General Information of the Disease (ID: DIS00117)
Name
Ulcerative colitis
ICD
ICD-11: DD71
Full List of Target(s) of This Ferroptosis-centered Disease
Unspecific Target
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Drug Caryophyllene Phase 2
Responsed Regulator Cannabinoid receptor 2 (CNR2) Suppressor
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model RAW 264.7 cells Leukemia Mus musculus CVCL_0493
In Vivo Model
After 10 days of acclimation, the mice were randomly assigned to five groups (n = 6 each): control, model (3% DSS), BCP (50 mg/kg body weight), AM630 (10 mg/kg body weight) and AM630 + BCP. All mice (except those in the control group) were provided with a solution of filtered water containing 3% (w/v) DSS ad libitum during the experiment period. The mice in the control group received only normal drinking water. For the treatment groups, BCP was dissolved in corn oil at doses of 50 mg/kg and administered orally once a day. The mice in the AM630 group were injected intraperitoneally with AM630 (10 mg/kg). The mice in the AM630 + BCP group received an intraperitoneal injection of AM630 (10 mg/kg) given 30 min before the BCP (50 mg/kg). During the study, symptomatic parameters including body weight, stool character and bleeding were recorded daily. The disease activity index (DAI) was calculated according to our previous study. After 8 days of treatment, all mice were anesthetized with pentobarbital sodium. The blood and colon samples were collected for subsequent analysis. The collected blood was left to coagulate for 20 min at room temperature and centrifuged for 15 min at 3000 g to obtain the serum.

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Response regulation B-Caryophyllene (BCP) activated the type 2 cannabinoid receptor (CB2R) to inhibit macrophage ferroptosis and its induced inflammatory response both in vivo and in vitro. These results revealed that macrophage ferroptosis is a potential therapeutic target for ulcerative colitis and identified a novel mechanism of BCP in ameliorating experimental colitis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [7]
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Regulator Transcription factor p65 (RELA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
NF-kappa B signaling pathway hsa04064
Cell Process Cell ferroptosis
In Vitro Model HCoEpiC (Human normal colonic epithelial cells)
In Vivo Model
All mice involved had a C57BL/6 gene background. All mice with age- and sex-matched between 6 and 8 weeks of age were assigned randomly to groups. To induce experimental colitis, the mice were challenged with 3% dextran sulfate sodium (DSS; MP Biomedicals, LLC, Solon, OH) in drinking water for 7 days. The control mice were allowed to drink water only at the same time. To administer ferrostatin-1 (Fer1) in vivo, we intraperitoneal injected mice daily with Fer1 (Merck, Darmstadt, Germany, 2.5 umol/kg body weight), and the corresponding control mice were injected intraperitoneally with normal saline.

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Response regulation Ferroptosis contributes to ulcerative colitis (UC) via ER stress-mediated IEC cell death, and that NF-B p65 (RELA) phosphorylation suppresses ER stress-mediated IEC ferroptosis to alleviate UC.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [8]
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Regulator Medium-chain acyl-CoA ligase ACSF2, mitochondrial (ACSF2) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model IEC-6 cells Normal Rattus norvegicus CVCL_0343
In Vivo Model
C57BL/6 mice were randomly divided into two groups: control group (n = 7) and DSS group (n = 7). Mice in the DSS group were given 3.0% (w/v) dextran sulfate sodium (DSS, molecular weight, 36-50 kDa; MP Biomedicals, UK) in the drinking water for 7 days. Mice in the control group were fed with normal drinking water throughout the experimental period.

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Response regulation Ferroptosis is closely associated with the development of ulcerative colitis (UC), and the ferroptosis-related gene ACSF2 can be used as a potential biomarker for the diagnosis and treatment of UC.
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Drug Curculigoside Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model IEC-6 cells Normal Rattus norvegicus CVCL_0343
In Vivo Model
Male C57BL/6J mice (8 weeks) were housed in a controlled condition at 25 , 45-55% humidity and 12 h light/dark cycle. All mice were randomly divided into five groups: Vehicle group, mice received dextran sulfate sodium (DSS group), DSS mice received ferrostatin-1 (DSS + Fer-1 group), DSS mice received low dose of CUR (DSS + CUR-L group), and DSS mice received high dose of CUR (DSS + CUR-H group). In the experiments, 3% DSS (D122347, Aladdin, Shanghai, China) in drinking water for 7 days was prepared to induce UC models. Mice in DSS + Fer-1 group were intraperitoneally injected with 5 mg/kg Fer-1 (S7243, Selleck, Shanghai, China) every two days from the day before DSS induction. In addition, mice in DSS + CUR-L or DSS + CUR-H group received intragastric administration with CUR (HY-N0705, Med Chem Express, Shanghai, China) at 50 mg/kg or 100 mg/kg once a day for 7 days during DSS administration.

