Astrocytic ALKBH5 in stress response contributes to depressive-like behaviors in mice.

Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients' blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

The Association of Malnutrition and Health-Related Factors among 474,467 Older Community-Dwellers: A Population-Based Data Mining Study in Guangzhou, China.

BACKGROUND: This study aimed to examine the prevalence and associated factors of malnutrition in older community-dwellers and explore the interaction between associated factors. METHODS: A total of 474,467 older community-dwellers aged 65 or above were selected in Guangzhou, China. We used a two-step methodology to detect the associated factors of malnutrition and constructed logistic regression models to explore the influencing factors and interactive effects on three patterns of malnutrition. RESULTS: The prevalence of malnutrition was 22.28%. Older adults with both hypertension and diabetes (RERI = 0.13), both meat or fish diet and hypertension (RERI = 0.79), and both meat or fish diet and diabetes (RERI = 0.81) had positive additive interaction effects on the risk of obesity, whereas those on a vegetarian diet with hypertension (RERI = -0.25) or diabetes (RERI = -0.19) had negative additive interaction effects. Moreover, the interactions of physical activity with a meat or fish diet (RERI = -0.84) or dyslipidemia (RERI = -0.09) could lower the risk of obesity. CONCLUSIONS: Malnutrition was influenced by different health factors, and there were interactions between these influencing factors. Pertinent dietary instruction should be given according to different nutritional status indexes and the prevalence of metabolic diseases to avoid the occurrences of malnutrition among older adults.

O-GlcNAc transferase in astrocytes modulates depression-related stress susceptibility through glutamatergic synaptic transmission.

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.

Peripheral interleukin-6-associated microglial QUIN elevation in basolateral amygdala contributed to cognitive dysfunction in a mouse model of postoperative delirium.

Background: Developing effective approaches for postoperative delirium has been hampered due to the lack of a pathophysiologically similar animal model to offer insights into the pathogenesis. The study, therefore, aimed to develop a delirium-like mouse model and explore the underlying mechanism. Methods: The three cycles of 10-min clamp following 5-min reopening of the superior mesenteric artery (SMA) were performed in adult male C57BL/6 mice to induce a delirium-like phenotype. Composite Z score calculated based on the results of Open Field, Y Maze and Buried Food Tests was employed to assess the delirium phenotype in mice. Microglia activities were monitored by immunofluorescence staining and comprehensive morphological analysis. Systemic administration of minocycline (MINO), IL-6 antibody or IL-6 neutralizing antibody, was applied to manipulate microglia. The expressions of Indoleamine 2,3-dioxygenase-1 (IDO-1) and quinolinic acid (QUIN) were examined by RT-PCR and High-Performance Liquid Chromatography/Mass Spectrometry, respectively. Cytokines were measured using fluorescence activated cell sorting method. Results: The repeated ischemia/reperfusion (I/R) surgery caused significant anxiety (P < 0.05) and cognition decline in working memory and orientation (P < 0.05) in mice at postoperative 24 h. The composite Z score, indicating an overall disturbance of brain function, fluctuated over 24 h after I/R surgery (P < 0.001). Immunofluorescent staining showed that the percentage of microglia in the basolateral amygdala (BLA) (P < 0.05) was reactivated after I/R surgery and was negatively correlated with dwell time at Y maze (R = -0.759, P = 0.035). Inhibiting microglia activities by MINO reduced QUIN productions (P < 0.01) that improved cognitive deficits (P < 0.05). The peripheral IL-6 might cause IL-6 elevation in the BLA. Systemic administration of IL-6 antibodies suppressed I/R-induced IL-6 elevations (P < 0.05), microglial reactivations (P < 0.05), IDO-1 expressions (P < 0.01), and neuroactive metabolite QUIN productions (P < 0.05) in the BLA, resulting in a recovery of cognitive deficits (P < 0.05). Injection of IL-6 exerted opposite effects. Conclusion: The repeated intestinal I/R surgery-induced mouse model is a simple and reproducible one of postoperative delirium. Peripheral IL-6-associated microglial QUIN elevations in the BLA contributed to cognitive dysfunction in the model of postoperative delirium.

