Cerbera manghas methanol extract exerts anti-inflammatory activity by targeting c-Jun N-terminal kinase in the AP-1 pathway. (4th December 2016)

• Record Type: Journal Article
• Authors: Yi, Young-Su; Cho, Jae Youl; Kim, Daewon
• Is Part Of: Journal of ethnopharmacology. Volume 193(2016)
• Page Start: 387
• Page End: 396
• Publication Date: 2016-12-04
• Subjects: PG prostaglandin -- NO nitric oxide -- COX cyclooxygenase -- TNF-α tumor necrosis factor-alpha -- IL-1β interleukin-1 beta -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- NO nitric oxide -- TLR toll-like receptor -- AP-1 activator protein-1 -- ERK xtracellular signal-regulated kinase -- JNK c-Jun N-terminal kinase -- MKK mitogen-activated protein kinase kinase -- TAK transforming growth factor beta-activated kinase -- IRAK interleukin-1 receptor-associated kinase -- MTT 3–4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- LPS lipopolysaccharide -- RT-PCR reverse transcriptase-polymerase chain reaction -- PMA phorbol 12-myristate 13-acetate -- MyD88 myeloid differentiation primary response gene (88) -- TRIF TIR-domain-containing adapter-inducing interferon-β -- IκBα inhibitor of kappa B alpha -- IKK IκB kinase -- PEI polyethylenimine -- D-GalN D-galactosamine -- AST aspartate aminotransferase -- ALT alanine aminotransferase; Cerbera manghas L. -- AP-1 -- JNK3 -- MKK4 -- Anti-inflammatory effect -- Inflammatory mediator; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2016.08.033
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: Cerbera manghas L. (Apocynaceae) is a medicinal plant traditionally used to ameliorate the clinical signs of inflammatory diseases and hypertension. Aim of study: Although C. manghas L. has long been used as a traditional remedy for various diseases, the underlying molecular and cellular mechanisms are poorly understood. A detailed investigation of these mechanisms is necessary to demonstrate the ethnopharmaceutical utility of this plant. Materials and Methods: The effects of C. manghas methanol extract (Cm-ME) on the production of inflammatory mediators and the expression of proinflammatory cytokines and identification of molecular targets were investigated using lipopolysaccharide (LPS)-treated macrophages in vitro . In addition, the inhibitory effects of Cm-ME orally administered were tested by LPS/D -galactosamine (D -GalN)-induced hepatitis and LPS-induced peritonitis mouse models in vivo . Results: Cm-ME downregulated the production of prostaglandin (PG)E2 and the mRNA expression of cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β in LPS-stimulated RAW264.7 cells under non-toxic concentration of Cm-ME. This extract inhibited the nuclear translocation of c-Jun and p-ATF2, the phosphorylation of JNK and p38, and AP-1 activity. Western blot analysis and in vitro kinase assay confirmed that JNK is a direct pharmacological target of Cm-ME action. In addition, Cm-ME significantly ameliorated the clinical signs of LPS/D -GalN-induced hepatitis and lowered the production of nitric oxide (NO) and the phosphorylation of JNK in LPS-induced peritonitis conditions. Conclusion: Cm-ME exerts anti-inflammatory actions on LPS-stimulated macrophages and in mouse models of acute inflammatory disease. These actions are predominantly mediated by targeting JNK in the AP-1 signaling pathway. Graphical abstract: