Research Article

DOI :10.26650/IstanbulJPharm.2023.1005935   IUP :10.26650/IstanbulJPharm.2023.1005935    Full Text (PDF)

The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice

Ayşe Karatuğ KaçarOnur ErtikZeynep Mine Coşkun YazıcıSema BolkentRefiye YanardağŞehnaz Bolkent

Background and Aims: The aim of this study was to investigate the histological and biochemical effects of the antioxidant combination on liver tissue of streptozotocin (STZ)-induced diabetic mice.

Methods: Five groups of mice were given a citrate buffer (CB), the antioxidant solvents (AS), the antioxidant combination (A) (α-lipoic acid, selenium, and vitamin E), STZ (D), the antioxidant combination and STZ (A+D). The mice were sacrificed, and their liver tissues were taken out. The liver tissues were examined histologically and immune+ cell numbers of cannabinoid receptors (CB1R and CB2R) were detected. Xanthine oxidase (XO) activity, glutathione (GSH) and lipid peroxidation (LPO) levels, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), γ-glutamyl transferase (GGT), paraoxonase (PON), glucose-6-phosphate dehydrogenase (G6PD) activities, protein carbonyl content (PCC) and advanced oxidation protein product (AOPP), sialic acid, fucose, hexose and hydroxyproline (OH-proline) levels were biochemically determined.

Results: Certain degenerative changes were reduced in the A+D group compared histologically to the D group. There were no significant changes in the number of CB1R immune+ cells. The number of CB2R immune+ cells was significantly reduced in the D group compared to the CB group. The GSH level, CAT, SOD, GR, GPx, GST, PON, and G6PD activities were increased while XO and GGT activity, LPO, PCC, AOPP, hexose, fucose, sialic acid, and OH-proline level were biochemically decreased in the A+D group compared to the D group.

Conclusion: The use of the antioxidant combination had a positive effect on the livers of diabetic mice with histochemical and biochemical changes, while there was no effect on the regulation of cannabinoid receptors expressions.

