title: uPA dependent and independent mechanisms of wound healing by C-phycocyanin.
abstract: Wound repair requires both recruitment and well co-ordinated actions of many cell types including inflammatory cells, endothelial cells, epithelial cells and importantly fibroblast cells. Urokinase-type plasminogen activator (uPA) system plays a vital role in wound healing phenomenon. We have previously demonstrated that C-phycocyanin (C-pc), a biliprotein from blue-green algae, transcriptionally regulates uPA through cAMP-dependent protein kinase A (PKA) pathway. To date, a role for C-pc in wound-healing scenario is not elucidated. This study was designed to examine the wound-healing property of C-pc in relation to fibroblast proliferation and migration. C-pc increased fibroblast proliferation in a dose-dependent manner. It also enhanced G1 phase of cell cycle and increased the expressions of cyclin-dependent kinases 1 and 2, which facilitate cell cycle progression, in a uPA-independent manner. In vitro wound healing and migration assays revealed the pro-migratory properties of C-pc. Short-interference RNA studies demonstrated that uPA was necessary for C-pc-induced fibroblast migration. C-pc also significantly elevated the expressions of chemokines (MDC, RANTES, Eotaxin, GRO alpha, ENA78 and TARC) and Rho-GTPases (Cdc 42 and Rac 1) in a uPA-dependent manner. Pre-treatment of C-pc-stimulated cells with pharmacological inhibitor of PI-3K (LY294002) annulled the expression of GTPases implying that Rac 1 and Cdc 42 were induced through PI-3K pathway. C-pc-induced cellular migration towards wounded area was also negatively affected by PI-3K inhibition. In vivo wound-healing experiments in mice validated our finding that C-pc accelerates wound healing. Our data provides conclusive evidence of a novel therapeutic usage for C-pc as a wound-healing agent. C-pc is a food and drug administration (FDA)-approved health supplement. We believe this compound can also be beneficial in healing of internal wounds, such as ulcers.
authors.affiliation: Department of Applied Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: H K
authors.initials: HK
authors.lastname: Madhyastha
authors.forename: K S
authors.initials: KS
authors.lastname: Radha
authors.forename: Y
authors.initials: Y
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Omura
authors.forename: M
authors.initials: M
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D020405:Dermis / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010798:Phycocyanin / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D018925:Chemokines; D010798:Phycocyanin; D019869:Phosphatidylinositol 3-Kinases; D018844:Cyclin-Dependent Kinases; D014568:Urokinase-Type Plasminogen Activator; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein