Search Results (26)

Male infertility contributes to approximately half of all infertility cases, with most cases associated with oxidative stress. Spermatozoa depend on finely tuned redox signaling for critical processes such as capacitation, motility, and fertilization competence; however, their unique structural and metabolic features render them particularly vulnerable to oxidative damage. Reversible oxidative modifications regulate enzymatic activity, signaling cascades, and structural stability, supporting normal sperm function, whereas irreversible oxidative damage impairs motility, acrosome reaction, and DNA integrity, contributing to male infertility. The intricate balance between physiological redox signaling and pathological oxidative stress demonstrates the potential of redox modifications as biomarkers for infertility diagnosis and as targets for antioxidant-based therapeutic interventions. This review explores the role of redox-induced protein modifications in sperm function, focusing on thiol oxidation, S-nitrosylation, sulfhydration, glutathionylation, CoAlation, and protein carbonylation. By uncovering the mechanisms of these redox modifications, we provide a framework for their modulation in the development of targeted redox interventions to improve male fertility. Full article

The plant hormone ethylene elicits crucial regulatory effects on plant growth, development, and stress resistance. As the enzyme that catalyzes the final step of ethylene biosynthesis, 1-Aminocyclopropane-1-carboxylic acid oxidase (ACO) plays a key role in precisely controlling ethylene production. However, the functional characterization of the ACO gene family in rice remains largely unexplored. In this study, we performed a phylogenetic analysis of seven OsACO genes (OsACO1–OsACO7), which were classified into three subfamilies (Types I, II, and III). The members within the same clades exhibited similar tertiary structures and conserved protein motifs. We conducted inter/intraspecies covariance assays of OsACOs to elucidate their evolutionary and duplication events. Numerous cis-acting elements identified in OsACO promoter regions are associated with development, hormonal stimuli, and environmental responses. The expression assay by RT-qPCR revealed that OsACO genes exhibited tissue-specific expression and were significantly altered under various abiotic stresses, indicating their potential involvement in these processes regulated at the transcriptional level. Additionally, we predicted candidate-targeting miRNAs and identified putative cysteine sites of S-nitrosylation (SNO) and S-sulfhydration (SSH) in OsACOs, providing insights into their post-transcriptional and post-translational regulatory mechanisms. These findings pave the way for the further investigation of OsACO functions and their potential applications in improving rice growth and stress resilience by modulating ethylene biosynthesis. Full article

The intricate relationship between hydrogen sulfide (H₂S), gut microbiota, and sirtuins (SIRTs) can be seen as a paradigm axis in maintaining cellular homeostasis, modulating oxidative stress, and promoting mitochondrial health, which together play a pivotal role in aging and neurodegenerative diseases. H₂S, a gasotransmitter synthesized endogenously and by specific gut microbiota, acts as a potent modulator of mitochondrial function and oxidative stress, protecting against cellular damage. Through sulfate-reducing bacteria, gut microbiota influences systemic H₂S levels, creating a link between gut health and metabolic processes. Dysbiosis, or an imbalance in microbial populations, can alter H₂S production, impair mitochondrial function, increase oxidative stress, and heighten inflammation, all contributing factors in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Sirtuins, particularly SIRT1 and SIRT3, are NAD⁺-dependent deacetylases that regulate mitochondrial biogenesis, antioxidant defense, and inflammation. H₂S enhances sirtuin activity through post-translational modifications, such as sulfhydration, which activate sirtuin pathways essential for mitigating oxidative damage, reducing inflammation, and promoting cellular longevity. SIRT1, for example, deacetylates NF-κB, reducing pro-inflammatory cytokine expression, while SIRT3 modulates key mitochondrial enzymes to improve energy metabolism and detoxify reactive oxygen species (ROS). This synergy between H₂S and sirtuins is profoundly influenced by the gut microbiota, which modulates systemic H₂S levels and, in turn, impacts sirtuin activation. The gut microbiota–H₂S–sirtuin axis is also essential in regulating neuroinflammation, which plays a central role in the pathogenesis of neurodegenerative diseases. Pharmacological interventions, including H₂S donors and sirtuin-activating compounds (STACs), promise to improve these pathways synergistically, providing a novel therapeutic approach for neurodegenerative conditions. This suggests that maintaining gut microbiota diversity and promoting optimal H₂S levels can have far-reaching effects on brain health. Full article

