玄参提取物对甲亢模型大鼠肝脏代谢组学的影响
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摘要
目的探讨玄参提取物对甲亢模型大鼠肝脏代谢组学的作用及作用机制。方法通过超高效液相色谱-飞行时间-质谱技术分析优甲乐及玄参提取物作用下的大鼠肝脏代谢物谱。应用正交偏最小二乘判别分析法研究空白组和模型组之间的代谢物谱差异,并通过变量重要性投影(VIP)在肝脏中发现了潜在生物标志物。通过比较潜在生物标志物的含量差异,探讨玄参的干预作用。结果在模型组大鼠肝脏代谢物中发现了21个潜在生物标志物,而玄参提取物显著回调的代谢物有14个,分别参与糖基磷脂酰肌醇(GPI)锚生物合成、花生四烯酸代谢、嘌呤代谢、α-亚麻酸代谢、亚油酸代谢、谷胱甘肽代谢和甘油磷脂代谢。结论玄参提取物可能通过改善甲亢模型大鼠肝脏中相关潜在生物标志物表达及其相关代谢通路发挥治疗甲亢的作用。
Objective To investigate the effect and possible mechanism of extracts of Xuanshen(Scrophularia Root,Radix Scrophulariae)on liver metabolome in rat model of hyperthyroidism.Methods The rat liver metabolites spectrums effected by Euthyrox and Xuanshen extracts were analyzed by using ultra high performance liquid chromatography-time of-flight-mass spectrometry(UPLC-TOF-MS).The difference in metabolites spectrums was studied between blank group and model group by using orthogonal partial least squares-discriminant analysis(OPLS-DA).The potential biomarkers were found in liver through variable importance projection(VIP).The interventional effects of Xuanshen extracts were discussed through comparing the difference in content of potential biomarkers.Results There were 21 potential biomarkers found in rat liver in model group,and among them14 metabolites were significantly called back by Xuanshen extracts.The biosynthesis of glycosylphosphatidylinositol(GPI)-anchor,and metabolisms of arachidonic acid,purine,α-linolenic acid,linoleic acid,glutathione and glycerophospholipid were significantly improved by Xuanshen extracts in Euthyrox-induced hyperthyroidism rat model.Conclusion Xuanshen extracts can play a role of treating hyperthyroidism through improving relevant liver potential biomarkers and metabolism pathways in hyperthyroidism rat model.
Objective To investigate the effect and possible mechanism of extracts of Xuanshen(Scrophularia Root,Radix Scrophulariae)on liver metabolome in rat model of hyperthyroidism.Methods The rat liver metabolites spectrums effected by Euthyrox and Xuanshen extracts were analyzed by using ultra high performance liquid chromatography-time of-flight-mass spectrometry(UPLC-TOF-MS).The difference in metabolites spectrums was studied between blank group and model group by using orthogonal partial least squares-discriminant analysis(OPLS-DA).The potential biomarkers were found in liver through variable importance projection(VIP).The interventional effects of Xuanshen extracts were discussed through comparing the difference in content of potential biomarkers.Results There were 21 potential biomarkers found in rat liver in model group,and among them14 metabolites were significantly called back by Xuanshen extracts.The biosynthesis of glycosylphosphatidylinositol(GPI)-anchor,and metabolisms of arachidonic acid,purine,α-linolenic acid,linoleic acid,glutathione and glycerophospholipid were significantly improved by Xuanshen extracts in Euthyrox-induced hyperthyroidism rat model.Conclusion Xuanshen extracts can play a role of treating hyperthyroidism through improving relevant liver potential biomarkers and metabolism pathways in hyperthyroidism rat model.
引文
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[10]肖航,谭成,窦德强.3种寒性中药对优甲乐所致甲亢模型动物的影响[J].中华中医药学刊,2016,34(9):2122-2125.Xiao H,Tan C,Dou DQ.Effects of 3 Chinese drugs with cold property on hyperthyrosis rats induced by Euthyrox[J].Chinese Archives of Traditional Chinese Medicine,2016,34(9):2122-2125.
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[13]Ly-Verdu S,Schaefer A,Kahle M,et al.The impact of blood on liver metabolite profiling-a combined metabolomic and proteomic approach[J].Biomedical Chromatography,2014,28(2):231-240.
[14]张宁,李自辉,于卉,等.玄参及其各组分的降血糖作用[J].中药药理与临床,2016,32(5):55-60.Zhang N,Li ZH,Yu H,et al.Antidiabetic activity of Radix Scrophulariae and its split fraction[J].Pharmacology and Clinics of Chinese Materia Medica,2016,32(5):55-60.
[15]Lin L,Lin H,Zhang M,et al.A novel method to analyze hepatotoxic components in Polygonum multiflorum using ultra-performance liquid chromatography-quadrupole timeof-flight mass spectrometry[J/OL].Journal of Hazardous Materials,2015(299):249-259[2015-12-15].http://www.sciencedirect.com/science/article/pii/So30438 941500463x?via%3 Dihub.
