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Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental disorders, including autistic disorder, Asperger's syndrome, pervasive developmental disorder and childhood disintegrative disorder. Mitochondria not only provide neurons with energy in the form of ATP to sustain neuron growth, proliferation and neurodevelopment, but also regulate neuron apoptosis, intracellular calcium ion (Ca2+) homeostasis, and reactive oxygen species (ROS) clearance. Due to their postmitotic state and high energy-demanded feature, neurons are particularly prone to mitophagy and mitochondrial disfunction. Mitophagy, a selective autophagy, is critical for sustaining mitochondrial turnover and quality control via eliminating unwanted and dysfunctional mitochondria in neurons. Dysfunctional mitochondria and dysregulated mitophagy have been closely associated with the onset of ASDs. In this review, we summarize the mechanism of mitophagy and its role in neurons, and the consequence of mitophagy dysfunction in ASDs. Deeper appreciation of the role of mitophagy in ASDs pathology is required for developing new therapeutic approaches.

Atherosclerosis, a complex multifactorial disease, is the leading cause of acute cardiovascular events. Substantial evidence confirms that chronic stress plays a pivot role in the occurrence and development of atherosclerosis, but the specific mechanism remains unclear. Autophagy serves as a safeguard mechanism for sustaining cellular homeostasis via eliminating unnecessary or/and harmful components, and damaged organelles in response to various stress. An increasing number of studies indicate that autophagy plays vital roles in the development of atherosclerosis. Therefore, understanding the role of chronic stress in the regulation of autophagy may provide new insight into prevention and treatment atherosclerotic disease, especially with respect to emerging targeted therapy. In present review, we focus on changes in autophagic function under chronic stress and its relationship to atherosclerosis.

Objective: To investigate whether hydrogen sulfide (H2S) counteracts formaldehyde (FA)-induced cognitive defects and whether the underlying mechanism is involved in the upregulation of hippocampal brain-derived neurotrophic factor (BDNF) expression. Methods: The cognitive function of rats was evaluated by the Morris water maze (MWM) test and the novel object recognition test. The content of superoxide dismutase (SOD) and malondialdehyde (MDA) in the hippocampus were detected by enzyme-linked immunosorbent assay (ELISA). The neuronal apoptosis in the hippocampal CA1 region was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) staining. The expression of the BDNF protein was detected by Western blot and immunohistochemistry. Results: We found that sodium hydrosulfide (NaHS, a donor of H2S) significantly reversed the impairment in the function of learning and memory in the MWM test and the novel objective recognition task induced by intracerebroventricular injection of FA. We also showed that NaHS significantly reduced the level of MDA, elevated the level of SOD, and decreased the amount of TUNEL-positive neurons in the hippocampus of FA-exposed rats. Moreover, NaHS markedly increased the expression of hippocampal BDNF in FA-exposed rats. Conclusions: H2S attenuates FA-induced dysfunction of cognition and the underlying mechanism is involved in the reduction of hippocampal oxidative damage and apoptosis as well as upregulation of hippocampal BDNF.

Aims Our previous study indicated that chronic stress caused autophagy impairment and subsequent neuron apoptosis in hippocampus. However, the mechanism underlying the stress‐induced damage to neurons is unclear. In present work, we investigated whether stress‐level glucocorticoids (GCs) GCs promoted PC12 cell damage via AMPK/mTOR signaling‐mediated autophagy. Methods Chronic stress‐induced PC12 cell injury model was built by treatment with high level corticosterone (CORT). Cell injury was evaluated by flow cytometry assay and transmission electron microscopy observation. Results Autophagy flux was measured based on the changes in LC3‐II and P62 protein expressions, and the color alteration of mCherry‐GFP‐LC3‐II transfection. Our results showed that CORT not only increased cell injury and apoptosis, but also dysregulated AMPK/mTOR signaling‐mediated autophagy flux, as indicated by the upregulated expression of LC3‐II and P62 proteins, and the lowered ration of autolysosomes to autophagosomes. Mechanistically, our results demonstrated that autophagy activation by AMPK activator metformin or mTOR inhibitor rapamycin obviously promotes cell survival and autophagy flux, improved mitochondrial ultrastructure, and reduced expression of Cyt‐C and caspase‐3 in CORT‐induced PC12 cells. Conclusion These results indicate that high CORT triggers PC12 cell damage through disrupting AMPK/mTOR‐mediated autophagy flux. Targeting this signaling may be a promising approach to protect against high CORT and chronic stress‐induced neuronal impairment.

