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Hudi enteric-coated capsule and its active constituent polydatin suppress Th1/Th17-mediated intestinal inflammation
Xiaohan Wu1,2, Lei Shi3, Lei Zhu4
1Xinxiang Key Laboratory of Precision Diagnosis and Treatment for Inflammatory Bowel Disease, Henan Key Laboratory of the Prevention and Treatment of Gastrointestinal Cancer, Department of Gastroenterology, the First Affiliated Hospital of Henan Medical University, Xinxiang 453100, China.
Objective:
To investigate the anti-inflammatory mechanisms of Hudi enteric-coated capsule (HDEC) and its major bioactive constituent, polydatin, in ulcerative colitis (UC).
Methods:
Mouse models of colitis were established by transplantation adoptive transfer of CD45RBhighCD4+ T cells and treated with or without HDEC/polydatin. Therapeutic efficacy was evaluated by assessing disease activity, colon length, and histopathological damage. The differentiation of Th1, Th17, and Treg cells was analyzed using quantitative real-time polymerase chain reaction and flow cytometry. In vitro cultures of mouse and human CD4+ T cells were utilized to assess the immunomodulatory activity. RNA sequencing, Western blotting, and immunofluorescence were used to explore the underlying mechanism. Molecular docking, molecular dynamics, and surface plasmon resonance (SPR) assays were employed to confirm the interaction between polydatin and KEAP1.
Results:
Treatment with HDEC and polydatin significantly ameliorated murine colitis and mucosal damage. Mechanistically, polydatin directly binds to KEAP1 to promote NFE2L2 nuclear translocation. This NFE2L2 activation reduces intracellular oxidative stress, thereby inhibiting pathogenic Th1/Th17 differentiation and enhancing Treg generation. Importantly, these effects were consistently validated in human CD4+ T cells and UC mucosal tissues.
Conclusion:
HDEC and polydatin alleviate UC by targeting the KEAP1-NFE2L2 axis to reduce oxidative stress, thereby restoring the Th1/Th17/Treg balance. This highlights polydatin as a promising KEAP1-targeting agent with strong translational potential.