摘要：
The mechanisms underlying formaldehyde (FA)-induced neurotoxicity have not yet been fully clarified. Ferroptosis is a novel regulatory cell death and the Warburg effect is involved in regulating neural function. In this study, we investigated whether FA-induced neurotoxicity is implicated in neuronal ferroptosis and determined whether the Warburg effect mediates FA-induced neuronal ferroptosis. We found that FA (0.1, 0.5 and 1.0 mM, 6 h) induced cell death in HT22 cells (a cell line of mouse hippocampal neuron), as evidenced by a decrease in cell viability and an increase in cell mortality; enhanced oxidative stress, as evidenced by a decrease in glutathione (GSH) and increases in malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), as well as reactive oxygen species (ROS); increased the iron content; and upregulated the ferroptosis-associated genes, including Ptgs2 (prostaglandin-endoperoxide synthase 2), GLS2 (glutaminase 2), solute carrier family 1 member 5 (SLC1A5), and solute carrier family 38 member 1 (SLC38A1) in HT22 cells, indicating the inductive role of FA in the ferroptosis of HT22 cells. Meanwhile, we found that FA (0.1, 1, 10 μmol) decreased the cross-sectional of mitochondria, increased the level of lipid ROS and iron content in primary hippocampal cells. We showed that FA (0.1, 0.5 and 1.0 mM, 6 h) upregulated the Warburg effect in HT22 cells, as evidenced by up-regulations of pyruvate kinase M2 (PKM2), pyruvate dehydrogenase kinase 1(PDK-1), and lactate dehydrogenase (LDHA) proteins; down-regulation of pyruvate dehydrogenase (PDH); and an increase in lactate production. Also, we found that FA (0.1, 1, 10 μmol, 7 d) upregulated the Warburg effect in hippocampal tissue, as evidenced by up-regulations of PKM2, PDK-1, and LDHA proteins; down-regulation of PDH. Furthermore, the inhibition of the Warburg effect by dichloroacetate (DCA) protected HT22 cells against FA-induced ferroptosis and cell death. Collectively, these data indicated that FA induces ferroptosis in hippocampal neuronal cells by upregulation of the Warburg effect.
摘要：
Aggregation of microtubule-associated protein Tau (MAPT) may underlie abnormalities of the intracellular matrix and neuronal death in tauopathies. Tau proteins can be secreted to the extracellular space and internalized into adjacent cells. The internalization of Tau is a complex but critical step in Tau propagation. This review summarizes the internalization pathways of Tau, including macropinocytosis, Clathrin-mediated endocytosis (CME), lipid raft dependent endocytosis, Tunneling nanotubes dependent endocytosis (TNTs) and phagocytosis. The conformation of Tau fibrils and the types of recipient cell determine the internalization pathway. However, the HSPGs-dependent endocytosis seems to be the predominant pathway of Tau internalization. After internalization, Tau fibrils undergo clearance and seeding. Imbalance among Tau secretion, internalization and clearance may result in the propagation of misfolded Tau in the brain, thereby inducing Tauopathies. A better understanding of the internalization of Tau proteins may facilitate the discovery of novel therapeutic strategies to block the propagation of Tau pathology.
作者机构：
[弓慧; 赵剑锋; 唐小卿] Dept of Physiology, Hengyang Medical College, University of South China, Hunan, Hengyang, 421001, China;[贺仕清] Dept of Neurosurgery, Affiliated Nanhua Hospital, University of South China, Hunan, Hengyang, 421001, China
摘要：
Postoperative cognitive dysfunction (POCD) is deemed to a severe surgical complication without effective treatment. Previous work has confirmed the important modulatory role of hydrogen sulfide (H2S) in cognitive function. This study was proposed to explore whether H2S relieves POCD and the possible mechanisms. We demonstrated that NaHS (a donor of H2S) reversed the inhibited endogenous H2S generation in the hippocampus of postoperative rats. NaHS attenuated the cognitive impairment of postoperative rats in the Y-maze, Novel object recognition, and Morris water maze tests. NaHS enhanced the expressions of synaptic plasticity-related proteins, synapsin-1 and PSD-95, increased the synaptic density, and decreased the destruction of synaptic structures in the hippocampus of postoperative rats. Moreover, NaHS promoted Warburg effect in the hippocampus of postoperative rats, as reflected by increases in the expressions of hexokinase 2, pyruvate kinase M2, lactate dehydrogenase A, and pyruvate dehydrogenase kinase 1, an enhancement in the content of lactate, and a reduction in the expression of pyruvate dehydrogenase. The inhibitor of Warburg effect, 2-Deoxy-D-glucose (2-DG), not only reversed NaHS-enhanced Warburg effect in the hippocampus of postoperative rats, but also significantly abolished NaHS-exerted protective effect on cognitive function. Furthermore, 2-DG reversed NaHS-exerted enhancement in the expressions of synapsin-1 and PSD-95, increase in the synaptic density, and decrease in the destruction of synaptic structures in the hippocampus of postoperative rats. Collectively, these results indicate that H2S alleviates POCD through enhancing hippocampal Warburg effect, which subsequently improves synaptic plasticity in the hippocampus.
