Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats

Li, Jing; Liu, Peng; Zhang, Ruixiu; Cao, Lu; Qian, Haihua; Liao, Jian; Xu, Wen; Wu, Mengchao; Yin, Zheng

doi:10.1016/j.jep.2011.06.030

Cited by 46 publications

(26 citation statements)

References 43 publications

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“…The protein concentration of the tissue homogenate was determined by the previous study 22) with bovine serum albumin (BSA) as a standard. Sixty micrograms of protein from liver homogenates was loaded per lane on 8% polyacrylamide gels and electrophoresed.…”

Section: Determination Of Serum Levels Of Hyaluronic Acid (Ha) Type mentioning

confidence: 99%

Combination Therapy with Taurine, Epigallocatechin Gallate and Genistein for Protection against Hepatic Fibrosis Induced by Alcohol in Rats

Zhuo

Liao

et al. 2012

Biological & Pharmaceutical Bulletin

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This study was to investigate the possibility of enhancing the anti-fibrotic effect by using a combination therapy with taurine, epigallocatechin gallate and genistein in a rat liver fibrosis model induced by alcohol, and to explore its underlying mechanism. Hepatic fibrosis was induced by intragastric administration with various amount of alcohol (5.0-9.5 g/kg) within 24 weeks in rats. The model group received alcohol only, and treatment groups received the corresponding drugs plus alcohol respectively, while the normal control group received an equal volume of saline. The antifibrotic effects of combination therapy were assessed directly by hepatic histology, and indirectly by measurement of serum biochemical markers, the fibrosis markers and related key cytokines/proteins. The results showed that combination therapy could significantly improve the liver function, as indicated by decreasing levels of alanine transaminase, aspartate transaminase, alkaline phosphatase, γ-glutamyltransferase, interleukin-6 and tumor necrosis factor-α. Moreover, combination therapy could effectively suppress the serum levels of fibrosis markers and hepatic hydroxyproline content, inhibit collagen deposition and reduce the pathological tissue damage. Research on mechanism showed that combination therapy was able to markedly reduce lipid peroxidation and recruit the anti-oxidative defense system, and inhibit the expression of B-cell lymphoma 2, α-smooth muscle actin, transforming growth factor β 1 and small mothers against decapentaplegic homolog 3 proteins. Our results showed that combination therapy is effective in attenuating hepatic injury and fibrosis in the alcohol-induced rat model. The improved efficacy of the combination therapy with its good safety profile could represent a new protective approach for liver fibrosis.

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Section: Determination Of Serum Levels Of Hyaluronic Acid (Ha) Type mentioning

confidence: 99%

Combination Therapy with Taurine, Epigallocatechin Gallate and Genistein for Protection against Hepatic Fibrosis Induced by Alcohol in Rats

Zhuo

Liao

et al. 2012

Biological & Pharmaceutical Bulletin

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“…It has previously been demonstrated that certain Chinese natural ingredients, or herbal formulas, have preventive and therapeutic effects against cancer. In particular, the development of icaritin has gained attention as an antifibrotic and antineoplastic monomer, purified from the herb Epimedium (23)(24)(25). The present study demonstrated that icaritin may inhibit growth and significantly induce apoptosis in SMMC-7721 cells, with an effective concentration range between 8 and 32 µM.…”

Section: Discussionmentioning

confidence: 49%

Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells

Sun

Peng

et al. 2014

Molecular Medicine Reports

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Abstract.Icaritin is an active ingredient derived from the plant Herba epimedium, which exhibits various pharmacological and biological activities. However, the function, and the underlying mechanisms of icaritin on the growth of SMMC-7721 human hepatoma cells have yet to be elucidated. The present study aimed to investigate the function and underlying mechanisms of icaritin in the growth of SMMC-7721 cells. The cells were treated with varying concentrations of icaritin for 12, 24 and 48 h, respectively, prior to cytotoxic analysis. Apoptosis of SMMC-7721 cells following treatment with icaritin was measured using flow cytometry. The gene expression of mitochondria-and Fas-mediated caspase-dependent pathways was detected by reverse transcription-quantitative polymerase chain reaction and western blotting. Statistical analysis was performed by Student's t-test and one-way analysis or variance. The present study demonstrated that treatment with icaritin significantly inhibited growth, and induced apoptosis of SMMC-7721 cells, in a time-and dose-dependent manner. In addition, icaritin triggered the mitochondrial/caspase apoptotic pathway, by decreasing the Bcl-2/Bax protein ratio and increasing activation of caspase-3. Icaritin also activated the Fas-mediated apoptosis pathway, as was evident by the increased expression levels of Fas and activation of caspase-8. These data suggest that icaritin may be a potent growth inhibitor and induce apoptosis of SMMC-7721 cells through the mitochondria-and Fas-mediated caspase-dependent pathways. The present study may provide experimental evidence for preclinical and clinical evaluations of icaritin for HCC therapy.

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“…In both Huh-7 (another established HCC cell line [32, 33]) and primary human HCC cells (two lines, “Pri_1/Pri _2”, see Method), treatment with TIC10 (10 μM, 72 hours) similarly inhibited cell proliferation (Figure 1D). Remarkably, the very same TIC10 treatment (10 μM, 72 hours) failed to inhibit the proliferation (MTT OD) of non-cancerous HL-7702 hepatocytes ([5, 34]) and primary human adult hepatocytes (Figure 1D). Collectively, these results demonstrate that TIC10 selectively inhibits human HCC cell proliferation in vitro .…”

Section: Resultsmentioning

confidence: 96%

Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells

Cheng

Liu

et al. 2017

Oncotarget

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The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation. DNA-PKcs inhibition, knockdown or mutation facilitated TIC10-induced Foxo3a nuclear translocation, TRAIL/DR5 expression and cell apoptosis. Reversely, exogenous DNA-PKcs over-expression inhibited above actions by TIC10. In vivo, oral administration of TIC10 significantly inhibited HepG2 tumor growth in nude mice, which was further potentiated with Nu7026 co-administration. Thus, TIC10 shows promising anti-HCC activity, alone or together with DNA-PKcs inhibitors.

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Icaritin induces cell death in activated hepatic stellate cells through mitochondrial activated apoptosis and ameliorates the development of liver fibrosis in rats

Cited by 46 publications

References 43 publications

Combination Therapy with Taurine, Epigallocatechin Gallate and Genistein for Protection against Hepatic Fibrosis Induced by Alcohol in Rats

Combination Therapy with Taurine, Epigallocatechin Gallate and Genistein for Protection against Hepatic Fibrosis Induced by Alcohol in Rats

Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells

Identification of DNA-PKcs as a primary resistance factor of TIC10 in hepatocellular carcinoma cells

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