Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cause of diabetic neuropathy remains unclear but several mechanisms have been considered. Hyperglycemia with all its metabolic and vascular consequences probably plays the main role. Metabolic consequences of hyperglicemia including increased level of sorbitol and fructose, myoinositol deficiency and Na+/K+ adenosine triphosphate deficiency alter the function of peripheral nerves and lead to an oxidative stress, which changes fatty acid metabolism. Chronic hyperglycemia is also responsible for abnormalities in microcirculation that could lead to local ischemia evoking many endothelial changes. There are also some genetic factors, impaired neurotrophic support and autoimmune damage that influence sensitivity to peripheral nerve damage in diabetes mellitus.
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PMID:[Etiopathogenesis of diabetic neuropathy]. 1139 97

Bimoclomol, the recently developed non-toxic heat shock protein (HSP) coinducer, was shown to display multilateral protective activities against various forms of stress or injuries at the level of the cell, tissue or organism. The compound enhanced the transcription, translation and expression of the 70 kD heat shock protein (HSP-70) in myogenic and HeLa cell lines exposed to heat stress, and increased cell survival on exposure to otherwise lethal thermal injury. Bimoclomol increased contractility of the working mammalian heart, this effect was associated with the increased intracellular calcium transients due to increased probability of opening of ryanodine receptors in the sarcoplasmic reticulum (SR). In healthy tissues these cardiac effects were evident only at relatively high concentrations of the drug, while in the ischemic myocardium bimoclomol exerted significant cardioprotective and antiarrhythmic effects at submicromolar concentrations. It decreased ischemia-induced reduction of contractility and of cardiac output, and dramatically decreased the elevation of the ST-segment during ischemia as well as the occurrence of ventricular fibrillation upon reperfusion. Bimoclomol was also active in various pathological animal models subjected to acute or chronic stress. In the spontaneously hypertensive rats chronic pretreatment with bimoclomol restored sensitivity of aortic rings to acetylcholine; this effect was accompanied by accumulation of HSP-70 in the tissues. Bimoclomol pretreatment significantly diminished the consequences of vascular disorders associated with diabetes mellitus. Diabetic neuropathy, retinopathy, and nephropathy were prevented or diminished, while wound healing was enhanced by bimoclomol. Enhancement of wound healing by bimoclomol was observed after thermal injury as well as following ultraviolet (UV) irradiation. In addition to the beneficial effects on peripheral angiopathies, bimoclomol antagonized the increase in permeability of blood-brain barrier induced by subarachnoid hemorrhager or arachidonic acid. A general and very important feature of the above effects of bimoclomol was that the drug failed to cause alterations under physiological conditions (except the enhanced calcium release from cardiac sarcoplasmic reticulum). Bimoclomol was effective only under conditions of stress. Consistent with its HSP-coinducer property, bimoclomol alone had very little effect on HSP production. Its protective activity became apparent only in the presence of cell damage. Currently, bimoclomol reached the end of the Phase II clinical trial in a group of 410 patients with diabetic complications. Results of this trial will answer the question, whether a compound with promising in vitro and in vivo preclinical findings will produce the anticipated beneficial effects in humans. In the event of a positive outcome of this trial, the indications for bimoclomol will be substantially extended.
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PMID:Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, bimoclomol: results of preclinical studies. 1148 67

Human diabetic neuropathy is multifactorial in etiology, with ischemia as a final common pathology. Although impaired vascular endothelial cell function in diabetic microvascular injury is established, the role of thrombomodulin (TM)-dependent protein C antithrombotic mechanism in the pathogenesis of neuropathy is unclear. This neuropathologic case-control study investigated whether vascular endothelial TM expression is deficient in peripheral nerve microvessels in diabetic neuropathy. Sural nerve biopsies from 7 patients with diabetic neuropathy and 10 with axonal neuropathy without vasculopathy were immunostained with anti-TM and anti-von Willebrand factor (vWF; an endothelial cell marker) antibodies. The proportion of TM-positive microvessels was expressed relative to total vWF-staining vessels, according to vessel caliber and regional distribution within the nerve. In diabetic nerves compared with reference controls, the proportion of TM-positive endoneurial microvessels was 15-fold lower (0.02 vs. 0.30 in diabetic nerves vs. controls, P < 0.004), and the proportion of small-caliber epineurial microvessels was 10-fold lower (0.04 vs. 0.43, P < 0.001). No TM expression was detected at the perineurium in diabetic or control nerves. We demonstrate a substantial reduction of vascular endothelial TM expression throughout human diabetic neuropathy. These findings suggest that an impaired native TM-dependent protein C antithrombotic mechanism may contribute to microvascular ischemia in the pathogenesis of diabetic neuropathy.
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PMID:Thrombomodulin deficiency in human diabetic nerve microvasculature. 1203 86

