stilbenes and Diabetes-Mellitus--Type-1

Diabetes is a metabolic disorder that, during pregnancy, may affect fetal development. Fetal outcome depends on the type of diabetes present, the concentration of blood glucose and the extent of fetal exposure to elevated or frequently fluctuating glucose concentrations. The result of some diabetic pregnancies will be embryonic developmental abnormalities, a condition referred to as diabetic embryopathy. Tight glycemic control in type 1 diabetes during pregnancy using insulin therapy together with folic acid supplementation are partially able to prevent diabetic embryopathy; however, the protection is not complete and additional interventions are needed. Resveratrol, a polyphenol found largely in the skins of red grapes, is known to have antidiabetic action and is in clinical trials for the treatment of diabetes, insulin resistance, obesity and metabolic syndrome. Studies of resveratrol in a rodent model of diabetic embryopathy reveal that it significantly improves the embryonic outcome in terms of diminishing developmental abnormalities. Improvements in maternal and embryonic outcomes observed in rodent models may arise from resveratrol's antioxidative potential, antidiabetic action and antidyslipidemic nature. Whether resveratrol will have similar actions in human diabetic pregnancy is unknown. Here, we review the potential therapeutic use of resveratrol in diabetes and diabetic pregnancy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diabetes Complications; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Humans; Hypoglycemic Agents; Pregnancy; Pregnancy in Diabetics; Resveratrol; Stilbenes

Infertility is a common complication in diabetic men, mainly due to the loss of germ cells by apoptotic cell death. However, effective and safe approaches to prevent diabetic induction of testicular apoptosis for diabetic patients have not been available. Resveratrol (RSV), a group of compounds called polyphenols from plants, has been indicated its promising used clinically for cancers and cardiovascular diseases. Therefore, the present study aimed determining whether RSV attenuates type 1 diabetes (T1D)-induced testicular apoptotic cell death in a mouse model. We found that testicular apoptosis and oxidative stress levels were significantly higher in T1D mice than control mice. In addition, the phosphorylation level of metabolism-related Akt and GSK-3β was downregulated and Akt negative regulators PTEN, PTP1B and TRB3 were upregulated in the T1D group. These effects were partially prevented by RSV treatment. Nrf2 and its downstream genes, such as NQO-1, HO-1, SOD, catalase and metallothionein were significantly upregulated by RSV treatment. In addition, RSV-induced Nrf2 activation was found due to Keap1 degradation, mainly reliant on p62 that functions as an adaptor protein during autophagy. These results indicate that the attenuation of T1D-induced testicular oxidative stress and apoptosis by RSV treatment was mainly related to Akt-mediated Nrf2 activation via p62-dependent Keap1 degradation.

Topics: Animals; Antioxidants; Apoptosis; Diabetes Mellitus, Type 1; Kelch-Like ECH-Associated Protein 1; Male; Mice; NF-E2-Related Factor 2; Oxidative Stress; Proteolysis; Proto-Oncogene Proteins c-akt; Resveratrol; Sequestosome-1 Protein; Stilbenes; Testis

Topics: Animals; Antioxidants; Diabetes Mellitus, Type 1; DNA Damage; Glycation End Products, Advanced; Kidney Glomerulus; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. We previously found that the glomerular expression of Sirtuin-1 (SIRT1) is reduced in human diabetic glomeruli and that the podocyte-specific loss of SIRT1 aggravated albuminuria and worsened kidney disease progression in diabetic mice. SIRT1 encodes an NAD-dependent deacetylase that modifies the activity of key transcriptional regulators affected in diabetic kidneys, including NF-κB, STAT3, p53, FOXO4, and PGC1-α. However, whether the increased glomerular SIRT1 activity is sufficient to ameliorate the pathogenesis of diabetic kidney disease has not been explored. We addressed this by inducible podocyte-specific SIRT1 overexpression in diabetic OVE26 mice. The induction of SIRT1 overexpression in podocytes for six weeks in OVE26 mice with established albuminuria attenuated the progression of diabetic glomerulopathy. To further validate the therapeutic potential of increased SIRT1 activity against diabetic kidney disease, we developed a new, potent and selective SIRT1 agonist, BF175. In cultured podocytes BF175 increased SIRT1-mediated activation of PGC1-α and protected against high glucose-mediated mitochondrial injury. In vivo, administration of BF175 for six weeks in OVE26 mice resulted in a marked reduction in albuminuria and in glomerular injury in a manner similar to podocyte-specific SIRT1 overexpression. Both podocyte-specific SIRT1 overexpression and BT175 treatment attenuated diabetes-induced podocyte loss and reduced oxidative stress in glomeruli of OVE26 mice. Thus, increased SIRT1 activity protects against diabetes-induced podocyte injury and effectively mitigates the progression of diabetic kidney disease.

