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Nanoscale phase-variant ultrasound contrast agents have attracted the interest of many researchers. However, it is a challenge to design nanobubbles that are activated by low-frequency medical ultrasound that do not cause damage to normal tissues. In this study, we designed a new type of nanoparticle consisting of perfluoropentane and iron polyphthalocyanine loaded into liposomes. These nanoparticles can be activated by a low-frequency medical ultrasound imager at a frequency of 5 MHz for ultrasound imaging and clear reactive oxygen species at a rate of more than 50%. This ability to scavenge excess reactive oxygen species can alleviate the damage these species cause and protect macrophages. Moreover, these nanoparticles can effectively enhance ultrasound contrast imaging for real-time visualization in the diagnosis and treatment of diseases.

Hyperglycemia-induced neuronal endoplasmic reticulum (ER) stress is particularly important for the pathogenesis of diabetic encephalopathy. Spermidine (Spd) has neuroprotection in several nervous system diseases. Our current study to explore the potential protective role of Spd in hyperglycemia-induced neuronal ER stress and the underlying mechanisms. HT22 cells were treated with high glucose (HG) to establish an in-vitro model of hyperglycemia toxicity. The HT22 cells' activity was tested by cell counting kit-8 assay. RNA interference technology was used to silence the expression of growth differentiation factor 11 (GDF11) in HT22 cells. The GDF11 expression levels of mRNA were assessed using reverse transcription-PCR (RT-PCR). Western blotting analysis was applied to evaluate the expressions of GRP78 and cleaved caspase-12. Spd markedly abolished HG-exerted decline in cell viability as well as upregulations of GRP78 and cleaved caspase-12 in HT22 cells, indicating the protection of Spd against HG-induced neurotoxicity and ER stress. Furthermore, we showed that Spd upregulated the expression of GDF11 in HG-exposed HT22 cells. While, silenced GDF11 expression by RNA interference reversed the protective effects of Spd on HG-elicited neurotoxicity and ER stress in HT22 cells. These results indicated that Spd prevents HG-induced neurotoxicity and ER stress through upregulation of GDF11. Our findings identify Spd as a potential treatment for diabetic encephalopathy as well as ER stress-related neurologic diseases.

Arecoline, a major alkaloid of the areca nut, has potential toxicity to the nervous system. Our previous study reveals that the neurotoxicity of arecoline involves in inhibited endogenous hydrogen sulfide (H

Abstract: Differentiated embryo-chondrocyte expressed gene1 (DEC1), an important transcription factor that has a basic helix-loop-helix domain, is ubiquitously expressed in both human embryonic and adult tissues. DEC1 is involved in neural differentiation and neural maturation in the central nervous system (CNS). Recent studies suggest that DEC1 protects against Parkinson's disease (PD) by regulating apoptosis, oxidative stress, lipid metabolism, immune system, and glucose metabolism disorders. In this review, we summarize the recent progress on the role of DEC1 in the pathogenesis of PD and provide new insights into the prevention and treatment of PD and neurodegenerative diseases.

Identification of innovative therapeutic targets for the treatment of cognitive impairment in Parkinson’s disease (PD) is urgently needed. Hydrogen sulfide (H2S) plays an important role in cognitive function. Therefore, this work is aimed at investigating whether H2S attenuates the cognitive impairment in PD and the underlying mechanisms. In the rotenone- (ROT-) established PD rat model, NaHS (a donor of H2S) attenuated the cognitive impairment and promoted microglia polarization from M1 towards M2 in the hippocampus of PD rats. NaHS also dramatically upregulated the Warburg effect in the hippocampus of PD rats. 2-Deoxyglucose (2-DG, an inhibitor of the Warburg effect) abolished NaHS-upregulated Warburg effect in the hippocampus of PD rats. Moreover, the inhibited hippocampal Warburg effect by 2-DG abrogated H2S-excited the enhancement of hippocampal microglia M2 polarization and the improvement of cognitive function in ROT-exposed rats. Our data demonstrated that H2S inhibits the cognitive dysfunction in PD via promoting microglia M2 polarization by enhancement of hippocampal Warburg effect.

