从“化学成分谱-减毒作用谱-生物信息谱”关联分析整体评价雷公藤配伍金钱草的相杀减毒作用机制
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摘要
目的:整体评价雷公藤(LGT)配伍金钱草(JQC)后在荷瘤状态下的相杀减毒作用机制。方法:以配伍前后12个差异特征成分为化学成分谱,以丙氨酸氨基转移酶(ALT),天门冬氨酸氨基转移酶(AST),肌酐(Cr)和尿素氮(BUN),肝丙二醛(MDA),肾MDA共6指标为减毒作用谱,以肝和肾的谷胱甘肽(GSH),谷胱甘肽-S-转移酶(GST),谷胱甘肽过氧化物酶(GPx),超氧化物歧化酶(SOD),过氧化氢酶(CAT),白细胞介素(IL)-10共12个生物指标作为生物信息谱,通过主成分分析(PCA)整体评价LGT-JQC在荷瘤S180和H22肿瘤状态下的相杀减毒作用及其机制,通过对"化学成分谱-减毒作用谱-生物信息谱"灰色关联分析(GCA)评价化学成分和生物指标对其相杀减毒作用的贡献大小。结果:与模型组比较,LGT单用后使S180和H22的减毒作用谱得分Z_1值和Z_3值均显著升高(P<0.01);与LGT单用组比较,LGT-JQC在质量配比为4∶1,2∶1,1∶1,1∶2,1∶4配伍时均能显著降低LGT引起的过高水平的Z_1值和Z_3值(P<0.01);LGT-JQC在质量比为4∶1,1∶1,1∶2,1∶4配伍时的Z_1值和Z_3值均明显高于质量比在2∶1时相应的Z_1值和Z_3值(P<0.01)。LGT能使S180和H22荷瘤状态下生物信息谱得分Z_2值和Z_4值均显著降低,配伍JQC可使Z_2值和Z_4值显著升高。对二者在S180和H22肿瘤状态下相杀减毒作用贡献最大的化学成分分别为3#和10#特征成分,贡献最大的生物指标分别为肾GPx和肾GSH。结论:LGT和JQC在质量比为4∶1~1∶4配伍时,对LGT所致的荷瘤S180和H22肿瘤状态下的毒性均有减毒作用,二者相杀减毒的最佳配比均为2∶1,减毒作用体现了中医"有故无殒"思想,其减毒作用机制涉及肝、肾的抗氧化损伤及抗炎症反应,其中尤以肾GPx(S180)和肾GSH(H22)对减毒作用机制的贡献最大。
Objective:To overall evaluate the mutual detoxication mechanism of Tripterygii Radix et Rhizoma(LGT)compatible with Lysimachiae Herba(JQC)in tumor-bearing state.Method:Twelve differentially characteristic components before and after compatibility were used as chemical composition spectrum,six indicators including serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine(Cr)and urea nitrogen(BUN),malondialdehyde(MDA)levels in the liver and kidney tissues were used as attenuation spectrum,and twelve biological indicators including glutathione(GSH),glutathione-S-transferase(GST),glutathione peroxidase(GPx),superoxide dismutase(SOD),catalase(CAT)and interleukin(IL)-10 in the liver and kidney were used as the biological information spectrum.Mutual detoxication mechanisms of LGT compatible with JQC in tumor-bearing state were overall evaluated by principal component analysis(PCA),and the contribution of chemical components and biological indicators to mutual detoxication was further evaluated by gray correlation analysis(GCA)of"chemical composition spectrum-attenuation spectrumbiological information spectrum".Result:Compared with the model group,the attenuation spectrum scores Z values of S180(Z_1value)and H22(Z_3value)increased significantly after LGT being used alone(P<0.01).Compared with LGT alone group,the compatibility groups of LGT and JQC significantly reduced excessive Z_1value and Z_3value caused by LGT when the ratio of LGT and JQC was 4∶1,2∶1,1∶1,1∶2 and 1∶4(P<0.01).The overall efficacy of Z values(Z_1value and Z_3value)of LGT-JQC in the mass ratios including 4∶1,1∶1,1∶2and 1∶4 was significantly higher than that in the ratio of 2∶1(P<0.01).LGT also caused a significant decrease in the Z values of the bioinformatics scores in the S180(Z_2value)and H22(Z_4value)tumor-bearing state,these two values were significantly increased after compatibility with JQC.The chemical components contributing the most to the attenuating effect of S180 and H22 in tumor-bearing state were 3#and 10#,respectively.The most important biological indicators were kidney GPx and renal GSH.Conclusion:LGT combined with JQC in the mass ratio of 4∶1-1∶4 can attenuate LGT-induced subacute toxicity in S180 and H22 tumor-bearing state,and the best ratio of such effect is 2∶1.The attenuating effect reflects the thought of"there is no reason why there is no meteorology".The mechanism of attenuating action involves antioxidative damage and anti-inflammatory reaction of the liver and kidney,especially the renal GPx(S180)and renal GSH(H22)as the greatest contribution to the detoxication mechanism.
