柯因的肝保护效果及其作用机制研究进展
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摘要
柯因(5,7-二羟黄酮),别名白杨素,是杨树型蜂胶以及许多植物提取物中的一个主要黄酮类物质,具有诸如抗炎症、抗肿瘤、抗过敏、抗氧化、抗衰老、抗糖尿病发生以及免疫调节等多种生物活性,对多种器官(如肝脏、肾脏、结肠)具有保护效应。其中,针对柯因的肝保护活性,国内外研究者分别利用体内、体外实验进行了广泛研究,并对其肝保护的作用机制进行了探讨。本文针对柯因在化学毒物、高脂日粮和抗肿瘤药物所诱发的一系列肝脏损伤中所起的保护作用以及柯因在肝脏肿瘤治疗中的作用机制进行综述。
Chrysin(5,7-dihydroxyflavone), a major flavonoid existed in poplar-type propolis and many plants extracts, has various properties which include anti-inflammatory, anti-tumor, anti-allergic, anti-oxidant, anti-aging, anti-diabetic, immune regulation and other biological activities. Chrysin has been proved to have protective effects on a variety of organs(such as liver, kidney and colon). Of which, the hepato-protective effects of chrysin, as well as the mechanisms that involved, have been extensively studied by domestic and overseas researchers using both in vitro and in vivo experiments. This article reviews the protective effects of chrysin on a range of liver injuries induced by chemical poisons, high-fat diets and anti-tumor drugs. The role that chrysin plays in the treatment of liver tumors and the underlying mechanisms are also been reviewed.
Chrysin(5,7-dihydroxyflavone), a major flavonoid existed in poplar-type propolis and many plants extracts, has various properties which include anti-inflammatory, anti-tumor, anti-allergic, anti-oxidant, anti-aging, anti-diabetic, immune regulation and other biological activities. Chrysin has been proved to have protective effects on a variety of organs(such as liver, kidney and colon). Of which, the hepato-protective effects of chrysin, as well as the mechanisms that involved, have been extensively studied by domestic and overseas researchers using both in vitro and in vivo experiments. This article reviews the protective effects of chrysin on a range of liver injuries induced by chemical poisons, high-fat diets and anti-tumor drugs. The role that chrysin plays in the treatment of liver tumors and the underlying mechanisms are also been reviewed.
引文
[1]Gardana C,Scaglianti M,Pietta P,et al.Analysis of the polyphenolic fraction of propolis from different sources by liquid chromatography-tandem mass spectrometry[J].J Pharm Biomed Anal,2007,45(3):390-399.
[2]Garcia-Lafuente A,Guillamon E,Villares A,et al.Flavonoids as antiinflammatory agents:implications in cancer and cardiovascular disease[J].Inflamm Res,2009,58(9):537-552.
[3]Khoo BY,Chua SL,Balaram P.Apoptotic effects of chrysin in human cancer cell lines[J].Int J Mol Sci,2010,11(5):2188-2199.
[4]Anand KV,Mohamed Jaabir MS,Thomas PA,et al.Protective role of chrysin against oxidative stress in d-galactose-induced aging in an experimental rat model[J].Geriatr Gerontol Int,2012,12(4):741-750.
[5]Chen SS,Corteling R,Stevanato L,et al.Polyphenols inhibit indoleamine3,5-dioxygenase-1 enzymatic activity--a role of immunomodulation in chemoprevention[J].Discov Med,2012,14(78):327-333.
[6]Anandhi R.Evaluation of the anti-atherogenic potential of chrysin in Wistar rats[J].Mol Cell Biochem,2014,385(1-2):103-113.
[7]Sultana S,Verma K,Khan R.Nephroprotective efficacy of chrysin against cisplatin-induced toxicity via attenuation of oxidative stress[J].JPharm Pharmacol,2012,64(6):872-881.
[8]Khan R,Khan AQ,Qamar W,et al.Chrysin protects against cisplatininduced colon.toxicity via amelioration of oxidative stress and apoptosis:probable role of p38MAPK and p53[J].Toxicol Appl Pharmacol,2012,258(3):315-329.
