Acrolein (ACR) is a ubiquitous environmental pollutant and byproduct of lipid peroxidation that has been implicated in male infertility. However, the molecular mechanisms underlying ACR-induced toxicity in Sertoli cells remain unclear. Given its role in inducing oxidative stress, we examined whether ferroptosis, an iron-dependent form of regulated cell death, could mediate ACR toxicity in Sertoli cells. We also tested if hydrogen sulfide (H2S), which has antioxidant and ACR detoxifying properties, could protect Sertoli cells from ACR-induced ferroptosis. ACR exposure decreased Sertoli cell viability, increased protein carbonylation and p38 MAPK phosphorylation, indicating oxidative injury. ACR also depleted glutathione (GSH), downregulated the cystine importer SLC7A11, increased intracellular ferrous iron (Fe2+) and lipid peroxidation, suggesting activation of ferroptosis. Consistently, the ferroptosis inhibitor deferoxamine (DFO) markedly attenuates ACR-induced cell death. Further studies revealed that ACR-induced ferroptotic changes were prevented by exogenous H2S and exaggerated by inhibition of endogenous H2S production. Furthermore, H2S also suppressed GPX4 inhibitor RSL3-induced intracellular ACR accumulation and ferroptosis. In summary, our study demonstrates that ACR induces ferroptotic cell death in Sertoli cells, which can be prevented by H2S through multiple mechanisms. Targeting the H2S pathway may represent a therapeutic strategy to mitigate ACR-induced Sertoli cell injury and preserve male fertility.

Hydrogen sulfide (H2S) is a poisonous pollutant that endangers the environment, and H2S is also produced during food spoilage. Herein, we constructed a dicyanoisophorone-based near-infrared (NIR) fluorescent probe (DCID) to detect H2S. DCID exhibited significant turn-on fluorescence at 700 nm with a low limit of detection (LOD = 74 nM), large Stokes shift (220 nm), prominent selectivity, and response time (100 s) toward H2S. Importantly, the DCID probe had powerful applications in the detection of H2S in environmental samples and food spoilage. In addition, based on DCID-loaded test strips and combined a smartphone sensing platform, which provided a portable and convenient approach for the detection of H2S.

The ancient messenger molecule hydrogen sulfide (H2S) modulates myriad signaling cascades and has been conserved across evolutionary boundaries. Although traditionally known as an environmental toxin, H2S is also synthesized endogenously to exert modulatory and homeostatic effects in a broad array of physiologic functions. Notably, H2S levels are tightly physiologically regulated, as both its excess and paucity can be toxic. Accumulating evidence has revealed pivotal roles for H2S in neuroprotection and normal cognitive function, and H2S homeostasis is dysregulated in neurodegenerative conditions. Here, we review the normal neuroprotective roles of H2S that go awry in Alzheimer\'s disease, the most common form of neurodegenerative disease.

Necroptosis is a programmed cell death form executed by receptor-interacting protein kinase (RIPK) 1, RIPK3 and mixed lineage kinase domain-like protein (MLKL), which assemble into an oligomer called necrosome. Accumulating evidence reveals that necroptosis participates in many types of pathological processes. Hence, clarifying the mechanism of necroptosis in pathological processes is particularly important for the prevention and treatment of various diseases. For over 300 years, hydrogen sulfide (H2S) has been widely known in the scientific community as a toxic and foul-smelling gas. However, after discovering the important physiological and pathological functions of H2S, human understanding of this small molecule changed, believing that H2S is the third gas signaling molecule after carbon monoxide (CO) and nitric oxide (NO). H2S plays an important role in various diseases, but the related mechanisms are not yet fully understood. In recent years, more and more studies have shown that H2S regulation of necroptosis is involved in various pathological processes. Herein, we focus on the recent progress on the role of H2S regulation of necroptosis in different pathological processes and profoundly analyze the related mechanisms.