Isorhamnetin (ISO) is an active flavonoid compound mainly isolated from the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. Previous studies have revealed the antifibrotic action of ISO in the liver and lungs, although its potential protective effects against renal fibrosis and the underlying mechanisms are still poorly understood. Given that many actions of ISO could be similarly attained by hydrogen sulfide (H₂S), we speculated that ISO may work through the induction of endogenous H₂S. To test the hypothesis, we established the unilateral ureteral obstruction (UUO) renal fibrosis rat model and transforming growth factor-β1(TGF-β1)-induced fibrosis in cultured renal tubular cells. ISO treatment inhibited epithelial–mesenchymal transition (EMT) formation, decreased extracellular matrix (ECM) deposition, and relieved renal fibrosis. Further analysis revealed that ISO stimulated the expression of the H₂S-synthesizing enzyme cystathionine lyase (CSE) and cystathionine beta-synthase (CBS), and promoted H₂S production in vivo and in vitro. The elevated H₂S attenuated oxidative stress and elevated the thiol level. It induced Keap1 sulfhydration, disrupted Keap1-Nrf2 interaction, and promoted the entry of Nrf2 into the nucleus. Finally, we found that circulating H₂S mainly derived from the liver, and not the kidney. Collectively, our study revealed that ISO alleviated renal fibrosis by inducing endogenous H₂S and regulating Keap1-Nrf2 interaction through sulfhydration of Keap1. Endogenous H₂S could be an important mediator underlying the pharmacological actions of ISO. Due to the multifunctional properties of H₂S, the H₂S-inducing nature of ISO could be exploited to treat various diseases. Full article

Hydrogen sulfide (H₂S), a gas traditionally considered toxic, is now recognized as a vital endogenous signaling molecule with a complex physiology. This comprehensive study encompasses a systematic literature review that explores the intricate mechanisms underlying H₂S-induced vasodilation. The vasodilatory effects of H₂S are primarily mediated by activating ATP-sensitive potassium (K_ATP) channels, leading to membrane hyperpolarization and subsequent relaxation of vascular smooth muscle cells (VSMCs). Additionally, H₂S inhibits L-type calcium channels, reducing calcium influx and diminishing VSMC contraction. Beyond ion channel modulation, H₂S profoundly impacts cyclic nucleotide signaling pathways. It stimulates soluble guanylyl cyclase (sGC), increasing the production of cyclic guanosine monophosphate (cGMP). Elevated cGMP levels activate protein kinase G (PKG), which phosphorylates downstream targets like vasodilator-stimulated phosphoprotein (VASP) and promotes smooth muscle relaxation. The synergy between H₂S and nitric oxide (NO) signaling further amplifies vasodilation. H₂S enhances NO bioavailability by inhibiting its degradation and stimulating endothelial nitric oxide synthase (eNOS) activity, increasing cGMP levels and potent vasodilatory responses. Protein sulfhydration, a post-translational modification, plays a crucial role in cell signaling. H₂S S-sulfurates oxidized cysteine residues, while polysulfides (H₂Sn) are responsible for S-sulfurating reduced cysteine residues. Sulfhydration of key proteins like K_ATP channels and sGC enhances their activity, contributing to the overall vasodilatory effect. Furthermore, H₂S interaction with endothelium-derived hyperpolarizing factor (EDHF) pathways adds another layer to its vasodilatory mechanism. By enhancing EDHF activity, H₂S facilitates the hyperpolarization and relaxation of VSMCs through gap junctions between endothelial cells and VSMCs. Recent findings suggest that H₂S can also modulate transient receptor potential (TRP) channels, particularly TRPV4 channels, in endothelial cells. Activating these channels by H₂S promotes calcium entry, stimulating the production of vasodilatory agents like NO and prostacyclin, thereby regulating vascular tone. The comprehensive understanding of H₂S-induced vasodilation mechanisms highlights its therapeutic potential. The multifaceted approach of H₂S in modulating vascular tone presents a promising strategy for developing novel treatments for hypertension, ischemic conditions, and other vascular disorders. The interaction of H₂S with ion channels, cyclic nucleotide signaling, NO pathways, ROS (Reactive Oxygen Species) scavenging, protein sulfhydration, and EDHF underscores its complexity and therapeutic relevance. In conclusion, the intricate signaling paradigms of H₂S-induced vasodilation offer valuable insights into its physiological role and therapeutic potential, promising innovative approaches for managing various vascular diseases through the modulation of vascular tone. Full article

