CN111067890A - 一种调节萎缩性胃炎免疫功能的物质及其制剂与应用 - Google Patents
一种调节萎缩性胃炎免疫功能的物质及其制剂与应用 Download PDFInfo
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Abstract
本发明公开了一种调节萎缩性胃炎免疫功能的物质及其制剂与应用,所述的调节萎缩性胃炎免疫功能的物质为新川芎内酯、齐墩果酸、白术内酯Ⅰ、桉油精、异鼠李素和黄连碱中的一种或几种。制剂为所述的调节萎缩性胃炎免疫功能的物质中加入药学上可接受的辅料制备的片剂、胶囊剂、丸剂、针剂、缓释剂、控释剂、粉剂或口服液体制剂。应用为所述的调节萎缩性胃炎免疫功能的物质在制备治疗萎缩性胃炎免疫功能低下的药物中的应用。本发明通过网络药理学计算预测和实验验证,识别出了中成药摩罗丹中能够调节萎缩性胃炎伴有免疫功能低下的成分。体外验证实验表明,这些成分能够提高萎缩性胃炎伴免疫低下的CD40、CD44、TRAF6等免疫相关指标。
Description
技术领域
本发明属于医药技术领域,具体涉及一种调节萎缩性胃炎免疫功能的物质及其制剂与应用。
背景技术
萎缩性胃炎是一种以胃黏膜上皮固有腺体数量减少或消失、或伴纤维替代、肠腺化生等为病理特点的消化系统常见疾病。其发病机制涉及细胞增殖、细胞凋亡、细胞分化、免疫、代谢和消化等方面变化。萎缩性胃炎伴免疫功能低下是临床上一类常见的亚群,该类患者通常表现为细胞免疫和体液免疫功能低下。慢性萎缩性胃炎伴免疫功能低下患者血清IgG、IgA、IgM等免疫球蛋白水平明显降低,CD3~+T细胞、CD4~+T细胞水平明显下降。
摩罗丹是由百合、麦冬、茯苓、鸡内金等18味中药制成的丸剂,具有和胃降逆、健脾消胀、通络定痛的传统功效。临床上用于胃痛、胃胀、嗳气等胃部不适症状的改善,主要用于萎缩性胃炎、幽门螺杆菌相关性胃炎、功能性消化不良等疾病的治疗。摩罗丹被中华医学会消化病学分会制定的《中国慢性胃炎共识意见》(2017)、中华中医药学会发布的《慢性胃炎中医专家诊疗共识意见》(2017)等推选为治疗慢性胃炎、慢性萎缩性胃炎的首选推荐用药。摩罗丹中的白芍、泽泻、茵陈等都具有免疫系统的双向调节作用,尤其是百合、 石斛、当归可以增强免疫功能,乌药、白芍等具有抑制细胞增殖和促进细胞凋亡、分化的作用。然而,以往研究中针对摩罗丹中能够调节萎缩性胃炎免疫功能以及调节免疫功能低下状态下的细胞增殖和细胞凋亡等作用的核心有效成分的研究比较欠缺。
以“网络靶标”为核心的中药网络药理学为中药药效物质的发现提供了一个新思路。“网络靶标”,即将疾病的生物分子网络作为靶标,由此来设计和预测最佳的药物干预方式。与“单基因、单药物”研究模式相比,“网络靶标”的研究模式强调针对药物的系统性机制开展研究,即“网络靶标-系统调节”,这种方式更加符合生物系统的本质。该研究思路和方法在理解多种中药方剂和天然药物的药效物质和作用机理上已经取得了较好的应用。
中国专利CN201610272270.7公开了一种治疗萎缩性胃炎的胶囊剂及其制备方法,该专利公开了一种包括异鼠李素3-5份、四氢黄连碱的配方,但是并没有公开胶囊剂中异鼠李素、四氢黄连碱和其他组分在治疗萎缩性胃炎的各自的作用和功效。中国专利CN199510019655.X公开了一种治疗萎缩性胃炎病药物的制备方法,其以黄芪、党参、白术、当归、三七粉、丹参、砂仁、升麻、陈皮和内金为原料,但是并不清楚其中促进细胞再生和机体免疫功能的组分和化合物。同样,中国专利CN200310021887.4公开了一种治疗慢性萎缩性胃炎的中药物组合物,该组合物由百合、茯苓、玄参、川芎、鸡内金、乌药、泽泻、麦冬、三七、白术、当归、茵陈、地榆、蒲黄、延胡索、白芍、石斛、九节菖蒲组成,这也是大多中药配方普遍存在的问题。再比如,异鼠李素是存在于中药材中的一类黄酮醇类化合物,具有抗炎、抗氧化等多种药理学活性。异鼠李素与槲皮素肉桂酸等中草药组合,用于清肺止咳的蒙药及其制备工艺(见中国专利CN201910597460.X)。
下面罗列检索到的现有技术及文献资料,以备正文引用:
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[3]慢性胃炎粘膜免疫相关指标研究进展; proceedings of the 第十三届全国免疫学学术大会摘要汇编, F, 2018 [C].