Topics: Albuminuria; Animals; Blood Glucose; Boronic Acids; Cell Line; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Models, Animal; Enzyme Induction; Mice, Transgenic; Mitochondria; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Podocytes; Signal Transduction; Sirtuin 1; Stilbenes

This study investigated if resveratrol ameliorates diabetic cardiomyopathy by targeting associated oxidative stress mechanisms.. Type 1 diabetes mellitus (DM) in FVB mice was induced by several intraperitoneal injections of a low dose of streptozotocin. Hyperglycemic and age-matched control mice were given resveratrol (10 mg/kg per day) for 1 month and subsequently monitored for an additional 6 months. Mice were assigned to four groups: control, resveratrol, DM, and DM/resveratrol. Cardiac function and blood pressure were assessed at 1, 3, and 6 months after DM induction. Oxidative damage and cardiac fibrosis were analyzed by histopathology, real-time PCR, and Western blot.. Mice in the DM group exhibited increased blood glucose levels, cardiac dysfunction, and high blood pressure at 1, 3, and 6 months after DM induction. Resveratrol did not significantly affect blood glucose levels and blood pressure; however, resveratrol attenuated cardiac dysfunction and hypertrophy in DM mice. Resveratrol also reduced DM-induced fibrosis. In addition, DM mice hearts exhibited increased oxidative damage, as evidenced by elevated accumulation of 3-nitrotyrosine and 4-hydroxynonenal, which were both attenuated by resveratrol. Mechanistically, resveratrol increased NFE2-related factor 2 (Nrf2) expression and transcriptional activity, as well as Nrf2's downstream antioxidative targets.. We demonstrated that resveratrol prevents DM-induced cardiomyopathy, in part, by increasing Nrf2 expression and transcriptional activity.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Cardiomyopathies; Gene Expression Regulation; Male; Mice; NF-E2-Related Factor 2; Resveratrol; Stilbenes; Transcription, Genetic

The progression of diabetes mellitus leads to several complications including overproduction of reactive oxygen species and reproductive alterations. As resveratrol (RES) is a powerful anti-oxidant and an anti-apoptotic compound, we hypothesized that side effects of type-1 diabetes (DM1) on male reproduction could be reduced by the RES treatment. Eighty-four prepubertal male rats were distributed into seven groups: sham-control (SC), RES-treated (R), resveratrol-vehicle-treated (RV), diabetic (D), diabetic-insulin-treated (DI), diabetic-RES-treated (DR), diabetic-insulin and RES-treated (DIR). DM1 was induced by a single intraperitoneal streptozotocin (STZ) injection (65 mg/kg) on the 30th day postpartum (dpp). Animals of DR, DIR and R groups received 150 mg/day of RES by gavage for 43 consecutive days (from the 33 to 75 dpp). DI and DIR rats received subcutaneous injections of insulin (1 U/100 g b.w./day) from 5th day after the DM1 induction. The blood glucose level was monitored. At 75 dpp, the euthanasia was performed for morphometric and biometric testicular analyses, spermatic evaluation and hormonal doses. In the D group, the blood glucose level was higher than in the DR, DI and DIR groups. Besides morphometric testicular measurements, testosterone and estradiol doses were lower in D group than in DR and DIR groups; LH dose was also lower than in DR. The preputial separation age was delayed in diabetes-induced groups. The DR and DIR groups showed an improvement in sperm mitochondrial activity, epididymal sperm counts and the frequency of morphologically normal sperms. RES treatment improved glycaemic level, sperm quantitative and qualitative parameters and the hormonal profile in DM1-induced rats and seems to be a good reproductive protector.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Epididymis; Male; Oxidative Stress; Rats, Wistar; Reactive Oxygen Species; Reproduction; Resveratrol; Sperm Motility; Spermatozoa; Stilbenes; Testis

