大肠癌脾虚湿热证和湿热蕴结证临床表型组的代谢组学机制

田园; 杨忠明; 杜鑫; 黄进; YE Lingyu Linda; DUAN Dayue Darrel

doi:10.3969/j.issn.1006-2157.2023.12.013

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大肠癌脾虚湿热证和湿热蕴结证临床表型组的代谢组学机制

实验研究 | 更新时间：2024-01-03

- 大肠癌脾虚湿热证和湿热蕴结证临床表型组的代谢组学机制
- Metabolomic mechanisms for the clinical phenomes of spleen deficiency and dampness-heat syndrome and dampness-heat accumulation syndrome associated with colorectal cancer
- 北京中医药大学学报 2023年46卷第12期页码：1728-1741
- 作者机构：
  
  1.西南医科大学附属中医医院　中医药表型组学研究中心　泸州　646000
  2.西南医科大学中西医结合学院
  3.四川省肿瘤医院中西医结合科
  4.西南医科大学附属中医医院肿瘤科
- 作者简介：
  
  田园，女，硕士
  #DUAN Dayue Darrel，男，教授，博士生导师，主要研究方向：中医药表型组学，E-mail: dduan@swmu.edu.cn
- 基金信息：
  
  国家中医药管理局中医药循证能力建设项目(2019XZZX-ZL005);泸州市人民政府－西南医科大学高层次人才引进专项资助(2019LZXNYD-P01DUAN);泸州市人民政府－西南医科大学科技战略合作项目(2018LZXNYD-ZK37)
- DOI：10.3969/j.issn.1006-2157.2023.12.013
  中图分类号： R273
- 纸质出版日期：2023-12-30，
  
  网络出版日期：2023-08-14，
  
  收稿日期：2023-03-27，
- 稿件说明：
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田园, 杨忠明, 杜鑫, 等. 大肠癌脾虚湿热证和湿热蕴结证临床表型组的代谢组学机制[J]. 北京中医药大学学报, 2023,46(12):1728-1741.

TIAN Yuan, YANG Zhongming, DU Xin, et al. Metabolomic mechanisms for the clinical phenomes of spleen deficiency and dampness-heat syndrome and dampness-heat accumulation syndrome associated with colorectal cancer[J]. Journal of Beijing University of Traditional Chinese Medicine, 2023,46(12):1728-1741.
田园, 杨忠明, 杜鑫, 等. 大肠癌脾虚湿热证和湿热蕴结证临床表型组的代谢组学机制[J]. 北京中医药大学学报, 2023,46(12):1728-1741. DOI： 10.3969/j.issn.1006-2157.2023.12.013.

TIAN Yuan, YANG Zhongming, DU Xin, et al. Metabolomic mechanisms for the clinical phenomes of spleen deficiency and dampness-heat syndrome and dampness-heat accumulation syndrome associated with colorectal cancer[J]. Journal of Beijing University of Traditional Chinese Medicine, 2023,46(12):1728-1741. DOI： 10.3969/j.issn.1006-2157.2023.12.013.

摘要

目的

阐明大肠癌脾虚湿热证表型组和湿热蕴结证表型组的代谢组学机制。

方法

2021年3月—2021年10月于西南医科大学附属中医医院招募大肠癌脾虚湿热证患者68例、湿热蕴结证患者58例，同时纳入于此进行体检的健康平和质人员62名。建立脾虚湿热证表型组、湿热蕴结证表型组和健康平和质表型组队列，以超高液相色谱和质谱联用技术对各队列血清代谢物进行分离鉴定，并进行主成分分析(PCA)、正交偏最小二乘判别分析法(OLPS-DA)分析及生物信息学分析。

结果

与健康平和质表型组相比，脾虚湿热证表型组有胍基乙酸下调，亚氨甲基谷氨酸、咪唑乙酸、脱氧尿苷、胞苷、假尿苷、鸟氨酸、

－乙酰鸟氨酸、5－羟吲哚乙酸、胆色素原、琥珀酸半醛、甜醇表达上调等12种差异代谢，涉及能量代谢异常为主的7条代谢途径；湿热蕴结证表型组有脱氧尿苷、胞苷、胆色素原、花生酸、前列腺素B

