Clinica Chimica Acta 439 (2015) 212–218

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Invited critical review

Hydrogen sulfide in signaling pathways Beata Olas ⁎ Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland

a r t i c l e

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Article history: Received 3 July 2014 Received in revised form 23 October 2014 Accepted 24 October 2014 Available online 29 October 2014 Keywords: Hydrogen sulfide Gasotransmitter Garlic Signaling pathways

a b s t r a c t For a long time hydrogen sulfide (H2S) was considered a toxic compound, but recently H2S (at low concentrations) has been found to play an important function in physiological processes. Hydrogen sulfide, like other well-known compounds — nitric oxide (NO•) and carbon monoxide (CO) is a gaseous intracellular signal transducer. It regulates the cell cycle, apoptosis and the oxidative stress. Moreover, its functions include neuromodulation, regulation of cardiovascular system and inflammation. In this review, I focus on the metabolism of hydrogen sulfide (including enzymatic pathways of H2S synthesis from L- and D-cysteine) and its signaling pathways in the cardiovascular system and the nervous system. I also describe how hydrogen sulfide may be used as therapeutic agent, i.e. in the cardiovascular diseases. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biogenesis and metabolic pathways of hydrogen sulfide in vivo and in vitro. Hydrogen sulfide as a signaling molecule . . . . . . . . . . . . . . . . 3.1. H2S as a gasotransmitter in cardiovascular system . . . . . . . . . 3.2. H2S as a signaling molecule in the nervous system . . . . . . . . . 4. Role of garlic compounds in the cardiovascular system . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Hydrogen sulfide (H2S), like other molecules (nitric oxide (NO•); various isoforms of NO• synthase catalyze NO• production [1], and carbon monoxide (CO) — a product of heme metabolism [1]) is the inorganic gas, referred to as a gasotransmitter. Gasotransmitters are endogenously generated gaseous signaling molecules [1–3]. Their Abbreviations: CAT, cysteine aminotransferase; CBS, cystathionine β-synthase; CO, carbon monoxide; CSE, cystathionine γ-lyase; DAO, D-amino acid oxidase; ERK, extracellular signal-regulated kinase; eNOS, endothelial nitric oxide synthase; GSH, reduced form of glutathione; H2O2, hydrogen peroxide; HOCl, hypochlorous acid; HS−, hydrosulfide anion; H2S, hydrogen sulfide; MAPK, mitogen activated protein kinase; MST, 3mercaptopyruvate sulfurtransferase; NaHS, sodium hydrosulfide; Na2S, sodium sulfide; − NMDA, N-methyl-D-aspartic; NO•, nitric oxide; O− 2 •, superoxide anion; ONOO , peroxynitrite; PKA, protein kinase A; RNS, reactive nitrogen species; ROS, reactive oxygen 2− species; SO2, sulfur dioxide; S2O2− 3 , thiosulfate; SO4 , sulfate; VSMC, vascular smooth muscle cell. ⁎ Tel.: +48 42 665 58 08; fax: +48 42 635 44 84. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.cca.2014.10.037 0009-8981/© 2014 Elsevier B.V. All rights reserved.

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production does not rely on complicated chemical processes or on supplies from multiple substrates. The simplicity of gasotransmitters allows them to travel intracellularly and intercellularly quickly and on short notice [1]. They are present on all organs, cells, and different intracellular organelles in significant abundance [1]. The pathways of H2S, CO and NO• biosynthesis interact with each other, i.e. they have positive or negative impact on the concentration and properties of the other. However, there are differences between these gasotransmitters, i.e. half lives (hydrogen sulfide, like NO• is short lived and acts only close to sites of biosynthesis) [4–7]. H2S is a mediator of many physiological and/or pathological processes. Some of these effects are ascribed to the formation of protein persulfides, or protein S-sulfhydration, i.e. conversion of cysteine residues –SH to persulfides –S–SH [8]. H2S plays an important role in regulating the nervous system and the cardiovascular system. It regulates apoptosis, the cell cycle and the oxidative stress. H2S has cardioprotective action, neuromodulation properties and may modulate inflammation process, gastrointestinal function, mitochondrial function

