title: A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity.
abstract: The TLR/IL-1R pathway is a critical signaling module that is misregulated in pathologies like inflammation and cancer. Extracts from turmeric (Curcuma longa L.) enriched in curcumin and carbonyls like turmerones have been shown to exert potent anti-inflammatory effects. The present study evaluated the anti-inflammatory activity, cytotoxic effect and the underlying mechanism of a novel chemically modified, non-carbonyl compound enriched Curcuma longa L. (C. longa) extract (CMCE). CMCE (1 or 10 μg/mL; 14 h) significantly decreased LPS (50-100 ng/mL) induced TNF-α and IL-1β production in THP-1 cells, human, and mouse whole blood as measured by ELISA. LPS-induced IRAK1, MAPK activation, TLR4 expression, TLR4-MyD88 interaction, and IκBα degradation were significantly reduced in CMCE pre-treated THP-1 cells as assessed by Western blotting. CMCE (30, 100, and 300 mg/kg; 10 days p.o.) pre-treated and LPS (10 mg/kg) challenged Swiss mice exhibited attenuated plasma TNF-α, IL-1β, nitrite, aortic iNOS expression, and vascular dysfunction. In a PI permeability assay, cell lines derived from acute myeloid leukemia were most sensitive to the cytotoxic effects of CMCE. Analysis of Sub-G1 phase, Annexin V-PI positivity, loss of mitochondrial membrane potential, increased caspase-3, and PARP-1 activation confirmed CMCE induced apoptosis in HL-60 cells. IRAK inhibition also sensitized HL-60 cells to CMCE induced cytotoxicity. The present study defines the mechanism underlying the action of CMCE and suggests a therapeutic potential for its use in sepsis and leukemia.
authors: Pharmacology Division, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Minakshi
authors: M
authors: Rana
authors: Pharmacology Division, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Preeti
authors: P
authors: Maurya
authors: Pharmacology Division, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Sukka S
authors: SS
authors: Reddy
authors: Pharmacology Division, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Vishal
authors: V
authors: Singh
authors: Division of Pharmaceutics, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Hafsa
authors: H
authors: Ahmad
authors: Division of Pharmaceutics, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Anil K
authors: AK
authors: Dwivedi
authors: Pharmacology Division, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Madhu
authors: M
authors: Dikshit
authors: Pharmacology Division, Council of Scientific and Industrial Research - Central Drug Research Institute Lucknow, India.
authors: Manoj K
authors: MK
authors: Barthwal
keywords: caspase-3; chemically modified Curcuma longa extract; endotoxemia; interleukin-1 receptor-associated kinase 1; mitochondrial membrane potential