[4]刘仲秋. 摩罗丹治疗浅表性和萎缩性胃炎224例疗效观察 [J]. 河北医药, 2006,28(8): 766-.
[5]刘岗. 摩罗丹治疗老年人功能性消化不良96例临床观察 [J]. 中国中医急症,2012, 21(1): 129-30.
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[2]董环, 王彦刚. 慢性萎缩性胃炎发病机制的研究进展; proceedings of the 全国中西医结合消化系统疾病学术会议, F, 2015 [C].
[3]慢性胃炎粘膜免疫相关指标研究进展; proceedings of the 第十三届全国免疫学学术大会摘要汇编, F, 2018 [C].
[4]刘仲秋. 摩罗丹治疗浅表性和萎缩性胃炎224例疗效观察 [J]. 河北医药, 2006,28(8): 766-.
[5]刘岗. 摩罗丹治疗老年人功能性消化不良96例临床观察 [J]. 中国中医急症,2012, 21(1): 129-30.
[6]摩罗丹药理作用及临床应用的研究进展 [J]. 中国药物经济学, 2018, 13(9):129-31.
[7]徐硕, 夏路风, 金鹏飞, et al. 泽泻的化学成分及生物活性研究进展 [J]. 中国医药导报, 2015, 27): 47-51.
[8]章林平, 孙倩, 王威, et al. 茵陈有效成分的药理作用及其临床应用的研究进展 [J]. 抗感染药学, 2014, 1): 28-31.
[9]蒲黄对大白鼠巨噬细胞活力及胆固醇肉芽肿的影响 [J]. 中国中西医结合杂志,1984, 3): 176-8.
[10]张红玉, 戴关海, 马翠, et al. 铁皮石斛多糖对S180肉瘤小鼠免疫功能的影响[J]. 浙江中医杂志, 2009, 44(5): 380-1.
[11]李新华, 弥曼, 李汾, et al. 百合多糖免疫调节作用的实验研究 [J]. 现代预防医学, 2010, 37(14): 2708-9.
[12]张利. 白芍的药理作用及现代研究进展 [J]. 中医临床研究, 2014, 29): 25-6.
[13]晏润纬, 花金红. 乌药根挥发油对HepG2细胞增殖和凋亡的影响 [J]. 南昌大学学报(理科版), 2014, 38(05): 483-7.
[14]鲍舒洁, 张丹, 张红, et al. 白芍总苷脂质体诱导胃癌BGC-823细胞凋亡的实验研究 [J]. 中国药学杂志, 2016, 51(24): 2109-13.
[15]李梢. 网络靶标:中药方剂网络药理学研究的一个切入点; proceedings of the中国天然药物研究与发展论坛, F, 2011 [C].
[16]LI S. Mapping ancient remedies: Applying a network approach totraditional Chinese medicine [J]. Science, 2015, 350(6262): S72-S4.
[17]ZHENG J, WU M, WANG H, et al. Network Pharmacology to Unveil theBiological Basis of Health-Strengthening Herbal Medicine in Cancer Treatment[J]. Cancers (Basel), 2018, 10(11).
[18]LIANG X, LI H, LI S. A novel network pharmacology approach to analysetraditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study [J].Mol Biosyst, 2014, 10(5): 1014-22.
[19]ZHAO S, LI S. Network-based relating pharmacological and genomicspaces for drug target identification [J]. PLoS One, 2010, 5(7): e11764.
[20]LI H, ZHOU H, WANG D, et al. Versatile pathway-centric approach basedon high-throughput sequencing to anticancer drug discovery [J]. Proceedingsof the National Academy of Sciences, 2012, 109(12): 4609-14.
[21]HAMOSH A, SCOTT A F, AMBERGER J S, et al. Online MendelianInheritance in Man (OMIM), a knowledgebase of human genes and geneticdisorders [J]. Nucleic acids research, 2005, 33(suppl_1): D514-D7.
[22]KANEHISA M, FURUMICHI M, TANABE M, et al. KEGG: new perspectives ongenomes, pathways, diseases and drugs [J]. Nucleic acids research, 2016, 45(D1): D353-D61.