A little-noticed clinical report indicates that a low-fat, whole-food vegan diet, coupled with daily walking exercise, leads to rapid remission of neuropathic pain in the majority of type 2 diabetics expressing this complication. Concurrent marked improvements in glycemic control presumably contribute to this benefit, but are unlikely to be solely responsible. Consideration should be given to the possibility that improved blood rheology - decreased blood viscosity and increased blood filterability - plays a prominent role in mediating this effect. There is considerable evidence that neural hypoxia, secondary to impaired endoneurial microcirculatory perfusion, is a crucial etiologic factor in diabetic neuropathy; the unfavorable impact of diabetes on hemorheology would be expected to exacerbate endoneurial ischemia. Conversely, measures which improve blood fluidity would likely have a beneficial impact on diabetic neuropathy. There is indeed evidence that vegan diets, as well as exercise training, tend to decrease the viscosity of both whole blood and plasma; reductions in hematocrit and in fibrinogen may contribute to this effect. The fact that vegan diets decrease the white cell count is suggestive of an improvement in blood filterability as well; filterability improves with exercise training owing to an increase in erythrocyte deformability. Whether these measures influence the activation of leukocytes in diabetics - an important determinant of blood filterability - remains to be determined. There are various reasons for suspecting that a vegan diet can reduce risk for other major complications of diabetes - retinopathy, nephropathy, and macrovascular disease - independent of its tendency to improve glycemic control in type 2 patients. The vegan diet/exercise strategy represents a safe, 'low-tech' approach to managing diabetes that deserves far greater attention from medical researchers and practitioners.
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PMID:Favorable impact of a vegan diet with exercise on hemorheology: implications for control of diabetic neuropathy. 1232 13

The current therapeutic angiogenesis strategy to treat ischemic disease by using angiogenic growth factors has been limited to use of a single gene. However, as vasodilator substances such as prostacyclin are widely used for the treatment of peripheral arterial disease, it might be useful to combine angiogenesis with vasodilation of new vessels. In a mouse hind limb ischemia model, cotransfection of the hepatocyte growth factor (HGF) gene with the prostacyclin synthase gene demonstrated a further increase in blood flow and capillary density compared with a single gene. Even in the rabbit ischemia model, cotransfection of HGF plasmid with the prostacyclin synthase gene demonstrated a further increase in angiogenic activity compared with HGF alone. Because peripheral neuropathy due to diabetes is common for significant morbidity, we examined the hypothesis that experimental diabetic neuropathy can be reversed by HGF and prostacyclin synthase genes. Severe peripheral neuropathy, characterized by significant slowing of nerve conduction velocity compared with nondiabetic control animals, was ameliorated. Overall, cotransfection of the prostacyclin synthase and HGF genes is more effective than single-gene transfection to stimulate angiogenesis, and it significantly improved neuropathy. These data provide important information relating to the clinical application of therapeutic angiogenesis to treat peripheral arterial disease.
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PMID:Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene. 1258 36

This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-induced vascular and neural dysfunction. Oxidative stress occurs when the balance between the production of oxidation products and the ability of antioxidant mechanisms to neutralize these products is tilted in the favor of the former. The production of reactive oxygen species has been shown to be increased in patients with diabetes. The possible sources for the overproduction of reactive oxygen species is widespread and include enzymatic pathways, autoxidation of glucose and the mitochondria. Increase in oxidative stress has clearly been shown to contribute to the pathology of vascular disease not only in diabetes but also in hypertension, stroke and ischemia. Since the etiology of diabetic neuropathy is considered to have a large vascular component, prevention of oxidative stress in diabetes is considered by many investigators to be a primary defense against the development of diabetic vascular disease. Potential therapies for preventing increased oxidative stress in diabetes and the neural vasculature will be discussed.
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PMID:The role of oxidative stress in diabetic vascular and neural disease. 1279 66