Tissue factor pathway inhibitor (TFPI) reduces the development of atherosclerosis by regulating tissue factor (TF) mediated coagulation pathway. In this review, we focus on recent findings on the inhibitory effects of TFPI on endothelial cell activation, vascular smooth muscle cell (VSMC) proliferation and migration, inflammatory cell recruitment and extracellular matrix which are associated with the development of atherosclerosis. Meanwhile, we are also concerned about the impact of TFPI levels and genetic polymorphisms on clinical atherogenesis. This article aims to explain the mechanism in inhibiting the development of atherosclerosis and clinical effects of TFPI, and provide new ideas for the clinical researches and mechanism studies of atherothrombosis.

Atherosclerosis results from the excessive accumulation of lipids within the arterial wall. Lipophagy, referred to as the autophagic degradation of lipids, is a critical mechanism that regulates lipid metabolism in numerous cell types. The contribution of lipophagy to intracellular lipid turnover makes it a major player in the development and progression of atherosclerosis. This review addresses recent advances in lipid metabolism via lipophagy. The relationship between lipophagy and atherosclerosis is discussed focusing on the roles of lipophagy in vascular endothelial cell injury, vascular smooth muscle cells phenoypic shift, and macrophage lipid accumulation. A further understanding of lipophagy in these processes may provide promising new therapeutic options for atherosclerotic diseases.

// Wei Zou 1, 2, * , Juan Yuan 1, 2, * , Zhuo-Jun Tang 1, 2 , Hai-Jun Wei 2 , Wei-Wen Zhu 2 , Ping Zhang 1, 2 , Hong-Feng Gu 2 , Chun-Yan Wang 3 and Xiao-Qing Tang 1, 2, 4 1 Department of Neurology, Nanhua Affiliated Hospital, University of South China, Hengyang 421001, Hunan, P.R. China 2 Institute of Neuroscience, Medical College, University of South China, Hengyang 421001, Hunan, P.R. China 3 Department of Pathophysiology, Medical College, University of South China, Hengyang 421001, Hunan, P.R. China 4 Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang 421001, Hunan, P.R. China * These authors have contributed equally to this work Correspondence to: Xiao-Qing Tang, email: tangxq-usc@qq.com Ping Zhang, email: zhangp-usc@foxmail.com Keywords: cognitive dysfunction, diabetes, endoplasmic reticulum stress, hydrogen sulfide, streptozotocin Received: November 04, 2016 Accepted: April 20, 2017 Published: July 22, 2017 ABSTRACT Diabetes induces impairment in cognitive function. There is substantial evidence that hippocampal endoplasmic reticulum (ER) stress is involved in diabetic cognitive impairment. Hydrogen sulfide (H 2 S) attenuates the learning and memory decline in experimental Alzheimer’s disease and inhibits the hippocampal ER stress in homocysteine-exposed rats. Therefore, this aim of the present work was to investigate whether H 2 S ameliorates the diabetic cognitive dysfunction involving inhibition of hippocampal ER stress. In the present work, we found that stretozotocin (STZ, 40 mg/kg)-induced diabetic rats exhibited impairment in cognitive function, as judged by the novel objective recognition task (NOR) test, the Y-maze test and the Morris water maze (MWM) test. Notably, treatment of diabetic rats with sodium hydrosulfide (NaHS, a donor of H 2 S, 30 or 100 μmol/kg/d, for 30 d) significantly reversed diabetes-induced impairment in cognitive function. We also found that STZ (40 mg/kg)-induced diabetic rats exhibited hippocampal ER stress, as evidenced by upregulations of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12 in the hippocampus. However, treatment with NaHS (30 or 100 μmol/kg/d, for 30 d) markedly suppressed the increases in GRP78, CHOP, and cleaved caspase-12 expressions in the hippocampus of diabetic rats. In addition, we noted that NaHS (30 or 100 μmol/kg/d, for 30 d) significantly enhanced the generation of hippocampal endogenous H 2 S in STZ-induced diabetic rats. These results suggest that H 2 S exhibits therapeutic potential for diabetes-associated cognitive dysfunction, which is most likely related to its protective effects against hippocampal ER stress.

