Chronic low-dose deltamethrin exposure induces colon injury and aggravates DSS-induced colitis via promoting cellular senescence.

OBJECTIVE: Deltamethrin (DLM) is a commonly used insecticide, which is harmful to many organs. Here, we explored the effects of chronic low-dose DLM residues on colon tissue and its potential mechanism. METHODS: The mice were given long-term low-dose DLM by intragastric administration, and the body weights and disease activity index (DAI) scores of the mice were regularly recorded. The colon tissues were then collected for hematoxylin-eosin, immunofluorescence and immunohistochemistry staining. Besides, the RNA sequencing was performed to explore the potential mechanism. RESULTS: Our results showed that long-term exposure to low-dose DLM could cause inflammation in mice colon tissue, manifested as weight loss, increased DAI score, increased apoptosis of colonic epithelial cells, and increased infiltration of inflammatory cells. However, we observed that after long-term exposure to DLM and withdrawal for a period of time, although apoptosis was restored, the recovery of colon inflammation was not ideal. Subsequently, we performed RNA sequencing and found that long-term DLM exposure could lead to the senescence of some cells in mice colon tissue. The results of staining of cellular senescence markers in colon tissue showed that the level of cellular senescence in the DLM group was significantly increased, and the p53 signalling related to senescence was also significantly activated, indicating that cellular senescence played a key role in DLM-induced colitis. We further treated mice with quercetin (QUE) after long-term DLM exposure, and found that QUE could indeed alleviate DLM-induced colitis. In addition, we observed that long-term accumulation of DLM could aggravate DSS-induced colitis in mice, and QUE treatment could reverse this scenario. CONCLUSION: Continuous intake of DLM caused chronic colitis in mice, and the inflammation persisted even after discontinuation of DLM intake. This was attributed to the induction of cellular senescence in colon tissue. Treatment with QUE alleviated DLM-induced colitis by reducing cellular senescence. Long-term DLM exposure also aggravated DSS-induced colitis, which could be mitigated by QUE treatment.

Chronic exposure to low-dose deltamethrin can lead to colon tissue injury through PRDX1 inactivation-induced mitochondrial oxidative stress injury and gut microbial dysbiosis.

OBJECTIVE: To date, it is unclear whether deltamethrin (DLM) intake causes damage to colon tissue. Hence, in this study, we aimed to clarify the effect of long-term exposure to low-dose DLM on colon tissues, and its potential mechanisms. METHODS: Mice were treated with DLM (0.2 mg/kg/day) or DLM combined with N-acetyl-l-cysteine (NAC) (50 mg/kg/day) for 8 weeks. Human colon cancer cells (HCT-116) were treated with DLM (0, 25, 50, or 100 µM), NAC (2 mM), or overexpression plasmids targeting peroxiredoxin 1 (PRDX1) for 48 h. DLM was detected using a DLM rapid detection card. Colon injury was evaluated using haematoxylin and eosin staining and transmission electron microscopy. Apoptosis was determined using immunofluorescence staining (IF), western blotting (WB) and flow cytometry (FC) assays. MitoTracker, JC-1, and glutathione (GSH) detection were used to detect mitochondrial oxidative stress. Intestinal flora were identified by 16 S rDNA sequencing. RESULTS: DLM accumulation was detected in the colon tissue and faeces of mice following long-term intragastric administration. Interestingly, our results showed that, even at a low dose, long-term intake of DLM resulted in severe weight loss and decreased the disease activity index scores and colon length. The results of IF, WB, and FC showed that DLM induced apoptosis in the colon tissue and cells. MitoTracker, JC-1, and GSH assays showed that DLM increased mitochondrial stress in colonic epithelial cells. Mechanistic studies have shown that increased mitochondrial stress and apoptosis are mediated by PRDX1 inhibition. Further experiments showed that PRDX1 overexpression significantly reduced DLM-induced oxidative stress injury and apoptosis. In addition, we observed that chronic exposure to DLM altered the composition of the intestinal flora in mice, including an increase in Odoribacter and Bacteroides and a decrease in Lactobacillus. The gut microbial richness decreased after DLM exposure in mice. Supplementation with NAC both in vivo and in vitro alleviated DLM-induced oxidative stress injury, colonic epithelial cell apoptosis, and gut microbial dysbiosis. CONCLUSION: Chronic exposure to DLM, even at small doses, can cause damage to the colon tissue, which cannot be ignored. The production and use of pesticides such as DLM should be strictly regulated during agricultural production.