[23]WU X, JIANG R, ZHANG M Q, et al. Network‐based global inference ofhuman disease genes [J]. Molecular systems biology, 2008, 4(1):
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发明内容
为了解决上述技术问题,本发明针对摩罗丹治疗萎缩性胃炎伴免疫功能低下的药效物质基础不清楚的问题,通过网络药理学计算分析和实验验证,识别出了摩罗丹中治疗萎缩性胃炎尤其是伴免疫功能低下的成分,并通过实验验证该成分能够提升萎缩性胃炎免疫功能低下的客观指标。
本发明的第一目的在于提供一种调节萎缩性胃炎免疫功能的物质;第二目的在于提供所述的调节萎缩性胃炎免疫功能的物质的制剂;第三目的在于提供所述的调节萎缩性胃炎免疫功能的物质的应用。
具体地讲,本发明公开了一种调节萎缩性胃炎免疫功能的物质,其特征在于,所述的物质为新川芎内酯、齐墩果酸、白术内酯Ⅰ、桉油精、异鼠李素和黄连碱中的一种或几种。其中,新川芎内酯和黄连碱可促进CD40表达,齐墩果酸、白术内酯I、异鼠李素用于促进CD55表达,齐墩果酸、白术内酯I、异鼠李素、桉油精用于促进CD44表达,新川芎内酯和黄连碱用于促进TRAF6表达,从而激活T淋巴细胞、引起分泌免疫球蛋白分泌,增强细胞免疫和体液免疫,改善萎缩性胃炎伴免疫功能低下。
所述的异鼠李素、桉油精、白术内酯Ⅰ和齐墩果酸中的一种或几种,用于抑制CDK2、CDK4表达,抑制细胞增殖。
所述的异鼠李素、白术内酯Ⅰ和齐墩果酸中的一种或几种,用于抑制CDK6、CCND1表达,抑制细胞增殖。
所述的黄连碱用于促进BAX、BAD、CASP3表达,促进细胞凋亡。
本发明还公开一种所述的调节萎缩性胃炎免疫功能的物质的制剂,即所述的调节萎缩性胃炎免疫功能的物质中加入药学上可接受的辅料制备的片剂、胶囊剂、丸剂、针剂、缓释剂、控释剂、粉剂或口服液体制剂。
本发明还公开所述的调节萎缩性胃炎免疫功能的物质的应用,所述的调节萎缩性胃炎免疫功能的物质在制备治疗萎缩性胃炎免疫功能低下的药物中的应用。
本发明通过网络药理学计算预测和实验验证,识别出了中成药摩罗丹中能够调节萎缩性胃炎伴有免疫功能低下的成分。体外验证实验表明,这些成分能够提高萎缩性胃炎伴免疫低下的CD40、CD44、TRAF6等免疫相关指标。为治疗萎缩性胃炎伴免疫功能低下疾病奠定了基础。
附图说明
图1是基于网络药理学发现摩罗丹治疗萎缩性胃炎伴免疫功能低下成分的分析流程图;
图2是摩罗丹代表性化合物靶标预测准确性的文献验证图;
图3是摩罗丹多成分调控萎缩性胃炎免疫生物功能模块的化合物-分子网络图;
图4是摩罗丹多成分调控萎缩性胃炎细胞凋亡生物功能模块的化合物-分子网络图;
图5是摩罗丹多成分调控萎缩性胃炎细胞增殖生物功能模块的化合物-分子网络图;
图6是摩罗丹中成分提升免疫功能的实验验证图;
其中,A为CD40的表达量;B为CD55的表达量;C为CD44的表达量;D为TRAF6的表达量;
图7是摩罗丹中成分调节免疫功能低下细胞凋亡模块的实验验证图;
其中,A为BAX的表达量;B为BAD的表达量;C为CASP3的表达量;
图8是摩罗丹中成分调节免疫功能低下细胞增殖模块的实验验证图;
其中,A为CDK2的表达量;B为CDK4的表达量;C为CDK6的表达量;D为CCND1的表达量。
具体实施方式
下面结合实施例和附图对本发明作进一步的说明,但不以任何方式对本发明加以限制,基于本发明教导所作的任何变换或替换,均属于本发明的保护范围。
本发明所述的调节萎缩性胃炎免疫功能的物质为新川芎内酯、齐墩果酸、白术内酯Ⅰ、桉油精、异鼠李素和黄连碱中的一种或几种。其中,新川芎内酯和黄连碱可促进CD40表达,齐墩果酸、白术内酯I、异鼠李素用于促进CD55表达,齐墩果酸、白术内酯I、异鼠李素、桉油精用于促进CD44表达,新川芎内酯和黄连碱用于促进TRAF6表达,从而激活T淋巴细胞、引起分泌免疫球蛋白分泌,增强细胞免疫和体液免疫,改善萎缩性胃炎伴免疫功能低下。
