Barrier integrity and chronic inflammation mediated by HIF-1 impact on intestinal tumorigenesis

Robrahn, Laura; Jiao, Long R.; Cramer, Thorsten

doi:10.1016/j.canlet.2020.07.002

Cited by 23 publications

(8 citation statements)

References 94 publications

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“…HIF is instrumental in inducing cellular adaptive responses under hypoxia ( Robrahn et al, 2020 ). HIF comprises an α subunit (divided into HIF-1α, HIF-2α, and HIF-3α) and a β subunit (HIF-1β).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor-Dependent Protective Effect of Moderate Hypoxia in a Mouse Colitis Model

Wang

Yang

et al. 2022

Front. Physiol.

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Although hypoxia is important for maintaining the intestinal barrier, its effect on the barrier during acute colitis and the underlying mechanisms are not fully understood. To explore the influence of hypoxia in dextran sulfate sodium (DSS)-induced colitis mice and the role of hypoxia-inducible factor (HIF) and vitamin D receptor (VDR) in the process. Colitis mice were subjected to hypoxia to detect intestinal barrier function changes. And the mechanisms were explored in vitro. First, compared with colitis mice without hypoxia stimulation, those with hypoxia stimulation showed significantly decreased pathological damage and improved permeability of the intestinal barrier. The expression of tight junction proteins (occludin, ZO-1), HIF-1α as well as VDR was up-regulated in colitis mice with hypoxia stimulation. However, in VDR gene knockout (KO)colitis mice, hypoxia treatment showed no protective effect, suggesting the VDR dependency of this effect. Similarly although hypoxia stimulation could enhance the single-layer epithelial transmembrane electrical resistance in DLD-1 and NCM460 cells, these effects disappeared in VDR-knockdown cells. Furthermore, over-expression of HIF-1α in DLD-1 and NCM460 increased the expression of VDR, whereas HIF-1α-knockdown reduced the VDR expression directly. Chromatin immunoprecipitation and luciferase assays confirmed that HIF-1α can bind to the promoter region of the VDR gene under hypoxia. Finally, compared with their wild-type siblings, VDR-KO mice showed reduced abundance of anaerobic bacteria and SCFA-producing bacteria. Hypoxia was protective against DSS-induced colitis, and VDR is instrumental in it. Furthermore, HIF-1α-VDR mediates the effect of hypoxia on the barrier function. Moreover, intestinal flora may be an important link between hypoxia and VDR.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Receptor-Dependent Protective Effect of Moderate Hypoxia in a Mouse Colitis Model

Wang

Yang

et al. 2022

Front. Physiol.

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“…Hypoxia is closely related to the hypoxia- Evidence-Based Complementary and Alternative Medicine inducible factor 1 (HIF-1) signaling pathway [37]. HIF-1 plays an essential role in executing an optimal inflammatory response by immune cells [38].…”

Section: Discussionmentioning

confidence: 99%

“…e keywords "hyperuricemia" and "gout" were entered into the TTD, Drugbank, Dis-GeNET, Genecards, OMIM, and PharmGkb databases to obtain gout-related targets. e numbers of disease-related targets were 20, 66, 258, 2319, 13, and 4, respectively, and after deduplication were 20,38,234,1971,13, and 4, respectively. A total of 2081 targets were obtained.…”

Section: Disease Targets Of Goutmentioning

confidence: 99%

Treatment of Gout with TCM Using Turmeric and Corn Silk: A Concise Review Article and Pharmacology Network Analysis

Zhang

Jiang

Zhao

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. This work aimed to study the compounds, targets, and pathways of turmeric and corn silk for gout and to explore the mechanism of “the same disease with different treatments” based on network pharmacology and molecular docking. Methods. We used the TCMSP, PubChem, and SEA databases to screen the compounds and targets of turmeric and corn silk, gout-related proteins through TTD, Drugbank, DisGeNET, GeneCards, OMIM, and PharmGkb, and used Cytoscape to construct a “compound-target-disease” network. Then, we constructed a protein-protein interaction network (PPI) and used Metascape to perform GO and KEGG analysis. Finally, molecular docking (SYBYL) was used to verify the degree of binding between key targets and compounds. Results. We found bisacumol, campesterol, and stigmasterol to be the main turmeric compounds that exerted a marked effect on gout treatment by targeting protein processing in the endoplasmic reticulum through the HSPA1B, HSP90AB1, and STUB1 proteins. The main corn silk compound, Mandenol, treated gout by targeting the Hippo signaling pathway through the CTNNB1, YWHAG, and YWHAZ proteins. Conclusion. Turmeric and corn silk can treat the same disease, gout, through different pathways and targets. The scientific connotation of “same disease with different treatments” can be preliminarily clarified by analyzing targets and pathways.

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“…especially IBD and DSS-induced colitisand thereby to play a critical role in intestinal tumorigenesis 18,64 . important to note that our study did not address the effects of (pharmacological) stabilization of HIF-α.…”

Section: Different Research Groups Have Reported Hif-1 To Impact Entementioning

confidence: 99%

Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection withSalmonellaTyphimurium

Robrahn

Dupont

Jumpertz

et al. 2021

Preprint

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The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to ameliorate different bacterial infections through enhancement of microbial killing. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the intestine remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of the HIF-1 transcription factor after oral infection of mice with Salmonella Typhimurium. This prompted us to apply lineage-restricted deletion of the Hif1a locus in mice to examine cell type-specific functions of HIF-1 in this model. We show hypoxia-independent induction of HIF-1 activity upon Salmonella infection in the intestinal epithelium as well as in macrophages. Surprisingly, Hif1a deletion in intestinal epithelial cells impacted neither disease outcome nor inflammatory activity. The conditional knockout of Hif1a in myeloid cells enhanced the mRNA expression of the largely pro-inflammatory chemokine Cxcl2, revealing a potentially inflammatory effect of HIF-1 deficiency in myeloid cells in the gut in vivo. Again, the disease outcome was not affected. In vitro HIF-1-deficient macrophages showed an overall impaired transcription of pro-inflammatory factors, however, Salmonella bypassed direct intracellular, bactericidal HIF-1-dependent mechanisms in a Salmonella pathogenicity island (SPI)-2 independent manner. Taken together, our data suggest that HIF-1 in intestinal epithelial and myeloid cells is either dispensable or compensable in the immune defense against Salmonella Typhimurium.

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Barrier integrity and chronic inflammation mediated by HIF-1 impact on intestinal tumorigenesis

Cited by 23 publications

References 94 publications

Vitamin D Receptor-Dependent Protective Effect of Moderate Hypoxia in a Mouse Colitis Model

Vitamin D Receptor-Dependent Protective Effect of Moderate Hypoxia in a Mouse Colitis Model

Treatment of Gout with TCM Using Turmeric and Corn Silk: A Concise Review Article and Pharmacology Network Analysis

Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection withSalmonellaTyphimurium

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