[9]El-Bassossy HM,Abo-Warda SM,Fahmy A.Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation:effect on lipid profile,AGEs and NO generation[J].Phytother Res,2013,27(11):1678-1684.
[10]Sirovina D,Orsolic N,Koncic MZ,et al.Quercetin vs chrysin:effect on liver histopathology in diabetic mice[J].Hum Exp Toxicol,2013,32(10):1058-1066.
[11]Lo HM,Wu MW,Pan SL,et al.Chrysin restores PDGF-induced inhibition on protein tyrosine phosphatase and reduces PDGF signaling in cultured VSMCs[J].J Nutr Biochem,2012,23(6):667-678.
[12]Manibusan MK,Odin M,Eastmond D.Postulated carbon tetrachloride mode of action:a review[J].J Environ Sci Health C Environ Carcinog Ecotoxicol Rev,2007,25(3):185-209.
[13]Tirkey N,Pilkhwal S,Kuhad A,et al.Hesperidin,a citrus bioflavonoid,decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney[J].BMC Pharmacol,2005,5(1):2.
[14]Zhang Q,Hu X,Hui F,et al.Ethanol extract and its dichloromethane fraction of Alpinia oxyphylla Miquel exhibited hepatoprotective effects against CCl4-induced oxidative damage in vitro and in vivo with the involvement of Nrf2[J].Biomed Pharmacother,2017,91:812-822.
[15]Chen XL,Dodd G,Thomas S,et al.Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression[J].Am J Physiol Heart Circ Physiol,2006,290(5):H1862-1870.
[16]Dong D,Zhang S,Yin L,et al.Protective effects of the total saponins from Rosa laevigata Michx fruit against carbon tetrachloride-induced acute liver injury in mice[J].Food Chem Toxicol,2013,62(6):120-130.
[17]Kamel R,El Morsy EM.Hepatoprotective effect of methylsulfonylmethane against carbon tetrachloride-induced acute liver injury in rats[J].Arch Pharm Res,2013,36(9):1140-1148.
[18]Gao B.Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease[J].J Gastroenterol Hepatol,2012,27(Suppl 2):89-93.
[19]Hermenean A,Mariasiu T,Navarro-Gonzalez I,et al.Hepatoprotective activity of chrysin is mediated through TNF-alpha in chemically-induced acute liver damage:An in vivo study and molecular modeling[J].Exp Ther Med,2017,13(5):1671-1680.
[20]Friedman SL.Mechanisms of hepatic fibrogenesis[J].Gastroenterology,2008,134(6):1655-1669.
[21]Breitkopf K,Godoy P,Ciuclan L,et al.TGF-beta/Smad signaling in the injured liver[J].Z Gastroenterol,2006,44(1):57-66.
[22]Horiguchi M,Ota M,Rifkin DB.Matrix control of transforming growth factor-beta function[J].J Biochem,2012,152(4):321-329.
[23]Balta C,Herman H,Boldura O,et al.Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-beta/Smad signaling pathway[J].Chem Biol Interact,2015,240:94-101.
[24]Farghali H,Kgalalelo KM,Wojnarova L,et al.In vitro and in vivo experimental hepatotoxic models in liver research:applications to the assessment of potential hepatoprotective drugs[J].Physiol Res,2016,65(Suppl 4):S417-S425.
[25]Keppler DO,Pausch J,Decker K.Selective uridine triphosphate deficiency induced by D-galactosamine in liver and reversed by pyrimidine nucleotide precursors.Effect on ribonucleic acid synthesis[J].J Biol Chem,1974,249(1):211-216.
[26]Stachlewitz RF,Seabra V,Bradford B,et al.Glycine and uridine prevent D-galactosamine hepatotoxicity in the rat:role of Kupffer cells[J].Hepatology,1999,29(3):737-745.
[27]Pushpavalli G,Veeramani C,Pugalendi KV.Influence of chrysin on hepatic marker enzymes and lipid profile against D-galactosamine-induced hepatotoxicity rats[J].Food Chem Toxicol,2010,48(6):1654-1659.
[28]Pushpavalli G,Kalaiarasi P,Veeramani C,et al.Effect of chrysin on hepatoprotective and antioxidant status in D-galactosamine-induced hepatitis in rats[J].Eur J Pharmacol,2010,631(1-3):36-41.
