(9S, 13R)-12-oxo-phytodienoic acid attenuates inflammation by inhibiting mPGES-1 and modulating macrophage polarization via NF-κB and Nrf2/HO-1 pathways. (August 2022)

• Record Type: Journal Article
• Authors: Zhang, Yan-Yu; Yao, Yun-Da; Chen, Fang; Guo, Xin; Kang, Jun-Li; Huang, Yu-Feng; He, Fan; Dong, Yan; Xie, Ying; Wu, Peng; Zhou, Hua
• Is Part Of: Pharmacological research. Volume 182(2022)
• Publication Date: 2022-08
• Subjects: 9S, 13R)− 12-oxo-phytodienoic acid (PubChem CID: 14037063) -- BAY 11–7085 (PubChem CID: 5353432) -- Dexamethasone (PubChem CID: 5743) -- MK886 (PubChem CID: 3651377); COX cyclooxygenases -- COX-1 cyclooxygenase-1 -- COX-2 cyclooxygenase-2 -- cPLA2 cytosolic phospholipase A2 -- DEX dexamethasone -- HO-1 Heme oxygenase-1 -- iNOS Inducible nitric oxide synthase -- iUDP improved up-and-down procedure -- KO knockout -- LPS lipopolysaccharides -- mRNA messenger RNA -- NSAIDs non-steroidal anti-inflammatory drugs -- NO Nitric oxide -- OA osteoarthritis -- PGE2 prostaglandin E2 -- mPGES-1 prostaglandin E2 synthase-1 -- synthases PGG2 prostaglandin G2 -- PGI2 prostaglandin I2 -- PGs prostaglandins -- PPAR-γ peroxisome proliferator-activated receptor-gamma -- RT-qPCR Quantitative real-time polymerase chain reaction -- RA rheumatic arthritis -- TXA2 thromboxane A2; (9S, 13R)−12-oxo-phytodienoic acid -- MPGES-1 -- NF-κB -- Nrf2 -- Inflammation, Macrophage polarization; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106310
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) relieve inflammation by suppressing prostaglandin E2 /cyclooxygenase 2 (PGE2 /COX-2) with cardiovascular and gastrointestinal bleeding risk. Theoretically, suppressing PGE2 through inhibiting the terminal synthase microsomal prostaglandin E2 synthase-1 (mPGES-1) instead of upstream COX-2 is ideal for inflammation. Here, (9 S, 13 R )−12-oxo-phytodienoic acid (AA-24) extracted from Artemisia anomala was first screened as an anti-inflammatory candidate and decreased inducible nitric oxide synthase (iNOS), nitric oxide (NO), mPGES-1, and PGE2 without affecting COX-1/2, thromboxane A2 (TXA2 ) and prostaglandin I2 (PGI2 ). Besides, AA-24 suppressed the differentiation of M0 macrophages to M1 phenotype but enhanced it to M2 phenotype, blocked the activation of NF-κB pathway, and increased the activation of Nrf2 and heme oxygenase-1 (HO-1). Moreover, AA-24 selectively inhibited mPGES-1 and reduced inflamed paw edema in carrageenan-induced mice. In conclusion, AA-24 attenuates inflammation by inhibiting mPGES-1 and modulating macrophage polarization via the NF-κB and Nrf2/HO-1 pathways and could be a promising candidate for developing anti-inflammatory drugs. Graphical Abstract: ga1 Highlights: (9S, 13R)−12-oxo-phytodienoic acid (AA-24) was first extracted from Artemisia anomala . AA-24 selectively reduced inducible PGE2 via inhibiting mPGES-1 but not COX-1/2 in vivo and in vitro. AA-24 suppressed the differentiation of M0 macrophages to M1 phenotype but enhanced it to M2. AA-24 regulated the activation of NF-κB and Nrf2/HO-1 pathways but not the MAPK pathway. AA-24 could be developed as a promising drug to relieve inflammation.