Background: Peptic ulcer disease (PUD) is a chronic gastrointestinal disorder that may present acutely due to complications and poses significant clinical and economic challenges. Understanding the global burden of PUD and its contributing risk factors is essential for developing targeted prevention strategies. Therefore, our research aimed to comprehensively evaluate the epidemiological characteristics and associated risk factors of PUD, thereby providing evidence to support policymakers in formulating appropriate health policies. Methods: The data on PUD were retrieved from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. Incidence, prevalence, deaths and disability-adjusted life years (DALYs) were metrics used to measure PUD burden. The population attributable fractions (PAFs) were used to calculate the percentage contributions of primary potential risk factors to PUD deaths and DALYs. Results: The global incidence and prevalence cases of PUD increased by 11.1% and 8.8%, respectively, between 1990 and 2021. In contrast, the number of deaths and DALYs decreased by 15.94% and 27.8%, respectively, during the same period. The global age-standardized rates (ASRs) for incidence, prevalence, deaths and DALYs associated with PUD decreased by 40.3%, 41.1%, 61.5%, and 63.1%, respectively, between 1990 and 2021. Men exhibited higher numbers and ASRs of incidence, prevalence, deaths, and DALYs associated with PUD than women across most age cohorts in 2021.The average annual percentage change (AAPC) in age-standardized incidence (ASIR), prevalence (ASPR), deaths (ASMR), and DALYs (ASDR) rates for PUD were −1.65 (95% confidence interval (CI): −1.69, −1.61), −1.69 (95% CI: −1.74, −1.63), −3.02 (95% CI: −3.13, −2.91) and −3.17 (95% CI: −3.24,-3.10), respectively, from 1990 to 2021 on a global scale. In 2021, negative associations were observed globally among the ASIR, ASPR, ASMR, ASDR and the Socio-Demographic Index (SDI). Based on the ARIMA model, we projected that the global ASIR, ASPR, ASMR, and ASDR for PUD will exhibit decreasing trends from 2022 to 2040 for both sexes. We also identified smoking as the primary risk factor associated with PUD-related DALYs and deaths in both sexes in 1990 and 2021. Conclusion: Significant advancements have been noted in reducing the global burden of PUD. Nonetheless, significant geographical and gender disparities exist in PUD numbers and ASRs, suggesting that a substantial portion of the population still lacks access to quality healthcare or experiences variations in risk factors for PUD. Thus, precise prevention strategies are essential to mitigate the disease burden of PUD.

Galectin-3 (Gal-3) plays a multifaceted role in the development and progression of pancreatic adenocarcinoma (PAAD), which is associated with a poor prognosis. Its interaction with tumor microenvironment cells has been reported. However, the Gal-3-mediated tumor–stromal interaction and induced energy metabolism associated with drug resistance remain unknown. Our previous study has reported that Gal-3 secretion from tumor cells and inflammatory cytokine dependency are therapeutic targets. In this study, we revealed that the expression of Gal-3 was not only remarkably up-regulated in tumors but also significantly associated with the tumor-associated fibroblasts of PAAD patients. A coculture model of PAAD cells and pancreatic stellate cells revealed that Gal-3 mediated the Ca²⁺/−calcineurin–NFAT pathway to increase the transcription of CCL2 and BSG in tumor-associated fibroblasts. These findings ultimately lead to the observation of low energy metabolism in tumor cells. Particularly, mitochondrial oxidative phosphorylation was functionally arrested in Gal-3-high tumor cells, as demonstrated by a lower oxygen consumption rate and mitochondrial ATP production through abnormal mitochondrial morphology. The inhibition of the CCL2-CCR2 and PPIA-BSG pathways indicated the restoration of gemcitabine sensitivity when drug resistance was elicited by Gal-3. Oral administration of the natural Gal-3 inhibitor modified citrus pectin extract (MCP) showed therapeutic effect for Gal-3-activated tumors and stromal cells in orthotopic pancreatic xenograft models. Hence, our findings offer insights into the fact that low mitochondrial metabolism is dependent on Gal-3 activation-mediated gemcitabine resistance through tumor–stromal interactions.