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We previously revealed that hydrogen sulfide (H 2 S) attenuates chronic stress-induced cognitive impairment, but the underlying mechanism needs to be further clarified. Growth differentiation factor 11 (GDF11) plays an important regulatory role in cognitive function and that hippocampal NLRP3/caspase-1-mediated pyroptosis contributes to the pathogenesis of cognitive impairment. Hence, this research aimed to explore whether promoting GDF11 levels and suppressing hippocampal NLRP3/caspase-1-mediated pyroptosis mediate H 2 S to alleviate chronic stress-induced cognitive impairment. Sprague–Dawley rats were subjected to unpredictable chronic mild stress lasting four weeks to establish an animal model of chronic stress-induced cognitive impairment. Behavioral performance was assessed by the Y-maze test and the novel object recognition test. The expression levels of proteins were analyzed by Western blot analysis. The levels of IL-1β and IL-18 in the hippocampus were measured by ELISA. NaHS upregulated the expression of GDF11 in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats. Silencing GDF11 blocked NaHS-improved cognitive impairment in CUMS-exposed rats, according to the Y-maze test and the novel object recognition test. Furthermore, NaHS mitigated NLRP3/caspase-1-mediated pyroptosis in the hippocampus of CUMS-exposed rats and this effect was reversed by silencing GDF11. Moreover, overexpression of GDF11 alleviated CUMS-induced cognitive impairment and NLRP3/caspase-1-mediated hippocampal pyroptosis. GDF11 mediates H 2 S to attenuate chronic stress-induced cognitive impairment via inhibiting hippocampal NLRP3/caspase-1-mediated pyroptosis. [Display omitted] • H 2 S upregulates GDF11 expression and ameliorates pyroptosis in CUMS-exposed rats. • Silencing GDF11 blocks H 2 S to prevent cognitive dysfunction in CUMS-exposed rats. • Silencing GDF11 reverses H 2 S-blocking pyroptosis in CUMS-exposed rats. • GDF11 overexpression ameliorates the cognitive impairment in CUMS-exposed rats. • GDF11 overexpression inhibits pyroptosis in CUMS-exposed rats. [ABSTRACT FROM AUTHOR]

Depression is a highly prevalent comorbidity arising in patients with Parkinson's disease (PD). However, depression in patients with PD is poorly treated. Hydrogen sulfide (H 2 S), a neuromodulator, has the potential to relieve depression. To investigate whether H 2 S attenuates depression-like behaviours in a rat model of PD and examine the underlying mechanisms. We utilised rotenone to develop a PD model with subcutaneous injections in the dorsal cervical region of Sprague-Dawley rats. The depression-like behaviours in the rotenone-induced PD model rats were assessed through forced swimming, tail suspension, open field, novelty-suppressed feeding, and elevated plus-maze tests. The expression of postsynaptic density protein-95 and synapsin-1, related to synaptic plasticity, was detected using Western blot in the hippocampus. The hippocampal ultrastructure, including the synaptic density, length of the synaptic active zone, postsynaptic density thickness, and synaptic gap width, was detected using transmission electron microscopy. We proved that sodium hydrosulfide (NaHS; a donor of H 2 S) significantly attenuated the depression-like behaviours and disorders of hippocampal synaptic plasticity in rotenone-induced PD rats. Furthermore, inhibition of the hippocampal Warburg effect by 2-deoxyglucose abolished NaHS-enhanced hippocampal synaptic plasticity and reversed NaHS-attenuated depression-like behaviours in the rotenone-induced PD rats. H 2 S attenuates PD-associated depression by improving the hippocampal synaptic plasticity in a hippocampal Warburg effect-dependent manner. • H 2 S attenuates the depression-like behaviors in PD rats. • H 2 S prevents the disorders of hippocampal synaptic plasticity in PD rats. • Inhibited Warburg effect abolishes H 2 S-enhanced hippocampal synaptic plasticity. • Inhibited Warburg effect reverses H 2 S-attenuated depression-like behaviors. [ABSTRACT FROM AUTHOR]

Increasing evidence confirms that sleep deprivation (SD), which induces hippocampal neuroinflammation, is a risk factor for depression. Hydrogen sulfide (H 2 S) is a novel neuromodulator that plays antidepressant-like role. Silent mating type information regulation 2 homolog 1 (Sirt1) is well-characterized as a regulator of mood disorder. Furthermore, we have previously reported that H 2 S upregulates Sirt1 expression in the hippocampus of SD-exposed rats. Here, we explored whether H 2 S ameliorates depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory in SD-exposed rats and whether Sirt1 mediates these protective roles of H 2 S. In the present work, we showed that NaHS (a donor of H 2 S) significantly alleviated depression- and anxiety-like behaviors in the SD-exposed rats tested by novelty-suppressed feeding test (NST), forced swim test (FST), tail suspension test (TST), and elevated plus maze test (EPMT) and that NaHS attenuates neuroinflammatory in the hippocampus of SD-exposed rats, as evidenced by reducing the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokine CCL2, as well as increasing the levels of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. However, Sirt1 inhibitor reversed the protective effects of H 2 S against SD-induced depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory. In conclusion, H 2 S antagonizes SD-induced depression- and anxiety-like behaviors and neuroinflammation, which is required hippocampal Sirt1. These findings suggested that H 2 S is a novel approach to prevent SD-induced depression and anxiety. • H 2 S ameliorated SD-induced depression- and anxiety-like behaviors in rats. • H 2 S attenuated SD-induced neuroinflammatory responses in the hippocampus of rats. • Sirtinol abolished H 2 S to prevent depression- and anxiety-like behaviors. • Sirtinol blocked H 2 S to inhibit the hippocampal neuroinflammatory. [ABSTRACT FROM AUTHOR]

