PMID- 32187984 OWN - NLM STAT- MEDLINE DCOM- 20201217 LR - 20201217 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 21 IP - 6 DP - 2020 Mar 16 TI - Anti-Inflammatory and Anti-Oxidative Effects of luteolin-7-O-glucuronide in LPS-Stimulated Murine Macrophages through TAK1 Inhibition and Nrf2 Activation. LID - 10.3390/ijms21062007 [doi] LID - 2007 AB - Various herbal extracts containing luteolin-7-O-glucuronide (L7Gn) have been traditionally used to treat inflammatory diseases. However, systemic studies aimed at elucidating the anti-inflammatory and anti-oxidative mechanisms of L7Gn in macrophages are insufficient. Herein, the anti-inflammatory and anti-oxidative effects of L7Gn and their underlying mechanisms of action in macrophages were explored. L7Gn inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages by transcriptional regulation of inducible NO synthase (iNOS) in a dose-dependent manner. The mRNA expression of inflammatory mediators, including cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha), was inhibited by L7Gn treatment. This suppression was mediated through transforming growth factor beta-activated kinase 1 (TAK1) inhibition that leads to reduced activation of nuclear factor-kappaB (NF-kappaB), p38, and c-Jun N-terminal kinase (JNK). L7Gn also enhanced the radical scavenging effect and increased the expression of anti-oxidative regulators, including heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H quinone oxidoreductase 1 (NQO1), by nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) activation. These results indicate that L7Gn exhibits anti-inflammatory and anti-oxidative properties in LPS-stimulated murine macrophages, suggesting that L7Gn may be a suitable candidate to treat severe inflammation and oxidative stress. FAU - Cho, Young-Chang AU - Cho YC AD - College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Korea. FAU - Park, Jiyoung AU - Park J AD - College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea. FAU - Cho, Sayeon AU - Cho S AUID- ORCID: 0000-0002-8950-5704 AD - College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Korea. LA - eng GR - NRF2018R1A2B6005084, 2018M3A9B5060244, 2015R1A5A1008958, and NRF2016R1A6A3A11931134/National Research Foundation of Korea/ GR - 2018-3307/Chonnam National University/ PT - Journal Article DEP - 20200316 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (luteolin-7-O-glucuronide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) RN - EC 2.7.11.25 (MAP kinase kinase kinase 7) RN - KUX1ZNC9J2 (Luteolin) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Cell Survival/drug effects MH - Cyclooxygenase 2/metabolism MH - Heme Oxygenase-1/metabolism MH - Interleukin-1beta/metabolism MH - Interleukin-6/metabolism MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Lipopolysaccharides/*adverse effects MH - Luteolin/*antagonists & inhibitors/chemistry/pharmacology MH - MAP Kinase Kinase Kinases/*drug effects/metabolism MH - Macrophages/*drug effects/metabolism MH - Mice MH - NF-E2-Related Factor 2/*drug effects/metabolism MH - NF-kappa B/metabolism MH - Nitric Oxide Synthase Type II/metabolism MH - Phosphorylation MH - RAW 264.7 Cells MH - Tumor Necrosis Factor-alpha/metabolism PMC - PMC7139836 OTO - NOTNLM OT - RAW 264.7 macrophages OT - anti-inflammation OT - anti-oxidation OT - luteolin-7-O-glucuronide OT - nuclear factor-erythroid 2 p45-related factor 2 OT - transforming growth factor beta-activated kinase 1 COIS- The authors declare no conflict of interest. EDAT- 2020/03/20 06:00 MHDA- 2020/12/18 06:00 PMCR- 2020/03/01 CRDT- 2020/03/20 06:00 PHST- 2020/02/22 00:00 [received] PHST- 2020/03/12 00:00 [revised] PHST- 2020/03/13 00:00 [accepted] PHST- 2020/03/20 06:00 [entrez] PHST- 2020/03/20 06:00 [pubmed] PHST- 2020/12/18 06:00 [medline] PHST- 2020/03/01 00:00 [pmc-release] AID - ijms21062007 [pii] AID - ijms-21-02007 [pii] AID - 10.3390/ijms21062007 [doi] PST - epublish SO - Int J Mol Sci. 2020 Mar 16;21(6):2007. doi: 10.3390/ijms21062007.