Curculigoside mitigates dextran sulfate sodium‑induced colitis by activation of KEAP1‑NRF2 interaction to inhibit oxidative damage and autophagy of intestinal epithelium barrier

Li,Fang; Huang,Hua; Zhao,Ping; Jiang,Jie; Ding,Xufeng; Lu,Donxgue; Ji,Lijiang

doi:10.3892/ijmm.2023.5310

Curculigoside mitigates dextran sulfate sodium‑induced colitis by activation of KEAP1‑NRF2 interaction to inhibit oxidative damage and autophagy of intestinal epithelium barrier

Authors:
- Fang Li
- Hua Huang
- Ping Zhao
- Jie Jiang
- Xufeng Ding
- Donxgue Lu
- Lijiang Ji
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Affiliations: Department of Digestive System, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Suzhou 215500, P.R. China, Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, Suzhou 215500, P.R. China, Department of Clinical Nutrition, Academy of Health and Rehabilitation, Academy of Acupuncture and Tuina, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
Published online on: September 28, 2023 https://doi.org/10.3892/ijmm.2023.5310
Article Number: 107
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Curculigoside (CUR), a primary active ingredient of Curculigo orchioides Gaertn, serves an important role in the intervention of numerous diseases, including ulcerative colitis, rheumatoid arthritis, myocardial ischemia, etc. However its specific mechanisms of therapy have not been fully elucidated. The aim of the present study was to elucidate the mechanisms underlying the anti‑oxidative stress and anti‑ulcerative colitis (UC) effects of CUR. Mouse model of dextran sulfate sodium (DSS)‑induced colitis, along with Caco2 and mouse intestine organoid in vitro models were used. The effect of CUR on mitigating the symptoms of chronic colitis was investigated. Through ELISA experiments, it was observed that CUR alleviated the inflammation status in mice with chronic colitis. This was evidenced by the downregulation of inflammatory cytokines such as TNF‑α and IL‑6 and ‑1β and decreased neutrophil infiltration along with downregulated myeloperoxidase activity. CUR helped in maintaining the barrier functions of intestinal epithelium. In vitro TNF‑α stimulation of organoids and H2O2 stimulation of Caco2 cells demonstrated the capabilities of CUR to rescue cells from oxidative stress. There was activation of Nrf2 both in vivo and in vitro, accompanied by enhanced autophagy. Mechanistic studies of cells and Nrf2 knockout mice demonstrated that Nrf2 served a pivotal role in inhibition of UC by curculigoside via interaction with Kelch‑like ECH‑associated protein 1 (Keap1). In vitro and in vivo experiments confirmed that CUR activated Nrf2 via Keap1/Nrf2 interaction, resulting in decreased oxidative stress and promoted autophagy. These findings demonstrated that CUR could effectively mitigate colitis and may have clinical application in UC therapy.

