Association between the use of lipid-lowering drugs and the risk of inflammatory bowel disease.

BACKGROUND: Observational studies have suggested an association between lipid-lowering drugs and inflammatory bowel disease (IBD) risk. This study aimed to assess the causal influence of lipid-lowering agents on IBD risk using Mendelian randomization analysis. METHOD: In a population of 173,082 individuals of European ancestry, 55 single-nucleotide polymorphisms were identified as instrumental variables for 6 lipid-lowering drug targets (HMGCR, NPC1LC, PCSK9, LDLR, CETP and APOB). Summary statistics for the genome-wide association study of IBD, ulcerative colitis (UC) and Crohn's disease (CD) were obtained from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. Inverse-variance weighted was employed as the primary MR method, and odds ratios (ORs) with 95% confidence intervals were reported as the results. Sensitivity analyses using conventional MR methods were conducted to assess result robustness. RESULTS: Gene-proxied inhibition of Niemann-Pick C1-like 1 (NPC1L1) was associated with an increased IBD risk (OR [95% CI]: 2.31 [1.38, 3.85]; p = .001), particularly in UC (OR [95% CI]: 2.40 [1.21, 4.74], p = .012), but not in CD. This finding was replicated in the validation cohort. Additionally, gene-proxied inhibition of low-density lipoprotein receptor was associated with reduced IBD (OR [95% CI]: .72 [.60, .87], p < .001) and UC risk (OR [95% CI]: .74 [.59, .92], p = .006), although this result was not replicated in the validation cohort. Other drug targets did not show significant associations with IBD, UC or CD risk. CONCLUSION: Inhibition of the lipid-lowering drug-target NPC1L1 leads to an increased IBD risk, mainly in the UC population.

IL27 and IL1RN are causally associated with acute pancreatitis: a Mendelian randomization study.

BACKGROUND: The interleukin (IL) plays a role in the development of acute pancreatitis (AP). However, the specific IL in AP has not been fully revealed. Therefore, the association between prospective IL and AP was studied via Mendelian randomization (MR). METHODS: The HUGO Gene nomenclature committee (HGNC) database provided 47 interleukin related genes (ILRGs). ILRGs and differentially expressed genes (DEGs) from GSE194331 were overlapped to create differently expressed ILRGs (DE-ILRGs). The integrative epidemiology unit (IEU) open genome-wide association study (GWAS) database provided exposure and outcome datasets. Univariate MR (UVMR) analysis using MR-Egger, IVW, simple mode, and weighted mode was done. UVMR results were verified using sensitivity analysis. Drug prediction, MVMR analysis, and PPI network development were also performed. RESULTS: Six DE-ILRGs were obtained. IL27 and IL1RN were substantially causally linked with AP by UVMR analysis (OR = 0.926, P < 0.001 and OR = 1.031, P = 0.023). Our sensitivity analysis showed the dependability of our results. Direct effect of IL27 was suggested by MVMR analysis. In the cytokine receptor binding pathway, IL27 and IL1RN interacted with IL36G and IL1R2. TAE-684, ARQ-680, and 12 other IL1RN and 14 IL27 medications were predicted. CONCLUSIONS: IL1RN was identified as a risk factor for acute pancreatitis (AP), but IL27 was found to be a protective factor for AP.

The functions and mechanisms of long non-coding RNA in colorectal cancer.

CRC poses a significant challenge in the global health domain, with a high number of deaths attributed to this disease annually. If CRC is detected only in its advanced stages, the difficulty of treatment increases significantly. Therefore, biomarkers for the early detection of CRC play a crucial role in improving patient outcomes and increasing survival rates. The development of a reliable biomarker for early detection of CRC is particularly important for timely diagnosis and treatment. However, current methods for CRC detection, such as endoscopic examination, blood, and stool tests, have certain limitations and often only detect cases in the late stages. To overcome these constraints, researchers have turned their attention to molecular biomarkers, which are considered a promising approach to improving CRC detection. Non-invasive methods using biomarkers such as mRNA, circulating cell-free DNA, microRNA, LncRNA, and proteins can provide more reliable diagnostic information. These biomarkers can be found in blood, tissue, stool, and volatile organic compounds. Identifying molecular biomarkers with high sensitivity and specificity for the early and safe, economic, and easily measurable detection of CRC remains a significant challenge for researchers.

Alternative splicing of IRF3 plays an important role in the development of hepatocarcinoma.

