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H2S biosynthesis and catabolism: new insights from molecular studies

Peter Rose, Philip K. Moore, Yi Zhun Zhu

Cellular and Molecular Life Sciences · 2016 · Review

doi:10.1007/s00018-016-2406-8

Abstract

Hydrogen sulfide (H 2 S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H 2 S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H 2 S within tissues. Studies utilising these systems are revealing new insights into the biology of H 2 S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H 2 S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H 2 S gas within tissues.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Hydrogen sulfide (H2S) has gained acceptance by researchers, as the third gaseous mediator identified in mammals alongside nitric oxide (NO) and carbon monoxide (CO). Over the past decade, this molecule has been shown to be synthesised by a range of tissues in which it functions as a signalling molecule with distinct physiological and biochemical effects. To date, the spectrum of signalling systems identified include, but is not restricted to, nuclear factor-kappa beta (NF-κB), the activity of several kinases, including p38 mitogen-activated protein kinase (p38 MAPK), c-JunNH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase-protein kinase B (PI-3K-Akt), protein kinase C (PKC), nuclear factor erythroid 2-related factor 2 (Nrf-2), p53, AMP-activated protein kinase, proliferator-activated receptor γ, NAD-dependent deacetylase sirtuin-1 (SIRT1), SIRT3, and mechanistic target of rapamycin (mTOR). Studies focused on delineating these molecular networks have revealed H2S to have important roles in cytoprotection, inflammation, vascular function, neurological systems, tissue repair and healing, apoptosis and the cell cycle, mitochondrial function and energy metabolism and biogenesis, obesity, and in ageing. What function H2S which plays in these processes ranges from its ability to act as an antioxidant during episodes of elevated free-radical production to direct post-transcriptional modification of cellular proteins via S-sulfhydration. In practise, the signalling effects of H2S are more complex due to the fact that this gas readily interacts with other signalling molecules, such as reactive oxygen and nitric-oxide species. Aside from enzymatic routes of synthesis, recent evidence has also shown indirect or secondary sites of H2S production. These sites include the endogenous liberation from persulfides and polysulfide species, both endogenous and dietary derived, along with bacterial sources present within the gastrointestinal tract. How these pools of H2S are coordinated within localised, as well as distal sites, and how these systems influence disease pathology and longevity in mammals is one of the key questions currently being explored by researchers in this field.

H2S biosynthesis and catabolism

Biosynthetic and degradative pathways involved in H2S production and consumption are largely mediated by cystathionine β synthase (CBS, EC 4.2.1.22), cystathionine-γ-lyase (CSE, EC 4.4.1.1), 3-mercaptopyruvate sulfurtransferase (3-MST, EC 2.8.1.2), ethylmalonic encephalopathy protein 1 (ETHE1, EC: 1.13.11.18), mitochondrial sulfide–quinone oxidoreductase (SQR, EC 1.8.5.4), and cysteine dioxygenase (CDO, EC: 1.13.11.20) (Fig. 1). Biochemical and pharmacological aspects relating to these enzymatic systems have recently been covered in great detail and will, therefore, only be touched upon herein. Moreover, whilst the roles of ETHE1, SQR, and CDO may not appear obvious at first sight, their potential influence on H2S tissue levels, via catabolic effects on either H2S directly or on the amino-acid cysteine justifies inclusion. Since the potential importance of these enzymes has, until now, been largely ignored, we believe that some discussion is warranted, if only at the very least, to stimulate debate and hopefully encourage future studies using the available murine genetic knockout models. Furthermore, the possibility of the existence of polymorphisms linked to genes encoding H2S detoxification enzymes is intriguing. How such variants influence tissue H2S turnover rates and physiological effects remains largely unexplored. Thus, the expression levels and catabolic effects of each of these enzymes may well influence exposure levels of cells, tissues, and organs to this biologically active gas. It is for this reason that these systems will be described across physiologically relevant models, including the mouse, Mus musculus, and to a lesser extent in Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio. Collectively, these models will pave the way to a better understanding of the biological significance of this gaseous molecule and could potentially assist in the development of future pharmacologically active entities. The review will also address some of the recent findings relating to H2S biology in which genetic approaches, including gene knockdown and genetic model systems, have been employed to explore the functional role of this gas.

Pharmacological approaches to manipulate H2S levels within biological systems

In general, our current understanding of H2S biology has arisen from work focused on enzymes of the trans-sulfuration pathway. For detailed coverage of the biochemical aspects relating to these enzymatic systems, we refer interested readers elsewhere. By and large, the maintenance of the cellular H2S homeostatic equilibrium is governed by a small group of enzymes that are involved in the catabolism of the amino-acid cysteine, namely, CBS, CSE, and 3-MST. Both CBS and CSE appear to be the major enzymatic routes for the production of H2S within biological systems. Tissue specific expression of CBS predominates in the brain, nervous system, liver, and kidney, while CSE is expressed in the liver and in vascular and non-vascular smooth muscle. However, recent studies have reported on the expression of CBS in HUAEC cells, the uterine artery, mesenteric artery, and carotid body. Furthermore, the expression of CBS in the uterine artery was found to be stimulated at the hormonal level. This finding suggests a critical role for H2S within the reproductive tract. 3-MST is localised to mitochondria and produces H2S in a coupled reaction with the enzyme cysteine aminotransferase. Information on the degradative and detoxification routes for H2S within biological systems is less widely reported. What is known is that the degradation or loss of tissue H2S appears to occur via a number of distinct pathways that likely working in concert. For example, chemical processes, such as (1) the direct oxidation of H2S to thiosulfate in the presence of O2 and transition metals or (2) via enzymatic processes that include SQR and ETHE1 systems. Functional roles for the enzymes rhodanese (EC 2.8.1.1) and sulfite oxidase (EC 1.8.3.1) have also been proposed, yet data are currently lacking for these detoxification routes. For many studies, manipulation of cellular and tissue levels of H2S is required and historically, this has been achieved utilising inhibitor and/or donor molecules targeting the H2S biosynthetic pathway (Fig. 2). The widely used CSE inhibitor, dl-proparylglycine, for example, can increase disease severity in animal models of colitis, myocardial ischemia–reperfusion-induced injury, and also has anti-hyperalgesic effects and has reported inflammatory as well as anti-inflammatory effects in rodent models. These studies indicate that the inhibition of H2S biosynthetic enzymes, and therefore, the production of H2S within tissues and cells typically leads to increased disease severity which effects are reversed by the use of H2S donor molecules. To date, several pharmacological inhibitors are now available for use in this field, including hydroxylamine (HA), trifluoroalanine, aminooxyacetate (AOAA) (for CBS), and d,l-propargylglycine (PAG) or β-cyanoalanine (BCA) (for CSE), that have provided a means to manipulate tissue H2S levels. Other newer inhibitory molecules with greater specificity and enhanced potency have also been characterized, but sadly, many of these are not currently commercially available. For instance, in the work of Thorson, a marine invertebrate compound library consisting of 160 characterized marine natural products and 80 purified synthetic derivatives aided in the identification of several small molecular weight inhibitors of CBS with IC50 values below 200 μM (range 83–187 μM). So far, a number of similar library-based screening approaches have proven fruitful in the identification of novel inhibitory molecules targeting CSE, CBS, and/or both. Indeed, Zhou and colleagues have utilised a tandem well-plate screening system to assess potential inhibitory molecules that target CSE and CBS. This approach involved screening 21599 chemical entities that lead to the identification of several potent inhibitory molecules designated NSC111041, NSC67078, and SP14311008. Interestingly, NSC111041 and SP14311008 appear to target these enzymes at sites distal to the PLP binding site. This finding could perhaps serve to assist in the development of new classes of inhibitory molecules. Lastly, the pharmacological targeting of 3-mercaptopyruvate sulfotransferase is less widely reported, however, several inhibitor molecules have been identified base on their abilities to affect the rate of enzyme catalyzed thiocyanate formation in vitro. This structurally diverse class of inhibitor molecule includes hypotaurine, methanesulfinic acid along with pyruvate, phenylpyruvate, oxobutyrate, and oxoglutarate. These molecules appear to inhibit 3-MST in a concentration-dependent manner and have been determined to be uncompetitive inhibitors of 3-MST with respect to 3-mercaptopyruvate. Typical IC50 values for all three alpha-keto acids ranging between 9.5 and 13.7 mM. In spite of this information, no direct confirmation of their inhibitory action towards 3-MST and it ability to generate H2S has been reported.

Genetic evidence for a role of CBS, CSE, and 3-MST in health and disease

The established roles for CBS, CSE in sulfur amino-acid metabolism are widely recognised and it is of interest that a number of polymorphisms in the genes coding for these proteins are linked to a range of pathophysiological conditions in humans. For example, there are an estimated 150 mutations in the CBS locus and of these approximately 20 appear to have altered enzymatic activity. A consequence for this loss often being homocystinuria. Interestingly, the CBS T833C variant has been associated with premature coronary artery disease, essential hypertension, and an increased risk of stroke. Similarly, the CBS 844ins68 polymorphism is linked to increase risk of breast cancer, spontaneous cervical artery dissections, raised plasma homocysteine levels, and elevated homocysteine–thiolactone concentrations. Homocysteine–thiolactone is pro-atherogenic, and can promote optic lens dislocation. Of equal interest, are polymorphisms linked to the CSE gene that predispose individuals to hypertension and in some cases raised plasma homocysteine levels. Several of these polymorphisms have been described in patients with cystathioninuria, and a single nucleotide polymorphism in CSE, c.1364G>T, is linked to elevated plasma homocysteine levels. The influence of the rs1021737 and rs482843 CSE polymorphisms in preeclampsia has been raised, and a proposed role in the development of chronic hypertension reported. Importantly, many of these polymorphic variants have reduced V max for the substrate cystathionine. Polymorphisms linked to the 3-MST gene are also known and the recent characterisation of a nonsense mutation (Tyr85Stop) that leads to the production of a severely truncated protein lacking enzymatic activity has been described. In spite of the information relating to H2S biosynthetic enzymes, data are currently lacking as to whether these polymorphic variants influence H2S biosynthetic rates. However, supporting evidence would indicate that this may be the case. Research utilising site-directed mutagenesis studies of the CBS protein has identified several key cysteine residues that are directly involved in the regulation of basal CBS activity and in H2S production, and changes in the CBS binding site of the allosteric activator S-adenosylmethionine reduce H2S synthesis by this enzyme. Similarly, several amino-acid residues in CSE have been identified that are actively involved in H2S production. Therefore, the possibility that known polymorphisms for CBS, CSE, and 3-MST would influence enzymatic activity of these proteins, and therefore, tissue H2S levels is not unreasonable.

