CN116920066B - 一种治疗肺结节及肺癌的中药组合物及其制剂和应用 - Google Patents
一种治疗肺结节及肺癌的中药组合物及其制剂和应用 Download PDFInfo
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Abstract
本发明公开了一种治疗肺结节及肺癌的中药组合物及其制剂和应用,属于中医药及网络药理学技术领域,所述中药组合物包含如下原料药:天葵子、白英、红景天、莪术、白花蛇舌草、桔梗、牛膝、预知子、山慈菇、浙贝母、半夏、天花粉。本发明的中药组合物所用原料价廉,制备简便,使用方便,经多年临床应用和药理研究,在抑制肺部结节生成与发展、改善肺脏功能、促进肺结节消散等方面疗效显著。本发明的中药组合物相关作用机理明确,并且通过网络药理学研究,为临床遣方用药提供了更多选择与探讨依据。
Description
技术领域
本发明涉及中医药及网络药理学技术领域,特别是涉及一种治疗肺结节及肺癌的中药组合物及其制剂和应用。
背景技术
肺结节是影像学检查肺部有直径≤3cm的局灶性、类圆形、密度增高的实性或者亚实性肺部阴影,可为孤立性或多发性,不伴发肺不张、肺门***肿大和胸腔积液的一种疾病。肺结节的治疗主要采取保守观察、外科手术、SBRT或热消融治疗等。近年来,由于全民健康意识的增强,体检的人次的增加,肺结节的检出率也随之逐渐增加。肺结节发病机制尚无定论,可能与感染、慢性炎症、肿瘤的产生与转移等相关。中医认为肺主气,司呼吸,主宣发肃降,朝百脉而主治节。肺为娇脏,肺气通于天,易于受外邪侵袭,发生病变。患者平素吸烟抑或总处于雾霾、油烟等有害环境中,或是患者禀赋不足或后天失养,感受邪毒。邪毒致肺气宣发肃降不利,气机受损,无法推动津液的运行,输布失常,水湿停聚,日久不除,导致变生痰浊,内停于肺。肺朝百脉主治节,肺可以辅心行血,对血液的运行具有推动和调节的作用。肺的宣降运动失调,气机不利,血液运行不畅,形成淤血。加之,痰浊邪毒内停,影响血行,日久成瘀。
肺癌是当今世界最常诊断的癌症之一,也是癌症相关死亡的主要原因,估计每年有2万肺癌新增病例和1.76万死亡病例。在中国肺癌的发病率及死亡率均居前列且发病年龄愈发趋于年轻化。现代医学治疗肺癌以手术、放疗及化疗为主,靶向与免疫治疗方兴未艾但不可抗风险明显。中医将肺癌归属为“肺积”范畴,《难经集注》曰“肺之积,名为息贲,在右胁下,覆大如杯,久不已,令人洒淅寒热,喘咳”,其病机可能多为素体邪盛正虚,受多种因素致癌毒痰瘀抟结积于肺,发为癌病。
虽然中医对肺结节和肺癌已有一定的研究,但目前临床对于肺结节和肺癌的处理以早期排查监测为主,且无相关针对性特效药物以供广泛使用,效果良好具有明确作用机制的中药组方亦未见报道。
发明内容
基于此,有必要针对目前用于治疗肺结节及肺癌的中药组方治疗效果欠佳、临床作用机制不明确等问题,提供一种治疗肺结节及肺癌的中药组合物及其制剂和应用。
本发明提供了一种治疗肺结节及肺癌的中药组合物,所述中药组合物包含如下原料药:天葵子、白英、红景天、莪术、白花蛇舌草、桔梗、牛膝、预知子、山慈菇、浙贝母、半夏、天花粉。
优选地,所述中药组合物包含如下重量份的原料药:天葵子5-25份、白英5-25份、红景天5-25份、莪术10-20份、白花蛇舌草10-30份、桔梗5-15份、牛膝5-25份、预知子10-30份、山慈菇10-30份、浙贝母10-30份、半夏5-15份、天花粉10-30份。
优选地,所述中药组合物包含如下重量份的原料药:天葵子10份、白英10份、红景天12份、莪术10份、白花蛇舌草30份、桔梗6份、牛膝10份、预知子10份、山慈菇10份、浙贝母20份、半夏9份、天花粉15份。
本发明还提供了一种治疗肺结节及肺癌的中药制剂,所述中药制剂由前述任一技术方案中所述的治疗肺结节及肺癌的中药组合物制备得到。
优选地,所述中药制剂为汤剂,所述汤剂按照如下步骤制备得到:
(1)按照重量份称取原料药,加入5-10倍重量份的水浸泡30-120分钟;
