H2S Donor Research Articles

Degradable tumor-specific H2S nanogenerators for disrupting tumor metabolic symbiosis and activating anti-tumor immune responses

The design of highly efficacious nanotherapeutic agents that target tumors and degrade in specific response is of great relevance and developmental promise. We have designed a tumor-specific decomposable H2S nanogenerator for the purpose of safely and effectively disrupting tumor metabolic symbiosis and activating anti-tumor immune responses. Dendritic mesoporous organosilica doped with Mn2+ (DMOM) was used as a H2S donor that could be specifically degraded in response to glutathione (GSH), and then α-Cyano-4-hydroxycinnamic acid (CHC, a monocarboxylate transporter protein inhibitor) was loaded on the pores and surface of the organosilica through a condensation reaction, and further modified with hyaluronic acid (HA). The H2S nanogenerator could target the tumor site and undergo continuous self-degradation, releasing doped Mn2+ and loaded CHC while depleting GSH and generating large amounts of H2S, which could ultimately destroy lactate metabolic symbiosis, induce multiple acidosis in tumor cells, reduce intracellular adenosine triphosphate (ATP) and enhance chemodynamic therapy. More importantly, both the H2S produced and the inhibition of lactate efflux could have an immunomodulatory effect and exert a positive influence on the activation of the immune system. Therefore, the tumor-specific degradable H2S nanogenerator with diverse therapeutic functions introduced in this work is expected to provide a new idea and a new paradigm for efficient anti-tumor therapy.

H2S prevents the disruption of the blood-brain barrier in rats with prenatal hyperhomocysteinemia

Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors –NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite – nitrites and proinflammatory cytokines (IL-1β, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.

Hydrogen Sulfide Increases Drought Tolerance by Modulating Carbon and Nitrogen Metabolism in Foxtail Millet Seedlings

Hydrogen sulfide (H2S), a novel gas signaling molecule, has been shown to enhance plant resistance to various abiotic stresses. Here, we investigated the effect of sodium hydrosulfide (NaHS, a H2S donor) on the growth, photosynthetic parameters, and enzyme activities related to carbon and nitrogen metabolism, as well as the levels of carbohydrates and nitrogen metabolites in foxtail millet seedlings subjected to drought stress conditions in pots. The findings revealed that drought stress led to a significant 41.2% decline in the total dry weight (DW) after 12 days of treatment, whereas plants treated with NaHS showed a lesser reduction of 18.7% in total DW. Under drought stress, exogenous NaHS was found to enhance carbon metabolism in foxtail millet seedlings by significantly enhancing photosynthetic capacity, starch, and sucrose content. Additionally, exogenous NaHS was observed to improve nitrogen metabolism by substantially increasing soluble protein content, nitrogen assimilate activity, and synthesis of nitrogen-containing compounds in foxtail millet seedlings. In summary, the exogenous application of NaHS stimulated seedling growth and enhanced drought resistance in foxtail millet by modulating carbon and nitrogen metabolism processes affected by drought stress.

Hydrogen sulfide-mitigated salinity stress impact in sunflower seedlings was associated with improved photosynthesis performance and osmoregulation

BackgroundSalinity is one major abiotic stress affecting photosynthesis, plant growth, and development, resulting in low-input crops. Although photosynthesis underlies the substantial productivity and biomass storage of crop yield, the response of the sunflower photosynthetic machinery to salinity imposition and how H2S mitigates the salinity-induced photosynthetic injury remains largely unclear. Seed priming with 0.5 mM NaHS, as a donor of H2S, was adopted to analyze this issue under NaCl stress. Primed and nonprime seeds were established in nonsaline soil irrigated with tape water for 14 d, and then the seedlings were exposed to 150 mM NaCl for 7 d under controlled growth conditions.ResultsSalinity stress significantly harmed plant growth, photosynthetic parameters, the structural integrity of chloroplasts, and mesophyll cells. H2S priming improved the growth parameters, relative water content, stomatal density and aperture, photosynthetic pigments, photochemical efficiency of PSII, photosynthetic performance, soluble sugar as well as soluble protein contents while reducing proline and ABA under salinity. H2S also boosted the transcriptional level of ribulose 1,5-bisphosphate carboxylase small subunit gene (HaRBCS). Further, the transmission electron microscope showed that under H2S priming and salinity stress, mesophyll cells maintained their cell membrane integrity and integrated chloroplasts with well-developed thylakoid membranes.ConclusionThe results underscore the importance of H2S priming in maintaining photochemical efficiency, Rubisco activity, and preserving the chloroplast structure which participates in salinity stress adaptation, and possibly sunflower productivity under salinity imposition. This underpins retaining and minimizing the injury to the photosynthetic machinery to be a crucial trait in response of sunflower to salinity stress.

