Hidrojen Sülfür’ün Fizyolojik ve Patolojik Olaylara Katkısı ve Klinikte Kullanımı

Yıl 2022, , 122 - 131, 30.06.2022

Kübra Gönbe Fatma Aydınoğlu , Nuran Öğülener

https://doi.org/10.17827/aktd.1066415

Öz

Enzimatik veya non-enzimatik yollarla sentezlenen hidrojen sülfür (H2S), nitrik okside (NO) ve karbonmonoksite (CO) benzer üçüncü bir gaz nörotransmitterdir. Vücutta sentezinden sorumlu enzimler çeşitli dokularda eksprese edilmektedir. Antiinflamatuvar, antiapoptotik, nöroprotektif, gastroprotektif, antispazmotik, sitoprotektif, antioksidan, bronkodilatör, kan basıncı regülasyonu gibi birçok fizyolojik etkisi olan H2S’in, hipertansiyon, ateroskleroz, depresyon, astım, kronik obstrüktif akciğer hastalığı, ülser, erektil disfonksiyon, parkinson ve alzheimer gibi çeşitli patolojik durumlarda da rolü olduğu bilinmektedir. Fizyopatolojik durumlardaki potansiyel önemi göz önüne alınarak H2S salıveren aspirin ve naproksenle kombine çeşitli preperatlar geliştirilmiştir. Bu kapsamda antiinflamatuvar, analjezik, antioksidan, sitoprotektif ve kardiyoprotektif etkiler gösteren bazı aday ilaçlar geliştirilmiştir. ATB-346, GIC-1001, NBS-1120, SG-1002, AP-39 ve MZe76 aday ilaçlar arasında yer almaktadır. S-zofenoprilin isimli ilacın ise faz çalışmaları tamamlanmıştır. L-sistein/H2S yolağıyla ilgili preklinik ve klinik araştırmaların gerçekleştirilmesi fizyolojik, patolojik ve terapötik açıdan önem taşımakta ve bu doğrultuda yeni preperatların geliştirilmesinin tedavi yaklaşımları için umut verici olduğu düşünülmektedir.

Anahtar Kelimeler

Hidrojen sülfür, Gaz nörotransmitter, H2S donörleri

Contribution of Hydrogen Sulfide to Physiological and Pathological Events and Clinical Use

Öz

Hydrogen sulfide (H2S), synthesized by enzymatic or non-enzymatic means, is a third gas neurotransmitter similar to nitric oxide (NO) and carbon monoxide (CO). Enzymes responsible for their synthesis in the body are expressed in various tissues. H2S has many physiological effects such as anti-inflammatory, antiapoptotic, neuroprotective, gastroprotective, antispasmodic, cytoprotective antioxidant, a bronchodilator, blood pressure regulation. Also, it is known that H2S has a role in various pathological conditions such as hypertension, atherosclerosis, depression, asthma, chronic obstructive pulmonary disease (COPD), ulcer, erectile dysfunction, Alzheimer's, and Parkinson's disease. Considering its potential importance in physiopathological conditions, various drugs have been developed in combination with H2S-releasing aspirin and naproxen. In this context, some drugs with anti-inflammatory, analgesic, antioxidant, cytoprotective, and cardioprotective effects have been developed. ATB-346, GIC-1001, NBS-1120, SG-1002, AP-39, and MZe76 are among the candidate drugs. Phase studies of S-zofenopril have been completed. The realization of preclinical and clinical studies on the L-cysteine/H2S pathway is important physiologically, pathologically, and therapeutically, and the development of new drugs in this direction is considered to be promising for treatment approaches.

Anahtar Kelimeler

Hydrogen sulfide, Gas neurotransmitter, H2S donors

Kaynakça

• KAYNAKLAR 1. Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996; 16(3): 1066-71.
• 2. Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 2002; 16(13):1792-8.
• 3. Paul BD, Snyder SH. Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol. 2018; 149:101-109.
• 4. Tang C, Li X, Du J. Hydrogen sulfide as a new endogenous gaseous transmitter in the cardiovascular system. Curr Vasc Pharmacol. 2006; 4(1):17-22.
• 5. Shibuya N, Tanaka M, Yoshida M, Ogasawara Y., Togawa T., Ishii K et al. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxidants & Redox Signaling 2009; 11(4):703-714.