Objective:To overall evaluate the mutual detoxication mechanism of Tripterygii Radix et Rhizoma(LGT)compatible with Lysimachiae Herba(JQC)in tumor-bearing state.Method:Twelve differentially characteristic components before and after compatibility were used as chemical composition spectrum,six indicators including serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine(Cr)and urea nitrogen(BUN),malondialdehyde(MDA)levels in the liver and kidney tissues were used as attenuation spectrum,and twelve biological indicators including glutathione(GSH),glutathione-S-transferase(GST),glutathione peroxidase(GPx),superoxide dismutase(SOD),catalase(CAT)and interleukin(IL)-10 in the liver and kidney were used as the biological information spectrum.Mutual detoxication mechanisms of LGT compatible with JQC in tumor-bearing state were overall evaluated by principal component analysis(PCA),and the contribution of chemical components and biological indicators to mutual detoxication was further evaluated by gray correlation analysis(GCA)of"chemical composition spectrum-attenuation spectrumbiological information spectrum".Result:Compared with the model group,the attenuation spectrum scores Z values of S180(Z_1value)and H22(Z_3value)increased significantly after LGT being used alone(P<0.01).Compared with LGT alone group,the compatibility groups of LGT and JQC significantly reduced excessive Z_1value and Z_3value caused by LGT when the ratio of LGT and JQC was 4∶1,2∶1,1∶1,1∶2 and 1∶4(P<0.01).The overall efficacy of Z values(Z_1value and Z_3value)of LGT-JQC in the mass ratios including 4∶1,1∶1,1∶2and 1∶4 was significantly higher than that in the ratio of 2∶1(P<0.01).LGT also caused a significant decrease in the Z values of the bioinformatics scores in the S180(Z_2value)and H22(Z_4value)tumor-bearing state,these two values were significantly increased after compatibility with JQC.The chemical components contributing the most to the attenuating effect of S180 and H22 in tumor-bearing state were 3#and 10#,respectively.The most important biological indicators were kidney GPx and renal GSH.Conclusion:LGT combined with JQC in the mass ratio of 4∶1-1∶4 can attenuate LGT-induced subacute toxicity in S180 and H22 tumor-bearing state,and the best ratio of such effect is 2∶1.The attenuating effect reflects the thought of"there is no reason why there is no meteorology".The mechanism of attenuating action involves antioxidative damage and anti-inflammatory reaction of the liver and kidney,especially the renal GPx(S180)and renal GSH(H22)as the greatest contribution to the detoxication mechanism.
引文
[1]刘莹,仲青香,邱辉辉,等.基于肝毒性的雷公藤中药复方配伍减毒的研究进展[J].中国中药杂志,2017,42(16):3044-3048.
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[11] LI X X,DU F Y,LIU H X,et al. Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity[J]. J Ethnopharmacol,2015,162:238-243.
[12]钟赣生.中药学[M].北京:中国中医药出版社,2016:38.
[13]丁中连.金钱草的药用小方[J].农村百事通,2010(2):74-75.
[14]王君明,李金花,蔡泓,等.基于主成分分析和灰色关联分析方法评价雷公藤配伍金钱草的相杀减毒作用的化学基础[J].中国全科医学,2018,21(21):2622-2626.
[15]王君明,李金花,李金洋,等.基于主成分分析评价雷公藤配伍金钱草的相杀减毒作用[J].中国实验方剂学杂志,2018,24(21):1-6.
[16] H9gberg J,Larson R E,Kristoferson A,et al. NADPHdependent reductase solubilized from microsomes by peroxidation and its activity[J]. Biochem Biophys Res Commun,1974,56(3):836-842.
[17]于海帅.基于主成分分析、聚类分析和典型相关分析的漏芦抗胃癌谱效关系探索[J].中国实验方剂学杂志,2016,22(21):27-31.
