Hydrogen Sulfide Donor Research Articles

Hydrogen sulfide facilities production of nitric oxide via the Akt/endothelial nitric oxide synthases signaling pathway to protect human umbilical vein endothelial cells from injury by angiotensin II.

Angiotensin II (Ang II) has been reported as key in inducing endothelial cell injury, and endothelial cells may produce nitric oxide (NO) to protect themselves. However, the underlying mechanism remains elusive. Human umbilical vein endothelial cells (HUVECs) were divided into five treatment groups as follows: Normal control, Ang II, Ang II + sodium hydrosulfide [NaHS; hydrogen sulfide (H2S) donor], Ang II + Akt inhibitors + NaHS, and Ang II + endothelial nitric oxide synthases (eNOS) inhibitors + NaHS. Subsequently, cell viability, apoptosis, migration, proliferation and adhesion ability were determined. In addition, tubular structure formation was observed, and the NO and phosphorylation levels of Akt and eNOS were evaluated. Compared with the normal control group, Ang II treatment reduced the viability of HUVECs and increased the level of cell apoptosis (P<0.05). Furthermore, Ang II treatment inhibited the phosphorylation level of eNOS and Akt, as well as the generation of NO (P<0.05). H2S reversed the above‑mentioned effects significantly and increased cell proliferation, adhesion ability and promoted tubular structure formation (P<0.05); however, H2S did not reverse the impact of eNOS and Akt phosphorylation levels after being processed with Akt and eNOS inhibitors, which indicates that H2S is capable of protecting HUVECs via the eNOS/Akt signaling pathway (P<0.05). Thus, H2S stimulates the production of NO and protects HUVECs via inducing the Akt/eNOS signaling pathway.

Role of Cyclic Nucleotides in the Effect of Hydrogen Sulfide on Contractions of Rat Jejunum.

We studied the role of cyclic nucleotides in the influence of hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS, 200 μM), on motor activity of rat jejunum. NaHS reduced spontaneous and carbachol-induced contractions of rat jejunum segment, which suggests that H2S can act through mechanisms involving muscarinic receptor activation. Against the background of a membrane-penetrating non-hydrolyzable cAMP analogue or under conditions of adenylate cyclase blockade, the inhibitory effect of NaHS on the carbachol-induced contractions was maintained. Against the background of elevated cGMP concentration or guanylate cyclase inhibition, the reduction of carbachol-induced contractions upon exposure to NaHS was less pronounced than in control. It was hypothesized that H2S induces relaxation of carbachol-induced jejunum contractions, affecting protein kinase G targets or activating cGMP synthesis.

A novel pH-controlled hydrogen sulfide donor protects gastric mucosa from aspirin-induced injury.

Hydrogen sulphide (H2S) serves as a vital gastric mucosal defence under acid condition. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are among widely prescribed medications with effects of antipyresis, analgesia and anti‐inflammation. However, their inappropriate use causes gastric lesions and endogenous H2S deficiency. In this work, we reported the roles of a novel pH‐controlled H2S donor (JK‐1) in NSAID‐related gastric lesions. We found that JK‐1 could release H2S under mild acidic pH and increase solution pH value. Intragastrical administration of aspirin (ASP), one of NSAIDs, to mice elicited significant gastric lesions, evidenced by mucosal festering and bleeding. It also led to infiltration of inflammatory cells and resultant releases of IL‐6 and TNF‐α, as well as oxidative injury including myeloperoxidase (MPO) induction and GSH depletion. In addition, the ASP administration statistically inhibited H2S generation in gastric mucosa, while up‐regulated cyclooxygenase (COX)‐2 and cystathionine gamma lyase (CSE) expression. Importantly, these adverse effects of ASP were prevented by the intragastrical pre‐administration of JK‐1. However, JK‐1 alone did not markedly alter the property of mouse stomachs. Furthermore, in vitro cellular experiments showed the exposure of gastric mucosal epithelial (GES‐1) cells to HClO, imitating MPO‐driven oxidative injury, decreased cell viability, increased apoptotic rate and damaged mitochondrial membrane potential, which were reversed by pre‐treatment with JK‐1. In conclusion, JK‐1 was proved to be an acid‐sensitive H2S donor and could attenuate ASP‐related gastric lesions through reconstruction of endogenous gastric defence. This work indicates the possible treatment of adverse effects of NSAIDs with pH‐controlled H2S donors in the future.

