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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular inflammation is involved in the initiation and progression of atherosclerosis, and is also present in hypertension- and diabetes-induced vascular complications. Angiotensin II (Ang II), the key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of blood pressure and electrolyte homeostasis. There is accumulating evidence to indicate that Ang II is also capable of inducing inflammatory response in the vascular wall. This review summarizes the current understanding of the molecular mechanisms and signal transduction pathways of Ang II-induced vascular inflammation. The roles of modulators of Ang II-induced inflammatory response, such as nitric oxide (NO), bradykinin, cyclooxygenase-2 (COX-2), endothelin-1 (ET-1), and epoxyeicosatrienoic acids (EETs), are also discussed. The current data suggest that Ang II modifies several steps of inflammatory response, such as increase of vascular permeability, leukocyte infiltration, tissue hypertrophy/proliferation, and fibrosis. Ang II, via the type 1 (AT1) receptors, enhances the production of reactive oxygen species (ROS) through stimulation of NAD(P)H oxidase in the vascular wall. Increased oxidative stress contributes to endothelial dysfunction and to vascular inflammation by stimulating the redox-sensitive transcription factors (NF-kappaB) and by upregulating adhesion molecules, cytokines, and chemokines. The pro-inflammatory action of Ang II may help us to understand the molecular mechanisms of hypertension- and diabetes-induced vascular complication as well as the pleiotropic actions of drugs interfering with RAS.
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PMID:Angiotensin II and vascular inflammation. 1591 31

The effect of atorvastatin (Lipitor) on diabetes-induced changes in plasma lipids, oxidative stress and the ability of aortic tissues to generate prostacyclin was studied in streptozotocin diabetic rats. In diabetic rats, plasma total cholesterol, triglycerides and serum glucose significantly increased compared to nondiabetic rats. Atorvastatin administration to diabetic rats did not affect hyperglycemia but significantly reduced plasma total cholesterol and triglycerides compared to diabetic rats. The oxidative stress markers urinary isoprostane, liver thiobarbituric acid reactive substances (TBARS) and plasma protein carbonyl content significantly increased in diabetic rats compared to nondiabetic rats. Atorvastatin admnistration to diabetic rats significantly reduced oxidative stress levels compared to diabetic rats, but urinary isoprostane and liver TBARS remained significantly higher than nondiabetic rats. Prostacyclin (PGI(2)) generation by aortic tissues significantly decreased in diabetic rats compared to nondiabetic rats. Atorvastatin administration to diabetic rats did not reverse that inhibition. These results were discussed in the light of the possible effects of hyperglycemia and statins on NAD(P)H-oxidase and cyclooxygenase-2 activities and the genetic difference between rats and other mammals regarding the level of vascular superoxide dismutase (SOD) activity.
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PMID:Atorvastatin reduces the plasma lipids and oxidative stress but did not reverse the inhibition of prostacyclin generation by aortas in streptozotocin diabetic rats. 1596 62

Diabetes mellitus leads to a high incidence of several so-called complications, sharing similar pathophysiological features in several territories. Previous reports points at early nonenzymatic glycosylation products (Amadori adducts) as mediators of diabetic vascular complications. In the present study, we analysed a possible role for Amadori adducts as stimulators of proinflammatory pathways in human peritoneal mesothelial cells (HPMCs). Cultured HPMCs isolated from 13 different patients (mean age 38.7+/-16 years) were exposed to different Amadori adducts, that is, highly glycated haemoglobin (10 nM) and glycated bovine serum albumin (0.25 mg ml(-1)), as well as to their respective low glycosylation controls. Amadori adducts, but not their respective controls, elicited a marked increase of NF-kappaB activation, as determined by electromobility shift assays and transient transfection experiments. Additionally, Amadori adducts significantly increased the production of NF-kappaB-related proinflammatory molecules, including cytokines, such as TNF-alpha, IL-1beta or IL-6, and enzymes, such as cyclooxygenase-2 and inducible nitric oxide (NO) synthase, this latter leading to the release of NO by HPMCs. The effects of Amadori adducts were mediated by different reactive oxygen and nitrosative species (e.g. superoxide anions, hydroxyl radicals, and peroxynitrite), as they were blunted by coincubation with the appropriate scavengers. Furthermore, NO generated upon exposure to Amadori adducts further stimulated NF-kappaB activation, either directly or after combination with superoxide anions to form peroxynitrite. We conclude that Amadori adducts can favour peritoneal inflammation by exacerbating changes in NO synthesis pathway and triggering NF-kappaB-related proinflammatory signals in human mesothelial cells.
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PMID:Amadori adducts activate nuclear factor-kappaB-related proinflammatory genes in cultured human peritoneal mesothelial cells. 1599 35