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[17]Huynh F K,Neumann U H,Wang Y,et al.A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice[J].Hepatology,2013,57(2):543-554.
[18]Zheng YJ,Zhao C,Zhang NJ,et al.Serum microRNAmiR-206 is decreased in hyperthyroidism and mediates thyroid hormone regulation of lipid metabolism in HepG2human hepatoblastoma cells[J].Molecular Medicine Reports,2018,17(4):5635-5641.
[19]Lin YC,Liu YC,Nakamura Y.The choline/ethanolamine kinase family in arabidopsis:essential role of CEK4 in phospholipid biosynthesis and embryo development[J].The Plant Cell,2015,27(5):1497-1511.
[20]Lozano-Paniagua D,Parrón T,Alarcón R,et al.Biomarkers of oxidative stress in blood of workers exposed to non-cholinesterase inhibiting pesticides[J/OL].Ecotoxicology and Environmental Safety,2018(162),121-128[2018-10-30].http://www.sciencedirect.com/science/article/pii/So147651318 305645?via%3Dihub.
[21]Modis K,Gero D,Stangl R,et al.Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury[J].International Journal of Molecular Medicine,2013,31(2):437-446.
[22]Ledesma-Amaro R,Buey RM,Revuelta JL.Increased production of inosine and guanosine by means of metabolic engineering of the purine pathway in Ashbya gossypii[J/OL].Microbial Cell Factories,2015,14:58[2015-04-17].http://microbialcellfactories.biomedcentral.com/articles/10.1186/S12934-015-0234-4.
[23]Godo S,Kawazoe Y,Ozaki H,et al.Switching therapy from intravenous landiolol to transdermal bisoprolol in a patient with thyroid storm complicated by decompensated heart failure and gastrointestinal dysfunction[J].Internal Medicine,2017,56(19):2603-2609.
[24]Cao L,Waldon D,Teffera Y,et al.Ratios of biliary glutathione disulfide(GSSG)to glutathione(GSH):a potential index to screen drug-induced hepatic oxidative stress in rats and mice[J].Anal Bioanal Chem,2013,405(8):2635-2642.
[25]Giustarini D,Tsikas D,Colombo G,et al.Pitfalls in the analysis of the physiological antioxidant glutathione(GSH)and its disulfide(GSSG)in biological samples:An elephant in the room[J/OL].Journal of Chromatography B,2016(1019):21-28[2016-04-15].http://sciencedirect.com/science/article/pii/S15700232163009 52?via%3D ihub.
[2]Cao HX,Zhang AH,Zhang HM,et al.The application of metabolomics in traditional Chinese medicine opens up a dialogue between Chinese and Western medicine[J].Phytotherapy Research:PTR,2015,29(2):159-166.
[3]夏聪华,石森林,葛卫红,等.玄参药理活性研究进展[J].中国药师,2008,11(8):911-913.Xia CH,Shi SL,Ge WH,et al.Advances in research on pharmacological activities of Scrophularia[J].China Pharmacist,2008,11(8):911-913.
[4]王宁.滋阴降火为主治疗原发性甲状腺机能亢进症29例[J].安徽中医临床杂志,2000,12(2):96-97.Wang N.Treatment of 29 cases of primary hyperthyroidism with therapy of nourishing yin and downbearing fire[J].Clinical Journal of Anhui Traditional Chinese Medicine,2000,12(2):96-97.
[5]刘树民,甄喆,李健英,等.芪玄抑甲宁对甲亢大鼠的Th17细胞相关因子的调控影响[J].中药药理与临床,2017,33(1):144-148.Liu SM,Zhen Z,Li JY,et al.Regulatory effect of Qixuanyijianing on Th17 cells of rats with hyperthyroidism[J].Pharmacology and Clinics of Chinese Materia Medica,2017,33(1):144-148.
[6]刘树民,甄喆,王可心,等.芪玄抑甲宁治疗甲亢的主要药效学研究[J].中医药学报,2017,45(5):48-51.Liu SM,Zhen Z,Wang KX,et al.Pharmacodynamic research of Qixuan Yijianing in the treatment of hyperthyroidism[J].Acta Chinese Medicine and Pharmacology,2017,45(5):48-51.
[7]郭翔,欧明,黄菱.养阴益气中药合剂对甲亢类阴虚病理模型大鼠作用的实验研究[J].中国中药杂志,1993,18(8):494-495.Guo X,Ou M,Huang L.Effect of yin and qi tonifying herbs on hyperthyroid model of yin-deficient rats[J].Chin JChin Mater Med,1993,18(8):494-495.
[8]刘树民,崔晓旭,丰光,等.益气养阴方在甲亢治疗中的应用[J].辽宁中医药大学学报,2014,16(9):5-7.Liu SM,Cui XX,Feng G,et al.Supplementing qi and nourishing yin prescription in treatment of hyperthyroidism[J].Journal of Liaoning University of Traditional Chinese Medicine,2014,16(9):5-7.
