Myricetin ameliorates bleomycin-induced pulmonary fibrosis in mice by inhibiting TGF-β signaling via targeting HSP90β

Li, Xiaohe; Yu, Haiyan; Liang, Lu; Bi, Zhun; Wang, Yanhua; Gao, Shaoyan; Wang, Mukuo; Li, Hailong; Yang, Miao; Deng, Ruru; Ma, Ling; Luan, Jiaoyan; Li, Shuangling; Liu, Menghan; Lin, Jianping; Yang, Cheng

doi:10.1016/j.bcp.2020.114097

Cited by 35 publications

(23 citation statements)

References 43 publications

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“…However, the detailed mechanisms still are not very clear. In our previous study, we reported that myricetin could effectively attenuate pulmonary fibrosis of BLM-treated mice ( Li et al, 2020 ). Here, we evaluated the effect of dihydromyricetin in vivo on BLM-induced pulmonary inflammatory and fibrosis, and the results indicated that dihydromyricetin also could effective improve pulmonary inflammatory and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis

Tu¹,

Wei²,

Cui³

et al. 2021

Phytomedicine

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Background COVID-19 (Coronavirus Disease-2019) has spread widely around the world and impacted human health for millions. The lack of effective targeted drugs and vaccines forces scientific world to search for new effective antiviral therapeutic drugs. It has reported that flavonoids have potential inhibitory activity on SARS-CoV-2 M pro and anti-inflammatory properties. Dihydromyricetin, as a flavonol, also has antiviral and anti-inflammatory potential. However, the inhibition of dihydromyricetin on SARS-CoV-2 M pro and the protective effect of dihydromyricetin on pulmonary inflammation and fibrosis have not been proved and explained. Purpose The coronavirus main protease (M pro ) is essential for SARS-CoV-2 replication and to be recognized as an attractive drug target, we expect to find the inhibitor of M pro . Novel coronavirus infection can cause severe inflammation and even sequelae of pulmonary fibrosis in critically ill patients. We hope to find a drug that can not only inhibit virus replication but also alleviate inflammation and pulmonary fibrosis in patients. Methods FRET-based enzymatic assay was used to evaluate the inhibit activity of dihydromyricetin on SARS-CoV-2 M pro . Molecular docking was used to identify the binding pose of dihydromyricetin with SARS-CoV-2 M pro . The protective effects of dihydromyricetin against BLM-induced pulmonary inflammation and fibrosis were investigated in C57BL6 mice. BALF and lung tissue were collected for inflammation cells count, ELISA, masson and HE staining, western blotting and immunohistochemistry to analyze the effects of dihydromyricetin on pulmonary inflammation and fibrosis. MTT, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and wound healing were used to analyze the effects of dihydromyricetin on lung fibrosis mechanisms in Mlg cells. Results In this study, we found that dihydromyricetin is a potent inhibitor targeting the SARS-CoV-2 M pro with a half-maximum inhibitory concentration (IC 50 ) of 1.716±0.419μM, using molecular docking and the FRET-based enzymatic assay. The binding pose of dihydromyricetin with SARS-CoV-2 M pro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 M pro , the dihydrochromone ring of dihydromyricetin interact with the imidazole side chain of His163 through π-π stacking. The 1-oxygen of dihydromyricetin forms a hydrogen bond with the backbone nitrogen of Glu166. The 3-, 7-, 3’- and 4’-hydroxyl of dihydromyricetin interact with Gln189, Leu141, Arg188 and Thr190 through hydrogen bonds. Moreover, our results showed that dihydromyricetin can significantly alleviate BLM-induced pulmonary inflammation by i...

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Section: Discussionmentioning

confidence: 99%

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis

Tu¹,

Wei²,

Cui³

et al. 2021

Phytomedicine

Self Cite

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“…It is important to note a recent report showing that myricetin, a flavonoid commonly found in dietary sources, inhibits Smad2 phosphorylation and MAPK and Akt signaling through interaction with HSP90β and TGF-β receptor 2. The authors of this report also showed that myricetin at a dose of 25-100 mg/kg ameliorated BLM-induced pulmonary fibrosis in mice [32]. Further study will be required to clarify the involvement of HSP90 in the inhibitory effects of kurarinone on TGF-β signaling and pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 63%

Kurarinone Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting TGF-β Signaling Pathways

Park

Kim

Lee

et al. 2021

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a refractory interstitial lung disease for which there is no effective treatment. Although the pathogenesis of IPF is not fully understood, TGF-β and epithelial–mesenchymal transition (EMT) have been shown to be involved in the fibrotic changes of lung tissues. Kurarinone is a prenylated flavonoid isolated from Sophora Flavescens with antioxidant and anti-inflammatory properties. In this study, we investigated the effect of kurarinone on pulmonary fibrosis. Kurarinone suppressed the TGF-β-induced EMT of lung epithelial cells. To assess the therapeutic effects of kurarinone in bleomycin (BLM)-induced pulmonary fibrosis, mice were treated with kurarinone daily for 2 weeks starting 7 days after BLM instillation. Oral administration of kurarinone attenuated the fibrotic changes of lung tissues, including accumulation of collagen and improved mechanical pulmonary functions. Mechanistically, kurarinone suppressed phosphorylation of Smad2/3 and AKT induced by TGF-β1 in lung epithelial cells, as well as in lung tissues treated with BLM. Taken together, these results suggest that kurarinone has a therapeutic effect on pulmonary fibrosis via suppressing TGF-β signaling pathways and may be a novel drug candidate for pulmonary fibrosis.

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“…However, the potential impact of 17-DMAG in the preclinical models of SSc on serum levels of other cytokines and chemokines, which play vital roles in the pathogenesis of SSc and the progression of fibrosis, such as TGF-β [3] and IL-8 [71], needs to be elucidated by further investigation. Several studies involving different Hsp90 inhibitors have already demonstrated antifibrotic effects mediated by the inhibition of the TGF-β pathway in experimental models of lung fibrosis [51][52][53][54][55][56]. Interestingly, in the study by Sibinska et al [55], only the lower dose of 17-DMAG (i.e., 10 mg/kg vs. 25 mg/kg) significantly decreased both the bronchoalveolar lavage fluid and serum levels of TGF-β in the bleomycin-induced pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 96%

“…Furthermore, inhibition of Hsp90 by 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) efficiently reduced TGF-β-driven activation of fibroblasts and production of ECM in vitro and attenuated progression of established fibrosis in a mouse model of pulmonary fibrosis [51]. More recently, five other studies have confirmed potent antifibrotic effects of various Hsp90 inhibitors, including 17-DMAG, in several preclinical models of pulmonary fibrosis [52][53][54][55][56]. Similarly, the treatment with 17-AAG blocked the TGF-β-induced production of ECM in renal fibroblasts in vitro and suppressed renal fibrosis in a murine model of unilateral ureteral obstruction [48].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin

Štorkánová

Navrátilová

et al. 2021

Biomedicines

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Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.

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Myricetin ameliorates bleomycin-induced pulmonary fibrosis in mice by inhibiting TGF-β signaling via targeting HSP90β

Cited by 35 publications

References 43 publications

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis

Kurarinone Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting TGF-β Signaling Pathways

Inhibition of Hsp90 Counteracts the Established Experimental Dermal Fibrosis Induced by Bleomycin

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