Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

Roy, Saptarshi and Dutta, Devawati and Satyavarapu, Eswara M and Yadav, Pawan K and Mandal, Chhabinath and Kar, Susanta and Mandal, Chitra (2017) Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis. Scientific Reports, 7 (4141).

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    Abstract

    Earlier we have established a carbazole alkaloid (mahanine) isolated from an Indian edible medicinal plant as an anticancer agent with minimal effect on normal cells. Here we report for the first time that mahanine-treated drug resistant and sensitive virulent Leishmania donovani promastigotes underwent apoptosis through phosphatidylserine externalization, DNA fragmentation and cell cycle arrest. An early induction of reactive oxygen species (ROS) suggests that the mahanine-induced apoptosis was mediated by oxidative stress. Additionally, mahanine-treated Leishmania-infected macrophages exhibited anti-amastigote activity by nitric oxide (NO)/ROS generation along with suppression of uncoupling protein 2 and Th1-biased cytokines response through modulating STAT pathway. Moreover, we have demonstrated the interaction of a few antioxidant enzymes present in parasite with mahanine through molecular modeling. Reduced genetic and protein level expression of one such enzyme namely ascorbate peroxidase was also observed in mahanine-treated promastigotes. Furthermore, oral administration of mahanine in acute murine model exhibited almost complete reduction of parasite burden, upregulation of NO/iNOS/ROS/IL-12 and T cell proliferation. Taken together, we have established a new function of mahanine as a potent antileishmanial molecule, capable of inducing ROS and exploit antioxidant enzymes in parasite along with modulation of host’s immune response which could be developed as an inexpensive and nontoxic therapeutics either alone or in combination.

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/2715
    Subjects: Cancer Biology and Inflammatory Disorder Division
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 08 Aug 2017 10:35
    Last Modified: 08 Aug 2017 10:36
    Official URL: http://dx.doi.org/10.1038/s41598-017-03943-y
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