Abstract
Artocarpus heterophyllus, a popular tropical fruit commonly known as the jackfruit tree, is normally planted in subtropical or tropical areas. Since a variety of phytochemicals isolated from A. heterophyllus have been found to possess potently anti-inflammatory, antiviral and antimalarial activities, researchers have devoted much interest to its potential pharmaceutical value. However, the exact mechanism underlying its anti-inflammatory activity is not well characterized. In this study, seven natural products isolated from A. heterophyllus, including 25-Hydroxycycloart-23-en-3-one (HY), Artocarpin (AR), Dadahol A (DA), Morachalcone A (MA), Artoheterophyllin B (AB), Cycloheterophyllin (CY) and Moracin C (MC) were collected. Lipopolysaccharide (LPS)-stimulated inflammatory response in RAW264.7 macrophages were used in this study. Among these compounds, MC significantly inhibited LPS-activated reactive oxygen species (ROS) and nitric oxide (NO) release without marked cytotoxicity. Furthermore, MC effectively reduced LPS stimulated up-regulation of mRNA and protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and serval pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α)). Mechanistic studies revealed that the anti-inflammatory effect of MC was associated with the activation of the mitogen activated protein kinases (MAPKs) (including p38, ERK and JNK) and nuclear factor-κB (NF-κB) pathways, especially reducing the nuclear translocation of NF-κB p65 subunit as revealed by nuclear separation experiment and confocal microscopy.
Highlights
Inflammation is a complex and highly orchestrated network of immunological, physiological, and behavioral events that takes place following exposure to various harmful stimuli from intrinsic and extrinsic sources including tissue injury, extreme temperature, stimulant, infection of pathogens, and metabolic disorder [1,2]
Toll-like receptors complex (TLRs) signal pathway is activated by the binding of LPS, which triggers downstream of nuclear factor κB (NF-κB) and the mitogen activated protein kinases (MAPKs) pathways [6,7]
Luciferase reporter assay was conducted to investigate the transcriptional activity and we found that Moracin C (MC) significantly inhibited tumor necrosis factor α (TNF-α)-induced and LPS-induced NF-κB expression (Figure 6C)
Summary
Inflammation is a complex and highly orchestrated network of immunological, physiological, and behavioral events that takes place following exposure to various harmful stimuli from intrinsic and extrinsic sources including tissue injury, extreme temperature, stimulant, infection of pathogens, and metabolic disorder [1,2]. Releasing of inflammatory mediators during chronic inflammatory diseases is controlled by activation of intracellular signaling cascades. Once the encountered inflammatory stimuli such as LPS, IκB is phosphorylated and degraded, NF-κB is released and transferred from the cytoplasm to the nucleus, which leads to the overexpression of several inflammatory mediators, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [7,9]. A. heterophyllus, because of the nutritive value of its fruits and their biopharmaceutical activities, has attracted much research interest for decades Extracts of this species, the chemical constituents of which are mainly flavonoids, especially flavones, isoflavones, chalcones, xanthones and prenylated stilbenes, have been reported to possess several positive effects, such as anti-inflammatory [17], antioxidant, anti-hyperglycemic, antiviral [18], and antimalarial activities [19]. Our findings implied that MC might represent a potential therapy for treatment of inflammatory diseases
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