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Volume 42 Issue 1
Jan.  2024
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PAN Yujiong, HE Zhigao, CHEN Shixiu, ZHOU Gui, ZHOU Xin, YU Chao. Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(1): 24-31. doi: 10.12206/j.issn.2097-2024.202208111
Citation: PAN Yujiong, HE Zhigao, CHEN Shixiu, ZHOU Gui, ZHOU Xin, YU Chao. Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(1): 24-31. doi: 10.12206/j.issn.2097-2024.202208111

Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking

doi: 10.12206/j.issn.2097-2024.202208111
  • Received Date: 2022-08-31
  • Rev Recd Date: 2023-09-18
  • Available Online: 2024-01-19
  • Publish Date: 2024-01-25
  •   Objective  To investigate the mechanism of Qizhenziyin mixture in the treatment of hypogonadism by using the network pharmacology approach.   Methods  The active components of Qizhenziyin mixture were obtained by searching TCMSP , TCMID and HIT databases.The related targets of candidate compounds were obtained by searching STITCH databases. The potential targets of Qizhenziyin mixture in the treatment of hypogonadism were obtained by mapping the disease genes of hypogonadism with Genecards and DisGeNet databases. The protein interaction platform database (STRING) was used to construct the interaction relationship between action targets. The target protein interaction (PPI) network was constructed by introducing Cytoscape software. The mechanism of Qizhenziyin mixture in the treatment of hypogonadism was explained through the enrichment analysis of GO, KEGG and molecular docking technology.   Results  A total of 148 drug-disease chemical compounds, 96 drug-disease intersection targets, 1085 disease targets were obtained; the components for treating diseases are: quercetin, kaempferol, luteolin, etc; enrichment analysis of GO revealed 1792 biological processes (BP), 31 cellular components (CC) and 79 molecular functions (MF); the results of KEGG pathway enrichment analysis indicated such as FOXO signaling pathway, prostate cancer, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, etc.The results of molecular docking showed that kaempferol and LEP had the best and stable binding energy.   Conclusion  The active components of Qizhenziyin mixture may play a role of the treatment of hypogonadism by improving insulin resistance and the expression of testosterone synthetase of Leydig cells.
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Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking

doi: 10.12206/j.issn.2097-2024.202208111

Abstract:   Objective  To investigate the mechanism of Qizhenziyin mixture in the treatment of hypogonadism by using the network pharmacology approach.   Methods  The active components of Qizhenziyin mixture were obtained by searching TCMSP , TCMID and HIT databases.The related targets of candidate compounds were obtained by searching STITCH databases. The potential targets of Qizhenziyin mixture in the treatment of hypogonadism were obtained by mapping the disease genes of hypogonadism with Genecards and DisGeNet databases. The protein interaction platform database (STRING) was used to construct the interaction relationship between action targets. The target protein interaction (PPI) network was constructed by introducing Cytoscape software. The mechanism of Qizhenziyin mixture in the treatment of hypogonadism was explained through the enrichment analysis of GO, KEGG and molecular docking technology.   Results  A total of 148 drug-disease chemical compounds, 96 drug-disease intersection targets, 1085 disease targets were obtained; the components for treating diseases are: quercetin, kaempferol, luteolin, etc; enrichment analysis of GO revealed 1792 biological processes (BP), 31 cellular components (CC) and 79 molecular functions (MF); the results of KEGG pathway enrichment analysis indicated such as FOXO signaling pathway, prostate cancer, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, etc.The results of molecular docking showed that kaempferol and LEP had the best and stable binding energy.   Conclusion  The active components of Qizhenziyin mixture may play a role of the treatment of hypogonadism by improving insulin resistance and the expression of testosterone synthetase of Leydig cells.

PAN Yujiong, HE Zhigao, CHEN Shixiu, ZHOU Gui, ZHOU Xin, YU Chao. Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(1): 24-31. doi: 10.12206/j.issn.2097-2024.202208111
Citation: PAN Yujiong, HE Zhigao, CHEN Shixiu, ZHOU Gui, ZHOU Xin, YU Chao. Mechanism of Qizhenziyin mixture in the treatment of hypogonadism based on network pharmacology analysis and molecular docking[J]. Journal of Pharmaceutical Practice and Service, 2024, 42(1): 24-31. doi: 10.12206/j.issn.2097-2024.202208111
  • 性腺功能减退症是一种由多种原因引起的睾酮水平低于健康青年男子正常范围的疾病,临床症状为焦躁不安、健忘出汗、性功能减退等。从流行病学分析,该病在肥胖和糖尿病人群中发病较多;其次,多发病于中老年男性患者,也称迟发性性腺功能减退症(LOH)[1]。目前,西医治疗男性肥胖和LOH多以外源性和内源性补充睾酮为主,治疗手法单一,且存在诸多的争议。例如,在临床中,对于 LOH症状中失眠、潮热、健忘、注意力不集中等精神心理症状,单纯用睾酮补充治疗(TST),症状改善不显著[2-5]。中医治疗则根据患者在TST过程中所表现的不同证候采用不同的治疗方法,如心功能不全患者以补肾为主,情志精神患者以疏肝为主,生理体能欠佳者以健脾、补益为主等不同的治疗方法[5]