[29]Hassoun EA,Li F,Abushaban A,et al.The relative abilities of TCDDand its congeners to induce oxidative stress in the hepatic and brain tissues of rats after subchronic exposure[J].Toxicology,2000,145(2-3):103-113.
[30]Ciftci O,Vardi N,Ozdemir I.Effects of quercetin and chrysin on2,3,7,8-tetrachlorodibenzo-p-dioxin induced hepatotoxicity in rats[J].Environ Toxicol,2013,28(3):146-154.
[31]Ciftci O,Ozdemir I.Protective effects of quercetin and chrysin against 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)induced oxidative stress,body wasting and altered cytokine productions in rats[J].Immunopharmacol Immunotoxicol,2011,33(3):504-508.
[32]Ponnappa BC,Rubin E.Modeling alcohol’s effects on organs in animal models[J].Alcohol Res Health,2000,24(2):93-104.
[33]Nordmann R.Alcohol and antioxidant systems[J].Alcohol Alcohol,1994,29(5):513-522.
[34]Lieber CS.Metabolism of alcohol[J].Clin Liver Dis,2005,9(1):1-35.
[35]Helander A,Lindahl-Kiessling K.Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor[J].Mutat Res,1991,264(3):103-107.
[36]Nordmann R,Ribière C,Rouach H.Implication of free radical mechanisms in ethanol-induced cellular injury[J].Free Radical Biology and Medicine,1992,12(3):219-240.
[37]Enomoto N,Ikejima K,Bradford BU,et al.Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury[J].J Gastroenterol Hepatol,2000,15(Suppl):D20-25.
[38]Sathiavelu J,Senapathy GJ,Devaraj R,et al.Hepatoprotective effect of chrysin on prooxidant-antioxidant status during ethanol-induced toxicity in female albino rats[J].J Pharm Pharmacol,2009,61(6):809-817.
[39]Tahir M,Sultana S.Chrysin modulates ethanol metabolism in Wistar rats:a promising role against organ toxicities[J].Alcohol Alcohol,2011,46(4):383-392.
[40]Jahovic N,Cevik H,Sehirli AO,et al.Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats[J].J Pineal Res,2003,34(4):282-287.
[41]Tunali-Akbay T,Sehirli O,Ercan F,et al.Resveratrol protects against methotrexate-induced hepatic injury in rats[J].J Pharm Pharm Sci,2010,13(2):303-310.
[42]Ali N,Rashid S,Nafees S,et al.Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis[J].Mol Cell Biochem,2014,385(1-2):215-223.
[43]Rehman MU,Ali N,Rashid S,et al.Alleviation of hepatic injury by chrysin in cisplatin administered rats:probable role of oxidative and inflammatory markers[J].Pharmacol Rep,2014,66(6):1050-1059.
[44]Nathan C,Ding A.Nonresolving inflammation[J].Cell,2010,140(6):871-882.
[45]周宪宾.巨噬细胞M1/M2极化分型的研究进展[J].中国免疫学杂志,2012,28(10):957-960.
[46]Jakobsdottir G,Xu J,Molin G,et al.High-fat diet reduces the formation of butyrate,but increases succinate,inflammation,liver fat and cholesterol in rats,while dietary fibre counteracts these effects[J].PLo SOne,2013,8(11):e80476.
[47]Uetake Y,Ikeda H,Irie R,et al.High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice[J].Lipids Health Dis,2015,14(1):6.
[48]van der Heijden RA,Sheedfar F,Morrison MC,et al.High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice[J].Aging(Albany NY),2015,7(4):256-268.
[49]Feng X,Qin H,Shi Q,et al.Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARgamma[J].Biochem Pharmacol,2014,89(4):503-514.
[50]Jemal A,Bray F,Center MM,et al.Global cancer statistics[J].CACancer J Clin,2011,61(2):69-90.
[51]Ferlay J,Shin HR,Bray F,et al.Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008[J].Int J Cancer,2010,127(12):2893-2917.
[52]Oishi N,Wang XW.Novel therapeutic strategies for targeting liver cancer stem cells[J].Int J Biol Sci,2011,7(5):517-535.
