Exogenous Hydrogen Sulfide Research Articles

Si-coumarin-based fluorescent probes for ultrafast monitoring H2S in vivo

Fluorescent probes with high sensitivity, selectivity, and fast response are urgently required for fluorescent imaging. The introduction of silicon atom into coumarin skeleton have resolved abrupt and instant increment in fluorescent quantum yield (from 0.002 into 0.93) when the 3-azide was reduced to 3-amine. The hydrogen sulfide triggered reduction process has ultrafast kinetic and reached equilibrium within 25 s. A group of silicon substituted coumarins SiC-Azs were designed for sensitively monitoring cellular hydrogen sulfide in vivo. The probe SiC-Az2 can be highly selective and sensitive to monitor endogenous and exogenous hydrogen sulfide in Hela cells and zebrafish.

Administration of H2S improves erectile dysfunction by inhibiting phenotypic modulation of corpus cavernosum smooth muscle in bilateral cavernous nerve injury rats

Phenotypic modulation of Corpus Cavernosum Smooth Muscle Cells (CCSMCs) is an important step in the development and progression of bilateral cavernous nerve injury induced erectile dysfunction (BCNI-ED). To investigate the effect of exogenous hydrogen sulfide (H2S) on the phenotypic modulation of CCSMCs in BCNI-ED rats, a total of 18 male Sprague-Dawley rats were equally divided into 3 groups, including sham-operated (Sham) group, BCNI group and BCNI treated with NaHS (BCNI + NaHS) group. The treated group received intraperitoneal injection of NaHS (100 μmol kg−1day−1) for 4 weeks starting day 1 postoperatively. Erectile function was measured by the ratio of intracavernous pressure (ICP)/mean arterial pressure (MAP), and relevant tissues were harvested for Immunohistochemistry, Hematoxylin and eosin (H&E), Masson's trichrome staining, H2S fluorescent probe WSP-1 and Western blot. The primary CCSMCs were isolated and pretreatment with NaHS before exposed to PDGF-BB (platelet-derived growth factor). Relative expression mRNA and protein of phenotypic biomarkers, RhoA, ROCK-1 and cell cycle proteins were detected. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST) and H2S levels in penile tissue was significantly decreased in the BCNI group compared with the Sham group. Compared with the BCNI group, administration of NaHS significantly increased the ratio of ICP/MAP, ratio of smooth muscle to collagen, expressions of a-SMA, calponin and decreased the expression of OPN, collagen-I, RhoA, ROCK1 in the penile tissue. PDGF-BB-treated CCSMCs exhibited higher expression of OPN, RhoA, ROCK1, and lower α-SMA, calponin, which were attenuated by NaHS pretreatment. NaHS suppressed RhoA/ROCK activity and decreased the expression of CDK2, Cyclin E1, while increased the expression of P27kip1 induced by PDGF-BB in CCSMCs. Taken together, this study indicated that exogenous H2S inhibited the phenotypic modulation of CCSMCs by suppressing RhoA/ROCK1 signaling and affecting its downstream factor, CDK2, Cyclin E1, P27kip1, thereby improved BCNI rat erectile function.

Exogenous hydrogen sulfide inhibits apoptosis by regulating endoplasmic reticulum stress-autophagy axis and improves myocardial reconstruction after acute myocardial infarction.

