Gastric Cytoprotection as Basis of Gastrointestinal Mucosa Protection and Repair in Erosive Ulcerative Lesions of Various Aetiologies

Aim. Assessment of efficacy and the mechanism of action of gastrointestinal mucosa (GM) protection in current treatment settings with methylmethionine-sulfonium chloride (vitamin U) to illustrate its applicability in erosive ulcerative lesions of various aetiologies.

Key points. Aside to damage prevention in exposure to aggressive agents, gastroprotection implies healing promotion under the preserved level of hydrochloric acid secretion. Prostaglandins (PG) and SH-antioxidants are key mediators of gastroprotection in acute and chronic damage. SH-containing endogenous substances (L-cysteine, D,L-methionine, GSH) and exogenous molecules (methylmethionine-sulfonium chloride (MMSC), N-acetylcysteine) prevent damage due to the ability to absorb/neutralise free radicals released in xenobiotic-triggered cell damage, inhibit TNF-α expression, reduce the aspirin-induced leukocyte-endothelium adhesion and stimulate mucin release. In experiment, MMSC prevented the ethanol-induced GM damage, stimulated mucin release and its redistribution on the GM surface; in clinical trials, MMSC effectively facilitated remission in duodenal ulcer.

Conclusion. Preparations exerting a protective effect on gastroduodenal mucosa, such as methylmethionine-sulfonium chloride (vitamin U), may improve basic treatment settings and facilitate remission in erosive ulcerative lesions of upper gastrointestinal tract.

1. Ivashkin V.T., Mayev I.V., Lapina T.L., Sheptulin A.A., Trukhmanov A.S., Baranskaya Y.K., et al. Diagnostics and treatment of Helicobacter pylori infection in adults: Clinical guidelines of the Russian gastroenterological association. Rus J Gastroenterol Hepatol Coloproctol. 2018;28(1):55–70 (In Russ.). DOI: 10.22416/1382-4376-2018-28-1-55-70

2. Karateev A.E., Nasonov E.L., Ivashkin V.T., Martynov A.I., Yakhno N.N., Arutyunov G.P. et al. Rational use of nonsteroidal anti-inflammatory drugs. Clinical guidelines. Rheumatology Science and Practice. 2018;56:1–29. (In Russ.) DOI: 10.14412/1995-4484-2018-1-29

3. Nazarov V.E. Failures of eradication therapy unrelated to Helicobacter pylori antibiotic resistance and routes to their solution. RMJ. Medical Review. 2018. 26(3):4–12. (In Russ.).

4. Evseev M.A. NSAID-induced bleeding-complicated gastroduodenal ulcers. RMJ. 2006;15:1099–107. (In Russ.).

5. Shostak N.A., Ryabkova A.A., Savelyev V.S., and Malyarova L.P. Gastrointestinal bleeding as complication of NSAID-associated gastropathies. Terapevticheskiy archiv. 2003;5:70–4. (In Russ.).

6. Washio E., Esaki M., Maehata Y., Miyazaki M., Kobayashi H., Ishikawa H., et al. Proton Pump Inhibitors Increase Incidence of Nonsteroidal Anti-Inflammatory Drug-Induced Small Bowel Injury: A Randomized, Placebo-Controlled Trial. Clin. Gastroenterol. Hepatol. 2016;14(6):809–15. DOI: 10.1016/j.cgh.2015.10.022

7. Flores M., Glusman G., Brogaard K., Price N.D., Hood L. P4 medicine: How systems medicine will transform the healthcare sector and society. Personalized Medicine. 2013;10(6):565–76. DOI: 10.2217/pme.13.57

8. Robert A. Antisecretory and antiulcer properties of prostaglandins. Compr Ther. 1978;4(7):3–10.

9. Robert A., Nezamis J.E., Lancaster C. Duodenal ulcers produced in rats by propionitrile: factors inhibiting and aggravating such ulcers. Toxicol Appl Pharmacol. 1975;31(2):201–7. DOI: 10.1016/0041-008x(75)90156-8

10. Robert A., Nezamis J.E., Lancaster C., Hanchar A.J. Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury. Gastroenterology. 1979;77(3):433–43. DOI: 10.1016/0016-5085(79)90002-7

11. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979;77(4):761–7. DOI: 10.1016/0016-5085(79)90235-X