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  • Adeyemi, D. O., Ukwenya, V. O., Obuotor, E. M., & Adewole, S. O. (2014). Antihepatotoxic activities of Hibiscus sabdariffa L. in animal model of streptozotocin diabetes-induced liver damage. BMC Complementary Medicine and Therapies, 14, 277-288. google scholar
  • Aebi, H. (1984). Catalase in vitro. Methods in Enzymology, 105, 121-126. google scholar
  • Al-Attar, A. M., & Alsalmi, F. A. (2019). Influence of olive leaves ex-tract on hepatorenal injury in streptozotocin diabetic rats. Saudi Journal of Biological Sciences, 26, 1865-1874. google scholar
  • Asmat, U., Abad, K., & Ismail, K. (2016). Diabetes mellitus and oxidative stress-A concise review. Saudi Pharmaceutical Journal, 24(5), 547-553. google scholar
  • Aydin, S., Bacanli, M., Anlar, H. G., Cal, T., Ari, N., Undeger Bucurgat, U., Başaran, A. A., & Basaran, N. (2019). Preventive role of Pycno-genol against the hyperglycemia-induced oxidative stress and DNA damage in diabetic rats. Food and Chemical Toxicology, 124, 54-63. google scholar
  • Ballestri, S., Zona, S., Targher, G., Romagnoli, D., Baldelli, E., Nascim-beni, F., Roverato, A., Guaraldi, G., & Lonardo, A. (2016). Nonalco-holic fatty liver disease is associated with an almost twofold in-creased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. Journal of Gastroenterology and Hepatology, 31, 936-944. google scholar
  • Barbosa, N. B., Rocha, J. B., Soares, J. C., Wondracek, D. C., Gon-calves, J. F., Schetinger, M. R. C., & Nogueira, C. W. (2008). Dietary diphenyl diselenide reduces the STZ-induced toxicity. Food and Chemical Toxicology, 46(1), 186-194. google scholar
  • Baskol, G., Gumus, K., Oner, A., Arda, H., & Karakucuk, S. (2008). The role of advanced oxidation protein products and total thiols in diabetic retinopathy. European Journal of Ophthalmology, 18, 792-798. google scholar
  • Bazwinsky-Wutschke, I., Zipprich, A., & Dehghani, F. (2017). Day-time-dependent changes of cannabinoid receptor type 1 and type 2 expression in rat liver. International Journal of Molecular Sciences, 18(9), 1844. google scholar
  • Bazwinsky-Wutschke, I., Zipprich, A., & Dehghani, F. (2019). En-docannabinoid system in hepatic glucose metabolism, fatty liver disease, and cirrhosis. International Journal of Molecular Sci-ences, 20(10), 2516. google scholar
  • Beutler, E. (1971). Red cell metabolism. A manual of biochemical methods. Vol. 12. London: Academic Press, 68-70. google scholar
  • Beutler, E. (1975). Red cell metabolism. A manual of biochemical methods, 2nd edn. Grune and Stratton, New York, 112-114. google scholar
  • Beutler, E. (1984). Red cell metabolism. A Manual of Biochemical Methods; 3rd ed., Orlando, grune and siration, 68-70. google scholar
  • Camps, J., Marsillach, J., & Joven, J. (2009). The paroxanases: role in human diseases and methodological difficulties in measure-ment. Critical Reviews in Clinical Laboratory Sciences, 46, 83-106. google scholar
  • Corte, E. D., & Stirpe, F. (1968). Regulation of xanthine oxidase in rat liver: modifications of the enzyme activity of rat liver super-natant on the storage at 20 degrees. Biochemical Journal, 108, 349-351. google scholar
  • Daniel, O. O., Adeoye, A. O., Ojowu, J., & Olorunsogo, O. O. (2018). Inhibition of liver mitochondrial membrane permeability transi-tion pore opening by quercetin and vitamin E in streptozotocin-induced diabetic rats. Biochemical and Biophysical Research Com-munications, 504(2), 460-469. google scholar
  • Dayanand, C. D., Kumar Vegi, P., & Kutty, A. V. M. (2012). Protein carbonyl content as a stable oxidative stress marker in type II dia-betes. International Journal of Biological and Medical Research, 3(4), 2362-2365. google scholar
  • Di Marzo, V. (2008). The endocannabinoid system in obesity and type 2 diabetes. Diabetologia, 51(8), 1356-1367. google scholar
  • Dische, Z., & Shettles, L. B. (1948). A specific color reaction of methylpentoses and a spectrophotometric micromethod for their determination. Journal of Biological Chemistry, 175, 595. google scholar