During acute myocardial infarction, endoplasmic reticulum (ER) stress-induced autophagy and apoptosis have been shown as important pathogeneses of myocardial reconstruction. Importantly, hydrogen sulfide (H2S), as a third endogenous gas signaling molecule, exerts strong cytoprotective effect on anti-ER stress, autophagy regulation and antiapoptosis. Here, we showed that H2S treatment inhibits apoptosis by regulating ER stress-autophagy axis and improves myocardial reconstruction after acute myocardial infarction. We found that H2S intervention improved left ventricle function, reduced glycogen deposition in myocardial tissue mesenchyme, and inhibited apoptosis. Moreover, the expressions of fibrosis indicators (Col3a1 and Col1a2), ER stress-related proteins (CHOP and BIP/ERP78), autophagy-related proteins (Beclin and ATG5), apoptosis protein (Bax), as well as fibrosis protein Col4a3bp were all decreased after treatment with H2S. H2S administration also maintained MMP/TIMP balance. Mechanistically, H2S activated the PI3K/AKT signaling pathway. In addition, H2S treatment also reduced the expressions of ER stress-related proteins, autophagy-related proteins, and apoptins in in vitro experiments. Interestingly, activation of ER stress-autophagy axis could reverse the inhibitory effect of H2S on myocardial apoptosis. Altogether, these results suggested that exogenous H2S suppresses myocardial apoptosis by blocking ER stress-autophagy axis, which in turn reverses cardiac remodeling after myocardial infarction.

Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway

AimCyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of H2S, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity. MethodsMale Wistar rats were treated with saline or NaHS (100 μM/kg/day, H2S donor) or dl-propargylglycine (PAG) (30 mg/kg/day, H2S blocker) for 10 days before a single i.p injection of CP (200 mg/kg). Then, rats were sacrificed, and renal functions were assessed in serum. Histopathological changes, as well as oxidant defenses, inflammatory and apoptotic markers in the renal tissue, were evaluated. Key findingsPretreatment with NaHS significantly reduced the urea and creatinine levels that were elevated in CP-intoxicated rats. NaHS increased the expression of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2) and its subsequent antioxidant proteins; heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, NaHS prohibited the histopathological damage induced by CP. The inhibition of caspase-3 and nuclear factor kappa B (NF-κB) supported the protective role of H2S against CP-induced kidney damage. On the other hand, blocking endogenous H2S did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status. SignificanceExogenous H2S donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous H2S may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP.

H2 S donor improves heart function and vascular relaxation in diabetes.

Diabetes dramatically increases the risk of cardiovascular complications and mortality. Hydrogen sulphide plays an important role in reducing oxidative stress. Several studies demonstrated that hydrogen sulphide protects islet beta cells from oxidant stress damage and decreases apoptosis. The aim of the work is to investigate the effect of hydrogen sulphide donor on heart functions and endothelium-dependent relaxation of aortic smooth muscle in diabetes. Rats were divided into control and diabetic groups. Diabetes mellitus was induced with a single intraperitoneally injection of streptozotocin (60mgkg-1 ). The functional cardiohemodynamic indicators were registered via microcatheter and Pressure-Volume System. The sodium hydrosulphide NaHS (15.8mgkg-1 ) was administered intraperitoneally. The contractile activity of the muscle preparations of the thoracic aorta was recorded using a strain gauge. We demonstrate that the NaHS improves pumping function and restores diastolic heart function in streptozotocin-induced (STZ) diabetes rats. We show that pretreatment with NaHS increased the stroke volume by 43.1%, and the ejection fraction increased by 48.64%. NaHS improves the ventriculo-arterial coupling and increases by 3.4 times acetylcholine-induced relaxation of the aorta in diabetic rats. The inhibition of NOS activity by blocker L-NAME abolished NaHS-mediated vasodilatation in the intact endothelium of the aorta in diabetes. It indicates that the NaHS caused vasodilatation by a NOS-dependent mechanism. The exogenous hydrogen sulphide can improve pumping function and restore diastolic heart function in diabetes. The pretreatment with NaHS can prevent endothelial dysfunction in diabetes due to the NOS-dependent mechanism.

Hydrogen Sulfide Alleviates Skeletal Muscle Fibrosis via Attenuating Inflammation and Oxidative Stress.