PPARγ Dysfunction in the Medial Prefrontal Cortex Mediates High-Fat Diet-Induced Depression.

Epidemiological studies suggest a bidirectional association between depression and obesity; however, the biological mechanisms that link the development of depression to a metabolic disorder remain unclear. Even though nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists show anti-depressive effect, and high-fat diet-(HFD)-induced PPARγ dysfunction is involved in the pathogenesis of metabolic disorders, the neuronal PPARγ has never been studied in HFD-induced depression. Thus, we aimed to investigate the effect of neuronal PPARγ on depressive-like behaviors in HFD-induced obese mice.We fed male C57BL/6 J mice with HFD to generate obese mice and conducted a series of behavioral tests to assess the effects of HFD feeding on depression. We generated neuron-specific PPARγ knockout mice (NKO) to determine whether neuronal PPARγ deficiency was correlated with depressive-like behaviors. To further prove whether PPARγ in the medial prefrontal cortex (mPFC) neurons is involved in depressive-like behaviors, we applied AAV- CaMKIIα-Cre approach to specifically knockout PPARγ in the mPFC neurons of LoxP mice and used AAV-syn-PPARγ vectors to overexpress PPARγ in the mPFC neurons of NKO mice.We observed a low mPFC PPARγ level and an increase in depressive-like behaviors in the HFD-fed mice. Moreover, neuronal-specific PPARγ deficiency in mice induced depressive-like behaviors, which could be abolished by imipramine. Furthermore, overexpressing PPARγ in the mPFC reversed the depressive-like behaviors in HFD-fed mice as well as in neuronal-specific PPARγ knockout mice.These results implicate that dysregulation of neuronal PPARγ in the mPFC may contribute to an increased risk for depression in obese populations.

Bioaccumulation of manganese and its effects on oxidative stress and immune response in juvenile groupers (Epinephelus moara ♀ × E. lanceolatus ♂).

We evaluated the effects of Mn in juvenile Yunlong groupers (Epinephelus moara ♀ × E. lanceolatus ♂). The groupers were exposed to Mn2+ (0, 0.5, 1, 2, and 4 mg/L) for 30 days after which they were assessed. The results indicate the accumulation of Mn in fish depended on dose and time. Mn2+ accumulation in tissues occurred in the following order: liver > gills > intestine > muscle. The concentrations of SOD and CAT in the fish significantly increased after 10 and 20 days of treatment with 4 mg/L Mn2+ but decreased after 30 days. Similarly, GSH and GPx levels increased after 10 days of exposure to 2 and 4 mg/L Mn2+ but decreased after 20 and 30 days of exposure. Additionally, malondialdehyde levels significantly increased after exposing the fish to 2 and 4 mg/L Mn2+ for 10, 20, and 30 days. In addition, liver HSP70 and HSP90 levels significantly increased at days 20 and 30 in all fish exposed to Mn2+. In addition, when Mn2+ concentration was 1, 2, and 4 mg/L, liver C3 and C4 levels were significantly increased after 10, 20, and 30 days. Conversely, the levels of LZM and IgM significantly decreased. Mn2+ also significantly upregulated the expression of genes associated with immunity (tlr3, tnf-α, il-1ß, and il-6) in the fish, which suggests that it induces immunotoxicity by altering the immune response. Overall, the findings showed that Mn2+ can disrupt grouper health by bioaccumulating in the fish and subsequently inducing oxidative stress and immune responses. These results can help elucidate the mechanism by which manganese induces toxicity in marine fish. Additionally, they provide a new perspective regarding the detrimental effects of heavy metals in fish.