H2S is involved in drought-mediated stomatal closure through PLDα1 in Arabidopsis.

PLDα1 promoted H2S production by positively regulating the expression of LCD. Stomatal closure promoted by PLDα1 required the accumulation of H2S under drought stress. Phospholipase Dα1 (PLDα1) acting as one of the signal enzymes can respond to drought stress. It is well known that hydrogen sulfide (H2S) plays an important role in plant responding to biotic or abiotic stress. In this study, the functions and relationship between PLDα1 and H2S in drought stress resistance in Arabidopsis were explored. Our results indicated that drought stress promotes PLDα1 and H2S production by inducing the expression of PLDα1 and LCD genes. PLDα1 and LCD enhanced plant tolerance to drought by regulating membrane lipid peroxidation, proline accumulation, H2O2 content and stomatal closure. Under drought stress, the H2O2 content of PLDα1-deficient mutant (pldα1), L-cysteine desulfhydrase (LCD)-deficient mutant (lcd) was higher than that of ecotype (WT), the stomatal aperture of pldα1 and lcd was larger than that of WT. The transcriptional and translational levels of LCD were lower in pldα1 than that in WT. Exogenous application of the H2S donor NaHS or GYY reduced the stomatal aperture of WT, pldα1, PLDα1-CO, and PLDα1-OE lines, while exogenous application of the H2S scavenger hypotaurine (HT) increased the stomatal aperture. qRT-PCR analysis of stomatal movement-related genes showed that the expression of CAX1, ABCG5, SCAB1, and SLAC1 genes in pldα1 and lcd were down-regulated, while ACA1 and OST1 gene expression was significantly up-regulated. Thus, PLDα1 and LCD are required for stomatal closure to improve drought stress tolerance.

An Expanded Palette of Fluorescent COS/H2S‐Releasing Donors for H2S Delivery, Detection, and In Vivo Application

AbstractHydrogen sulfide (H2S) is an important reactive sulfur species that is involved in many biological functions, and H2S imbalances have been indicated as a potential biomarker for various diseases. Different H2S donors have been developed to deliver H2S directly to biological systems, but few reports include donors with optical responses that allow for tracking of H2S release. Moreover, donor systems that use the same chemistry to deliver H2S across a palette of fluorescent responses remain lacking. Here we report five thiol‐activated fluorescence turn‐on COS/H2S donors that utilize blue, yellow, orange, red, and near infrared‐emitting dyes functionalized with an H2S‐releasing sulfenyl thiocarbonate scaffold. Upon treatment with thiols, each donor provides a fluorescence turn‐on response (3–310‐fold) and high H2S release efficiencies (>60 %). Using combined electrode and fluorescence experiments, we directly correlate the measured H2S release with the fluorescence response. All donors are biocompatible and release H2S in live cell environments. In addition, we demonstrate that the NIR donor allows for imaging H2S release in live rats via subcutaneous injection of the donor loaded into an alginate gel, which to the best of our knowledge is the first in vivo tracking of H2S release from a fluorogenic donor in non‐transparent organisms.

An Expanded Palette of Fluorescent COS/H2S-Releasing Donors for H2S Delivery, Detection, and In Vivo Application.

