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silibinin induces hepatic stellate cell cycle arrest via enhancing p53/p27 and inhibiting Akt downstream signaling protein expression

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Hepatobiliary & Pancreatic Diseases International 2017年第1期16卷 80-87页

作者： Devaraj Ezhilarasan Jonathan Evraerts Brice Sid Pedro Buc Calderon Sivanesan Karthikeyan Etienne Sokal Mustapha Najimi institut de recherche expérimentale et clinique (irec) laboratory of pediatric hepatology and cell therapyuniversité catholique de louvain，1200，Brussels，Belgium louvain drug research institute toxicology and cancer biology research group pmnt unituniversité catholique de louvain，1200，Brussels，Belgium facultad de ciencias de la salud universidad arturo prat，Iquique，Chil department of pharmacology and environmental toxicology food and hepatotoxicology laboratory dr. alm post graduate institute of basic medical sciences university of madrastaramani campus，Chennai-600 l13，India

BACKGROUND： Proliferation of hepatic stellate cells （HSCs） plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS： The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin （10, 50 and 100 μmol/L） for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS： silibinin inhibits LX-2 cell proliferation in doseand time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin- inhibited proliferation of LX-2 cells. CONCLUSION： The anti-proliferative effect of silibinin on LX-2 human steUate cells is via the inhibition of the expres- sions of various cell cycle targets including p27, Akt and sir- tuin signaling.

关键词： silibinin hepatic stellate cells in vitro cell cycle arrest proliferation

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silibinin alleviates N-nitrosodimethylamine-induced glutathione dysregulation and hepatotoxicity in rats

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Chinese Journal of Natural Medicines 2016年第1期14卷 40-47页

作者： Devaraj Ezhilarasan Slvanesan Karthikeyan Food and Hepatotoxicology Laboratory Department of Pharmacology and Environmental Toxicology University of MadrasTaramani Chennai 600113 India

The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat *** liver damage was induced in Wistar albino rats by repeated administration of DMN(10 mg·kg-1 b.w.,i.p.)on 3 consecutive days per week for 3 ***(100 mg·kg-1 b.w.,p.o.)was given daily to the DMN treated rats for two *** marker enzymes of liver toxicity and second-line enzymic and non-enzymic antioxidants were evaluated in serum and liver tissues before and after SBN *** of the liver was evaluated by H & E *** DMN treatment produced a progressive increase in all the serum marker enzymes(AST,ALT,ALP,LDH,and γ-GT),peaking on Day *** treatment produced highly significant decreases in all the second-line antioxidant parameters(GSH,GST,GR,GPx,and vitamins C and E).The SBN treatment significantly reversed the DMN-induced damages,towards *** studies confirmed the development of liver toxicity in DMN-treated rats,which was reversed by SBN treatment in corroboration with the aforementioned biochemical results,indicating the hepatoprotective and antioxidant properties of *** conclusion,the DMN-induced degenerative changes in the liver were alleviated by SBN treatment and this protective ability may be attributed to its antioxidant,free radical scavenging,and membrane stabilizing properties.

关键词： Dimethylnitrosamine silibinin Oxidative stress Hepatotoxicity Glutathione dysregulation

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silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway

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Acta Pharmaceutica Sinica B 2019年第4期9卷 745-757页

作者： Yayun Liu Wei Xu Ting Zhai Jiaojiao You Yong Chen Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology Hubei University

Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57 BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h,then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. silibininsignificantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2 E1 and CYP4 A in *** effects were confirmed by the in vitro experiments. silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity(CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity(CYP2 E1 and CYP4 A) to relieve oxidative stress.

关键词： silibinin NASH CFLAR Lipid accumulation Oxidation stress

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Combinatorial strategies for cancer eradication by silibinin and cytotoxic agents:efficacy and mechanisms

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Acta Pharmacologica Sinica 2007年第9期28卷 1466-1475页

作者： Komal RAINA Rajesh AGARWAI Department of Pharmaceutical Sciences School of PharmacyUniversity of Colorado Health Sciences CenterDenverCO 80262USA Department of Pharmaceutical Sciences School of PharmacyUniversity of Colorado Health Sciences CenterDenverCO 80262USA University of Colorado Cancer CenterUniversity of Colorado Health Sciences CenterDenverCO 80262USA

