Search Results (163)

Objectives: Downregulation of the endogenous gasotransmitter hydrogen sulfide (H₂S) contributes to the pathogenesis of pulmonary arterial hypertension (PAH). While prophylactic H₂S supplementation prevents PAH initiation in different rat models, its ability to reverse fully established PAH and pulmonary vascular structural remodeling is unknown. In this study, we aimed to test whether H₂S donor therapy can reverse the existing PAH in a chronic-hypoxia rat model. Methods: After 3 weeks of hypoxia exposure, rats with established hypoxia-induced pulmonary hypertension (HPH) were randomized to receive either continued hypoxia alone or hypoxia plus the H₂S donor NaHS (56 μmol/kg·d, ip) for an additional 6 weeks. Pulmonary artery pressure, pulmonary artery muscularization, and right ventricular hypertrophy were assessed. Furthermore, the cell proliferation (Ki-67 and PCNA), ERK1/2 phosphorylation, and persulfidation of the endothelin type A receptor (ETAR) were examined and detected in rat lung tissues and pulmonary artery smooth muscle cells (PASMCs). Results: H₂S therapy effectively reversed established HPH and pulmonary artery structural remodeling, reducing RVSP, mPAP, and the proportion of fully muscularized small pulmonary arteries by 13.8%, 12.0%, and 62.7%, respectively. Moreover, the PAT/PET ratio was normalized to normoxic levels. The right ventricular hypertrophy index decreased by 29.2%. Mechanistically, H₂S therapy suppressed PASMC proliferation, reduced ERK1/2 phosphorylation, and enhanced ETAR persulfidation. Furthermore, dithiothreitol-mediated reduction of ETAR persulfidation abrogated these antiproliferative effects of H₂S therapy, establishing persulfidation as an obligatory mechanism. Conclusions: H₂S donor therapy effectively reverses established HPH and pulmonary vascular structural remodeling by inhibiting PASMC proliferation, which is linked to enhanced ETAR persulfidation. These data provide preclinical proof-of-concept for H₂S-based interventions in patients with manifest PAH. Full article

Background: Polysaccharide-based dynamic hydrogels are promising for wound management due to their biocompatibility, injectability, and tunable biofunctionality. The integration of therapeutic gasotransmitter donors offers a strategy to modulate the wound microenvironment. Objectives: This study aimed to develop an injectable, self-healing carbohydrate hydrogel capable of sustained hydrogen sulfide (H₂S) release for burn wound therapy, and to evaluate its physicochemical properties, in vivo efficacy, and mechanism of action. Methods: A dynamic hydrogel (ACMOD) was fabricated via Schiff-base crosslinking between oxidized dextran (OD) and carboxymethyl chitosan (CMCS), incorporating the H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH). Rheological and recovery tests characterized its mechanical and self-healing properties. Efficacy and mechanisms were assessed in a rat full-thickness burn model, analyzing wound closure, histology, oxidative stress, macrophage polarization, angiogenesis, and collagen deposition. Results: ACMOD exhibited shear-thinning, rapid self-healing, and strong tissue adherence. Sustained H₂S release from ACMOD significantly accelerated wound closure and improved tissue regeneration compared to controls. Mechanistically, H₂S attenuated oxidative stress, promoted a pro-regenerative M2 macrophage phenotype, enhanced angiogenesis via VEGF upregulation, and fostered organized collagen deposition and extracellular matrix remodeling. Conclusions: This work demonstrates a versatile, carbohydrate-based dynamic hydrogel platform that synergizes polymer network dynamics with bioactive H₂S delivery to effectively promote burn wound healing. The findings underscore the potential of polysaccharide hydrogels with integrated gasotransmitter release for regenerative therapy and biomaterials applications. Full article

