Hydrogen sulfide-based therapeutics: Exploiting a unique but ubiquitous gasotransmitter

Nature Reviews Drug Discovery

Volumn 14, Issue 5, 2015, Pages 329-345

  Wallace, John L ^a,b   Wang, Rui ^c  

^a UNIVERSITY OF CALGARY   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c LAKEHEAD UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; ANTIHYPERTENSIVE AGENT; AP 39; ATB 346; GIC 1001; GYY 4137; HYDROGEN SULFIDE; ION CHANNEL; LARGE CONDUCTANCE CALCIUM ACTIVATED POTASSIUM CHANNEL; NAPROXEN DERIVATIVE; PROTECTIVE AGENT; SG 1002; SODIUM CHLORIDE; SULFUR; UNCLASSIFIED DRUG; VOLTAGE GATED CALCIUM CHANNEL; GASOTRANSMITTER;

ANGIOGENESIS; ARTHRITIS; ATHEROSCLEROSIS; BIOLOGICAL ACTIVITY; BIOSYNTHESIS; CELL COMPARTMENTALIZATION; CELL METABOLISM; CLINICAL TRIAL (TOPIC); DEGENERATIVE DISEASE; DIABETES MELLITUS; DISEASE COURSE; DRUG DESIGN; DRUG RESPONSE; DRUG SAFETY; DRUG STRUCTURE; GASTROINTESTINAL DISEASE; GENETIC DISORDER; HEART FAILURE; HUMAN; HYPERTENSION; LIPID METABOLISM; LIVER DISEASE; MOLECULAR INTERACTION; NONHUMAN; OXIDATION REDUCTION STATE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN MODIFICATION; PROTEIN SULFHYDRATION; REVIEW; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION; URINARY EXCRETION; VASCULAR REMODELING; VISCERAL PAIN; ANIMAL; METABOLISM; MOLECULARLY TARGETED THERAPY; PHYSIOLOGY;

ANIMALS; GASOTRANSMITTERS; HUMANS; HYDROGEN SULFIDE; MOLECULAR TARGETED THERAPY; SIGNAL TRANSDUCTION;

EID: 84929031571     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4433     Document Type: Review

References (193)

1. Wang, R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 16, 1792-1798 (2002)
2. Kimura, H., Shibuya, N. & Kimura, Y. Hydrogen sulfide is a signaling molecule and a cytoprotectant. Antioxid. Redox Signal. 17, 45-57 (2012)
3. Olson, K. R., Donald, J. A., Dombkowski, R. A. & Perry, S. F. Evolutionary and comparative aspects of nitric oxide, carbon monoxide and hydrogen sulfide. Respir. Physiol. Neurobiol. 184, 117-129 (2012)
4. Yamanishi, M., Kabil, O., Sen, S. & Banerjee, R. Structural insights into pathogenic mutations in heme-dependent cystathionine-β-synthase. J. Inorg. Biochem. 100, 1988-1995 (2006)
5. Teng, H. et al. Oxygen-sensitive mitochondrial accumulation of cystathionine β synthase mediated by Lon protease. Proc. Natl Acad. Sci. USA 110, 12679-12684 (2013)
6. Wang, R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol. Rev. 92, 791-896 (2012)
7. Nagahara, N., Okazaki, T. & Nishino, T. Cytosolic mercaptopyruvate sulfurtransferase is evolutionarily related to mitochondrial rhodanese. Striking similarity in active site amino acid sequence and the increase in the mercaptopyruvate sulfurtransferase activity of rhodanese by site-directed mutagenesis. J. Biol. Chem. 270, 16230-16235 (1995)
8. Yang, G., Cao, K. & Wang, R. Cystathionine γ-lyase overexpression inhibits cell proliferation via a H2S-dependent modulation of ERK1/2 phosphorylation and p21 Cip/WAK 1. J. Biol. Chem. 279, 49199-49205 (2004)
9. Caliendo, G., Cirino, G., Santagada, V. & Wallace, J. L. Synthesis and biological effects of hydrogen sulfide (H2S): development of H2S-releasing drugs as pharmaceuticals. J. Med. Chem. 53, 6275-6286 (2010)
10. Levitt, M. D., Abdel-Rehim, M. S. & Furne, J. Free and acid-labile hydrogen sulfide concentrations in mouse tissues: anomalously high free hydrogen sulfide in aortic tissue. Antioxid. Redox Signal. 15, 373-378 (2011)
11. Insko, M. A., Deckwerth, T. L., Hill, P., Toombs, C. F. & Szabo, C. Detection of exhaled hydrogen sulphide gas in rats exposed to intravenous sodium sulphide. Br. J. Pharmacol. 157, 944-951 (2009)
12. Hosoki, R., Matsiki, N. & Kimura, H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem. Biophys. Res. Commun. 237, 527-531 (1997)
13. Zhao, W., Zhang, J., Lu, Y. & Wang, R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. 20, 6008-6016 (2001)
14. Yang, G. et al. Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid. Redox Signal. 18, 1906-1919 (2013)
