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Chrysoeriol ameliorates COX-2 expression through NF-κB, AP-1 and MAPK regulation via the TLR4/MyD88 signaling pathway in LPS-stimulated murine macrophages.

ABSTRACT: Chrysoeriol is a flavonoid that has diverse biological properties, including antioxidation, anti-inflammation, chemoprevention and immunomodulation. Despite its reported anti-inflammatory activity, the exact underlying molecular mechanism has not yet been elucidated. In the current study, the anti-inflammatory mechanism of chrysoeriol involving lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2) and its upstream signaling molecules was investigated in RAW 264.7 cells. The mechanism was evaluated via ELISA and western blotting assays. Chrysoeriol significantly inhibited LPS-induced prostaglandin E₂ (PGE₂) production and COX-2 expression without cytotoxicity. Activated transcription factors that further induced the inflammation response, including nuclear factor (NF)-κB and activator protein-1 (AP-1), were significantly attenuated by chrysoeriol treatment. Furthermore, LPS-induced phosphorylation levels of phosphoinositide-3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) were abolished by chrysoeriol treatment, which was confirmed by selective inhibitors. Additionally, chrysoeriol significantly inhibited the LPS-induced activation of adaptor molecules in RAW 264.7 cells, including toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88. Therefore, the results suggested that chrysoeriol ameliorates TLR4-mediated inflammatory responses by inhibiting NF-κB and AP-1 activation as well as suppressing PI3K/Akt and MAPK phosphorylation in LPS-stimulated RAW 264.7 cells.

SUBMITTER: Yoon HS

PROVIDER: S-EPMC8120564 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Salidroside (Sal) is an active ingredient that is isolated from Rhodiola rosea, which has been reported to have anti-inflammatory activities and a renal protective effect. However, the role of Sal on renal fibrosis has not yet been elucidated. Here, the purpose of the current study is to test the protective effects of Sal against renal interstitial fibrosis (RIF), and to explore the underlying mechanisms using both in vivo and in vitro models. In this study, we establish the unilateral ureteric obstruction (UUO) or folic acid (FA)-induced mice renal interstitial fibrosis in vivo and the transforming growth factor (TGF)-β1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro. The levels of kidney functional parameters and inflammatory cytokines in serum are examined. The degree of renal damage and fibrosis is determined by histological assessment. Immunohistochemistry and western blotting are used to determine the mechanisms of Sal against RIF. Our results show that treatment with Sal can ameliorate tubular injury and deposition of the extracellular matrix (ECM) components (including collagen Ш and collagen I). Furthermore, Sal administration significantly suppresses epithelial-mesenchymal transition (EMT), as evidenced by a decreased expression of α-SMA, vimentin, TGF-β1, snail, slug, and a largely restored expression of E-cadherin. Additionally, Sal also reduces the levels of serum biochemical markers (serum creatinine, Scr; blood urea nitrogen, BUN; and uric acid, UA) and decreases the release of inflammatory cytokines (IL-1β, IL-6, TNF-α). Further study revealed that the effect of Sal on renal interstitial fibrosis is associated with the lower expression of TLR4, p-IκBα, p-NF-κB and mitogen-activated protein kinases (MAPK), both in vivo and in vitro. In conclusion, Sal treatment improves kidney function, ameliorates the deposition of the ECM components and relieves the protein levels of EMT markers in mouse kidneys and HK-2 cells. Furthermore, Sal treatment significantly decreases the release of inflammatory cytokines and inhibits the TLR4/NF-κB and MAPK signaling pathways. Collectively, these results suggest that the administration of Sal could be a novel therapeutic strategy in treating renal fibrosis.

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Chrysoeriol ameliorates COX-2 expression through NF-κB, AP-1 and MAPK regulation via the TLR4/MyD88 signaling pathway in LPS-stimulated murine macrophages.

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