Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways

Zhang, Feng; Ni, Chao; Kong, Desong; Zhang, Xiaoping; Zhu, Xiaojing; Chen, Li; Lu, Yin; Zheng, Shizhong

doi:10.1016/j.taap.2012.09.016

Cited by 52 publications

(40 citation statements)

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“…As the main collagen producing cells in the chronic liver injury [27] , hepatic stellate cells are considered the key therapeutic target for hepatic fibrosis [5] . Oxidative stress represents a direct or indirect pro-fibrogenic stimulus for HSC activation [28][29][30] . In the search for therapeutic strategies for hepatic fibrosis, many antioxidants show promising results [24,[30][31][32][33][34][35][36] , including ginseng extracts [22,37] .…”

Section: Discussionmentioning

confidence: 99%

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

Gao

Chu

et al. 2014

Acta Pharmacol Sin

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Aim: To investigate the anti-fibrosis effects of ginsenoside Rg1 on alcohol-and CCl 4 -induced hepatic fibrosis in rats and to explore the mechanisms of the effects. Methods: Rats were given 6% alcohol in water and injected with CCl 4 (2 mL/kg, sc) twice a week for 8 weeks. Rg1 (10, 20 and 40 mg/kg per day, po) was administered in the last 2 weeks. Hepatic fibrosis was determined by measuring serum biochemical parameters, HE staining, Masson's trichromic staining, and hydroxyproline and α-SMA immunohistochemical staining of liver tissues. The activities of antioxidant enzymes, lipid peroxidation, and Nrf2 signaling pathway-related proteins (Nrf2, Ho-1 and Nqo1) in liver tissues were analyzed. Cultured hepatic stellate cells (HSCs) of rats were prepared for in vitro studies. Results: In the alcohol-and CCl 4 -treated rats, Rg1 administration dose-dependently suppressed the marked increases of serum ALT, AST, LDH and ALP levels, inhibited liver inflammation and HSC activation and reduced liver fibrosis scores. Rg1 significantly increased the activities of antioxidant enzymes (SOD, GSH-Px and CAT) and reduced MDA levels in liver tissues. Furthermore, Rg1 significantly increased the expression and nuclear translocation of Nrf2 that regulated the expression of many antioxidant enzymes. Treatment of the cultured HSCs with Rg1 (1 μmol/L) induced Nrf2 translocation, and suppressed CCl 4 -induced cell proliferation, reversed CCl 4-induced changes in MDA, GPX, PCIII and HA contents in the supernatant fluid and α-SMA expression in the cells. Knockdown of Nrf2 gene diminished these actions of Rg1 in CCl 4 -treated HSCs in vitro. Conclusion: Rg1 exerts protective effects in a rat model of alcohol-and CCl 4 -induced hepatic fibrosis via promoting the nuclear translocation of Nrf2 and expression of antioxidant enzymes.

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Section: Discussionmentioning

confidence: 99%

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

Gao

Chu

et al. 2014

Acta Pharmacol Sin

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“…Real-time PCR was performed as we described previously. 22 Glyceraldehyde phosphate dehydrogenase (GAPDH) was used as the invariant control. Fold changes in the mRNA levels of target genes related to the invariant control GAPDH were calculated according to the suggested method.…”

Section: Real-time Pcrmentioning

confidence: 99%

Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells

Lian

Jiang

Zhang

et al. 2015

Laboratory Investigation

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Accumulating evidence indicates that Hedgehog (Hh) signaling becomes activated in chronic liver injury and plays a role in the pathogenesis of hepatic fibrosis. Hepatic stellate cells (HSCs) are Hh-responsive cells and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Targeting Hh signaling may be a novel therapeutic strategy for treatment of liver fibrosis. We previously reported that curcumin has potent antifibrotic effects in vivo and in vitro, but the underlying mechanisms are not fully elucidated. This study shows that curcumin downregulated Patched and Smoothened, two key elements in Hh signaling, but restored Hhip expression in rat liver with carbon tetrachlorideinduced fibrosis and in cultured HSCs. Curcumin also halted the nuclear translocation, DNA binding, and transcription activity of Gli1. Moreover, the Hh signaling inhibitor cyclopamine, like curcumin, arrested the cell cycle, induced mitochondrial apoptosis, reduced fibrotic gene expression, restored lipid accumulation, and inhibited invasion and migration in HSCs. However, curcumin's effects on cell fate and fibrogenic properties of HSCs were abolished by the Hh pathway agonist SAG. Furthermore, curcumin and cyclopamine decreased intracellular levels of adenosine triphosphate and lactate, and inhibited the expression and/or function of several key molecules controlling glycolysis. However, SAG abrogated the curcumin effects on these parameters of glycolysis. Animal data also showed that curcumin downregulated glycolysis-regulatory proteins in rat fibrotic liver. These aggregated data therefore indicate that curcumin modulated cell fate and metabolism by disrupting the Hh pathway in HSCs, providing novel molecular insights into curcumin reduction of HSC activation.

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“…RNA isolation and real-time PCR were performed as we previously described (Zhang et al, 2012b). Glyceraldehyde phosphate dehydrogenase (GAPDH) was used as the invariant control.…”

Section: Real-time Pcrmentioning

confidence: 99%

“…HSCs were lysed and prepared as we previously described (Zhang et al, 2012b) with the corresponding primary antibodies or b-actin control. Representative blots from three independent experiments are shown.…”

Section: Western Blot Analysismentioning

confidence: 99%

Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction via transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells

Zhang

Kong

Chen

et al. 2013

Journal of Cell Science

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Hepatic stellate cells (HSCs) are liver-specific pericytes that are recruited to vessels and secret pro-angiogenic cytokines, and thus actively involved in pathological vascularization during liver fibrosis. Peroxisome proliferator-activated receptor-c (PPARc) is a switch molecule controlling HSC activation. We investigated PPARc regulation of angiogenic signal transduction and the molecular mechanisms involved in HSCs. Primary rat HSCs and liver sinusoidal endothelial cells (LSECs) were isolated and used in this study. Boyden chamber and tubulogenesis assays, identified that focal adhesion kinase (FAK)-RhoA signaling activated by platelet-derived growth factor (PDGF) was required for HSC motility and the associated vascularization. PDGF also stimulated vascular endothelial growth factor (VEGF) expression and HSC-driven vascularization through signals mediated by extracellular signalregulated kinase (ERK) and mammalian target of rapamycin (mTOR). Gain-and loss-of-function analyses demonstrated that activation of PPARc interrupted FAK-RhoA, ERK and mTOR cascades and inhibited HSC-based vascularization. Molecular evidence further revealed that PPARc attenuation of HSC angiogenic properties was dependent on inhibition of PDGF-b receptor expression. We concluded that PPARc inhibited angiogenic signal transduction through transrepression of PDGF-b receptor leading to reduced HSC motility, reduced VEGF expression, and thereby attenuated HSC-driven angiogenesis. PPARc could be a molecular target for preventing vascular remolding in hepatic fibrosis.

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Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways

Cited by 52 publications

References 50 publications

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells

Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction via transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells

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