Diabetes induces oxidative stress, DNA damage and alters several intracellular signaling pathways in organ systems. This study investigated modulatory effects of Trans-Resveratrol on type 1 diabetes mellitus (T1DM)-induced abnormal spermatogenesis, DNA damage and alterations in poly (ADP-ribose) polymerase (PARP) signaling in rat testis. Trans-Resveratrol administration (5mg/kg/day, ip) to Streptozotocin-induced T1DM adult male Wistar rats from day 22-42 resulted in recovery of induced oxidative stress, abnormal spermatogenesis and inhibited DNA synthesis, and led to mitigation of 8-hydroxy-2'-deoxyguanosine formation in the testis and spermatozoa, and DNA double-strand breaks in the testis. Trans-Resveratrol aggravated T1DM-induced up-regulation of aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 expression; however, it did not modify the up-regulated total PARP and down-regulated PARP1 expressions, but recovered the decreased SirT1 (Sirtuin 1) levels in T1DM rat testis. Trans-Resveratrol, when given alone, reduced the poly (ADP-ribosyl)ation (pADPr) process in the testis due to an increase in PAR glycohydrolase activity, but when given to T1DM rats it did not affect the pADPr levels. T1DM with or without Trans-Resveratrol did not induce nuclear translocation of apoptosis-inducing factor and the formation of 50 kb DNA breaks, suggesting to the lack of caspase-3-independent cell death called parthanatos. T1DM with or without Trans-Resveratrol did not increase necrotic cell death in the testis. Primary spermatocytes, Sertoli cells, Leydig cells and intra-testicular vessels showed the expression of PARP pathway related proteins. In conclusion, Trans-Resveratrol mitigates T1DM-induced sperm abnormality and DNA damage, but does not significantly modulate PARP signaling pathway, except the SirT1 expression, in the rat testis.

Topics: Animals; Diabetes Mellitus, Type 1; DNA Damage; Hyperglycemia; Male; Oxidation-Reduction; Oxidative Stress; Poly(ADP-ribose) Polymerases; Rats; Rats, Wistar; Resveratrol; Signal Transduction; Spermatogenesis; Spermatozoa; Stilbenes; Testis

To compare the protective effects of resveratrol, gliclazide, and losartan, at biochemical and histopathological levels, on the rat kidney with experimentally induced type 1 diabetes.. A total of 35 adult male Wistar rats were divided into control, diabetic, diabetic gliclazide, diabetic resveratrol, and diabetic losartan groups. For biochemical analysis, based on one of the kidneys, superoxide dismutase, malondialdehyde, and catalase were used for measurement. The other kidney was stained for histochemical and immunohistochemical markers and examined by light microscopy.. Nephropathy due to diabetes was developed at the end of the third week in the diabetic group: in the glomeruli, contraction from Bowman distance, diffuse mesangial matrix increasing and tubular dilation, and cytoplasmic vacuolar changes were observed. In tubulointerstitial areas, some tubular structures, an increased expression of VEGF was observed.. As a result, in diabetic rats, the effects of gliclazide, resveratrol, and losartan cure were equivalent to each other according to the parameters which were followed. Resveratrol, gliclazide, and losartan significantly protected renal glomeruli and the proximal and distal tubules.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enzyme-Linked Immunosorbent Assay; Gliclazide; Hypoglycemic Agents; Immunohistochemistry; Kidney; Losartan; Male; Rats; Rats, Wistar; Resveratrol; Stilbenes

