甘草次酸保肝功效的通路作用机制
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摘要
甘草的活性成分包括甘草甜素(glycyrrhizin,GL)和甘草次酸(glycyrrhetinic acid,GA),而GA是甘草中的主要生物活性成分,是GL的主要代谢产物,部分GL通过细菌在肠内代谢为GA。在许多以往的研究中已经证实其具有多种药理学效果,例如抗炎、抗过敏、抗致癌、抗损伤和抗氧化特性以及肝脏保护。最近的研究表明,GA可以降低逆转录因子、二氧化钛纳米粒子和环磷酰胺诱导的肝毒性,并且可以保护免受四氯化碳诱导的肝损伤。已报道的GA的保肝作用机制主要归因于诱导抗氧化剂防御,抑制炎症反应和细胞色素P450表达,本文将对GA在不同信号通路中发挥保肝作用进行综述。
The active ingredients of liquorice root include Glycyrrhizin(GL) and Glycyrrhetinic acid(GA), while GA is the main biological active ingredient as well as the main metabolite of glycyrrhizin(GL). Part of GL is metabolized to GA in the intestine by bacteria. It has been demonstrated in many previous studies that GA has a variety of pharmacological effects, such as anti-inflammatory, anti-allergic, anti-carcinogenic, anti-injury, antioxidant properties and hepatoprotection. Recent studies have shown that GA can reduce hepatotoxicity induced by reverse transcription factors, titanium dioxide nanoparticles, cyclophosphamide, and protect against liver damage induced by carbon tetrachloride. The reported hepatoprotective mechanism of GA is mainly attributed to the induction of antioxidant defense, inhibition of inflammatory response and cytochrome P450 expression. The role of GA in hepatoprotective effects in different signaling pathways will be introduced in this article.
The active ingredients of liquorice root include Glycyrrhizin(GL) and Glycyrrhetinic acid(GA), while GA is the main biological active ingredient as well as the main metabolite of glycyrrhizin(GL). Part of GL is metabolized to GA in the intestine by bacteria. It has been demonstrated in many previous studies that GA has a variety of pharmacological effects, such as anti-inflammatory, anti-allergic, anti-carcinogenic, anti-injury, antioxidant properties and hepatoprotection. Recent studies have shown that GA can reduce hepatotoxicity induced by reverse transcription factors, titanium dioxide nanoparticles, cyclophosphamide, and protect against liver damage induced by carbon tetrachloride. The reported hepatoprotective mechanism of GA is mainly attributed to the induction of antioxidant defense, inhibition of inflammatory response and cytochrome P450 expression. The role of GA in hepatoprotective effects in different signaling pathways will be introduced in this article.
引文
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[3]LamP,FanC, TanHY,etal.Hepatoprotectiveeffectsof Chinese Medicinal Herbs:a focus on anti-inflammatory and anti-oxidative activities. Int J Mol Sci, 2016, 17(4):465.
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[5]Huo T, Fang Y, Zhang Y, et al. Plasma metabolomics study of the hepatoprotective effect of glycyrrhetinic acid on realgar-induced sub-chronic hepatotoxicity in mice via 1H-NMR analysis. J Ethnopharmacol, 2017, 208:36-43.
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[7]Yang G, Wang L, Yu X, et al. Protective effect of 18?2-Glycyrrhetinic Acidagainst Triptolide-InducedHepatotoxicityinrats.EvidBasedComplement AlternatMed,2017,2017(2):1-12.
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[10] Su L, Wang Z, Huang F, et al. 18β-Glycyrrhetinic acid mitigates radiation-induced skin damage via NADPH oxidase/ROS/p38MAPK and NF-κB pathways. Environ Toxicol Pharmacol, 2018, 60:82-90.
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[13] Cao L, Ding W, Jia R, et al. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp(Cyprinus carpio var. jian)through inhibition of the nf-k?pathway.Fish Shellfish Immunol, 2017, 64:234-242.
[14] Cai H, Chen X, Zhang J, et al. 18β-glycyrrhetinic acid inhibits migration and invasion of human gastric cancer cells via the ROS/PKC-α/ERK pathway. J Nat Med, 2018, 72(1):252-259.
[15] Jung JC, Lee YH, Kim SH, et al. Hepatoprotective effect of licorice, the root of Glycyrrhiza uralensis Fischer, in alcohol-induced fatty liver disease. BMCComplement Altern Med, 2016, 16(1):1-10.
[16] Yin X, Gong X, Zhang L, et al. Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure inδ-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M. Toxicol Appl Pharmacol, 2017, 320:8-16.
