Phycocyanin stimulates ulcerative colitis healing via selective activation of cannabinoid receptor-2, intestinal mucosal healing, Treg accumulation, and p38MAPK/MK2 signaling inhibition

Theodor Bilharz Research Institute

Bibliographic Information

Authors: El-Maadawy W.H.; Hafiz E.; Okasha H.; Osman N.A.; Ali G.H.; Hussein R.A.

Journal: Life Sciences

Publisher: Elsevier Inc.

Publication Date: September 2022

Volume / Issue: Volume 305

Article No.: 120741

ISSN: 243205

DOI: 10.1016/j.lfs.2022.120741

Scopus: View on Scopus

PubMed: 35777583

Document Type: Article

Authors and Affiliations

El-Maadawy W.H., Pharmacology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Hafiz E., Electron Microscopy Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Okasha H., Biochemistry and Molecular Biology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba (P.O. 30), Giza, 12411, Egypt; Osman N.A., Pharmaceutical Chemistry Department, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt; Ali G.H., Water Pollution Department, National Research Centre, 33 El Buhouth St., Dokki, P.O.12622, Giza, Egypt; Hussein R.A., Pharmacognosy Department, National Research Centre, 33 El Buhouth St., Dokki, P.O.12622, Giza, Egypt

Abstract

Ulcerative colitis (UC) is a chronic inflammatory condition that until this date, lacks curative treatments. Previously, synthetic selective CB2 receptor (CB2R) agonists demonstrated effective preclinical anti-inflammatory activities in UC. Phycocyanin (PC), photosynthetic assistant protein isolated from Microcystis aeruginosa Kützing blue green algae, has multiple pharmacological effects, however, it's effect against UC remains unexplored. Our study aimed at investigating the therapeutic effectiveness of PC against UC, and correlating its mechanisms with CB2R agonistic activities. In silico; PC showed structural similarity with endocannabinoid receptors' ligand “Δ9-tetrahydrocannabinol”, target prediction studies suggested high affinity for G-coupled protein family-receptors, and molecular docking affirmed preferable affinity towards CB2R vs CB1R. In LPS-exposed-Caco-2 cell line; PC demonstrated comparable interaction with CB2R, and downregulation of CB2R, p38 and MK2 gene expressions with reference agonist “6d”, and exhibited preferred selectivity towards CB2R over CB1R. In DSS-induced mice; PC-treatment ameliorated DSS-induced colon shortening, elevated disease activity index, and colonic pathological alterations. PC showed effective CB2R activation through potent anti-inflammatory activities, Treg-cell accumulation, suppression in p38MAPK/MK2 signaling, and tight junction barrier restoration as indicated by ultrastructural examinations, elevated ZO-1 and occludin protein expressions, and Ki67 immunohistochemical expression in colonic tissues. Additionally, PC alleviated intestinal dysbiosis via downregulating LPS/TLR4/NF-κB signaling and gut microbiota maintenance. Notably, PC-protective activities were abolished when co-administered with SR144528 (selective CB2 antagonist) except for gut microbiota maintenance, which was independent from CB2R activation. Our findings provide evidence of PC effectiveness against UC through acting as CB2R agonist, thus expanding its possible therapeutic application against other inflammatory diseases. © 2022 Elsevier Inc.

Keywords

Microcystis aeruginosa Kützing microalgae, CB2 receptors; p38MAPK/MK2 pathway; Phycocyanin; TLR4/NF-κB pathway; Ulcerative colitis; Animals; Anti-Inflammatory Agents; Caco-2 Cells; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Humans; Lipopolysaccharides; Mice; Molecular Docking Simulation; Receptors, Cannabinoid; T-Lymphocytes, Regulatory; 5 (4 chloro 3 methylphenyl) 1 (4 methylbenzyl) n (1,3,3 trimethylbicyclo[2.2.1]heptan 2 yl) 3 pyrazolecarboxamide; cannabinoid 2 receptor; Ki 67 antigen; mitogen activated protein kinase p38; occludin; protein ZO1; toll like receptor 4; transforming growth factor beta; antiinflammatory agent; cannabinoid receptor; lipopolysaccharide; adult; animal experiment; animal model; antiinflammatory activity; Article; binding affinity; bioinformatics; biotinylation; CD4+ T lymphocyte; controlled study; dysbiosis; genetic algorithm; healing; human; human cell; human tissue; immunohistochemistry; immunomodulation; lamina propria; male; molecular docking; mouse; nonhuman; p38MAPK MK2 signaling; protein binding; protein conformation; protein expression; protein protein interaction; regulatory T lymphocyte; RNA extraction; signal transduction; TLR4 NF kB signaling; animal; Caco-2 cell line; disease model; metabolism; pathology

Citation Information

Scopus Citations: 17

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