[53]Yamashita T,Budhu A,Forgues M,et al.Activation of hepatic stem cell marker Ep CAM by Wnt-beta-catenin signaling in hepatocellular carcinoma[J].Cancer Res,2007,67(22):10831-10839.
[54]Quan MF,Xiao LH,Liu ZH,et al.8-bromo-7-methoxychrysin inhibits properties of liver cancer stem cells via downregulation of betacatenin[J].World J Gastroenterol,2013,19(43):7680-7695.
[55]Zou H,Cao X,Xiao Q,et al.Synergistic inhibition of characteristics of liver cancer stem-like cells with a combination of sorafenib and 8-bromo-7-methoxychrysin in SMMC-7721 cell line[J].Oncol Rep,2016,36(3):1731-1738.
[56]Ren KQ,Cao XZ,Liu ZH,et al.8-bromo-5-hydroxy-7-methoxychrysin targeting for inhibition of the properties of liver cancer stem cells by modulation of Twist signaling[J].Int J Oncol,2013,43(5):1719-1729.
[57]Sun X,Huo X,Luo T,et al.The anticancer flavonoid chrysin induces the unfolded protein response in hepatoma cells[J].J Cell Mol Med,2011,15(11):2389-2398.
[58]Li X,Huang Q,Ong CN,et al.Chrysin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells via suppression of nuclear factor-kappa B[J].Cancer Lett,2010,293(1):109-116.
[59]Huang C,Wei YX,Shen MC,et al.Chrysin,abundant in Morinda citrifolia fruit water-Et OAc extracts,combined with apigenin synergistically induced apoptosis and inhibited migration in human breast and liver cancer cells[J].J Agric Food Chem,2016,64(21):4235-4245.
[60]Li X,Huang JM,Wang JN,et al.Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53[J].Chem Biol Interact,2015,232:12-20.
[61]Yang XH,Zheng X,Cao JG,et al.8-Bromo-7-methoxychrysininduced apoptosis of hepatocellular carcinoma cells involves ROS and JNK[J].World J Gastroenterol,2010,16(27):3385-3393.
[62]Zhang Q,Cui C,Chen CQ,et al.Anti-proliferative and pro-apoptotic activities of Alpinia oxyphylla on Hep G2 cells through ROS-mediated signaling pathway[J].J Ethnopharmacol,2015,169:99-108.
[63]Khan MS,Devaraj H,Devaraj N.Chrysin abrogates early hepatocarcinogenesis and induces apoptosis in N-nitrosodiethylamineinduced preneoplastic nodules in rats[J].Toxicol Appl Pharmacol,2011,251(1):85-94.
[64]Khan MS,Halagowder D,Devaraj SN.Methylated chrysin induces coordinated attenuation of the canonical Wnt and NF-k B signaling pathway and upregulates apoptotic gene expression in the early hepatocarcinogenesis rat model[J].Chem Biol Interact,2011,193(1):12-21.
[65]Zhao X,Shu G,Chen L,et al.A flavonoid component from Docynia delavayi(Franch.)Schneid represses transplanted H22 hepatoma growth and exhibits low toxic effect on tumor-bearing mice[J].Food Chem Toxicol,2012,50(9):3166-3173.
[2]Garcia-Lafuente A,Guillamon E,Villares A,et al.Flavonoids as antiinflammatory agents:implications in cancer and cardiovascular disease[J].Inflamm Res,2009,58(9):537-552.
[3]Khoo BY,Chua SL,Balaram P.Apoptotic effects of chrysin in human cancer cell lines[J].Int J Mol Sci,2010,11(5):2188-2199.
[4]Anand KV,Mohamed Jaabir MS,Thomas PA,et al.Protective role of chrysin against oxidative stress in d-galactose-induced aging in an experimental rat model[J].Geriatr Gerontol Int,2012,12(4):741-750.
[5]Chen SS,Corteling R,Stevanato L,et al.Polyphenols inhibit indoleamine3,5-dioxygenase-1 enzymatic activity--a role of immunomodulation in chemoprevention[J].Discov Med,2012,14(78):327-333.
[6]Anandhi R.Evaluation of the anti-atherogenic potential of chrysin in Wistar rats[J].Mol Cell Biochem,2014,385(1-2):103-113.
