title: Coagulin-L ameliorates TLR4 induced oxidative damage and immune response by regulating mitochondria and NOX-derived ROS.
abstract: Withanolides possess diverse biological and pharmacological activity but their immunomodulatory function is less realized. Hence, coagulin-L, a withanolide isolated from Withania coagulans Dunal has been studied for such an effect in human and murine cells, and mice model. Coagulin-L (1, 3, 10μM) exhibited immunomodulatory effect by suppressing TLR4 induced immune mediators such as cytokines (GMCSF, IFNα, IFNγ, IL-1α, IL-1Rα, IL-1β, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12 (p40/p70), IL-13, IL-15, IL-17), chemokines (IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10, KC, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5, eotaxin/CCL11), growth factors (FGF-basic, VEGF), nitric oxide and intracellular superoxide. Mechanistically, coagulin-L abrogated LPS induced total and mitochondrial ROS generation, NOX2, NOX4 mRNA expression, IRAK and MAPK (p38, JNK, ERK) activation. Coagulin-L also attenuated IκBα degradation, which prevented NFκB downstream iNOS expression and pro-inflammatory cytokine release. Furthermore, coagulin-L (10, 25, 50mg/kg, p.o.), undermined the LPS (10mg/kg, i.p.) induced endotoxemia response in mice as evinced from diminished cytokine release, nitric oxide, aortic p38 MAPK activation and endothelial tissue impairment besides suppressing NOX2 and NOX4 expression in liver and aorta. Moreover, coagulin-L also alleviated the ROS mediated oxidative damage which was assessed through protein carbonyl, lipid hydroperoxide, 8-isoprostane and 8-hydroxy-2-deoxyguanosine quantification. To extend, coagulin-L also suppressed carrageenan-induced paw edema and thioglycollate-induced peritonitis in mice. Therefore, coagulin-L can be of therapeutic importance in pathological conditions induced by oxidative damage.
authors: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Sukka Santosh
authors: SS
authors: Reddy
authors: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Parul
authors: P
authors: Chauhan
authors: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research, New Delhi 110025, India.
authors: Preeti
authors: P
authors: Maurya
authors: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors: Deepika
authors: D
authors: Saini
authors: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: pp_yadav@cdri.res.in.
authors: Prem Prakash
authors: PP
authors: Yadav
authors: Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: manojbarthwal@cdri.res.in.
authors: Manoj Kumar
authors: MK
authors: Barthwal
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D054358:Withanolides; C000593591:coagulin-L; D019255:NADPH Oxidases
keywords: Coagulin-L; Endotoxemia; NADPH oxidase; Oxidative stress; ROS; TLR4