Chronic alcohol consumption is associated with an increased risk for cancers of many organs, such as oral cavity, pharynx, larynx, and esophagus; breast; liver; ovary; colon; rectum; stomach; and pancreas. An understanding of the underlying mechanisms by which chronic alcohol consumption promotes carcinogenesis is important for development of appropriate strategies for prevention and treatment of alcohol-associated cancers. The National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, Office of Rare Diseases, National Cancer Institute, National Institute on Drug Abuse, and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, sponsored an international symposium on Mechanisms of Alcohol-Associated Cancers in Bethesda, Maryland, USA, October 2004. The following is a summary of the symposium. Chronic ethanol consumption may promote carcinogenesis by (1) production of acetaldehyde, which is a weak mutagen and carcinogen; (2) induction of cytochrome P450 2E1 and associated oxidative stress and conversion of procarcinogens to carcinogens; (3) depletion of S-adenosylmethionine and, consequently, induction of global DNA hypomethylation; (4) induction of increased production of inhibitory guanine nucleotide regulatory proteins and components of extracellular signal-regulated kinase-mitogen-activated protein kinase signaling; (5) accumulation of iron and associated oxidative stress; (6) inactivation of the tumor suppressor gene BRCA1 and increased estrogen responsiveness (primarily in breast); and (7) impairment of retinoic acid metabolism. Nicotine may promote carcinogenesis through activation of extracellular signal-regulated kinase/cyclooxygenase-2/vascular endothelial growth factor signaling pathway.
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PMID:Mechanisms of alcohol-associated cancers: introduction and summary of the symposium. 1605 76

The "Third International Conference on Mechanisms of Action of Nutraceuticals" (ICMAN 3) was held to bring investigators from around the world together to find answers and share experience relevant to the role of nutraceuticals in health and disease. Dietary supplements are currently receiving recognition as being beneficial in coronary heart disease, cancer, osteoporosis and other chronic and degenerative diseases such as diabetes, Parkinson's and Alzheimer's diseases. This gave impetus to investigate the mechanisms of action of nutraceuticals and related bioactive compounds in disease pathologies. Many lines of evidence indicate that the mechanistic actions of natural compounds involve a wide array of biological processes, including activation of antioxidant defenses, signal transduction pathways, cell survival-associated gene expression, cell proliferation and differentiation and preservation of mitochondrial integrity. Furthermore, many of these compounds exert anti-inflammatory actions through inhibition of oxidative stress-induced transcription factors (e.g., NF-kappaB, AP-1), cytotoxic cytokines and cyclooxygenase-2. It appears that these properties play a crucial role in the protection against the pathologies of numerous age-related or chronic diseases. This review summarizes the latest research finding in functional foods and micronutrients in the promotion of health and reduction of risk for major chronic diseases as presented in this symposium.
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PMID:Proceedings from the "Third International Conference on Mechanism of Action of Nutraceuticals". 1611 39