[7]Sultana S,Verma K,Khan R.Nephroprotective efficacy of chrysin against cisplatin-induced toxicity via attenuation of oxidative stress[J].JPharm Pharmacol,2012,64(6):872-881.
[8]Khan R,Khan AQ,Qamar W,et al.Chrysin protects against cisplatininduced colon.toxicity via amelioration of oxidative stress and apoptosis:probable role of p38MAPK and p53[J].Toxicol Appl Pharmacol,2012,258(3):315-329.
[9]El-Bassossy HM,Abo-Warda SM,Fahmy A.Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation:effect on lipid profile,AGEs and NO generation[J].Phytother Res,2013,27(11):1678-1684.
[10]Sirovina D,Orsolic N,Koncic MZ,et al.Quercetin vs chrysin:effect on liver histopathology in diabetic mice[J].Hum Exp Toxicol,2013,32(10):1058-1066.
[11]Lo HM,Wu MW,Pan SL,et al.Chrysin restores PDGF-induced inhibition on protein tyrosine phosphatase and reduces PDGF signaling in cultured VSMCs[J].J Nutr Biochem,2012,23(6):667-678.
[12]Manibusan MK,Odin M,Eastmond D.Postulated carbon tetrachloride mode of action:a review[J].J Environ Sci Health C Environ Carcinog Ecotoxicol Rev,2007,25(3):185-209.
[13]Tirkey N,Pilkhwal S,Kuhad A,et al.Hesperidin,a citrus bioflavonoid,decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney[J].BMC Pharmacol,2005,5(1):2.
[14]Zhang Q,Hu X,Hui F,et al.Ethanol extract and its dichloromethane fraction of Alpinia oxyphylla Miquel exhibited hepatoprotective effects against CCl4-induced oxidative damage in vitro and in vivo with the involvement of Nrf2[J].Biomed Pharmacother,2017,91:812-822.
[15]Chen XL,Dodd G,Thomas S,et al.Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression[J].Am J Physiol Heart Circ Physiol,2006,290(5):H1862-1870.
[16]Dong D,Zhang S,Yin L,et al.Protective effects of the total saponins from Rosa laevigata Michx fruit against carbon tetrachloride-induced acute liver injury in mice[J].Food Chem Toxicol,2013,62(6):120-130.
[17]Kamel R,El Morsy EM.Hepatoprotective effect of methylsulfonylmethane against carbon tetrachloride-induced acute liver injury in rats[J].Arch Pharm Res,2013,36(9):1140-1148.
[18]Gao B.Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease[J].J Gastroenterol Hepatol,2012,27(Suppl 2):89-93.
[19]Hermenean A,Mariasiu T,Navarro-Gonzalez I,et al.Hepatoprotective activity of chrysin is mediated through TNF-alpha in chemically-induced acute liver damage:An in vivo study and molecular modeling[J].Exp Ther Med,2017,13(5):1671-1680.
[20]Friedman SL.Mechanisms of hepatic fibrogenesis[J].Gastroenterology,2008,134(6):1655-1669.
[21]Breitkopf K,Godoy P,Ciuclan L,et al.TGF-beta/Smad signaling in the injured liver[J].Z Gastroenterol,2006,44(1):57-66.
[22]Horiguchi M,Ota M,Rifkin DB.Matrix control of transforming growth factor-beta function[J].J Biochem,2012,152(4):321-329.
[23]Balta C,Herman H,Boldura O,et al.Chrysin attenuates liver fibrosis and hepatic stellate cell activation through TGF-beta/Smad signaling pathway[J].Chem Biol Interact,2015,240:94-101.
[24]Farghali H,Kgalalelo KM,Wojnarova L,et al.In vitro and in vivo experimental hepatotoxic models in liver research:applications to the assessment of potential hepatoprotective drugs[J].Physiol Res,2016,65(Suppl 4):S417-S425.
[25]Keppler DO,Pausch J,Decker K.Selective uridine triphosphate deficiency induced by D-galactosamine in liver and reversed by pyrimidine nucleotide precursors.Effect on ribonucleic acid synthesis[J].J Biol Chem,1974,249(1):211-216.
