stilbenes and Diabetic-Angiopathies

Progressive microvascular dysfunction in type 2 diabetes mellitus (T2DM) may impair the ability of cerebral vessels to supply blood to brain regions during local metabolic demand, thereby increasing risks of dementia. Having previously demonstrated that resveratrol can enhance vasodilator function in the systemic circulation, we hypothesised that resveratrol could similarly benefit the cerebral circulation. We aimed to determine the most efficacious dose of resveratrol to improve cerebral vasodilator responsiveness (CVR) in T2DM.. In a double-blind, placebo-controlled, balanced crossover intervention, 36 dementia-free, non-insulin dependent T2DM older adults (49-78 years old) consumed single doses of synthetic trans-resveratrol (0, 75, 150, and 300 mg) at weekly intervals. Transcranial Doppler ultrasound was used to assess CVR to a hypercapnic stimulus, both before and 45 min after treatment. CVR, measured bilaterally in the middle cerebral arteries (MCA) and posterior cerebral arteries (PCA), was expressed as the percentage change in mean blood flow velocity from baseline to the peak velocity attained during hypercapnia. Resveratrol consumption increased CVR in the MCA; mean within-individual changes for each dose from placebo were 13.8 ± 3.5% for 75 mg (P = 0.001), 8.9 ± 3.5% for 150 mg (P = 0.016), and 13.7 ± 3.3% for 300 mg (P < 0.001); only the 75 mg dose was efficacious in the PCA (13.2 ± 4.5%, P = 0.016).. Our results provide the first clinical evidence of an acute enhancement of vasodilator responsiveness in cerebral vessels following consumption of resveratrol in this population who are known to have endothelial dysfunction and sub-clinical cognitive impairment. Importantly, maximum improvement was observed with the lowest dose used.. ACTRN12614000891628 (www.anzctr.org.au).

Topics: Aged; Blood Flow Velocity; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognition; Cognition Disorders; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Middle Cerebral Artery; Posterior Cerebral Artery; Resveratrol; Stilbenes; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Transcranial; Vasodilation; Victoria

Hyperglycemia and increased levels of methylglyoxal (MGO) can trigger the development of vascular complications in diabetes. Resveratrol and quercetin are red wine polyphenols with known beneficial cardiovascular properties, including an antioxidant capacity. This study evaluated whether resveratrol and/or quercetin could prevent in vitro-induced diabetic changes in neurogenic and vascular relaxant responses of mouse arteries and corpora cavernosa.. Isometric tension of isolated aorta, mesenteric arteries and corpora cavernosa was measured using organ bath systems. Diabetic conditions were mimicked in vitro by co-incubating the tissues for 2 h with high glucose (HG, 30 mM) and MGO (120 µM).. The presence of HG and MGO significantly blunted acetylcholine (Ach)-induced relaxations in corpora cavernosa and mesenteric arteries but not in aorta. Electrical field stimulated (EFS) responses of corpora cavernosa were also significantly inhibited by these diabetic conditions. In corpora cavernosa 2 h co-incubation with resveratrol (30 µM) or quercetin (30 µM) significantly attenuated HG and MGO-induced deficits in Ach- and EFS-responses.. Our study demonstrates that in mouse arteries, HG and MGO rather affect endothelium derived hyperpolarizing factor-mediated than nitric oxide (NO)-mediated relaxations. In corpora cavernosa HG and MGO interfere with NO release. Resveratrol and quercetin protect mouse corpora cavernosa from diabetic-induced damage to NO-mediated relaxant responses. This might rely on their antioxidant capacity.