• 6. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science. 2008; 322(5901):587-90.
• 7. Hosoki R, Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997; 237(3): 527-31.
• 8. d'Emmanuele di Villa Bianca R, Sorrentino R, Maffia P, Mirone V, Imbimbo C, Fusco F et al. Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci. 2009; 106(11):4513-8.
• 9. Li L, Bhatia M, Moore PK. Hydrogen sulphide—a novel mediator of inflammation?. Curr Opin Pharmacol. 2006; 6(2):125-9.
• 10. Kanagy NL, Szabo C, Papapetropoulos A. Vascular biology of hydrogen sulfide. American Journal of Physiology-Cell Physiology. 2017; 312(5):C537-C549.
• 11. Gui DD, Luo W, Yan BJ, Ren Z, Tang ZH, Liu SH, Zhang, JF ve Jiang ZS. Effects of gut microbiota on atherosclerosis through hydrogen sulfide. European Journal of Pharmacology. 2021; 5(896):173916.
• 12. Lv B, Chen S, Tang C, Jin H, Du J, ve Huang Y. Hydrogen sulfide and vascular regulation-An update. Journal of Advanced Research. 2020; 16(27):85-97.
• 13. Kimura Y, Kimura H. Hydrogen sulfide protects neurons from oxidative stress. The FASEB J. 2004; 18(10):1165-1167.
• 14. Fiorucci S, Antonelli E, Distrutti E, Rizzo G, Mencarelli A, Orlandi S et al. Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology. 2005; 129(4):1210-24.
• 15. Srilatha B, Hu L, Adaikan GP, Moore PK. Initial characterization of hydrogen sulfide effects in female sexual function. J Sex Med. 2009; 6(7):1875-84.
• 16. Zhao P, Huang X, Wang ZY, Qiu ZX, Han YF, Lu HL et al. Dual effect of exogenous hydrogen sulfide on the spontaneous contraction of gastric smooth muscle in guinea-pig. Eur J Pharmacol. 2009; 616(1-3):223-8.
• 17. You XJ, Xu C, Lu JQ, Zhu XY, Gao L, Cui XR et al. Expression of cystathionine β-synthase and cystathionine γ-lyase in human pregnant myometrium and their roles in the control of uterine contractility. PLoS One. 2011; 6(8):e23788.
• 18. Chen Y, Wang R. The message in the air: hydrogen sulfide metabolism in chronic respiratory diseases. Respir Physiol Neurobiol. 2012; 184(2):130-8.
• 19. Sun HJ, Wu ZY, Nie XW ve Bian JS. Role of endothelial dysfunction in cardiovascular diseases: the link between inflammation and hydrogen sulfide. Frontiers in Pharmacology, 2020; 10:1568.
• 20. Wallace JL, Dicay M, McKnight W, Martin GR. Hydrogen sulfide enhances ulcer healing in rats. The FASEB Journal. 2007; 21(14):4070-4076.
• 21. Beltowski J, Jamroz-Wisniewska A, Tokarzewska D. Hydrogen sulfide and its modulation in arterial hypertension and atherosclerosis. Cardiovascular Hematological Agents in Medicinal Chemistry. 2010; 8(4):173-186. doi: 10.2174/187152510792481207.
• 22. Hirata I, Naito Y, Takagi T, Mizushima K, Suzuki T, Omatsu T et al. Endogenous hydrogen sulfide is an anti-inflammatory molecule in dextran sodium sulfate-induced colitis in mice. Digestive Diseases and Sciences. 2011; 56(5):1379-1386.
• 23. Bazhanov N, Ansar M, Ivanciuc T, Garofalo RP, Casola A. Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses. Am J Respir Cell Mol Biol. 2017; 57(4):403-410.
• 24. Tabassum R, Jeong NY. Potential for therapeutic use of hydrogen sulfide in oxidative stress-induced neurodegenerative diseases. International Journal of Medical Sciences. 2019; 16(10):1386.
• 25. Özatik FY, Özatik O, Tekşen Y, Yiğitaslan S, Ari NS. Protective and therapeutic effect of Hydrogen sulfide on hemorrhagic cystitis and testis dysfunction induced with Cyclophosphamide. Turk J Med Sci, 2021.
• 26. Szabó C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 2007; 6(11):917-35.