Further circumstantial evidence linking impaired tissue biosynthesis rates of H2S and disease are provided from a range of additional sources. Loss of function in either CBS or CSE can increase the risk of individual developing cardiovascular diseases. Moreover, decreased H2S production rates in mice predispose animals to vascular remodeling, hypertension, and early the development of atherosclerosis. Therefore, the idea that H2S may have an important function within the cardiovascular system and at other sites is not a new concept. Indeed, H2S and allied donor drugs can reduce homocysteine mediate cellular stress responses and tissue damage in mammalian systems. In addition, it is widely recognised that H2S can directly affect blood pressure, alter lipid metabolism, inhibit monocytes adhesion and activate the endothelium, promote vasorelaxation, and induce angiogenesis. H2S also mediates vascular smooth muscle cell proliferation, migration, and apoptosis, inhibits macrophage foam cell formation, chemotaxis, and inflammation, and decreases vascular calcification, platelet aggregation, and thrombogenesis (reviewed in). Importantly, in humans, decreased plasma H2S concentrations are found to correlate with the activation of protein kinase CβII in uremic accelerated atherosclerosis patients and in chronic haemodialysis patients with diabetic nephropathy. Diminished levels of plasma H2S are also reported to be significantly lowered in CHD patients and in smokers as compared to normal subjects, in essential hypertensive children suffering from a metabolic imbalance of homocysteine and hydrogen sulfide, and are decreased in patients on chronic haemodialysis due to reduced CSE expression. Lower H2S levels also correlate with the accumulation of lanthionine in the blood of uremic patients. These changes potentially contribute to hyperhomocysteinemia in uraemia. Intriguingly, homocysteine has been reported to decrease H2S production in macrophages by increasing promoter DNA methylation and transcriptional repression of CSE. In addition, the cardioprotective effects of atorvastatin appear to be partly mediated by the effects of this drug on the expression of CSE and associated increases in the generation of H2S. Therefore, from the available evidence, it is clear that multiple pathologies and mechanisms underpin these diseases, but, intriguingly, a lack of H2S production seems to be at least one common thread. For this reason, the characterisation of gene polymorphisms linked with enzymes associated with H2S synthesis and its degradation requires further exploration. This could provide a greater understanding of how such polymorphisms influence enzymatic function and this may, in the future, be found to translate to changes in circulatory H2S levels. A key question is how do changes in the expression levels of enzymes involved in H2S homeostatic regulation, and their associated mutations cause disease and what are the molecular mechanisms responsible for this? To answer these questions, new approaches that include genetic models of H2S deficiency and/or overproduction have been adopted. Specifically, knockout animals lacking genes encoding for CSE, CBS, 3-MST, CDO and ETHE1. In the case of studies utilising these models, a greater understanding of how H2S functions as a signalling molecule and how this translates to influencing physiological and biochemical processes in vivo is pushing the boundaries of our current views for this gas. Importantly, findings from such work may provide routes for patient screening prior to pharmacological intervention with H2S releasing drugs to restore H2S levels.

Molecular approaches to alter H2S biosynthetic capacity in cells and animals

In addition to pharmacological approaches to alter tissue H2S concentrations, a number of researchers have adopted siRNA methodologies to assist in loss of function studies by targeting H2S biosynthetic enzyme expression levels. These techniques have been particularly amenable for use in cell-culture systems. As shown in Table 1, these approaches have assisted researchers in the manipulation of the expression levels of enzymes involved in H2S homeostatic regulation across a range of cell types. These technologies, while technically more challenging, have shown that H2S is involved in cellular proliferation and apoptosis, endoplasmic reticulum stress, and insulin secretion, and NF-κB and MAP kinase signalling and inflammation in macrophages. Curiously, the silencing of 3-MST has revealed this enzyme to be involved in the H2S production that in turn supports mitochondrial bioenergetics. Currently, siRNA and shRNA systems targeting CSE and CBS can be obtained from a range of commercial suppliers, including, but not exclusively by, CAYMAN chemicals, Addgene (Cambridge, MA, USA), and Santa Cruz Biotechnology (Texas, USA) or can be custom synthesised by IDT DNA technologies (Glasgow, UK).

In vivo knockout models of H2S research

Over the last two decades, much has been learnt regarding the biological roles ascribed to H2S, yet many questions still remain to be answered. Indeed, little is known regarding the compensatory mechanisms that may exist to maintain physiological levels of H2S nor the interplay between biosynthetic routes and the recently characterised detoxification pathways involving ETHE1 and SQR. Establishing links between these two metabolic processes will be important in the future developed of pharmacologically active drugs and inhibitor molecules that target the H2S system. The possibility that inhibitors targeting ETHE1 or SQR could offer an alternate means to manipulate H2S levels is intriguing. These approaches will most certainly require work within whole physiological systems and perhaps in this instance in the use of transgenic mouse models in which genes encoding for H2S synthesising enzymes have been manipulated. Of relevance here then are the approaches taken to generate mice devoid of H2S biosynthetic enzymes as described previously (reviewed in).

Cystathionine-β-synthase knockout mouse models

Watanabe and colleagues were the first group to report on the generation of a CBS deficiency mouse line using gene targeting of embryonic stem (ES) cells followed by incorporation into C57BL/6J mice. This early work establishes an in vivo system to explore aspects relating to homocysteine and its associated pathophysiological effects in cardiovascular diseases. Homozygous animals completely lacked CBS and mice suffer from severe homocysteinemia, have severe growth retardation and many die within 5 weeks following birth. Heterozygous animals show greater viability and have a 50% reduction in CBS expression and enzyme activity in the liver and have twice normal plasma homocysteine levels. Studies using this model are, therefore, restricted to younger animals and may consequently be influenced by the age-dependent expression of other H2S biosynthetic enzymes, such as CSE. For this reason, some authorities have called into question the use of this model.

Problems associated with early lethality in the CBS model were later overcome by the work of Wang et al.. In the first approach taken by this group, mice were produced with the aim of overexpressing CBS. This was achieved using a transgenic system in which the human CBS cDNA was placed under the control of the zinc-inducible metallothionein promoter (Tg-CBS). Zinc supplementation in Tg-CBS mice causes a two–four-fold increase in liver and kidney CBS activity and a 45% decrease in serum homocysteine levels. In contrast to previous model systems, these animals do not develop hepatic steatosis, fibrosis, or suffer from high rates of neonatal death. The second approach was to engineer mice that express the human I278T and I278T/T424N mutant CBS proteins under the control of a metallothionein driven transgene. These animals were rescued from early lethality yet still showed severe elevations in both plasma and tissue levels of homocysteine, methionine, S-adenosylmethionine, and S-adenosylhomocysteine and a concomitant decrease in plasma and tissue levels of cysteine. Finally, MacClean and colleagues developed a mouse model null for the mouse CBS gene that carried copies of the human CBS gene expressed at low levels. So far, CBS KO models have supported a range of studies focused on folate metabolism, blood brain barrier function, endothelial dysfunction, cerebral vascular dysfunction, brain function linked to changes in the SAPK/JNK signalling pathway, redox homeostasis microvascular remodelling, blood–brain barrier integrity, lung fibrosis, lipid homeostasis, retinal neuron death, infertility, and susceptibility to drug induced toxicity. Of relevance here then is the growing body of work indicating that H2S plays a part in many of these processes.

Cystathionine γ-lyase knockout mouse models

So far, the most widely used animal system in H2S research is the CSE-KO model. To date, CSE-KO animals have been utilised to explore the role of H2S within the cardiovascular disease, diabetes, and in studying interactions of H2S with other important gaseous signalling molecules, such as nitric oxide. The production of viable and fertile CSE-KO animals was first reported in the work of Yang et al. In these homozygous animals, CSE mRNA and protein levels were absent in heart, aorta, mesenteric artery, liver, and kidneys. Importantly, both tissue and serum levels of H2S were significantly reduced in KO animals with this correlated with an age-dependent increase in blood pressure and impaired endothelium-dependent vasorelaxation. This is in contrast to the CSE-KO model reported by Ishii et al., in which animals appeared both normotensive and hyperhomocysteinemic. Interestingly, these mice were extremely sensitive to sulfur amino-acid restriction and homozygous animals maintained on a low cysteine diet, succumbed to acute skeletal muscle atrophy, and reduced tissue glutathione levels and lethality. Hepatocytes isolated from these animals were also highly sensitive to oxidative stress. To date, the CSE-KO model developed by Yang has been widely used to explore the role of H2S across a range of pathophysiological conditions. These studies are summarised in Table 2 and include hypertension, cellular proliferation, oxygen sensing, cellular senescence pressure overload heart failure, asthma, vasorelaxation, ischemia/reperfusion injury, atherosclerosis, caerulein-induced acute pancreatitis, postischemic cerebral vasodilation/hyperemia, arteriogenesis, pain, gluconeogenesis, M2 macrophage polarization, antiviral effects, and infiltration and migration. Particularly interesting are the functional aspects relating to interaction of H2S with other gaseous signalling molecules. It is now widely accepted that H2S and NO readily interact at physiological pH to produce a range of biologically active species. An established link between NO and H2S has now been reported utilising the CSE-KO systems. Studies by Kondo and colleagues reported on the influence of H2S and its interaction with NO in a murine model of pressure overload-induced heart failure using CSE-KO animals. CSE knockout (KO) animals had reduced circulating H2S levels and cardiac dilatation and dysfunction. In this instance, H2S therapy was found to be cardioprotective. This corresponding with the upregulation of the VEGF-Akt-eNOS-nitric-oxide-cGMP pathway, preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density. Elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury are also reported for CSE-KO animals. Collectively, this work suggesting that H2S and NO interact and that H2S is particularly important in the regulation of NO within the cardiovascular system.

Several newer reports have focused on the overexpression of CSE within mammalian systems. For example, in the work of Elrod et al, a transgenic mouse model was developed in which CSE is overexpressed within cardiac tissues leading to increased myocardial levels of H2S. These mice had a reduction in infarct size following MI-R injury and were used to establish that a localised increase of H2S within cardiac tissues protects against myocardial infarction. Similarly, manipulation of CSE either via knockdown or overexpression in mammalian cells has also shed additional light on the cardioprotective effects of H2S. Wang and colleagues found that CSE overexpression reduces ox-LDL-stimulated tumor necrosis factor-α (TNF-α) generation in Raw264.7 and primary macrophage, while CSE knockdown enhanced it. Under pathophysiological conditions linked to CVD, Cheung et al. reported that overexpression of CSE reduces markers associated with atherosclerosis. Using transgenic ApoE knockout mice overexpressing CSE (Tg/KO), increased endogenous H2S production in aortic tissue was demonstrated that correlated with reduced atherosclerotic plaque sizes and reduced plasma lipid profiles in mice maintained on an atherogenic diet. Moreover, an upregulation in plasma glutathione peroxidase, indicative of reduced oxidative stress, and an increase in the expression of p-p53 and downregulation of inflammatory nuclear factor-kappa B (NF-κB) were noted. Decreased CSE expression and its influence on H2S metabolism and atherosclerosis are currently an active area of investigation. Utilising the CSE knockout mouse, Mani et al. revealed a functional role of the CSE enzyme in atherosclerosis development. In CSE-KO animals, maintained on an atherogenic diet, cholesterol levels were found to be twofold higher within the plasma of CSE-KO animals compared to the WT animals. Moreover, fatty acid streaks, atherogenic lesions, and reduced blood flow were seen in CSE-KO animals. In this instance, KO animals treated with NaHS for 12 weeks showed significant improvements in plasma lipid profiles and decreased atherosclerotic lesions thus confirming a role of H2S in atherosclerosis. Furthermore, by combining the CSE-KO with the ApoE-1 KO genetic background to produce a double KO system (DKO), the authors were again able to demonstrate reduced lesion formation in DKO animals when treated with NaHS. Thus, endogenous loss of CSE has been shown to increase disease severity across several independent studies utilising the CSE-KO model.

