao H, Rahman I.
Source

Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, United States of America.
Abstract
BACKGROUND:

Nuclear factor (NF)-?B inducing kinase (NIK) is a central player in the non-canonical NF ?B pathway, which phosphorylates I?B kinase a (IKKa) resulting in enhancement of target gene expression. We have recently shown that IKKa responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-?B activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNFa with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFa increase NIK levels causing phosphorylation of IKKa, which leads to histone acetylation.
METHODOLOGY:

To test this hypothesis, we investigated whether NIK mediates effects of CS and TNFa on histone acetylation in human lung epithelial cells in vitro and in lungs of mouse exposed to CS in vivo. CS increased the phosphorylation levels of IKKa/NIK in lung epithelial cells and mouse lungs. NIK is accumulated in the nuclear compartment, and is recruited to the promoters of pro-inflammatory genes, to induce posttranslational acetylation of histones in response to CS and TNFa. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNFa-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKKß/NF-?B pathway in CS-induced histone acetylation suggests that the canonical pathway does not play a role in histone acetylation particularly in response to CS in mouse lungs.
CONCLUSIONS:

Overall, our findings provide a novel role for NIK in CS- and TNFa-induced histone acetylation, especially on histone H3K9.

PMID:
    21887257

J Immunol. 2010 Jul 1;185(1):588-96. Epub 2010 May 26.
Nicotine inhibits Fc epsilon RI-induced cysteinyl leukotrienes and cytokine production without affecting mast cell degranulation through alpha 7/alpha 9/alpha 10-nicotinic receptors.
Mishra NC, Rir-sima-ah J, Boyd RT, Singh SP, Gundavarapu S, Langley RJ, Razani-Boroujerdi S, Sopori ML.
Source

Immunology and Asthma Division, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
Abstract

Smokers are less likely to develop some inflammatory and allergic diseases. In Brown-Norway rats, nicotine inhibits several parameters of allergic asthma, including the production of Th2 cytokines and the cysteinyl leukotriene LTC(4). Cysteinyl leukotrienes are primarily produced by mast cells, and these cells play a central role in allergic asthma. Mast cells express a high-affinity receptor for IgE (FcepsilonRI). Following its cross-linking, cells degranulate and release preformed inflammatory mediators (early phase) and synthesize and secrete cytokines/chemokines and leukotrienes (late phase). The mechanism by which nicotine modulates mast cell activation is unclear. Using alpha-bungarotoxin binding and quantitative PCR and PCR product sequencing, we showed that the rat mast/basophil cell line RBL-2H3 expresses nicotinic acetylcholine receptors (nAChRs) alpha7, alpha9, and alpha10; exposure to exceedingly low concentrations of nicotine (nanomolar), but not the biologically inactive metabolite cotinine, for > or = 8 h suppressed the late phase (leukotriene/cytokine production) but not degranulation (histamine and hexosaminidase release). These effects were unrelated to those of nicotine on intracellular free calcium concentration but were causally associated with the inhibition of cytosolic phospholipase A(2) activity and the PI3K/ERK/NF-kappaB pathway, including phosphorylation of Akt and ERK and nuclear translocation of NF-kappaB. The suppressive effect of nicotine on the late-phase response was blocked by the alpha7/alpha9-nAChR antagonists methyllycaconitine and alpha-bungarotoxin, as well as by small interfering RNA knockdown of alpha7-, alpha9-, or alpha10-nAChRs, suggesting a functional interaction between alpha7-, alpha9-, and alpha10-nAChRs that might explain the response of RBL cells to nanomolar concentrations of nicotine. This "hybrid" receptor might serve as a target for novel antiallergic/antiasthmatic therapies.

PMID:
    20505147

Psychopharmacology (Berl). 2004 Apr;172(4):375-83. Epub 2004 Jan 15.
AR-R 17779 improves social recognition in rats by activation of nicotinic alpha7 receptors.
Van Kampen M, Selbach K, Schneider R, Schiegel E, Boess F, Schreiber R.
Source

CNS Research, Bayer AG, 42096 Wuppertal, Germany.
Abstract
RATIONALE:

Nicotine and agonists at alpha(4)beta(2) and alpha(7) nicotinic acetylcholine receptors (nAChRs) improve learning and memory. The alpha(7)-nAChR subtype is of special interest, since it appears to play no role in the abuse liability of nicotine.
OBJECTIVES AND METHODS:

To further investigate the role of the alpha(7)-nAChR in learning and memory, the effects of the specific alpha(7)-nAChR agonist AR-R17779 on cognition were measured in the rat social recognition test (SRT) and the effect of the alpha(7)-nAChR antagonist methyllycaconitine (MLA) was studied. The SRT and a scopolamine-induced deficit version were validated with the acetylcholinesterase inhibitor metrifonate. Social memory was measured by the ability of an adult rat to recognize a juvenile rat after a delay. The difference in social interaction time (SIT) was measured between two encounters. The difference in SIT is expressed as percent reduction in social interaction time (%RSIT).
RESULTS:

Metrifonate (10 and 30 mg/kg PO) increased %RSIT in a behaviorally specific manner, employing a 24-h interval and reversed the scopolamine-induced deficit at a retention time of 15 min. Likewise, AR-R17779 increased %RSIT in unimpaired animals (1, 3, 10 and 30 mg/kg SC) employing a 24-h retention interval, and reversed the scopolamine-induced deficit (0.3 and 1 mg/kg SC) after a 15-min retention interval. The effects of AR-R17779 (1 mg/kg SC) in unimpaired animals were reversed by MLA (10 micro g ICV), which induced a decrease of %RSI at a 15-min retention interval when given alone.
CONCLUSIONS:

AR-R17779 increased social recognition memory by activation of alpha(7)-nAChRs, suggesting that alpha(7)-nAChR agonists possess cognitive-enhancing properties.

PMID:
    14727003

Behav Pharmacol. 1999 Nov;10(6-7):675-80.
AR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats.
Levin ED, Bettegowda C, Blosser J, Gordon J.
Source

Psychiatry Department, Duke University Medical Center, Durham, North Carolina 27710, USA. edlevin@duke.edu
Abstract

Nicotinic acetylcholine systems have been found to be important for learning and memory function. The prototypic nicotinic agonist nicotine has been shown in a variety of studies to improve aspects of cognitive function. The specific involvement of nicotinic receptor subtypes is now being investigated. The involvement of alpha7 nicotinic receptors was assessed in this project using a novel alpha7 nicotinic agonist, AR-R 17779. Repeated doses (subcutaneous injection 20 min before testing) of the racemic mixture AR-R 13489 and its active isomer AR-R 17779 were assessed in adult female Sprague-Dawley rats using the eight-arm radial maze. AR-R 13489 (2 mg/kg) caused a significant improvement of long-term win-shift acquisition after 3 weeks of training (n = 10 per group). The same dose of AR-R 17779 also caused a significant improvement in repeated acquisition within each daily session in the radial-arm maze. In another study, the active isomer AR-R 17779 significantly improved radial-arm maze working memory function in rats with lesions to the septohippocampal projection. Fimbria-fornix lesions significantly impaired working memory performance and AR-R 17779 significantly reversed that impairment. These studies showed that alpha7 nicotinic agonist treatment improved learning in two radial-arm maze tasks and reversed working memory impairment caused by fimbria-fornix sections, providing evidence for alpha7 involvement in learning and memory, and the potential therapeutic use of AR-R 17779.

