Gasotransmitters do not prevent changes in transepithelial ion transport induced by hypoxia followed by reoxygenation.

OBJECTIVES: How gaseous signalling molecules affect ion transport processes contributing to the physiological functions of the gastrointestinal tract under hypoxic conditions still needs to be clarified. The objective of the present study was to characterize the impact of gaseous signalling molecules on parameters of colonic ion transport during a hypoxia/reoxygenation cycle and the remaining secretory capacity of the epithelium after such a cycle. METHODS: Short-circuit current (Isc) and tissue conductance (Gt) recordings in Ussing chamber experiments were performed on rat colon samples using CORM-2 (putative CO donor; 35 and 350 µM), sodium nitroprusside (NO donor; 100 µM), NaHS (fast H2S donor; 10 - 1,000 µM), GYY 4137 (slow H2S donor; 50 µM) and Angeli's salt (HNO donor; 100 µM) as donors for gasotransmitters. Inhibition of endogenous synthesis of H2S was operated by inhibitors of cystathionin-γ-lyase, i.e. dl-propargylglycine (1 mM) or ß-cyano-l-alanine (5 mM), and the inhibitor of cystathionine-ß-synthase, amino-oxyacetate (5 mM). RESULTS: The fast gasotransmitter donors NaHS, sodium nitroprusside and Angeli's salt, administered 5 min before the onset of hypoxia, induced an increase in Isc. The response to the subsequently applied hypoxia was characterized by a decrease in Isc, which tended to be reduced only in the presence of the lowest concentration of NaHS (10 µM) tested. Reoxygenation resulted in a slow increase in Isc, which was unaffected by all donors or inhibitors tested. The stable acetylcholine derivative carbachol (50 µM) was administered at the end of each hypoxia/reoxygenation cycle to test the secretory capacity of the epithelium. Pretreatment of the tissue with the putative CO donor CORM-2 suppressed the secretory response induced by carbachol. The same was observed when cystathionin-γ-lyase and cystathionin-γ-synthase were inhibited simultaneously. Under both conditions, Gt drastically increased suggesting an impaired tissue integrity. CONCLUSIONS: The present results demonstrate that none of the exogenous gasotransmitter releasing drugs significantly ameliorated the changes in epithelial ion transport during the hypoxia/reoxygenation cycle ex vivo. In contrast, the putative CO donor CORM-2 exerted a toxic effect on the epithelium. The endogenous production of H2S, however, seems to have a protective effect on the mucosal integrity and the epithelial transport functions, which - when inhibited - leads to a loss of the secretory ability of the mucosa. This observation together with the trend for improvement observed with a low concentration of the H2S donor NaHS suggests a moderate protective role of low concentrations of H2S under hypoxic conditions.

Gasotransmitter ammonia accelerates seed germination, seedling growth, and thermotolerance acquirement in maize.

Ammonia (NH3), as an intermediate product of nitrogen metabolism, is recognized as a novel gasotransmitter (namely gaseous signaling molecule), its signaling role being revealed in plants. NH3 exists in two different chemical forms, namely the weak base (free molecule: NH3) and the weak acid (ammonium: NH4+), which are generally in equilibrium with each other in plants. However, the effect of NH3 on seed germination, seedling growth, and thermotolerance acquirement in maize remains unclear. Here, maize seeds were imbibed in the different concentrations of NH3·H2O (NH3 donor), and then germinated and calculated seed germination rate at the various time points. Also, the 60-h-old seedlings were irrigated in the different concentrations of NH3·H2O, and then subjected to heat stress and counted survival rate. The data implied that the appropriate concentrations (6, 9, and 12 mM) of NH3·H2O accelerated seed germination as well as increased seedling height and root length compared with the control without NH3 treatment. Also, the suitable concentrations (2 and 4 mM) of NH3·H2O improved tissue vitality, relieved an increase in malondialdehyde content, and enhanced survival rate of maize seedlings under heat stress compared with the control. These results firstly suggest that NH3 could accelerate seed germination, seedling growth, and thermotolerance acquirement in maize.

Development of Hydrogen Sulfide-Releasing Carbonic Anhydrases IX- and XII-Selective Inhibitors with Enhanced Antihyperalgesic Action in a Rat Model of Arthritis.

