Table of Contents

    Topic review

    Hydrogen Sulfide

    Subjects: Others
    View times: 108
    Submitted by: Angeles Aroca


    Hydrogen sulfide is a colorless gas with a characteristic smell like rotten eggs. It is flammable and corrosive at very high concentrations. It has been always considered a toxic molecule, but more recently, it has been proved it is a metabolite and signaling molecule in biological tissues that regulates many physiological processes.

    1. Introduction

    Hydrogen sulfide (H2S) has always been considered toxic, but a huge number of articles published more recently showed the beneficial biochemical properties of its endogenous production throughout all regna.

    2. Physiological Role

    During the past century, H2S was thought to only be a toxic molecule, and it was not until 1990 that Kimura and coworkers revealed its role in essential functions in human physiology, opening a new emerging field in life science [1]. The first physiological assay published in 1996 demonstrated that H2S acts as an endogenous neuromodulator [2]. The participation of H2S in many physiological and pathological processes in animals has been described over the last two decades, including its role in the regulation of cell proliferation, apoptosis, inflammatory processes, hypoxia, neuromodulation, and cardioprotection [3][4][5]. Therefore, H2S is now accepted as playing roles as a gasotransmitter (gaseous signaling compound) that is as important as nitric oxide (NO) and carbon monoxide (CO) in mammals, and as a signaling molecule that is as important as hydrogen peroxide (H2O2) in plants [2][6][7].

    Although the first descriptions of the effects of H2S in plants were from the 1960s [8], interest in the role of H2S in plant systems arose later. It was not until the past decade that the effects of H2S were described in seed germination [9], the number and length of adventitious roots [10] and the regulation of genes involved in photosynthesis [11]. Thereafter, the protective effects of exogenous H2S against different stresses were documented, such as protection against oxidative and metal stresses [9][12][13][14][15][16][17], drought and heat tolerance [16][18], and osmotic and saline stresses [19]. Thus, publications on these dose-dependent effects of H2S have emerged, postulating H2S to be an important signaling molecule that has analogous functions in plant systems to those previously described in mammals. H2S was also shown to be a regulator of other important physiological processes in plants, such as stomatal closure/aperture [20][21][22][23]; thus, its importance in drought stress relief is due to the ability of H2S to induce stomatal closure in Arabidopsis thaliana [23][24].

    More recently, there has been increasing interest in the effect of H2S on autophagy regulation in the scientific community. In mammals, the protective effect of H2S against some of the diseases mentioned above has been linked with the regulation of autophagy [25][26]. Autophagy is a cellular catabolic pathway that is evolutionarily conserved from yeast to mammals, and it involves the digestion of cell contents to recycle nutrients or to degrade damaged or toxic components. The AMP-dependent kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways play important roles in the control of autophagy. To this end, activation of AMPK or inhibition of mTOR has been shown to activate autophagy [27]. Exposure to H2S has been shown to cause a significant increase in AMPK phosphorylation, which increases its activity and inhibits the activation of downstream targets, such as mTOR [28]. In plants, H2S was shown to inhibit autophagy by preventing ATG8 (autophagy-related ubiquitin-like protein) accumulation [29]. H2S is able to inhibit starvation-induced autophagy in Arabidopsis roots, and this repression is independent of redox conditions [30].

    The first mechanism proposed for H2S was based on its chemical properties, since this nucleophilic molecule is able to react with reactive oxygen/nitrogen species and reduce the cellular oxidative state [31][32]. In addition, H2S is able to regulate several antioxidant enzymes, such as ascorbate peroxidase (APX) [33][34][35], catalase (CAT) [36][37], superoxide dismutase (SOD) [36][38], and glutathione reductase (GR) [35], and non-enzymatic compounds, such as the glutathione anti-oxidant pool [39][40].

    The antioxidant role of H2S has been the focus of numerous studies in mammalian systems as a critical mediator of multiple pathophysiological processes [41]. In plants, the number of studies on the effects of H2S in the model plant Arabidopsis has increased in recent years; in addition, the effects of H2S in agricultural crops are relevant as an exogenous treatment to cope with economic loss due to environmental stress. The effects of exogenous (pre-)treatment with water-soluble donors of H2S have been the focus of numerous studies in several agricultural species. Fotopoulos et al. have reviewed these studies regarding the effects of H2S on plant growth, its ability to improve resistance against abiotic and biotic stress, and its positive postharvest effects [42]. Thus, a better understanding of the mechanism of action of H2S is important to fight against crop loss. This knowledge would help in agricultural sustainability and in producing the food required by the increasing world population [43].

