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A deficiency in hydrogen sulfide has been implicated in the development and progression of diabetic chronic kidney disease. The purpose of this study was to determine the effect of diabetes on the H2S system in early-stage diabetic kidney disease. We characterised gene and protein expression profile of the enzymes that regulate H2S production and degradation, and H2S production capacity, in the kidney from 10-week-old C57BL6Jdb/db mice (n = 6), in age-matched heterozygous controls (n = 7), and in primary endothelial cells (HUVECs) exposed to high glucose. In db/db mice, renal H2S levels were significantly reduced (P = 0.009). Protein expression of the H2S production enzymes was differentially affected by diabetes: cystathionine β-synthase (CBS) was significantly lower in both db/db mice and high glucose-treated HUVECs (P < 0.0001; P = 0.0318) whereas 3-mercatopyruvate sulfurtransferase (3-MST) expression was higher in the db/db kidney (P < 0.0001), yet lower in the HUVECs (P = 0.0001). Diabetes had no effect on the expression of cystathionine γ-lyase (CSE) in the db/db kidney (P = ns) but was associated with reduced expression in the HUVECs (P = 0.0004). Protein expression of degradation enzyme sulfide quinone reductase (SQOR) was significantly higher in db/db kidney (P = 0.048) and lower in the high glucose-treated HUVECs (P = 0.008). Immunofluorescence studies revealed differential localisation of the H2S enzymes in the kidney, including both tubular and vascular localisation, suggestive of functionally distinct actions in the kidney. The results of this study provide foundational knowledge for future research looking at the H2S system in both kidney physiology and the aetiology of chronic diabetic kidney disease.

Crop plants face severe yield losses worldwide owing to their exposure to multiple abiotic stresses. The study described here, was conducted to comprehend the response of cucumber seedlings to drought (induced by 15% w/v polyethylene glycol 8000; PEG) and nickel (Ni) stress in presence or absence of titanium dioxide nanoparticle (nTiO 2 ). In addition, it was also investigated how nitrogen (N) and carbohydrate metabolism, as well as the defense system, are affected by endogenous potassium (K + ) and hydrogen sulfide (H 2 S). Cucumber seedlings were subjected to Ni stress and drought, which led to oxidative stress and triggered the defense system. Under the stress, N and carbohydrate metabolism were differentially affected. Supplementation of the stressed seedlings with nTiO 2 (15 mg L -1 ) enhanced the activity of antioxidant enzymes, ascorbate-glutathione (AsA-GSH) system and elevated N and carbohydrates metabolism. Application of nTiO 2 also enhanced the accumulation of phytochelatins and activity of the enzymes of glyoxalase system that provided additional protection against the metal and toxic methylglyoxal. Osmotic stress brought on by PEG and Ni, was countered by the increase of proline and carbohydrates levels, which helped the seedlings keep their optimal level of hydration. Application nTiO 2 improved the biosynthesis of H 2 S and K + retention through regulating Cys biosynthesis and H + -ATPase activity, respectively. Observed outcomes lead to the conclusion that nTiO 2 maintains redox homeostasis, and normal functioning of N and carbohydrates metabolism that resulted in the protection of cucumber seedlings against drought and Ni stress. Use of 20 mM tetraethylammonium chloride (K + - channel blocker), 500 μM sodium orthovanadate (PM H + -ATPase inhibitor), and 1 mM hypotaurine (H 2 S scavenger) demonstrate that endogenous K + and H 2 S were crucial for the nTiO 2 -induced modulation of plants' adaptive responses to the imposed stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Glucose-6-phosphate dehydrogenases (G6PDs) are essential regulators of cellular redox. Hydrogen sulfide (H 2 S) is a small gasotransmitter that improves plant adaptation to stress; however, its role in regulating G6PD oligomerization to resist oxidative stress remains unknown in plants. Persulfidation of cytosolic G6PDs was analyzed by mass spectrometry (MS). The structural change model of AtG6PD6 homooligomer was built by chemical cross-linking coupled with mass spectrometry (CXMS). We isolated AtG6PD6 C159A and SlG6PDC C155A transgenic lines to confirm the in vivo function of persulfidated sites with the g6pd5,6 background. Persulfidation occurs at Arabidopsis G6PD6 Cystine (Cys)159 and tomato G6PDC Cys155, leading to alterations of spatial distance between lysine (K)491-K475 from 42.0 Å to 10.3 Å within the G6PD tetramer. The structural alteration occurs in the structural NADP + binding domain, which governs the stability of G6PD homooligomer. Persulfidation enhances G6PD oligomerization, thereby increasing substrate affinity. Under high salt stress, cytosolic G6PDs activity was inhibited due to oxidative modifications. Persulfidation protects these specific sites and prevents oxidative damage. In summary, H 2 S-mediated persulfidation promotes cytosolic G6PD activity by altering homotetrameric structure. The cytosolic G6PD adaptive regulation with two kinds of protein modifications at the atomic and molecular levels is critical for the cellular stress response., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Either H 2 S or iron is essential for cellular processes. Abnormal metabolism of H 2 S and iron has increased risk for cardiovascular diseases. The aim of the present study is to examine the mutual interplay of iron and H 2 S signals in regulation of vascular smooth muscle cell (SMC) functions. Here we found that deficiency of cystathionine gamma-lyase (CSE, a major H 2 S-producing enzyme in vascular system) induced but NaHS (a H 2 S donor) administration attenuated iron accumulation in aortic tissues from angiotensin II-infused mice. In vitro, iron overload induced labile iron levels, promoted cell proliferation, disrupted F-actin filaments, and inhibited protein expressions of SMC-specific markers (αSMA and calponin) more significantly in SMCs from CSE knockout mice (KO-SMCs) than the cells from wild-type mice (WT-SMCs), which could be reversed by exogenously applied NaHS. In contrast, KO-SMCs were more vulnerable to iron starvation-induced cell death. Either iron overload or NaHS did not affect elastin level and gelatinolytic activity. We further found that H 2 S induced more aconitase activity of iron regulatory protein 1 (IRP1) but inhibited its RNA binding activity accompanied with increased protein levels of ferritin and ferriportin, which would contribute to the lower level of labile iron level inside the cells. In addition, iron was able to suppress CSE-derived H 2 S generation, while iron also non-enzymatically induced H 2 S release from cysteine. This study reveals the mutual interaction between iron and H 2 S signals in regulating SMC phenotypes and functions; CSE/H 2 S system would be a target for preventing iron metabolic disorder-related vascular diseases., Competing Interests: Declaration of Competing Interest The authors declare they have no conflicts of interest with the contents of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Myeloperoxidase (MPO) and its principal reaction product hypochlorous acid (HOCl) are part of the innate immune response but are also associated with endothelial dysfunction, thought to involve a reduction in nitric oxide (NO) bioavailability. We aimed to investigate the effect of MPO and HOCl on vasorelaxation of coronary arteries and to assess directly the involvement of NO. In addition, we hypothesised that the slow release hydrogen sulfide (H 2 S) donor GYY4137 would salvage coronary artery endothelial function in the presence of MPO and HOCl., Methods and Results: Contractility of porcine coronary artery segments was measured using isometric tension recording. Incubation with MPO (50 ng/ml) plus hydrogen peroxide (H 2 O 2 ) (30 μM; substrate for MPO) impaired endothelium-dependent vasorelaxation to bradykinin in coronary arteries. HOCl (10-500 μM) also impaired endothelium-dependent relaxations. There was no effect of MPO plus H 2 O 2 , or HOCl, on endothelium-independent relaxations to 5'-N-ethylcarboxamidoadenosine and sodium nitroprusside. L-NAME (300 μM), a NO synthase inhibitor, attenuated bradykinin relaxations, leaving L-NAME-resistant relaxations to bradykinin mediated by endothelium-dependent hyperpolarization. In the presence of L-NAME, MPO plus H 2 O 2 largely failed to impair endothelium-dependent relaxations to bradykinin. Similarly, HOCl failed to inhibit endothelium-dependent relaxations to bradykinin in the presence of L-NAME. GYY4137 (1-100 μM) protected endothelium-dependent relaxations to bradykinin from dysfunction caused by MPO plus H 2 O 2 , and HOCl, with no effect alone on bradykinin relaxation responses. The specific MPO inhibitor aminobenzoic acid hydrazide (ABAH) (1 and 10 μM) also protected against MPO plus H 2 O 2 -induced endothelial dysfunction (at 10 μM ABAH), but was less potent than GYY4137., Conclusions: MPO plus H 2 O 2 , and HOCl, impair coronary artery endothelium-dependent vasorelaxation via inhibition of NO. GYY4137 protects against endothelial dysfunction in arteries exposed to MPO plus H 2 O 2 , and HOCl. H 2 S donors such as GYY4137 are possible therapeutic options to control excessive MPO activity in cardiovascular diseases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

