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Proteomics and metabolomics are widely used in the study of diabetes, but rarely in prediabetes research. This study aimed to explore the mechanisms of early-onset T2DM by analyzing proteomic changes at different stages of glucose metabolism.A total of 40 individuals undergoing routine physical health examinations between December 2016 and April 2017 were enrolled. Subjects were divided into four groups based on fasting blood glucose (FPG) levels: FPG5.6 mmol/L (group A); FPG ≥5.6 mmol/L and6.1 mmol/L (group B); FPG ≥6.1 mmol/L and7.0 mmol/L (group C); and FPG ≥7.0 mmol/L (group D); each group had 10 cases. Sera from these 40 subjects were analyzed by label-free quantitative liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). LC-MS/MS with multiple reaction monitoring (MRM) mode was also performed for qualitative and quantitative metabolomics analysis. Differentially expressed proteins were identified. Partial least squares discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to analyze the differentially expressed metabolites.A total of 202 differentially expressed proteins were screened and were identified as mainly secreted proteins. Comparing group A with group B, 32 proteins were up-regulated and 18 proteins were down-regulated. Comparing group A with group C, 24 proteins were up-regulated and 24 proteins were down-regulated. Comparing group A with group D, 19 proteins were up-regulated and 17 proteins were down-regulated. The fold change for up-regulated proteins was1.2, p0.05, while the fold change for down-regulated proteins was-1.2, p0.05. PLS-DA and OPLS-DA revealed 113 differentially expressed metabolites. Correlation analysis of differentially expressed metabolites of group A vs. group B revealed that among the down-regulated differential proteins, transforming growth factor β-induced protein ig-h3 correlated negatively with metabolite L-saccharin, while among the up-regulated differential proteins, apolipoprotein C-IV correlated negatively with metabolite 3-methyloxindole. Among all differentially expressed proteins, 19 proteins were associated with early initiation of chronic inflammation, including CD14 and CSF-1R, which were newly identified in the early onset of T2DM.Many proteins are differentially expressed between prediabetes and after T2DM diagnosis, although the specific mechanism remains unclear. The expression level of CD14 was significantly up-regulated and CSF-1R was significantly down-regulated when FPG was ≥5.6 mmol/L, suggesting that CD14 and CSF-1R may be important markers for early-onset T2DM and may serve as new targets for T2DM treatment.

Xiaomin Xie,* Guirong Bai,* Huili Liu, Li Zhang, YanTing He, Dan Qiang, Xiaoyan Zou Department of Endocrinology, The First People’s Hospital of Yinchuan, Yinchuan, 750001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaomin XieDepartment of Endocrinology, The First People’s Hospital of Yinchuan, 2 Liqun Street, Xingqing District, Yinchuan, 750001, Ningxia, People’s Republic of ChinaTel +86 13895189599Email xxm2324@126.comPurpose: This study investigates the possible roles and potential prediction ability of metabolic parameters in the early development of T2D by detecting their serum levels at different fasting blood glucose (FBG) levels.Methods: The subjects were included and divided into normal glucose tolerance (NGT), prediabetes (PD), and T2Dsubgroups. Apart from detecting the levels of routine biochemical parameters, fasting serum insulin (FINS), 25(OH)D, thioredoxin-interacting protein (TXNIP), thioredoxin (TRX), and NOD-like receptor family, pyrin domain-containing 3 (NLRP3) were detected. β-cell dysfunction (HOMA-β) and insulin resistance (HOMA-IR) were assessed by homeostasis model assessment. Both univariate and multivariate logistic regression analyses were used to estimate the risk of metabolic parameters, and their optimal cut-off values were obtained in the receiver operating characteristic (ROC) curve analysis and the Youden index.Results: Among the 207 subjects, aged from 20 to 60 years (44.62+12.92) contain 118 males and 89 females. There was a significantly lower trend of TRX, HOMA-β, and 25(OH)D following the higher FBG level among these three subgroups, while a significantly higher trend of all the other metabolic parameters. The multivariate analysis showed that subjects with higher values of TRX, HOMA-β, and 25(OH)D had a significantly lower risk for patients to be diagnosed as PD (aOR: 0.945, 0.961, and 0.543) and T2D (aOR: 0.912, 0.947, 0.434). Under the reliable 95% CI, TXNIP with a cut-off value of 119.27 showed the highest AUC value, sensitivity, and specificity (AUC: 0.981, 95% CI: 0.8524– 0.9839, 91.49%, and 83.33%) to diagnose PD. FINS with a cut-off value of 28.1 also showed the highest ones (AUC=0.9872, 95% CI: 0.9753– 0.9992, 100%, and 92.91%) to diagnose T2D.Conclusion: Early prediction of T2D is vital for timely intervention. Based on the FBG ≥ 100.8 mg/dl, the results provide evidence that 25(OH)D might be the protective factor in the early development of T2D. Besides, TXNIP and FINS might be the predictor for PD and T2D, respectively.Keywords: prediabetes, PD, type 2 diabetes, T2D, 25-hydroxyvitamin D, 25(OH)D, thioredoxin-interacting protein, TXNIP, β-cell dysfunction, insulin resistance