  • Durrington, P. N., Mackness, B., & Mackness, M. I. (2001). Paraox-onase and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascu-lar Biology, 21, 473. google scholar
  • Faddladdeen, K. A. J. (2021). Ameliorating effect of pomegranate peel extract supplement against type 1 diabetes-induced hepatic changes in the rat: biochemical, morphological and ultrastructural microscopic studies. Folia Morphologica (Warsz), 80(1), 149-157. google scholar
  • Furlong, C. E., Rchter, R. J., & Seidel, S. L. (1988). Role of genetic polymorphism of human plasma paraoxonase/arylesterase in hydrolysis of the insecticide metabolites chlorpyrifos oxon and paraoxon. The American Journal of Human Genetics, 43, 230-238. google scholar
  • Gezginci-Oktayoglu, S., Sacan, O., Yanardag, R., Karatug, A., & Bolkent, S. (2011). Exendin 4 improves hepatocyte injury by de-creasing proliferation through blocking NGF/TrkA in diabetic mice. Peptides, 32, 223-231. google scholar
  • Girotti, M. W. (1985). Mechanism of lipid peroxidation. Free Radical Biology & Medicine, 1, 87-95. google scholar
  • Gruden, G., Barutta, F., Kunos, G., & Pacher, P. (2016). Role of the en-docannabinoid system in diabetes and diabetic complications British Journal of Pharmacology, 173(7), 1116-1127. google scholar
  • Gocmen, C., Secilmis, A., Kumcu, E. K., Ertug, P. U., Onder, S., Dikmen, A., & Baysal, F. (2000). Effects of vitamin E and sodium sel-enate on neurogenic and endothelial relaxation of corpus caver-nosum in the diabetic mouse. European Journal of Pharmacology, 398(1), 93-98. google scholar
  • Habig, W. H., & Jakoby, W. B. (1981). Assays for differentiation of glutathione-S-transferase. Methods in Enzymology, 77, 398-405. google scholar
  • Harini, R., & Pugalendi, K. V. (2010). Antioxidant and antihyperlipi-daemic activity of protocatechuic acid on streptozotocin-diabet-ic rats. Redox Report, 15, 71-80. google scholar
  • Heppenstall, C., Bunce, S., & Smith, J. C. (2012). Relationships be-tween glucose, energy intake and dietary composition in obese adults with type 2 diabetes receiving the cannabinoid 1 (CB1) re-ceptor antagonist. rimonabant. Nutrition Journal, 11, 50. google scholar
  • Holst, J. J., Vilsboll, T., & Deacon, C. F. (2009). The incretin system and its role in type 2 diabetes mellitus. Molecular and Cellular En-docrinology, 297, 127-136. google scholar
  • IDF, Diabetes A. G. (2015). Update of mortality attributable to diabetes for the IDF diabetes atlas: Estimates for the year 2013. Diabetes Research and Clinical Practice, 109(3), 461-465. google scholar
  • Jablonska, E., Reszka, E., Gromadzinska, J., Wieczorek, E., Krol, M. B., Raimondi, S., Socha, K., Borawska, M. H., & Wasowicz, W. (2016). The effect of selenium supplementation on glucose homeostasis and the expression of genes related to glucose metabolism. Nu-trients, 8(12), 772. google scholar
  • Jacobs, E. T., Lance, P., Mandarino, L. J., Ellis, N. A., Chow, H. S., Foote, J., Martinez, J. A., Hsu, C. P., Batai, K., Saboda, K., & Thompson, P. A. (2019). Selenium supplementation and insulin resistance in a randomized, clinical trial. BMJ Open Diabetes Research & Care, 7(1), e000613. google scholar
  • Jamuna Rani, A., Mythili, S. V., & Nagarajan, S. (2014). Study on paraoxonase 1 in type 2 diabetes mellitus. Indian Journal of Physi-ology and Pharmacology, 58(1), 13-16. google scholar
  • Jourdan, T., Godlewski, G., & Kunos, G. (2016). Endocannabi-noid regulation of Ş-cell functions: implications for glycaemic control and diabetes. Diabetes, Obesity and Metabolism, 18(6), 549-557. google scholar
  • Kanbagli, O., Balkan, J., Aykac Toker, G., & Uysal, M. (2002). Hepatic mitochondrial prooxidant and antioxidant status in ethanol-in-duced liver injury in rats. Biological and Pharmaceutical Bulletin, 25(11), 1482-1484. google scholar
  • Karatug, A., & Bolkent, S. (2013). The potential role of combined antioxidant treatment on pancreas of STZ-diabetic mice. Experi-mental and Toxicologic Pathology, 65(3), 255-262. google scholar
  • Kojima, M., Sun, L., Hata, I., Sakamoto, Y., Sasaki, H., & Sasaki, K. (2007). Efficacy of alpha lipoic acid against diabetic cataract in rat. Japanese Journal of Ophthalmology, 51(1), 10-13. google scholar
