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2.
J Biol Chem ; 286(6): 4690-702, 2011 Feb 11.
Article in English | MEDLINE | ID: mdl-21127062

ABSTRACT

Considering the role of retinoids in regulation of more than 500 genes involved in cell cycle and growth arrest, a detailed understanding of the mechanism and its regulation is useful for therapy. The extract of the medicinal plant Neem (Azadirachta indica) is used against several ailments especially for anti-inflammatory, anti-itching, spermicidal, anticancer, and insecticidal activities. In this report we prove the detailed mechanism on the regulation of retinoic acid-mediated cell signaling by azadirachtin, active components of neem extract. Azadirachtin repressed all trans-retinoic acid (ATRA)-mediated nuclear transcription factor κB (NF-κB) activation, not the DNA binding but the NF-κB-dependent gene expression. It did not inhibit IκBα degradation, IκBα kinase activity, or p65 phosphorylation and its nuclear translocation but inhibited NF-κB-dependent reporter gene expression. Azadirachtin inhibited TRAF6-mediated, but not TRAF2-mediated NF-κB activation. It inhibited ATRA-induced Sp1 and CREB (cAMP-response element-binding protein) DNA binding. Azadirachtin inhibited ATRA binding with retinoid receptors, which is supported by biochemical and in silico evidences. Azadirachtin showed strong interaction with retinoid receptors. It suppressed ATRA-mediated removal of retinoid receptors, bound with DNA by inhibiting ATRA binding to its receptors. Overall, our data suggest that azadirachtin interacts with retinoic acid receptors and suppresses ATRA binding, inhibits falling off the receptors, and activates transcription factors like CREB, Sp1, NF-κB, etc. Thus, azadirachtin exerts anti-inflammatory and anti-metastatic responses by a novel pathway that would be beneficial for further anti-inflammatory and anti-cancer therapies.


Subject(s)
Antineoplastic Agents/pharmacology , Azadirachta/chemistry , Cell Nucleus/metabolism , Insecticides/pharmacology , Limonins/pharmacology , Receptors, Retinoic Acid/metabolism , Tretinoin/pharmacology , Active Transport, Cell Nucleus/drug effects , Active Transport, Cell Nucleus/physiology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cell Nucleus/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Humans , I-kappa B Proteins/genetics , I-kappa B Proteins/metabolism , Insecticides/chemistry , Limonins/chemistry , NF-KappaB Inhibitor alpha , Phosphorylation/drug effects , Phosphorylation/physiology , Receptors, Retinoic Acid/genetics , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/metabolism , TNF Receptor-Associated Factor 2/genetics , TNF Receptor-Associated Factor 2/metabolism , TNF Receptor-Associated Factor 6/genetics , TNF Receptor-Associated Factor 6/metabolism , Transcription Factor RelA/genetics , Transcription Factor RelA/metabolism , U937 Cells
3.
J Biol Chem ; 285(15): 11617-27, 2010 Apr 09.
Article in English | MEDLINE | ID: mdl-20133937

ABSTRACT

The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P(3)-25) is known to possess anti-bacterial, anti-fungal, and anti-tubercular activities. In this report, we provide evidence that P(3)-25 inhibits NF-kappaB, known to induce inflammatory and tumorigenic responses. It activates AP-1, another transcription factor. It inhibits TRAF2-mediated NF-kappaB activation but not TRAF6-mediated NF-kappaB DNA binding by preventing its association with TANK (TRAF for NF-kappaB). It facilitates binding of MEKK1 with TRAF2 and thereby activates JNK and AP-1. We provide evidence, for the first time, that suggests that the interaction of P(3)-25 with TRAF2 leads to inhibition of the NF-kappaB pathway and activation of AP-1 pathway. These results suggest novel approaches to design of P(3)-25 as an anti-cancer/inflammatory drug for therapy through regulation of the TRAF2 pathway.


Subject(s)
Gene Expression Regulation , NF-kappa B/metabolism , Thiadiazoles/pharmacology , Transcription Factor AP-1/metabolism , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Jurkat Cells , Ligands , MAP Kinase Kinase 4/metabolism , Models, Biological , T-Lymphocytes/metabolism , TNF Receptor-Associated Factor 2/metabolism
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