Effects of Gancao Nourish-Yin Decoction on Liver Metabolic Profiles in hTNF-αTransgenic Arthritic Model Mice  

甘草养阴汤对hTNF-α转基因关节炎模型小鼠肝脏代谢的影响

作　　者：Rongbin Pan Kok Suen Cheng Yanjuan Chen Xingwang Zhu Wenting Zhao Changhong Xiao Yong Chen 潘荣斌;KokSuen Cheng;陈艳娟;朱兴旺;赵文婷;肖长虹;陈永(江西中医药大学癌症研究中心,江西南昌;北京大学工程学院,北京;暨南大学药学院,广东广州;南方医科大学中西医结合医院免疫学风湿病科,广东广州;深圳市人民医院免疫学风湿病科(暨南大学第二临床医学院,南方医科大学第一附属医院),广东深圳)

机构地区：[1]Jiangzhong Cancer Research Center,Jiangxi University of Chinese Medicine,Nanchang,Jiangxi,China [2]College of Engineering,Peking University,Beijing,China [3]School of Medicine,Ji'nan University,Guangzhou Guangdong,China [4]Department of Immunology and Rheumatology,Integrative Hospital of Traditional Chinese Medicine,Southern Medical University,Guangzhou Guangdong,China [5]Department of Rheumatology and Immunology,Shenzhen People's Hospital(The Second Clinical Medical College,Ji'nan University,The First Hospital Affiliated to Southern University of Science and Technology),Shenzhen,Guangdong,China

出　　处：《Chinese Medicine and Natural Products》2022年第1期19-27,共9页中医学报（英文）

基　　金：supported by the Scientific Research Project of Guangdong Province Traditional Chinese Medicine Bureau(20201229)and China Postdoctoral Science Foundation Project(2021M701438).

摘　　要：Objective Gancao Nourish-Yin Decoction(GNYD)has been applied to clinical rheumatoid arthritis(RA)patients,and it had shown effectiveness not only in disease activity controlling but also in improving patients'physical status.However,its mechanism of function has not been investigated.Metabolic perturbations have been associated with RA,and targeting the metabolic profile is one of the ways to manage the disease.The aim of this study is to observe the effect of GNYD on metabolic changes of human tumor necrosis factorα(hTNF-α)transgenic arthritic model mice.Methods hTNF-αtransgenic arthritic model mice were divided into the control group and the GNYD group with six mice in each group.After 8 weeks of treatment,liver tissues of mice in both groups were obtained for liquid chromatography-mass spectrometry analysis.Significantly regulated metabolites by GNYD treatment were first identified,followed by Kyoto Encyclopedia of Genes and Genomes pathway and network analysis.Results A total of 126 metabolites were detected in the liver.Compared with the control group,17 metabolites in the GNYD group were significantly altered.Specifically,thiamine,gamma-L-glutamyl-L-valine,pantothenic acid,pyridoxal(vitamin B6),succinic acid,uridine 5′-diphospho-glucuronic acid,uridine,allantoic acid,N-acetyl-D-glucosamine,nicotinamide ribotide,and N2,N2-dimethylguanosine were down-regulated by GNYD treatment,whereas isobutyrylglycine,N-acetylcadaverine,N-carbamoyl-L-aspartic acid,L-anserine,creatinine,and cis-4-hydroxy-D-proline were up-regulated.Six metabolic pathways were significantly altered including the alanine,aspartate,and glutamate metabolism;pyrimidine metabolism;thiamine metabolism;amino sugar and nucleotide sugar metabolism;pantothenate and CoA biosynthesis;and citrate cycle.Integrative metabolic network analysis suggested the possibility of GNYD having both positive and negative effects on RA through the suppression of angiogenesis and the promotion of leukocyte extravasation into the synovium,respectively.Conclusions GNY目的:甘草养阴汤(Gancao Nourish Yin,GCNY)已应用于临床类风湿性关节炎患者,其不仅可以控制疾病的发生发展,还可以改善患者的身体状况,但作用机制尚未得到研究。代谢紊乱与类风湿性关节炎相关,靶向代谢特征是控制该疾病的方法之一。本研究的目的是观察GCNY对人肿瘤坏死因子-α(human tumor necrosis factor alpha,hTNF-α)转基因关节炎模型小鼠代谢变化的影响。方法:将hTNF-α转基因关节炎模型小鼠分为对照组和甘草养阴汤组,每组6只。治疗8周后,取两组小鼠的肝组织进行液相色谱-质谱分析(liquid chromatography-mass spectrometry,LC/MS)。首先确定甘草养阴汤处理后发生显著变化的代谢物,之后对这些代谢物进行京都基因和基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析和网络分析。结果:肝脏中共检测到126种代谢物,与对照组比较,甘草养阴汤组17种代谢物发生显著变化。具体来说,甘草养阴汤处理后,硫胺素、γ-L-谷氨酰-L-缬氨酸、泛酸、吡哆醛(维生素B6)、琥珀酸、尿苷5′-二磷酸-葡萄糖醛酸、尿苷、尿囊酸、N-乙酰基-D-葡萄糖,葡萄糖胺、烟酰胺核糖苷和N2,N2-二甲基鸟苷显著下调,而异丁酰甘氨酸、N-乙酰尸胺、N-氨基甲酰-L-天冬氨酸、L-鹅肌氨酸、肌酸酐和顺式4-羟基-D-脯氨酸显著上调。六种代谢途径发生显著改变,包括丙氨酸、天冬氨酸和谷氨酸代谢、嘧啶代谢、硫胺素代谢、氨基糖和核苷酸糖代谢、泛酸和CoA生物合成以及柠檬酸循环(TCA循环)。综合代谢网络分析表明,甘草养阴汤可能分别通过抑制血管生成和促进白细胞渗入滑膜对类风湿性关节炎发挥双向调节作用。结论:甘草养阴汤可调节hTNF-α转基因关节炎模型小鼠的肝脏代谢。该汤剂的进一步优化可能会对类风湿性关节炎患者产生更好的疗效。

关 键 词：rheumatoid arthritis Gancao Nourish Yin Decoction hTNF α liver metabolism metabolomics 

分 类 号：R28[医药卫生—中药学]