[26]Stachlewitz RF,Seabra V,Bradford B,et al.Glycine and uridine prevent D-galactosamine hepatotoxicity in the rat:role of Kupffer cells[J].Hepatology,1999,29(3):737-745.
[27]Pushpavalli G,Veeramani C,Pugalendi KV.Influence of chrysin on hepatic marker enzymes and lipid profile against D-galactosamine-induced hepatotoxicity rats[J].Food Chem Toxicol,2010,48(6):1654-1659.
[28]Pushpavalli G,Kalaiarasi P,Veeramani C,et al.Effect of chrysin on hepatoprotective and antioxidant status in D-galactosamine-induced hepatitis in rats[J].Eur J Pharmacol,2010,631(1-3):36-41.
[29]Hassoun EA,Li F,Abushaban A,et al.The relative abilities of TCDDand its congeners to induce oxidative stress in the hepatic and brain tissues of rats after subchronic exposure[J].Toxicology,2000,145(2-3):103-113.
[30]Ciftci O,Vardi N,Ozdemir I.Effects of quercetin and chrysin on2,3,7,8-tetrachlorodibenzo-p-dioxin induced hepatotoxicity in rats[J].Environ Toxicol,2013,28(3):146-154.
[31]Ciftci O,Ozdemir I.Protective effects of quercetin and chrysin against 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)induced oxidative stress,body wasting and altered cytokine productions in rats[J].Immunopharmacol Immunotoxicol,2011,33(3):504-508.
[32]Ponnappa BC,Rubin E.Modeling alcohol’s effects on organs in animal models[J].Alcohol Res Health,2000,24(2):93-104.
[33]Nordmann R.Alcohol and antioxidant systems[J].Alcohol Alcohol,1994,29(5):513-522.
[34]Lieber CS.Metabolism of alcohol[J].Clin Liver Dis,2005,9(1):1-35.
[35]Helander A,Lindahl-Kiessling K.Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor[J].Mutat Res,1991,264(3):103-107.
[36]Nordmann R,Ribière C,Rouach H.Implication of free radical mechanisms in ethanol-induced cellular injury[J].Free Radical Biology and Medicine,1992,12(3):219-240.
[37]Enomoto N,Ikejima K,Bradford BU,et al.Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury[J].J Gastroenterol Hepatol,2000,15(Suppl):D20-25.
[38]Sathiavelu J,Senapathy GJ,Devaraj R,et al.Hepatoprotective effect of chrysin on prooxidant-antioxidant status during ethanol-induced toxicity in female albino rats[J].J Pharm Pharmacol,2009,61(6):809-817.
[39]Tahir M,Sultana S.Chrysin modulates ethanol metabolism in Wistar rats:a promising role against organ toxicities[J].Alcohol Alcohol,2011,46(4):383-392.
[40]Jahovic N,Cevik H,Sehirli AO,et al.Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats[J].J Pineal Res,2003,34(4):282-287.
[41]Tunali-Akbay T,Sehirli O,Ercan F,et al.Resveratrol protects against methotrexate-induced hepatic injury in rats[J].J Pharm Pharm Sci,2010,13(2):303-310.
[42]Ali N,Rashid S,Nafees S,et al.Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis[J].Mol Cell Biochem,2014,385(1-2):215-223.
[43]Rehman MU,Ali N,Rashid S,et al.Alleviation of hepatic injury by chrysin in cisplatin administered rats:probable role of oxidative and inflammatory markers[J].Pharmacol Rep,2014,66(6):1050-1059.
[44]Nathan C,Ding A.Nonresolving inflammation[J].Cell,2010,140(6):871-882.
[45]周宪宾.巨噬细胞M1/M2极化分型的研究进展[J].中国免疫学杂志,2012,28(10):957-960.
[46]Jakobsdottir G,Xu J,Molin G,et al.High-fat diet reduces the formation of butyrate,but increases succinate,inflammation,liver fat and cholesterol in rats,while dietary fibre counteracts these effects[J].PLo SOne,2013,8(11):e80476.
[47]Uetake Y,Ikeda H,Irie R,et al.High-salt in addition to high-fat diet may enhance inflammation and fibrosis in liver steatosis induced by oxidative stress and dyslipidemia in mice[J].Lipids Health Dis,2015,14(1):6.
