Oxyberberine Alleviates Lipopolysaccharide-induced Intestinal Barrier Disruption and Inflammation in Human Colonic Caco-2 Cells

Overview

Journal Front Pharmacol

Date 2025 Jan 22

PMID 39840109

Authors

Cailan Li

Jiahao Wang

Hongmei Yang

Shuang Luo

Qiang Lu

Affiliations

Soon will be listed here.

Abstract

Background: Oxyberberine (OBB) is a naturally occurring isoquinoline alkaloid that is believed to possess various health-promoting properties, including anti-fungus, hepatoprotection, anti-inflammation, and anti-intestinal mucositis effects. Despite several studies reporting the health benefits of OBB in treating ulcerative colitis (UC), its specific mechanism of action has yet to be fully elucidated.

Purpose: This investigation is designed to explore the potential protective efficacy of OBB and the latent mechanism using an model of UC-like inflammatory intestinal cells.

Methods: Caco-2 cells were pretreated with OBB and subsequently exposed to lipopolysaccharide (LPS). The transepithelial electrical resistance (TEER), paracellular permeability, and the distribution and expression of tight- and adherent junction proteins were determined to assess barrier integrity. The levels of proinflammatory cytokines, reactive oxygen species (ROS), Nrf2, and NF-κB signaling cascade were analyzed via ELISA, qRT-PCR, immunofluorescence, or Western blotting.

Results: OBB was found to mitigate the effects of LPS on Caco-2 cell monolayers, as evidenced by the improvement in TEER and the decrease in FITC-dextran flux. Moreover, OBB ameliorated the LPS-induced decrease in the distribution and expression of several tight junction markers, including ZO-1, occludin, and E-cadherin. In addition, OBB treatment effectively inhibited LPS-induced increases in ROS, apoptosis, and Keap1 and decreases in Nrf2 and HO-1. LPS-induced elevations in nuclear NF-κB p65 and p-IκBα were suppressed by OBB. In addition, ML385, an antagonist of Nrf2, abolished the protective role of OBB.

Conclusion: OBB has a pronounced beneficial effect on LPS-induced damage to enteral barrier function, and the regulation of the Nrf2/NF-κB pathway is an important mechanism responsible for the protection afforded by OBB.

References

Qian X, Zhang L, Tao Y, Huang P, Li J, Chai C . Simultaneous determination of ten alkaloids of crude and wine-processed Rhizoma Coptidis aqueous extracts in rat plasma by UHPLC-ESI-MS/MS and its application to a comparative pharmacokinetic study. J Pharm Biomed Anal. 2014; 105:64-73. DOI: 10.1016/j.jpba.2014.11.049. View

Tian Y, Zhang D . Biological Clock and Inflammatory Bowel Disease Review: From the Standpoint of the Intestinal Barrier. Gastroenterol Res Pract. 2022; 2022:2939921. PMC: 8938076. DOI: 10.1155/2022/2939921. View

Singh S, Verma M, Malhotra M, Prakash S, Singh T . Cytotoxicity of alkaloids isolated from Argemone mexicana on SW480 human colon cancer cell line. Pharm Biol. 2015; 54(4):740-5. DOI: 10.3109/13880209.2015.1073334. View

Cichewicz A, Tencer T, Gupte-Singh K, Egodage S, Burnett H, Kumar J . A Systematic Review of the Economic and Health-Related Quality of Life Impact of Advanced Therapies Used to Treat Moderate-to-Severe Ulcerative Colitis. Adv Ther. 2023; 40(5):2116-2146. PMC: 10130125. DOI: 10.1007/s12325-023-02488-z. View

Feng R, Shou J, Zhao Z, He C, Ma C, Huang M . Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep. 2015; 5:12155. PMC: 4502414. DOI: 10.1038/srep12155. View

Han H, You Y, Cha S, Kim T, Sohn M, Park J . Multi-Species Probiotic Strain Mixture Enhances Intestinal Barrier Function by Regulating Inflammation and Tight Junctions in Lipopolysaccharides Stimulated Caco-2 Cells. Microorganisms. 2023; 11(3). PMC: 10056128. DOI: 10.3390/microorganisms11030656. View

Li C, Tan L, Wang Y, Luo C, Chen H, Lu Q . Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo. Phytomedicine. 2019; 52:272-283. DOI: 10.1016/j.phymed.2018.09.228. View