Topics: Acetylcholine; Animals; Arteries; Biological Factors; Cytoprotection; Diabetic Angiopathies; Dose-Response Relationship, Drug; Electric Stimulation; Glucose; In Vitro Techniques; Male; Mice; Nitric Oxide; Penis; Pyruvaldehyde; Quercetin; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents

Microvascular complications are now recognized to play a major role in diabetic complications, and understanding the mechanisms is critical. Endothelial dysfunction occurs early in the course of the development of complications; the precise mechanisms remain poorly understood. Mitochondrial dysfunction may occur in a diabetic rat heart and may act as a source of the oxidative stress. However, the role of endothelial cell-specific mitochondrial dysfunction in diabetic vascular complications is poorly studied. Here, we studied the role of diabetes-induced abnormal endothelial mitochondrial function and the resultant endothelial dysfunction. Understanding the role of endothelial mitochondrial dysfunction in diabetic vasculature is critical in order to develop new therapies. We demonstrate that hyperglycaemia leads to mitochondrial dysfunction in microvascular endothelial cells, and that mitochondrial inhibition induces endothelial dysfunction. Additionally, we show that resveratrol acts as a protective agent; resveratrol-mediated mitochondrial protection may be used to prevent long-term diabetic cardiovascular complications.

Topics: Animals; Blood Glucose; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Artery Disease; Coronary Circulation; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelial Cells; Humans; Isolated Heart Preparation; Male; Microcirculation; Microvessels; Mitochondria; Myocardial Contraction; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Time Factors; Vasodilation

To investigate the effects of resveratrol on high glucose (HG)-induced vascular injury, and to establish the mechanism(s) underlying these effects.. Human umbilical vein endothelial cells (HUVECs) were treated with glucose, and then incubated with resveratrol in the presence or absence of Compound C, an AMP-activated protein kinase (AMPK) inhibitor. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) method. Reactive oxygen species, malondialdehyde, and superoxide dismutase were detected by flow cytometry, thiobarbituric acid reaction, and the nitroblue tetrazolium method, respectively. Protein levels of total and phosphorylated AMPKα and acetyl-CoA carboxylase were detected by immunoblotting.. Resveratrol significantly ameliorated HG-induced decreases in cell viability and superoxide dismutase levels and increases in reactive oxygen species and MDA levels. Moreover, resveratrol significantly reversed HG-induced dephosphorylation of AMPKα and acetyl-CoA carboxylase. However, treatment with Compound C curtailed the beneficial effects of resveratrol on HG-treated HUVECs.. Resveratrol ameliorates HG-induced injury in HUVECs by activation of AMPKα, leading to increased cellular reductive reactions and decreased oxidative stress. These results provide further evidence for resveratrol-mediated activation of AMPKα.

Topics: Adenylate Kinase; Cells, Cultured; Diabetic Angiopathies; Drug Evaluation, Preclinical; Enzyme Activation; Enzyme Activators; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Malondialdehyde; Oxidative Stress; Reactive Oxygen Species; Resveratrol; Stilbenes; Superoxide Dismutase

Diabetic vascular complication is one of the manifestations of endothelial dysfunction. Resveratrol (RV) is considered to be beneficial in protecting endothelial function. However, the exact protective effect and mechanisms involved have not been fully clarified. In this study, we investigated the relationship between Akt/endothelial nitric oxide synthase (eNOS) activation and RV in diabetes-induced endothelial dysfunction. Aortas were dissected and placed in organ chambers, and nitric oxide (NO) production in response to acetylcholine (ACh) and RV was measured. ACh-induced endothelium-dependent relaxation was markedly increased in controls by RV pretreatment. Furthermore, RV caused NO-dependent relaxation via the Akt signaling pathway, which was weaker in the aortas of diabetic mice than age-matched controls. To further examine the underlying mechanisms, we measured the phosphorylation of Akt and eNOS by Western blotting. RV caused the phosphorylation of Akt and eNOS in aortas, which was decreased in diabetic mice. However, RV augmented the impaired clonidine-induced relaxation in diabetic mice. Interestingly, the phosphorylation of Akt and eNOS was increased under stimulation with RV and clonidine only in diabetic mice. Thus, either RV or clonidine causes Akt-dependent NO-mediated relaxation, which is weaker in diabetic mice than controls. However, additional exposure to RV and clonidine has an augmenting effect on the Akt/eNOS signaling pathway under diabetic conditions. RV-induced Akt/eNOS activity may be a common link involved in the clonidine-induced Akt/eNOS activity, so RV and clonidine may have a synergistic effect.

Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Antioxidants; Clonidine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Synergism; Endothelium, Vascular; Male; Mice, Inbred ICR; Nitric Oxide Synthase; Phosphorylation; Plant Extracts; Proto-Oncogene Proteins c-akt; Resveratrol; Stilbenes; Vasodilation

This paper studies the expression of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and IFN-γ and anti-inflammatory cytokines such as IL-10 in diabetic rat aortas, the effects of resveratrol on these cytokines, and the potential epigenetic mechanisms involved. The experiment was performed on rats divided into four groups: normal group (NC), normal interventional group (NB), diabetic group (DM), and diabetic interventional group (DB). The NB and DB groups were treated with resveratrol. After more than 3 months, the rats' aortas were removed and analyzed for cytokines by using immunohistochemistry, Western blotting, real-time PCR, and methylation-specific PCR. Histological localization of these cytokines was mainly found in the arterial intima of diabetic rats. The protein and mRNA expression levels of IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in the DM group than in the NC group (p < 0.05), whereas in the resveratrol-treated groups (NB and DB), the levels were relatively lower than those in the corresponding groups. The DM group showed reduced levels of DNA methylation at the specific cytosine phosphate guanosine sites of IL-1β, IL-6, TNF-α, and IFN-γ, relative to those in the NC group (p < 0.01), and these levels were increased by resveratrol. In contrast, IL-10 was dramatically methylated and showed decreased expression in response to high glucose, and resveratrol reversed this effect. These results demonstrate that the inflammatory response is involved in diabetic macroangiopathy. Resveratrol inhibits the expression of proinflammatory cytokines and thus may have a protective effect on the aorta in hyperglycemia. Thus, DNA methylation, an epigenetic gene silencing signal, may be responsible for these two phenomena.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aorta; Cytokines; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Angiopathies; DNA Methylation; Gene Expression Regulation; Humans; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Th1-Th2 Balance

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

Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.. Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES.. Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.

Topics: Animals; Aortic Diseases; Atherosclerosis; Cardiovascular Agents; Cell Line; Chemokine CCL2; Chemotaxis, Leukocyte; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Female; Humans; Hyperlipidemias; Kidney; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Oxidative Stress; Receptors, CCR2; Receptors, LDL; Resveratrol; Stilbenes; Time Factors; Triterpenes; Ursolic Acid

We undertook this study to investigate the roles of SIRT1 in high glucose-induced endothelial impairment and their association with diabetic atherosclerosis.. Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic rats of the same genetic background were included. Real-time PCR was used to detect SIRT1 mRNA expression in abdominal aorta at week 42. To further investigate the roles of SIRT1 on the function of endothelial cells in high glucose, human endothelial cells were treated with SIRT1 activator resveratrol for 24 h before being cultured in high glucose medium for 48 h.. Along with the early manifestation of atherosclerosis, SIRT1 mRNA level in OLETF group was significantly lower than that in control group (p <0.05). Compared with control cells, high glucose decreased nitric oxide (NO) secretion, but resveratrol treatment increased the expression of SIRT1 and the secretion of NO. After interfering with the expression of SIRT1 using SIRT1 siRNA, the effects of resveratrol on NO secretion were impaired. SIRT1 also counteracted the other pro-atherosclerotic effects of high glucose including the upregulating roles of high glucose on the expression of E-selectin mRNA and the downregulating roles of high glucose on the expression of endothelial nitric oxide synthase.. Decreased expression of SIRT1 in artery may be involved in the initiation and development of diabetic atherosclerosis. Increasing SIRT1 expression may hold great promise in the prevention and therapy of atherosclerosis in diabetic patients.

