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Formaldehyde (FA) causes neurotoxicity and contributes to the occurrence of neurodegenerative diseases. However, the mechanism of FA-induced neurotoxicity has not been fully elucidated. Ferritinophagy, an autophagy process of ferritin mediated by the nuclear receptor coactivator 4 (NCOA4), is a potential mechanism of neurotoxicity. In this study, we explored whether ferritinophagy is associated with the neurotoxicity of FA. Our results showed that FA (50, 100, 200 μM; 24 h) exposure upregulated ferritinophagy in the mouse hippocampal neuronal HT22 cells, which was evidenced by the upregulated autophagic flux, the increased colocalizations of NCOA4 with ferritin heavy chain (FTH1) and NCOA4 with microtubule-associated protein 1 light chain-3B (LC3B), the augmented expression of NCOA4, and the reduced content of FTH1. We also found that FA (0.1, 1, and 10 μmol, i.c.v., 7d) administration boosted ferritinophagy in the hippocampus of Sprague-Dawley (SD) rats, which was demonstrated by the accumulated autophagosomes, the increased expressions of LC3II/I and NCOA4, and the decreased contents of p62 and FTH1 in the hippocampus. Further, we confirmed that inhibition of ferritinophagy by silencing the expression of NCOA4 decreased FA-induced toxic damage in HT22 cells. These results indicated that FA induces neurotoxicity by promoting ferritinophagy. Our findings suggest a potential mechanism insight into the FA-induced neurotoxicity, which in turn provides a new thought for the treatment of FA-related neurodegenerative diseases.

Angiotensin-converting enzyme 2 (ACE2) has been identified as the key receptor of SARS coronavirus that plays a key role in the pathogenesis of SARS. It is known that ACE2 mRNA can be expressed in most organs. However, the protein expression of ACE2 is not clear yet. To explore the role of ACE2 as a precipitating factor in digestive organ damage in COVID-19, this study investigated the expression of ACE2 protein in the human liver, esophagus, stomach, and colon. The result showed that ACE2 can be expressed in the liver, esophagus, stomach, and colon, which suggests SARS-CoV-2 may enter the digestive system through ACE2 and cause liver damage and gastrointestinal damage. It is hoped that the result of the study will provide a new strategy for the prevention and treatment of digestive organ damage under COVID-19.

We have previously demonstrated that hydrogen sulfide (H2S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H2S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H2S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H2S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H2S in STZ-induced diabetic rats and enhance our understanding of the robustness of H2S as a therapeutic strategy for treatment of depression in diabetes mellitus.

Coronavirus disease 2019 (COVID-19) combined with liver injury has become a very prominent clinical problem. Due to the lack of a clear definition of liver injury in patients with COVID-19, the different selection of evaluation parameters and statistical time points, there are the conflicting conclusions about the incidence rate in different studies. The mechanism of COVID-19 combined with liver injury is complicated, including the direct injury of liver cells caused by severe acute respiratory syndrome coronavirus 2 replication and liver injury caused by cytokines, ischemia and hypoxia, and drugs. In addition, underlying diseases, especially chronic liver disease, can aggravate COVID-19 liver injury. In the treatment of COVID-19 combined with liver injury, the primary and basic treatment is to treat the etiology and pathogenesis, followed by support, liver protection, and symptomatic treatment according to the clinical classification and severity of liver injury. This article evaluates the incidence, pathogenesis and prevention and treatment of COVID-19 combined with liver injury, and aims to provide countermeasures for the prevention and treatment of COVID-19 combined with liver injury.

Introduction We have previously demonstrated the antagonistic role of hydrogen sulfide (H2S) in the cognitive dysfunction of streptozotocin (STZ)-induced diabetic rats. It has been confirmed that the impaired hippocampal autophagic flux has a key role in the pathogenesis of cognitive impairment and that ornithine decarboxylase (ODC)/spermidine (Spd) pathway plays an important role in the formation of memory by promoting autophagic flux. Objectives To investigate the roles of hippocampal ODC/Spd pathway and autophagic flux in H2S-attenuated cognitive impairment in STZ-induced diabetic rats. Methods Cognitive function is judged by the novel objective recognition task (NOR), the Y-maze, and the Morris water maze (MWM) tests. The ODC/Spd pathway in hippocampus was evaluated using the expression of ODC detected by western blot and the level of Spd assayed by GC-MS. Autophagic flux was assessed using the expressions of Beclin-1, LC3II/I, and P62 detected by western blot, and the number of autophagosomes observed by transmission electron microscope. Results Sodium hydrosulfide (NaHS, a donor of H2S) markedly improved the autophagic flux in the hippocampus of STZ-exposed rats, as evidenced by a decrease in the number of autophagosomes as wells as downregulations in the expressions of LC3-II, Beclin-1, and P62 in the hippocampus of cotreatment with NaHS and STZ rats. NaHS also up-regulated the expression of ODC and the level of Spd in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited hippocampal ODC/Spd pathway by difluoromethylornithine (DFMO) markedly reversed the protections of NaHS against the hippocampal autophagic flux impairment as well as the cognitive dysfunction in STZ-exposed rats. Conclusion These findings indicated that improving hippocampal autophagic flux plays a key role in H2S-attenuated cognitive impairment in STZ-induced diabetic rats, as results of up-regulating hippocampal ODC/Spd pathway.

