FG-4592 alleviates radiation-induced intestinal injury by facilitating recovery of intestinal stem cell and reducing damage of intestinal epithelial

Xia, Penglin; Yang, Yong; Liu, Ruling; Feng, Zhenlan; Lin, Yuhan; Tang, Huiqin; Du, Jicong; Cheng, Ying; Cai, Jianming; Hu, Hao; Liu, Cong; Xu, Xiaotian; Hu, Liu

doi:10.1016/j.toxlet.2021.12.011

Cited by 9 publications

(6 citation statements)

References 10 publications

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“…HIEC cells (CRL-3266™, normal human intestinal epithelial cell line) was obtained from American Type Culture Collection and cultured in DMEM with 10% FBS at 37 °C in a 5% CO 2 humidified chamber. After reviewing the literature and CCK-8 pre-experiments, cells were treated with FG-4592 (10 μM) for 12 and 2 h before irradiation [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway

Feng

Xu²,

He³

et al. 2022

Stem Cell Res Ther

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Background Severe ionizing radiation (IR)-induced intestinal injury associates with high mortality, which is a worldwide problem requiring urgent attention. In recent years, studies have found that the PHD-HIF signaling pathway may play key roles in IR-induced intestinal injury, and we found that FG-4592, the PHD inhibitor, has significant radioprotective effects on IR-induced intestinal injury. Methods In the presence or absence of FG-4592 treatment, the survival time, pathology, cell viability, cell apoptosis, and organoids of mice after irradiation were compared, and the mechanism was verified after transcriptome sequencing. The data were analyzed using SPSS ver. 19 software. Results Our results show that FG-4592 had significant radioprotective effects on the intestine. FG-4592 improved the survival of irradiated mice, inhibited the radiation damage of intestinal tissue, promoted the regeneration of intestinal crypts after IR and reduced the apoptosis of intestinal crypt cells. Through organoid experiments, it is found that FG-4592 promoted the proliferation and differentiation of intestinal stem cells (ISCs). Moreover, the results of RNA sequencing and Western blot showed that FG-4592 significantly upregulated the TLR4 signaling pathway, and FG-4592 had no radioprotection on TLR4 KO mice, suggesting that FG-4592 may play protective role against IR by targeting TLR4. Conclusion Our work proves that FG-4592 may promote the proliferation and regeneration of ISCs through the targeted regulation of the TLR4 signaling pathway and ultimately play radioprotective roles in IR-induced injury. These results enrich the molecular mechanism of FG-4592 in protecting cells from IR-induced injury and provide new methods for the radioprotection of intestine.

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Section: Methodsmentioning

confidence: 99%

FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway

Feng

Xu²,

He³

et al. 2022

Stem Cell Res Ther

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“…Vitamin E supplementation, in particular, compared to vitamins A and C, proved to be most effective in ameliorating the activities of intestinal digestive enzymes (Anwar et al, 2013). FG-4592, a novel up-regulator of hypoxia Inducible factor, could remit radiation enteritis by promoting regeneration and differentiation of intestinal stem cells (Xia et al, 2022). The CBP and p300 protein family consists of cyclic-AMP response element-binding protein-binding protein (CBP) and E1Abinding protein (P300).…”

Section: Drug Therapy Of Radiation Enteritismentioning

confidence: 99%

Pathogenesis and therapy of radiation enteritis with gut microbiota

et al. 2023

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Radiotherapy is widely used in clinic due to its good effect for cancer treatment. But radiotherapy of malignant tumors in the abdomen and pelvis is easy to cause radiation enteritis complications. Gastrointestinal tract contains numerous microbes, most of which are mutualistic relationship with the host. Abdominal radiation results in gut microbiota dysbiosis. Microbial therapy can directly target gut microbiota to reverse microbiota dysbiosis, hence relieving intestinal inflammation. In this review, we mainly summarized pathogenesis and novel therapy of the radiation-induced intestinal injury with gut microbiota dysbiosis and envision the opportunities and challenges of radiation enteritis therapy.

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“…Proliferation suppression by prolyl hydroxylase inhibitor FG-4592 on the small intestinal organoids was inhibited by the HIF-2α inhibitor PT2385. Further investigation of the activation of Wnt/β-catenin pathway also verified that PT2385 could significantly block the up-regulation of Wnt3a and Axin that were induced by FG-4592 [ 81 ]. These effects may be due to HIF-2α driven WNT5a expression [ 58 ].…”

Section: Hif-2α In Different Cell Typesmentioning

confidence: 99%

The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review

Steinberger

Eubank

2023

Oxygen

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Low tissue oxygenation, termed hypoxia, is a characteristic of solid tumors with negative consequences. Tumor-associated macrophages (TAMs) accumulate in hypoxic tumor regions and correlate with worse outcomes in cancer patients across several tumor types. Thus, the molecular mechanism in which macrophages respond to low oxygen tension has been increasingly investigated in the last decade. Hypoxia stabilizes a group of hypoxia-inducible transcription factors (HIFs) reported to drive transcriptional programs involved in cell survival, metabolism, and angiogenesis. Though both tumor macrophage HIF-1α and HIF-2α correlate with unfavorable tumor microenvironments, most research focuses on HIF-1α as the master regulator of hypoxia signaling, because HIF-1α expression was originally identified in several cancer types and correlates with worse outcome in cancer patients. The relative contribution of each HIFα subunit to cell phenotypes is poorly understood especially in TAMs. Once thought to have overlapping roles, recent investigation of macrophage HIF-2α has demonstrated a diverse function from HIF-1α. Little work has been published on the differential role of hypoxia-dependent macrophage HIF-2α when compared to HIF-1α in the context of tumor biology. This review highlights cellular HIF-2α functions and emphasizes the gap in research investigating oxygen-dependent functions of tumor macrophage HIF-2α.

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FG-4592 alleviates radiation-induced intestinal injury by facilitating recovery of intestinal stem cell and reducing damage of intestinal epithelial

Cited by 9 publications

References 10 publications

FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway

FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway

Pathogenesis and therapy of radiation enteritis with gut microbiota

The Underexplored Landscape of Hypoxia-Inducible Factor 2 Alpha and Potential Roles in Tumor Macrophages: A Review

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