Glucocorticoid Receptor-Dependent Astrocytes Mediate Stress Vulnerability.

BACKGROUND: Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood. METHODS: Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods. RESULTS: GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5'-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase-Akt) signaling pathway, which was required for astrocytic GR-mediated ATP release. CONCLUSIONS: These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability.

Risk Factors and Prognosis in Patients with COVID-19 and Liver Injury: A Retrospective Analysis.

PURPOSE: COVID-19 is a new infectious disease with global spread. The aim of the present study was to explore possible risk factors and evaluate prognosis in COVID-19 with liver injury. METHODS: A retrospective study was conducted on 356 COVID-19 patients in the Third People's Hospital of Yichang, Hubei, China. Clinical characteristics and laboratory tests between patients with and without liver injury were compared, while risk factors of COVID-19-related liver injury were analyzed. Univariate and multivariate Cox regression analyses were conducted to identify risk factors of in-hospital death. RESULTS: Of the patients with liver injury, severe and critical types of COVID-19 comprised 12.43% and 14.69%, respectively, higher than in patients without liver injury (both P<0.05). CRP and male sex were independent risk factors for for patients with liver injury, while decreased lymphocyte count (HR 0.024, 95% CI 0.001-0.821) and elevated monocytes (HR 1.951, 95% CI 1.040-3.662) and CRP (HR 1.028, 95% CI 1.010-1.045) were independent risk factors of prognosis of death in COVID-19 patients with liver injury. CONCLUSION: Liver injury is a common complication in severe COVID-19 patients. Male sex and elevated CRP were independent risk factors in COVID-19 complicated by liver damage. Liver damage with increased CRP and monocyte count and decreased lymphocyte count may imply a poor prognosis.

MFG-E8 alleviates oxygen-glucose deprivation-induced neuronal cell apoptosis by STAT3 regulating the selective polarization of microglia.

Background: Ischemic stroke is a complex pathological process, involving inflammatory reaction, energy metabolism disorder, free radical injury, cell apoptosis and other aspects. Accumulating evidences have revealed that MFG-E8 had a protective effect on multiple organ injuries. However, the comprehensive function and mechanism of MFG-E8 in ischemic brain remain largely unclear.Methods: BV-2 cells were treated with recombinant murine MFG-E8 (rmMFG-E8) or/and Colivelin TFA after exposing for 4 h with oxygen glucose deprivation (OGD). Cell viability and apoptosis were assessed by MTT assay and Flow cytometry. RT-qPCR and Western blot assays were applied to examine the expression levels of MFG-E8, apoptosis-related proteins and M1/M2 polarization markers.Results: Our results demonstrated that OGD significantly inhibited microglial viability and facilitated apoptosis. In addition, we found that OGD downregulated MFG-E8 expression, and MFG-E8 inhibited OGD-induced microglial apoptosis and promoted microglial M2 polarization. In terms of mechanism, we proved that MFG-E8 regulated OGD-induced microglial M1/M2 polarization by inhibiting p-STAT3 and SOCS3 expressions, which was reversed by STAT3 activator (Colivelin TFA). Finally, we verified MFG-E8 alleviated OGD-induced neuronal cell apoptosis by M2 polarization of BV-2 cells.Conclusions: We demonstrated that MFG-E8 reduced neuronal cell apoptosis by enhancing activation of microglia via STAT3 signaling. Therefore, we suggested that MFG-E8 might provide a novel mechanism for ischemic stroke.

Investigating the nonlinear effect of ego depletion on safety compliance: The moderating role of rumination.