    3. H2S Mechanism of Action

    The underlying mechanisms of H2S action are poorly understood. There is an important effect of H2S binding to heme moieties in target proteins such as cytochrome c oxidase, hemoglobin and myoglobin, among others [44]. It has, however, become widely accepted that a huge number of the processes controlled by H2S are caused by a posttranslational modification of cysteine residues called persulfidation [45][46][47]. Protein persulfidation is an oxidative posttranslational modification of cysteine residues caused by H2S, in which a thiol group (–SH) is transformed to a persulfide group (–SSH). Sulfane sulfur species, persulfides and polysulfides are more nucleophilic than H2S and therefore more effective at persulfidation [48]. Due to the intrinsic instability of persulfides and their higher reactivity than thiols, protein persulfides largely remain understudied. Nevertheless, over the last decade, study of this protein modification has become more relevant for researchers because it can affect protein function, localization inside cells, stability, and resistance to oxidative stress [7][33][49][50][51]. The broad physiological importance of persulfidation has only recently started to emerge; a proteomic analysis revealed that approximately 10–25% of liver proteins contain this modification [51], and at least 5–10% of the entire proteome may undergo persulfidation in plants [52].

    In mammals, the mechanism of action of H2S has been deeply studied since 2009, when Mustafa et al. described this new posttranslational modification [51]. By contrast, in the plant system, persulfidation has been described more recently [33], but a greater number of proteins have been shown to undergo this modification [52]. A total of 3147 proteins were found to be persulfidated in Arabidopsis leaves under physiological conditions, suggesting that this number may be higher under certain stress conditions [52]. These proteins are mainly involved in important biological pathways, such as the tricarboxylic acid cycle, glycolysis, Calvin cycle, photorespiration and autophagy. Further physiological studies of these proteins must be performed to decipher the role of persulfidation in these biological pathways. Nevertheless, initial studies in plants demonstrated that persulfidation regulates the enzymatic activity of chloroplastic glutamine synthetase (GS2), cytosolic ascorbate peroxidase (APX1), and cytosolic glyceraldehyde 3-phosphate dehydrogenase (GapC1) [33]. Persulfidation regulates the cytosolic/nuclear localization of GapC1, allowing it to likely act as a transcription factor [49]. The actin cytoskeleton and root hair growth are regulated through persulfidation of ACTIN2 [53]. Furthermore, ethylene biosynthesis is regulated by persulfidation of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO1) in tomato [54]. Recently, a peroxisomal proteome study in Arabidopsis revealed that the interplay of different PTMs such as s-nitrosation, nitration, persulfidation, and acetylation regulates redox signaling to protect proteins against oxidative damage [55]. From an evolutionary point of view, it is reasonable to assume that ancestral purple and green sulfur bacteria lived in an H2S-rich atmosphere; and therefore bacteria developed H2S-mediated signaling processes to resist oxidative stress. Similarly as peroxide (H2O2) produces ROS, persulfide (H2S2) produces RSS (reactive sulfide species), but with the difference that persulfides can be produced with several sulfur molecules (Sx) and stored [56].

    4. H2S in Human and Plant Therapies

    It is well known that sulfurous water baths were used by ancient civilizations and were known to have healing effects against particular diseases. H2S has been recognized as having anti-inflammatory, anti-bacterial, vasodilator, and anti-fungal properties owing to its sulfur content [41][57][58]. Several extracts from the genus Allium, mainly onion and garlic, and their derivatives have been used since ancient times in China as medicines to treat numerous diseases, including cancer [59], cardiovascular disease [60] and other diseases. It is known that these extracts are a source of sulfur-containing flavor compounds such as diallyl sulfide, allicin and cycloalliin, among others, and which release H2S in cells upon interaction with reductants [61][62].

    Currently, these beneficial effects are still under study to develop new strategies and therapies to treat certain diseases in mammals and to address agricultural challenges. In mammals, therapies that include H2S are used for their anti-inflammatory effects, cytoprotective properties and antiapoptotic features [63]. The aim of these therapies is to be able to use this signaling molecule in heart failure, neurodegenerative diseases and stroke, and ischemia, among others. There has recently been an increasing number of publications indicating that deficiency or excess sulfur amino acids (SAAs), namely, methionine and cysteine, in the diet affect the normal growth of animals and that it is important that SAAs are ingested at the appropriate dose [64][65], since they affect signaling in cells through H2S [66]. These amino acids are metabolized through the transsulfuration pathway, which is the one of the main sources of H2S in cells; H2S has been shown to increase the lifespan of C. elegans [67] and even humans [68].