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1	Thorsteinsdottir S, Gudjonsson T, Nielsen OH, Vainer B and Seidelin JB: Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis. Nat Rev Gastroenterol Hepatol. 8:395–404. 2011. View Article : Google Scholar : PubMed/NCBI
2	Le Berre C, Honap S and Peyrin-Biroulet L: Ulcerative colitis. Lancet. 402:571–584. 2023. View Article : Google Scholar : PubMed/NCBI
3	Aarestrup J, Jess T, Kobylecki CJ, Nordestgaard BG and Allin KH: Cardiovascular risk profile among patients with inflammatory bowel disease: A population-based study of more than 100 000 individuals. J Crohns Colitis. 13:319–323. 2019. View Article : Google Scholar
4	Larabi A, Barnich N and Nguyen HTT: New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy. 16:38–51. 2020. View Article : Google Scholar :
5	Nikolaus S and Schreiber S: Diagnostics of inflammatory bowel disease. Gastroenterology. 133:1670–1689. 2007. View Article : Google Scholar : PubMed/NCBI
6	Zhao J, Gao W, Cai X, Xu J, Zou D, Li Z, Hu B and Zheng Y: Nanozyme-mediated catalytic nanotherapy for inflammatory bowel disease. Theranostics. 9:2843–2855. 2019. View Article : Google Scholar : PubMed/NCBI
7	Huang S, Fu Y, Xu B, Liu C, Wang Q, Luo S, Nong F, Wang X, Huang S, Chen J, et al: Wogonoside alleviates colitis by improving intestinal epithelial barrier function via the MLCK/pMLC2 pathway. Phytomedicine. 68:1531792020. View Article : Google Scholar : PubMed/NCBI
8	Zhong Y, Liu W, Xiong Y, Li Y, Wan Q, Zhou W, Zhao H, Xiao Q and Liu D: Astragaloside IV alleviates ulcerative colitis by regulating the balance of Th17/Treg cells. Phytomedicine. 104:1542872022. View Article : Google Scholar
9	Wang S, Liu W, Wang J and Bai X: Curculigoside inhibits ferroptosis in ulcerative colitis through the induction of GPX4. Life sci. 259:1183562020. View Article : Google Scholar : PubMed/NCBI
10	Elmaksoud HAA, Motawea MH, Desoky AA, Elharrif MG and Ibrahimi A: Hydroxytyrosol alleviate intestinal inflammation, oxidative stress and apoptosis resulted in ulcerative colitis. Biomed Pharmacother. 142:1120732021. View Article : Google Scholar : PubMed/NCBI
11	Roessner A, Kuester D, Malfertheiner P and Schneider-Stock R: Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract. 204:511–524. 2008. View Article : Google Scholar : PubMed/NCBI
12	Colombo BB, Fattori V, Guazelli CFS, Zaninelli TH, Carvalho TT, Ferraz CR, Bussmann AJC, Ruiz-Miyazawa KW, Baracat MM, Casagrande R and Verri WA Jr: Vinpocetine ameliorates acetic acid-induced colitis by inhibiting NF-κB activation in mice. Inflammation. 41:1276–1289. 2018. View Article : Google Scholar : PubMed/NCBI
13	Torrente L and DeNicola GM: Targeting NRF2 and its downstream processes: Opportunities and challenges. Annu Rev Pharmacol Toxicol. 62:279–300. 2022. View Article : Google Scholar
14	Liu S, Pi J and Zhang Q: Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway. Redox Biol. 54:1023892022. View Article : Google Scholar : PubMed/NCBI
15	Bauer C, Duewell P, Mayer C, Lehr HA, Fitzgerald KA, Dauer M, Tschopp J, Endres S, Latz E and Schnurr M: Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut. 59:1192–1199. 2010. View Article : Google Scholar : PubMed/NCBI
16	Cai X, Hua S, Deng J, Du Z, Zhang D, Liu Z, Khan NU, Zhou M and Chen Z: Astaxanthin activated the Nrf2/HO-1 pathway to enhance autophagy and inhibit ferroptosis, ameliorating acetaminophen-induced liver injury. ACS Appl Mater Interfaces. 14:42887–42903. 2022. View Article : Google Scholar : PubMed/NCBI