INTRODUCTION: A general view in previous research is that employees are reluctant to follow safe work procedures when confronting the shortage of self-control resources. However, this argument is constrained by the restricted view of ego depletion. To fill this gap, this study constructs the nonlinear relationship between ego depletion and safety compliance drawing from the perspective of dual-process theory. METHOD: Regression analysis and hierarchical linear model are used to test our hypothesis. RESULTS: By investigating 241 medical staffs, we find that the relationship between ego depletion and safety compliance is U-shaped. This U-shaped relationship is replicated through 221 daily data for 50 medical staffs. In addition, the U-shaped relationship between ego depletion and safety compliance can be enhanced by rumination. DISCUSSIONS: Findings of our study contribute to providing a nuanced explanation about the effect of ego depletion on safety compliance. Also, this study has important implications for High Reliability Organizations to motivate depleted employees to engage in safety compliance behaviors.

Inhibition of NLRP3 Inflammasome Ameliorates Cerebral Ischemia-Reperfusion Injury in Diabetic Mice.

Sustained activation of NLRP3 inflammasome is closely related to diabetes and stroke. However, it is unknown whether NLRP3 inflammasome plays an essential role in stroke in diabetes. We aim to investigate the effect and the potential mechanism of NLRP3 inflammasome in diabetic mice with cerebral ischemia-reperfusion injury. A type 2 diabetic mouse model was induced by a high-fat diet and streptozotocin (STZ). Diabetic mice received MCC950 (the specific molecule NLRP3 inhibitor) or vehicle 60 minutes before the middle cerebral artery occlusion (MCAO) and reperfusion. MCC950 reduced the neurological deficit score of 24 h after cerebral ischemia reperfusion and improved the 28-day survival rate of cerebral ischemia-reperfusion injury in diabetic mice. Furthermore, we found that the mRNA transcription levels of NLRP3, IL-1ß, and caspase-1 in the core ischemic area were remarkably amplified in diabetic mice with cerebral ischemia-reperfusion injury, whereas this phenomenon was obviously attenuated by MCC950 pretreatment. In conclusion, the NLRP3 inflammasome was involved in the complex diseases of diabetic stroke. MCC950, the NLRP3 specific inhibitor, ameliorated diabetic mice with cerebral ischemia-reperfusion injury and improved the 28-day survival rate during the recovery stage of ischemic stroke.

[Effect and mechanism of Yunkang oral liquid in regulating endocrine system and VEGF signaling pathway and reducing abortion rate in recurrent abortion mice].

This experiment focuses on the effect of Yunkang oral liquid on abortion rate, endocrine system and VEGF signal pathway in Clark classical recurrent abortion model mice. RSA mice were randomly divded into model group, low, middle and high-dose groups and progesterone group. The normal pregnancy mice were included into normal group. Since the first day of pregnancy, the normal group and the RSA model group were given the same dose of distilled water, while low, middle and high-dose groups were given Yunkang oral liquid at the dose of 9, 18, 36 mL·kg¹·d⁻¹; progesterone group were given progesterone by 0.039 g·kg¹·d⁻¹. The mice were put to deathat the 15th day of pregnancy, and the embryo loss rate of each group was observed. Serum estradiol (E2), progesterone (P), prolactin (PRL), luteinizing hormone (LH), follicle stimulating hormone (FSH) level were tested; the protein expressions of estrogen receptor(ER), progesterone receptor (PR), prolactin receptor (PRLR) in decidua and RAS, MAPK, VEGF, VEGFR-2 gene and protein expressions in deciduas were studied. The results showed that middle, high dose Yunkang and progesterone could significantly decrease the embryo loss rate of RSA mice. The levels of FSH, LH, PRL, P and E2 in serum in Yunkang and progesterone groups were increased, and the serum levels of FSH, LH, and E2 in Yunkang group were higher than those in progesterone group. Western blot analysis showed that Yunkang oral liquid and progesterone can significantly increase the expressions of PRLR, PR in the uterine decidua of RSA mice, and the expression of ER in Yunkang group was higher than that in progesterone group. Western blot and PCR showed that the Yunkang oral liquid and progesterone can significantly increase RAS, MAPK, VEGF, VEGFR-2 gene and protein expressions in the uterine decidua of RSA mice. The results showed that Yunkang oral liquid can effectively reduce the embryo loss rate of RSA model mice, increase the levels of FSH, LH, PRL, P and E2 in serum, promote the expressions of PRLR, PR, ER protein in decidua and the RAS, MAPK, VEGF, VEGFR-2 gene and protein expressions in the decidua, improve the vascular remodeling of fetal interface, the endometrial receptivty, the development of decidua and the blastocyst implantation.