所述的调节萎缩性胃炎免疫功能的物质为异鼠李素、桉油精、白术内酯Ⅰ和齐墩果酸中的一种或几种,用于抑制CDK2、CDK4表达,抑制细胞增殖。
所述的调节萎缩性胃炎免疫功能的物质为异鼠李素、白术内酯Ⅰ和齐墩果酸中的一种或几种,用于抑制CDK6、CCND1表达,抑制细胞增殖。
所述的调节萎缩性胃炎免疫功能的物质为黄连碱,用于促进BAX、BAD、CASP3表达,促进细胞凋亡。
本发明所述的调节萎缩性胃炎免疫功能的物质的制剂为所述的调节萎缩性胃炎免疫功能的物质中加入药学上可接受的辅料制备的片剂、胶囊剂、丸剂、针剂、缓释剂、控释剂、粉剂或口服液体制剂。
本发明所述的调节萎缩性胃炎免疫功能的物质的应用为所述的调节萎缩性胃炎免疫功能的物质在制备治疗萎缩性胃炎免疫功能低下的药物中的应用。
针对摩罗丹治疗萎缩性胃炎伴免疫功能低下药效物质基础不清楚的问题,本发明通过对摩罗丹所含化合物进行靶标预测和生物功能富集分析,阐释摩罗丹治疗萎缩性胃炎的网络调节机制。进一步,通过实验验证了摩罗丹治疗萎缩性胃炎伴免疫功能低下的药效物质。
分析流程如图1所示。本发明所进行的工作包括:
(1)摩罗丹成分靶标预测和预测准确性的计算验证
从文献中搜集摩罗丹各个中药部分已报道成分,利用一种具有自主知识产权高精度药物靶标预测方法,预测出摩罗丹各成分的靶标谱,通过文献挖掘相关成分报道的生物分子,验证了预测靶标谱的准确性。预测准确率计算公式:
(2)摩罗丹成分的生物功能富集分析
将步骤1预测的摩罗丹成分靶标谱和萎缩性胃炎相关生物功能进行富集分析,识别出摩罗丹中调控萎缩性胃炎相关免疫、细胞凋亡、细胞增殖等生物功能模块的物质;
(3)实验验证摩罗丹中提高免疫功能的物质
针对步骤2识别出的调控免疫、细胞凋亡、细胞增殖生物功能模块的物质,发明人采用HTS2转录组检测实验技术,在HCT-116细胞系上检测摩罗丹中成分并行干预下对各个生物功能模块基因表达的影响。该技术通过在Illumina流动池中使用独特的引物,可实现在大批量样本中并行检测大量基因的转录组数据。在本实验中,384孔板中每个孔接种约3000个HCT-116细胞,培养24小时之后将摩罗丹成分溶于DMSO,并添加到细胞培养24小时,并包含8组DMSO重复作为阴性对照,每个成分设置一个浓度。选择一组从OMIM数据库、KEGG数据库等搜集得到的和利用疾病相关生物分子预测算法CIPHER预测得到的炎症和炎癌转化相关基因,经过相应的基因探针设计,利用HTS2实验平台检测该基因探针的信号。这些基因参与免疫、细胞凋亡、细胞增殖等生物过程,测定实验组和对照组CD40、CD44、CD55、TRAF6等基因的表达量,作为评价萎缩性胃炎免疫功能的客观指标。文献报道表明,CD44为分布极为广泛的细胞表面跨膜糖蛋白,主要参与异质性粘附,即肿瘤细胞与宿主细胞和宿主基质的粘附,异质性粘附在肿瘤细胞侵袭转移中起促进作用。CD44基因位于11号染色体短臂,全长约50kb,共由20个高度保守的外显子组成,每个外显子长度70-210bp不等,中间由长短不一的内含子分隔。CD44基因的20个外显子按照转录方式不同可分为组成型外显子(C)和变异型拼接外显子(V)两大类。组成型外显子共有10个,存在于所有转录产物之中。仅含有组成外显子的CD44转录子称为标准CD44(CD44S),其编码产物由361个氨基酸组成,该蛋白质有4个功能区。CD44能够激活T淋巴细胞。CD40 (Bp50)是与T细胞和B细胞功能有关的一种表面抗原,其前体含有297aa,为I型跨膜糖蛋白,由N端信号肽(20aa)、胞膜外区(193aa)、跨膜区(22aa)和胞浆区(62aa)组成,CD40通过和TRAF6结合,激活ERK相关信号通路,从而引起B细胞等分泌免疫球蛋白。