NaHS Protects against the Impairments Induced by Oxygen-Glucose Deprivation in Different Ages of Primary Hippocampal Neurons.

Brain ischemia leads to poor oxygen supply, and is one of the leading causes of brain damage and/or death. Neuroprotective agents are thus in great need for treatment purpose. Using both young and aged primary cultured hippocampal neurons as in vitro models, we investigated the effect of sodium hydrosulfide (NaHS), an exogenous donor of hydrogen sulfide, on oxygen-glucose deprivation (OGD) damaged neurons that mimick focal cerebral ischemia/reperfusion (I/R) induced brain injury. NaHS treatment (250 μM) protected both young and aged hippocampal neurons, as indicated by restoring number of primary dendrites by 43.9 and 68.7%, number of dendritic end tips by 59.8 and 101.1%, neurite length by 36.8 and 66.7%, and spine density by 38.0 and 58.5% in the OGD-damaged young and aged neurons, respectively. NaHS treatment inhibited growth-associated protein 43 downregulation, oxidative stress in both young and aged hippocampal neurons following OGD damage. Further studies revealed that NaHS treatment could restore ERK1/2 activation, which was inhibited by OGD-induced protein phosphatase 2 (PP2A) upregulation. Our results demonstrated that NaHS has potent protective effects against neuron injury induced by OGD in both young and aged hippocampal neurons.

Cysteine deprivation prevents induction of peroxisome proliferator-activated receptor gamma-2 and adipose differentiation of 3T3-L1 cells

Plasma cysteine is strongly associated with body fat mass in human cohorts and diets low in cysteine prevents fat accumulation in mice. It is unclear if plasma cysteine affects fat development or if fat accumulation raises plasma cysteine. To determine if cysteine affects adipogenesis, we differentiated 3T3-L1 preadipocytes in medium with reduced cysteine. Cells incubated in media with 10–20μM cysteine exhibited reduced capacity to differentiate into triacylglycerol-storing mature adipocytes compared with cells incubated with 50μM cysteine. Low cysteine severely reduced expression of peroxisome proliferator-activated receptor gamma2 (Pparγ2) and its target genes perlipin1 (Plin1) and fatty acid binding protein-4 (Fabp4). Expression of stearoyl-CoA desaturase-1 (Scd1), known to be repressed with cysteine depletion, was also reduced with low cysteine. Medium depletion of the essential amino acids leucine, valine, and isoleucine had only a modest effect on adipocyte specific gene expression and differentiation. Stimulation with the PPARγ agonist BRL-49653 or addition of a hydrogen sulfide donor enhanced differentiation of 3T3-L1 cells cultured in low cysteine. This demonstrates that the ability to induce PPARγ expression is preserved when cells are cultured in low cysteine. It therefore appears that cysteine depletion inhibits adipogenesis by specifically affecting molecular pathways required for induction of PPARγ expression, rather than through a general reduction of global protein synthesis. In conclusion, we show that low extracellular cysteine reduces adipocyte differentiation by interfering with PPARγ2 and PPARγ target gene expression. Our results provide further evidence for the hypothesis that plasma cysteine is a casual determinant for body fat mass.