[9]柳长凤,刘洪毓,苗晶囡,等.国家已公开专利中治疗甲亢的中药用药规律探讨[J].中医药信息,2013,30(2):61-64.Liu CF,Liu HY,Miao JN,et al.Discussion on administrative laws of Chinese medicinals for treating hyperthyroidism in national public patents[J].Information on Traditional Chinese Medicine,2013,30(2):61-64.
[10]肖航,谭成,窦德强.3种寒性中药对优甲乐所致甲亢模型动物的影响[J].中华中医药学刊,2016,34(9):2122-2125.Xiao H,Tan C,Dou DQ.Effects of 3 Chinese drugs with cold property on hyperthyrosis rats induced by Euthyrox[J].Chinese Archives of Traditional Chinese Medicine,2016,34(9):2122-2125.
[11]赵洪伟,张宁,庞牧,等.玄参及其拆分组分对热证大鼠物质与能量代谢的影响[J].中药药理与临床,2017,33(6):93-96.Zhao HW,Zhang N,Pang M,et al.The effect of Radix Scrophulariae and split components on material and energy metabolism in pyretic syndrome rats[J].Pharmacology and Clinics of Chinese Materia Medica,2017,33(6):93-96.
[12]Kowalik MA,Columbano A,Perra A.Thyroid hormones,thyromimetics and their metabolites in the treatment of liver disease[J/OL].Frontiers in Endocrinology,2018(9):382[2018-07-10].http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048875.
[13]Ly-Verdu S,Schaefer A,Kahle M,et al.The impact of blood on liver metabolite profiling-a combined metabolomic and proteomic approach[J].Biomedical Chromatography,2014,28(2):231-240.
[14]张宁,李自辉,于卉,等.玄参及其各组分的降血糖作用[J].中药药理与临床,2016,32(5):55-60.Zhang N,Li ZH,Yu H,et al.Antidiabetic activity of Radix Scrophulariae and its split fraction[J].Pharmacology and Clinics of Chinese Materia Medica,2016,32(5):55-60.
[15]Lin L,Lin H,Zhang M,et al.A novel method to analyze hepatotoxic components in Polygonum multiflorum using ultra-performance liquid chromatography-quadrupole timeof-flight mass spectrometry[J/OL].Journal of Hazardous Materials,2015(299):249-259[2015-12-15].http://www.sciencedirect.com/science/article/pii/So30438 941500463x?via%3 Dihub.
[16]Vance JE,Vance DE.A deazaadenosine-insensitive methylation of phosphatidylethanolamine is involved in lipoprotein secretion[J].FEBS letters,1986,204(2):243-246.
[17]Huynh F K,Neumann U H,Wang Y,et al.A role for hepatic leptin signaling in lipid metabolism via altered very low density lipoprotein composition and liver lipase activity in mice[J].Hepatology,2013,57(2):543-554.
[18]Zheng YJ,Zhao C,Zhang NJ,et al.Serum microRNAmiR-206 is decreased in hyperthyroidism and mediates thyroid hormone regulation of lipid metabolism in HepG2human hepatoblastoma cells[J].Molecular Medicine Reports,2018,17(4):5635-5641.
[19]Lin YC,Liu YC,Nakamura Y.The choline/ethanolamine kinase family in arabidopsis:essential role of CEK4 in phospholipid biosynthesis and embryo development[J].The Plant Cell,2015,27(5):1497-1511.
[20]Lozano-Paniagua D,Parrón T,Alarcón R,et al.Biomarkers of oxidative stress in blood of workers exposed to non-cholinesterase inhibiting pesticides[J/OL].Ecotoxicology and Environmental Safety,2018(162),121-128[2018-10-30].http://www.sciencedirect.com/science/article/pii/So147651318 305645?via%3Dihub.
[21]Modis K,Gero D,Stangl R,et al.Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury[J].International Journal of Molecular Medicine,2013,31(2):437-446.
[22]Ledesma-Amaro R,Buey RM,Revuelta JL.Increased production of inosine and guanosine by means of metabolic engineering of the purine pathway in Ashbya gossypii[J/OL].Microbial Cell Factories,2015,14:58[2015-04-17].http://microbialcellfactories.biomedcentral.com/articles/10.1186/S12934-015-0234-4.
[23]Godo S,Kawazoe Y,Ozaki H,et al.Switching therapy from intravenous landiolol to transdermal bisoprolol in a patient with thyroid storm complicated by decompensated heart failure and gastrointestinal dysfunction[J].Internal Medicine,2017,56(19):2603-2609.
[24]Cao L,Waldon D,Teffera Y,et al.Ratios of biliary glutathione disulfide(GSSG)to glutathione(GSH):a potential index to screen drug-induced hepatic oxidative stress in rats and mice[J].Anal Bioanal Chem,2013,405(8):2635-2642.
[25]Giustarini D,Tsikas D,Colombo G,et al.Pitfalls in the analysis of the physiological antioxidant glutathione(GSH)and its disulfide(GSSG)in biological samples:An elephant in the room[J/OL].Journal of Chromatography B,2016(1019):21-28[2016-04-15].http://sciencedirect.com/science/article/pii/S15700232163009 52?via%3D ihub.