An effective therapeutic approach based on the anti-inflammatory action of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs) IX and XII is proposed here for the management of arthritis. H2S is a human gasotransmitter that modulates inflammatory response at low concentrations. Inhibition of CAs IX and XII can repristinate normal pH in the acidic inflamed synovial fluid, alleviating arthritis symptoms. We report here the design of H2S donor─CA inhibitor (CAI) hybrid derivatives. The latter were tested in vitro as inhibitors of human CAs I, II, IV, IX, and XII, showing a markedly increased inhibition potency/isoform selectivity compared to the CAI synthetic precursors. The best compounds demonstrated the ability to consistently release H2S and produce a potent pain-relieving effect in a rat model of arthritis. Compound 26 completely reverted the pain state 45 min after administration with enhanced antihyperalgesic effect in vivo compared to the single H2S donor, CAI fragment, or their co-administration.

Carbon monoxide and ß-cell function: Implications for type 2 diabetes mellitus.

Carbon monoxide (CO), a member of the multifunctional gasotransmitters family produced by heme oxygenases (i.e., HO-1 and HO-2), has received significant attention because of its involvement in carbohydrate metabolism. Experimental evidence indicates that both HO-2- and HO-1-derived CO stimulate insulin secretion, but the latter mainly acts as a compensatory response in pre-diabetes conditions. CO protects pancreatic ß-cell against cytokine- and hypoxia-induced apoptosis and promotes ß-cell regeneration. CO cross-talks with nitric oxide (NO) and hydrogen sulfide (H2S), other important gasotransmitters in carbohydrate metabolism, in regulating ß-cell function and insulin secretion. These data speak in favor of the potential therapeutic application of CO in type 2 diabetes mellitus (T2DM) and preventing the progression of pre-diabetes to diabetes. Either CO (as both gaseous form and CO-releasing molecule) or pharmacological formulations made of natural HO inducers (i.e., bioactive components originating from plant-based foods) are potential candidates for developing CO-based therapeutics in T2DM. Future studies are needed to assess the safety/efficacy and potential therapeutic applications of CO in T2DM.

The two faces of cyanide: an environmental toxin and a potential novel mammalian gasotransmitter.

Cyanide is traditionally viewed as a cytotoxic agent, with its primary mode of action being the inhibition of mitochondrial Complex IV (cytochrome c oxidase). However, recent studies demonstrate that the effect of cyanide on Complex IV in various mammalian cells is biphasic: in lower concentrations (nanomolar to low micromolar) cyanide stimulates Complex IV activity, increases ATP production and accelerates cell proliferation, while at higher concentrations (high micromolar to low millimolar) it produces the previously known ('classic') toxic effects. The first part of the article describes the cytotoxic actions of cyanide in the context of environmental toxicology, and highlights pathophysiological conditions (e.g., cystic fibrosis with Pseudomonas colonization) where bacterially produced cyanide exerts deleterious effects to the host. The second part of the article summarizes the mammalian sources of cyanide production and overviews the emerging concept that mammalian cells may produce cyanide, in low concentrations, to serve biological regulatory roles. Cyanide fulfills many of the general criteria as a 'classical' mammalian gasotransmitter and shares some common features with the current members of this class: nitric oxide, carbon monoxide, and hydrogen sulfide.

H2S Donors and Their Use in Medicinal Chemistry.

Hydrogen sulfide (H2S) is a ubiquitous gaseous signaling molecule that has an important role in many physiological and pathological processes in mammalian tissues, with the same importance as two others endogenous gasotransmitters such as NO (nitric oxide) and CO (carbon monoxide). Endogenous H2S is involved in a broad gamut of processes in mammalian tissues including inflammation, vascular tone, hypertension, gastric mucosal integrity, neuromodulation, and defense mechanisms against viral infections as well as SARS-CoV-2 infection. These results suggest that the modulation of H2S levels has a potential therapeutic value. Consequently, synthetic H2S-releasing agents represent not only important research tools, but also potent therapeutic agents. This review has been designed in order to summarize the currently available H2S donors; furthermore, herein we discuss their preparation, the H2S-releasing mechanisms, and their -biological applications.