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Response regulation Curculigoside (CUR) could increase the selenium sensitivity and promote GPX4 transcription level in IEC-6 cells. Knockdown of GPX4 significantly blocked the protective effects of CUR on cell death, GSH and MDA contents as well as LDH activity in ferroptotic IEC-6 cells. Taken together, CUR protects against ferroptosis in ulcerative colitis (UC) by the induction of GPX4, which presents a potential agent for UC treatment.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Regulator Furin (FURIN) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCM460 cells Normal Homo sapiens CVCL_0460
In Vivo Model
Male C57BL/6 mice wild-type (WT), 8 weeks of age, were from Chongqing Medical University, China. Mice were divided into four groups (n = 10-13 per group), control group, MPTP group, h-Trx-1 Tg group, and h-Trx-1 Tg + MPTP group. Control and h-Trx-1 Tg groups were administered saline only. For the Trx-1 knockdown experiment, mice were divided into six groups (n = 10-13 per group), control + saline group, control + MPTP group, AAV9-vehicle + saline group, AAV9-vehicle + MPTP group, AAV9-shRNA-mTrx-1 + saline group, and AAV9-shRNA-mTrx-1 + MPTP.

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Response regulation Furin protects epithelial cells from DSS-induced ferroptosis-like cell injury and alleviates experimental ulcerative colitis by activating the Nrf2-Gpx4 signaling pathway.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Drug Astragalus polysaccharide Investigative
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model Caco-2 cells Colon adenocarcinoma Homo sapiens CVCL_0025
In Vivo Model
Six-eight-week-old male C57BL/6 mice weighing 19.74 ± 0.77 g were purchased from Shanghai Laboratory. To investigate the therapeutic effect of APS on DSS-induced colitis, mice were randomly divided into the following 5 groups (n = 5 each): control, DSS, DSS + APS (100 mg/kg), DSS + APS (200 mg/kg), and DSS + APS (300 mg/kg). The mice in the DSS + APS (100 mg/kg), DSS + APS (200 mg/kg), and DSS + APS (300 mg/kg) groups were intraperitoneally injected with 100, 200, and 300 mg/kg APS once a day, respectively from day 3 to day 10.

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Response regulation The therapeutic effects of Astragalus polysaccharide on DSS-induced Ulcerative colitis by blocking ferroptosis in IECs. Furthermore, our results revealed that APS-mediated inhibition of ferroptosis was associated with the NRF2/HO-1 pathway.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [5]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Intestinal mucositis [ICD-11: DD71]
Responsed Drug Tert-Butylhydroquinone Investigative
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model HIEC-6 cells Normal Homo sapiens CVCL_6C21
In Vivo Model
Male C57/BL6 mice (eight weeks old, 18-20 g) were purchased from Chengdu Dossy Experimental Animals (China). All the mice were housed in plastic cages with free access to food and water at 25 with a 12 h light/dark cycle. The mice were randomly divided into four groups (n = 6 mice/group): the control group, 5-FU group, 5-FU + TBHQ group, and 5-FU + Fer-1 group. 50 mg/kg body weight 5-FU was intraperitoneally (i.p.) injected into the mice of the 5-FU, 5-FU + TBHQ and 5-FU + Fer-1 group per day for five days to induce intestinal mucositis. Starting on the same day, the mice in the 5-FU + TBHQ and 5-FU + Fer-1 group were treated with TBHQ (10 mg/kg body weight; in DMSO, i.p. injection) or Fer-1 (2.5 mol/kg body weight; in DMSO; i.p. injection) once daily for eight days (days 18). Starting on the same day, the mice of the 5-FU group were treated with equivalent volumes of dimethyl sulfoxide (DMSO) for eight days.