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, emerged as an important contributor to the pathogenesis of diabetes and its complications. Impaired glucose and iron metabolism, and increased oxidative stress, predispose cells—particularly pancreatic β-cells and vascular tissues—to ferroptotic cell death, contributing to β-cell dysfunction, insulin resistance, and the progression of diabetic complications. Hydrogen sulfide (H₂S), an important gasotransmitter, plays a pivotal role in regulating various pathophysiological processes by interfering with key cellular signaling pathways, including those related to cell death. In the context of ferroptosis, H₂S exerts protective effects by activating the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4/glutathione (Nrf2/GPX4/GSH) axis, enhancing cellular antioxidative defenses and inhibiting lipid peroxidation. Furthermore, H₂S modulates key regulators of iron homeostasis and lipid metabolism, including hepcidin, ferritin, and the cystine/glutamate antiporter system (xCT) antiporter, further attenuating ferroptosis. Exogenous administration of H₂S can reverse ferroptosis-induced cellular injury in several pathological settings and improve metabolic outcomes in diabetic models. These findings suggest that targeting H₂S signaling is a promising therapeutic strategy to inhibit ferroptosis and mitigate diabetes-related organ dysfunction. This review summarizes current insights into the molecular interplay between H₂S and diabetes-related signaling pathways, primarily ferroptosis, emphasizing the antiferroptotic therapeutic potential of H₂S-based interventions for the prevention and treatment of diabetic complications. Full article

Alcohol use disorder (AUD) is highly comorbid with psychiatric conditions and is increasingly recognized as a modifiable factor associated with cognitive decline and dementia, including Alzheimer’s disease (AD). While epidemiological and experimental studies consistently demonstrate that chronic alcohol exposure exacerbates neurodegenerative vulnerability rather than implying a single dominant causal pathway, accumulating evidence supports a multifactorial and context-dependent framework in which alcohol acts as a disease-modifying stressor that perturbs endogenous adaptive and resilience mechanisms. Hydrogen sulfide (H₂S), involved in redox regulation, mitochondrial function, neuroinflammatory control, and vascular homeostasis, has emerged as a candidate pathway that may be indirectly affected by alcohol exposure and relevant to neurodegenerative processes. This narrative mechanistic review synthesizes preclinical and clinical data examining alcohol-induced perturbations and H₂S-related signaling pathways in the context of AD. We analyzed studies on the effects of acute and chronic alcohol exposure, as well as on cellular processes influenced by H₂S bioavailability and signaling. Across experimental models and human studies, alcohol exposure was consistently associated with oxidative and mitochondrial stress, neuroinflammation, and vascular dysfunction—processes that overlap with biological domains normally regulated by H₂S. Alcohol-related cognitive impairment frequently occurs in the absence of proportional increases in classical AD pathology, suggesting that alcohol may accelerate disease progression through non-canonical mechanisms. H₂S signaling confers resilience against oxidative, inflammatory, and mitochondrial stress, whereas reduced H₂S bioavailability or disrupted sulfide-dependent signaling increases neuronal vulnerability and cognitive impairment. However, the available data do not support a unidirectional or exclusive role for H₂S as an integrative driver of alcohol-related AD pathology. H₂S signaling represents a biologically plausible convergent and modulatory pathway linking alcohol exposure to AD risk. Full article

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, often resulting in multiorgan dysfunction. Among affected systems, the gastrointestinal tract plays a central role in sepsis progression by promoting systemic inflammation through impaired barrier function, immune imbalance, and microbiome alterations. Recent research has identified selected medical gases and gasotransmitters as promising therapeutic candidates for preserving gut integrity in sepsis. In particular, hydrogen, carbon monoxide, and hydrogen sulfide exhibit antioxidative, anti-inflammatory, and cytoprotective properties. These gases act through defined molecular pathways, including activation of Nrf2, inhibition of NF-κB, and preservation of tight junction integrity, thereby supporting intestinal barrier function. In addition, they influence immune cell phenotypes and autophagy, with indirect effects on the gut microbiome. Although most supporting evidence derives from preclinical models, translational findings and emerging safety data highlight the potential of gut-targeted gas-based strategies. This review summarizes current mechanistic and translational evidence for gut-protective medical gases in sepsis and discusses their integration into future organ-specific and mechanism-based therapeutic approaches. Full article