TRAF6(TNF receptor associated factor 6)是一个泛素连接酶(ubiquitin-ligase),当它被激活的时候,会在自身和其它蛋白上产生短小蛋白链。因此TRAF6作为一个开关,能够决定在细胞内开启何种信号。TGF-利用TRAF6特定地激活激酶TAK1,TAK1随后激活其它的应激活化激酶,导致细胞死亡。CD55、CD59检测是对衰变加速因子(DAF,CD55)和反应性溶血膜抑制物(MIRL,CD59)进行检查,检测其是否缺失,结合临床明确诊断不排除溶血性贫血的情况,目前尚未发现有用于免疫相关的实验。因此,CD40、CD44、CD55、TRAF6可以在一定程度上作为评价慢性萎缩性胃炎细胞免疫和体液免疫的客观指标。同时,在免疫功能低下状态下,测定BAX、BAD、CASP3等细胞凋亡相关分子的表达水平,作为细胞凋亡的检测指标。Bcl-2基因是在细胞凋亡时作用的一段基因。Bcl-2家族可以分为两大类,一类是抗凋亡的,主要有Bcl-2、Bcl-XL、Bcl-W、Mcl-1、CED9等。另一类是促细胞死亡的,主要包括BAX、Bak、Bcl-XS、BAD、Bik、Bid等。BAX属于兔抗人单克隆抗体。试验中适用组织为石蜡切片,其阳性部位为细胞浆,阳性对照为乳腺癌,组织处理为热修复。BAX是与BCL-2同源的水溶性相关蛋白,是BCL-2基因家族中细胞凋亡促进基因,BAX的过度表达可拮抗BCL-2的保护效应而使细胞趋于死亡。目前多和BCL-2一起用于肿瘤的研究。BAX基因是人体最主要的凋亡基因,属于Bcl-2基因家族,编码的BAX蛋白可与Bcl-2形成异二聚体,对Bcl-2产生阻抑作用。BAX/Bcl-2两蛋白之间的比例关系是决定对细胞凋亡(Apoptosis)抑制作用强弱的关键因素,因此,BAX是极重要的促细胞凋亡(Apoptosis)基因之一。BAX的表达更为广泛,它可出现在肝细胞、肾小管上皮细胞、呼吸系上皮细胞和支气管平滑肌、血管平滑肌细胞中。BAD是Bcl-2家族中与Bcl-2和Bcl-xL相关的促凋亡基因。Bcl-2家族促凋亡蛋白和抗凋亡蛋白通过竞争性相互作用来调控细胞凋亡。BAD在多种细胞中表达,近年研究表明BAD可通过细胞信号转导通路和与Caspase家族成员的作用来参与细胞凋亡的全过程。CASP3是细胞凋亡过程中最主要的终末剪切酶,也是CTL细胞杀伤机制的重要组成部分。测定CDK2、CDK4、CDK6、CCND1等细胞周期和细胞增殖相关分子的表达水平,作为细胞增殖的检测指标。CDK,即周期蛋白依赖性激酶(cyclin-dependent kinases)是与细胞周期进程相对应的一套Ser/Thr激酶系统。CDK家族有CDK 1-8等8种,每种CDK结合不同类型的cyclin形成复合物,调节细胞从G1期过渡到S期或G2期过渡到M期以及退出M期的进程。各种CDK沿细胞周期时相交替活化,磷酸化相应底物,使细胞周期事件有条不紊地进行下去。周期蛋白依赖性蛋白激酶,是一组丝氨酸/苏氨酸蛋白激酶,CDK通过对丝氨酸/苏氨酸蛋白的化学作用驱动细胞周期和周期蛋白cyclin协同作用,是细胞周期调控中的重要因子。CDK可以和cyclin结合形成异二聚体,其中CDK为催化亚基,cyclin为调节亚基,不同的cyclin—CDK复合物,通过CDK活性,催化不同底物磷酸化,而实现对细胞周期不同时相的推进和转化作用。CDK的活性依赖于其正调节亚基cyclin的顺序性表达和其负调节亚基CKI(cyclin dependentkinase inhibitor,CDK抑制因子)的浓度。同时,CDK的活性还受到磷酸化和去磷酸化,以及癌基因和抑癌基因的调节。CCND1基因编码的蛋白质属于高度保守的细胞周期蛋白家族,其成员在整个细胞周期内具有显著的蛋白质丰度周期性。细胞周期蛋白起着调节CDK激酶的作用。不同的细胞周期蛋白表现出不同的表达和降解模式,这有助于每个有丝分裂事件的时间协调。该细胞周期蛋白与CDK4或CDK6形成复合物并作为其调节亚单位发挥作用,其活性是细胞周期G1/S转换所必需的。该蛋白与肿瘤抑制蛋白Rb相互作用,该基因的表达受到Rb的正调控。这种基因的突变、扩增和过度表达改变了细胞周期的进程,在多种肿瘤中经常观察到,并可能有助于肿瘤的发生。