12. Guth P.H., Aures D., Paulsen G. Topical aspirin plus HCl gastric lesions in the rat. Cytoprotective effect of prostaglandin, cimetidine, and probanthine. Gastroenterology. 1979;76(1):88–93. DOI: 10.1016/S0016-5085(79)80133-X

13. Szabo S., Gallagher G.T., Horner H.C., Frankel P.W., Underwood R.H., Konturek S.J., et al. Role of the Adrenal Cortex in Gastric Mucosal Protection by Prostaglandins, Sulfhydryls, and Cimetidine in the Rat. Gastroenterology. 1983;85(6):1384–90. DOI: 10.1016/S0016-5085(83)80022-5

14. Szabo S., Tache Y., Tarnawski A. The ‘gastric cytoprotection’ concept of Andre Robert and the origins of a new series of international symposia. Cell/Tissue Inj Cytoprot Gastrointest Tract Mech Prev Treat. 2012;30:1–23. DOI: 10.1159/000338742

15. Szabo S., Trier J.S., Frankel P.W. Sulfhydryl compounds may mediate gastric cytoprotection. Science. 1981;214(4571):200–2. DOI: 10.1126/science.7280691

16. Lacy E.R., Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology. 1982;83:619–25. DOI: 10.1016/S0016-5085(82)80198-4

17. Lacy E.R., Ito S. Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Lab Invest. 1984;51(5):573–83.

18. Szabo S., Trier J.S., Brown A., Schnoor J. Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat. Gastroenterology. 1985;88(1):228–36. DOI: 10.1016/s0016-5085(85)80176-1

19. Szabo S., Szelenyi I. ‘Cytoprotection’ in gastrointestinal pharmacology. Trends in Pharmacological Sciences. Elsevier Current Trends. 1987;8(4):149–54. DOI: 10.1016/0165-6147(87)90185-4

20. Ivashkin V.T., Mayev I.V., Ivashkin K.V., Korochanskaya N.V., Lopina O.D., Lapina T.L. et al. Protection factor disorders in acid-related diseases (Expert Council Resolution of 12–13 March, 2016). Rus J Gastroenterol Hepatol Coloproctol. 2016;26(3):115–6 (In Russ.). DOI: 10.22416/1382-4376-2016-26-3-115-116

21. Laine L., Takeuchi K., Tarnawski A. Gastric Mucosal Defense and Cytoprotection: Bench to Bedside. Gastroenterology. 2008;135(1):41–60. DOI: 10.1053/j.gastro.2008.05.030

22. Trier J.S., Szabo S., Allan C.H. Ethanol-induced damage to mucosal capillaries of rat stomach. Ultrastructural features and effects of prostaglandin F2β and cysteamine. Gastroenterology. 1987;92(1):13–22. DOI: 10.1016/0016-5085(87)90834-1

23. Szabo S. ‘Gastric cytoprotection’ is still relevant. J. Gastroenterol. Hepatol. 2014;29(S4):124–32. DOI: 10.1111/jgh.12735

24. Leung F.W., Robert A., Guth P.H. Gastric mucosal blood flow in rats after administration of 16,16-dimethyl prostaglandin E2 at a cytoprotective dose. Gastroenterology. 1985;88(6):1948–53. DOI: 10.1016/0016-5085(85)90024-1

25. Samsonov A.A., Golubev N.N., Andreev N.G., Shcherbakova N.A. Gastric mucosa protective barrier and prospects of drug cytoprotection. Spravochnik poliklinicheskogo vracha. 2018;6:40–8 (In Russ.).

26. Tarnawski A., Stachura J., Gergely H., Hollander D. Microvascular endothelium-a major target for alcohol injury of the human gastric mucosa. Histochemical and ultrastructural study. J Clin Gastroenterol. 1988;10(Suppl 1):53–64.