To evaluate the in vitro effects of resveratrol (RSV) incubation on platelets from compensated and decompensated diabetic patients in order to use it as an adjuvant therapy. The study was performed on 77 diabetic patients and divided into two phases: 29 compensated and 48 decompensated diabetic platelets were analyzed at recruitment (T₀) and after in vitro RSV incubation (20 μg/ml) for 3 h at 37 °C (T₁). Lipoperoxide and nitric oxide (NO) levels, superoxide dismutase (SOD) and Na(+)/K(+) ATPase activities, total antioxidant capacity (TAC), and membrane fluidity tested by anisotropy of fluorescent probes TMA-DPH and DPH were determined. In vitro RSV incubation counteracts oxidative damage associated with diabetes and its complications; it is able to improve platelet function through augmented membrane fluidity and Na(+)/K(+) ATPase activity; it enhances antioxidant systems' functionality by increasing NO levels, SOD activity, and TAC and by decreasing lipoperoxide levels in both compensated and decompensated patients. Such platelet functionality enhancement suggests a new method of secondary prevention of complications associated with platelet dysfunction. Being free from one of the major risks associated with many antidiabetic agents, it can be assumed that RSV utilization in the diabetic diet may have a preventive and protective role in the progression of diabetic oxidative damage.

Topics: Adult; Aged; Antioxidants; Blood Platelets; Cells, Cultured; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Membrane Fluidity; Middle Aged; Oxidative Stress; Resveratrol; Stilbenes

Trans-resveratrol (RSV) is a natural compound occurring in different foods and plants, which in vivo is rapidly conjugated with glucuronic acid and sulfate. Despite its demonstrated cardioprotective activity, the bioaccumulation of RSV or its metabolites in cardiac tissue is still unknown.. Diabetic rats were randomized to 1, 3 or 6 weeks of RSV treatment at two different doses (1 or 5 mg/kg/day). A dose and time-dependent accumulation was observed, with no detectable levels of RSV metabolites found in heart tissues after 1 week and significant concentrations of RSV-3-sulfate and RSV-3-glucuronide after 6 weeks of treatment (0.05 nmol/g of tissue and 0.01 nmol/g of tissue, respectively). Tissue accumulation of RSV metabolites was accompanied by an improvement of cardiac function in long-term diabetes, when myocardial morpho-functional damage is more evident, with an almost complete recovery of all hemodynamic parameters, at the highest RSV dose.. Even if a higher concentration of RSV in tissues cannot be ruled out after constant oral administration, an accumulation coherent with what is usually evaluated in cell based mechanistic studies is largely unattainable and the RSV unconjugated form would not be present in this paradigm. The current investigation provides data on myocardial tissue concentrations of RSV metabolites, after short/medium term RSV treatment. This knowledge constitutes a basic requirement for future studies aimed at reliably defining the molecular pathways underlying RSV-mediated cardioprotective effects and opens up new perspectives for research focused on testing phenolic compounds as adjuvants in degenerative heart diseases.

Topics: Animals; Biotransformation; Blood Glucose; Body Weight; Cardiotonic Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Glucuronides; Heart Diseases; Hemodynamics; Male; Myocardium; Rats, Wistar; Resveratrol; Stilbenes; Sulfates; Time Factors

Several lines of evidence support a role for oxidative stress in diabetic complications. Diabetic patients have increased O(2)(-) production in monocytes. Loss of SIRT1 activity may be associated with metabolic diseases such as diabetes. Several studies have shown that SIRT1 can regulate mammalian FOXO transcription factors through direct binding and/or deacetylation. However, interactions between SIRT1 and FOXO under diabetic conditions are unclear. The phytochemical resveratrol has recently gained attention for its protection against metabolic disease. Resveratrol has been shown to increase mitochondrial function by activating SIRT1. In this study, we tested the protective effect of resveratrol on cellular oxidative stress through the SIRT1-FOXO pathway under high-glucose conditions. Human monocytic (THP-1) cells were cultured in the presence of mannitol (osmolar control) or normoglycemic (NG, 5.5 mmol/l glucose) or hyperglycemic (HG, 25 mmol/l glucose) conditions in absence or presence of resveratrol (3 and 6 μmol/l) for 48 h. We first examined SIRT1 activity and oxidative stress in monocytes of Type 1 diabetes mellitus (T1DM) patients compared with healthy controls. In T1DM patients, monocytic SIRT1 expression was significantly decreased and p47phox expression was increased compared with controls. Under HG in vitro, SIRT1 and FOXO3a were significantly decreased compared with NG, and this was reversed by resveratrol treatment, concomitant with reduction in HG-induced superoxide production and p47phox. Under HG, SIRT1 small interfering RNA (siRNA) inhibited FOXO3a, and there was no beneficial effect of resveratrol in siRNA-treated HG-induced cells. Thus, resveratrol decreases HG-induced superoxide production via up-regulation of SIRT1, induction of FOXO3a and inhibition of p47phox in monocytes.