As a gas signal molecule, hydrogen sulfide (H 2 S) can participate in many physiological and biochemical processes such as seed germination and photosynthesis regulation. In order to explore the regulatory effect of H 2 S on the growth of Miscanthus sacchariflorus under Cd stress and to provide sufficient theoretical basis for the complex action of H 2 S and energy plants to remediate soil pollution. In this experiment, the effects of different concentrations of H 2 S (10, 25, 50, 100, 300, 400, 500 μmol·L -1 (μM)) pretreatment on the growth index, lipid peroxidation degree, chlorophyll (Chl) content, osmoregulation substance content, antioxidant enzyme activity and non-enzymatic antioxidant content of M. sacchariflorus under Cd stress (50 μM) were studied. The results showed that under Cd stress, the reactive oxygen species (ROS) content in the body of M. sacchariflorus was unbalanced, and the growth were severely inhibited, the activities of antioxidant enzymes, such as catalase (CAT) and superoxide dismutase (SOD) significantly decreased, and the content of osmoregulation substance, ascorbic acid (AsA) and glutathione (GSH) significantly increased. With the increase of H 2 S concentration, its effect on resisting Cd stress can be shown as "low concentration promotes, high concentration inhibits". When the concentration of H 2 S ≤ 300 μM, although there was no significant difference in Cd content compared with Cd treatment alone, it can regulate the activities of peroxidase (POD), SOD, glutathione reductase (GR) and monodehydroascorbate reductase (MDHAR), increase the content of osmoregulation substances, oxidized glutathione (GSSG), and the transformation rate of AsA and dehydroascorbic acid (DHA) to reduce the oxidative damage and improve the growth and photosynthetic indicators of plants; when the concentration of H 2 S ≥ 400 μM, Cd content in the ground and root decreased significantly, but the transport factor increased significantly, the growth status of M. sacchariflorus were more severely inhibited by the combined stress of H 2 S and Cd. In this experiment, it was found that the concentration of H 2 S pretreatment ≤ 300 μM could regulate the growth of M. sacchariflorus under Cd stress to normal level, and when the treatment concentration was 50 μM, the effect was the best. It will provide a new idea for the treatment of contaminated soil by energy plants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The global donor kidney shortage crisis has necessitated the use of suboptimal kidneys from donors-after-cardiac-death (DCD). Using an ex vivo porcine model of DCD kidney transplantation, the present study investigates whether the addition of hydrogen sulfide donor, AP39, to University of Wisconsin (UW) solution improves graft quality. Renal pedicles of male pigs were clamped in situ for 30 min and the ureters and arteries were cannulated to mimic DCD. Next, both donor kidneys were nephrectomized and preserved by static cold storage in UW solution with or without AP39 (200 nM) at 4 °C for 4 h followed by reperfusion with stressed autologous blood for 4 h at 37 °C using ex vivo pulsatile perfusion apparatus. Urine and arterial blood samples were collected hourly during reperfusion. After 4 h of reperfusion, kidneys were collected for histopathological analysis. Compared to the UW-only group, UW+AP39 group showed significantly higher pO 2 ( p < 0.01) and tissue oxygenation ( p < 0.05). Also, there were significant increases in urine production and blood flow rate, and reduced levels of urine protein, serum creatinine, blood urea nitrogen, plasma Na + and K + , as well as reduced intrarenal resistance in the UW+AP39 group compared to the UW-only group. Histologically, AP39 preserved renal structure by reducing the apoptosis of renal tubular cells and immune cell infiltration. Our finding could lay the foundation for improved graft preservation and reduce the increasingly poor outcomes associated with DCD kidney transplantation.

Multiple sclerosis (MS) is a progressive neuro-inflammatory and neuro-autoimmune disease. Although hydrogen sulfide has recently shown potential therapeutic impacts in different neurological diseases, its effects on MS are still obscure. MiR-146a is considered a vital target for different therapeutic approaches in treating MS. The present study is directed to explore the therapeutic effects of NaHS (hydrogen sulfide donor) on cuprizone-induced MS and to explore whether NaHS can mediate its effects via regulating miR-146a expression. A total of 28 male C57Bl/6 mice were divided into 4 groups; control, cuprizone-intoxicated, NaHS control (100 μmol/kg/day, i.p), and NaHS-treated groups. Intriguingly, NaHS treatment managed to improve locomotor coordination and curb neuronal inflammation and demyelination as evidenced by hematoxylin & eosin, and Luxol fast blue staining and the increased myelin basic protein (MBP) content. Additionally, NaHS reduced interleukin-1 receptor-associated kinase-1 (IRAK-1), nuclear transcription factor kappa B (NF-κB), interleukin (IL)-17, and IL-1β brain levels along with downregulation of miR-146a expression compared with the untreated cuprizone-intoxicated group. Furthermore, NaHS-treated animals revealed much less oxidative stress compared to the untreated animals as evidenced by elevated glutathione and reduced malondialdehyde contents. Altogether, the current work reported that NaHS could improve motor dysfunction and reduce axonal demyelination, oxidative stress, as well as neuro-inflammation in mice with MS. Thus, using H 2 S-releasing compounds could be a promising approach in MS treatment strategies. The mechanism of these beneficial effects may involve the regulation of miR-146a/NF-κB/IL-1β axis.

Background: Hydrogen sulfide (H 2 S) is a gasotransmitter deeply involved in cardiovascular homeostasis and implicated in the myocardial protection against ischemia/reperfusion. The post-translational persulfidation of cysteine residues has been identified as the mechanism through which H 2 S regulates a plethora of biological targets. Erucin (ERU) is an isothiocyanate produced upon hydrolysis of the glucosinolate glucoerucin, presents in edible plants of Brassicaceae family, such as Eruca sativa Mill., and it has emerged as a slow and long-lasting H 2 S-donor., Aim: In this study the cardioprotective profile of ERU has been investigated and the action mechanism explored, focusing on the possible role of the recently identified mitochondrial Kv7.4 (mitoKv7.4) potassium channels., Results: Interestingly, ERU showed to release H 2 S and concentration-dependently protected H9c2 cells against H 2 O 2 -induced oxidative damage. Moreover, in in vivo model of myocardial infarct ERU showed protective effects, reducing the extension of ischemic area, the levels of troponin I and increasing the amount of total AnxA1, as well as co-related inflammatory outcomes. Conversely, the pre-treatment with XE991, a blocker of Kv7.4 channels, abolished them. In isolated cardiac mitochondria ERU exhibited the typical profile of a mitochondrial potassium channels opener, in particular, this isothiocyanate produced a mild depolarization of mitochondrial membrane potential, a reduction of calcium accumulation into the matrix and finally a flow of potassium ions. Finally, mitoKv7.4 channels were persulfidated in ERU-treated mitochondria., Conclusions: ERU modulates the cardiac mitoKv7.4 channels and this mechanism may be relevant for cardioprotective effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetic cardiomyopathy (DCM) is one serious and common complication in diabetes without effective treatments. Hydrogen sulfide (H 2 S) fights against a variety of cardiovascular diseases including DCM. Retinoic acid-related orphan receptor α (RORα) has protective effects on cardiovascular system. However, whether RORα mediates the protective effect of H 2 S against DCM remains unknown. The present research was to explore the roles and mechanisms of RORα in H 2 S against DCM. The study demonstrated that H 2 S donor sodium hydrosulfide (NaHS) alleviated cell injury but enhanced RORα expression in high glucose (HG)-stimulated cardiomyocytes. However, NaHS no longer had the protective effect on attenuating cell damage and oxidative stress, improving mitochondrial membrane potential, inhibiting necroptosis and enhanced signal transducer and activator of transcription 3 (STAT3) Ser727 phosphorylation in HG-stimulated cardiomyocytes after RORα siRNA transfection. Moreover, NaHS improved cardiac function, attenuated myocardial hypertrophy and fibrosis, alleviated oxidative stress, inhibited necroptosis, but increased STAT3 phosphorylation in wild type (WT) mice but not in RORα knockout mice (a spontaneous staggerer mice, sg/sg mice) with diabetes. Additionally, NaHS increased RORα promoter activity in cardiomyocytes with HG stimulation, which was related to the binding sites of E2F transcription factor 1 (E2F1) in the upstream region of RORα promoter. NaHS enhanced E2F1 expression and increased the binding of E2F1 to RORα promoter in cardiomyocytes with HG stimulation. In sum, H 2 S promoted RORα transcription via E2F1 to alleviate necroptosis and protect against DCM. It is helpful to propose a novel therapeutic implication for DCM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hydrogen sulphide (H 2 S) is a gaseous neurotransmitter that can be self-synthesized by living organisms. With the deepening of research, the pathophysiological mechanisms of endogenous H 2 S in cancer have been increasingly elucidated: (1) promote angiogenesis, (2) stimulate cell bioenergetics, (3) promote migration and proliferation thereby invasion, (4) inhibit apoptosis and (5) activate abnormal cell cycle. However, the increasing H 2 S levels via exogenous sources show the opposite trend. This phenomenon can be explained by the bell-shaped pharmacological model of H 2 S, that is, the production of endogenous (low concentration) H 2 S promotes tumour growth while the exogenous (high concentration) H 2 S inhibits tumour growth. Here, we review the impact of endogenous H 2 S synthesis and metabolism on tumour progression, summarize the mechanism of action of H 2 S in tumour growth, and discuss the possibility of H 2 S as a potential target for tumour treatment., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