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths influenced by both genetic and environmental factors. Per- and polyfluoroalkyl substances (PFAS) are widely recognized environment pollutants known for their high bioaccumulation potential and a long elimination half-life, which have been implicated in the development and progression of CRC. However, the underlying mechanism by which these substances cause CRC still remains unclear. The PFAS-associated differentially expressed genes (DEGs) were identified by intersecting the DEGs in CRC with the interactive genes from the Comparative Toxicogenomics Database (CTD) database. Subsequently, the consensus genes were employed to develop a prognostic model using univariate Cox and LASSO analyses. Additionally, we examined the differences in clinicopathological characteristics, genetic variants, and potential drug sensitivity between the high-risk and low-risk groups. The effects of PRAME, one gene of the prognostic model, on CRC were further validated through both bioinformatics and experimental approaches. A total of 192 PFAS-related DEGs were screened and used to develop a prognostic model for CRC through univariate Cox and LASSO analyses. The feasibility of the model was validated using both an internal training set and an external validation set. The RiskScore was also identified as an independent prognostic factor for overall survival in CRC patients. Furthermore, CRC patients in high-risk group were suggested to possess a greater number of genetic variants and exhibit enhanced responses to a range of potential drugs and immunotherapies. We also observed that PRAME was highly expressed and correlated with poor prognosis in CRC. PFOS exposure induced the upregulation of PRAME in CRC cells, which subsequently enhanced cell proliferation and invasion capacity through PI3K/Akt/mTOR signalling pathway. We constructed a novel prognostic model based on 15 PFAS-related DEGs to predict the survival and responses to potential drugs and immunotherapy of CRC patients. Furthermore, we identified and assessed the feasibility of the critical gene PRAME in prognostic model as a vital marker for CRC. Our findings further suggested that PFOS exposure may increase the risk of CRC development via upregulation of PRAME-mediated PI3K/Akt/mTOR signalling pathway, indicating its potential as a novel therapeutic target for CRC in the future.

Previous studies have suggested a potential link between the gut microbiota and diverticulitis. However, the causal relationships as well as underlying mechanisms remain unclear. The causal effects of gut microbiota on diverticulosis & diverticulitis was assessed using two-sample Mendelian randomization analysis. The sensitivity analyses were also performed. We then used integrative bioinformatics tools to identify core genes associated with diverticulitis and explore their potential mechanisms and therapeutic targets. Inverse variance weighted analysis indicated that Family XIII (OR=0.281, 95 % CI: 0.093–0.853, P = 0.025) and Defluviitaleaceae UCG-011 (OR=0.382, 95 % CI: 0.162–0.898, P = 0.027) were negatively associated with the risk of diverticulosis and diverticulitis, whereas Oscillospira (OR=3.514, 95 % CI: 1.146–10.779, P = 0.028), Ruminiclostridium 6 (OR=2.629, 95 % CI: 1.093–6.322, P = 0.031), Lachnoclostridium (OR=2.458, 95 % CI: 1.014–5.962, P = 0.047), and Desulfovibrionales (OR=2.157, 95 % CI: 1.038–4.480, P = 0.039) were positively associated with disease risk. The sensitivity analyses validated these correlations. Through SNP annotation, we identified 23 host genes associated with pathogenic gut microflora in diverticulosis and diverticulitis, and retrieved 213 diverticulitis-related genes from GeneCards. Intersection analysis revealed LRRC4C as the sole shared gene. Differential expression analysis further showed that LRRC4C was significantly downregulated in diverticulitis compared to infective colitis. Finally, eight candidate drugs were identified as potential inducers of LRRC4C expression. The research revealed potential causal relationships between gut microbiota and diverticulitis. LRRC4C was identified as a core gene associated with pathogenic microbial traits in diverticulitis, and candidate therapeutic drugs for diverticulitis based on LRRC4C were predicted, offering novel strategies for the prevention and management of the disease.