Background Hydrogen sulfide (H2S) is a crucial signaling molecule with a wide range of physiological functions. Previously, we confirmed that stress-induced depression is accompanied with disturbance of H2S generation in hippocampus. The present work attempted to investigate the inhibitory effect of H2S on chronic unpredictable mild stress-induced depressive-like behaviors and the underlying mechanism. Methods We established the rat model of chronic unpredictable mild stress to simulate depression. Open field test, forced swim test, and tail suspension test were used to assess depressive-like behaviors. The expression of Sirt-1 and three marked proteins related to endoplasmic reticulum stress (GRP-78, CHOP, and cleaved caspase-12) were detected by western blot. Results We found that chronic unpredictable mild stress-exposed rats exhibit depression-like behavior responses, including significantly increased immobility time in the forced swim test and tail suspension test, and decreased climbing time and swimming time in the forced swim test. In parallel, chronic unpredictable mild stress-exposed rats showed elevated levels of hippocampal endoplasmic reticulum stress and reduced levels of Sirt-1. However, NaHS (a donor of H2S) not only alleviated chronic unpredictable mild stress-induced depressive-like behaviors and hippocampal endoplasmic reticulum stress, but it also increased the expression of hippocampal Sirt-1 in chronic unpredictable mild stress-exposed rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the protective effects of H2S against chronic unpredictable mild stress-induced depression-like behaviors and hippocampal endoplasmic reticulum stress. Conclusion These results demonstrated that H2S has an antidepressant potential, and the underlying mechanism is involved in the inhibition of hippocampal endoplasmic reticulum stress by upregulation of Sirt-1 in hippocampus. These findings identify H2S as a novel therapeutic target for depression.

Formaldehyde (FA), a common environmental contaminant, has toxic effects on the central nervous system (CNS). We have previously found that hydrogen sulphide (H2 S), the third endogenous gaseous mediator, protects neuron against the toxicity of FA. However, the underlying mechanism is poor. Aldehyde-dehydrogenase-2 (ALDH2) plays a major role in detoxification of reactive aldehyde in a range of organs and cell types. Therefore, we speculated that H2 S antagonizes FA-induced neurotoxicity by modulating ALDH2. In the present study, we found that the exposure of PC12 cells to FA causes increase in ALDH2 expression and activity. Daidzin, an inhibitor of ALDH2, significantly antagonizes FA-exerted cytotoxicity and oxidative stress including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA), in PC12 cells. We also showed that daidzin markedly attenuated FA-induced apoptosis in PC12 cells. Furthermore, we found that H2 S reverses FA-elicited upregulation of ALDH2 in PC12 cells. Our results demonstrated the involvement of downregulation of ALDH2 in the protection of H2 S against FA neurotoxicity.

Aims Although oxidized low-density lipoprotein (ox-LDL) in the brain induces neuronal death, the mechanism underlying the damage effects remains largely unknown. Given that the ultimate outcome of a cell is depended on the balance between autophagy and apoptosis, this study was performed to explore whether ox-LDL induced HT-22 neuronal cell damage via autophagy impairment and apoptosis enhancement. Methods Flow cytometry and transmission electron microscopy (TEM) were used to evaluate changes in cell apoptosis and autophagy, respectively. The protein expression of LC3-II, p62, Bcl-2, and Bax in HT-22 cells was measured by Western bolt analysis. Results Our study confirmed that 100 μg/mL of ox-LDL not only promoted TH-22 cell apoptosis, characterized by elevated cell apoptosis rate and Bax protein expression, decreased Bcl-2 protein expression, and damaged cellular ultrastructures, but also impaired autophagy as indicated by the decreased LC3-II levels and the increased p62 levels. Importantly, all of these effects of ox-LDL were significantly aggravated by cotreatment with chloroquine (an inhibitor of autophagy flux). In contrast, cotreatment with rapamycin (an inducer of autophagy) remarkably reversed these effects of ox-LDL. Conclusions Taken together, our results indicated that ox-LDL-induced shift from autophagy to apoptosis contributes to HT-22 cell damage.