Objectives. To evaluate the role of short-term low-dose glucocorticoids in mild COVID-19 patients. Methods. We conducted a retrospective, cross-sectional, single-center study in Kunming, China. A total of 33 mild COVID-19 cases were divided into two treatment groups (with and without glucocorticoids, methylprednisolone, were used in this setting), and the absolute value of peripheral blood lymphocyte count; CD3+, CD4+, and CD8+ T cell counts; and the time to achieve negative transformation of a nucleic acid pharyngeal swab were recorded. Peripheral blood lymphocyte and T cell counts were compared between the treatment group and 25 healthy individuals. At the point of time when there was a 50% accumulation conversion rate (positive to negative nucleic acid on pharyngeal swab), and the nucleic acid turned negative in half of the patients in two groups, the peripheral blood lymphocyte and T cell counts were compared between treatment groups. Results. The mean cumulative time for the 50% negative conversion rate of the nucleic acid in the pharyngeal swab was 17.7±5.1 days and 13.9±5.4 days in the glucocorticoid group and the nonglucocorticoid group, respectively. The absolute peripheral blood lymphocyte count and the T cell subset count in the glucocorticoid group were lower than those in the nonglucocorticoid group. When the nucleic acid turned negative in half of the patients, the absolute value of peripheral blood lymphocyte count and CD4+ T cells of the glucocorticoid group and the nonglucocorticoid group was not significantly different; the CD3+ and CD8+ T cells in the glucocorticoid group were lower than those in the nonglucocorticoid group. The absolute peripheral blood lymphocyte count, CD3+ T cells, and CD4+ T cells in the glucocorticoid group were lower than those of the healthy group during the whole disease period, and CD8+ T cells returned to normal at 19-21 days of the disease period. There was no significant difference between the nonglucocorticoid group and the healthy group for absolute peripheral blood lymphocyte and CD8+ T cells; moreover, CD3+ T cells and CD4+ T cells were lower in the nonglucocorticoid group than those in the healthy group from the day of admission to the 18th day and returned to normal at the period of 19-21 days. The absolute peripheral lymphocyte count (P=0.048, effect size d=0.727) and T cell subset count (CD3: P=0.042, effect size d=0.655; CD4: P<0.01, effect size d=0.599; and CD8: P=0.034, effect size d=0.550) in the nonglucocorticoid group were higher than those in the glucocorticoid group, and the difference between the groups was statistically significant. Conclusions. This study found that the use of short-term, low-dose glucocorticoids does not negatively influence the clinical outcome, without affecting the final clearance of viral nucleic acid in mild COVID-19 patients.

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.

Sleep deprivation (SD) is widespread in society causing serious damage to cognitive function. Hydrogen sulfide (H2S), the third gas signal molecule, plays important regulatory role in learning and memory functions. Inhibition of excessive autophagy and upregulation of silent information regulator 1 (Sirt-1) have been reported to prevent cognitive dysfunction. Therefore, this present work was to address whether H2S attenuates the cognitive impairment induced by SD in Wistar rats and whether the underlying mechanisms involve in inhibition of excessive autophagy and upregulation of Sirt-1. After treatment with SD for 72 h, the cognitive function of Wistar rats was evaluated by Y-maze, new object recognition, object location, and Morris water maze tests. The results shown that SD-caused cognitive impairment was reversed by treatment with NaHS (a donor of H2S). NaHS also prevented SD-induced hippocampal excessive autophagy, as evidenced by the decrease in autophagosomes, the down-regulation of Beclin1, and the up-regulation of p62 in the hippocampus of SD-exposed Wistar rats. Furthermore, Sirtinol, an inhibitor of Sirt-1, reversed the inhibitory roles of NaHS in SD-induced cognitive impairment and excessive hippocampal autophagy in Wistar rats. Taken together, our results suggested that H2S improves the cognitive function of SD-exposed rats by inhibiting excessive hippocampal autophagy in a hippocampal Sirt-1-dependent way.