Dexmedetomidine Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy through Up-Regulating HIF-1α.

Stroke is the leading cause of death in China and produces a heavy socio-economic burden in the past decades. Previous studies have shown that dexmedetomidine (DEX) is neuroprotective after cerebral ischemia. However, the role of autophagy during DEX-mediated neuroprotection after cerebral ischemia is still unknown. In this study, we found that post-conditioning with DEX and DEX+3-methyladenine (3-MA) (autophagy inhibitor) reduced brain infarct size and improved neurological deficits compared with DEX+RAPA (autophagy inducer) 24 h after transient middle cerebral artery artery occlusion (tMCAO) model in mice. DEX inhibited the neuronal autophagy in the peri-ischemic brain, and increased viability and decreased apoptosis of primary cultured neurons in oxygen-glucose deprivation (OGD) model. DEX induced expression of Bcl-1 and p62, while reduced the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin 1 in primary cultured neurons through inhibition of apoptosis and autophagy. Meanwhile, DEX promoted the expression of hypoxia-inducible factor-1α (HIF-1α) both in vivo and in vitro, and 2-Methoxyestradiol (2ME2), an inhibitor of HIF-1α, could reverse DEX-induced autophagic inhibition. In conclusion, our study suggests that post-conditioning with DEX at the beginning of reperfusion protects mouse brain from ischemia-reperfusion injury via inhibition of neuronal autophagy by upregulation of HIF-1α, which provides a potential therapeutic treatment for acute ischemic injury.

Prognostic significance of C5a2 on polymorphonuclear neutrophil and C5a2intra/C5a2 ratio level for early sepsis in an ED.

INTRODUCTION: The current study was designed to evaluate the expression of the second C5a receptor (C5a2) on polymorphonuclear neutrophil and in the cytoplasm of polymorphonuclear neutrophils (C5a2intra) in patients with sepsis in the emergency department (ED) for risk stratification and mortality. METHODS: Consecutive patients fulfilling the criteria for systemic inflammatory response syndrome (n = 357) were admitted to Beijing Chao-Yang Hospital ED between January 2015 and July 2015. They were enrolled to identify the expression of C5a2 and C5a2intra and categorized into the following 4 groups: systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock. RESULTS: We report that the surface C5a2 decreased and the C5a2intra/C5a2 ratio level increased with sepsis severity. As independent predictors of 28-day mortality, the areas under the receiver operating characteristic curves of combination of C5a2 or C5a2intra/C5a2 ratio level and the Mortality in ED Sepsis score were significantly higher than that of procalcitonin alone in predicting 28-day mortality in septic patients. CONCLUSION: The C5a2 and the C5a2intra/C5a2 ratio levels are probably valuable for the risk stratification of sepsis and are associated with the mortality of early sepsis in the ED.

Astrocyte-derived ATP modulates depressive-like behaviors.

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the world's population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein-coupled receptor only in astrocytes to enable selective activation of astrocytic Ca(2+) signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

Astrocytic adenosine 5'-triphosphate release regulates the proliferation of neural stem cells in the adult hippocampus.

Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5'-triphosphate (ATP) as a proliferative factor required for astrocyte-mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1-mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease.

An L-type calcium channel agonist, bay K8644, extends the window of intervention against ischemic neuronal injury.