The purpose of this study was to investigate the effect of exogenous hydrogen sulfide (H2S) treatment on skeletal muscle contusion. We established a skeletal muscle contusion model (S group) and an H2S treated of skeletal muscle contusion model (H2S group). Gastrocnemius muscles (GMs) were collected at day 1, day 5, day 10, and day 15 after injury, and comprehensive morphological and genetic analyses was conducted. H2S treatment reduced M1 macrophage (CD68), profibrotic cytokines (TGF-β), pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6), chemokines (CCL2, CCR2, CCL3, CCL5, CXCL12, and CXCR4), matrix metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-14) and oxidative stress factor (gp91phox) expression levels, improved M2 macrophage (CD206) level. Thus, exogenous H2S treatment reduced inflammation and oxidative stress, attenuated skeletal muscle fibrosis, and partly improved skeletal muscle injury.

РОЛЬ ГАЗОТРАНСМІТТЕРІВ У РЕАЛІЗАЦІЇ ІМУННИХ РЕАКЦІЙ

The review analyzes the literature data on the participation of molecules of nitrogen oxide, dihydrogen sulfide and carbon monoxide in the processes of activation of the immune system, inflammatory and anti-inflammatory reactions. Nitrogen oxide is produced by immune system cells (NK cells, mast cells, dendritic cells, phagocytic cells) and cells that play an important role in the implementation of the immune response (epitheliocytes, endothelial cells, fibroblasts, vascular smooth muscle cells, kecytocytes, kecirates, kecytes, keratocytes, keratocytes, keratocytes, kecytes, keratocytes, keratocytes, kecytes, keratocytes, keratocytes, keratocytes, kecytes, kecytes, keratocytes, keratocytes, keratocytes, keratocytes, vasculature, keratocytes The enzyme responsible for the formation of this gas transmitter is NO synthase and has at least three isoforms. The expression of isoforms is regulated by the production of cytokines, microbial stimuli, the presence of a substrate - arginine. Nitrogen oxide plays a significant role in the selection and development of T cells in the thymus, inhibits the adhesion of platelets and leukocytes to the endothelium, disrupts the process of diapedesis of monocytes and granulocytes In the case of autoimmune processes, nitrogen oxide protects the body from immunopathological influences. Hydrogen sulfide has anti-inflammatory effects due to inhibition of anti-inflammatory cytokines, expression of cyclooxygenase-2, prostaglandin E2. Treatment of cells with hydrogen sulfide donors inhibits the expression of ox-LDL-lectin-like receptors. In addition, endogenous and exogenous hydrogen sulfide reduces the formation of atherogenic foam cells. The use of exogenous hydrogen sulfide inhibits the activation of NFκB by a hemoxygenase-1-dependent mechanism in macrophages. Although the vast majority of studies indicate anti-inflammatory effects, there is an increase in the level of tumor necrosis factor-alpha. It is important to find donors of hydrogen sulfide in order to use them as anti-inflammatory drugs. Carbon monoxide in living organisms is formed endogenously as a result of the cleavage of heme-containing proteins. This process is catalyzed by the enzyme hemoxygenase. There is no doubt that carbon monoxide at low concentrations can affect cellular signaling pathways of transduction, which lead to modification of cellular functions, the formation of adaptive changes. The biological properties of low concentrations of carbon monoxide vary from the regulation of vascular tone, mitochondrial biogenesis, modulation of inflammation, apoptosis and cell proliferation. To control the amount of carbon monoxide released, new donor compounds are used that have already shown their anti-inflammatory properties. Hemoxygenase-1 is an enzyme involved in the implementation of anti-inflammatory functions of this gas transmitter.

Functional Interaction of ROS and Nitric Oxide during Induction of Heat Resistance of Wheat Seedlings by Hydrogen Sulfide Donor

