Diabetes-associated Oxidative Stress Research Articles

Myrtenal attenuates oxidative stress and inflammation in a rat model of streptozotocin-induced diabetes

The present study was aimed to investigate the effect of myrtenal on diabetes-associated oxidative stress, lipid peroxidation (LPO), and inflammation using a rat model of streptozotocin (STZ)-induced diabetes. Following the induction of diabetes in male Wistar rats using STZ (40 mg/kg body weight), myrtenal (80 mg/kg body weight) was administered orally to diabetic rats for four weeks and then sacrificed to harvest tissues. We measured the levels of antioxidants, LPO, and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and the p65 subunit of nuclear factor-kappa B (NF-kB p65). Diabetic rats revealed increased levels of LPO, proinflammatory cytokines, and NF-kB p65, and decreased levels of antioxidants in the liver and pancreas. Supplementation with myrtenal significantly attenuated the diabetes-induced changes in the liver and pancreas of diabetic rats. Our findings suggest that myrtenal may serve as an antioxidant and anti-inflammatory agent against diabetes-associated oxidative stress and inflammation. Highlights Oral administration of myrtenal improved the antioxidant status in the liver and pancreas of diabetic rats. Myrtenal treatment diminished inflammation in the liver and pancreas of diabetic rats. Myrtenal supplementation averts oxidative stress and inflammation in diabetic rats. Myrtenal could serve as a potent antioxidant and anti-inflammatory agent in the management of diabetes.

Oxidant/antioxidant status of Sudanese Type II diabetic patients with multiple complications

Background: Diabetes-associated oxidative stress is induced by both increase in production of plasma-free radical concentrations and a significant reduction in antioxidant defence mechanisms, and it is associated with the pathophysiology of diabetes mellitus and its complications. Objectives: To evaluate the oxidant and antioxidant status in Type II diabetic patients with complications and diabetic patients without complications (DWC) compared to normal subjects and their association with diabetic complications. Materials and Methods: Plasma levels of malondialdehyde (MDA), antioxidant Vitamin C and antioxidant enzyme, superoxide dismutase (Cu-Zn SOD) activity were estimated in patients with diabetic nephropathy (DN), patients with diabetic neuropathy (DNe), diabetic patients with coronary artery disease (CAD), DWC, and controls matched for age, sex, body mass index and study region. Spectrophotometry and enzyme-linked immunosorbent assay techniques have been applied for the determination of MDA, Vitamin C and superoxide dismutase (SOD). Results: Comparing the level of Vitamin C and activity of SOD in all groups, it was observed that the lowest concentrations were found in CAD, DN and DNe groups, higher in DWC, and the highest in the control group. On the contrary, MDA levels (as an indicator of oxidative stress) were found to be increased in CAD, DN and DNe groups as compared to DWC and control groups. SOD and Vitamin C were found inversely correlated with glycosylated haemoglobin and MDA levels in all diabetic groups regardless of their complications. Multivariate model showed that all the variables independently associated with the diabetic complications. Conclusions: There is an imbalance between the oxidants and antioxidants in diabetic patients with complications and patients of DWC as compared to healthy groups.

Molecular pathways associated with oxidative stress in diabetes mellitus.

The role of oxidative stress in the occurrence and development of diabetes mellitus is both critical and pivotal. Several molecular event cascade in different metabolic pathways such as glycolytic, hexosamine, protein kinase C, polyol and advanced glycation end-product (AGE) pathways have been identified as pro-oxidative processes and are usually up-regulated in the diabetics. Inhibition of glyceraldehyde-3-P dehydrogenase by poly-ADP-ribose polymerase 1 and subsequent accumulation of the enzyme substrate (glyceraldehyde-3-P) appears to be central to diabetes-associated oxidative stress. Increased level of glyceraldehyde-3-P activates two major pro-oxidative pathways in diabetes: (i) It activates the AGE pathway, precisely the synthesis of methylglyoxal from non-enzymatic dephosphorylation of the triose phosphates (ii) It activates protein kinase C (PKC) pathway by promoting the synthesis of diacylglycerol. In addition, it causes the accumulation of glycolytic metabolites upstream, and this leads to excessive stimulation of other pro-oxidative pathways such as hexosamine and polyol pathways. This review tends to highlight the main oxidative processes associated with diabetes mellitus.