We investigated the role of RhoA/Rho-kinase (ROCK) and PKC in the inhibitory effect of L-cysteine/hydrogen sulfide (H 2 S) pathway on the carbachol-mediated contraction of mouse bladder smooth muscle. Carbachol (10 -8 -10 -4  M) induced a concentration-dependent contraction in bladder tissues. L-cysteine (H 2 S precursor; 10 -2  M) and exogenous H 2 S (NaHS; 10 -3  M) reduced the contractions evoked by carbachol by ~ 49 and ~ 53%, respectively, relative to control. The inhibitory effect of L-cysteine on contractions to carbachol was reversed by 10 -2  M PAG (~ 40%) and 10 -3  M AOAA (~ 55%), cystathionine-gamma-lyase (CSE) and cystathionine-β-synthase (CBS) inhibitor, respectively. Y-27632 (10 -6  M) and GF 109203X (10 -6  M), a specific ROCK and PKC inhibitor, respectively, reduced contractions evoked by carbachol (~ 18 and ~ 24% respectively), and the inhibitory effect of Y-27632 and GF 109203X on contractions was reversed by PAG (~ 29 and ~ 19%, respectively) but not by AOAA. Also, Y-27632 and GF 109203X reduced the inhibitory responses of L-cysteine on the carbachol-induced contractions (~ 38 and ~ 52% respectively), and PAG abolished the inhibitory effect of L-cysteine on the contractions in the presence of Y-27632 (~ 38%). Also, the protein expressions of CSE, CBS, and 3-MST enzymes responsible for endogenous H 2 S synthesis were detected by Western blot method. H 2 S level was increased by L-cysteine, Y-27632, and GF 109203X (from 0.12 ± 0.02 to 0.47 ± 0.13, 0.26 ± 0.03, and 0.23 ± 0.06 nmol/mg respectively), and this augmentation in H 2 S level decreased with PAG (0.17 ± 0.02, 0.15 ± 0.03, and 0.07 ± 0.04 nmol/mg respectively). Furthermore, L-cysteine and NaHS reduced carbachol-induced ROCK-1, pMYPT1, and pMLC20 levels. Inhibitory effects of L-cysteine on ROCK-1, pMYPT1, and pMLC20 levels, but not of NaHS, were reversed by PAG. These results suggest that there is an interaction between L-cysteine/H 2 S and RhoA/ROCK pathway via inhibition of ROCK-1, pMYPT1, and pMLC20, and the inhibition of RhoA/ROCK and/or PKC signal pathway may be mediated by the CSE-generated H 2 S in mouse bladder., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hydrogen sulfide (H 2 S) is a multifunctional gaseous signaling molecule involved in the regulation of Cr stress responses. In the present study, we combined transcriptomic and physiological analyses to elucidate the mechanism underlying the mitigation of Cr toxicity by H 2 S in maize (Zea mays L.). We showed that treatment with sodium hydrosulfide (NaHS, a donor of H 2 S) partially alleviated Cr-induced growth inhibition. However, Cr uptake was not affected. RNA sequencing suggested that H 2 S regulates the expression of many genes involved in pectin biosynthesis, glutathione metabolism, and redox homeostasis. Under Cr stress, NaHS treatment significantly increased pectin content and pectin methylesterase activity; thus, more Cr was retained in the cell wall. NaHS application also increased the content of glutathione and phytochelatin, which chelate Cr and transport it into vacuoles for sequestration. Furthermore, NaHS treatment mitigated Cr-induced oxidative stress by enhancing the capacity of enzymatic and non-enzymatic antioxidants. Overall, our results strongly support that H 2 S alleviates Cr toxicity in maize by promoting Cr sequestration and re-establishing redox homeostasis rather than by reducing Cr uptake from the environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chemodynamic immunotherapy that utilizes catalysts to produce reactive oxygen species (ROS) for killing tumor cells and arousing antitumor immunity has received considerable attention. However, it is still restricted by low ROS production efficiency and insufficient immune activation, due to intricate redox homeostasis in the tumor microenvironment (TME). Herein, a metalloprotein-like hybrid nanozyme (FeS@GOx) is designed by in situ growth of nanozyme (ferrous sulfide, FeS) in a natural enzyme (glucose oxidase, GOx) to amplify ROS cascade for boosting chemodynamic immunotherapy. In FeS@GOx, GOx allows the conversion of endogenous glucose to gluconic acid and hydrogen peroxide, which provides favorable increasing hydrogen peroxide for subsequent Fenton reaction of FeS nanozymes, thus reinforcing ROS production. Notably, hydrogen sulfide (H 2 S) release is activated by the gluconic acid generation-related pH decrease, which can suppress the activity of endogenous thioredoxin reductase and catalase to further inhibit ROS elimination. Thus, FeS@GOx can sustainably amplify ROS accumulation and perturb intracellular redox homeostasis to improve chemodynamic therapy and trigger robust immunogenic cell death for effective immunotherapy combined with immune checkpoint blockade. This work proposes a feasible H 2 S amplified ROS cascade strategy employing a bioinspired hybrid nanozyme, providing a novel pathway to multi-enzyme-mediated TME modulation for precise and efficient chemodynamic immunotherapy., (© 2023 Wiley-VCH GmbH.)

Background: Iron-sulfur clusters play a central role in cellular function and are regulated by the ATM protein. Iron-sulfur clusters are part of the cellular sulfide pool, which functions to maintain cardiovascular health, and consists of free hydrogen sulfide, iron-sulfur clusters, protein bound sulfides, which constitute the total cellular sulfide fraction. ATM protein signaling and the drug pioglitazone share some cellular effects, which led us to examine the effects of this drug on cellular iron-sulfur cluster formation. Additionally, as ATM functions in the cardiovasculature and its signaling may be diminished in cardiovascular disease, we examined pioglitazone in the same cell type, with and without ATM protein expression., Methods: We examined the effects of pioglitazone treatment on the total cellular sulfide profile, the glutathione redox state, cystathionine gamma-lyase enzymatic activity, and on double-stranded DNA break formation in cells with and without ATM protein expression., Results: Pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions and reduced cystathionine gamma-lyase enzymatic activity in cells with and without ATM protein expression. Interestingly, pioglitazone also increased reduced glutathione and lowered DNA damage in cells without ATM protein expression, but not in ATM wild-type cells. These results are interesting as the acid-labile (iron-sulfur cluster), bound sulfur cellular fractions, and reduced glutathione are low in cardiovascular disease., Conclusion: Here we found that pioglitazone increased the acid-labile (iron-sulfur cluster) and bound sulfur cellular fractions, impinges on hydrogen sulfide synthesis, and exerts beneficial effect on cells with deficient ATM protein signaling. Thus, we show a novel pharmacologic action for pioglitazone., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Published by Elsevier Inc.)

Hydrogen sulfide (H 2 S), as an endogenous gas signaling molecule, plays an important role in plant growth regulation and resistance to abiotic stress. This study aims to investigate the mechanism of exogenous H 2 S on the growth and development of Reaumuria soongorica seedlings under salt stress and to determine the optimal concentration for foliar application. To investigate the regulatory effects of exogenous H 2 S (donor sodium hydrosulfide, NaHS) at concentrations ranging from 0 to 1 mM on reactive oxygen species (ROS), antioxidant system, and osmoregulation in R. soongorica seedlings under 300 mM NaCl stress. The growth of R. soongorica seedlings was inhibited by salt stress, which resulted in a decrease in the leaf relative water content (LRWC), specific leaf area (SLA), and soluble sugar content in leaves, elevated activity levels of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT); and accumulated superoxide anion (O 2 - ), proline, malondialdehyde (MDA), and soluble protein content in leaves; and increased L-cysteine desulfhydrase (LCD) activity and endogenous H 2 S content. This indicated that a high level of ROS was produced in the leaves of  R. soongorica  seedlings and seriously affected the growth and development of R. soongorica seedlings. The exogenous application of different concentrations of NaHS reduced the content of O 2 - , proline and MDA, increased the activity of antioxidant enzymes and the content of osmoregulators (soluble sugars and soluble proteins), while the LCD enzyme activity and the content of endogenous H 2 S were further increased with the continuous application of exogenous H 2 S. The inhibitory effects of salt stress on the growth rate of plant height and ground diameter, the LRWC, biomass, and SLA were effectively alleviated. A comprehensive analysis showed that the LRWC, POD, and proline could be used as the main indicators to evaluate the alleviating effect of exogenous H 2 S on R. soongorica seedlings under salt stress. The optimal concentration of exogenous H 2 S for R. soongorica seedlings under salt stress was 0.025 mM. This study provides an important theoretical foundation for understanding the salt tolerance mechanism of R. soongorica and for cultivating high-quality germplasm resources., Competing Interests: The authors declare there are no competing interests., (©2023 Liu et al.)

Mounting evidence demonstrates that hydrogen sulfide (H 2 S) promotes anti-inflammatory molecules and inhibits pro-inflammatory cytokines in endothelial cells (ECs). This study aims to investigate the favorable action of H 2 S on endothelial function in senescence by inhibiting the production of inflammatory molecules. Senescent ECs exhibit a reduction in H 2 S, endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor δ (PPARδ), coupled with increased inflammatory molecules, sodium glucose transporter type 2 (SGLT2) and phosphorylation of STAT3, which could be reversed by the administration of a slow but sustained release agent of H 2 S, GYY4137. Decreased production of eNOS and upregulated p-STAT3 and SGLT2 levels in senescent ECs are reversed by replenishment of the SGLT2 inhibitor EMPA and the PPARδ agonist GW501516. The PPARδ antagonist GSK0660 attenuates eNOS expression and increases the production of p-STAT3 and SGLT2. However, supplementation with GYY4137 has no beneficial effect on GSK0660-treated ECs. GYY4137, GW501516 and EMPA preserve endothelial-dependent relaxation (EDR) in D-gal-treated aortae, while GSK0660 destroys aortic relaxation even with GYY4137 supplementation. In summary, senescent ECs manifest aggravated the expressions of the inflammatory molecules SGLT2 and p-STAT3 and decreased the productions of PPARδ, eNOS and CSE. H 2 S ameliorates endothelial dysfunction through the anti-inflammatory effect of the PPARδ/SGLT2/p-STAT3 signaling pathway in senescent ECs and may be a potential therapeutic target for anti-ageing treatment.

