Abstract
As part of our continuous effort to find potential anti-inflammatory agents from endophytic fungi, a Fusarium solani strain, isolated from the plant Aponogeton undulatus Roxb., was investigated. Cerevisterol (CRVS) was identified from endophytic fungi, a Fusarium solani strain, and moreover exhibited anti-inflammatory activity. However, the underlying mode of action remains poorly understood. The aim of this study is to reveal the potential mechanisms of CRVS against inflammation on a molecular level in LPS-activated RAW 264.7 peritoneal macrophage cells. CRVS was isolated from F. solani and characterized based on spectral data analysis. The MTT assay was performed to measure cell viability in CRVS-treated macrophages. Anti-inflammatory activity was assessed by measurement of nitric oxide (NO) and prostaglandin E2 (PGE2) levels, as well as the production of various cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and -6 (IL-6) in LPS-stimulated macrophages. RT-PCR and immunoblotting analyses were done to examine the expression of various inflammatory response genes. A reporter gene assay was conducted to measure the level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein-1 (AP-1) transactivation. CRVS suppresses the LPS-induced production of NO and PGE2, which is a plausible mechanism for this effect is by reducing the expression of iNOS and COX-2. CRVS also decreases the expression of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β. CRVS halted the nuclear translocation of NF-κB by blocking the phosphorylation of inhibitory protein κBα (IκBα) and suppressing NF-κB transactivation. The mitogen-activated protein kinases (MAPK) signaling pathways are also suppressed. CRVS treatment also inhibited the transactivation of AP-1 and the phosphorylation of c-Fos. Furthermore, CRVS could induce the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) by down-regulating Kelch-like ECH-associated protein 1 (Keap-1) and up-regulating hemeoxygenases-1 (HO-1) expression. The results suggest that CRVS acts as a natural agent for treating inflammatory diseases by targeting an MAPK, NF-κB, AP-1, and Nrf2-mediated HO-1 signaling cascade.
Highlights
Inflammation is a physiological defense response of the body to tissue injury and infection caused by wounding, microbial pathogen infections, or chemical irritation [1]
Several evidence suggest that hemeoxygenase-1 (HO-1), which is tightly regulated by the activation of mitogen activated protein kinases (MAPK)-mediated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, has a crucial role in inhibiting the production of reactive oxygen species (ROS) and pro-inflammatory cytokines in LPS-stimulated macrophages [11,12]
264.7 cells by 6.2 fold and 3.25 fold, respectively, whereas CRVS causes a significant reduction in the level of phosphorylated c-Fos in a concentration-dependent manner but does not change the level of phosphorylated c-Jun (Figure 2E). These results suggest a prospective role for NF-κB and AP-B1iominoltechuelesa2t0t2e0n, u10a, t1i9o9n of pro-inflammatory mediators by CRVS in activated macrophages. 6 of 13
Summary
Inflammation is a physiological defense response of the body to tissue injury and infection caused by wounding, microbial pathogen infections, or chemical irritation [1]. Various innate immune cells such as macrophages, fibroblasts, mast cells, and neutrophils are activated in response to infection Among these responses, the activation of macrophages plays a pivotal role in the progression of multiple inflammatory diseases via the release of large amounts of nitric oxide (NO), prostaglandin (PG), and pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and -6 (IL-6), and reactive oxygen species (ROS) [2,3]. Several evidence suggest that hemeoxygenase-1 (HO-1), which is tightly regulated by the activation of MAPK-mediated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, has a crucial role in inhibiting the production of ROS and pro-inflammatory cytokines in LPS-stimulated macrophages [11,12]. Scavenging of ROS and activating cellular anti-oxidation systems are thought to be strategies for defeating inflammation
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