Xanthohumol and 8-prenylnaringenin reduce type 2 diabetes-associated oxidative stress by downregulating galectin-3.

Background:Galectin-3 (Gal3) expression is associated with accumulation of Advanced Glycation End products (AGE), a common feature in diabetes mellitus (DM). The role of Gal3 in oxidative stress is, however, controversial, being considered in the literature to play either a protective role or exacerbating disease.Methods:Herein, we examined the interplay between Gal3 and oxidative stress in a high-fat diet -induced type 2 DMC57Bl/6 mice model. Because natural polyphenols are known to play antioxidant and anti-inflammatory roles and to modulate metabolic activity, we further evaluated the effect of xanthohumol and 8-prenylnaringenin polyphenols in this crosstalk.Results:Gal3 expression was accompanied by 3-nitrotyrosine and AGE production in liver and kidney of diabetic mice compared to healthy animals (fed with standard diet). Oral supplementation with polyphenols decreased the levels of these oxidative biomarkers as evaluated by immunohistochemistry and western blotting. Interestingly, blocking Gal3 by incubating human microvascular endothelial cells with modified citrus pectin increased 3-nitrotyrosine protein expression.Conclusions:These findings imply that Gal3 overexpression is probably controlling oxidative stress in endothelial cells. In conclusion, our results indicate that supplementation with 8-prenylnaringenin or xanthohumol reverses diabetes-associated oxidation in liver and kidney, and consequently decreases this diabetic biomarker that predispose to cardiovascular complications.

Nanoliposomal Resveratrol as a Novel Approach to Treatment of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disease and the subgroup of DM is called type II which is the most common form. The incidence of type II is increasing worldwide and it focuses on several new approaches to efficiently treatment of diabetes. Resveratrol (RSV) is known to be strong antioxidant and has an insulin-like effect in streptozotocin (STZ)-induced diabetic cells. It plays an active role at treatment of diabetes with reducing the oxidative stress, lowering glucose levels and protection of beta cells which are responsible for insulin secretion. In our study, we prepared two different RSV-loaded nanoliposomes (LPs), characterized in vitro and evaluated efficiencies of LPs on diabetes and related oxidative stress. Release and transport studies of RSV through dialyse membrane and pancreatic beta TC (β TC) cells were investigated from its solution and LPs. Stability studies were performed at two different conditions (4 °C and 25 °C ± 60% relative humidity) for 3 months. Particle size (PS), zeta potential (ZP), polydispersity index (PDI), encapsulation efficiency (EE) and type of the formulations were determined. β TC cell line was used in cell culture studies and cell viability was measured with using 3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity test. The antidiabetic effects of RSV LPs were investigated on β TC cell induced with glucose and STZ and we evaluated relationship between glucose and insulin concentration before and after incubation with LPs containing RSV. Antioxidant and preventive effects of RSV-loaded LPs against diabetes-associated oxidative stress were determined with superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme assay. When all results were evaluated together, these new developed liposomal formulations significantly decreased high glucose levels in diabetic cell groups synchronous with increasing insulin levels and they showed prolonged antioxidant activity against oxidative stress for 24 hours compared to RSV solution.