We previously reported that brain α7 nicotinic acetylcholine receptors inhibited the rat micturition reflex. To elucidate the mechanisms underlying this inhibition, we focused on the relationship between α7 nicotinic acetylcholine receptors and hydrogen sulphide (H 2 S) because we found that H 2 S also inhibits the rat micturition reflex in the brain. Therefore, we investigated whether H 2 S is involved in the inhibition of the micturition reflex induced by the activation of α7 nicotinic acetylcholine receptors in the brain. Cystometry was performed in male Wistar rats under urethane anesthesia (0.8 g/kg, ip) to examine the effects of icv pre-treated GYY4137 (H 2 S donor, 1 or 3 nmol/rat) or aminooxyacetic acid (AOAA; non-selective H 2 S synthesis inhibitor, 3 or 10 μg/rat) on PHA568487 (α7 nicotinic acetylcholine receptor agonist, icv)-induced prolongation of intercontraction intervals. PHA568487 administration at a lower dose (0.3 nmol/rat, icv) had no significant effect on intercontraction intervals, while under pre-treatment with GYY4137 (3 nmol/rat icv), PHA568487 (0.3 nmol/rat, icv) significantly prolonged intercontraction intervals. PHA568487 at a higher dose (1 nmol/rat, icv) induced intercontraction interval prolongation, and the PHA568487-induced prolongation was significantly suppressed by AOAA (10 μg/rat, icv). The AOAA-induced suppression of the PHA568487-induced intercontraction interval prolongation was negated by supplementing H 2 S via GYY4137 at a lower dose (1 nmol/rat, icv) in the brain. GYY4137 or AOAA alone showed no significant effect on intercontraction intervals at each dose used in this study. These findings suggest a possible involvement of brain H 2 S in inhibiting the rat micturition reflex induced by activation of brain α7 nicotinic acetylcholine receptors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Hydrogen sulfide (H 2 S) is a recently discovered gaseous neurotransmitter in the nervous and gastrointestinal systems. It exerts its effects through multiple signaling pathways, impacting various physiological activities. The nucleus tractus solitarius (NTS), a vital nucleus involved in visceral sensation, was investigated in this study to understand the role of H 2 S in regulating gastric function in rats., Aim: To examine whether H 2 S affects the nuclear factor kappa-B (NF-κB) and transient receptor potential vanilloid 1 pathways and the neurokinin 1 (NK1) receptor in the NTS., Methods: Immunohistochemical and fluorescent double-labeling techniques were employed to identify cystathionine beta-synthase (CBS) and c-Fos co-expressed positive neurons in the NTS during rat stress. Gastric motility curves were recorded by inserting a pressure-sensing balloon into the pylorus through the stomach fundus. Changes in gastric motility were observed before and after injecting different doses of NaHS (4 nmol and 8 nmol), physiological saline, Capsazepine (4 nmol) + NaHS (4 nmol), pyrrolidine dithiocarbamate (PDTC, 4 nmol) + NaHS (4 nmol), and L703606 (4 nmol) + NaHS (4 nmol)., Results: We identified a significant increase in the co-expression of c-Fos and CBS positive neurons in the NTS after 1 h and 3 h of restraint water-immersion stress compared to the expressions observed in the control group. Intra-NTS injection of NaHS at different doses significantly inhibited gastric motility in rats ( P < 0.01). However, injection of saline, first injection NF-κB inhibitor PDTC or transient receptor potential vanilloid 1 (TRPV1) antagonist Capsazepine or NK1 receptor blockers L703606 and then injection NaHS did not produce significant changes ( P > 0.05)., Conclusion: NTS contains neurons co-expressing CBS and c-Fos, and the injection of NaHS into the NTS can suppress gastric motility in rats. This effect may be mediated by activating TRPV1 and NK1 receptors via the NF-κB channel., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Beryllium sulfate (BeSO 4 ) can result to lung injuries, such as leading to lipid peroxidation and autophagy, and the treatment of beryllium disease has not been well improved. Ferroptosis is a regulated cell death process driven by iron-dependent and lipid peroxidation, while ferritinophagy is a process mediated by nuclear receptor coactivator 4 (NCOA4), combined with ferritin heavy chain 1 (FTH1) degradation and release Fe 2+ , which regulated intracellular iron metabolism and ferroptosis. Hydrogen sulfide (H 2 S) has the effects of antioxidant, antiautophagy, and antiferroptosis. This study aimed to investigate the effect of H 2 S on BeSO 4 -induced ferroptosis and ferritinophagy in 16HBE cells and the underlying mechanism. In this study, BeSO 4 -induced 16HBE cell injury model was established based on cellular level and pretreated with deferoxamine (DFO, a ferroptosis inhibitor), sodium hydrosulfide (NaHS, a H 2 S donor), or NCOA4 siRNA and, subsequently, performed to detect the levels of lipid peroxidation and Fe 2+ and the biomarkers of ferroptosis and ferritinophagy. More importantly, our research found that DFO, NaHS, or NCOA4 siRNA alleviated BeSO 4 -induced ferroptosis and ferritinophagy by decreasing the accumulation of Fe 2+ and lipid peroxides. Furthermore, the relationship between ferroptosis, ferritinophagy, H 2 S, and beryllium disease is not well defined; therefore, our research is innovative. Overall, our results provided a new theoretical basis for the prevention and treatment of beryllium disease and suggested that the application of H 2 S, blocking ferroptosis, and ferritinophagy may be a potential therapeutic direction for the prevention and treatment of beryllium disease., (© 2023 John Wiley & Sons, Ltd.)

Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H 2 S) has been previously described to be involved in macrophage polarization, in this study we examined H 2 S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H 2 S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H 2 S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H 2 S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H 2 S induction. In addition, we observed that intraarticular administration of H 2 S donor attenuated synovial abundance of CD68 + cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H 2 S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology., (© 2023. The Author(s).)

Key Message: A new interaction was found between PMA1 and GRF4. H 2 S promotes the interaction through persulfidated Cys446 of PMA1. H 2 S activates PMA1 to maintain K + /Na + homeostasis through persulfidation under salt stress. Plasma membrane H + -ATPase (PMA) is a transmembrane transporter responsible for pumping protons, and its contribution to salt resistance is indispensable in plants. Hydrogen sulfide (H 2 S), a small signaling gas molecule, plays the important roles in facilitating adaptation of plants to salt stress. However, how H 2 S regulates PMA activity remains largely unclear. Here, we show a possible original mechanism for H 2 S to regulate PMA activity. PMA1, a predominant member in the PMA family of Arabidopsis, has a non-conservative persulfidated cysteine (Cys) residue (Cys446), which is exposed on the surface of PMA1 and located in cation transporter/ATPase domain. A new interaction of PMA1 and GENERAL REGULATORY FACTOR 4 (GRF4, belongs to the 14-3-3 protein family) was found by chemical crosslinking coupled with mass spectrometry (CXMS) in vivo. H 2 S-mediated persulfidation promoted the binding of PMA1 to GRF4. Further studies showed that H 2 S enhanced instantaneous H + efflux and maintained K + /Na + homeostasis under salt stress. In light of these findings, we suggest that H 2 S promotes the binding of PMA1 to GRF4 through persulfidation, and then activating PMA, thus improving the salt tolerance of Arabidopsis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hydrogen sulfide (H 2 S) is an endogenous gasotransmitter with anti-inflammatory actions that also reduces itching. To test whether a combination of an antihistamine with a H 2 S donor has improved antipruritic efficacy, bifunctional molecules with antihistamine and H 2 S-releasing pharmacophores were synthesized and tested in vitro and in vivo . H 2 S release from the hybrid molecules was evaluated with the methylene blue and lead acetate methods, and H1-blocking activity was assessed by determining tissue factor expression inhibition. All new compounds released H 2 S in a dose-dependent manner and retained histamine blocking activity. Two compounds with the highest potency were evaluated in vivo for their antipruritic as well as sedative action; they proved to possess higher efficacy in inhibiting histamine-induced pruritus and decreased sedative effects compared to the parent compounds (hydroxyzine and cetirizine), suggesting that they exhibit superior antipruritic action and limited side effects that likely arise from the H 2 S-releasing moiety.