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and energy metabolism [9]. Hundreds of papers and books with the keywords: “hydrogen sulfide” and “H2S” have been published [1,10]. Numerous papers have demonstrated different roles of H2S in signaling pathways in a range of organisms, including both animals and plants [1,2,11–19]. Plasma concentration of H2S is in 34–65 μM range [20], but in the brain the physiological concentration of H2S is up to threefold higher than in serum [21,22]. Results of Olson [23] showed that H2S concentrations are between 30 and 300 μM in plasma or blood. The level of H2S in various human tissues may depend on the donor's age and the method, which is used for measurement [18,24]. Endogenous level of H2S is modulated by different metabolic pathways, including H2S oxidation [25–27], which occurs in the mitochondria [9]. The oxidation products 2− include persulfide, sulfite, thiosulfate (S2O2− 3 ) and sulfate (SO4 ) [9]. The gas/water coefficient of distribution for hydrogen sulfide is 0.39, and physiological pH about 20% (at 37 °C) of the total free sulfide is present as dissolved gas (Fig. 1) [28–30]. At high concentration or, administered in the short time, hydrogen sulfide becomes toxic via inhibition of mitochondrial cytochrome c oxidase and mitochondrial respiration [31]. Wedmann et al. [32] demonstrated that when working with H2S, the final experiment outcome depends on the source of hydrogen sulfide and used methods. There are different ways to donate H2S to cells. Common compounds such as sodium hydrosulfide (NaHS) and sodium sulfide (Na2S) have been used extensively to give a short burst of hydrogen sulfide, i.e. NaHS dissociated to Na+ and HS−, and then partially binding to H+ to form un-dissociated hydrogen sulfide [33]. GYY4137, AP97 and AP105 are donors, which release H2S in a more physiological manner, and can be targeted to organelles [13,14,34]. The purpose of this work is the characteristics of the signal pathways of hydrogen sulfide.

2. Biogenesis and metabolic pathways of hydrogen sulfide in vivo and in vitro

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brain development [43,44]. Its expression is up-regulated in reactive astrocytes [44]. Recent different results have reported that H2S production can use also D-cysteine [17,45]. D-Cysteine is metabolized by D-amino acid oxidase (DAO) to an achiral 3-mercaptopyruvate, which is also produced by CAT from L-cysteine in the presence of α-ketoglutarate [17]. Fig. 2 demonstrates the known enzymatic pathways of endogenous H2S biosynthesis from L-cysteine and D-cysteine. There are two possible sources of D-cysteine: racemase-induced hiral change of L-cysteine and absorption from food. Cysteine is structurally similar to serine with an OH replaced by an SH. Aspartate racemase is homologous to CAT, which has an affinity for both aspartate and cysteine [45,46]. It is possible that serine racemase or aspartate racemase changes L-cysteine to D-cysteine [45]. D-Cysteine-dependent pathway operates predominantly in the brain (especially in the cerebellum) and the kidney [17,45]. Moreover, the production of H2S from D-cysteine is higher in the cerebellum than in other regions of the brain; but the production of hydrogen sulfide in the kidney is 7 times greater than in the cerebellum. The generation of H2S from D-cysteine is 80 times greater than from L-cysteine in the kidney [17,45]. D-Cysteine may have therapeutic potential. Moreover, it is less toxic than L-cysteine [17]. Administration of D-cysteine protects primary cultures of cerebellar neurons from the oxidative stress by hydrogen peroxide (H2O2) and attenuates ischemia–reperfusion injury in the kidney more than L-cysteine [45]. Recently, Kimura [17] has demonstrated that the production of H2S by CSE and the 3MST/CAT pathway may be regulated by Ca2+. In the steady state, low intracellular concentrations of Ca2+, CSE and 3MST/ CAT pathway produce H2S. When cells are stimulated and the intracellular level of Ca2+ is increased by Ca2+ influx and/or Ca2+ release from the intracellular stores, the generation of hydrogen sulfide by CSE is decreased by approximately 50% and that via 3MST/CAT pathway is stopped [17]. 3. Hydrogen sulfide as a signaling molecule

