title: In vitro and in vivo anti-inflammatory effects of a novel 4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione.
abstract: Inflammation plays a critical defensive role in the human body. However, uncontrolled or aberrant inflammatory responses contribute to various acute and chronic diseases. The Nrf2-ARE pathway plays a pivotal role in the regulation of inflammatory markers, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). On the basis of this concept, we synthesized a novel anti-inflammatory 4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione (HPT), and in vitro experiments using HepG2-C8 ARE-luciferase-transfected cells demonstrated the induction of Nrf2-ARE activity. In lipopolysaccharide (LPS)-induced RAW 264.7 cells, HPT treatment reduced the production of nitric oxide (NO) as well as the protein and mRNA expression levels of COX-2 and iNOS, in a dose-dependent manner. In addition, HPT suppressed the mRNA expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. In LPS-induced macrophages, HPT inhibited COX-2 and iNOS by blocking the activation of p38 and c-Jun NH2-terminal kinase (JNK) but not extracellular signal-regulated kinase (ERK1/2). Furthermore, an in vivo anti-inflammatory study was performed using a TPA-induced skin inflammation mouse model, and the results showed that HPT reduced TPA-induced inflammation and attenuated the expression of COX-2 and iNOS in TPA-induced mouse skin tissue. Thus, HPT demonstrated anti-inflammatory activity both in LPS-induced RAW 264.7 cells and TPA-stimulated mouse skin and may therefore serve as a potential anti-inflammatory agent.
authors.affiliation: Center for Cancer Prevention Research, Department of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, The State University of New Jersey , 160 Frelinghuysen Road, Piscataway, New Jersey 08854, United States.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Lee
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.forename: Zheng-Yuan
authors.initials: ZY
authors.lastname: Su
authors.forename: Sarandeep S-S
authors.initials: SS
authors.lastname: Boyanapalli
authors.forename: Dipti N
authors.initials: DN
authors.lastname: Barman
authors.forename: Mou-Tuan
authors.initials: MT
authors.lastname: Huang
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Sadgopan
authors.initials: S
authors.lastname: Magesh
authors.forename: Longqin
authors.initials: L
authors.lastname: Hu
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; C000594451:4,6-bis ((E)-4-hydroxy-3-methoxystyryl)-1-phenethylpyrimidine-2(1H)-thione; D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D011743:Pyrimidines; D013871:Thiones; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate