Volume 9, Issue 1 (Vol.9 No.1 Apr 2020)                   rbmb.net 2020, 9(1): 115-128 | Back to browse issues page


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Ahmed Mobasher M, Galal El-Tantawi H, Samy El-Said K. Metformin Ameliorates Oxidative Stress Induced by Diabetes Mellitus and Hepatocellular Carcinoma in Rats. rbmb.net. 2020; 9 (1) :115-128
URL: http://rbmb.net/article-1-445-en.html
Department of Pathology, Biochemistry Division, College of Medicine, Jouf University, Sakaka, Saudi Arabia. & Department of Clinical Pathology, El Ahrar Educational Hospital, Ministry of Health, Zagazig, Egypt.
Abstract:   (350 Views)
Background: Several studies have found an association between Diabetes mellitus (DM) and an increased risk for hepatocellular carcinoma (HCC). Evidence suggests that Metformin (Met) may have a therapeutic and protective effect against both DM and HCC. Therefore, the aim of this study was to evaluate the antioxidant effect of Met against DM and HCC-induced oxidative stress in rat model.

Methods: Forty-two male albino rats were randomly divided into six groups. Group 1 (Gp1) was the control group, Gp2 received an intraperitoneal (i.p.) injection with streptozotocin (STZ), Gp3 was injected i.p. with diethyl nitrosamine (DEN), Gp4 received an oral administration of Met, Gp5 and Gp6 received the same injections as Gp2 and Gp3, respectively, then received an additional injection of Met. Oxidative stress biomarkers, including superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and malondialdehyde (MDA), were examined. Furthermore, biochemical parameters including liver function tests were assessed. Histopathological and immunohistochemical alterations of the liver were also examined.

Results: Our results demonstrate that Gp2 and Gp3 had significant signs of liver dysfunction and had elevated levels of MDA and reduced levels of SOD, CAT, and GSH. Additionally, Gp2 and Gp3 showed significant alterations in the liver architecture shown by high PCNA and caspase-3 expression. In the Gp5 and Gp6, treatment with Met showed an improvement in liver function, oxidative stress biomarkers, and reduced histopathological changes in hepatocytes.

Conclusions: This study offers insight into the potential for Metformin as a novel therapeutic against the oxidative stress induced by DM or HCC.
Full-Text [PDF 432 kb]   (105 Downloads)    
Type of Article: Original Article | Subject: Biochemistry
Received: 2020/01/10 | Accepted: 2020/02/2 | Published: 2020/07/18