To analyse the differential indicators of COVID-19 in severe and mild cases and to study the factors affecting the immune function of patients and the time required for oropharyngeal swabs to become negative. Age, albumin (ALB) levels, prealbumin (PAB) levels, high-sensitivity C-reactive protein (hs-CRP) levels, platelet counts, lymphocyte counts, neutrophil counts, CD3+, CD4+, CD8+ T cell counts and the time for oropharyngeal swabs to become negative were collected from 37 patients with COVID-19; the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated as indicators of inflammation. An independent-sample t test was used to analyse differences between the severe and mild groups, and factors affecting the CD3+, CD4+ and CD8+ T cell counts and the time for the nucleic acid tests of oropharyngeal to convert to negative were identified by single-factor and multifactor analyses. Lymphocyte, ALB, PAB, CD3+, CD4+ and CD8+ T cell levels in the severe group were lower than those in the mild group, the P values were 0.048, 0.004, 0.033, 0.033, 0.015 and 0.013, respectively. The neutrophil count and PLR were higher in the severe group compared with that in the patients of mild group; the P values were all 0.000. Single-factor analysis showed that age, ALB level, PAB level, hs-CRP level, platelet count, the NLR, the PLR and the time to a negative nucleic acid test were the main factors influencing CD3+ T cells; the P values were 0.001, 0.031, 0.001, 0.010, 0.005, 0.002, 0.000 and 0.048, respectively. Age, ALB level, PAB level, hs-CRP level, platelet count, the NLR, the PLR and time to a negative nucleic acid test were the main factors influencing CD8+ T cells; the P values were 0.000, 0.012, 0.000, 0.005, 0.002, 0.004, 0.005 and 0.003, respectively. Age, PAB level, hs-CRP level, platelet count, the NLR and the PLR were the main factors influencing CD4+ T cells; the P values were 0.001, 0.006, 0.030, 0.041, 0.005 and 0.001, respectively. Age, ALB level, PAB level, hs-CRP level, platelet count, the NLR, CD3+ T cell count and CD8+ T cell count were the main factors influencing the time to a negative nucleic acid test in oropharyngeal swabs, and the P values were 0.032, 0.043, 0.013, 0.016, 0.042, 0.049, 0.048 and 0.003, respectively. Multivariate analysis showed that the PLR and platelet count were the main factors influencing CD3+ T cells. The P values were all 0.000. The PLR and platelet count were the main factors influencing CD4+ T cells. The P values were 0.000 and 0.001, respectively. The PLR and platelet count were also the main factors influencing CD8+ T cells. The P values were 0.004 and 0.001. CD8+ T cells affected the time to a negative nucleic acid test in oropharyngeal swab samples, and the P value was 0.002. There were differences in the PLR, PAB level, ALB level and T cells between the severe and mild groups. The platelet count and PLR were the main factors influencing the immune function of patients with COVID-19, and CD8+ T cells influenced the negative conversion time of the nucleic acid test in oropharyngeal swabs.

Background: Coronavirus disease-2019 (COVID-19) caused by SARS-CoV-2 is a rapidly escalating epidemic in most of countries. Symptom of COVID-19 usually present as the normal or decrease of leucocytes and the decrease of lymphocytes, which may be the body’s response for SARS-CoV-2 infection. However, it is unknown that whether rising leukocytes, especially neutrophils, will aggravate lung injury in COVID-19. Here we report a case of aggravated lung injury induced by rising neutrophils with the usage of recombinant human granulocyte stimulating factor (GSF) for the first time.Case presentation: A patient aged 46 years old was infected with SARS-CoV-2 without hypoxemia on admission, but his leucocytes decreased gradually after admission. After following injected with recombinant human granulocyte stimulating factor(GSF) 150 μg , the absolute value of leucocytes reached to 32.81×109 /L, and neutrophils were 31.57×109/L. Then, the patient’s condition deteriorated rapidly and he appeared a series of symptoms, such as short breath, hemoptysis, hypoxemia, increased range of lung lesions and secondary acute respiratory distress syndrome (ARDS). However, those symptoms were alleviated and leucocytes recover to normal level gradually after stopping recombinant human GSF treatment. Eventually, Re-examination of CT showed that lung lesions were absorbed significantly and he was cured and discharged from hospital.Conclusion: This case report showed that iatrogenic increase of leucocytes (especially neutrophils) may worsen lung injury and leucocyte increasing agents were used with caution in the early stage of COVID-19 patients. At the same time, the phenomenon remains to be further confirmed in the future study.

