Objective-Hyperuricemia is common in patients with metabolic syndrome. We investigated the role of xanthine oxidoreductase (XOR) in atherosclerosis development, and the effects of the XOR inhibitor allopurinol on this process. Methods and Results-Oral administration of allopurinol to ApoE knockout mice markedly ameliorated lipid accumulation and calcification in the aorta and aortic root. In addition, allopurinol treatment or siRNA-mediated gene knockdown of XOR suppressed transformation of J774.1 murine macrophage cells, treated with acetylated LDL or very low density lipoprotein (VLDL) into foam cells. This inhibitory effect of allopurinol was also observed in primary cultured human macrophages. In contrast, overexpression of XOR promoted transformation of J774.1 cells into foam cells. Interestingly, SR-A1, SR-B1, SR-B II, and VLDL receptors in J774.1 cells were reduced by XOR knockdown, and increased by XOR overexpression. Conversely, expressions of ABCA1 and ABCG1 were increased by XOR knockdown and suppressed by XOR overexpression. Finally, productions of inflammatory cytokines accompanied by foam cell formation were also reduced by allopurinol administration. Conclusion-These results strongly suggest XOR activity and/or its expression level to contribute to macrophage foam cell formation. Thus, XOR inhibitors may be useful for preventing atherosclerosis. Key Words: atherosclerosis Ⅲ cell physiology Ⅲ cytokines Ⅲ macrophages Ⅲ xanthine oxidoreductase A relationship between serum uric acid levels and atherosclerotic disease development has been suggested. [1][2][3] In addition, there is epidemiological evidence of an association between hyperuricemia and metabolic syndrome, 1 type 2 diabetes, 4 chronic kidney diseases, 5,6 heart failure incidence in older adults, 7 and with mortality in patients undergoing percutaneous coronary intervention or with acute myocardial infarction. 8 -10 Uric acid itself reportedly functions as an antioxidant, 11 though the process of uric acid synthesis is accompanied by the generation of reactive oxygen species.Xanthine oxidoreductase (XOR) is a key enzyme in the uric acid production pathway; XOR oxidizes hypoxanthine from nucleic acid metabolites into xanthine, and xanthine into uric acid. XOR basically oxidizes a variety of purines and pterins, classified as molybdenum iron-sulfur flavin hydroxylases. XOR tissue and cellular distributions are high in the mammalian liver and intestine due to XOR-rich parenchymal cells. 12 XOR activity is low in human serum, brain, heart, and skeletal muscle, though a recent study revealed microvascular endothelial cells to be rich in XOR activity. 13 It seems that XOR does not induce harmful reactive oxygen species production under normal conditions but in pathological states such as ischemic congestive heart failure, XOR activity increases drastically and XOR localizes within CD68 positive macrophages. 14 Allopurinol, a xanthine oxidase (XO) inhibitor, has been widely used for hyperuricemia treatment. Oxypurinol, a hydroxide and the main met...

Gut microbiota alterations are associated with various disorders. In this study, gut microbiota changes were investigated in a methionine-choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH) rodent model, and the effects of administering Lactobacillus casei strain Shirota (LcS) on the development of NASH were also investigated. Mice were divided into three groups, given the normal chow diet (NCD), MCD diet, or the MCD diet plus daily oral administration of LcS for 6 wk. Gut microbiota analyses for the three groups revealed that lactic acid bacteria such as Bifidobacterium and Lactobacillus in feces were markedly reduced by the MCD diet. Interestingly, oral administration of LcS to MCD diet-fed mice increased not only the L. casei subgroup but also other lactic acid bacteria. Subsequently, NASH development was evaluated based on hepatic histochemical findings, serum parameters, and various mRNA and/or protein expression levels. LcS intervention markedly suppressed MCD-diet-induced NASH development, with reduced serum lipopolysaccharide concentrations, suppression of inflammation and fibrosis in the liver, and reduced colon inflammation. Therefore, reduced populations of lactic acid bacteria in the colon may be involved in the pathogenesis of MCD diet-induced NASH, suggesting normalization of gut microbiota to be effective for treating NASH.

Background: NASH is a disease characterized by fat accumulation and chronic inflammation in the liver. Results: Pin1 expression was increased in NASH model mouse livers. Pin1 KO mice were resistant to NASH development. Conclusion: Pin1 plays critical roles in NASH development. Significance: A Pin1 inhibitor might be a novel agent for treating NASH.

A growing body of evidence highlights the role of gut microbiota in the development of dysbiosis, which in turn influences host metabolism and disease phenotypes. Further studies are required to elucidate the precise mechanisms by which gut microbiota-derived mediators induce metabolic disorders and modulating interventions exert their beneficial effects in humans. The gut microbiota represents a novel potential therapeutic target for a range of metabolic disorders.

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by hepatic lipid accumulation followed by the inflammation-induced death of hepatocytes and fibrosis. In this process, oxidative stress contributes to the induction of several inflammatory cytokines including TNF-α andIL-1β in macrophages, while, in hepatocytes, NF-κB reportedly induces the expressions of cell survival genes for protection from apoptosis. Recently, it was reported that the new ubiquitin ligase complex termed linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on NF-κB essential modulator (NEMO) and thereby induces NF-κB pathway activation. In this study, we demonstrated the formation of LUBAC to be impaired in the livers of NASH rodent models produced by methionine and choline deficient (MCD) diet feeding, first by either gel filtration or Blue Native-PAGE, with subsequent confirmation by western blotting. The reduction of LUBAC is likely to be attributable to markedly reduced expression of SHARPIN, one of its components. Thus, impaired LUBAC formation, which would result in insufficient NF-κB activation, may be one of the molecular mechanisms underlying the enhanced apoptotic response of hepatocytes in MCD diet-induced NASH livers.

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Objective: In Japan, no study has compared the perioperative outcomes observed between robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC). This study aimed at a prospective comparison of the perioperative outcomes between RARC and ORC performed by a single surgeon. Methods: Between 2008 and 2011, 26 bladder cancer patients underwent radical cystectomy by one surgeon, 11 robotically and 15 by open procedure. We prospectively collected perioperative and pathological data for these 26 patients, and retrospectively compared these two different surgical procedures. Results: The RARC cohort had a significant decrease in both estimated blood loss (656.9 vs. 1788.7 ml, P ¼ 0.0015) and allogeneic transfusion requirement (0 vs. 40%, P ¼ 0.0237). The total operative time was almost the same (P ¼ 0.2306) but increased duration of bladder removal and lymphadenectomy was observed in the RARC cohort (P ¼ 0.0049). Surgeryrelated complication rates within 30 days were not significantly different (P ¼ 0.4185). Positive surgical margin was observed in three patients in the ORC cohort and in one patient in the RARC cohort (P ¼ 0.4664). The RARC cohort had a larger number of removed lymph nodes than the ORC cohort, and the difference was statistically significant (20.7 vs. 13.8, P ¼ 0.0421). Conclusions: We confirmed that RARC is safe and yields acceptable outcomes in comparison with ORC for the treatment of bladder cancer if it is performed by a surgeon who has experience of over 60 cases of robot-assisted radical prostatectomy. It is hoped that RARC will gain acceptance in Japan as a minimally invasive surgery for muscle-invasive bladder cancer.