15. Zhang, G., Wang, P., Yang, G., Cao, Q. & Wang, R. The inhibitory role of hydrogen sulfide in airway hyperresponsiveness and inflammation in a mouse model of asthma. Am. J. Pathol. 182, 1188-1195 (2013)
16. Fiorucci, S., Distrutti, E., Cirino, G. & Wallace, J. L. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 131, 259-271 (2006)
17. Schicho, R. et al. Hydrogen sulfide is a novel prosecretory neuromodulator in the guinea-pig and human colon. Gastroenterology 131, 1542-1552 (2006)
18. Wallace, J. L., Vong, L., McKnight, W., Dicay, M. & Martin, G. R. Endogenous and exogenous hydrogen sulfide promotes resolution of colitis in rats. Gastroenterology 137, 569-578 (2009)
19. Martin, G. R. et al. Hydrogen sulphide synthesis in the rat and mouse gastrointestinal tract. Dig. Liver Dis. 42, 103-109 (2010)
20. Erickson, P. F., Maxwell, I. H., Su, L. J., Baumann, M. & Glode, L. M. Sequence of cDNA for rat cystathionine γ-lyase and comparison of deduced amino acid sequence with related Escherichia coli enzymes. Biochem. J. 269, 335-340 (1990)
21. Paul, B. D. et al. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease. Nature 509, 96-100 (2014)
22. Abe, K. & Kimura, H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J. Neurosci. 16, 1066-1071 (1996)
23. Robert, K. et al. Expression of the cystathionine β synthase (CBS) gene during mouse development and immunolocalization in adult brain. J. Histochem. Cytochem. 51, 363-371 (2003)
24. Mani, S., Untereiner, A., Wu, L. & Wang, R. Hydrogen sulfide and the pathogenesis of atherosclerosis. Antioxid. Redox Signal. 20, 805-817 (2014)
25. Chen, Y. & Wang, R. The message in the air: hydrogen sulfide metabolism in chronic respiratory diseases. Resp. Physiol. Neurobiol. 184, 130-138 (2012)
26. Szabo, 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 110, 12474-12479 (2013)
27. Kondo, K. et al. H2S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation 12, 1116-1127 (2013)
28. Fu, M., Zhang, W., Yang, G. & Wang, R. Is cystathionine γ-lyase protein expressed in the heart? Biochem. Biophys. Res. Commun. 428, 469-474 (2012)
29. Nagahara, N., Ito, T., Kitamura, H. & Nishino, T. Tissue and subcellular distribution of mercaptopyruvate sulfurtransferase in the rat: confocal laser fluorescence and immunoelectron microscopic studies combined with biochemical analysis. Histochem. Cell. Biol. 110, 243-250 (1998)
30. Shibuya, N. et al. 3-mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid. Redox Signal. 11, 703-714 (2009)
31. Shibuya, N., Mikami, Y., Kimura, Y., Nagahara, N. & Kimura, H. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J. Biochem. 146, 623-626 (2009)
32. Módis, K., Panopoulos, P., Coletta, C., Papapetropoulos, A. & Szabo, C. Hydrogen sulfide-mediated stimulation of mitochondrial electron transport involves inhibition of the mitochondrial phosphodiesterase 2A, elevation of cAMP and activation of protein kinase A. Biochem. Pharmacol. 86, 1311-1309 (2013)
33. Fu, M. et al. Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc. Natl Acad. Sci. USA 109, 2943-2948 (2012)
34. Tang, G., Wu, L., Liang, W. & Wang, R. Direct stimulation of KATP channels by exogenous and endogenous hydrogen sulfide in vascular smooth muscle cells. Mol. Pharmacol. 68, 1757-1764 (2005)
35. Yang, W., Yang, G., Jia, X., Wu, L. & Wang, R. Activation of KATP channels by H2S in rat insulin-secreting cells and the underlying mechanisms. J. Physiol. 569, 519-531 (2005)
36. Fitzgerald, R. et al. H2S relaxes isolated human airway smooth muscle cells via the sarcolemmal KATP channel. Biochem. Biophys. Res. Commun. 446, 393-398 (2014)
37. Dawe, G. S., Han, S. P., Bian, J. S. & Moore, P. K. Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats. Neuroscience 152, 169-177 (2008)
38. Kimura, Y., Dargusch, R., Schubert, D. & Kimura, H. Hydrogen sulfide protects HT22 neuronal cells from oxidative stress. Antioxid. Redox Signal. 8, 661-670 (2006)
39. Distrutti, E. et al. Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels. J. Pharm. Exp. Therap. 316, 325-335 (2006)
