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23 pages, 4767 KiB  
Review
Self-Reporting H2S Donors: Integrating H2S Release with Real-Time Fluorescence Detection
by Changlei Zhu and John C. Lukesh
Chemistry 2025, 7(4), 116; https://doi.org/10.3390/chemistry7040116 - 21 Jul 2025
Viewed by 374
Abstract
Hydrogen sulfide (H2S), once regarded solely as a highly toxic gas, is now recognized as a crucial signaling molecule in plants, bacteria, and mammals. In humans, H2S signaling plays a role in numerous physiological and pathological processes, including vasodilation, [...] Read more.
Hydrogen sulfide (H2S), once regarded solely as a highly toxic gas, is now recognized as a crucial signaling molecule in plants, bacteria, and mammals. In humans, H2S signaling plays a role in numerous physiological and pathological processes, including vasodilation, neuromodulation, and cytoprotection. To exploit its biological functions and therapeutic potential, a wide range of H2S-releasing compounds, known as H2S donors, have been developed. These donors are designed to release H2S under physiological conditions in a controlled manner. Among them, self-reporting H2S donors are seen as a particularly innovative class, combining therapeutic delivery with real-time fluorescence-based detection. This dual functionality enables spatiotemporal monitoring of H2S release in biological environments, eliminating the need for additional sensors or probes that could disrupt cellular homeostasis. This review summarizes recent advancements in self-reporting H2S donor systems, organizing them based on their activation triggers, such as specific bioanalytes, enzymes, or external stimuli like light. The discussion covers their design strategies, performance in biological applications, and therapeutic potential. Key challenges are also highlighted, including the need for precise control of H2S release kinetics, accurate signal quantification, and improved biocompatibility. With continued refinement, self-reporting H2S donors offer great promise for creating multifunctional platforms that seamlessly integrate diagnostic imaging with therapeutic H2S delivery. Full article
(This article belongs to the Special Issue Organic Chalcogen Chemistry: Recent Advances)
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23 pages, 739 KiB  
Review
Dietary Nitrogen and Its Role in the Gut Microbiome and Inflammatory Bowel Disease: A Narrative Review
by Matthew Herrera and Lauri O. Byerley
Nutrients 2025, 17(14), 2373; https://doi.org/10.3390/nu17142373 - 20 Jul 2025
Cited by 1 | Viewed by 685
Abstract
In recent years, gut microbiota has emerged as a critical regulator of gastrointestinal health and disease, with its role in inflammatory bowel disease (IBD)—including Crohn’s disease and ulcerative colitis—being particularly significant. Among the many factors influencing the gut microbiota, dietary components such as [...] Read more.
In recent years, gut microbiota has emerged as a critical regulator of gastrointestinal health and disease, with its role in inflammatory bowel disease (IBD)—including Crohn’s disease and ulcerative colitis—being particularly significant. Among the many factors influencing the gut microbiota, dietary components such as fibers, fats, and polyphenols have received substantial attention. However, nitrogen-containing compounds, such as amino acids, nitrates, urea, and even nucleic acids, such as purines, remain underexplored despite their integral role in shaping microbial ecology, host metabolism, and immune responses. Some of these compounds are metabolized by gut bacteria into bioactive molecules such as short-chain fatty acids, ammonia, and nitric oxide, which exert diverse effects on mucosal integrity and inflammation. IBD pathophysiology is characterized by chronic inflammation, microbial dysbiosis, and compromised epithelial barriers. Nitrogen metabolism contributes significantly to these processes by influencing microbial composition, metabolite production, and host immune pathways. The breakdown of various nitrogen-containing compounds in the body leads to the production of byproducts, such as ammonia and hydrogen sulfide, which have been implicated in mucosal damage and immune dysregulation. At the same time, nitrogen-derived molecules, such as short-chain fatty acids and nitric oxide, exhibit protective effects, underscoring the dual role of dietary nitrogen in health and disease. This narrative review highlights the complex interactions between dietary nitrogen sources, gut microbiota, and IBD pathogenesis. We summarize the mechanisms by which nitrogen compounds influence microbial dynamics, identify their contributions to inflammation and barrier dysfunction, and explore their therapeutic potential. Multidisciplinary approaches integrating clinical, metabolomic, and microbiome research are essential to unravel the full scope of nitrogen’s role in gut health and identify novel therapeutic targets. Full article
(This article belongs to the Special Issue Diet–Microbiome Interaction in Gastrointestinal Disorders)
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42 pages, 18742 KiB  
Article
Mitochondrial Unfolded Protein Response (mtUPR) Activation Improves Pathological Alterations in Cellular Models of Ethylmalonic Encephalopathy
by José Manuel Romero-Domínguez, Paula Cilleros-Holgado, David Gómez-Fernández, Rocío Piñero-Pérez, Diana Reche-López, Ana Romero-González, Mónica Álvarez-Córdoba, Alejandra López-Cabrera, Marta Castro De Oliveira, Andrés Rodríguez-Sacristán, Susana González-Granero, José Manuel García-Verdugo, Angeles Aroca and José A. Sánchez-Alcázar
Antioxidants 2025, 14(6), 741; https://doi.org/10.3390/antiox14060741 - 16 Jun 2025
Viewed by 2572
Abstract
Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, [...] Read more.
Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H2S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H2S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants. Full article
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23 pages, 4894 KiB  
Article
Hydrogen Sulfide (H2S) Metabolism, Iron Overload, and Apoptosis–Autophagy Equilibrium in Vascular Smooth Muscle Cells
by Hassan Mustafa Arif, Ming Fu and Rui Wang
Antioxidants 2025, 14(5), 560; https://doi.org/10.3390/antiox14050560 - 8 May 2025
Cited by 1 | Viewed by 806
Abstract
Iron overload contributes to proliferative vascular diseases, yet its interplay with hydrogen sulfide (H2S) in vascular smooth muscle cell (VSMC) proliferation remains poorly understood. This study elucidates H2S’s role in mitigating iron-overload-induced oxidative stress and cellular damage. Using aortic [...] Read more.
Iron overload contributes to proliferative vascular diseases, yet its interplay with hydrogen sulfide (H2S) in vascular smooth muscle cell (VSMC) proliferation remains poorly understood. This study elucidates H2S’s role in mitigating iron-overload-induced oxidative stress and cellular damage. Using aortic VSMCs from wildtype (WT) and cystathionine γ-lyase-knockout (CSE-KO) mice treated with ferric ammonium citrate (FAC) at concentrations equivalent to serum levels of iron and citrate, we demonstrate that FAC triggers the integrated stress response (ISR) in WT cells, upregulating CSE to enhance H2S production. The ISR mediator ATF4 activates caspases but simultaneously induces CSE, which inhibits caspase activity and promotes autophagy via AMPK signaling. In CSE-KO cells, iron overload leads to diminished Ferritin upregulation, unchecked Caspase activation, and impaired autophagy compared to WT cells. Exogenous H2S restored iron homeostasis by enhancing Ferritin expression, activating NRF2 antioxidant pathways, and restoring apoptosis–autophagy equilibrium in both WT and KO cells. These findings establish H2S as a critical regulator of iron-induced VSMC dysfunction, highlighting its therapeutic potential in managing vascular pathologies linked to iron dysregulation. Full article
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16 pages, 1396 KiB  
Review
Therapeutic Potential of Alpha-Lipoic Acid: Unraveling Its Role in Oxidative Stress and Inflammatory Conditions
by Aqsa Shahid, Khadeeja Nasir and Madhav Bhatia
Curr. Issues Mol. Biol. 2025, 47(5), 322; https://doi.org/10.3390/cimb47050322 - 30 Apr 2025
Viewed by 4380
Abstract
Alpha-lipoic acid (ALA) is an essential organosulfur compound with a wide range of therapeutic applications, particularly in conditions involving inflammation and oxidative stress. In this review, we describe our current understanding of the multifaceted role of ALA in several inflammatory diseases (acute pancreatitis, [...] Read more.