Recombinant granulocyte colony-stimulating factor (G-CSF), with a direct repair effect on injured cardiomyocytes against myocardial infarction ischemia-reperfusion-injury (IRI), displays a poor effect owing to the limited cardiac targeting efficacy. There are almost no reports of nanomaterials that deliver G-CSF to the IRI site. Herein, we propose a way to protect G-CSF by constructing one layer of nitric oxide (NO)/hydrogen sulfide (H 2 S) nanomotors on its outside. NO/H 2 S nanomotors with specific chemotactic ability to high expression of reactive oxygen species (ROS)/induced nitric oxide synthase (iNOS) at the IRI site can deliver G-CSF to the IRI site efficiently. Meanwhile, superoxide dismutase is covalently bound to the outermost part, reducing ROS at the IRI site through a cascade effect with NO/H 2 S nanomotors. The synergistic effect between NO and H 2 S on the effective regulation of the IRI microenvironment can not only avoid toxicity caused by excessive concentration of a single gas but also reduce inflammation level and relieve calcium overload, so as to promote G-CSF to play a cardioprotective role.

Objective: Research has shown that hydrogen sulfide (H2S) plays a protective role in many diseases of the nervous system. The aim of this study is to investigate the effect of hypoxia on endogenous H2S concentration in the cerebral cortex of Alzheimer's disease (AD) transgenic mice and its mechanism., Methods: AD transgenic mice were raised in closed boxes and pure nitrogen was introduced to reduce the oxygen concentration to 8%-10%, establishing an animal model of hypoxia. Oxygen partial pressure was measured with an oxygen meter. The expression of cystathionine-β-synthase (CBS) in cerebral cortex tissue was determined by Western blot, and H2S concentration was measured by a modified methylene blue method., Results: (1) Hypoxia down-regulated CBS expression in cerebral cortex tissue of AD transgenic mice (p < 0.05). (2) The concentration of H2S in the cerebral cortex tissue of the hypoxic transgenic group was significantly lower than that of the Control group (p < 0.01). (3) Overexpression of CBS reversed the hypoxia-induced decrease of H2S concentration in the cerebral cortex tissue of AD transgenic mice (p < 0.01)., Conclusions: Hypoxia decreased the concentration of endogenous H2S in the cerebral cortex tissue of AD transgenic mice by down-regulating the expression of CBS.

Considering the important cytoprotective and signaling roles but relatively narrow therapeutic index of hydrogen sulfide (H 2 S), advanced H 2 S donors are required to achieve a therapeutic effect. In this study, we proposed glutathione dithiophosphates as new combination donors of H 2 S and glutathione. The kinetics of H 2 S formation in dithiophosphate solutions suggested a continuous H 2 S release by the donors, which was higher for the dithiophosphate of reduced glutathione than oxidized glutathione. The compounds, unlike NaHS, inhibited the proliferation of C2C12 myoblasts at submillimolar concentrations due to an efficient increase in intracellular H 2 S. The H 2 S donors more profoundly affected reactive oxygen species and reduced glutathione levels in C2C12 myocytes, in which these parameters were elevated compared to myoblasts. Oxidized glutathione dithiophosphate as well as control donors exerted antioxidant action toward myocytes, whereas the effect of reduced glutathione dithiophosphate at (sub-)micromolar concentrations was rather modulating. This dithiophosphate showed an enhanced negative inotropic effect mediated by H 2 S upon contraction of the atrial myocardium, furthermore, its activity was prolonged and reluctant for washing. These findings identify glutathione dithiophosphates as redox-modulating H 2 S donors with long-acting profile, which are of interest for further pharmacological investigation.

Chromium (Cr), a highly toxic redox-active metal cation in soil, seriously threatens global agriculture by affecting nutrient uptake and disturbing various physio-biochemical processes in plants, thereby reducing yields. Here, we examined the effects of different concentrations of Cr alone and in combination with hydrogen sulfide (H 2 S) application on the growth and physio-biochemical performance of two mungbeans (Vigna radiata L.) varieties, viz. Pusa Vishal (PV; Cr tolerant) and Pusa Ratna (PR; Cr sensitive), growing in a pot in hydroponics. Plants were grown in the pot experiment to examine their growth, enzymatic and non-enzymatic antioxidant levels, electrolyte balance, and plasma membrane (PM) H + -ATPase activity. Furthermore, root anatomy and cell death were analysed 15 days after sowing both varieties in hydroponic systems. The Cr-induced accumulation of reactive oxygen species caused cell death and affected the root anatomy and growth of both varieties. However, the extent of alteration in anatomical features was less in PV than in PR. Exogenous application of H 2 S promoted plant growth, thereby improving plant antioxidant activities and reducing cell death by suppressing Cr accumulation and translocation. Seedlings of both cultivars treated with H 2 S exhibited enhanced photosynthesis, ion uptake, glutathione, and proline levels and reduced oxidative stress. Interestingly, H 2 S restricted the translocation of Cr to aerial parts of plants by improving the nutrient profile and viability of root cells, thereby relieving plants from oxidative bursts by activating the antioxidant machinery through triggering the ascorbate-glutathione cycle. Overall, H 2 S application improved the nutrient profile and ionic homeostasis of Cr-stressed mungbean plants. These results highlight the importance of H 2 S application in protecting crops against Cr toxicity. Our findings can be utilised to develop management strategies to improve heavy metal tolerance among crops., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Aim: Increasing evidence has proposed that mitochondrial abnormalities may be an important factor contributing to the development of heart failure with preserved ejection fraction (HFpEF). Hydrogen sulfide (H 2 S) has been suggested to play a pivotal role in regulating mitochondrial function. Therefore, the present study was designed to explore the protective effect of H 2 S on mitochondrial dysfunction in a multifactorial mouse model of HFpEF., Methods: Wild type, 8-week-old, male C57BL/6J mice or cardiomyocyte specific-Cse (Cystathionine γ-lyase, a major H 2 S-producing enzyme) knockout mice (CSE cko ) were given high-fat diet (HFD) and l-NAME (an inhibitor of constitutive nitric oxide synthases) or standardized chow. After 4 weeks, mice were randomly administered with NaHS (a conventional H 2 S donor), ZLN005 (a potent transcriptional activator of PGC-1α) or vehicle. After additional 4 weeks, echocardiogram and mitochondrial function were evaluated. Expression of PGC-1α, NRF1 and TFAM in cardiomyocytes was assayed by Western blot., Results: Challenging with HFD and l-NAME in mice not only caused HFpEF but also inhibited the production of endogenous H 2 S in a time-dependent manner. Meanwhile the expression of PGC-1α and mitochondrial function in cardiomyocytes were impaired. Supplementation with NaHS not only upregulated the expression of PGC-1α, NRF1 and TFAM in cardiomyocytes but also restored mitochondrial function and ultrastructure, conferring an obvious improvement in cardiac diastolic function. In contrast, cardiac deletion of CSE gene aggravated the inhibition of PGC-1α-NRF1-TFAM pathway, mitochondrial abnormalities and diastolic dysfunction. The deleterious effect observed in CSE cko HFpEF mice was partially counteracted by pre-treatment with ZLN005 or supplementation with NaHS., Conclusion: Our findings have demonstrated that H 2 S ameliorates left ventricular diastolic dysfunction by restoring mitochondrial abnormalities via upregulating PGC-1α and its downstream targets NRF1 and TFAM, suggesting the therapeutic potential of H 2 S supplementation in multifactorial HFpEF., Competing Interests: Declaration of competing interest The authors declares that there is no conflict of interest regarding the publication of this article., (Copyright © 2023. Published by Elsevier Inc.)

Chronic inflammation is a key factor that accelerates the progression of inflammatory vascular disease. Hydrogen sulfide (H 2 S) has potent anti‑inflammatory effects; however, its underlying mechanism of action has not been fully elucidated. The present study aimed to investigate the potential effect of H 2 S on sirtuin 1 (SIRT1) sulfhydration in trimethylamine N‑oxide (TMAO)‑induced macrophage inflammation, and its underlying mechanism. Pro‑inflammatory M1 cytokines (MCP‑1, IL‑1β, and IL‑6) and anti‑inflammatory M2 cytokines (IL‑4 and IL‑10) were detected by RT‑qPCR. CSE, p65 NF‑κB, p‑p65 NF‑κB, IL‑1β, IL‑6 and TNF‑α levels were measured by Western blot. The results revealed that cystathionine γ‑lyase protein expression was negatively associated with TMAO‑induced inflammation. Sodium hydrosulfide (a donor of H 2 S) increased SIRT1 expression and inhibited the expression of inflammatory cytokines in TMAO‑stimulated macrophages. Furthermore, nicotinamide, a SIRT1 inhibitor, antagonized the protective effect of H 2 S, which contributed to P65 NF‑κB phosphorylation and upregulated the expression of inflammatory factors in macrophages. H 2 S ameliorated TMAO‑induced activation of the NF‑κB signaling pathway via SIRT1 sulfhydration. Moreover, the antagonistic effect of H 2 S on inflammatory activation was largely eliminated by the desulfhydration reagent dithiothreitol. These results indicated that H 2 S may prevent TMAO‑induced macrophage inflammation by reducing P65 NF‑κB phosphorylation via the upregulation and sulfhydration of SIRT1, suggesting that H2S may be used to treat inflammatory vascular diseases.