、异柠檬酸、古洛糖酸表达上调，胍基乙酸、尿苷、羟脯氨酸、吡咯－2－羧酸、腺苷、5，6－DHET、8，9－DiHETrE、9，10－DHOME、亚油酸、羟基丙酮酸表达下调等17种差异代谢，涉及脂类代谢和三羧酸循环异常为主的9条代谢途径；脾虚湿热证表型组与湿热蕴结证表型组存在4个相同特征性代谢物(胍基乙酸、脱氧尿苷、胞苷、胆色素原)差异。

结论

这些结果揭示了形成大肠癌脾虚湿热证和湿热蕴结证两个常见临床表型组的代谢组学机制，并为中医辨证和诊治提供临床表型组的循证依据和特异性代谢组学客观依据。

Abstract

Objective

To elucidate the metabolomic mechanisms for the clinical phenomes of spleen deficiency and dampness-heat syndrome (PXSR) and the dampness-heat accumulation syndrome (SRYJ) associated with colorectal cancer (CRC).

Methods

From March 2021 to October 2021

A total of 68 patients with spleen deficiency and dampness-heat syndrome and 58 patients with dampness-heat accumulation syndrome of colorectal cancer were recruited in the Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University

and 62 healthy control with balanced constitution personnel who underwent physical examination here. Cohorts were established for PXSR phenome (PXSRP)

SRYJ phenome (SRYJP)

and healthy control with balanced constitution (BC). Serum metabolites were isolated and identified by non-targeted metabolomics and ultra-high liquid chromatography and mass spectrometry (UHPLC-QE-MS); the results were further analyzed by principal component analysis (PCA)

Orthogonal partial least squares discriminant analysis (OLPS-DA) analysis and bioinformatics analysis.

Results

Compared with Group BC

Group PXSRP had 12 metabolite differences

including downregulation of guanidoacetic acid

and upregulation of formiminoglat-amic acid

imidazoleacetic acid

deoxyuridine

cytidine

pseudouridine

ornithine

N-acetylornithine

5-hydroxyindoleacetic acid

porphobilinogen

succinic acid semialdehyde

and galactitol.7 metabolic pathways were involved

mainly involving abnormal energy metabolism. Group SRYJP had 17 metabolite differences

including upregulation of deoxyuridine

cytidine

porphobilinogen

arachidonic acid

prostaglandin B2

isocitric acid

L-gulonolactone

and downregulation of guanidoacetic acid

uridine

hydroxyproline

pyrrole-2-carboxylic acid

adenosine

6-DHET

9-DiHETrE

10-DHOME

bovinic acid

and hydroxypyruvic acid. Nine metabolic pathways were involved

mainly with lipid metabolism and tricarboxylic acid cycle abnormality. There were 4 identical characteristic metabolite differences(guanidoacetic acid

deoxyuridine

cytidine

porphobilinogen) between group PXSRP and group SRYJP.

Conclusion

These results reveal the metabolomic mechanism of the formation of the clinical phenomes of PXSR and SRYJ associated with CRC and provide objective metabolomic evidence for the precise diagnosis of CRC clinical phenomes.

关键词

大肠癌脾虚湿热证湿热蕴结证中医证候表型组表型组学代谢组学

Keywords

colorectal cancerspleen deficiency and dampness-heat syndromedampness-heat accumulation syndromephenomics of TCMphenomicsmetabolomics

references

ZHENG RS, ZHANG SW, ZENG HM, et al. Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1－9.

蒋海燕，张士强，杨蕴，等. 基于“肺与大肠相表里”研究健脾固肠方通过调节肠道免疫平衡抑制肺癌小鼠肿瘤转移的机制[J]. 上海中医药杂志，2020, 54(3): 91－96.

周锦玲. 大肠癌TNM分期与中医体质、证型的相关性研究[D]. 福州：福建中医药大学，2021.

容景瑜，林丽珠，林清，等. 大肠癌中医证候的回顾性研究[J]. 肿瘤基础与临床，2015, 28(3): 238－241.

卢文杰，曹建春，李慧苹，等. 早期大肠癌及癌前病变中医证候分布规律研究[J]. 浙江中医杂志，2019, 54(7): 488－489.

YANG MD, CHEN XL, HU XQ, et al. Traditional Chinese medicine syndromes distribution in colorectal cancer and its association with western medicine treatment and clinical laboratory indicators[J]. World J Tradit Chin Med, 2019, 5(2): 81－87.

段大跃. 药物表型组学与传统中医药(英文)[J]. 中国药理学与毒理学杂志，2015, 29(S1): 1－2.

王小强，杜鑫，曹谦，等. 中医药表型组学相关术语释义与应用[J]. 南京中医药大学学报，2023, 39(3): 210－220.