Characterization of Cognitive Impairment in Type 2 Diabetic Rats

Among all the secondary complications of type 2 diabetes, cognitive impairment associated with diabetes is less well studied and characterized. We made an attempt to investigate the molecular mechanisms involved in cognitive decline in high fat diet-streptozotocin model of type 2 diabetes. High-fat diet and a single low dose streptozotocin (25 mg/kg) were used to induce diabetes in Sprague-Dawley rats. Developments of cognitive deficit in these animals were measured using change in transfer latency in elevated plus maze test and step-down latency in passive avoidance test. This was followed by biochemical estimation of acetylcholinesterase and reduced glutathione levels followed by histological evaluation of cortical and hippocampal slices. The high fat diet-streptozotocin animals developed type 2 diabetes, characterized by an increase in fasting blood glucose levels >250 mg/kg, marked increase (P<0.001) in triglyceride (207±7.2) and total cholesterol level (125.3±2.7) with a decrease (P<0.001) in high-density lipoproteins (14.27±1.1) when compared to control animals. After 4 weeks of development of type 2 diabetes high fat diet-streptozotocin animals showed signs of cognitive deficit with a significant decline in step-down latency (P<0.001) and a significant increase in transfer latency (P<0.001) compared to controls. The high fat diet-streptozotocin animals also showed significant decrease (P<0.001) in cortico-hippocampal glutathione levels and increase in (P<0.001) acetylcholinesterase activity as compared to control animals suggesting type 2 diabetes-associated oxidative stress and decrease in hippocampal Ach activity. Immunohistochemical studies in these animals showed pronounced astrogliosis and microglial activation in the cortical and hippocampal slices suggesting neuroinflammatory changes. We also found significant loss (P<0.001) of hippocampal neurons at CA1 and CA3 region in the diabetic rats as compared with healthy controls. Antidiabetic compound glibenclamide (10 mg/kg for 3 weeks) partly reversed the above neurobehavioral, biochemical and histological changes in the diabetic rat brain. Hence we show that high fat diet-streptozotocin type 2 diabetic rats may develop signs of cognitive impairment. This cognitive decline was found to be associated with an increase in acetylcholinesterase activity and loss of hippocampal neurons. Oxidative stress and neuroinflammatory changes in the brain of these animals may be responsible for hippocampal neuronal loss, which could be partly reversed upon glibenclamide treatment.

Antioxidant and antidiabetic properties of tartary buckwheat rice flavonoids after in vitro digestion.

Oxidative stress and diabetes have a tendency to alter protein, lipid, and DNA moieties. One of the strategic methods used to reduce diabetes-associated oxidative stress is to inhibit the carbohydrate-digesting enzymes, thereby decreasing gastrointestinal glucose production. Plant-derived natural antioxidant molecules are considered a therapeutic tool in the treatment of oxidative stress and diabetes. The objective of this study was to identify tartary buckwheat rice flavonoids and evaluate the effect of in vitro digestion on their antioxidant and antidiabetic properties. High performance liquid chromatography (HPLC) analysis indicated the presence of rutin as a major component and quercitrin as a minor component of both digested and non-digested flavonoids. Both extracts showed a significant antioxidant capacity, but digested flavonoids showed reduced activity compared to non-digested. There were some decreases of the antioxidant activities (2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS), 2,2-diphenyl-1-picrylhydrazy (DPPH) radical, and ferric reducing antioxidant power (FRAP)) of digested tartary buckwheat rice flavonoids compared with non-digested. Flavonoids from both groups significantly inhibited reactive oxygen species (ROS) production and α-glucosidase activity. Both digested and non-digested flavonoids markedly increased glucose consumption and glycogen content in HepG2 cells. Tartary buckwheat rice flavonoids showed appreciable antioxidant and antidiabetic properties, even after digestion. Tartary buckwheat rice appears to be a promising functional food with potent antioxidant and antidiabetic properties.

Cardioprotective effects of rutin via alteration in TNF-α, CRP, and BNP levels coupled with antioxidant effect in STZ-induced diabetic rats.

Diabetic cardiomyopathy (DCM) is a dreadful complication of diabetes responsible for 80% mortality in diabetic patients, but unfortunately its pharmacotherapy is still incomplete. Rutin is a naturally occurring flavonoid having a long history of use in nutritional supplements for its action against oxidative stress, inflammation, and hyperglycemia, the key players involved in the progression of DCM, but remains unexplored for its role in DCM. This study was conducted to address this lacuna. It was performed in 4-week-old Streptozotocin-induced (45mg/kg) diabetic rats for a period of 24weeks to mimic the cardiotoxic effect of chronic hyperglycemia in diabetic patient's heart and to investigate the effect of rutin (50mg/kg/day) in ameliorating these effects. Heart of the diabetic rats showed altered ECG parameters, reduced total antioxidant capacity, increased inflammatory assault, and degenerative changes. Interestingly, rutin treatment significantly ameliorated these changes with decrease in blood glucose level (p>0.001), % HbA1c (p>0.001) and reduced expression of TNF-α (p<0.001), CRP (p<0.001), and BNP (p<0.01) compared to diabetic control rats. In addition, rutin provided significant protection against diabetesassociated oxidative stress (p<0.05), prevented degenerative changes in heart, and improved ECG parameters compared to diabetic control rats. The heart-to-body weight ratio was significantly reduced in rutin treatment group compared to diabetic control rats (p<0.001). In conclusion, this study implicates that oxidative stress and inflammation are the central players involved in the progression of DCM and rutin ameliorates DCM through its antioxidant and anti-inflammatory actions on heart.

English

Diabetes-associated oxidative stress causes glomerular hypertrophy, decrease of glomerular filtration rate and inhibits cell proliferation that lead to the decrease of renal function as indiated by the increase of serum creatinine level and the presence of protein in urine. Mahogany seed (Swietenia macrophylla King) has been proven to have antidiabetic activity. This study was conducted to evaluate the effect of the ethanolic extract of mahogany seeds on the renal function of streptozotocin-induced diabetic rats. Six normal rats as control (Group I) and 24 diabetic rats were used in this study. The diabetic rats were randomized allocated into four groups with six rats in each group. Group II was considered as diabetic rats control and received aquadest. Group III-V were considered as extract administered diabetic group and received ethanolic extract of S. macrophylla seed for 21 days at a dose of 50, 100 and 200 mg/kg BW, respectively. Serum malondialdehyde (MDA), serum creatinine, and urine protein levels were monitored, before and after the ethanolic extract of S. macrophylla seed administration. Serum MDA, serum creatinine and urine protein levels of all rats after STZ induction (Group II-V) were significantly higher than without STZ induction (p < 0.05). A significant decrease in the serum MDA and serum creatinine as well as urine protein levels were observed after the treatment with ethanolic extract of S. macrophylla seed compared to before treatment (p < 0.05). In conclusion, the ethanolic extract of S. macrophylla seed is able to correct renal dysfunction of streptozotocin-induced diabetic rats.

Taurine attenuates maternal and embryonic oxidative stress in a streptozotocin-diabetic rat model

