The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance.

Background: To identify key and shared insulin resistance (IR) molecular signatures across all insulin-sensitive tissues (ISTs), and their potential targeted drugs. Methods: Three datasets from Gene Expression Omnibus (GEO) were acquired, in which the ISTs (fat, muscle, and liver) were from the same individual with obese mice. Integrated bioinformatics analysis was performed to obtain the differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was carried out to determine the "most significant trait-related genes" (MSTRGs). Enrichment analysis and PPI network were performed to find common features and novel hub genes in ISTs. The shared genes of DEGs and genes between DEGs and MSTRGs across four ISTs were identified as key IR therapeutic target. The Attie Lab diabetes database and obese rats were used to verify candidate genes. A medical drug-gene interaction network was conducted by using the Comparative Toxicogenomics Database (CTD) to find potential targeted drugs. The candidate drug was validated in Hepa1-6 cells. Results: Lipid metabolic process, mitochondrion, and oxidoreductase activity as common features were enriched from ISTs under an obese context. Thirteen shared genes (Ubd, Lbp, Hp, Arntl, Cfd, Npas2, Thrsp., Tpx2, Pkp1, Sftpd, Mthfd2, Tnfaip2, and Vnn3) of DEGs across ISTs were obtained and confirmed. Among them, Ubd was the only shared gene between DEGs and MSTRGs across four ISTs. The expression of Ubd was significantly upregulated across four ISTs in obese rats, especially in the liver. The IR Hepa1-6 cell models treated with dexamethasone (Dex), palmitic acid (PA), and 2-deoxy-D-ribose (dRib) had elevated expression of Ubd. Knockdown of Ubd increased the level of p-Akt. A lowing Ubd expression drug, promethazine (PMZ) from CTD analysis rescued the decreased p-Akt level in IR Hepa1-6 cells. Conclusion: This study revealed Ubd, a novel and shared IR molecular signature across four ISTs, as an effective biomarker and provided new insight into the mechanisms of IR. PMZ was a candidate drug for IR which increased p-Akt level and thus improved IR by targeting Ubd and downregulation of Ubd expression. Both Ubd and PMZ merit further clinical translational investigation to improve IR.

Endovascular treatment of cerebrovascular stenosis with stent for patients with ischemic cerebrovascular disease.

This study aimed to investigate the therapeutic effect of cerebrovascular stent implantation in southwest Chinese patients with ischemic cerebrovascular disease and underlying risk factors for stent restenosis.We made a retrospectively analysis of occurring risk, cerebrovascular lesion, stent implantation, complication treatment, and prognosis of 54 patients with ischemic cerebrovascular disease in our department.A total of 85 stents were implanted into 54 patients, involving 44 of the internal carotid artery system, 34 of the vertebral-basal artery system and 7 of the subclavian artery system. All patients with stenosis were reduced by >70%, with all stenosis complete reduction in 5 (9%) patients and reduction of over 90% in 25 (46%) patients. A total of 50 patients were followed up for 28.5 (21-35) months. The stents in 42 patients exhibited satisfactory shape and location while restenosis occurred in 8 patients. Univariate analysis revealed that hyperlipidemia, hyperuricemia, surgery duration, and total length of hospital stay are significantly correlated with stent restenosis, and hyperlipidemia and hyperuricemia were proven to be independent risk factors for restenosis using logistic regression analysis.Cerebrovascular stent implantation and balloon inflation surgery can assist in abating angiostenosis and improving blood supplement effectively in patients with ischemic cerebrovascular disease. Besides, an overall evaluation, strict care, and regular check-up in perioperative period may reduce the occurrence of complications. Finally, several clinical parameters may need to be highly focused on in surgery for better prognosis.

Overexpression of LncRNA PSMG3-AS1 Distinguishes Glioblastomas from Sarcoidosis.

In clinical practices, glioblastomas (GBM) in some cases can be misdiagnosed as sarcoidosis. This study aimed to develop a biomarker to distinguish GBM from sarcoidosis. In this study, we found that PSMG3-AS1 was upregulated in plasma of GBM patients in comparison with that in sarcoidosis patients and healthy controls. Receiver operating characteristic (ROC) curve analysis showed that upregulation of PSMG3-AS1 effectively separated GBM patients from sarcoidosis patients and healthy controls. In GBM cells, overexpression of PSMG3-AS1 led to downregulated miR-34a and increased methylation of miR-34a gene. In addition, overexpression of PSMG3-AS1 reduced the inhibitory effects of miR-34a on GBM cell proliferation. In conclusion, overexpression of PSMG3-AS1 distinguishes GBM patients from patients with sarcoidosis, and PSMG3-AS1 may promote GBM cell proliferation by downregulating miR-34a through methylation.

Autocrine interleukin-23 promotes self-renewal of CD133+ ovarian cancer stem-like cells.