Hydrogen sulfide prevents postoperative adhesion in a rat uterine horn model

ObjectiveAbdominal adhesions are primarily severe postoperative complications that can cause gynecological problems such as infertility and chronic pelvic pain. Inflammatory mediators are significantly related to adhesion formation, and hydrogen sulfide plays a significant anti-inflammatory role in multiple physiological processes. Therefore, the effect of NaHS, a hydrogen sulfide donor, on postoperative adhesion formation was examined in a rat uterine horn model. Materials and methodsA rat uterine horn model was created to evaluate whether NaHS, a hydrogen sulfide donor, could decrease postoperative adhesion formation. Rats were randomly grouped and administrated with different doses of NaHS, where DL-propargylglycine and low-molecular-weight heparin acted as negative and positive controls, respectively. The extent and severity of adhesions were assessed on the 14th postoperative day. Serum of rats was sampled for the determination of 27 cytokines using a chip. ResultsThe severity and total scores of adhesion in rats given 112μM/kg and 56μM/kg NaHS were significantly less compared with those of the control group (p<0.01). Scores for the extent of adhesion re-formation in the DL-propargylglycine and control groups did not differ (p>0.05). At least six cytokines were involved in the procedures for the prevention of adhesion formation, as they varied significantly among different groups. ConclusionAdministration of NaHS could apparently reduce postoperative adhesion in the rat uterine horn model. This preventive effect may be associated with the variation of cytokine that is related to inflammatory.

Placental Stem Villus Arterial Remodeling Associated with Reduced Hydrogen Sulfide Synthesis Contributes to Human Fetal Growth Restriction

Intrauterine fetal growth restriction (IUGR) is often associated with compromised umbilical arterial flow, indicating increased placental vascular resistance. Oxidative stress is causatively implicated. Hydrogen sulfide maintains differentiated smooth muscle in vascular beds, and its synthetic enzymecystathionine-γ-lyase (CSE) is down-regulated in growth-restricted placentas. We hypothesized that remodeling of resistance arteries in stem villi contributes to IUGR by compromising umbilical blood flow via oxidative stress, reducing hydrogen sulfide signaling. Stem villus arteries in human IUGR placentasdisplaying absent or reversed end-diastolic flow contained reduced myosin heavy chain, smooth muscle actin, and desmin, and increased markers of dedifferentiation, cellular retinol-binding protein 1, and matrix metalloproteinase 2, compared to term and preterm controls. Wall thickness/lumen ratio was increased, lumen diameter decreased, but wall thickness remained unchanged in IUGR placentas. CSE correlated positively with myosin heavy chain, smooth muscle actin, and desmin. Birth weight correlated positively with CSE, myosin heavy chain, smooth muscle actin, and desmin, and negatively with cellular retinol-binding protein 1 and matrix metalloproteinase 2. These findings could be recapitulated invitro by subjecting stem villus artery explants to hypoxia-reoxygenation, or inhibiting CSE. Treatment with a hydrogen sulfide donor, diallyl trisulfide, prevented these changes. IUGR is associated with vascular remodeling of the stem villus arteries. Oxidative stress results in reduction of placental CSE activity, decreased hydrogen sulfide production, and smooth muscle cell dedifferentiation invitro. This vascular remodeling isreversible,and hydrogen sulfide donors are likely to improve pregnancy outcomes.

AP39, a mitochondria-targeting hydrogen sulfide (H2 S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling.

