Benzimidazole-based structure optimization to discover novel anti-gastric cancer agents targeting ROS/MAPK pathway.

Given the malignancy of gastric cancer, developing highly effective and low-toxic targeted drugs is essential to prolong patient survival and improve patient outcomes. In this study, we conducted structural optimizations based on the benzimidazole scaffold. Notably, compound 8 f presented the most potent antiproliferative activity in MGC803 cells and induced cell cycle arrest at the G0/G1 phase. Further mechanistic studies demonstrated that compound 8 f caused the apoptosis of MGC803 cells by elevating intracellular reactive oxygen species (ROS) levels and activating the mitogen-activated protein kinase (MAPK) signaling pathway, accompanied by corresponding markers change. In vivo investigations additionally validated the inhibitory effect of compound 8 f on tumor growth in xenograft models bearing MGC803 cells without obvious toxicity. Our studies suggest that compound 8 f holds promise as a potential and safe lead compound for developing anti-gastric cancer agents.

Inflammation mediates the association between furan exposure and the prevalence and mortality of chronic obstructive pulmonary disease: National Health and Nutrition Examination Survey 2013-2018.

BACKGROUND: Although extensive research has established associations between chronic obstructive pulmonary disease (COPD) and environmental pollutants, the connection between furan and COPD remains unclear. This study aimed to explore the association between furan and COPD while investigating potential mechanisms. METHODS: The study involved 7,482 adults from the National Health and Nutrition Examination Survey 2013-2018. Exposure to furan was assessed using blood furan levels. Participants were categorized into five groups based on quartiles of log10-transformed blood furan levels. Logistic regression and restricted cubic spline regression models were used to assess the association between furan exposure and COPD risk. Mediating analysis was performed to assess the contribution of inflammation to the effects of furan exposure on COPD prevalence. Cox regression was used to assess the association between furan exposure and the prognosis of COPD. RESULTS: Participants with COPD exhibited higher blood furan levels compared to those without COPD (P < 0.001). Log10-transformed blood furan levels were independently associated with an increased COPD risk after adjusting for all covariates (Q5 vs. Q1: OR = 4.47, 95% CI = 1.58-12.66, P = 0.006, P for trend = 0.001). Inflammatory cells such as monocytes, neutrophils, and basophils were identified as mediators in the relationship between furan exposure and COPD prevalence, with mediated proportions of 8.73%, 20.90%, and 10.94%, respectively (all P < 0.05). Moreover, multivariate Cox regression analysis revealed a positive correlation between log10-transformed blood furan levels and respiratory mortality in COPD patients (HR = 41.00, 95% CI = 3.70-460.00, P = 0.003). CONCLUSIONS: Exposure to furan demonstrates a positive correlation with both the prevalence and respiratory mortality of COPD, with inflammation identified as a crucial mediator in this relationship.

Comprehensive landscape and future perspectives of non-coding RNAs in esophageal squamous cell carcinoma, a bibliometric analysis from 2008 to 2023.

Objectives: Summarize the progress and hot topic evolution of non-coding RNAs (ncRNAs) research in esophageal squamous cell carcinoma (ESCC) in recent years and predict future research directions. Methods: Relevant articles from the Web of Science until 31 October 2023 were obtained. Bibliometric analysis of included articles was performed using software (VOSviewer, CiteSpace, and Bibliometrix). The volume and citation of publications, as well as the country, institution, author, journal, keywords of the articles were used as variables to analyze the research trends and hot spot evolution. Results: 1,118 literature from 2008 to 2023 were retrieved from database, with 25 countries/regions, 793 institutions, 5,426 authors, 261 journals involved. Global cooperation was centered on China, Japan, and the United States. Zhengzhou University, an institution from China, had the highest publication. The most prolific author was Guo Wei, and the most prolific journal was Oncology Letters. Analysis of keywords revealed that the research in this field revolved around the role of ncRNAs in the occurrence, development, diagnosis, treatment, and prognosis of ESCC, mainly including micro RNAs, long non-coding RNAs, and then circular RNAs. Conclusion: Overall, research on ncRNAs in ESCC remains strong. Previous research has mainly focused on the basic research, with a focus on the mechanism of ncRNAs in the occurrence, development, diagnosis, treatment, and prognosis of ESCC. Combining current research with emerging disciplines to further explore its mechanisms of action or shifting the focus of research from preclinical research to clinical research based on diagnosis, treatment, and prognosis, will be the main breakthrough in this field in the future.

Cuproptosis-associated hub gene identification and immune cell infiltration patterns in silicosis.

Recent research has hinted at a potential connection between silicosis, a fibrotic lung disease caused by exposure to crystalline silica particles, and cuproptosis. The aim of the study was to explore how cuproptosis-related genes (CRGs) may influence the development of silicosis and elucidate the underlying mechanisms. An analysis of genes associated with both silicosis and cuproptosis was conducted. Key gene identification was achieved through the application of two machine learning techniques. Additionally, the correlation between these key genes and immune cell populations was explored and the critical pathways were discerned. To corroborate our findings, the expression of key genes was verified in both a publicly available silica-induced mouse model and our own silicosis mouse model. A total of 12 differentially expressed CRGs associated with silicosis were identified. Further analysis resulted in the identification of 6 CRGs, namely LOX, SPARC, MOXD1, ALB, MT-CO2, and AOC2. Elevated immune cell infiltration of CD8 T cells, regulatory T cells, M0 macrophages, and neutrophils in silicosis patients compared to healthy controls was indicated. Validation in a silica-induced pulmonary fibrosis mouse model supported SPARC and MT-CO2 as potential signature genes for the prediction of silicosis. These findings highlight a strong association between silicosis and cuproptosis. Among CRGs, LOX, SPARC, MOXD1, ALB, MT-CO2, and AOC2 emerged as pivotal players in the context of silicosis by modulating CD8 T cells, regulatory T cells, M0 macrophages, and neutrophils.