Sulfur dioxide (SO₂) is a colorless, pungent gas that is a significant contributor to air pollution, with well-documented environmental and health impacts. It is emitted both naturally (e.g., in volcanic activities) and anthropogenically (e.g., fossil fuel combustion, sulfuric acid production, papermaking, and wine preservation). Inhalation represents the primary route of human exposure, particularly in urban and industrial settings. Acute SO₂ exposure can lead to airway irritation, laryngospasm, bronchoconstriction, pulmonary edema, and death in severe cases. Chronic exposure, even at low concentrations, can contribute to the development of pulmonary and extrapulmonary diseases. Despite its classification as a hazardous air pollutant, a comprehensive understanding of dose-response relationships, exposure thresholds, and mechanisms of toxicity for SO₂ remains limited. This review synthesizes current knowledge on environmental sources, exposure routes, mechanisms of toxicity, and health impacts of SO₂, highlighting findings from epidemiological, toxicological, and mechanistic studies. We also discuss gaps in knowledge regarding SO₂, approaches to monitor and assess SO₂ exposure in ambient environments, the emerging role of SO₂ as a gasotransmitter, and areas where further research is needed to better understand health risks and support evidence-based public health decision-making. Full article

Cerebral ischemia–reperfusion injury triggers mitochondrial dysfunction and oxidative stress, exacerbating neuronal apoptosis. Emerging evidence highlights hydrogen sulfide (H₂S) as a gasotransmitter modulating redox balance, autophagy, and apoptosis. This study investigates the neuroprotective mechanisms of Enriched Environment (EE) against ischemic injury, focusing on mitochondrial dynamics and H₂S-mediated pathways. Using MCAO mice and OGD/R-treated SH-SY5Y neurons, interventions targeting H₂S synthesis, hypoxia-inducible factor 1-alpha (HIF-1α), and mitophagy were implemented. Behavioral, histological, and molecular analyses demonstrated EE significantly improved neurological outcomes, suppressed apoptosis, and attenuated oxidative damage (reduced MDA, elevated MnSOD/glutathione). Mechanistically, EE enhanced mitophagy via dual pathways: canonical PINK1/parkin-mediated mitochondrial clearance, corroborated by transmission electron microscope and LC3B/parkin colocalization, and non-canonical HIF-1α/BNIP3L axis activation. Transcriptomic and Co-immunoprecipitation (Co-IP) data revealed EE upregulated endogenous H₂S biosynthesis post-injury by promoting dopamine-induced calcium influx, which activated calmodulin-dependent signaling to stimulate cystathionine β-synthase/γ-lyase expression. Pharmacological blockade of H₂S synthesis or HIF-1α abolished mitochondrial protection, confirming H₂S as a central mediator. Notably, H₂S exerted antiapoptotic effects by restoring mitochondrial integrity through synergistic mitophagy activation and oxidative stress mitigation. These findings propose a novel neuroprotective cascade: EE-induced dopaminergic signaling potentiates H₂S production, which coordinates PINK1/parkin and HIF-1α/BNIP3L pathways to eliminate dysfunctional mitochondria, thereby preserving neuronal homeostasis. This study elucidates therapeutic potential of EE via H₂S-driven mitochondrial quality control, offering insights for ischemic brain injury intervention. Full article