40. Medeiros, J. V. et al. Role of KATP channels and TRPV1 receptors in hydrogen sulfide-enhanced gastric emptying of liquid in awake mice. Eur. J. Pharmacol. 693, 57-63 (2012)
41. Jiang, B., Tang, G., Cao, K., Wu, L. & Wang, R. Molecular mechanism for H2S-induced activation of KATP channels. Antioxid. Redox Signal. 12, 1167-1178 (2010)
42. Gade, A. R., Kang, M. & Akbarali, H. I. Hydrogen sulfide as an allosteric modulator of ATP-sensitive potassium channels in colonic inflammation. Mol. Pharmacol. 83, 294-306 (2013)
43. Mustafa, A. K. et al. H2S signals through protein S-sulfhydration. Sci. Signal. 2, ra72 (2009)
44. Tang, G., Zhang, L., Yang, G., Wu, L. & Wang, R. Hydrogen sulfide-induced inhibition of L-type Ca2+ channels and insulin secretion in mouse pancreatic β cells. Diabetologia 56, 533-541 (2013)
45. Zhang, R. et al. Hydrogen sulfide inhibits L-type calcium currents depending upon the protein sulfhydryl state in rat cardiomyocytes. PLoS ONE 7, e37073 (2012)
46. Elies, J. et al. Hydrogen sulfide inhibits Cav3.2 T-type Ca2+ channels. FASEB J. 28, 5376-5387 (2014)
47. Avanzato, D. et al. Role of calcium channels in the protective effect of hydrogen sulfide in rat cardiomyoblasts. Cell. Physiol. Biochem. 33, 1205-1214 (2014)
48. Sekiguchi, F. et al. Endogenous and exogenous hydrogen sulfide facilitates T-type calcium channel currents in Cav3.2-expressing HEK293 cells. Biochem. Biophys. Res. Commun. 445, 225-229 (2014)
49. Maeda, Y. et al. Hyperalgesia induced by spinal and peripheral hydrogen sulfide: evidence for involvement of Cav3.2 T type calcium channels. Pain 142, 127-132 (2009)
50. Tang, G. et al. H2S is an endothelium-derived hyperpolarizing factor. Antioxid. Redox Signal. 19, 1634-1646 (2013)
51. Mustafa, A. K. et al. Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ. Res. 109, 1259-1268 (2011)
52. Telezhkin, V. et al. Hydrogen sulfide inhibits human BKCa channels. Adv. Exp. Med. Biol. 648, 65-72 (2009)
53. Li, Q. et al. A crucial role for hydrogen sulfide in oxygen sensing via modulating large conductance calcium-Activated potassium channels. Antioxid. Redox Signal. 12, 1179-1189 (2010)
54. Sitdikova, G. F., Weiger, T. M. & Hermann, A. Hydrogen sulfide increases Ca2+-Activated K+ (BK) channel activity of rat pituitary tumor cells. Pflugers. Arch. 459, 389-397 (2010)
55. 2+ sparks. Am. J. Physiol. Heart Circ. Physiol. 304, H1446-H1454 (2013)
56. Han, Y. F. et al. Evidence that endogenous hydrogen sulfide exerts an excitatory effect on gastric motility in mice. Eur. J. Pharmacol. 673, 85-95 (2011)
57. Cheang, W. S. et al. 4-Aminopyridine-sensitive K+ channels contributes to NaHS-induced membrane hyperpolarization and relaxation in the rat coronary artery. Vascul. Pharmacol. 53, 94-98 (2010)
58. Tang, G., Wu, L. & Wang, R. Interaction of hydrogen sulfide with ion channels. Clin. Exp. Pharmacol. Physiol. 37, 753-763 (2010)
59. Bucci, M. et al. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler. Thromb. Vasc. Biol. 30, 1998-2004 (2010)
60. Coletta, C. et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. Natl Acad. Sci. USA 109, 9161-9166 (2012)
61. Wang, R. Shared signaling pathways among gasotransmitters. Proc. Natl Acad. Sci. USA 109, 8801-8802 (2012)
62. Lu, M. et al. Hydrogen sulfide inhibits plasma renin activity. J. Am. Soc. Nephrol. 21, 993-1002 (2010)
63. Moccia, F. et al. Hydrogen sulfide regulates intracellular Ca2+ concentration in endothelial cells from excised rat aorta. Curr. Pharm. Biotechnol. 12, 1416-1426 (2011)
64. Bauer, C. C., Boyle, J. P., Porter, K. E. & Peers, C. Modulation of Ca2+ signalling in human vascular endothelial cells by hydrogen sulfide. Atherosclerosis 209, 374-380 (2010)
65. 2+ sparks to induce cerebral arteriole dilatation. J. Physiol. 590, 2709-2720 (2012)
66. Altaany, Z., Ju, Y., Yang, G. & Wang, R. The coordination of S-sulfhydration, S-nitrosylation, and phosphorylation of endothelial nitric oxide synthase by hydrogen sulfide. Sci. Signal. 7, ra87 (2014)
67. Zhang, D. et al. Detection of protein S-sulfhydration by a tag-switch technique. Angew. Chem. Int. Ed. Engl. 53, 575-581 (2014)
68. Sen, N. et al. Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol. Cell 45, 13-24 (2012)
69. Kelleher, Z. T., Matsumoto, A., Stamler, J. S. & Marshall, H. E. NOS2 regulation of NF-κB by S-nitrosylation of p65. J. Biol. Chem. 282, 30667-30672 (2007)
70. Beigi, F. et al. Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. Proc. Natl Acad. Sci. USA 109, 4314-4319 (2012)
71. Wu, C. et al. Thioredoxin 1-mediated post-translational modifications: reduction, transnitrosylation, denitrosylation, and related proteomics methodologies. Antioxid. Redox Signal. 15, 2565-2604 (2011)
72. Kabil, O. & Banerjee, R. Characterization of patient mutations in human persulfide dioxygenase (ETHE1) involved in H2S catabolism. J. Biol. Chem. 287, 44561-44567 (2012)
73. Yan, S. K. et al. Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 351, 485-491 (2006)
74. Chang, T., Untereiner, A., Liu, J. & Wu, L. Interaction of methylglyoxal and hydrogen sulfide in rat vascular smooth muscle cells. Antioxid. Redox Signal. 12, 1093-1100 (2010)
75. Jeney, V. et al. Suppression of hemin-mediated oxidation of low-density lipoprotein and subsequent endothelial reactions by hydrogen sulfide (H2S). Free Radic. Biol. Med. 46, 616-623 (2009)
76. Liu, Y. Y. & Bian, J. S. Hydrogen sulfide protects amyloid β-induced cell toxicity in microglia. J. Alzheimers Dis. 22, 1189-1200 (2010)
77. Vacek, T. P., Gillespie, W., Tyagi, N., Vacek, J. C. & Tyagi, S. C. Hydrogen sulfide protects against vascular remodeling from endothelial damage. Amino Acids 39, 1161-1169 (2010)
78. Xu, Z. S. et al. Hydrogen sulfide protects MC3T3 E1 osteoblastic cells against H2O2-induced oxidative damage-implications for the treatment of osteoporosis. Free Radic. Biol. Med. 50, 314-323 (2011)
79. Módis, K., Asimakopoulou, A., Coletta, C., Papapetropoulos, A. & Szabo, C. Oxidative stress suppresses the cellular bioenergetic effect of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway. Biochem. Biophys. Res. Commun. 433, 401-407 (2013)
80. Szczesny, B. et al. AP39, a novel mitochondria-targeted sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro. Nitr. Oxide 41, 120-130 (2014)
81. Trionnaire, S. et al. The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor, (10-oxo-10-(4-(3-thioxo-3H-1, 2-dithiol-5-yl)phenoxy)decyl)triphenylphosphonium bromide (AP39). Med. Chem. Commun. 5, 728-736 (2014)
82. Yang, G. et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 322, 587-590 (2008)
83. Papapetropolous, A. et al. Hydrogen sulfide is an endogenous stimulator of angiogenesis. Proc. Natl Acad. Sci. USA 106, 21972-21977 (2009)
84. Madden, J. A., Ahlf, S. B., Dantuma, M. W., Olson, K. R. & Roerig, D. L. Precursors and inhibitors of hydrogen sulfide synthesis affect acute hypoxic pulmonary vasoconstriction in the intact lung. J. Appl. Physiol. 112, 411-418 (2012)
85. Skovgaard, N. & Olson, K. R. Hydrogen sulfide mediates hypoxic vasoconstriction through a production of mitochondrial ROS in trout gills. Am. J. Physiol. Regul. Integr. Comp. Physiol. 303, R487-R494 (2012)
86. Goubern, M. et al. Sulfide, the first inorganic substrate for human cells. FASEB J. 21, 1699-1706 (2007)
87. Módis, K., Coletta, C., Erdélyi, K., Papapetropoulos, A. & Szabo, C. Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J. 27, 601-611 (2013)
88. Olson, K. R. Hydrogen sulfide as an oxygen sensor. Clin. Chem. Lab. Med. 51, 623-632 (2013)
89. Chunyu, Z. et al. The regulatory effect of hydrogen sulfide on hypoxic pulmonary hypertension in rats. Biochem. Biophys. Res. Commun. 302, 810-816 (2003)
90. Ariyaratnam, P., Loubani, M. & Morice, A. H. Hydrogen sulphide vasodilates human pulmonary arteries: a possible role in pulmonary hypertension? Microvasc. Res. 90, 135-137 (2013)
91. Wallace, J. L. et al. Anti-inflammatory and cytoprotective actions of hydrogen sulfide: translation to therapeutics. Antiox. Redox Signal. 22, 398-410 (2015)
92. Zhao, W. & Wang, R. H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am. J. Physiol. Heart Circ. Physiol. 283, H474-H480 (2002)