    Nevertheless, clinical research on H2S is not easy to perform due to its toxicity, and H2S therapy is still in a preliminary preclinical stage. A bottleneck for developing gasotransmitter-based therapeutics is the lack of a safe administration drug. There are some candidate compounds for CO and NO prodrugs [69][70][71] and more interestingly, some H2S-releasing drugs are currently in clinical trials [72][73]. In a recent study, intraperitoneal injections of JK-1 (a H2S donor) were administered to mice after transverse aortic constriction and were shown to have substantial beneficial effects on renal and vascular function [74]. Another exciting approach was a high increase in the dietary intake of taurine, which boosted CSE-mediated H2S production to exert significant protective effects in atherogenesis, hypertension and heart failure [75]. However, most therapies use an increase in the dietary intake of sulfur amino acids or directly use slow-releasing H2S donors to avoid the toxicity of high H2S concentrations [76]. These therapies in mouse models can be used as models to study H2S donors in humans. A recent study revealed that persulfidation decreases with aging and that dietary/pharmacological interventions could be used to increase persulfidation and extend lifespan [77]. Moreover, a few recently published articles described the interplay between H2S, CO and NO within the gastrointestinal tract, especially in ulcer healing and prevention of non-steroidal anti-inflammatory drugs (NSAIDs)—induced gastropathy [78][79]. In addition, a novel H2S donor not only increases H2S levels, but also increases circulating NO bioavailability in heart failure patients, highlighting the crosstalk between these gasotransmitters in therapeutic trials [80].

    In plants, new therapies or strategies using H2S are being used to deal with economic losses due to fruit and vegetable ripening or crop stress resistance. It has been shown that H2S fumigation slows fruit ripening and senescence in fruits and vegetables by inducing antioxidant activities, such as ascorbate peroxidase, catalase, peroxidase, glutathione reductase, and superoxide dismutase [81][82][83]. Treatments with exogenous H2S have also been used to control the color degradation of certain horticultural vegetables and fruits by suppressing the degradation of anthocyanins [81] and downregulating some chlorophyll degradation genes [84]. Interactions between H2S and other signaling molecules, such as NO and ethylene, have also been a focus of recent investigations on the senescence of flowers or ripening of fruits. Hydrogen sulfide alleviates postharvest ripening and senescence of fruits by antagonizing the effect of ethylene [85][86]. In addition, a cooperative effect of H2S and NO has been observed on delaying the softening and decay of fruits [87], and the crosstalk between these two gasotransmitters is associated with the inhibition of ethylene biosynthesis [88].

    There is a long list of publications on the beneficial effects of H2S treatments in crops, such as enhancing resistance to metal, heat, cold, salt and drought stresses, which have been recently summarized [89]. It has been demonstrated that sulfur fertilization of crops reduces sensitivity to pathogens, in a process mediated by hydrogen sulfide [90]. H2S-induced pathogen resistance is conferred through increased expression of salicylic acid-dependent pathogen-related (PR) genes [91] and increased transcription levels of microRNA393 (MIR393) genes [16]. Another important beneficial effect of H2S treatment of crops is its influence on the modulation of photosynthesis [11] and autophagy regulation [30]. Apparently, H2S is able to regulate energy production in mitochondria, protecting against aging and increasing the lifespan of plants in a similar way as in animals [92]. All of these advantageous outcomes lead to increased yields and biomass and enhanced germination of agricultural crops after H2S administration [93][94].