Topics: Antioxidants; Cell Line; Diabetes Mellitus, Type 1; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Mitochondria; Monocytes; NADPH Oxidases; Oxidative Stress; Resveratrol; RNA, Small Interfering; Sirtuin 1; Stilbenes; Superoxides; Up-Regulation

Resveratrol (3,5,4'-trihydroxystilbene; RSV) is one kind of polyphenolic phytoalexin that has many effects on metabolic diseases. This study aimed to evaluate the protective effect of RSV pretreatment on β-cell. Male Sprague Dawley rats weighing 200-230 g were divided into 4 groups: (1) RSV; (2) streptozotocin (STZ, 70 mg/kg, intraperitoneally); (3) STZ after 7 days pretreatment with RSV; and (4) STZ pretreated with nicotinamide. Fasting glucose concentration was measured and an intraperitoneal glucose tolerance test was performed 72 h after STZ injection to determine the diabetic condition. The pancreas was removed 3, 6, 36, and 48 h after STZ injection. STZ induced diabetes in all rats not given RSV pretreatment, whereas none of the RSV-pretreated rats developed diabetes. Pretreatment with RSV inhibited apoptosis and reduced the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). However, expression of the total length PARP was not affected by pretreatment. Our findings suggest that RSV protects β-cells from STZ simultaneously with inhibiting the activation of PARP.

Topics: Animals; Antioxidants; Apoptosis; Blood Glucose; Caspase 3; Diabetes Mellitus, Type 1; Enzyme Activation; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; In Situ Nick-End Labeling; Insulin-Secreting Cells; Male; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Proteolysis; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Streptozocin; Time Factors

Emerging evidence suggests that both adult cardiac cell and the cardiac stem/progenitor cell (CSPC) compartments are involved in the patho-physiology of diabetic cardiomyopathy (DCM). We evaluated whether early administration of Resveratrol, a natural antioxidant polyphenolic compound, in addition to improving cardiomyocyte function, exerts a protective role on (i) the progenitor cell pool, and (ii) the myocardial environment and its impact on CSPCs, positively interfering with the onset of DCM phenotype. Adult Wistar rats (n = 128) with streptozotocin-induced type-1 diabetes were either untreated (D group; n = 54) or subjected to administration of trans-Resveratrol (i.p. injection: 2.5 mg/Kg/day; DR group; n = 64). Twenty-five rats constituted the control group (C). After 1, 3 or 8 weeks of hyperglycemia, we evaluated cardiac hemodynamic performance, and cardiomyocyte contractile properties and intracellular calcium dynamics. Myocardial remodeling and tissue inflammation were also assessed by morphometry, immunohistochemistry and immunoblotting. Eventually, the impact of the diabetic "milieu" on CSPC turnover was analyzed in co-cultures of healthy CSPCs and cardiomyocytes isolated from D and DR diabetic hearts. In untreated animals, cardiac function was maintained during the first 3 weeks of hyperglycemia, although a definite ventricular remodeling was already present, mainly characterized by a marked loss of CSPCs and adult cardiac cells. Relevant signs of ventricular dysfunction appeared after 8 weeks of diabetes, and included: 1) a significant reduction in ±dP/dt in comparison with C group, 2) a prolongation of isovolumic contraction/relaxation times, 3) an impaired contraction of isolated cardiomyocytes associated with altered intracellular calcium dynamics. Resveratrol administration reduced atrial CSPC loss, succeeded in preserving the functional abilities of CSPCs and mature cardiac cells, improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart, leading to a marked recovery of ventricular function. These findings indicate that RSV can constitute an adjuvant therapeutic option in DCM prevention.

