Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress

Yang, Ji Hye; Kim, Sang Chan; Kim, Kyu Min; Jang, Chang Ho; Cho, Sam Seok; Kim, Seung Jung; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

doi:10.1016/j.ejphar.2016.04.042

Cited by 100 publications

(79 citation statements)

References 35 publications

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“…Isorhamnetin was reported to be efficacious in protecting hepatocytes against oxidative stress through the activation of AMPK pathways [51]. A recent study verified the hepatoprotective function of isorhamnetin in attenuating liver fibrosis by inhibiting TGF- β /Smad and Nrf2 signalings [52]. It was also shown that narcissin possessed significant antioxidant effects on non-enzyme-induced lipid peroxidation in isolated microsomes and increased hepatic cell viability in both CCl 4 - and t-BuOOH-induced injury models [53].…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Wu¹,

Zhang²,

Huang³

et al. 2017

Oxidative Medicine and Cellular Longevity

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Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and α-glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol-enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1–6 cells from hydrogen peroxide- (H2O2-) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP-induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP-mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase-3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP-intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2-related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1(HO-1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin-3-O-β-D-glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP-induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2-mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components.

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Section: Discussionmentioning

confidence: 99%

Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Wu¹,

Zhang²,

Huang³

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…Regardless of etiology, profibrotic signaling pathways are associated with oxidative stress (Jiang et al 2014; Ramirez et al 2007; Sueblinvong et al 2016; Yang et al 2016; Zhang et al 2015). Stress fiber formation is regulated by pathways involving GTPase signaling and actin depolymerization (Pellegrin and Mellor 2007) which is affected by Cd-induced oxidative stress in mouse lung fibroblast (Go et al 2013a) (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

Fernandes

Jones

et al. 2017

Toxicology

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Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis. Contributions of exogenous exposures, such as dietary Cd, to pulmonary fibrosis remain incompletely defined. In the current study, we tested whether Cd activates fibrotic signaling in human fetal lung fibroblasts (HFLF) at micromolar and submicromolar Cd concentrations that do not cause cell death. Exposure of HFLF to low-dose Cd (≤1.0 μM) caused an increase in stress fibers and increased protein levels of myofibroblast differentiation markers, including α-smooth muscle actin (α-SMA) and extra-domain-A-containing fibronectin (ED-A-FN). Assay of transcription factor (TF) activity using a 45-TF array showed that Cd increased activity of 12 TF, including SMAD2/3/4 (mothers against decapentaplegic homolog) signaling differentiation and fibrosis. Results were confirmed by real-time PCR and supported by increased expression of target genes of SMAD2/3/4. Immunocytochemistry of lungs of mice exposed to Cd (0.3 and 1.0 mg/L in drinking water) showed increased α-SMA staining with lung Cd accumulation similar to lung Cd in non-smoking humans. Together, the results show that relatively low Cd exposures stimulate pulmonary fibrotic signaling and myofibroblast differentiation by activating SMAD2/3/4–dependent signaling. The results indicate that dietary Cd intake could be an important variable contributing to pulmonary fibrosis in humans.

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“…Increased SMAD3/TGF-β1 signaling contributes to the development of hepatic fibrosis in cholestatic liver disease, 19,32 but menin’s role in liver pathology has not been well defined. We have previously shown that menin expression is downregulated in cholangiocarcinoma and overexpressing menin in a xenograft model inhibits cholangiocarcinoma growth.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2 −/− mice

Hall

Ehrlich

Meng

et al. 2017

Journal of Surgical Research

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Background Liver transplantation remains the primary treatment for primary sclerosing cholangitis (PSC). Mdr2−/− mice provide a reliable in vivo model of PSC and develop characteristic biliary inflammation and fibrosis. We tested the hypothesis that the tumor suppressor protein menin is implicated in the progression of liver fibrosis and that menin expression can be regulated in the liver via microRNA-24 (miR-24). Materials and methods Menin expression was measured in human PSC and Mdr2−/− mice. Twelve-week-old FVB/NJ wild-type (WT) and Mdr2−/− mice were treated with miR-24 Vivo-Morpholino to knockdown miR-24 expression levels. Liver fibrosis was evaluated by Sirius Red staining and quantitative polymerase chain reaction (qPCR) for genes associated with liver fibrosis, such as fibronectin 1, collagen type 1 alpha 1, transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin. Studies were also performed in vitro using immortalized murine cholangiocyte lines treated with miR-24 hairpin inhibitor and mimic. Results Menin gene expression was increased in Mdr2−/− mice and late-stage human PSC samples. Treatment of FVB/NJ WT and Mdr2−/− mice with miR-24 Vivo-Morpholino increased menin expression, which correlated with increased expression of fibrosis genes. In vitro, inhibition of miR-24 also significantly increased the expression of fibrosis genes. Conclusions Inhibition of miR-24 increases menin and TGF-β1 expression, subsequently increasing hepatic fibrosis in FVB/NJ WT and Mdr2−/− mice. Modulation of the menin/miR-24 axis may provide novel targeted therapies to slow the progression of hepatic fibrosis into cirrhosis in PSC patients by altering TGF-β1 expression.

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Isorhamnetin attenuates liver fibrosis by inhibiting TGF-β/Smad signaling and relieving oxidative stress

Cited by 100 publications

References 35 publications

Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Hepatoprotective Effect of Polyphenol‐Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen‐Induced Liver Injury in Mice

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis

Inhibition of microRNA-24 increases liver fibrosis by enhanced menin expression in Mdr2 −/− mice

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