BACKGROUND In December 2019, an ongoing outbreak of coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China. The characteristics of COVID-19 patients treated in local hospitals in Wuhan are not fully representative of patients outside Wuhan. Therefore, it is highly essential to analyze the epidemiological and clinical characteristics of COVID-19 in areas outside Wuhan or Hubei Province. To date, a limited number of studies have concentrated on the epidemiological and clinical characteristics of COVID-19 patients with different genders, clinical classification, and with or without basic diseases. AIM To study the epidemiological and clinical characteristics of COVID-19 patients in Hengyang (China) and provide a reliable reference for the prevention and control of COVID-19. METHODS From January 16 to March 2, 2020, a total of 48 confirmed cases of COVID-19 were reported in Hengyang, and those cases were included in this study. The diagnostic criteria, clinical classification, and discharge standard related to COVID-19 were in line with the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) released by National Health Commission and National Administration of Traditional Chinese Medicine. The presence of SARS-CoV-2 in pharyngeal swab specimens was detected by quantitative reverse transcription polymerase chain reaction. All the data were imported into the excel worksheet and statistically analyzed by using SPSS 25.0 software. RESULTS A total of 48 cases of COVID-19 were collected, of which 1 was mild, 38 were moderate, and 9 were severe. It was unveiled that there were 31 (64.6%) male patients and 17 (35.4%) female patients, with a female-to-male ratio of 1.82:1. The range of age of patients with COVID-19 was dominantly 30-49 years old [25 (52.1%) of 48], followed by those aged over 60 years old [11 (22.9%)]. Besides, 29.2% (14 of 48) of patients had basic diseases, and 57.2% (8 of 14) of patients with basic diseases were aged over 60 years old. The occupations of 48 COVID-19 patients were mainly farmers working in agricultural production [15 (31.5%) of 48], rural migrant workers from Hengyang to Wuhan [15 (31.5%)], and service workers operating in the service sector [8 (16.7%)]. The mean latent period was 6.86 ± 3.57 d, and the median was 7 [interquartile range (IQR): 4-9] d. The mean time from onset of symptoms to the first physician visit was 3.38 ± 2.98 (95%CI: 2.58-9.18) d, with a median of 2 (IQR: 1-5) d, and the mean time from hospital admission to confirmed diagnosis was 2.29 ± 2.11 (95%CI: 1.18-6.42) d, with a median of 2 (IQR: 1-3) d. The main symptoms were fever [43 (89.6%) of 48], cough and expectoration [41 (85.4%)], fatigue [22 (45.8%)], and chills [22 (45.8%)]. Other symptoms included poor appetite [13 (27.1%)], sore throat [9 (18.8%)], dyspnea [9 (18.8%)], diarrhea [7 (14.6%)], dizziness [5 (10.4%)], headache [5 (10.4%)], muscle pain [5 (10.4%)], nausea and vomiting [4 (8.3%)], hemoptysis [4 (8.3%)], and runny nose [1 (2.1%)]. The numbers of peripheral blood leukocytes, lymphocytes, and eosinophils were significantly reduced in the majority of the patients. The levels of C-reactive protein, fibrinogen, blood glucose, lactate dehydrogenase, D-dimer, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (γ-GT), myoglobin (MB), and creatine kinase (CK) were increased in 64.6%, 44.7%, 43.2%, 37.0%, 29.5%, 22.9%,20.8%, 21.6%, 13.6%, and 12.8% of patients, respectively. The incidence of ALT elevation in male patients was remarkably higher than that in females (P < 0.01), while the incidences of AST, CK, and blood glucose elevations in severe patients were remarkably higher than those in moderate patients (P < 0.05, respectively). Except for the mild patients, chest computed tomography showed characteristic pulmonary lesions. All the patients received antiviral drugs, 38 (79.2%) accepted traditional Chinese medicine, and 2 (4.2%) received treatment of human umbilical-cord mesenchymal stem cells. On March 2, 2020, 48 patients with COVID-19 were all cured and discharged. CONCLUSION Based on our results, patients with COVID-19 often have multiple organ dysfunction or damage. The incidences of ALT elevation in males, and AST, CK, and blood glucose elevations in severe patients are remarkably higher.

Background Our previous works demonstrated that β2-microglobulin (β2m), a systemic pro-aging factor, induce depressive-like behaviors. Hydrogen sulfide (H 2 S) is identified as a potential target for treatment of depression . The aim of the present work is to explore whether H 2S antagonizes β2m-induced depressive-like behaviors and the underlying mechanisms. Methods The depressive-like behaviors were detected using the novelty suppressed feeding test (NSFT), tail suspension test (TST), forced swimming test (FST) and open field test (OFT). The expressions of Warburg-related proteins , including hexokinase II (HK II), pyruvate kinase M2 (PKM2), Lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase 1(PDK1), and synaptic plasticity-related proteins, including postsynaptic density protein 95 (PSD95) and synaptophysin1 (SYN1), were determined by western blotting . Result we found that NaHS (the donor of H2 S) attenuated the depressive-like behaviors in the β2m-exposed rats, as judged by NSFT, TST, FST, and OFT. We also demonstrated that NaHS enhanced the synaptic plasticity , as evidenced by the upregulations of PSD95 and SYN1 expressions in the hippocampus of β2m-exposed rats. Furthermore, NaHS improved the Warburg effect in the hippocampus of β2m-exposed rats, as evidenced by the upregulations of HK II, PKM2, LDHA and PDK1 expressions, and the downregulation of PDH expression. Conclusion H2S prevents β2m-induced depressive-like behaviors, which is involved in improvement of hippocampal synaptic plasticity as a result of enhancement of hippocampal Warburg effect.

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 of different dose of Spd. Then, the viability of cells was measured by 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 p16INK4a , p21CIP1 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 p16INK4a and p21CIP1 ) 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.

Our previous works have shown that hydrogen sulfide (H2S) significantly attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and hippocampal endoplasmic reticulum (ER) stress. Brain-derived neurotrophic factor (BDNF) generates an antidepressant-like effect by its receptor tyrosine protein kinase B (TrkB). We have previously found that H2S upregulates the expressions of BDNF and p-TrkB in the hippocampus of CUMS-exposed rats. Therefore, the present work was to explore whether BDNF/TrkB pathway mediates the antidepressant-like role of H2S by blocking hippocampal ER stress. We found that treatment with K252a (an inhibitor of BDNF/TrkB pathway) significantly increased the immobility time in the forced swim test and tail suspension test and increased the latency to feed in the novelty-suppressed feeding test in the rats cotreated with sodium hydrosulfide (NaHS, a donor of H2S) and CUMS. Similarly, K252a reversed the protective effect of NaHS against CUMS-induced hippocampal ER stress, as evidenced by increases in the levels of ER stress-related proteins, glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12. Taken together, our results suggest that BDNF/TrkB pathway plays an important mediatory role in the antidepressant-like action of H2S in CUMS-exposed rats, which is by suppression of hippocampal ER stress. These data provide a novel mechanism underlying the protection of H2S against CUMS-induced depressive-like behaviors.