Cancer stem cells (CSCs) are a group of cells which possess the ability of self-renewing and unlimited proliferation. And these CSCs are thought to be the cause of metastasis, recurrence and resistance. Recent study has found that pro-inflammatory cytokine and chemotactic factor mediate the self-renewing and differentiation of most of CSCs. Thus we speculate that ovarian cancer stem cells (OCSCs) can also maintain the ability of self-renewing and differentiation by releasing inflammatory factor. This report we discuss the biological characteristics and the specific molecular mechanism mediated by interleukin-23 (IL-23) and its receptor on the self-renewing of OCSCs. We found that OCSCs had high expression of IL-23 and IL-23R. IL-23 could promote the self-renewal ability of OCSCs and played a very important role to maintain the stable expression of stem cell markers in vitro. Moreover, we verified that IL-23 could maintain the potential tumorigenic of OCSCs in vivo and mediate the self-renewal ability and the formation of tumor in OCSCs by activating the signal pathways of STAT3 and NF-κB. In addition, human low differentiation tissues showed overexpression of IL-23. And IL-23 positively correlated to the expression level of CD133, Nanog and Oct4. In conclusion, Our discoveries demonstrate that autocrine IL-23 contribute to ovarian cancer malignancy through promoting the self-renewal of CD133+ ovarian cancer stem-like cells, and this suggests that IL-23 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer.

EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB.

Non-small-cell lung cancer (NSCLC) is a severe disease threatening human health. Targeted therapy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has obtained potent efficacy in the treatment of NSCLC patients. However, the effects of EGFR-TKIs on tumor immune microenvironment are unclear. In this study, we show that NSCLCs with EGFR mutation express higher programmed cell death ligand 1 (PD-L1) than NSCLCs with wild type EGFR. The EGFR activation is also associated with high expression of PD-L1. The EGFR-TKI gefitinib can reduce PD-L1 expression, via inhibiting NF-κB, in EGFR mutant NSCLC in vitro and in vivo. These findings elucidate a novel anti-tumor mechanism of EGFR-TKI and provide the possibility of combined strategy of targeted therapy and immunotherapy for EGFR mutant NSCLC patients.

Effect of the urinary tryptin inhibitor ulinastatin on cardiopulmonary bypass-related inflammatory response and clinical outcomes: a meta-analysis of randomized controlled trials.

PURPOSE: Cardiopulmonary bypass (CPB) can cause systemic inflammatory responses and a series of subsequent complications that may harm patients. The aim of this study was to explore the effects of ulinastatin on inflammatory responses and clinical outcomes of CPB via a meta-analysis of published randomized controlled trials. METHODS: A literature search was conducted, both manually and by using the PubMed, EMBASE, Cochrane Library, and Web of Knowledge databases from inception to February 2013, to identify randomized controlled trials. The abstracted efficacy measures included changes in the plasma levels of cytokines (interleukin-6 [IL-6], IL-8, and tumor necrosis factor-α [TNF-α]) measured during the perioperative period and clinical indicators of efficacy, including the duration of mechanical ventilation and the length of intensive care unit stay. Ten ulinastatin-related randomized controlled trials related to cardiac surgeries involving CPB were selected. FINDINGS: In terms of cytokine concentrations, there were no significant differences between patients who received ulinastatin and those who received placebo before CPB. However, as the surgeries progressed, cytokine concentrations were all significantly lower in the ulinastatin group (P < 0.05 at 1 hour; P < 0.0001 at 6 hours), and the respective plasma concentrations returned to baseline values 24 hours after CPB. In terms of the clinical outcome indices, the length of intensive care unit stay was not significantly different, but the duration of mechanical ventilation (95% CI, -6.75 to -0.39; P = 0.03) was significantly shorter in the ulinastatin group. IMPLICATIONS: This meta-analysis found that changes in inflammatory cytokines occurred in a time-dependent manner and that the use of ulinastatin resulted in decreased duration of mechanical ventilation with CPB compared with placebo.

Complement component 3 is a prognostic factor of non­small cell lung cancer.

Lung cancer is the leading cause of cancer­related mortality worldwide. The complement component 3 (C3) is a central protein of the complement system, expressed in numerous cancer tissues and considered crucial for tumor progression. This study aimed to investigate the prognostic value of C3 in non­small cell lung cancer (NSCLC) and the underlying mechanisms. We used immunohistochemistry to observe the expression of C3 in malignant pulmonary lesion specimens from biopsy of 80 patients with NSCLC at stages I­III, who underwent lobectomy. We further assessed the correlation between C3 expression and a number of clinical features, as well as its prognostic value. To investigate the mechanism by which C3 exerts its effects, the correlation of C3 expression to T lymphocyte infiltration was also assessed. There was no significant correlation between the C3 level and clinical features such as gender, smoking status, degree of differentiation, histological type and malignant tumor stage based on the TNM classification system, while a significant correlation was found to age. However, analysis of overall survival (OS) and disease­free survival (DFS) rates showed that low C3 expression was related to poor prognosis. Univariate survival analysis revealed that C3 level and TNM stage are independent prognostic factors. Multivariate analysis demonstrated that the low level of C3 and TNM stage are also associated with poor prognosis. Furthermore, in tissues from biopsies, the C3 level positively correlated to the number of infiltrated CD4+ and CD8+ T lymphocytes (P<0.01). These findings indicate that C3 is a valuable marker for prognostic evaluation of NSCLC and may be considered as a therapeutic target for the treatment of lung cancer.