Hydrogen sulfide (H2S) is an important reactive sulfur species that is involved in many biological functions, and H2S imbalances have been indicated as a potential biomarker for various diseases. Different H2S donors have been developed to deliver H2S directly to biological systems, but few reports include donors with optical responses that allow for tracking of H2S release. Moreover, donor systems that use the same chemistry to deliver H2S across a palette of fluorescent responses remain lacking. Here we report five thiol-activated fluorescence turn-on COS/H2S donors that utilize blue, yellow, orange, red, and near infrared-emitting dyes functionalized with an H2S-releasing sulfenyl thiocarbonate scaffold. Upon treatment with thiols, each donor provides a fluorescence turn-on response (3-310-fold) and high H2S release efficiencies (>60 %). Using combined electrode and fluorescence experiments, we directly correlate the measured H2S release with the fluorescence response. All donors are biocompatible and release H2S in live cell environments. In addition, we demonstrate that the NIR donor allows for imaging H2S release in live rats via subcutaneous injection of the donor loaded into an alginate gel, which to the best of our knowledge is the first in vivo tracking of H2S release from a fluorogenic donor in non-transparent organisms.

Hydrogen Sulfide Delivery to Enhance Bone Tissue Engineering Cell Survival.

Though crucial for natural bone healing, local calcium ion (Ca2+) and phosphate ion (Pi) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H2S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca2+/Pi concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H2S donor, were applied to assess the influence of H2S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca2+ (32 mM) and/or Pi (16 mM). To controllably deliver H2S over time, a novel donor molecule (thioglutamic acid-GluSH) was synthesized and evaluated for its H2S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H2S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca2+/Pi concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H2S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications.

Glutathione‐induced hydrogen sulfide enhances drought tolerance in sweet pepper (Capsicum annuum L.)

AbstractGlutathione (GSH) has been studied for its potential to enhance stress tolerance in plant systems, but the role of hydrogen sulfide (H2S) in GSH‐induced water stress tolerance in sweet pepper (Capsicum annuum L.) is still under investigation. This study explores how H2S and GSH modulate water stress tolerance in pepper plants, addressing a research gap. The joint effect of sodium hydrosulfide (NaHS), a donor of H2S, and GSH on water stress tolerance was determined through pre‐treatment with the H2S scavenger 0.1 mM hypotaurine (HT). Pepper seedlings were sprayed with 1.0 mM GSH or GSH + 0.2 mM NaHS once a week, with soil moisture content set at 80% and 40% for full irrigation and water stress conditions for a duration of 2 weeks. The results showed that water stress significantly reduced total plant dry weight, chlorophyll a and b content, Fv/Fm, leaf water potential, and relative water content by 50%, 56%, 33%, 27%, 52%, and 34%, while increasing hydrogen peroxide (H2O2), proline, and H2S levels by 152%, 134%, and77%, respectively. Treatment with GSH and NaHS reduced water stress‐induced H2O2 production and improved plant growth, photosynthetic traits, proline, and the activity of L‐cysteine desulfhydrase (L‐DES), leading to the generation of H2S content. GSH reduced NADPH oxidase (NOX), superoxide dismutase (SOD), and H2O2 but increased glutathione peroxidase (GPX) activities. The interaction of NaHS and GSH led to further reductions in NOX, SOD, and H2O2 values but increased GPX activity. The combined GSH and NaHS treatment increased nitric oxide (NO) production but decreased the activity of S‐nitrosoglutathione reductase (GSNOR), potentially accelerating S‐nitrosylation. Hypotaurine negated the positive impacts of GSH on water stress tolerance by reducing H2S concentration in pepper plants, but this was corrected by the concurrent application of NaHS and GSH + HT. Therefore, water stress tolerance requires H2S.

The functions of hydrogen sulfide on the urogenital system of both males and females: from inception to the present.