Atherosclerosis is a chronic inflammatory condition marked by endothelial dysfunction, lipid accumulation, inflammatory cell infiltration, and extracellular matrix (ECM) remodeling within arterial walls, leading to plaque formation and potential cardiovascular events. Key players in ECM remodeling and inflammation are matrix metalloproteinases (MMPs) and CD147/EMMPRIN, a cell surface glycoprotein expressed on endothelial cells, vascular smooth muscle cells (VSMCs), and immune cells, that regulates MMP activity. Hydrogen sulfide (H₂S), a gaseous signaling molecule, has emerged as a significant modulator of these processes including oxidative stress mitigation, inflammation reduction, and vascular remodeling. This systematic review investigates the mechanistic pathways through which H₂S influences MMPs and CD147/EMMPRIN and assesses its impact on atherosclerosis progression. A comprehensive literature search was conducted across PubMed, Scopus, and Web of Science databases, focusing on studies examining H₂S modulation of MMPs and CD147/EMMPRIN in atherosclerosis contexts. Findings indicate that H₂S modulates MMP expression and activity through transcriptional regulation and post-translational modifications, including S-sulfhydration. By mitigating oxidative stress, H₂S reduces MMP activation, contributing to plaque stability and vascular remodeling. H₂S also downregulates CD147/EMMPRIN expression via transcriptional pathways, diminishing inflammatory responses and vascular cellular proliferation within plaques. The dual regulatory role of H₂S in inhibiting MMP activity and downregulating CD147 suggests its potential as a therapeutic agent in stabilizing atherosclerotic plaques and mitigating inflammation. Further research is warranted to elucidate the precise molecular mechanisms and to explore H₂S-based therapies for clinical application in atherosclerosis. Full article

Hydrogen sulfide (H₂S) and polysulfides (H₂S_n, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, and energy formation. H₂S_n, which have additional sulfur atoms to H₂S, and other S-sulfurated molecules such as cysteine persulfide and S-sulfurated cysteine residues of proteins, are produced by enzymes including 3-mercaptopyruvate sulfurtransferase (3MST). H₂S_n are also generated by the chemical interaction of H₂S with NO, or to a lesser extent with H₂O₂. S-sulfuration (S-sulfhydration) has been proposed as a mode of action of H₂S and H₂S_n to regulate the activity of target molecules. Recently, we found that H₂S/H₂S₂ regulate the release of neurotransmitters, such as GABA, glutamate, and D-serine, a co-agonist of N-methyl-D-aspartate (NMDA) receptors. H₂S facilitates the induction of hippocampal long-term potentiation, a synaptic model of memory formation, by enhancing the activity of NMDA receptors, while H₂S₂ achieves this by activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading to the activation of nearby neurons. The recent findings show the other aspects of TRPA1 channels—that is, the regulation of the levels of sulfur-containing molecules and their metabolizing enzymes. Disturbance of the signalling by H₂S/H₂S_n has been demonstrated to be involved in various diseases, including cognitive and psychiatric diseases. The physiological and pathophysiological roles of these molecules will be discussed. Full article

The gaseous signaling molecule hydrogen sulfide (H₂S) critically modulates a plethora of physiological processes across evolutionary boundaries. These include responses to stress and other neuromodulatory effects that are typically dysregulated in aging, disease, and injury. H₂S has a particularly prominent role in modulating neuronal health and survival under both normal and pathologic conditions. Although toxic and even fatal at very high concentrations, emerging evidence has also revealed a pronounced neuroprotective role for lower doses of endogenously generated or exogenously administered H₂S. Unlike traditional neurotransmitters, H₂S is a gas and, therefore, is unable to be stored in vesicles for targeted delivery. Instead, it exerts its physiologic effects through the persulfidation/sulfhydration of target proteins on reactive cysteine residues. Here, we review the latest discoveries on the neuroprotective roles of H₂S in Alzheimer’s disease (AD) and traumatic brain injury, which is one the greatest risk factors for AD. Full article

Endothelial dysfunction is implicated in the development and aggravation of cardiovascular complications. Among the endothelium-released vasoactive factors, hydrogen sulfide (H₂S) has been investigated for its beneficial effects on the vasculature through anti-inflammatory and redox-modulating regulatory mechanisms. Reduced H₂S bioavailability is reported in chronic diseases such as cardiovascular disease, diabetes, atherosclerosis and preeclampsia, suggesting the value of investigating mechanisms, by which H₂S acts as a vasoprotective gasotransmitter. We explored whether the protective effects of H₂S were linked to the mitochondrial health of endothelial cells and the mechanisms by which H₂S rescues apoptosis. Here, we demonstrate that endothelial dysfunction induced by TNF-α increased endothelial oxidative stress and induced apoptosis via mitochondrial cytochrome c release and caspase activation over 24 h. TNF-α also affected mitochondrial morphology and altered the mitochondrial network. Post-treatment with the slow-releasing H₂S donor, GYY4137, alleviated oxidising redox state, decreased pro-caspase 3 activity, and prevented endothelial apoptosis caused by TNF-α alone. In addition, exogenous GYY4137 enhanced S-sulfhydration of pro-caspase 3 and improved mitochondrial health in TNF-α exposed cells. These data provide new insights into molecular mechanisms for cytoprotective effects of H₂S via the mitochondrial-driven pathway. Full article