OBJECTIVE: Hydrogen sulfide (H2S) secreted by perivascular adipose tissue (PVAT) is a critical vasodilator, which might be involved during the pathogenesis of hypertension. The present study aimed to investigate the exact role of H2S on the regulation of PVAT anti-contraction by long-term exercise in obesity hypertension.
METHODS: After the establishment of obesity hypertension (24 weeks) through a high-fat diet, male Sprague-Dawley rats were randomly assigned to control group (HC), exercise group (HE), cystathionine γ-lyase (CSE) blocking group (HCB), and exercise combined with CSE blocking group (HEB). Exercise and CSE inhibitor regimens were performed throughout 13 weeks.
RESULTS: After 13 weeks of intervention, blood pressure was significantly decreased by long-term exercise (HC vs. HE, P < 0.05) but not by exercise combined with the CSE inhibitor regimen. Meanwhile, the CSE inhibitor significantly blocked the production of H2S in PVAT even after exercise (HE vs. HEB, P < 0.05). Furthermore, long-term exercise altered the expressions of voltage-dependent K+ (Kv) channel subunits 7 (KCNQs), which were diminished by CSE inhibition in mesenteric arteries. As for vascular tension assessment, after incubation with or without KCNQ opener (retigabine), the anti-contractile effect of PVAT (with or without transferred bath solution of PVAT) was significantly enhanced by long-term exercise and eliminated by the CSE inhibitor regimen (P < 0.05); KCNQ inhibitor (XE991) blunted this effect except for HE.
CONCLUSIONS: These results collectively suggest that endogenous H2S is a strong regulator of the anti-contractile effect of PVAT in obesity hypertension by long-term exercise, and KCNQ in the resistance artery might be involved during this process but not the only target channel mediated by H2S.

UNASSIGNED: Even in the absence of inflammation, persistent symptoms in Crohn\'s disease (CD) are prevalent and worsen quality of life. Amongst patients without inflammation (quiescent CD), we hypothesized that microbial community structure and function, including tryptophan metabolism, would differ between patients with persistent symptoms (qCD + S) and without persistent symptoms (qCD-S).
UNASSIGNED: We performed a multicenter observational study nested within the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease. Quiescent inflammation was defined by fecal calprotectin level <150 mcg/g. Persistent symptoms were defined by Crohn\'s Disease Patient-Reported Outcome-2. Active CD, diarrhea-predominant irritable bowel syndrome, and healthy controls were included as controls. Stool samples underwent whole-genome shotgun metagenomic sequencing.
UNASSIGNED: Thirty-nine patients with qCD + S, 274 qCD-S, 21 active CD, 40 diarrhea-predominant irritable bowel syndrome, and 50 healthy controls were included for analysis. Patients with qCD + S had a less-diverse microbiome. Furthermore, patients with qCD + S showed significant enrichment of bacterial species that are normal inhabitants of the oral microbiome (eg Rothia dentocariosa, Fusobacterium nucleatum) and sulfidogenic microbes (eg Prevotella copri, Bilophila spp.). Depletion of important butyrate and indole producers (eg Eubacterium rectale, Faecalibacterium prausnitzii) was also noted in qCD + S. Potential metagenome-related functional changes in cysteine and methionine metabolism, ATP transport, and redox reactions were disturbed in qCD + S, also suggestive of altered sulfur metabolism. Finally, qCD + S showed significant reductions in bacterial tnaA genes, which mediate tryptophan metabolism to indole, and significant tnaA allelic variation compared with qCD-S.
UNASSIGNED: The microbiome in qCD + S showed significant differences in sulfidogenesis, butyrate producers, and typically oral microbes compared to qCD-S and active CD. These results suggest that inflammation may lead to durable microbiome alterations which may mediate persistent symptoms through testable mechanisms.

Obesity is a major source of morbidity worldwide with more than 2 billion adults being overweight or obese. The incidence of obesity has tripled in the last 50 years, leading to an increased risk for a variety of noncommunicable diseases. Previous studies have demonstrated the positive effects of green leafy vegetables on weight gain and obesity and have attributed these beneficial properties, at least in part, to nitrates and isothiocyanates. Nitrates are converted to nitric oxide (NO) and isothiocyanates are known to release hydrogen sulfide (H2S). Herein, we investigated the effect of extracts and fractions produced from Beta vulgaris and Eruca sativa for their ability to limit lipid accumulation, regulate glucose homeostasis, and reduce body weight. Extracts from the different vegetables were screened for their ability to limit lipid accumulation in adipocytes and hepatocytes and for their ability to promote glucose uptake in skeletal muscle cultures; the most effective extracts were next tested in vivo. Wild type mice were placed on high-fat diet for 8 weeks to promote weight gain; animals receiving the selected B. vulgaris and E. sativa extracts exhibited attenuated body weight. Treatment with extracts also led to reduced white adipose tissue depot mass, attenuated adipocyte size, reduced expression of Dgat2 and PPARγ expression, and improved liver steatosis. In contrast, the extracts failed to improve glucose tolerance in obese animals and did not affect blood pressure. Taken together, our data indicate that extracts produced from B. vulgaris and E. sativa exhibit anti-obesity effects, suggesting that dietary supplements containing nitrates and sulfide-releasing compounds might be useful in limiting weight gain.