The participation of reactive oxygen species (ROS) and nitric oxide (NO), and also enzymatic systems generating them, in the development of heat resistance of wheat (Triticumaestivum L.) seedlings, induced by the hydrogen sulfide (H2S) donor sodium hydrosulfide (NaHS), has been studied. It was found that 24-h pretreatment of seedlings with 0.1–1 mM NaHS increased their survival after the subsequent 10-min damaging heating at 45°C. The content of hydrogen peroxide and nitric oxide increased together with the nitrate reductase (NR) activity in the seedling roots within the first 4 h of their treatment with the H2S donor. The rise in the NO level significantly suppressed by the inhibitor of NR sodium tungstate but not the inhibitor of NO synthase (NG-nitro-L-arginine methyl ester, L-NAME). The hydrogen peroxide scavenger dimethylthiourea (DMTU) and the NADPH oxidase inhibitor imidazole abolished the increase in NR activity and NO content in the roots. However, the nitric oxide scavenger (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, PTIO) and the inhibitors of the NO-producing enzymes only weakly influenced the increase in H2O2 content caused by the root treatment with sodium hydrosulfide. The NaHS-induced rise in the seedling heat resistance was eliminated by both ROS antagonists (DMTU and imidazole) and NO antagonists (PTIO and tungstate). It is concluded that the boost in the wheat seedling heat resistance, which is caused by exogenous hydrogen sulfide, is mediated by the increased ROS generation, followed by NR activation, and resultant rise in the level of nitric oxide produced by this enzyme.

Effects of exogenous H2S on hepatic fibrosis in diabetic mice and its mechanism

To investigate the effects of exogenous hydrogen sulfide (H2S) on the hepatic fibrosis in diabetic mice and its mechanism. Twenty-four C57 male mice (weight 22±2 g) were randomly divided into three groups (n=8): ① Normal control group (Control): Mice were intraperitoneally injected equal amount of normal saline, the injection time was the same as that of the experimental groups; ② Diabetes model groups (HG): Streptozotocin (STZ) was injected intraperitoneally once according to body weight (150 mg/kg) to establish diabetes model; ③ NaHS treatment groups (HG + NaHS): Mice were intraperitoneally injected with NaHS (100 μmol/L·kg·d) once a day for 12 consecutive weeks. The hepatocyte injury was detected by HE staining; the hepatic fibrosis was observed through Masson staining; the protein expressions of cystathionine - β - synthetase (CBS), collagen-I (CoL-I), collagen-III (CoL-III) and matrix metalloproteinase-9 (MMP-9) were detected by Western blot. Compared with the control group, the damage and fibrosis of hepatocyte were significantly aggravated, the expression of CBS proteins was decreased (P＜0.01), and the expression levels of CoL-I, CoL-III and MMP-9 proteins were increased (P＜0.01) in the diabetic model group. Compared with the diabetic model group, the damage and fibrosis of hepatocyte were significantly lightened, the expression of CBS proteins was obviously increased (P＜0.01), and the expression levels of CoL-I, CoL-III and MMP-9 proteins were markedly decreased (P＜ 0.01). H2S inhibits the hepatic fibrosis in diabetic mice, and its mechanism is related to the decrease of collagen and matrix metalloproteinase-9.

Exogenous hydrogen sulfide reduces atrial remodeling and atrial fibrillation induced by diabetes mellitus via activation of the PI3K/Akt/eNOS pathway.

Diabetes mellitus (DM) facilitates atrial fibrosis and increases the risk of atrial fibrillation (AF). The underlying mechanism of DM in causing AF remains mostly unknown and potential therapeutic targets for DM-induced AF are rarely reported. Hydrogen sulfide (H2S) has drawn considerable attention in recent years for its potential as a cardiovascular protector. Thus, the aim of the present study was to investigate the effect of H2S on DM-induced AF and the mechanism of action. Sprague-Dawley rats were divided into four groups, including the control group, the DM group, the H2S group and the DM+H2S group. The DM group and the DM+H2S group were administered streptozotocin to induce DM, whereas the other two groups were given citrate buffer as a control. The H2S group and the DM+H2S group were administered with an intraperitoneal injection of sodium hydrosulfide (precursor of H2S). AF inducibility, AF duration, atrial fibrosis and vital protein expression of oxidative stress were compared among the four groups. The DM group showed significantly higher AF incidence rates and duration (P<0.05). Histology results demonstrated severe atrial fibrosis in the DM group, and the PI3K/Akt/endothelial nitric oxide synthase (eNOS) pathway was significantly downregulated (P<0.05). However, when H2S was administered, the rats showed lower AF incidence and duration compared with the DM group. Additionally, H2S was able to mitigate the atrial fibrosis induced by DM, as well as the proliferation and migration of cardiac fibroblasts, as demonstrated by an MTT assay and real-time cell analyzer migration experiment. Western blotting showed that the expression levels of the PI3K/Akt/eNOS pathway in the DM+H2S group were significantly upregulated compared with those of the DM group (P<0.05). In summary, DM status can lead to the structural remodeling of atrial fibrosis, facilitating AF incidence and persistence. Administration of H2S does not affect the glucose level, but can significantly mitigate atrial fibrosis and reduce the incidence of AF induced by DM, probably via activation of the PI3K/Akt/eNOS pathway.

