In Vitro and In Vivo Antifibrotic Effects of Fraxetin on Renal Interstitial Fibrosis via the ERK Signaling Pathway

Hsieh, Yi‐Hsien; Hung, Tung-Wei; Chen, Yong-Syuan; Huang, Yen‐Hua; Chiou, Hui‐Ling; Lee, Chu-Che; Tsai, Jen-Pi

doi:10.3390/toxins13070474

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…An interesting finding was that coumarin derivatives, including fraxetin, may enhance the production of IL-10 and IFN-α which are well documented to abrogate the inflammasome-driven augmentation of the in-flammatory process [39,40]. Moreover, TGF-β1 which is proven to initiate activation of the NLRP3 inflammasome and induce epithelial-to-mesenchymal transition with subsequent fibrosis is effectively inhibited by fraxetin administration [41].…”

Section: Discussionmentioning

confidence: 99%

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Kabel

Salama

Adwas³

et al. 2021

Pharmaceuticals

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Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.

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Section: Discussionmentioning

confidence: 99%

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Kabel

Salama

Adwas³

et al. 2021

Pharmaceuticals

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“…However, fraxetin was reported to be effective in protecting the liver, kidneys, and heart. [ 6,30–33 ] These reports suggest that fraxetin may serve as a promising anticancer drug. Our data revealed that fraxetin inhibited viability and promoted apoptosis of bladder cancer cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Fraxetin (7,8‐dihydroxy‐6‐methoxy coumarin) is a natural compound extracted from the Chinese herb Cortex Fraxini . [ 5,6 ] Fraxetin has been widely used in Chinese traditional medicine, and it serves as the essential ingredient of many dietary and herbal supplements. [ 7–9 ] Fraxetin is readily available and relatively cheap and is known to have few side effects.…”

Section: Introductionmentioning

confidence: 99%

Fraxetin inhibits proliferation and induces apoptosis of bladder cancer through the Akt pathway in vitro and in vivo

Weng,

Deng,

Huang

et al. 2023

J Biochem & Molecular Tox

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Fraxetin, a natural compound extracted from the Chinese herb Cortex Fraxini, is reported to boast extensive antitumor properties in various cancers. However, whether fraxetin exhibited an anticancer effect on bladder cancer remains unknown. In this study, cell counting kit‐8 was utilized to detect cell viability. Flow cytometry analysis was performed for cell apoptosis analysis. Western blot analysis and real‐time PCR were used to ascertain gene expression analysis. A mouse bladder cancer xenograft model was established and subjected to fraxetin treatment. Fraxetin reduced the viability of bladder cancer cells, induced apoptosis in vitro, and inhibited the growth of bladder cancer in vivo. Fraxetin inhibited the Akt pathway in J82 cells. In conclusion, the growth inhibitory properties of fraxetin against bladder cancer may be mediated via an Akt inhibitory effect and cell apoptosis promotion.

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“…In this study, HDHW components were identified by UHPLC-Q-Orbitrap-MS/MS and 14 components were identified. Among these 14 ingredients, the anti-renal fibrosis effects of Linoleic acid (Zhan et al, 2015;Zhou et al, 2017), Oleanolic acid (Zhao and Luan, 2020), Nicotinamide (Kumakura et al, 2021), Rutin (Han et al, 2015;Wang et al, 2016), Gallic acid (Yousuf and Vellaichamy, 2015), Ferulic acid (Mir et al, 2018;Qi et al, 2020), Fraxetin (natural derivatives of coumarin) (Hsieh et al, 2021), and Theophylline (adenosine antagonist) (Tang et al, 2015) have been demonstrated. They exert antifibrotic effects mainly through autophagy regulation, apoptosis regulation, antioxidant, and anti-inflammatory.…”

Section: Discussionmentioning

confidence: 99%

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

Tian

Pan

et al. 2022

Front. Pharmacol.

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Renal fibrosis is a common pathway for the progression of various chronic kidney diseases (CKD), and the formation and deterioration will eventually lead to end-stage renal failure, which brings a heavy medical burden to the world. HeidihuangWan (HDHW) is a herbal formulation with stable and reliable clinical efficacy in the treatment of renal fibrosis. However, the mechanism of HDHW in treating renal fibrosis is not clear. In this study, we aimed to investigate the mechanism of HDHW to improve renal fibrosis. Wistar rats were randomly divided into the normal control group, 5/6 Nephrectomy group, astragaloside IV (AS-IV) group, HDHW group, and HDHW + IGF-1R inhibitor (JB1) group. Except for the normal control group, the rat renal fibrosis model was established by 5/6 nephrectomy and intervened with drugs for 8 weeks. Blood samples were collected to evaluate renal function. Hematoxylin-Eosin (HE), Periodic Acid-Schiff (PAS), Modified Masson’s Trichrome (Masson) staining were used to evaluate the pathological renal injury, and immunohistochemistry and Western blotting were used to detect the protein expression of renal tissue. The results showed that HDHW was effective in improving renal function and reducing renal pathological damage. HDHW down-regulated the levels of fibrosis marker proteins, including α-smooth muscle actin (α-SMA), vimentin, and transforming growth factors–β(TGF-β), which in turn reduced renal fibrosis. Further studies showed that HDHW down-regulated the expression of autophagy-related proteins Beclin1 and LC3II, indicating that HDHW inhibited autophagy. In addition, we examined the activity of the class I phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway, an important signaling pathway regulating autophagy, and the level of insulin-like growth factor 1 (IGF-1), an upstream activator of PI3K/Akt/mTOR. HDHW upregulated the expression of IGF-1 and activated the PI3K/Akt/mTOR pathway, which may be a vital pathway for its inhibition of autophagy. Application of insulin-like growth factor 1 receptor (IGF-1R) inhibitor further confirmed that the regulation of autophagy and renal fibrosis by HDHW was associated with IGF-1-mediated activation of the PI3K/Akt/mTOR pathway. In conclusion, our study showed that HDHW inhibited autophagy by upregulating IGF-1 expression, promoting the binding of IGF-1 to IGF-1R, and activating the PI3K/Akt/mTOR signaling pathway, thereby reducing renal fibrosis and protecting renal function. This study provides support for the application and further study of HDHW.

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In Vitro and In Vivo Antifibrotic Effects of Fraxetin on Renal Interstitial Fibrosis via the ERK Signaling Pathway

Cited by 11 publications

References 43 publications

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity

Fraxetin inhibits proliferation and induces apoptosis of bladder cancer through the Akt pathway in vitro and in vivo

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

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