Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes mellitus is a major cause of peripheral neuropathy, commonly manifested as distal symmetrical polyneuropathy. This review examines evidence for the importance of vascular factors and their metabolic substrate from human and animal studies. Diabetic neuropathy is associated with risk factors for macrovascular disease and with other microvascular complications such as poor metabolic control, dyslipidaemia, body mass index, smoking, microalbuminuria and retinopathy. Studies in human and animal models have shown reduced nerve perfusion and endoneurial hypoxia. Investigations on biopsy material from patients with mild to severe neuropathy show graded structural changes in nerve microvasculature including basement membrane thickening, pericyte degeneration and endothelial cell hyperplasia. Arterio-venous shunting also contributes to reduced endoneurial perfusion. These vascular changes strongly correlate with clinical defects and nerve pathology. Vasodilator treatment in patients and animals improves nerve function. Early vasa nervorum functional changes are caused by the metabolic insults of diabetes, the balance between vasodilation and vasoconstriction is altered. Vascular endothelium is particularly vulnerable, with deficits in the major endothelial vasodilators, nitric oxide, endothelium-derived hyperpolarising factor and prostacyclin. Hyperglycaemia and dyslipidaemia driven oxidative stress is a major contributor, enhanced by advanced glycation end product formation and polyol pathway activation. These are coupled to protein kinase C activation and omega-6 essential fatty acid dysmetabolism. Together, this complex of interacting metabolic factors accounts for endothelial dysfunction, reduced nerve perfusion and function. Thus, the evidence emphasises the importance of vascular dysfunction, driven by metabolic change, as a cause of diabetic neuropathy, and highlights potential therapeutic approaches.
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PMID:Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. 1171 28

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

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.
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PMID:ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes. 1531 96

Diabetes mellitus is associated to micro- and macro-vascular lesions responsible for myocardial infarction, nephropathy, retinopathy and polyneuropathy. Four main pathogenic mechanisms have been proposed, all associated with hyperglycaemia: 1) increased flux in the polyol pathway; 2) increased flux in the hexosamine pathway; 3) protein kinase C activation; and 4) increased formation of advanced glycation endproducts. A common mechanism seems to play a central role in the activation of these various pathways. Indeed, an increased production of free radicals by mitochondria induced by hyperglycaemia may be responsible for the observed metabolic disturbances. The present article describes that theory and presents its possible therapeutic implications.
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PMID:[A central pathological mechanism explaining diabetic complications?]. 1603 14

Capsaicin-sensitive, TRPV1 (transient receptor potential vanilloid 1) receptor-expressing primary sensory neurons exert local and systemic efferent effects besides the classical afferent function. The TRPV1 receptor is considered a molecular integrator of various physico-chemical noxious stimuli. In the present study its role was analysed in acute nociceptive tests and chronic neuropathy models by comparison of wild-type (WT) and TRPV1 knockout (KO) mice. The formalin-induced acute nocifensive behaviour, carrageenan-evoked inflammatory mechanical hyperalgesia and partial sciatic nerve lesion-induced neuropathic mechanical hyperalgesia were not different in WT and KO animals. Acute nocifensive behaviour after intraplantar injection of phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), was absent in TRPV1 KO animals showing that PKC activation elicits nociception exclusively through TRPV1 receptor sensitization/activation. Thermal hyperalgesia (drop of noxious heat threshold) and mechanical hyperalgesia induced by a mild heat injury (51 degrees C, 15s) was smaller in KO mice suggesting a pronociceptive role for TRPV1 receptor in burn injury. Chronic mechanical hyperalgesia evoked by streptozotocin-induced diabetic and cisplatin-evoked toxic polyneuropathy occurred earlier and were greater in the TRPV1 KO group. In both polyneuropathy models, at time points when maximal difference in mechanical hyperalgesia between the two groups was measured, plasma somatostatin concentrations determined by radioimmunoassay significantly increased in WT but not in TRPV1 KO mice. It is concluded that sensitization/activation of the TRPV1 receptor plays a pronociceptive role in certain models of acute tissue injury but under chronic polyneuropathic conditions it can initiate antinociceptive counter-regulatory mechanisms possibly mediated by somatostatin released from sensory neurons.
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PMID:Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice. 1615 May 43

This paper reviews emerging interventions from the recent clinical literature that demonstrate the potential for effectiveness in the therapy of the diverse forms of diabetic neuropathy. Diabetic sensorimotor polyneuropathy is the primary focus of this review given that it is the most common form of diabetic neuropathy. For this condition, several promising disease-modifying drugs--including inhibitors of the aldose reductase and protein kinase C metabolic pathways--are currently in phase III development. Additional pharmacological agents with an indication to relieve painful symptoms of diabetic neuropathy have been approved by regulatory agencies in the past year. Therapies for other forms of diabetic neuropathy are discussed briefly: For example, evidence exists to suggest that immunomodulation may be effective for diabetic lumbosacral plexoradiculoneuropathy ('diabetic amyotrophy'), and is effective in diabetic patients with chronic inflammatory demyelinating polyneuropathy regardless of the coexistence of diabetic sensorimotor polyneuropathy. Furthermore, strategies for the management of autonomic neuropathies are itemized. As a whole, current evidence suggests that diabetic neuropathy should not be dismissed as an untreatable disorder, and physicians need to focus on the accurate diagnosis of this complication in order to subsequently offer appropriate therapy to patients.
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PMID:Emerging therapies for diabetic neuropathy: a clinical overview. 1822 Jun 3

Despite the high prevalence and impact on quality of life, costs, and survival, there are still unresolved issues regarding diabetic polyneuropathy (DPN): the lack of definite knowledge of its pathogenesis; the limited preventive action of glycaemic control in type 2 diabetes; and the unavailability of evidence-based effective disease-modifying treatment. How can genetics provide the tools to address these gaps? Ziegler et al for the GDS Group explore the novel hypothesis that genetic variability in transketolase (TKT) might contribute to susceptibility to DPN in patients with newly diagnosed type 1 and type 2 diabetes (well characterised for DPN). Transketolase diverts excess glycolytic metabolites from the hexosamine, protein kinase C, and advanced glycation endproduct pathways to the pentose phosphate pathway, with a protective effect against hyperglycaemia-induced damage. Moreover, thiamine and its derivative benfotiamine are among the few disease-modifying agents still under consideration as DPN treatment. The authors find significant associations of single-nucleotide polymorphisms of the TKT gene with the Total Symptom Score and thermal thresholds, in particular in male participants with type 2 diabetes. Moreover, they measure plasma methylglyoxal (a glycating agent, whose availability is hindered by TKT) without however finding a relation with TKT single-nucleotide polymorphisms. The link found between TKT genetic variability and nerve function measures is considered here in the context of DPN genetic studies and of experimental and clinical findings regarding thiamine and benfotiamine. The conclusion is that available data supports the decision to maintain focus on both the search for DPN genetic biomarkers and the therapeutic attempts to target thiamine, TKT, and methylglyoxal.
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PMID:Might genetics play a role in understanding and treating diabetic polyneuropathy? 2710 86