// 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.

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.

Background and aim Accumulation of β2-microglobulin (B2M), a systemic pro-aging factor, regulates negatively cognitive function. Hydrogen sulfide (H2S), a novel gas signaling molecule, exerts protection against cognitive dysfunction. Therefore, the present work was designed to explore whether H2S attenuates cognitive dysfunction induced by B2M and the underlying mechanism. Materials and methods The cognitive function of rats was assessed by Y-maze, Novel object recognition (NOR), and Morris water maze (MWM) tests. The levels of autophagosome and autolysosome in hippocampus were observed by transmission electron microscopy. The expression of p62 protein in hippocampus was detected by western blot analysis. Results NaHS (a donor of H2S) significantly alleviated cognitive impairments in the B2M-exposed rats tested by Y-maze test, NOR test and MWM test. Furthermore, NaHS recovered autophagic flux in the hippocampus of B2M-exposed rats, as evidenced by decreases in the ratio of autophagosome to autolysosome and the expression of p62 protein in the hippocampus. Conclusion In summary, these data indicated that H2S attenuates B2M-induced cognitive dysfunction, involving in recovery of the blocked autophagic flux in the hippocampus, and suggested that H2S may be a novel approach to prevent B2M-induced cognitive dysfunction.

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.

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.

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-β-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.

// Juan Peng 1,* , Qin Yang 1,* , A-Fang Li 1,* , Rong-Qing Li 1 , Zuo Wang 1 , Lu-Shan Liu 1 , Zhong Ren 1 , Xi-Long Zheng 2 , Xiao-Qing Tang 3 , Guo-Hua Li 1 , Zhi-Han Tang 1 , Zhi-Sheng Jiang 1 and Dang-Heng Wei 1 1. Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China 2. Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, Calgary, Alberta, Canada 3. Department of Physiology & Institute of Neuroscience, Medical School, University of South China, Hengyang, PRC, China * Co-first author Correspondence to: Zhi-Han Tang, email: // Zhi-Sheng Jiang, email: // Dang-Heng Wei, email: // Keywords : TET2, autophagy, endothelial cells, inflammation, atherosclerosis, Pathology Section Received : June 08, 2016 Accepted : October 21, 2016 Published : November 04, 2016 Abstract Tet methylcytosine dioxygenase 2 (TET2) mediates the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The loss of TET2 is associated with advanced atherosclerotic lesions. Our previous study showed that TET2 improves endothelial cell function by enhancing endothelial cell autophagy. Accordingly, this study determined the role of TET2 in atherosclerosis and potential mechanisms. In ApoE −/− mice fed high-fat diet, TET2 overexpression markedly decreased atherosclerotic lesions with uniformly increased level of 5hmC and decreased level of 5mC in genomic DNA. TET2 overexpression also promoted autophagy and downregulated inflammation factors, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, monocyte chemotactic protein 1, and interleukin-1. Consistently, TET2 knockdown with small hairpin RNA (shRNA) in ApoE −/− mice decreased 5hmC and increased 5mC levels in atherosclerotic lesions. Meanwhile, autophagy was inhibited and atherosclerotic lesions progressed with an unstable lesion phenotype characterized by large lipid core, macrophage accumulation, and upregulated inflammation factor expression. Experiments with the cultured endothelial cells revealed that oxidized low-density lipoprotein (ox-LDL) inhibited endothelial cell autophagy. TET2 shRNA strengthened impaired autophagy and autophagic flux in the ox-LDL-treated endothelial cells. TET2 overexpression reversed these effects by decreasing the methylation level of the Beclin 1 promoter, which contributed to the downregulation of inflammation factors. Overall, we identified that TET2 was downregulated during the pathogenesis of atherosclerosis. The downregulation of TET2 promotes the methylation of the Beclin 1 promoter, leading to endothelial cell autophagy, impaired autophagic flux, and inflammatory factor upregulation. Upregulation of TET2 may be a novel therapeutic strategy for treating atherosclerosis.

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.

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.

Background Hydrogen sulfide (H2S) has therapeutic effects on Parkinson's disease (PD). Warburg effect, namely aerobic glycolysis, is benefit to PD. Leptin, a hormone secreted in adipose, plays an important role in the treatment of PD. Objective To determine whether the mechanism underlying protection of H2S against PD is involved in promoting Warburg effect via upregulation of leptin. Methods We set a PD model via unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA) in Sprague Dawley rat. PD-like behavior was analyzed by apomorphine-induced rotations, open field activity test, stepping test and cylinder test. Dopaminergic neurons were detected by immunohistochemistry. The expressions of Hexokinase-2, pyruvate kinase M-2, lactate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase, and leptin were measured by Western blot. Lactate dehydrogenase (LDHA) activity was monitored by ELISA. The lactate content was measured by lactate assay kit. Results We showed that NaHS (a donor of H2S) prevented 6-OHDA-induced PD-like behaviors as well as the loss of dopaminergic neurons. We also found that NaHS enhanced the Warburg effect and upregulated leptin expression in the substantia nigra of 6-OHDA-exposed rats. While, inhibited leptin signaling by OBR13-A reversed the protections of H2S against 6-OHDA-exerted PD-like behaviors and the loss of dopaminergic neurons in the substantia nigra, and abolished H2S-enhanced in the Warburg effect in the substantia nigra. Conclusion: These data indicated that leptin mediates the protection of H2S against PD, which involves enhancing the Warburg effect of the substantia nigra.

