Effects of naringenin on vascular changes in prolonged hyperglycaemia in fructose-STZ diabetic rat model (original) (raw)
Related papers
Diabetes, Obesity and Metabolism, 2008
Aim: The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) in normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute and subchronic time periods. Possible modes of action of NG were investigated and its acute toxicity determined. Methods: Normoglycaemic and non-insulin-dependent diabetes mellitus (NIDDM) rat models were treated for acute and subchronic (5 days) time periods with 50 mg/kg/day of NG. Blood biochemical profiles were determined after 5 days of the treatment in normoglycaemic and NIDDM rats using commercial kits for GLU, triglycerides (TG), total cholesterol (CHOL) and high-density lipoprotein (HDL). In order to elucidate its antidiabetic mode of action, NG was administered intragastrically and an oral glucose tolerance test performed using GLU and sucrose (2 g/kg) as substrates. The inhibitory effect of a single concentration of NG (10 mM) on 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activity in vitro was determined. Finally, the preclinical safety and tolerability of NG was determined by toxicological evaluation in mice and rats using Organization for Economic Cooperation and Development (OECD) protocols. Results: Intragastrically administered NG (50 mg/kg) induced a significant decrease in plasma GLU in normoglycaemic and NIDDM rat models (p < 0.05) following acute and subchronic time periods. After 5 days of administration, NG produced significant diminished blood GLU and TG levels in streptozotocin-nicotinamide-induced diabetic rats. The administration of NG to normal rats significantly increased the levels of TG, CHOL and HDL (p < 0.05). NG (5 and 50 mg/kg) induced a total suppression in the increase of plasma GLU levels after administration of substrates (p < 0.01), but NG did not produce inhibition of a-glucosidase activity in vitro. However, NG (10 mM) was shown to inhibit 11b-HSD1 activity by 39.49% in a cellular enzyme assay. Finally, NG showed a Medium Lethal Dose LD 50 > 5000 mg/kg and ranking at level five based on OECD protocols. Conclusion: Our findings suggest that NG may exert its antidiabetic effect by extra-pancreatic action and by suppressing carbohydrate absorption from intestine, thereby reducing the postprandial increase in blood GLU levels.
2020
Nitric oxide (NO) is a key regulating factor for physiological functions, when elevated during inflammatory conditions can lower endogenous antioxidant levels. Increased NO interacts with oxygen or other ROS to generate peroxynitrite, a potent oxidant which induces oxidative stress. Analgesic effects of naringenin (NRN), a flavanone has been demonstrated by inducing anti-inflammatory effects in O2−•-mediated inflammation. NRN stimulates antioxidant enzymes and also improves glucose uptake. Hence this study was designed to look for therapeutic effects of NRN and in comparison, to metformin (MET) on inflammation-mediated increased NO and decreased antioxidant superoxide dismutase (SOD) in diabetic rat model with compromised glycemic and lipid profile. After single intraperitoneal injection of alloxan (120 mg/kg), the rats were equally divided as Group 1 and 2 which received normal saline and no-treatment respectively while group 3 and 4 received MET 50 mg/kg/day and NRN 50 mg/kg/day r...
Current Vascular Pharmacology, 2010
The vascular manifestations associated with diabetes mellitus (DM) result from the dysfunction of several vascular physiology components mainly involving the endothelium, vascular smooth muscle and platelets. It is also known that hyperglycemia-induced oxidative stress plays a role in the development of this dysfunction. This review considers the basic physiology of the endothelium, especially related to the synthesis and function of nitric oxide. We also discuss the pathophysiology of vascular disease associated with DM. This includes the role of hyperglycemia in the induction of oxidative stress and the role of advanced glycation end-products. We also consider therapeutic strategies.