In mammalian cells, endogenous H2S is synthesized by four enzymes: cystathionine γ-lyase (CSE, EC 4.4.1.1), cystathionine βsynthase (CBS, EC 4.2.1.22), cysteine aminotransferase (CAT, EC 2.6.1.3) and 3-mercaptopyruvate sulfurtransferase (MST, EC 2.8.1.2). These enzymes are involved in the transsulfuration and reverse transsulfuration pathways as described earlier [10,18,34–37]. CBS (the main H2S-producing enzyme in the central nervous system) and CSE (presents in the vasculature, liver and kidney) are the enzymes using amino acids: L-cysteine (which is synthesized from L-methionine through the transsulfuration), L-homocysteine and L-cystathionine to produce hydrogen sulfide with pyridoxal 5′ phosphate (vitamin B6) as a cofactor [10,37–42]. The level of CBS is low in the embryonic brain, but it significantly increases from the late prenatal to the early postnatal period and then declines in the adult brains [43,44]. CBS expression is associated with the generation and differentiation of the lineage in

Hydrogen sulfide as a signaling molecule is involved in cell signal transduction in the nervous system, the circulatory system, as well as in many organs [47–58]. H2S exerts powerful effects on smooth muscle cells, inflammatory cells, endothelial cells, nuclear transcription factors, endoplasmic reticulum and mitochondria [59–61]. Hong et al. [62] demonstrated that H2S promotes proliferation and migration of human colon cancer SW 480 cells in vitro; and the mechanisms of its action may involve up-regulation of SIRT1 expression. In colorectal and ovarian cancers, an increase in the intratumor synthesis of H2S by CBS plays an important function in promoting the cellular bioenergetics, proliferation and migration of cancer cells [63]. H2S upregulates Porphyromonas gingivalis lipopolysaccharide-induced expression of Il-6 and Il-8 in periodontal fibroblast via activation of nuclear factor-kappa B signaling, which may promote the development of periodontitis [64]. 3.1. H2S as a gasotransmitter in cardiovascular system

Fig. 1. Different forms of hydrogen sulfide in aqueous (H2S and hydrosulfide anion (HS−)) and gaseous phase (H2S) [30,131; modified].

Preclinical experiments concerning cardiovascular illnesses have shown that the administration of physiological or pharmacological concentrations of H2S protects blood vessels, attenuates myocardial injury, regulates blood pressure and limits inflammation [61]. H2S showing activity in the circulatory system causes dilation of blood vessels, because H2S functions as an endothelial-derived hyperpolarizing factor (EDHF) and its vasorelaxant activity is ascribed to activation of KATP channels [9]. KATP channels are widely distributed in mitochondrial and plasma membranes [9]. KATP-sensitive potassium channels are found in many structures, i.e. in smooth muscle cells of blood vessels. H2S through impact on the KATP channels affect contractility of smooth muscle of the blood, regulating blood pressure. Opening the channels KATP protects against excessive contraction of smooth muscle cells and lowers

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Fig. 2. Pathways of endogenous H2S synthesis from L- and D-cysteine [17,44; modified].