Investigation of H2S Donor Treatment on Neutrophil Extracellular Traps in Experimental Colitis.

Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders, which affect the gastrointestinal tract with intermittent ulceration. It is increasingly clear that neutrophil extracellular traps (NETs) seem to have a role in IBD; however, the associated pathogenesis is still not known. Furthermore, several conventional therapies are available against IBD, although these might have side effects. Our current study aimed to investigate the effects of hydrogen sulfide (H2S) treatment on NETs formation and on the expression of inflammatory mediators in experimental rat colitis. To model IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was administered intracolonically (i.c.) to Wistar-Harlan male rats. Animals were treated (2 times/day) with H2S donor Lawesson's reagent per os. Our results showed that H2S treatment significantly decreased the extent of colonic lesions. Furthermore, the expression of members of NETs formation: peptidyl arginine deiminase 4 (PAD4), citrullinated histone H3 (citH3), myeloperoxidase (MPO) and inflammatory regulators, such as nuclear transcription factor-kappa B (NF-κB) and high-mobility group box 1 (HMGB1) were reduced in H2S treated group compared to TNBS. Additionally, H2S donor administration elevated the expression of ubiquitin C-terminal hydroxylase L1 (UCHL-1), a potential anti-inflammatory mediator. Taken together, our results showed that H2S may exert anti-inflammatory effect through the inhibition of NETs formation, which suggests a new therapeutic approach against IBD.

Necroptosis Inhibition by Hydrogen Sulfide Alleviated Hypoxia-Induced Cardiac Fibroblasts Proliferation via Sirtuin 3.

Myocardial ischemia or hypoxia can induce myocardial fibroblast proliferation and myocardial fibrosis. Hydrogen sulfide (H2S) is a gasotransmitter with multiple physiological functions. In our present study, primary cardiac fibroblasts were incubated with H2S donor sodium hydrosulfide (NaHS, 50 µM) for 4 h followed by hypoxia stimulation (containing 5% CO2 and 1% O2) for 4 h. Then, the preventive effects on cardiac fibroblast proliferation and the possible mechanisms were investigated. Our results showed that NaHS reduced the cardiac fibroblast number, decreased the hydroxyproline content; inhibited the EdU positive ratio; and down-regulated the expressions of α-smooth muscle actin (α-SMA), the antigen identified by monoclonal antibody Ki67 (Ki67), proliferating cell nuclear antigen (PCNA), collagen I, and collagen III, suggesting that hypoxia-induced cardiac fibroblasts proliferation was suppressed by NaHS. NaHS improved the mitochondrial membrane potential and attenuated oxidative stress, and inhibited dynamin-related protein 1 (DRP1), but enhanced optic atrophy protein 1 (OPA1) expression. NaHS down-regulated receptor interacting protein kinase 1 (RIPK1) and RIPK3 expression, suggesting that necroptosis was alleviated. NaHS increased the sirtuin 3 (SIRT3) expressions in hypoxia-induced cardiac fibroblasts. Moreover, after SIRT3 siRNA transfection, the inhibitory effects on cardiac fibroblast proliferation, oxidative stress, and necroptosis were weakened. In summary, necroptosis inhibition by exogenous H2S alleviated hypoxia-induced cardiac fibroblast proliferation via SIRT3.

Gasotransmitters: Potential Therapeutic Molecules of Fibrotic Diseases.