• 27. Wallace JL, Wang R. Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter. Nat Rev Drug Discov. 2015; 14(5):329-45.
• 28. Araujo-Alvarez JM, Trujillo-Ferrara JG. De Morbis Artificum Diatriba 1700-2000 ["De Morbis Artificum Diatriba." 1700-2000. ]. Salud Publica Mex. 2002; 44(4):362-70.
• 29. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001; 20(21):6008-16.
• 30. Pae HO, Lee YC, Jo EK, Chung HT. Subtle interplay of endogenous bioactive gases (NO, CO and H(2)S) in inflammation. Arch Pharm Res. 2009; 32(8):1155-62.
• 31. Mathai JC, Missner A, Kügler P, Saparov SM, Zeidel ML, Lee JK et al. No facilitator required for membrane transport of hydrogen sulfide. Proc Natl Acad Sci. 2009; 106(39):16633-8.
• 32. Munaron L, Avanzato D, Moccia F, Mancardi D. Hydrogen sulfide as a regulator of calcium channels. Cell Calcium. 2013; 53(2):77-84.
• 33. Liu YH, Lu M, Hu LF, Wong PT, Webb GD, Bian JS. Hydrogen sulfide in the mammalian cardiovascular system. Antioxid Redox Signal. 2012; 17(1):141-85.
• 34. Łowicka E, Bełtowski J. Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. Pharmacol Rep. 2007; 59(1):4-24.
• 35. Li L, Rose P, Moore PK. Hydrogen sulfide and cell signaling. Annu Rev Pharmacol Toxicol. 2011; 51:169-87.
• 36. Singh S, Banerjee R. PLP-dependent H(2)S biogenesis. Biochim Biophys Acta. 2011; 1814(11):1518-27.
• 37. Kabil O, Banerjee R. Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal. 2014; 20(5):770-82.
• 38. Kery V, Bukovska G, Kraus JP. Transsulfuration depends on heme in addition to pyridoxal 5'-phosphate. Cystathionine beta-synthase is a heme protein. J Biol Chem. 1994; 269(41):25283-8.
• 39. Meier M, Janosik M, Kery V, Kraus JP, Burkhard P. Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein. EMBO J. 2001; 20(15):3910-6.
• 40. Bao L, Vlcek C, Paces V, Kraus JP. Identification and tissue distribution of human cystathionine beta-synthase mRNA isoforms. Arch Biochem Biophys. 1998; 350(1):95-103.
• 41. Patel P, Vatish M, Heptinstall J, Wang R, Carson RJ. The endogenous production of hydrogen sulphide in intrauterine tissues. Reprod Biol Endocrinol. 2009; 7(1):1-9.
• 42. Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH et al. Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem. 2009; 284(5):3076-3085.
• 43. Diwakar L, Ravindranath V. Inhibition of cystathionine-gamma-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS. Neurochem Int. 2007; 50(2):418-26.
• 44. Wang R. Hydrogen sulfide: a new EDRF. Kidney Int. 2009; 76(7):700-4.
• 45. Martin GR, McKnight GW, Dicay MS, Coffin CS, Ferraz JGP, Wallace JL. Hydrogen sulphide synthesis in the rat and mouse gastrointestinal tract. Digestive and Liver Disease. 2010; 42(2):103-109.
• 46. Fu M, Zhang W, Wu L, Yang G, Li H, Wang R. Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proceedings of the National Academy of Sciences. 2012; 109(8):2943-8.
• 47. Fräsdorf B, Radon C, Leimkühler S. Characterization and interaction studies of two isoforms of the dual localized 3-mercaptopyruvate sulfurtransferase TUM1 from humans. J Biol Chem. 2014; 289(50):34543-56.
• 48. Nagahara N. Multiple role of 3-mercaptopyruvate sulfurtransferase: antioxidative function, H2 S and polysulfide production and possible SOx production. Br J Pharmacol. 2018; 175(4):577-589.
• 49. 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 Bio. 1998;110(3):243-50.
• 50. Corsello T, Komaravelli N, Casola A. Role of Hydrogen Sulfide in NRF2- and Sirtuin-Dependent Maintenance of Cellular Redox Balance. Antioxidants. 2018; 7(10):129
• 51. Nagahara N, Katayama A. Post-translational regulation of mercaptopyruvate sulfurtransferase via a low redox potential cysteine-sulfenate in the maintenance of redox homeostasis. J Biol Chem. 2005; 280(41):34569-76.