    The entry is from 10.3390/antiox9070621


    1. Kimura, J. Message from the editor’s office. Muscle Nerve 1990, 13, 1095.
    2. Abe, K.; Kimura, H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J. Neurosci. Off. J. Soc. Neurosci. 1996, 16, 1066–1071.
    3. Wang, R. Gasotransmitters: Growing pains and joys. Trends Biochem. Sci. 2014, 39, 227–232.
    4. Olas, B. Hydrogen sulfide in signaling pathways. Clin. Chim. Acta Int. J. Clin. Chem. 2015, 439, 212–218.
    5. Paul, B.D.; Snyder, S.H. Modes of physiologic H2S signaling in the brain and peripheral tissues. Antioxid. Redox Signal. 2015, 22, 411–423.
    6. Martelli, A.; Testai, L.; Breschi, M.C.; Blandizzi, C.; Virdis, A.; Taddei, S.; Calderone, V. Hydrogen sulphide: Novel opportunity for drug discovery. Med. Res. Rev. 2012, 32, 1093–1130.
    7. Paul, B.D.; Snyder, S.H. H2S signalling through protein sulfhydration and beyond. Nat. Rev. Mol. Cell Biol. 2012, 13, 499–507.
    8. Rodriguez-Kabana, R.; Jordan, J.W.; Hollis, J.P. Nematodes: Biological Control in Rice Fields: Role of Hydrogen Sulfide. Science 1965, 148, 524–526.
    9. Zhang, H.; Hu, L.Y.; Hu, K.D.; He, Y.D.; Wang, S.H.; Luo, J.P. Hydrogen sulfide promotes wheat seed germination and alleviates oxidative damage against copper stress. J. Integr. Plant Biol. 2008, 50, 1518–1529.
    10. Zhang, H.; Tang, J.; Liu, X.P.; Wang, Y.; Yu, W.; Peng, W.Y.; Fang, F.; Ma, D.F.; Wei, Z.J.; Hu, L.Y. Hydrogen sulfide promotes root organogenesis in Ipomoea batatas, Salix matsudana and Glycine max. J. Integr. Plant Biol. 2009, 51, 1086–1094.
    11. Chen, J.; Wu, F.H.; Wang, W.H.; Zheng, C.J.; Lin, G.H.; Dong, X.J.; He, J.X.; Pei, Z.M.; Zheng, H.L. Hydrogen sulphide enhances photosynthesis through promoting chloroplast biogenesis, photosynthetic enzyme expression, and thiol redox modification in Spinacia oleracea seedlings. J. Exp. Bot. 2011, 62, 4481–4493.
    12. Zhang, H.; Tan, Z.Q.; Hu, L.Y.; Wang, S.H.; Luo, J.P.; Jones, R.L. Hydrogen sulfide alleviates aluminum toxicity in germinating wheat seedlings. J. Integr. Plant Biol. 2010, 52, 556–567.
    13. Wang, B.L.; Shi, L.; Li, Y.X.; Zhang, W.H. Boron toxicity is alleviated by hydrogen sulfide in cucumber (Cucumis sativus L.) seedlings. Planta 2010, 231, 1301–1309.
    14. Li, L.; Wang, Y.; Shen, W. Roles of hydrogen sulfide and nitric oxide in the alleviation of cadmium-induced oxidative damage in alfalfa seedling roots. BioMetals 2012, 25, 617–631.
    15. Sun, J.; Wang, R.; Zhang, X.; Yu, Y.; Zhao, R.; Li, Z.; Chen, S. Hydrogen sulfide alleviates cadmium toxicity through regulations of cadmium transport across the plasma and vacuolar membranes in Populus euphratica cells. Plant Physiol. Biochem. PPB 2013, 65, 67–74.
    16. Shen, J.; Xing, T.; Yuan, H.; Liu, Z.; Jin, Z.; Zhang, L.; Pei, Y. Hydrogen Sulfide Improves Drought Tolerance in Arabidopsis thaliana by MicroRNA Expressions. PLoS ONE 2013, 8, e77047.
    17. Fang, H.; Liu, Z.; Jin, Z.; Zhang, L.; Liu, D.; Pei, Y. An emphasis of hydrogen sulfide-cysteine cycle on enhancing the tolerance to chromium stress in Arabidopsis. Environ. Pollut. (Barking Essex 1987) 2016, 213, 870–877.
    18. Li, Z.G.; Gong, M.; Xie, H.; Yang, L.; Li, J. Hydrogen sulfide donor sodium hydrosulfide-induced heat tolerance in tobacco (Nicotiana tabacum L) suspension cultured cells and involvement of Ca(2+) and calmodulin. Plant Sci. Int. J. Exp. Plant Biol. 2012, 185, 185–189.
    19. Shi, H.; Ye, T.; Chan, Z. Exogenous application of hydrogen sulfide donor sodium hydrosulfide enhanced multiple abiotic stress tolerance in bermudagrass (Cynodon dactylon (L). Pers.). Plant Physiol. Biochem. 2013, 71, 226–234.
