Curcumin, Hesperidin, and Rutin Selectively Interfere with Apoptosis Signaling and Attenuate Streptozotocin-Induced Oxidative Stress-Mediated Hyperglycemia.
Type I Diabetes is characterized by the presence of hyperglycemia due to insulin deficiency and consequent impaired hepatic glucose metabolism. During diabetes, the liver becomes the most important tissue for the regulation of serum glucose. However, elevated glucose causes continuous oxidative damage to the liver, reducing its capacity to ameliorate hyperglycemia, which contributes to macrovascular complications [1]. Numerous epidemiological studies have demonstrated that excess human consumption of diets rich in specific bioflavonoid phytochemicals attenuates the effects of diabetes. Thus, this study was designed to investigate whether a bioflavonoid mixture could : i) attenuate streptozotocin (STZ)-induced hyperglycemia, ii) potentiate antioxidant signaling in the liver, and iii) ameliorate the apoptotic signaling cascade in the liver of STZ-induced hyperglycemic mice. In order to examine our hypothesis, three well-investigated antioxidant phytochemicals, curcumin, hesperidin and rutin, were combined into a mixture (CHR) for this study. Diabetes was induced in 6-month-old female ICR mice by STZ (100 mg/kg, i.p.) administration, and CHR or vehicle control was orally administered (200 mg/kg per body weight of each ingredient) to the hyperglycemic mice (blood glucose levels > 250 mg/dl) for a period of 14 days. Administration of CHR to the hyperglycemic mice significantly reduced blood glucose levels, attenuated STZ-induced lipid peroxidation and total nitrate/nitrite levels, and significantly augmented the expression of superoxide dismutase and glutathione in the liver. STZ-induced hyperglycemia resulted in downregulation of antiapoptotic proteins Bcl-2 by 66% and Bcl-XL by 51%, and upregulation of the pro-apoptotic Bad (69%) with an increase in the ratio of cytosolic/mitochondrial cytochrome c by 81% in hepatic tissue. Administration of CHR significantly ameliorated apoptotic signaling in STZ-induced diabetic mice, significantly increasing Bad/Bcl-2 and Bad/Bcl-XL ratios to 410% and 244% respectively in the hyperglycemic group. This study demonstrated that a bioflavonoid mixture of curcumin, hesperidin and rutin (CHR) ameliorates hepatic oxidative stress caused by STZ-induced hyperglycemia, resulting in improved hepatic function and glucose regulation.
Mayur S
MS
Parmar
Ismail
I
Syed
Joshua P
JP
Gray
Molecular Toxicology Laboratories, Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Fort Wayne, IN 46845, Fort Wayne, IN, USA. sdray@manchester.edu.
Sidhartha D
SD
Ray
D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose; D003474:Curcumin / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D005419:Flavonoids / Q000378:metabolism; D006569:Hesperidin / Q000627:therapeutic use; D008099:Liver / Q000473:pathology; D008813:Mice, Inbred ICR; D009566:Nitrates / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D012431:Rutin / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D005419:Flavonoids; D009566:Nitrates; D012431:Rutin; D006569:Hesperidin; D013482:Superoxide Dismutase; D003474:Curcumin