HTS2自动处理平台经过RNA退火、选择和连接等步骤,输出原始的测序结果,通过对原始信号进行序列匹配、归一化处理和差异表达基因分析,进一步开展实验数据分析。
实施例1
摩罗丹治疗萎缩性胃炎伴免疫功能低下的成分
萎缩性胃炎与细胞增殖、细胞凋亡、细胞分化、DNA损伤及其修复、免疫—代谢平衡等信号通路在特定顺序、特定阶段的协同突变具有密切关系。发明人通过网络药理学计算预测和实验验证,阐释摩罗丹治疗萎缩性胃炎的网络调节机制,识别出了摩罗丹中治疗萎缩性胃炎伴免疫功能低下的药效物质,包括摩罗丹化合物收集、化合物靶标预测及预测准确性验证、生物功能富集分析和关键生物功能模块的化合物-分子网络构建、实验验证四个步骤,现依次分别介绍如下:
1.摩罗丹所含化合物收集
摩罗丹共包含百合、茯苓、玄参、乌药、泽泻、麦冬、当归、白术、茵陈、白芍、石斛、九节菖蒲、川芎、三七、地榆、延胡索、蒲黄、鸡内金18味中药,从文献中收集了各个中药部分已报道化合物。各个中药所含化合物数如表1所示(主要参考文献序号见背景技术)。
表1 摩罗丹所含中药的化合物信息
2.化合物靶标预测和预测准确性的文献验证
本发明使用了一种具有自主知识产权的高精度化合物靶标预测算法,对步骤1中摩罗丹每味化合物的直接作用或间接作用的靶标谱进行计算预测。为了检验化合物预测靶标的可靠性,本发明分析了摩罗丹代表性化合物预测靶标谱被文献报道生物效应分子的涵盖情况。分析发现,摩罗丹代表性化合物预测靶标谱能够覆盖文献中已报道的75%及以上生物效应分子。例如,白术里的化合物白术内酯I 86%的文献报道生物效应分子被白术内酯I的预测靶标谱覆盖(图2)。验证结果表明了预测的靶标谱具有较强的可靠性、能够较为全面地刻画丹摩罗丹中化合物的生物活性,摩罗丹代表性化合物靶标谱的文献验证结果如图2所示。图2中化合物洋川芎内酯H为代表性化合物,与本发明图3中的新川芎内酯及图4中川芎内酯A无关。
3.摩罗丹成分的生物功能富集分析
为了评价摩罗丹成分和萎缩性胃炎相关生物功能之间的关系,发明人使用Fisher精确检验度量步骤2预测的摩罗丹成分靶标谱和萎缩性胃炎相关生物功能的显著性水平并筛选出和显著的生物功能(P<0.05)。进一步地,基于发明人前期研究建立的、由细胞增殖、分化、凋亡、DNA损伤及其修复、免疫-代谢平衡等构成的生物功能模块网络中,本发明将摩罗丹成分显著富集的生物功能映射到该生物功能网络中,发现摩罗丹成分显著富集的生物功能主要分布在细胞增殖、分化、凋亡、DNA损伤、免疫、代谢、消化生物功能模块,这样就构成了摩罗丹成分干预的生物功能模块网络,进一步地识别出摩罗丹调节萎缩性胃炎相关免疫生物功能模块的成分。
针对免疫、细胞凋亡、细胞增殖三个关键生物功能模块,发明人分别构建了该免疫(图3)、细胞凋亡(图4)、细胞增殖(图5)生物功能模块的化合物-分子网络。其中,化合物选取的规则为:(1)中国药典2015年版一部中标明的含量测定成分;(2)文献报道的中药含量较多的成分或中药发挥药效的主要成分;(3)预测靶标能够和至少一个前述我们分析出的摩罗丹整体靶标相关生物功能/信号通路显著富集的成分;(4)wQED≥0.3,具有良好的成药性。分子的选取规则为:(1)能够表征该生物功能模块变化的分子;(2)在至少一个化合物的预测可药靶标谱的前100位的分子。
4. 摩罗丹调节萎缩性胃炎免疫功能的物质