Alternative splicing is a process causing mRNA translation to produce different proteins, and it is crucial for the development of tumours. In this study, we constructed a prognostic model related to alternative splicing events in hepatocarcinoma using bioinformatics analysis, including the alternative splicing of CSAD, AFMID, ZDHHC16, and IRF3. The model is an independent prognostic factor and can accurately predict a patient's prognosis. IRF3 is a transcription factor related to the immune response. Its alternative splicing can affect the expression of various genes related to prognosis and plays an essential role in the tumour microenvironment. We also verified the expression of IRF3 exon skipping isoform in hepatocarcinoma at the mRNA level. In conclusion, we discovered that the alternative splicing of IRF3 is essential for the development of hepatocarcinoma. This study provides new insight into the development of treatments for hepatocarcinoma.

Fucosyltransferases Regulated by Fusobacterium Nucleatum and Act as Novel Biomarkers in Colon Adenocarcinoma.

Purpose: Colon adenocarcinoma (COAD) is one of the leading causes of cancer-associated mortality worldwide. Fucosyltransferases (FUTs) are associated with numerous cancers. We aimed to investigate the functions of FUTs in COAD. Patients and Methods: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to analyze the expression and clinical relevance of FUTs in COAD. Real Time Quantitative PCR (RT-qPCR), Western blot, immunohistochemistry and ELISA were used to detect the relative RNA and protein expression levels. Colitis-associated cancer mice treated with Fusobacterium nucleatum were used to illustrate the effects of Fusobacterium nucleatum on FUTs and COAD. Luciferase reporting assay was used to investigate the binding of miRNA to mRNA. Results: TCGA and GEO datasets showed abnormal expression of FUTs in COAD at transcript level. RT-qPCR, Western blot and immunohistochemistry showed increased expression of FUT1, POFUT1 and POFUT2 in COAD. COAD patients with a high expression of FUT1, FUT11, FUT13 (POFUT2) had a worse prognosis, while patients with a high expression of FUT2, FUT3, FUT6 had a better prognosis. FUT1 and POFUT2 could independently predict the prognosis of COAD patients. Functional analysis by CancerSEA database showed that FUT3, FUT6, FUT8, FUT12 (POFUT1) and FUT13 are associated with differentiation, apoptosis, invasion, quiescence, and hypoxia. FUTs are associated with the tumor microenvironment of COAD. FUT1 regulated by miR-939-3p inhibit the expression of MUC2. Fusobacterium nucleatum may affect the expression of FUTs by affecting their transcription factors and miRNA levels. Moreover, Fusobacterium nucleatum promotes COAD progression through the miR-939-3p/FUT1/MUC2 axis. Conclusion: Fucosyltransferases play an important role and may be the mediator of Fusobacterium nucleatum promoting COAD progression.

The lncRNA TCONS_00021785/miR-21-5p/Trim33 axis regulates VMP1-mediated zymophagy, reduces the activation of trypsinogen, and promotes acinar cell recovery.

In the early stage of acute pancreatitis, trypsinogen in acinar cells is activated, and the cells clear trypsin through zymophagy to avoid damage. Studies have shown that the substrate of zymophagy is ubiquitinated pancreatin, but the mechanism of pancreatin ubiquitination and the regulatory mechanism of zymophagy are not fully understood. Our results show that Trim33 can enhance cell viability, reduce cell necrosis, and reduce trypsinogen activation. Trim33 is a key E3 ligase enzyme that mediates trypsin ubiquitination. The results showed that overexpression of Trim33 can significantly increase VMP1 mRNA and protein levels. However, knocking down Trim33 produced the opposite effect, which indicates that Trim33, as a transcriptional mediator, affects zymophagy by regulating the expression of VMP1. In addition, we explored the transcriptional regulation mechanism of the Trim33 molecule. Our research shows that lncRNA TCONS_00021785 can competitively bind miR-21-5p to upregulate Trim33, thereby initiating enzyme autophagy and reducing zymogen activation.

The Rabep1-Mediated Endocytosis and Activation of Trypsinogen to Promote Pancreatic Stellate Cell Activation.