Formaldehyde (FA) has neurotoxic characteristics and causes neurodegenerative disease. Our previous study demonstrated the neuroprotective effects of hydrogen sulfide (H 2 S) on FA-induced neurotoxicity in HT22 cells. Emerging evidence have supported that ferroptosis is involved in FA-induced neurotoxicity. To understand the mechanism of the protection of H 2 S against FA-induced neurotoxicity, this study explored the regulatory effect of H 2 S on FA-induced ferroptosis and the underlying mechanisms. The researcher found that H 2 S (100, 200, and 400 μM, 30 min) reverses the ferroptosis induced by FA (100 μM, 24 h) in HT22 cells (a cell line of mouse hippocampal neurons), including decreases in free iron, reactive oxygen species (ROS), 4-hydroxy-2-trans-nominal (4-HNE), and malondialdehyde (MDA) contents, as well as an increase in glutathione (GSH) content. H 2 S (100, 200, and 400 μM, 30 min) also inhibited ferritinaphagy in FA-exposed HT22 cells, as evidenced by the downregulation of the ferritinophagy receptor nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain-3B (LC3B) as well as the upregulation of the main iron storage protein ferritin heavy chain 1 (FTH1) and p62. H 2 S (100, 200, and 400 μM, 30 min) also up-regulated the expression of growth differentiation factor-11 (GDF11) in FA-exposed HT22 cells. Furthermore, knockdown of GDF11 in HT22 cells cancelled the beneficial effects of H 2 S in FA-induced ferroptosis and ferritinaphagy. These data indicated that the protective mechanism underlying H 2 S-prevented neurotoxicity of FA is involved in alleviating FA-induced ferroptosis via inhibiting ferritinaphagy by upregulation of GDF11. [Display omitted] • Hydrogen sulfide upregulates GDF11 protein expression in formaldehyde-treated HT22 cells. • Hydrogen sulfide antagonizes formaldehyde-induced ferritinophagy and ferroptosis. • Silencing GDF11 reversed the protective effect of hydrogen sulfide on formaldehyde-induced ferritinophagy. • Silencing GDF11 reversed the protective effect of hydrogen sulfide on formaldehyde-induced ferroptosis. [ABSTRACT FROM AUTHOR]

Homocysteine (Hcy) causes cognitive deficits and hippocampal endoplasmic reticulum (ER) stress. Our previous study has confirmed that Hydrogen sulfide (H 2 S) 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 H 2 S against Hcy-induced cognitive dysfunction. We found that NaHS (a donor of H 2 S) 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 H 2 S 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 H 2 S in Hcy-induced cognitive dysfunction. [ABSTRACT FROM AUTHOR]

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 2 S antagonizes β2m-induced depressive-like behaviors and the underlying mechanisms. 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. we found that NaHS (the donor of H 2 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. H 2 S prevents β2m-induced depressive-like behaviors, which is involved in improvement of hippocampal synaptic plasticity as a result of enhancement of hippocampal Warburg effect. • H 2 S attenuates β2m-induced depressive-like behaviour. • H 2 S improves synaptic plasticity in the hippocampus of β2m-exposed rat. • H 2 S enhances Warburg effect in the hippocampus of β2m-exposed rat. • H 2 S prevents β2m-induced depression via Warburg effect- synaptic plasticity axis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Exposure of rats to homocysteine (Hcy) leads to learning and memory dysfunctions. [•] Hcy decreases the generation of endogenous H2S in the hippocampus of rats. [•] Hcy up-regulates the endoplasmic reticulum (ER) stress in the hippocampus of rats. [•] Disturbed H2S formation and ER stress involve in Hcy-caused memory disorder. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) 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. To determine whether the mechanism underlying protection of H 2 S against PD is involved in promoting Warburg effect via upregulation of leptin. 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. We showed that NaHS (a donor of H 2 S) 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 H 2 S against 6-OHDA-exerted PD-like behaviors and the loss of dopaminergic neurons in the substantia nigra, and abolished H 2 S-enhanced in the Warburg effect in the substantia nigra. Conclusion : These data indicated that leptin mediates the protection of H 2 S against PD, which involves enhancing the Warburg effect of the substantia nigra. • H 2 S attenuates dopaminergic neurons loss and enhances Warburg effect in the substantial nigra of PD rats. • H 2 S increases leptin expression in the substantial nigra of PD rats. • Inhibited leptin signaling pathway reverses H 2 S-blocked PD-like behaviors. • Inhibited leptin signaling pathway reverses H 2 S-reduced dopaminergic neurons loss. • Inhibited leptin signaling pathway reverses H 2 S-enhanced Warburg effect. [ABSTRACT FROM AUTHOR]