BackgroundInsulin resistance with elevated glucose is a risk factor for non-alcoholic steatohepatitis (NASH). We investigated the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor luseogliflozin on NASH development using a rodent model.MethodsMice were treated with both nicotinamide and streptozotocin (NA/STZ) to reduce insulin secretory capacity, and then fed a high fat diet containing trans fatty acids (HFDT) for 8 weeks. The NA/STZ HFDT-fed mice were divided into two groups, either treated with luseogliflozin or untreated, during this period. The glucose elevations in the NA/STZ-treated and HFDT-fed mice were significantly improved by luseogliflozin administration. While HFDT feeding induced NASH development as shown by liver weight gain with lipid accumulation and increased serum alanine aminotransferase, these changes were all attenuated in the group treated with luseogliflozin. In addition, fibrotic change and increases in collagen deposition with upregulations of collagen1 and smooth muscle actin and inflammatory cytokine expressions observed in the HFDT-fed mouse livers were also normalized by luseogliflozin administration.ConclusionsTaken together, these results obtained in mice demonstrate the favorable effects of administering SGLT2 inhibitors, for the treatment of NASH associated with diabetes mellitus. We anticipate that these agents would be applicable to humans.

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia.

BackgroundProstate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis. In addition, the effects of Juglone, a commercially available Pin1 inhibitor were also examined.MethodsTwo prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), were treated with Pin1 siRNA and its effects on gene expressions were analyzed by microarray. Individual gene regulations induced by Pin1 siRNA or the Pin1 inhibitor Juglone were examined using RT-PCR. In addition, the effects of Juglone on the growth of LNCaP and DU145 transplanted into mice were investigated.ResultsMicroarray analysis revealed that transcriptional factors regulated by Pin1 differed markedly between LNCaP and DU145 cells, the only exception being that Nrf was regulated in the same way by Pin1 siRNA in both cell lines. Despite this marked difference in gene regulations, Pin1 siRNA and Juglone exert a strong inhibitory effect on both the LNCaP and the DU145 cell line, suppressing in vitro cell proliferation as well as tumor enlargement when transplanted into mice.ConclusionsDespite Pin1-regulated gene expressions differing between these two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), Pin1 inhibition suppresses proliferation of both cell-lines. These findings suggest the potential effectiveness of Pin1 inhibitors as therapeutic agents for prostate cancers, regardless of their androgen sensitivity.

The present study aimed to investigate the impact of pre-treatment C-reactive protein (CRP) levels on the prediction of prognosis in patients with metastatic renal cell carcinoma (mRCC), who were classified as intermediate-risk patients using the Memorial Sloan Kettering Cancer Center (MSKCC) risk classification and who received molecular targeted therapy. The oncological outcome of 140 patients with mRCC who underwent molecular targeted therapy was analyzed. Patients were divided into favorable-, intermediate- and poor-risk groups (groups F, I and P, respectively) based on the MSKCC risk classification. The patients in group I were then further classified into two groups based on pre-treatment serum CRP levels. The overall survival (OS) rates of the patients in these groups were then assessed. The OS rate of the patients in group I with normal pre-treatment CRP levels was found to be significantly increased compared with that of patients with high pre-treatment CRP levels (P<0.0001), while there was no significant difference in the OS rate in the patients with normal pre-treatment CRP levels in group I compared with those in group F. Multivariate analyses revealed that high pre-treatment CRP levels were an independent prognostic factor for OS in the patients in group I (P<0.0001; hazard ratio, 3.898). Thus, pre-treatment CRP levels may be a candidate predictor for OS in patients with intermediate-risk mRCC.

We describe how we performed retroperitoneoscopic surgery for a 15.5-cm fibroepithelial polyp, which originated in the lowest portion of the right upper ureter, protruded intermittently into the bladder, and caused ureteral invagination. To our knowledge, this is the first report of the retroperitoneoscopic management of ureteral invagination caused by a long fibroepithelial polyp.

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