H2 S protects myocardium against ischaemia/reperfusion injury. This protection may involve the cytosolic reperfusion injury salvage kinase (RISK) pathway, but direct effects on mitochondrial function are possible. Here, we investigated the potential cardioprotective effect of a mitochondria-specific H2 S donor, AP39, at reperfusion against ischaemia/reperfusion injury. Anaesthetized rats underwent myocardial ischaemia (30 min)/reperfusion (120 min) with randomization to receive interventions before reperfusion: vehicle, AP39 (0.01, 0.1, 1μmol·kg-1 ), or control compounds AP219 and ADT-OH (1μmol·kg-1 ). LY294002, L-NAME or ODQ were used to investigate the involvement of the RISK pathway. Myocardial samples harvested 5min after reperfusion were analysed for RISK protein phosphorylation and isolated cardiac mitochondria were used to examine the direct mitochondrial effects of AP39. AP39, dose-dependently, reduced infarct size. Inhibition of either PI3K/Akt, eNOS or sGC did not affect this effect of AP39. Western blot analysis confirmed that AP39 did not induce phosphorylation of Akt, eNOS, GSK-3β or ERK1/2. In isolated subsarcolemmal and interfibrillar mitochondria, AP39 significantly attenuated mitochondrial ROS generation without affecting respiratory complexes I or II. Furthermore, AP39 inhibited mitochondrial permeability transition pore (PTP) opening and co-incubation of mitochondria with AP39 and cyclosporine A induced an additive inhibitory effect on the PTP. AP39 protects against reperfusion injury independently of the cytosolic RISK pathway. This cardioprotective effect could be mediated by inhibiting PTP via a cyclophilin D-independent mechanism. Thus, selective delivery of H2 S to mitochondria may be therapeutically applicable for employing the cardioprotective utility of H2 S.

Sustained-Release Delivery System of a Slow Hydrogen Sulfide Donor, GYY 4137, for Potential Application in Glaucoma.

Hydrogen sulfide (H2S) targets both underlying factors in glaucoma pathogenesis by reducing elevated intraocular pressure (IOP) and providing retinal neuroprotection, whereas the current clinical approaches targets only reducing IOP. Therefore, H2S could be a potential superior candidate for glaucoma pharmacotherapy. However, H2S could be toxic in a concentration greater than 200μM and its donors are unstable in water. Therefore, this study investigated the preparation and characterization of a non-aqueous in situ gelling sustained-release delivery system for H2S donors. The delivery system was prepared by dissolving GYY 4137, a H2S donor, in poly lactide-co-glycolide polymer (PLGA) (Resomer® RG 502H) solution prepared by dissolving polymer in a mixture of benzyl alcohol and benzyl benzoate in a ratio of 7:3, respectively. The GYY 4137 formulation was characterized for syringeability/injectability, change in pH and tonicity, moisture content, GYY 4137 degradation, and toxicity using rheometer, pH and osmometer, Karl Fisher titrimeter, NMR spectrometer, and Y79 retinoblastoma cells, respectively. The formulation was easily syringeable and injectable as evidenced by rheological data (plastic flow pattern with 43.89 ± 3.21cP viscosity and 1.12 ± 0.15Pa yield value). The pH, tonicity, and moisture content values were within acceptable range. NMR spectroscopy indicated presence of 4-methoxyphenylphosphonic acid (GYY 4137 degradation product). The GYY 4137 formulation did not show any significant (p < 0.05) toxicity except the solvent mixture. A sustained release of H2S was observed up to 72h. The in situ gel forming PLGA-based system can be manipulated to achieve sustained release of H2S from its donor GYY 4137.

Hydrogen sulfide donors or related derivatives are the future medicines of renal diseases

Hydrogen sulfide (H2S) is one of the three gasotransmitters that possess anti-inflammatory, antiapoptotic, and antioxidant properties. It maintains the function of the kidney through its effect on the glomeruli and the renal transport system. Literature review using PubMed, Excerpta Medica database (EMBASE), Google scholar, and Cochrane review revealed that H2S donors are introduced as exogenous H2S and have been found to target many organs in in-vitro and in-vivo studies. This review provides the main research that was performed on the H2S donors in the context of kidney disease. Exogenous H2S supplementation can be administered in different therapeutic areas promising therapeutic strategy in the setting of kidney diseases. Therefore, suitable pharmaceutical preparations of H2S donors are necessary to be launched in the markets for the prevention and treatment of acute/chronic renal diseases.