PMID:
    10780509

J Clin Endocrinol Metab. 1978 Dec;47(6):1348-51.
Stimulation of prolactin and growth hormone secretion by muscimol, a gamma-aminobutyric acid agonist.
Tamminga CA, Neophytides A, Chase TN, Frohman LA.
Abstract

The alteration in circulating levels of PRL, GH, TSH, and cortisol was studied after the oral administration of muscimol (3-hydroxy-5-aminomethylisoxazole) to human subjects with Huntington's disease (n = 4) and chronic schizophrenia (n = 5). PRL levels rose significantly in a dose-dependent fashion within a 120-min time interval. GH rose significantly but modestly over the same time interval, whereas TSH and cortisol levels remained unchanged. Since muscimol is thought to be a potent and specific gamma-aminobutyric acid agonist, these data indicate that gamma-aminobutyric acid-mediated neural transmission may function to stimulate the release of plasma PRL and GH in human subjects.

PMID:
    162520

Neuropsychopharmacology. 2010 Mar;35(4):999-1007. Epub 2009 Dec 23.
Prototypic GABA(A) receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites.
Chandra D, Halonen LM, Linden AM, Procaccini C, Hellsten K, Homanics GE, Korpi ER.
Source

Departments of Anesthesiology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Abstract

Muscimol has been regarded as a universal agonist for all gamma-aminobutyric acid type A receptor (GABA(A)-R) subtypes. However, brain regional distribution of muscimol's high-affinity binding sites greatly differs from those of other binding sites of the GABA(A)-R. To test whether behavioral effects of muscimol correlated with the density of high-affinity [(3)H]muscimol binding, we examined several GABA(A)-R subunit gene-modified mouse lines: alpha1, alpha4, or delta-knockouts (KO), alpha4+delta-double KO, and Thy1.2 promoter-driven alpha6 transgenic mice (Thy1alpha6). We determined the high-affinity [(3)H]muscimol binding in brain sections by quantitative autoradiography and sedative/ataxic effects induced in vivo by muscimol using a constant speed rotarod. alpha4-KO mice had reduced [(3)H]muscimol binding in the caudate-putamen, thalamus, and hippocampus, and were less sensitive to the behavioral impairment by muscimol. Similarly, delta-KO mice also had reduced binding to forebrain regions and a lower behavioral sensitivity to muscimol than their wild-type controls. In contrast, alpha1-KO mice had unaltered behavioral sensitivity to muscimol and unaltered [(3)H]muscimol binding, even though previous studies have demonstrated dramatically reduced binding to various other GABA(A)-R sites in these mice. Finally, Thy1alpha6 mice exhibited increased behavioral sensitivity to muscimol, and to another direct GABA-site agonist gaboxadol, and increased [(3)H]muscimol binding in the cerebral cortex and hippocampus. Thus, the differences in sedative and motor-impairing actions of muscimol in various mouse models correlated with the level of forebrain high-affinity [(3)H]muscimol binding. These data suggest that a small special population of GABA(A)-Rs, most likely extrasynaptic non-alpha1-containing receptors, strongly contributes to the in vivo pharmacological effects of muscimol.

PMID:
    20032968

DNA Cell Biol. 2011 Jul 20. [Epub ahead of print]
Regulation of Insulin Gene Transcription by Multiple Histone Acetyltransferases.
Sampley ML, Ozcan S.
Source

Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky , Lexington, Kentucky.
Abstract

Glucose-stimulated insulin gene transcription is mainly regulated by a 340-bp promoter region upstream of the transcription start site by beta-cell-enriched transcription factors Pdx-1, MafA, and NeuroD1. Previous studies have shown that histone H4 hyperacetylation is important for acute up-regulation of insulin gene transcription. Until now, only the histone acetyltransferase (HAT) protein p300 has been shown to be involved in this histone H4 acetylation event. In this report we investigated the role of the additional HAT proteins CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and general control of amino-acid synthesis 5 (GCN5) in regulation of glucose-stimulated insulin gene transcription. Utilizing quantitative chromatin immunoprecipitation analysis, we demonstrate that glucose regulates the binding of p300, CBP, PCAF, and GCN5 to the proximal insulin promoter. siRNA-mediated knockdown of each of these HAT proteins revealed that depletion of p300 and CBP leads to a drastic decrease in histone H4 acetylation at the insulin promoter and in insulin gene expression, whereas knockdown of PCAF and GCN5 leads to a more moderate decrease in histone H4 acetylation and insulin gene expression. These data suggest that high glucose mediates the recruitment of p300, CBP, PCAF, and GCN5 to the insulin promoter and that all four HATs are important for insulin gene expression.

PMID:
    21774670

Expert Opin Ther Pat. 2011 Oct;21(10):1651-6. Epub 2011 Jul 15.
Epigenetic modulation of PGC-1a activity by GCN5 inhibitors: WO2010007085.
Carradori S, Secci D, Mai A.
Source

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco , Sapienza University of Rome, P.le A. Moro 5, 00185 Rome , Italy +0039 06 4991 3392 ; +0039 06 4969 3268 ; antonello.mai@uniroma1.it.
Abstract

The transcriptional peroxisome proliferator-activated receptor ? (PPAR?) co-activator PGC-1a plays a central role in the regulation of cellular energy metabolism. Among the wide range of its activities, PGC-1a controls mitochondrial biogenesis and function and is one of the main factors involved in hormonal and nutrient regulation of hepatic gluconeogenesis. PGC-1a is present in a multiprotein complex, and its activity can also be modulated through epigenetic modifications. In particular, it is directly acetylated by the HAT enzyme general control nonderepressible 5 (GCN5), resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci, whereas it is deacetylated by SIRT1 at multiple lysine sites, with a subsequent increase in its activity leading to induction of liver gluconeogenic gene transcription. Thus, both GCN5 and SIRT1 may be pharmacological targets to regulate the activity of PGC-1a, providing a potential treatment for metabolic disorders in which hepatic glucose output is altered.

PMID:
    21756203

Oncogene. 2011 Jul 4. doi: 10.1038/onc.2011.261. [Epub ahead of print]
And-1 is required for the stability of histone acetyltransferase Gcn5.
Li Y, Jaramillo-Lambert AN, Yang Y, Williams R, Lee NH, Zhu W.
Source

Department of Biochemistry and Molecular Biology, The George Washington University Medical School, Washington, DC, USA.
Abstract

Histone acetyltransferases (HATs) have a central role in the modification of chromatin as well as in the pathogenesis of a broad set of diseases including cancers. Gcn5 is the first identified transcription-related HAT that has been implicated in the regulation of diverse cellular functions. However, how Gcn5 proteins are regulated remains largely unknown. Here we show that acidic nucleoplasmic DNA-binding protein (And-1, a high mobility group domain-containing protein) has remarkable capability to regulate the stability of Gcn5 proteins and thereby histone H3 acetylation. We find that And-1 forms a complex with both histone H3 and Gcn5. Downregulation of And-1 results in Gcn5 degradation, leading to the reduction of H3K9 and H3K56 acetylation. And-1 overexpression stabilizes Gcn5 through protein-protein interactions in vivo. Furthermore, And-1 expression is increased in cancer cells in a manner correlating with increased Gcn5 and H3K9Ac and H3K56Ac. Thus, our data reveal not only a functional link between Gcn5 and And-1 that is essential for Gcn5 protein stability and histone H3 acetylation, but also a potential role of And-1 in cancer.Oncogene advance online publication, 4 July 2011; doi:10.1038/onc.2011.261.