Protective effect of exogenous hydrogen sulfide on diaphragm muscle fibrosis in streptozotocin-induced diabetic rats.

Diabetes mellitus is a group of chronic metabolic disorders, which causes serious damage to a variety of organs, such as the retina, heart, and skeletal muscle. The diaphragm is an important skeletal muscle involved in respiration in mammals. Fibrosis of the diaphragm muscle affects its contractility, which in turn impairs respiratory function. Accumulating evidence suggests that exogenous hydrogen sulfide (H2S) exhibits anti-fibrotic activity in diabetes mellitus, but whether and how H2S exerts this anti-fibrotic effect in the diabetic diaphragm remains unclear. The current work for the first time reveals that exogenous H2S attenuates hyperglycemia-induced fibrosis of the diaphragm muscle and strengthens diaphragmatic biomechanical properties in diabetes mellitus, and the mechanism may involve the alleviation of collagen deposition by suppression of the nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome-mediated inflammatory reaction. Therefore, H2S supplementation could be used as an efficient targeted therapy against the NLRP3 inflammasome in the diabetic diaphragm.

Exogenous hydrogen sulfide for the treatment of mesenteric damage associated with fructose-induced malfunctions via inhibition of oxidative stress

Exogenous hydrogen sulfide for the treatment of mesenteric damage associated with fructose-induced malfunctions via inhibition of oxidative stress

The role of nitric oxide in the inhibitory effects of exogenous hydrogen sulfide on rat colonic smooth muscle contraction

Objective: To investigate the role of nitric oxide (NO) in hydrogen sulfide (H(2)S)-induced inhibition upon colonic smooth muscle contraction. Methods: Immunohistochemistry was applied to observe the distribution of H(2)S-producing enzymes CBS and CSE in adult male Wistar rats. Organ bath system was used to observe the spontaneous contraction of colonic smooth muscle. Patch clamp technique was applied to record currents of L-type calcium channel (I(Ca,L)) in smooth muscle cells. Results: Specific immunoreactivity for CSE and CBS was observed in mucosa, smooth muscle and enteric plexus of rat proximal colon. NaHS elicited relaxation in a concentration-dependent manner upon muscle contraction in the presence of tetrodotoxin. The NaHS IC(50) of LM was 917.6 μmol/L (95% CI: 776.3-1 085 μmol/L, n=6) and the NaHS IC(50) of CM was 730.4 μmol/L (95% CI: 592.2-900.8 μmol/L, n=6). The SNP-induced relaxation in muscle strips was partially reversed by NaHS (P<0.05). Instead, the relaxation caused by NaHS was decreased by the sGC inhibitor ODQ but affected neither by NO precursor L-arginine, the NO inhibitor L-NNA nor the competitive cGMP antagonist PET-cGMP. NaHS (100 μmol/L) increased I(Ca,L) while NaHS (300 μmol/L) decreased the peak I(Ca,L) with modifying the ion channel characteristics (P<0.05). Conclusions: Exogenous hydrogen sulfide might have a dual effect on colonic motility and its inhibitory effect might be independent of NO signaling system. L-type calcium channel may play an important role during the process of H(2)S modulating colonic contraction.