93. Zhao, W., Ndisang, J. F. & Wang, R. Modulation of endogenous production of H2S in rat tissues. Can. J. Physiol. Pharmacol. 81, 848-853 (2003)
94. Du, J., Yan, H. & Tang, C. [Endogenous H2S is involved in the development of spontaneous hypertension]. Beijing Da Xue Xue Bao 35, 102 (2003)
95. Ahmad, F. U. et al. Exogenous hydrogen sulfide attenuates oxidative stress in spontaneously hypertensive rats. Int. J. Pharm. Sci. Res. 4, 2916-2926 (2013)
96. Yanfei, W., Lin, S., Junbao, D. & Chaoshu, T. Impact of l-Arginine on hydrogen sulfide/cystathionine- γ-lyase pathway in rats with high blood flow-induced pulmonary hypertension. Biochem. Biophys. Res. Commun. 345, 851-857 (2006)
97. Wei, H. L., Zhang, C. Y., Jin, H. F., Tang, C. S. & Du, J. B. Hydrogen sulfide regulates lung tissue-oxidized glutathione and total antioxidant capacity in hypoxic pulmonary hypertensive rats. Acta Pharmacol. Sin. 29, 670-679 (2008)
98. Wang, K. et al. Dysregulation of hydrogen sulfide producing enzyme cystathionine γ-lyase contributes to maternal hypertension and placental abnormalities in preeclampsia. Circulation 127, 2514-2522 (2013)
99. Holwerda, K. M. et al. Hydrogen sulfide attenuates sFlt1 induced hypertension and renal damage by upregulating vascular endothelial growth factor. J. Am. Soc. Nephrol. 25, 717-725 (2014)
100. Altaany, Z.L., Yang, G. & Wang, R. Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells. J. Cell. Mol. Med. 17, 879-888 (2013)
101. Wang, Y. et al. Role of hydrogen sulfide in the development of atherosclerotic lesions in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 29, 173-179 (2009)
102. Mani, S. et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation 127, 2523-2534 (2013)
103. -/- mice. Br. J. Pharmacol. 169, 1795-1809 (2013)
104. Zhang, H. et al. Hydrogen sulfide inhibits the development of atherosclerosis with suppressing CX3CR1 and CX3CL1 expression. PLoS ONE 7, e41147 (2012)
105. Namekata, K. et al. Abnormal lipid metabolism in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia. J. Biol. Chem. 279, 52961-52969 (2004)
106. Robert, K. et al. Cystathionine β synthase deficiency promotes oxidative stress, fibrosis, and steatosis in mice liver. Gastroenterology 128, 1405-1415 (2005)
107. Mani, S., Yang, G. & Wang, R. A critical life-supporting role for cystathionine γ-lyase in the absence of dietary cysteine supply. Free Radic. Biol. Med. 50, 1280-1287 (2011)
108. Jain, S. K., Micinski, D., Lieblong, B. J. & Stapleton, T. Relationship between hydrogen sulfide levels and HDL-cholesterol, adiponectin, and potassium levels in the blood of healthy subjects. Atherosclerosis 225, 242-245 (2012)
109. Fiorucci, S. et al. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology 42, 539-548 (2005)
110. Tan, G. et al. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats. PLoS ONE 6, e25943 (2011)
111. Morsy, M. A., Ibrahim, S. A., Abdelwahab, S. A., Zedan, M. Z. & Elbitar, H. I. Curative effects of hydrogen sulfide against acetaminophen-induced hepatotoxicity in mice. Life Sci. 87, 692-698 (2010)
112. Li, L. et al. Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J. 19, 1196-1198 (2005)
113. Norris, E. J. et al. Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic microcirculatory dysfunction during endotoxemia. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1070-G1078 (2013)
114. Wu, L. et al. Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats. Lab. Invest. 89, 59-67 (2009)
115. Lipson, K. L., Fonseca, S. G. & Urano, F. Endoplasmic reticulum stress-induced apoptosis and auto-immunity in diabetes. Curr. Mol. Med. 6, 71-77 (2006)
116. 2S, endoplasmic reticulum stress, and apoptosis of insulin-secreting β cells. J. Biol. Chem. 282, 16567-16576 (2007)
117. Jia, X. et al. The role of H2S in insulin resistance. 57th Annual Meeting of the Canadian Cardovascular Congress [online], http: //www.pulsus.com/ccc2004/ abs/a041.htm (2004)
118. Veldman, B. A., Vervoort, G., Blom, H. & Smits, P. Reduced plasma total homocysteine concentrations in type 1 diabetes mellitus is determined by increased renal clearance. Diabet. Med. 22, 301-305 (2005)