PMID:
    21725360

J Cell Sci. 1997 May;110 ( Pt 9):1051-62.
AND-1, a natural chimeric DNA-binding protein, combines an HMG-box with regulatory WD-repeats.
Köhler A, Schmidt-Zachmann MS, Franke WW.
Source

Division of Cell Biology, German Cancer Research Center, Heidelberg, Germany.
Abstract

Using a specific monoclonal antibody (mAb AND-1/23-5-14) we have identified, cDNA-cloned and characterized a novel DNA-binding protein of the clawed toad, Xenopus laevis, that is accumulated in the nucleoplasm of oocytes and various other cells. This protein comprises 1,127 amino acids, with a total molecular mass of 125 kDa and a pI of 5.27. It is encoded by a mRNA of approximately 4 kb and contains, in addition to clusters of acidic amino acids, two hallmark motifs: the amino-terminal part harbours seven consecutive 'WD-repeats', which are sequence motifs of about 40 amino acids that are characteristic of a large group of regulatory proteins involved in diverse cellular functions, while the carboxy terminal portion possesses a 63-amino-acid-long 'HMG-box', which is typical of a family of DNA-binding proteins involved in regulation of chromatin assembly, transcription and replication. The DNA-binding capability of the protein was demonstrated by DNA affinity chromatography and electrophoretic mobility shift assays using four-way junction DNA. Protein AND-1 (acidic nucleoplasmic DNA-binding protein) appears as an oligomer, probably a homodimer, and has been localized throughout the entire interchromatinic space of the interphase nucleoplasm, whereas during mitosis it is transiently dispersed over the cytoplasm. We also identified a closely related, perhaps orthologous protein in mammals. The unique features of protein AND-1, which is a 'natural chimera' combining properties of the WD-repeat and the HMG-box families of proteins, are discussed in relation to its possible nuclear functions.

PMID:
    9175701

J Biol Chem. 2010 Mar 26;285(13):9493-505. Epub 2010 Jan 19.
Influence of the human cohesion establishment factor Ctf4/AND-1 on DNA replication.
Bermudez VP, Farina A, Tappin I, Hurwitz J.
Source

Program of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Abstract

Ctf4/AND-1 is a highly conserved gene product required for both DNA replication and the establishment of sister chromatid cohesion. In this report, we examined the mechanism of action of human Ctf4 (hCtf4) in DNA replication both in vitro and in vivo. Our findings show that the purified hCtf4 exists as a dimer and that the hCtf4 SepB domain likely plays a primary role determining the dimeric structure. hCtf4 binds preferentially to DNA template-primer structures, interacts directly with the replicative DNA polymerases (alpha, delta, and epsilon), and markedly stimulates the polymerase activities of DNA polymerases alpha and epsilon in vitro. Depletion of hCtf4 in HeLa cells by small interfering RNA resulted in G(1)/S phase arrest. DNA fiber analysis revealed that cells depleted of hCtf4 exhibited a rate of DNA replication slower than cells treated with control small interfering RNA. These findings suggest that in human cells, hCtf4 plays an essential role in DNA replication and its ability to stimulate the replicative DNA polymerases may contribute to this effect.

PMID:
    20089864

Genes Cells. 2009 Jul;14(7):807-20. Epub 2009 Jun 3.
Ctf4 coordinates the progression of helicase and DNA polymerase alpha.
Tanaka H, Katou Y, Yagura M, Saitoh K, Itoh T, Araki H, Bando M, Shirahige K.
Source

Laboratory of Chromosome Structure and Function, Department of Biological Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama City, Kanagawa, Japan.
Abstract

Ctf4 is a protein conserved in eukaryotes and a constituent of the replisome progression complex. It also plays a role in the establishment of sister chromatid cohesion. In our current study, we demonstrate that the replication checkpoint is activated in the absence of Ctf4, and that the interaction between the MCM helicase-go ichi ni san (GINS) complex and DNA polymerase alpha (Pol alpha)-primase is destabilized specifically in a ctf4Delta mutant. An in vitro interaction between GINS and DNA Pol alpha was also found to be mediated by Ctf4. The same interaction was not affected in the absence of the replication checkpoint mediators Tof1 or Mrc1. In ctf4Delta cells, DNA pol alpha became significantly unstable and was barely detectable at the replication forks in HU. In contrast, the quantities of helicase and DNA pol epsilon bound to replication forks were almost unchanged but their localizations were widely and abnormally dispersed in the mutant cells compared with wild type. These results lead us to propose that Ctf4 is a key connector between DNA helicase and Pol alpha and is required for the coordinated progression of the replisome.

PMID:
    19496828

J Neurochem. 2009 Feb;108(3):676-84. Epub 2008 Nov 28.
Hydrogen sulfide evokes neurite outgrowth and expression of high-voltage-activated Ca2+ currents in NG108-15 cells: involvement of T-type Ca2+ channels.
Nagasawa K, Tarui T, Yoshida S, Sekiguchi F, Matsunami M, Ohi A, Fukami K, Ichida S, Nishikawa H, Kawabata A.
Source

Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.
Abstract

We investigated if stimulation of T-type Ca(2+) channels with sodium hydrosulfide (NaHS), a donor of hydrogen sulfide (H(2)S), could cause neuronal differentiation of NG108-15 cells. Like dibutyryl cyclic AMP (db-cAMP), treatment with NaHS at 1.5-13.5 mM for 16 h enhanced neurite outgrowth in a concentration-dependent manner. Synergistic neuritogenic effect was obtained in the cells stimulated with NaHS in combination with db-cAMP at subeffective concentrations. Exposure to NaHS or db-cAMP for 2 days resulted in enhancement of expression of high-voltage-activated currents consisting of N-, P/Q-, L- and also other types, but not of T-type currents. Mibefradil, a pan-T-type channel blocker, abolished the neuritogenesis induced by NaHS, but not by db-cAMP. The NaHS-evoked neuritogenesis was also completely blocked by pretreatment with BAPTA/AM, a chelator of intracellular Ca(2+), and by zinc chloride at a concentration known to selectively inhibit Ca(v)3.2 isoform of T-type Ca(2+) channels, but not Ca(v)3.1 or Ca(v)3.3. Further, L-ascorbate, recently proven to selectively inhibit Ca(v)3.2, abolished the neuritogenic effect of NaHS, but not db-cAMP. Our data thus demonstrate that NaHS/H(2)S is a novel inducer of neuronal differentiation in NG108-15 cells, as characterized by neuritogenesis and expression of high-voltage-activated currents, and suggest the involvement of T-type Ca(2+) channels, especially Ca(v)3.2.

PMID:
    19054275

Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13823-8. Epub 2011 Aug 1.
The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus.
Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P, Adelman JP, Lüthi A.
Source

Department of Cell Biology and Morphology, University of Lausanne, CH-1005 Lausanne, Switzerland.
Abstract

Low-threshold (T-type) Ca(2+) channels encoded by the Ca(V)3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca(V)3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca(V)3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca(V)3.3(-/-) mouse line and demonstrate that Ca(V)3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca(V)3.3 channels prevented oscillatory bursting in the low-frequency (4-10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca(V)3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca(V)3.3(-/-) mice were <30% compared with those in WT mice, and the remaining current, carried by Ca(V)3.2 channels, generated dendritic [Ca(2+)](i) signals insufficient to provoke oscillatory bursting that arises from interplay with Ca(2+)-dependent small conductance-type 2 K(+) channels. Finally, naturally sleeping Ca(V)3.3(-/-) mice showed a selective reduction in the power density of the s frequency band (10-12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca(V)3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.

