Anti-Inflammatory Effects of Ribes diacanthum Pall Mediated via Regulation of Nrf2/HO-1 and NF-κB Signaling Pathways in LPS-Stimulated RAW 264.7 Macrophages and a TPA-Induced Dermatitis Animal Model

• Published in: Antioxidants 2020-07, Vol.9 (7), p.622
• Main Authors: Kim, Na Yeon, Cheong, Sun Hee, Lee, Kun Jong, Sok, Dai-Eun, Kim, Mee Ree
• Format: Article
• Language: English
• Subjects: 12-O-Tetradecanoylphorbol-13-acetate; Acetic acid; Acids; AKT protein; Animal models; anti-inflammation; Bioassays; Cell death; Cyclooxygenase-2; Cytokines; Cytotoxicity; Dermatitis; Enzymes; Flavonoids; Gene expression; Heme; Heme oxygenase (decyclizing); HO-1; Inflammation; Inflammatory diseases; Interleukin 6; Kinases; Lipopolysaccharides; Macrophages; Malondialdehyde; MAP kinase; NF-κB; NF-κB protein; Nitric oxide; Nitric-oxide synthase; Nrf2; Nuclear transport; Oxidative stress; Oxygenase; Penicillin; Phosphorylation; Protein kinase; Proteins; RAW 264.7 macrophages; Reactive oxygen species; Ribes diacanthum; Ribes diacanthum Pall; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox9070622

Ribes diacanthum Pall (RDP) is a Mongolian traditional medicine used to treat renal inflammation. In the present study, we initially investigated the anti-inflammatory effects and mechanisms of action of ethylacetate extract of RDP (EARDP) in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS) and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced dermatitis in mice. We demonstrated that EARDP protected against LPS-induced cell death by inhibiting intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) production, as well as the synthesis of pro-inflammatory mediators and cytokines, such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. EARDP inhibited the phosphorylation and degradation of inhibitory κB-α (IκB-α) and the activation of nuclear factor (NF)-κB, indicating that the anti-inflammatory effect of EARDP was mediated via the suppression of NF-κB nuclear translocation. In addition, EARDP induced the heme oxygenase-1 (HO-1) expression and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2), indicating that EARDP induced HO-1 via the Nrf2 pathway in RAW 264.7 cells. Furthermore, EARDP significantly suppressed the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW 264.7 macrophages. However, ZnPP, a specific inhibitor of HO-1, reversed the EARDP-mediated inhibition of NO and TNF-α production in LPS-stimulated RAW 264.7 macrophages. EARDP blocked the phosphorylation of mitogen-activated protein kinase (MAPK) and Akt in LPS-stimulated RAW 264.7 cells. In the in vivo animal model, EARDP significantly and dose-dependently reduced TPA-induced secretion of TNF-α and IL-6 in mouse ear. Based on these results, EARDP represents a promising natural compound, protective against oxidative stress and inflammatory diseases.