The role of hypoxia‐inducible factor 1‐alpha in inflammatory bowel disease

Yin, Jiuheng; Ren, Yanru; Yang, Kunqiu; Wang, Wensheng; Wang, Ting; Xiao, Weidong; Yang, Hua

doi:10.1002/cbin.11712

Cited by 26 publications

(15 citation statements)

References 64 publications

(66 reference statements)

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“…After macrophages were activated, it adapted to the stimulation of inflammatory factors through the transformation of metabolic pathways. The hypoxic environment in our experiment significantly upregulated HIF‐1α expression, which resulted in an increase in the glycolysis pathway 22 …”

Section: Discussionmentioning

confidence: 66%

“…The hypoxic environment in our experiment significantly upregulated HIF-1α expression, which resulted in an increase in the glycolysis pathway. 22 In conclusion, in the C. rodentium-induced colitis mouse model, MPO can not only affect bacterial clearance but also participate in pathological damage to tissues. A hypoxic environment can reduce the innate immune function of mice.…”

Section: Discussionmentioning

confidence: 89%

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Effects of myeloperoxidase on inflammatory responses with hypoxia in Citrobacter rodentium‐infectious mice

Gao,

Zhang,

Zhu

et al. 2024

Immunity Inflam & Disease

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PurposeMyeloperoxidase (MPO) has been identified as a mediator in various inflammatory diseases. Bacterial infection of the intestine and hypoxia can both lead to inflammatory responses, but the role of MPO in these phenomena remains unclear.MethodsBy building the MPO‐/‐ mice, we evaluated relevant inflammatory factors and tissue damage in mice with intestinal Citrobacter rodentium infection and hypoxia. The body weight and excreted microorganisms were monitored. Intestinal tissues were collected 7 days after bacterial infection under hypoxia to undergo haematoxylin‐eosin staining and assess the degree of pathological damage. ELISA assays were performed to quantify the serum levels of TNF‐α, IFN‐γ, IL‐6, and IL‐1β inflammatory cytokines. PCR, WB, and IF assays were conducted to determine the expression of chemokines MCP1, MIP2, and KC in the colon and spleen.ResultsThe C. rodentium infection and hypoxia caused weight loss, intestinal colitis, and splenic inflammatory cells active proliferation in wild‐type mice. MPO deficiency alleviated this phenomenon. MPO‐/‐ mice also displayed a significant decline in bacteria clearing ability. The level of TNF‐α in the serum and spleen was both lower in MPO‐/‐ hypoxia C. rodentium‐infected mice than that in wild‐type mice. The chemokines expression levels of MIP2, KC, and MCP1 in the spleen and colon of each bacterial infected group were significantly increased (p < .05), while in hypoxia, the factors in the spleen and colon were decreased (p < .05). MPO deficiency was found to lower the levels of these chemokines compared with wild‐type mice.ConclusionMPO plays an important role of the inflammatory responses in infectious enteritis and hypoxia in mice, and the loss of MPO may greatly reduce the body's inflammatory responses to fight diseases.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 89%

Effects of myeloperoxidase on inflammatory responses with hypoxia in Citrobacter rodentium‐infectious mice

Gao,

Zhang,

Zhu

et al. 2024

Immunity Inflam & Disease

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“…Hypoxia-induced activation of the HIF signaling pathway is a common feature of inflammatory diseases, including IBD ( 54 ). Hypoxia-inducible factor 1-alpha (HIF-1α) acts as a transcription factor that regulates cellular adaptation to low oxygen levels and supports the development and function of the gut barrier, thereby conferring protection against IBD ( 55 ), while constitutive activation of HIF-2α leads to the development or exacerbation of IBD in colitis models ( 56 ). In DKD, tubular HIF activity is inhibited, and HIF activation protects mitochondrial function and prevents diabetes-induced tissue hypoxia, tubulointerstitial fibrosis, and proteinuria ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Investigate the genetic mechanisms of diabetic kidney disease complicated with inflammatory bowel disease through data mining and bioinformatic analysis

Zhang

Xiao²,

Fu³

et al. 2023

Front. Endocrinol.

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BackgroundPatients with diabetic kidney disease (DKD) often have gastrointestinal dysfunction such as inflammatory bowel disease (IBD). This study aims to investigate the genetic mechanism leading to IBD in DKD patients through data mining and bioinformatics analysis.MethodsThe disease-related genes of DKD and IBD were searched from the five databases of OMIM, GeneCards, PharmGkb, TTD, and DrugBank, and the intersection part of the two diseases were taken to obtain the risk genes of DKD complicated with IBD. A protein–protein interaction (PPI) network analysis was performed on risk genes, and three topological parameters of degree, betweenness, and closeness of nodes in the network were used to identify key risk genes. Finally, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the risk genes to explore the related mechanism of DKD merging IBD.ResultsThis study identified 495 risk genes for DKD complicated with IBD. After constructing a protein–protein interaction network and screening for three times, six key risk genes were obtained, including matrix metalloproteinase 2 (MMP2), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), interleukin (IL)-18, IL-13, and C–C motif chemokine ligand 5 (CCL5). Based on GO enrichment analysis, we found that DKD genes complicated with IBD were associated with 3,646 biological processes such as inflammatory response regulation, 121 cellular components such as cytoplasmic vesicles, and 276 molecular functions such as G-protein-coupled receptor binding. Based on KEGG enrichment analysis, we found that the risk genes of DKD combined with IBD were associated with 181 pathways, such as the PI3K-Akt signaling pathway, advanced glycation end product–receptor for AGE (AGE-RAGE) signaling pathway and hypoxia-inducible factor (HIF)-1 signaling pathway.ConclusionThere is a genetic mechanism for the complication of IBD in patients with CKD. Oxidative stress, chronic inflammatory response, and immune dysfunction were possible mechanisms for DKD complicated with IBD.

