Nitric Oxide (NO) and Hydrogen Sulfide (H2S) in Biology, Illness, and Therapies—2nd Edition

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (30 June 2025) | Viewed by 4094

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Guest Editor
Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA
Interests: nitric oxide; hydrogen sulfide; persulfide/polysulfide; sulfur metabolism; redox reaction; interaction/crosstalk; antioxidants; disease; therapy; detection methods
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Special Issue Information

Dear Colleagues,

In light of the great response that we received to our previous Special Issue, "Nitric Oxide (NO) and Hydrogen Sulfide (H2S) in Biology, Illness, and Therapies", we decided to revisit this topic.

Gaseous signaling molecules, including nitric oxide (NO), carbon dioxide (CO), and hydrogen sulfide (H2S), have been emerging as physiologically and pathophysiologically important mediators in mammals. Manipulating these mediators as a therapeutic measure appears promising in various diseases, and has already, at least partly, enhanced their clinical application, mostly through the inhalation of NO. The manipulation of H2S or persulfide/polysulfide, oxidative products of H2S, is being explored in clinical trials. However, these therapies still face challenges regarding broader clinical application, such as their toxicity, rapid diffusion, short half-life, and narrow therapeutic window. Novel therapeutic methods or strategies are required to enable more successful clinical applications for these gaseous mediators. These mediators or their metabolites also crosstalk/interact with each other and could exhibit nonspecific diverse reactions, which complicate our understanding of the biology of gaseous mediators and remain to be elucidated.

In this Special Issue, we welcome original research articles or review articles that focus on the physiology/pathophysiology, therapies, detection methods, and redox reactions related to NO, H2S, and their metabolites, facilitating the establishment of novel therapies for illnesses.

Dr. Eizo Marutani
Guest Editor

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Keywords

  • nitric oxide
  • hydrogen sulfide
  • persulfide/polysulfide
  • sulfur metabolism
  • redox reaction
  • interaction/crosstalk
  • antioxidants
  • disease
  • therapy
  • detection methods

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Published Papers (4 papers)