Hydrogen sulfide (H2S) is known as a chemical gas in nature with both enzymatic and non-enzymatic biosynthesis in different human organs. A couple of studies have demonstrated the function of H2S in regulating the homeostasis of the human body. Additionally, they have shown its synthesis, measurement, chemistry, protective effects, and interaction in various aspects of scientific evidence. Furthermore, many researches have demonstrated the beneficial impacts of H2S on genital organs and systems. According to various studies, it is recognized that H2S-producing enzymes and the endogenous production of H2S are expressed in male and female reproductive systems in different mammalian species. The main goal of this comprehensive review is to assess the potential therapeutic impacts of this gasotransmitter in the male and female urogenital system and find underlying mechanisms of this agent. This narrative review investigated the articles that were published from the 1970s to 2022. The review's primary focus is the impacts of H2S on the male and female urogenital system. Medline, CINAHL, PubMed, and Google scholar databases were searched. Keywords used in this review were "Hydrogen sulfide," "H2S," "urogenital system," and "urogenital tract". Numerous studies have demonstrated the therapeutic and protective effects of sodium hydrosulfide (Na-HS) as an H2S donor on male and female infertility disorders. Furthermore, it has been observed that H2S plays a significant role in improving different diseases such as ameliorating sperm parameters. The specific localization of H2S enzymes in the urogenital system provides an excellent opportunity to comprehend its function and role in various disorders related to this system. It is noteworthy that H2S has been demonstrated to be produced in endocrine organs and exhibit diverse activities. Moreover, it is important to recognize that alterations in H2S biosynthesis are closely linked to endocrine disorders. Therefore, hormones can be pivotal in regulating H2S production, and H2S synthesis pathways may aid in establishing novel therapeutic strategies. H2S possesses pharmacological effects on essential disorders, such as anti-inflammation, anti-apoptosis, and anti-oxidant activities, which render it a valuable therapeutic agent for human urogenital disease. Furthermore, this agent shows promise in ameliorating the detrimental effects of various male and female diseases. Despite the limited clinical research, studies have demonstrated that applying H2S as an anti-oxidant source could ameliorate adverse effects of different conditions in the urogenital system. More clinical studies are required to confirm the role of this component in clinical settings.

Construction of a NIR hydrogen sulfide fluorescent probe for revealing the role of astrocytes in hypothalamic inflammation

Hydrogen sulfide (H2S) is a crucial endogenous gas signaling molecule in the central nervous system, playing a significant role in anti-inflammation, anti-oxidation, and neuroprotection. Our studies have shown that the level of H2S is closely related to hypothalamic inflammation-induced obesity. Compared to neurons, astrocytes, exhibit a preferential activation in response to high-fat diet-induced hypothalamic inflammation. Whether the reduction of hydrogen sulfide in astrocytes is the cause of neuronal damage leading to hypothalamic inflammation is worth exploring. The key to discussing the role of astrocytes is to accurately and quickly detect the levels of H2S in the complex microenvironment of the brain. In this work, we designed and synthesized a H2S near-infrared fluorescence probe (NIR-HS) based on dicyanideisophorone. NIR-HS selectively responds to H2S at 668 nm, with an effective linear range (0–20 μM), high sensitivity (35 nM). This probe has been successfully applied to detect hydrogen sulfide levels in astrocytes and to perform H2S fluorescence imaging on the slices of the ventromedial nucleus of the hypothalamus. Additionally, the effect of the H2S donor drug allicin on the levels of H2S in the hypothalamus and its therapeutic effect on hypothalamic inflammation were confirmed using NIR-HS and a series of signal pathway studies. Ultimately, we revealed the mechanism of that H2S inhibits hypothalamic neuronal inflammation by suppressing the expression of the pro-inflammatory factor IL-1β in astrocytes.

