title: Ginsenosides Regulate PXR/NF-κB Signaling and Attenuate Dextran Sulfate Sodium-Induced Colitis.
abstract: Pregnane X receptor (PXR) activation exhibits anti-inflammatory effects via repressing nuclear factor-κB (NF-κB); however, its overactivation may disrupt homeostasis of various enzymes and transporters. Here we found that ginsenosides restore PXR/NF-κB signaling in inflamed conditions without disrupting PXR function in normal conditions. The effects and mechanisms of ginsenosides in regulating PXR/NF-κB signals were determined both in vitro and in vivo. Ginsenosides significantly inhibited NF-κB activation and restored the expression of PXR target genes in tumor necrosis factor-α-stimulated LS174T cells. Despite not being PXR agonists, ginsenosides repressed NF-κB activation in a PXR-dependent manner. Ginsenosides significantly increased the physical association between PXR and the NF-κB p65 subunit and thereby decreased the nuclear translocation of p65. Ginsenoside Rb1 and compound K (CK) were major bioactive compounds in the regulating PXR/NF-κB signaling. Consistently, ginsenosides significantly attenuated dextran sulfate sodium-induced experimental colitis, which was associated with restored PXR/NF-κB signaling. This study indicates that ginsenosides may elicit anti-inflammatory effects via targeting PXR/NF-κB interaction without disrupting PXR function in healthy conditions. Ginsenoside Rb1 and CK may serve as leading compounds in the discovery of new drugs that target PXR/NF-κB interaction in therapy for inflammatory bowel disease.
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Tingting
authors.initials: T
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Sijing
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.).
authors.forename: Mengqiu
authors.initials: M
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.) guangjiwang@hotmail.com hhp_770505@hotmail.com.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China (J.Z., L.C., H.W., X.C., L.W., L.Z., T.Y., Y.X., Y.W., M.Z., S.M., M.W., G.W., H.H.); and School of Pharmacy, Nanjing Medical University, Nanjing, China (J.Z.) guangjiwang@hotmail.com hhp_770505@hotmail.com.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate; D036145:Ginsenosides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D036145:Ginsenosides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C442759:ginsenoside Rb1; D016264:Dextran Sulfate