    20. Papanatsiou, M.; Scuffi, D.; Blatt, M.R.; Garcia-Mata, C. Hydrogen sulfide regulates inward-rectifying k+ channels in conjunction with stomatal closure. Plant Physiol. 2015, 168, 29–35.
    21. Scuffi, D.; Nunez, A.; Laspina, N.; Gotor, C.; Lamattina, L.; Garcia-Mata, C. Hydrogen sulfide generated by L-cysteine desulfhydrase acts upstream of nitric oxide to modulate ABA-dependent stomatal closure. Plant Physiol. 2014, 166, 2065–2076.
    22. Lisjak, M.; Srivastava, N.; Teklic, T.; Civale, L.; Lewandowski, K.; Wilson, I.; Wood, M.E.; Whiteman, M.; Hancock, J.T. A novel hydrogen sulfide donor causes stomatal opening and reduces nitric oxide accumulation. Plant Physiol. Biochem. 2010, 48, 931–935.
    23. Garcia-Mata, C.; Lamattina, L. Hydrogen sulphide, a novel gasotransmitter involved in guard cell signalling. New Phytol. 2010, 188, 977–984.
    24. Jin, Z.; Xue, S.; Luo, Y.; Tian, B.; Fang, H.; Li, H.; Pei, Y. Hydrogen sulfide interacting with abscisic acid in stomatal regulation responses to drought stress in Arabidopsis. Plant Physiol. Biochem. 2013, 62, 41–46.
    25. Wu, Y.C.; Wang, X.J.; Yu, L.; Chan, F.K.; Cheng, A.S.; Yu, J.; Sung, J.J.; Wu, W.K.; Cho, C.H. Hydrogen sulfide lowers proliferation and induces protective autophagy in colon epithelial cells. PLoS ONE 2012, 7, e37572.
    26. Zhang, M.; Shan, H.; Chang, P.; Wang, T.; Dong, W.; Chen, X.; Tao, L. Hydrogen sulfide offers neuroprotection on traumatic brain injury in parallel with reduced apoptosis and autophagy in mice. PLoS ONE 2014, 9, e87241.
    27. Diaz-Troya, S.; Perez-Perez, M.E.; Florencio, F.J.; Crespo, J.L. The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 2008, 4, 851–865.
    28. Gwinn, D.M.; Shackelford, D.B.; Egan, D.F.; Mihaylova, M.M.; Mery, A.; Vasquez, D.S.; Turk, B.E.; Shaw, R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 2008, 30, 214–226.
    29. Álvarez, C.; Garcia, I.; Moreno, I.; Perez-Perez, M.E.; Crespo, J.L.; Romero, L.C.; Gotor, C. Cysteine-generated sulfide in the cytosol negatively regulates autophagy and modulates the transcriptional profile in Arabidopsis. Plant Cell 2012, 24, 4621–4634.
    30. Laureano-Marin, A.M.; Moreno, I.; Romero, L.C.; Gotor, C. Negative Regulation of Autophagy by Sulfide Is Independent of Reactive Oxygen Species. Plant Physiol. 2016, 171, 1378–1391.
    31. Kabil, O.; Banerjee, R. Redox biochemistry of hydrogen sulfide. J. Biol. Chem. 2010, 285, 21903–21907.
    32. Fukuto, J.M.; Carrington, S.J.; Tantillo, D.J.; Harrison, J.G.; Ignarro, L.J.; Freeman, B.A.; Chen, A.; Wink, D.A. Small molecule signaling agents: The integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species. Chem. Res. Toxicol. 2012, 25, 769–793.
    33. Aroca, A.; Serna, A.; Gotor, C.; Romero, L.C. S-sulfhydration: A cysteine posttranslational modification in plant systems. Plant Physiol. 2015, 168, 334–342.
    34. Shan, C.; Wang, T.; Zhou, Y.; Wang, W. Hydrogen sulfide is involved in the regulation of ascorbate and glutathione metabolism by jasmonic acid in Arabidopsis thaliana. Biol. Plant. 2018, 62, 188–193.
    35. Shan, C.; Zhang, S.; Zhou, Y. Hydrogen sulfide is involved in the regulation of ascorbate-glutathione cycle by exogenous ABA in wheat seedling leaves under osmotic stress. Cereal Res. Commun. 2017, 45, 411–420.
    36. Xie, Z.-Z.; Liu, Y.; Bian, J.-S. Hydrogen Sulfide and Cellular Redox Homeostasis. Oxid. Med. Cell. Longev. 2016, 2016, 6043038.
    37. Yu, L.-X.; Zhang, C.-J.; Shang, H.-Q.; Wang, X.-F.; Wei, M.; Yang, F.-J.; Shi, Q.-H. Exogenous Hydrogen Sulfide Enhanced Antioxidant Capacity, Amylase Activities and Salt Tolerance of Cucumber Hypocotyls and Radicles. J. Integr. Agric. 2013, 12, 445–456.
    38. Li, Z.G. Analysis of some enzymes activities of hydrogen sulfide metabolism in plants. Methods Enzym. 2015, 555, 253–269.