Postharvest hydrogen sulfide infiltration modulates antioxidative metabolism and increases shelf life of litchi

Litchi fruits are highly perishable in nature and start deteriorating immediately after harvest, which can be characterized by pericarp browning. In this study, the effect of exogenous hydrogen sulfide (H2S) on different biochemical events linked to pericarp browning and oxidative damage in litchi were assessed at 1 day interval during 4 days storage. Fruits were vacuum infiltrated with H2S (1 and 2 mM) at ambient temperature. The untreated control fruits were subjected to dipping in distilled water and were stored at ambient (28 °C, RH 70–75%) conditions. H2S treatment maintained the postharvest quality of litchi fruit during storage by alleviating oxidative damage and modulating enzymatic activities. Control fruits lost their postharvest quality at initial storage with visible pericarp browning and other biochemical degradative changes when compared with treated fruits. Postharvest H2S (2 mM) infiltration significantly reduced weight loss, pericarp browning and ROS production (H2O2 and O2−) as well as suppressed the activity of polyphenol oxidase (PPO) and peroxidase (POD) enzymes and exhibited higher TSS, titratable acidity, total phenolic, anthocyanin, antioxidant activities, membrane integrity, phenylalanine ammonia lyase (PAL) activity and reduced quinone and malondialdehyde (MDA) accumulation. Thus, H2S (2 mM) infiltration treatment could be suggested to enhance the storage life of litchi fruits at ambient storage condition.

Amelioration of metaflammation induced in rats by exogenous hydrogen sulfide: Focus on mesenteric adipocyte oxidative stress

Metaflammation (metabolic inflammation) is low‐grade chronic inflammatory status linking to nutrient excess. Visceral adipocytes in mesenterium (AM) related to high fructose diet (HFD) are sources for metaflammation process, seriously threatening human health. Novel pathogenesis of AM is still unclear and there are no specific effective drugs for treatment of AM. Recently hydrogen sulfide (H2S) demonstrated potent vasodilatation actions which is promised for AM that have reduced vascularization Therefore, the aim of this study was designed to investigate the effects and underlying mechanisms of H2S on the prevention and treatment of experimental rats with AM during HFD.MethodsThe study was done on rats with standard diet (SD, control group) and 28 days HFD, and acute water immersion restraint stress (WRS) was induced for evaluation AM adaptive response and testing therapeutic potential of exogenous H2S donor NaHS (100 μmol/kg/day) and the hybrid H2S‐Aspirin (ATB 340, H2S‐ASA, 17,5 mg/kg/day) vs conventional aspirin (ASA, 10 mg/kg/day) on AM were evaluated by damage index by electronic microscopic study, and glucose level, activity of Cystathionine gamma‐lyase (CSE), Cystathionine beta‐synthase (CBS), Thiosulfate‐dithiol sulfurtransferase (TST) and Carbonyl group (CG) level in blood were examined biochemically (Institutional Ethical Committee Approval: 23/04/2018 № 4).ResultsIn HSD group with NaHS treatment protected the endothelial and sub‐endothelial structures in mesenterium destructions were absent, the nucleus of endothelial cells it was observed an uneven condensation of chromatin. Effect of hybrid H2S‐aspirin characterized as a protective on AM against HFD and WRS‐induced injury, exhibited a downward trend in the inflammatory infiltration, lowering the level CG, which may indicate a reduction in oxidative stress under the influence of hybrid H2S‐aspirin. ATB‐340 showed an increase CSE, CBS and TST activities vs ASA pretreatment (p&lt;0.05). The use of aspirin and NaHS has shown an increase on 67% CSE and CBS activities in HSD rats vs saline group.ConclusionThese findings suggested that exogenous H2S prevented and ameliorated AM metflammation via reduction of oxidative damage, and provided a theoretical basis for effective tool for prevention of HFD‐related AM against long‐term postprandial hyperglycemia.AcknowledgmentAuthors would like to thank Prof. JL Wallace for ATB 340 providing and his expert suggestions.