C-reactive protein (CRP) is a liver-derived pattern recognition molecule that is increased in inflammatory states. It rapidly increases within hours after tissue injury, and it is suggested that it is part of the innate immune system and contributes to host defense. Since cardiovascular disease is at least in part an inflammatory process, CRP has been investigated in the context of arteriosclerosis and subsequent vascular disorders. Based on multiple epidemiological and intervention studies, minor CRP elevation [high-sensitivity CRP (hsCRP)] has been shown to be associated with future major cardiovascular risk (hsCRP:<1 mg/L=low risk; 1-3 mg/L=intermediate risk; 3-10 mg/L=high risk; >10 mg/L=unspecific elevation). It is recommended by the American Heart Association that patients at intermediate or high risk of coronary heart disease may benefit from measurement of hsCRP with regard to their individual risk prediction. Elevation of hsCRP is associated with increased risk of type 2 diabetes development in patients with all levels of metabolic syndrome. In type 1 and type 2 diabetes mellitus, hemoglobin A1c significantly correlates with hsCRP levels and future cardiovascular risk. Also, hsCRP levels increase with the stage of beta-cell dysfunction and insulin resistance. Non-diabetes drugs that have been shown to reduce hsCRP concentrations include aspirin, statins, cyclooxygenase-2 inhibitors, and fibrates. Recent intervention studies have also demonstrated the distinct efficacy of different anti-diabetes treatments on a variety of cardiovascular risk markers. Intensive insulin therapy may reduce inflammation, but this effect may be influenced by the degree of weight gain. Treatment with peroxisome proliferator-activated receptor gamma has lead to substantial reduction of hsCRP and other cardiovascular risk markers in several comparator studies. Since this effect was shown to be independent of the degree of glycemic improvement, it can be regarded as a classspecific effect. Whether these findings translate into a reduction of overall cardiovascular mortality will soon be shown by the currently running thiazolidinedione outcome studies. Positive results in these trials will further strengthen the value and acceptance of hsCRP, which is recommended as a predictive laboratory marker for cardiovascular disease risk also in patients with diabetes mellitus.
Diabetes Technol Ther 2006 Feb
PMID:High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. 1647 48

Neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) regulate the tubuloglomerular feedback (TGF) and renin-angiotensin system (RAS) in the kidney. In type 1 diabetic rats, renal overproduction of these enzymes and their relationship to the pathogenesis of diabetic nephropathy has been demonstrated. In the present study, we histologically and immunohistochemically investigated the kidneys of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, as a model of type 2 diabetes, at 62 weeks of age (chronic phase of diabetes). The kidneys of OLETF rats showed typical diabetic nephropathy. Quantitative scores for glomerulosclerosis and interstitial fibrosis in OLETF rats were significantly higher than those of age-matched control Long-Evans Tokushima Otsuka (LETO) rats. nNOS- and COX-2-positive immunoreactions were observed in the distal tubules and collecting ducts. These reactions appeared to be more widely distributed in OLETF, and the number of nNOS-and COX-2-positive sites in the OLETF were significantly more than those in LETO rats. Expression of renin, angiotensin II, and inducible nitric oxide synthase (iNOS) were also examined immunohistochemically, and no differences between OLETF and LETO rats were observed in the distributions and the number of immunoreactive-sites. In conclusion, the overproduction of nNOS and COX-2 in the kidney of OLETF rats was confirmed, suggesting that the overproduction of nNOS and/or COX-2 does not affect the intrarenal RAS or iNOS production but does affect TGF.
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PMID:Neuronal nitric oxide synthase and cyclooxygenase-2 in diabetic nephropathy of type 2 diabetic OLETF rats. 1650 8