3-Mercaptopyruvate sulfurtransferase knockout mouse models

The roles for both CBS and CSE and their part played in the production of H2S within biological systems have been broadly defined in recent years, yet the view that these two enzymes are perhaps the only ones responsible for maintaining physiological levels of H2S is rather simplistic. As mentioned, an additional enzymatic system is known, that of 3-MST. In view of this, efforts have been made to generate a 3-MST murine model that could potentially provide a detailed picture of how this enzyme functions and its role in diseases. From a biochemical perspective 3-MST is a multifunctional enzyme involved in (1) cysteine catabolism, since it catalyses the trans-sulfuration of the substrate 3-mercaptopyruvate to pyruvate and (2) functions in cyanide detoxification. Also, the protein has a potential redox function since in the presence of the oxidant hydrogen peroxide (H2O2), enzyme activity is inhibited. Oxidant-mediated inhibition appears to occur via the formation of a sulfenate (SO−) moiety at the catalytic site cysteine. Enzymatic activity can be re-established in the presence of reducing agents DTT or reduced thioredoxin but not the cellular antioxidant glutathione. Under conditions of mild oxidative stress, such as those found in physiological systems, 3-MST activity is reduced leading to a resultant increase in cysteine concentrations in vitro. Thus, the current views suggest that 3-MST serves as an antioxidant protein. The curious fact that this enzyme is localised to mitochondria has further bolstered work on this enzyme, especially given the known inhibitory effects of H2S on cytochrome c oxidase function. Ongoing work in this area has shown that 3-mercaptopyruvate stimulates mitochondrial H2S production that in turn stimulates electron transport and bioenergetics at low concentrations (10–100 nM). Conversely, siRNA-mediated silencing of 3-MST reduces basal bioenergetics and prevents the stimulatory effects of 3-MP on mitochondrial energetics. In this scenario, H2S can be seen to serve as an electron donor that functions as an inorganic source of energy that supports electron transport and ATP production in mammalian cells. Interestingly, oxidant-mediated stress reverses these effects in cells. Shibuya reported that that tissue levels and production of H2S within brain tissues were similar in CBS KO mice with this supporting the notion that an alternate H2S production system must exist within brain tissues. Indeed, this work confirmed that CBS was not the primary source of H2S within this organ. Further characterisation led to the realisation that two proteins work in concert to produce H2S within brain tissues, these being, cysteine aminotransferase and 3-MST respectively. While a 3-MST-KO model has been developed currently only one report exists citing the generation and utilised of this model. Nagahara et al. were the first to describe a homozygous (null) MST-knockout (MST-KO) mouse model. These mice have increased anxiety-like behaviour, with increased serotonin levels in the prefrontal cortex. In this instance, 3-MST was proposed to function as an antioxidant redox-sensing protein involved in maintaining cellular redox homeostasis.

Genetic models of H2S detoxification systems in animals

Three major enzymatic routes for the removal of H2S from tissues are currently recognised these constituting the aforementioned proteins SQR, ETHE1, and CDO. At present, the sites and rates of H2S detoxification have been less well defined than that of the biosynthetic routes of production. However, these systems likely play an equally important function in maintaining physiologically relevant tissue concentrations of H2S. Changes in the expression levels of these proteins would alter the physiological concentrations of this sulfurous gas in vivo and therefore, the response of cells to exposure to this molecule. Even with their recognised association with H2S detoxification, only now are we beginning to see how these enzymes influence physiological levels of this gas.

Sulfide–quinone reductase-like protein knockout models

In mammalian systems, sulfide is oxidized by the mitochondrial sulfide–quinone reductase-like protein (SQR), a homologue of bacterial sulfide–ubiquinone oxidoreductase (SQR), and fission yeast heavy metal tolerance 2 protein. This protein is involved in the transfer of an electron from sulfide to membrane intrinsic quinones. The process of sulfide oxidation, therefore, links sulfide catabolism to oxidative phosphorylation and the subsequent production of ATP. This whole process allowing for sulfide to be used as an inorganic substrate for the human electron transfer chain. SQR is a component of several mammalian tissues, and protein expression has been confirmed within heart, lung, colon, liver, kidney, thyroid, brain, leukocytes, and penis and testicles of mice and rats. Fractionation experiments revealed this protein to be localised to mitochondria. SQR mRNA levels can be increased following exposure to sulfide in T cells and also with increasing age within the kidney. This finding indicating that the expression levels of this protein show some plasticity that allows for SQR to respond to changes in tissue H2S levels. It is easy to envisage that changes in SQR protein levels would influence H2S oxidation rates and the role of H2S in the production of ATP, ROS formation, oxygen sensing and subsequently the effects of this gas on cell-signalling networks and on S-sulfhydration of proteins. Recently, polymorphisms have been identified for the SQR gene, which are linked to pathophysiological conditions in humans. Jin et al. reported on the SQR I264T gene variant that increases susceptibility to osteoporosis in Korean postmenopausal women. In another study, genomic-wide screening in Filipino women reported that the rs12594514 SNP in the SQR gene is associated with two obesity-related phenotypes. Interestingly, the cellular levels of H2S are critical determinants in the regulation of bone remodelling and osteoclast differentiation. Moreover, it is now widely recognised that H2S has a range of functions linked to metabolism and obesity. Therefore, it is likely that SQR has the potential to influence some of the biological effects of H2S in vivo. To date, there are no reported murine SQR KO models however, SQR KO C.elegans systems are known. Using gene knockout strategies in C. elegans, SQR was found to be important in the maintenance of protein translation. In SQR mutant worms, exposure to H2S leads to phosphorylation of eIF2α and the inhibition of protein synthesis. The authors speculating that SQR may be involved in H2S signalling relating to proteostasis. Of relevance, here is the potential link with H2S, proteostasis and the anti-ageing effects of this gas.

Ethylmalonic encephalopathy knockout mouse models

Another candidate protein potentially involved in H2S detoxification is that of ETHE1. The ETHE1 gene codes for an iron-containing protein from the metallo β-lactamase family are required in the mitochondrial sulfide oxidation pathway and for the oxidation of glutathione persulfide (GSSH) to give glutathione and persulfate. ETHE1 protein catalyses the second step in the mitochondrial sulfide oxidation pathway downstream of SQR. Mutations in this gene cause the rare condition known as ethylmalonic encephalopathy (EE) that affects the brain, gastrointestinal tract, and peripheral vessels. This inborn error of metabolism is an autosomal recessive condition that is invariably fatal and characterised by encephalopathy, microangiopathy, chronic diarrhea, and defective cytochrome c oxidase (COX) in muscle and brain. The latter oxidizes H2S to persulfide and transfers electrons to the electron transport chain via reduced quinone. Indeed, recombinant expression of human SQR is known to enhance sulfide oxidation in mammalian cells. More revealing insights as to the functional role of ETHE1 have been reported. Adopting a proteomic approach Hildbrant and colleagues conducted an analysis of ETHE1 KO mouse tissues and confirmed a role of ETHE1 in the sulfide oxidation pathway while also revealing more subtle effects on post-translational protein modifications linked to protein cysteine modification. Elevated H2S levels caused by loss of ETHE1 likely cause an increase in S-sulfhydration of cellular proteins via persulfide-mediated reactions. Of particular interest, from this work is that sulfide signalling seems to play a pivotal part in regulating mitochondrial catabolism of fatty acids and branched-chain amino acids. Interestingly, sulfide concentrations are decreased in the plasma of overweight men and low sulfide levels are associated with the development of insulin resistance in Type 2 diabetes. Moreover, in rats fed high-fat diets ETHE1 and SQR are reported to be decreased by more than 50% in tissues.

Cysteine dioxygenase knockout mouse models

Finally, a common component linking all of the enzymatic systems described herein is their reliance on intermediates derived from sulfur amino-acid metabolism, specifically, the interplay between cysteine synthesis, its cellular uses, and its degradation. Cysteine homeostasis and the relative rates of synthesis versus degradation will clearly influence how and when H2S will be produced within tissues. This coupled with the relative rates of oxidation of both molecules further adding complexity to the H2S story. One particularly interesting model is the cysteine dioxygenase (CDO; EC: 1.13.11.20) KO mouse model. Ordinarily, CDO oxidizes cysteine-to-cysteine sulfinate, which is further metabolized to either taurine or to pyruvate plus sulfate. This metabolic pathway is believed to function in maintaining cysteine levels and to supply circulatory taurine. In the CDO KO mouse line, there is postnatal mortality, growth deficit, and connective tissue pathology. Moreover, KO animals have reduced taurine levels, elevated cysteine levels, and increased desulfuration in liver tissues that correlates with the elevated production of H2S. This reported to be due to CBS activation. Importantly, CDO null mice also exhibit lower hepatic cytochrome c oxidase levels, suggesting impaired electron transport capacity. Cytochrome c oxidase being a known cellular target prone to H2S-mediated inhibition. Similarly, in hepatocytes isolated from CDO null mice increased synthesis of H2S within cells occurs that is perhaps due to an increase in the endogenous pool of cysteine within tissues. Also reported in the CDO KO mice is an increase in the urinary excretion of thiosulfate, coupled with higher tissue and serum cystathionine and lanthionine levels. Importantly, the inhibition and destabilization of cytochrome c oxidase are observed that again is consistent with increased production of H2S. Thus, it would appear that the ability of CDO to control cysteine levels may be necessary to maintain low H2S/sulfane sulfur pools within tissues to facilitate the use of H2S as a signalling molecule. This model, therefore, provides a unique system to explore cysteine metabolism and its influence of H2S production and redox-signalling networks.

Availability of knockout mouse models for H2S research

At this time, it may be of interest to researchers that CBS KO mice are now commercially available and can be obtained from the Jackson laboratories which supplies the JAX® Mice derived from the fully sequenced mouse strain, C57BL/6J. This particular line is useful for studying the in vivo role of elevated levels of homocysteine in the aetiology of cardiovascular diseases and was developed in the lab of Dr Nobuyo Maeda at the University of North Carolina at Chapel Hill. A number of researchers have utilised this mouse model to determine the functional role of H2S in colitis for the role of H2S in alveolarization and in the prevention of hyperhomocysteinemia associated chronic renal failure, however, studies are limited primarily due to the high mortality rates in offspring. In the case of research using CSE knockout (CSE-KO) animals, this model is more widely reported in the literature. These animals have markedly reduced H2S levels in the serum, heart, aorta, and other tissues and mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. Again, this model is particularly useful for studying cardiovascular disease. Although not commercially available at present several institutions maintain the CSE-KO mouse model that was originally developed in the laboratory of Rui Wang, Lakehead University, Thunder Bay, Ontario, Canada. This model is the most widely used physiologically relevant model and has been the focus of research ranging from the role of H2S in vasorelaxation, to O2 sensing in the carotid body. 3-MST and ETHE1 KO animals are maintained at the Isotope Research Centre, Nippon Medical School, Tokyo and at the Institute of Neurology Carlo Besta-Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy. Hopefully in the future, these models will become more common place in research focused on H2S biology.