Synergistic effects of melatonin and hydrogen sulfide in alleviating cognitive decline and BDNF dysregulation in a rat model of depression

ABSTRACT This research aimed to investigate the possible anti-amnesic effects of a combined therapy involving melatonin and H2S in a rat model displaying Depressive-Like Behaviors caused by Chronic Unpredictable Mild Stress (CUMS). Our study aims to assess the efficacy of this treatment in mitigating oxidative stress and neuroinflammation in the striatum and hippocampus. Furthermore, we seek to investigate its ability to restore BDNF levels within this specific rat model. The rats underwent a 4-week CUMS protocol and were administered sodium hydrosulfide (a H2S donor) at a dose of 5.6 μmol/100 g/day, as well as melatonin at a dose of 1 mg/100 g/day from the first day of the CUMS protocol. Following the CUMS exposure, the rats were assessed through various behavioral tests. Subsequently, the rats were euthanized after the behavioral tests, and blood samples were collected for corticosterone analysis. Oxidative stress (OS) markers, BDNF and TNF-α levels were analyzed in both the striatum and HP. Concurrently administering H2S and melatonin in a rat model of CUMS-induced depression demonstrates antidepressant-like effects. Furthermore, this combined treatment effectively prevents the development of learning and memory impairments associated with CUMS. Additionally, it reduces Malondialdehyde and nitric oxide levels, enhances glutathione peroxidase and superoxide dismutase activity in the striatum and HP, and mitigates CUMS-induced elevations in TNF-α levels in both brain regions. Significantly, long-term administration of this combination reverses the chronic stress-induced reduction of hippocampal BDNF levels. These findings suggest that the synergy between H2S and melatonin holds promise in alleviating cognitive impairments.

Exogenous Hydrogen Sulfide Prevents Necroptosis by Inhibiting p38MAPK Pathway Activation in JEG-3 Trophoblast Cells: A Role in Preeclampsia

Objectives: Necroptosis, a form of programmed cell death, can occur in the placenta of patients with preeclampsia (PE). Hydrogen sulfide (H2S) can inhibit necroptosis of human umbilical vein endothelial cells under the high glucose-induced injury. Whether H2S can protect trophoblasts against necroptosis underlying PE has not been elucidated. This study aimed to explore the protective role of H2S in trophoblast cells against necroptosis underlying PE. Design: This is an in vitro experimental study. Participants: A total of 10 pregnant women with severe PE and 10 matched control normotensive pregnant women were included. The placenta tissues were extracted from participators. The human JEG-3 trophoblasts were commercially available. Methods: The expression and localization of necrotic proteins were assayed in human placenta samples, and the effect of necrotic cell death on the proliferation and apoptosis of human JEG-3 trophoblasts was evaluated. The component expressions of inflammatory cytokine and p38MAPK signaling pathway were measured in samples pretreated with or without NaHS (H2S donor) and SB203580 (p38 inhibitor). Results: RIPA1, RIPA3, and p-p38 levels were significantly higher in PE placental tissue, whereas cystathionine β-synthase expression was decreased. In JEG-3 trophoblasts, necroptosis increased apoptotic cell numbers, suppressed cell proliferation, increased inflammatory cytokine expression, and increased p38MAPK activation, which can be prevented by NaHS. Limitations: In the present study, we did not provide sufficient evidence that necroptosis was a part of the pathogenesis of PE. Conclusions: We proposed the putative role of necroptosis in early-onset PE, reflected by the blockage of caspase-8/3 and increased expression of RIPA1 and RIPA3 in PE placenta tissues. Furthermore, we demonstrated that exogenous H2S protected cytotrophoblasts against ceramide-induced necroptosis via the p38MAPK pathway.

The role of exogenous hydrogen sulfide in mitigating cadmium toxicity in plants: A comprehensive meta-analysis.