    39. Kimura, Y.; Goto, Y.; Kimura, H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid. Redox Signal. 2010, 12, 1–13.
    40. Singh, V.P.; Singh, S.; Kumar, J.; Prasad, S.M. Hydrogen sulfide alleviates toxic effects of arsenate in pea seedlings through up-regulation of the ascorbate-glutathione cycle: Possible involvement of nitric oxide. J. Plant Physiol. 2015, 181, 20–29.
    41. Stein, A.; Bailey, S.M. Redox biology of hydrogen sulfide: Implications for physiology, pathophysiology, and pharmacology. Redox Biol. 2013, 1, 32–39.
    42. Fotopoulos, V.; Christou, A.; Antoniou, C.; Manganaris, G.A. REVIEW ARTICLE Hydrogen sulphide: A versatile tool for the regulation of growth and defence responses in horticultural crops. J. Hortic. Sci. Biotechnol. 2015, 90, 227–234.
    43. Godfray, H.C.; Beddington, J.R.; Crute, I.R.; Haddad, L.; Lawrence, D.; Muir, J.F.; Pretty, J.; Robinson, S.; Thomas, S.M.; Toulmin, C. Food security: The challenge of feeding 9 billion people. Science 2010, 327, 812–818.
    44. Ríos-González, B.B.; Román-Morales, E.M.; Pietri, R.; López-Garriga, J. Hydrogen sulfide activation in hemeproteins: The sulfheme scenario. J. Inorg. Biochem. 2014, 133, 78–86.
    45. Filipovic, M.R. Persulfidation (S-sulfhydration) and H2S. Handb. Exp. Pharmacol. 2015, 230, 29–59.
    46. Mustafa, A.K.; Sikka, G.; Gazi, S.K.; Steppan, J.; Jung, S.M.; Bhunia, A.K.; Barodka, V.M.; Gazi, F.K.; Barrow, R.K.; Wang, R.; et al. Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ. Res. 2011, 109, 1259–1268.
    47. Nishida, M.; Sawa, T.; Kitajima, N.; Ono, K.; Inoue, H.; Ihara, H.; Motohashi, H.; Yamamoto, M.; Suematsu, M.; Kurose, H.; et al. Hydrogen sulfide anion regulates redox signaling via electrophile sulfhydration. Nat. Chem. Biol. 2012, 8, 714–724.
    48. John I. Toohey; Sulfur signaling: Is the agent sulfide or sulfane?. Analytical Biochemistry 2011, 413, 1-7, 10.1016/j.ab.2011.01.044.
    49. Aroca, A.; Schneider, M.; Scheibe, R.; Gotor, C.; Romero, L.C. Hydrogen Sulfide Regulates the Cytosolic/Nuclear Partitioning of Glyceraldehyde-3-Phosphate Dehydrogenase by Enhancing its Nuclear Localization. Plant Cell Physiol. 2017, 58, 983–992.
    50. Kimura, H. Physiological Roles of Hydrogen Sulfide and Polysulfides. Handb. Exp. Pharmacol. 2015, 230, 61.
    51. Mustafa, A.K.; Gadalla, M.M.; Sen, N.; Kim, S.; Mu, W.; Gazi, S.K.; Barrow, R.K.; Yang, G.; Wang, R.; Snyder, S.H. H2S Signals Through Protein S-Sulfhydration. Sci. Signal. 2009, 2, ra72.
    52. Angeles Aroca; Juan M Benito; Cecilia Gotor; Luis C Romero; Persulfidation proteome reveals the regulation of protein function by hydrogen sulfide in diverse biological processes in Arabidopsis. Journal of Experimental Botany 2017, 68, 4915-4927, 10.1093/jxb/erx294.
    53. Li, J.; Chen, S.; Wang, X.; Shi, C.; Liu, H.; Yang, J.; Shi, W.; Guo, J.; Jia, H. Hydrogen Sulfide Disturbs Actin Polymerization via S-Sulfhydration Resulting in Stunted Root Hair Growth. Plant Physiol. 2018, 178, 936–949.
    54. Jia, H.; Chen, S.; Liu, D.; Liesche, J.; Shi, C.; Wang, J.; Ren, M.; Wang, X.; Yang, J.; Shi, W.; et al. Ethylene-Induced Hydrogen Sulfide Negatively Regulates Ethylene Biosynthesis by Persulfidation of ACO in Tomato Under Osmotic Stress. Front. Plant Sci. 2018, 9, 1517.
    55. Sandalio, L.M.; Gotor, C.; Romero, L.C.; Romero-Puertas, M.C. Multilevel Regulation of Peroxisomal Proteome by Post-Translational Modifications. Int. J. Mol. Sci. 2019, 20, 4881.
    56. Olson, K.R. Hydrogen sulfide, reactive sulfur species and coping with reactive oxygen species. Free Radic. Biol. Med. 2019, 140, 74–83.
    57. Matz, H.; Orion, E.; Wolf, R. Balneotherapy in dermatology. Dermatol. Ther. 2003, 16, 132–140.