Topics: Actins; Animals; Apoptosis; Blood Glucose; Body Weight; Calcium Signaling; Cell Count; Coculture Techniques; Diabetes Mellitus, Type 1; Endothelial Cells; Hemodynamics; HMGB1 Protein; Intracellular Space; Male; Myocardium; Myocytes, Cardiac; Rats; Rats, Wistar; Resveratrol; Stem Cells; Stilbenes; Ventricular Remodeling

Resveratrol has been shown to have vasoprotective effects by upregulating oxidative defense mechanisms in a variety of pathophysiological conditions. However, the effect of resveratrol on diabetic oxidative stress and vascular and metabolic abnormalities is not completely understood. Therefore, this study was designed to evaluate whether long-term resveratrol supplementation has a protective effect on vascular function and integrity in association with metabolic parameters and oxidative stress in insulin-dependent diabetes.. Diabetes was induced in rabbits with alloxan and maintained for 8 weeks. We used a resveratrol dose of 5 mg/L (10 weeks, starting 14 days before alloxan injection) and 50 mg/L (8 or 10 weeks, starting concomitantly or 14 days before alloxan injection) in the drinking water of rabbits.. Relaxation to acetylcholine was impaired (control 75.6 ± 3.59%, versus diabetic 42.23 ± 2.53%) and contractions to phenylephrine increased (control 136.89 ± 2.27%, versus diabetic 159.37 ± 6.27%) in aortas from diabetic animals. These changes were associated with increased basal or NAD(P)H-induced superoxide production, as well as lipid peroxide and superoxide dismutase (SOD) levels in the aortic samples. The maximal relaxation to acetylcholine improved by 75.74 ± 9.04% in diabetic rabbits treated with resveratrol. The increased contractions to phenylephrine were not restored to control values after resveratrol treatments, but sensitivity to the contractions tended to decrease. Resveratrol increased nitrite/nitrate levels and suppressed basal or NAD(P)H-induced superoxide production and lipid peroxide levels in the aortas. Importantly, resveratrol increased serum insulin levels without affecting blood glucose and the lipid profile in diabetic rabbits. Using electron microscopic examinations, resveratrol was found to markedly protect the endothelial integrity from diabetes.. Overall, there was no noticeable difference between resveratrol treatment groups on the recovery from diabetes. Our results indicate that resveratrol alleviates type 1 diabetes-induced vasculopathy by decreasing vascular oxidative stress and thereby increasing the bioavailability of nitric oxide without changing metabolic abnormalities.

Topics: Acetylcholine; Animals; Antioxidants; Blood Glucose; Body Weight; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Estrogens; Insulin; Lipid Peroxides; Lipids; Male; NADP; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rabbits; Resveratrol; Stilbenes; Superoxide Dismutase; Testosterone; Time Factors; Vascular Diseases

Topics: Animals; Antioxidants; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Male; Oxidative Stress; Resveratrol; Stilbenes; Vascular Diseases

We recently found that activation of the type III histone deacetylase sirtuin 1 suppresses T cell immune responses. Here we sought to determine the therapeutic potential of the sirtuin 1 activator resveratrol in the treatment of diabetes in the NOD mouse model of type 1 diabetes and the mechanisms underlying such potential.. NOD mice were fed or subcutaneously injected with resveratrol and evaluated for development of diabetes. Splenocytes from resveratrol-treated and control mice were analysed by gene array. The altered expression of inflammatory genes induced by resveratrol was validated and the role of changed gene expression in prevention of diabetes was determined.. Resveratrol administration potently prevented and treated type 1 diabetes in NOD mice. Gene array analysis indicated a dramatic decrease in expression of Ccr6, which encodes chemokine (C-C motif) receptor (CCR) 6, in the splenocytes from resveratrol-treated mice. CCR6 abundance on IL-17-producing cells and CD11b(+)F4/80(hi) macrophages was inhibited by resveratrol treatment. Interestingly, CCR6(+) IL-17-producing cells and CD11b(+)F4/80(hi) macrophages accumulated in the spleens and pancreatic lymph nodes, but their presence in the pancreas was reduced, suggesting that resveratrol blocks their migration from peripheral lymphoid organs to the pancreas. Indeed, the migration of splenocytes toward media containing chemokine (C-C motif) ligand 20 (CCL20) was impaired by resveratrol treatment. CCL20 peptides, which block CCR6 binding to CCL20, inhibited development of type 1 diabetes.. Inhibition of CCR6-mediated migration of inflammatory cells by resveratrol may provide a powerful approach for treatment of type 1 diabetes and possibly of other inflammatory diseases.