  • Konrad, D., Somwar, R., Sweeney, G., Yaworsky, K., Hayashi, M., Ramlal, T., & Klip, A. (2001). The antihyperglycemic drug alpha-li-poic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes, 50(6), 1464-1471. google scholar
  • Kunutsor, S. K., Apekey, T. A., & Walley, J. (2013). Liver aminotrans-ferases and risk of incident type 2 diabetes: a systematic review and meta-analysis. American Journal of Epidemiology, 178, 159171. google scholar
  • Lateef, H., Aslam, M. N., Stevens, M. J., & Varani, J. (2005). Pretreat-ment of diabetic rats with lipoic acid improves healing of sub-sequently-induced abrasion wounds. Archives of Dermatological Research, 297(2), 75-83. google scholar
  • Lavine, J. E., Schwimmer, J. B., Van Natta, M. L., Molleston, J. P., Mur-ray, K. F., Rosenthal, P., Abrams, S. H., Scheimann, A. O., Sanyal, A. J., Chalasani, N., Tonascia, J., Ünalp, A., Clark, J. M., Brunt, E. M., Kleiner, D. E., Hoofnagle, J. H., & Robuck, P. R. (2011). Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. Journal of the American Medical Association, 305(16), 1659-1668. google scholar
  • Ledwozyw, A., Michalak, J., Stepien, A., & Kadziotka, A. (1986). The relationship between plasma triglycerides, cholesterol, total lip-ids and lipid peroxidation products during human atherosclero-sis. Clinica Chimica Acta, 155, 275-283. google scholar
  • Lee, W. J., Song, K. H., Koh, E. H., Won, J. C., Kim, H. S., Park, H. S., Kim, M. S., Kim, S. W., Lee, K. U., & Park, J. Y. (2005). Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochemical and Biophysical Research Communications, 332(3), 885-891. google scholar
  • Levine, R. L., Garland, D., Oliver, C. N., Amici, A., Climent, I., Lenz, A. G., Ahn, B. W., Shaltiel, S., & Stantman, E. R. (1990). Determination of carbonyl content in oxidatively modified proteins. In: Packer L, Glazer AN (eds) Methods in enzymology, oxygen radicals in bio-logical systems, Academic Press, California. 186, 464-478. google scholar
  • Li, X., Kaminski, N. E., & Fischer, L. J. (2001). Examination of the immunosuppressive effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes. International Im-munopharmacology, 1(4), 699-712. google scholar
  • Liebler, D. C. (1993). The role of metabolism in the antioxidant function of vitamin E. Critical Reviews in Toxicology, 23, 147-169. google scholar
  • Lorentz, K., Weiss, T., & Kraas, E. (1986). Sialic acid in human serum and cerebrospinal fluid. Comparison of methods and reference values. Journal of Clinical Chemistry and Clinical Biochemistry, 24(3), 189-198. google scholar
  • Loria, P., Lonardo, A., & Anania, F. (2013). Liver and diabetes. A vi-cious circle. Hepatology Research, 43, 51-64. google scholar
  • Lowry, O. H., Rosebrough, H. J., Farr, A. L., & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193, 265-275. google scholar
  • Lozano, I., Van der Werf, R., Bietiger, W., Seyfritz, E., Peronet, C., Pin-get, M., Jeandidier, N., Maillard, E., Marchioni, E., Sigrist, S., & Dal, S. (2016). High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Jour-nal of Nutrition and Metabolism, 13, 15. google scholar
  • Lu, J., & Holmgren, A. (2009). Selenoproteins. Journal of Biological Chemistry, 284, 723-727. google scholar
  • Maritim, A. C., Sanders, R. A., & Watkins, J. B. (2003). Diabetes, oxi-dative stress, and antioxidants: a review. Journal of Biochemical and Molecular Toxicology, 17(1), 24-38. google scholar
  • Masarone, M., Rosato, V., Dallio, M., Gravina, A. G., Aglitti, A., Logu-ercio, C., Federico, A., & Persico, M. (2018). Role of oxidative stress in pathophysiology of nonalcoholic fatty liver disease. Oxidative Medicine and Cellular Longevity, 2018, 9547613. google scholar
  • Matsumoto, S., Koshiishi, I., Inoguchi, T., Nawata, H., & Utsumi, H. (2003). Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice. Free Radical Re-search, 37, 767-772. google scholar
  • Mohamed, J., Nazratun, N. A., Zariyantey, A. H., & Budin, S. B. (2016). Mechanisms of diabetes-induced liver damage: The role of oxidative stress and inflammation. Sultan Qaboos University Medical Journal, 16, 132-141. google scholar