Arecoline, the most abundant alkaloid of the areca nut, induces toxicity to neurons. Hydrogen sulfide (H(2)S) is an endogenous gas with neuroprotective effects. We recently found that arecoline reduced endogenous H(2)S content in PC12 cells. In addition, exogenously administration of H(2)S alleviated the neurotoxicity of arecoline on PC12 cells. Increasing evidence has demonstrated the neuroprotective role of improvement of autophagic flux. Therefore, the aim of the present work is to explore whether improvement of autophagic flux mediates the protection of H(2)S against arecoline-caused neurotoxicity. Transmission electron microscope (TEM) for observation of ultrastructural morphology. Western blotting was used to detect protein expression of the related markers. Functional analysis contained LDH release assay, Hoechst 33,258 nuclear staining and flow cytometry were used to detect cytotoxicity and apoptosis. In the present work, we found that arecoline disrupted autophagy flux in PC12 cells as evidenced by accumulation of autophagic vacuoles, increase in LC3II/LC3I, and upregulation of p62 expression in PC12 cells. Notably, we found that sodium hydrosulfide (NaHS), the donor of H(2)S improved arecoline-blocked autophagy flux in PC12 cells. Furthermore, we found that blocking autophagic flux by chloroquine (CQ), the inhibitor of autophagy flux, antagonized the inhibitory role of NaHS in arecoline-induced cytotoxicity apoptosis and endoplasmic reticulum (ER) stress. In conclusion, H(2)S improves arecoline-caused disruption of autophagic flux to exert its protection against the neurotoxicity of arecoline.

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.

Corticosterone (CORT) damages hippocampus neurons as well as induces neuroinflammation. Tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis acts as programmed cell death triggering neuroinflammation. The deficiency of Menin, a multifunctional scaffold protein, aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation and necroptosis as well as the mediatory role of Menin in this protective effect of itaconate using an exposure of CORT to HT22 hippocampal neuronal cells. The viability of HT22 cells was examined by the Cell Counting Kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/ RIP1, p-RIP3/ RIP3, and p-MLKL/ MLKL) were evaluated by Western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1β, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL4, IL10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/ RIP1, p-RIP3/ RIP3, and p-MLKL/ MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis to HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.

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.

In the rice-wheat rotation system, 24 and 23 wheat cultivars were separately planted in Yangzhou and Suining of Jiangsu province in 2016–2017 and 2017–2018. According to nitrogen utilization rate (NUR), these cultivars were clustered into three groups, i.e., NUR-H (NUR ≥ 50%), NUR-M (NUR 40%–50%), and NUR-L (NUR ≤ 40%), to identify the differences in grain yield, yield components, and population quality, which would provide a reference for cultivar selection for high-yield and high-efficiency in wheat production. Yangmai 25 and Ningmai 21 in Yangzhou and Huaimai 35 in Suining showed NUR-H phenotypes in consecutive two years. Grain yield of the NUR-H cultivars was more than 6500 kg hm–2 in Yangzhou and 7000 kg hm–2 in Suining, which were significantly higher than those of NUR-M and NUR-L groups. NUR-H group had more spikes, and it grains per spike and 1000-grain weight were not significantly different from those of the other groups. Grain yield and spikes number were significantly positively correlated with NUR among different cultivars. More stem and tiller number, higher percentage of fertile tillers and higher leaf area index (LAI) at the milk-ripening stage were shown in the NUR-H group. A higher dry matter accumulation at stages of booting, anthesis, and maturity, after anthesis, and in the vegetative organs at maturity were found in the NUR-H group. However, there were no differences in dry matter remobilization and harvest index among different cultivars. Number of stems and tillers at booting and anthesis, LAI at the milk-ripe stage, and dry matter accumulation at each stage after anthesis, and in the vegetative organs at maturity were significantly positively correlated with NUR in the all cultivar in two sites. A vigorous tillering capacity at the early growing phase and a higher LAI and photosynthetic production at the late growth stages could be observed in NUR-H cultivars, resulting in more photosynthate for grain-filling. Furthermore, the critical parameters of cultivar screening for high-yield and high-efficiency in wheat following rice were proposed, that is 16,000–20,000 kg hm–2 dry matter accumulation at maturity and 4100–6700 kg hm–2 dry matter accumulation after anthesis.

Homocysteine (Hcy) accelerates neuronal senescence and induces age-related neurodegenerative diseases. Silence signal regulating factor 1 (SIRT1) prolongs lifespan and takes neuroprotective effects. We have previously demonstrated that hydrogen sulfide (H2S) prevents Hcy-induced apoptosis of neuronal cells and has neuroprotective effect. In the present work, we aimed to investigate whether H2S protects HT22 cells against Hcy-induced neuronal senescence and whether SIRT1 mediates this role of H2S. We found that Hcy induced cellular senescence in HT22 cells, as determined by β-galactosidase staining, expressions of P16INK4a, P21CIPL, and trypan blue Staining, which are the markers of cellular senescence. However, sodium hydrosulfide (NaHS, the donor of H2S) significantly reversed Hcy-induced cellular senescence. Interestingly, NaHS not only up-regulated the expression of SIRT1 in HT22 cells but also reversed Hcy-downregulated the expression of SIRT1 in HT22 cells. Furthermore, we found that pretreatment with Sirtinol (an inhibitor of SIRT1) markedly reversed the protection of NaHS against Hcy-induced HT22 cells senescence and apoptosis. Our findings illustrated that H2S protects HT22 cells against Hcy-induced senescence by up-regulating SIRT1.