Fibrosis is defined as the pathological progress of excessive extracellular matrix (ECM), such as collagen, fibronectin, and elastin deposition, as the regenerative capacity of cells cannot satisfy the dynamic repair of chronic damage. The well-known features of tissue fibrosis are characterized as the presence of excessive activated and proliferated fibroblasts and the differentiation of fibroblasts into myofibroblasts, and epithelial cells undergo the epithelial-mesenchymal transition (EMT) to expand the number of fibroblasts and myofibroblasts thereby driving fibrogenesis. In terms of mechanism, during the process of fibrosis, the activations of the TGF-ß signaling pathway, oxidative stress, cellular senescence, and inflammatory response play crucial roles in the activation and proliferation of fibroblasts to generate ECM. The deaths due to severe fibrosis account for almost half of the total deaths from various diseases, and few treatment strategies are available for the prevention of fibrosis as yet. Recently, numerous studies demonstrated that three well-defined bioactive gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), generally exhibited anti-inflammatory, antioxidative, antiapoptotic, and antiproliferative properties. Besides these effects, a number of studies have reported that low-dose exogenous and endogenous gasotransmitters can delay and interfere with the occurrence and development of fibrotic diseases, including myocardial fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, diabetic diaphragm fibrosis, and peritoneal fibrosis. Furthermore, in animal and clinical experiments, the inhalation of low-dose exogenous gas and intraperitoneal injection of gaseous donors, such as SNAP, CINOD, CORM, SAC, and NaHS, showed a significant therapeutic effect on the inhibition of fibrosis through modulating the TGF-ß signaling pathway, attenuating oxidative stress and inflammatory response, and delaying the cellular senescence, while promoting the process of autophagy. In this review, we first demonstrate and summarize the therapeutic effects of gasotransmitters on diverse fibrotic diseases and highlight their molecular mechanisms in the process and development of fibrosis.

Hydrogen sulfide in ageing, longevity and disease.

Hydrogen sulfide (H2S) modulates many biological processes, including ageing. Initially considered a hazardous toxic gas, it is now recognised that H2S is produced endogenously across taxa and is a key mediator of processes that promote longevity and improve late-life health. In this review, we consider the key developments in our understanding of this gaseous signalling molecule in the context of health and disease, discuss potential mechanisms through which H2S can influence processes central to ageing and highlight the emergence of novel H2S-based therapeutics. We also consider the major challenges that may potentially hinder the development of such therapies.

Engineering macromolecular nanocarriers for local delivery of gaseous signaling molecules.

In addition to being notorious air pollutants, nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) have also been known as endogenous gaseous signaling molecules (GSMs). These GSMs play critical roles in maintaining the homeostasis of living organisms. Importantly, the occurrence and development of many diseases such as inflammation and cancer are highly associated with the concentration changes of GSMs. As such, GSMs could also be used as new therapeutic agents, showing great potential in the treatment of many formidable diseases. Although clinically it is possible to directly inhale GSMs, the precise control of the dose and concentration for local delivery of GSMs remains a substantial challenge. The development of gaseous signaling molecule-releasing molecules provides a great tool for the safe and convenient delivery of GSMs. In this review article, we primarily focus on the recent development of macromolecular nanocarriers for the local delivery of various GSMs. Learning from the chemistry of small molecule-based donors, the integration of these gaseous signaling molecule-releasing molecules into polymeric matrices through physical encapsulation, post-modification, or direct polymerization approach renders it possible to fabricate numerous macromolecular nanocarriers with optimized pharmacokinetics and pharmacodynamics, revealing improved therapeutic performance than the small molecule analogs. The development of GSMs represents a new means for many disease treatments with unique therapeutic outcomes.

Gasotransmitter CO Attenuates Bleomycin-Induced Fibroblast Senescence via Induction of Stress Granule Formation.

Cellular senescence is recognized as a phenomenon wherein a proliferative cell undergoes a permanent growth arrest. The accumulation of senescent cells over time can become harmful and result in diseases and physiological decline. Plasminogen activator inhibitor (PAI-1) is considered as a critical marker and mediator of cellular senescence. The formation of stress granules (SGs) could prevent senescence through the sequestration of PAI-1, and we previously suggested that exogenous carbon monoxide (CO) could induce SG assembly via integrated stress response (ISR). Although CO is known to possess anti-inflammatory, antioxidative, and antiapoptotic properties, whether it exerts antisenescent effect is still not well defined. Here, to address whether CO-induced SGs could protect against cellular senescence, we first treated lung fibroblasts with bleomycin (BLM) to establish DNA damage-induced cellular senescence, and observed a significant increase of several hallmarks of senescence through SA-ß-gal staining, immunofluorescence, qRT-PCR, and Western blot assay. However, pre- and posttreatment of CO could remarkably attenuate these senescent phenotypes. According to our immunofluorescence results, CO-induced SGs could inhibit BLM-induced cellular senescence via sequestration of PAI-1, while it was abolished after the cotreatment of ISR inhibitor (ISRIB) due to the inhibition of SG assembly. Overall, our results proposed a novel role of CO in suppressing bleomycin-induced lung fibroblast senescence through the assembly of SGs.

