title: Berberine Decreased Inducible Nitric Oxide Synthase mRNA Stability through Negative Regulation of Human Antigen R in Lipopolysaccharide-Induced Macrophages.
abstract: Berberine, a major isoquinoline alkaloid found in medicinal herbs, has been reported to possess anti-inflammatory effects; however, the underlying mechanisms responsible for its actions are poorly understood. In the present study, we investigated the inhibitory effects of berberine and the molecular mechanisms involved in lipopolysaccharide (LPS)-treated RAW 264.7 and THP-1 macrophages and its effects in LPS-induced septic shock in mice. In both macrophage cell types, berberine inhibited the LPS-induced nitric oxide (NO) production and inducible NO synthase (iNOS) protein expression, but it had no effect on iNOS mRNA transcription. Suppression of LPS-induced iNOS protein expression by berberine occurred via a human antigen R (HuR)-mediated reduction of iNOS mRNA stability. Molecular data revealed that the suppression on the LPS-induced HuR binding to iNOS mRNA by berberine was accompanied by a reduction in nucleocytoplasmic HuR shuttling. Pretreatment with berberine reduced LPS-induced iNOS protein expression and the cytoplasmic translocation of HuR in liver tissues and increased the survival rate of mice with LPS-induced endotoxemia. These results show that the suppression of iNOS protein expression by berberine under LPS-induced inflammatory conditions is associated with a reduction in iNOS mRNA stability resulting from inhibition of the cytoplasmic translocation of HuR.
authors.affiliation: Department of Pharmaceutical Biochemistry (J.-S.S., H.-E.C., SH.S., K.-T.L.), Department of Life and Nanopharmaceutical Science (H.-E.C., SH.S., J.-H.C.,K.-T. L), and Department of Oriental Pharmaceutical Science, College of Pharmacy (J.-H.C.), Kyung Hee University, Seoul, Republic of Korea; and Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea (N.-I.B.).
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Department of Pharmaceutical Biochemistry (J.-S.S., H.-E.C., SH.S., K.-T.L.), Department of Life and Nanopharmaceutical Science (H.-E.C., SH.S., J.-H.C.,K.-T. L), and Department of Oriental Pharmaceutical Science, College of Pharmacy (J.-H.C.), Kyung Hee University, Seoul, Republic of Korea; and Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea (N.-I.B.).
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Choi
authors.affiliation: Department of Pharmaceutical Biochemistry (J.-S.S., H.-E.C., SH.S., K.-T.L.), Department of Life and Nanopharmaceutical Science (H.-E.C., SH.S., J.-H.C.,K.-T. L), and Department of Oriental Pharmaceutical Science, College of Pharmacy (J.-H.C.), Kyung Hee University, Seoul, Republic of Korea; and Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea (N.-I.B.).
authors.forename: SeungHwan
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Pharmaceutical Biochemistry (J.-S.S., H.-E.C., SH.S., K.-T.L.), Department of Life and Nanopharmaceutical Science (H.-E.C., SH.S., J.-H.C.,K.-T. L), and Department of Oriental Pharmaceutical Science, College of Pharmacy (J.-H.C.), Kyung Hee University, Seoul, Republic of Korea; and Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea (N.-I.B.).
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Pharmaceutical Biochemistry (J.-S.S., H.-E.C., SH.S., K.-T.L.), Department of Life and Nanopharmaceutical Science (H.-E.C., SH.S., J.-H.C.,K.-T. L), and Department of Oriental Pharmaceutical Science, College of Pharmacy (J.-H.C.), Kyung Hee University, Seoul, Republic of Korea; and Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea (N.-I.B.).
authors.forename: Nam-In
authors.initials: NI
authors.lastname: Baek
authors.affiliation: Department of Pharmaceutical Biochemistry (J.-S.S., H.-E.C., SH.S., K.-T.L.), Department of Life and Nanopharmaceutical Science (H.-E.C., SH.S., J.-H.C.,K.-T. L), and Department of Oriental Pharmaceutical Science, College of Pharmacy (J.-H.C.), Kyung Hee University, Seoul, Republic of Korea; and Graduate School of Biotechnology & Plant Metabolism Research Center, Kyung Hee University, Suwon, Republic of Korea (N.-I.B.) ktlee@khu.ac.kr.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001599:Berberine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D011485:Protein Binding; D020871:RNA Stability / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D012772:Shock, Septic / Q000201:enzymology / Q000517:prevention & control
chemical_list: D000893:Anti-Inflammatory Agents; D000067780:ELAV-Like Protein 1; D008070:Lipopolysaccharides; D001599:Berberine; D052247:Nitric Oxide Synthase Type II