Oxidative stress mechanisms have been implicated in congenital anomalies and morbidity/mortality of fetus/newborn in diabetic pregnancy. Numerous antioxidant treatments have shown varied beneficial effects in improving both maternal and fetal outcomes. The present study examined the propensity of taurine to attenuate the degree of embryopathy and oxidative stress among pregnant diabetic rats. Adult rats (CFT-Wistar) were rendered diabetic with an acute dose of streptozotocin (STZ; 45mg/kg bodyweight) on gestation day (GD) 4. Both Diabetic and non-diabetic dams were given oral supplements of taurine (0.5 and 1g/kg bodyweight/day) from GD 5 to GD 12. Maternal diet intake, bodyweight gain and urine output were monitored and dams were killed on GD 13. Markers of oxidative stress were determined in embryos and maternal livers. STZ treatment induced marked embryopathy (32%) and taurine supplements markedly reduced the degree of embryopathy (54% protection). The STZ-induced higher oxidative stress was significantly attenuated in rats given taurine supplements (P<0.05) and a similar effect was seen in embryos (P<0.05). These data suggest that dietary taurine during pregnancy provides significant protection against diabetes-induced oxidative stress in both the mother and the embryos and thus may serve as a therapeutic supplement during diabetic pregnancy.Diabetes during pregnancy affects >5% of all pregnancies, causing reproductive abnormalities that enhance spontaneous abortion – congenital anomalies, morbidity and mortality of both mother and fetus/newborn. One of the major mechanisms is increased oxidative stress caused by hyperglycaemia and the most prominent anti-teratogenic effect was achieved using antioxidative agents. Management of oxidative stress is considered, along with tight glycaemic control, to be beneficial both before conception and during pregnancy. Taurine, a ubiquitous amino acid found in almost all mammalian tissues, constitutes more than 50% of free amino acids. The aim of the study was to determine whether oral taurine supplementation given to pregnant diabetic rats during the post-implantation period could reduce embryo lethality and protect the developing embryos against maternal hyperglycaemia-induced oxidative stress. Adult rats were rendered diabetic with an acute dose of streptozotocin on gestation day (GD) 4. Both diabetic and non-diabetic dams were administered oral taurine for a period of 8days (GD 5–13). Maternal diet intake, bodyweight gain and urine output were monitored and dams were killed on GD 13. Markers of oxidative stress and antioxidant defences were studied in embryos and maternal livers. STZ induced marked embryopathy (32%) and taurine supplementation offered significant protection (54%). Taurine significantly offset diabetes-associated oxidative stress in the embryos of diabetic rats. These data suggest that dietary taurine supplementation during pregnancy provides significant protection against diabetes-induced oxidative stress both in mother and embryos and thus may serve as a therapeutic supplement under diabetic pregnancy.

Effects of Phenolic Compounds of Fermented Thai Indigenous Plants on Oxidative Stress in Streptozotocin‐Induced Diabetic Rats

We investigated the effects of antioxidant activity of fermentation product (FP) of five Thai indigenous products on oxidative stress in Wistar rats with streptozotocin (STZ)-induced diabetes type II. The rats were fed with placebo and with the FP (2 and 6 mL/kg body weight/day) for 6 weeks. Rutin, pyrogallol and gallic acid were main compounds found in the FP. Plasma glucose levels in diabetic rats receiving the higher dose of the FP increased less when compared to the diabetic control group as well as the group receiving the lower FP dose (13.1%, 29%, and 21.1%), respectively. A significant dose-dependent decrease in plasma levels of thiobarbituric acid reactive substance (P < .05) was observed. In addition, the doses of 2 and 6 mL FP/kg/day decreased the levels of erythrocyte ROS in diabetic rats during the experiment, but no difference was observed when compared to the untreated diabetic rat group. Results imply that FP decreased the diabetes-associated oxidative stress to a large extent through the inhibition of lipid peroxidation. The FP also improved the abnormal glucose metabolism slightly but the difference was not statistically significant. Thus, FP may be a potential therapeutic agent by reducing injury caused by oxidative stress associated with diabetes.

Metformin Protects the Brain Against the Oxidative Imbalance Promoted by Type 2 Diabetes

