References 1. Konturek PC, Celinski K, Slomka M, Cichoz-Lach H, Burnat G, et al. (2008) Melatonin and its precursor L-tryptophan prevent acute gastric mucosal damage induced by aspirin in humans. J Physiol Pharmacol 59 Suppl 2: 67–75. 2. Blandizzi C, Tuccori M, Colucci R, Fornai M, Antonioli L, et al. (2009) Role of coxibs in the strategies for gastrointestinal protection in patients requiring chronic non-steroidal anti-inflammatory therapy. Pharmacol Res 59: 90–100. 3. Becker JC, Domschke W, Pohle T (2004) Current approaches to prevent NSAID-induced gastropathy–COX selectivity and beyond. Br J Clin Pharmacol 58: 587–600. 4. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, et al. (1995) Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A ran- domized, double-blind, placebo-controlled trial. Ann Intern Med 123: 241–249. 5. Naesdal J, Brown K (2006) NSAID-associated adverse effects and acid control aids to prevent them: a review of current treatment options. Drug Saf 29: 119– 132. 6. Blandizzi C, Tuccori M, Colucci R, Gori G, Fornai M, et al. (2008) Clinical efficacy of esomeprazole in the prevention and healing of gastrointestinal toxicity associated with NSAIDs in elderly patients. Drugs Aging 25: 197–208. 7. Wang R (2002) Two’s company, three’s a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16: 1792–1798. 8. Yang G, Wu L, Jiang B, Yang W, Qi J, et al. (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322: 587–590. 9. Lu M, Hu LF, Hu G, Bian JS (2008) Hydrogen sulfide protects astrocytes against H(2)O(2)-induced neural injury via enhancing glutamate uptake. Free Radic Biol Med 45: 1705–1713. 10. Hu LF, Lu M, Wu ZY, Wong PT, Bian JS (2009) Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. Mol Pharmacol 75: 27–34. 11. Hu LF, Wong PT, Moore PK, Bian JS (2007) Hydrogen sulfide attenuates lipopolysaccharide-induced inflammation by inhibition of p38 mitogen-activated protein kinase in microglia. J Neurochem 100: 1121–1128. 12. Qingyou Z, Junbao D, Weijin Z, Hui Y, Chaoshu T, et al. (2004) Impact of hydrogen sulfide on carbon monoxide/heme oxygenase pathway in the pathogenesis of hypoxic pulmonary hypertension. Biochem Biophys Res Commun 317: 30–37. 13. Erdmann K, Cheung BW, Immenschuh S, Schroder H (2008) Heme oxygenase- 1 is a novel target and antioxidant mediator of S-adenosylmethionine. Biochem Biophys Res Commun 368: 937–941. 14. Szabo C (2007) Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov 6: 917–935. 15. Sparatore A, Perrino E, Tazzari V, Giustarini D, Rossi R, et al. (2009) Pharmacological profile of a novel H(2)S-releasing aspirin. Free Radic Biol Med 46: 586–592. 16. Rossoni G, Manfredi B, Tazzari V, Sparatore A, Trivulzio S, et al. (2010) Activity of a new hydrogen sulfide-releasing aspirin (ACS14) on pathological cardiovascular alterations induced by glutathione depletion in rats. Eur J Pharmacol 648: 139–145. 17. Li L, Rossoni G, Sparatore A, Lee LC, Del Soldato P, et al. (2007) Anti- inflammatory and gastrointestinal effects of a novel diclofenac derivative. Free Radic Biol Med 42: 706–719. 18. Bian JS, Yong QC, Pan TT, Feng ZN, Ali MY, et al. (2006) Role of hydrogen sulfide in the cardioprotection caused by ischemic preconditioning in the rat heart and cardiac myocytes. J Pharmacol Exp Ther 316: 670–678. 19. Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, et al. (2010) Neuroprotective effects of hydrogen sulfide on Parkinson’s disease rat models. Aging Cell 9: 135–146. 20. Pan TT, Feng ZN, Lee SW, Moore PK, Bian JS (2006) Endogenous hydrogen sulfide contributes to the cardioprotection by metabolic inhibition precondi- tioning in the rat ventricular myocytes. J Mol Cell Cardiol 40: 119–130. 21. Pohle T, Brzozowski T, Becker JC, Van der Voort IR, Markmann A, et al. (2001) Role of reactive oxygen metabolites in aspirin-induced gastric damage in humans: gastroprotection by vitamin C. Aliment Pharmacol Ther 15: 677–687. 22. Giustarini D, Del Soldato P, Sparatore A, Rossi R (2010) Modulation of thiol homeostasis induced by H2S-releasing aspirin. Free Radic Biol Med 48: 1263– 1272. 23. Vulcano M, Dusi S, Lissandrini D, Badolato R, Mazzi P, et al. (2004) Toll receptor-mediated regulation of NADPH oxidase in human dendritic cells. J Immunol 173: 5749–5756. 24. Li JM, Shah AM (2001) Differential NADPH- versus NADH-dependent superoxide production by phagocyte-type endothelial cell NADPH oxidase. Cardiovasc Res 52: 477–486. 25. Muzaffar S, Jeremy JY, Sparatore A, Del Soldato P, Angelini GD, et al. (2008) H2S-donating sildenafil (ACS6) inhibits superoxide formation and gp91phox expression in arterial endothelial cells: role of protein kinases A and G. Br J Pharmacol 155: 984–994. 26. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353: 2373–2383. 