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“…T-AOC can reflect the total antioxidant capacity of the body, and its level directly reflects the changes of the antioxidant capacity of the body (39). HIF-1a acts as a transcription factor that can regulates cell adaptation to hypoxia levels and supports intestinal barrier development and function (40). This study showed that the mesalazine group and the artemisinin group could reduce the contents of MDA and HIF-1a in serum to different degrees, increase the contents of T-AOC and SOD, and at the same time improve the pathological damage of colon tissue, while the effect of artemisinin group was better than that of mesalazine group, indicating that artemisinin could increase the anti-inflammatory and antioxidant capacity of UC rats.…”

Section: Discussionmentioning

confidence: 99%

To investigate the effects of artemisinin on inflammatory factors and intestinal microbiota in rats with ulcerative colitis based on network pharmacology

Guo¹,

Li²,

Chen³

et al. 2022

Front. Gastroenterol.

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ObjectiveTo investigate the therapeutic effect and possible mechanism of artemisinin on ulcerative colitis (UC) induced by sodium glucan sulfate (DSS) in rats based on network pharmacology.MethodsFirst, according to the 3D structure of artemisinin, the effective targets of the active compounds were obtained through the Swissstarge website (www.swisstargetprediction.ch/) and the TargetNet website (http://targetnet.scbdd.com/). With the aid of Genecards (https://www.genecards.org/), OMIM (https://omim.org/), TTD (http://db.idrblab.net/ttd/) to obtain effective targets of disease. The disease gene-drug target network was constructed by extracting the intersection targets of the two, and the visualization operation and analysis were performed by using Cytoscape 3.7.2. Gene function enrichment analysis and pathway analysis were performed on the intersection targets with the help of R language software. Autidock Vina was used for molecular docking of artemisinin to key targets. Then, 40 male Wistar rats were randomly divided into normal group, model group, mesalazine group (0.315 g/kg·d) and artemisinin group (0.1 g/kg·d), with 10 rats in each group. Except for the normal group, the rats in the other groups were given 3.5% DSS solution freely for 10 days to replicate the UC model. After the successful modeling, the rats were given intragastric administration. The normal group and the model group were given the same amount of 0.9% normal saline, once a day, for 14 days. The general condition of the rats was recorded every day and the disease activity index (DAI) score was performed. After the administration, the colonic mucosal damage index (CMDI) was scored, the histopathological changes of the colon were observed by HE staining, and the levels or activities of serum CRP, TNF-α, MDA, SOD, HIF-1α and T-AOC were detected by ELISA, and fecal and intestinal microbiota of rats were detected by 16S rDNA sequencing.ResultsNetwork pharmacology shows that, there were 98 key targets of artemisinin screening, 4853 effective targets of UC, and 43 intersection targets for artemisinin and UC, involving 48 signaling pathways. The molecular docking results showed that the binding energies of the key proteins to artemisinin were less than -5.0 kJ·mol-1, and the binding energy of PTGS2 NOS3 to artemisinin was the best. Animal experiments have shown that, Compared with the model group, the DAI and CMDI scores of the artemisinin group and the mesalazine group decreased, the levels and activities of serum CRP, TNF-α, MDA and HIF-1α decreased, the levels and activities of SOD and T-AOC increased, the abundance and diversity of inteatinal microbiota increased, and the abundance of p-Acidobacteria, p-Chloroflexi, p-Gemmatimonadetes, p-Nitrospirae in artemisinin group increased (P＜0.05), and there was no significant change in others.ConclusionArtemisinin intervenes with UC through key target proteins such as PTGS2 and ESR1, and involves various biological processes such as inflammation and intestinal microbiota, revealing that molecular basis of artemisinin in the treatment of UC. Artemisinin is effective in improving the symptoms of UC rats, and its mechanism may be to relieve oxidative stress response by inhibiting inflammation, thus promoting intestinal mucosal repair. The regulatory effect on intestinal microbiota needs to be further studied.

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The role of hypoxia‐inducible factor 1‐alpha in inflammatory bowel disease

Cited by 26 publications

References 64 publications

Effects of myeloperoxidase on inflammatory responses with hypoxia in Citrobacter rodentium‐infectious mice

Effects of myeloperoxidase on inflammatory responses with hypoxia in Citrobacter rodentium‐infectious mice

Investigate the genetic mechanisms of diabetic kidney disease complicated with inflammatory bowel disease through data mining and bioinformatic analysis

To investigate the effects of artemisinin on inflammatory factors and intestinal microbiota in rats with ulcerative colitis based on network pharmacology

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