WANG M, RONG C. Poly(ε－L-lysine) and poly(L-diaminopropionic acid) co-produced from spent mushroom substrate fermentation: potential use as food preservatives[J]. Bioengineered, 2022, 13(3): 5892－5902.

马素娜，关亚奇，张淼，等. 代谢组学技术在中医证候学研究中的应用优势[J]. 时珍国医国药，2019, 30(7): 1714－1716.

DUAN DY, YE LY. Pharmacophenomics and Fangjiomics: new pharmacological research paradigm in era of precision medicine[J]. 中国药理学与毒理学杂志，2019, 33(9): 662－663.

中华人民共和国国家卫生健康委员会医政医管局，中华医学会肿瘤学分会．中国结直肠癌诊疗规范(2020年版) [J]. 中国实用外科杂志，2020, 40(6): 601－625.

中华中医药学会. 肿瘤中医诊疗指南：ZYYXH/T136～156－2008[S]. 北京：中国中医药出版社，2008: 13.

DONG W, TANG XL ，SHANG GB, et al. Dampness-heat accelerates DMBA-induced mammary tumors in rats[J].Chin J Integr Med，2018，24(10)：758－762.

原淳淳，王晶，舒冰，等. 中医表型组学的概念与相关研究体系的构建[J]. 中医杂志，2022, 63(5)：407－411.

DAYUE DARREL DUAN, 韩业山，李立，等. 药物表型组学：药理毒理学和个体化医学的新模式[J]. 中国药理学与毒理学杂志，2014, 28(1): 1－9.

左玲，陈建新，王伟，等. 中医信息学与表型组学：症状的遗传突变与证候的生物学基础初探[J]. 北京中医药大学学报，2022, 45(2): 140－147.

仝小林，赵林华，张博荀. 表型组学与中医药创新发展[J]. 科学，2022, 74(1): 22－25.

李维前，高立永，王恒，等. 大肠癌相关检查中的肠镜及肠镜活检病理学对于大肠癌诊治的现实应用分析[J]. 中国现代医生，2018, 56(4): 126－129.

郑安锐，顾园，王品发，等. 溃疡性结肠炎的中医证候与内镜分型及黏膜组织分期的相关性研究[J]. 时珍国医国药，2022, 33(9): 2209－2210.

赵鲁卿，王澍青，邓鑫，等． 463例慢性便秘患者结直肠息肉发病特点及其与中医虚实证候的相关性研究[J].中国中西医结合消化杂志，2023，31(6)：425－428.

林志宾. 炎症性肠病肠镜表现与中医证型相关性研究[D]. 广州：广州中医药大学，2018.

OSTOJIC SM, RATGEBER L, OLAH A, et al. Guanidinoacetic acid deficiency: a new entity in clinical medicine？[J]. Int J Med Sci, 2020, 17(16): 2544－2550.

司徒金水，王杰，高萍，等. 无动物性蛋白质饲粮添加胍基乙酸对断奶仔猪生长性能和肠道屏障的影响[J]. 动物营养学报，2020, 32(6): 2601－2610.

LEE JS, ADLER L, KARATHIA H, et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures[J]. Cell, 2018, 174(6): 1559－1570.

MA WW, SAIF MW, EL-RAYES BF, et al. Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5－fluorouracil and capecitabine toxicity[J]. Cancer, 2017, 123(2): 345－356.

刘畅，苟小军，黄迪，等. 基于代谢组学方法的湿热证“异病同证”研究[J]. 世界科学技术－中医药现代化，2017, 19(3): 392－407.

SUH Y, GANDHI J, SEYAM O, et al. Neurological and neuropsychiatric manifestations of porphyria[J]. Int J Neurosci, 2019, 129(12): 1226－1233.

YAO W, YANG C, WEN Y, et al. Treatment effects and mechanisms of Yujin Powder on rat model of large intestine dampness-heat syndrome[J]. J Ethnopharmacol, 2017, 202: 265－280.

李锦霞. 基于GC-MS生当归及其不同炮制品挥发油干预LPS炎症大鼠的代谢组学研究[D]. 兰州：甘肃农业大学，2015.

TILLEY SL, COFFMAN TM, KOLLER BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes[J]. J Clin Invest, 2001, 108(1): 15－23.

任越，姚美村，霍晓乾，等. 抗新型冠状病毒方剂基于花生四烯酸代谢通路防治“细胞因子风暴”的研究[J]. 中国中药杂志，2020, 45(6): 1225－1231.