Topics: Atherosclerosis; Base Sequence; Cells, Cultured; Diabetic Angiopathies; DNA Primers; Endothelium, Vascular; Glucose; Humans; Nitric Oxide; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sirtuin 1; Stilbenes

Resveratrol (RSV) has been shown to ameliorate hyperglycaemia and hyperlipidaemia in streptozotocin-induced diabetic rats. In the present study, we examined the beneficial effects of RSV on diabetes mellitus (DM)-induced vasculopathy and explored its possible mechanism.. Male Sprague-Dawley rats were injected with streptozotocin at 65 mg/kg body weight The induction of DM was confirmed by a fasting plasma glucose level > or = 300 mg/dL and symptoms of polyphagia and polydipsia. The DM rats were treated with or without RSV at 0.75 mg/kg body weight three times a day for 4-8 weeks. Animals were sacrificed and vessel wall histology was examined by microscopy. The vascular smooth muscle cell activation was assessed by the medial thickness, collagen deposition, and the expressions receptor for advanced glycation end product, NF-kappaB, proliferation cell nuclear antigen, and the levels of Erk1/2 phosphorylation.. In RSV-treated DM rats, the vascular wall thickening, collagen deposition/cross-linking, and vascular permeability were all alleviated compared with that of the untreated DM rats. The vascular smooth muscle cell of the RSV-treated rats was characterized with less proliferation, lower NF-kappaB, and Erk1/2 activation, decreased proliferation cell nuclear antigen and receptor for advanced glycation end product expression. Moreover, the plasma fructosamine was significantly reduced in RSV-treated DM rats.. RSV alleviated DM-induced vasculopathy through attenuation of advanced glycation end product-receptor for advanced glycation end product-NF-kappaB signalling pathway.

Topics: Analysis of Variance; Animals; Aorta; Blood Glucose; Blotting, Western; Collagen; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Glycation End Products, Advanced; Immunohistochemistry; Insulin; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Resveratrol; Signal Transduction; Stilbenes

Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD(+)-dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood.. Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes.. These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.

Topics: Acetylation; Animals; Aorta; Cells, Cultured; Cellular Senescence; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelial Cells; Endothelium, Vascular; Enzyme Activators; Forkhead Transcription Factors; Glucose; Humans; Mice; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes; Time Factors; Transfection; Tumor Suppressor Protein p53

Diabetic heart disease contributes to the high mortality in diabetics, although effective clinical management is lacking. The protease inhibitor 5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) was reported to protect the hearts against ischemic injury. This study examined the role of UCF-101 on streptozotocin (STZ)-induced diabetic heart defect. Vehicle or UCF-101 was administrated to STZ diabetic mice, and cardiomyocyte mechanical properties were analyzed. UCF-101 reduced STZ-induced hyperglycemia and alleviated STZ-induced aberration in cardiomyocyte contractile mechanics. Diabetes dramatically decreased AMPK phosphorylation at Thr(172) of catalytic alpha-subunit, which was restored by UCF-101. Neither diabetes nor UCF-101 affected the expression of HtrA2/Omi and XIAP or caspase-3 activity. The AMPK activator resveratrol mimicked the UCF-101-induced beneficial effect against diabetic cardiac dysfunction. Mechanical properties in cardiomyocytes from the AMPK-kinase-dead (KD) mice displayed markedly impaired contractile function reminiscent of diabetes. STZ injection in AMPK-KD mice failed to elicit any additional cardiomyocyte contractile defect. UCF-101 significantly downregulated the AMPK-degrading enzymes PP2A and PP2C, the effect of which was mimicked by resveratrol. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiac dysfunction, possibly through AMPK signaling.

Topics: Adenylate Kinase; Animals; Antioxidants; Blood Glucose; Blotting, Western; Caspase 3; Cell Separation; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Isoenzymes; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocytes, Cardiac; Phosphorylation; Protease Inhibitors; Protein Phosphatase 2; Pyrimidinones; Resveratrol; Stilbenes; Thiones