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[DOI] [PubMed] [Google Scholar] 11.Lehman AJ, Esdaile JM, Klinkhoff AV, Grant E, Fitzgerald A, Canvin J, et al

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Research status preclinical Sequence Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val Molecular weight 1419.53 Da Molecular formula C62H98N16O22 Studied applications Tissue repair pathways: studied in tendon, ligament, and muscle injury models with histological and biomechanical endpoints Vascular and NO signaling: investigated for effects on microcirculation and endothelial behavior in stress and injury contexts Protective signaling: examined in gastrointestinal, neural, and systemic injury models across multiple organ systems Fibroblast activity: associated with extracellular matrix remodeling and cell migration in connective tissue models Gastrointestinal integrity: studied in gastric ulcer, IBD, and intestinal anastomosis models for mucosal protection Central nervous system: explored in nerve injury and neurodegenerative disease models in rodents Mechanisms of action VEGF and angiogenesis: upregulates VEGF expression in vivo, activates VEGFR2 receptors on endothelial cells, triggers Akt-eNOS pathway phosphorylation Nitric oxide modulation: enhances endothelial NOS (eNOS) activity via Src-Cav-1-eNOS pathways, influences NO synthase activity and vascular tone Cell migration signaling: modulates FAK (focal adhesion kinase) and paxillin pathways affecting cell migration and adhesion Growth hormone receptor: boosts GHR expression in tendon fibroblasts, enhancing collagen synthesis in rodent studies ERK1/2 phosphorylation: activates downstream targets (c-Fos, c-Jun, Egr-1) promoting cell growth and migration Cytoprotective action: functions as membrane stabilizer and free radical scavenger in controlled studies No completed human clinical trials establishing safety or efficacy - majority of evidence is preclinical (in vitro and animal models) Preclinical findings do not establish clinical efficacy in humans and should be interpreted within experimental model limitations Research originates predominantly from a limited number of research groups, with variable independent replication Not approved by FDA, EMA, or any regulatory agency for therapeutic, medical, or supplemental use in humans Classified as Category 2 bulk drug substance by FDA (2023) - cannot be compounded by commercial pharmaceutical companies Sikiric P, et al