blood pressure [9,22]. Activation of KATP channel is associated with persulfidation at Cys34 in the pore-forming Kir6.1 subunit [9,65]. Modulation of KATP channel activity by hydrogen sulfide is not only important for myocardial protection against ischemia/reperfusion injury [66], but also for other diseases or pathological processes, including inflammation process [67]. Results of Cooper and Brown [68] have demonstrated that H2S that may act as an inhibitor of cytochrome c oxidase results in reduced ATP levels, which activate KATP channels. It is known that hydrogen sulfide is also a modulator of other channels, i.e. Ca2+-sensitive K+ channel, L-type and T-type Ca2+ channels, and chloride channels [9]. In addition, the voltage-dependent calcium channels, L-type are inactivated leading to relaxation of the cells and increase in light of the blood vessels, as a result of a reduction in the concentrations of free ion Ca2+ in the cells. H2S, as opposed to nitric oxide and carbon monoxide demonstrates vasodilation activity regardless of the signaling pathway of protein kinase G, and this mechanism is independent of cGMP-mediated pathway [69,70]. H2S can also constrict blood vessels of light, which is confirmed by a study carried out on mouse and rat animal models. This phenomenon occurs at low concentrations of this factor [71,72]. Chronic shortage of hydrogen sulfide has its share in the development of hypertension. Experiments on animal models showed that in rats, which had spontaneous hypertension (SHR), the level of hydrogen sulfide and gene expression and activity of the CSE was reduced. Inhibition of CSE activity, using calcium-propargylglycine, results in a reduced synthesis and the concentration of H2S and increasing blood pressure. H2S plays an important role in maintaining the proper tension of the blood vessels, and exogenous H2S protects against the development of hypertension [71,73]. Some studies indicate that H2S causes apoptosis of human aortic smooth muscle cells [74,75]. Exogenous H2S induces apoptosis through activation of the mitogen activated protein kinase (MAPK) pathway [73, 74]. Other in vivo experiments have reported the pro-angiogenic property of H2S in endothelial cells, probably via phosphoinositide 3-kinase pathway [18]. The results of Castro-Piedras and Perez-Zaghbi [76] have demonstrated that H2S reduces calcium level through inositol1,4,5-trisphosphate receptors and relaxes airway smooth muscle. Mazza et al. [77] suggest that S-sulfhydration of cardiac proteins and Akt/endothelial nitric oxide synthase (eNOS) are involved in cardiac relaxation induced by H2S. The pathogenesis of cardiovascular diseases is associated with the modulation of hemostasis. However, the effect of H2S on hemostatic process is not still well known. The recent experiments have shown that H2S may modulate properties and functions of different

elements of hemostasis, including blood platelets and plasma, i.e. plasma proteins — fibrinogen [17,78–81]. Anti-aggregatory, anti-adhesion or anti-coagulatory activity of H2S was reported by various authors [80–84]. Anti-platelet properties of hydrogen sulfide may involve different mechanisms, i.e. S-sulfhydration of blood platelet proteins [84], the decrease of calcium levels in platelets [84] and the decrease of superoxide anion (O− 2 •) that may behave as second messengers and may regulate platelet functions (Fig. 3) [80,85]. The experiments of Kram et al. [79] showed that H2S has the anti-thrombotic action by an upregulation of NO• synthesis. Mazza et al. [77] suggest that H2S induces vasoconstriction by scavenging endothelial nitric oxide. Koenitzer et al. [86] demonstrated that vasorelaxatory action of hydrogen sulfide may involve cyclooxygenase-generated prostaglandins. Wang et al. [87] observed the correlation between endogenous H2S and atherosclerosis. Hydrogen sulfide has anti-atherosclerotic action by attenuating oxidative stress, reducing blood platelet activation, reducing inflammation process and preventing proliferation of vascular smooth muscle cells [18,88,89]. Results of Palinkas et al. [90] showed that endogenous H2S levels are likely to inhibit the activity of circulating and endothelium bound myeloperoxidase (a major player in promoting inflammatory oxidative stress). Qiao et al. [88] reported that hydrogen sulfide suppressed vascular smooth muscle cell (VSMC) proliferation in various ways (Fig. 4). The anti-atherogenic property of H2S was mainly based on the use of NaHS as H2S donor, but recent experiments have reported that NaHS releases hydrogen sulfide too rapidly (within seconds) [10]. Moreover, NaHS has dramatic effects on protein structure as it is enriched with polysulfides able to cleave intramolecular disulfide bonds [32]. H2S has a protective functions in hyperhomocysteinemia [91,92]. More information about the role of H2S in hemostasis has been described by Olas [18]. Recently, Zhu et al. [93] have suggested that endogenous sulfur dioxide (SO2), which is produced in the cardiovascular system, may be a bioactive compound regulating the physiological properties, including cardiovascular oxidative stress. 3.2. H2S as a signaling molecule in the nervous system Hydrogen sulfide as a signaling molecule plays an important role in regulating the function of the nervous system. In the central nervous system, hydrogen sulfide is involved in physiological processes, i.e. neuroprotection [51,94–96] and neurotransmission in various models [97–99]. Studies using, H2S inhalation demonstrated a neuroprotective action in a mouse model of Parkinson's disease [100]. Hydrogen sulfide may be involved in protecting neurons from apoptosis and degeneration [101]. Moreover, the mechanisms underlying the neuroprotective