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Research

28 pages, 10207 KB  
Article
Hydrogen Sulfide Deficiency Contributes to Tubular Damage and Calcium Oxalate Crystal Formation in Hyperoxaluria Nephropathy: Role of Osteopontin and Tamm–Horsfall Protein
by Chien-Lin Lu, Yi-Shiou Tseng, Wen-Bin Wu, Chun-Hou Liao and Ming-Chieh Ma
Antioxidants 2025, 14(9), 1088; https://doi.org/10.3390/antiox14091088 - 5 Sep 2025
Viewed by 335
Abstract
Hydrogen sulfide (H2S) exerts regulatory functions in kidney diseases. However, its protective role against kidney stone formation remains unclear. Here, we demonstrate that hyperoxaluria or oxalate exposure impairs H2S formation, leading to tubular injury and calcium oxalate (CaOx) crystal [...] Read more.
Hydrogen sulfide (H2S) exerts regulatory functions in kidney diseases. However, its protective role against kidney stone formation remains unclear. Here, we demonstrate that hyperoxaluria or oxalate exposure impairs H2S formation, leading to tubular injury and calcium oxalate (CaOx) crystal deposition in both in vivo and in vitro models. In male rats fed 5% hydroxy-L-proline (HP), time-dependent increases in urinary supersaturation, tubular damage, and renal CaOx deposition were observed compared to controls. These changes were associated with the decreased expression of H2S-producing enzymes and elevated urinary secretion of osteopontin (OPN) and Tamm–Horsfall protein (THP). Notably, the protein level and activity of specificity protein 1 (Sp1), a transcription factor regulating these enzymes, were markedly decreased in HP-treated kidneys. Chronic supplementation with the H2S donor GYY4137 (GYY) significantly attenuated HP-induced tubular injury and CaOx deposition by reducing OPN and THP secretion. Consistent with in vivo results, H2S donors mitigated oxalate-induced tubular cell damage and CaOx formation in MDCK cells. Mechanistically, oxalate activated cyclic AMP/protein kinase A (PKA) signaling, which promoted OPN and THP secretion; these effects were eradicated by the PKA inhibitor H89 or GYY. These findings indicate that hyperoxaluria impairs Sp1 transcriptional activity, resulting in H2S deficiency and compromised anticrystallization defense in oxalate-induced tubulopathy. Full article
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23 pages, 2748 KB  
Article
Relationships Between H2S and OT/OTR Systems in Preeclampsia
by Tamara Merz, Sarah Ecker, Nicole Denoix, Oscar McCook, Stefanie Kranz, Ulrich Wachter, Edit Rottler, Thomas Papadopoulos, Christoph Fusch, Cosima Brucker, Jakob Triebel, Thomas Bertsch, Peter Radermacher and Christiane Waller
Antioxidants 2025, 14(7), 880; https://doi.org/10.3390/antiox14070880 - 18 Jul 2025
Viewed by 443
Abstract
Pre-eclampsia (PE) is a hypertensive pregnancy complication. Oxidative stress is hypothesized to contribute to the pathophysiology of PE. Both the hydrogen sulfide (H2S) and oxytocin (OT) systems might play a role in the pathophysiology of PE, like their antioxidant and hypotensive [...] Read more.
Pre-eclampsia (PE) is a hypertensive pregnancy complication. Oxidative stress is hypothesized to contribute to the pathophysiology of PE. Both the hydrogen sulfide (H2S) and oxytocin (OT) systems might play a role in the pathophysiology of PE, like their antioxidant and hypotensive effects. Thus, the role of the interaction of the OT and H2S systems in the context of PE was further elucidated in the present clinical case–control study “NU-HOPE” (Nürnberg-Ulm: The role of H2S and Oxytocin Receptor in Pre-Eclampsia; ethical approval by the Landesärztekammer Bayern, file number 19033, 29 August 2019), comparing uncomplicated pregnancies, early onset PE (ePE, onset < 34 weeks gestational age) and late onset PE (lPE, onset > 34 weeks gestational age). Routine clinical data, serum H2S and homocysteine levels, and tissue protein expression, as well as nitrotyrosine formation, were determined. The main findings were (i) unchanged plasma sulfide levels, (ii) significantly elevated homocysteine levels in ePE, but not lPE, (iii) significantly elevated expression of H2S enzymes and OT receptor in the placenta in lPE, and (iv) significantly elevated nitrotyrosine formation in the lPE myometrium. Taken together, these findings suggest a role for the interaction of the endogenous H2S- and OT/OTR systems in the pathophysiology of pre-eclampsia, possibly linked to impaired antioxidant protection. Full article
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12 pages, 1833 KB  
Article
Antihypertensive Effects of a Sodium Thiosulfate-Loaded Nanoparticle in a Juvenile Chronic Kidney Disease Rat Model
by You-Lin Tain, Chien-Ning Hsu, Chih-Yao Hou and Chih-Kuang Chen
Antioxidants 2024, 13(12), 1574; https://doi.org/10.3390/antiox13121574 - 20 Dec 2024
Cited by 2 | Viewed by 1149
Abstract
Sodium thiosulfate (STS), a precursor of hydrogen sulfide (H2S), has demonstrated antihypertensive properties. Previous studies have suggested that H2S-based interventions can prevent hypertension in pediatric chronic kidney disease (CKD). However, the clinical application of STS is limited by its [...] Read more.
Sodium thiosulfate (STS), a precursor of hydrogen sulfide (H2S), has demonstrated antihypertensive properties. Previous studies have suggested that H2S-based interventions can prevent hypertension in pediatric chronic kidney disease (CKD). However, the clinical application of STS is limited by its rapid release and intravenous administration. To address this, we developed a poly-lactic acid (PLA)-based nanoparticle system for sustained STS delivery and investigated whether weekly treatment with STS-loaded nanoparticles (NPs) could protect against hypertension in a juvenile CKD rat model. Male Sprague Dawley rats, aged three weeks, were fed a diet containing 0.5% adenine for three weeks to induce a model of pediatric CKD. STS-loaded NPs (25 mg/kg) were administered intravenously during weeks 6, 7, and 8, and at week 9, all rats were sacrificed. Treatment with STS-loaded NPs reduced systolic and diastolic blood pressure by 10 mm Hg and 8 mm Hg, respectively, in juvenile CKD rats. The protective effect of STS-loaded NPs was linked to increased renal expression of H2S-producing enzymes, including cystathionine γ-lyase (CSE) and D-amino acid oxidase (DAO). Additionally, STS-loaded NP therapy restored nitric oxide (NO) signaling, increasing L-arginine levels, which were disrupted in CKD. Furthermore, the beneficial effects of STS-loaded NPs were associated with inhibition of the renin–angiotensin system (RAS) and the enhancement of the NO signaling pathway. Our findings suggest that STS-loaded NP treatment provides sustained STS delivery and effectively reduces hypertension in a juvenile CKD rat model, bringing us closer to the clinical translation of STS-based therapy for pediatric CKD-induced hypertension. Full article
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14 pages, 2756 KB  
Article
Chondroitin Sulfate Ameliorates Hypertension in Male Offspring Rat Born to Mothers Fed an Adenine Diet
by You-Lin Tain, Chih-Yao Hou, Guo-Ping Chang-Chien, Shu-Fen Lin and Chien-Ning Hsu
Antioxidants 2024, 13(8), 944; https://doi.org/10.3390/antiox13080944 - 2 Aug 2024
Cited by 1 | Viewed by 1436
Abstract
Pregnant women with chronic kidney disease (CKD) face increased risks of adverse outcomes in their adult offspring. Offspring rats born to dams fed an adenine diet develop hypertension, coinciding with dysregulated hydrogen sulfide (H2S) and nitric oxide (NO) pathways, as well [...] Read more.
Pregnant women with chronic kidney disease (CKD) face increased risks of adverse outcomes in their adult offspring. Offspring rats born to dams fed an adenine diet develop hypertension, coinciding with dysregulated hydrogen sulfide (H2S) and nitric oxide (NO) pathways, as well as alterations in gut microbiota. Chondroitin sulfate (CS) is a multifunctional food known for its diverse bioactivities. As a sulfate prebiotic, CS has shown therapeutic potential in various diseases. Here, we investigated the protective effects of maternal CS supplementation against hypertension in offspring induced by an adenine diet. Mother rats were administered regular chow, 0.5% adenine, 3% CS, or a combination throughout gestation and lactation. Maternal CS supplementation effectively protected offspring from hypertension induced by the adenine diet. These beneficial effects of CS were connected with increased renal mRNA and protein levels of 3-mercaptopyruvate sulfurtransferase, an enzyme involved in H2S production. Furthermore, maternal CS treatment significantly enhanced alpha diversity and altered beta diversity of gut microbiota in adult offspring. Specifically, perinatal CS treatment promoted the abundance of beneficial microbes such as Roseburia hominis and Ruminococcus gauvreauii. In conclusion, perinatal CS treatment mitigates offspring hypertension associated with maternal adenine diet, suggesting that early administration of sulfate prebiotics may hold preventive potential. These findings warrant further translational research to explore their clinical implications. Full article
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