Alpha-lipoic acid (ALA) is an essential organosulfur compound with a wide range of therapeutic applications, particularly in conditions involving inflammation and oxidative stress. In this review, we describe our current understanding of the multifaceted role of ALA in several inflammatory diseases (acute pancreatitis, arthritis, osteoarthritis, asthma, and sepsis), cardiovascular disorders (CVDs), and neurological conditions. The dual redox nature of ALA, shared with its reduced form dihydrolipoic acid (DHLA), underpins its powerful antioxidant and anti-inflammatory properties, including reactive oxygen species scavenging, metal chelation, and the regeneration of endogenous antioxidants such as glutathione. A substantial body of evidence from preclinical and clinical studies suggests that ALA modulates the key signaling pathways involved in inflammation and cellular stress responses, making it a promising candidate for mitigating inflammation and its systemic consequences. Notably, we also discuss a novel perspective that attributes some of the therapeutic effects of ALA to its ability to release hydrogen sulfide (H2S), a gaseous signaling molecule. This mechanism may offer further insights into the efficacy of ALA in the treatment of several diseases. Together, these findings support the potential of ALA as a multifunctional agent for managing inflammatory and oxidative stress-related diseases. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)
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15 pages, 8400 KiB  
Article
Hydrogen Sulfide (H2S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis
by Kai Ma, Jingwen Huang, Jin Zhang, Yuan Tian, Jing Hu, Linhao Ma and Changnan Wang
Pathogens 2025, 14(5), 439; https://doi.org/10.3390/pathogens14050439 - 30 Apr 2025
Viewed by 579
Abstract
Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H2S) in sepsis-induced adrenal dysfunction. Methods: A [...] Read more.
Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H2S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine β-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNFα-stimulated Y1 adrenocortical cells. The treatments included the H2S donor NaHS, TNFα inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin–eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNFα levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H2S treatment attenuated adrenal damage, reduced TNFα, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNFα induced Y1 cell necroptosis, which was reversed by H2S or NSA. AOAA exacerbated TNFα-induced necroptosis in Y1 cells. Conclusions: H2S inhibits TNFα-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNFα–necroptosis axis and enhancing endogenous H2S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction. Full article
(This article belongs to the Special Issue Sepsis and Group A Streptococcus)
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29 pages, 2589 KiB  
Review
The Intestinal Thread of Fate: How the Microbiota Shapes the Story of Liver Disease
by Carlo Acierno, Riccardo Nevola, Luca Rinaldi, Ferdinando Carlo Sasso, Luigi Elio Adinolfi and Alfredo Caturano
Livers 2025, 5(2), 17; https://doi.org/10.3390/livers5020017 - 10 Apr 2025
Cited by 3 | Viewed by 2776
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is a multifactorial condition linked to liver injury, insulin resistance, and disrupted gut–liver interactions. A key aspect of MASLD pathogenesis is the dysfunction of intestinal barriers, including mechanical, immunological, and microbial alterations that amplify liver damage. The [...] Read more.