Reducing the accumulation of cadmium (Cd) and mitigating its toxicity are pivotal strategies for addressing Cd pollution's threats to agriculture and human health. Hydrogen sulfide (H2S) serves as a signaling molecule, playing a crucial role in plant stress defense mechanisms. Nevertheless, a comprehensive assessment of the impact of exogenous H2S on plant growth, antioxidant properties, and gene expression under Cd stress remains lacking. In this meta-analysis, we synthesized 575 observations from 27 articles, revealing that exogenous H2S significantly alleviates Cd-induced growth inhibition in plants. Specifically, it enhances root length (by 8.71%), plant height (by 15.67%), fresh weight (by 15.15%), dry weight (by 22.54%), and chlorophyll content (by 27.99%) under Cd stress conditions. H2S boosts antioxidant enzyme activity, particularly catalase (CAT), by 39.51%, thereby reducing Cd-induced reactive oxygen species (ROS) accumulation. Moreover, it impedes Cd translocation from roots to shoots, resulting in a substantial 40.19% reduction in stem Cd content. Additionally, H2S influences gene expression in pathways associated with antioxidant enzymes, metal transport, heavy metal tolerance, H2S biosynthesis, and energy metabolism. However, the efficacy of exogenous H2S in alleviating Cd toxicity varies depending on factors such as plant species, concentration of the H2S donor sodium hydrosulfide (NaHS), application method, and cultivation techniques. Notably, NaHS concentrations exceeding 200 μM may adversely affect plants. Overall, our study underscores the role of exogenous H2S in mitigating Cd toxicity and elucidates its mechanism, providing insights for utilizing H2S to combat Cd pollution in agriculture.

Infection Microenvironment-Responsive Coating on Titanium Surfaces for On-Demand Release of Therapeutic Gas and Antibiotic.

Aseptic loosening and bacterial infection pose significant challenges in the clinical application of titanium (Ti) orthopedic implants, which are primarily caused by insufficient osseointegration and bacterial contamination. To address these issues, a responsive coating on Ti surface is constructed, which achieves enhanced osseointegration and infection elimination by on-demand release of therapeutic gas hydrogen sulfide (H2S) and antibiotic. TiO2 nanotubes (TNT) are anodized on the Ti surface to enhance its bioactivity and serve as reservoirs for the antibiotic. An infection microenvironment-responsive macromolecular H2S donor layer is coated on top of TNT to inhibit premature leakage of antibiotic. This layer exhibits a sustained release of low-dosage H2S, which is capable of promoting the osteogenic differentiation and migration of cells. Moreover, the compactness of the macromolecular H2S donor layer could be broken by bacterial invasion, leading to rapid antibiotic release thus preventing infection. In vitro antibacterial experiments validates significant antibacterial activity of the coating against both Gram-negative (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). Crucially, this coating effectively suppresses implant-associated infection with 98.7% antibacterial efficiency in a rat femoral bone defect model, mitigates inflammation at the defect site and promotes osseointegration of the Ti orthopedic implant.

Hydrogen sulfide regulates macrophage polarization and necroptosis to accelerate diabetic skin wound healing

Hydrogen sulfide (H2S), recognized as the third gasotransmitter, plays a pivotal role in the pathophysiological processes of various diseases. Cystathionine γ-lyase (CSE) is the main enzyme for H2S production in the skin. However, effects and mechanisms of H2S in diabetic skin wound healing remain unclear. Our findings revealed a decrease in plasma H2S content in diabetic patients with skin wounds. CSE knockout (KO) diabetic mice resulted in delayed wound healing, reduced blood perfusion, and CD31 expression around the wounds. It also led to increased infiltration of inflammatory cells and M1-type macrophages, decreased collagen levels, α-smooth muscle actin (α-SMA), and proliferating cell nuclear antigen (PCNA) expression. Additionally, there were enhanced expressions of necroptosis related proteins, including receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain like protein (MLKL). In comparison, sodium hydrosulfide (NaHS), H2S donor, accelerated skin wound healing in leptin receptor deficiency (db/db) mice. This acceleration was accompanied by increased blood perfusion and CD31 expression, reduced infiltration of inflammatory cells and M1-type macrophages, elevated collagen levels, α-SMA, and PCNA expressions, and decreased necroptosis-related protein expressions together with nuclear factor-κB (NF-κB) p65 phosphorylation. In conclusion, H2S regulates macrophage polarization and necroptosis, contributing to the acceleration of diabetic skin wound healing. These findings offer a novel strategy for the treatment of diabetic skin wounds.

AP39, a novel mitochondria-targeted hydrogen sulfide donor ameliorates doxorubicin-induced cardiotoxicity by regulating the AMPK/UCP2 pathway.