[18]罗益远,刘娟秀,刘训红,等.不同加工方法何首乌中多元功效物质的测定及主成分分析[J].中草药,2016,47(2):318-323.
[19]梁健钦,王剑,熊万娜,等.基于灰色关联分析的芒果叶提取物抗炎作用的谱效关系[J].中国实验方剂学杂志,2015,21(1):121-125.
[20]刘维,张祎楠,裴瑾,等.川牛膝品种与品质的灰色关联度分析研究[J].中国药学杂志,2014,49(20):1796-1801.
[2] CHAN S F,CHEN Y Y,LIN J J,et al. Triptolide induced cell death through apoptosis and autophagy in murine leukemia WEHI-3 cells in vitro and promoting immune responses in WEHI-3 generated leukemia mice in vivo[J]. Environ Toxicol,2017,32(2):550-568.
[3] CHANG H J,Kim M H,Baek M K,et al. Triptolide inhibits tumor promoter-induced u PAR expression via blocking NF-кB signaling in human gastric AGS cells[J]. Anticancer Res,2007,27(5A):3411-3417.
[4] Kim M J,Lee T H,Kim S H,et al. Triptolide inactivates Akt and induces caspase-dependent death in cervical cancer cells via the mitochondrial pathway[J]. Int J Oncol,2010,37(5):1177-1185.
[5] LIU J,JIANG Z,XIAO J,et al. Effects of triptolide from Tripterygium wilfordii on ERαand p53 expression in two human breast cancer cell lines[J]. Phytomedicine,2009,16(11):1006-1013.
[6] XIE C Q,ZHOU P,ZUO J,et al. Triptolide exerts proapoptotic and cell cycle arrest activity on drug-resistant human lung cancer A549/Taxol cells via modulation of MAPK and PI3K/Akt signaling pathways[J]. Oncol Lett,2016,12(5):3586-3590.
[7] WANG Z,Ravula R,SHI L,et al. Overcoming chemoresistance in prostate cancer with Chinese medicine Tripterygium wilfordii via multiple mechanisms[J]. Oncotarget,2016,7(38):61246-61261.
[8] BAO J,DAI S M. A Chinese herb Tripterygium wilfordii Hook F in the treatment of rheumatoid arthritis:mechanism,efficacy,and safety[J]. Rheumatol Int,2011,31(9):1123-1129.
[9] HUANG L,FENG S,WANG H. Decreased bone mineral density in female patients with systemic lupus erythematosus after long-term administration of Tripterygium wilfordii Hook. F.[J]. Chin Med J(Engl),2000,113(2):159-161.
[10] WAN Y G,ZHAO Q,SUN W,et al. Contrasting doseeffects of multi-glycoside of Tripterygium wilfordii HOOK. f. on glomerular inflammation and hepatic damage in two types of anti-Thy1. 1 glomerulonephritis[J]. J Pharmacol Sci,2012,118(4):433-446.
[11] LI X X,DU F Y,LIU H X,et al. Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity[J]. J Ethnopharmacol,2015,162:238-243.
[12]钟赣生.中药学[M].北京:中国中医药出版社,2016:38.
[13]丁中连.金钱草的药用小方[J].农村百事通,2010(2):74-75.
[14]王君明,李金花,蔡泓,等.基于主成分分析和灰色关联分析方法评价雷公藤配伍金钱草的相杀减毒作用的化学基础[J].中国全科医学,2018,21(21):2622-2626.
[15]王君明,李金花,李金洋,等.基于主成分分析评价雷公藤配伍金钱草的相杀减毒作用[J].中国实验方剂学杂志,2018,24(21):1-6.
[16] H9gberg J,Larson R E,Kristoferson A,et al. NADPHdependent reductase solubilized from microsomes by peroxidation and its activity[J]. Biochem Biophys Res Commun,1974,56(3):836-842.
[17]于海帅.基于主成分分析、聚类分析和典型相关分析的漏芦抗胃癌谱效关系探索[J].中国实验方剂学杂志,2016,22(21):27-31.
[18]罗益远,刘娟秀,刘训红,等.不同加工方法何首乌中多元功效物质的测定及主成分分析[J].中草药,2016,47(2):318-323.
[19]梁健钦,王剑,熊万娜,等.基于灰色关联分析的芒果叶提取物抗炎作用的谱效关系[J].中国实验方剂学杂志,2015,21(1):121-125.
[20]刘维,张祎楠,裴瑾,等.川牛膝品种与品质的灰色关联度分析研究[J].中国药学杂志,2014,49(20):1796-1801.