通讯机构：
[Tang, Xiao-Qing] U;Univ South China, Inst Neurosci, 28 West Chang Sheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
Y-maze test;acute liver failure;cognition;hydrogen sulfide;novel object recognition test
摘要：
Acute liver failure (ALF) is a devastating clinical syndrome with a high mortality rate if not treated promptly. Previous studies have demonstrated the beneficial effects of hydrogen sulfide (H(2)S) on the brain and liver. The present study aimed to investigate the potential protective effects of H(2)S in ALF. A mouse model of ALF was established following treatment with thioacetamide (TAA). Mice with TAA-induced ALF were intraperitoneally injected with 30 or 100 µmol/kg/day sodium hydrosulfide (NaHS; a H(2)S donor drug) for two weeks. According to results from novel object recognition and Y-maze tests, in the present study, NaHS treatment alleviated cognitive deficiency and preserved spatial orientation learning ability in TAA-induced ALF mice compared with those of untreated mice. In addition, NaHS treatment reduced serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and the concentration of ammonia compared with those that received control treatment, resulting in weight loss prevention. These findings suggested a beneficial effect of H(2)S on liver function. In conclusion, results from the present study suggested that H(2)S treatment may alleviate cognitive deficiency and hepatic dysfunction in mice with ALF, indicating the potential therapeutic benefits of applying H(2)S for the treatment of ALF.
期刊：
Clinical and Experimental Pharmacology and Physiology,2020年47(2):302-312 ISSN：0305-1870
通讯作者：
Tang, Xiao-Qing;Zou, Wei
作者机构：
[Tang, Xiao-Qing; Zou, Wei; Liu, Hai-Yao; Liu, Su-Mei; Zhang, Ping; Wu, Lin] Univ South China, Affiliated Nanhua Hosp, Dept Neurol, Hengyang, Peoples R China.;[Wei, Hai-Jun; Wang, Chun-Yan; Tang, Xiao-Qing; Zou, Wei; Liu, Hai-Yao; Liu, Su-Mei; Zhang, Ping; Tang, Yi-Yun; Wu, Lin] Univ South China, Med Coll, Inst Neurosci, 28 W Changsheng Rd, Hengyang, Hunan, Peoples R China.;[Liu, Hai-Yao] Hengyang Ctr Hosp, Dept Neurol, Hengyang, Peoples R China.;[Wei, Hai-Jun; Tang, Xiao-Qing] Univ South China, Affiliated Hosp 1, Inst Neurol, Hengyang, Peoples R China.;[Tang, Xiao-Qing] Univ South China, Med Coll, Dept Physiol, 28 W Changsheng Rd, Hengyang, Hunan, Peoples R China.
通讯机构：
[Tang, Xiao-Qing; Zou, Wei] U;Univ South China, Med Coll, Inst Neurosci, 28 W Changsheng Rd, Hengyang, Hunan, Peoples R China.;Univ South China, Med Coll, Dept Physiol, 28 W Changsheng Rd, Hengyang, Hunan, Peoples R China.;Univ South China, Nanhua Affiliated Hosp, Dept Neurol, 336 E Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China.
摘要：
Hydrogen sulfide (H2S) plays antidepressant-like roles in diabetic rats. However, the underlying mechanisms remain unclear. Brain-derived neurotropic factor (BDNF), a neurotrophic factor, plays important regulatory roles in depression by its high-affinity tropomysin-related kinase B (TrkB) receptor. Autophagy also is implicated in modulation of depression. Previous work confirmed the modulatory roles of H2S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF-TrkB pathway mediates the antidepressant-like effects of H2S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H2S upregulated the expressions of BDNF and p-TrkB proteins in the hippocampus of streptozotocin (STZ)-induced diabetic rats. K252a (an inhibitor of BDNF-TrkB pathway) reversed the antidepressant-like roles of H2S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus-maze tests. Furthermore, K252a abolished H2S-promoted hippocampal autophagy in diabetic rats, as evidenced by a decrease in the number of autolysosome, downregulation of Beclin-1 (a regulator of autophagy in the early stage of the formation of autophagosomal membranes and its level is positively correlated with autophagic activity) expression, and upregulation of P62 (a substrate of autophagic degradation and its level is inversely correlated with autophagic activity) expression, in the hippocampus of rats co-treated with NaHS and STZ. Taken together, these data indicated that the BDNF-TrkB pathway mediates the antidepressant-like roles of H2S in diabetic rats by enhancing hippocampal autophagy.
