ABSTRACT
The association between psoriasis and alcohol consumption has been inconsistent across various studies. However, to the best of our knowledge, no dose-response meta-analysis has been performed to date. This study aims to investigate the association between alcohol consumption and psoriasis. The search was performed on July 27, 2021, using Embase and MEDLINE. The restricted cubic spline analysis was used to perform a dose-response analysis. We identified 3,904 studies, of which 48 studies with 1,702,847 individuals across 24 countries were included. Alcohol consumption was positively associated with psoriasis (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.27-1.70). In addition, a significantly increased OR for psoriasis was observed in males (OR, 1.84; 95% CI, 1.13-3.01) but not in females (OR, 1.22; 95% CI, 0.97-1.54). Based on eight studies, including three cohort and five case-control studies, the analysis revealed that with each additional gram of daily alcohol intake, the OR for psoriasis increased by 4%. We found a positive association between alcohol consumption and psoriasis. The association is more prominent in the group drinking more than 45 g of alcohol per day (3.2 alcoholic drink equivalent).
Subject(s)
Alcohol Drinking , Psoriasis , Psoriasis/epidemiology , Humans , Alcohol Drinking/epidemiology , Alcohol Drinking/adverse effects , Female , Male , Risk Factors , Sex Factors , Dose-Response Relationship, DrugABSTRACT
Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts. The K63-linkage poly-ubiquitinated TRAF4 formed complexes with NOX2 or NOX4 by mediating phosphorylated p47-phox in normal lung fibroblasts. Moreover, we showed that TRAF4 stabilized NOX complexes by decreasing lysosomal degradation of NOX2 and NOX4 after irradiation. NOX complexes increased endosomal ROS levels that were permeable into cytoplasm, leading to NF-κB-mediated ICAM1 up-regulation. Soluble ICAM1 was subsequently secreted into conditioned media of radiation-activated normal lung fibroblasts. The conditioned media from irradiated normal fibroblasts enhanced proliferation and epithelial-mesenchymal transition of non-small cell lung cancer cells both in vitro and in vivo. These results demonstrate that TRAF4 in irradiated fibroblasts is positively associated with aggressiveness of adjacent cancer cells by altering the tumor microenvironment. Thus, we suggest that regulation of TRAF4 might be a promising strategy for cancer therapy.
Subject(s)
Fibroblasts/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , TNF Receptor-Associated Factor 4/genetics , Tumor Microenvironment/genetics , Animals , Cell Line, Tumor , Disease Progression , Endosomes/metabolism , Fibroblasts/pathology , Fibroblasts/radiation effects , Gene Expression Regulation , Humans , Intercellular Adhesion Molecule-1/blood , Intercellular Adhesion Molecule-1/metabolism , Lung Neoplasms/metabolism , Lysosomes/metabolism , Male , Mice , Models, Biological , NADPH Oxidase 2/genetics , NADPH Oxidase 2/metabolism , NADPH Oxidase 4/genetics , NADPH Oxidase 4/metabolism , NF-kappa B/metabolism , Protein Binding , Radiation, Ionizing , Reactive Oxygen Species/metabolism , Signal Transduction , TNF Receptor-Associated Factor 4/metabolism , Ubiquitination , Xenograft Model Antitumor AssaysABSTRACT
Radiation-induced pulmonary fibrosis (RIPF) is one of the most common side effects of lung cancer radiotherapy. This study was conducted to identify the molecular mechanism responsible for RIPF. We revealed that the transcriptional level of cytochrome P450 2E1 (CYP2E1) was elevated by examining expression profile analysis of RIPF mouse models. We also confirmed that CYP2E1 regulated levels of endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in alveolar epithelial type II (AE2) cells and lung fibroblasts. Inhibition of CYP2E1 via its siRNA or inhibitor significantly attenuated epithelial-to-mesenchymal transition and apoptosis of AE2 cells, as well as myofibroblast formation induced by radiation. Finally, the effects of a CYP2E1 inhibitor on development of RIPF were evaluated by in vivo studies. Taken together, the results of the present study suggest that CYP2E1 is an important mediator of RIPF development that functions by increasing cellular ER stress and ROS levels.