119. Yusuf, M. et al. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem. Biophys. Res. Commun. 333, 1146-1152 (2005)
120. Yang, G., Tang, G., Zhang, L., Wu, L. & Wang, R. The pathogenic role of cystathionine γ-lyase/hydrogen sulfide in streptozotocin-induced diabetes in mice. Am. J. Pathol. 179, 869-879 (2011)
121. Whiteman, M. et al. Adiposity is a major determinant of plasma levels of the novel vasodilator hydrogen sulfide. Diabetologia 53, 1722-1726 (2010)
122. Szabo, C. Roles of hydrogen sulfide in the pathogenesis of diabetes mellitus and its complications. Antioxid. Redox Signal. 17, 68-80 (2012)
123. Suzuki, K. et al. Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function. Proc. Natl Acad. Sci. USA 108, 13829-13834 (2011)
124. Liu, F. et al. Hydrogen sulfide improves wound healing via restoration of endothelial progenitor cell functions and activation of angiopoietin 1 in type 2 diabetes. Diabetes 63, 1763-1778 (2014)
125. Zhong, X. et al. Exogenous hydrogen sulfide attenuates diabetic myocardial injury through cardiac mitochondrial protection. Mol. Cell. Biochem. 371, 187-198 (2012)
126. Eto, K., Asada, T., Arima, K., Makifuchi, T. & Kimura, H. Brain hydrogen sulfide is severely decreased in Alzheimer's disease. Biochem. Biophys. Res. Commun. 293, 1485-1488 (2002)
127. Tang, X. Q. et al. Effect of hydrogen sulfide on β-Amyloid-induced damage in PC12 cells. Clin. Exp. Pharmacol. Physiol. 35, 180-186 (2008)
128. Fan, H. et al. Hydrogen sulfide protects against amyloid β-peptide induced neuronal injury via attenuating inflammatory responses in a rat model. J. Biomed. Res. 27, 296-304 (2013)
129. Xuan, A. et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in β-Amyloid rat model of Alzheimer's disease. J. Neuroinflamm. 9, 202 (2012)
130. Zhang, L. M., Jiang, C. X. & Liu, D. W. Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats. Neurochem. Res. 34, 1984-1992 (2009)
131. Hu, L. F. et al. Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models. Aging Cell 9, 135-146 (2010)
132. Kida, K. et al. Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson's disease. Antioxid. Redox Signal. 15, 343-352 (2011)
133. Campolo, M. et al. A hydrogen sulfide-releasing cyclooxygenase inhibitor markedly accelerates recovery from experimental spinal cord injury. FASEB J. 27, 4489-4499 (2013)
134. Distrutti, E. et al. 5-Amino 2 hydroxybenzoic acid 4-(5 thioxo 5H-[1, 2]dithiol 3yl)-phenyl ester (ATB-429), a hydrogen sulfide-releasing derivative of mesalamine, exerts antinociceptive effects in a model of postinflammatory hypersensitivity. J. Pharmacol. Exp. Ther. 319, 447-458 (2006)
135. Matsunami, M. et al. Luminal hydrogen sulfide plays a pronociceptive role in mouse colon. Gut 58, 751-771 (2009)
136. Ekundi-Valentim, E. et al. Differing effects of exogenous and endogenous hydrogen sulphide in carrageenan-induced knee joint synovitis in the rat. Br. J. Pharmacol. 159, 1463-1474 (2010)
137. Donatti, A. F. et al. Role of hydrogen sulfide in the formalin-induced orofacial pain in rats. Eur. J. Pharmacol. 738, 49-56 (2014)
138. Paquette, J. M. et al. Safety, tolerability and pharmacokinetics of trimebutine 3-thiobarbamoylbenzenesulfonate (GIC-1001) in a randomized Phase I integrated design study: single and multiple ascending doses and effect of food in healthy volunteers. Clin. Ther. 36, 1650-1664 (2014)
139. Fiorucci, S. et al. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology 129, 1210-1224 (2005)
140. Wallace, J. L. Physiological and pathophysiological roles of hydrogen sulfide in the gastrointestinal tract. Antioxid. Redox Signal. 12, 1125-1133 (2010)
141. Mard, S. A. et al. Gastroprotective effect of NaHS against mucosal lesions induced by ischemia-reperfusion injury in rat. Dig. Dis. Sci. 57, 1496-1503 (2012)
142. Zanardo, R. C. et al. Hydrogen sulfide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J. 20, 2118-2120 (2006)
