03069nas a2200289   4500008004100000022001400041245020400055210006900259260010300328300001600431490000800447520193000455100001602385700001902401700003702420700001702457700001802474700002502492700001702517700001702534700001702551700001902568700001502587700002102602700002402623856013202647       2012                        eng d  a0021-925800aNovel anti-inflammatory activity of epoxyazadiradione against macrophage migration inhibitory factor inhibition of tautomerase and proinflammatory activities of macrophage migration inhibitory factor0 aNovel antiinflammatory activity of epoxyazadiradione against mac  a9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USAbAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INCcJUL  a24844-248610 v2873 a<p>Macrophage migration inhibitory factor (MIF) is responsible for proinflammatory reactions in various infectious and noninfectious 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 mu M). 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-kappa B 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-1 alpha, IL-1 beta, IL-6, and TNF-alpha 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 knowledge base. 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.</p>1 aAlam, Athar1 aHaldar, Saikat1 aThulasiram, Hirekodathakallu, V.1 aKumar, Rahul1 aGoyal, Manish1 aIqbal, Mohd, Shameel1 aPal, Chinmay1 aDey, Sumanta1 aBindu, Samik1 aSarkar, Souvik1 aPal, Uttam1 aMaiti, Nakul, C.1 aBandyopadhyay, Uday  uhttps://library.ncl.res.in/content/novel-anti-inflammatory-activity-epoxyazadiradione-against-macrophage-migration-inhibitory-002732nas a2200241   4500008004100000245010700041210006900148260000800217300001400225490000800239520187700247100001802124700001902142700002002161700001802181700002302199700003302222700002702255700002202282700003702304700002102341856012802362       2016                        eng d00aNotch1-MAPK signaling axis regulates CD133+ cancer stem cell-mediated melanoma growth and angiogenesis0 aNotch1MAPK signaling axis regulates CD133 cancer stem cellmediat  cDEC  a2462-24740 v1363 a<p>Functional characterization and understanding of the intricate signaling mechanisms in stem-like cells is crucial for the development of effective therapies in melanoma. We have studied whether melanoma cells are phenotypically distinct and hierarchically organized according to their tumorigenic nature. We report that melanoma-specific CD133(+) cancer stem cells exhibit increased tumor-initiating potential, tumor-endothelial cell interaction, and lung metastasis. These cells are able to transdifferentiate into an endothelial-like phenotype when cultured under endothelial differentiation-promoting conditions. Mechanistically, Notch1 upregulates mitogen-activated protein kinase activation through CD133, which ultimately controls vascular endothelial growth factor and matrix metalloproteinase expression in CD133(+) stem cells leading to melanoma growth, angiogenesis, and lung metastasis. Blockade or genetic ablation of Notch1 and mitogen-activated protein kinase pathways abolishes melanoma cell migration and angiogenesis. Chromatin immunoprecipitation and reporter assays revealed that Notch1 intracellular domain regulates CD133 expression at the transcriptional level. Andrographolide inhibits Notch1 intracellular domain expression, Notch1 intracellular domaindependent CD133-mediated mitogen-activated protein kinase and activator protein-1 activation, and epithelial to mesenchymal-specific gene expression, ultimately attenuating melanoma growth and lung metastasis. Human malignant melanoma specimen analyses revealed a strong correlation between Notch1 intracellular domain, CD133, and p-p38 mitogen-activated protein kinase expression and malignant melanoma progression. Thus, targeting Notch1 and its regulated signaling network may have potential therapeutic implications for the management of cancer stem cell-mediated melanoma progression.</p>1 aKumar, Dhiraj1 aKumar, Santosh1 aGorain, Mahadeo1 aTomar, Deepti1 aPatil, Harshal, S.1 aRadharani, Nalukurthi, N. V.1 aKumar, Totakura, V. S.1 aPatil, Tushar, V.1 aThulasiram, Hirekodathakallu, V.1 aKundu, Gopal, C.  uhttps://library.ncl.res.in/content/notch1-mapk-signaling-axis-regulates-cd133-cancer-stem-cell-mediated-melanoma-growth-and01797nas a2200181   4500008004100000245004600041210004600087260000800133300001200141490000600153520123400159100002801393700001601421700002401437700003701461700003601498856008101534       2021                        eng d00aNeem derivatives inhibits tau aggregation0 aNeem derivatives inhibits tau aggregation  cJAN  a169-1780 v33 aTau is a phosphoprotein with natively unfolded conformation that functions to stabilize microtubules in axons. Alzheimer's disease pathology triggers several modifications in tau, which causes it to lose its affinity towards microtubule, thus, leading to microtubule disassembly and loss of axonal integrity. This elicit accumulation of tau as paired helical filaments is followed by stable neurofibrillary tangles formation. A large number of small molecules have been isolated from Azadirachta indica with varied medicinal applications. The intermediate and final limonoids, nimbin and salannin respectively, isolated from Azadirachta indica, were screened against tau aggregation. ThS and ANS fluorescence assay showed the role of intermediate and final limonoids in preventing heparin induced cross-β sheet formation and also decreased hydrophobicity, which are characteristic nature of tau aggregation. Transmission electron microscopy studies revealed that limonoids restricted the aggregation of tau to fibrils; in turn, limonoids led to the formation of short and fragile aggregates. Both the limonoids were non-toxic to HEK293T cells thus, substantiating limonoids as a potential lead in overcoming Alzheimer's disease.1 aNalini, Gorantla, Vijay1 aDas, Rashmi1 aMulani, Fayaj, Alam1 aThulasiram, Hirekodathakallu, V.1 aChinnathambi, Subashchandrabose  uhttps://library.ncl.res.in/content/neem-derivatives-inhibits-tau-aggregation