PMID:
    21808016

Neuroscientist. 2002 Aug;8(4):335-46.
Two phylogenetic specializations in the human brain.
Allman J, Hakeem A, Watson K.
Source

Division of Biology, California Institute of Technology, Pasadena, California 91125, USA. cebus@caltech.edu
Abstract

In this study, two anatomical specializations of the brain in apes and humans are considered. One of these is a whole cortical area located in the frontal polar cortex (Brodmann's area 10), and the other is a morphologically distinctive cell type, the spindle neuron of the anterior cingulate cortex. The authors suggest that the spindle cells may relay to other parts of the brain--especially to area 10, the outcome of processing within the anterior cingulate cortex. This relay conveys the motivation to act. It particularly concerns the recognition of having committed an error that leads to the initiation of adaptive responses to these adverse events so as to reduce error commission. This capacity is related to the development of self-control as an individual matures and gains social insight. Although the anterior cingulate deals with the individual's immediate response to changing conditions, area 10 is involved in the retrieval of memories from the individual's past experience and the capacity to plan adaptive responses. The authors suggest that these neurobehavioral specializations are crucial aspects of intelligence as defined as the capacity to make adaptive responses to changing conditions. The authors further hypothesize that these specializations facilitated the evolution of the unique capacity for the intergenerational transfer of the food and information characteristic of human extended families.

PMID:
    12194502

Am J Psychiatry. 2011 Jul;168(7):727-34. Epub 2011 Apr 15.
Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study.
Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A, Burger C, Auberson YP, Sovago J, Stockmeier CA, Buck A, Hasler G.
Source

PET Center, Division of Nuclear Medicine, University Hospital, Zurich.
Abstract
OBJECTIVE:

Clinical and preclinical evidence suggests a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for novel therapeutic approaches to depression. The goal of this study was to compare mGluR5 binding (in a positron emission tomography [PET] study) and mGluR5 protein expression (in a postmortem study) between individuals with major depressive disorder and psychiatrically healthy comparison subjects.
METHOD:

Images of mGluR5 receptor binding were acquired using PET with [(11)C]ABP688, which binds to an allosteric site with high specificity, in 11 unmedicated individuals with major depression and 11 matched healthy comparison subjects. The amount of mGluR5 protein was investigated using Western blot in postmortem brain samples of 15 depressed individuals and 15 matched comparison subjects.
RESULTS:

The PET study revealed lower levels of regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus, and the hippocampus in the depression group relative to the comparison group. Severity of depression was negatively correlated with mGluR5 binding in the hippocampus. The postmortem study showed lower levels of mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in the depression group relative to the comparison group, while prefrontal mGluR1 protein expression did not differ between groups.
CONCLUSIONS:

The lower levels of mGluR5 binding observed in the depression group are consonant with the lower levels of protein expression in brain tissue in the postmortem depression group. Thus, both studies suggest that basal or compensatory changes in excitatory neurotransmission play roles in the pathophysiology of major depression.

PMID:
    21498461

Neurol Res Int. 2010;2010:671421. Epub 2010 Jun 10.
Medial orbitofrontal cortex is associated with fatigue sensation.
Tajima S, Yamamoto S, Tanaka M, Kataoka Y, Iwase M, Yoshikawa E, Okada H, Onoe H, Tsukada H, Kuratsune H, Ouchi Y, Watanabe Y.
Source

Hyogo Children's Sleep and Development Medical Research Center, Hyogo Rehabilitation Centre Central Hospital, 1070 Akebono-cho, Nishi-ku, Kobe 651-2181, Japan.
Abstract

Fatigue is an indispensable bioalarm to avoid exhaustive state caused by overwork or stresses. It is necessary to elucidate the neural mechanism of fatigue sensation for managing fatigue properly. We performed H(2) ( 15)O positron emission tomography scans to indicate neural activations while subjects were performing 35-min fatigue-inducing task trials twice. During the positron emission tomography experiment, subjects performed advanced trail-making tests, touching the target circles in sequence located on the display of a touch-panel screen. In order to identify the brain regions associated with fatigue sensation, correlation analysis was performed using statistical parametric mapping method. The brain region exhibiting a positive correlation in activity with subjective sensation of fatigue, measured immediately after each positron emission tomography scan, was located in medial orbitofrontal cortex (Brodmann's area 10/11). Hence, the medial orbitofrontal cortex is a brain region associated with mental fatigue sensation. Our findings provide a new perspective on the neural basis of fatigue.

PMID:
    21188225

J Neurosci. 2010 Jul 28;30(30):10039-47.
Multiple mechanisms of consciousness: the neural correlates of emotional awareness.
Amting JM, Greening SG, Mitchell DG.
Source

Department of Psychiatry and Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 339 Windermere Road, London, Ontario, Canada.
Abstract

Emotional stimuli, including facial expressions, are thought to gain rapid and privileged access to processing resources in the brain. Despite this access, we are conscious of only a fraction of the myriad of emotion-related cues we face everyday. It remains unclear, therefore, what the relationship is between activity in neural regions associated with emotional representation and the phenomenological experience of emotional awareness. We used functional magnetic resonance imaging and binocular rivalry to delineate the neural correlates of awareness of conflicting emotional expressions in humans. Behaviorally, fearful faces were significantly more likely to be perceived than disgusted or neutral faces. Functionally, increased activity was observed in regions associated with facial expression processing, including the amygdala and fusiform gyrus during emotional awareness. In contrast, awareness of neutral faces and suppression of fearful faces were associated with increased activity in dorsolateral prefrontal and inferior parietal cortices. The amygdala showed increased functional connectivity with ventral visual system regions during fear awareness and increased connectivity with perigenual prefrontal cortex (pgPFC; Brodmann's area 32/10) when fear was suppressed. Despite being prioritized for awareness, emotional items were associated with reduced activity in areas considered critical for consciousness. Contributions to consciousness from bottom-up and top-down neural regions may be additive, such that increased activity in specialized regions within the extended ventral visual system may reduce demands on a frontoparietal system important for awareness. The possibility is raised that interactions between pgPFC and the amygdala, previously implicated in extinction, may also influence whether or not an emotional stimulus is accessible to consciousness.

PMID:
    20668188

Neuroimage. 2011 Jan 1;54(1):645-52. Epub 2010 Jul 27.
Neural substrates of implicit cueing effect on prospective memory.
Hashimoto T, Umeda S, Kojima S.
Source

Riken BSI Symbolic Cognitive Development, Wako, Saitama, Japan. t-hashimoto@brain.riken.jp
Abstract

Functional magnetic resonance imaging was used to examine the maintenance of intentions during an ongoing task involving implicit cues. Participants were required to detect target words while engaging in the ongoing task. Cues matched to the target category and cues matched to the action for targets were presented implicitly during the ongoing task. Implicit categorical target cues were found to enhance prospective memory performance, and implicit action cues accelerated responses more than irrelevant implicit cues in the prospective memory task. We found increased caudal anterior cingulate cortex (cACC) activity during the ongoing task with both implicit target and action cues, suggesting that alertness or preparatory attentional processes were strengthened by implicit cues. Implicit target cues elicited enhanced activity in the lateral anterior prefrontal cortex (Brodmann's area 10), which may be involved in dual processing of the ongoing task and the maintained intention. These results suggest that implicit cues may boost primitive attention toward an intended action and may be accessible to off-line maintenance. The facilitation of prospective target detection and the action execution by target cues were associated with increased supplementary motor area (SMA) activity. In contrast, we found enhanced premotor cortex (PMC) activation with action cue during the prospective memory task, suggesting that the PMC may be involved in stimulus-induced and rather automatic action. These results demonstrate the effectiveness of implicit cues for examining the maintenance of intention. Overall, we found that implicit target cues can facilitate prospective memory performance, and implicit action cues can accelerate responses. The above-mentioned neural underpinnings suggest that attentional and motor control processes are involved in the enhancement of prospective memory.