    58. Moss, G.A. Water and health: A forgotten connection? Perspect. Public Health 2010, 130, 227–232.
    59. Omar, S.H.; Al-Wabel, N.A. Organosulfur compounds and possible mechanism of garlic in cancer. Saudi Pharm. J. SPJ Off. Publ. Saudi Pharm. Soc. 2010, 18, 51–58.
    60. Banerjee, S.K.; Maulik, S.K. Effect of garlic on cardiovascular disorders: A review. Nutr. J. 2002, 1, 4.
    61. Benavides, G.A.; Squadrito, G.L.; Mills, R.W.; Patel, H.D.; Isbell, T.S.; Patel, R.P.; Darley-Usmar, V.M.; Doeller, J.E.; Kraus, D.W. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl. Acad. Sci. USA 2007, 104, 17977–17982. [
    62. Rose, P.; Moore, P.K.; Whiteman, M.; Zhu, Y.Z. An Appraisal of Developments in Allium Sulfur Chemistry: Expanding the Pharmacopeia of Garlic. Molecules 2019, 24, 4006.
    63. Zhang, J.-Y.; Ding, Y.-P.; Wang, Z.; Kong, Y.; Gao, R.; Chen, G. Hydrogen sulfide therapy in brain diseases: From bench to bedside. Med. Gas Res. 2017, 7, 113–119.
    64. Bin, P.; Huang, R.; Zhou, X. Oxidation Resistance of the Sulfur Amino Acids: Methionine and Cysteine. BioMed Res. Int. 2017, 2017, 6.
    65. Yoshida, S.; Yamahara, K.; Kume, S.; Koya, D.; Yasuda-Yamahara, M.; Takeda, N.; Osawa, N.; Chin-Kanasaki, M.; Adachi, Y.; Nagao, K.; et al. Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice. Aging Cell 2018, 17, e12796.
    66. Kabil, O.; Vitvitsky, V.; Banerjee, R. Sulfur as a Signaling Nutrient Through Hydrogen Sulfide. Annu. Rev. Nutr. 2014, 34, 171–205.
    67. Miller, D.L.; Roth, M.B. Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 2007, 104, 20618–20622.
    68. Dong, Z.; Sinha, R.; Richie, J.P., Jr. Disease prevention and delayed aging by dietary sulfur amino acid restriction: Translational implications. Ann. N. Y. Acad. Sci. 2018, 1418, 44–55.
    69. Ji, X.; Pan, Z.; Li, C.; Kang, T.; De La Cruz, L.K.C.; Yang, L.; Yuan, Z.; Ke, B.; Wang, B. Esterase-Sensitive and pH-Controlled Carbon Monoxide Prodrugs for Treating Systemic Inflammation. J. Med. Chem. 2019, 62, 3163–3168.
    70. Liang, H.; Nacharaju, P.; Friedman, A.; Friedman, J.M. Nitric oxide generating/releasing materials. Future Sci. OA 2015, 1, FSO54.
    71. Qin, L.; Gao, H. The application of nitric oxide delivery in nanoparticle-based tumor targeting drug delivery and treatment. Asian J. Pharm. Sci. 2019, 14, 380–390.
    72. Wallace, J.L.; Nagy, P.; Feener, T.D.; Allain, T.; Ditrói, T.; Vaughan, D.J.; Muscara, M.N.; de Nucci, G.; Buret, A.G. A proof-of-concept, Phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide-releasing anti-inflammatory drug. Br. J. Pharmacol. 2020, 177, 769–777.
    73. Wallace, J.L.; Vaughan, D.; Dicay, M.; MacNaughton, W.K.; de Nucci, G. Hydrogen Sulfide-Releasing Therapeutics: Translation to the Clinic. Antioxid. Redox Signal. 2018, 28, 1533–1540.
    74. Nabeebaccus, A.A.; Shah, A.M. Hydrogen Sulfide Therapy Promotes Beneficial Systemic Effects in Experimental Heart Failure. JACC Basic Transl. Sci. 2018, 3, 810–812.
    75. DiNicolantonio, J.J.; OKeefe, J.H.; McCarty, M.F. Boosting endogenous production of vasoprotective hydrogen sulfide via supplementation with taurine and N-acetylcysteine: A novel way to promote cardiovascular health. Open Heart 2017, 4, e000600.
    76. Zhou, J.; Lv, X.-H.; Fan, J.-J.; Dang, L.-Y.; Dong, K.; Gao, B.; Song, A.-Q.; Wu, W.-N. GYY4137 Promotes Mice Feeding Behavior via Arcuate Nucleus Sulfur-Sulfhydrylation and AMPK Activation. Front. Pharmacol. 2018, 9, 966.
    77. Zivanovic, J.; Kouroussis, E.; Kohl, J.B.; Adhikari, B.; Bursac, B.; Schott-Roux, S.; Petrovic, D.; Miljkovic, J.L.; Thomas-Lopez, D.; Jung, Y.; et al. Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration. Cell Metab. 2019, 30, 1152–1170.e13.
