2. Academic Validation
  3. Swiprosin-1 participates in the berberine-regulated AMPK/MLCK pathway to attenuate colitis-induced tight junction damage

Swiprosin-1 participates in the berberine-regulated AMPK/MLCK pathway to attenuate colitis-induced tight junction damage

  • Phytomedicine. 2024 Sep 30:135:156111. doi: 10.1016/j.phymed.2024.156111.
Zhibin Wang 1,  Yuting Zhong 2,  Meng Xin 3,  Jiaqi Zhang 4,  Xiaohui Dong 5,  Wenzhao Zhang 6,  Xin Lu 6,  Ling Li 7,  Ye Tu 8,  Lichao Zhang 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China; Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai 200433, China.
  • 2 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China; Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai 200433, China; Shanghai TCM-Integrated Institute of Vascular Disease, Shanghai TCM- Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China; The People's Hospital of Sixian County, Anhui province, China.
  • 3 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
  • 4 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China; Shanghai TCM-Integrated Institute of Vascular Disease, Shanghai TCM- Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
  • 5 Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
  • 6 Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai 200433, China.
  • 7 Shanghai TCM-Integrated Institute of Vascular Disease, Shanghai TCM- Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China. Electronic address: lingli_z163@163.com.
  • 8 Department of Pharmacy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China. Electronic address: dan16065@163.com.
  • 9 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China. Electronic address: zhanglichao@shutcm.edu.cn.
PMID: 39369569 DOI: 10.1016/j.phymed.2024.156111
Abstract

Background and purpose: Activation of AMP-activated protein kinase (AMPK) is essential in maintaining the epithelial tight junction (TJ) barrier. Berberine, a phytochemical AMPK agonist, has been widely reported to ameliorate colitis. Berberine or AMPK activation inhibits cytoskeletal contraction induced by Myosin light chain kinase (MLCK), thereby ameliorating TJ barrier defects. We previously found that swiprosin-1, an actin-binding protein, affects MLCK expression. Here, we aimed to reveal the role of swiprosin-1 in the regulation of AMPK/MLCK by berberine.

Methods: Caco-2 monolayer transfected with AMPKα1 (or swiprosin-1) siRNA was treated with berberine after being stimulated with TNFα/IFNγ to assess the effect on the TJ barrier. Intestinal epithelial conditional knockout mice for AMPKα1 (or swiprosin-1) were treated with berberine after experimental colitis to evaluate the effect on the TJ barrier. TJ integrity was evaluated by immunoblotting and immunofluorescence for ZO-1 and Occludin.

Results: The protection of berberine against TJ barrier damage was blocked by AMPK Inhibitor or knockout of AMPKα1 in epithelial cells. Swiprosin-1 was distributed in colonic epithelial cells and upregulated in colitis. Knockout of swiprosin-1 in intestinal epithelial cells ameliorated TJ barrier damage and abolished the protective effect of berberine. Impaired assembly of TJ caused by overexpression of swiprosin-1 was alleviated by MLCK inhibitor, and inhibition of the MLCK pathway by berberine also required the presence of swiprosin-1. In addition, berberine downregulated swiprosin-1 expression in an AMPK-dependent manner.

Conclusion: Swiprosin-1 may be a key intermediate molecule in the regulation of the AMPK/MLCK pathway by berberine to attenuate colitis-induced TJ barrier damage.

Keywords

AMPK; Berberine; Colitis; MLCK; Swiprosin-1; Tight junction.

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