Copyright © 2010 Elsevier Inc. All rights reserved.

PMID:
    20673802

Neuroimage. 2005 Dec;28(4):787-96. Epub 2005 Jun 17.
Thinking about intentions.
den Ouden HE, Frith U, Frith C, Blakemore SJ.
Source

Institute of Cognitive Neuroscience, Department of Psychology, University College London, UK.
Abstract

In this fMRI study, we investigated the convergence of underlying neural networks in thinking about a scenario involving one's own intentional action and its consequences and setting up and holding in mind an intention to act. A factorial design was employed comprising two factors: i. Causality (intentional or physical events) and ii. Prospective Memory (present or absent). In each condition, subjects answered questions about various hypothetical scenarios, which related either to the link between the subject's own intentions and consequential actions (Intentional Causality) or to the link between a natural, physical event and its consequences (Physical Causality). A prospective memory task was embedded in half the blocks. In this task, subjects were required to keep in mind an intention (to press a key on seeing a red stimulus background) whilst carrying out the ongoing Causality task. Answering questions about intentional causality versus physical causality activated a network of regions that have traditionally been associated with Theory of Mind, including the medial prefrontal cortex (mPFC), the superior temporal sulcus and the temporal poles bilaterally. In addition, the precuneus bordering with posterior cingulate cortex, an area involved in self-awareness and self-related processing, was activated more when thinking about intentional causality. In the prospective memory task, activations were found in the right parietal cortex, frontopolar cortex (BA 10) and precuneus. Different subregions within the precuneus/posterior cingulate cortex were activated in both main effects of intentional causality and prospective memory. Therefore, the precuneus/posterior cingulate cortex subserves separately thinking about one's own intentions and consequent actions and bearing in mind an intention to make an action. Previous studies have shown that prospective memory, requiring the formation of an intention and the execution of a corresponding action, is associated with decreased activation in the dorsal mPFC, close to the region activated in Theory of Mind tasks. Here, we found that holding in mind an intention to act and at the same time thinking about an intentional action led to reduced activity in a dorsal section of the mPFC. This was a different region from a more anterior, inferior dorsal mPFC region that responded to intentional causality. This suggests that different regions of mPFC play different roles in thinking about intentions.

PMID:
    15964210

J Biol Chem. 2011 Sep 2;286(35):30561-70. Epub 2011 Jul 11.
Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise.
Philp A, Chen A, Lan D, Meyer GA, Murphy AN, Knapp AE, Olfert IM, McCurdy CE, Marcotte GR, Hogan MC, Baar K, Schenk S.
Source

Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616, USA.
Abstract

The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-? coactivator-1a (PGC-1a). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1a and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1a expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1a expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1a after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1a. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1a or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1a activity after exercise.

PMID:
    21757760

J Neuroinflammation. 2010 Dec 17;7:93.
Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide.
Corona AW, Huang Y, O'Connor JC, Dantzer R, Kelley KW, Popovich PG, Godbout JP.
Source

Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, 333 W. 10th Ave., Columbus, OH 43210, USA. Angela.Wynne@osumc.edu
Abstract
BACKGROUND:

Interactions between fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX3CL1 and CX3CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS). Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX3CR1-deficient mice (CX3CR1-/-).
METHODS:

CX3CR1-/- mice or control heterozygote mice (CX3CR1+/-) were injected with LPS (0.5 mg/kg i.p.) or saline and behavior (i.e., sickness and depression-like behavior), microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.
RESULTS:

LPS injection caused a prolonged duration of social withdrawal in CX3CR1-/- mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1ß, indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO) in microglia 4 h after LPS. Moreover, elevated expression of IL-1ß and CD14 was still detected in microglia of CX3CR1-/- mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX3CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX3CR1-/- mice. This depression-like behavior in CX3CR1-/- mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex.
CONCLUSIONS:

Taken together, these data indicate that a deficiency of CX3CR1 is permissive to protracted microglial activation and prolonged behavioral alterations in response to transient activation of the innate immune system.

PMID:
    21167054

J Biol Chem. 2011 Sep 16;286(37):32713-22. Epub 2011 Jul 19.
CX3CR1 Protein Signaling Modulates Microglial Activation and Protects against Plaque-independent Cognitive Deficits in a Mouse Model of Alzheimer Disease.
Cho SH, Sun B, Zhou Y, Kauppinen TM, Halabisky B, Wes P, Ransohoff RM, Gan L.
Source

From the Gladstone Institute of Neurological Disease and.
Abstract

Aberrant microglial activation has been proposed to contribute to the cognitive decline in Alzheimer disease (AD), but the underlying molecular mechanisms remain enigmatic. Fractalkine signaling, a pathway mediating the communication between microglia and neurons, is deficient in AD brains and down-regulated by amyloid-ß. Although fractalkine receptor (CX3CR1) on microglia was found to regulate plaque load, no functional effects have been reported. Our study demonstrates that CX3CR1 deficiency worsens the AD-related neuronal and behavioral deficits. The effects were associated with cytokine production but not with plaque deposition. Ablation of CX3CR1 in mice overexpressing human amyloid precursor protein enhanced Tau pathology and exacerbated the depletion of calbindin in the dentate gyrus. The levels of calbindin in the dentate gyrus correlated negatively with those of tumor necrosis factor a and interleukin 6, suggesting neurotoxic effects of inflammatory factors. Functionally, removing CX3CR1 in human amyloid precursor protein mice worsened the memory retention in passive avoidance and novel object recognition tests, and their memory loss in the novel object recognition test is associated with high levels of interleukin 6. Our findings identify CX3CR1 as a key microglial pathway in protecting against AD-related cognitive deficits that are associated with aberrant microglial activation and elevated inflammatory cytokines.

PMID:
    21771791

Behav Neurosci. 2010 Oct;124(5):645-55.
Dopamine activity in the lateral anterior hypothalamus modulates AAS-induced aggression through D2 but not D5 receptors.
Schwartzer JJ, Melloni RH Jr.
Source

Behavioral Neuroscience Program, Department of Psychology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Abstract

Treatment with anabolic-androgenic steroids (AAS) throughout adolescence facilitates offensive aggression in Syrian hamsters. In the anterior hypothalamus (AH), the dopaminergic neural system undergoes alterations after repeated exposure to AAS, producing elevated aggression. Previously, systemic administration of selective dopamine receptor antagonists has been shown to reduce aggression in various species and animal models. However, these reductions in aggression occur with concomitant alterations in general arousal and mobility. Therefore, to control for these systemic effects, the current studies utilized microinjection techniques to determine the effects of local antagonism of D2 and D5 receptors in the AH on adolescent AAS-induced aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the D2 antagonist eticlopride, or the D5 antagonist SCH-23390, into the AH. Treatment with eticlopride showed dose-dependent suppression of aggressive behavior in the absence of changes in mobility. Conversely, while injection of SCH-23390 suppressed aggressive behavior, these reductions were met with alterations in social interest and locomotor behavior. To elucidate a plausible mechanism for the observed D5 receptor mediation of AAS-induced aggression, brains of AAS and sesame oil-treated animals were processed for double-label immunofluorescence of GAD67 (a marker for GABA production) and D5 receptors in the lateral subdivision of the AH (LAH). Results indicate a sparse distribution of GAD67 neurons colocalized with D5 receptors in the LAH. Together, these results indicate that D5 receptors in the LAH modulate non-GABAergic pathways that indirectly influence aggression control, while D2 receptors have a direct influence on AAS-induced aggression.