Vitamin D deficiency can damage the human immune system, and the complement system is a key component of the immune system. This study aimed to elucidate the mechanism by which vitamin D affects the immune system by analyzing the changes in the protein expression of the complement system under different vitamin D levels. We selected 40 participants and divided them into three groups according to their serum levels of 25-hydroxyvitamin D (25(OH)VD): group A, 25(OH)VD ≥ 40 ng/mL; group B, 30 ng/mL ≤ 25(OH)VD

A series of novel vorapaxar analogues with different amino substitutes at the C-7, C-9a and aromatic substitutes at the C-4 position were designed, synthesized, and evaluated for their inhibitory activity to PAR-1. Several compounds showed good potency in antagonist activity based on the intracellular calcium mobilization assay and excellent pharmacokinetics profile in rats. Among these analogues, 3d exhibited excellent PAR-1 inhibitory activity (IC50 = 0.18 μM) and the lower ability to cross the blood-brain barrier compared with vorapaxar (IC50 = 0.25 μM). Compound 3d has the potential to be developed as a new generation of PAR-1 antagonists with a better therapeutic window.

Temozolomide (TMZ) combination with whole-brain radiotherapy (WBRT) has been tested by many randomized controlled trials in the treatment of brain metastases (BMs) in China and other countries. We performed an up-to-date meta-analysis to determine (i) the log odds ratios (LORs) of objective response (ORR) and adverse effects (AEs) for all-grade, and (ii) the T value of mean overall survival in patients with BMs treated with WBRT combined with TMZ versus WBRT alone. PubMed, Chinese National Knowledge Infrastructure, and WanFang Data were searched for articles published up to 28 January 2015. Eligible studies were selected according to the PRISMA statement. ORR, AEs, and 95% confidence intervals were calculated using random-effects models. Eighteen studies were included in our analysis. A total of 1028 participants were enrolled. Summary LORs of ORR were 1.0239 (P

Influenza A and B viruses are viral respiratory pathogens that can cause severe infections among birds and mammals. Neutralization assays using human sera are useful to evaluate the risk of circulating viruses to humans. In this study, 359 serum samples from healthy Thai volunteers, who had not been vaccinated against influenza for at least five years, were investigated by microneutralization (MN) assays against influenza A H3N2 and influenza B viruses in 2009. There was no significant difference in neutralization activities against 2006 and 2008 isolates of influenza A H3N2 viruses. However, neutralization titers to influenza B viruses among 2008 isolates were quite low. The results indicate the non-vaccinated study population had some neutralizing antibodies against influenza A H3N2 but not against influenza B viruses.