Abstract
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.
Highlights
Inflammation is an important mechanism contributing to the host defense against pathogenic challenges and the restoration of normal tissue structure [1]
Our results revealed that extract of RDP (EARDP) clearly inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK), Jun N-terminal kinases (JNK), and Akt in RAW 264.7 macrophages stimulated by LPS
In order to further establish that the inhibition of inflammatory signaling molecules by EARDP was related to the down-regulation of MAPKs and the Akt signaling pathway, we evaluated the effect of specific inhibitors of MAPKs and Akt on LPS-induced nitric oxide (NO) generation
Summary
Inflammation is an important mechanism contributing to the host defense against pathogenic challenges and the restoration of normal tissue structure [1]. Macrophages are the main pro-inflammatory cells, and they protect the body from external intruders, by releasing pro-inflammatory mediators and cytokines such as nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and IL-1β [2]. Under inflammatory conditions, these pro-inflammatory enzymes and cytokines induce cell and tissue injury involved in chronic inflammatory disorders such as hepatitis, rheumatoid arthritis, and atherosclerosis [3,4]. NF-κB regulates the gene expression of several pro-inflammatory cytokines, including TNF-α and IL-1β [5]. The expression of HO-1 is related to several signaling pathways, such as mitogen activated protein kinases (MAPKs), phosphoinositide
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