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Purpose This study aimed to evaluate the role of social participation in the relationship between internet use and depressive symptoms among Chinese older adults and investigate how the internet use interact with social participation to reduce the risk of depressive symptoms. Methods Based on the survey from the China Health and Retirement Longitudinal Study (CHARLS) in 2018, we identified 4645 subjects and used the Ordinary Least Square method (OLS) and Propensity Score Matching method (PSM) to identify the association between Internet use and depression of older people, and further test how social participation played a role in the relationship. Results The level of depression of older people was significantly reduced in those who using internet in China, and the effect was still robust under different identification methods. The mental health was improved when using internet because of the increase of social participation and social capital. Further, The positive effect was stronger especially in those who were female, living in rural areas, has low education attainments and were 70–79 years old. Conclusions The popularity of internet use has a positive effect on the depressive symptoms of Chinese older adults. Effective measures were encouraged to improve the friendliness of internet for older people and promote the popularization of the Internet and older group, achieving the spiritual well-being of them in the Internet society.

Purpose: Poverty and hunger are still severe problems faced by the world today, especially in developing countries. Starvation in childhood usually damaged mental health in later years. But, does this proposition apply China? The answer could not only verify the validity of the current research findings, but also provide certain significance for the intervention and formulation of global public health policy.Method: This research was based on the data of the Chinese Longitudinal Healthy Longevity Survey data in 2018, and 1820 elderly people were investigated. The impact of childhood starvation on mental health in later years was investigated by the Ordinary Least Squares method. Moreover, the robustness tests conducted by replacing independent variable to severity of childhood starvation and dividing the samples to different age ranges. Furthermore, heterogeneity was also analyzed based on different gender, different domicile where they born, and different level of education.Results: The childhood starvation was associated with less mental health scores in later life. The older who suffered from childhood starvation showed worsen mental health in later years, especially in the illiterate samples and the rural samples. However, there was no significant difference when considering different gender.Conclusions: Childhood starvation worsened the mental health in later life, and the level of education and being born in urban had a mediating effect to the relationship. In order to reduce the negative impact of childhood starvation on mental health, anti-poverty strategies, such as providing assistance to children who are hungry, and developing early intervention programs for children's development, should be promoted around the world. Meanwhile, the local development, industrialization and modernization, as well as children's educational attainment should also be promoted while preventing child hunger.

Homocysteine (Hcy) is an important intermediate in methionine metabolism and generation of one-carbon units, and its dysfunction is associated with many pathological states. Although Hcy is a non-protein amino acid, many studies have demonstrated protein-related homocysteine metabolism and possible mechanisms underlying homocysteinylation. Homocysteinylated proteins lose their original biological function and have a negative effect on the various disease phenotypes. Hydrogen sulfide (H2S) has been recognized as an important gaseous signaling molecule with mounting physiological properties. H2S modifies small molecules and proteins via sulfhydration, which is supposed to be essential in the regulation of biological functions and signal transduction in human health and disorders. This review briefly introduces Hcy and H2S, further discusses pathophysiological consequences of homocysteine modification and sulfhydryl modification, and ultimately makes a prediction that H2S might exert a protective effect on the toxicity of homocysteinylation of target protein via sulfhydration. The highlighted information here yields new insights into the role of protein modification by Hcy and H2S in diseases.

Hydrogen sulfide (H2 S) 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 H2 S in BDNF protein expression and autophagy. Thus, in this study, we explored whether the BDNF-TrkB pathway mediates the antidepressant-like effects of H2 S in diabetic rats and whether this process is achieved via promoting hippocampal autophagy. We demonstrated that H2 S 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 H2 S, as evidenced by the tail suspension, forced swimming, novelty suppressed feeding, and elevated plus-maze tests. Furthermore, K252a abolished H2 S-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 H2 S in diabetic rats by enhancing hippocampal autophagy.

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.

