Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1

Xin Liu; Yunwei Wei; Xue Bai; Mingqi Li; Huimin Li; Lei Wang; Shuqian Zhang; Xia Li; Tong Zhao; Yang Liu; Rui Geng; Hao Cui; Hui Chen; Ranchen Xu; Heng Liu; Yong Zhang; Baofeng Yang

doi:10.1016/j.apsb.2020.02.003

Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1

Acta Pharm Sin B. 2020 May;10(5):812-824. doi: 10.1016/j.apsb.2020.02.003. Epub 2020 Feb 19.

Authors

Xin Liu^{1

2}, Yunwei Wei³, Xue Bai¹, Mingqi Li¹, Huimin Li¹, Lei Wang¹, Shuqian Zhang¹, Xia Li¹, Tong Zhao¹, Yang Liu³, Rui Geng³, Hao Cui¹, Hui Chen¹, Ranchen Xu¹, Heng Liu¹, Yong Zhang^{1

4

2}, Baofeng Yang^{1

5

2}

Affiliations

¹ Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
² Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019 Research Unit 070, Harbin 150081, China.
³ Department of Oncological and Laparoscopic Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
⁴ Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150086, China.
⁵ Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and HealthSciences University of Melbourne, Melbourne VIC 3010, Australia.

Abstract

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and represent the major cause of postsurgical morbidity. Enterolysis at repeat surgeries induces adhesion reformation that is more difficult to prevent than primary adhesion. Here we studied the preventive effects of different approaches of berberine treatment for primary adhesion, and its effects on adhesion reformation compared to Interceed. We found the primary adhesion was remarkably prevented by berberine through intraperitoneal injection 30 min before abrasive surgery (pre-berberine) or direct addition into injured cecum immediately after the surgery (inter-berberine). Rats with adhesion reformation had a more deteriorative collagen accumulation and tissue injury in abrasive sites than rats with primary adhesion. The dysregulated TIMP-1/MMP balance was observed in patients after surgery, as well as adhesion tissues from primary adhesion or adhesion reformation rats. Inter-berberine treatment had a better effect for adhesion reformation prevention than Interceed. Berberine promoted the activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core, which was reversed by TIMP-1 overexpression in fibroblasts. In conclusion, this study suggests berberine as a reasonable approach for preventing primary adhesion formation and adhesion reformation.

Keywords: ABSO, adhesive small bowel obstruction; Adhesion reformation; BBR, berberine; Berberine; ECM, extracellular matrix; EDC, 1-ethyl-3-(3-dimethylpropyl)-carbodiimide; FSP-1, fibroblasts specific protein 1; H&E, hemotoxylin and eosin; HPX, hemopexin-like; ICAM-1, intercellular cell adhesion molecule-1; LSPR, localized surface plasmon resonance; MMP-3, matrix metallopeptidase 3; MMP-8, matrix metallopeptidase 8; NHS, N-hydroxysuccinimide; NMR, nuclear magnetic resonance; PEG, polyethylene glycol; Peritoneal adhesion; SPR, surface plasmon resonance; TIMP-1; TIMP-1, tissue inhibitor of metalloproteinases 1; Vegfα, vascular endothelial growth factor α.