Environmental Toxicology最新文献

Cigarette smoking causes multiple cancers by directly influencing mutation burden of driver mutations. However, the mechanism between somatic mutation caused by cigarette smoking and bladder tumorigenesis remains elusive. Smoking-related mutation profile of bladder cancer was characterized by The Cancer Genome Atlas cohort. Integraticve OncoGenomics database was utilized to detect the smoking-related driver genes, and its biological mechanism predictions were interpreted based on bulk transcriptome and single-cell transcriptome, as well as cell experiments. Cigarette smoking was associated with an increased tumor mutational burden under 65 years old (p = 0.031), and generated specific mutational signatures in smokers. RB1 was identified as a differentially mutated driver gene between smokers and nonsmokers, and the mutation rate of RB1 increased twofold after smoking (p = 0.008). RB1 mutations and the 4-aminobiphenyl interference could significantly decrease the RB1 expression level and thus promote the proliferation, invasion, and migration ability of bladder cancer cells. Enrichment analysis and real-time quantitative PCR (RT-qPCR) data showed that RB1 mutations inhibited cytochrome P450 pathway by reducing expression levels of UGT1A6 and AKR1C2. In addition, we also observed that the component of immunological cells was regulated by RB1 mutations through the stronger cell-to-cell interactions between epithelial scissor⁺ cells and immune cells in smokers. This study highlighted that RB1 mutations could drive smoking-related bladder tumorigenesis through inhibiting cytochrome P450 pathway and regulating tumor immune microenvironment.

Inflammation is an intrinsic protective mechanism against various forms of cellular injuries in humans; however, its undesired activation results in tissue damage and cell death. The onset of chronic inflammation and oxidative stress are the key characteristics of autoimmune inflammatory diseases such as rheumatoid arthritis (RA), for which an effective treatment is yet to be developed. Therefore, in this study, we investigated the protective effects and molecular mechanisms of a novel herbal preparation, Jing-Si herbal tea (JS), against H₂O₂-induced inflammation and cellular damage in HIG-82 synoviocytes. We found that JS did not show any significant alterations in cell viability at <188 μg/mL; however, a cytotoxic effect was observed at 188–1883 μg/mL concentrations tested. We found that expressions of inflammation associated extracellular matrix (ECM)-degrading proteases MMP-13, ADAMTS-2, -8, and -17 were abnormally enhanced under H₂O₂-induced pathological oxidative stress (ROS) in HIG-82 cells. Interestingly, JS treatment not only reduced the ROS levels but also significantly repressed the protein expressions of collagen degrading proteases in a dose-dependent manner. Treatment with JS showed enhanced cell viability against H₂O₂-induced toxic ROS levels. The expressions of cell protective aggrecan, Collagen II, and Bcl-2 were increased, whereas MMP-13, ADAMTS-2, Cytochrome C, and cleaved Caspase 3 were decreased by JS under inflammatory agents H₂O₂, MIA, LPS, and TNF-α treatment, respectively, in HIG-82 cells. Interestingly, the cytoprotective effect of JS treatment was attributed to a decreased mitochondrial localization of Bax and a reduction of Cytochrome C release into the cytoplasm of H₂O₂-treated HIG-82 cells. Collectively, our results suggest a novel protective mechanism of JS for RA treatment, which could be potentially applied as a complementary treatment or as an alternative therapeutic approach to mitigate inflammatory diseases.

Clear cell renal cell carcinoma (ccRCC) is characterized by its aggressive behavior and complex molecular heterogeneity, posing significant challenges for treatment and prognostication. This study offers a comprehensive analysis of ccRCC by leveraging both bulk and single-cell RNA sequencing data, with a specific aim to unravel the complexities of sphingolipid metabolism and the intricate dynamics within the tumor microenvironment (TME). By examining ccRCC samples sourced from public databases, our investigation delves deep into the genetic and transcriptomic landscape of this cancer type. Employing advanced analytical techniques, we have identified pivotal patterns in gene expression and cellular heterogeneity, with a special focus on the roles and interactions of various immune cells within the TME. Significantly, our research has unearthed insights into the dynamics of sphingolipid metabolism in ccRCC, shedding light on its potential implications for tumor progression and strategies for immune evasion. A novel aspect of this study is the development of a risk score model designed to enhance prognostic predictions for ccRCC patients, which is currently pending external validation to ascertain its clinical utility. Despite its contributions, the study is mindful of its limitations, including a reliance on observational data from public sources and a primary focus on RNA sequencing data, which may constrain the depth and generalizability of the findings. The study does not encompass critical aspects, such as protein expression, posttranslational modifications, and comprehensive metabolic profiles. Moreover, its retrospective design underscores the necessity for future prospective studies to solidify these preliminary conclusions. Our findings illuminate the intricate interplay between genetic alterations, sphingolipid metabolism, and immune responses in ccRCC. This research not only enhances our understanding of the molecular foundations of ccRCC but also paves the way for the development of targeted therapies and personalized treatment modalities. The study underlines the importance of cautious interpretation of results and champions ongoing research using diverse methodologies to thoroughly comprehend and effectively combat this formidable cancer type.