Extracellular acidification in atherosclerosis-prone regions of arterial walls is considered pro-atherosclerotic by exerting detrimental effect on macrophages, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Acid-sensing ion channels (ASICs), a family of extracellular H+ (proton)-gated cation channels, are present extensively in the nervous system and other tissues, implying physiologic as well as pathophysiologic importance. Aberrant activation of ASICs is thought to be associated in EC dysfunction, macrophage phenotypic switch, and VSMC migration and proliferation. Although in vitro evidence acknowledges the contribution of ASIC activation in atherosclerosis, no direct evidence confirms their pro-atherosclerotic roles in vivo. In this review, the effect of extracellular acidity on three major contributors, ECs, macrophages, and VSMCs, is discussed focusing on the potential roles of ASICs in atherosclerotic development and underlying pathology. A more comprehensive understanding of ASICs in these processes may provide promising new therapeutic targets for treatment and prevention of atherosclerotic diseases.

Background: Although our previous studies have confirmed that the activation of TLR4 is implicated in the development of atherosclerosis induced by chronic unpredicted mild stress (CUMS), the underling mechanism is largely unclear. Here, we hypothesized that CUMS accelerates atherosclerotic development through lowering PPARγ/LXRα-ABCA1 expression via HMGB1/TLR4 signaling. Methods: In present study, CUMS atherosclerotic animal models were established with AopE-/- mice, and CUMS Raw 264.7 macrophage models were mimicked by high corticosterone treatment, These models were treated with Ethyl pyruvate (EP, an inhibitor of HMGB1), TLR4 inhibitor TAK-242, and PPARγ agonist RSG (Rosiglitazone) to test our hypothesis, respectively. Results: Our results indicated that the protein levels of HMGB1, TLR4, and pro-inflammatory cytokines including IL-1β, TNF-α were elevated with the development of atherosclerosis in CUMS mice, while the expressions of PPARγ, LXRα, and ABCA1 declined. Notably, HMGB1 inhibition by EP reversed CUMS-induced atherosclerotic development, pro-inflammatory cytokines upregulation, and PPARγ/LXRα-ABCA1 downregulation. The same trend was observed in the stressed mice treatment with TAK-242. Further experimental evidences indicated that EP, TAK-242, and RSG treatment notably corrected foam cell formation, HMGB1 release, and down-regulation of LXRα and ABCA1 in CUMS Raw 264.7 macrophage model. Conclusion: These results indicate that CUMS exacerbates atherosclerosis is likely via HMGB1-mediated downregulation of PPARγ/LXRα-ABCA1 through TLR4. These data reveal a novel mechanism by which CUMS aggravates atherosclerosis and may offer a potential therapeutic target for this disease.

We have previously demonstrated the protective action of hydrogen sulfide (H2S) in 1-Methy-4-Phenylpyridinium Ion (MPP+)-induced neurotoxicity. However, the exact mechanisms of this protection remain largely unknown. Aldehyde stress and endoplasmic reticulum (ER) stress play significant roles in the neurotoxicity of MPP+. Brain derived neurotrophic factor (BDNF) is an important endogenous neuroprotectant. Therefore, we speculated that the protection of H2S against MPP+ neurotoxicity results from inhibiting MPP+-induced aldehyde stress and ER stress via upregulation of BDNF. In the present study, we found that NaHS, a donor of H2S, inhibited MPP+-induced aldehyde stress (the accumulations of the intracellular 4-HNE and MDA) and ER stress (the increases in the expressions of GRP78 and Cleaved-caspase-12) in PC12 cells and upregulated the BDNF expression in MPP+-exposed PC12 cells. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, not only markedly reversed the inhibitiory role of NaHS in MPP+-induced aldehyde stress and ER stress, but also ablated the protection of NaHS against MPP+-induced neurotoxicity. These data demonstrated that the protective role of H2S against MPP+-induced neurotoxicity by inhibiting aldehyde stress and ER stress, which is involved in upregulation of BDNF.

