Excessive hydrogen sulfide-induced activation of NMDA receptors in the colon participates in anxiety- and compulsive-like behaviors in a rodent model of hemorrhagic shock and resuscitation

Article

作者: Wang, Jun ; Zhou, Ting-Ting ; Zhang, Li-Min ; Lv, Rui-Zhao ; Jia, Shi-Yan ; Fu, Yue ; Li, Xiao-Ming ; Li, Bao-Dong ; Wang, Han ; Song, Rong-Xin ; Jing, Yu-Mo ; Ma, Xiao-Yi ; Yu, Zhi-Fang

OBJECTIVEHemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H₂S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H₂S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl-d-Aspartate (NMDA) receptor function.METHODSMice were immediately administered dl-propargylglycine (PAG) intragastrically as an H₂S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala.RESULTSWithin 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H₂S-induced intestinal and cerebral injury.CONCLUSIONThis experimental data suggests that H₂S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.

2024-11-01·Nitric Oxide

H2S alleviated sepsis-induced acute kidney injury by inhibiting PERK/Bax-Bcl2 pathway

Article

作者: Tian, Danyang ; Wu, Yuming ; He, Kaichuan ; Guo, Qi ; Jin, Sheng ; Xu, Jiao ; Chen, Qian ; Song, Chengqing ; Teng, Xu ; An, Cuixia ; Xiao, Lin ; Xue, Hongmei

To investigate the protective mechanisms of hydrogen sulfide (H₂S) in sepsis-induced acute kidney injury (SAKI), we conducted an in vivo study using a SAKI mouse model induced by intraperitoneal lipopolysaccharide (LPS) injection. Following 6 h of LPS injection, levels of tumor necrosis factor-alpha (TNF-α) and blood urea nitrogen (Bun) were significantly elevated in mouse plasma. In the kidneys of SAKI mice, expression of H₂S-generating enzymes cysteinyl-tRNA synthetase (CARS), cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) was markedly downregulated, while glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase (p-PERK/PERK), and B-cell lymphoma-2 recombinant protein X/B-cell lymphoma-2 (Bax/Bcl2) expression was significantly upregulated. H₂S improved renal function and attenuated renal histopathological changes in SAKI mice, thereby alleviating LPS-induced endoplasmic reticulum stress (ERS). Additionally, it inhibited the expression of p-PERK/PERK and Bax/Bcl2. After inhibiting CSE activity with dl-propargylglycine (PPG i. p.), the renal tissue pathology in LPS-induced AKI mice was further exacerbated, leading to enhanced activation of the PERK/Bax-Bcl2 pathway. Our findings suggest that endogenous H₂S influences the pathogenesis of SAKI, while exogenous H₂S protects against LPS-induced AKI by inhibiting the PERK/Bax-Bcl2 pathway involved in ERS.

2024-06-01·Biomedicine & Pharmacotherapy

Protective role of hydrogen sulfide against diabetic cardiomyopathy by inhibiting pyroptosis and myocardial fibrosis

Article

作者: Deng, Simin ; Zeng, Cheng ; Liu, Maojun ; Zhang, Yifeng ; Hu, Xinqun ; Xin, Ying

Diabetic cardiomyopathy (DCM) contributes significantly to the heightened mortality rate observed among diabetic patients, with myocardial fibrosis (MF) being a pivotal element in the disease's progression. Hydrogen sulfide (H₂S) has been shown to mitigate MF, but the specific underlying mechanisms have yet to be thoroughly understood. A connection has been established between the evolution of DCM and the incidence of cardiomyocyte pyroptosis. Our research offers insights into H₂S protective impact and its probable mode of action against DCM, analyzed through the lens of MF. In this study, a diabetic rat model was developed using intraperitoneal injections of streptozotocin (STZ), and hyperglycemia-stimulated cardiomyocytes were employed to replicate the cellular environment of DCM. There was a marked decline in the expression of cystathionine γ-lyase (CSE), a catalyst for H₂S synthesis, in both the STZ-induced diabetic rats and hyperglycemia-stimulated cardiomyocytes. Experimental results in vivo indicated that H₂S ameliorates MF and enhances cardiac functionality in diabetic rats by mitigating cardiomyocyte pyroptosis. In vitro assessments highlighted the induction of cardiomyocyte pyroptosis and the subsequent decline in cell viability under hyperglycemic conditions. However, the administration of sodium hydrosulfide (NaHS) curtailed cardiomyocyte pyroptosis and augmented cell viability. In contrast, propargylglycine (PAG), a CSE inhibitor, reversed the effects rendered by NaHS administration. Additional exploration indicated that the mitigating effect of H₂S on cardiomyocyte pyroptosis is modulated through the ROS/NLRP3 pathway. In essence, our findings corroborate the potential of H₂S in alleviating MF in diabetic subjects. This therapeutic effect is likely attributable to the regulation of cardiomyocyte pyroptosis via the ROS/NLRP3 pathway. This discovery furnishes a prospective therapeutic target for the amelioration and management of MF associated with diabetes.

项与 PAG (University of Chicago) 相关的新闻（医药）

2023-04-11

·PRNewswire

70% of classic homocystinuria patients are unhappy with their treatment (MARKETVUE® REPORT)

Drug development for homocystinuria is limited to just three clinical-stage products, two of which are injectable enzyme replacement therapies (ERTs). NEWTON, Mass., April 11, 2023 /PRNewswire/ -- Classic homocystinuria (HCU) is a rare, inherited metabolic disease resulting from cystathionine beta-synthase deficiency. When left untreated or poorly managed, HCU is associated with severe symptoms such as: Developmental delays Stroke Bone weakness or deformities Lens dislocation Increased risk of blood clots Betaine is the only FDA-approved treatment for homocystinuria, however, according to REACH Market Research 's MarketVue® assessment, medical geneticists state that its efficacy is limited in reducing total plasma homocysteine levels (tHcy), the primary goal of treatment. HCU patients who are pyridoxine-responsive are well managed with pyridoxine, however, most HCU patients are pyridoxine partial or non-responsive, and these patients represent the population for a which there is a large unmet need for efficacious tHcy lowering treatments. Medical geneticist, U.S.: I think everybody who isn't pyridoxine responsive is unhappy because they're not getting where they need to go. To access REACH's MarketVue® Report on classic HCU, visit or contact us at [email protected]. Medical geneticists interviewed by REACH are excited about the prospect of ERTs. The HCU pipeline contains two ERTs: Travere Therapeutics' human-modified PEGylated cystathionine beta-synthase – pegtibatinase Aeglea BioTherapeutics' human engineered PEGylated cystathionine gamma-lyase inhibitor – pegtarviliase Medical geneticists report that preliminary results from Travere's clinical trials for pegtibatinase, showing a 55% reduction in tHcy, are promising. Pooja Patel, Analyst at REACH: Physicians hope that emerging ERTs will allow pyridoxine partial and non-responsive patients to liberalize their diet. Although current treatments can lower tHcy for pyridoxine partial and non-responsive patients, they require strict monitoring of dietary protein intake, which is nearly impossible for most patients to sustain. About MarketVue® MarketVue® reports are a rare disease focused, fresh alternative to traditionally long and outdated market research reports. MarketVue® reports cover rare disease epidemiology and key market dynamics based on research from key opinion leader interviews, physician surveys, and secondary data. About REACH Market Research REACH is an independent pharmaceutical market research company focused on rare and niche diseases. With decades of experience in pharmaceutical market research and life sciences consulting, REACH fills an important gap in the market – accessible market research solutions for rare and niche diseases. SOURCE REACH Market Research

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