(2)将浸泡后的原料药连水一同加热煎煮,过滤,收集滤液;
(3)将滤渣重新加入5-10倍重量份的水,煎煮,过滤,收集滤液;
(4)将两次煎煮后过滤得到的滤液合并,加热浓缩,即得汤剂。
优选地,两次煎煮的时间均为30-60分钟。
优选地,滤液合并后加热浓缩至原体积的10%-20%。
此外,本发明还提供了如前述任一技术方案中所述的治疗肺结节及肺癌的中药组合物在制备治疗肺结节及肺癌的药物中的应用。
本发明治疗肺结节及肺癌的中药组合物方解如下:
本发明治疗肺结节及肺癌的中药组合物中:天葵子、白英清热散结、祛风利湿解毒,为君药;配伍浙贝母、山慈菇加强清热化痰、散结消痈之效,为臣药;半夏燥湿化痰以降逆散结;天花粉滋养津液以消肿排脓;取入肺经血分之红景天和清肺经热气之白花蛇舌草共行益气活血散结之功效;莪术、预知子共奏行气破血、消积止痛之功,加强散结之效;配伍药性上浮之桔梗与载药下行之牛膝以通气机升降,利肺气宣降。该中药组合物的诸药合用,气血同调,标本兼顾,共奏宣畅肺气,活血益气,化痰散结之功效。具有攻邪不伤正,疗效可观,应用安全等特点。
具体地,各中药原料药具有以下药理特性:
天葵子:为毛茛科植物天葵Semiaquilegia adozoides(DC.)Makino的干燥块根,味甘、苦,寒。归肝、胃经,有清热解毒,消肿散结之功效;
白英:茄科植物白英Solanum lyratum Thunb.的全草,性寒,味甘、苦。归肝经、胆经、肾经,有清热、利湿、祛风、解毒之功效;
红景天:为景天科植物大花红景天Rhodiola crenulata(Hook.f.et Thoms.)H.Ohba的干燥根和根茎,味甘、苦,平。归肺、心经,有益气活血,通脉平喘之功效;
莪术:为姜科植物蓬莪术Curcumap haeocaulis VaL、广西莪术Curcumakuuangsiensis S.G.LeeetC.F.Liang或温郁金Curcuma wenyujin Y.H.ChenetC.Ling的干燥根茎,味辛、苦,温。归肝、脾经,有行气破血,消积止痛之功效;
白花蛇舌草:为茜草科耳草属植物白花蛇舌草Hedyotis diffusa Willd.[Oldenlandia diffusa(Willd.)Roxb.]的全草,味苦、淡,性寒,有清热解毒、消痛散结、利尿除湿之功效;
桔梗:为桔梗科植物桔梗Platycodon grandiflorum(Jacq.)A.DC.的干燥根,味苦、辛,平。归肺经,有宣肺,利咽,祛痰,排脓之功效;
牛膝:为苋科植物牛膝Achyranthes bidentata Bl.的干燥根,味酸、苦,平,有逐瘀通经,补肝肾,强筋骨,利尿通淋,引血下行之功效;
预知子:为木通科植物木通Akebia quinata(Thunb.)Decne.、三叶木通Akebiatrifoliate(Thunb.)Koidz.或白木通Akebia trifoliata(Thunb.)Koidz.var.australis(Diels)Rehd.的干燥近成熟果实,味苦,寒。归肝、胆、胃、膀胱经,有疏肝理气,活血止痛,散结,利尿之功效;
山慈菇:为兰科植物杜鹃兰Cremastra appendiculata(D.Don)Makino、独蒜兰Pleione bulbocodioides(Franch.)Rolfe或云南独蒜兰Pleione yunnanensis Rolfe的干燥假鳞茎,味甘、微辛,凉。归肝、脾经,有清热解毒,化痰散结之功效;
浙贝母:为百合科植物浙贝母Fritillaria thunbergii Miq.的干燥鳞茎,味苦,寒。归肺、心经,有清热化痰止咳,解毒散结消痈之功效;
半夏:为天南星科植物半夏Pinellia ternata(Thunb.)Breit.的干燥块茎,味辛、温;有毒。归脾、胃、肺经,有燥湿化痰,降逆止呕,消痞散结之功效;