Our previous data indicate that the inhibition of L-type calcium channels (LTCCs) might be the cause of post-ischemic neuronal injury and that the activation of LTCCs can give rise to neuroprotection. In the present study, we aimed to profile the intervention window of Bay K8644, an LTCC agonist, and determine the involved mechanisms. The four vessel occlusion and oxygen-glucose deprivation models were employed to mimic ischemia/reperfusion damage in vivo and in vitro. Neuronal injury was analyzed using Nissl and Fluoro-Jade B staining in vivo and Hoechst 33342 and propidium iodide staining in vitro. The behavioral effects were tested using the Morris water maze. The phosphorylation of P38, Jun N-terminal kinase, and extracellular-regulated kinase (ERK) was detected by Western blotting. Our results show that Bay K8644 administered as late as 24 h after reperfusion prevented CA1 neuronal death and ameliorated the deficiencies in spatial learning performance induced by global ischemia. In oxygen-glucose deprivation (OGD), Bay K8644 delivered from 1 to 12 h after re-oxygenation reduced neuronal death. The decrease in p-ERK1/2 that was observed at 1 h after OGD was reversed by Bay K8644, and the effect of Bay K8644 was blocked by treatment with U0126 and MEK kinase dead transfection. Moreover, similar to Bay K8644, FPL 64176, another potent LTCC agonist, extends the window of intervention against neuronal injury in an in vitro model of ischemia. In conclusion, our data suggest that opening LTCCs may be a practicable approach for stroke therapy.

Fuzi polysaccharide-1 produces antidepressant-like effects in mice.

Current antidepressants are clinically effective only after several weeks of administration. We show that Fuzi polysaccharide-1 (FPS), a new water-soluble polysaccharide isolated from Fuzi, which has been used to treat mood disorders in traditional Chinese medicine for centuries, increases the number of newborn cells in the dentate gyrus in adult mice, and most of these cells subsequently differentiate into new neurons. We also found that FPS administration reduces immobility in the forced swim test, and latency in the novelty suppressed-feeding test. Moreover, a 14-d regimen with FPS reverses avoidance behaviour and inhibition of hippocampal neurogenesis induced by chronic defeat stress. In contrast, imipramine, a well known antidepressant, reverses this avoidance behaviour only after 4 wk of continuous administration. Finally, acute treatment with FPS had no effect on brain monoamine levels in frontal cortex but significantly increases BDNF in the hippocampus, while the antidepressant effect and enhancement of cell proliferation induced by FPS administration were totally blocked by K252a, an inhibitor of trkB in a chronic social defeat depression model, suggesting that the neurogenic and antidepressant effects of FPS may involve BDNF signalling. In conclusion, our findings suggest that FPS could be developed as a putative antidepressant with a rapid onset of action.

[Clinical manifestations and molecular genetics of spinal bulbar muscular atrophy: report of 5 cases].

OBJECTIVE: To study the clinical and molecular genetic characteristics of spinal bulbar muscular atrophy (SBMA). METHODS: The clinical data, including case history, physical examination, biochemical analyses of blood, EMG, and muscle biopsy, of 5 Chinese patients with SBMA, all males, aged 29 - 58, with the onset age of 36 (17 - 49), were collected the information of in 5 cases. Four patients underwent PCR to examine the number of copies of CAG repeat region in androgen receptor (AR) gene. RESULTS: The clinical characteristics of the 5 patients included atrophy of lingualis, dysarthria, weakness and waste of the limbs, especially in the hands, and elevated creatine kinase (CK), fasting glucose, testosterone, and progesterone in the blood. EMG showed denervation motor potentials in all cases. The muscle biopsy in one case showed neurogenic atrophy. The number of (CAG) n repeat in AR gene was 50 - 62 in the, remarkably from that of 13 normal controls (19 - 20) without overlapping. CONCLUSION: SBMA affects the middle age males, shows a slowly progressing muscular atrophy in spinal and bulbar muscles. The different number of (CAG) n repeat of AR gene between the SBMA patients and the normal controls may be an important identification to differentiate SBMA from other motor neuron diseases.