(PsycINFO Database Record (c) 2010 APA, all rights reserved).

PMID:
    20939664

Neuroscience. 2011 Jun 30;185:85-96. Epub 2011 Apr 1.
Glutamate-vasopressin interactions and the neurobiology of anabolic steroid-induced offensive aggression.
Carrillo M, Ricci LA, Melloni RH.
Source

Behavioral Neuroscience Program, Department of Psychology, 125 Nightingale Hall, Northeastern University, 360 Huntington Avenue, Boston, MA 02155, USA.
Abstract

In the latero-anterior hypothalamus (LAH) increased glutamate and vasopressin (AVP) activity facilitate anabolic androgenic steroid (AAS)-induced offensive aggression. In addition, adolescent AAS treatment increases the strength of glutamate-mediated connections between the LAH and the brain nucleus of stria terminalis (BNST). The current set of studies used male Syrian hamsters exposed to AAS during adolescence to examine whether increased glutamate-mediated stimulation of the BNST is dependent on LAH-AVP signaling and whether this neural pathway modulates adolescent AAS-induced offensive aggression. In the first set of AAS-treated animals offensive aggression was measured following blockade of glutamate activity within the BNST using NBQX. Then, in a second group of AAS-treated animals aggression levels were examined following simultaneous blockade of LAH-AVP activity using Manning compound and stimulation of BNST glutamate using AMPA. Lastly, the number of AVP fibers in apposition to glutamate cells was examined in AAS and control animals, using double-label immunofluorescence. The results showed that administration of NBQX into the BNST dose-dependently reduced aggressive behavior in AAS-treated animals. Further, the current results replicated previous findings showing that blockade of LAH-AVP significantly reduces aggressive behavior in AAS-treated animals. In these animals stimulation of BNST-AMPA receptors had a linear effect on aggression, where the smallest dose exacerbated the inhibitory effect of the V1a antagonist, the medium dose had no effect and the highest dose recuperated aggression to control levels. Finally when compared with control animals, AAS treatment produced a significant increase in the number of AVP fibers in apposition to LAH-glutamate cells. Overall, these results identify the BNST as a key brain region involved in aggression control and provide strong evidence suggesting that AVPergic-mediated stimulation of BNST-glutamate is a possible mechanism that facilitates aggression expression in adolescent AAS-treated animals.

Copyright © 2011. Published by Elsevier Ltd.

PMID:
    21459130

Brain Struct Funct. 2011 Sep 21. [Epub ahead of print]
Orexinergic innervation of the extended amygdala and basal ganglia in the rat.
Schmitt O, Usunoff KG, Lazarov NE, Itzev DE, Eipert P, Rolfs A, Wree A.
Source

Institute of Anatomy, University of Rostock, P. O. Box 100888, 18055, Rostock, Germany, schmitt@med.uni-rostock.de.
Abstract

The orexinergic system interacts with several functional states of emotions, stress, hunger, wakefulness and behavioral arousal through four pathways originating in the lateral hypothalamus (LH). Hundreds of orexinergic efferents have been described by tracing studies and direct immunohistochemistry of orexin in the forebrain, olfactory regions, hippocampus, amygdala, septum, basal ganglia, thalamus, hypothalamus, brain stem and spinal cord. Most of these tracing studies investigated the whole orexinergic projection to all regions of the intracranial part of the CNS. To identify the orexinergic efferents at the subnuclear level of resolution, we focussed on the orexinergic target in the amygdala, which is substantially involved in the LH output and contributes mostly to the functional outcome of the orexinergic system and the basal ganglia. Immunohistochemical identification of axonal orexin A and orexin B in male adult rats has been performed on serial sections. In the extended amygdala many new orexinergic targets were found in the anterior amygdaloid area (dense), anterior cortical nucleus (moderate), amygdalostriatal transition region (moderate), basolateral regions (moderate), basomedial nucleus (moderate), several bed nucleus of the stria terminals regions (few to dense), central amygdaloid subdivisions (dense), posteromedial cortical nucleus (moderate) and medial amygdaloid subnuclei (dense). Furthermore, the entopeduncular nucleus has been newly identified as another target for orexinergic fibers with a high density. These results suggest that subdivisions and subnuclei of the extended amygdala are specific targets of the orexinergic system.

PMID:
    21935673

Zh Evol Biokhim Fiziol. 2011 May-Jun;47(3):223-31.
[Functional role of hypothalamic D1 and D2 receptors in organization of some forms of behavior of the common frog].
[Article in Russian]
Aristakesian EA.
Abstract

Dopamine is one of the most ancient, widely spread neurotransmitters that performs a great number of neuromodulator effects in the vertebrate CNS. For the last few years there considerably increases an interest in study of functional role of this neurotransmitter in regulation of various forms of behavior of poikilothermal vertebrates. The present work deals with study of the role of the dopaminergic system, specifically of the hypothalamic dophaminergic system in providing some behavioral frog reactions. We studies behavior of the animals in the "open field" before and after administration to them of antagonists of D1 (SCH 23390) and D2 (haloperidol) receptors as well as of animals with destructed anterior and posterior parts of hypothalamis. Administration of SCH 23390 to intact frogs caused a statistically significant decrease of the number of exploratory reactions and goal-oriented jumps, whereas haloperidol only moderately increased the number of the above reactions. Destruction of the posterior part of hypothalamus inhibited essentially all kinds of activity, while destruction of the anterior part suppressed them completely. Antagonists of D1 and D2 receptors of dopamin little changed the initial motor and emotional activity of the operated animals. The obtained data are discussed in the light of evolutionary origin of D1 and D2 receptors in the vertebrate subphylum and allow concluding that D1 and D2 receptors of hypothalamic dophamin of the common frog are located predominantly in the anterior hypothalamic areas and that their effect on behavior can be mediated and is associated with other brain neurotransmitter systems in such brain structures as lateral hypothalamus, locus coereleus, and striatum that provide different aspects of wakefulness.

PMID:
    21780642

Curr Opin Clin Nutr Metab Care. 2011 Jan;14(1):41-8.
The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation.
Sykiotis GP, Habeos IG, Samuelson AV, Bohmann D.
Source

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA.
Abstract
PURPOSE OF REVIEW:

The vertebrate cap'n'collar family transcription factor Nrf2 and its invertebrate homologues SKN-1 (in worms) and CncC (in flies) function as master mediators of antioxidant and detoxification responses and regulators of the cellular redox state. Nrf2 controls gene expression programs that defend various tissues against diverse electrophilic stressors and oxidative insults, thus protecting the organism from disorders that are caused or exacerbated by such stresses. Moreover, studies on model organisms implicate the Nrf2 pathway in the prevention of aging-related diseases and suggest that SKN-1-regulated and CncC-regulated gene expression can promote longevity. These facets of Nrf2 signaling have been thoroughly reviewed. This article discusses another aspect of the Nrf2 pathway's function that has not yet received the same degree of attention, but emerges as a topic of increasing interest and potential clinical impact: its role in metabolic regulation and its interaction with central signaling systems that respond to nutritional inputs.
RECENT FINDINGS:

Recent evidence identifies Nrf2 signaling as a mediator of the salutary effects of caloric restriction. Nrf2 signaling also crosstalks with metabolic signaling systems such as the insulin/Akt pathway as well as with the metabolism of lipids. Moreover, Nrf2 has a protective role in models of diabetic nephropathy.
SUMMARY:

The emerging role of Nrf2 as an effector of metabolic and longevity signals offers new therapeutic perspectives. The potential impact of pharmacological manipulation of Nrf2 signaling as a strategy for the prevention and treatment of metabolic disease can be envisioned.