期刊：
Frontiers in Neuroscience,2020年14:512334 ISSN：1662-4548
通讯作者：
Zou, Wei;Tang, Xiao-Qing
作者机构：
[Li, Min; Zou, Wei; Zuo, Jin-Xi; Jiang, Li; Zhang, Ping] Univ South China, Affiliated Nanhua Hosp, Dept Neurol, Hengyang, Peoples R China.;[Lan, Fang] Univ South China, Affiliated Hosp 1, Dept Neurol, Hengyang, Peoples R China.;[Tang, Xiao-Qing; Lan, Fang] Univ South China, Inst Neurol, Affiliated Hosp 1, Hengyang, Peoples R China.;[Wang, Chun-Yan; Tang, Xiao-Qing; Kang, Xuan; Tang, Yi-Yun] Univ South China, Hengyang Med Coll, Dept Physiol, Hengyang, Peoples R China.
通讯机构：
[Zou, Wei; Tang, Xiao-Qing] U;Univ South China, Affiliated Nanhua Hosp, Dept Neurol, Hengyang, Peoples R China.;Univ South China, Inst Neurol, Affiliated Hosp 1, Hengyang, Peoples R China.;Univ South China, Hengyang Med Coll, Dept Physiol, Hengyang, Peoples R China.
关键词：
Sleep Deprivation;Hydrogen Sulfide;Hippocampal damage;Silence information regulating factor 1;Oxidative Stress
摘要：
Sleep deprivation (SD) induces hippocampal damage. Hydrogen sulfide (H2S) is a neuronal protective factor. Silence information regulating factor 1 (Sirt1) plays an important role in neuroprotection. Therefore, this study was aimed at exploring whether H2S meliorates SD-induced hippocampal damage and whether Sirt1 mediates this protective role of H2S. We found that sodium hydrosulfide (NaHS, a donor of H2S) alleviated SD-generated hippocampal oxidative stress, including increases in the activation of SOD and the level of GSH as well as a decrease in the level of MDA. Meanwhile, we found that NaHS reduced SD-exerted hippocampal endoplasmic reticulum (ER) Stress, including downregulations of GRP78, CHOP, and cleaved-caspase-12 expression. Moreover, NaHS reduced the apoptosis in the SD-exposed hippocampus, and this included decreases in the number of apoptotic cells and the activation of caspase-3, downregulation of Bax expression, and upregulation of Bcl-2 expression. NaHS upregulated the expression of Sirt1 in the hippocampus of SD-exposed rats. Furthermore, Sirtinol, the inhibitor of Sirt1, abrogated the protection of NaHS against SD-exerted hippocampal oxidative stress, ER stress, and apoptosis. These results suggested that H2S alleviates SD-induced hippocampal damage by upregulation of hippocampal Sirt1.
摘要：
Background and Aim: Sleep deprivation (SD) causes deficit of cognition, but the mechanisms remain to be fully established. Hydrogen sulfide (H2S) plays an important role in the formation of cognition, while excessive and prolonged autophagy in hippocampus triggers cognitive disorder. In this work, we proposed that disturbances in hippocampal endogenous H2S generation and autophagy might be involved in SD-induced cognitive impairment. Methods: After treatment of adult male wistar rats with 72-h SD, the Y-maze test, object location test (OLT), novel object recognition test (NORT) and the Morris water maze (MWM) test were performed to determine the cognitive function. The autophagosome formation was observed with electron microscope. Generation of endogenous H2S in the hippocampus of rats was detected using unisense H2S microsensor method. The expressions of cystathionine-beta-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), beclin-1, light chain LC3 II/LC3 I, and p62 in the hippocampus were assessed by western blotting. Results: The Y-maze, OLT, NORT, and MWM test demonstrated that SD-exposed rats exhibited cognitive dysfunction. SD triggered the elevation of hippocampal autophagy as evidenced by enhancement of autophagosome, up-regulations of beclin-1 and LC3 II/LC3 I, and down-regulation of p62. Meanwhile, the generation of endogenous H2S and the expressions of CBS and 3-MST (H2S producing enzyme) in the hippocampus of SD-treated rats were reduced. Conclusion: These results suggested that inhibition of endogenous H2S generation and excessiveness of autophagy in hippocampus are involved in SD-induced cognitive impairment.
摘要：
Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H2S) is a novel neuroprotectant. The present work was to investigate the potential effect of H2S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H2S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16INK4a and p21CIP1. NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H2S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H2S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H2S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H2S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.