Hydrogen sulfide attenuates induction and prevents progress of the 6-hydroxydopamine-induced Parkinsonism in rat through activation of ATP-sensitive potassium channels and suppression of ER stress.

PURPOSE: Studies argue in favor of hydrogen sulfide (H2S) as the next potent therapeutic agent for neurodegenerative diseases. In present study, we investigated the effect of long term treatment with NaHS (as donor of H2S) on induction and progress of the 6-hydroxydopamine (6-OHDA) -induced Parkinsonism in rat. METHODS: The 6-OHDA was injected into medial forebrain bundle of right hemisphere by stereotaxic surgery. Behavioral tests and treatments were carried out to eight weeks after the toxin. Immunohistochemistry and western blotting were carried out to evaluate the survival of tyrosine hydroxylase (TH) -positive neurons in substantia nigra (SN) and also expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), the markers of endoplasmic reticulum (ER) stress, in striatum and SN. RESULTS: Eight weeks assessment of the behavioral symptoms showed that NaHS especially at dose of 100 µmol/kg attenuates remarkably induction of the Parkinsonism and prevents its progress. NaHS also increased the survival of TH- positive neurons and suppressed 6-OHDA- induced overexpression of GRP78 and CHOP. Blockade of ATP-sensitive potassium (K-ATP) channels with glibenclamide (Glib) prevented markedly the effect of NaHS on both the induction phase and survival of TH- positive neurons. But Glib did not affect the preventing effect of NaHS on the progress phase and its suppressing effect on the overexpression of ER stress markers. CONCLUSION: H2S attenuates induction of the 6-OHDA- induced Parkinsonism and also increases the survival of dopaminergic neurons through activation of K-ATP channels. H2S also prevents progress of the Parkinsonism probably through suppression of ER stress.

Hydrogen sulfide alleviates the anxiety-like and depressive-like behaviors of type 1 diabetic mice via inhibiting inflammation and ferroptosis.

Studies reported that sodium hydrosulfide (NaHS) can remit the depressive-like and anxiety-like behaviors induced by type 1 diabetes mellitus (T1DM). However, the mechanism is still unclear. In this study, we aimed to investigate the mechanism of NaHS on T1DM. Mice were randomly divided into four groups, including the control group (CON group), DM group, DM + 5.6 mg/kg NaHS group, and CON + 5.6 mg/kg NaHS group. Data showed that NaHS did attenuate the depressive-like and anxiety-like behaviors by OFT, EPM test, FST, and TST. Results suggest that NaHS markedly alleviated the ferroptosis in the prefrontal cortex (PFC) of diabetic mice by reducing iron deposition and oxidative stress, increasing the expression of GPX4 and SLC7A11. Moreover, NaHS could dampen the activation of microglias and the release of pro-inflammatory cytokines, enhance the protein expression of sirtuin 6 (Sirt6) and the interaction between Sirt6 and the acetylation of histoneH3 lysine9 (H3K9ac), and decrease the protein expressions of the Notch1 receptor and H3K9ac. In vitro experiment, NaHS ameliorated the ferroptosis via increasing the protein expressions of SLC7A11, glutathione peroxidase 4 (GPX4), and cystathionine ß-synthase (CBS), reducing the pro-inflammatory cytokines, decreasing the levels of Fe2+, MDA, ROS, and lipid ROS. In conclusion, our results suggested that NaHS did alleviate anxiety-like and depressive-like behaviors. It can inhibit inflammation via modulating Sirt6 and was able to decrease the ferroptosis in the PFC of type 1 diabetic mice and the BV2 cells.

Fructose Intake Impairs the Synergistic Vasomotor Manifestation of Nitric Oxide and Hydrogen Sulfide in Rat Aorta.