143. Wallace, J. L., Keenan, C. M. & Granger, D. N. Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am. J. Physiol. 259, G462-G467 (1990)
144. Blackler, R. W., Gemici, B., Manko, A. & Wallace, J. L. NSAID-gastroenteropathy: new aspects of pathogenesis and prevention. Curr. Opin. Pharmacol. 19, 11-16 (2014)
145. Takeuchi, K. et al. Gas mediators involved in modulating duodenal HCO3 secretion. Curr. Med. Chem. 19, 43-54 (2012)
146. Wallace, J. L., Caliendo, G., Santagada, V., Cirino, G. & Fiorucci, S. Gastrointestinal safety and anti-inflammatory effects of hydrogen sulfide-releasing diclofenac derivative in the rat. Gastroenterology 132, 261-271 (2007)
147. Li, L. et al. Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative. Free Radic. Biol. Med. 42, 706-719 (2007)
148. Wallace, J. L., Caliendo, G., Santagada, V. & Cirino, G. Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br. J. Pharmacol. 159, 1236-1246 (2010)
149. Blackler, R. et al. Gastrointestinal sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS ONE 7, e35196 (2012)
150. Wallace, J. L. Hydrogen sulfide-releasing anti-inflammatory drugs. Trends Pharmacol. Sci. 28, 501-505 (2007)
151. Wallace, J. L., Ferraz, J. G. P. & Muscara, M. N. Hydrogen sulfide: an endogenous mediator of resolution of inflammation and injury. Antioxid. Redox Signal. 17, 58-67 (2012)
152. Wallace. J. L., Dicay, M., McKnight, W., Martin, G. R. Hydrogen sulfide enhances ulcer healing in rats. FASEB J. 21, 4070-4076 (2007)
153. Zayachkivska, O. et al. Cytoprotective effects of hydrogen sulfide in novel rat models of non-erosive esophagitis. PLoS ONE 9, e110688 (2014)
154. Wallace, J. L. Polypharmacy of osteoarthritis: the perfect intestinal storm. Dig. Dis. Sci. 58, 3088-3093 (2013)
155. Blackler, R. W. et al. Hydrogen sulfide protects against NSAID-enteropathy through modulation of bile and the microbiota. Br. J. Pharmacol. http: //dx.doi.org/10.1111/bph.12961 (2014)
156. Flannigan, K. L., Ferraz, J. G. P., Wang, R. & Wallace, J. L. Enhanced synthesis and diminished degradation of hydrogen sulfide in experimental colitis: a site-specific, pro-resolution mechanism. PLoS ONE 8, e71962 (2013)
157. Fiorucci, S. et al. Enhanced activity of a hydrogen sulphide-releasing derivative of mesalamine (ATB-429) in a mouse model of colitis. Br. J. Pharmacol. 150, 996-1002 (2007)
158. Flannigan, K. L. et al. Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-Associated exacerbation of colitis. Proc. Natl Acad. Sci. USA 111, 13559-13564 (2014)
159. Wang, J. & Hegele, R. A. Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine γ-lyase (CTH). Hum. Genet. 112, 404-408 (2003)
160. Zhu, W., Lin, A. & Banerjee, R. Kinetic properties of polymorphic variants and pathogenic mutants in human cystathionine γ-lyase. Biochemistry 47, 6226-6232 (2008)
161. Banerjee, R. & Zou, C. G. Redox regulation and reaction mechanism of human cystathionine-β-synthase: a PLP-dependent hemesensor protein. Arch. Biochem. Biophys. 433, 144-156 (2005)
162. Ichinohe, A. et al. Cystathionine β-synthase is enriched in the brains of Down's patients. Biochem. Biophys. Res. Commun. 338, 1547-1550 (2005)
163. Billaut-Laden, I. et al. Evidence for a functional genetic polymorphism of the human mercaptopyruvate sulfurtransferase (MPST), a cyanide detoxification enzyme. Toxicol. Lett. 165, 101-111 (2006)
164. Blackstone, E., Morrison, M. & Roth, M. B. H2S induces a suspended animation-like state in mice. Science 308, 515 (2005)
165. Szabo, C. Hydrogen sulfide and its therapeutic potential. Nature Rev. Drug Discov. 6, 917-935 (2007)
166. Wallace, J. L. Mechanisms, prevention & clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World J. Gastroenterol. 19, 1861-1876 (2013)
167. Kearney, P. M. et al. Do selective cyclo-oxygenase 2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-Analysis of randomized trials. BMJ 332, 1302-1308 (2006)
168. Chattopadhyay, M., Kodela, R., Olson, K. R. & Kashfi, K. NOSH-Aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model. Biochem. Biophys. Res. Commun. 419, 523-528 (2012)