• 52. Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK et al. A Review of Hydrogen Sulfide Synthesis, Metabolism, and Measurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic for Cancer? Antioxid Redox Signal. 2019; 31(1):1-38.
• 53. Tomasova L, Konopelski P, Ufnal M. Gut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis. Molecules. 2016; 21(11):1558.
• 54. Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proceedings of the National Academy of Sciences. 2007; 104(46):17977-82.
• 55. Donnarumma E, Trivedi RK, Lefer DJ. Protective Actions of H2S in Acute Myocardial Infarction and Heart Failure. Compr Physiol. 2017; 7(2):583-602.
• 56. Beauchamp RO Jr, Bus JS, Popp JA, Boreiko CJ, Andjelkovich DA. A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol. 1984; 13(1):25-97.
• 57. Smith RP, Abbanat RA. Protective effect of oxidized glutathione in acute sulfide poisoning. Toxicol Appl Pharmacol. 1966; 9(2):209-17.
• 58. Martelli A, Testai L, Marino A, Breschi MC, Da Settimo F, Calderone V. Hydrogen sulphide: biopharmacological roles in the cardiovascular system and pharmaceutical perspectives. Curr Med Chem. 2012;19(20):3325-36.
• 59. Meng G, Ma Y, Xie L, Ferro A, Ji Y. Emerging role of hydrogen sulfide in hypertension and related cardiovascular diseases. British Journal of Pharmacology. 2015; 172(23):5501-5511.
• 60. Hart JL. Vasorelaxation elicited by endogenous and exogenous hydrogen sulfide in mouse mesenteric arteries. Naunyn-Schmiedeberg's Archives of Pharmacology. 2020; 393(4):551-564.
• 61. Meng QH, Yang G, Yang W, Jiang B, Wu L, Wang R. Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries. The American Journal of Pathology. 2007; 170(4):1406-1414.
• 62. Yang N, Liu Y, Li T, Tuo Q. Role of hydrogen sulfide in chronic diseases. DNA and Cell Biology. 2020; 39(2):187-196.
• 63. Al-Magableh MR, Hart JL. Mechanism of vasorelaxation and role of endogenous hydrogen sulfide production in mouse aorta. Naunyn-Schmiedeberg's Archives of Pharmacology. 2011; 383(4):403-413.
• 64. Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiological Reviews. 2012; 92(2):791-896.
• 65. Wang R, Szabo C, Ichinose F, Ahmed A, Whiteman M, Papapetropoulos A. The role of H2S bioavailability in endothelial dysfunction. Trends in Pharmacological Sciences. 2015; 36(9):568-578.
• 66. d'Emmanuele di Villa Bianca R, Sorrentino R, Coletta C, Mitidieri E, Rossi A et al. Hydrogen sulfide-induced dual vascular effect involves arachidonic acid cascade in rat mesenteric arterial bed. Journal of Pharmacology and Experimental Therapeutics. 2011; 337(1):59-64.
• 67. Tang G, Yang G, Jiang B, Ju Y, Wu L, Wang R. H2S is an endothelium-derived hyperpolarizing factor. Antioxidants & Redox Signaling. 2013;19(14):1634-1646.
• 68. Kubo S, Kajiwara M, Kawabata A. Dual modulation of the tension of isolated gastric artery and gastric mucosal circulation by hydrogen sulfide in rats. Inflammopharmacology. 2007; 15(6):288-292.
• 69. Du J, Hui Y, Cheung Y, Bin G, Jiang H, Chen X et al. The possible role of hydrogen sulfide as a smooth muscle cell proliferation inhibitor in rat cultured cells. Heart Vessels. 2004; 19(2):75-80.
• 70. Bełtowski J, Jamroz-Wiśniewska A. Hydrogen sulfide and endothelium-dependent vasorelaxation. Molecules. 2014; 19(12):21183-21199.
• 71. Sun NL, Yang Xi, Yang SN, Ma Z, Tang CS. Plasma hydrogen sulfide and homocysteine levels in hypertensive patients with different blood pressure levels and complications. Zhonghua Xin Xue Guan Bing Za Zhi. 2007; 35(12):1145-1148.
