Model Construction and Preliminary Validation of Disease-syndrome Combined Molecular Networks for Type 2 Diabetes Mellitus with Yin Deficiency Syndrome

GUO Hang; ZHAN Libin; SUN Xiaoxia; CHEN Ning; WENG Zebin

doi:10.13288/j.11-2166/r.2022.15.013

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Model Construction and Preliminary Validation of Disease-syndrome Combined Molecular Networks for Type 2 Diabetes Mellitus with Yin Deficiency Syndrome

更新时间：2023-02-21

- Model Construction and Preliminary Validation of Disease-syndrome Combined Molecular Networks for Type 2 Diabetes Mellitus with Yin Deficiency Syndrome
- Journal of Traditional Chinese Medicine Vol. 63, Issue 15, Pages: 1470-1478(2022)
- 作者机构：
  
  1.南京中医药大学中医学院/中西医结合学院，江苏省南京市栖霞区仙林大道138号，210023
  2.辽宁中医药大学
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2022.15.013
  CLC：
- Received：06 December 2021，
  
  Revised：2022-05-09，
  
  Published：02 August 2022
- 稿件说明：
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郭航,战丽彬,孙晓霞等.2型糖尿病阴虚证病证结合分子网络模型的构建与初证[J].中医杂志,2022,63(15):1470-1478.

GUO Hang,ZHAN Libin,SUN Xiaoxia,et al.Model Construction and Preliminary Validation of Disease-syndrome Combined Molecular Networks for Type 2 Diabetes Mellitus with Yin Deficiency Syndrome[J].Journal of Traditional Chinese Medicine,2022,63(15):1470-1478.
郭航,战丽彬,孙晓霞等.2型糖尿病阴虚证病证结合分子网络模型的构建与初证[J].中医杂志,2022,63(15):1470-1478. DOI： 10.13288/j.11-2166/r.2022.15.013.

GUO Hang,ZHAN Libin,SUN Xiaoxia,et al.Model Construction and Preliminary Validation of Disease-syndrome Combined Molecular Networks for Type 2 Diabetes Mellitus with Yin Deficiency Syndrome[J].Journal of Traditional Chinese Medicine,2022,63(15):1470-1478. DOI： 10.13288/j.11-2166/r.2022.15.013.

摘要

目的

运用网络生物学方法构建2型糖尿病（T2DM）阴虚证病证结合分子网络，探究其生物学基础，并进行实验验证。

方法

整合DisGeNET、DrugBank、TTD、MalaCards、OMIM、CTD、GEO数据库信息，获得T2DM疾病相关基因。运用社团发现算法将STRING数据库中的PPI网络划分为拓扑模块，将疾病相关基因映射至模块中获得T2DM疾病模块。将从SymMap、HPO、GeneCards数据库获取的阴虚证症状对应基因映射至疾病模块，从而筛选出T2DM阴虚证病证结合模块。再通过治疗T2DM西药对应靶点与模块靶点对应关系，以及滋阴方剂靶点与病证结合模块的相关性分析，验证结果的可靠性。借助Metascape平台对分子网络进行GO和KEGG富集分析。最后采用温热伤阴法构建病证结合小鼠模型，分为正常对照组、单纯阴虚证组、2型糖尿病组、2型糖尿病阴虚证组，取血清和下丘脑组织对预测的关键靶点进行验证。

结果

筛选出1514个T2DM疾病相关基因以及1547个T2DM阴虚证相关基因，确定了19个与T2DM密切相关的疾病模块，并将其中的7个与阴虚证相关的模块定义为T2DM阴虚证病证结合模块。经过西药靶点、滋阴方剂的验证，最终确立T2DM阴虚证病证结合核心模块Mem3、5、39。富集分析揭示生物学基础可能涉及糖脂代谢紊乱、免疫炎症、内分泌紊乱等诸多病理过程。对Mem5及Mem39的核心靶点白细胞介素6（IL-6）及鸟嘌呤核苷酸结合蛋白q多肽（GNAQ）介导通路相关蛋白即异源三聚体嘌呤核苷酸结合蛋白（Gq）、磷脂酶Cβ1（PLCβ1）、磷脂酶Cβ3（PLCβ3）蛋白进行验证，结果提示2型糖尿病阴虚证组小鼠血清中IL-6水平及下丘脑Gq、PLCβ1蛋白表达显著高于正常对照组和2型糖尿病组（

＜0.05或

＜0.01）。

结论

G蛋白信号转导系统、糖脂代谢、免疫功能、炎症反应、内分泌紊乱等是2型糖尿病阴虚证核心生物学过程。

Abstract

Objective

To construct the disease-syndrome combined molecular network for type 2 diabetes mellitus （T2DM） using network biology approaches， and to explore its biological basis and validate it through experimental data.

Methods

The DisGeNET， DrugBank， TTD， MalaCards， OMIM， CTD， and GEO databases were integrated to obtain T2DM-related genes. The PPI network in the STRING database was divided into topological modules using the algorithm for community discovery， and the disease-related genes were mapped into the modules to obtain the disease module of T2DM. The genes corresponding to the symptoms of

yin

deficiency syndrome obtained from SymMap， HPO， and GeneCards databases were mapped into the disease module， so as to get the disease-syndrome combined module for T2DM with

yin

deficiency syndrome. Furthermore， the results were verified through the corresponding relationship between the T2DM western medicine targets and the module targets， and the correlation analysis between nourishing

yin

formula targets and the disease-syndrome combined module. GO and KEGG enrichment analysis was performed for the molecular networks based on the Metascape platform. Finally， the warm-heat damaging

yin

method was used to construct the disease-syndrome combined mice model， which was divided into normal control group，

yin

deficiency syndrome group， T2DM group， and T2DM with

yin

deficiency syndrome group， and the serum and hypothalamic tissues were taken to validate the predicted key targets.

Results

Totally， 1514 T2DM-related genes and 1547 T2DM with

yin

deficiency syndrome-related genes were obtained， and 19 disease modules closely related to T2DM were identified， of which 7 modules related to

yin

deficiency syndrome were defined as the disease-syndrome combined modules for T2DM with

yin

deficiency syndrome. Through validation by western medicine targets and nourishing

yin

formulas， Mem3， 5， and 39 as the core disease-syndrome combined modules for T2DM with

yin

deficiency syndrome were finally established. The enrichment analysis revealed that the biological basis may be involved with glucose and lipid metabolism disorders， immune inflammation and endocrine disorders， and other pathological processes. The validation analysis of the interleukin-6 （IL-6）， the core targets of Mem5 and Mem39， as well as the proteins related to Guanine nucleotide-binding protein q polypeptide （GNAQ）-mediated pathway， namely heterotrimeric purine nucleotide-binding protein （Gq）， phospholipase Cβ1 （PLCβ1）， and phospholipase Cβ3 （PLCβ3） showed that the IL-6 level in serum and the protein expression of Gq and PLCβ1 in the hypothalamus in the T2DM with

yin

deficiency syndrome group were significantly higher than those in the normal control group and T2DM group （

＜0.05 or

＜0.01）.

Conclusion

The core biological processes of T2DM with

yin

deficiency syndrome are involved with G protein linked signal transduction system， glucose and lipid metabolism， immune function， inflammatory response， and endocrine disorders.

关键词

Keywords

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