肖正华，林长喜，陈激扬，等. 胃病患者不同舌苔的细菌学及炎性细胞对比[J]. 中国中西医结合消化杂志，2005, 13(6): 395－396.

刘雁，李志军. 非甾体抗炎药物的药理及临床应用进展[J]. 中国医院药学杂志，2000, 20(12): 748－750.

李岩，冯会红，蒋雨薇，等. 酸浆对炎症及花生四烯酸代谢途径的影响[J]. 北京理工大学学报，2015, 35(7): 762－766.

BOCHICCHIO B, LAURITA A, HEINZ A, et al. Investigating the role of (2S, 4R)－4－hydroxyproline in elastin model peptides[J]. Biomacromolecules, 2013, 14(12): 4278－4288.

MAEKAWA S, TAKADA S, NAMBU H, et al. Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure[J/OL]. Cell Commun Signal, 2019, 17(1): 128[2023－02－12]. https://biosignaling.biomedcentral.com/articles/10.1186/s12964-019-0445-0https://biosignaling.biomedcentral.com/articles/10.1186/s12964-019-0445-0 .

CAI XX, ZHU CJ, XU YQ, et al. Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways[J/OL]. Sci Rep, 2016, 6: 26802[2023－02－12]. https://www.nature.com/articles/srep26802https://www.nature.com/articles/srep26802 .

RASHID J, KUMAR SS, JOB KM, et al. Therapeutic potential of citrulline as an arginine supplement: a clinical pharmacology review[J]. Paediatr Drugs, 2020, 22(3): 279－293.

KING NE, ROTHENBERG ME, ZIMMERMANN N. Arginine in asthma and lung inflammation[J]. J Nutr, 2004, 134(10 Suppl): 2830S－2836S.

VAHORA H, KHAN MA, ALALAMI U, et al. The potential role of nitric oxide in halting cancer progression through chemoprevention[J/OL]. J Cancer Prev, 2016, 21(1): 1－12[2023－02－12]. https://www.jcpjournal.org/journal/view.html?doi=10.15430/JCP.2016.21.1.1https://www.jcpjournal.org/journal/view.html?doi=10.15430/JCP.2016.21.1.1 .

IGARASHI J, MICHEL T. S1P and eNOS regulation[J]. Biochim Biophys Acta, 2008, 1781(9): 489－495.

ZHENG HK, ZHAO JH, YAN Y, et al. Metabolic reprogramming of the urea cycle pathway in experimental pulmonary arterial hypertension rats induced by monocrotaline[J/OL]. Respir Res, 2018, 19(1): 94[2023－12－12]. https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0800-5https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0800-5 .

VOIGT JP, FINK H. Serotonin controlling feeding and satiety[J]. Behav Brain Res, 2015, 277: 14－31.

MOSKWA A, CHOJNACKI J, WIŚIEWSKA-JAROSIŃSKA M, et al. Serum serotonin concentration and urine 5-hydroxyindole acetic acid excretion in patients with irritable bowel syndrome[J]. Pol Merkur Lekarski, 2007, 22(131): 366－368.

段虹飞，李巧艳，董玲芳，等. UPLC－MS/MS法测定人血清中的神经内分泌肿瘤标志物5－羟基吲哚乙酸[J].华西药学杂志，2015，30(4)：481－483.

COOPERMAN JM, LOPEZ R. The role of histidine in the anemia of folate deficiency[J]. Exp Biol Med (Maywood), 2002，227(11)：998－1000.

MARTIR JF, BOZDAGI O, MARTINELLI GP, et al. Imidazoleacetic acid-ribotide in the rodent striatum: a putative neurochemical link between motor and autonomic deficits in Parkinson's disease[J]. Acta Biol Hung, 2012, 63(Suppl 1): 5－18.

成映霞，杜娟，杨晓轶，等. 脾气虚大鼠小肠组织Ca2＋/CaM信号通路关键分子的表达变化[J]. 中华中医药杂志，2015, 30(10): 3624－3628.

赵洁，李福凤，钱鹏. 舌苔生物信息研究方法与技术概况[J]. 中医杂志，2011, 52(7): 612－615.

刘俊秋. 补气药黄芪、人参及其配伍免疫调节和代谢组学研究[D]. 北京：中国中医科学院，2018.

吴桂彬. 左、右半结肠癌中医辨证分型与RAS、BRAF基因的相关研究[D]. 福州：福建中医药大学，2018.

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