Both H 2 S and H 2 O 2 affect many cellular events, such as cell differentiation, cell proliferation and cell death. However, there is some controversy about the roles of H 2 S and H 2 O 2, since the detailed mechanisms they are involved remain unclear. In this study, low concentration of H 2 O 2 (40 μM) increased the viability of hepatocellular carcinoma cells HepG2, while both H 2 S and high concentration of H 2 O 2 decreased the cell viability in a dose-dependent manner. Wound healing assay indicated that 40 μM H 2 O 2 promoted migration of HepG2 cells, which was suppressed by exogenous H 2 S. Further analysis revealed that administration of exogenous H 2 S and H 2 O 2 changed the redox status of Wnt3a in HepG2 cells. Altered expression of proteins including Cyclin D1, TCF-4, and MMP7, which are downstream of the Wnt3a/β-catenin signaling pathway, were found after treatment with exogenous H 2 S and H 2 O 2 . Compared with H 2 S, low concentration of H 2 O 2 showed opposite effects on these protein expression levels in HepG2 cells. These results suggest that H 2 S suppressed H 2 O 2 -induced proliferation and migration of HepG2 through regulating Wnt3a/β-catenin signaling pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The voltage-gated K + channel plays a key role in atrial excitability, conducting the ultra-rapid rectifier K + current (I Kur ) and contributing to the repolarization of the atrial action potential. In this study, we examine its regulation by hydrogen sulfide (H 2 S) in HL-1 cardiomyocytes and in HEK293 cells expressing human Kv1.5. Pacing induced remodeling resulted in shorting action potential duration, enhanced both Kv1.5 channel and H 2 S producing enzymes protein expression in HL-1 cardiomyocytes. H 2 S supplementation reduced these remodeling changes and restored action potential duration through inhibition of Kv1.5 channel. H 2 S also inhibited recombinant hKv1.5, lead to nitric oxide (NO) mediated S-nitrosylation and activated endothelial nitric oxide synthase (eNOS) by increased phosphorylation of Ser1177, prevention of NO formation precluded these effects. Regulation of I kur by H 2 S has important cardiovascular implications and represents a novel and potential therapeutic target., (© 2023. The Author(s).)

The effect of lipopolysaccharide (LPS)-based neuroinflammation following cerebral ischemia/reperfusion (I/R) on the genotypic transformation of reactive astrocytes and its relationship with endogenous hydrogen sulfide (H 2 S) were investigated in present study. We found that LPS promoted the cerebral I/R-induced A1 astrocytes proliferation in mouse hippocampal tissues and deteriorated the reduction of hydrogen sulfide (H 2 S) content in mouse sera, H 2 S donor NaHS could inhibit A1 astrocytes proliferation. Similarly, knockout of cystathionine γ-lyase (CSE), one of endogenous H 2 S synthases, likewise up-regulated the cerebral I/R-induced A1 astrocytes proliferation, which could also be blocked by NaHS. Besides, supplement with H 2 S promoted the A2 astrocytes proliferation in hippocampal tissues of CSE knockout (CSE KO) mice or LPS-treated mice following cerebral I/R. In the oxygen glucose deprivation/reoxygenation (OGD/R) model of astrocytes, H 2 S also promoted the transformation of astrocytes into A2 subtype. Moreover, we found that H 2 S could up-regulate the expression of α-subunit of large-conductance Ca 2+ -activated K + (BK Ca ) channels in astrocytes, and the channel opener BMS-191011 likewise promoted the transformation of astrocyte into A2 subtype. In conclusion, H 2 S inhibits the proliferation of A1 astrocytes induced by LPS-based neuroinflammation following cerebral I/R and promotes the transformation of astrocytes into A2 subtype, which may be related to up-regulation of BK Ca channels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Peripheral artery disease (PAD) affects more than 230 million people worldwide. PAD patients suffer from reduced quality of life and are at increased risk of vascular complications and all-cause mortality. Despite its prevalence, impact on quality of life and poor long-term clinical outcomes, PAD remains underdiagnosed and undertreated compared to myocardial infarction and stroke. PAD is due to a combination of macrovascular atherosclerosis and calcification, combined with microvascular rarefaction, leading to chronic peripheral ischemia. Novel therapies are needed to address the increasing incidence of PAD and its difficult long-term pharmacological and surgical management. The cysteine-derived gasotransmitter hydrogen sulfide (H 2 S) has interesting vasorelaxant, cytoprotective, antioxidant and anti-inflammatory properties. In this review, we describe the current understanding of PAD pathophysiology and the remarkable benefits of H 2 S against atherosclerosis, inflammation, vascular calcification, and other vasculo-protective effects.

As a critical endogenous signaling molecule, hydrogen sulfide may induce reversible post-translational modifications on cysteine residues of proteins, generating a persulfide bond known as S-sulfhydration. A systemic overview of the biofunctions of S-sulfhydration will equip us better to characterize its regulatory roles in antioxidant defense, inflammatory response, and cell fate, as well as its pathological mechanisms related to cardiovascular, neurological, and multiple organ diseases, etc. Nevertheless, the understanding of S-sulfhydration is mostly built on mammalian cells and animal models. We subsequently summarized the mediation effects of this specific post-transcriptional modification on physiological processes and virulence in bacteria. The high-sensitivity and high-throughput detection technologies are required for studying the signal transduction mechanism of H 2 S and protein S-sulfhydration modification. Herein, we reviewed the establishment and development of different approaches to assess S-sulfhydration, including the biotin-switch method, modified biotin-switch method, alkylation-based cysteine-labelled assay, and Tag-switch method. Finally, we discussed the limitations of the impacts of S-sulfhydration in pathogens-host interactions and envisaged the challenges to design drugs and antibiotics targeting the S-sulfhydrated proteins in the host or pathogens., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Hydrogen sulfide (H 2 S) plays an important role in cardiac protection by regulating various redox signalings associated with myocardial ischemia/reperfusion (I/R) induced injury. The goal of the present investigations is the synthesis of a newly designed H 2 S-releasing ibuprofen derivative, BM-88, and its pharmacological characterization regarding the cardioprotective effects in isolated rat hearts. Cytotoxicity of BM-88 was also estimated in H9c2 cells. H 2 S-release was measured by an H 2 S sensor from the coronary perfusate. Increasing concentrations of BM-88 (1.0 to 20.0 µM) were tested in vitro studies. Preadministration of 10 µM BM-88 significantly reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from its drug-free control value of 92% to 12%. However, no clear dose dependent reduction in the incidence of reperfusion-induced VF was observed while different concentrations of BM-88 were used. It was also found that 10 µM BM-88 provided a substantial protection and significantly reduced the infarct size in the ischemic/reperfused myocardium. However, this cardiac protection was not reflected in any significant changes in coronary flow and heart rates. The results support the fact that H 2 S release plays an important role mitigating reperfusion-induced cardiac damage., Competing Interests: Declaration of Competing Interest All the authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Cyclophosphamide is a commonly used anticancer and immunosuppressive agent; however, hepatotoxicity is one of its severe toxicities. Hydrogen sulfide is a gaseous signaling molecule that plays crucial regulatory roles in various physiological functions. This study aimed to evaluate the hepatoprotective effect of hydrogen sulfide against cyclo phosp hamid e-ind uced hepatic damage in rats., Methods: Hepatotoxicity was induced by the single intraperitoneal administration of cyclophosphamide (200 mg/kg). Sprague-Dawley rats were treated by hydrogen sulfide donor, sodium hydrosulfide (25, 50, and 100 μmol/kg, intraperitoneal) 7 days before and 7 days after the administration of a single intraperitoneal injection of cyclophosphamide (200 mg/kg). Cyclo phosp hamide-ind uced hepatotoxicity was evaluated by serum and tissue biochemical and histopathological assessments. The levels of hydrogen sulfide, nitric oxide, cyclic guanosine monophosphate, interleukin 6, and interleukin 10 in liver homogenates were also determined by ELISA. One-way analysis of variance and Kruskal-Wallis tests were used as statistical analyses., Results: Cyclophosphamide increased liver function enzymes (alanine aminotransferase and aspartate aminotransferase), immunoreactivity to caspase-3 and Apaf-1, and proinflammatory cytokines. Cyclophosphamide also induced histopathological alterations including pycnotic nucleus with eosinophilic cytoplasm, increased sinusoidal dilatation, congestion, and edema. Hydrogen sulfide cotreatment significantly reduced cyclo phosp hamid e-ind uced inflammation, histological alterations, and apoptosis in the liver. 50 mg/kg sodium hydrosulfide was more effective against cyclo phosp hamid e-ind uced hepatotoxicity., Conclusion: In conclusion, hydrogen sulfide with its anti-inflammatory and anti-apoptotic effects seems to be beneficial as an adjunct to cyclophosphamide treatment to reduce cyclo phosp hamid e-ind uced hepatotoxicity and thereby can be suggested as a promising agent to increase the therapeutic efficacy of cyclophosphamide.

