Abstract
In this study, we investigated the anti-inflammatory effect of rosmarinic acid methyl ester (RAME) isolated from a mutant cultivar of Perilla frutescens (L.) Britton. We found that RAME inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production, with an IC50 of 14.25 µM, in RAW 264.7 cells. RAME inhibited the LPS-induced expression of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein-1, interferon-β, and inducible nitric oxide synthase (iNOS). Moreover, RAME suppressed the activation of nuclear factor kappa B. These results suggest that the downregulation of iNOS expression by RAME was due to myeloid differentiation primary response gene 88 (MyD88)-dependent and -independent pathways. Furthermore, RAME induced the expression of heme oxygenase-1 (HO-1) through activation of nuclear factor-erythroid 2-related factor 2. Treatment with tin protoporphyrin, an inhibitor of HO-1, reversed the RAME-induced suppression of NO production. Taken together, RAME isolated from P. frutescens inhibited NO production in LPS-treated RAW 264.7 cells through simultaneous induction of HO-1 and inhibition of MyD88-dependent and -independent pathways.
Highlights
Inflammation, involved in the non-specific immune system, occurs in response to bodily injury and is required for the continuation of health in the presence of bacterial and viral infections [1].Acute and chronic inflammation can prove harmful, contributing to the pathogenesis of a variety of diseases including inflammatory bowel disease, multiple sclerosis, atherosclerosis, arthritis, and asthma [2,3]
By rosmarinic acid methyl ester (RAME) in a dose-dependent manner (Figure 2c). These results suggest that nitric oxide (NO) production was
We found that heme oxygenase-1 (HO-1) mRNA and protein expression levels were increased by RAME via translocation of Nrf2 to the nucleus (Figure 6a–c)
Summary
Inflammation, involved in the non-specific immune system, occurs in response to bodily injury and is required for the continuation of health in the presence of bacterial and viral infections [1].Acute and chronic inflammation can prove harmful, contributing to the pathogenesis of a variety of diseases including inflammatory bowel disease, multiple sclerosis, atherosclerosis, arthritis, and asthma [2,3]. Macrophages play an important role in inflammatory diseases related to over-production of inflammatory mediators including interleukin (IL)-1β, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α reactive oxygen species (ROS), and nitric oxide (NO) [4,5]. Nitric oxide synthase (NOS), which is responsible for NO synthesis from L-arginine, has three isoforms: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) [6,7]. Macrophages express iNOS in response to inflammatory mediators such as lipopolysaccharide (LPS). A decrease in NO production by iNOSby inhibition has therapeutic potential [12],diabetes and diabetes [12]. A decrease in NO production iNOS inhibition has therapeutic in variousin inflammatory conditionsconditions [13]
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