[17] Yan T, Wang H, Zhao M, et al. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factorα-Mediated Apoptosis. Drug Metab Dispos, 2016, 44(5):720-731.
[18] Yang G, Li Z, Li M, et al. Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice. Int Immunopharmacol, 2017, 50:186-193.
[19] CaoLJ,HouZY,LiHD,etal.TheEthanolExtractof Licorice(Glycyrrhizauralensis)Protectsagainst Triptolide-Induced Oxidative Stress through Activation of Nrf2.EvidBasedComplement AlternatMed,2017,2017(12):2752389.
[20] Mahmoud AM, Hussein OE, Hozayen WG, et al. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγand Nrf2:Protective effect of18β-Glycyrrhetinic acid. Chem Biol interact, 2017, 270:59.
[21] Cao L, Ding W, Jia R, et al. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp(Cyprinus carpio var. jian)through inhibition of the NF-k?pathway.Fish Shellfish Immunol, 2017, 64:234.
[22]邢燕,历飞,林大勇等.甘草次酸通过PI3K-AKT途径抑制H_2O_2所致大鼠心肌细胞氧化损伤.现代生物医学进展, 2018, 18(06):54-59.
[23] Ayman M.Mahmoud, HusseinS. Al Dera HS. 18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity:potential role of PPARγand Nrf2 upregulation. Genes Nutr, 2015, 10(6):1-13.
[24] Wang GW, Zhang XL, Wu QH, et al. The hepatoprotective effects of Sedum sarmentosum extract and its isolated major constituent through Nrf2 activation and NF-κB inhibition.Phytomedicine, 2018.
[25] Zheng L, Haihua F, Yue W, et al. Rosmarinic acid protects mice from lipopolysaccharide/D-galactosamine-T induced acute liver injury by inhibiting MAPKs/NF-κB and activating Nrf2/HO-1 signaling pathways. Int Immunopharmacol,2019, 67:465-472.
[26] Bian X, Liu X, Liu J, et al. Hepatoprotective effect of chiisanosidefrom AcanthopanaxsessiliflorusagainstLPS/D-GalN-induced acute liver injury by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways. Sci Food Agric,2018, doi:10.1002/jsfa.9541.
[27] Wu T,LiJ,Li Y,etal. Antioxidantandhepatoprotective effect of swertiamarin on carbon tetrachloride-induced hepatotoxicity via the Nrf2/HO-1pathway. Cell Physiol Biochem,2017, 41(6):2242-2254
[28] Yang Y, Yang L, Han Y, et al. Protective effects of hepatocyte-specific glycyrrhetic derivatives against carbon tetrachloride-induced liver damage in mice. Bioorg Chem, 2017,72:42-50.
[2]Li JY, Cao HY, Liu P, et al. Glycyrrhizic acid in the treatment of liver diseases:literature review. Biomed Res Int, 2014,2014(8):872139.
[3]LamP,FanC, TanHY,etal.Hepatoprotectiveeffectsof Chinese Medicinal Herbs:a focus on anti-inflammatory and anti-oxidative activities. Int J Mol Sci, 2016, 17(4):465.
[4]Sun YQ, Dai CM, Zheng Y, et al. Binding effect of fluorescence labeled glycyrrhetinic acid with GA receptors in hepatocellular carcinoma cells. Life Sci, 2017, 188:186.
[5]Huo T, Fang Y, Zhang Y, et al. Plasma metabolomics study of the hepatoprotective effect of glycyrrhetinic acid on realgar-induced sub-chronic hepatotoxicity in mice via 1H-NMR analysis. J Ethnopharmacol, 2017, 208:36-43.
[6]Wang H, Fang ZZ, Meng R, et al. Glycyrrhizin and glycyrrhetinic acid inhibits alpha-naphthyl isothiocyanate-induced liver injury and bile acid cycle disruption. Toxicology, 2017,386.
[7]Yang G, Wang L, Yu X, et al. Protective effect of 18?2-Glycyrrhetinic Acidagainst Triptolide-InducedHepatotoxicityinrats.EvidBasedComplement AlternatMed,2017,2017(2):1-12.
[8]Darwish AG,SamyMN,SugimotoS,etal.Effectsof hepatoprotective compounds from the leaves of lumnitzera racemosa on acetaminophen-induced liver damage in vitro.Chem Pharm Bull(Tokyo),2016, 64(4):360-365
[9]Hasan SK, Khan R, Ali N, et al. 18-βGlycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in Wistar rats:Role in hyperproliferation, inflammation and oxidative stress. Hum Exp Toxicol, 2015, 34(6):628-641.