• 72. d'Emmanuele di Villa Bianca R, Mitidieri E, Donnarumma E, Tramontano T, Brancaleone V, Cirino G et al. Hydrogen sulfide is involved in dexamethasone-induced hypertension in rat. Nitric Oxide. 2015; 46:80-86.
• 73. Li L, Whitemann M, Guan YY, Neo KL, Cheng Y, Lee SW et al. Characterization of a novel, water-soluble hydrogen sulfide-releasing molecule (GYY4137). Circulation. 2008; 117(18):2351-2360.
• 74. Sun L, Sun S, Li Y, Pan W, Xie Y, Wang S et al. Potential biomarkers predicting risk of pulmonary hypertension in congenital heart disease: the role of homocysteine and hydrogen sulfide. Chinese Medical Journal. 2014; 127(5):893-899.
• 75. Mani S, Li H, Untereiner A, Wu L, Yang G, Austin RC et al. Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation. 2013; 127(25):2523-2534.
• 76. Lee SW, Hu YS, Hu LF, Lu Q, Dawe GS, Moore PK et al. Hydrogen sulphide regulates calcium homeostasis in microglial cells. Glia. 2006; 54(2):116-124.
• 77. Hu LF, Wong PT, Moore PK, Bian JS. Hydrogen sulfide attenuates lipopolysaccharide‐induced inflammation by inhibition of p38 mitogen‐activated protein kinase in microglia. Journal of Neurochemistry. 2007; 100(4):1121-1128.
• 78. Tang XQ, Yang CT, Chen J, Yin WL, Tian SW, Hu B et al. Effect of hydrogen sulphide on beta-amyloid-induced damage in PC12 cells. Clin Exp Pharmacol Physiol. 2008; 35(2):180-6.
• 79. Lu M, Choo CH, Hu LF, Tan BH, Hu G, Bian JS. Hydrogen sulfide regulates intracellular pH in rat primary cultured glia cells. Neuroscience Research. 2010; 66(1):92-98.
• 80. Nagai Y, Tsugane M, Oka J, Kimura H. Hydrogen sulfide induces calcium waves in astrocytes. The FASEB Journal. 2004; 18(3):557-559.
• 81. Kimura Y, Goto Y, Kimura H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxidants & Redox Signaling. 2010; 554:169-186.
• 82. Xue X, Bian JS. Neuroprotective effects of hydrogen sulfide in Parkinson's disease animal models: methods and protocols. Methods in Enzymology. 2015; 554:169-186.
• 83. Liu L, Wang J, Wang H. Hydrogen sulfide alleviates oxidative stress injury and reduces apoptosis induced by MPP+ in Parkinson’s disease cell model. Molecular and Cellular Biochemistry. 2020; 472(1):231-240.
• 84. Xuan A, Long D, Li J, Ji W, Zhang M, Hong L et al. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s disease. Journal of Neuroinflammation. 2012; 9(1):1-11.
• 85. Liu SY, Li D, Zeng HY, Kan LY, Zou W, Zhang P et al. Hydrogen sulfide inhibits chronic unpredictable mild stress-induced depressive-like behavior by upregulation of Sirt-1: involvement in suppression of hippocampal endoplasmic reticulum stress. International Journal of Neuropsychopharmacology. 2017; 20(11):867-876.
• 86. Tan H, Zou W, Jiang J, Tian Y, Xiao Z, Bi L et al. Disturbance of hippocampal H2S generation contributes to CUMS-induced depression-like behavior: involvement in endoplasmic reticulum stress of hippocampus. Acta Biochimica et Biophysica Sinica. 2015; 47(4):285-291.
• 87. Zhang LM, Jiang CX, Liu DW. Hydrogen sulfide attenuates neuronal injury induced by vascular dementia via inhibiting apoptosis in rats. Neurochemical Research. 2009; 34(11):1984-1992.
• 88. Distrutti E, Sediari L, Mencarelli A, Renga B, Orlandi S, Antonelli E et al. Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels. Journal of Pharmacology and Experimental Therapeutics. 2006; 316(1):325-335.
• 89. Linden DR, Sha L, Mazzone A, Stoltz GJ, Bernard CE, Furne JK et al. Production of the gaseous signal molecule hydrogen sulfide in mouse tissues. Journal of Neurochemistry. 2008; 106(4):1577-1585.
