Uttam Pal - Novel anti-inflammatory activity of epoxyazadiradione against macrophage migration inhibitory factor: inhibition of tautomerase and proinflammatory activities of macrophage migration inhibitory factor

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      Alam, Athar, Haldar, Saikat, Thulasiram, Hirekodathakallu V,   Kumar, Rahul, Goyal, Manish, Iqbal, Mohd Shameel, Pal, Chinmay,   Dey, Sumanta, Bindu, Samik, Sarkar, Souvik, Pal, Uttam, Maiti,   Nakul C, Bandyopadhyay, Uday 287 (29) 24844-24861

      Abstract: Macrophage migration inhibitory factor   (MIF) is responsible for proinflammatory reactions in various   infectious and non-infectious diseases. We have investigated the   mechanism of anti-inflammatory activity of epoxyazadiradione, a   limonoid purified from neem (Azadirachta indica) fruits, against   MIF. Epoxyazadiradione inhibited the tautomerase activity of MIF   of both human (huMIF) and malaria parasites (Plasmodium   falciparum (PfMIF) and Plasmodium yoelii (PyMIF))   non-competitively in a reversible fashion (K(i), 2.11-5.23 μm).   Epoxyazadiradione also significantly inhibited MIF (huMIF, PyMIF,   and PfMIF)-mediated proinflammatory activities in RAW 264.7   cells. It prevented MIF-induced macrophage chemotactic migration,   NF-κB translocation to the nucleus, up-regulation of inducible   nitric-oxide synthase, and nitric oxide production in RAW 264.7   cells. Epoxyazadiradione not only exhibited anti-inflammatory   activity in vitro but also in vivo. We tested the   anti-inflammatory activity of epoxyazadiradione in vivo after   co-administering LPS and MIF in mice to mimic the disease state   of sepsis or bacterial infection. Epoxyazadiradione prevented the   release of proinflammatory cytokines such as IL-1α, IL-1β, IL-6,   and TNF-α when LPS and PyMIF were co-administered to BALB/c mice.   The molecular basis of interaction of epoxyazadiradione with MIFs   was explored with the help of computational chemistry tools and a   biological knowledgebase. Docking simulation indicated that the   binding was highly specific and allosteric in nature. The well   known MIF inhibitor   (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid   methyl ester (ISO-1) inhibited huMIF but not MIF of parasitic   origin. In contrast, epoxyazadiradione inhibited both huMIF and   plasmodial MIF, thus bearing an immense therapeutic potential   against proinflammatory reactions induced by MIF of both malaria   parasites and human.

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