17	Gao K, Shi Q, Liu Y and Wang C: Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven prostate cancer. Autophagy. 18:2013–2015. 2022. View Article : Google Scholar : PubMed/NCBI
18	Debnath J, Gammoh N and Ryan KM: Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Bio. 24:560–575. 2023. View Article : Google Scholar
19	Kumariya S, Ubba V, Jha RK and Gayen JR: Autophagy in ovary and polycystic ovary syndrome: Role, dispute and future perspective. Autophagy. 17:2706–2733. 2021. View Article : Google Scholar : PubMed/NCBI
20	Gao Z, Yi W, Tang J, Sun Y, Huang J, Lan T, Dai X, Xu S, Jin ZG and Wu X: Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2. Int J Biol Sci. 18:2146–2162. 2022. View Article : Google Scholar : PubMed/NCBI
21	Negrette-Guzmán M, Huerta-Yepez S, Tapia E and Pedraza-Chaverri J: Modulation of mitochondrial functions by the indirect antioxidant sulforaphane: A seemingly contradictory dual role and an integrative hypothesis. Free Radical Bio Med. 65:1078–1089. 2013. View Article : Google Scholar
22	Piotrowska M, Swierczynski M, Fichna J and Piechota-Polanczyk A: The Nrf2 in the pathophysiology of the intestine: Molecular mechanisms and therapeutic implications for inflammatory bowel diseases. Pharmacol Res. 163:1052432021. View Article : Google Scholar
23	Wirtz S, Neufert C, Weigmann B and Neurath MF: Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2:541–546. 2007. View Article : Google Scholar : PubMed/NCBI
24	Corpetti C, Del Re A, Seguella L, Palenca I, Rurgo S, De Conno B, Pesce M, Sarnelli G and Esposito G: Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/Caspase-1 signaling suppression in Caco-2 cell line. Phytother Res. 35:6893–6903. 2021. View Article : Google Scholar : PubMed/NCBI
25	Geng H, Bu HF, Liu F, Wu L, Pfeifer K, Chou PM, Wang X, Sun J, Lu L, Pandey A, et al: In inflamed intestinal tissues and epithelial cells, interleukin 22 signaling increases expression of H19 long noncoding RNA, which promotes mucosal regeneration. Gastroenterology. 155:144–155. 2018. View Article : Google Scholar : PubMed/NCBI
26	Podolsky DK: Inflammatory bowel disease. New Engl J Med. 347:417–429. 2002. View Article : Google Scholar : PubMed/NCBI
27	Wu Y, Jha R, Li A, Liu H, Zhang Z, Zhang C, Zhai Q and Zhang J: Probiotics (Lactobacillus plantarum HNU082) supplementation relieves ulcerative colitis by affecting intestinal barrier functions, immunity-related gene expression, gut microbiota, and metabolic pathways in mice. Microbiol Spectr. 10:e1651222022. View Article : Google Scholar
28	Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha JDB, Girardin SE and Philpott DJ: How autophagy controls the intestinal epithelial barrier. Autophagy. 18:86–103. 2022. View Article : Google Scholar :
29	Michielan A and D'Incà R: Intestinal permeability in inflammatory bowel disease: Pathogenesis, clinical evaluation, and therapy of leaky gut. Mediat Inflamm. 2015:6281572015. View Article : Google Scholar
30	Perico L, Morigi M, Rota C, Breno M, Mele C, Noris M, Introna M, Capelli C, Longaretti L, Rottoli D, et al: Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun. 8:9832017. View Article : Google Scholar : PubMed/NCBI
31	Tang Z, Hu B, Zang F, Wang J, Zhang X and Chen H: Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration. Cell Death Dis. 10:5102019. View Article : Google Scholar : PubMed/NCBI
32	Ghafouri-Fard S, Eghtedarian R and Taheri M: The crucial role of non-coding RNAs in the pathophysiology of inflammatory bowel disease. Biomed Pharmacother. 129:1105072020. View Article : Google Scholar : PubMed/NCBI