Neurotoxicity is induced by different toxic substances, including environmental chemicals, drugs, and pathogenic toxins, resulting in oxidative damage and neurodegeneration in mammals. The nervous system is extremely vulnerable to oxidative stress because of its high oxygen demand. Mitochondria are the main source of ATP production in the brain neuron, and oxidative stress-caused mitochondrial dysfunction is implicated in neurodegenerative diseases. H₂S was initially identified as a toxic gas; however, more recently, it has been recognized as a neuromodulator as well as a neuroprotectant. Specifically, it modulates mitochondrial activity, and H₂S oxidation in mitochondria produces various reactive sulfur species, thus modifying proteins through sulfhydration. This review focused on highlighting the neuron modulation role of H₂S in regulating neurodegenerative diseases through anti-oxidative, anti-inflammatory, anti-apoptotic and S-sulfhydration, and emphasized the importance of H₂S as a therapeutic molecule for neurological diseases. Full article

Because hydrogen sulfide (H₂S) is classified as a gaseous signaling molecule, protein S-sulfhydration is known to be one of the mechanisms by which H₂S signals are conducted. PTP1B, a negative regulator in insulin signaling, has been found to be S-sulfhydrated at Cys215-SH to form Cys215-SSH in response to endoplasmic reticulum (ER) stress. Therefore, we aimed to understand the change in PTP1B S-sulfhydration and cellular redox homeostasis in response to insulin stimulation. We demonstrated a feasible PEG-switch method to determine the levels of PTP1B S-sulfhydration. According to the results obtained from HEK293T and MDA-MB-231 cells, insulin induced a change in PTP1B S-sulfhydration that was similar to the change in Insulin receptor substrate 1 (IRS1) phosphorylation in both cell lines. However, insulin-induced PTP1B S-sulfhydration and IRS1 phosphorylation were only significantly affected by metformin in HEK293T cells. Insulin also induced an increase in reactive oxygen species (ROS) in both cell lines. However, the level of H₂S, GSH, and GSSG was only significantly affected by insulin and metformin in HEK293T cells. HEK293T cells maintained high levels of H₂S and cysteine, but low levels of GSSG and GSH in general compared to MDA-MB-231 cells. From these findings, we suggest that PTP1B activity is modulated by H₂S and redox-regulated S-sulfhydration during insulin signaling. Full article

Hydrogen sulfide (H₂S), as a gasotransmitter, is involved in various pathophysiological processes. Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus (DM), which leads to structural and functional abnormalities of the myocardium and eventually causes heart failure (HF). Systolic and diastolic dysfunction are fundamental features of heart failure. SERCA2a, as a key enzyme for calcium transport in the endoplasmic reticulum (ER), affects the process of myocardial relaxation and contraction. H₂S can protect the cardiac function against diabetic hearts, however, its mechanisms are unclear. This study found that exogenous H₂S affects cellular calcium transport by regulating the H₂S/MuRF1/SERCA2a/cardiac contractile pathway. Our results showed that, compared with the db/db mice, exogenous H₂S restored the protein expression levels of CSE and SERCA2a, and the activity of SERCA2a, while reducing cytosolic calcium concentrations and MuRF1 expression. We demonstrated that MuRF1 could interact with SERCA2a via co-immunoprecipitation. Using LC-MS/MS protein ubiquitylation analysis, we identified 147 proteins with increased ubiquitination levels, including SERCA2a, in the cardiac tissues of the db/db mice compared with NaHS-treated db/db mice. Our studies further revealed that NaHS administration modified MuRF1 S-sulfhydration and enhanced the activity and expression of SERCA2a. Under hyperglycemia and hyperlipidemia, overexpression of the MuRF1-Cys44 mutant plasmid reduced the S-sulfhydration level of MuRF1 and decreased the ubiquitination level of SERCA2a and the intracellular Ca²⁺ concentration. These findings suggested that H₂S modulates SERCA2a ubiquitination through MuRF1 S-sulfhydration of Cys44 to prevent decreased myocardial contractility due to increased cytosolic calcium. Full article