摘要：
<jats:title>Summary</jats:title><jats:p>Hyperglycaemia‐induced neurotoxicity involved in the pathogenesis of diabetic encephalopathy and neuronal senescence is one of the worst effects of hyperglyceamic neurotoxicity. Cannabinoid receptor type 1 (CB1) has neuroprotective function in a series of neuropathy. Spermidine (Spd) has anti‐aging function in many tissues. However, the role of Spd in hyperglyceamia‐induced neuronal senescence remains unexplored. Therefore, we used high glucose (HG)‐treated HT‐22 cell as vitro model to investigate whether Spd protects neurons against hyperglyceamia‐induced senescence and the mediatory role of CB1 receptor. The HT‐22 cells were cultured in HG condition in the presence ofdifferent dose of Spd. Then, the viability of cells was measuredby Cell Counting Kit‐8 (CCK‐8) assay. The senescence of cells was detected by Senescence‐associated β‐galactosidase (SA‐β‐Gal) staining. The expressions of p16<jats:sup>INK4a</jats:sup>, p21<jats:sup>CIP1</jats:sup> and CB1 receptor were measured by western blot. We found that Spd inhibited HG‐induced neurotoxicity (the loss of cell viability) and senescence (the increase of SA‐β‐Gal positive cells, the upregulation of p16<jats:sup>INK4a</jats:sup> and p21<jats:sup>CIP1</jats:sup>) in HT‐22 cells. Also, Spd prevented HG‐induced downregulation of CB1 receptor in HT‐22 cells. Furthermore, we demonstrated that AM251 (a specific inhibitor of the CB1 receptor) reversed the protective effects of Spd on HG‐induced neurotoxicity and senescence. These results indicated that Spd prevents HG‐induced neurotoxicity and senescence via the upregulation of CB1 receptor. Our findings provide a promising future of Spd‐based preventions and therapies for diabetic encephalopathy.</jats:p>
作者机构：
[Wang, Ai-Ping; Wei, Hai-Jun; Wang, Chun-Yan; Li, Man-Hong; Tang, Xiao-Qing; Zou, Wei; Li, Xiang; Tang, Yi-Yun; Zhang, Ping] Univ South China, Inst Neurosci, Med Coll, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Hunan, Peoples R China.;[Wei, Hai-Jun; Tang, Xiao-Qing; Tang, Yi-Yun] Univ South China, Dept Physiol, Med Coll, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Wang, Ai-Ping] Univ South China, Dept Anat, Med Coll, Hengyang 421001, Hunan, Peoples R China.;[Li, Man-Hong; Tang, Xiao-Qing; Zou, Wei; Zhang, Ping] Univ South China, Nanhua Affiliated Hosp, Dept Neurol, 336 E Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China.;[Li, Xiang] Univ South China, Dept Anaesthesiol, Affiliated Hosp 1, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Tang, Xiao-Qing; Zou, Wei] U;Univ South China, Dept Physiol, Med Coll, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Nanhua Affiliated Hosp, Dept Neurol, 336 E Dongfeng Rd, Hengyang 421001, Hunan, Peoples R China.;Univ South China, Inst Neurosci, Med Coll, 28 W Changsheng Rd, Hengyang, Hunan, Peoples R China.
关键词：
Hydrogen sulfide;Homocysteine;Silent mating type information regulation 2 homolog 1;Endoplasmic reticulum stress;Cognitive dysfunction
摘要：
Homocysteine (Hcy) causes cognitive deficits and hippocampal endoplasmic reticulum (ER) stress. Our previous study has confirmed that Hydrogen sulfide (H2S) attenuates Hcy-induced cognitive dysfunction and hippocampal ER stress. Silent information regulator 1 (Sirt-1) is indispensable in the formation of learning and memory. Therefore, the aim of this study was to explore the role of Sirt-1 in the protective effect of H2S against Hcy-induced cognitive dysfunction. We found that NaHS (a donor of H2S) markedly up-regulated the expression of Sirt-1 in the hippocampus of Hcy-exposed rats. Sirtinol, a specific inhibitor of Sirt-1, reversed the improving role of NaHS in the cognitive function of Hcy-exposed rats, as evidenced by that sirtinol increased the escape latency and the swim distance in the acquisition trial of morris water maze (MWM) test, decreased the times crossed through and the time spent in the target quadrant in the probe trail of MWM test, and reduced the discrimination index in the novel object recognition test (NORT) in the rats cotreated with NaHS and Hcy. We also found that sirtinol reversed the protection of NaHS against Hcy-induced hippocampal ER-stress, as evidenced by up-regulating the expressions of GRP78, CHOP, and cleaved caspase-12 in the hippocampus of rats cotreated with NaHS and Hcy. These results suggested the contribution of upregulation of hippocampal Sirt-1 to the improving role of H2S in the cognitive function of Hcy-exposed rats, which involves suppression of hippocampal ER stress. Our finding provides a new insight into the mechanism underlying the inhibitory role of H2S in Hcy-induced cognitive dysfunction.