PMID:
    21102319

Chem Biol Interact. 2011 Jun 30;192(1-2):37-45. Epub 2010 Oct 23.
The cap'n'collar transcription factor Nrf2 mediates both intrinsic resistance to environmental stressors and an adaptive response elicited by chemopreventive agents that determines susceptibility to electrophilic xenobiotics.
Higgins LG, Hayes JD.
Source

Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.
Abstract

Transcription factor Nrf2 regulates genes encoding drug-metabolising enzymes and drug transporters, as well as enzymes involved in the glutathione, thioredoxin and peroxiredoxin antioxidant pathways. Using mouse embryonic fibroblast (MEF) cells from Nrf2(+/+) and Nrf2(-/-) mice, in conjunction with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay, we have shown that loss of Nrf2 diminishes the intrinsic resistance of mutant fibroblasts towards isothiocyanates (i.e. sulforaphane), epoxides (i.e. (2S,3S)-(-)-3-phenylglycidol, ethyl 3-phenylglycidate and styrene-7,8-epoxide), peroxides, hydroquinones and quinones (i.e. tert-butylhydroperoxide, tert-butylhydroquinone and 2,3-dimethoxynaphthoquinone), NaAsO(2), and various mutagens, including ß-propiolactone, cisplatin, mechlorethamine and methyl methanesulfonate to ~50% of that observed in equivalent wild-type cells. Exposure of Nrf2(+/+) fibroblasts, but not Nrf2(-/-) fibroblasts, to a non-toxic dose (3µmol/l) of the chemopreventive agent sulforaphane (Sul) stimulated an adaptive response that, 18h after first being subjected to the isothiocyanate, caused an induction of between 2- and 10-fold in the levels of mRNA for glutamate-cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, glutathione S-transferases and NAD(P)H:quinone oxidoreductase-1 (Nqo1); this was accompanied by an increase in total glutathione of between 1.5- and 1.9-fold. Pre-treatment of Nrf2(+/+) MEF cells with 3µM Sul for 18h prior to challenge with xenobiotics, conferred between 2.0- and 4.0-fold protection against isothiocyanates, reactive carbonyls, peroxides, quinones, NaAsO(2), and the anticancer nitrogen mustard chlorambucil, but pre-treatment with 3µM Sul produced no such increased tolerance in Nrf2(-/-) MEF cells. The inducible resistance towards acrolein, cumene hydroperoxide and chlorambucil, produced by pre-treating wild-type fibroblasts with 3µM Sul, was dependent on glutathione because simultaneous pre-treatment with 5µmol/l buthionine sulfoximine abolished the increased tolerance of these xenobiotics. However, inducible resistance towards menadione that occurred upon pre-treatment with 3µM Sul was independent of glutathione and may be due to upregulation of Nqo1. Thus Nrf2 controls cellular resistance against electrophiles.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

PMID:
    20932822

Planta Med. 2008 Oct;74(13):1526-39. Epub 2008 Oct 20.
Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals.
Surh YJ, Kundu JK, Na HK.
Source

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul, South Korea. surh@plaza.snu.ac.kr
Abstract

A wide array of dietary phytochemicals have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and elimination/inactivation of electrophilic carcinogens. Induction of such cytoprotective enzymes by edible phytochemicals largely accounts for their cancer chemopreventive and chemoprotective activities. Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc. In resting cells, Nrf2 is sequestered in the cytoplasm as an inactive complex with the repressor Kelch-like ECH-associated protein 1 (Keap1). The release of Nrf2 from its repressor is most likely to be achieved by alterations in the structure of Keap1. Keap1 contains several reactive cysteine residues that function as sensors of cellular redox changes. Oxidation or covalent modification of some of these critical cysteine thiols would stabilize Nrf2, thereby facilitating nuclear accumulation of Nrf2. After translocation into nucleus, Nrf2 forms a heterodimer with other transcription factors, such as small Maf, which in turn binds to the 5'-upstream CIS-acting regulatory sequence, termed antioxidant response elements (ARE) or electrophile response elements (EpRE), located in the promoter region of genes encoding various antioxidant and phase 2 detoxifying enzymes. Certain dietary chemopreventive agents target Keap1 by oxidizing or chemically modifying one or more of its specific cysteine thiols, thereby stabilizing Nrf2. In addition, phosphorylation of specific serine or threonine residues present in Nrf2 by upstream kinases may also facilitate the nuclear localization of Nrf2. Multiple mechanisms of Nrf2 activation by signals mediated by one or more of the upstream kinases, such as mitogen-activated protein kinases, phosphatidylionositol-3-kinase/Akt, protein kinase C, and casein kinase-2 have recently been proposed. This review highlights the cytoprotective gene expression induced by some representative dietary chemopreventive phytochemicals with the Nrf2-Keap1 system as a prime molecular target.

PMID:
    18937164

Carcinogenesis. 2009 Oct;30(10):1754-62. Epub 2009 Jul 24.
1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic alpha,beta-unsaturated aldehyde acrolein.
Kelleher MO, McMahon M, Eggleston IM, Dixon MJ, Taguchi K, Yamamoto M, Hayes JD.
Source

Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.
Abstract

Epithionitriles represent a previously unrecognized class of cancer chemopreventive phytochemical generated from alkenyl glucosinolates in cruciferous vegetables. In rat liver RL-34 epithelial cells, 1-cyano-2,3-epithiopropane (CETP), 1-cyano-3,4-epithiobutane (CETB) and 1-cyano-4,5-epithiopentane (CETPent) were shown to induce cytoprotective enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione (GSH) S-transferase A3 and the glutamate-cysteine ligase modifier subunit; CETP was more potent in this regard than were either CETB or CETPent, with 50 microM CETP eliciting a remarkable approximately 10-fold induction of NQO1. Furthermore, 50 microM CETP stimulated a 2.0-fold overproduction of GSH in RL-34 cells. Transfection experiments demonstrated that epithionitriles induced gene expression through an antioxidant response element (ARE) and that transactivation of an Nqo1-luciferase reporter plasmid was dependent on NF-E2 p45-related factor 2 (Nrf2), a cap'n'collar basic region leucine zipper transcription factor. Evidence is presented that CETP affected Nrf2-mediated induction of ARE-driven transcription by inhibiting Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase substrate adaptor that negatively regulates Nrf2. We found that Nqo1 was expressed constitutively at high levels in Keap1(-/-) mouse embryonic fibroblasts (MEFs) and it was not further induced by CETP. However, knock-in of mouse Keap1 or zebrafish Keap1a into Keap1(-/-) MEFs repressed Nqo1-luciferase reporter gene activity, but repression by the murine or zebrafish proteins was antagonized by CETP. Pre-treatment of Nrf2(+/+) MEFs, but not Nrf2(-/-) MEFs, with 15 microM CETP for 24 h conferred 2.4-fold resistance against subsequent exposure to the alpha,beta-unsaturated aldehyde acrolein, indicating that the phytochemical exerts chemopreventive properties against genotoxic xenobiotics.