Sm-like 5 knockdown inhibits proliferation and promotes apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B.

BACKGROUND: The role of Sm-like 5 (LSM5) in colon cancer has not been determined. In this study, we investigated the role of LSM5 in progression of colon cancer and the potential underlying mechanism involved. AIM: To determine the role of LSM5 in the progression of colon cancer and the potential underlying mechanism involved. METHODS: The Gene Expression Profiling Interactive Analysis database and the Human Protein Atlas website were used for LSM5 expression analysis and prognosis analysis. Real-time quantitative polymerase chain reaction and Western blotting were utilized to detect the expression of mRNAs and proteins. A lentivirus targeting LSM5 was constructed and transfected into colon cancer cells to silence LSM5 expression. Proliferation and apoptosis assays were also conducted to evaluate the growth of the colon cancer cells. Human GeneChip assay and bioinformatics analysis were performed to identify the potential underlying mechanism of LSM5 in colon cancer. RESULTS: LSM5 was highly expressed in tumor tissue and colon cancer cells. A high expression level of LSM5 was related to poor prognosis in patients with colon cancer. Knockdown of LSM5 suppressed proliferation and promoted apoptosis in colon cancer cells. Silencing of LSM5 also facilitates the expression of p53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and tumor necrosis factor receptor superfamily 10B (TNFRSF10B). The inhibitory effect of LSM5 knockdown on the growth of colon cancer cells was associated with the upregulation of p53, CDKN1A and TNFRSF10B. CONCLUSION: LSM5 knockdown inhibited the proliferation and facilitated the apoptosis of colon cancer cells by upregulating p53, CDKN1A and TNFRSF10B.

Factors affecting the ORR after neoadjuvant therapy of TP regimen combined with PD-1 inhibitors for esophageal cancer.

The aim of this study is to evaluate the factors affecting the objective response rate (ORR) after neoadjuvant therapy of taxol plus platinum (TP) regimen combined with programmed cell death protein-1 (PD-1) inhibitors for esophageal cancer, and establish a predictive model for forecasting ORR. According to the inclusion and exclusion criteria, consecutive esophageal cancer patients who were treated in the First Affiliated Hospital of Xi'an Jiaotong University from January 2020 to February 2022 were enrolled in this study as a training cohort, while patients who were treated in the Shaanxi Provincial Cancer Hospital Affiliated to Medical College of Xi'an Jiaotong University from January 2020 to December 2021 were enrolled as a validation cohort. All patients were treated with resectable locally advanced esophageal cancer and received neoadjuvant chemotherapy combined with immunotherapy. The ORR was defined as the sum of complete pathological response, major pathological response and partial pathological response. Logistic regression analysis was performed to determine the factors that might be related to the ORR of the patients after neoadjuvant therapy. The nomogram based on the result of regression analysis was established and verified to predict the ORR. In this study, 42 patients were included as training cohort and 53 patients were included as validation cohort. Chi-square analysis showed that neutrophil, platelet, platelet-to-lymphocytes ratio (PLR), systemic immune-inflammation index (SII), D-dimer and carcinoembryonic antigen (CEA) between ORR group and non-ORR group were significantly different. Logistic regression analysis showed that aspartate aminotransferase (AST), D-dimer and CEA were independent predictors of ORR after neoadjuvant immunotherapy. Finally, a nomogram was established based on AST, D-dimer and CEA. Internal validation and external validation revealed that the nomogram had a good ability to predict ORR after neoadjuvant immunotherapy. In conclusion, AST, D-dimer and CEA were the independent predictors of ORR after neoadjuvant immunotherapy. The nomogram based on these three indicators showed a good predictive ability.