Combinatory effect of hesperetin and mesenchymal stem cells on the deteriorated lipid profile,heart and kidney functions and antioxidant activity in STZ-induced diabetic rats

This study aimed to assess the effect of hesperetin and/or bone marrow-derived mesenchymal stem cells(BM-MSCs)on disturbed lipid profile,heart and kidney functions,oxidative stress and antioxidant defense system in streptozotocin(STZ)-induced diabetic rats.Type 1 diabetes mellitus(T1DM)was induced in male Wistar rats by injecting 40 mg/kg body weight(b.w.)STZ dissolved in citrate buffer(pH 4.5).The diabetic rats were treated with hesperetin orally administered at dose 20 mg/kg b.w.,BM-MSCs intravenously injected at a dose of 1 x 106 cells/rat/week and their combination for 6 weeks.The diabetic rats exhibited lipid abnormalities manifested by elevated serum levels of total cholesterol,triglycerides,LDL-cholesterol and VLDL-cholesterol and lowered HDL-cholesterol as well as elevated liver cholesterol and triglycerides content in association with the resultant fasting and postprandial hyperglycemia and insulin deficiency.The heart function biomarkers including CK-MB,AST and LDH activities as well as levels of kidney function parameters,creatinine,and urea,were significantly raised in the serum of diabetic rats.These changes were concomitant with abnormal redox balance represented by elevated lipid peroxidation,decreased glutathione content,and suppressed antioxidant enzyme activities in both heart and kidney of diabetic rats.The previous deleterious alterations were significantly ameliorated after the treatment of diabetic rats with hesperetin and BM-MSCs singly or in combination;the treatment with hesperetin together with BM-MSCs was the most potent.Based on these findings,it can be concluded that the use of hesperetin with BM-MSCs may have more additive therapeutic value than their uses singly in T1DM.In addition,the ameliorative effects of hesperetin and BM-MSCs on lipid profile and heart and kidney functions in diabetic rats may be mediated,at least in part,via their suppressive effects on oxidative stress and ameliorative effects on the antioxidant defense system secondary to improvement in the hyperglycemia and insulin secretory response.