It has been previously demonstrated that hydrogen sulfide (H2S) prevents formaldehyde (FA)-induced neurotoxicity. However, the exact mechanisms underlying this protection remain to be fully elucidated. Neuronal senescence is involved in FA-induced neurotoxicity. Leptin signaling has anti-aging function. The present work was to investigate the protection of H2S against FA-induced neuronal senescence and the mediatory role of leptin signaling. FA-exposed HT-22 cells were used as the vitro model of FA-induced neuronal senescence. The senescence-associated β-galactosidase (SA-β-Gal) positive cell was detected by β-galactosidase staining. The expressions of P16INK4a, P21CIP1, leptin, and lepRb (leptin receptor) were measured by western blot. The proliferation, viability, and apoptosis of cells were evaluated by Trypan blue exclusion assay, Cell Counting Kit-8 (CCK-8) assay, and Flow cytometry analysis, respectively. We found that H2S suppressed FA-induced senescence, as evidenced by the decrease in SA-β-Gal positive cells, the downregulations of P16INK4a and P21CIP1, as well as decrease in cell growth arrest, in HT-22 cells. Also, H2S upregulated the expressions of leptin and lepRb in FA-exposed HT-22 cells. Furthermore, leptin tA (a specific inhibitor of the leptin) abolished the protective effects of H2S on FA-induced senescence and neurotoxicity (as evidenced by the increase in cell viability and the decrease in cell apoptosis) in HT-22 cells. These results indicated that H2S prevents FA-induced neuronal senescence via upregulation of leptin signaling. Our findings offer a novel insight into the mechanisms underlying the protection of H2S against FA-induced neurotoxicity. FA upregulates the expressions of P16INK4a and P21CIP1 via inhibiting leptin signaling, which in turn induces senescence in HT-22 cells; H2S downregulates the expressions of P16INK4a and P21CIP1 via reversing FA-downregulated leptin signaling, which in turn prevents FA-induced senescence in HT-22 cells.

Backgroud: Chronic restraint stress (CRS) induces depressive-like behaviors in rodents, which involves dysregulation of hippocampal synapse formation and excessive autophagy. Adiponectin has antidepressant activity. Hydrogen sulfide (H2S) is a novel gasotransmitter. The present work was to investigate whether H2S antagonizes CRS-induced depressive-like behaviors in rats and to explore whether its potential mechanism involves ameliorated synaptic and autophagic dysregulation by upregulation of adiponectin. Methods: Depressive-like behavior was analyzed by the tail suspension test (TST), novelty suppressed feeding test (NSFT), and open field test (OFT). The structure of autophagy was observed under transmission electron microscopy. The expressions of adiponectin, beclin1, and sequestosome 1 (p62/SQSTMI) protein in hippocampus were measured by Western blot. The levels of synapsin1 (SYN1) in the hippocampus were calculated by Western blot and immunofluorescence technique. Results: The behavior experiments, including TST, NSFT, and OFT, showed that NaHS (a donor of H2S) reduced CRS-induced depressive-like behaviors. NaHS decreased the loss of hippocampal synapse as evidenced by increased the level of SYN1 in the hippocampus of CRS-exposed rats. NaHS rescued CRS-induced excessive hippocampal autophagy as evidenced by declines in the number of autophagosomes and the expression of beclin1 as well as increase in the expression of P62 in the hippocampus of CRS-exposed rats. NaHS upregulated hippocampal adiponectin expression in the CRS-exposed rats. Furthermore, neutralizing adiponectin by Anti-acrp30 reversed the protective response of NaHS to CRS-produced depressive-like behaviors as well as hippocampal synaptic disruption and excessive autophagy. Conclusion: H2S mitigates CRS-induced depressive behavior via upregulation of adiponectin, which in turn results in amelioration in hippocampal synapse formation dysfunction and excessive autophagy.

β2-microglobulin (B2M), the light chain of major histocompatibility complex class I (MHC I) molecules, has been found to impair hippocampal neurogenesis. Based on the crucial role of hippocampal neurogenesis disturbance in the process of depression and anxiety, the aim of the present study is to investigate whether B2M leads to depressive- and anxiety-like behaviors. We found that 6 days after intracerebroventricular injection with B2M (0.3 μg), the immobility times of rats in the tail suspension test and the forced swimming test were increased, the swimming and climbing time in the forced swimming test was decreased, and the latency to feed in the novelty-suppressed feeding test was increased, indicating that B2M induces depressive-like behaviors. In addition, in the elevated plus maze test, B2M-treated rats displayed obvious decline in the number of entries into and the proportion of time spent in the open arm, while the number of total arm entries was no change, which indicated that B2M induces anxiety-like behaviors. Our present findings suggest that target B2M might represent a novel approach for treatment of depression and anxiety.

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.