Non-mammalian genetic models

The majority of work highlighting a biological role for H2S has been derived from mammalian models. Information derived from non-mammalian models reflects on the evolutionary importance of H2S and its role in biochemical and physiological processes across different taxa. Several reports now describe the homeostatic systems and physiological effects of H2S across a range of animal and plant systems particularly in the model organisms C. elegans, D. melanogaster, D. rerio, and Arabidopsis thaliana. The reason for this work is one of translation, since, for example, the exploitation of the H2S biosynthetic pathway in animals and in plants may assist in Agritech for the purpose of improving crop yields or resistance to pathogen attack. To date, only a handful of studies have been described in which the targeted deletion or overexpression of H2S synthesising enzymes has been manipulated in non-mammalian systems. Much of this work has utilised molecular approaches to alter the expression levels of H2S synthesising enzymes in the nematode worm, C. elegans. These studies have identified roles for H2S in the ageing process, in longevity, and in the health benefits attributed to caloric/dietary restriction. It is widely known that worms exposed to exogenous H2S have increased longevity and thermotolerance. However, direct molecular confirmations that these physiological processes can be controlled via endogenous H2S synthesis have only recently been described. In these studies, siRNA-mediated silencing approaches were utilised to knock down C. elegans targets. Deletion of CYST-2, a cysteine sulfhydrylase, caused a significant reduction in lifespan in worms exposed to stress conditions. This finding establishing a clear link between H2S synthesis and the ability of worms to adapt and recover from stress insults associated with the ageing process. Indeed, deficiency in mpst-1, mammalian 3-MST orthologue 1, reduces lifespan in C. elegans. It has subsequently been demonstrated in the work of Hine et al. that H2S production in C. elegans is linked to the health benefits attributed to caloric/dietary restriction. In this study, utilising siRNA technologies, individual KO experiments were performed that focused on a number of proteins associated with the trans-sulfuration pathway, namely, the cystathione-γ-lyase worm homologues CTH-1 and CTH-2 and the CBS homolog CBS-1 and CBL-1. Loss of functional CBL-1 and CBS-2 protein appears to have no effects on longevity when expressed in the eat-2 mutant worms; the eat-2 mutant serving as a genetic model of life extension that mimics dietary restriction. Interestingly, eat-2 worms produce more H2S than their wild-type counterparts. Importantly, the overexpression of CBS-1 extends the median lifespan of wild-type worms this clearly showing that H2S mediates the beneficial effects attributed to dietary/caloric restriction in C. elegans.

Similar finding has also been reported for Drosophila melanogaster. In this model, dietary restriction promotes the upregulation and increased activity of the trans-sulfuration pathway leading to increased tissue synthesis rates of H2S. Transgene-mediated increases in gene expression and enzyme activity of Drosophila cystathionine β-synthase (dCBS) are sufficient to increase fly lifespan. Moreover, the inhibition of the trans-sulfuration pathway effectively blocks the lifespan extension normally observed in diet-restricted animals. These findings are of particular interest, since they provide an additional evidence that H2S plays important functional roles in the ageing process of living organisms. Besides, ageing, H2S also appears to mediate neurodegenerative processes in Drosophila models. For example, overexpression of CSE in Drosophila suppresses spinocerebellar ataxia type 3-associated damage and neurodegeneration. The observed decreased in cellular damage being attributed to a reduction in oxidative stress and a reduced immune response in flies. Clearly, these findings correlate well with the known antioxidant and anti-inflammatory effects attributed to H2S.

Work using teleost’s species, such as Danio, are rare, but, nonetheless, provides important information on the physiological role of H2S. In the work of Kumai et al., H2S was found to influence Na+ homeostatic regulation in the larva of D. rerio. Translational gene knockdown was used to reduce CSE expression in tissues. Using this approach Kumai and colleagues were able to elegantly demonstrate that H2S is an endogenous inhibitor of Na+ uptake in developing zebrafish.

Conclusions

Over the last decade, considerable evidence has been accumulated which collectively points to a functional role for H2S in a number of physiological systems. Much of these data have been derived from pharmacological intervention in which inhibition of enzymatic systems linked to the production of H2S has been targeted or via direct drug targeting using small molecular weight H2S donor molecules. Invariably, these studies have highlighted a role of H2S levels within a number of pathophysiological states and that restoration of tissue H2S levels is protective in the majority of cases. Despite the current knowledge, and continued breakthroughs, one can envisage that transgenic models will be at the forefront of future work in this area. Developments based on the approach taken by Mani et al. in which a double knockout mouse model in which both the CSE and the apolipoprotein E gene are silenced may be particularly revealing. Studies using these models have been fruitful and have shown how changes in cellular H2S levels influence physiological processes. Yet, the true power of these models is still to be realised. Since the discovery that cross talk exists between H2S with other gaseous signalling molecules, such as NO, the use of transgenic models in which one or both sets of synthesising enzymes are silenced may be invaluable in future studies. Data on the interactions of NO with H2S are only just emerging and it would be fascinating to explore the effects of incorporating the CSE-KO background into other transgenic systems such as that of iNOS or eNOS KO mouse models. How would the loss of each gas alter the formation and levels of circulatory nitrosothiols for example? What would be the consequences of this systemically? Could biologically active persulfides compensate for the loss of nitrosothiols? More revealing is the current evidence showing that both gases can influence mitochondrial function, energy metabolism, and tissue homeostasis, but the functional consequences of combined defects in H2S and NO production are not known. Could these interactions, or lack off, underpin dysregulation in metabolism as seen in diabetes or obesity? The development of these models would also be particularly useful in the screening of H2S/NO hybrid donor drugs. Finally, could double knockout models be developed to explore the influence of H2S detoxification enzymes on cardiovascular function and on inflammatory responses in animals? What, for example, would be the effect of loss of CBS, or 3-MST in the apolipoprotein E KO murine model? Would this further predisposes animals to atherosclerosis, and would similar effects be found with the overexpression of SQR and ETHE1? With the development of these transgenic models, there are certainly more questions than answers and much remains to be explored regarding the role of this gas within biological systems. Hopefully, a greater understanding will come from the use of these newer tools that will hopefully assist in the development and introduction of new H2S releasing pro-drugs within the clinic.

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  74. 74.

    Ida T, Sawa T, Ihara H, et al. Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling. Proc Natl Acad Sci USA. 2014;111:7606-7611.

    Not in our library10.1073/pnas.1321232111

  75. 75.

    Benavides GA, Squadrito GL, Mills RW, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA. 2007;104:17977-17982.

    Not in our library10.1073/pnas.0705710104

  76. 76.

    Pei Y, Wu B, Cao Q, et al. Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells. Toxicol Appl Pharmacol. 2011;257:420-428.

    Not in our library10.1016/j.taap.2011.09.026

  77. 77.

    Tocmo R, Liang D, Lin Y, et al. Chemical and biochemical mechanisms underlying the cardioprotective roles of dietary organopolysulfides. Front Nutr. 2015.

    Not in our library10.3389/fnut.2015.00001

  78. 78.

    Tocmo R, Lin Y, Huang D. Effect of processing conditions on the organosulfides of shallot (Allium cepa L. Aggregatum group). J Agric Food Chem. 2014;62:5296-5304.

    Not in our library10.1021/jf500739n

  79. 79.

    Liang D, Wanga C, Tocmo R, et al. Hydrogen sulphide (H2S) releasing capacity of essential oils isolated from organosulphur rich fruits and vegetables. J Funct Foods. 2015;14:634-640.

    Not in our library10.1016/j.jff.2015.02.007

  80. 80.

    Kabil O, Banerjee R. Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal. 2014;20:770-782.

    Not in our library10.1089/ars.2013.5339

  81. 81.

    Huang CW, Moore PK. H2S synthesizing enzymes: biochemistry and molecular aspects. Handb Exp Pharmacol. 2016;230:3-25.

    Not in our library10.1007/978-3-319-18144-8_1

  82. 82.

    Kabil O, Banerjee R. Redox biochemistry of hydrogen sulfide. J Biol Chem. 2010;285:21903-21907.

    Not in our library10.1074/jbc.r110.128363

  83. 83.
    Hydrogen Sulfide and Cellular Redox Homeostasis · 2016
    No notice
  84. 84.

    Paul BD, Snyder SH. H2S: a novel gasotransmitter that signals by sulfhydration. Trends Biochem Sci. 2015;40:687-700.

    Not in our library10.1016/j.tibs.2015.08.007

  85. 85.

    Saha S, Chakraborty PK, Xiong X. Cystathionine β-synthase regulates endothelial function via protein S-sulfhydration. FASEB J. 2016;30:441-456.

    Not in our library10.1096/fj.15-278648

  86. 86.

    Lechuga TJ, Zhang HH, Sheibani L. Estrogen replacement therapy in ovariectomized nonpregnant ewes stimulates uterine artery hydrogen sulfide biosynthesis by selectively up-regulating cystathionine β-synthase expression. Endocrinology. 2015;156:2288-2298.

    Not in our library10.1210/en.2015-1086

  87. 87.

    Shibuya N, Tanaka M, Yoshida M, et al. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal. 2009;11:703-714.

    Not in our library10.1089/ars.2008.2253

  88. 88.

    Tiranti V, Viscomi C, Hildebrandt T, et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med. 2009;15:200-205.

    Not in our library10.1038/nm.1907

  89. 89.

    Jackson MR, Melideo SL, Jorns MS. Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry. 2012;51:6804-6815.

    Not in our library10.1021/bi300778t

  90. 90.

    Di Meo I, Fagiolari G, Prelle A, et al. Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy. Antioxid Redox Signal. 2011;15:353-362.

    Not in our library10.1089/ars.2010.3520

  91. 91.

    Kabil O, Banerjee R. Characterization of patient mutations in human persulfide dioxygenase (ETHE1) involved in H2S catabolism. J Biol Chem. 2012;287:44561-44567.

    Not in our library10.1074/jbc.m112.407411

  92. 92.

    Nagahara N, Okazaki T, Nishino T. Cytosolic mercaptopyruvate sulfurtransferase is evolutionarily related to mitochondrial rhodanese. J Biol Chem. 1995;270:16230-16235.

    Not in our library10.1074/jbc.270.27.16230

  93. 93.

    Picton R, Eggo MC, Merrill GA, et al. Mucosal protection against sulphide: importance of the enzyme rhodanese. Gut. 2002;50:201-205.