  • Moon, S., Chung, H. S., Yu, J. M., Yoo, H. J., Park, J. H., Kim, D. S., Park, Y. K., & Yoon, S. N. (2019). Association between serum selenium level and the prevalence of diabetes mellitus in U.S. population. Journal of Trace Elements in Medicine and Biology, 52, 83-88. google scholar
  • Moura, L. I. F., Lemos, C., Ledent, C., Carvalho, E., & Köfalvi, A. (2019). Chronic insulinopenia/hyperglycemia decreases canna-binoid CB(1) receptor density and impairs glucose uptake in the mouse forebrain. Brain Research Bulletin, 147, 101-109. google scholar
  • Mukherjee, B., Anbazhagan, S., Roy, A., Ghosh, R., & Chatterjee, M. (1998). Novel implications of the potential role of selenium on antioxidant status in streptozotocin-induced diabetic mice. Bio-medicine & Pharmacotherapy, 52(2), 89-95. google scholar
  • Mylorie, A. A., Colins, H., Umbles, C., & Kyle, J. (1986). Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicology and Applied Phar-macology, 82, 512-520. google scholar
  • Nair, S. P., Shah, N. C., Taggarsi, A., & Nayak, U. (2011). PON1 and its association with oxidative stress in type I and type II diabetes mellitus. Diabetology & Metabolic Syndrome, 5(3), 126-129. google scholar
  • Ozougwu, J. C. (2017). Physiology of the liver. International Journal of Research in Pharmacy and Biosciences, 4(8), 13-24. google scholar
  • Paglia, D. E., & Valentine, W. N. (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione per-oxidase. Journal of Laboratory and Clinical Medicine, 70, 158-169. google scholar
  • Papaccio, G., Pisanti, F. A., Latronico, M. V. G., Ammendola, E., & Galdieri, M. (2000). Multiple low- dose and single high-dose treat-ments with streptozotocin do not generate nitric oxide. Journal of Cellular Biochemistry, 77(1), 82-91. google scholar
  • Peh, H. Y., Tan, W. S., Liao, W., & Wong, W. S. (2016). Vitamin E ther-apybeyond cancer: tocopherol versus tocotrienol. Pharmacology & Therapeutics, 162, 152-169. google scholar
  • Rayman, M. P. (2012). Selenium and human health. Lancet, 379, 1256-1268. google scholar
  • Reedy, G. K., & Enwemeka, C. S. (1996). A simplified method for the analysis of hydroxyproline in biological tissues. Clinical Biochem-istry, 29, 225-229. google scholar
  • Rochette, L., Ghibu, S., Richard, C., Zeller, M., Cottin, Y., & Vergely, C. (2013). Direct and indirect antioxidant properties of a-lipoic acid and therapeutic potential. Molecular Nutrition & Food Research, 57, 114-125. google scholar
  • Rochette, L., Ghibu, S., Muresan, A., & Vergely, C. (2015). Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. Canadian Journal of Physiology and Pharmacology, 93(12), 1021-1027. google scholar
  • Sabanayagam, C., Shankar, A., Li, J., Pollard, C., & Ducatman, A. (2009). Serum gamma-glutamyl transferase level and diabetes mellitus among US adults. European Journal of Epidemiology, 24, 369-373. google scholar
  • Sacan, O., Turkyılmaz, I. B., Bayrak, B. B., Mutlu, O., Akev, N., & Ya-nardag, R. (2016). Zinc supplementation ameliorates glycopro-tein components and oxidative stress changes in the lung of streptozotocin diabetic rats. Biometals, 29(2), 239-248. google scholar
  • Salinthone, S., Schillace, R. V., Tsang, C., Regan, J. W., Bourdette, D. N., & Carr, D. W. (2011). Lipoic acid stimulates cAMP production via G protein-coupled receptor-dependent and -independent mechanisms. Journal of Nutrition Biochemistry, 22(7), 681-690. google scholar
  • Sanyal, A. J., Chalasani. N., Kowdley, K. V., McCullough, A., Diehl, A. M., Bass, N. M., Neuschwander-Tetri, B. A., Lavine, J. E., Tonascia, J., Unalp, A., Natta, M. V., Clark, J., Brunt, E. M., Kleiner, D. E., Hoofnagle, J. H., & Robuck, P. R. (2010). Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. The New England Journal of Medi-cine, 362, 1675-1685. google scholar
  • Sena, C. M., Cipriano, M. A., Botelho, M. F., & Seiça, R. M. (2018). lipoic acid prevents high-fat diet-induced hepatic steatosis in Goto Kakizaki rats by reducing oxidative stress through nrf2 ac-tivation. International Journal of Molecular Sciences, 19(9), E2706. google scholar