Hydrogen sulfide (H₂S) is a gasotransmitter that plays a crucial role in regulating pathological processes following injury to the central and peripheral nervous systems. This review systematizes current data on various classes of H₂S donors and inhibitors of its biosynthesis in neurotrauma and related experimental models. Inorganic donors (e.g., NaHS, Na₂S, and STS) rapidly suppress oxidative stress and inflammation, supporting the recovery of synaptic plasticity and cognitive function. Organic donors (e.g., GYY4137, ACS67, ACS84, SPRC, ADT-OH and its derivatives, S-memantine, and MTC) provide sustained H₂S release, stabilize the blood–brain barrier, and exhibit antiapoptotic activity. Natural donors (e.g., DADS, DATS, and SAMe) demonstrate high biocompatibility, inhibit pyroptosis, and enhance antioxidant defense mechanisms. Hybrid systems—including nanoparticles and hydrogels—enable targeted delivery and prolonged action, thereby stimulating regeneration and angiogenesis. Thiol-activated donors (e.g., COS/H₂S and AlaCOS) allow controlled H₂S release, offering broad opportunities for precise modulation of its concentration within target tissues. Inhibitors (e.g., AOAA, PAG, oxamic hydrazide 1, L-aspartic acid, benserazide, and NSC4056) of H₂S biosynthesis underscore the physiological importance of this gasotransmitter, as their administration enhances neuroinflammation and diminishes neuroprotection. The analysis reveals a general pattern: all classes of H₂S donors effectively modulate key pathological mechanisms, differing in their rate, duration, and specificity of action. These findings highlight the therapeutic promise of H₂S-based pharmacological agents in clinical neurotraumatology, while emphasizing the need for further research to optimize delivery systems, enhance efficacy, and minimize adverse effects. Full article

Recent scientific reports have highlighted the physiological role, toxicological effects, and pathophysiological aspects of gasotransmitters, particularly hydrogen sulfide (H₂S), which is recognized as a new member of this family. Endogenous generation of H₂S in the skin occurs through both enzymatic and non-enzymatic pathways. The main enzymes involved in its endogenous production are cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase. 3-MST and CSE are crucial for maintaining the epidermal barrier. H₂S may play a role in oncogenesis, acting as a gas signaling molecule that disrupts mitochondrial respiration and influences immune modulation, cell proliferation, apoptosis, tumor cell survival, and metastasis. Interestingly, H₂S exhibits dual effects in the biology of skin cancer, promoting tumor growth in some contexts and exerting antitumor activities in others. Data from the European Cancer Information System and Global Cancer Observatory show a significant global increase in skin cancer cases. The most common types of cutaneous malignancies, from both epidemiological and clinical perspectives, are basal cell carcinoma. squamous cell carcinoma, and melanoma. This review aims to evaluate the dysfunctional metabolism of H₂S and the specific profiles of the enzymes that synthesize H₂S in skin cancer. By comparing the roles of H₂S in normal cells with those in cancer cells, we can enhance current understanding of its implications in skin cancer biology. This research paves the way for new clinical strategies, including the development of H₂S-modulatory therapies tailored to the dynamics of tumor progression, which could help overcome therapeutic resistance. Full article

This review integrates the biology and clinical translation of hydrogen sulfide (H₂S) in balneology. It frames H₂S as a gasotransmitters with dual chemical and biological actions and summarizes the H₂S/HS⁻ equilibrium as a function of pH, temperature, and oxygenation, which governs bioaccessibility in sulfurous waters. Endogenous and exogenous sources, transport, and mitochondrial catabolism are outlined, together with core cellular mechanisms: protein persulfidation; activation of Nrf2/ARE; modulation of NF-κB; regulation of ion channels; and engagement of PI3K/Akt, MAPK/ERK, and Wnt pathways, plus epigenetic interactions with HDACs and sirtuins. Preclinical and clinical evidence in dermatology, musculoskeletal disease, and respiratory care is synthesized, alongside metabolic, cardiovascular, gastrointestinal, and renal effects. Technical aspects that preserve the bioactive fraction of H₂S while meeting environmental safety limits are highlighted. Routes of administration (bathing, peloids, inhalation, and drinking cures) and key operational parameters are described. Overall, the review links physicochemical and molecular foundations with clinical indications for sulfurous waters and derivatives and identifies opportunities for research and development in H₂S donors and thermal cosmetics without extrapolating beyond the available data. Full article