Participation of melatonin in regulation of blood oxygen-transport function in oxidative stress induced by injection of lipopolisaccharide

The contribution of melatonin to the regulatoin of the blood oxygen transport function was studied during oxidative stress induced by a triple injection of lipopolysaccharide (at a dose of 5 mg/kg) in conditions of erythropoietin and gasetransmitters (nitrogen monoxide, hydrogen sulfide) action. In the experimental groups, intraperitoneal injections of melatonin (5 mg/kg), erythropoietin (1000 U/kg), hydrogen sulfide donor (NaHS 5 mg/kg), and L-arginine (100 mg/kg), were performed. The use of melatonin alone or in combination with erythropoietin, sodium hydrosulfide or L-arginine led to a decrease in lipid peroxidation products and an increase in the antioxidant protection. Melatonin, during lipopolysaccharide administration, caused changes of blood oxygen transport function: blood oxygen saturation increased, hemoglobin oxygen affinity increased. The modifying effect of melatonin on the blood oxygen transport function in combination with erythropoietin and gastransmitters did not exceed the effect of melatonin alone.

Индуцирование антиоксидантной системы и теплоустойчивости колеоптилей пшеницы донором сероводорода: связь эффектов с образованием активных форм кислорода

Индуцирование антиоксидантной системы и теплоустойчивости колеоптилей пшеницы донором сероводорода: связь эффектов с образованием активных форм кислорода

Effect of Hydrogen Sulfide Donor on Intraocular Pressure in Rats

We studied the effect of 1% sodium hydrosulfide solution (NaHS) on intraocular pressure (IOP) in intact rats and those with simulated ocular hypertension induced by prolonged systemic administration of adrenaline. A single administration of hydrogen sulfide donor as drops into the eye cavity caused the hypotensive effect, which was rather weak in the eyes of intact rats and pronounced in those with ocular hypertension. Long-term administration of NaHS by the scheme, against the background of applying adrenaline as inductor, to a large extent, prevented the IOP rise. It has been concluded that hydrogen sulfide is involved in the regulation of intraocular hydrodynamics and maintaining normal IOP levels.

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cognitive Dysfunction by Inhibition of Reactive Aldehydes Involving Upregulation of ALDH2.

Background:Homocysteine, a risk factor for Alzheimer’s disease, induces cognitive dysfunction. Reactive aldehydes play an important role in cognitive dysfunction. Aldehyde-dehydrogenase 2 detoxifies reactive aldehydes. Hydrogen sulfide, a novel neuromodulator, has neuroprotective effects and regulates learning and memory. Our previous work confirmed that the disturbance of hydrogen sulfide synthesis is invovled in homocysteine-induced defects in learning and memory. Therefore, the present work was to explore whether hydrogen sulfide ameliorates homocysteine-generated cognitive dysfunction and to investigate whether its underlying mechanism is related to attenuating accumulation of reactive aldehydes by upregulation of aldehyde-dehydrogenase 2.Methods:The cognitive function of rats was assessed by the Morris water maze test and the novel object recognition test. The levels of malondialdehyde, 4-hydroxynonenal, and glutathione as well as the activity of aldehyde-dehydrogenase 2 were determined by enzyme linked immunosorbent assay; the expression of aldehyde-dehydrogenase 2 was detected by western blot.Results:The behavior experiments, Morris water maze test and novel objects recognition test, showed that homocysteine induced deficiency in learning and memory in rats, and this deficiency was reversed by treatment of NaHS (a donor of hydrogen sulfide). We demonstrated that NaHS inhibited homocysteine-induced increases in generations of MDA and 4-HNE in the hippocampus of rats and that hydrogen sulfide reversed homocysteine-induced decreases in the level of glutathione as well as the activity and expression of aldehyde-dehydrogenase 2 in the hippocampus of rats.Conclusion:Hydrogen sulfide ameliorates homocysteine-induced impairment in cognitive function by decreasing accumulation of reactive aldehydes as a result of upregulations of glutathione and aldehyde-dehydrogenase 2.