References
1. Lam DW, LeRoith D. The worldwide diabetes epidemic. Curr Opin Endocrinol Diabetes Obes. 2012;19(2):93-96. [DOI:10.1097/MED.0b013e328350583a] [PMID]
2. Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol. 2017;9(16):715-732. [DOI:10.4254/wjh.v9.i16.715] [PMID] [PMCID]
3. Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis. 2015;19(2):361-79. [DOI:10.1016/j.cld.2015.01.012] [PMID] [PMCID]
4. Abdullaev FI, Rivera LR, Roitenburd BV, Espinosa AJ. Pattern of childhood cancer mortality in Mexico. Arch Med Res. 2000;31(5):526-31. [DOI:10.1016/S0188-4409(00)00094-1]
5. Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene. 2006;25(27):3771-7. [DOI:10.1038/sj.onc.1209560] [PMID]
6. Huang Y, Cai X, Qiu M, Chen P, Tang H, Hu Y, et al. Prediabetes and the risk of cancer: a meta-analysis. Diabetologia. 2014;57(11):2261-9. [DOI:10.1007/s00125-014-3361-2] [PMID]
7. Mantovani A, Targher G. Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease. Ann Transl Med. 2017;5(13):270. [DOI:10.21037/atm.2017.04.41] [PMID] [PMCID]
8. Tan Y, Wei S, Zhang W, Yang J, Yang J, Yan L. Type 2 diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection: a meta-analysis and systematic review. Cancer Manag Res. 2019;11:705-713. [DOI:10.2147/CMAR.S188238] [PMID] [PMCID]
9. DeCensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and metaanalysis. Cancer Prev Res (Phila). 2010;3(11):1451-61. [DOI:10.1158/1940-6207.CAPR-10-0157] [PMID]
10. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674-85. [DOI:10.2337/dc10-0666] [PMID] [PMCID]
11. Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, et al. Pathological aspects of lipid peroxidation. Free Radic Res. 2010;44(10):1125-71. [DOI:10.3109/10715762.2010.498478] [PMID]
12. Halliwell B. Free radicals and antioxidants-quo vadis?. Trends Pharmacol Sci. 2011;32(3):125-30. [DOI:10.1016/j.tips.2010.12.002] [PMID]
13. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. [DOI:10.2337/dc08-9025] [PMID] [PMCID]
14. Bosetti C, Franchi M, Nicotra F, Asciutto R, Merlino L, La Vecchia C, et al. Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases. Pharmacoepidemiol Drug Saf. 2015;24(7):771-8. [DOI:10.1002/pds.3801] [PMID]
15. DePeralta DK, Wei L, Ghoshal S, Schmidt B, Lauwers GY, Lanuti M, et al. Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis. Cancer. 2016;122(8):1216-27. [DOI:10.1002/cncr.29912] [PMID] [PMCID]
16. Gallagher EJ, LeRoith D. Diabetes, cancer, and metformin: connections of metabolism and cell proliferation. Ann N Y Acad Sci. 2011;1243(1):54-68. [DOI:10.1111/j.1749-6632.2011.06285.x] [PMID]
17. Alzoubi KH, Khabour OF, Al-Azzam SI, Tashtoush NH, Mhaidat NM. Metformin eased cognitive impairment induced by chronic L-methionine administration: potential role of oxidative stress. Curr Neuropharmacol. 2014;12(2):186-92. [DOI:10.2174/1570159X11666131120223201] [PMID] [PMCID]
18. Brondum E, Nilsson H, Aalkjaer C. Functional abnormalities in isolated arteries from Goto-Kakizaki and streptozotocin-treated diabetic rat models. Horm Metab Res. 2005;37(Suppl 1):56-60. [DOI:10.1055/s-2005-861370] [PMID]
19. Salemi Z, Rafie E, Goodarzi MT, Ghaffari MA. Effect of Metformin, Acarbose and Their Combination on the Serum Visfatin Level in Nicotinamide/Streptozocin-Induced Type 2 Diabetic Rats. Iran Red Crescent Med J. 2016;18(3):e23814. [DOI:10.5812/ircmj.23814]
20. Kaplan RM. The connection between clinical health promotion and health status: A critical overview. Am Psychol. 1984,39(7):755-65. [DOI:10.1037/0003-066X.39.7.755] [PMID]
21. Belfield A, Goldberg DM. Revised assay for serum phenyl phosphatase activity using 4-amino-antipyrine. Enzyme. 1971;12(5):561-73. [DOI:10.1159/000459586] [PMID]
22. Patil NB, Somvanshi BS, Kothari RM. A simple and rapid high recovery protocol for the purification of arginase. Biotechnol Tech. 1990;4(2):133-36. [DOI:10.1007/BF00163287]
23. Lowry OH, Roserbrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.
24. Burtis C, Bruns D. Tietz fundamentals of clinical chemistry. 6th ed. Elsevier Health Sciences; 2007.
