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Molecular Mechanisms Underlying Intestinal Ischemia/Reperfusion Injury: Bioinformatics Analysis and In Vivo Validation.

ABSTRACT: BACKGROUND Intestinal ischemia/reperfusion (I/R) injury is a serious clinical complication. This study aimed to explore the hub genes and pathways of intestinal I/R injury. MATERIAL AND METHODS GSE96733 from the GEO website was extracted to analyze the differentially expressed genes (DEGs) of intestinal I/R injured and sham-operated mice at 3 h and 6 h after surgery. The DAVID and STRING databases were used to construct functional enrichment analyses of DEGs and the protein-protein interaction (PPI) network. In Cytoscape software, cytoHubba was used to identify hub genes, and MCODE was used for module analysis. Testing by qRT-PCR detected the expression of hub genes in intestinal I/R injury. Western blot analysis detected the key proteins involved with the important pathways of intestinal I/R injury. RESULTS IL-6, IL-10, CXCL1, CXCL2, and IL-1ß were identified as critical upregulated genes, while IRF7, IFIT3, IFIT1, Herc6, and Oasl2 were identified as hub genes among the downregulated genes. The qRT-PCR testing showed the expression of critical upregulated genes was significantly increased in intestinal I/R injury (P<0.05), while the expression of hub downregulated genes was notably reduced (P<0.05). The proteins of CXCL1 and CXCR2 were upregulated following intestinal I/R injury (P<0.05) and the CXCL1/CXCR2 axis was involved with intestinal I/R injury. CONCLUSIONS The results of the present study identified IL-6, IL-10, CXCL1, CXCL2, IL-1ß, IRF7, IFIT3, IFIT1, Herc6, and Oasl2 as hub genes in intestinal I/R injury and identified the involvement of the CXCL1/CXCR2 axis in intestinal I/R injury.

SUBMITTER: Chen F

PROVIDER: S-EPMC7733309 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Molecular Mechanisms Underlying Intestinal Ischemia/Reperfusion Injury: Bioinformatics Analysis and In Vivo Validation.

Chen Fengshou F Wang Dan D Li Xiaoqian X Wang He H

Medical science monitor : international medical journal of experimental and clinical research 20201208

BACKGROUND Intestinal ischemia/reperfusion (I/R) injury is a serious clinical complication. This study aimed to explore the hub genes and pathways of intestinal I/R injury. MATERIAL AND METHODS GSE96733 from the GEO website was extracted to analyze the differentially expressed genes (DEGs) of intestinal I/R injured and sham-operated mice at 3 h and 6 h after surgery. The DAVID and STRING databases were used to construct functional enrichment analyses of DEGs and the protein-protein interaction ( ...[more]

PMID: 33290384

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Project description:BackgroundBK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) causes renal allograft dysfunction and graft loss. However, the mechanism of BKPyV replication after kidney transplantation is unclear. Clinical studies have demonstrated that immunosuppressants and renal ischemia-reperfusion injury (IRI) are risk factors for BKPyV infection. Studying the pathogenic mechanism of BKPyV is limited by the inability of BKPyV to infect the animal. Mouse polyomavirus (MPyV) is a close homolog of BKPyV. We used a model of MPyV infection to investigate the core genes and underlying mechanism of IRI and immunosuppressants to promote polyomavirus replication.Materials and methodsOne-day-old male C57BL/6 mice were intraperitoneally injected with MPyV. At week 9 post-infection, all mice were randomly divided into IRI, immunosuppressant, and control groups and treated accordingly. IRI was established by clamping the left renal pedicle. Subsequently, kidney specimens were collected for detecting MPyV DNA, histopathological observation, and high-throughput RNA sequencing. Weighted gene correlation network analysis (WGCNA), protein-protein interaction network analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to screen for core genes and common signaling pathways involved in promoting MPyV replication by IRI and immunosuppressants.ResultsAfter primary infection, MPyV established persistent infection in kidneys and subsequently was significantly increased by IRI or immunosuppressant treatment individually. In the IRI group, viral loads peaked on day 3 in the left kidney, which were significantly higher than those in the right kidney and the control group. In the immunosuppressant group, viral loads in the left kidney were significantly increased on day 3, which were significantly higher than those in the control group. Protein-protein interaction network analysis and WGCNA screened complement C3, epidermal growth factor receptor (EGFR), and FN1 as core genes. Pathway enrichment analysis based on the IRI- or immunosuppressant-related genes selected by WGCNA indicated that the NF-κB signaling pathway was the main pathway involved in promoting MPyV replication. The core genes were further confirmed using published datasets GSE47199 and GSE75693 in human polyomavirus-associated nephropathy.ConclusionsOur study demonstrated that IRI and immunosuppressants promote polyomavirus replication through common molecular mechanisms. In future studies, knockdown or specific inhibition of C3, EGFR, FN1, and NF-κB signaling pathway will further validate their critical roles in promoting polyomavirus replication.

Project description:Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-?, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting.

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Dataset Information

Molecular Mechanisms Underlying Intestinal Ischemia/Reperfusion Injury: Bioinformatics Analysis and In Vivo Validation.

Publications

Molecular Mechanisms Underlying Intestinal Ischemia/Reperfusion Injury: Bioinformatics Analysis and In Vivo Validation.

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