Sleep deprivation (SD) is widespread in society causing serious damage to cognitive function. Hydrogen sulfide (H

Our previous works demonstrated that β2-microglobulin (β2m), a systemic pro-aging factor, induce depressive-like behaviors. Hydrogen sulfide (HThe 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.we found that NaHS (the donor of HH

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.

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.

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.

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.

Graphical abstract, 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.

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.

In this research,we explored the effect of three groups of water treatments,including severe drought(the corresponding water content of cultivated substrate 5%-10%),moderate drought(45%-50%) and control(85%-90%),and different drought stress time(15,30,45 d) on the glandular trichome density(TD),stomatal density(SD) and volatile exudates of Schizonepeta tenuifolia.The results showed that there were two kinds of glandular trichomes on the surface of S. tenuifolia leaves: peltate and capitate glandular trichomes. The density of capitate glandular trichomes(CTD) was higher than that of peltate glandular trichomes(PTD). Both CTD and PTD on the abaxial surface of leaf were higher than those on the adaxial surface. Under severe drought stress,the CTD and SD were higher than the other two treatments. Under the same stress time,the biomass and leaf surface area of S. tenuifolia decreased with the deepening of stress degree. As the stress time prolonged,the surface area of leaves and biomass gradually increased,and the TD and SD decreased. The most abundant compound in volatile exudates of S. tenuifolia was pulegone. Under drought stress,the relative content of pulegone decreased,and the relative content of other monoterpenoids such as D-limonene and menthone increased. The n-hexadeconic acid and 2-methyl-1-hexadecanol were detected only at the stress of 15 d,while menthone was detected at the stress of 30 d and45 d. Drought stress affected the leaf growth and secondary metabolism of S. tenuifolia.

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.

Hydrogen sulfide (H

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.

Isatis indigotica Fortune is a popular herb in traditional Chinese medicine, and various types of metabolites are the basis for its pharmacological efficacy. The biosynthesis and accumulation of these metabolites are closely linked to nitrogen availability; the benefits of low nitrogen application on the environment and herb quality are increasingly prominent. To analyze metabolic changes in the leaves and roots of I.indigotica in nitrogen deficiency conditions, and to identify the pathways and metabolites induced by low nitrogen availability, we used untargeted liquid chromatography coupled with mass spectrometry (UHPLC-TripleTOF) to obtain metabolomics profiling of I.indigotica under two N-deficiency treatments (0 kg/hm2; 337.5 kg/hm2) and normal nitrogen treatment (675 kg/hm2). A total of 447 metabolites were annotated. Principal component analysis separated the three nitrogen treatments. A greater diversity of metabolites was observed in roots than in leaves under N-deficiency treatments, suggesting that roots have a more important function in low N tolerance. Differential metabolites were mainly enriched in purine metabolism, phenylpropanoid biosynthesis, the shikimate pathway, tryptophan metabolism, and flavonoid biosynthesis that notably induced only in leaves in low nitrogen stress. Moderate N-deficiency benefits carbohydrate accumulation, whereas accumulation of most amino acids decreases. Uniquely, L-tryptophan was maintained at a high concentration in N-deficiency conditions. Low nitrogen stress induced the accumulation of some specialized metabolites (matairesinol, dictamnine, 5-hydroxyindoleacetate (serotonin) in roots and vitexin, xanthohumol, sinapyl alcohol in leaves). N-deficiency also increased the accumulation of adenosine and quality indicators of I.indigotica (indirubin-indigo, epigoitrin and anthranilic acid) in a certain degree. Our findings showed that nitrogen deficiency modified roots and leaves conditions of I.indigotica, affecting both the primary and secondary metabolism. Moderate nitrogen reduction was beneficial to the accumulation of active ingredients. Our methods and analysis are expected to provide an insight regarding the diversity of metabolites and regulation of their synthesis in low nitrogen application, and better investigate the nitrogen deficiency effect on I.indigotica., Graphical abstract Image 1049134, Highlights • A greater diversity of metabolites was observed in roots than in leaves under N-deficiency treatments. • Differential metabolites were mainly enriched in purine metabolism, phenylpropanoid biosynthesis, the shikimate pathway, and tryptophan metabolism. • Flavonoid biosynthesis was significantly induced only in leaves. • Moderate N deficiency benefits carbohydrate and specialized metabolites accumulations, whereas decrease the most amino acid accumulation (except for L-tryptophan). • N-deficient treatments induced the synthesis and accumulation of quality indicators (indigo-indirubin, epigoitrin and anthranilic acid) in a certain degree.