The root barrier to radial O 2 loss (ROL) is a key root trait preventing O 2 loss from roots to anoxic soils, thereby enabling root growth into anoxic, flooded soils. We hypothesized that the ROL barrier can also prevent intrusion of hydrogen sulphide (H 2 S), a potent phytotoxin in flooded soils. Using H 2 S- and O 2 -sensitive microsensors, we measured the apparent permeance to H 2 S of rice roots, tested whether restricted H 2 S intrusion reduced its adverse effects on root respiration, and whether H 2 S could induce the formation of a ROL barrier. The ROL barrier reduced apparent permeance to H 2 S by almost 99%, greatly restricting H 2 S intrusion. The ROL barrier acted as a shield towards H 2 S; O 2 consumption in roots with a ROL barrier remained unaffected at high H 2 S concentration (500 μM), compared to a 67% decline in roots without a barrier. Importantly, low H 2 S concentrations induced the formation of a ROL barrier. In conclusion, the ROL barrier plays a key role in protecting against H 2 S intrusion, and H 2 S can act as an environmental signalling molecule for the induction of the barrier. This study demonstrates the multiple functions of the suberized/lignified outer part of the rice root beyond that of restricting ROL., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Diabetes is associated with severe vascular complications involving the impairment of endothelial nitric oxide synthase (eNOS) as well as cystathionine γ-lyase (CSE) activity. eNOS function is suppressed in hyperglycaemic conditions, resulting in reduced NO bioavailability, which is paralleled by reduced levels of hydrogen sulfide (H 2 S). Here we have addressed the molecular basis of the interplay between the eNOS and CSE pathways. We tested the impact of H 2 S replacement by using the mitochondrial-targeted H 2 S donor AP123 in isolated vessels and cultured endothelial cells in high glucose (HG) environment, at concentrations not causing any vasoactive effect per se. Aorta exposed to HG displayed a marked reduction of acetylcholine (Ach)-induced vasorelaxation that was restored by the addition of AP123 (10 nM). In HG condition, bovine aortic endothelial cells (BAEC) showed reduced NO levels, downregulation of eNOS expression, and suppression of CREB activation (p-CREB). Similar results were obtained by treating BAEC with propargylglycine (PAG), an inhibitor of CSE. AP123 treatment rescued eNOS expression, as well as NO levels, and restored p-CREB expression in both the HG environment and the presence of PAG. This effect was mediated by a PI3K-dependent activity since wortmannin (PI3K inhibitor) blunted the rescuing effects operated by the H 2 S donor. Experiments performed in the aorta of CSE -/- mice confirmed that reduced levels of H 2 S not only negatively affect the CREB pathway but also impair Ach-induced vasodilation, significantly ameliorated by AP123. We have demonstrated that the endothelial dysfunction due to HG involves H 2 S/PI3K/CREB/eNOS route, thus highlighting a novel aspect of the H 2 S/NO interplay in the vasoactive response., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Acrolein (ACR), a highly toxic α,β-unsaturated aldehyde, is considered to be a common mediator behind the reproductive injury induced by various factors. However, the understanding of its reproductive toxicity and prevention in reproductive system is limited. Given that Sertoli cells provide the first-line defense against various toxicants and that dysfunction of Sertoli cell causes impaired spermatogenesis, we, therefore, examined ACR cytotoxicity in Sertoli cells and tested whether hydrogen sulfide (H 2 S), a gaseous mediator with potent antioxidative actions, could have a protective effect. Exposure of Sertoli cells to ACR led to cell injury, as indicated by reactive oxygen species (ROS) generation, protein oxidation, P38 activation and ultimately cell death that was prevented by antioxidant N-acetylcysteine (NAC). Further studies revealed that ACR cytotoxicity on Sertoli cells was significantly exacerbated by the inhibition of H 2 S-synthesizing enzyme cystathionine γ-lyase (CSE), while significantly suppressed by H 2 S donor Sodium hydrosulfide (NaHS). It was also attenuated by Tanshinone IIA (Tan IIA), an active ingredient of Danshen that stimulated H 2 S production in Sertoli cells. Apart from Sertoli cells, H 2 S also protected the cultured germ cells from ACR-initiated cell death. Collectively, our study characterized H 2 S as endogenous defensive mechanism against ACR in Sertoli cells and germ cells. This property of H 2 S could be used to prevent and treat ACR-related reproductive injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Formaldehyde (FA) has neurotoxic characteristics and causes neurodegenerative disease. Our previous study demonstrated the neuroprotective effects of hydrogen sulfide (H 2 S) on FA-induced neurotoxicity in HT22 cells. Emerging evidence have supported that ferroptosis is involved in FA-induced neurotoxicity. To understand the mechanism of the protection of H 2 S against FA-induced neurotoxicity, this study explored the regulatory effect of H 2 S on FA-induced ferroptosis and the underlying mechanisms. The researcher found that H 2 S (100, 200, and 400 μM, 30 min) reverses the ferroptosis induced by FA (100 μM, 24 h) in HT22 cells (a cell line of mouse hippocampal neurons), including decreases in free iron, reactive oxygen species (ROS), 4-hydroxy-2-trans-nominal (4-HNE), and malondialdehyde (MDA) contents, as well as an increase in glutathione (GSH) content. H 2 S (100, 200, and 400 μM, 30 min) also inhibited ferritinaphagy in FA-exposed HT22 cells, as evidenced by the downregulation of the ferritinophagy receptor nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain-3B (LC3B) as well as the upregulation of the main iron storage protein ferritin heavy chain 1 (FTH1) and p62. H 2 S (100, 200, and 400 μM, 30 min) also up-regulated the expression of growth differentiation factor-11 (GDF11) in FA-exposed HT22 cells. Furthermore, knockdown of GDF11 in HT22 cells cancelled the beneficial effects of H 2 S in FA-induced ferroptosis and ferritinaphagy. These data indicated that the protective mechanism underlying H 2 S-prevented neurotoxicity of FA is involved in alleviating FA-induced ferroptosis via inhibiting ferritinaphagy by upregulation of GDF11., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is the sixth most frequent human cancer and the world's third most significant cause of cancer mortality. HCC treatment has recently improved, but its mortality continues to increase worldwide due to its extremely complicated and heterogeneous genetic abnormalities. After nitric oxide (NO) and carbon monoxide (CO), the third gas signaling molecule discovered is hydrogen sulfide (H 2 S), which has long been thought to be a toxic gas. However, numerous studies have proven that H 2 S plays many pathophysiological roles in mammals. Endogenous or exogenous H 2 S can decrease cell proliferation, promote apoptosis, block cell cycle, invasion and migration through various cellular signaling pathways. This review analyzes and discusses the recent literature on the function and molecular mechanism of H 2 S and H 2 S donors in HCC, so as to provide convenience for the scientific research and clinical application of H 2 S in the treatment of liver cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: Hydrogen sulfide (H2S) is widely distributed throughout the nervous system with various antioxidant and anti-inflammatory properties. Hypertension involves an increase in reactive oxygen species (ROS) and inflammation in the hypothalamic paraventricular nucleus (PVN). However, it is unclear how H2S in PVN affects hypertension., Methods: Our study used spontaneously hypertensive rats (SHR) and control Wistar Kyoto (WKY) rats, microinjected with adenovirus-associated virus (AAV)-CBS (cystathionine beta-synthase overexpression) or AAV-ZsGreen in bilateral PVN, or simultaneously injected with virus-carrying nuclear factor erythroid 2-related factor 2 (Nrf2)-shRNA for 4 weeks. Blood pressure (BP) and plasma noradrenaline level were detected, and the PVN was collected. Finally, levels of CBS, H2S, Nrf2, Fra-LI, ROS, gp91phox, p47phox, superoxide dismutase 1, interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α, tyrosine hydroxylase, and glutamate decarboxylase 67 were measured., Results: We found that AAV-CBS increased H2S in the PVN, and BP, neuronal activation, oxidative stress, and inflammation of PVN were substantially reduced. Furthermore, endogenous H2S in the PVN activated Nrf2 and corrected the PVN's imbalance of excitatory and inhibitory neurotransmitters. However, Nrf2 knockdown in the PVN was similarly observed to abolish the beneficial effect of H2S on hypertension., Conclusions: The findings imply that endogenous H2S in SHR PVN is reduced, and PVN endogenous H2S can alleviate hypertension via Nrf2-mediated antioxidant and anti-inflammatory effects., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mitochondrial dysfunction has been shown to contribute to the pathophysiology of airway diseases. Therefore, mitochondria are targeted in the development of new therapeutic approaches. Hydrogen sulfide (H 2 S) has been shown to be involved in the pathophysiological processes of airway inflammation. We aimed to evaluate the effect of mitochondria-targeted slow H 2 S releasing donor AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)phenoxy)decyl)triphenylphosphoniumbromide)] on lipopolysaccharide (LPS)-induced airway inflammation in mice. LPS was applied to female Balb/c mice by intranasal (i.n.) route to induce airway inflammation and the subgroups of mice were treated with i.n. AP39 (250-1000 nmol/kg). 48 h after LPS administration airway reactivity was evaluated in vivo, then bronchoalveolar lavage (BAL) fluid and lungs were collected. LPS application led to bronchial hyperreactivity and neutrophil infiltration into the lung tissues along with increased TNF-α, IL-1β and IL-6 levels in BAL fluid. LPS also induced an increase in the rate of glycolysis, glycogenolysis and Krebs-cycle. AP39 treatment prevented the LPS-induced bronchial hyperreactivity and reversed the increase in TNF-α and IL-6 levels in BAL fluid. The increase in neutrophil numbers in BAL fluid was also prevented by AP39 treatment at the highest dose. Our results indicate that AP39 can prevent bronchial hyperreactivity and decrease airway inflammation. Targeting H 2 S to the mitochondria may be a new therapeutic approach in airway inflammation., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Astrocyte activation is key in neurodegenerative diseases. Hydrogen sulfide (H 2 S) exhibits neuroprotective effects on astrocytes, although the underlying molecular mechanism remains unclear. Here, we explored the effects of H 2 S on lipopolysaccharide (LPS)-induced astrocyte activation and astrocyte-mediated neuroinflammation. After inducing primary astrocytes via LPS exposure, H 2 S levels were altered. The generation and secretion of inflammatory mediators by astrocytes and their interrelation with P-glycoprotein (P-gp), an important transporter belonging to the ABC transporter family, were assessed. Activated astrocytes showed upregulated glial fibrillary acidic protein (GFAP) mRNA expression, and significantly increased proinflammatory factor mRNA/protein expression and release. The secretory capacity of astrocytes was reduced, with significantly decreased proinflammatory factor levels in culture supernatant after P-gp inhibitor verapamil pretreatment. The increase in the intracellular H 2 S level inhibited LPS-induced GFAP expression and P65 nuclear entry in astrocytes. mRNA expression and release of proinflammatory factors were reduced significantly, with no significant changes in cytoplasmic protein expression. S-sulfhydration levels increased significantly with the increased concentration of sodium hydrosulfide or S-adenosyl-L-methionine addition, with only moderate changes in astrocyte P-gp expression. H 2 S regulates NF-κB activation, leads to S-sulfhydration of P-gp, and inhibits the biosynthesis and secretion of proinflammatory factors by astrocytes. The regulatory effects of H 2 S on astrocytes may have clinical value for exploring new therapeutic strategies against neurodegenerative diseases., (© 2022. The Author(s).)