天花粉:为葫芦科植物栝楼Trichosanthes kirilowii Maxim.或双边栝楼Trichosanthes rosthornii Harms的干燥根,味甘、微苦,微寒。归肺、胃经,有清热泻火,生津止渴,消肿排脓之功效。
本发明与现有技术相比具有如下优点:
本发明的中药组合物所用原料价廉,制备简便,使用方便,经多年临床应用和药理研究,在抑制肺部结节生成与发展、改善肺脏功能、促进肺结节消散等方面疗效显著。
本发明中药组合物治疗肺结节及肺癌主要成分包括顺式二十碳-11-烯酸、山柰酚、槲皮素、豆甾醇、β-谷甾醇、菠菜甾醇、黄芩甙元等,研究证实上述成分主要发挥抗炎、抗肿瘤作用;在肺结节及肺癌治疗过程中经PI3K-Akt、MAPK、Ras、Rap1、HIF-1等信号通路调控TNF-α、IL6、AKT1、GAPDH、VEGFA、EGFR等靶点,作用于肺组织或全身多组织器官,改善机体炎症反应,有助于缓解患者临床不适症状;涉及的生物学过程主要有细胞炎性因子与炎症反应、表皮生长因子与血管内皮生长因子表达失调、肿瘤微环境(如高糖、低氧及炎症等)、肿瘤生长、增殖、侵袭,血管生成和转移、细胞的代谢、缺氧等,复方药物主要发挥抗炎、抗癌及调控相关蛋白与细胞因子等作用。同时通过网络药理学研究,为临床遣方用药提供了更多选择与探讨依据。
附图说明
图1为本发明实施例1中药组合物的药物-成分-靶点图;
图2为本发明实施例1中药组合物治疗肺结节的潜在治疗靶点和肺结节疾病靶点的韦恩图;
图3为本发明实施例1中药组合物148个潜在治疗靶点的蛋白-蛋白互作网络图;
图4为本发明实施例1中药组合物治疗肺结节的潜在核心基因靶点图;
图5为本发明实施例1中药组合物治疗肺结节的潜在治疗靶点GO功能富集分析图;
图6为本发明实施例1中药组合物治疗肺结节的潜在治疗靶点KEGG通路富集分析图;
图7为本发明实施例1中药组合物靶点-通路图;
图8为本发明实施例2中药组合物治疗肺癌的潜在治疗靶点和肺癌疾病靶点的韦恩图;
图9为本发明实施例2中药组合物108个潜在治疗靶点的蛋白-蛋白互作网络图;
图10为本发明实施例2中药组合物重要功能模块基因图;
图11为本发明实施例2中药组合物治疗肺癌的潜在核心基因靶点图;
图12为本发明实施例2中药组合物治疗肺癌的潜在治疗靶点GO功能富集分析图;
图13为本发明实施例2中药组合物治疗肺癌的潜在治疗靶点KEGG通路富集分析图。
具体实施方式
一种治疗肺结节及肺癌的中药组合物,所述中药组合物包含如下原料药:天葵子、白英、红景天、莪术、白花蛇舌草、桔梗、牛膝、预知子、山慈菇、浙贝母、半夏、天花粉。
在其中一个较佳的实施例中,所述中药组合物包含如下重量份的原料药:天葵子5-25份、白英5-25份、红景天5-25份、莪术10-20份、白花蛇舌草10-30份、桔梗5-15份、牛膝5-25份、预知子10-30份、山慈菇10-30份、浙贝母10-30份、半夏5-15份、天花粉10-30份。
在其中一个较佳的实施例中,所述中药组合物包含如下重量份的原料药:天葵子10份、白英10份、红景天12份、莪术10份、白花蛇舌草30份、桔梗6份、牛膝10份、预知子10份、山慈菇10份、浙贝母20份、半夏9份、天花粉15份。
一种治疗肺结节及肺癌的中药制剂,所述中药制剂由前述任一技术方案中所述的治疗肺结节及肺癌的中药组合物制备得到。
在其中一个较佳的实施例中,所述中药制剂为汤剂,所述汤剂按照如下步骤制备得到:
(1)按照重量份称取原料药,加入5-10倍重量份的水浸泡30-120分钟;
(2)将浸泡后的原料药连水一同加热煎煮,过滤,收集滤液;
(3)将滤渣重新加入5-10倍重量份的水,煎煮,过滤,收集滤液;
(4)将两次煎煮后过滤得到的滤液合并,加热浓缩,即得汤剂。
在其中一个较佳的实施例中,两次煎煮的时间均为30-60分钟。
在其中一个较佳的实施例中,滤液合并后加热浓缩至原体积的10%-20%。
所述治疗肺结节及肺癌的中药组合物可以应用于制备治疗肺结节及肺癌的药物。
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似改进,因此本发明不受下面公开的具体实施例的限制。