Metabolic dysfunction–associated steatotic liver disease (MASLD) is a multifactorial condition linked to liver injury, insulin resistance, and disrupted gut–liver interactions. A key aspect of MASLD pathogenesis is the dysfunction of intestinal barriers, including mechanical, immunological, and microbial alterations that amplify liver damage. The disruption of tight junctions and increased intestinal permeability allow microbial products, such as lipopolysaccharides, to enter the bloodstream, triggering liver inflammation via Kupffer cell activation. In MASLD, the gut vascular barrier is also compromised, marked by increased expression of PV-1. Additionally, dysbiosis, driven by high-fat, high-sugar diets, shifts the gut microbiota toward pro-inflammatory species, exacerbating systemic inflammation and intestinal permeability. This imbalance activates Toll-like receptor signaling, which promotes endotoxin-induced liver injury. Gut dysbiosis further impairs lipid metabolism, contributing to hepatic steatosis and MASLD progression. The gut–liver axis plays a critical role, with factors like altered bile acid metabolism and toxic metabolites such as hydrogen sulfide worsening intestinal barrier function and fueling chronic inflammation. This review aims to explore the complex role of the gut–liver axis in MASLD progression, highlighting the mechanisms of intestinal barrier dysfunction, dysbiosis, and microbial contributions to liver injury. It also discusses therapeutic strategies targeting intestinal barriers, including dietary and microbiota-based interventions, while acknowledging the challenges of personalized treatment approaches. Future research should focus on multi-omics technologies and the safety and efficacy of microbiota-targeted therapies in MASLD management. Full article
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20 pages, 4246 KiB  
Review
Hydrogen Sulfide (H2S- or H2Sn-Polysulfides) in Synaptic Plasticity: Modulation of NMDA Receptors and Neurotransmitter Release in Learning and Memory
by Constantin Munteanu, Anca Irina Galaction, Gelu Onose, Marius Turnea and Mariana Rotariu
Int. J. Mol. Sci. 2025, 26(7), 3131; https://doi.org/10.3390/ijms26073131 - 28 Mar 2025
Viewed by 2497
Abstract
Hydrogen sulfide (H2S) has emerged as a pivotal gaseous transmitter in the central nervous system, influencing synaptic plasticity, learning, and memory by modulating various molecular pathways. This review examines recent evidence regarding how H2S regulates NMDA receptor function and [...] Read more.
Hydrogen sulfide (H2S) has emerged as a pivotal gaseous transmitter in the central nervous system, influencing synaptic plasticity, learning, and memory by modulating various molecular pathways. This review examines recent evidence regarding how H2S regulates NMDA receptor function and neurotransmitter release in neuronal circuits. By synthesizing findings from animal and cellular models, we investigate the impacts of enzymatic H2S production and exogenous H2S on excitatory synaptic currents, long-term potentiation, and intracellular calcium signaling. Data suggest that H2S interacts directly with NMDA receptor subunits, altering receptor function and modulating neuronal excitability. Simultaneously, H2S promotes the release of neurotransmitters such as glutamate and GABA, shaping synaptic dynamics and plasticity. Furthermore, reports indicate that disruptions in H2S metabolism contribute to cognitive impairments and neurodegenerative disorders, underscoring the potential therapeutic value of targeting H2S-mediated pathways. Although the precise mechanisms of H2S-induced changes in synaptic strength remain elusive, a growing body of evidence positions H2S as a significant regulator of memory formation processes. This review calls for more rigorous exploration into the molecular underpinnings of H2S in synaptic plasticity, paving the way for novel pharmacological interventions in cognitive dysfunction. Full article
(This article belongs to the Special Issue Advances in Synaptic Transmission and Plasticity)
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18 pages, 3537 KiB  
Article
The Dual Role of Exogenous Hydrogen Sulfide (H2S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions
by Domenica Mallardi, Guglielmina Chimienti, Fatima Maqoud, Antonella Orlando, Simona Drago, Eleonora Malerba, Caterina De Virgilio, Hamid I. Akbarali and Francesco Russo
Antioxidants 2025, 14(4), 384; https://doi.org/10.3390/antiox14040384 - 25 Mar 2025
Viewed by 772
Abstract
Hydrogen sulfide (H2S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H2S exert cytoprotective effects, excessive concentrations can lead to toxicity, oxidative stress, and [...] Read more.