Triple negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis due to its high rates of proliferation and metastasis. Recently, hydrogen sulfide (H 2 S) has been recognized as a novel gasotransmitter that plays a significant role in various pathological processes, including cancer. Here, we show that exogenous H 2 S inhibited TNBC cancer cell proliferation, migration and invasion in vitro, and also decreased cancer malignances in the mouse model of TNBC. To investigate the underlying mechanisms of H 2 S's anti-cancer effects in TNBC, we performed transcriptome sequencing and bioinformatic analyses. 2121 differentially expressed genes (DEGs) were revealed, and mainly enriched in cell cycle and DNA replication pathways. Further analysis revealed changes in alternative splicing after exogenous H 2 S treatment. Protein-protein interaction (PPI) network analysis was performed, which identified 458 interactions among 276 DEGs enriched in cell cycle and DNA replication pathways.We identified seven hub genes (MCM3, MCM4, MCM5, MCM6, CDC6, CDC45, and GINS2) through PPI network analysis, which were up-regulated in clinical human breast cancer but down-regulated after H 2 S treatment. Based on the hub genes selected, we developed a model predicting that exogenous H 2 S mainly exerts its anti-TNBC role by delaying DNA replication. Our findings suggest that exogenous H 2 S has potential as a therapeutic agent in TNBC and may exert its therapeutic potential through DNA replication and the cell cycle pathway., Competing Interests: Conflict of interest statement The authors declare that they have no conflicts of interest related to this research, including any financial or personal relationships with other people or organizations that could inappropriately influence or bias their work., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Hydrogen sulfide (H 2 S) is considered to mediate plant growth and development. However, whether H 2 S regulates the adaptation of mangrove plant to intertidal flooding habitats is not well understood. In this study, sodium hydrosulfide (NaHS) was used as an H 2 S donor to investigate the effect of H 2 S on the responses of mangrove plant Avicennia marina to waterlogging. The results showed that 24-h waterlogging increased reactive oxygen species (ROS) and cell death in roots. Excessive mitochondrial ROS accumulation is highly oxidative and leads to mitochondrial structural and functional damage. However, the application of NaHS counteracted the oxidative damage caused by waterlogging. The mitochondrial ROS production was reduced by H 2 S through increasing the expressions of the alternative oxidase genes and increasing the proportion of alternative respiratory pathway in the total mitochondrial respiration. Secondly, H 2 S enhanced the capacity of the antioxidant system. Meanwhile, H 2 S induced Ca 2+ influx and activated the expression of intracellular Ca 2+ -sensing-related genes. In addition, the alleviating effect of H 2 S on waterlogging can be reversed by Ca 2+ chelator and Ca 2+ channel blockers. In conclusion, this study provides the first evidence to explain the role of H 2 S in waterlogging adaptation in mangrove plants from the mitochondrial aspect., (© 2023 John Wiley & Sons Ltd.)

Hydrogen sulfide (H 2 S) has been widely recognized as one of gasotransmitters. Endogenous H 2 S plays a crucial role in the progression of cancer. However, the effect of endogenous H 2 S on the development of nasopharyngeal carcinoma (NPC) is still unknown. In this study, aminooxyacetic acid (AOAA, an inhibitor of cystathionine-β-synthase), dl-propargylglycine (PAG, an inhibitor of cystathionine-γ-lyase), and l-aspartic acid (l-Asp, an inhibitor of 3-mercaptopyruvate sulfurtransferase) were adopted to detect the role of endogenous H 2 S in NPC growth. The results indicated that the combine (PAG + AOAA + l-Asp) group had higher inhibitory effect on the growth of NPC cells than the PAG, AOAA, and l-Asp groups. There were similar trends in the levels of apoptosis and reactive oxygen species (ROS). In addition, the combine group exhibited lower levels of phospho (p)-extracellular signal-regulated protein kinase but higher expressions of p-p38 and p-c-Jun N-terminal kinase than those in the AOAA, PAG, and l-Asp groups. Furthermore, the combine group exerted more potent inhibitory effect on NPC xenograft tumor growth without obvious toxicity. In summary, suppression of endogenous H 2 S generation could dramatically inhibit NPC growth via the ROS/mitogen-activated protein kinase pathway. Endogenous H 2 S may be a novel therapeutic target in human NPC cells. Effective inhibitors for H 2 S-producing enzymes could be designed and developed for NPC treatment., (© 2023 Wiley Periodicals LLC.)

Hydrogen sulfide (H 2 S) and nitric oxide (NO) are two relevant signal molecules that can affect protein function throughout post-translational modifications (PTMs) such as persulfidation, S -nitrosation, metal-nitrosylation, and nitration. Lipoxygenases (LOXs) are a group of non-heme iron enzymes involved in a wide range of plant physiological functions including seed germination, plant growth and development, and fruit ripening and senescence. Likewise, LOXs are also involved in the mechanisms of response to diverse environmental stresses. Using purified soybean ( Glycine max L.) lipoxygenase type 1 (LOX 1) and nitrosocysteine (CysNO) and sodium hydrosulfide (NaHS) as NO and H 2 S donors, respectively, the present study reveals that both compounds negatively affect LOX activity, suggesting that S -nitrosation and persulfidation are involved. Mass spectrometric analysis of nitrated soybean LOX 1 using a peroxynitrite (ONOO - ) donor enabled us to identify that, among the thirty-five tyrosine residues present in this enzyme, only Y214 was exclusively nitrated by ONOO - . The nitration of Y214 seems to affect its interaction with W500, a residue involved in the substrate binding site. The analysis of the structure 3PZW demonstrates the existence of several tunnels that directly communicate the surface of the protein with different internal cysteines, thus making feasible their potential persulfidation, especially C429 and C127. On the other hand, the CysNO molecule, which is hydrophilic and bulkier than H 2 S, can somehow be accommodated throughout the tunnel until it reaches C127, thus facilitating its nitrosation. Overall, a large number of potential persulfidation targets and the ease by which H 2 S can reach them through the diffuse tunneling network could be behind their efficient inhibition.

L-Cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen sulfide (H 2 S) in aqueous and cellular media. Considering the cytoprotective roles of H 2 S, the present adjuvant strategy would be helpful in minimizing the anti-cancer drug-induced side-effects.

Contamination of soils with chromium (Cr) jeopardized agriculture production globally. The current study was planned with the aim to better comprehend how melatonin (Mel) and hydrogen sulfide (H 2 S) regulate antioxidant defense system, potassium (K) homeostasis, and nitrogen (N) metabolism in tomato seedlings under Cr toxicity. The data reveal that application of 30 μM Mel to the seedlings treated with 25 μM Cr has a positive effect on H 2 S metabolism that resulted in a considerable increase in H 2 S. Exogenous Mel improved phytochelatins content and H + -ATPase activity with an associated increase in K content as well. Use of tetraethylammonium chloride (K + -channel blocker) and sodium orthovanadate (H + -ATPase inhibitor) showed that Mel maintained K homeostasis through regulating H + -ATPase activity under Cr toxicity. Supplementation of the stressed seedlings with Mel substantially scavenged excess reactive oxygen species (ROS) that maintained ROS homeostasis. Reduced electrolyte leakage and lipid peroxidation were additional signs of Mel's ROS scavenging effects. In addition, Mel also maintained normal functioning of nitrogen (N) metabolism and ascorbate-glutathione (AsA-GSH) system. Improved level of N fulfilled its requirement for various enzymes that have induced resilience during Cr stress. Additionally, the AsA-GSH cycle's proper operation maintained redox equilibrium, which is necessary for the biological system to function normally. Conversely, 1 mM hypotaurine (H 2 S scavenger) abolished the Mel-effect and again Cr-induced impairment on the above-mentioned parameters was observed even in presence of Mel. Therefore, based on the observed findings, we concluded that Mel needs endogenous H 2 S to alleviate Cr-induced impairments in tomato seedlings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)