Causal Association Between Allergic Diseases and Dementia: Evidence from Multivariate Mendelian Randomization Study.

Background: The link between allergic diseases and dementia remains controversial, and the genetic causality of this link is unclear. Objective: This study investigated the causal relationship between allergic diseases and dementia using univariate and multivariate Mendelian randomization (MR) methods. Methods: We selected genome-wide association studies including 66,645 patients with allergic diseases and 12,281 patients with dementia, with statistical datasets derived from the FinnGen Consortium of European origin. After a rigorous screening process for single nucleotide polymorphisms to eliminate confounding effects, MR estimation was performed mainly using the inverse variance weighting method and the MR-Egger method. Sensitivity analyses were performed using Cochran's Q test, MR-PRESSO test, MR Pleiotropy residuals and leave-one-out analysis. Results: Univariate and multivariate MR together demonstrated a causal relationship between atopic dermatitis and reduced vascular dementia (VaD) risk (OR = 0.89, 95% CI: 0.81-0.99, p = 0.031; OR = 0.85, 95% CI: 0.76-0.95, p = 0.003). MVMR confirmed asthma was associated with a reduction in the risk of Alzheimer's disease (AD) (OR = 0.82, 95% CI: 0.71-0.94, p = 0.005) and may be associated with a reduction in the risk of VaD (OR = 0.80, 95% CI: 0.65-0.99, p = 0.042); allergic rhinitis may be causally associated with an increased risk of AD (OR = 1.16, 95% CI: 1.00-1.35, p = 0.046) and VaD (OR = 1.29, 95% CI: 1.03-1.62, p = 0.027). In sensitivity analyses, these findings were reliable. Conclusions: MR methods have only demonstrated that allergic rhinitis dementia is associated with an increased risk of developing dementia. Previously observed associations between other allergic diseases and dementia may be influenced by comorbidities and confounding factors rather than causality.

The causal relationship between sarcoidosis and autoimmune diseases: a bidirectional Mendelian randomization study in FinnGen.

Background: Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs. Methods: We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases. Results: The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, P IVW-FE = 1.01 × 10-21), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, P IVW-MRE = 9.88 × 10-2). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All P < 6.25 × 10-3). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (P < 6.25 × 10-3). Conclusion: The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.

Progressive pulmonary fibrosis in myositis-specific antibody-positive interstitial pneumonia: a retrospective cohort study.

Objectives: Idiopathic inflammatory myopathy (IIM) frequently coexists with interstitial pneumonia (IP) and is commonly the initial or sole manifestation accompanied by positive myositis-specific autoantibodies (MSAs), even in the absence of meeting diagnostic criteria. This study aims to evaluate the proportion of progressive pulmonary fibrosis (PPF) and identify potential predictors influencing the progression of pulmonary fibrosis in patients with MSA-IP. Methods: This descriptive study employed a retrospective cohort design, enrolling patients diagnosed with interstitial pneumonia and positive MSAs at Beijing Chao-Yang Hospital in a sequential manner. Clinical data were systematically collected from the patients' medical records during regular follow-up visits conducted every 3 to 6 months. Cox regression analysis was utilized to identify independent predictors of PPF in patients with positive MSAs and interstitial pneumonia. Results: A total of 307 patients were included in the study, with 30.6% of them developing PPF during a median follow-up period of 22 months. Kaplan-Meier survival curves demonstrated a significantly lower survival in the PPF patients compared to the non-PPF patients (median 11.6 months vs. 31 months, p = 0.000). An acute/subacute onset of interstitial pneumonia (HR 3.231, 95%CI 1.936-5.392, p = 0.000), lower diffusing capacity of the lungs for carbon monoxide (DLCO) % predicted (HR 6.435, 95%CI 4.072-10.017, p = 0.001), and the presence of diffuse alveolar damage (DAD) on high-resolution computed tomography (HRCT) (HR 8.679, 95%CI 1.974-38.157, p = 0.004) emerged as independent predictors of PPF. Notably, the implementation of triple therapy comprising glucocorticoids, immunosuppressants, and antifibrotic drugs was associated with a reduced risk of developing PPF (HR 0.322, 95%CI 0.115-0.899, p = 0.031). Conclusion: Approximately 30.6% of patients with MSA-IP may develop PPF within the follow-up period. Patients presenting with an acute/subacute onset of interstitial pneumonia, lower predicted DLCO SB% and evidence of DAD on HRCT are more susceptible to developing PPF. Conversely, the administration of triple therapy appears to serve as a protective factor against the development of PPF in patients with MSA-IP.