Doxorubicin (DOX) is a broad-spectrum, highly effective antitumor agent; however, its cardiotoxicity has greatly limited its use. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter that exerts cardioprotective effects via the regulation of oxidative stress and apoptosis and maintenance of mitochondrial function, among other mechanisms. AP39 is a novel mitochondria-targeted H2S donor that, at appropriate concentrations, attenuates intracellular oxidative stress damage, maintains mitochondrial function, and ameliorates cardiomyocyte injury. In this study, DOX-induced cardiotoxicity models were established using H9c2 cells and Sprague-Dawley rats to evaluate the protective effect of AP39 and its mechanisms of action. Both in vivo and in vitro experiments showed that DOX induces oxidative stress injury, apoptosis, and mitochondrial damage in cardiomyocytes and decreases the expression of p-AMPK/AMPK and UCP2. All DOX-induced changes were attenuated by AP39 treatment. Furthermore, the protective effect of AP39 was significantly attenuated by the inhibition of AMPK and UCP2. The results suggest that AP39 ameliorates DOX-induced cardiotoxicity by regulating the expression of AMPK/UCP2.

Synergistic interplay between melatonin and hydrogen sulfide enhances cadmium-induced oxidative stress resistance in stock (Matthiola incana L.)

ABSTRACT Ornamental crops particularly cut flowers are considered sensitive to heavy metals (HMs) induced oxidative stress condition. Melatonin (MLT) is a versatile phytohormone with the ability to mitigate abiotic stresses induced oxidative stress in plants. Similarly, signaling molecules such as hydrogen sulfide (H2S) have emerged as potential options for resolving HMs related problems in plants. The mechanisms underlying the combined application of MLT and H2S are not yet explored. Therefore, we evaluated the ability of individual and combined applications of MLT (100 μM) and H2S in the form of sodium hydrosulfide (NaHS), a donor of H2S, (1.5 mM) to alleviate cadmium (Cd) stress (50 mg L−1) in stock (Matthiola incana L.) plants by measuring various morpho-physiological and biochemical characteristics. The results depicted that Cd-stress inhibited growth, photosynthesis and induced Cd-associated oxidative stress as depicted by excessive ROS accumulation. Combined application of MLT and H2S efficiently recovered all these attributes. Furthermore, Cd stress-induced oxidative stress markers including electrolyte leakage, malondialdehyde, and hydrogen peroxide are partially reversed in Cd-stressed plants by MLT and H2S application. This might be attributed to MLT or H2S induced antioxidant plant defense activities, which effectively reduce the severity of oxidative stress indicators. Overall, MLT and H2S supplementation, favorably regulated Cd tolerance in stock; yet, the combined use had a greater effect on Cd tolerance than the independent application.

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels

Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

Decreased levels of hydrogen sulfide in the hypothalamic paraventricular nucleus contribute to sympathetic hyperactivity induced by cerebral infarction.

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS), but its mechanism is poorly understood. We aimed to investigate the role of H2S in the pathogenesis of PSH. IS patients were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) group. IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN). Compared with the NMCI group, patients in the MCI group showed PSH, including tachycardia, hypertension, and more plasma norepinephrine (NE) that was positively correlated with levels of creatine kinase, glutamate transaminase, and creatinine respectively. The 1-year survival rate of patients with high plasma NE levels was lower. The hypothalamus of rats with MCAO showed increased activity, especially in the PVN region. The levels of H2S in PVN of the rats with MCAO were reduced, while the blood pressure and renal sympathetic discharge were increased, which could be ameliorated by NaHS and exacerbated by AOAA. NaHS completely reduced the disulfide bond of NMDAR1 in PC12 cells. The inhibition of NMDAR by MK-801 microinjected in PVN of rats with MCAO also could lower blood pressure and renal sympathetic discharge. In conclusion, PSH may be associated with disease progression and survival in patients with IS. Decreased levels of H2S in PVN were involved in regulating sympathetic efferent activity after cerebral infarction. Our results might provide a new strategy and target for the prevention and treatment of PSH.