实施例1中药组合物与治疗肺结节有关的网络药理学实验
1.1中药组合物治疗肺结节的有效成分筛选
在数据库TCMSP中,并以TCMID等作为补充数据库,以口服生物利用度(OB)≥30%,类药性指数(DL)≥0.18为筛选条件,针对肺结节搜集本发明的中药组合物12味中药的有效成分;此外,联合文献数据库如知网、万方、Pubmed等,挖掘文献中与本发明的中药组合物12味中药所含的中药有效成分作为补充。
从TCMSP、TCMID等数据库中检索,本发明的中药组合物所含中药有效成分,通过OB≥30%和DL≥0.18,进行筛选并根据文献报道补充后,获得针对肺结节的有效成分73个,如表1所示(表1有8个重复有效成分)。
表1中药组合物针对肺结节的主要有效成分
1.2中药组合物治疗肺结节的“药物-有效成分-靶点”网络构建及分析
使用数据库TCMSP查出主要有效成分相关的靶蛋白,并结合Uniprot数据库查询其对应的Gene Symbol;通过TCMSP数据库链接,在Pubchem中获得中药有效成分的化合物SMILES结构,并在数据库Swiss Target Prediction中输入上述所得SMILES结构,以“Homosapiens”为筛选条件进行查询,选取高匹配度靶点,将两个数据库获得的靶点去重;使用Cytoscape3.8.2构建本发明中药组合物“活性成分-靶点网络”,其中用“节点”来表示成分或靶点,用“边”来表示两者之间的关系。利用Cytoscape3.8.2对本发明中药组合物药物有效成分及其作用靶点的关系网络图进行绘制和分析,共获得749个结点(包括73个活性成分和676个靶点),3057条关系,结果见图1。越多条边与该节点进行连接,说明此节点重要性越大。
1.3中药组合物治疗肺结节的主要潜在靶点筛选
以“Gene”和“Homo sapiens”为检索条件,以“pulmonary nodule”在疾病数据库Genecards中进行检索与筛选,并根据文献报道补充未预测到的有效成分的已知靶点。
将药物相关作用靶点与疾病基因在Venny2.1中进行映射,筛选出本发明中药组合物治肺结节相关作用靶点共148个。后在STRING11.5数据库中,输入交集靶点,以“Homosapiens”作为物种选择的条件,获得PPI互作网络。
以“pulmonary nodule”为检索词,在疾病基因数据库Gnencards中检索到3193条靶基因,与清肺散结方的676个靶点进行映射,最终获得148个潜在治疗靶点,见图2;在STRING11.5数据库中对148个靶点进行蛋白-蛋白互作网络分析并绘图,见图3;根据节点连接度Degree值进行筛选,得出节点连接度排名前15位的关键靶点,绘制条形图,见图4。
1.4中药组合物治疗肺结节的通路富集分析
在DAVID数据库中对本发明中药组合物治疗肺结节及肺癌潜在靶点做GO和KEGG富集分析,保存结果并利用ImageGP进行可视化。
对148个潜在治疗靶点进行GO功能富集分析,根据“FDR<0.05”筛选得到125个符合条件的条目,包括BP82个、CC8个和MF35个。分别取BP、MF的前十个条目与CC的8个条目进行可视化,见图5。在BP方面,包括了RNA聚合酶II启动子转录的阳性调控、蛋白质磷酸化、RNA聚合酶II启动子的转录负调控、蛋白水解作用、多细胞生物的发育、蛋白质自身磷酸化、肽基酪氨酸磷酸化、跨膜受体蛋白酪氨酸激酶信号通路、激酶活性的正向调节、细胞内钙离子浓度的正向调节等;在CC方面,包括质膜的有机组成部分、受体复合物、细胞外基质、晚期核内体、磷脂酰肌醇3-激酶复合物、磷脂酰肌醇3-激酶复合物(IA类)、丝氨酸蛋白酶抑制剂复合物等;在MF方面,包括ATP结合、蛋白激酶活性、锌离子结合、跨膜受体蛋白酪氨酸激酶活性、蛋白质酪氨酸激酶活性、蛋白丝氨酸/苏氨酸激酶活性、蛋白丝氨酸/苏氨酸激酶活性、肽链内切酶活性、丝氨酸型内肽酶活性、金属内肽酶活性等。