In this study, we evaluated the effect of eight weeks of administration of 10% fructose solution to adult Wistar Kyoto (WKY) rats on systolic blood pressure (SBP), plasma and biometric parameters, vasoactive properties of the thoracic aorta (TA), NO synthase (NOS) activity, and the expression of enzymes producing NO and H2S. Eight weeks of fructose administration did not affect SBP, glycaemia, or the plasma levels of total cholesterol or low-density and high-density lipoprotein; however, it significantly increased the plasma levels of γ-glutamyl transferase and alanine transaminase. Chronic fructose intake deteriorated endothelium-dependent vasorelaxation (EDVR) and increased the sensitivity of adrenergic receptors to noradrenaline. Acute NOS inhibition evoked a reduction in EDVR that was similar between groups; however, it increased adrenergic contraction more in fructose-fed rats. CSE inhibition decreased EDVR in WKY but not in fructose-fed rats. The application of a H2S scavenger evoked a reduction in the EDVR in WKY rats and normalized the sensitivity of adrenergic receptors in rats treated with fructose. Fructose intake did not change NOS activity but reduced the expression of eNOS and CBS in the TA and CSE and CBS in the left ventricle. Based on our results, we could assume that the impaired vascular function induced by increased fructose intake was probably not directly associated with a decreased production of NO, but rather with impairment of the NO-H2S interaction and its manifestation in vasoactive responses.

Hydrogen sulfide inhibits calcium and phosphorus loss after fracture by negatively regulating glucocorticoid/glucocorticoid receptor α.

AIMS: Post-fracture calcium and phosphorus excretion is greater than influx, which might be caused by stress. Glucocorticoid is known to enhance calcium and phosphorous excretion, and hydrogen sulfide (H2S) has been shown to exert inhibitory effects on glucocorticoid. Therefore, this study explored whether H2S could inhibit calcium and phosphorus loss after fracture by regulating glucocorticoid and/or its receptor. MAIN METHODS: The following properties were analyzed in rats with femur fractures: serum and urinary calcium and phosphorus (by colorimetry); bone turnover markers alkaline phosphatase, serum type 1 collagen amino terminal peptide, type 1 procollagen carboxy terminal peptide, and anti-tartaric acid phosphatase (by ELISA); factors related to calcium-phosphorus metabolism including glucocorticoid, parathyroid hormone, calcitonin, fibroblast growth factor 23, and 1,25(OH)2D3 (by ELISA); and sulfhydration of glucocorticoid receptor α in the kidney (by immunoprecipitation linked biotin-switch assay), after supplementing with mifepristone, the H2S donor GYY4137 or H2S generating enzyme inhibitors aminooxyacetic acid and propargylglycine. KEY FINDINGS: Serum H2S decreased and glucocorticoid secretion increased in rats post-fracture. The glucocorticoid receptor inhibitor mifepristone partly blunted calcium and phosphorus loss. Furthermore, supplementation with GYY4137 reduced glucocorticoid secretion; inhibited glucocorticoid receptor α activity by sulfhydration; downregulated vitamin D 1α-hydroxylase expression; and upregulated 24-hydroxylase, calbindin-D28k, and sodium phosphate cotransporter 2a expression in the kidney; thereby inhibiting calcium and phosphorus loss induced by fracture. Moreover, inhibiting endogenous H2S generation showed opposite effects. SIGNIFICANCE: Our findings suggest that H2S antagonized calcium and phosphorus loss after fracture by reducing glucocorticoid secretion and inhibiting glucocorticoid receptor α activity by sulfhydration.

Effect of sulfur dioxide on vascular biology.

Gasotransmitters, such as nitric oxide, carbon monoxide and hydrogen sulfide, can be generated endogenously. These gasotransmitters play important roles in vascular biology, including vasorelaxation and inhibition of vascular smooth muscle cell (VSMC) proliferation. In recent years, sulfur dioxide (SO2) has been considered as a fourth gasotransmitter. SO2 is present in air pollution. Moreover, SO2 toxicity, including oxidative stress and DNA damage, has been extensively reported in previous studies. Recent studies have shown that SO2 can be endogenously generated in various organs and vascular tissues, where it regulates vascular tone, vascular smooth cell proliferation and collagen synthesis. SO2 can decrease blood pressure in rats, inhibit smooth muscle cell proliferation and collagen accumulation and promote collagen degradation, and improve vascular remodelling. SO2 can decrease cardiovascular atherosclerotic plaques by enhancing the antioxidant effect and upregulating nitric oxide/nitric oxide synthase and hydrogen sulfide/cystathionine-γ-lyase pathways. SO2 can also ameliorate vascular calcification via the transforming growth factor - ß1/Smad pathway. The effect of SO2 on vascular regulation has attracted great interest. SO2 may be a novel mediator in vascular biology.