Corticosterone, one of the glucocorticoids, is toxic to neurons and plays an important role in depressive-like behavior and depression. We previously showed that hydrogen sulfide (H2S), a novel physiological mediator, plays an inhibitory role in depression. However, the mechanism underlying H2S-triggered antidepressant-like role is not clearly known. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor, plays a neuroprotective role that is mediated by its high-affinity tropomysin-related kinase B (TrkB) receptor. In this study, to investigate the underlying mechanism of H2S-induced antidepressant-like role, we explored whether H2S could protect neurons against corticosterone-mediated cyctotoxicity and whether this protective role of H2S was involved in the regulation of BDNF-TrkB pathway. Our data demonstrated that sodium hydrosulfide (NaHS), the donor of H2S, could prevent corticosterone-induced cytotoxicity, apoptosis, accumulation of intracellular reactive oxygen species (ROS) and loss of mitochondrial membrane potential (MMP) in PC12 cells. NaHS not only induced the up-regulation of BDNF but also prevented the down-regulation of BDNF by corticosterone. It was also found that blocking BDNF-TrkB pathway by K252a, an inhibitor of TrkB, abolished the protection of H2S against corticosterone-induced cytotoxicity, apoptosis, accumulation of ROS, and loss of MMP. These results suggest that H2S protects against the neurotoxicity of corticosterone by modulation of the BDNF-TrkB pathway.

We have previously demonstrated the protective action of hydrogen sulfide (H

Chronic unpredictable mild stress (CUMS) induces hippocampal oxidative stress. H2S functions as a neuroprotectant against oxidative stress in brain. We have previously shown the upregulatory effect of H2S on BDNF protein expression in the hippocampus of rats. Therefore, we hypothesized that H2S prevents CUMS-generated oxidative stress by upregulation of BDNF-TrkB pathway. We showed that NaHS (0.03 or 0.1 mmol/kg/day) ameliorates the level of hippocampal oxidative stress, including reduced levels of malondialdehyde (MDA) and 4-hydroxy-2-trans-nonenal (4-HNE), as well as increased level of glutathione (GSH) and activity of superoxide dismutase (SOD) in the hippocampus of CUMS-treated rats. We also found that H2S upregulated the level of BDNF and p-TrkB protein in the hippocampus of CUMS rats. Furthermore, inhibition of BDNF signaling by K252a, an inhibitor of the BDNF receptor TrkB, blocked the antioxidant effects of H2S on CUMS-induced hippocampal oxidative stress. These results reveal the inhibitory role of H2S in CUMS-induced hippocampal oxidative stress, which is through upregulation of BDNF/TrkB pathway.

Formaldehyde (FA), a well-known indoor and outdoor pollutant, has been implicated as the responsible agent in the development of neurocognitive disorders. Hydrogen sulfide (H(2)S), the third gasotransimitter, is an endogenous neuromodulator, which facilitates the induction of hippocampal long-term potentiation, involving the functions of learning and memory. In the present study, we analyzed the effects of intracerebroventricular injection of FA on the formation of learning and memory and the generation of endogenous H(2)S in the hippocampus of rats. We found that the intracerebroventricular injection of FA in rats impairs the function of learning and memory in the Morris water maze and novel object recognition test and increases the formation of apoptosis and lipid peroxidation in the hippocampus. We also showed that FA exposure inhibits the expression of cystathionine β-synthase, the major enzyme responsible for endogenous H(2)S generation in hippocampus and decreases the production of endogenous H(2)S in hippocampus in rats. These results suggested that FA-disturbed generation of endogenous H(2)S in hippocampus leads to the oxidative stress-mediated neuron damage, ultimately impairing the function of learning and memory. Our findings imply that the disturbance of endogenous H(2)S generation in hippocampus is a potential contributing mechanism underling FA-caused learning and memory impairment.