In an effort to develop effective alternative strategies that increase the therapeu-tic efficacy and minimize the systemic toxicity of chemotherapeutic agents,moreefforts are being directed towards the investigation of dietary supplements andother phytotherapeutic agents for their synergistic efficacy in combination withanticancer *** such agent is silibinin,which has shown promisingchemopreventive and anticancer effects in various in vitro and in vivo *** present review summarizes the effects of the combination of silibinin andchemotherapeutic drugs on the growth inhibition,cell cycle regulation,andapoptosis induction in prostate,breast,and lung cancer ***,theresults indicate a synergistic effect of silibinin on growth inhibition,reversal ofchemoresistance,apoptosis induction,and a strong increase in G2-M checkpointarrest when given in combination with these *** results are highlysignificant with respect to the combined chemotherapy approach,wherein thecriteria for combination is that the response has to be synergistic and that thedrugs should not share common mechanisms of resistance and not overlap intheir major side-effects.

关键词： silibinin chemotherapeutic agents combined chemotherapy phytotherapeutic agents

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Effects and mechanisms of silibinin on human hepatoma cell lines

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World Journal of Gastroenterology 2007年第40期13卷 5299-5305页

作者： John J Lah Division of Gastroenterology University of CaliforniaIrvine Medical Center101 The City DriveBuilding 53Suite 113OrangeCA 92868United States

AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined. RESULTS： We demonstrated that silibinin significantly reduced the growth of HUH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. silibinin-reduced HuH7 cell growth was associated with significantly up- regulated p21/CDK4 and p27/CDK4 complexes, down- regulated Rb-phosphorylation and E2F1/DP1 complex. silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and upregulated activated caspase-3 and -9. silibinin＇s antiangiogenic effects were indicated by down-regulated metalloproteinase-2 （MMP2） and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten （PTEN） and decreased p-Akt production, indicating the role of PTEN/ PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 （AC-H3 and AC-H4）, indicating a possible role of altered histone acetylation in silibininreduced HCC cell proliferation. CONCLUSION： Our results defined silibinin＇s in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.

关键词： Hepatocellular carcinoma HuH7 cells silibinin Chemoprevention Cell cycle Cell cycleprogression Apoptosis Acetylation of histone

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Activation of extracellular signal-regulated kinase during silibinin-protected,isoproterenol-induced apoptosis in rat cardiac myocytes is tyrosine kinase pathway-mediated and protein kinase C-dependent

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Acta Pharmacologica Sinica 2007年第6期28卷 803-810页

作者： Shin-ichi TASHIRO Satoshi ONODERA Fumiaki UCHIUMI Takashi IKEJIMA Department of Clinical and BiomedicalSciences Showa Pharmaceutical UniversityTokyo 194-8543Japan Department of Gene Regulation Faculty of Pharmaceutical SciencesTokyo University of ScienceChiba 278-8510Japan China-Japan Research Institute of Medieal and Pharmaceutical Sciences Shenyang Pharmaceutical UniversityShenyang 110016China

Aim:To investigate the mechanism of silibinin-protected isoproterenol-inducedapoptosis in rat cardiac ***:The viability of rat cardiac myocyteswas measured by MTT *** apoptotic ratio was measured by terminaldeoxynucleotidyl transferase-mediated dUTP nick *** kinase C(PKC) activity assay was carried out according to the instructions of the PepTagnon-radioactive protein kinase C assay *** blot analysis was used toevaluate the level of Ras,Raf-1 and mitogen-activated protein kinase (MAPK)***:The protective effects of silibinin were significantly sup-pressed by inhibitors,including genistein,manumycin A and GW5074 [inhibitorsfor protein tyrosine kinases (PTK),Ras and Raf-1,respectively].The exposure ofrat cardiac myocytes to isoproterenol alone caused decreased PKC activity,whichwas prevented by pretreatment with silibinin ***,the increased expression of Ras and Raf-1 activated by silibinin were blocked bythe PKC inhibitor,*** addition,the extracellularly responsive kinase(ERK) inhibitor,PD98059,suppressed silibinin-protected apoptosis,whereas thep38 MAPK inhibitor,SB203580,protected cardiac myocytes from isoproterenol-induced injury,and the c-Jun N-terminal kinase (JNK) inhibitor,SP600125 had noprotective ***,Western blot analysis showed that the expres-sion of phosphorylated ERK was increased by silibinin,the expression of phos-phorylated p38 MAPK was decreased and total ERK,p38,JNK and phosphory-lated JNK MAPK did not change after treatment with both isoproterenol ***,pretreatment of cardiac myocyte with PKC,Ras and Rafinhibitors significantly blocked ERK ***:silibinin issuggested to protect isoproterenol-induced rat cardiac myocyte apoptosis byactivating the tyrosine kinase pathway,PKC and MAPK pathways.