We aimed to investigate whether metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. This study analyzed the effect of metformin on oxidative stress markers (thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA) and carbonyl groups), hydrogen peroxide (H(2)O(2)) levels, non-enzymatic antioxidant defenses [reduced (GSH) and oxidized (GSSG) glutathione and vitamin E] and enzymatic antioxidant defenses [glutathione peroxidase (GPx), glutathione reductase (GRed) and manganese superoxide dismutase (MnSOD)] in brain homogenates of diabetic GK rats, a model of type 2 diabetes. For this purpose we compared brain homogenates obtained from untreated GK rats versus GK rats treated with metformin during a period of 4 weeks. Brain homogenates obtained from Wistar rats were used as control. The MDA levels, GPx and GRed activities are significantly higher in untreated GK rats, while TBARS levels, carbonyl groups, glutathione content and vitamin E levels remain statistically unchanged when compared with control rats. In contrast, MnSOD activity and the levels of H(2)O(2) are significantly decreased in untreated GK rats when compared with control animals. However, metformin treatment normalized the majority of the parameters altered by diabetes. We observed that metformin, besides its antihyperglycemic action, induces a significant decrease in TBARS and MDA levels, GPx and GRed activities and a significant increase in GSH levels and MnSOD activity. These results indicate that metformin protects against diabetes-associated oxidative stress suggesting that metformin could be an effective neuroprotective agent.

The effect of hyperglycemia on the values of antioxidative parameters in type 2 diabetic patients with cardiovascular complications

Summary: Oxidative stress and hyperglycemia play an important role in the aethiology of vascular complications in diabetes. Hyperglycemia induces a large number of alterations in vascular tissue that potentially accelerate the atherosclerotic process. Nonenzymatic glycosylation of proteins and lipids which can interfere with their normal function by disrupting molecular conformation, alter enzymatic activity, reduce degradative capacity and interfere with receptor recognition, oxidative stress and protein kinase C activations are the major processes that encompass most of the pathological alterations in the diabetic vasculature. Diabetes-associated oxidative stress is a consequence of both increased production of free radicals and reduced capacity for antioxidative defense. The aim of this study was to test the parameters of antioxidative defense: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and total antioxidant status (TAS), in type 2 diabetic patients with and without cardiovascular complications in order to determine the effect of hyperglycemia on the extent of disorders of antioxidative parameters. Sixty nine type 2 diabetic patients with cardiovascular complications, along with 48 diabetics without complications and 42 healthy subjects were examined. Determination of antioxidant parameters was performed using commercial tests manufactured by Randox Laboratories, UK, based on spectrophotometer determination methods. Statistical data processing revealed significantly lower SOD, GSH-Px, GR and TAS values in type 2 diabetic patients with cardiovascular complications in comparison to the control group (p<0.0001), as well as in comparison to diabetics without complications (p<0.01).

How does glucose generate oxidative stress in peripheral nerve?

Diabetes-associated oxidative stress is clearly manifest in peripheral nerve, dorsal root, and sympathetic ganglia of the peripheral nervous system and endothelial cells and is implicated in nerve blood flow and conduction deficits, impaired neurotrophic support, changes in signal transduction and metabolism, and morphological abnormalities characteristic of peripheral diabetic neuropathy (diabetic peripheral neuropathy). Hyperglycemia has a key role in oxidative stress in diabetic nerve, whereas the contribution of other factors, such as endoneurial hypoxia, transition metal imbalance, and hyperlipidemia, has not been rigorously proven. It has been suggested that oxidative stress, particularly mitochondrial superoxide production, is responsible for sorbitol pathway hyperactivity, nonenzymatic glycation/glycooxidation, and activation of protein kinase C. However, this concept is not supported by in vivo studies demonstrating the lack of any inhibition of the sorbitol pathway activity in peripheral nerve, retina, and lens by antioxidants, including potent superoxide scavengers. Its has been also hypothesized that aldose reductase (AR) detoxifies lipid peroxidation products, and therefore, the enzyme inhibition in diabetes is detrimental rather than benefical. However, the role for AR in lipid peroxdation product metabolism has never been demonstrated in vivo, and the effects of aldose reductase inhibitors and antioxidants on diabetic peripheral neuropathy are unidirectional, i.e., both classes of agents prevent and correct functional, metabolic, neurotrophic, and morphological changes in diabetic nerve. Growing evidence indicates that AR has a key role in oxidative stress in the peripheral nerve and contributes to superoxide production by the vascular endothelium. The potential mechanisms of this phenonmenon are discussed.