Depression is highly prevalent in individuals with diabetes, and depressive symptoms are less responsive to current antidepressant therapies. Oxidative stress plays a major role both in the pathogenesis of diabetes and in major depression and anxiety disorders. Hydrogen sulfide (H2S), the third gaseous mediator, is a novel signaling molecule in the brain that has both antioxidative activity and antidepressant-like and anxiolytic-like effects. We hypothesized that H2S could produce antidepressant-like and anxiolytic-like effects in diabetic patients through its antioxidative effect. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic rats. We found that H2S alleviated depressive-like behaviors of STZ-induced diabetic rats in the forced swimming and tail suspension tests and reduced their anxiety-like behaviors in the elevated plus maze test. We also found that H2S significantly reduced levels of malondialdehyde and 4-hydroxynonenal and elevated levels of superoxide dismutase and reduced glutathione in the hippocampus of STZ-induced diabetic rats. The results provide evidence for antidepressant-like and anxiolytic-like effects of H2S in STZ-induced diabetic rats and suggest that the therapeutic effects may result from inhibition of hippocampal oxidative stress. These findings suggest that elevating H2S signaling is a potential target for treatment of depressive and anxiety disorders related to diabetes.

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.

Chronic restraint stress (CRS) has detrimental effects on cognitive function. Hydrogen sulfide (H2S), as a neuromodulator, regulates learning and memory. Hippocampus is a key structure in learning and memory. Sirt1 (silence signal regulating factor 1) plays an important role in modulating cognitive function. Therefore, our present work was to investigate whether H2S meliorates CRS-induced damage in hippocampus and impairment in cognition, and further to explore whether the underlying mechanism is via upreglulating Sirt1. In our present work, the behavior experiments [Y-maze test, Novel object recognition (NOR) test, Morris water maze (MWM) test] showed that sodium hydrosulfide (NaHS, a donor of H2S) blocked CRS-induced cognitive impairments in rats. NaHS inhibited CRS-induced hippocampal oxidative stress as evidenced by decrease in MDA level as well as increases in GSH content and SOD activity. NaHS rescued CRS-generated ER stress as evidenced by downregulations of CPR78, CHOP, and cleaved caspase-12. NaHS reduced CRS-exerted apoptosis as evidenced by decreases in the number of TUNEL-positive cells and Bax expression as well as increase in Bcl-2 expression. NaHS upregulated the expression of Sirt1 in the hippocampus of CRS-exposed rats. Furthermore, inhibited Sirt1 by Sirtinol reversed the protective effects of NaHS against CRS-produced cognitive dysfunction and oxidative stress, ER stress as well as apoptosis in hippocampus. Together, these results suggest that H2S meliorates CRS-induced hippocampal damage and cognitive impairment by upregulation of hippocampal Sirt1.

Hydrogen sulfide (H2S), an endogenously generated gaseous mediator, has been discovered to regulate a series of physiological and pathological processes in mammalian systems. In recent decades scientific interest has grown in the physiological and pathological implications of H2S, specifically its role in the central nervous system (CNS). H2S can work in the CNS as a neuromodulator to promote long-term potentiation and regulate intracellular calcium concentration and pH level in brain cells. H2S may protect the nervous system from oxidative stress, apoptosis, or degeneration. The aim of this review is to present the current understanding of H2S as a potential agent for the treatment of Alzheimer's disease (AD). Dysregulation of H2S homeostasis is implicated in the pathological processes of AD. Substantial evidence from both in vivo and in vitro studies shows that H2S prevents neuronal impairment and attenuates cognitive dysfunction in the experimental model of AD. The mechanisms underlying the protective role of H2S in AD involve its antioxidant, anti-apoptotic, and anti-inflammatory effects. We conclude that H2S has potential therapeutic value for the treatment of AD.

Homocysteine (Hcy) can elicit neuronal cell death, and hyperhomocysteinemia is a strong independent risk factor for Alzheimer's disease. The aim of this study was to examine the effects of hydrogen sulfide (H2S) on Hcy-induced endoplasmic reticulum (ER) stress and neuronal apoptosis in rat hippocampus.Adult male SD rats were intracerebroventricularly (icv) injected with Hcy (0.6 μmol/d) for 7 d. Before Hcy injection, the rats were treated with NaHS (30 or 100 μmol·kg(-1)·d(-1), ip) and/or k252a (1 μg/d, icv) for 2 d. The apoptotic neurons were detected in hippocampal coronal slices with TUNEL staining. The expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and BDNF in the hippocampus were examined using Western blotting assays. The generation of H2S in the hippocampus was measured with the NNDPD method.Hcy markedly inhibited the production of endogenous H2S and increased apoptotic neurons in the hippocampus. Furthermore, Hcy induced ER stress responses in the hippocampus, as indicated by the upregulation of GRP78, CHOP, and cleaved caspase-12. Treatment with the H2S donor NaHS increased the endogenous H2S production and BDNF expression in a dose-dependent manner, and significantly reduced Hcy-induced neuronal apoptosis and ER stress responses in the hippocampus. Treatment with k252a, a specific inhibitor of TrkB (the receptor of BDNF), abolished the protective effects of NaHS against Hcy-induced ER stress in the hippocampus.H2S attenuates ER stress and neuronal apoptosis in the hippocampus of Hcy-treated rats via upregulating the BDNF-TrkB pathway.

Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Hydrogen sulfide (H2S) acts as an endogenous neuromodulator and neuroprotectant. It has been shown that endoplasmic reticulum (ER) stress is involved in the pathological mechanisms of the learning and memory dysfunctions and that H2S exerts its neuroprotective role via suppressing ER stress. In the present work, we explored the effects of intracerebroventricular injection of Hcy on the formation of learning and memory, the generation of endogenous H2S, and the expression of ER stress in the hippocampus of rats. We found that intracerebroventricular injection of Hcy in rats leads to learning and memory dysfunctions in the Morris water maze and novel of object recognition test and decreases in the expression of cystathionine-β-synthase, the major enzyme responsible for endogenous H2S generation, and the generation of endogenous H2S in the hippocampus of rats. We also showed that exposure of Hcy could up-regulate the expressions of glucose-regulated protein 78 (GRP78), CHOP, and cleaved caspase-12, which are the major mark proteins of ER stress, in the hippocampus of rats. Taken together, these results suggest that the disturbance of hippocampal endogenous H2S generation and the increase in ER stress in the hippocampus are related to Hcy-induced defect in learning and memory.

Depression is a common and debilitating mental illness and is often comorbid with anxiety disorders. Altered synaptic plasticity is considered to be an important mechanism underlying antidepressant drug action. It has been reported that hydrogen sulfide (H2S), the third gaseous transmitter, facilitates the induction of hippocampal long-term potentiation and augments synaptic neurotransmission, involved in the regulation of synaptic plasticity. The aim of this study was to clarify the antidepressant-like and anxiolytic-like effects of H2S. H2S (NaHS, 1.68 or 5.6 mg/kg, intraperitoneally, for 7 days) exerts a specific antidepressant-like effect in the forced swimming test of mice and rats and the tail suspension test of mice, and reduces the anxiety-like behaviors of both mice and rats in the elevated plus-maze test. These results reveal a unique antagonistic action of H2S in depressive-like and anxiety-like behaviors and suggest that elevating H2S signaling in the brain may represent a novel approach for the treatment of depressive and anxiety disorders.

It was previously confirmed that hydrogen sulfide (H2S) has a neuroprotective effect, preventing homocysteine‑induced neurotoxicity. However, the exact molecular mechanisms underlying this protective effect remain to be fully elucidated. Endoplasmic reticulum (ER) stress contributes to homocysteine‑induced neurotoxicity. Silent mating type information regulator 2 homolog 1 (SIRT‑1) can attenuate ER stress, exerting its neuroprotective effect. Therefore, the present study aimed to investigate whether H2S protects PC12 cells against homocysteine‑induced ER stress and whether SIRT‑1 mediates this protective effect of H2S. Western blotting was used to detect the expression of SIRT‑1, glucose‑regulated protein 78 (GRP78), and cleaved caspase‑12 in PC12 cells. It was observed that sodium hydrosulfide (NaHS), an exogenous H2S donor, significantly attenuated the homocysteine‑induced ER stress responses, including increases in the protein expression levels of GRP78 and cleaved caspase‑12. Simultaneously, NaHS upregulated the expression of SIRT‑1 and reversed the homocysteine‑induced downregulation of SIRT‑1 in PC12 cells. Sirtinol, a specific inhibitor of SIRT‑1, eliminated the protective effects of H2S in homocysteine‑induced ER stress. These data indicated that H2S prevented homocysteine‑induced ER stress via enhancing the expression of SIRT‑1. These findings offer novel insight into the protective mechanisms of H2S against homocysteine‑induced neurotoxicity.

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.

We previously reported that hydrogen sulfide (H(2)S) produces protection in PC12 cells during 1-methy-4-phenylpyridinium ion (MPP(+)) challenge. The present study aims to clarify the mechanisms underlying the neuroprotective effects of H(2)S. We showed that both glybenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker, and LY294002, a specific PI(3)K-AKT pathway inhibitor, reversed the neuroprotective effect of NaHS (a H(2)S donor) against MPP(+)-induced cytotoxicity to PC12 cells and that NaHS up-regulated the activity of AKT in PC12 cells, which was abolished by blockade of K(ATP) channels with glybenclamide. In addition, NaHS up-regulated the expression of Bcl-2 and blocked MPP(+)-induced down-regulation of Bcl-2, and this augmentation of Bcl-2 expression was prevented by both glybenclamide and LY294002. These data provided the evidence that the neuroprotective action of H(2)S against MPP(+) toxicity to PC12 cells is via the K(ATP)/PI(3)K/AKT/Bcl-2 pathway. We also demonstrated that NaHS attenuated the inhibitory effect of MPP(+) ERK1/2 activation in PC12 cells, whereas U0126, a specific MEK inhibitor, did not reverse the neuroprotective effect of NaHS, which indicated that attenuating MPP(+)-triggered down-regulation of ERK1/2 activation is involved in the protection of H(2)S against MPP(+) neurotoxicity, but ERK1/2 is not an essential effector mediating the neuroprotective effect of H(2)S. In conclusion, the present observations identify a crucial role of the K(ATP)/PI(3)K/AKT/Bcl-2 pathway in H(2)S-exerted neuroprotection against the toxicity of MPP(+). Findings from the present study will help shed light on the mechanisms of H(2)S-elicited neuroprotective effects on MPP(+) toxicity.