Hydrogen sulfide (H2S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H2S exert cytoprotective effects, excessive concentrations can lead to toxicity, oxidative stress, and inflammation. The aim of this study was to investigate the dose-dependent effects of exogenous H2S on mitochondrial functions and biogenesis in intestinal epithelial cells under non-stressed conditions. Using a Caco-2 monolayer model, we evaluated the impact of sodium hydrosulfide (NaHS) at concentrations ranging from 1 × 10−7 M to 5 × 10−3 M on mitochondrial metabolism, redox balance, antioxidant defense, inflammatory responses, autophagy/mitophagy, and apoptosis. Our results demonstrated a biphasic response: low-to-moderate H2S concentrations (1 × 10−7 M–1.5 × 10−3 M) enhance mitochondrial biogenesis through PGC-1α activation, upregulating TFAM and COX-4 expression, and increasing the mtDNA copy number. In contrast, higher concentrations (2 × 10−3–5 × 10−3 M) impair mitochondrial function, induce oxidative stress, and promote apoptosis. These effects are associated with elevated reactive oxygen species (ROS) production, dysregulation of antioxidant enzymes, and COX-2-mediated inflammation. H2S-induced autophagy/mitophagy is a protective mechanism at intermediate concentrations but fails to mitigate mitochondrial damage at toxic levels. This study underscores the delicate balance between the cytoprotective and cytotoxic effects of exogenous H2S in intestinal cells, helping to develop new therapeutic approaches for gastrointestinal disorders. Full article
(This article belongs to the Section ROS, RNS and RSS)
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28 pages, 1589 KiB  
Review
The Janus Face of Oxidative Stress and Hydrogen Sulfide: Insights into Neurodegenerative Disease Pathogenesis
by Constantin Munteanu, Anca Irina Galaction, Gelu Onose, Marius Turnea and Mariana Rotariu
Antioxidants 2025, 14(3), 360; https://doi.org/10.3390/antiox14030360 - 19 Mar 2025
Viewed by 1085
Abstract
Oxidative stress plays an essential role in neurodegenerative pathophysiology, acting as both a critical signaling mediator and a driver of neuronal damage. Hydrogen sulfide (H2S), a versatile gasotransmitter, exhibits a similarly “Janus-faced” nature, acting as a potent antioxidant and cytoprotective molecule [...] Read more.
Oxidative stress plays an essential role in neurodegenerative pathophysiology, acting as both a critical signaling mediator and a driver of neuronal damage. Hydrogen sulfide (H2S), a versatile gasotransmitter, exhibits a similarly “Janus-faced” nature, acting as a potent antioxidant and cytoprotective molecule at physiological concentrations, but becoming detrimental when dysregulated. This review explores the dual roles of oxidative stress and H2S in normal cellular physiology and pathophysiology, focusing on neurodegenerative disease progression. We highlight potential therapeutic opportunities for targeting redox and sulfur-based signaling systems in neurodegenerative diseases by elucidating the intricate balance between these opposing forces. Full article
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27 pages, 5191 KiB  
Review
Harnessing Gasotransmitters to Combat Age-Related Oxidative Stress in Smooth Muscle and Endothelial Cells
by Constantin Munteanu, Anca Irina Galaction, Gelu Onose, Marius Turnea and Mariana Rotariu
Pharmaceuticals 2025, 18(3), 344; https://doi.org/10.3390/ph18030344 - 27 Feb 2025
Viewed by 1074
Abstract
Age-related oxidative stress is a critical factor in vascular dysfunction, contributing to hypertension and atherosclerosis. Smooth muscle cells and endothelial cells are particularly susceptible to oxidative damage, which exacerbates vascular aging through cellular senescence, chronic inflammation, and arterial stiffness. Gasotransmitters—hydrogen sulfide (H2 [...] Read more.
Age-related oxidative stress is a critical factor in vascular dysfunction, contributing to hypertension and atherosclerosis. Smooth muscle cells and endothelial cells are particularly susceptible to oxidative damage, which exacerbates vascular aging through cellular senescence, chronic inflammation, and arterial stiffness. Gasotransmitters—hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO)—are emerging as promising therapeutic agents for counteracting these processes. This review synthesizes findings from recent studies focusing on the mechanisms by which H2S, NO, and CO influence vascular smooth muscle and endothelial cell function. Therapeutic strategies involving exogenous gasotransmitter delivery systems and combination therapies were analyzed. H2S enhances mitochondrial bioenergetics, scavenges ROS, and activates antioxidant pathways. NO improves endothelial function, promotes vasodilation, and inhibits platelet aggregation. CO exhibits cytoprotective and anti-inflammatory effects by modulating heme oxygenase activity and ROS production. In preclinical studies, gasotransmitter-releasing molecules (e.g., NaHS, SNAP, CORMs) and targeted delivery systems show significant promise. Synergistic effects with lifestyle modifications and antioxidant therapies further enhance their therapeutic potential. In conclusion, gasotransmitters hold significant promise as therapeutic agents to combat age-related oxidative stress in vascular cells. Their multifaceted mechanisms and innovative delivery approaches make them potential candidates for treating vascular dysfunction and promoting healthy vascular aging. Further research is needed to translate these findings into clinical applications. Full article
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23 pages, 3305 KiB  
Review
CSE/H2S Signaling Pathways in Enhancing Muscle Function and Insulin Sensitivity During Exercise
by Miaomiao Xu, Xiaoguang Liu, Danting Hu, Zhaowei Li and Liming Lu
Int. J. Mol. Sci. 2025, 26(4), 1741; https://doi.org/10.3390/ijms26041741 - 18 Feb 2025
Viewed by 1352
Abstract
Exercise plays a crucial role in maintaining metabolic health, enhancing muscle function, and improving insulin sensitivity, thereby preventing metabolic diseases such as type 2 diabetes. Emerging evidence highlights the significance of the cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) signaling pathway as a [...] Read more.