Programmed cell death or apoptosis is a physiologically important process in neurogenesis wherein approximately 50% of the neurons apoptose during maturation of the nervous system. However, premature apoptosis and/or aberrations in apoptosis control contribute to the pathogenesis of a variety of neurological disorders including acute brain injury such as trauma, spinal cord injury, ischemic stroke and ischemia/reperfusion as well as chronic disease states such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, spinal muscular atrophy, and diabetic neuropathy. The current review will focus on two major topics, namely, the general concepts of our current understanding of the apoptosis death machinery, its mediators and regulation, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. This knowledge of apoptosis mechanisms will underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.
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PMID:Apoptosis in acute and chronic neurological disorders. 1497 68

Strong evidence implicates oxidative stress as a mediator of diabetes-induced microvascular complications, including distal symmetric polyneuropathy. Dorsal root ganglia neurons are particularly susceptible to glucose-mediated oxidative stress and die by apoptotic mechanisms in animal and cell culture models of diabetes. Key mediators of glucose-induced oxidative injury are superoxide anions and nitric oxide (NO). Superoxides are believed to underlie many of the oxidative changes in hyperglycemic conditions, including increases in aldose reductase and protein kinase C activity. Superoxides can also react with NO, forming peroxynitrite (ONOO-), which rapidly causes protein nitration or nitrosylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and cell death. ONOO- formation is dependent on both superoxide and NO concentrations; therefore, cells that constitutively express NO synthase, such as endothelial cells and neurons, may be more vulnerable to ONOO(-)-induced cell death in conditions favoring the production of superoxides. Although NO and ONOO can cause endothelial and neuronal cell death in vitro, in animal models of diabetes, reductions in endothelial NO production can inhibit vasodilatation and cause nerve ischemia. Therefore, ideal therapeutic approaches should limit the formation of superoxides and ONOO while preventing reductions in vascular NO. Despite strong evidence that oxidative stress is associated with complications of diabetes, including neuropathy, the results of clinical trials of antioxidants have shown some promise but not established therapeutic efficacy. Clinical studies of several antioxidants, including alpha-lipoic acid, vitamins C and E, aldose reductase inhibitors, and growth factors, in diabetic neuropathy are discussed.
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PMID:Nitrosative injury and antioxidant therapy in the management of diabetic neuropathy. 1498 68

Erectile dysfunction (ED) is commonly associated with risk factors for cardiovascular disease, including diabetes. The prevalence of ED in diabetic patients is high--about 75% of diabetic men 60 yr of age or older had ED in one study. Endothelial dysfunction, accelerated atherosclerosis, and diabetic neuropathy likely contribute to ED in diabetics. As silent ischemia is common in the diabetic patient, and diabetes is now often thought of as a coronary heart disease risk equivalent, diabetic men seeking therapy for ED may be considered candidates for exercise stress testing. Phosphodiesterase 5 (PDE5) inhibitors improve erectile function in diabetic men with ED; however, efficacy rates may be somewhat lower than in nondiabetic men. Studies to date have suggested that PDE5 inhibitors per se do not cause an increase in myocardial infarction rates in men being treated for ED.
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PMID:Assessment of cardiovascular risk in patients with erectile dysfunction: focus on the diabetic patient. 1514 90

The authors have determined that epineurial arterioles of the sciatic nerve are innervated by nonadrenergic, noncholinergic nerves that contribute to the regulation of vasodilation. Using immunohistochemistry, the authors determined that nerves innervating epineurial arterioles contain the neuropeptide calcitonin gene-related peptide (CGRP). Using streptozotocin-induced diabetic rats, the authors demonstrated that CGRP content in sensory nerves innervating epineurial arterioles and vasodilation in response to exogenous CGRP was decreased. In summary, epineurial arterioles of the sciatic nerve are innervated by sensory nerves containing the neuropeptide CGRP. The diabetes-like condition induced by streptozotocin reduces the content of CGRP in these nerves and exogenous CGRP-mediated vasodilation. CGRP is likely an important regulator of vascular tone and compromising its function could contribute to nerve ischemia and diabetic neuropathy.
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PMID:Sensory nerve innervation of epineurial arterioles of the sciatic nerve containing calcitonin gene-related peptide: effect of streptozotocin-induced diabetes. 1551 86


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