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Fig. 3. Hypothetic anti-platelet mechanism of H2S action.

effects of H2S appear to include also anti-inflammation action and upregulation antioxidative enzymes [96]. Results of Lu et al. [102] indicate that hydrogen sulfide regulates intracellular pH in microglial cells and it limits the damage of activated microglia at the site of injury providing a neuroprotective function [101]. It is known that H2S inhibits cytochrome c oxidase or causes excessive NMDA receptor stimulation (leading to the death of neurons), via the secondary transmitter cAMP. NMDA receptor is built of the three subunits of NMDAR1, NMDAR2A and NMDAR2B. Endogenous ligands of the receptor include: acid, N-methyl-D-aspartic (NMDA), and the glutamic acid. After joining glutamate receptor subunit phosphorylation occurs inside the NMDAR1 ion channel by protein kinase A (PKA) which activity is dependent on the cAMP. As a result, followed by the opening of the channel and the influx of ions of Ca2+ is observed. In next step, the signal pathway is changing the long-term strengthening of synaptic, which is associated with increasing the efficiency of the conduction of nerve impulses across synapses. Hydrogen sulfide also affects the function of the hypothalamic–pituitary–adrenal glands. H2S reduces the stimulated by potassium hormone release by the hypothalamus. H2S is a negative regulator of the hypothalamic–pituitary–adrenal glands. This compound also affects intracellular stores of Ca2 +, stimulating their release to the inside of the cells causes excitation of neurons [97, 99,103–106]. Recently, it has been observed that hydrogen sulfide reduces cysteine disulfide bond of NMDA receptor to enhance its activity [17]. Subsequently, H2S-derived polysulfides (H2Sn) enhance the activity by generating bound sulfane sulfur (sulfurhydrate or sulfurate) in cysteine residues of the receptors. H2Sn also activates channels in

astrocytes to increase the intracellular concentrations of Ca2+, which facilitate the release of serine that enhances the activity of NMDA receptors [44]. H2S-derived potential signaling molecules such as HSNO have also been identified [107]. Wang et al. [108] showed involvement of H2S in neuronal cell differentiation. Other authors suggest that H2S protects neurons from oxidative stress. In addition, hydrogen sulfide reduces the level of reactive oxygen species (ROS) [17] and reduces the accumulation of lipid peroxidation products [103]. H2S inhibits the biological activity of peroxynitrite (ONOO−), which is formed in the reaction of nitric oxide with superoxide anion. Superoxide anion reacts rapidly with NO• in an aqueous solution (k = 3.7 × 107 M−1 s−1) to form the peroxynitrite anion, which in turn decomposes to HO• at neutral pH [109]. ONOO− induces lipid peroxidation, oxidation of thiols, and electron transport chain imparts in the mitochondria. Activity of ONOO− stated in neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's disease, or amyotrophic lateral sclerosis. ONOO− may induce nitration of phenolic groups in tryptophan and tyrosine in proteins. Peroxynitrite particularly strongly nitrates tyrosine, and consequently a 3-nitrotyrosine is formed. Protective effect of H2S is related with the inhibiting effect of ONOO− on tyrosine. Activity of H2S is compared to the glutathione (GSH), which is considered to be a key factor in protecting cells against ONOO−. The level of H2S in these diseases is reduced, leading to an increased activity of ONOO− and degeneration of neurons [110,111]. Hydrogen sulfide inhibits the activity of other reactive oxygen species, reactive nitrogen species (RNS) or chlorine, i.e. hypochlorous acid (HOCl) (Fig. 5). HOCl is formed in the reaction of hydrogen peroxide with chloride anion (Cl−), and the process is catalyzed by myeloperoxidase. HOCl is toxic to neurons, interacts with tyrosine, like ONOO− causing the formation of 3-chlorotyrosine. However, H2S significantly reduces the toxic activity of HOCl, through its elimination before there will be the neurodegenerative changes [106,111,112]. H2S protects neuroblastoma cells from oxidative/nitrative stress induced by ONOO− or HOCl [111,112]. Other authors found that hydrogen sulfide may protect retinal neurons from light-stimulated degeneration [17,113]. Hydrogen sulfide increases the concentration of the reduced form of glutathione by enhancing the activity of cysteine transporter, cysteine/ glutamate antiporter [17] and γ-glutamylcysteine synthetase (γ-GCS) [17,114].