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Response regulation Ferroptosis was shown to be involved in 5-FU-induced intestinal mucositis, and Tertiary butylhydroquinone markedly hampered its activation. Mechanistically, TBHQ activated Nrf2 effectively and selective Nrf2 knockdown significantly reduced the anti-ferroptotic functions of TBHQ in 5-FU-treated HIECs.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Regulator Furin (FURIN) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model NCM460 cells Normal Homo sapiens CVCL_0460
In Vivo Model
Male C57BL/6 mice wild-type (WT), 8 weeks of age, were from Chongqing Medical University, China. Mice were divided into four groups (n = 10-13 per group), control group, MPTP group, h-Trx-1 Tg group, and h-Trx-1 Tg + MPTP group. Control and h-Trx-1 Tg groups were administered saline only. For the Trx-1 knockdown experiment, mice were divided into six groups (n = 10-13 per group), control + saline group, control + MPTP group, AAV9-vehicle + saline group, AAV9-vehicle + MPTP group, AAV9-shRNA-mTrx-1 + saline group, and AAV9-shRNA-mTrx-1 + MPTP.

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Response regulation Furin protects epithelial cells from DSS-induced ferroptosis-like cell injury and alleviates experimental ulcerative colitis by activating the Nrf2-Gpx4 signaling pathway.
Natural resistance-associated macrophage protein 2 (SLC11A2)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [6]
Target for Ferroptosis Driver
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Regulator Interferon regulatory factor 7 (IRF7) Driver
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model hCCs (Colon cells)
In Vivo Model
Mice were orally administered 0.1 g/kg Co-Q10 daily for 8 weeks after the DMM model was established to investigate the therapeutic effect of Co-Q10 in GPX4-CKO mice with osteoarthritis. Mice and rats were anaesthetized with pentobarbital. Destabilization of the medial meniscus (DMM) surgery was performed under a microscope. The incision was sutured and disinfected daily until it healed.

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Response regulation IRF7 upregulated SLC11A2 transcription by inhibiting miR-375-3p expression, thereby prompting ferroptosis of colonic ECs and ulcerative colitis progression in DSS-treated mice.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [6]
Target for Ferroptosis Driver
Responsed Disease Ulcerative colitis [ICD-11: DD71]
Responsed Regulator mmu-miR-375-3p (miRNA) Suppressor
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model hCCs (Colon cells)
In Vivo Model
Mice were orally administered 0.1 g/kg Co-Q10 daily for 8 weeks after the DMM model was established to investigate the therapeutic effect of Co-Q10 in GPX4-CKO mice with osteoarthritis. Mice and rats were anaesthetized with pentobarbital. Destabilization of the medial meniscus (DMM) surgery was performed under a microscope. The incision was sutured and disinfected daily until it healed.

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Response regulation IRF7 upregulated SLC11A2 transcription by inhibiting miR-375-3p expression, thereby prompting ferroptosis of colonic ECs and ulcerative colitis progression in DSS-treated mice.
References
Ref 1 -Caryophyllene Acts as a Ferroptosis Inhibitor to Ameliorate Experimental Colitis. Int J Mol Sci. 2022 Dec 16;23(24):16055. doi: 10.3390/ijms232416055.
Ref 2 Curculigoside inhibits ferroptosis in ulcerative colitis through the induction of GPX4. Life Sci. 2020 Oct 15;259:118356. doi: 10.1016/j.lfs.2020.118356. Epub 2020 Aug 28.
Ref 3 Furin inhibits epithelial cell injury and alleviates experimental colitis by activating the Nrf2-Gpx4 signaling pathway. Dig Liver Dis. 2021 Oct;53(10):1276-1285. doi: 10.1016/j.dld.2021.02.011. Epub 2021 Feb 25.
Ref 4 Astragalus polysaccharide prevents ferroptosis in a murine model of experimental colitis and human Caco-2cells via inhibiting NRF2/HO-1 pathway. Eur J Pharmacol. 2021 Nov 15;911:174518. doi: 10.1016/j.ejphar.2021.174518. Epub 2021 Sep 23.
Ref 5 TBHQ attenuates ferroptosis against 5-fluorouracil-induced intestinal epithelial cell injury and intestinal mucositis via activation of Nrf2. Cell Mol Biol Lett. 2021 Nov 18;26(1):48. doi: 10.1186/s11658-021-00294-5.
Ref 6 Promotive role of IRF7 in ferroptosis of colonic epithelial cells in ulcerative colitis by the miR-375-3p/SLC11A2 axis. Biomol Biomed. 2023 May 1;23(3):437-449. doi: 10.17305/bjbms.2022.8081.
Ref 7 Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis. Cell Death Dis. 2020 Feb 3;11(2):86. doi: 10.1038/s41419-020-2299-1.
Ref 8 ACSF2-mediated ferroptosis is involved in ulcerative colitis. Life Sci. 2023 Jan 15;313:121272. doi: 10.1016/j.lfs.2022.121272. Epub 2022 Dec 9.