Numerous studies revealed that spinal inflammation and immune response play an important role in neuropathic pain. In this study, we investigated the effects of intrathecal injection of a Toll-like receptor (TLR4) inhibitor epigallocatechin gallate (EGCG) on neuropathic pain induced by chronic constriction injury of the sciatic nerve (CCI). A total of 120 rats were randomly assigned into 4 groups: sham-operated group, CCI group, CCI plus normal saline group and CCI plus EGCG group. CCI and sham surgeries were performed and both thermal hyperalgesia and mechanical allodynia were tested. Lumbar spinal cord was sampled and the mRNA and protein expressions of TLR4 and High Mobility Group 1 protein (HMGB1) were detected, the contents of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-10 (IL-10) were measured by ELISA, and immunohistochemistry for nuclear factor kappa B (NF-κB) was also carried out. When compared with the sham group, both mechanical and heat pain thresholds were significantly decreased, and the mRNA and protein expressions of TLR4 and HMGB1, the contents of TNF-α, IL-1β and IL-10 in the spinal cords and NF-κB expression in the spinal dorsal horn were markedly increased in CCI rats (P

Here, we investigated the effect of chronic mild stress (CMS) on the development of atherosclerosis as well as the expression of Toll-like receptors (TLRs) signaling pathway in adolescent apolipoprotein E knockout (apoE-/-) mice. Mice were subjected to daily CMS for 0, 4, and 12 weeks, respectively. To identify the expression of Toll-like receptor 4 signaling pathway in adolescent apolipoprotein E knockout mice subjected to CMS, we compared gene expression in aortas of stressed and unstressed mice using TLRs signaling pathway real-time PCR microarrays consisting of 87 genes. We found that atherosclerosis lesions both in aortic tress and sinuses of CMS mice were significantly increased linearly in response to duration of CMS exposure. Among 87 genes analyzed, 15 genes were upregulated in stressed mice, especially TLR4, myeloid differentiation factor 88 (MyD88), and IL-1β, and 28 genes were downregulated compared with nonstressed mice. CMS mice demonstrated markedly increased aortic atherosclerosis that were associated with significant increases in levels of expression of TLR4, MyD88, nuclear factorκB (NF-κB), MCP-1, IL-1β, TNF-α, and sICAM-1. Taken together, our results suggest an important role for TLR4 signaling pathway in atherosclerosis in a CMS mouse model.

Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity.

Epigallocatechin gallate (EGCG) is a major polyphenol in green tea with beneficial effects on the impairment in learning and memory. Autophagy is a cellular process that protects neurons from stressful conditions. The present study was designed to investigate whether EGCG can rescue chronic unpredictable mild stress (CUMS)-induced cognitive impairment in rats and whether its protective effect involves improvement of autophagic flux. As expected, our results showed that CUMS significantly impaired memory performance and inhibited autophagic flux as indicated by elevated LC3-II and p62 protein levels. At the same time, we observed an increased neuronal loss and activated mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6k) signaling in the CA1 regions. Interestingly, chronic treatment with EGCG (25 mg/kg, i.p.) significantly improved those behavioral alterations, attenuated histopathological abnormalities in hippocampal CA1 regions, reduced amyloid beta1-42 (Aβ1-42) levels, and restored autophagic flux. However, blocking autophagic flux with chloroquine, an inhibitor of autophagic flux, reversed these effects of EGCG. Taken together, these findings suggest that the impaired autophagy in CA1 regions of CUMS rats may contribute to learning and memory impairment. Therefore, we conclude that EGCG attenuation of CUMS-induced learning and memory impairment may be through rescuing autophagic flux.