关键词： silibinin rat cardiac myocytes tyrosine kinase: protein kinase C mitngen-activated protein kinases

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Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice

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World Journal of Gastroenterology 2009年第16期15卷 1943-1950页

作者： Wei Cui Fan Gu Ke-Qin Hu Division of Gastroenterology and Chao Family Comprehensive Cancer Center University of California Orange School of Medicine Orange CA 92868 United States Department of Surgery Nanfang Hospital Southern Medical University Guangzhou 510515 Guangdong Province China

AIM:To investigate the in vivo effects and mechanisms of silibinin on the growth of hepatocellular carcinoma (HCC) xenografts in nude ***: Nude mice bearing HuH7 xenografts were used to assess the anti-HCC effects and mechanisms of ***: silibinin resulted in a potent dosedependent reduction of HuH7 xenografts in association with a significant decrease in Ki-67 and α-fetoprotein production, nuclear NF-κB content, polo-like kinase 1, Rb phosphorylation, and E2F1/DP1 complex, but increased p27/CDK4 complex and checkpoint kinase 1 expression, suggesting that the in vivo effects of silibinin are mediated by inhibiting G1-S transition of the cell cycle. silibinin-induced apoptosis of HuH7 xenografts was associated with inhibited survivin phosphorylation. silibinin-reduced growth of HuH7 xenografts was associated with decreased p-ERK, increased PTEN expression and the activity of silibinin was correlated with decreased p-Akt production, indicating involvement of PTEN/PI3K/Akt and ERK pathways in its in vivo anti-HCC effects. silibinin-reduced growth of HuH7 xenografts was also associated with a significant increase in AC-H3 and AC-H4 expression and the production of superoxide dismutase (SOD)-***: silibinin reduces HCC xenograft growth through the inhibition of cell proliferation, cell cycle progression and PTEN/P-Akt and ERK signaling, inducing cell apoptosis, and increasing histone acetylation and SOD-1 expression.

关键词： Apoptosis Cell cycle Chemoprevention Hepatocellular carcinoma Histone acetylation silibinin

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Protective Effect of silibinin on Lipopolysaccharide-Induced Endotoxemia by Inhibiting Caspase-11-Dependent Cell Pyroptosis

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Chinese Journal of Integrative Medicine 2024年第10期30卷 917-926页

作者： OU Jin-ying LIU Shan-hong TANG Dong-kai SHI Ling-zhu YAN Li-jun HUANG Jing-yan ZOU Li-fang QUAN Jing-yu YOU Yan-ting CHEN Yu-yao YU Lin-zhong LU Zi-bin Third Level Research Laboratory of State Administration of Traditional Chinese Medicine School of Traditional Chinese MedicineSouthern Medical UniversityGuangzhou510515China Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics Guangzhou510515China School of Traditional Chinese Medicine Southern Medical UniversityGuangzhou510515China

Objective:To explore the protective effect and the underlying mechanism of silibinin(SIB),one of the active compounds from Silybum marianum(L.)Gaertn in ***:Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate *** viability was assessed using the cell counting kit-8,while cytotoxicity was determined through lactate dehydrogenase cytotoxicity *** protein expressions of interleukin(IL)-1α,IL-1β,and IL-18 were determined by enzyme-linked immunosorbent *** lipopolysaccharide(LPS)levels were measured by employing both the limulus amoebocyte lysate assay and flow ***,proximity ligation assay was employed for the LPS and caspase-11 *** were divided into 4 groups:the control,LPS,high-dose-SIB(100 mg/kg),and low-dose-SIB(100 mg/kg)groups(n=8).Zebrafish were divided into 4 groups:the control,LPS,high-dose-SIB(200μmol/L),and low-dose-SIB(100μmol/L)groups(n=30 for survival experiment and n=10 for gene expression analysis).The expression of caspase-11,gasdermin D(GSDMD),and N-GSDMD was determined by Western blot and the expressions of caspy2,gsdmeb,and IL-1βwere detected using quantitative real-time *** observation was performed through hematoxylineosin staining,and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein ***:SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1α,IL-1β,and IL-18 induced by LPS(P<0.05).Moreover,SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS(P<0.05).SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD,inhibited the relative cytokines,prolonged the survival time,and up-regulated the survival rate in the endotoxemia models(P<0.05).Conclusions:SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model,at l