169. Kashfi, K. Anti-cancer activity of new designer hydrogen sulfide-donating hybrids. Antioxid. Redox Signal. 20, 831-846 (2014)
170. Karabulut, G. S. et al. The incidence of irritable bowel syndrome in children using Rome III criteria and the effect of trimebutine treatment. J. Neurogastroenterol. Motil. 19, 90-93 (2013)
171. Elrod, J. W. et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc. Natl Acad. Sci. USA 104, 15560-15565 (2007)
172. Li, L. et al. Characterization of a novel, water soluble hydrogen sulfide-releasing molecule (GYY4137): new insights into the biology of hydrogen sulfide. Circulation 117, 2351-2360 (2008)
173. Li, L. et al. GYY4137, a novel hydrogen sulfide-releasing molecule, protects against endotoxic shock in the rat. Free Radic. Biol. Med. 47, 103-113 (2009)
174. Li, L. et al. The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells. J. Cell. Mol. Med. 17, 365-376 (2013)
175. Bucci, M. et al. Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition. Cardiovasc. Res. 102, 128-147 (2014)
176. McCook, O. et al. H2S during circulatory shock: some unresolved questions. Nitr. Oxide http: //dx.doi.org/10.1016/j.niox.2014.03.163 (2014)
177. Olson, K. A practical look at the chemistry and biology of hydrogen sulfide. Antiox. Redox Signal. 17, 32-44 (2012)
178. Shen, X., Peter, E. A., Bir, S., Wang, R. & Kevil, C. G. Analytical measurement of discrete hydrogen sulfide pools in biological specimens. Free Radic. Biol. Med. 52, 2276-2283 (2012)
179. Peter, E. A. et al. Plasma-free H2S levels are elevated in patients with cardiovascular disease. J. Am. Heart Assoc. 2, e000387 (2013)
180. Bos, E. M. et al. Cystathionine β lyase protects against renal ischemia/reperfusion by modulating oxidative stress. J. Am. Soc. Nephrol. 24, 759-770 (2013)
181. Shirozu, K. et al. Cystathionine β lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure. Antioxid. Redox Signal. 20, 204-216 (2014)
182. Shen, X. et al. Microbial regulation of host hydrogen sulfide bioavailability and metabolism. Free Radic. Biol. Med. 60, 195-200 (2013)
183. Flannigan, K. L., McCoy, K. D. & Wallace, J. L. Eukaryotic and prokaryotic contributions to colonic hydrogen sulfide synthesis. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G188-G193 (2011)
184. Mimoun, S. et al. Detoxification of H2S by differentiated colonic epithelial cells: implication of the sulfide oxidizing unit and of the cell respiratory capacity. Antioxid. Redox Signal. 17, 1-10 (2012)
185. Motta, J. P. et al. Hydrogen sulfide protects from colitis and restores intestinal microbiota biofilm and mucus production. Inflamm. Bowel Dis. http: //dx.doi.org/10.1097/MIB.0000000000000345 (2015)
186. Rey, F. E. et al. Metabolic niche of a prominent sulfate-reducing human gut bacterium. Proc. Natl Acad. Sci. USA 110, 13582-13587 (2013)
187. Berg, J. S. et al. Polysulfides as intermediates in the oxidation of sulfide to sulfate by Beggiatoa spp. Appl. Environ. Microbiol. 80, 629-636 (2014)
188. Furne, J., Saeed, A. & Levitt, M. D. Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than present accepted values. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1479-R1485 (2008)
189. Magee, E. A., Richardson, C. J., Hughes, R. & Cummings, J. H. Contribution of dietary protein to sulfide production in the large intestine: an in vitro and a controlled feeding study in humans. Am. J. Clin. Nutr. 72, 1488-1494 (2000)
190. Roediger, W. E., Duncan, A., Kapaniris, O. & Millard, S. Sulphide impairment of substrate oxidation in rat colonocytes: a biochemical basis for ulcerative colitis? Clin. Sci. 85, 623-627 (1993)
191. Attene-Ramos, M. S., Wagner, E. D., Plewa, M. J. & Gaskins, H. R. Evidence that hydrogen sulfide is a genotoxic agent. Mol. Cancer Res. 4, 9-14 (2006)
192. Cao, Q. et al. Butyrate-stimulated H2S production in colon cancer cells. Antioxid. Redox Signal. 12, 1101-1109 (2010)
193. Chan, M. V. & Wallace, J. L. Hydrogen sulfide-based therapeutics and gastrointestinal diseases: translating physiology to treatments. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G467-G473 (2013