Exogenous hydrogen sulfide donor NaHS alleviates nickel-induced epithelial-mesenchymal transition and the migration of A549cells by regulating TGF-β1/Smad2/Smad3 signaling.

Nickel compounds are known to be common environmental and occupational carcinogens which also promote the migration of lung cancer cells. However, the molecular mechanism yet remains to be clarified. Hydrogen sulfide (H2S) is involved in cancer biological processes. However, the exact effect and functionality of H2S on nickel, towards the promotion of the migration ability of lung cancer cells, remains to be unknown. In this study, we have found that the nickel chloride (NiCl2) treatment significantly downregulates the protein levels of endogenous H2S enzyme cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-Mercaptopyruvate sulfurtransferase (3-MST). A correlation between NiCl2-induced epithelial-mesenchymal transition (EMT) and the migration ability of lung cancer A549cells has been observed. Exogenous H2S donor, sodium hydrogen sulfide (NaHS) (100μmol/L), can reverse NiCl2-induced EMT as well as the migration ability of A549cells. NiCl2 treatment is able to upregulate the protein level of transforming growth factor-β1 (TGF-β1), p-Smad2, p-Smad3, p-JNK, p-ERK and p-P38 in a time-dependent fashion, indicating that both TGF-β1/Smad2/Smad3 and mitogen-activated protein kinase (MAPK) signaling cascades (a non-Smad pathway) may play essential roles in NiCl2-dependent EMT as well as cell migration of human lung cancer cells. Furthermore, exogenous NaHS alleviates the NiCl2-induced EMT and the migration ability of A549cells only by regulating TGF-β1/Smad2/Smad3, rather than the MAPK, signaling pathway. These results indicate that the exogenous administration of NaHS might be a potential therapeutic strategy against nickel-induced lung cancer progression.

Involvement of the JIN1/MYC2 Transcription Factor in Inducing Salt Resistance in Arabidopsis Plants by Exogenous Hydrogen Sulfide

The JIN1/MYC2 transcription factor, which is currently considered to be the key in jasmonate signaling, is also involved in the transduction of abscisic acid signals and, probably, in the effects of other intermediaries involved in the formation of plants’ adaptive responses. Arabidopsisjin1 mutants were used to study its possible involvement in protective effects of hydrogen sulfide (H2S) against salt stress. The treatment of wild-type Arabidopsis plants (Col-0) with the donor of hydrogen sulfide (50 μmol NaHS) led to an increase in their salt resistance, which was expressed in a decrease in oxidative damages, a decrease in water deficit, and preservation of a pool of photosynthetic pigments under 150 mmol NaCl. The treatment of Col-0 plants with NaHS prevented the stress-induced decrease in the activity of antioxidant enzymes, i.e., superoxide dismutase and catalase, and contributed to the increase in the activity of guaiacol peroxidase. In addition, leaves’ proline content in wild-type plants treated with the H2S donor was lower and sugar was higher after salt stress than in untreated plants. The treatment of jin1 mutants did not contribute to their salt resistance and did not have a noticeable effect on the functioning of the studied protective systems. The obtained results make it possible to assume the involvement of the JIN1/MYC2 transcription factor in the effects of hydrogen sulfide and/or intermediaries of its signaling pathways involved in the formation of plants’ adaptive responses to salt stress.

Improving Photosynthetic Capacity, Alleviating Photosynthetic Inhibition and Oxidative Stress Under Low Temperature Stress With Exogenous Hydrogen Sulfide in Blueberry Seedlings.