• 90. Liu H, Bai XB, Shi S, Cao YX. Hydrogen sulfide protects from intestinal ischaemia–reperfusion injury in rats. Journal of Pharmacy and Pharmacology. 2009; 61(2):207-212.
• 91. Li B, Lee C, Martin Z, Li X, Koike Y, Hock A et al. Intestinal epithelial injury induced by maternal separation is protected by hydrogen sulfide. Journal of Pediatric Surgery. 2017; 52(1):40-44.
• 92. Hirata I, Naito Y, Takagi T, Mizushima K, Suzuki T, Omatsu T et al. Endogenous hydrogen sulfide is an anti-inflammatory molecule in dextran sodium sulfate-induced colitis in mice. Dig Dis Sci. 2011; 56(5):1379-86.
• 93. Fernandes VS, Ribeiro AS, Martínez MP, Orensanz LM, Barahona MV, Martínez-Sáenz A et al. Endogenous hydrogen sulfide has a powerful role in inhibitory neurotransmission to the pig bladder neck. J Urol. 2013; 189(4):1567-1573.
• 94. Gai JW, Wahafu W, Guo H, Liu M, Wang XC, Xiao YX et al. Further evidence of endogenous hydrogen sulphide as a mediator of relaxation in human and rat bladder. Asian J Androl. 2013; 15(5):692-6.
• 95. Zou S, Shimizu T, Shimizu S, Higashi Y, Nakamura K, Ono H et al. Possible role of hydrogen sulfide as an endogenous relaxation factor in the rat bladder and prostate. Neurourol Urodyn. 2018; 37(8):2519-2526.
• 96. d'Emmanuele di Villa Bianca R, Mitidieri E, Fusco F, Russo A, Pagliara V, Tramontano T et al. Urothelium muscarinic activation phosphorylates CBS(Ser227) via cGMP/PKG pathway causing human bladder relaxation through H2S production. Sci Rep. 2016; 6:31491.
• 97. Fusco F, di Villa Bianca Rd, Mitidieri E, Cirino G, Sorrentino R, Mirone V. Sildenafil effect on the human bladder involves the L-cysteine/hydrogen sulfide pathway: a novel mechanism of action of phosphodiesterase type 5 inhibitors. Eur Urol. 2012; 62(6):1174-80.
• 98. Liu H, Chang J, Zhao Z, Li Y, Hou J. Effects of exogenous hydrogen sulfide on the proliferation and invasion of human Bladder cancer cells. J Cancer Res Ther.2017; 13(5):829-832.
• 99. Guo H, Gai JW, Wang Y, Jin HF, Du JB, Jin J. Characterization of hydrogen sulfide and its synthases, cystathionine β-synthase and cystathionine γ-lyase, in human prostatic tissue and cells. Urology. 2012; 79(2):483.e1.
• 100. Wang YH, Huang JT, Chen WL, Wang RH, Kao MC, Pan YR et al. Dysregulation of cystathionine γ-lyase promotes prostate cancer progression and metastasis. EMBO Rep. 2019; 20(10):e45986.
• 101. Cao X, Bian JS. The Role of Hydrogen Sulfide in Renal System. Front Pharmacol. 2016; 7:385.
• 102. Azizi F, Seifi B, Kadkhodaee M, Ahghari P. Administration of hydrogen sulfide protects ischemia reperfusion-induced acute kidney injury by reducing the oxidative stress. Ir J Med Sci. 2016; 185(3):649-654.
• 103. Gratzke C, Streng T, Waldkirch E, Sigl K, Stief C, Andersson KE et al. Transient receptor potential A1 (TRPA1) activity in the human urethra--evidence for a functional role for TRPA1 in the outflow region. Eur Urol. 2009; 55(3):696-704.
• 104. Srilatha B, Adaikan PG, Moore PK. Possible role for the novel gasotransmitter hydrogen sulphide in erectile dysfunction--a pilot study. Eur J Pharmacol. 2006; 535(1-3): 280-2.
• 105. Srilatha B, Adaikan PG, Li L, Moore PK. Hydrogen sulphide: a novel endogenous gasotransmitter facilitates erectile function. J Sex Med. 2007; 4(5):1304-11.