Soil salinity poses a significant threat to agricultural productivity, impacting the growth and yield of wheat (Triticum aestivum L.) plants. This study investigates the potential of melatonin (MT; 100 µM) and hydrogen sulfide (H2S; 200 µM sodium hydrosulfide, NaHS) to confer the tolerance of wheat plants to 100 mM NaCl. Salinity stress induced the outburst of reactive oxygen species (ROS) resulting in damage to the chloroplast structure, growth, photosynthesis, and yield. Application of either MT or NaHS augmented the activity of antioxidant enzymes, superoxide dismutase, ascorbate peroxidase, glutathione reductase, and reduced glutathione (GSH) levels, upregulated the expression of Na+ transport genes (SOS1, SOS2, SOS3, NHX1), resulting in mitigation of salinity stress. Thus, improved stomatal behavior, gas-exchange parameters, and maintenance of chloroplast structure resulted in enhanced activity of the Calvin cycle enzymes and overall enhancement of growth, photosynthetic, and yield performance of plants under salinity stress. The use of DL-propargylglycine (PAG, an inhibitor of hydrogen sulfide biosynthesis) and p-chlorophenyl alanine (p-CPA, an inhibitor of melatonin biosynthesis) to plants under salt stress showed the comparative necessity of MT and H2S in mitigation of salinity stress. In the presence of PAG, more pronounced detrimental effects were observed than in the presence of p-CPA, emphasizing that MT was involved in mitigating salinity through various potential pathways, one of which was through H2S.

Inflammatory bowel diseases (IBD) are often associated with dysregulated gut microbiota and excessive inflammatory microenvironment. Probiotic therapy combined with inflammation management is a promising approach to alleviate IBD, but the efficacy is hindered by the inferior colonization of probiotics in mucus-depleted inflammatory bowel segments. Here, we present modified montmorillonite armed probiotic Escherichia coli Nissle 1917 (MMT-Fe@EcN) with enhanced intestinal colonization and hydrogen sulfide (H2S) scavenging for synergistic alleviation of IBD. The montmorillonite layer that can protect EcN against environmental assaults in oral delivery and improve on-site colonization of EcN in the mucus-depleted intestinal segment due to its strong adhesive capability and electronegativity, with a 22.6-fold increase in colonization efficiency compared to EcN. Meanwhile, MMT-Fe@EcN can manage inflammation by scavenging H2S, which allows for enhancing probiotic viability and colonization for restoring the gut microbiota. As a result, MMT-Fe@EcN exhibits extraordinary therapeutic effects in the dextran sulfate sodium-induced mouse colitis models, including alleviating intestinal inflammation and restoring disrupted intestinal barrier function, and gut microbiota. These findings provide a promising strategy for clinical IBD treatment and potentially other mucus-depletion-related diseases.

Cystathionine γ-lyase (CSE) is a major enzyme that produces hydrogen sulfide (H2S). Herein, we report how CSE plays a previously unknown role in regulating the antioxidant effects of the mitochondria in human umbilical vein endothelial cells by releasing H2S nearby under stress conditions. We found that H2S partially promoted angiogenesis in the endothelial cells through the AKT/nuclear factor erythroid 2-related factor 2 (AKT/NRF2) signaling pathway. H2S improved mitochondrial function by altering the expressions of the mitofusin2 and dynamin-1-like mitochondrial fission proteins to inhibit oxidative stress and enhance NRF2 nuclear translocation. CSE is located only in the cytoplasm and not in the mitochondria, but it is transported to the vicinity of the mitochondria to produce H2S, which plays an antioxidant role in human umbilical vein endothelial cells under stress. The CSE mutant (with mutated CSE activity center: CSED187A) partially decreased the effects on promoting angiogenesis, resisting oxidative stress, and entering the mitochondria. These results show that CSE translocation is a unique mechanism that promotes H2S production inside the mitochondria under stress stimulation. Therefore, the CSE mutant site (CSED187A) may be a potential target for drug therapy.