Suchergebnisse

Hydroxysteroid (17-beta)dehydrogenase 1(HSD17B1) plays a central role in sex steroid hormone metabolism. HSD17B1 polymorphic variants may contribute to cancer susceptibility. Numerous investigations have been conducted to assess the association between HSD17B1 Ser312Gly polymorphism and cancer risk in multiple ethnicities, yet these have produced inconsistent results. We therefore performed this comprehensive meta-analysis to attempt to provide a quality assessment of the association of interest. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. After a systematic literature search of several major public databases, 20 studies involving 29,460 cases and 36,687 controls were included in this meta-analysis. No significant association was found between HSD17B1 Ser312Gly polymorphism and cancer risk. However, Ser312Gly polymorphism showed a significantly decreased risk for Caucasians (there were 44,284 Caucasians for analysis, comprising 19,889 cases and 24,395 controls) in the subgroup analysis by ethnicity (dominant: OR = 0.958, 95% CI = 0.919–0.998; and allele comparing: OR = 0.973, 95% CI = 0.947–0.999). And there was the same trend towards risk in the population-based (PB) controls (homozygous: OR = 0.951, 95% CI = 0.908–0.997 and allele comparing: OR = 0.976, 95% CI = 0.954–0.999), but not among Asians or hospital-based (HB) controls. In addition, no association was observed in the stratified analysis for breast cancer studies by source of control, ethnicity and quality score. These findings suggested that the HSD17B1 Ser312Gly polymorphism might confer genetic cancer susceptibility in an ethnic-dependent manner, especially among Caucasians. Well-designed, large-scale studies are warranted to validate these findings.

Qian Chen,1,2,* Zhigang Qin,1,* Yibing Sun,3 Xiangfeng Liu,1 Aurelie Pac Soo,2 Enqiang Chang,2 Qizhe Sun,2 Bin Yi,1 Dong-Xin Wang,3 Hailin Zhao,2 Daqing Ma,2 Jianteng Gu1 1Department of Anaesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China; 2Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK; 3Department of Anaesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, People's Republic of China*These authors contributed equally to this workCorrespondence: Jianteng Gu, Department of Anaesthesiology, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Road, Chongqing, People's Republic of China, Tel +86 23 68765366, Fax +86 2365463270, Email jiantenggu@hotmail.com Daqing Ma, Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK, Tel +44 020 3315 8495, Fax +44 020 3315 5109, Email d.ma@imperial.ac.ukPurpose: This study aims to investigate the cytoprotective and anti-inflammatory effects of an α2-adrenoreceptor (α2-AR) agonist, dexmedetomidine (Dex), on lipopolysaccharides (LPS)-induced acute lung injury and underlying mechanisms with focus on alveolar macrophage polarization modulation.Methods: C57BL/6 mice were intraperitoneally injected LPS (10 mg/kg) with or without Dex (25 μg/kg) and/or α2-AR antagonist atipamezole (Atip, 500 μg/kg). Lung tissues were then analysed to determine injuries. In vitro, human pulmonary epithelial cells (A549) and mice alveolar macrophages (MH-S) were exposed to LPS (10 ng/mL) with or without different concentrations of Dex (0.1– 100 nM). Alveolar macrophage polarization, NLRP3 inflammasome activation and inflammatory responses were determined. PTEN/Akt signaling and its downstream transcriptional factors as targets for macrophage polarization were assessed.Results: Dex treatment significantly reduced pro-inflammatory M1 macrophage polarization and NLRP3 inflammasome activation in the lungs relative to the mice treated with LPS. The similar pattern reduction of NLRP3 inflammasome activation by Dex was also found in A549 cells. Atip partly reversed the anti-inflammatory effects of Dex. In cultured alveolar macrophages, Dex reduced LPS-mediated expression of IL-1, − 6 and TNF-α receptors while promoting alveolar macrophages differentiation towards a M2 anti-inflammatory phenotype. Additionally, LPS increased Akt signaling activation in a time-dependent manner, which was further activated by Dex via inhibiting phosphatase and tensin homolog (PTEN). The action of Dex on Akt signaling shifted alveolar macrophages from M1 to M2 phenotype through increasing STAT6 and IRF4 transcriptional factors.Conclusion: Dex protected against LPS-induced lung injury and suppressed LPS-induced pulmonary inflammatory responses by attenuating the NLRP3 inflammasome activation and promoting anti-inflammatory M2 macrophage polarization.Keywords: sepsis, acute lung injury, macrophage polarization, dexmedetomidine, Akt signaling