Tsujii Y, Nishida T, Osugi N, Fujii Y, Sugimoto A, Nakamatsu D . Classification and clinical features of adverse drug reactions in patients with ulcerative colitis treated with 5-aminosalicylate acid: a single-center, observational study. Scand J Gastroenterol. 2021; 57(2):190-196. DOI: 10.1080/00365521.2021.1998601. View

Lu Q, Xie Y, Luo J, Gong Q, Li C . Natural flavones from edible and medicinal plants exhibit enormous potential to treat ulcerative colitis. Front Pharmacol. 2023; 14:1168990. PMC: 10268007. DOI: 10.3389/fphar.2023.1168990. View

10.

Cao M, Wang P, Sun C, He W, Wang F . Amelioration of IFN-γ and TNF-α-induced intestinal epithelial barrier dysfunction by berberine via suppression of MLCK-MLC phosphorylation signaling pathway. PLoS One. 2013; 8(5):e61944. PMC: 3643960. DOI: 10.1371/journal.pone.0061944. View

11.

Huang R, Ai G, Zhong L, Mai L, Chen J, Liu Y . Protective Effects of Oxyberberine in 5-Fluorouracil-Induced Intestinal Mucositis in the Mice Model. Evid Based Complement Alternat Med. 2022; 2022:1238358. PMC: 9170416. DOI: 10.1155/2022/1238358. View

12.

Li C, Ai G, Wang Y, Lu Q, Luo C, Tan L . Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway. Pharmacol Res. 2019; 152:104603. DOI: 10.1016/j.phrs.2019.104603. View

13.

Kumar P, Nagarajan A, Uchil P . Analysis of Cell Viability by the Lactate Dehydrogenase Assay. Cold Spring Harb Protoc. 2018; 2018(6). DOI: 10.1101/pdb.prot095497. View

14.

Peng J, Li H, Ayodele Olaolu O, Ibrahim S, Ibrahim S, Wang S . Natural Products: A Dependable Source of Therapeutic Alternatives for Inflammatory Bowel Disease through Regulation of Tight Junctions. Molecules. 2023; 28(17). PMC: 10488775. DOI: 10.3390/molecules28176293. View

15.

Ning H, Liu J, Tan J, Yi M, Lin X . The role of the Notch signalling pathway in the pathogenesis of ulcerative colitis: from the perspective of intestinal mucosal barrier. Front Med (Lausanne). 2024; 10:1333531. PMC: 10796567. DOI: 10.3389/fmed.2023.1333531. View

16.

Zheng J, Ahmad A, Yang Y, Liang Z, Shen W, Feng M . CY12 Enhances Intestinal Barrier Function by Regulating Tight Junction Protein Expression, Oxidative Stress, and Inflammation Response in Lipopolysaccharide-Induced Caco-2 Cells. Int J Mol Sci. 2022; 23(19). PMC: 9569798. DOI: 10.3390/ijms231911162. View

17.

Kim Y, Kim D, Kim J . Ginger Extract Suppresses Inflammatory Response and Maintains Barrier Function in Human Colonic Epithelial Caco-2 Cells Exposed to Inflammatory Mediators. J Food Sci. 2017; 82(5):1264-1270. DOI: 10.1111/1750-3841.13695. View

18.

Saxami G, Kerezoudi E, Mitsou E, Koutrotsios G, Zervakis G, Pletsa V . Fermentation Supernatants of Mushroom Ameliorate Intestinal Epithelial Barrier Dysfunction in Lipopolysaccharide-Induced Caco-2 Cells via Upregulation of Tight Junctions. Microorganisms. 2021; 9(10). PMC: 8539016. DOI: 10.3390/microorganisms9102071. View

19.

Khoshandam A, Imenshahidi M, Hosseinzadeh H . Pharmacokinetic of berberine, the main constituent of Berberis vulgaris L.: A comprehensive review. Phytother Res. 2022; 36(11):4063-4079. DOI: 10.1002/ptr.7589. View

20.

Wei S, Sollano J, Hui Y, Yu W, Santos Estrella P, Llamado L . Epidemiology, burden of disease, and unmet needs in the treatment of ulcerative colitis in Asia. Expert Rev Gastroenterol Hepatol. 2020; 15(3):275-289. DOI: 10.1080/17474124.2021.1840976. View