Exercise plays a crucial role in maintaining metabolic health, enhancing muscle function, and improving insulin sensitivity, thereby preventing metabolic diseases such as type 2 diabetes. Emerging evidence highlights the significance of the cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) signaling pathway as a pivotal regulator in the molecular and physiological adaptations induced by exercise. This review comprehensively examines the biosynthesis and metabolism of H2S, its distribution in different muscle tissues, and the mechanisms by which CSE/H2S influences muscle contraction, repair, and protein synthesis. Additionally, it explores how CSE/H2S modulates insulin signaling pathways, glucose uptake, and lipid metabolism, thereby enhancing insulin sensitivity. The potential of H2S donors as exercise supplements is also discussed, highlighting their ability to improve exercise performance and metabolic health. Current research advancements, including the application of multi-omics approaches, are reviewed to provide a deeper understanding of the complex molecular networks involved. Furthermore, the challenges and future directions in CSE/H2S research are addressed, emphasizing the need for further mechanistic studies and clinical applications. This review underscores the therapeutic potential of targeting the CSE/H2S pathway to optimize the benefits of exercise and improve metabolic health. Full article
(This article belongs to the Special Issue Molecular and Physiological Mechanisms of Exercise)
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14 pages, 1242 KiB  
Article
Effects of Hydrogen Sulfide at Normal Body Temperature and in the Cold on Isolated Tail and Carotid Arteries from Rats and TRPA1 Knockout and Wild-Type Mice
by Leonardo Kelava, Eszter Pakai, Kazushi Ogasawara, Kata Fekete, Gabor Pozsgai, Erika Pinter and Andras Garami
Biomedicines 2024, 12(12), 2874; https://doi.org/10.3390/biomedicines12122874 - 18 Dec 2024
Cited by 1 | Viewed by 925
Abstract
Background: Hydrogen sulfide (H2S) is a gasotransmitter that modulates vascular tone, causing either vasodilation or vasoconstriction depending on the vascular bed, species, and experimental conditions. The cold-sensitive transient receptor potential ankyrin-1 (TRPA1) channel mediates H2S-induced effects; however, its contribution [...] Read more.
