Chronic hypoxia in the renal parenchyma is thought to induce epithelial-to-mesenchymal transition (EMT), leading to fibrogenesis and ultimately end-stage renal failure. Biliverdin reductase, recently identified as a serine/threonine/tyrosine kinase that may activate phosphatidylinositol 3-kinase (PI3K) and Akt, is upregulated in response to reactive oxygen species that may accompany hypoxia. We investigated this potential role of biliverdin reductase in hypoxia-induced renal tubular EMT. Expression of biliverdin reductase was upregulated in a human proximal tubule cell line (HK-2) cultured in hypoxic conditions (1% O 2 ), and this was accompanied by reduced expression of E-cadherin and increased expression of the mesenchymal marker vimentin. Inhibiting PI3K reversed these changes, consistent with EMT. In normoxic conditions, overexpression of biliverdin reductase promoted similar characteristics of EMT, which were also reversed by inhibiting PI3K. Furthermore, using small interfering RNA (siRNA) to knockdown biliverdin reductase, we demonstrated that the enzyme associates with phosphorylated Akt and mediates the hypoxia-induced EMT phenotype. In vivo, expression of biliverdin reductase increased in the tubular epithelia of 5/6-nephrectomized rats, and immunohistochemistry of serial sections demonstrated similar localization of phosphorylated Akt and biliverdin reductase. In conclusion, biliverdin reductase mediates hypoxia-induced EMT through a PI3K/Akt-dependent pathway.

Aims/IntroductionPrevious studies have shown that glucose peak time during the oral glucose tolerance test varies in type 2 diabetes patients; however, characteristics of this heterogeneity remain unclear. This research aimed to investigate the characteristics of delayed glucose peak time in type 2 diabetes.Materials and MethodsA total of 178 participants who underwent the oral glucose tolerance test were divided into five groups according to glucose peak time.ResultsA total of 25 participants with normal glucose tolerance had a glucose peak at 30 min. Among participants with type 2 diabetes, 28 had a glucose peak at 60 min, 48 at 90 min, 45 at 120 min and 32 at 150 min. With the glucose peak time delayed, glycated hemoglobin, area under the glucose curve and homeostatic model assessment of insulin resistance increased gradually (P = 0.038, P < 0.0001, P < 0.0001, respectively), and oral glucose insulin sensitivity, homeostatic model assessment of β‐cell function, insulinogenic index, modified β‐cell function index and disposition indices decreased (P < 0.0001 for all). On multinominal logistic regression, insulinogenic index (odds ratio 0.73, 95% confidence interval 0.57–0.93, P = 0.01), modified β‐cell function index (odds ratio 0.67, 95% confidence interval 0.47–0.94, P = 0.023) and oral glucose insulin sensitivity (odds ratio 0.91, 95% confidence interval 0.87–0.96, P < 0.0001) were independently correlated with delayed glucose peak time.ConclusionsDelay in glucose peak time indicated an increase in blood glucose and a decrease in insulin sensitivity and secretion. Furthermore, insulinogenic index, modified β‐cell function index and oral glucose insulin sensitivity contributed to delayed glucose peak time.

Background: The aim of this study was to investigate the correlation between serum uric acid level and central body fat distribution in patients with type 2 diabetes (T2DM). Methods: A total of 867 patients with T2DM were enrolled. Measurements of central fat distribution were obtained by dual energy X-ray absorptiometry. Patients were stratified into three groups according to their levels of serum uric acid (SUA). Multiple linear regression analysis was used to determine the association between SUA and central body fat distribution. Logistic regression analysis was used to estimate the risk factors for hyperuricemia (HUA). Mediation analysis was applied to assess the overall, direct, and indirect mediators of SUA levels. Results: Multiple linear regression analysis showed that SUA levels were significantly positively correlated with waist circumference (WC), body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), Android fat mass, Gynoid fat mass, fasting c-peptide (F-CP), and area under the curve of C-peptide (P < 0.05 for all). VAT [odds ratio (OR), 2.367; 95% confidence interval (CI), 1.078-5.197; P < 0.001)], WC (OR, 1.041; 95% CI, 1.011-1.072; P < 0.001), high-density lipoprotein (OR, 0.274; 95% CI, 0.104-0.727; P < 0.001), and estimated glomerular filtration rate (OR, 0.966; 95% CI, 0.959-0.973; P < 0.001) were found to be independent risk factors for T2DM patients with HUA. After mediation analysis, BMI and central obesity were found to have different partial effects on the association between SUA and F-CP (P < 0.001). Conclusion: In patients with T2DM, HUA was positively correlated with F-CP and central body fat distribution, especially VAT. These results suggest that central obesity may play a role in the positive correlation between HUA and insulin resistance (IR).

Purpose:Using bibliometrics, we analyzed the research status of immune checkpoint blockade (ICB, a popular tumor immunotherapy method represented by antibodies targeted CTLA-4 and PD-1/PD-L1) in tumor immunotherapy in China during the past 2 decades.Methods:Articles in Science Citation Index Expanded (SCI-EXPANDED), patents in Thomson Innovation, and drugs in Cortellis Competitive Intelligence in the field of ICB for tumor immunotherapy from 1996 to 2015 were the subjects of bibliometric analysis. Using database-attached software and Excel, quantitative analyses were performed including examination of the number of documents, citation frequency, h-index, key projects, quantity of publications, public patents, and status of new drug research.Results:The number of publications from 1996 to 2015 in the field of ICB for tumor immunotherapy that came out of China was 380, which was 14.3% of the total publications worldwide and was second only to that of the USA. In the past decade, China has rapidly increased the number of publications and patents in this field. However, indicators of publication influence, such as citation frequency and h-index, were far behind other advanced countries. In addition, the total number of patents in China was much lower than that of the USA. China has introduced 5 drugs for ICB that are being developed for the healthcare market.Conclusion:Tumor immunotherapy research such as ICB in China has developed rapidly with increasing influence in the last 2 decades. However, there is still a relatively large gap compared with the USA. It is expected that China will have greater influence on tumor immunotherapy research in the near future.

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