    Not in our library10.1136/gut.50.2.201

  94. 94.

    Wilson K, Mudra M, Furne J, et al. Differentiation of the roles of sulfide oxidase and rhodanese in the detoxification of sulfide by the colonic mucosa. Dig Dis Sci. 2008;53:277-283.

    Not in our library10.1007/s10620-007-9854-9

  95. 95.

    Ramasamy S, Singh S, Taniere P, et al. Sulfide-detoxifying enzymes in the human colon are decreased in cancer and upregulated in differentiation. Am J Physiol Gastrointest Liver Physiol. 2006;291:G288-G296.

    Not in our library10.1152/ajpgi.00324.2005

  96. 96.

    Hirata I, Naito Y, Takagi T, et al. Endogenous hydrogen sulfide is an anti-inflammatory molecule in dextran sodium sulfate-induced colitis in mice. Dig Dis Sci. 2011;56:1379-1386.

    Not in our library10.1007/s10620-010-1461-5

  97. 97.

    Gao Y, Yao X, Zhang Y, et al. The protective role of hydrogen sulfide in myocardial ischemia-reperfusion-induced injury in diabetic rats. Int J Cardiol. 2011;152:177-183.

    Not in our library10.1016/j.ijcard.2010.07.012

  98. 98.

    Takahashi T, Aoki Y, Okubo K, et al. Upregulation of Ca(v)3.2 T-type calcium channels targeted by endogenous hydrogen sulfide contributes to maintenance of neuropathic pain. Pain. 2010;150:183-191.

    Not in our library10.1016/j.pain.2010.04.022

  99. 99.

    Abeles RH, Walsh CT. Acetylenic enzyme inactivators. Inactivation of gamma-cystathionase, in vitro and in vivo, by propargylglycine. J Am Chem Soc. 1973;95:6124-6125.

    Not in our library10.1021/ja00799a053

  100. 100.

    Washtien W, Abeles RH. Mechanism of inactivation of gamma-cystathionase by the acetylenic substrate analogue propargylglycine. Biochemistry. 1977;16:2485-2491.

    Not in our library10.1021/bi00630a026

  101. 101.
    Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase ( CBS ) and cystathionine γ lyase ( CSE ) · 2013
    No notice
  102. 102.

    Steegborn C, Clausen T, Sondermann P, et al. Kinetics and inhibition of recombinant human cystathionine gamma-lyase. Toward the rational control of transsulfuration. J Biol Chem. 1999;274:12675-12684.

    Not in our library10.1074/jbc.274.18.12675

  103. 103.

    Yao K. Effects of several unusual sulfur-containing amino acids on rat liver cystathionine-gamma-lyase. Physiol Chem Phys. 1975;7:401-408.

    Not in our library

  104. 104.

    Thorson MK, Majtan T, Kraus JP, et al. Identification of cystathionine β-synthase inhibitors using a hydrogen sulfide selective probe. Angew Chem Int Ed Engl. 2013;52:4641-4644.

    Not in our library10.1002/anie.201300841

  105. 105.

    Thorson MK, Van Wagoner RM, Harper MK, et al. Marine natural products as inhibitors of cystathionine beta-synthase activity. Bioorg Med Chem Lett. 2015;25:1064-1066.

    Not in our library10.1016/j.bmcl.2015.01.013

  106. 106.

    Zhou Y, Yu J, Lei X, et al. High-throughput tandem-microwell assay identifies inhibitors of the hydrogen sulfide signaling pathway. Chem Commun (Camb). 2013;49:11782-11784.

    Not in our library10.1039/c3cc46719h

  107. 107.

    Wing DA. Modifiers of mercaptopyruvate sulfurtransferase catalyzed conversion of cyanide to thiocyanate in vitro. J Biochem Toxicol. 1992;7:65-72.

    Not in our library10.1002/jbt.2570070203

  108. 108.

    Porter DW, Baskin SI. Specificity studies of 3-Mercaptopyruvate sulfurtransferase. J Biochem Toxicol. 1995;10:287-292.

    Not in our library10.1002/jbt.2570100602

  109. 109.

    Porter DW, Baskin SI. The effect of three alpha-keto acids on 3-mercaptopyruvate sulfurtransferase activity. J Biochem Toxicol. 1996;11:45-50.

    Not in our library10.1002/(sici)1522-7146(1996)11:1<45::aid-jbt6>3.0.co;2-v

  110. 110.

    Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006;136:1636S-1640S.

    Not in our library10.1093/jn/136.6.1636s

  111. 111.

    Stipanuk MH. Metabolism of sulfur-containing amino acids. Annu Rev Nutr. 1986;6:179-209.

    Not in our library10.1146/annurev.nu.06.070186.001143

  112. 112.

    Stipanuk MH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr. 2004;24:539-577.

    Not in our library10.1146/annurev.nutr.24.012003.132418

  113. 113.

    Beard RS, Bearden SE. Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research. Am J Physiol Heart Circ Physiol. 2011;300:H13-H26.

    Not in our library10.1152/ajpheart.00598.2010

  114. 114.

    Wang J, Hegele RA. Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH) Hum. Genet. 2003;112:404-408.

    Not in our library10.1007/s00439-003-0906-8

  115. 115.

    Meier M, Oliveriusova J, Kraus JP, et al. Structural insights into mutations of cystathionine beta-synthase. Biochim Biophys Acta. 2003;1647:206-213.

    Not in our library10.1016/s1570-9639(03)00048-7

  116. 116.

    Finkelstein JD. Inborn errors of sulfur-containing amino acid metabolism. J Nutr. 2006;136:1750S-1754S.

    Not in our library10.1093/jn/136.6.1750s

  117. 117.

    Tsai MY, Hanson NQ, Bignell M, et al. Simultaneous detection and screening of T833C and G919A mutations of the cystathionine beta-synthase gene by single-strand conformational polymorphism. Clin Biochem. 1996;29:473-477.

    Not in our library10.1016/0009-9120(96)00045-8

  118. 118.

    Shi H, Yang S, Liu Y, et al. Study on environmental causes and SNPs of MTHFR, MS and CBS genes related to congenital heart disease. PLoS One. 2015;10:e0128646.

    Not in our library10.1371/journal.pone.0128646

  119. 119.

    Ding R, Lin S, Chen D. The association of cystathionine β synthase (CBS) T833C polymorphism and the risk of stroke: a meta-analysis. J Neurol Sci. 2012;312:26-30.

    Not in our library10.1016/j.jns.2011.08.029

  120. 120.

    Gallegos-Arreola MP, Figuera-Villanueva LE, Ramos-Silva A, et al. The association between the 844ins68 polymorphism in the CBS gene and breast cancer. Arch Med Sci. 2014;10:1214-1224.

    Not in our library10.5114/aoms.2014.47830

  121. 121.

    Konrad C, Müller GA, Langer C, et al. Plasma homocysteine, MTHFR C677T, CBS 844ins68 bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections. J Neurol. 2004;251:1242-1248.

    Not in our library10.1007/s00415-004-0523-z

  122. 122.

    Zhang Z, Dai C. Correlation analysis between plasma homocysteine level and polymorphism of homocysteine metabolism related enzymes in ischemic cerebrovascular or cardiovascular diseases. Zhonghua Xue Ye Xue Za Zhi. 2002;23:126-129.

    Not in our library

  123. 123.

    Chwatko G, Boers GH, Strauss KA, et al. Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J. 2007;21:1707-1713.

    Not in our library10.1096/fj.06-7435com

  124. 124.

    Harker LA, Slichter SJ, Scott CR, et al. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med. 1974;291:537-543.

    Not in our library10.1056/nejm197409122911101

  125. 125.

    Endo N, Nishiyama K, Otsuka A, et al. Antioxidant activity of vitamin B6 delays homocysteine-induced atherosclerosis in rats. Br J Nutr. 2006;95:1088-1093.

    Not in our library10.1079/bjn20061764

  126. 126.

    Maestro de las Casas C, Epeldegui M, Tudela C, et al. High exogenous homocysteine modifies eye development in early chick embryos. Birth Defects Res A Clin Mol Teratol. 2003;67:35-40.

    Not in our library10.1002/bdra.10014

  127. 127.

    Li Y, Zhao Q, Liu XL, et al. Relationship between cystathionine gamma-lyase gene polymorphism and essential hypertension in Northern Chinese Han population. Chin Med J (Engl). 2008;121:716-720.

    Not in our library

  128. 128.

    Wang J, Huff AM, Spence JD, et al. Single nucleotide polymorphism in CTH associated with variation in plasma homocysteine concentration. Clin Genet. 2004;65:483-486.

    Not in our library10.1111/j.1399-0004.2004.00250.x

  129. 129.

    Mrozikiewicz PM, Bogacz A, Omielańczyk M, et al. The importance of rs1021737 and rs482843 polymorphisms of cystathionine gamma-lyase in the etiology of preeclampsia in the Caucasian population. Ginekol Pol. 2015;86:119-125.

    Not in our library10.17772/gp/1998

  130. 130.

    Zhu W, Lin A, Banerjee R. Kinetic properties of polymorphic variants and pathogenic mutants in human cystathionine gamma-lyase. Biochemistry. 2008;47:6226-6232.

    Not in our library10.1021/bi800351a

  131. 131.

    Billaut-Laden I, Rat E, Allorge D, et al. Evidence for a functional genetic polymorphism of the human mercaptopyruvate sulfurtransferase (MPST), a cyanide detoxification enzyme. Toxicol Lett. 2006;165:101-111.

    Not in our library10.1016/j.toxlet.2006.02.002

  132. 132.

    Eto K, Kimura H. A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase. J Biol Chem. 2002;277:42680-42685.

    Not in our library10.1074/jbc.m205835200

  133. 133.

    Ereño-Orbea J, Majtan T, Oyenarte I, et al. Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. Proc Natl Acad Sci USA. 2014;111:E3845-E3852.

    Not in our library10.1073/pnas.1414545111

  134. 134.

    Huang S, Chua JH, Yew WS, et al. Site-directed mutagenesis on human cystathionine-gamma-lyase reveals insights into the modulation of H2S production. J Mol Biol. 2010;396:708-718.

    Not in our library10.1016/j.jmb.2009.11.058

  135. 135.

    Tang XQ, Chen RQ, Ren YK, et al. ACS6, a Hydrogen sulfide-donating derivative of sildenafil, inhibits homocysteine-induced apoptosis by preservation of mitochondrial function. Med Gas Res. 2011.

    Not in our library10.1186/2045-9912-1-20

  136. 136.

    Tang XQ, Chen RQ, Dong L, et al. Role of paraoxonase-1 in the protection of hydrogen sulfide-donating sildenafil (ACS6) against homocysteine-induced neurotoxicity. J Mol Neurosci. 2013;50:70-77.

    Not in our library10.1007/s12031-012-9862-x

  137. 137.

