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.

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.

Epigallocatechin-3-gallate reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis.

Neutrophil extracellular traps (NETs) promote intra-acinar trypsin activation and tissue damage. Therefore, reducing NET formation can reduce tissue damage in severe acute pancreatitis (SAP). However, NET formation pathways may differ among disease models. In this study, we evaluated the role of the myeloperoxidase-neutrophil elastase (NE) pathway in NET formation in SAP. SAP was induced by intraperitoneal injection of cerulein and LPSs in mice, and NE activity was inhibited by GW311616. Pancreatic tissues were collected for multiplex immunofluorescence, scanning electron microscopy, and western blotting to detect NET formation and the effect of NE on citrullinated histone H3, followed by analyses of serum amylase and cytokine levels. Pretreatment with GW311616 significantly reduced NET formation, pancreatic tissue damage, and systemic inflammatory responses in SAP. Network pharmacology analyses using NE as the target revealed the monomeric compound epigallocatechin-3-gallate (EGCG). Binding between EGCG and NE was validated using molecular docking, and the ability of EGCG to inhibit NE activity was verified experimentally. NET formation by PMA-stimulated neutrophils was significantly reduced in vitro when the cells were pretreated with 40 µM EGCG. Pretreatment with EGCG significantly reduced NET formation, pancreatic tissue damage, and systemic inflammatory responses in vivo. These results reveal that NET formation requires the myeloperoxidase-NE pathway, and citrullination of histone H3 is affected by NE activity in SAP. EGCG shows therapeutic potential for affecting NE activity, NET formation, and systemic inflammation in SAP.

Amadis: A Comprehensive Database for Association Between Microbiota and Disease.

The human gastrointestinal tract represents a symbiotic bioreactor that can mediate the interaction of the human host. The deployment and integration of multi-omics technologies have depicted a more complete image of the functions performed by microbial organisms. In addition, a large amount of data has been generated in a short time. However, researchers struggling to keep track of these mountains of information need a way to conveniently gain a comprehensive understanding of the relationship between microbiota and human diseases. To tackle this issue, we developed Amadis (http://gift2disease.net/GIFTED), a manually curated database that provides experimentally supported microbiota-disease associations and a dynamic network construction method. The current version of the Amadis database documents 20167 associations between 221 human diseases and 774 gut microbes across 17 species, curated from more than 1000 articles. By using the curated data, users can freely select and combine modules to obtain a specific microbe-based human disease network. Additionally, Amadis provides a user-friendly interface for browsing, searching and downloading. We hope it can serve as a useful and valuable resource for researchers exploring the associations between gastrointestinal microbiota and human diseases.

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.

Regulation of Pancreatic Fibrosis by Acinar Cell-Derived Exosomal miR-130a-3p via Targeting of Stellate Cell PPAR-γ.

INTRODUCTION: As endogenous miRNA carriers, exosomes play a role in the pathophysiological processes of various diseases. However, their functions and regulation mechanisms in pancreatic fibrosis remain unclear. METHODS: In this study, an RNA microarray was used to detect differentially expressed exosomal miR-130a-3p in AR42J cells before and after taurolithocholate (TLC) treatment. mRNA-seq was used to screen differentially expressed genes before and after pancreatic stellate cell (PSC) activation. We used the STRING database to construct a protein-protein interaction (PPI) network for differentially expressed genes, used CytoNCA to analyze the centrality of the PPI network, and identified 10 essential proteins in the biological network. Then, the TargetScan and miRanda databases were used to predict the target genes of miR-130a-3p. The intersections of the target genes and the mRNAs encoding the 10 essential proteins were identified to construct miR-130a-3p/peroxisome proliferator-activated receptor gamma (PPAR-γ) pairs. Fluorescence labeling of exosomes and dynamic tracing showed that exosomes can fuse with the cell membranes of PSCs and transport miR-130a-3p into PSCs. A luciferase reporter gene assay was used to confirm that miR-130a-3p can bind to PPAR-γ to inhibit PPAR-γ expression. In vitro and in vivo functional experiments were performed for gain-of-function studies and loss-of-function studies, respectively. RESULTS: The studies showed that acinar cell-derived exosomal miR-130a-3p promotes PSC activation and collagen formation through targeting of stellate cellular PPAR-γ. Knockdown of miR-130a-3p significantly improved pancreatic fibrosis. Notably, miR-130a-3p knockdown reduced serum levels of hyaluronic acid (HA) and ß-amylase and increased the C-peptide level to protect endocrine and exocrine pancreatic functions and the function of endothelial cells. CONCLUSION: This study revealed that the exosomal miR-130a-3p/PPAR-γ axis participates in PSC activation and the mechanism of chronic pancreatitis (CP) with fibrosis, thus providing a potential new target for the treatment of chronic pancreatic fibrosis.

Association of lnc-IL17RA-11 with increased radiation sensitivity and improved prognosis of HPV-positive HNSCC.

Human papillomavirus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a far better prognosis than HPV negative HNSCC. Recent studies suggest that long noncoding RNA (lncRNA) moieties may play a role in HPV associated differential HNSCC prognoses. In this study, we examined differential expression of lncRNAs in HPV+ vs HPV- HNSCC using The Cancer Genome Atlas database. LncRNAs were categorized based on expression level and survival analysis. A group of eight lncRNAs was identified in which altered expression was associated with both HPV infection and better prognosis. Subsequently, genes coexpressed with these lncRNAs in HNSCC cells were sorted into corresponding co-expression modules. The lnc-IL17RA-11 coexpression module exhibited the greatest correlation with HPV infection and radiotherapy efficacy. We identified the lnc-IL17RA-11 transcription factor ER-alpha as the most likely HPV infection associated factor promoting increased lnc-IL17RA-11 levels. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed enrichment among lnc-IL17RA-11 co-expressed genes for functions related to DNA replication and cell proliferation. These observations are consistent with a model in which HPV infection upregulates transcription factor ER-alpha, which increases levels of lnc-IL17RA-11 and coexpressed genes that promote HNSCC cell sensitivity to radiotherapy, thereby improving disease prognosis.