Nutraceuticals, Glycemic Health and …, 2008
Oxidant stress plays a central role in mediating the macro-and microvascular complications of diabetes and metabolic syndrome. Radicals antagonize protective nitric oxide (NO) bioactivity, through direct quenching of NO and uncoupling of NO synthase, while promoting inflammation and fibrosis via activation of NF-kappaB and TGF-beta, respectively. Oxidants are key mediators of insulin resistance in hypertrophied adipocytes-which gives rise to systemic insulin resistance-and may also promote beta cell dysfunction. In diabetics, a major effect of peroxynitrite is to trigger PARP-mediated inhibition of glyceraldehyde-3-phosphate dehydrogenase; glycolytic intermediates pile up behind this bottleneck, boosting the activity of 3 key pathways known to mediate complications: diacylglycerol synthesis (leading to protein kinase C activation), and the hexosamine and polyol pathways. The chief sources of excess oxidant stress in metabolic syndrome and diabetes are NADPH oxidase (activated by PKC, angiotensin II, and advanced glycation/lipoxidation endproducts), uncoupled NO synthase, and-in diabetics-mitochondria. Fortunately, it may be feasible to suppress the production and downstream effects of the radicals overproduced in these disorders, using safe nutraceuticals. Phycocyanobilin (PCB), a biliverdin-derived chromophore found in bluegreen algae, has recently been shown to potently inhibit NADPH oxidase in a manner analogous to bilirubin; efforts to develop PCB-enriched algae extracts as antioxidant supplements are underway. High-dose folate can somehow "pinch-hit" for deficient tetrahydrobiopterin, effectively "recoupling" NO synthase and restoring its normal activity. Lipoic acid-as well as the drug metformin-boost the antioxidant defenses of endothelial mitochondria by activating AMP-activated kinase and PGC-1α; lipoic acid may also combat oxidant stress via phase II induction of glutathione and heme oxygenase-1. High doses of thiamine-or its better-absorbed analog benfotiamine-can increase transketolase activity, decreasing excess substrate in the upper glycolytic pathway by drawing it into the pentose phosphate pathway. Taurine has the potential to ameliorate the impact of myeloperoxidase-derived oxidants on diabetic complications, and suppresses development of neuropathy in diabetic rodents. The vitamer pyridoxamine can aid control of oxidative stress by inhibiting production of advanaced glycation/lipoxidation end products. Thus, a regimen of PCB, high-dose folate, lipoic acid, taurine, pyridoxamine, and benfotiamine may have considerable potential for preventing complications in patient who are diabetic and/or insulin resistant. Selenium, vitamin C, niacinamide, melatonin, and oligopeptide ACE inhibitors may also have some value in this regard. Clearly, there is considerable scope for the development of rational, well tolerated nutraceutical regimens which could substantially mitigate the health risks associated with metabolic syndrome and diabetes. Recently, Inoguchi and colleagues have examined risk for vascular complications in diabetics who have Gilbert syndrome, a genetic variant in which free unconjugated
Diabetes, 2011
OBJECTIVE-Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS-After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and oxidative protein modifications, vascular function was determined by isometric tension recordings, protein expression was measured by Western blotting, RNA expression was assessed by quantitative RT-PCR, and HO-1 promoter activity in stable transfected cells was determined by luciferase assays. RESULTS-PETN, but not ISMN, improved endothelial dysfunction. NADPH oxidase and serum xanthine oxidase activities were significantly reduced by PETN but not by ISMN. Both organic nitrates had minor effects on the expression of NADPH oxidase subunits, eNOS and dihydrofolate reductase (Western blotting). PETN, but not ISMN, normalized the expression of GTP cyclohydrolase-1, extracellular superoxide dismutase, and S-glutathionylation of eNOS, thereby preventing eNOS uncoupling. The expression of the antioxidant enzyme, HO-1, was increased by STZ treatment and further upregulated by PETN, but not ISMN, via activation of the transcription factor NRF2. CONCLUSIONS-In contrast to ISMN, the organic nitrate, PETN, improves endothelial dysfunction in diabetes by preventing eNOS uncoupling and NADPH oxidase activation, thereby reducing oxidative stress. Thus, PETN therapy may be suited to treat patients with cardiovascular complications of diabetes.
Current Pharmaceutical Design
Diabetes mellitus is associated to an increased risk of cardiovascular diseases. Hyperglycemia is an important factor in cardiovascular damage, working through different mechanisms such as activation of protein kinase C, polyol and hexosamine pathways, advanced glycation end products production. All of these pathways, in association to hyperglycemia-induced mitochondrial dysfunction and endoplasmic reticulum stress, promote reactive oxygen species (ROS) accumulation that, in turn, promote cellular damage and contribute to the diabetic complications development and progression. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression and, therefore, irreversible oxidative modifications. Hyperglycemia-induced oxidative stress induces endothelial dysfunction that plays a central role in the pathogenesis of micro- and macro-vascular diseases. It may also increase pro-inflammatory and pro-coagulant factors expression, induce apoptosis and impair nitric oxide release. Oxidative stress induces several phenotypic alterations also in vascular smooth-muscle cell (VSMC). ROS is one of the factors that can promote both VSMC proliferation/migration in atherosclerotic lesions and VSMC apoptosis, which is potentially involved in atherosclerotic plaque instability and rupture. Currently, there are contrasting clinical evidences on the benefits of antioxidant therapies in the prevention/treatment of diabetic cardiovascular complications. Appropriate glycemic control, in which both hypoglycemic and hyperglycemic episodes are reduced, in association to the treatment of dyslipidemia, hypertension, kidney dysfunction and obesity, conditions which are also associated to ROS overproduction, can counteract oxidative stress and, therefore, both microvascular and macrovascular complications of diabetes mellitus.
Diabetes, 1993
This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [ 12S l]albumin permeation was increased about two-to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only-7 % as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was-1-5 % as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine-and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that
Journal of Cellular Physiology, 2018
Many vascular complications are related to exposure of tissues to elevated levels of glucose, a condition that promotes oxidative stress. The primary goal of antidiabetic medication is for normalization of blood glucose. However, antidiabetic medications may have antioxidant effects that go beyond their hypoglycemic influences. Therefore, antidiabetic drugs may be doubly beneficial in preventing diabetic complications. Vascular dysfunction due to uncontrolled diabetes is a serious complication of the disease and one which has a severe impact on quality of life. Readjustment of the oxidative balance in subjects with diabetes, and the positive effects thereof is a topic of intense interest at present. In the current review, we highlight the antioxidant effects of antidiabetic medications which may prevent or delay the onset of vascular dysfunction.