27. Suzuki T, Yoshida N, Nakabe N, Isozaki Y, Kajikawa H, et al. (2008) Prophylactic effect of rebamipide on aspirin-induced gastric lesions and S-Aspirin Protects Aspirin-Induced Gastric Injury disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci 106: 469–477. 28. Sorensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH, et al. (2000) Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol 95: 2218–2224. 29. Derry S, Loke YK (2000) Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 321: 1183–1187. 30. Garcia Rodriguez LA, Hernandez-Diaz S, de Abajo FJ (2001) Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol 52: 563–571. 31. Fiorucci S, Antonelli E, Distrutti E, Rizzo G, Mencarelli A, et al. (2005) Inhibition of hydrogen sulfide generation contributes to gastric injury caused by anti-inflammatory nonsteroidal drugs. Gastroenterology 129: 1210–1224. 32. Wallace JL, Caliendo G, Santagada V, Cirino G, Fiorucci S (2007) Gastrointestinal safety and anti-inflammatory effects of a hydrogen sulfide- releasing diclofenac derivative in the rat. Gastroenterology 132: 261–271. 33. Wallace JL (2007) Building a better aspirin: gaseous solutions to a century-old problem. Br J Pharmacol 152: 421–428. 34. Wallace JL, Caliendo G, Santagada V, Cirino G (2010) Markedly reduced toxicity of a hydrogen sulphide-releasing derivative of naproxen (ATB-346). Br J Pharmacol 159: 1236–1246. 35. Osborne NN, Ji D, Abdul Majid AS, Fawcett RJ, Sparatore A, et al. (2010) ACS67, a hydrogen sulfide-releasing derivative of latanoprost acid, attenuates retinal ischemia and oxidative stress to RGC-5 cells in culture. Invest Ophthalmol Vis Sci 51: 284–294. 36. Osborne NN, Ji D, Majid AS, Sodato PD, Sparatore A (2012) Glutamate oxidative injury to RGC-5 cells in culture is necrostatin sensitive and blunted by a hydrogen sulfide (H(2)S)-releasing derivative of aspirin (ACS14). Neurochem Int. 37. Hu LF, Pan TT, Neo KL, Yong QC, Bian JS (2008) Cyclooxygenase-2 mediates the delayed cardioprotection induced by hydrogen sulfide preconditioning in isolated rat cardiomyocytes. Pflugers Arch 455: 971–978. 38. D’Argenio G, Mazzone G, Tuccillo C, Grandone I, Gravina AG, et al. (2008) Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa. Br J Nutr 100: 1228–1236. 39. Fiorucci S, de Lima OM Jr, Mencarelli A, Palazzetti B, Distrutti E, et al. (2002) Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin- induced damage. Gastroenterology 123: 1598–1606. 40. Davies NM, Sharkey KA, Asfaha S, Macnaughton WK, Wallace JL (1997) Aspirin causes rapid up-regulation of cyclo-oxygenase-2 expression in the stomach of rats. Aliment Pharmacol Ther 11: 1101–1108. 41. Brzozowski T, Konturek PC, Konturek SJ, Pajdo R, Schuppan D, et al. (2000) Involvement of cyclooxygenase (COX)-2 products in acceleration of ulcer healing by gastrin and hepatocyte growth factor. J Physiol Pharmacol 51: 751– 773. 42. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, et al. (1997) Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 112: 387–397. 43. Hatazawa R, Tanaka A, Tanigami M, Amagase K, Kato S, et al. (2007) Cyclooxygenase-2/prostaglandin E2 accelerates the healing of gastric ulcers via EP4 receptors. Am J Physiol Gastrointest Liver Physiol 293: G788–797. 44. Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30: 1191–1212. 45. Geng B, Chang L, Pan C, Qi Y, Zhao J, et al. (2004) Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun 318: 756–763. 46. Devai I, Delaune RD (2002) Effectiveness of selected chemicals for controlling emission of malodorous sulfur gases in sewage sludge. Environ Technol 23: 319– 329. 47. Kimura H (2010) Hydrogen sulfide: its production, release and functions. Amino Acids. 48. Goubern M, Andriamihaja M, Nubel T, Blachier F, Bouillaud F (2007) Sulfide, the first inorganic substrate for human cells. FASEB J 21: 1699–1706. 49. Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, et al. (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preser- vation of mitochondrial function. Proc Natl Acad Sci U S A 104: 15560–15565. 50. Yonezawa D, Sekiguchi F, Miyamoto M, Taniguchi E, Honjo M, et al. (2007) A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium. Toxicology 241: 11–18. 51. Kimura Y, Kimura H (2004) Hydrogen sulfide protects neurons from oxidative stress. FASEB J 18: 1165–1167. 52. Qu K, Lee SW, Bian JS, Low CM, Wong PT (2008) Hydrogen sulfide: neurochemistry and neurobiology. Neurochem Int 52: 155–165. 53. Kimura Y, Goto Y, Kimura H (2010) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal 12: 1–13. 54. Kimura Y, Dargusch R, Schubert D, Kimura H (2006) Hydrogen sulfide protects HT22 neuronal cells from oxidative stress. Antioxid Redox Signal 8: 661–670. PLOS ONE | www.plosone.org 9 September 2012 | Volume 7 | Issue 9 | e46301