Inflammatory cell infiltration is a characteristic feature of COPD and correlates directly with the severity of the disease. Interleukin-23 (IL-23) is a pro-inflammatory cytokine that regulates Th-17 inflammation, which mediates many pathophysiological events in COPD. The primary goal of this study was to determine the role of IL-23 as a mediator of key pathologic processes in cigarette smoke-induced COPD. In this study, we report an increase in IL23 gene expression in the lung biopsies of COPD patients compared to controls and identified a positive correlation between IL23 gene expression and disease severity. In a cigarette smoke-induced murine emphysema model, the suppression of IL-23 with a monoclonal blocking antibody reduced the severity of cigarette smoke-induced murine emphysema. Mechanistically, the suppression of IL-23 was associated with a reduction in immune cell infiltration, oxidative stress injury, and apoptosis, suggesting a role for IL-23 as an essential immune mediator of the inflammatory processes in the pathogenesis of CS-induced emphysema.

RING finger protein 135 (RNF135) is identified as a regulator in certain cancer types. However, its role and molecular mechanisms in lung adenocarcinoma (LUAD) are still unclear. Herein, we investigated the level of RNF135 in tumor tissues of LUAD patients using the UALCAN database and confirmed the data by real-time PCR and western blot analysis. The effects of RNF135 on stemness maintenance and migration/invasion capability of LUAD cells were investigated by sphere formation, flow cytometry, wound healing, and transwell assay. Limiting dilution xenograft assay and intracardiac injection of LUAD cells were applied to assess the implications of RNF135 in tumorigenesis and brain metastasis. Our results revealed that RNF135 was upregulated in tumor tissues of LUAD patients and was positively correlated with poor prognosis. Knockdown of RNF135 suppressed cancer stem cells (CSCs)-like properties, and migration/invasion capability of A549 and NCI-H1975 cells. Conversely, overexpression of RNF135 augmented CSCs-like traits and migration/invasion ability of LUAD cells. Limiting dilution xenograft assay demonstrated that RNF135 was required for the self-renewal of CSCs to initiate LUAD development. Overexpression of RNF135 in A549 cells increased their ability to metastasize to the brain in vivo. Mechanistically, the transcriptional activation of RNF135 by LSD1 involved H3K9me2 demethylation at the promoter region of RNF135. Reexpression of RNF135 in LSD1-silenced A549 cells was able to reverse LSD1-mediated stemness maintenance and migration/invasion capability. Overall, our results implied that targeting of LSD1/RNF135 axis might be a feasible method to suppress tumorigenesis and brain metastasis of LUAD patients.

Nicotine exposure is a common adverse environment during pregnancy and causes developmental toxicity of long bones in offspring. However, the effect of prenatal nicotine exposure (PNE) on bone mass accumulation in female offspring and its mechanism remained to be further investigated. In this study, we constructed a PNE rat model and collected the long bone and the bone marrow mesenchymal stem cells (BMSCs) from female offspring rats for the detection of bone mass, cell apoptosis, and the expressions of osteogenesis- and apoptosis-related genes. The results revealed that PNE induced low bone mass in female offspring rats and was associated with the suppression of osteogenic function. Moreover, the apoptosis of BMSCs derived from the PNE female offspring rats was raised, and the expression ratio of apoptosis marker genes BAX/BCL-2 was significantly increased. Further, PNE inhibited the expression and function of insulin-like growth factor l (IGF1) signaling pathway in BMSCs. However, the exogenous IGF1 treatment partially ameliorated the increased apoptosis of BMSCs derived from the PNE female offspring rats. In conclusion, PNE induced low bone mass in female offspring rats, which was attributed to the increased apoptosis of BMSCs due to functional inhibition of IGF1 signaling pathway.