[10] Su L, Wang Z, Huang F, et al. 18β-Glycyrrhetinic acid mitigates radiation-induced skin damage via NADPH oxidase/ROS/p38MAPK and NF-κB pathways. Environ Toxicol Pharmacol, 2018, 60:82-90.
[11] Sil R, Ray D, Chakraborti AS. Glycyrrhizin ameliorates metabolic syndrome-induced liver damage in experimental rat model. Mol Cell Biochem, 2015, 409(1-2):177-189.
[12] Wang W, Li X, Xu J. Magnesium isoglycyrrhizinate attenuatesD-galactosamine/lipopolysaccharidesinducedacute liver injury of rat via regulation of the p38-MAPK and NF-κB signaling pathways. Immunopharmacol Immunotoxicol,2018, 40(3):262-267.
[13] Cao L, Ding W, Jia R, et al. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp(Cyprinus carpio var. jian)through inhibition of the nf-k?pathway.Fish Shellfish Immunol, 2017, 64:234-242.
[14] Cai H, Chen X, Zhang J, et al. 18β-glycyrrhetinic acid inhibits migration and invasion of human gastric cancer cells via the ROS/PKC-α/ERK pathway. J Nat Med, 2018, 72(1):252-259.
[15] Jung JC, Lee YH, Kim SH, et al. Hepatoprotective effect of licorice, the root of Glycyrrhiza uralensis Fischer, in alcohol-induced fatty liver disease. BMCComplement Altern Med, 2016, 16(1):1-10.
[16] Yin X, Gong X, Zhang L, et al. Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure inδ-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M. Toxicol Appl Pharmacol, 2017, 320:8-16.
[17] Yan T, Wang H, Zhao M, et al. Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factorα-Mediated Apoptosis. Drug Metab Dispos, 2016, 44(5):720-731.
[18] Yang G, Li Z, Li M, et al. Glycyrrhetinic acid prevents acetaminophen-induced acute liver injury via the inhibition of CYP2E1 expression and HMGB1-TLR4 signal activation in mice. Int Immunopharmacol, 2017, 50:186-193.
[19] CaoLJ,HouZY,LiHD,etal.TheEthanolExtractof Licorice(Glycyrrhizauralensis)Protectsagainst Triptolide-Induced Oxidative Stress through Activation of Nrf2.EvidBasedComplement AlternatMed,2017,2017(12):2752389.
[20] Mahmoud AM, Hussein OE, Hozayen WG, et al. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγand Nrf2:Protective effect of18β-Glycyrrhetinic acid. Chem Biol interact, 2017, 270:59.
[21] Cao L, Ding W, Jia R, et al. Anti-inflammatory and hepatoprotective effects of glycyrrhetinic acid on CCl4-induced damage in precision-cut liver slices from Jian carp(Cyprinus carpio var. jian)through inhibition of the NF-k?pathway.Fish Shellfish Immunol, 2017, 64:234.
[22]邢燕,历飞,林大勇等.甘草次酸通过PI3K-AKT途径抑制H_2O_2所致大鼠心肌细胞氧化损伤.现代生物医学进展, 2018, 18(06):54-59.
[23] Ayman M.Mahmoud, HusseinS. Al Dera HS. 18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity:potential role of PPARγand Nrf2 upregulation. Genes Nutr, 2015, 10(6):1-13.
[24] Wang GW, Zhang XL, Wu QH, et al. The hepatoprotective effects of Sedum sarmentosum extract and its isolated major constituent through Nrf2 activation and NF-κB inhibition.Phytomedicine, 2018.
[25] Zheng L, Haihua F, Yue W, et al. Rosmarinic acid protects mice from lipopolysaccharide/D-galactosamine-T induced acute liver injury by inhibiting MAPKs/NF-κB and activating Nrf2/HO-1 signaling pathways. Int Immunopharmacol,2019, 67:465-472.
[26] Bian X, Liu X, Liu J, et al. Hepatoprotective effect of chiisanosidefrom AcanthopanaxsessiliflorusagainstLPS/D-GalN-induced acute liver injury by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways. Sci Food Agric,2018, doi:10.1002/jsfa.9541.
[27] Wu T,LiJ,Li Y,etal. Antioxidantandhepatoprotective effect of swertiamarin on carbon tetrachloride-induced hepatotoxicity via the Nrf2/HO-1pathway. Cell Physiol Biochem,2017, 41(6):2242-2254
[28] Yang Y, Yang L, Han Y, et al. Protective effects of hepatocyte-specific glycyrrhetic derivatives against carbon tetrachloride-induced liver damage in mice. Bioorg Chem, 2017,72:42-50.