Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway

Baltă, Cornel; Herman, Hildegard; Boldura, Oana Maria; Gasca, I.; Rosu, Marcel; Ardelean, Aurel; Hermenean, Anca

doi:10.1016/j.cbi.2015.08.013

Cited by 66 publications

(66 citation statements)

References 30 publications

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“…Once activated, MCs release numerous factors into the tissue environment including inflammatory cytokines like TGF‐β1, histamine, and other growth factors . Our present study also includes an examination of HSCs that, once activated, promote fibrosis through numerous mechanisms including TGF‐β1, nuclear factor κB, and hedgehog signaling . We found that HSC activation and TGF‐β1 expression were increased in Mdr2 −/− mice compared to WT but that when mice were treated with cromolyn sodium there was a decrease in activated HSCs .…”

Section: Discussionmentioning

confidence: 73%

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

et al. 2016

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Background and Aim Hepatic fibrosis is marked by activation of hepatic stellate cells (HSCs). Cholestatic injury precedes liver fibrosis and cholangiocytes interact with HSCs promoting fibrosis. Mast cells (MCs) infiltrate following liver injury and release histamine increasing biliary proliferation. We evaluated if inhibition of MC-derived histamine decreases biliary proliferation and fibrosis. Methods WT and Mdr2−/− mice (9-11 weeks) were treated with cromolyn sodium for 1 week to block MC-derived histamine. Biliary mass and proliferation were evaluated by immunohistochemistry for CK-19 and Ki-67. Bile flow, bicarbonate excretion and total bile acids were measured in all mice. Fibrosis was evaluated by Sirius Red/Fast Green staining and by qPCR for α-SMA, fibronectin, collagen type 1a and TGF-β1. HSC activation was evaluated by qPCR in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by EIA. Mouse liver and human liver samples from control or PSC patients were evaluated for MC markers by qPCR and immunohistochemistry. In vitro, cultured MCs were transfected with HDC shRNA to decrease histamine secretion and subsequently co-cultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation and TGF-β1 secretion. Results Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in Mdr2−/− mice. PSC mice and patients have increased MCs. Knockdown of MC HDC decreased cholangiocyte and HSC proliferation/activation. Conclusion MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis and regulation of MC mediators may be a therapeutic for PSC.

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Section: Discussionmentioning

confidence: 73%

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

et al. 2016

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“…MCs release numerous factors, but the main component of MCs is HA, which has been recognized now to be more than just a mediator of allergic events . We have demonstrated in numerous studies that HA is a trophic, growth‐promoting factor that induces biliary hyperplasia, fibrosis, and CCA progression .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to HSCs, cholangiocytes also play a role in paracrine signaling during fibrosis and may also contribute to activation of HSCs . During fibrosis, several growth factors are released from multiple cell types, including transforming growth factor‐beta 1 (TGF‐β1) . These factors contribute to hyperplastic‐induced fibrosis, which can eventually lead to liver failure.…”

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confidence: 99%

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

et al. 2017

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Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL) increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC deficient mice. Methods: WT and KitW-sh mice were subjected to sham or BDL for up to 7 days and KitW-sh mice were injected with cultured mast cells or 1X PBS before collecting serum, liver blocks and cholangiocytes. Liver damage was assessed by H&E and ALT levels. IBDM was detected by CK-19 expression and proliferation by Ki-67 immunohistochemistry. Fibrosis was detected by immunohistochemistry, hydroxyproline content and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and TGF-β1 expression/secretion were evaluated. HDC and histamine receptor (HR) expression were detected by qPCR and HA secretion by EIA. To evaluate vascular cells, Von Willebrand (vWF) and VEGF-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and α-SMA measured. Results: BDL-induced liver damage was reduced in the BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL KitW-sh mice, IBDM, proliferation, HSC activation/fibrosis and TGF-β1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW-sh mice. vWF and VEGF-C expression decreased in BDL KitW-sh mice. In KitW-sh mice injected with MCs, IBDM, proliferation, fibrosis and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW-sh mice. Conclusion: MCs promote hyperplasia, fibrosis and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies.

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“…Chrysin has not been as well-studied as silymarin, but is known to be present in high levels in honey, propolis and numerous plant extracts (15). Chrysin has been identified to possess antioxidant (16–18), anti-allergic (19), anti-inflammatory (20), anti-fibrotic (21) and anti-cancer (22,23) properties. However, there are previous reports in the literature regarding the hepatoprotective activity of chrysin, but these did not reveal how its protective activity is initiated in acute liver damage condition.…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective activity of chrysin is mediated through TNF-α in chemically-induced acute liver damage: An in vivo study and molecular modeling

Hermenean

Mariasiu

Navarro‐González

et al. 2017

Experimental and Therapeutic Medicine

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Chrysin (5,7-dihydroxyflavone) is a naturally occurring flavonoid present at high levels in honey, propolis and numerous plant extracts. Chrysin is known to have hepatoprotective activity, however, the mechanisms by which it exerts this effect remain unclear. In the present study, the effects of chrysin in carbon tetrachloride (CCl4)-induced acute liver damage were investigated and the results used to infer a possible mechanism behind chrysin's hepatoprotective activity. Prior to an intraperitoneal injection of CCl4 (1 ml/kg) to induce acute liver damage, chrysin (50 mg/kg) was administered orally to mice for 7 days. The positive control group was given 50 mg/kg standardized silymarin, a well-studied hepatoprotective flavonoid. Twenty-four h following CCl4 administration, an increase in the activity levels of serum aspartate-amino-transferase and alanine-amino-transferase was found. This was accompanied by extended centrilobular necrosis, steatosis and an altered hepatocyte ultrastructure. In addition, CCl4-induced acute hepatotoxicity was associated with an increase in hepatic tumor necrosis factor-α (TNF-α) and α-smooth muscle actin (α-SMA) protein expression, which was significantly decreased in the livers of mice pre-treated with chrysin (P<0.001), similar to the results of the silymarin pre-treated group (P<0.001). Treatment with chrysin prior to CCl4 exposure significantly reduced the activity of enzymes used as biochemical markers of poor liver function compared with the group which did not receive pre-treatment (P<0.001). In addition, the results of histopathological and electron microscopy liver examination showed chrysin pre-treatment reduced the effects of CCl4 treatment. Molecular modeling results demonstrated that the hepatoprotective activity of chrysin is mediated through TNF-α, as it reduces soluble TNF-α generation via blocking TNF-α-converting enzyme activity. In conclusion, the results of the present study suggest that inflammatory pathways are activated in CCl4-induced acute liver damage, which are ameliorated by chrysin pre-treatment. This indicates that chrysin is a potent hepatoprotective agent, similarly to silymarin at the same dose, which has the potential to be a viable alternative to conventional hepatoprotective treatments.

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Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-β/Smad signaling pathway

Cited by 66 publications

References 30 publications

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

Hepatoprotective activity of chrysin is mediated through TNF-α in chemically-induced acute liver damage: An in vivo study and molecular modeling

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