PMID:
    19633057

Expert Rev Mol Med. 2009 Jun 3;11:e17.
The Nrf2-ARE cytoprotective pathway in astrocytes.
Vargas MR, Johnson JA.
Source

Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI 53705, USA.
Abstract

The expression of phase-II detoxification and antioxidant enzymes is governed by a cis-acting regulatory element named the antioxidant response element (ARE). ARE-containing genes are regulated by the nuclear factor erythroid-2-related factor 2 (Nrf2), a member of the Cap'n'Collar basic-leucine-zipper family of transcription factors. ARE-regulated genes are preferentially activated in astrocytes, which consequently have more efficient detoxification and antioxidant defences than neurons. Astrocytes closely interact with neurons to provide structural, metabolic and trophic support, as well as actively participating in the modulation of neuronal excitability and neurotransmission. Therefore, functional alterations in astrocytes can shape the interaction with surrounding cells, such as neurons and microglia. Activation of Nrf2 in astrocytes protects neurons from a wide array of insults in different in vitro and in vivo paradigms, confirming the role of astrocytes in determining the vulnerability of neurons to noxious stimuli. Here, we review the current data supporting Nrf2 activation in astrocytes as a viable therapeutic approach, not only in acute neuronal damage, but also in chronic neurodegeneration related to oxidative stress.

PMID:
    19490732

Acta Pharmacol Sin. 2007 Apr;28(4):459-72.
Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells.
Nair S, Li W, Kong AN.
Source

Graduate Program in Pharmaceutical Sciences and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, NJ 08854, USA.
Abstract

Many dietary phytochemicals exhibit health-beneficial effects including prevention of diseases such as cancer, as well as neurological, cardiovascular, inflammatory, and metabolic diseases. Evolutionarily, herbivorous and omnivorous animals have been ingesting plants. This interaction between "animal-plant" ecosystems has resulted in an elaborate system of detoxification and defense mechanisms evolved by animals including humans. Mammalian cells, including human cells, respond to these dietary phytochemicals by "non-classical receptor sensing" mechanisms of electrophilic chemical-stress typified by "thiol-modulated" cellular signaling events primarily leading to the gene expression of pharmacologically beneficial effects, but sometimes unwanted cytotoxicity also. Our laboratory has been studying two groups of dietary phytochemical cancer-chemopreventive compounds (isothiocyanates and polyphenols), which are effective in chemical-induced, as well as genetically-induced, animal carcinogenesis models. These compounds typically generate "cellular stress" and modulate gene expression of phase II detoxifying/antioxidant enzymes. Electrophiles, reactive oxygen species, and reactive nitrogen species are known to act as second messengers in the modulation of many cellular signaling pathways leading to gene expression changes and pharmacological responses. Redox-sensitive transcription factors such as nuclear factor-E2-related factor 2 (Nrf2), AP-1, NF-kappaB, to cite a few examples, sense and transduce changes in the cellular redox status and modulate gene expression responses to oxidative and electrophilic stresses, presumably via sulfhydryl modification of critical cysteine residues found on these proteins and/or other upstream redox-sensitive molecular targets. In the current review, we will explore dietary cancer chemopreventive phytochemicals, discuss the link between oxidative/electrophilic stresses and the redox circuitry, and consider different redox-sensitive transcription factors. We will also discuss the kelch-like erythroid Cap'n'Collar homologue-associated protein 1 (Keap1)-Nrf2 axis in redox signaling of induction of phase II detoxifying/antioxidant defense mechanisms, an important target and preventive strategy for normal cells against carcinogenesis, and the converse inhibition of cell growth/inflammatory signaling pathways that would confer therapeutic intervention in many types of cancers. Finally, we will summarize the Nrf2 paradigm in gene expression, the pharmacotoxicogenomic relevance of redox-sensitive Nrf2, and the redox regulation of cell death mechanisms.

PMID:
    17376285

Chin Med. 2010 Oct 27;5:37.
Anti-cancer and potential chemopreventive actions of ginseng by activating Nrf2 (NFE2L2) anti-oxidative stress/anti-inflammatory pathways.
Saw CL, Wu Q, Kong AN.
Source

Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, USA. constancesaw@gmail.com.
Abstract

This article reviews recent basic and clinical studies of ginseng, particularly the anti-cancer effects and the potential chemopreventive actions by activating the transcriptional factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2)-mediated anti-oxidative stress or anti-inflammatory pathways. Nrf2 is a novel target for cancer prevention as it regulates the antioxidant responsive element (ARE), a critical regulatory element in the promoter region of genes encoding cellular phase II detoxifying and anti-oxidative stress enzymes. The studies on the chemopreventive effects of ginseng or its components/products showed that Nrf2 could also be a target for ginseng's actions. A number of papers also demonstrated the anti-inflammatory effects of ginseng. Targeting Nrf2 pathway is a novel approach to the investigation of ginseng's cancer chemopreventive actions, including some oxidative stress and inflammatory conditions responsible for the initiation, promotion and progression of carcinogenesis.

PMID:
    20979613

AAPS J. 2011 Mar;13(1):1-13. Epub 2010 Oct 22.
Anti-inflammatory/Anti-oxidative stress activities and differential regulation of Nrf2-mediated genes by non-polar fractions of tea Chrysanthemum zawadskii and licorice Glycyrrhiza uralensis.
Wu TY, Khor TO, Saw CL, Loh SC, Chen AI, Lim SS, Park JH, Cai L, Kong AN.
Source

Graduate Program in Pharmaceutical Science, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.
Abstract

Accumulating evidence from epidemiological studies indicates that chronic inflammation and oxidative stress play critical roles in neoplastic development. The aim of this study was to investigate the anti-inflammatory, anti-oxidative stress activities, and differential regulation of Nrf2-mediated genes by tea Chrysanthemum zawadskii (CZ) and licorice Glycyrrhiza uralensis (LE) extracts. The anti-inflammatory and anti-oxidative stress activities of hexane/ethanol extracts of CZ and LE were investigated using in vitro and in vivo approaches, including quantitative real-time PCR (qPCR) and microarray. Additionally, the role of the transcriptional factor Nrf2 (nuclear erythroid-related factor 2) signaling pathways was examined. Our results show that CZ and LE extracts exhibited potent anti-inflammatory activities by suppressing the mRNA and protein expression levels of pro-inflammatory biomarkers IL-1ß, IL-6, COX-2 and iNOS in LPS-stimulated murine RAW 264.7 macrophage cells. CZ and LE also significantly suppressed the NO production of LPS-stimulated RAW 264.7 cells. Additionally, CZ and LE suppressed the NF-?B luciferase activity in human HT-29 colon cancer cells. Both extracts also showed strong Nrf2-mediated antioxidant/Phase II detoxifying enzymes induction. CZ and LE induced NQO1, Nrf2, and UGT and antioxidant response element (ARE)-luciferase activity in human hepatoma HepG2 C8 cells. Using Nrf2 knockout [Nrf2 (-/-)] and Nrf2 wild-type (+/+) mice, LE and CZ showed Nrf2-dependent transactivation of Nrf2-mediated antioxidant and phase II detoxifying genes. In summary, CZ and LE possess strong inhibitory effects against NF-?B-mediated inflammatory as well as strong activation of the Nrf2-ARE-anti-oxidative stress signaling pathways, which would contribute to their overall health promoting pharmacological effects against diseases including cancer.

PMID:
    20967519

AAPS J. 2011 Sep;13(3):417-26. Epub 2011 Jun 3.
Examination of the pharmacokinetics of active ingredients of ginger in humans.
Yu Y, Zick S, Li X, Zou P, Wright B, Sun D.
Source

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, Ann Arbor, 48109-1065, USA.