    78. Wallace, J.L.; Dicay, M.; McKnight, W.; Martin, G.R. Hydrogen sulfide enhances ulcer healing in rats. FASEB J. 2007, 21, 4070–4076.
    79. Magierowski, M.; Magierowska, K.; Hubalewska-Mazgaj, M.; Sliwowski, Z.; Ginter, G.; Pajdo, R.; Chmura, A.; Kwiecien, S.; Brzozowski, T. Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre-existing gastric ulcers. Br. J. Pharmacol. 2017, 174, 3654–3668.
    80. Polhemus, D.J.; Li, Z.; Pattillo, C.B.; Gojon, G., Sr.; Gojon, G., Jr.; Giordano, T.; Krum, H. A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients. Cardiovasc. Ther. 2015, 33, 216–226.
    81. Hu, H.; Shen, W.; Li, P. Effects of hydrogen sulphide on quality and antioxidant capacity of mulberry fruit. Int. J. Food Sci. Technol. 2014, 49, 399–409.
    82. Hu, H.; Liu, D.; Li, P.; Shen, W. Hydrogen sulfide delays leaf yellowing of stored water spinach (Ipomoea aquatica) during dark-induced senescence by delaying chlorophyll breakdown, maintaining energy status and increasing antioxidative capacity. Postharvest Biol. Technol. 2015, 108, 8–20.
    83. Zhu, L.; Wang, W.; Shi, J.; Zhang, W.; Shen, Y.; Du, H.; Wu, S. Hydrogen sulfide extends the postharvest life and enhances antioxidant activity of kiwifruit during storage. J. Sci. Food Agric. 2014, 94, 2699–2704.
    84. Li, Z.R.; Hu, K.; Zhang, F.Q.; Li, S.P.; Hu, L.Y.; Li, Y.H.; Wang, S.H.; Zhang, H. Hydrogen Sulfide Alleviates Dark-promoted Senescence in Postharvest Broccoli. HortScience 2015, 50, 416–420.
    85. Yao, G.-F.; Wei, Z.-Z.; Li, T.-T.; Tang, J.; Huang, Z.-Q.; Yang, F.; Li, Y.-H.; Han, Z.; Hu, F.; Hu, L.-Y.; et al. Modulation of Enhanced Antioxidant Activity by Hydrogen Sulfide Antagonization of Ethylene in Tomato Fruit Ripening. J. Agric. Food Chem. 2018, 66, 10380–10387.
    86. Ge, Y.; Hu, K.D.; Wang, S.S.; Hu, L.Y.; Chen, X.Y.; Li, Y.H.; Yang, Y.; Yang, F.; Zhang, H. Hydrogen sulfide alleviates postharvest ripening and senescence of banana by antagonizing the effect of ethylene. PLoS ONE 2017, 12, e0180113.
    87. Chang, Z.; Jingying, S.; Liqin, Z.; Changle, L.; Qingguo, W. Cooperative effects of hydrogen sulfide and nitric oxide on delaying softening and decay of strawberry. Int. J. Agric. Biol. Eng. 2014, 7, 114–122.
    88. Mukherjee, S. Recent advancements in the mechanism of nitric oxide signaling associated with hydrogen sulfide and melatonin crosstalk during ethylene-induced fruit ripening in plants. Nitric Oxide Biol. Chem. Off. J. Nitric Oxide Soc. 2019, 82, 25–34.[Google Scholar] [CrossRef]
    89. Zhong-Guang Li; Xiong Min; Zhi-Hao Zhou; Hydrogen Sulfide: A Signal Molecule in Plant Cross-Adaptation. Frontiers in Plant Science 2016, 7, 1621, 10.3389/fpls.2016.01621.
    90. Elke Bloem; Anja Riemenschneider; Julia Volker; Jutta Papenbrock; Ahlert Schmidt; Ioana Salac; Silvia Haneklaus; Ewald Schnug; Sulphur supply and infection with Pyrenopeziza brassicae influence L-cysteine desulphydrase activity in Brassica napus L.. Journal of Experimental Botany 2004, 55, 2305-2312, 10.1093/jxb/erh236.
    91. Consolación Álvarez; M. Ángeles Bermúdez; Luis C. Romero; Cecilia Gotor; Irene García; Cysteine homeostasis plays an essential role in plant immunity. New Phytologist 2011, 193, 165-177, 10.1111/j.1469-8137.2011.03889.x.
    92. Jin, Z.; Sun, L.; Yang, G.; Pei, Y. Hydrogen Sulfide Regulates Energy Production to Delay Leaf Senescence Induced by Drought Stress in Arabidopsis. Front. Plant Sci. 2018, 9, 1722.
    93. Frederick D. Dooley; Suven P. Nair; Peter D. Ward; Increased Growth and Germination Success in Plants following Hydrogen Sulfide Administration. PLOS ONE 2013, 8, e62048, 10.1371/journal.pone.0062048.
    94. Thompson, C.R.; Kats, G. Effects of continuous hydrogen sulfide fumigation on crop and forest plants. Environ. Sci. Technol. 1978, 12, 550–553.