ABSTRACT
@#Periodontitis is associated with abnormal purine metabolism, which is manifested by increased uric acid in host blood and increased expression of the purine-degrading enzyme, xanthine oxidoreductase (XOR), in periodontal tissues. Both XOR and uric acid are pro-oxidative and pro-inflammatory mediators under pathological conditions. Animal studies have found that injection of uric acid promotes the progression of periodontitis and that febuxostat (an XOR inhibitor) improves tissue destruction in periodontitis. Therefore, blocking the source of uric acid may be a therapeutic strategy to control the progression of periodontitis. In this article, the rationality of XOR inhibitors as potential therapeutic drugs for periodontitis is reviewed. The literature review results suggest that XOR inhibitors show antioxidative, anti-inflammatory, and anti-osteoclastic effects, and XOR inhibitors show clinical efficacy in the treatment of infectious, inflammatory and osteolytic diseases. Although there is no direct evidence to support the finding that XOR inhibitors can ameliorate periodontal microecological dysbiosis, these drugs can modulate intestinal microflora dysbiosis, and there is indirect evidence to support a beneficial effect of XOR inhibitors on periodontal microecological dysbiosis. In conclusion, XOR inhibitors may be used as immunomodulators for the adjuvant treatment of periodontitis by inhibiting inflammation, oxidative stress and anti-osteoclast effects.
ABSTRACT
Xanthine oxidoreductase (XOR), the key enzyme catalyzing purine to produce uric acid, including two subtypes, xanthine dehydrogenase (XDH) and xanthine oxidase (XO), respectively, in vivo. Usually, XDH and XO can transform to each other. In this study, based on the principle that the subtype XO or XDH uses different electron acceptors, the methods for the measuring the activities of bovine milk XOR (pure enzyme) and its subtypes were established. The optimal concentrations of substrate xanthine (50 μmol·L-1) and electron acceptor NAD+ (50 μmol·L-1), pH value (7.80) were investigated. The ranges of the XOR, XO, XDH activity which could be determined were 0.97-17.5 U·L-1, 1-9 U·L-1, and 66-1 191 mU·L-1, respectively. Furthermore, the methods for determining the activities of XOR and its subtypes in mouse liver were established. The preparation of liver samples, the optimal concentrations of xanthine (100 μmol·L-1) and NAD+ (100 μmol·L-1) were researched. And the activity ranges of XOR, XO and XDH in mouse liver which could be determined were 0.67-3.98, 0.19-1.08, and 0.52-3.55 U·gprot-1, respectively. With the methods above, the effects of classic XOR inhibitor allopurinal (Allo) on XOR, XO and XDH from both milk and mouse liver were determined. All animal experiments have been approved by the Animal Experimental Center, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College (00003346). This study established new methods for the determination of XOR and its subtypes activity in pure enzyme system and in mouse liver, respectively, which were accurate and convenient. It laid the experimental foundation for exploring the different pathophysiological effects of XOR in the body and developing new XOR inhibitors.
ABSTRACT
Gout is a common disease in the elderly men. The prevalence rate of gout is rising worldwide in recent years,and gout has become a serious metabolic disease threatening human health. Moreover,gout is also closely related to incidence of many dis?eases and symptoms such as hypertension,hyperlipidemia,atherosclerosis,obesity and insulin resistance. Recently,investigation and development of new drugs have attracted increasing attention. This paper summarizes the research advances in new agents for treat?ment of gout,including the uric acid reduction drugs that target the key enzymes of purine metabolism,the drugs which target the re?nal tubular urate transporters to lower the uric acid level,the dual inhibitors of xanthine oxidoreductase(XOR)and renal tubular urate transporters,and the uricase.
ABSTRACT
Gout is a common disease in the elderly men. The prevalence rate of gout is rising worldwide in recent years, and gout has become a serious metabolic disease threatening human health. Moreover, gout is also closely related to incidence of many diseases and symptoms such as hypertension, hyperlipidemia, atherosclerosis, obesity and insulin resistance. Recently, investigation and development of new drugs have attracted increasing attention. This paper summarizes the research advances in new agents for treatment of gout, including the uric acid reduction drugs that target the key enzymes of purine metabolism, the drugs which target the renal tubular urate transporters to lower the uric acid level, the dual inhibitors of xanthine oxidoreductase(XOR) and renal tubular urate transporters, and the uricase.
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[Summary] Hyperuricemia is a syndrome caused by increased production or reduced excretion of uric acid which is characterized by oliguria, anuria, and uremia. Recent studies found that hyperuricemia was correlated with the risk, recurrence, metastasis, and prognosis of cancer. The mechanism may be uric acid associated chronic inflammation and decrease of xanthine oxidoreductase expression in cancer cells. Current treatment of hyperuricemia is to reduce the production of uric acid by inhibition of xanthine oxidoreductase, but the side effects of systemic inhibition of xanthine oxidoreductase received more and more attention. These unwanted side effects underscore the urgent need for mechanism based preclinical studies that can identify optimal strategies for management of hyperuricemia in relevant cancer models.
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Objective Increased serum uric acid level is associated with type 2 diabetes (T2DM) through the mechanism of oxidative stress.As the rate-limiting enzyme in the degradation of purines in humans,xanthine oxidoreductase (XOR)catalyzes the final two reactions of purine catabolism,oxidizing hypoxanthine to xanthine,and xanthine to uric acid.The aim of this study is to investigate the association between serum XOR activity and T2DM.Methods A total of 270 patients with T2DM and 140 age-and-gender-matched health controls were enrolled in the study.The clinical examinations such as weight and height were conducted in the morning after an overnight fast.Serum XOR activity and other biochemical parameters like triglyceride,total cholesterol,high density lipoprotein cholesterol,fasting plasma glucose and uric acid levels were measured.Results Serum XOR activity was significantly elevated in T2DM patients compared with that in the controls (31.2 ± 8.91 vs 4.6 ± 0.91 U/L,P ＜0.01).Serum XOR activity was significantly elevated in T2DM patients complicated with lower extremity arterial disease compared to that in patients without lower extremity arterial disease (42.1 ± 8.43 vs 23.7 ± 5.31 U/L,P ＜ 0.01).Conclusion High XOR activity plays an important role in onset and development of T2DM.
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Objective To study the changes of xanthine oxidoreductase(XOD) activity induced by acute urinary retention(AUR) in rats and its significance.Methods Twenty-eight female Wistar rats were used to establish acute urinary retention model by filling bladder with 2fold bladder volume and maintaining for 2 h.Cystometry,XOD activity and malondialdehyde(MDA) concentration assays were performed at the end of over-distention and 1 h,2 h,3 h,4 h after emptying respectively.The effect of superoxide dismutase(SOD) was observed by injecting 500 U SOD into the left cardiac ventricle of 7 model rats 10 min before emptying.Another 7 rats were filled with normal bladder volume as controls and underwent filling cystonetry.Results The frequency of detrusor over-activity increased more obviously after emptying than during over-distention.XOD activity increased obviously during over-distention period as compared to controls,reduced 1 h after emptying,then increased again 2 h after emptying,finally down to normal level slowly.The concentration of MDA increased during over-distention and early period after emptying and peaked at 1 h after emptying and then recovered slowly.After SOD treatment,the frequency of detrusor over-activity,XOD activity and MDA concentration reduced as compared with that in model rats 2 h after emptying(P