对148个潜在治疗靶点做KEGG通路分析,以FDR<0.05作为筛选条件,发现与本发明中药组合物治疗肺结节及肺癌作用机理相关的通路共128条。取排名前25的通路,利用ImageGP进行可视化分析,见图6。利用Cytoscape3.8.2绘制靶点-通路图,见图7。相关通路主要包括PI3K-Akt信号通路、MAPK信号通路、Ras信号通路、Rap1信号通路、趋化因子信号通路、磷脂酶D信号通路、HIF-1信号通路等。
1.5中药组合物治疗肺结节的相关网络药理学分析
通过筛选本发明中药组合物的主要成分并构建多层次相互作用的成分与靶点相互作用网络示意图,发现顺式二十碳-11-烯酸、山柰酚、槲皮素、豆甾醇、β-谷甾醇、菠菜甾醇、黄芩甙元/黄芩黄素、Baicalin黄芩苷为核心化合物,且大多数主要有抗炎作用、抗肿瘤作用。其中,顺式二十碳-11-烯酸,通过抑制ROS的产生和抑制PKCθ、ERK、STAT3信号通路来改善Kupffer细胞的炎症反应,从而达到抗炎的作用。山柰酚具有显著的抗炎以及抑制肿瘤的作用。经研究,山柰酚通过下调ERRα抑制非小细胞肺癌A549细胞的侵袭和迁移,通过下调UBF的磷酸化水平影响rRNA的转录和细胞的增殖,还可以在肝细胞中通过抑制miR21的表达,抑制癌细胞增殖。槲皮素和菠菜甾醇可以分别通过调节TLR4/NF-κB信号通路和下调MAP激酶信号通路,抑制LPS诱导小鼠RAW264.7细胞分泌TNF-α、IL-6等炎症因子,减轻细胞炎性损伤。此外,槲皮素增强了病毒感染后16-HBE细胞增殖活性,并抑制了细胞凋亡及TNF-α、IL-6等炎症因子的分泌,保护细胞损伤。豆甾醇经研究有良好的抗氧化作用,能起到抑制肿瘤生长、在体内破坏肿瘤血管的生成、抑制癌细胞迁移等多种抗肿瘤作用。经报道,豆甾醇还有良好的抗炎症作用。β-谷甾醇可能通过抑制肺组织细胞凋亡、降低炎症反应及减轻纤维化,改善LPS诱导的急性肺损伤。此外,其还可以通过激活PI3K-Akt信号通路,增加P-AKT和PI3K3CA蛋白表达水平促进颗粒细胞增殖,降低Caspase-s蛋白表达水平,从而抑制颗粒细胞凋亡。黄芩甙元被证明可以增强IRF-1,抑制12-脂氧合酶活性增加,增加肿瘤坏死因子相关的诱导配体凋亡受体D5,还可以激活AMPK,从而抑制mTOR的一种途径。达到抗肿瘤增殖的效果。黄芩苷可以通过促进并积累ROS产生,抑制PI3K-Akt信号通路,诱导肿瘤细胞凋亡和自噬。
根据Degree值筛选,排名靠前靶点的主要是TNF-α(肿瘤坏死因子-α)、IL6(白细胞介素-6)、AKT1(蛋白激酶1)、GAPDH(甘油醛-3-磷酸脱氢酶)、VEGFA(血管内皮生长因子)、EGFR(表皮生长因子受体)、IL1β(白介素-1)、STAT3(信号传导与转录因子3)等。主要参与炎症、血管生成,肿瘤相关等多过程。经研究,TNF-a作为一种最重要的促炎细胞因子,TNF-a参与血管扩张和水肿形成,白细胞通过粘附分子的表达粘附上皮,调节血液凝固,有助于炎症部位的氧化应激。TNF-α局部高剂量给药具有一定的抗肿瘤作用,致肿瘤坏死活性强。低剂量慢性给药,可能作为内源性肿瘤启动子参与肿瘤发生的所有步骤,包括细胞转化,增殖,生长,侵袭,血管生成和转移。IL-6是一种具有功能性和多效性的典型细胞因子,在宿主防御中发挥重要作用。当感染或组织损伤发生时,单核细胞和巨噬细胞立即产生IL-6,并通过激活免疫、血液和急性期反应,帮助于清除感染因子和修复受损组织。一旦宿主的感染或组织损伤被消除,IL-6的合成就结束了,但不受控制的过量或持续的IL-6产生在各种炎症性疾病和癌症的发展中起着病理作用,这表明IL-6对宿主来说是一把双刃剑。血管内皮生长因子(VEGF)是启动和调节生理血管生成所需的重要细胞因子,是最强的血管生成激活剂之一。它们刺激内皮细胞在现有血管中的迁移和增殖,以生成和稳定新血管。VEGF-A是VEGF的一个亚型,控制许多组织中的血管形成。VEGF在缺氧条件下释放,是缺氧诱导因子(HIF-1α)作用的结果,与支气管细胞的细胞再调节和炎症有关。细胞再调节和炎症导致各种肺部疾病的发展,这表明肺疾病与VEGF过度表达有密切的联系。内皮细胞功能与血管内皮生长因子(VEGF)有关。肺组织中VEGF蛋白非常丰富,许多不同的肺细胞产生VEGF,也对VEGF有反应。VEGF对肺的发育至关重要,是肺组织的维持因子,但在T辅助性2型细胞介导的炎症反应(TH2),细胞因子的产生和气道重塑中,VEGF的过度表达参与了血管生成的发展,这也是许多肺部疾病的重要发病机制。Akt一直被认为是肿瘤发生和生长所必需的重要癌基因,参与肿瘤从产生到迁移的多过程。早期,Akt在癌细胞中的表达或活性增强,主要通过mTOR、GSK3α、GSK3β等下游靶点,致使癌细胞增殖、代谢和细胞周期增强。它还可以抑制细胞凋亡,诱导促肿瘤细胞因子,有利于炎症细胞浸润和肿瘤血管生成,进一步支持癌细胞生存和肿瘤生长。此外,Akt1还参与了癌细胞的迁移和侵袭。甘油醛-3-磷酸脱氢酶(GAPDH)是糖酵解途径中的关键酶。肿瘤细胞增殖高耗氧,在肿瘤局部形成缺氧环境,GAPDH作为一种糖酵解酶在缺氧时表达上调。且癌细胞经常上调葡萄糖代谢,导致在有氧条件下,葡萄糖的摄取和使用很高,但线粒体呼吸速率适中,糖酵解酶的上调。这将导致细胞代谢的增强,这已被证明与某些癌症的肿瘤侵袭性增加相关。此外,GAPDH还能参与细胞凋亡,起到抑制肿瘤的作用。ERBB1也被称为表皮生长因子受体(EGFR)。受体酪氨酸激酶(RTKs)是跨膜受体的一种特定类别,可以将配体结合事件转化为信号,并最终引起广泛的细胞反应,包括细胞生长,分化,***,粘附,迁移和凋亡。RTK的一个亚家族含有成红细胞白血病病毒癌基因同系物(ERBB)受体。在肺腺癌肿瘤中,ERBB受体信号传导失调,驱动肿瘤细胞不受控制的增殖,赋予逃避程序性细胞死亡的能力,增强其迁移能力并促进转移。该ERBB家族的RTK由四个受体组成:ERBB1、ERBB2、ERBB3和ERBB4。
根据KEGG通路分析相关通路主要包括PI3K-Akt信号通路、MAPK信号通路、Ras信号通路、Rap1信号通路、趋化因子信号通路、磷脂酶D信号通路、HIF-1信号通路等。
PI3K/AKT通路的组成性激活通常发生在人类癌症中,通过受体酪氨酸激酶的突变激活或扩增,RAS或PIK3CA基因的突变激活,AKT1/AKT2/AKT3的突变激活或扩增,以及通过PTEN或调控PI3K p85亚基(PIK3R1和PIK3R2)的失活。70%或更多的肺癌确诊病例中发生该通路的紊乱。
多种肺部疾病与肺组织供氧不足相关,PIK3/AKT、RAS、HIF-1信号通路参与其中。所以,如果氧气长时间供应持续不足,补充机制试图恢复氧合或帮助身体适应缺氧。此外,肿瘤细胞保持高增殖率,消耗营养和氧气,现有的局部血管无法支持。因此,在大多数实体肿瘤中,低氧区域会出现,细胞有不同的机制来适应缺氧。缺氧由缺氧诱导因子(HIFs)介导,分为HIF-1α/2α和1β。氧供应减少,HIF-1α通过翻译后修饰变得稳定,α亚基被分离并与β亚基结合异二聚体与大量含缺氧反应元件(HREs)的启动子结合,形成VEGF的转录靶基因。缺氧诱导因子(HIF-1)激活表皮生长因子(EGF),导致肺组织中VEGF过表达。RAS参与细胞内信号的传递,在细胞增殖、分化、凋亡等多种功能中发挥重要作用。RAS蛋白突变,通过HIF-1转录元件来激活PIK3/AKT通路增加VEGF表达。
除此之外,PI3K/AKT通路还通过内皮细胞一氧化氮信号级联调控血管生成过程。一氧化氮的合成受NO合成酶的调控,尤其是eNOS/NOS3亚型。这种亚型在VEGF诱导的血管生成中起着关键作用,而血管生成是通过AKT或缺氧将eNOS亚型丝氨酸1117残基磷酸化而获得的。ANG1(血管生成素1)通过诱导内皮细胞的NOs磷酸化、NO生成和血管生成,激活PI3K通路,促进内皮细胞存活。基质金属蛋白酶(MMPs)是一种高度调节的酶,能够降解细胞外基质。多种基质金属蛋白酶在血管生成过程中起重要作用,特别是MMP-2和MMP-9。MMP-2转录失活显著降低了整合素-αvβ3介导的、PI3K/AKT诱导的VEGF表达,最终降低了血管生成过程。炎症失控是各种肺部疾病发病的主要因素。炎症导致支气管上皮和肺微环境的改变。多种促炎标志物,如白细胞介素6(IL-6),白细胞介素8(IL-8),激活信号转导和转录激活因子3(STAT3)通路。随后的STAT3磷酸化参与了血管生成介质的上调,如VEGF,FGF-2和HIF1,导致血管生成,为肺部疾病提供条件。