Brassinin, a sulfur-containing phytoalexin, exerts anticancer and anti-inflammatory effects. Hydrogen sulfide (H₂S) is an important gasotransmitter with significant cardioprotective properties. The effects of brassinin on H₂S signaling and vascular smooth muscle cell (SMC) functions remain unexplored. This study found that brassinin protected against angiotensin II (Ang II)-induced SMC dysfunctions. These effects included the attenuation of excessive cell proliferation, migration, and oxidative stress; and upregulation of smooth muscle contractile protein expressions; and down-regulation of inflammatory gene expressions. Notably, brassinin did not directly release H₂S under the tested conditions; instead, it stimulated endogenous H₂S synthesis in cultured SMCs by inducing the expression of cystathionine gamma-lyase (CSE), a key H₂S-generating enzyme. Further mechanistic investigations revealed that brassinin may bind to the transcription factor C/EBPβ and enhance its interaction with the CSE promoter, thereby upregulating CSE transcription. In conclusion, our findings demonstrate that brassinin protects against SMC dysfunction, at least in part, by activating H₂S signaling rather than acting as a direct H₂S donor. These results provide new insights into the potential of brassinin as a therapeutic agent for improving vascular health and preventing cardiovascular diseases. Full article

Hydrogen sulfide (H₂S), nitric oxide (NO), and carbon monoxide (CO) are now recognized as key gasotranmitters that regulate vascular function, contributing to vasodilation, angiogenesis, inflammation control, and oxidative balance. Initially regarded as toxic gases, they are produced on demand by specific enzymes, including cystathionine γ-lyase (CSE), endothelial nitric oxide synthase (eNOS), and heme oxygenase-1 (HO-1). Their activity is tightly controlled by redox-sensitive pathways. Reactive oxygen species (ROS), particularly superoxide and hydrogen peroxide, modulate gasotransmitter biosynthesis at the transcriptional and post-translational levels. Moreover, ROS affect gasotransmitter availability through oxidative modifications, including thiol persulfidation, nitrosative signaling, and carbonylation. This redox regulation ensures a tightly coordinated response to environmental and metabolic cues within the vascular system. This review synthesizes the current understanding of redox–gasotransmitter interactions, highlighting how ROS modulate the vascular roles of H₂S, NO, and CO. Understanding these interactions provides critical insights into the pathogenesis of cardiovascular diseases and offers potential redox-targeted therapies. Full article

Carbon monoxide (CO) is generally recognized as a toxic gas; however, it has recently been identified as an endogenous gasotransmitter with significant cytoprotective properties. CO modulates key molecular pathways, including anti-inflammatory, anti-apoptotic, antioxidant, and vasodilatory signaling pathways, by targeting heme- and non-heme-containing proteins. These proteins include soluble guanylate cyclase, cytochrome P450 enzymes, MAPKs, and NLRP3. This review summarizes recent advances in understanding the molecular mechanisms associated with the protective effects of CO, particularly in the context of ischemia–reperfusion injury relevant to organ transplantation. We discuss preclinical data from rodent and large animal models, as well as therapeutic delivery strategies, such as inhalation, CO-releasing molecules, and gas-entrapping materials. We also reviewed early-phase clinical trials. The objective of this review is to provide a thorough exploration of CO as a potential therapeutic gas, with special emphasis on its application in transplantation. Full article

Oxidative stress in hypoxic conditions impairs the regenerative process in chronic wounds, highlighting the potential of reactive oxygen species (ROS) scavengers to accelerate wound healing. Nitric oxide (NO) in particular plays a pivotal role as an endogenous gasotransmitter and as a signaling molecule involved in regulating hypoxia. In this review, we examine hydrogel-based wound healing strategies for delivering gaseous NO molecules stably to the wound site. As carriers of NO donors, these hydrogels facilitate the controlled and sustained release of NO and offer high biocompatibility and hydrophilicity. First, we first introduce the hypoxic physiology of chronic wounds and elucidate the beneficial and detrimental effects of ROS. In addition, we discuss the role of NO in angiogenesis and the wound healing process. Finally, we review various NO donors and their incorporation into hydrogels for therapeutic applications. Given the extensive use of hydrogels in wound healing, this review will provide valuable avenues for the consideration of new functional hydrogels in regenerative treatments. Full article