[48]van der Heijden RA,Sheedfar F,Morrison MC,et al.High-fat diet induced obesity primes inflammation in adipose tissue prior to liver in C57BL/6j mice[J].Aging(Albany NY),2015,7(4):256-268.
[49]Feng X,Qin H,Shi Q,et al.Chrysin attenuates inflammation by regulating M1/M2 status via activating PPARgamma[J].Biochem Pharmacol,2014,89(4):503-514.
[50]Jemal A,Bray F,Center MM,et al.Global cancer statistics[J].CACancer J Clin,2011,61(2):69-90.
[51]Ferlay J,Shin HR,Bray F,et al.Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008[J].Int J Cancer,2010,127(12):2893-2917.
[52]Oishi N,Wang XW.Novel therapeutic strategies for targeting liver cancer stem cells[J].Int J Biol Sci,2011,7(5):517-535.
[53]Yamashita T,Budhu A,Forgues M,et al.Activation of hepatic stem cell marker Ep CAM by Wnt-beta-catenin signaling in hepatocellular carcinoma[J].Cancer Res,2007,67(22):10831-10839.
[54]Quan MF,Xiao LH,Liu ZH,et al.8-bromo-7-methoxychrysin inhibits properties of liver cancer stem cells via downregulation of betacatenin[J].World J Gastroenterol,2013,19(43):7680-7695.
[55]Zou H,Cao X,Xiao Q,et al.Synergistic inhibition of characteristics of liver cancer stem-like cells with a combination of sorafenib and 8-bromo-7-methoxychrysin in SMMC-7721 cell line[J].Oncol Rep,2016,36(3):1731-1738.
[56]Ren KQ,Cao XZ,Liu ZH,et al.8-bromo-5-hydroxy-7-methoxychrysin targeting for inhibition of the properties of liver cancer stem cells by modulation of Twist signaling[J].Int J Oncol,2013,43(5):1719-1729.
[57]Sun X,Huo X,Luo T,et al.The anticancer flavonoid chrysin induces the unfolded protein response in hepatoma cells[J].J Cell Mol Med,2011,15(11):2389-2398.
[58]Li X,Huang Q,Ong CN,et al.Chrysin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells via suppression of nuclear factor-kappa B[J].Cancer Lett,2010,293(1):109-116.
[59]Huang C,Wei YX,Shen MC,et al.Chrysin,abundant in Morinda citrifolia fruit water-Et OAc extracts,combined with apigenin synergistically induced apoptosis and inhibited migration in human breast and liver cancer cells[J].J Agric Food Chem,2016,64(21):4235-4245.
[60]Li X,Huang JM,Wang JN,et al.Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53[J].Chem Biol Interact,2015,232:12-20.
[61]Yang XH,Zheng X,Cao JG,et al.8-Bromo-7-methoxychrysininduced apoptosis of hepatocellular carcinoma cells involves ROS and JNK[J].World J Gastroenterol,2010,16(27):3385-3393.
[62]Zhang Q,Cui C,Chen CQ,et al.Anti-proliferative and pro-apoptotic activities of Alpinia oxyphylla on Hep G2 cells through ROS-mediated signaling pathway[J].J Ethnopharmacol,2015,169:99-108.
[63]Khan MS,Devaraj H,Devaraj N.Chrysin abrogates early hepatocarcinogenesis and induces apoptosis in N-nitrosodiethylamineinduced preneoplastic nodules in rats[J].Toxicol Appl Pharmacol,2011,251(1):85-94.
[64]Khan MS,Halagowder D,Devaraj SN.Methylated chrysin induces coordinated attenuation of the canonical Wnt and NF-k B signaling pathway and upregulates apoptotic gene expression in the early hepatocarcinogenesis rat model[J].Chem Biol Interact,2011,193(1):12-21.
[65]Zhao X,Shu G,Chen L,et al.A flavonoid component from Docynia delavayi(Franch.)Schneid represses transplanted H22 hepatoma growth and exhibits low toxic effect on tumor-bearing mice[J].Food Chem Toxicol,2012,50(9):3166-3173.