Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NFκB and MAPK pathway on dry eye

Yi Han; Shujia Guo; Yunpeng Li; Jiani Li; Linfangzi Zhu; Yuwen Liu; Yufei Lv; Dong Yu; Lan Zheng; Caihong Huang; Cheng Li; Jiaoyue Hu; Zuguo Liu

doi:10.1016/j.phymed.2023.155081

Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NFκB and MAPK pathway on dry eye

Phytomedicine. 2023 Dec:121:155081. doi: 10.1016/j.phymed.2023.155081. Epub 2023 Sep 18.

Authors

Yi Han¹, Shujia Guo², Yunpeng Li², Jiani Li², Linfangzi Zhu², Yuwen Liu², Yufei Lv³, Dong Yu⁴, Lan Zheng², Caihong Huang², Cheng Li⁵, Jiaoyue Hu⁶, Zuguo Liu⁷

Affiliations

¹ Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China; Department of Ophthalmology, the First Affiliated Hospital of University of South China, Postdoctoral mobile station of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
² Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China.
³ Department of Ophthalmology, the First Affiliated Hospital of University of South China, Postdoctoral mobile station of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
⁴ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
⁵ Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China; Department of Ophthalmology, the First Affiliated Hospital of University of South China, Postdoctoral mobile station of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: cheng-li@xmu.edu.cn.
⁶ Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address: mydear_22000@163.com.
⁷ Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute & Affiliated Xiamen Eye Center, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China; Department of Ophthalmology, the First Affiliated Hospital of University of South China, Postdoctoral mobile station of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: zuguoliu@xmu.edu.cn.

PMID: 37748390
DOI: 10.1016/j.phymed.2023.155081

Abstract

Background: Dry eye disease (DED) is a multifactorial disease in ocular surface, and inflammation plays an etiological role. Berberine (BBR) has shown efficacy in treating inflammatory diseases. Yet, there was no adequate information related to the therapeutic effects of BBR for DED.

Purpose: To detect the effects and explore the potential mechanisms of BBR on DED.

Study design: In vitro, in vivo study and network pharmacology analysis were involved.

Method: The human corneal epithelium cells viability was evaluated with different concentrations of BBR. Dry eye murine model was established by exposing to the desiccating stress, and Ciclosporin (CSA), BBR eye drops or vehicle were topical administration for 7 days. The phenol red cotton tests, Oregon-green-dextran staining and Periodic acid-Schiff staining were performed and evaluated the dry eye after treatment. Inflammation and apoptosis levels of ocular surface were quantified. The potential targets related to berberine and dry eye were collected from databases. The Protein-Protein interaction network analysis and GO & KEGG enrichment analysis were realized by STRING database, Metascape platform and Cytoscape software to find core targets and signaling pathways. The SchrÖdinger software was used to molecular docking and PyMOL software to visualization. Finally, the levels of PI3K/AKT/NFκB and MAPK pathways were detected.

Result: The data revealed BBR could rescue impaired HCE under hyperosmotic conditions. In addition, BBR eye drops could ameliorate dry eye. And BBR eye drops suppressed the inflammatory factors and CD4⁺T cells infiltration in conjunctiva. Besides, BBR eye drops protected ocular surface by avoiding the severe apoptosis and decreasing the level of MMP-3 and MMP-9. 148 common targets intersection between BBR and dry eye were found via network pharmacology analysis. Core proteins and core pathways were identified through PPI and GO&KEGG enrichment analysis. Molecular docking displayed excellent binding between BBR and those core targets. Finally, in vivo study verified that BBR eye drops had a therapeutic effect in dry eye by inhibiting PI3K/AKT/NFκB and MAPK pathways.

Conclusion: The research provided convincing evidence that BBR could be a candidate drug for dry eye.

Keywords: Apoptosis; Berberine; Dry eye disease; Inflammation; Network pharmacology.

MeSH terms

Animals
Apoptosis
Berberine* / chemistry
Dry Eye Syndromes* / drug therapy
Dry Eye Syndromes* / metabolism
Humans
Inflammation / drug therapy
Mice
Molecular Docking Simulation
NF-kappa B / metabolism
Ophthalmic Solutions / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism

Substances

Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Berberine
NF-kappa B
Ophthalmic Solutions