Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dupuytren's contracture is a deforming, fibrotic condition of the palmar fascia which has confounded clinicians and scientists since the early descriptions by Guillaume Dupuytren in 1831. It predominantly affects elderly, male caucasians, has a hereditary predisposition and has strong associations with diabetes, alcohol consumption, cigarette smoking and HIV infection. The major morphological features are an increase in fibroblasts, particularly around narrowed fibroblasts; a finding consistent with localised ischaemia. During ischaemia, adenosine triphosphate (ATP) is converted to hypoxanthine and xanthine, and endothelial xanthine dehydrogenase to xanthine oxidase (alcohol also mediates this change, a finding of particular relevance given the association of Dupuytren's contracture with alcohol intake). Xanthine oxidase catalyses the oxidation of hypoxanthine to xanthine and uric acid with the release of superoxide free radicals (O2-), hydrogen peroxide (H2O2) and hydroxyl radicals (OH.). These free radicals are highly reactive, with half-lives in the order of milliseconds and are toxic in high concentrations. A potential for free radical generation in Dupuytren's contracture was elicited by finding a sixfold increase in hypoxanthine concentrations in Dupuytren's contracture compared with control palmar fascia. In vitro studies affirmed the toxic effects of oxygen free radicals to Dupuytren's contracture fibroblasts, but also showed that, at lower concentrations (concentrations similar to those likely to occur in Dupuytren's contracture), free radicals had a stimulatory effect on fibroblast proliferation. Cultured fibroblasts were found to release their own O2-. These endogenously released free radicals were also found to be important in fibroblast proliferation. The collagen changes of Dupuytren's contracture were examined. The results established that fibroblast origin was unimportant, but that inhibition of type I collagen production at high fibroblast density accounted for the increase in type III/I collagen ratios observed by previous investigators. These biochemical and morphological observations throw new light on Dupuytren's contracture. They suggest that age, genetic and environmental factors may contribute to micro vessel narrowing with consequent localised ischaemia and free radical generation. Endothelial xanthine oxidase derived free radicals may both damage the surrounding stroma and stimulate fibroblasts to proliferate. Proliferating fibroblasts lay down and contract collagen in lines of stress.Progressive fibroblast proliferation and deposition of collagen is likely to encourage further microvessel narrowing with a positive feedback effect consistent with the progressive nature of the condition.
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PMID:An insight into Dupuytren's contracture. 161 55

The search for the causative factors in Dupuytren's disease has historically progressed form gross anatomical dissection, through microscopical tissue studies, to the biochemistry of the collagen produced. But these elements are merely the end products of cellular activity - not revealing the factors responsible for the changes in cellular activity. Recent biochemical investigations suggest that a number of conditions including localized microvascular ischemia and high alcohol concentrations transform the "benign" xanthine dehydrogenase of endothelial cells to the oxygen-free radical-releasing xanthine oxidase. Oxygen-free radicals are highly reactive species with half-lives in the order of milliseconds capable of both damaging the surrounding peri-microvasculature and stimulating fibroblast proliferation. It is this stimulation of fibroblast proliferation in the palmar fascia that is the key event in the pathogenesis of Dupuytren's contracture.
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PMID:Cell-controlling factors in Dupuytren's contracture. 169 16

Ultrastructural, immunohistochemical, and biochemical studies to date show that the fibroblast in Dupuytren's contracture is identical to palmar fascia fibroblasts in patients unaffected by Dupuytren's contracture, and to all other fibroblasts. The major difference relating to fibroblasts is that in Dupuytren's contracture there are more of them, and they are clustered around narrowed microvessels. It is probable that these two phenomena are linked because recent studies indicate a greater potential for ischemia-induced oxygen free radical generation in Dupuytren's contracture, and because oxygen free radicals in these concentrations can stimulate fibroblast proliferation. The major source of oxygen free radicals is likely to be from microvascular endothelial xanthine oxidase-catalyzed reactions. These observations also account for many of the epidemiologic associations of Dupuytren's contracture, because (1) age, race, and diabetes are associated with microvessel narrowing and (2) age, diabetes, alcohol consumption, HIV infection, cigarette smoking, and trauma are associated with increased free radical generation. Nonsteroidal anti-inflammatory drugs and allopurinol are two agents that decrease oxygen free radical release and may inhibit or prevent Dupuytren's contracture.
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PMID:The role of the fibroblast in Dupuytren's contracture. 176 89

The concentration of substrate expressed as hypoxanthine capable of reacting with xanthine oxidase to release superoxide free radicals (O2-) was measured in control and Dupuytren's contracture palmar fascia. In Dupuytren's contracture palmar fascia the concentration of hypoxanthine was six times that of control and was greatest in "nodular" areas. Xanthine oxidase activity was also detected in Dupuytren's contracture palmar fascia. These results suggest a greater potential for hypoxanthine-xanthine oxidase generated oxygen free radical formation in Dupuytren's contracture than in control palmar fascia. Production of free radicals may be an important factor in the pathogenesis of Dupuytren's contracture. The benefit of allopurinol in the management of Dupuytren's contracture and other fibrotic conditions may thus be explained, as allopurinol binds to xanthine oxidase and prevents release of free radicals.
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PMID:Free radicals and Dupuytren's contracture. 282 7