27. Kumar V., Abbas A.K., Fausto N., Aster J.C. Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult-Online. 2009.

28. Mozsik G., Szabo I.L., Czimmer J. Approaches to Gastrointestinal Cytoprotection: From Isolated Cells, Via Animal Experiments to Healthy Human Subjects and Patients with Different Gastrointestinal Disorders. Curr Pharm Des. 2011;17(16):1556–72. DOI: 10.2174/138161211796197016

29. Peskar B.M. Neural aspects of prostaglandin involvement in gastric mucosal defense. J Physiol Pharmacol. 2001;52(4):555–68. PMID: 11787758

30. Kang J.Y., Teng C.H., Chen F.C., Wee A. Role of capsaicin sensitive nerves in epidermal growth factor effects on gastric mucosal injury and blood flow. Gut. 1998;42(3):344–50. DOI: 10.1136/gut.42.3.344

31. Holzer P. Neural regulation of gastrointestinal blood flow. Physiology of the gastrointestinal tract. 4th Edition. New York: Academic Press. 2006:817–39.

32. Holzer P. Role of visceral afferent neurons in mucosal inflammation and defense. Current Opinion in Pharmacology. 2007;7(6):563–9. DOI: 10.1016/j.coph.2007.09.004

33. Robert A. Cytoprotection and adapted cytoprotection. Peptic Ulcer Disease: Basic and Clinical Aspects. Springer Netherlands. 1985:297–316.

34. Kokoska E.R., Smith G.S., Deshpande Y., Rieckenberg C.L., Miller T.A. Adaptive cytoprotection induced by ethanol in human intestinal cells: Role of prostaglandins and calcium homeostasis. Ann Surg. 1988;228(1):123–30. DOI: 10.1097/00000658-199807000-00018

35. Allen A., Flemström G. Gastroduodenal mucus bicarbonate barrier: Protection against acid and pepsin. Am J Physiol — Cell Physio. 2005;288(1):57–61. DOI: 10.1152/ajpcell.00102.2004

36. Ribeiro A.R.S., Valenca J.D.N., Santos J.S., Boeing Th., Silva L.M., Andrade S.F., et al. The effects of baicalein on gastric mucosal ulcerations in mice: Protective pathways and anti-secretory mechanisms. Chem Biol Interact. 2016;260:33–41. DOI: 10.1016/j.cbi.2016.10.016

37. Celli J.P., Turner B.S., Afdhal N.H., Keates S., Ghiran I., Kelly C.P., et al. Helicobacter pylori moves through mucus by reducing mucin viscoelasticity. Proc Natl Acad Sci USA. 2009;106(34):14321–6. DOI: 10.1073/pnas.0903438106

38. Terano A., Mach T., Stachura J., Tarnawski A., Ivey K.J. Effect of 16,16 dimethyl prostaglandin E2 on aspirin induced damage to rat gastric epithelial cells in tissue culture. Gut. 1984;25(1):19–25. DOI: 10.1136/gut.25.1.19

39. Tarnawski A., Brzozowski T., Sarfeh I.J., Krause W.J., Ulich T.R., Gergely H., et al. Prostaglandin protection of human isolated gastric glands against indomethacin and ethanol injury. Evidence for direct cellular action of prostaglandin. J Clin Invest. 1988;81(4):1081. DOI: 10.1172/JCI113420

40. Ham M., Kaunitz J.D. Gastroduodenal defense. Curr Opin Gastroenterol. 2007;23(6):607–16. DOI: 10.1097/MOG.0b013e3282f02607

41. 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. DOI: 10.1053/j.gastro.2005.07.060

42. Fiorucci S., Distrutti E., Cirino G., Wallace J.L. The Emerging Roles of Hydrogen Sulfide in the Gastrointestinal Tract and Liver. Gastroenterology. 2006;131(1):259–71. DOI: 10.1053/j.gastro.2006.02.033

43. Lamont J.T., Ventola A.S., Maull E.A., Szabo S. Cysteamine and prostaglandin F2 beta stimulate rat gastric mucin release. Gastroenterology. 1983;84(2):306–13.