Background: Hydrogen sulfide (H2S) is a gasotransmitter that modulates vascular tone, causing either vasodilation or vasoconstriction depending on the vascular bed, species, and experimental conditions. The cold-sensitive transient receptor potential ankyrin-1 (TRPA1) channel mediates H2S-induced effects; however, its contribution to the vasomotor responses of different arteries at different temperatures has remained unclear. Here, we aimed to fill this gap by comparing the effects of sodium sulfide (Na2S), which is a fast-releasing H2S donor, on the isolated carotid and tail skin arteries of rats and mice at cold and normal body temperature with wire myography. Under the same circumstances, we also aimed to compare the effects of the canonical endothelium-dependent and -independent vasodilators, acetylcholine and sodium nitroprusside, respectively. Methods: We isolated the carotid and tail arteries from 32 adult Wistar rats and 64 TRPA1 knockout and wild-type mice, and then we studied their vasomotor responses to increasing doses (10−6–10−3 M) of Na2S as well as to acetylcholine and sodium nitroprusside (10−5 M for both) at 37 °C and in cold (17 or 20 °C). Results: In rat vessels, Na2S caused constriction of the carotids and relaxation of the tail arteries, which were not influenced by temperature. In mouse carotids, Na2S caused vasorelaxation, which was more pronounced in the cold at a lower dose (10−4 M). At a higher dose (10−3 M), the dilation was markedly attenuated in the absence of the TRPA1 channel. In the mouse tail arteries, Na2S caused vasorelaxation at 37 °C and vasocontraction in the cold. The genetic blockade of TRPA1 channels did not influence the vasomotor responses of the mouse tail arteries. Sodium nitroprusside-induced vasorelaxation was not influenced by any of the investigated factors, while acetylcholine-induced dilation decreased in the cold in all vessel types. Conclusions: Our results reveal the function of TRPA1 in the H2S-induced dilation of carotid arteries in mice. We also highlight interspecies differences in the vasomotor responses between rats and mice, as well as the importance of the effect of temperature on vascular responses. The implementation of the identified variables in future research can advance our understanding of cardiovascular physiology, especially in conditions with hypothermia (either accidental or therapeutic). Full article
(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)
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21 pages, 1871 KiB  
Review
Role of Microbiota-Derived Hydrogen Sulfide (H2S) in Modulating the Gut–Brain Axis: Implications for Alzheimer’s and Parkinson’s Disease Pathogenesis
by Constantin Munteanu, Gelu Onose, Mariana Rotariu, Mădălina Poștaru, Marius Turnea and Anca Irina Galaction
Biomedicines 2024, 12(12), 2670; https://doi.org/10.3390/biomedicines12122670 - 23 Nov 2024
Cited by 11 | Viewed by 3258
Abstract
Microbiota-derived hydrogen sulfide (H2S) plays a crucial role in modulating the gut–brain axis, with significant implications for neurodegenerative diseases such as Alzheimer’s and Parkinson’s. H2S is produced by sulfate-reducing bacteria in the gut and acts as a critical signaling [...] Read more.
Microbiota-derived hydrogen sulfide (H2S) plays a crucial role in modulating the gut–brain axis, with significant implications for neurodegenerative diseases such as Alzheimer’s and Parkinson’s. H2S is produced by sulfate-reducing bacteria in the gut and acts as a critical signaling molecule influencing brain health via various pathways, including regulating inflammation, oxidative stress, and immune responses. H2S maintains gut barrier integrity at physiological levels and prevents systemic inflammation, which could impact neuroinflammation. However, as H2S has a dual role or a Janus face, excessive H2S production, often resulting from gut dysbiosis, can compromise the intestinal barrier and exacerbate neurodegenerative processes by promoting neuroinflammation and glial cell dysfunction. This imbalance is linked to the early pathogenesis of Alzheimer’s and Parkinson’s diseases, where the overproduction of H2S exacerbates beta-amyloid deposition, tau hyperphosphorylation, and alpha-synuclein aggregation, driving neuroinflammatory responses and neuronal damage. Targeting gut microbiota to restore H2S homeostasis through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation presents a promising therapeutic approach. By rebalancing the microbiota-derived H2S, these strategies may mitigate neurodegeneration and offer novel treatments for Alzheimer’s and Parkinson’s diseases, underscoring the critical role of the gut–brain axis in maintaining central nervous system health. Full article
(This article belongs to the Special Issue Cellular and Molecular Biology of Neurodegenerative Disorders)
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18 pages, 2118 KiB  
Systematic Review
Hydrogen Sulfide and Gut Microbiota: Their Synergistic Role in Modulating Sirtuin Activity and Potential Therapeutic Implications for Neurodegenerative Diseases
by Constantin Munteanu, Gelu Onose, Mădălina Poștaru, Marius Turnea, Mariana Rotariu and Anca Irina Galaction
Pharmaceuticals 2024, 17(11), 1480; https://doi.org/10.3390/ph17111480 - 4 Nov 2024
Cited by 10 | Viewed by 4938
Abstract
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. [...] Read more.
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
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