    杞贞滋阴合剂(沪药制备字Z20210006000),是上海市著名中医周智恒教授的经验方。该方中,君药是熟地黄、黄芪,起滋阴补肾、益气培元之功效;臣药是枸杞子、女贞子、山茱萸,起补肾、涩精、固肾之功效;佐药为沙苑子、当归,起益精养血之功效;锁阳阳中求阴为使药。全方共奏滋阴补肾、益气生精之功效。前期临床实验证明,杞贞滋阴合剂可以有效改善LOH患者体能不济、血管舒缩和睾酮水平低下等症状[6-7]

    网络药理学是通过“药物-基因-靶点-疾病”相互作用网络,预测药物作用机制的学科[8]。分子对接是通过受体和药物分子之间的相互作用来进行药物设计的方法。本研究通过网络药理学和分子对接技术,对杞贞滋阴合剂的作用机制进行研究,以期为该制剂的后期开发提供技术支持和理论依据。

    • 在中药综合数据库(TCMID)[9]、中药系统药理学数据库与分析平台(TCMSP) [10]、药物成分靶标数据库(HIT) [11]和文献中检索杞贞滋阴合剂的相关化学成分,再在TCMID,TCMSP,HIT,STITCH数据库中查找有效活性成分的靶点,取STITCH数据库中化合物靶标关联度400以上的靶标[12],并使用NCBI数据库中的基因模块对生物靶标信息进行标准化,建立相关的化学成分靶标数据库。

    • 将化合物的物理化学特征与上市药物特征进行比较,采用Bickerton等提出的有效的类药性评估指标(quantitative estimate of druglikeness,QED)评估化学成分的类药性[13]

      参考DRUGBANK上市药物QED值,选择0.3为阈值筛选化合物。

    • 采用基于二项分布的富集评分算法来筛选核心方的作用靶标[14]

      P<0.01时,表明该靶标基因被至少k个活性化合物同时作用是小概率事件,则该靶标基因是核心方的主要作用靶标基因,并将含有主要作用靶标基因的化合物作为主要作用化合物。

    • 在GENECARD数据库[15]的Malacard模块中查找“性腺功能减退症”的靶点数据,以得分双倍中位数为筛选条件,在DisGeNet数据库查找“性腺功能减退症疾病”的靶点数据。合并以上两个数据库的筛选结果,并删除重复靶标。最后,使用韦恩图确定杞贞滋阴合剂治疗性腺功能减退症的主要靶标,并使用STRING数据库进行蛋白PPI网络分析。

    • 将得到的97个疾病靶标进行富集分析,其中,通路信息来自KEGG通路数据库[16],基因本体GO富集分析信息数据来源于Gene Ontology数据库,再应用超几何分布模型评估靶标基因群是否与特定的GO及生物通路显著关联:

      经过错误发现率(False discovery rate, FDR) [17]法调整的P值,反映了杞贞滋阴合剂靶标或者疾病靶标与通路或GO的关联强度,本项目经调整后的P值,以小于0.01认为关联显著。

    • 利用Cytoscape软件的插件评估筛选核心靶标,组成核心网络,评估杞贞滋阴合剂疾病KEGG关联条目的关系。所有图片中形状大小、颜色深浅均以度值排序。

    • 取度值较高的核心靶点,导入PDB(https://www.pdbus.org/),筛选条件以X-RAY下Resolution值小为首选标准,下载PDB文件,使用PYMOL软件,去水、去配体后备用;从PubChem数据库下载活性成分,运用AutoDock-Tools软件对受体蛋白及配体进行加氢、平衡电荷等操作后,对处理好的活性化合物与靶蛋白进行对接,并进行能量计算,最终运用PYMOL软件进行绘图。