HCT-116细胞系是一种常用的、能稳定培养的细胞系,经过药物处理并检测其基因表达的变化能为所预测的药理活性提供一定的验证和支持。发明人采用HTS2(基于测序的基因表达标签检测技术)实验技术,检测摩罗丹成分并行干预下对步骤3中免疫、细胞凋亡、细胞增殖三个生物功能模块基因表达的影响。HTS2是一种转录组实验体系,通过在Illumina流动池中使用独特的条形码引物,该实验体系可实现大批量样本中并行检测大量基因的转录组数据。在本实验中,384孔板中每个孔接种约3000个HCT-116细胞,培养24小时之后将摩罗丹成分分别溶于DMSO,并添加到细胞系中培养24小时,另外还包含8组DMSO重复作为阴性对照。细胞在GentLys缓冲液中裂解。HTS2实验系统包含Agilent Bravo自动化液体处理平台(Agilent,美国)和Agilent台式机器人(Agilent,美国)。通过RNA退火、选择和连接等步骤,该平台自动完成HTS2实验,输基因探针的转录组信号。
从ChEMBL数据库和文献收集摩罗丹所含成分对人源细胞系的活性信息,选择公共数据中活性较好(IC50或IG50的中位数<100μM))的成分作为HTS2实验候选成分,进而考虑采购货源、纯度等,最后选择了6个摩罗丹成分作为HTS2实验成分。实验化合物信息(包括所属药材、购买公司、纯度等)如表2所示。每个成分设置一个HTS2实验浓度。以公共数据中的成分活性(IC50或IG50)的中位数作为成分实验初始设定浓度。
HTS2实验检测一组从OMIM数据库、KEGG数据库等搜集得到的,以及利用疾病相关基因预测算法CIPHER计算得到的与炎症和炎癌转化相关的基因,这些基因参与免疫、细胞凋亡、细胞增殖等生物功能,并包括若干管家基因。测定实验组和对照组CD40、CD44、CD55、TRAF6等基因的表达量,作为评价萎缩性胃炎免疫功能的客观指标。
同时,测定BAX、BAD、CASP3的表达水平,作为免疫功能低下细胞凋亡的检测指标。BAX是与BCL-2同源的水溶性相关蛋白,是BCL-2基因家族中细胞凋亡促进基因,BAX的过度表达可拮抗BCL-2的保护效应而使细胞趋于死亡。目前多和BCL-2一起用于肿瘤的研究。BAX基因是人体最主要的凋亡基因,属于Bcl-2 基因家族,编码的BAX 蛋白可与Bcl-2 形成异二聚体,对Bcl-2 产生阻抑作用。研究发现BAX/Bcl-2 两蛋白之间的比例关系是决定对细胞凋亡(Apoptosis)抑制作用强弱的关键因素,因此认为,BAX 是极重要的促细胞凋亡(Apoptosis)基因之一 。BAX 的表达更为广泛,它可出现在肝细胞、肾小管上皮细胞、呼吸系上皮细胞和支气管平滑肌、血管平滑肌细胞中。CASP 3是细胞凋亡过程中最主要的终末剪切酶,也是CTL细胞杀伤机制的重要组成部分。
测定CDK2、CDK4、CDK6 、CCND1的表达水平,作为免疫功能低下细胞增殖的检测指标。CDK,即周期蛋白依赖性激酶(cyclin-dependent kinases)是与细胞周期进程相对应的一套Ser/Thr激酶系统。各种CDK沿细胞周期时相交替活化,磷酸化相应底物,使细胞周期事件有条不紊地进行下去。周期蛋白依赖性蛋白激酶,是一组丝氨酸/苏氨酸蛋白激酶,CDK通过对丝氨酸/苏氨酸蛋白的化学作用驱动细胞周期, 和周期蛋白cyclin协同作用,是细胞周期调控中的重要因子。CDK可以和cyclin结合形成异二聚体,其中CDK为催化亚基,cyclin为调节亚基,不同的cyclin—CDK复合物,通过CDK活性,催化不同底物磷酸化,而实现对细胞周期不同时相的推进和转化作用。CDK的活性依赖于其正调节亚基cyclin的顺序性表达和其负调节亚基CKI(cyclin dependent kinase inhibitor,CDK抑制因子)的浓度。同时,CDK的活性还受到磷酸化和去磷酸化,以及癌基因和抑癌基因的调节。CDK家族有CDK 1-8等8种,每种CDK结合不同类型的cyclin形成复合物,调节细胞从G1期过渡到S期或G2期过渡到M期以及退出M期的进程。
HCT-116结直肠癌细胞系由中国医学科学院提供,细胞培养时使用含有10%胎牛血清以及100 U/mL青霉素和100 g/mL链霉素的DMEM培养基,在37度5% CO2的条件下进行孵育培养。
