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Antioxidant Analogue 6-Amino-2,4,5-Trimethylpyridin-3-ol Ameliorates Experimental Colitis in Mice

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Abstract

Background

Oxidative stress has been suggested to be a factor contributing to the disease severity of inflammatory bowel disease (IBD). BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, is reported to significantly inhibit the generation of reactive oxygen species (ROS) in vitro. However, whether this molecule affects intestinal inflammation is largely unknown. We aimed to investigate the effect of BJ-1108 on dextran sulfate sodium (DSS)-induced experimental colitis in mice.

Methods

Colitis was induced in mice with DSS, and disease severity was estimated by evaluating body weight, colon length, histology, immune cell infiltration, and intestinal permeability. We examined the protective effects of BJ-1108 on barrier function using Caco-2 cells. Last, we estimated the impact of BJ-1108 on the phosphorylation of NF-kB, PI3K/AKT, and mitogen-activated protein kinases.

Results

Mice treated with BJ-1108 exhibited improved disease severity, as indicated by evaluations of body weight, histological scores, spleen weight, and infiltrates of T cells and macrophages. The administration of BJ-1108 inhibited the colonic mRNA expression of IL-6 and IL-1β in vivo. Additionally, BJ-1108 limited intestinal permeability and enhanced the expression of tight junction (TJ) proteins such as claudin-1 and claudin-3 in the DSS-induced colitis model. In an in vitro model using Caco-2 cells, BJ-1108 ameliorated cytokine-induced ROS generation in a dose-dependent manner and remarkably recovered barrier dysfunction as estimated by evaluating transepithelial electrical resistance and TJ protein expression. BJ-1108 suppressed the NF-kB/ERK/PI3K pathway.

Conclusions

This study demonstrated that BJ-1108 ameliorated intestinal inflammation in an experimental colitis mouse model, suggesting possible therapeutic implications for IBD.

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Acknowledgments

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2017R1D1A1B03028512) and by a Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI15C0542).

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  1. Hoyul Lee and Joon Seop Lee have contributed equally to this work.

Authors and Affiliations

  1. Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, South Korea

    Hoyul Lee

  2. Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu, South Korea

    Hoyul Lee

  3. Division of Gastroenterology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea

    Joon Seop Lee, Hyun Jung Cho, Eun Soo Kim & Sung Kook Kim

  4. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea

    Yu-Jeong Lee, Eun Soo Kim & Sung Kook Kim

  5. College of Pharmacy, Hanyang University, Ansan, South Korea

    Tae-gyu Nam

  6. College of Pharmacy, Yeungnam University, Gyeongsan, South Korea

    Byeong-Seon Jeong & Jung-Ae Kim

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10620_2020_6267_MOESM1_ESM.jpg

Supplementary Figure 1.Gross image of a spleen (JPEG 553 kb)

10620_2020_6267_MOESM2_ESM.jpg

Supplementary Figure 2. LDH release by Caco-2 cells treated with BJ-1108 (0.1, 0.3, 1, 3, or 10 μM) for 48 hours (JPEG 380 kb)

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Lee, H., Lee, J.S., Cho, H.J. et al. Antioxidant Analogue 6-Amino-2,4,5-Trimethylpyridin-3-ol Ameliorates Experimental Colitis in Mice. Dig Dis Sci 66, 1022–1033 (2021). https://doi.org/10.1007/s10620-020-06267-6

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