Respiratory syncytial virus (RSV) can cause severe respiratory illness in infants, immunocompromised, and older adults. Despite its burden, no vaccine or specific treatment is available. RSV infection is associated with increased reactive oxygen species (ROS) production, degradation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), and decreased antioxidant enzymes (AOEs), leading to oxidative damage and lung injury. Hydrogen sulfide (H₂S) is an endogenous gaseous molecule that plays a physiological role in numerous cellular processes and a protective role in multiple pathological conditions, displaying vasoactive, cytoprotective, anti-inflammatory, and antioxidant activities. H₂S can promote NRF2 activation through the sulfhydration of Kelch-like ECH-associated protein 1, the cytoplasmic repressor of NRF2. Here we investigated whether increasing cellular H₂S levels could rescue NRF2 and NRF2-dependent gene expression in RSV-infected primary airway epithelial cells. We found that treatment with the H₂S donor GYY4137 significantly increased NRF2 levels and AOEs gene expression by decreasing KEAP1 levels, and by modulating pathways involved in RSV-induced NRF2 degradation, such as NRF2 ubiquitination, and promyelocytic leukemia (PML) protein levels. These results suggest that the administration of exogenous H₂S can positively impact the altered redox balance associated with RSV infection, which represents an important determinant of RSV-induced lung disease. Full article

Histone deacetylase 6 (HDAC6) acts as a regulator of the nuclear factor kappa-B (NF-κB) signaling pathway by deacetylating the non-histone protein myeloid differentiation primary response 88 (MyD88) at lysine residues, which is an adapter protein for the Toll-like receptor (TLR) and interleukin (IL)-1β receptor. Over-activated immune responses, induced by infiltrated immune cells, excessively trigger the NF-κB signaling pathway in other effector cells and contribute to the development of rheumatoid arthritis (RA). It has also been reported that HDAC6 can promote the activation of the NF-κB signaling pathway. In the present study, we showed that HDAC6 protein level was increased in the synovium tissues of adjuvant-induced arthritis rats. In addition, hydrogen sulfide (H₂S) donor S-propargyl-cysteine (SPRC) can inhibit HDAC6 expression and alleviate inflammatory response in vivo. In vitro study revealed that HDAC6 overexpression activated the NF-κB signaling pathway by deacetylating MyD88. Meanwhile, sodium hydrosulfide (NaHS) or HDAC6 inhibitor tubastatin A (tubA) suppressed the pro-inflammatory function of HDAC6. Furthermore, the reduced expression of HDAC6 appeared to result from transcriptional inhibition by S-sulfhydrating specificity protein 1 (Sp1), which is a transcription factor of HDAC6. Our results demonstrate that Sp1 can regulate HDAC6 expression, and S-sulfhydration of Sp1 by antioxidant molecular H₂S ameliorates RA progression via the HDAC6/MyD88/NF-κB signaling pathway. Full article

This review focuses on the effects of hydrogen sulfide (H₂S) on the unique bioenergetic molecular machines in mitochondria and bacteria—the protein complexes of electron transport chains and associated enzymes. H₂S, along with nitric oxide and carbon monoxide, belongs to the class of endogenous gaseous signaling molecules. This compound plays critical roles in physiology and pathophysiology. Enzymes implicated in H₂S metabolism and physiological actions are promising targets for novel pharmaceutical agents. The biological effects of H₂S are biphasic, changing from cytoprotection to cytotoxicity through increasing the compound concentration. In mammals, H₂S enhances the activity of F_oF₁-ATP (adenosine triphosphate) synthase and lactate dehydrogenase via their S-sulfhydration, thereby stimulating mitochondrial electron transport. H₂S serves as an electron donor for the mitochondrial respiratory chain via sulfide quinone oxidoreductase and cytochrome c oxidase at low H₂S levels. The latter enzyme is inhibited by high H₂S concentrations, resulting in the reversible inhibition of electron transport and ATP production in mitochondria. In the branched respiratory chain of Escherichia coli, H₂S inhibits the bo₃ terminal oxidase but does not affect the alternative bd-type oxidases. Thus, in E. coli and presumably other bacteria, cytochrome bd permits respiration and cell growth in H₂S-rich environments. A complete picture of the impact of H₂S on bioenergetics is lacking, but this field is fast-moving, and active ongoing research on this topic will likely shed light on additional, yet unknown biological effects. Full article