Foliar application of sodium hydrosulfide (NaHS), a hydrogen sulfide (H2S) donor, can protect seedlings against heat stress in wheat (Triticum aestivum L.)

Temperature extremes represent an important limiting factor to plant growth and productivity. Low concentration of hydrogen sulfide (H2S) has been proven to function in physiological responses to various stresses. The present study evaluated the effect of foliar application of wheat seedlings with a H2S donor, sodium hydrosulfide (NaHS), on the response to acute heat stress. The results showed that pretreatment with NaHS could promote heat tolerance of wheat seedlings in a dose-dependent manner. Again, it was verified that H2S, rather than other sulfur-containing components or sodion derived from NaHS solution, should contribute to the positive role in promoting wheat seedlings against heat stress. To further study antioxidant mechanisms of NaHS-induced heat tolerance, superoxide dismutase (SOD, EC 1.15.1.1), catalase (CAT, EC 1.11.1.6) and ascorbate peroxidase (APX, EC 1.11.1.11) activities, and H2S, hydrogen peroxide (H2O2), malonaldehyde (MDA), and soluble sugar contents in wheat seedlings were determined. The results showed that, under heat stress, the activities of SOD, CAT, and APX, H2S, H2O2, MDA, and soluble sugar contents in NaHS-pretreated seedlings and its control all increased. Meanwhile, NaHS-pretreated seedlings showed higher antioxidant enzymes activities and gene expression levels as well as the H2S and soluble sugar levels, and lower H2O2, MDA contents induced by heat stress. While little effect was detected in antioxidant enzymes activities and soluble substances contents in pretreated wheat seedlings compared with its control under normal culture conditions (data not shown). All of our results suggested that exogenous NaHS could alleviate oxidative damage and improve heat tolerance by regulating the antioxidant system in wheat seedlings under heat stress.

Nitric Oxide and Hydrogen Sulfide Interact When Modulating Gastric Physiological Functions in Rodents.

The objective was to evaluate the effects of nitric oxide (NO) and hydrogen sulfide (H2S) donors and possible interactions between these two systems in modulating gastric function. Mice received saline, sodium nitroprusside (SNP), or sodium hydrosulfite (NaHS), and after 1h, the animals were killed for immunofluorescence analysis of CSE or eNOS expressions, respectively. Other groups received saline, SNP, NaHS, Lawesson's reagent (H2S donor), PAG+SNP, L-NAME, L-NAME+NaHS, or L-NAME+Lawesson's reagent. Then, the gastric secretions (mucous and acid), gastric blood flow, gastric defense against ethanol, and gastric motility (gastric emptying and gastric contractility) were evaluated. SNP and NaHS increased the expression of CSE or eNOS, respectively. SNP or Lawesson's reagent did not alter gastric acid secretion but increased mucus production, and these effects reverted with PAG and L-NAME treatment, respectively. SNP or NaHS increased gastric blood flow and protected the gastric mucosa against ethanol injury, and these effects reverted with PAG and L-NAME treatments, respectively. SNP delayed gastric emptying when compared with saline, and PAG partially reversed this effect. NaHS accelerate gastric emptying, and L-NAME partially reversed this effect. SNP and NaHS alone induced gastric fundus and pylorus relaxation. However, pretreatment with PAG or L-NAME reversed these relaxant effects only in the pylorus but not in the gastric fundus. NO and H2S interact in gastric physiological functions, and this "cross-talk" is important in the control of mucus secretion, gastric blood flow, gastric mucosal defense, and gastric motility, but not in the control of basal gastric acid secretion.