• 106. Yetik-Anacak G, Dereli MV, Sevin G, Ozzayım O, Erac Y, Ahmed A. Resveratrol Stimulates Hydrogen Sulfide (H2 S) Formation to Relax Murine Corpus Cavernosum. J Sex Med. 2015; 12(10):2004-12.
• 107. Aydinoglu F, Ogulener N. Characterization of relaxant mechanism of H2 S in mouse corpus cavernosum. Clin Exp Pharmacol Physiol. 2016; 43(4):503-11.
• 108. Aydinoglu F, Dalkir FT, Demirbag HO, Ogulener N. The interaction of l-cysteine/H2S pathway and muscarinic acetylcholine receptors (mAChRs) in mouse corpus cavernosum. Nitric Oxide. 2017; 70:51-58.
• 109. Jupiter RC, Yoo D, Pankey EA, Reddy VV, Edward JA, Polhemus DJ et al. Analysis of erectile responses to H2S donors in the anesthetized rat. Am J Physiol Heart Circ Physiol. 2015; 309(5):H835-43.
• 110. Wang P, Zhang G, Wondimu T, Ross B, Wang R. Hydrogen sulfide and asthma. Exp Physiol. 2011; 96(9):847-52.
• 111. Rashid S, Heer JK, Garle MJ, Alexander SP, Roberts RE. Hydrogen sulphide-induced relaxation of porcine peripheral bronchioles. Br J Pharmacol. 2013; 168(8):1902-10.
• 112. Kubo S, Doe I, Kurokawa Y, Kawabata A. Hydrogen sulfide causes relaxation in mouse bronchial smooth muscle. J Pharmacol Sci. 2007; 104(4):392-6.
• 113. Chen YH, Yao WZ, Gao JZ, Geng B, Wang PP, Tang CS. Serum hydrogen sulfide as a novel marker predicting bacterial involvement in patients with community-acquired lower respiratory tract infections. Respirology. 2009; 14(5):746-52.
• 114. Chung KF. Hydrogen sulfide as a potential biomarker of asthma. Expert Rev Respir Med. 2014; 8(1):5-13
• 115. Suzuki Y, Saito J, Munakata M, Shibata Y. Hydrogen sulfide as a novel biomarker of asthma and chronic obstructive pulmonary disease. Allergol Int. 2021; 70(2):181-189.
• 116. Chen YH, Wu R, Geng B, Qi YF, Wang PP, Yao WZ et al. Endogenous hydrogen sulfide reduces airway inflammation and remodeling in a rat model of asthma. Cytokine. 2009; 45(2):117-23.
• 117. 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. 2013; 182(4):1188-95.
• 118. Tian M, Wang Y, Lu YQ, Yan M, Jiang YH, Zhao DY. Correlation between serum H2S and pulmonary function in children with bronchial asthma. Mol Med Rep. 2012; 6(2):335-8.
• 119. Chen YH, Wang PP, Wang XM, He YJ, Yao WZ, Qi YF et al. Involvement of endogenous hydrogen sulfide in cigarette smoke-induced changes in airway responsiveness and inflammation of rat lung. Cytokine. 2011; 53(3):334-41.
• 120. Wallace JL, Caliendo G, Santagada V, Cirino G. Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br J Pharmacol. 2010; 159(6):1236-46.
• 121. Blackler R, Syer S, Bolla M, Ongini E, Wallace JL. Gastrointestinal-sparing effects of novel NSAIDs in rats with compromised mucosal defence. PLoS One. 2012; 7(4):e35196.
• 122. Magierowski M, Magierowska K, Surmiak M, Hubalewska-Mazgaj M, Kwiecien S, Wallace JL et al. The effect of hydrogen sulfide-releasing naproxen (ATB-346) versus naproxen on formation of stress-induced gastric lesions, the regulation of systemic inflammation, hypoxia and alterations in gastric microcirculation. J Physiol Pharmacol. 2017; 68(5):749-756.
• 123. Wallace JL, Nagy P, Feener TD, Allain T, Ditrói T, Vaughan DJ et al. 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(4):769-777.
• 124. De Cicco P, Panza E, Ercolano G, Armogida C, Sessa G, Pirozzi G et al. ATB-346, a novel hydrogen sulfide-releasing anti-inflammatory drug, induces apoptosis of human melanoma cells and inhibits melanoma development in vivo. Pharmacol Res. 2016; 114:67-73.