  • Shirpoor, A., Ansari, M. H., Salami, S., Pakdel, F. G., & Rasmi, Y. (2007). Effect of vitamin E on oxidative stress status in small intestine of diabetic rat. World Journal of Gastroenterology, 13(32), 4340-4344. Smith, B. W., & Adams, L. A. (2011). Nonalcoholic fatty liver dis-ease and diabetes mellitus: pathogenesis and treatment. Nature Reviews Endocrinology, 7, 456-465. google scholar
  • Springer, S. C., Silverstein, J., Copeland, K., Moore, K. R., Prazar, G. E., Raymer, T., Shiffman, R. N., Thaker, V. V., Anderson, M., Spann, S. J., & Flinn, S. K. (2013). Management of type 2 diabetes mellitus in children and adolescents. Pediatrics, 131, e648-e664. google scholar
  • Stranges, S., Marshall, J. R., Natarajan, R., Donahue, R. P., Trevisan, M., Combs, G. F., Cappuccio, F. P., Ceriello, A. & Reid, M. E. (2007). Effects of long-term selenium supplementation on the incidence of type 2 di-abetes: a randomized trial. Annals of Internal Medicine, 147, 217-223. google scholar
  • Szasz, G. (1969). A kinetic photometric method for serum g-glu-tamyl transpeptidase. Clinical Chemistry, 15, 124-136. google scholar
  • Taylor, R. (2008). Pathogenesis of type 2 diabetes: tracing the re-verse route from cure to cause. Diabetologia, 51, 1781-1789. google scholar
  • Taylor, R., Al-Mrabeh, A., Zhyzhneuskaya, S., Peters, C., Barnes, A. C., Aribisala, B. S., Hollingsworth, K. G., Mathers, J. C., Sattar, N., & Lean, M. E. J. (2018). Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for p cell recovery. Cell Metabolism, 28(4), 547-556. google scholar
  • Tinggi, U. (2008). Selenium: its role as antioxidant in human health, Environmental Health and Preventive Medicine, 13, 102-108. Wangoo, A., Brown, I. N., Marshall, B. G., Cook, H. T., Young, D. B., & Shaw, R. J. (2000). Bacille Calmette-Guerin (BCG)-associated inflammation and fibrosis: modulation by recombinant BCG ex-pressing interferon-gamma (IFN-gamma). Clinical & Experimental Immunology, 119(1), 92-98. google scholar
  • Wannamethee, S. G., Shaper, A. G., Lennon, L., & Whincup, P. H. (2005). Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care, 28, 2913-2918. google scholar
  • Whitfield, J. B. (2001). Gamma glutamyl transferase. Critical Re-views in Clinical Laboratory Sciences, 38, 263-355. google scholar
  • Winzler, R. J. (1955). in: Methods of biochemical analysis. Determi-nation of serum glycoproteins, D. P. Glick, (ed.), vol. 2, Interscience Publisher Inc., New York 279. google scholar
  • Witko-Sarsat, V., Friedlander, M., Capeille're-Blandin, C., NguyenK-hoa, T., Nguyen, A. T., Zingraff, J., Jungers, P., & DescampsLatscha, B. (1996). Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney International, 49, 1304-1313. google scholar
  • Vinceti, M., Filippini, T., & Rothman, K. J. (2018). Selenium exposure and the risk of type 2 diabetes: A systematic review and meta-analysis. European Journal of Epidemiology, 33(9), 789-810. google scholar
  • Younossi, Z., Anstee, Q. M., Marietti, M., Hardy, T., Henry, L., Eslam, M., George, J., & Bugianesi, E. (2018). Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nature Re-views Gastroenterology & Hepatology, 15, 11-20. google scholar
  • Zeng, M. S., Li, X., Liu, Y., Zhao, H., Zhou, J. C., Li, K., Huang, J. Q., Sun, L. H., Tang, J. Y., Xia, X. J., Wang, K. N., & Lei, X. G. (2012). A high-se-lenium diet induces insulin resistance in gestating rats and their offspring. Free Radical Biology & Medicine, 52(8), 1335-1342. google scholar
  • Zhang, X., Gao, S., Niu, J., Li, P., Deng, J., Xu, S., Wang, Z., Wang, W.,Kong, D., & Li, C., (2016). Cannabinoid 2 receptor agonist improves systemic sensitivity to insulin in high-fat diet/streptozotocin-in-duced diabetic mice. Cellular Physiology and Biochemistry, 40(5), 1175-1185. google scholar
  • Zhou, B. H., Zhao, J., Liu, J., Zhang, J. L., Li, J., & Wang, H. W. (2015). Fluoride-induced oxidative stress is involved in the morphologi-cal damage and dysfunction of liver in female 15 mice. Chemo-sphere, 139, 504-511. google scholar
  • Zimmet, P,, Shi, Z., El-Osta, A., & Ji, L. (2018). Epidemic T2DM, early development and epigenetics: implications of the Chinese fam-ine. Nature Reviews Endocrinology, 14, 738-746. google scholar