Currently, in Japan, approximately 95% of patients with diabetes mellitus have non-insulin-dependent (type 2) diabetes mellitus (NIDDM), and diabetic nephropathy is a major cause of patients requiring chronic haemodialysis. A previous study showed that Hachimi-jio-gan has a protective effect in rats subjected to subtotal nephrectomy plus streptozotocin injection, a model of insulin-dependent (type 1) diabetic nephropathy. In this study, we used the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of human NIDDM, to investigate whether long-term administration of Hachimi-jio-gan affects glycaemic control and renal function in NIDDM. Male OLETF rats, aged 22 weeks, were divided into 4 groups of 10 and given Hachimi-jio-gan (50, 100 or 200 mg kg(-1) daily) orally or no treatment for 32 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats (n = 6) were used as non-diabetic normal controls. Hachimi-jio-gan reduced hyperglycaemia dose-dependently from 16 weeks of the administration period. Urinary protein excretion decreased significantly from an early stage, and creatinine clearance levels improved at 32 weeks. In addition, the levels of serum glycosylated protein and renal advanced glycation end-products were effectively reduced. Hachimi-jio-gan also significantly reduced the levels of thiobarbituric acid-reactive substances in renal mitochondria, although it showed only a tendency to reduce these in serum. Furthermore, long-term administration of Hachimi-jio-gan reduced renal cortical expression of proteins, such as transforming growth factor-beta1 (TGF-beta1), fibronectin, inducible nitric oxide synthase and cyclooxygenase-2. The 100- and 200-mg kg(-1) daily doses of Hachimi-jio-gan significantly reduced TGF-beta1 and fibronectin protein expression to levels below those of LETO rats. These data suggest that Hachimi-jio-gan may have a beneficial effect on the progression of diabetic nephropathy in OLETF rats by attenuating glucose toxicity and renal damage.
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PMID:Activity of the Chinese prescription Hachimi-jio-gan against renal damage in the Otsuka Long-Evans Tokushima fatty rat: a model of human type 2 diabetes mellitus. 1659 72

Renal cortical cyclooxygenase-2 (COX-2) is restricted to the macula densa and adjacent cortical thick ascending limbs (MD/cTALH). Renal cortical COX-2 increases in response to diabetes and renal ablation, both of which are characterized by hyperfiltration and reduced NaCl delivery to the MD due to increased proximal NaCl reabsorption. High-protein intake also induces hyperfiltration and decreases NaCl delivery to the MD due to increased NaCl reabsorption proximally. We investigated whether high protein induces cortical COX-2 and whether cortical COX-2 contributes to high protein-induced hyperfiltration and increased intrarenal renin biosynthesis. Cortical COX-2 increased after protein loading but decreased after protein restriction. COX-2 inhibition attenuated high protein-induced hyperfiltration but had no effect on high protein-induced intrarenal renin elevation. Therefore, induction of cortical COX-2 contributed to high protein-induced hyperfiltration but not intrarenal renin elevation. In the kidney cortex, neuronal nitric oxide synthase (nNOS) is also localized to the MD, and interactions between intrarenal nNOS and COX-2 systems have been proposed. Cortical COX-2 elevation seen in salt restriction was blocked by nNOS inhibiton. Cortical nNOS expression also increased after protein loading, and inhibition of nNOS activity completely reversed high protein-induced cortical COX-2 elevation and hyperfiltration. These results indicate that NO is a mediator of high protein-induced cortical COX-2 elevation and suggest that both intrarenal nNOS and COX-2 systems appear to regulate afferent arteriolar tone and subsequent hyperfiltration seen in high-protein intake.
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PMID:Role of renal cortical cyclooxygenase-2 expression in hyperfiltration in rats with high-protein intake. 1659 6

Proinsulin C-peptide causes multiple molecular and physiological effects, and improves renal and neuronal dysfunction in patients with diabetes. However, whether C-peptide controls the inhibitor kappaB (IkappaB)/NF-kappaB-dependent transcription of genes, including inflammatory genes is unknown. Here we showed that 1 nM C-peptide increased the expression of cyclooxygenase-2 (COX-2) mRNA and its protein in Swiss 3T3 fibroblasts. Consistently, C-peptide enhanced COX-2 gene promoter-activity, which was inhibited by GF109203X and Go6976, specific PKC inhibitors, and BAY11-7082, a specific nuclear factor-kappaB (NF-kappaB) inhibitor, accompanied by increased phosphorylation and degradation of IkappaB. These results suggest that C-peptide stimulates the transcription of inflammatory genes via activation of a PKC/IkappaB/NF-kappaB signaling pathway.
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PMID:Proinsulin C-peptide stimulates a PKC/IkappaB/NF-kappaB signaling pathway to activate COX-2 gene transcription in Swiss 3T3 fibroblasts. 1678 59


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