MAPK家族包括ERK(细胞外信号调节激酶)、p38和JNRK。ERK信号通路在癌细胞增殖、迁移和侵袭中起关键作用。RAS-MAPK(丝裂原活化蛋白激酶)信号通路(也称为RAS-RAF-MEK-ERK通路)的功能是整合细胞外信号,并通过随后控制细胞生长、存活和分化来协调合适的反应。该途径的异常激活存在于许多致癌事件中。在约80%的非小细胞肺癌病例中发现EGFR的异常激活。EGFR最常见的突变是酪氨酸激酶结构域的框架内缺失,这导致如PI3K-Akt和Raf-MEK-ERK通路介导的下游信号通路的激活。此外,有数据证明p38和炎症相关,它与癌症相关的细胞增殖、侵袭和凋亡有关。
Ras(鸟嘌呤核苷酸结合蛋白)是单个GTP酶分子,Ras的活化和失活是通过活性GTP结合和非活性GDP结合形式之间的循环切换来控制的。通常,配体与受体酪氨酸激酶结合诱导受体的二聚化和C末端区域中特定酪氨酸残基的自磷酸化,这为衔接蛋白产生结合位点。其在质膜上募集GEF Sos,进而通过催化GDP到GTP来激活膜结合的Ras。在其GTP结合的构象中,Ras与Raf结合并动员细胞质中的无活性蛋白,将Raf激酶募集到质膜。一旦Ras-Raf复合物转移到细胞膜上,Ras就会激活Raf亚型的丝氨酸/苏氨酸激酶功能。在激活Ras时,Raf充当MAPKK激酶(MAPKKK)来激活MEK1和MEK2,这反过来又催化效应ERK1和ERK2激酶的激活。这一过程为RAS-RAF-MEK-ERK通路。
Ras和Rap1具有序列相似性,它们的时空激活在下游途径的微调中发挥作用,例如ERK信号传导。因此,Rap1是一些Ras驱动癌症中致癌途径的潜在重要调节剂。除了其在细胞粘附中的核心作用外,大量证据表明Rap1能够促进各种***中的肿瘤发生。例如Rap1激活在各种细胞过程中的作用,例如细胞代谢,细胞骨架重塑,细胞增殖,迁移和转移,也可通过其对下游途径(如ERK,AKT,FAK和Wnt信号传导)的调节。
实施例2中药组合物与治疗肺癌有关的网络药理学实验
2.1中药组合物治疗肺癌的有效成分筛选
在数据库TCMSP中,并以TCMID等作为补充数据库,以口服生物利用度(OB)≥30%,类药性指数(DL)≥0.18为筛选条件,针对肺癌搜集本发明的中药组合物12味中药的有效成分;此外,联合文献数据库如知网、万方、Pubmed等,挖掘文献中与本发明的中药组合物12味中药所含的中药有效成分作为补充。
从TCMSP、TCMID等数据库中检索本发明的中药组合物所含中药有效成分,通过OB≥30%和DL≥0.18,进行筛选并根据文献报道补充后,获得针对肺癌的有效成分65个(其中天葵子7个、白毛藤3个、红景天8个、莪术3个、白花蛇舌草7个、桔梗7个、牛膝20个、预知子6个、山慈菇3个、浙贝母7个、半夏13个、天花粉2个,部分成分重复),如表2所示(列出每味药前5位有效成分)。
表2中药组合物针对肺癌的主要有效成分
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2.2中药组合物药物靶点筛选及肺癌疾病相关靶点收集
在PubChem中检索药物化合物对应的CanonicalSMILES结构,并在SwissTargetPrediction数据库中查找其有效对应靶点,保留“Probability>0.1”的靶点。
在GengCards及疾病基因数据库中以“lung cancer”为关键词、“Homosapiens”及“SCORE≥30”为条件检索并筛选肺癌疾病相关靶点。
