Bio-evaluation of Untapped Alkaloids from Vinca minor Enriched by Methyl-jasmonate-induced Stress: an Integrated Approach

Abstract

The low amount of metabolites isolated from natural products is one of the challenges preventing their biological evaluation. The modulation of biosynthetic pathways by stimulating stress-induced responses in plants, was proven to be a valuable tool for diversification of already known natural products. Recently, we reported the dramatic effect of Methyl jasmonate (MeJA) on Vinca minor alkaloids distribution. In this study, three compounds identified as 9-methoxy vincamine and minovincinine and minovincine were successfully isolated in good yield and subjected to several bioassays based on network pharmacology study. The extracts and isolated compounds showed weak to moderate antimicrobial and cytotoxic activities. Also, they were found to significantly promote wound healing in scratch assay and transforming growth factor-β (TGF-β) modulation was suggested to be the potential pathway based on bioinformatic analysis. Hence, western blotting was used to assess the expression of several markers related to this pathway and wound healing. V. minor isolates were able to increase the expression of Smad3, Phosphatidylinositol-3-kinase (PI3K) while downregulated the levels of Cyclin D1 and mammalian target of rapamycin (mTOR) except for minovincine which increased the mTOR expression inferring that it might act through different mechanism. Molecular docking was used to give insights on the ability of isolates to bind with different active sites in mTOR. Collectively, the integrated phytochemical, in silico and molecular biology approach revealed the potential repurposing of V. minor and its metabolites for management of dermatological disorders, which opens the gate to develop new therapeutics in the future.

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