    • 通过TCMSP、TCMID、HIT数据库和文献检索获得495个活性化合物;然后在STITCH数据库中,筛选靶标关联度400以上的靶标,获得靶标7627个;再通过类药性分析,共得到246个满足类药性成分的化合物;并使用二项分布算法筛选核心方的作用靶标,筛选得到701个成分靶标和213个主要作用化合物。

      通过GENECARD数据库筛选到1051个相关靶标,通过DisGeNet数据库筛选到305个相关靶标,合并删除重复疾病靶标后,共获得1085个与性腺功能减退症相关的疾病靶标基因。结合杞贞滋阴合剂的701个成分靶标,使用韦恩图确定杞贞滋阴合剂的96个疾病靶标和148种活性化合物,见表1

      化合物 编码 化合物来源 QED
      丁香酚 MOL000254 TCMSP 0.7
      香草酸 MOL000114 TCMSP 0.7
      异细辛醚 CID:636750 PUBCHEM 0.7
      2-甲氧基-4-乙烯基苯酚 MOL001752 TCMSP 0.7
      反式阿魏酸 MOL000360 TCMSP 0.72
      阿魏酸 MOL000360 TCMSP 0.72
      异丁香酚(正+反) MOL000206 TCMSP 0.73
      芹菜素 MOL000008 TCMSP 0.74
      DL-丁香树脂酚 MOL000396 TCMSP 0.74
      2,6-二叔丁基-4-甲基苯酚 MOL002850 TCMSP 0.75
      丁香酚甲基醚 MOL000207 TCMSP 0.81
      大豆异黄酮 MOL000390 TCMSP 0.82
      黄豆黄素 MOL008400 TCMSP 0.83
      刺芒柄花素 MOL000392 TCMSP 0.85
      毛蕊异黄酮 MOL000417 TCMSP 0.89
      槲皮素 MOL000098 TCMSP 0.51
      木犀草素 MOL000006 TCMSP 0.6
      山柰酚l MOL000422 TCMSP 0.64
      注:表中PUBCHEM为通过文献检索杞贞滋阴合剂查阅到的相关化合物。
    • 利用Cytoscape软件,以杞贞滋阴合剂的96个疾病靶标和148种活性化合物,建立“药物-成分-靶点”网络图,其中,度值较高的化合物有棕榈油、乙醇、槲皮素、木犀草素、山柰酚、果糖、硬脂酸等,见图1

    • 通过STRING数据库进行蛋白PPI网络分析,并利用Cytoscape软件,以疾病为靶标进行蛋白PPI网络分析,图中共有96个节点,1132条边,其中,度值排名前10的靶标是血清白蛋白(ALB)、INS、阿黑皮素原(POMC)、TNF、AKT1、LEP、IGF1、IL-6、FOS、ESR1,见图2

    • 对杞贞滋阴合剂治疗性腺功能减退症的靶标基因进行GO富集分析,以P值小于0.01为关联显著,以此进行筛选,生物过程(BP)有1792条、细胞组件(CC)有31条、分子功能(MF)有79条,并取P值前15条的BP、CC、MF分别制得条形图。其中,MF主要集中在受体激动剂活性、激素活性、RNA聚合酶Ⅱ转录因子活性、G蛋白偶联受体结合等;CC主要集中在分泌颗粒腔、细胞质膜结合囊泡腔、囊泡腔、内质网内腔等;BP主要集中在对肽类激素的反应、多细胞生物稳态、对营养水平的反应等,见图3

    • 对杞贞滋阴合剂治疗性腺功能减退症的靶标基因进行GO富集分析,以P值小于0.01为关联显著,并以此进行筛选,结果KEGG信号通路的富集分析报告中,复方靶标与性腺功能减退症相关的有132条信号通路,取P值前15条信号通路,制得气泡图和核心网络与前15条通路的关系图见图4

    • 根据“药物-成分-靶点”网络分析得到排名前17的核心活性成分,剔除其中成药性较差的,例如,乙醇、棕榈油、果糖、硬脂酸等,最后选取槲皮素、山柰酚、木犀草素作为核心活性成分;从度值排名前8的核心靶点中,剔除与槲皮素、山柰酚、木犀草素无密切度的ALB和POMC,最后选取INS、TNF、AKT1、LEP、IGF1、IL-6六个靶点进行分子对接。其中,对接得分(kcal/mol值)绝对值>4.25代表结合活性一般,绝对值>5.0代表结合活性较好,绝对值>7.0代表结合活性较强[18]。由结果可知,主要核心靶点与核心化合物的结合值都超过了5.0,核心靶点TNF 和LEP的结合值整体高于其他靶点,其中,LEP 与山柰酚的结合力较强,见表2图5

