Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial–mesenchymal transition and inflammation

Abstract

Idiopathic pulmonary fibrosis (IPF) is featured with inflammation and extensive lung remodeling caused by overloaded deposition of extracellular matrix. Scutellarin is the major effective ingredient of breviscapine and its anti-inflammation efficacy has been reported before. Nevertheless, the impact of scutellarin on IPF and the downstream molecular mechanism remain unclear. In this study, scutellarin suppressed BLM-induced inflammation via NF-κB/NLRP3 pathway both in vivo and in vitro. BLM significantly elevated p-p65/p65 ratio, IκBα degradation, and levels of NLRP3, caspase-1, caspase-11, ASC, GSDMDNterm, IL-1β, and IL-18, while scutellarin reversed the above alterations except for that of caspase-11. Scutellarin inhibited BLM-induced epithelial–mesenchymal transition (EMT) process in vivo and in vitro. The expression levels of EMT-related markers, including fibronectin, vimentin, N-cadherin, matrix metalloproteinase 2 (MMP-2) and MMP-9, were increased in BLM group, and suppressed by scutellarin. The expression level of E-cadherin showed the opposite changes. However, overexpression of NLRP3 eliminated the anti-inflammation and anti-EMT functions of scutellarin in vitro. In conclusion, scutellarin suppressed inflammation and EMT in BLM-induced pulmonary fibrosis through NF-κB/NLRP3 signaling.

Wenfei Buqi Tongluo Formula Against Bleomycin-Induced Pulmonary Fibrosis by Inhibiting TGF-β/Smad3 Pathway

“…Baicalin ameliorates BLM-induced PF by regulating the PI3K/Akt and TGF-β signaling pathways (Huang et al, 2016;Zhao et al, 2020). The in vitro and in vivo evidence demonstrates that scutellarein and scutellarin can inhibit PF progression through regulation of the TGF-β/Smad, PI3K/Akt, Bax/Bcl2, or NF-κB/NLRP3 pathways (Miao et al, 2020;Peng et al, 2020). Moreover, four compounds, namely, baicalein, 7-O-β-D-glucuronide, viscidulin I, and viscidulin III, were screened out as the top key compounds by topological property (Supplementary Figure S3) from the network pharmacology, which are from Huang qin (Supplementary Table S1).…”

“…The role of WBT on ECM accumulation might be related to the activation of matrix metalloproteinases (MMPs), including collagenases (MMP1 and MMP8), gelatinases (MMP2 and MMP9), and stromelysins (MMP3 and MMP7) (Mahalanobish et al, 2020); however, the specific effect and mechanisms of MMPs need to be further investigated for supporting the prediction of the network pharmacology. Furthermore, some of the chemical components of WBT, such as amygdalin, scutellarin, and salvianolic acid B, have been reported to inhibit the EMT by regulating several markers, including α-SMA, E-cadherin, and N-cadherin (Liu et al, 2016;Wang et al, 2019;Peng et al, 2020). In addition, other signaling pathways, such as FGF, EGFR, VEGFA, and MAPK, play potential roles in the pathogenesis of PF (Iyer et al, 2015;Venkataraman and Frieman, 2017;Koo et al, 2018;Guo et al, 2021), which have been enriched as potential targets of WBT and are involved in cytokine production, cell proliferation, adhesion and migration, ECM degradation, and MMP activation.…”

Hypermethylation of the Promoter of miR-338-5p Mediates Aberrant Expression of ETS-1 and Is Correlated With Disease Severity Of Astrocytoma Patients

“…Our results were consistent with those of Ren et al and would reveal the potential mechanism underlying the high expression of MMPs, that is, the high expression of ETS-1 in astrocytoma tissue may eventually participate in the high expression of MMPs. The highly aggressive characteristics of malignant tumor cells are closely related to disease progression; the main mechanism of this process is that malignant tumor cells destroy ECM through MMPs and so on to reshape the basic structure of tissues, thereby promoting both the growth of tumor cells and their transfer to other locations (44)(45)(46)(47)(48). As a transcription factor, ETS-1 can mediate the transcription of MMPs, etc.…”

Huoxue Qianyang Qutan recipe attenuates cardiac fibrosis by inhibiting the NLRP3 inflammasome signalling pathway in obese hypertensive rats

“…Myocardial fibrosis is a hallmark of myocardial remodelling in obesity and hypertension, reflecting abnormalities of extracellular matrix (ECM) synthesis and degradation (Talman and Ruskoaho 2016). There is increasing evidence that the NLRP3 inflammasome signal can mediate fibrotic diseases by promoting the profibrotic phenotype of various cells via IL-1b (Peng et al 2020). Local secretion of IL-1b can enhance inflammatory response and promote the process of myocardial fibrosis (Ren et al 2020) by regulating ECM metabolism and thus fibroblast function (Jia et al 2016).…”