4. Role of garlic compounds in the cardiovascular system

Fig. 4. The effect of H2S on inhibition of vascular structural remodeling [88; modified]. ERK — extracellular signal-regulated kinase, MAPK — mitogen activated protein kinase.

In recent years there have been many pre-clinical, clinical and in vitro experiments, which focus on the protective properties of garlic (Allium sativum L.) against different disorders, especially cardiovascular

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of garlic come from hydrogen sulfide derived from allicin or di-/tri-sulfide. Hydrogen sulfide mediates the vasoactivity of garlic-derived organic polysulfides [10,40,125]. Not only di- and tri-sulfide, but also S-allylcysteine are natural plant-derived compounds which are the precursors of H2S (Fig. 6) [126]. S-allylcysteine exhibits a range of cardioprotective actions, which include the reduction of blood platelet aggregation [122,123,127]. It has known that di-/tri-sulfide modulates the interaction between leukocyte and endothelial cells through the protein kinase A and enhances eNOS phosphorylation and stability [10,127–129]. Giustarini et al. [130] have demonstrated that H2S-releasing aspirin (ACS14) modulates thiol homeostasis. ACS14 induces a significant increase of various thiols, including GSH, cysteine and hydrogen sulfide.

5. Conclusion

Fig. 5. The neuroprotection properties of hydrogen sulfide by the interaction with reactive oxygen species (ROS), reactive nitrogen species (RNS) and hypochlorous acid (HOCl) [106; modified].

diseases [115]. Garlic not only exerts many positive healing effects in the cardiovascular system (it decreases cholesterol's concentration and blood pressure, and reduces blood platelet aggregation), but also has antifungal, antiviral and antibacterial activities [116–118]. For hundreds of years, garlic is an affective dietary supplement against atherosclerosis. Various authors suggest that regular consumption of cooked blanched garlic leaves may prevent cardiovascular thrombotic diseases [119,120]. Results of Wang and Di [119] have demonstrated that the cooked blanched garlic leaf juice may inhibit blood platelet aggregation in vivo and in vitro; the inhibition of aggregation pathway mainly is blocking the combination of fibrinogen with αIIbβ3 receptor on blood platelets. Garlic contains more than 2000 biologically active substances [115, 121], including different sulfur-containing compounds: allin, allicin, allyl-metane-thiosulfinian, diallyl disulfide, diallyl trisulfide, allyl trisulfide, S-allyl mercaptocysteine, ajoena and S-allyl cysteine, which may be the source of hydrogen sulfide (an important therapeutic compound in cardiovascular illnesses) [55,117,122–124]. Medicinal applications

Different studies demonstrated the important role of hydrogen sulfide in the body. Hydrogen sulfide, like other gaseous signal transducers has the protective and modulatory action in the circulatory system and the nervous system. H2S shows protective effect for ischemic heart disease or hypertension, and protects against ischemia of the brain. H2S acts also as an anti-oxidant and regulates the axis hypothalamus–pituitary–adrenal glands. However, mechanisms of H2S action have not yet well known, although their understanding will be key. Further experiences are needed for a thorough knowledge and understanding of all the mechanisms of its action.

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Hydrogen sulfide in signaling pathways.

For a long time hydrogen sulfide (H₂S) was considered a toxic compound, but recently H₂S (at low concentrations) has been found to play an important f...
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