Topics: Animals; Cell Movement; Cells, Cultured; Chemokine CCL20; Diabetes Mellitus, Type 1; Female; Flow Cytometry; Hypoglycemic Agents; Interleukin-17; Mice; Mice, Inbred NOD; Receptors, CCR6; Resveratrol; Stilbenes

Decreased dilation of cerebral arterioles via an increase in oxidative stress may be a contributing factor in the pathogenesis of diabetes-induced complications leading to cognitive dysfunction and/or stroke. Our goal was to determine whether resveratrol, a polyphenolic compound present in red wine, has a protective effect on cerebral arterioles during type 1 diabetes (T1D). We measured the responses of cerebral arterioles in untreated and resveratrol-treated (10 mg·kg(-1)·day(-1)) nondiabetic and diabetic rats to endothelial (eNOS) and neuronal (nNOS) nitric oxide synthase (NOS)-dependent agonists and to a NOS-independent agonist. In addition, we harvested brain tissue from nondiabetic and diabetic rats to measure levels of superoxide under basal conditions. Furthermore, we used Western blot analysis to determine the protein expression of eNOS, nNOS, SOD-1, and SOD-2 in cerebral arterioles and/or brain tissue from untreated and resveratrol-treated nondiabetic and diabetic rats. We found that T1D impaired eNOS- and nNOS-dependent reactivity of cerebral arterioles but did not alter NOS-independent vasodilation. While resveratrol did not alter responses in nondiabetic rats, resveratrol prevented T1D-induced impairment in eNOS- and nNOS-dependent vasodilation. In addition, superoxide levels were higher in brain tissue from diabetic rats and resveratrol reversed this increase. Furthermore, eNOS and nNOS protein were increased in diabetic rats and resveratrol produced a further increased eNOS and nNOS proteins. SOD-1 and SOD-2 proteins were not altered by T1D, but resveratrol treatment produced a decrease in SOD-2 protein. Our findings suggest that resveratrol restores vascular function and oxidative stress in T1D. We suggest that our findings may implicate an important therapeutic potential for resveratrol in treating T1D-induced cerebrovascular dysfunction.

Topics: Analysis of Variance; Animals; Antioxidants; Arterioles; Blotting, Western; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dose-Response Relationship, Drug; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Oxidative Stress; Pia Mater; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Superoxides; Vasodilation; Vasodilator Agents

Increased heme oxygenase-1 (HO-1) expression improves vascular function by decreasing superoxide and increasing antioxidant levels. We therefore examined if HO-1 induction increased serum adiponectin levels and ameliorated vascular dysfunction in Type 1 diabetes. Administration of either carbon monoxide (CORM-3) or the HO-1 inducers, Resveratrol, and cobalt protoporphyrin (CoPP), increased serum levels of adiponectin (high molecular weight) in diabetic (streptozotocin; STZ-induced) Sprague Dawley rats. Resveratrol and CoPP administration increased HO-1 protein expression and HO activity in the aorta and significantly (p<0.05) increased serum adiponectin levels, compared to untreated diabetic rats. The results obtained with the CO releasing molecule, CORM-3, indicate a direct involvement of CO leading to increased levels of adiponectin. The increase in adiponectin was associated with a significant decrease in circulating endothelial cells (CEC) (p<0.002), decreased EC fragmentations and a significant increase in thrombomodulin (TM) and CD31(+) cells (p<0.05). Increased adiponectin levels were associated with a decrease in TNF-alpha-induced ICAM-1 and VCAM-1 and caspase 3 activity in endothelial cells while phosphorylation of eNOS at Ser-1179 increased. The adiponectin mediated increase in peNOS and pAKT was prevented by the phosphatidylinositol-3 kinase inhibitor, LY294002. In conclusion, there appears to be a temporal HO-1-adiponectin relationship that has a key role in vascular protection in Type 1 diabetes via a mechanism that involves increased levels of carbon monoxide.

Topics: Adiponectin; Animals; Aorta; Carbon Monoxide; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Endothelial Cells; Enzyme Induction; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Male; Organometallic Compounds; Protoporphyrins; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Streptozocin