    Sen U, Sathnur PB, Kundu S, et al. Increased endogenous H2S generation by CBS, CSE, and 3MST gene therapy improves ex vivo renovascular relaxation in hyperhomocysteinemia. Am J Physiol Cell Physiol. 2012;303:C41-C51.

    Not in our library10.1152/ajpcell.00398.2011

  138. 138.

    Pushpakumar S, Kundu S, Sen U, et al. Endothelial dysfunction: the link between homocysteine and hydrogen sulfide. Curr Med Chem. 2014;21:3662-3672.

    Not in our library10.2174/0929867321666140706142335

  139. 139.

    Chang L, Geng B, Yu F, et al. Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. Amino Acids. 2008;34:573-585.

    Not in our library10.1007/s00726-007-0011-8

  140. 140.

    Wang R. Hydrogen sulfide: a new EDRF. Kidney Int. 2009;76:700-704.

    Not in our library10.1038/ki.2009.221

  141. 141.

    Pan LL, Liu XH, Gong QH, et al. Hydrogen sulfide attenuated tumor necrosis factor-α-induced inflammatory signaling and dysfunction in vascular endothelial cells. PLoS One. 2011.

    Not in our library10.1371/journal.pone.0019766

  142. 142.

    Li L, Whiteman M, Guan YY. Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation. 2008;117:2351-2360.

    Not in our library10.1161/circulationaha.107.753467

  143. 143.

    Lynn EG, Austin RC. Hydrogen sulfide in the pathogenesis of atherosclerosis and its therapeutic potential. Expert Rev Clin Pharmacol. 2011;4:97-108.

    Not in our library10.1586/ecp.10.130

  144. 144.

    Meng QH, Yang G, Yang W, et al. Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries. Am J Pathol. 2007;170:1406-1414.

    Not in our library10.2353/ajpath.2007.060939

  145. 145.

    Yang G, Li H, Tang G, et al. Increased neointimal formation in cystathionine gamma-lyase deficient mice: role of hydrogen sulfide in α5β1-integrin and matrix metalloproteinase-2 expression in smooth muscle cells. J Mol Cell Cardiol. 2012;52:677-688.

    Not in our library10.1016/j.yjmcc.2011.12.004

  146. 146.

    Yang G, Wu L, Wang R. Pro-apoptotic effect of endogenous H2S on human aorta smooth muscle cells. FASEB J. 2006;20:553-555.

    Not in our library10.1096/fj.05-4712fje

  147. 147.

    Zhao ZZ, Wang Z, Li GH, et al. Hydrogen sulfide inhibits macrophage-derived foam cell formation. Exp Biol Med (Maywood). 2011;236:169-176.

    Not in our library10.1258/ebm.2010.010308

  148. 148.

    Zhang H, Guo C, Wu D, et al. Hydrogen sulfide inhibits the development of atherosclerosis with suppressing CX3CR1 and CX3CL1 expression. PLoS One. 2012.

    Not in our library10.1371/journal.pone.0041147

  149. 149.

    Wang XH, Wang F, You SJ, et al. Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL-induced inflammation in macrophage. Cell Signal. 2013;25:2255-2262.

    Not in our library10.1016/j.cellsig.2013.07.010

  150. 150.

    Wu SY, Pan CS, Geng B, et al. Hydrogen sulfide ameliorates vascular calcification induced by vitamin D3 plus nicotine in rats. Acta Pharmacol Sin. 2006;27:299-306.

    Not in our library10.1111/j.1745-7254.2006.00283.x

  151. 151.

    Zagli G, Patacchini R, Trevisani M, et al. Hydrogen sulfide inhibits human platelet aggregation. Eur J Pharmacol. 2007;559:65-68.

    Not in our library10.1016/j.ejphar.2006.12.011

  152. 152.

    Grambow E, Mueller-Graf F, Delyagina E, et al. Effect of the hydrogen sulfide donor GYY4137 on platelet activation and microvascular thrombus formation in mice. Platelets. 2007;25:166-174.

    Not in our library10.3109/09537104.2013.786823

  153. 153.

    Qiao W, Chaoshu T, Hongfang J, et al. Endogenous hydrogen sulfide is involved in the pathogenesis of atherosclerosis. Biochem Biophys Res Commun. 2010;396:182-186.

    Not in our library10.1016/j.bbrc.2010.04.061

  154. 154.

    Xu S, Liu Z, Liu P. Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis. Int J Cardiol. 2014;172:313-317.

    Not in our library10.1016/j.ijcard.2014.01.068

  155. 155.

    Wang W, Feng SJ, Li H, et al. Correlation of lower concentrations of hydrogen sulfide with activation of protein kinase CβII in uremic accelerated atherosclerosis patients. Chin Med J. 2015;128:1465-1470.

    Not in our library10.4103/0366-6999.157653

  156. 156.

    Li H, Feng SJ, Zhang GZ, et al. Correlation of lower concentrations of hydrogen sulfide with atherosclerosis in chronic hemodialysis patients with diabetic nephropathy. Blood Purif. 2015;38:188-194.

    Not in our library10.1159/000368883

  157. 157.

    Jiang HL, Wu HC, Li ZL, et al. Changes of the new gaseous transmitter H2S in patients with coronary heart disease. Di Yi Jun Yi Da Xue Xue Bao. 2005;25:951-954.

    Not in our library

  158. 158.

    Chen L, Ingrid S, Ding YG, et al. Imbalance of endogenous homocysteine and hydrogen sulfide metabolic pathway in essential hypertensive children. Chin Med J (Engl). 2007;120:389-393.

    Not in our library

  159. 159.

    Perna AF, Luciano M, Ingrosso D, et al. Hydrogen sulphide-generating pathways in haemodialysis patients: a study on relevant metabolites and transcriptional regulation of genes encoding for key enzymes. Nephrol Dial Transplant. 2009;24:3756-3763.

    Not in our library10.1093/ndt/gfp378

  160. 160.

    Perna AF, Di Nunzio A, Amoresano A. Divergent behavior of hydrogen sulfide pools and of the sulfur metabolite lanthionine, a novel uremic toxin, in dialysis patients. Biochimie. 2016;126:97-107.

    Not in our library10.1016/j.biochi.2016.04.018

  161. 161.

    Li JJ, Li Q, Du HP, et al. Homocysteine triggers inflammatory responses in macrophages through inhibiting CSE-H2S signaling via DNA hypermethylation of CSE promoter. Int J Mol Sci. 2015;16:12560-12577.

    Not in our library10.3390/ijms160612560

  162. 162.

    Xu Y, Du HP, Li J, et al. Statins upregulate cystathionine γ-lyase transcription and H2S generation via activating Akt signaling in macrophage. Pharmacol Res. 2014;87:18-25.

    Not in our library10.1016/j.phrs.2014.06.006

  163. 163.

    Yang G, Cao K, Wu L, et al. Cystathionine gamma-lyase overexpression inhibits cell proliferation via a H2S-dependent modulation of ERK1/2 phosphorylation and p21Cip/WAK-1. J Biol Chem. 2004;279:49199-49205.

    Not in our library10.1074/jbc.m408997200

  164. 164.

    Shen Y, Shen Z, Miao L, et al. miRNA-30 family inhibition protects against cardiac ischemic injury by regulating cystathionine-γ-lyase expression. Antioxid Redox Signal. 2015;22:224-240.

    Not in our library10.1089/ars.2014.5909

  165. 165.

    Fox B, Schantz JT, Haigh R, et al. Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint? J Cell Mol Med. 2012;16:896-910.

    Not in our library10.1111/j.1582-4934.2011.01357.x

  166. 166.

    Badiei A, Rivers-Auty J, Ang AD, et al. Inhibition of hydrogen sulfide production by gene silencing attenuates inflammatory activity of LPS-activated RAW264.7 cells. Appl Microbiol Biotechnol. 2013;97:7845-7852.

    Not in our library10.1007/s00253-013-5080-x

  167. 167.

    Badiei A, Muniraj N, Chambers S, et al. Inhibition of hydrogen sulfide production by gene silencing attenuates inflammatory activity by downregulation of NF-κB and MAP kinase activity in LPS-activated RAW 264.7 cells. Biomed Res. 2014.

    Not in our library10.1155/2014/848570

  168. 168.

    Wang K, Ahmad S, Cai M, et al. Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Circulation. 2013;127:2514-2522.

    Not in our library10.1161/circulationaha.113.001631

  169. 169.

    Liu Y, Yang R, Liu X, et al. Hydrogen sulfide maintains mesenchymal stem cell function and bone homeostasis via regulation of Ca(2+) channel sulfhydration. Cell Stem Cell. 2014;15:66-78.

    Not in our library10.1016/j.stem.2014.03.005

  170. 170.

    Sen U, Givvimani S, Abe OA, et al. Cystathionine β-synthase and cystathionine γ-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generation. Am J Physiol Cell Physiol. 2007;300:C155-C163.

    Not in our library10.1152/ajpcell.00143.2010

  171. 171.

    Albertini E, Kozieł R, Dürr A, et al. Cystathionine beta synthase modulates senescence of human endothelial cells. Aging (Albany NY). 2012;4:664-673.

    Not in our library10.18632/aging.100491

  172. 172.
    Cystathionine Beta-Synthase (CBS) Contributes to Advanced Ovarian Cancer Progression and Drug Resistance · 2013
    No notice
  173. 173.

    Szabo C, Coletta C, Chao C, et al. Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Proc Natl Acad Sci USA. 2013;110:12474-12479.

    Not in our library10.1073/pnas.1306241110

  174. 174.

    Miller TW, Wang EA, Gould S, et al. Hydrogen sulfide is an endogenous potentiator of T cell activation. J Biol Chem. 2011;287:4211-4221.

    Not in our library10.1074/jbc.m111.307819

  175. 175.

    Sen S, Kawahara B, Gupta D, et al. Role of cystathionine β-synthase in human breast Cancer. Free Radic Biol Med. 2015;86:228-238.

    Not in our library10.1016/j.freeradbiomed.2015.05.024

  176. 176.

    Yang G, Yang W, Wu L, et al. H2S, endoplasmic reticulum stress, and apoptosis of insulin-secreting beta cells. J Biol Chem. 2007;282:16567-16576.

    Not in our library10.1074/jbc.m700605200

  177. 177.

    Watanabe M, Osada J, Aratani Y, et al. Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA. 1995;92:1585-1589.

    Not in our library10.1073/pnas.92.5.1585

  178. 178.

    Wang L, Jhee KH, Hua X, et al. Modulation of cystathionine beta-synthase level regulates total serum homocysteine in mice. Circ Res. 2004;94:1318-1324.

    Not in our library10.1161/01.res.0000129182.46440.4a

  179. 179.

    Wang L, Chen X, Tang B, et al. Expression of mutant human cystathionine beta-synthase rescues neonatal lethality but not homocystinuria in a mouse model. Hum Mol Genet. 2005;14:2201-2208.

    Not in our library10.1093/hmg/ddi224

  180. 180.

    Maclean KN, Sikora J, Kožich V, et al. A novel transgenic mouse model of CBS-deficient homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment. Mol Genet Metab. 2010;101:153-162.