HTS2实验数据处理包括三个步骤。首先,将实验产生的测序数据匹配到探针序列上,得到HTS2实验的原始转录组数据。这些数据表示通过HTS2实验检测到的基因探针的读数。其次,进行归一化处理,归一化后的基因表达值为原始读数除以管家基因原始读数的中位数。最后,进行差异表达分析。对于每一个成分,在该成分作用下基因表达量与8组DMSO阴性对照的表达量中位数相比,差异倍数大于2的基因为该成分作用下的差异表达基因。图4中的巴马汀、茯苓新酸A,泽泻醇A、图5中泽泻醇C、鲁斯可皂苷,由于这些化合物,有些是实验效果不好,有些是基因表达量差异倍数不大于2,所以不予考虑。图6、7、8中,DMSO为二甲基亚砜,是一种含硫有机化合物,常温下为无色无臭的透明液体,是一种吸湿性的可燃液体。具有高极性、高沸点、热稳定性好、非质子、与水混溶的特性,能溶于乙醇、丙醇、苯和氯仿等大多数有机物,被誉为“万能溶剂”。
表2 实验化合物采购信息
实验结果进一步验证了摩罗丹包含的部分成分对免疫功能相关生物分子的调控作用。新川芎内酯,又名新蛇床内酯是一种化学物质,化学式是C12H18O2,新川芎内酯和黄连碱可促进CD40表达(图6),齐墩果酸、白术内酯I、异鼠李素可促进CD55表达(图6),齐墩果酸、白术内酯I、异鼠李素、桉油精可促进CD44表达(图6),新川芎内酯和黄连碱可促进TRAF6表达(图6)。以上结果提示,摩罗丹包含的部分成分可能通过激活T淋巴细胞、引起分泌免疫球蛋白分泌等方式,增强细胞免疫和体液免疫,改善萎缩性胃炎伴免疫功能低下。
同时,实验还验证了摩罗丹部分化合物可以促进免疫功能低下状态下的细胞凋亡相关分子表达,黄连碱可促进BAX、BAD、CASP3表达(图7)。另外,实验结果显示摩罗丹中部分化合物可抑制免疫功能低下状态下的细胞周期及细胞增殖功能相关分子表达,白术内酯I、齐墩果酸、异鼠李素、桉油精可抑制CDK2、CDK4表达(图8), 白术内酯I、齐墩果酸、异鼠李素可抑制CDK6、CCND1表达(图8)。
Claims (7)
1.一种调节萎缩性胃炎免疫功能的物质,其特征在于,所述调节萎缩性胃炎免疫功能的物质为新川芎内酯、齐墩果酸、白术内酯Ⅰ、桉油精、异鼠李素和黄连碱中的一种或几种;其中,新川芎内酯和黄连碱可促进CD40表达,齐墩果酸、白术内酯I、异鼠李素用于促进CD55表达,齐墩果酸、白术内酯I、异鼠李素、桉油精用于促进CD44表达,新川芎内酯和黄连碱用于促进TRAF6表达,从而激活T淋巴细胞、引起分泌免疫球蛋白分泌,增强细胞免疫和体液免疫,改善萎缩性胃炎伴免疫功能低下。
2.根据权利要求1所述的调节萎缩性胃炎免疫功能的物质,其特征在于,所述的异鼠李素、桉油精、白术内酯Ⅰ和齐墩果酸中的一种或几种,用于抑制CDK2、CDK4表达,抑制细胞增殖。
3.根据权利要求1或2所述的调节萎缩性胃炎免疫功能的物质,其特征在于,所述的异鼠李素、白术内酯Ⅰ和齐墩果酸中的一种或几种,用于抑制CDK6、CCND1表达,抑制细胞增殖。
4.根据权利要求1或2所述的调节萎缩性胃炎免疫功能的物质,其特征在于,所述的黄连碱用于促进BAX、BAD、CASP3表达,促进细胞凋亡。
5.根据权利要求3所述的调节萎缩性胃炎免疫功能的物质,其特征在于,所述的黄连碱,用于促进BAX、BAD、CASP3表达,促进细胞凋亡。
6.一种权利要求1~5任一所述的调节萎缩性胃炎免疫功能的物质的制剂,其特征在于,所述的调节萎缩性胃炎免疫功能的物质中加入药学上可接受的辅料制备的片剂、胶囊剂、丸剂、针剂、缓释剂、控释剂、粉剂或口服液体制剂。
7.一种权利要求1~5任一所述的调节萎缩性胃炎免疫功能的物质的应用,其特征在于,所述的调节萎缩性胃炎免疫功能的物质在制备治疗萎缩性胃炎免疫功能低下的药物中的应用。
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