PDK1 in NF-κB signaling is a target of Xanthium strumarium methanolic extract-mediated anti-inflammatory activities

• Published in: Journal of ethnopharmacology 2016-08, Vol.190, p.251-260
• Main Authors: Hossen, Muhammad Jahangir, Cho, Jae Youl, Kim, Daewon
• Format: Article
• Language: English
• Subjects: 3-phosphoinositide-dependent kinase 1 (pdk1); 3-Phosphoinositide-Dependent Protein Kinases - antagonists & inhibitors; 3-Phosphoinositide-Dependent Protein Kinases - genetics; 3-Phosphoinositide-Dependent Protein Kinases - metabolism; Animals; Anti-Inflammatory Agents - isolation & purification; Anti-Inflammatory Agents - pharmacology; Anti-inflammatory effect; Asteraceae; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Gastritis - chemically induced; Gastritis - enzymology; Gastritis - genetics; Gastritis - prevention & control; HEK293 Cells; Humans; Hydrochloric Acid; Inflammation Mediators - metabolism; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - enzymology; Male; Methanol - chemistry; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; NF-kappa B - genetics; NF-kappa B - metabolism; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nuclear factor-kappaB; Phosphorylation; Phytotherapy; Plant Components, Aerial - chemistry; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Plants, Medicinal; Prostaglandin E2; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; RAW 264.7 Cells; Resveratrol; Signal Transduction - drug effects; Solvents - chemistry; Time Factors; Transfection; Xanthium - chemistry; Xanthium strumarium
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2016.06.019

Xanthium strumarium L. (Asteraceae) has traditionally been used to treat bacterial infections, nasal sinusitis, urticaria, arthritis, chronic bronchitis and rhinitis, allergic rhinitis, edema, lumbago, and other ailments. However, the molecular mechanisms by which this plant exerts its anti-inflammatory effects are poorly characterized. Here we studied the immunopharmacological activities of the methanolic extract of the aerial parts of this plant (Xs-ME) and validated its pharmacological targets. To evaluate the anti-inflammatory activity of Xs-ME, we employed lipopolysaccharide (LPS)-treated macrophages and an HCl/EtOH-induced mouse model of gastritis. We also used HPLC to identify the potentially active anti-inflammatory components of this extract. The molecular mechanisms of its anti-inflammatory activity were studied by kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes. The production of nitric oxide (NO) and prostaglandin E2 (PGE2) were both suppressed by Xs-ME. Moreover, orally administered Xs-ME ameliorated HCl/EtOH-induced gastric lesions. Furthermore, this extract downregulated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and reduced the nuclear levels of NF-κB. Signaling events upstream of NF-κB translocation, such as phosphorylation of AKT and the formation of PDK1-AKT signaling complexes, were also inhibited by Xs-ME. Moreover, Xs-ME suppressed the enzymatic activity of PDK1. Additionally, PDK1-induced luciferase activity and Akt phosphorylation were both inhibited by Xs-ME. We also identified the polyphenol resveratrol as a likely active anti-inflammatory component in Xs-ME that targets PDK1. Xs-ME exerts anti-inflammatory activity in vitro and in vivo by inhibiting PDK1 kinase activity and blocking signaling to its downstream transcription factor, NF-κB. [Display omitted]