    Not in our library10.1016/j.ymgme.2010.06.010

  181. 181.

    Lentz SR, Erger RA, Dayal S, et al. Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine beta-synthase-deficient mice. Am J Physiol Heart Circ Physiol. 2000;279:H970-H975.

    Not in our library10.1152/ajpheart.2000.279.3.h970

  182. 182.

    Clarke ZL, Moat SJ, Miller AL, et al. Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia. Eur J Pharmacol. 2006;551:92-97.

    Not in our library10.1016/j.ejphar.2006.08.085

  183. 183.

    Kalani A, Kamat PK, Familtseva A, et al. Role of microRNA29b in blood–brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism. J Cereb Blood Flow Metab. 2014;34:1212-1222.

    Not in our library10.1038/jcbfm.2014.74

  184. 184.

    Dayal S, Bottiglieri T, Arning E, et al. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine beta-synthase-deficient mice. Circ Res. 2001;88:1203-1209.

    Not in our library10.1161/hh1101.092180

  185. 185.

    Dayal S, Arning E, Bottiglieri T, et al. Cerebral vascular dysfunction mediated by superoxide in hyperhomocysteinemic mice. Stroke. 2004;35:1957-1962.

    Not in our library10.1161/01.str.0000131749.81508.18

  186. 186.

    Robert K, Santiard-Baron D, Chassé JF, et al. The neuronal SAPK/JNK pathway is altered in a murine model of hyperhomocysteinemia. J Neurochem. 2004;89:33-43.

    Not in our library10.1046/j.1471-4159.2003.02297.x

  187. 187.

    Vitvisky V, Dayal S, Stabler S, et al. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol. 2004;287:R39-R46.

    Not in our library10.1152/ajpregu.00036.2004

  188. 188.

    Kundu S, Kumar M, Sen U, et al. Nitrotyrosinylation, remodeling and endothelial-myocyte uncoupling in iNOS, cystathionine beta synthase (CBS) knockouts and iNOS/CBS double knockout mice. J Cell Biochem. 2009;106:119-126.

    Not in our library10.1002/jcb.21982

  189. 189.

    Mayo JN, Beard RS, Price TO, et al. Nitrative stress in cerebral endothelium is mediated by mGluR5 in hyperhomocysteinemia. J Cereb Blood Flow Metab. 2012;32:825-834.

    Not in our library10.1038/jcbfm.2011.185

  190. 190.

    Shastry S, Moning L, Tyagi N, et al. GABA receptors and nitric oxide ameliorate constrictive collagen remodeling in hyperhomocysteinemia. J Cell Physiol. 2005;205:422-427.

    Not in our library10.1002/jcp.20416

  191. 191.

    Kamath AF, Chauhan AK, Kisucka J, et al. Elevated levels of homocysteine compromise blood–brain barrier integrity in mice. Blood. 2006;107:591-593.

    Not in our library10.1182/blood-2005-06-2506

  192. 192.

    Hamelet J, Maurin N, Fulchiron R, et al. Mice lacking cystathionine beta synthase have lung fibrosis and air space enlargement. Exp Mol Pathol. 2007;83:249-253.

    Not in our library10.1016/j.yexmp.2007.04.005

  193. 193.

    Hamelet J, Demuth K, Paul JL, et al. Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice. J Hepatol. 2007;46:151-159.

    Not in our library10.1016/j.jhep.2006.07.028

  194. 194.

    Liao D, Tan H, Hui R, et al. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. Circ Res. 2006;99:598-606.

    Not in our library10.1161/01.res.0000242559.42077.22

  195. 195.

    Gupta S, Kruger WD. Cystathionine beta-synthase deficiency causes fat loss in mice. PLoS One. 2011.

    Not in our library10.1371/journal.pone.0027598

  196. 196.

    Ganapathy PS, Moister B, Roon P, et al. Endogenous elevation of homocysteine induces retinal neuron death in the cystathionine-beta-synthase mutant mouse. Invest Ophthalmol Vis Sci. 2009;50:4460-4470.

    Not in our library10.1167/iovs.09-3402

  197. 197.

    Nuño-Ayala M, Guillén N, Arnal C, et al. Cystathionine β-synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites. Physiol Genomics. 2012;44:702-716.

    Not in our library10.1152/physiolgenomics.00189.2010

  198. 198.

    Guzman MA, Navarro MA, Carnicer R, et al. Cystathionine beta-synthase is essential for female reproductive function. Hum Mol Genet. 2006;15:3168-3176.

    Not in our library10.1093/hmg/ddl393

  199. 199.

    Hagiya Y, Kamata S, Mitsuoka S, et al. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice. Toxicol Appl Pharmacol. 2015;282:195-206.

    Not in our library10.1016/j.taap.2014.11.015

  200. 200.

    Okomoto M, Yamaoka M, Takei M, et al. Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes. Biochem Biophys Res Commun. 2013;442:227-233.

    Not in our library10.1016/j.bbrc.2013.11.023

  201. 201.

    Tang G, Zhang L, Yang G, et al. Hydrogen sulfide-induced inhibition of L-type Ca2+ channels and insulin secretion in mouse pancreatic beta cells. Diabetologia. 2013;56:533-541.

    Not in our library10.1007/s00125-012-2806-8

  202. 202.

    King AL, Polhemus DJ, Bhushan S, et al. Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc Natl Acad Sci USA. 2015;111:3182-3187.

    Not in our library10.1073/pnas.1321871111

  203. 203.

    Ishii I, Akahoshi N, Yamada H, et al. Cystathionine gamma-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. J Biol Chem. 2010;285:26358-26368.

    Not in our library10.1074/jbc.m110.147439

  204. 204.

    Yang G, Wu L, Jiang B, et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science. 2008;322:587-590.

    Not in our library10.1126/science.1162667

  205. 205.

    Yang G, Wu L, Bryan S. Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells. Cardiovasc Res. 2010;86:487-495.

    Not in our library10.1093/cvr/cvp420

  206. 206.

    Peng YJ, Nanduri J, Raghuraman G, et al. H2S mediates O2 sensing in the carotid body. Proc Natl Acad Sci USA. 2010;107:10719-10724.

    Not in our library10.1073/pnas.1005866107

  207. 207.

    Yang G, Zhao K, Ju Y, et al. Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid Redox Signal. 2013;18:1906-1919.

    Not in our library10.1089/ars.2012.4645

  208. 208.

    Kondo K, Bhushan S, King AL, et al. H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. 2013;127:1116-1127.

    Not in our library10.1161/circulationaha.112.000855

  209. 209.

    Zhang G, Wang P, Yang G, et al. The inhibitory role of hydrogen sulfide in airway hyperresponsiveness and inflammation in a mouse model of asthma. Am J Pathol. 2013;182:1188-1195.

    Not in our library10.1016/j.ajpath.2012.12.008

  210. 210.

    Tang G, Yang G, Jiang B, et al. H2S is an endothelium-derived hyperpolarizing factor. Antioxid Redox Signal. 2013;19:1634-1646.

    Not in our library10.1089/ars.2012.4805

  211. 211.

    Bos EM, Wang R, Snijder PM, et al. Cystathionine γ-lyase protects against renal ischemia/reperfusion by modulating oxidative stress. J Am Soc Nephrol. 2013;24:759-770.

    Not in our library10.1681/asn.2012030268

  212. 212.

    Mani S, Li H, Untereiner A, et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation. 2013;127:2523-2534.

    Not in our library10.1161/circulationaha.113.002208

  213. 213.

    Ang AD, Rivers-Auty J, Hegde A, et al. The effect of CSE gene deletion in caerulein-induced acute pancreatitis in the mouse. Am J Physiol Gastrointest Liver Physiol. 2013;305:G712-G721.

    Not in our library10.1152/ajpgi.00044.2013

  214. 214.

    Jiang Z, Li C, Manuel ML, et al. Role of hydrogen sulfide in early blood–brain barrier disruption following transient focal cerebral ischemia. PLoS One. 2015.

    Not in our library10.1371/journal.pone.0117982

  215. 215.

    Kolluru GK, Bir SC, Yuan S, et al. Cystathionine γ-lyase regulates arteriogenesis through NO-dependent monocyte recruitment. Cardiovasc Res. 2015;107:590-600.

    Not in our library10.1093/cvr/cvv198

  216. 216.

    Syhr KM, Boosen M, Hohmann SW, et al. The H2S-producing enzyme CSE is dispensable for the processing of inflammatory and neuropathic pain. Brain Res. 2015;1624:380-389.

    Not in our library10.1016/j.brainres.2015.07.058

  217. 217.

    Untereiner AA, Wang R, Ju Y, et al. Decreased Gluconeogenesis in the Absence of Cystathionine Gamma-Lyase and the Underlying Mechanisms. Antioxid Redox Signal. 2016;24:129-140.

    Not in our library10.1089/ars.2015.6369

  218. 218.

    Ivanciuc T, Sbrana E, Ansar M, et al. Hydrogen sulfide: an antiviral and anti-inflammatory endogenous gasotransmitter in the airways. Role in respiratory syncytial virus infection. Am J Respir Cell Mol Biol. 2016.

    Not in our library10.1165/rcmb.2015-0385oc

  219. 219.

    Miao L, Xin X, Xin H, et al. Hydrogen sulfide recruits macrophage migration by integrin β1-Src-FAK/Pyk2-Rac pathway in myocardial infarction. Sci Rep. 2016.

    Not in our library10.1038/srep22363

  220. 220.

    Ali MY, Ping CY, Mok YY, et al. Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol. 2006;149:625-634.

    Not in our library10.1038/sj.bjp.0706906

  221. 221.

    Filipovic MR, Miljkovic JL, Nauser T, et al. Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols. J Am Chem Soc. 2012;134:12016-12027.

    Not in our library10.1021/ja3009693

  222. 222.
    Nitrosopersulfide (SSNO−) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide · 2014
    No notice
  223. 223.

    Cheung SH, Kwok WK, To KF, et al. Anti-atherogenic effect of hydrogen sulfide by over-expression of cystathionine gamma-lyase (CSE) gene. PLoS One. 2014.

    Not in our library10.1371/journal.pone.0113038

  224. 224.
    Identification of H2S3 and H2S produced by 3-mercaptopyruvate sulfurtransferase in the brain · 2015
    No notice
  225. 225.

    Yadav PK, Yamada K, Chiku T, et al. Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase. J Biol Chem. 2013;288:20002-20013.

    Not in our library10.1074/jbc.m113.466177

  226. 226.

    Nicholls P. Inhibition of cytochrome c oxidase by sulphide. Biochem Soc Trans. 1975;3:316-319.

    Not in our library10.1042/bst0030316

  227. 227.

    Nagahara N, Nagano M, Ito T, et al. Antioxidant enzyme, 3-mercaptopyruvate sulfurtransferase-knockout mice exhibit increased anxiety-like behaviors: a model for human mercaptolactate-cysteine disulfiduria. Sci Rep. 2013.

    Not in our library10.1038/srep01986

  228. 228.