• 125. Paul-Clark M, Elsheikh W, Kirkby N, Chan M, Devchand P, Agbor TA et al. Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis. PLoS One. 2016; 11(2):e0147289.
• 126. Chattopadhyay M, Kodela R, Olson KR, 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. 2012; 419(3):523-8.
• 127. Kodela R, Chattopadhyay M, Kashfi K. NOSH-Aspirin: A Novel Nitric Oxide-Hydrogen Sulfide-Releasing Hybrid: A New Class of Anti-inflammatory Pharmaceuticals. ACS Med Chem Lett. 2012; 3(3):257-262.
• 128. Fonseca MD, Cunha FQ, Kashfi K, Cunha TM. NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reduces inflammatory pain. Pharmacol Res Perspect. 2015; 3(3):e00133.
• 129. Cenac N, Castro M, Desormeaux C, Colin P, Sie M, Ranger M et al. A novel orally administered trimebutine compound (GIC-1001) is anti-nociceptive and features peripheral opioid agonistic activity and Hydrogen Sulphide-releasing capacity in mice. Eur J Pain. 2016; 20(5):723-30.
• 130. Paquette JM, Rufiange M, Iovu Niculita M, Massicotte J, Lefebvre M, Colin P et al. Safety, tolerability and pharmacokinetics of trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) in a randomized phase I integrated design study: single and multiple ascending doses and effect of food in healthy volunteers. Clin Ther. 2014; 36(11):1650-64.
• 131. Kondo K, Bhushan S, King AL, Prabhu SD, Hamid T, Koenig S et al. H₂S protects against pressure overload-induced heart failure via upregulation of endothelial nitric oxide synthase. Circulation. 2013; 127(10):1116-27.
• 132. Shimizu Y, Polavarapu R, Eskla KL, Nicholson CK, Koczor CA, Wang R et al. Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK. J Mol Cell Cardiol. 2018; 116:29-40.
• 133. Barr LA, Shimizu Y, Lambert JP, Nicholson CK, Calvert JW. Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress. Nitric Oxide. 2015; 46:145-56.
• 134. Rushing AM, Donnarumma E, Polhemus DJ, Au KR, Victoria SE, Schumacher JD et al. Effects of a novel hydrogen sulfide prodrug in a porcine model of acute limb ischemia. J Vasc Surg. 2019; 69(6):1924-1935.
• 135. Polhemus DJ, Li Z, Pattillo CB, Gojon G Sr, Gojon G Jr, Giordano T et al. A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients. Cardiovasc Ther. 2015; 33(4):216-26.
• 136. Le Trionnaire S, Perry A, Szczesny B, Szabo C, Winyard PG, Whatmore JL et al. The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor,(10-oxo-10-(4-(3-thioxo-3 H-1, 2-dithiol-5-yl) phenoxy) decyl) triphenylphosphonium bromide (AP39). Medchemcomm. 2014; 5(6):728-736.
• 137. Szczesny B, Módis K, Yanagi K, Coletta C, Le Trionnaire S, Perry A, Wood ME et al. AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro. Nitric Oxide. 2014; 41:120-30.
• 138. Rezai H, Ahmad S, Alzahrani FA, Sanchez-Aranguren L, Dias IH, Agrawal S et al. MZe786, a hydrogen sulfide-releasing aspirin prevents preeclampsia in heme oxygenase-1 haplodeficient pregnancy under high soluble flt-1 environment. Redox Biol. 2021; 38:101768.
• 139. Saif J, Ahmad S, Rezai H, Litvinova K, Sparatore A, Alzahrani FA et al. Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model. Redox Biol. 2021; 38:101814.
• 140. Sanchez-Aranguren LC, Rezai H, Ahmad S, Alzahrani FA, Sparatore A, Wang K et al. MZe786 Rescues Cardiac Mitochondrial Activity in High sFlt-1 and Low HO-1 Environment. Antioxidants. 2020; 9(7):598.
• 141. Bucci M, Vellecco V, Cantalupo A, Brancaleone V, Zhou Z, Evangelista S et al. Hydrogen sulfide accounts for the peripheral vascular effects of zofenopril independently of ACE inhibition. Cardiovasc Res. 2014; 102(1):138-47.
• 142. DRUGBANKonline. Erişim tarihi: 28.04.2021. Available from: https://go.drugbank.com/drugs/DB13166) 2021.