Background Formaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H(2)S), an endogenous gastransmitter, protects nerve cells against oxidative stress by its antioxidant effect. It has been shown that overproduction of nitric oxide (NO) inhibits the activity of cystathionine-beta-synthase (CBS), the predominant H(2)S-generating enzyme in the central nervous system. Objective We hypothesize that FA-caused neurotoxicity involves the deficiency of this endogenous protective antioxidant gas, which results from excessive generation of NO. The aim of this study is to evaluate whether FA disturbs H(2)S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO. Principal findings We showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H(2)S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H(2)S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells. Conclusion/significance Our data indicate that FA induces neurotoxicity by inhibiting the generation of H(2)S through excess of NO and suggest that strategies to manipulate endogenous H(2)S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity.

Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis.

It is well known that psychological stress is associated with increased atherosclerosis. This response is mainly mediated by altered immune reactions due to either activation or depression of the hypothalamic-pituitary-adrenal (HPA) regulatory feed back mechanisms that influence both the vascular endothelium function and the recruitment of circulating monocytes and their conversion to foam cells. Although the detailed mechanisms behind these processes are not well understood, it has been assumed that expression of pro- and anti-inflammatory cytokines by stress hormones, such as catecholamines and corticosteroids, maybe involved. In this review, we focus on evidences that various immunological factors are transformed under prolonged psychological stress by causing vascular low-grade inflammation. A better understanding of the bidirectional communication between the neuroendocrine and immune systems may contribute to new treatment strategies.

Hydrogen sulfide (H(2)S) has been shown to act as a neuroprotectant and antioxidant. Numerous studies have demonstrated that exposure to formaldehyde (FA) causes neuronal damage and that oxidative stress is one of the most critical effects of FA exposure. Accumulation of FA is involved in the pathogenesis of Alzheimer's disease (AD). The aim of present study is to explore the inhibitory effects of H(2)S on FA-induced cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. We show that sodium hydrosulfide (NaHS), a H(2)S donor, protects PC12 cells against FA-mediated cytotoxicity and apoptosis and that NaHS preserves the function of mitochondria by preventing FA-induced loss of mitochondrial membrane potential and release of cytochrome c in PC12 cells. Furthermore, NaHS blocks FA-exerted accumulation of intracellular reactive oxygen species (ROS), down-regulation of Bcl-2 expression, and up-regulation of Bax expression. These results indicate that H(2)S protects neuronal cells against neurotoxicity of FA by preserving mitochondrial function through attenuation of ROS accumulation, up-regulation of Bcl-2 level, and down-regulation of Bax expression. Our study suggests a promising future of H(2)S-based preventions and therapies for neuronal damage after FA exposure.

Blackouts of electric power often result in huge economic losses to power grid enterprises and society. To indicate the losses of accidents, this paper introduces the concept of the accident cost of distribution network failure, analyzes the various factors affecting it and figures out the calculation formula of it. On the basis of fuzzy theory, we use weight of power failure influence to describe the influence cost of blackout under different time and aera conditions together with the ROVTUE, etc. Finally, the paper proposes a new method to estimate the accident cost of distribution network failure and applies it in practical examples.

This paper analyzes different bidding strategies of hydro-thermal suppliers, taking into account the changes of power demand and the unit's limits. In order to gain maximal profit, hydropower suppliers (except for cascade hydropower stations) are equivalent to thermo-power suppliers in this paper. And Nash equilibrium equations are proposed when different bidding parameters are selected to maximize the profits of suppliers. Demand elasticity is also introduced to give descriptions of different power demands. Examples show that all suppliers will adopt high-priced strategy when power demand is high; reversely, when power demand is low, all suppliers will adopt low-priced strategy.

Although China is abundant in renewable resources, the development level of green power is rather low as it contributes less power to the society compared with conventional power. After drawing a comparison of domestic and overseas situations of green power development, this paper discusses the obstacle to green power existed nowadays in China and the impetus to development. Then a new market mode which is based on green power pricing mechanism is also put forward. Theoretically, the new mode is suitable to the national energy situation of China and will promote the sustainable development of power industry. In practice, China has already been focusing on the exploitation of sustainable and renewable energy, and also on power policy making.