      成分 靶点名称 PDB ID kcal/mol
      槲皮素
      INS 5HQI −5.3
      TNF 1QTN −6.8
      IL-6 YNXZ −6.3
      LEP 1ax8 −6.5
      IGF1 1imx −6.0
      AKT1 1unq −6.2
      山柰酚
      INS 5HQI −5.2
      TNF 1QTN −7.2
      IL-6 YNXZ −6.4
      LEP 1ax8 −7.2
      IGF1 1imx −5.9
      AKT1 1unq −6.1
      木犀草素
      INS 5HQI −5.4
      TNF 1QTN −6.8
      IL-6 YNXZ −6.4
      LEP 1ax8 −7.0
      IGF1 1imx −5.9
      AKT1 1unq −6.4
    • 睾酮已被证明是维持代谢稳态的关键调节因子。现代研究证明,睾酮与胰岛素抵抗、血脂异常、炎症细胞因子合成增加等因素密切相关[19-23]。因此,临床治疗LOH除了补充睾酮,多以控制体重、改善胰岛素抵抗的方法达到改善患者的血清睾酮水平和性功能的目的。

      本次研究,通过TCMSP、TCMID、HIT等数据库搜索,并进行类药性分析和二项分布算法筛选,共得到701个成分靶标和213个主要作用化合物,再通过建立“药物-成分-靶点”网络图,发现其中与疾病关联性较强的化合物是槲皮素、山柰酚、木犀草素等,主要作用的疾病靶点是AKT1、IL-6、IGF1、LEP等。有研究表明,槲皮素可刺激cAMP依赖性急性调节(Star)启动子的激活,增加Leydig细胞生成睾酮[24];山柰酚可以改善雄性小鼠生殖器官重量、精子质量,减少睾丸组织损伤[25];木犀草素能激活Star蛋白的表达,进而增加睾酮的产生[26]。又有研究表明,IL-6炎症细胞因子被释放到血液中,可能抑制Leydig细胞的发育[27];AKT1蛋白可通过磷酸化,进而调节哺乳动物的睾丸功能,而IGF1可刺激多种AKT1的活性[28];LEP可通过下丘脑PI3K/AKT通路刺激GnRH合成与释放,从而影响血清睾酮水平[29]

      通过KEGG富集分析共得到132条通路,并筛选出P值排名前15的通路,包括FOXO通路、糖尿病并发症中的AGE-RAGE信号通路、胰岛素抵抗、HIF-1通路等。其中,缺氧诱导因子-1(HIF1)是参与细胞缺氧反应的关键转录因子,并且在Leydig细胞中稳定表达,而Leydig细胞生成睾酮是雄性睾酮的主要来源,当HIF1上调时,睾酮水平显著降低[30]。在FOXO通路中,STAT3、IL-6、AKT1、IGF-1广泛参与了FOXO的激活,FOXO蛋白作为核转录因子,可以促进胰岛素或IGF-1在哺乳动物细胞的增殖[31]

      综上所述,杞贞滋阴合剂治疗LOH的主要活性成分和作用靶点主要涉及Leydig细胞睾酮合成酶表达和改善胰岛素抵抗。其中,Leydig睾丸间质细胞的功能和数量下降导致的雄激素缺乏是LOH的主要核心机制[32]。有研究表明,胰岛素可通过刺激下丘脑促性腺激素释放激素(GnRH)的产生和分泌,进而刺激黄体生成素(LH)和卵泡刺激素(FSH)的生物合成,而LH和FSH是睾丸功能的重要激素调节因子[33]。中医将糖尿病前期归于“消渴” 等范畴。《金匮要略》中消渴病篇提到:“男子消渴,小便反多,以饮一斗,小便一斗,肾气丸主之。”肾阳不足,则无力蒸腾气化水液[34],而杞贞滋阴合剂的创始者周智恒教授认为LOH的病因正是肾气衰、真水枯竭,该方正是有滋阴补肾、益气生精之功效[6]。众所周知,胰岛素抵抗正是糖尿病的病理基础。由上可见,杞贞滋阴合剂的中医治疗LOH的理论和胰岛素抵抗的中医治疗理论相一致,也为本研究指出的杞贞滋阴合剂治疗LOH多涉及改善胰岛素抵抗提供了理论依据。本研究为杞贞滋阴合剂治疗性腺机能减退症探索了新的防治思路,但由于数据统计来自于多平台的数据收录和总结,结果还需后续实验研究做进一步的验证,从而完善杞贞滋阴合剂治疗LOH的作用机制。

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