29 - Hydrogen Sulfide Donors Activated by Reactive Oxygen Species

Hydrogen sulfide (H2S) is an important biological signaling molecule and exhibits protective effects against a variety of (patho)physiological processes associated with oxidative stress. Here we report a new class of H2S donors that can be triggered by different stimuli to release carbonyl sulfide (COS), which is quickly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). This presentation will focus the design and evaluation of the PeroxyTCM class of H2S donors, which comprises the first class of reactive oxygen species (ROS)-triggered H2S donors. These donors are stable in aqueous solution and do not release H2S until triggered by ROS, such as hydrogen peroxide (H2O2), superoxide (O2–), and peroxynitrite (ONOO–). We demonstrate ROS-triggered H2S donation in live cells, both using exogenous H2O2 to trigger H2S release in HeLa cells, as well as endogenous H2O2 in Raw 264.7 cells. Additionally, we demonstrate that PeroxyTCM provides protection against H2O2-induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H2S-related therapies.

432 - Mitochondria-Targeted Hydrogen Sulfide Donors Protect Microvascular Endothelial Cells from Hyperglycaemia-Inducted Metabolic Changes and Oxidative Damage

There is decreased bioavailability of the gas hydrogen sulfide (H 2 S) in humans with diabetes and several animal models of this disease. The loss of H 2 S is thought to be due, at least in part, to its consumption by detrimental oxidants induced in the diabetic vasculature by periods of hyperglycaemia (HG) and results in mitochondrial and endothelial dysfunction, contributing to the development of diabetic vascular complications. Therefore, strategies which either protect or reverse HG-induced mitochondrial damage may represent a novel approach to treat diabetic angiopathies. We have previously shown that mitochondria-targeted H 2 S donor compounds such as AP39, prevented and/or reversed mitochondrial and cellular damage in in vivo models of cardiac arrest, myocardial infarction, hypertension, kidney IRI and organ transplantation leading us to propose that mitochondrial- H 2 S would also be beneficial in HG-induced endothelial toxicity. We have therefore synthesised a series of novel mitochondria-targeted hydrogen sulfide donors containing mitochondria-targeting motifs (such as triphenylphosphonium decanoate) coupled to molecules we have identified as H 2 S releasing agents (a) anethole dithiolethione (e.g. AP39), (b) thiohydroxybenzamide (e.g. AP123) as well as a novel H 2 S donor moiety (c) 5-(4-hydroxyphenyl)-3H-1,2-dithiol-3-one (e.g. RT-01). We investigated the protective effects of the compounds against HG-induced oxidative stress and metabolic changes in isolated mouse brain microvascular endothelial cells. HG induced significant increase TCA cycle activity, elevated mitochondrial membrane potential and mitochondrial oxidant production and lower mitochondrial electron transport. AP39, AP123 and RT-01 (30-300nM) decreased these detrimental metabolic changes, increased electron transport at respiratory complex III and improved the cellular metabolism. Mitochondrial targeting of H 2 S also induced >1000-fold increase in the potency of H 2 S against HG-induced injury c.f. non-targeted H 2 S. The high potency and long-lasting effect elicited by these H 2 S donors strongly suggests mitochondria-targeted H 2 S could be useful against diabetic angiopathies and other vascular disorders.

Hydrogen Sulfide Donors Activated by Reactive Oxygen Species.

Hydrogen sulfide (H2 S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H2 S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)-triggered H2 S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H2 S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H2 S until triggered by ROS, such as hydrogen peroxide (H2 O2 ), superoxide (O2- ), and peroxynitrite (ONOO- ). We demonstrate ROS-triggered H2 S donation in live cells and also demonstrate that PeroxyTCM-1 provides protection against H2 O2 -induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H2 S-related therapies.

Hydrogen Sulfide Donors Activated by Reactive Oxygen Species

AbstractHydrogen sulfide (H2S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H2S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)‐triggered H2S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H2S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H2S until triggered by ROS, such as hydrogen peroxide (H2O2), superoxide (O2−), and peroxynitrite (ONOO−). We demonstrate ROS‐triggered H2S donation in live cells and also demonstrate that PeroxyTCM‐1 provides protection against H2O2‐induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H2S‐related therapies.