Cardioprotection via Metabolism for Rat Heart Preservation Using the High-Pressure Gaseous Mixture of Carbon Monoxide and Oxygen.

The high-pressure gas (HPG) method with carbon monoxide (CO) and oxygen (O2) mixture maintains the preserved rat heart function. The metabolites of rat hearts preserved using the HPG method (HPG group) and cold storage (CS) method (CS group) by immersion in a stock solution for 24 h were assessed to confirm CO and O2 effects. Lactic acid was significantly lower and citric acid was significantly higher in the HPG group than in the CS group. Moreover, adenosine triphosphate (ATP) levels as well as some pentose phosphate pathway (PPP) metabolites and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were significantly higher in the HPG group than in the CS group. Additionally, reduced glutathione (GSH), which protects cells from oxidative stress, was also significantly higher in the HPG group than in the CS group. These results indicated that each gas, CO and O2, induced the shift from anaerobic to aerobic metabolism, maintaining the energy of ischemic preserved organs, shifting the glucose utilization from glycolysis toward PPP, and reducing oxidative stress. Both CO and O2 in the HPG method have important effects on the ATP supply and decrease oxidative stress for preventing ischemic injury. The HPG method may be useful for clinical application.

Porous materials as carriers of gasotransmitters towards gas biology and therapeutic applications.

The discovery of NO, CO, and H2S as gasotransmitters and their beneficial role in multiple physiological functions opened an era of research devoted to exogenously delivering them as therapeutic agents. However, the gaseous nature of these molecules demands new forms of administration that enable one to control the location, dosage and timing of their delivery. Porous materials are among the most suitable scaffolds to store, deliver and release gasotransmitters due to their high surface area, tunable composition and reactivity. This review highlights the strategies employed to load and release gasotransmitters from different kinds of porous materials, including zeolites, mesoporous silica, metal-organic frameworks and protein assemblies.

Hydrogen sulfide: An endogenous regulator of the immune system.

Hydrogen sulfide (H2S) is now recognized as an endogenous signaling gasotransmitter in mammals. It is produced by mammalian cells and tissues by various enzymes - predominantly cystathionine ß-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) - but part of the H2S is produced by the intestinal microbiota (colonic H2S-producing bacteria). Here we summarize the available information on the production and functional role of H2S in the various cell types typically associated with innate immunity (neutrophils, macrophages, dendritic cells, natural killer cells, mast cells, basophils, eosinophils) and adaptive immunity (T and B lymphocytes) under normal conditions and as it relates to the development of various inflammatory and immune diseases. Special attention is paid to the physiological and the pathophysiological aspects of the oral cavity and the colon, where the immune cells and the parenchymal cells are exposed to a special "H2S environment" due to bacterial H2S production. H2S has many cellular and molecular targets. Immune cells are "surrounded" by a "cloud" of H2S, as a result of endogenous H2S production and exogenous production from the surrounding parenchymal cells, which, in turn, importantly regulates their viability and function. Downregulation of endogenous H2S producing enzymes in various diseases, or genetic defects in H2S biosynthetic enzyme systems either lead to the development of spontaneous autoimmune disease or accelerate the onset and worsen the severity of various immune-mediated diseases (e.g. autoimmune rheumatoid arthritis or asthma). Low, regulated amounts of H2S, when therapeutically delivered by small molecule donors, improve the function of various immune cells, and protect them against dysfunction induced by various noxious stimuli (e.g. reactive oxygen species or oxidized LDL). These effects of H2S contribute to the maintenance of immune functions, can stimulate antimicrobial defenses and can exert anti-inflammatory therapeutic effects in various diseases.