33	Le Berre C, Roda G, Nedeljkovic PM, Danese S and Peyrin-Biroulet L: Modern use of 5-aminosalicylic acid compounds for ulcerative colitis. Expert Opin Biol Ther. 20:363–378. 2020. View Article : Google Scholar
34	Guo H, Zheng L, Guo Y, Han L, Yu J and Lai F: Curculigoside represses the proliferation and metastasis of osteosarcoma via the JAK/STAT and NF-κB signaling pathways. Biol Pharm Bull. 45:1466–1475. 2022. View Article : Google Scholar
35	Han J, Wan M, Ma Z, Hu C and Yi H: Prediction of targets of curculigoside A in osteoporosis and rheumatoid arthritis using network pharmacology and experimental verification. Drug Des Devel Ther. 14:5235–5250. 2020. View Article : Google Scholar : PubMed/NCBI
36	Shen Q, Zeng D, Zhou Y, Xia L, Zhao Y, Qiao G, Xu L, Liu Y, Zhu Z and Jiang X: Curculigoside promotes osteogenic differentiation of bone marrow stromal cells from ovariectomized rats. J Pharm Pharmacol. 65:1005–1013. 2013. View Article : Google Scholar : PubMed/NCBI
37	Yamamoto M, Kensler TW and Motohashi H: The KEAP1-NRF2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev. 98:1169–1203. 2018. View Article : Google Scholar : PubMed/NCBI
38	Huang CY, Deng JS, Huang WC, Jiang WP and Huang GJ: Attenuation of lipopolysaccharide-induced acute lung injury by hispolon in mice, through regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 pathways, and suppressing oxidative stress-mediated ER stress-induced apoptosis and autophagy. Nutrients. 12:17422020. View Article : Google Scholar : PubMed/NCBI
39	Wu C, Chen RL, Wang Y, Wu WY and Li G: Acacetin alleviates myocardial ischaemia/reperfusion injury by inhibiting oxidative stress and apoptosis via the Nrf-2/HO-1 pathway. Pharm Biol. 60:553–561. 2022. View Article : Google Scholar : PubMed/NCBI
40	Xue R, Wan Y, Sun X, Zhang X, Gao W and Wu W: Nicotinic mitigation of neuroinflammation and oxidative stress after chronic sleep deprivation. Front Immunol. 10:25462019. View Article : Google Scholar : PubMed/NCBI
41	Zou L, Liang B, Gao Y, Ye T, Li M, Zhang Y, Lu Q, Hu X, Li H, Yuan Y and Xing D: Nicotinic acid riboside regulates Nrf-2/P62-related oxidative stress and autophagy to attenuate doxorubicin-induced cardiomyocyte injury. Biomed Res Int. 2022:62933292022. View Article : Google Scholar : PubMed/NCBI
42	Nair N and Gongora E: Oxidative stress and cardiovascular aging: Interaction between NRF-2 and ADMA. Curr Cardiol Rev. 13:183–188. 2017. View Article : Google Scholar : PubMed/NCBI
43	Nazmeen A, Chen G and Maiti S: Dependence between estrogen sulfotransferase (SULT1E1) and nuclear transcription factor Nrf-2 regulations via oxidative stress in breast cancer. Mol Biol Rep. 47:4691–4698. 2020. View Article : Google Scholar : PubMed/NCBI
44	Xu J, Chu T, Yu T, Li N, Wang C, Li C, Zhang Y, Meng H and Nie G: Design of diselenide-bridged hyaluronic acid nano-antioxidant for efficient ROS scavenging to relieve colitis. Acs Nano. 16:13037–13048. 2022. View Article : Google Scholar : PubMed/NCBI
45	Moniruzzaman M, Ghosal I, Das D and Chakraborty SB: Melatonin ameliorates H₂O₂-induced oxidative stress through modulation of Erk/Akt/NFkB pathway. Biol Res. 51:172018. View Article : Google Scholar
46	Giustarini D, Dalle-Donne I, Milzani A, Fanti P and Rossi R: Analysis of GSH and GSSG after derivatization with N-ethylmaleimide. Nat Protoc. 8:1660–1669. 2013. View Article : Google Scholar : PubMed/NCBI
47	Tan SC, Rajendran R, Bhattamisra SK, Krishnappa P, Davamani F, Chitra E, Ambu S, Furman B and Candasamy M: Effect of madecassoside in reducing oxidative stress and blood glucose in streptozotocin-nicotinamide-induced diabetes in rats. J Pharm Pharmacol. 75:1034–1045. 2023. View Article : Google Scholar : PubMed/NCBI