In this study, we investigated the mechanism of photosynthesis and physiological function of blueberry leaves under low temperature stress (4–6°C) by exogenous hydrogen sulfide (H2S) by spraying leaves with 0.5 mmol·L–1 NaHS (H2S donor) and 200 μmol·L–1 hypotaurine (Hypotaurine, H2S scavenger). The results showed that chlorophyll and carotenoid content in blueberry leaves decreased under low temperature stress, and the photochemical activities of photosystem II (PSII) and photosystem I (PSI) were also inhibited. Low temperature stress can reduce photosynthetic carbon assimilation capacity by inhibiting stomatal conductance (Gs) of blueberry leaves, and non-stomatal factors also play a limiting role at the 5th day of low temperature stress. Low temperature stress leads to the accumulation of Pro and H2O2 in blueberry leaves and increases membrane peroxidation. Spraying leaves with NaHS, a donor of exogenous H2S, could alleviate the degradation of chlorophyll and carotenoids in blueberry leaves caused by low temperature and reduce the photoinhibition of PSII and PSI. The main reason for the enhancement of photochemical activity of PSII was that exogenous H2S promoted the electron transfer from QA to QB on PSII acceptor side under low temperature stress. In addition, it promoted the accumulation of osmotic regulator proline under low temperature stress and significantly alleviated membrane peroxidation. H2S scavengers (Hypotaurine) aggravated photoinhibition and the degree of oxidative damage under low temperature stress. Improving photosynthetic capacity as well as alleviating photosynthetic inhibition and oxidative stress with exogenous H2S is possible in blueberry seedlings under low temperature stress.

Exogenous hydrogen sulfide inhibits human melanoma cell development via suppression of the PI3K/AKT/ mTOR pathway

Background: Melanoma is one of the most aggressive, therapy-resistant skin cancers in the world. Hydrogen sulfide (H2S), a newly discovered gasotransmitter, plays a crucial role in the progression and development of many types of cancers. However, the effect of H2S on human skin melanoma remains to be elucidated. Objective: We aimed to explore the effect of exogenous H2S on melanoma cells and its underlying mechanisms. Methods: In this study, human skin melanoma cell lines, including A375 and SK-MEL-28, were treated with a donor of H2S (NaHS). CCK-8, scratch assay, flow cytometric analysis, western blotting and transmission electron microscopy (TEM) were performed to explore the effects of H2S on cell behaviors. Results: Treatment with NaHS inhibited cell proliferation, migration and division, while it could induce cell apoptosis and autophagy in melanoma cell lines. Moreover, NaHS significantly decreased the expression of p-PI3K, p-Akt and mTOR proteins. Furthermore, insulin-like growth factor-1 (IGF-1), the activator of PI3K/AKT/mTOR pathway, could reverse the cell behaviors caused by NaHS. Conclusion: Our results demonstrated that exogenous hydrogen sulfide could inhibit human melanoma cell development via suppression of the PI3K/AKT/mTOR pathway. Hydrogen sulfide might serve as a potential therapeutic option for melanoma.

Addition of volatile sulfur compounds to yeast at the early stages of fermentation reveals distinct biological and chemical pathways for aroma formation

Volatile sulfur compounds (VSCs) greatly influence the sensory properties and quality of wine and arise via both biological and chemical mechanisms. VSCs formed can also act as precursors for further downstream VSCs, thus elucidating the pathways leading to their formation is paramount. Short-term additions of exogenous hydrogen sulfide (H2S), ethanethiol (EtSH), S-ethylthio acetate (ETA), methanethiol (MeSH) and S-methylthio acetate (MTA) were made to exponentially growing fermentations of synthetic grape medium. The VSC profiles produced from live yeast cells were compared with those from dead cells and no cells. Interestingly, this experiment allowed the identification of specific biochemical and/or chemical pathways; e.g. most of the conversion of H2S to EtSH, and the further step from EtSH to ETA, required the presence of live yeast cells, as did the conversion of MeSH to MTA. In contrast, the reaction from MTA to MeSH and ETA to EtSH was due primarily to chemical degradation. Ultimately, this research unravelled some of the complex interactions and interconversions between VSCs, pinpointing the key biochemical and chemical nodes. These pathways are highly interconnected and showcase the complexity of both the sulfur pathways in yeast and the reactive chemistry of sulfur-containing compounds.