25. Walter M, Gerade H. A colorimetric method for determination bilirubin in serum and plasma. Micro Chem J. 1970;15:231-36. [DOI:10.1016/0026-265X(70)90045-7]
26. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20(4):470-475. [DOI:10.1093/clinchem/20.4.470] [PMID]
27. Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem. 1982;28(10):2077-80. [DOI:10.1093/clinchem/28.10.2077] [PMID]
28. Burstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970;11(6):583-95.
29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499-502. [DOI:10.1093/clinchem/18.6.499] [PMID]
30. Paoletti F, Mocali A. Determination of superoxide dismutase activity by purely chemical system based on NAD(P)H oxidation. Methods Enzymol. 1990;186:209-20. [DOI:10.1016/0076-6879(90)86110-H]
31. Aebi, H. Catalase in Vitro. Methods Enzymol. 1984;105:121-6. [DOI:10.1016/S0076-6879(84)05016-3]
32. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967;70(1):158-69.
33. Li XY, Chow CK. An improved method for the measurement of malondialdehyde in biological samples. Lipids. 1994;29(1):73-75. [DOI:10.1007/BF02537094] [PMID]
34. Bancroft JD, Stevens A. Theory and practical of histological techniques. 4th ed. Churchill Livingstone. New York: Edinburg and London;1996.
35. Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H, et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism. 2008;57(8):1071-7. [DOI:10.1016/j.metabol.2008.03.010] [PMID]
36. Bułdak L, Łabuzek K, Bułdak RJ, Kozłowski M, Machnik G, Liber S, et al. Metformin affects macrophages' phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep. 2014;66(3):418-29. [DOI:10.1016/j.pharep.2013.11.008] [PMID]
37. Wiernsperger NF. Oxidative stress as a therapeutic target in diabetes: revisiting the controversy. Diabetes Metab. 2003;29(6):579-85. [DOI:10.1016/S1262-3636(07)70072-1]
38. Vuppalanchi R, Juluri R, Bell LN, Ghabril M, Kamendulis L, Klaunig JE, et al. Oxidative stress in chronic liver disease: relationship between peripheral and hepatic measurements. Am J Med Sci. 2011;342(4):314-317. [DOI:10.1097/MAJ.0b013e31821d9905] [PMID] [PMCID]
39. Erejuwa OO, Gurtu S, Sulaiman SA, Ab Wahab MS, Sirajudeen KN, Salleh MS. Hypoglycemic and antioxidant effects of honey supplementation in streptozotocin-induced diabetic rats. Int J Vitam Nutr Res. 2010;80(1):74-82. [DOI:10.1024/0300-9831/a000008] [PMID]
40. Liu Z, Li J, Zeng Z, Liu M, Wang M. The antidiabetic effects of cysteinyl metformin, a newly synthesized agent, in alloxan- and streptozocin-induced diabetic rats. Chem Biol Interact. 2008;173(1):68-75. [DOI:10.1016/j.cbi.2007.11.012] [PMID]
41. Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711-60. [DOI:10.1146/annurev.bi.52.070183.003431] [PMID]
42. Maritim AC, Sanders RA, Watkins JB. Diabetes, oxidative stress and antioxidants: a review. J Biochem Mol Toxicol. 2003;17(1):24-38. [DOI:10.1002/jbt.10058] [PMID]
43. Erejuwa OO, Sulaiman SA, Wahab MS, Salam SK, Salleh MS and Gurtu S. Comparison of antioxidant effects of honey, glibenclamide, metformin, and their combinations in the kidneys of streptozotocin-induced diabetic rats. Int J Mol Sci. 2011;12(1):829-843. [DOI:10.3390/ijms12010829] [PMID] [PMCID]
44. Ahmad A, Alkreathy HM. Comparative biochemical and histopathological studies on the efficacy of metformin and Nigella sativa oil against thioacetamide-induced acute hepatorenal damage in rats. Biomed Res. 2018;29(15):3106-16. [DOI:10.4066/biomedicalresearch.29-18-914]
45. Hadi NR, Al-Amran FG, Swadi A. Metformin ameliorates methotrexate-induced hepatotoxicity. J Pharmacol Pharmacother. 2012;3(3):248-253. [DOI:10.4103/0976-500X.99426] [PMID] [PMCID]
46. Fu YL, Zhang QH, Wang XW, He H. Antidiabetic drug metformin mitigates ovarian cancer SKOV3 cell growth by triggering G2/M cell cycle arrest and inhibition of m-TOR/PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci. 2017;21(5):1169-1175.
47. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetol. 2017;60(9):1577-1585. [DOI:10.1007/s00125-017-4342-z] [PMID] [PMCID]

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


© 2015 All Rights Reserved | Reports of Biochemistry and Molecular Biology

Designed & Developed by : Yektaweb