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Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling via Targeting IKKα/β.

ABSTRACT: Acute lung injury (ALI) is life-threatening disease characterized by uncontrolled inflammatory response. IKKα/β, the key kinases in the activation of NF-κB pathway, are implicated in inflammatory pulmonary injury, and represent attractive targets for ALI therapy. Brevilin A (BVA) is a sesquiterpene lactone from Centipeda minima, a Chinese herb used to treat inflammatory diseases. This study aims to investigate the inhibition of BVA on ALI, with focus on clarifying the molecular mechanisms involved in BVA-mediated anti-inflammatory activity in macrophages. Briefly, BVA significantly inhibited the production of NO and PGE₂ by suppressing iNOS and COX2 expression, and suppressed the mRNA expression of IL-1β, IL-6, and TNFα in LPS/IFNγ-stimulated RAW264.7 macrophages. The anti-inflammatory activity of BVA was further confirmed in LPS/IFNγ-stimulated BMDMs and TNFα/IFNγ-exposed RAW264.7 cells. In vivo, BVA effectively attenuated LPS-induced lung damage, inflammatory infiltration, and production of pro-inflammatory cytokines, including MPO, IL-1β, IL-6, TNFα, and PGE₂. Mechanistically, BVA could covalently bind to the cysteine 114 of IKKα/β, and effectively inhibiting the activity and function of IKKα/β, thereby resulting in the suppression of phosphorylation and degradation of IκBα and the subsequent activation of NF-κB signaling. Furthermore, pretreatment of DTT, a thiol ligand donor, significantly abolished BVA-mediated effects in LPS/IFNγ-stimulated RAW264.7 cells, suggesting the crucial role of the electrophilic α, β-unsaturated ketone of BVA on its anti-inflammatory activity. These results suggest that BVA ameliorates ALI through inhibition of NF-κB signaling via covalently targeting IKKα/β, raising the possibility that BVA could be effective in the treatment of ALI and other diseases harboring aberrant NF-κB signaling.

SUBMITTER: Liu L

PROVIDER: S-EPMC9237443 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling <i>via</i> Targeting IKKα/β.

Liu Lu L Chen Xian X Jiang Yifang Y Yuan Yun Y Yang Luyao L Hu Qiongying Q Tang Jianyuan J Meng Xianli X Xie Chunguang C Shen Xiaofei X

Frontiers in pharmacology 20220614

Acute lung injury (ALI) is life-threatening disease characterized by uncontrolled inflammatory response. IKKα/β, the key kinases in the activation of NF-κB pathway, are implicated in inflammatory pulmonary injury, and represent attractive targets for ALI therapy. Brevilin A (BVA) is a sesquiterpene lactone from <i>Centipeda minima</i>, a Chinese herb used to treat inflammatory diseases. This study aims to investigate the inhibition of BVA on ALI, with focus on clarifying the molecular mechanisms ...[more]

PMID: 35774606

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Project description:BackgroundRenal fibrosis is considered an irreversible pathological process and the ultimate common pathway for the development of all types of chronic kidney diseases and renal failure. Diosmin is a natural flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether Diosmin protects kidneys by inhibiting renal fibrosis is unknown. We aimed to investigate the role of Diosmin in renal interstitial fibrosis and to explore the underlying mechanisms.MethodsThe UUO mouse model was established and gavaged with Diosmin (50 mg/kg·d and 100 mg/kg·d) for 14 days. HE staining, Masson staining, immunohistochemistry, western blotting and PCR were used to assess renal tissue injury and fibrosis. Elisa kits were used to detect the expression levels of IL-1β, IL-6, and TNF-α and the activity of SIRT3 in renal tissues. In addition, enrichment maps of RNA sequencing analyzed changes in signaling pathways. In vitro, human renal tubular epithelial cells (HK-2) were stimulated with TGF-β1 and then treated with diosmin (75 μM). The protein and mRNA expression levels of SIRT3 were detected in the cells. In addition, 3-TYP (selective inhibitor of SIRT3) and SIRT3 small interfering RNA (siRNA) were used to reduce SIRT3 levels in HK-2.ResultsDiosmin attenuated UUO-induced renal fibrosis and TGF-β1-induced HK-2 fibrosis. In addition, Diosmin reduced IL-1β, IL-6, and TNF-α levels in kidney tissues and supernatants of HK-2 medium. Interestingly, Diosmin administration increased the enzymatic activity of SIRT3 in UUO kidneys. In addition, Diosmin significantly increased mRNA and protein expression of SIRT3 in vitro and in vivo. Inhibition of SIRT3 expression using 3-TYP or SIRT3 siRNA abolished the anti-inflammatory effects of diosmin in HK-2 cells. Enrichment map analysis by RNA sequencing indicates that the nuclear factor-kappa B (NF-κB) signaling pathway was inhibited in the Diosmin intervention group. Furthermore, we found that TGF-β1 increased the nuclear expression of nuclear NF-κB p65 but had little significant effect on the total intracellular expression of NF-κB p65. Additionally, Diosmin reduced TGF-β1-caused NF-κB p65 nuclear translocation. Knockdown of SIRT3 expression by SIRT3 siRNA increased the nuclear expression of NF-κB p65 and abolished the inhibition effect of Diosmin in NF-κB p65 expression.ConclusionsDiosmin reduces renal inflammation and fibrosis, which is contributed by inhibiting nuclear translocation of NF-κB P65 through activating SIRT3.

Dataset Information

Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling via Targeting IKKα/β.

Publications

Brevilin A Ameliorates Acute Lung Injury and Inflammation Through Inhibition of NF-κB Signaling <i>via</i> Targeting IKKα/β.

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