BACKGROUND: The pathogenesis of chronic pancreatitis is still unclear. Trypsinogen activation is an active factor in acute pancreatitis that has not been studied in the occurrence of chronic pancreatitis. METHODS: Immunofluorescence was used to detect the location and expression of trypsinogen in chronic pancreatitis and normal tissues. Microarray and single-cell RNA-seq (scRNA-seq) were used to screen core genes and pathways in pancreatic stellate cells (PSCs). Western blotting and immunofluorescence were used to verify trypsinogen expression in PSCs after silencing Rabep1. Immunofluorescence and flow cytometry were used to validate trypsinogen activation and PSC activation after intervening in the endocytosis pathway. RESULTS: Endocytosed trypsinogen was found in PSCs in CP clinical samples. Bioinformatic analysis showed that Rabep1 is a core gene that regulates trypsinogen endocytosis through the endocytosis pathway, verified by Western blot and immunofluorescence. Immunofluorescence and flow cytometry analyses confirmed the activation of trypsinogen and PSCs through the endocytosis pathway in PSCs. CONCLUSION: This study discovered a new mechanism by which trypsinogen affects the activation of PSCs and the occurrence and development of CP. Through communication between pancreatic acinar cells and PSCs, trypsinogen can be endocytosed by PSCs and activated by the Rabep1 gene.

ScRNA-seq and bulk RNA-seq reveal the characteristics of ferroptosis and establish a risk signature in cholangiocarcinoma.

Ferroptosis is a recently discovered mode of cell death that inhibits tumor growth. Single-cell RNA sequencing (scRNA-seq) is a powerful tool for analyzing tumor heterogeneity and the immune microenvironment at the single-cell level. We used CIBERSORT to identify cellular immune scores and found that monocytes had significantly infiltrated and were correlated with prognosis in cholangiocarcinoma. scRNA-seq data were extracted from the Gene Expression Omnibus database, and the FindCluster() package was used for cell cluster analysis, which obtained 21 cell clusters, and there was increased TNFSF13B-TFRC intercellular communication between monocytes and cholangiocytes. A weighted correlation network analysis was performed with the WGCNA package to obtain monocyte-related gene modules. Univariate and multivariate Cox analyses were then performed to further establish the signature, and the reliability of the signature was assessed by receiver operating characteristic curve and decision curve analysis. A nomogram signature based on the Kaplan-Meier survival analysis was established. We found that the communication between monocytes and malignant cells in cholangiocarcinoma may be a regulatory factor of ferroptosis in cancer cells. The prognostic stratification system of the three-gene signature related to monocytes and ferroptosis can accurately assess the prognostic risk for cholangiocarcinoma.

Genetic instability-related lncRNAs predict prognosis and influence the immune microenvironment in breast cancer.

Genome instability is a hallmark of cancer, and the function of lncRNAs in regulating genomic stability has been gradually characterized. However, the prognostic value of lncRNAs related to genetic instability has not been found in breast cancer. Here we constructed a genetic instability-related lncRNA model including U62317.4, SEMA3B-AS1, MAPT-AS1, AC115837.2, LINC01269, AL645608.7, and GACAT2. This model can evaluate the risk and predict the survival outcomes of patients. Further analysis showed that the differentially expressed genes between the high- and low-risk groups were enriched in immunity and cornified envelope formation pathways. In addition, M2 macrophages infiltrated more obviously in the high-risk group. In summary, lncRNAs related to genetic instability may influence the development of breast cancer through immune infiltration and keratinization. This study provides a wider insight into breast cancer development and treatment.

Pan-Cancer Analysis of Prognostic and Immune Infiltrates for CXCs.

BACKGROUND: CXCs are important genes that regulate inflammation and tumor metastasis. However, the expression level, prognosis value, and immune infiltration of CXCs in cancers are not clear. METHODS: Multiple online datasets were used to analyze the expression, prognosis, and immune regulation of CXCs in this study. Network analysis of the Amadis database and GEO dataset was used to analyze the regulation of intestinal flora on the expression of CXCs. A mouse model was used to verify the fact that intestinal bacterial dysregulation can affect the expression of CXCs. RESULTS: In the three cancers, multiple datasets verified the fact that the mRNA expression of this family was significantly different; the mRNA levels of CXCL3, 8, 9, 10, 14, and 17 were significantly correlated with the prognosis of three cancers. CXCs were correlated with six types of immuno-infiltrating cells in three cancers. Immunohistochemistry of clinical samples confirmed that the expression of CXCL8 and 10 was higher in three cancer tissues. Animal experiments have shown that intestinal flora dysregulation can affect CXCL8 and 10 expressions. CONCLUSION: Our results further elucidate the function of CXCs in cancers and provide new insights into the prognosis and immune infiltration of breast, colon, and pancreatic cancers, and they suggest that intestinal flora may influence disease progression through CXCs.