    Vande Weghe JG, Ow DW. A fission yeast gene for mitochondrial sulfide oxidation. J Biol Chem. 1999;274:13250-13257.

    Not in our library10.1074/jbc.274.19.13250

  229. 229.

    Libiad M, Yadav PK, Vitvitsky V, et al. Organization of the human mitochondrial hydrogen sulfide oxidation pathway. J Biol Chem. 2014;289:30901-30910.

    Not in our library10.1074/jbc.m114.602664

  230. 230.

    Ackermann M, Kubitza M, Hauska G, et al. The vertebrate homologue of sulfide-quinone reductase in mammalian mitochondria. Cell Tissue Res. 2014;358:779-792.

    Not in our library10.1007/s00441-014-1983-9

  231. 231.

    Olson KR. Hydrogen sulfide as an oxygen sensor. Antioxid Redox Signal. 2015;22:377-397.

    Not in our library10.1089/ars.2014.5930

  232. 232.

    Jin HS, Kim J, Park S, et al. Association of the I264T variant in the sulfide quinone reductase-like (SQRDL) gene with osteoporosis in Korean postmenopausal women. PLoS One. 2016.

    Not in our library10.1371/journal.pone.0135285

  233. 233.

    Croteau-Chonka DC, Marvelle AF, Lange EM, et al. Genome-wide association study of anthropometric traits and evidence of interactions with age and study year in Filipino women. Obesity (Silver Spring). 2011;19:1019-1027.

    Not in our library10.1038/oby.2010.256

  234. 234.

    Itou T, Maldonado N, Yamada I, et al. Cystathionine gamma-lyase accelerates osteoclast differentiation: identification of a novel regulator of osteoclastogenesis by proteomic analysis. Arterioscler Thromb Vasc Biol. 2014;34:626-634.

    Not in our library10.1161/atvbaha.113.302576

  235. 235.

    Gambari L, Lisignoli G, Cattini L, et al. Sodium hydrosulfide inhibits the differentiation of osteoclast progenitor cells via NRF2-dependent mechanism. Pharmacol Res. 2014;87:99-112.

    Not in our library10.1016/j.phrs.2014.06.014

  236. 236.

    Pan Z, Wang H, Liu Y, et al. Involvement of CSE/H2S in high glucose induced aberrant secretion of adipokines in 3T3-L1 adipocytes. Lipids Health Dis. 2014.

    Not in our library10.1186/1476-511x-13-155

  237. 237.

    Geng B, Cai B, Liao F, et al. Increase or decrease hydrogen sulfide exert opposite lipolysis, but reduce global insulin resistance in high fatty diet induced obese mice. PLoS One. 2013.

    Not in our library10.1371/journal.pone.0073892

  238. 238.

    Carter RN, Morton NM. Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology. J Pathol. 2016;238:321-332.

    Not in our library10.1002/path.4659

  239. 239.

    Jain S, Micinski D, Lieblong BJ, et al. Relationship between hydrogen sulfide levels and HDL-cholesterol, adiponectin, and potassium levels in the blood of healthy subjects. Atherosclerosis. 2012;225:242-245.

    Not in our library10.1016/j.atherosclerosis.2012.08.036

  240. 240.

    Liang M, Jin S, Wu DD, et al. Hydrogen sulfide improves glucose metabolism and prevents hypertrophy in cardiomyocytes. Nitric Oxide. 2015;46:114-122.

    Not in our library10.1016/j.niox.2014.12.007

  241. 241.

    Horsman JW, Miller DL. Mitochondrial sulfide quinone oxidoreductase prevents activation of the unfolded protein response in hydrogen sulfide. J Biol Chem. 2016;291:5320-5325.

    Not in our library10.1074/jbc.m115.697102

  242. 242.

    Henriques BJ, Lucas TG, Rodrigues JV, et al. Ethylmalonic encephalopathy ETHE1 R163W/R163Q mutations alter protein stability and redox properties of the iron centre. PLoS One. 2014.

    Not in our library10.1371/journal.pone.0107157

  243. 243.

    Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, et al. Ethylmalonic encephalopathy: clinical and biochemical observations. Neuropediatrics. 2007;38:78-82.

    Not in our library10.1055/s-2007-984447

  244. 244.

    Lagoutte E, Mimoun S, Andriamihaja M, et al. Oxidation of hydrogen sulfide remains a priority in mammalian cells and causes reverse electron transfer in colonocytes. Biochim Biophys Acta. 2010;1797:1500-1511.

    Not in our library10.1016/j.bbabio.2010.04.004

  245. 245.

    Hildbrant TM, Di Meo I, Zeviani M, et al. Proteome adaptations in Ethe1-deficient mice indicate a role in lipid catabolism and cytoskeleton organization via post-translational protein modifications. Biosci Rep. 2013.

    Not in our library10.1042/bsr20130051

  246. 246.

    Ono K, Akaike T, Sawa T, et al. Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: implications of their possible biological activity and utility. Free Radic Biol Med. 2014;77:82-94.

    Not in our library10.1016/j.freeradbiomed.2014.09.007

  247. 247.

    Jain SK, Bull R, Rains JL, et al. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal. 2010;12:1333-1337.

    Not in our library10.1089/ars.2009.2956

  248. 248.

    Baiges I, Palmfeldt J, Bladé C, et al. Lipogenesis is decreased by grape seed proanthocyanidins according to liver proteomics of rats fed a high fat diet. Mol Cell Proteomics. 2010;9:1499-1513.

    Not in our library10.1074/mcp.m000055-mcp201

  249. 249.

    Jurkowska H, Roman HB, Hirschberger LL, et al. Primary hepatocytes from mice lacking cysteine dioxygenase show increased cysteine concentrations and higher rates of metabolism of cysteine to hydrogen sulfide and thiosulfate. Amino Acids. 2014;46:1353-1365.

    Not in our library10.1007/s00726-014-1700-8

  250. 250.

    Roman HB, Hirschberger LL, Krijt J, et al. The cysteine dioxgenase knockout mouse: altered cysteine metabolism in nonhepatic tissues leads to excess H2S/HS(–) production and evidence of pancreatic and lung toxicity. Antioxid Redox Signal. 2013;19:1321-1336.

    Not in our library10.1089/ars.2012.5010

  251. 251.

    Ueki I, Roman HB, Valli A, et al. Knockout of the murine cysteine dioxygenase gene results in severe impairment in ability to synthesize taurine and an increased catabolism of cysteine to hydrogen sulfide. Am J Physiol Endocrinol Metab. 2011;301:E668-E684.

    Not in our library10.1152/ajpendo.00151.2011

  252. 252.

    Weiss N, Heydrick S, Zhang YY, et al. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine b-synthase-deficient mice. Arterioscler Thromb Vasc Biol. 2002;22:34-41.

    Not in our library10.1161/hq1201.100456

  253. 253.

    Flannigan KL, Ferraz JG, Wang R, et al. Enhanced synthesis and diminished degradation of hydrogen sulfide in experimental colitis: a site-specific, pro-resolution mechanism. PLoS One. 2013;8:e71962.

    Not in our library10.1371/journal.pone.0071962

  254. 254.

    Madurga A, Golec A, Pozarska A, et al. The H2S-generating enzymes cystathionine β-synthase and cystathionine γ-lyase play a role in vascular development during normal lung alveolarization. Am J Physiol Lung Cell Mol Physiol. 2015;309:L710-L724.

    Not in our library10.1152/ajplung.00134.2015

  255. 255.

    Sen U, Basu P, Abe OA, et al. Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure. Am J Physiol Renal Physiol. 2009;297:F410-F419.

    Not in our library10.1152/ajprenal.00145.2009

  256. 256.

    Módis K, Wolanska K, Vozdek R. Hydrogen sulfide in cell signaling, signal transduction, cellular bioenergetics and physiology in C. elegans. Gen Physiol Biophys. 2013;32:1-22.

    Not in our library10.4149/gpb_2013001

  257. 257.

    Calderwood A, Kopriva S. Hydrogen sulfide in plants: from dissipation of excess sulfur to signaling molecule. Nitric Oxide. 2014;41:72-78.

    Not in our library10.1016/j.niox.2014.02.005

  258. 258.

    Miller DL, Roth MB. Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proc Natl Acad Sci USA. 2007;104:20618-20622.

    Not in our library10.1073/pnas.0710191104

  259. 259.

    Budde MW, Roth MB. The response of Caenorhabditis elegans to hydrogen sulfide and hydrogen cyanide. Genetics. 2011;189:521-532.

    Not in our library10.1534/genetics.111.129841

  260. 260.

    Hine C, Harputlugil E, Zhang Y, et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell. 2015;160:132-144.

    Not in our library10.1016/j.cell.2014.11.048

  261. 261.

    Hine C, Mitchell JR. Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. Exp Gerontol. 2015;68:26-32.

    Not in our library10.1016/j.exger.2014.12.010

  262. 262.

    Kabil H, Kabil O, Banerjee R, et al. Increased transsulfuration mediates longevity and dietary restriction in Drosophila. Proc Natl Acad Sci USA. 2011;108:16831-16836.

    Not in our library10.1073/pnas.1102008108

  263. 263.

    Snijder PM, Baratashvili M, Grzeschik NA, et al. Overexpression of cystathionine γ-lyase suppresses detrimental effects of spinocerebellar ataxia type 3. Mol Med. 2015.

    Not in our library10.2119/molmed.2015.00221

  264. 264.

    Kumai Y, Porteus CS, Kwong RW, et al. Hydrogen sulfide inhibits Na+ uptake in larval zebrafish, Danio rerio. Pflugers Arch. 2015;467:651-664.

    Not in our library10.1007/s00424-014-1550-y

  265. 265.

    Laubach VE, Shesely EG, Smithies O, et al. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA. 1995;92:10688-10692.

    Not in our library10.1073/pnas.92.23.10688

  266. 266.

    Shesely EG, Maeda N, Kim HS, et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 1996;93:13176-13181.

    Not in our library10.1073/pnas.93.23.13176

  267. 267.

    Duplain H, Burcelin R, Sartori C, et al. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation. 2001;104:342-345.

    Not in our library10.1161/01.cir.104.3.342

  268. 268.

    Kodela R, Chattopadhyay M, Kashfi K. NOSH-aspirin: a novel nitric oxide-hydrogen sulfide-releasing hybrid: a new class of anti-inflammatory pharmaceuticals. ACS Med Chem Lett. 2012;3:257-262.

    Not in our library10.1021/ml300002m

  269. 269.

    Fonseca MD, Cunha FQ, Kashfi K, et al. NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reduces inflammatory pain. Pharmacol Res Perspect. 2015.

    Not in our library10.1002/prp2.133

  270. 270.

    Hu Q, Wu D, Ma F, et al. Novel angiogenic activity and molecular mechanisms of ZYZ-803, a slow-releasing hydrogen sulfide-nitric oxide hybrid molecule. Antioxid Redox Signal. 2016.

    Not in our library10.1089/ars.2015.6607

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