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Karatuğ Kaçar, A., Ertik, O., Coşkun Yazıcı, Z.M., Bolkent, S., Yanardağ, R., & Bolkent, Ş. (2023). The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice. İstanbul Journal of Pharmacy, 53(2), 199-210.


Karatuğ Kaçar A, Ertik O, Coşkun Yazıcı Z M, Bolkent S, Yanardağ R, Bolkent Ş. The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice. İstanbul Journal of Pharmacy. 2023;53(2):199-210.


Karatuğ Kaçar, A.; Ertik, O.; Coşkun Yazıcı, Z.M.; Bolkent, S.; Yanardağ, R.; Bolkent, Ş. The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice. İstanbul Journal of Pharmacy, [Publisher Location], v. 53, n. 2, p. 199-210, 2023.

Chicago: Author-Date Style

Karatuğ Kaçar, Ayşe, and Onur Ertik and Zeynep Mine Coşkun Yazıcı and Sema Bolkent and Refiye Yanardağ and Şehnaz Bolkent. 2023. “The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice.” İstanbul Journal of Pharmacy 53, no. 2: 199-210.

Chicago: Humanities Style

Karatuğ Kaçar, Ayşe, and Onur Ertik and Zeynep Mine Coşkun Yazıcı and Sema Bolkent and Refiye Yanardağ and Şehnaz Bolkent. The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice.” İstanbul Journal of Pharmacy 53, no. 2 (Jul. 2024): 199-210.

Harvard: Australian Style

Karatuğ Kaçar, A & Ertik, O & Coşkun Yazıcı, ZM & Bolkent, S & Yanardağ, R & Bolkent, Ş 2023, 'The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice', İstanbul Journal of Pharmacy, vol. 53, no. 2, pp. 199-210, viewed 17 Jul. 2024,

Harvard: Author-Date Style

Karatuğ Kaçar, A. and Ertik, O. and Coşkun Yazıcı, Z.M. and Bolkent, S. and Yanardağ, R. and Bolkent, Ş. (2023) ‘The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice’, İstanbul Journal of Pharmacy, 53(2), pp. 199-210. (17 Jul. 2024).


Karatuğ Kaçar, Ayşe, and Onur Ertik and Zeynep Mine Coşkun Yazıcı and Sema Bolkent and Refiye Yanardağ and Şehnaz Bolkent. The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice.” İstanbul Journal of Pharmacy, vol. 53, no. 2, 2023, pp. 199-210. [Database Container],


Karatuğ Kaçar A, Ertik O, Coşkun Yazıcı ZM, Bolkent S, Yanardağ R, Bolkent Ş. The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice. İstanbul Journal of Pharmacy [Internet]. 17 Jul. 2024 [cited 17 Jul. 2024];53(2):199-210. Available from: doi: 10.26650/IstanbulJPharm.2023.1005935


Karatuğ Kaçar, Ayşe - Ertik, Onur - Coşkun Yazıcı, ZeynepMine - Bolkent, Sema - Yanardağ, Refiye - Bolkent, Şehnaz. The combined ameliorative effects of α-lipoic acid, selenium, and vitamin E on the livers of STZ-diabetic mice”. İstanbul Journal of Pharmacy 53/2 (Jul. 2024): 199-210.


Published Online28.08.2023


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