关键词： silibinin caspase-11 endotoxemia pyroptosis inflammation

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Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells

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World Journal of Gastroenterology 2015年第14期21卷 4169-4177页

作者： Cheng-Chia Tsai Tang-Wei Chuang Li-Jen Chen Ho-Shan Niu Kun-Ming Chung Juei-Tang Cheng Kao-Chang Lin Department of Surgery Mackay Memorial Hospital Graduate Institute of Disease Prevention and Control College of MedicineTaipei Medical University Division of Hepatogastroenterology Department of Internal MedicineChi Mei Medical Center Institute of Basic Medical Science College of MedicineNational Cheng Kung University Department of Nursing Tzu Chi College of Technology Division of Gastroenterology Department of Internal MedicineChi-Mei Medical Center Institute of Medical Sciences Chang Jung Christian University Department of Neurology Chi Mei Medical Center Department of Medical Research Chi Mei Medical Center Institute of Biotechnology Southern Taiwan University

AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer(COLO 205) ***: MTT assays were performed to quantify cell *** blot assays were applied to identify the expression of signaling ***: The combined treatment of COLO 205 cells with metformin and silibinin decreased cell survival at a dose insufficient to influence the non-malignant cells [Human colonic epithelial cells(HCo Epi C)].silibinin and metformin increased phosphatase and tensin homolog and 5'-adenosine monophosphate-activated protein kinase expression in COLO 205 cells and inhibited the phosphorylation of mammol/Lalian target of *** combined treatment resulted in an increase in the expression of activated caspase 3 and apoptosis inducing factor, indicating ***: The combined treatment of human colorectal cancer cells with silibinin and metformin may induce apoptosis at a dose that does not affect HCo Epi *** finding reveals a potential therapeutic strategy for the treatment of colorectal cancer.

关键词： silibinin Metformin COLO 205 Mammol/ Lalian target

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Combinatorial treatment of curcumin or silibinin with doxorubicin sensitises high-risk neuroblastoma

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 63-73页

作者： Pamali Fonseka Lahiru Gangoda Mohashin Pathan Di Giannatale Angela Suresh Mathivanan Department of Biochemistry and Genetics La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVictoria 3086Australia Department of Hematology/Oncology Bambino GesùChildren’s HospitalIRCCSRome 00165Italy.#Authors contributed equally

Aim:Neuroblastoma is a pediatric cancer of the sympathetic nervous *** various parameters including stage of the disease,amplification status of N-Myc,DNA index and histopathology,neuroblastoma can be stratified into low-and high-risk *** advances in treatment have significantly improved the survival rate of lowrisk neuroblastoma ***,the overall survival rate of high-risk neuroblastoma group,especially N-Myc amplified patients,is ***,the survivors of both low-and high-risk neuroblastoma manifest adverse side effects to chemotherapy and thus their quality of life is *** all these factors,there is an urgent need to develop therapeutic strategies with natural compounds to improve the survival rate and to reduce the side *** this study,we hypothesised that the mesenchymal nature of neuroblastoma cells is a reason,at least in part,for the aggressive and treatment resistant ***:In order to validate our hypothesis,we used publicaly available RNA-Seq data,in vitro assays and xenograft mouse ***:Using a combinatorial treatment of mesenchymal-to-epithelial inducers(curcumin or silibinin)with doxorubicin significantly increased the cell death in a panel of neuroblastoma cells in *** up analysis in vivo,confirmed the therapeutic benefit of utilising the combination of curcumin with *** combinatorial therapy significantly reduced the tumor burden and increased the survival of mice implanted with high-risk neuroblastoma ***:Taken together,this study shows the efficacy of using curcumin in combination with doxorubicin to improve the survival rate and has the potential to enhance the quality of life of neuroblastoma patients.

关键词： Neuroblastoma epithelial-to-mesenchymal transition curcumin silibinin combinatorial therapy

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