44. Gustafson J., Welling D. ‘No Acid, No Ulcer’ — 100 Years Later: A Review of the History of Peptic Ulcer Disease. J Am Coll Surg. 2010; 210(1):110–6. DOI: 10.1016/j.jamcollsurg.2009.08.014

45. Szabo S., Vincze A. Growth factors in ulcer healing: lessons from recent studies. J. Physiol. Paris. 2000;94(2):77–81. DOI: 10.1016/s0928-4257(00)00146-7

46. Sandor Z., Nagata M., Kusstatscher S., Szabo S. Stimulation of mucosal glutathione and angiogenesis: New mechanisms of gastroprotection and ulcer healing by sucralfate. Scand J Gastroenterol. 1995;30(S210):19–21. DOI: 10.3109/00365529509090263

47. Salim A.S. Role of sulfhydryl-containing agents in the healing of erosive gastritis and chronic gastric ulceration in the rat. J Pharm Sci. 1992;81(1):70–3. DOI: 10.1002/jps.2600810114

48. Cheney G. Anti-peptic ulcer dietary factor (vitamin ‘U’) in the treatment of peptic ulcer. J Am Diet Assoc.1950;26(9):668–72.

49. Nesterova A.P., Tayts N.S. Application of vitamin U in complex peptic ulcer therapy. Institute of Nutrition, USSR Academy of Medical Sciences. Vitamin U (S-methylmethionine). Nature, properties and application. Moscow: Nauka, 1973:53–60 (In Russ.).

50. Samson E.I., Lukanev G.D. Therapeutic efficacy of vitamin U in peptic ulcer. Institute of Nutrition, USSR Academy of Medical Sciences. Vitamin U (S-methylmethionine). Nature, properties and application. Moscow: Nauka, 1973:96–101 (In Russ.).

51. Watanabe T., Ohara S., Miyazawa S., Saigenji K., Hotta K. Augmentative effects of L-cysteine and methylmethionine sulfonium chloride on mucin secretion in rabbit gastric mucous cells. J Gastroenterol Hepatol. 2000;15(1):45–52.DOI: 10.1046/j.1440-1746.2000.02037.x

52. Watanabe T., Ohara S., Ichikawa T., Saigenji K., Hotta K. Mechanisms for cytoprotection by vitamin U from ethanol-induced gastric mucosal damage in rats. Dig Dis Sci. 1996;41(1):49–54. DOI: 10.1007/BF02208583

53. Ichikawa T., Ito Y., Saegusa Y., Iwai T., Goso Y., Ikezawa T., et al. Effects of combination treatment with famotidine and methylmethionine sulfonium chloride on the mucus barrier of rat gastric mucosa. J Gastroenterol Hepatol. 2009;24(3):488–92. DOI: 10.1111/j.1440-1746.2008.05667.x

54. Patel A.D., Prajapati N.K. Review on Biochemical Importance of Vitamin-U. J Chem Pharm Res. 2012;1:209–15.

55. Nakamura N., Uzawa H., Kanazawa K., Tamai Y., Tashiro Y., Koide M. Hypolipidemic effect of L-form Smethylmethionine sulfonium chloride in man. Arzneimittel-Forschung/Drug Res. 1981;31(4):725–9. PMID: 7195721

56. Lee N.Y., Park K.Y., Min H.J., Song K.Y. Inhibitory effect of vitamin U (S-methylmethionine sulfonium chloride) on differentiation in 3T3-L1 pre-adipocyte cell lines. Ann Dermatol. 2012;24(1):39–44. DOI: 10.5021/ad.2012.24.1.39

57. Tunali S., Kahraman S., Yanardag R. Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid. Hum Exp Toxicol. 2015;34(9):904–10. DOI: 10.1177/0960327114561665

58. Sokmen B.B., Tunali S., Yanardag R. Effects of vitamin U (S-methyl methionine sulphonium chloride) on valproic acid induced liver injury in rats. Food Chem Toxicol. 2012;50(10):3562–6. DOI: 10.1016/j.fct.2012.07.056

59. Kim W.S., Yang Y.J., Min H.G., Song M.G., Lee J.S., Park K.Y., et al. Accelerated Wound Healing by S-Methylmethionine Sulfonium: Evidence of Dermal Fibroblast Activation via the ERK1/2 Pathway. Pharmacology. 2010;85(2):68–76. DOI: 10.1159/000276495

60. Kim W.S., Seo H.M., Kim W.K., Choi J.S., Kim I., Sung J.H. The photoprotective effect of S-methylmethionine sulfonium in skin. Int J Mol Sci. 2015;16(8):17088–100. DOI: 10.3390/ijms160817088

61. Salim A.S. Sulphydryl-containing agents and the prevention of duodenal ulcer relapse. Pharmacology.1993;46(5):281–8. DOI: 10.1159/000139056