在SwissTarget Prediction中检索整合得到本发明中药组合物的有效成分共包含603个药物靶点;在疾病基因数据库中检索并删除重复后得到765个肺癌疾病相关靶点。
2.3中药组合物治疗肺癌潜在靶点预测
将药物靶点与肺癌疾病相关靶点在Venny2.1中进行韦恩分析,以筛选出潜在治疗靶点;在STRIG11.5中绘制蛋白-蛋白互连作业网络图,并在Cytoscape3.9.1中可视化,同时应用MCODE插件筛选出功能模块及核心靶点。
将603个药物靶点与765个肺癌疾病相关靶点进行韦恩分析后得到108个潜在治疗靶点,见图8。在STRING中对108个靶点进行蛋白-蛋白互作网络分析并绘图,见图9。在Cytoscape中可视化,包含108个节点,2240条边,并使用cytoHubba筛选出top20的重要功能模块(主要包含20个节点,190条边),见图10,并取节点连接度排名前15的靶点绘制条形图,见图11。
2.4中药组合物治疗肺癌潜在相关靶点的功能富集分析及通路富集分析以“Homosapiens”为条件,在DAVID数据库中对潜在治疗靶点进行GO(Gene Ontology,GO)功能富集分析与KEGG(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析,其中“FDR(false discovery rate,FDR)<0.05”的条目有意义。
将得到的108个潜在治疗靶点进行GO功能富集分析后,得到189条结果,根据FDR值筛选后,得到符合要求的有140项,其中BP(biological process,BP)87项、CC(cellularcomponent,CC)14项和MF(molecular function,MF)39项,各取其前10个条目可视化分析,见图12。在BP方面,涉及蛋白质磷酸化及自磷酸化、MAPK级联的正向调节、肽基-酪氨酸磷酸化等;在CC中,涉及受体复合体、染色体端粒、铬质等;在MF方面,包含蛋白丝氨酸/苏氨酸/酪氨酸激酶活性、ATP结合、血红蛋白结合等。
将108个潜在治疗靶点进行KEGG通路富集分析后,共得到129条通路,其中有120条符合条件,取前20条通路可视化分析,主要PI3K-Akt信号通路AGE-RAGE及HIF-1等信号通路相关,见图13。
2.5中药组合物治疗肺癌的相关网络药理学分析
通过筛查,发现本发明中药组合物的主要有效成分有豆甾醇、β-谷甾醇、菠菜甾醇、顺式二十碳-11-烯酸、山柰酚、槲皮素等。其中,豆甾醇具有良好的抗炎、抗氧化与抗癌作用,可通过抑制肿瘤血管生成发展、炎性细胞作用与肿瘤细胞迁移的方式达到抑制肿瘤发生发展的作用。β-谷甾醇具有止咳祛痰、抑制肿瘤及修复组织的作用,可调控肺脏组织细胞凋亡并促进脂质体修复细胞,降低炎性因子反应改善纤维化及LPS诱导的急性肺损伤从而抑制肿瘤生长修复组织。顺式二十碳-11-烯酸可抑制ROS产生,调控ERK、STAT3信号通路进而抑制Kupffer细胞炎性反应以达抗炎作用。研究表明,山柰酚具有显著的抗炎、抗癌作用,可下调ERRα抑制肺癌A549细胞的侵袭迁移,并可通过下调UBF磷酸化水平调控rRNA转录与细胞增殖,抑制癌细胞增殖。菠菜甾醇可通过下调MAP激酶信号通路,抑制LPS诱导TNF-α、IL-6等炎症因子的产生从而减轻炎性损伤。槲皮素可增强16-HBE细胞活性,抑制细胞凋亡及TNF-α、IL-6等炎性因子分泌,还可激活PI3K-Akt信号通路上调P-AKT及PI3K3CA蛋白表达水平降低Caspase-s蛋白表达水平抑制颗粒细胞凋亡。
根据Degree值筛选,前列关键治疗靶点有TP53(抑癌基因转录因子)、EGFR(表皮生长因子受体)、VEGFA(血管内皮生长因子)等。与细胞癌变、炎症反应、血管生成等多个过程密切相关。抑癌基因转录因子TP53功能缺陷不仅会导致肿瘤发展,还会损害抗癌药物(如诱导DNA损伤的药物)的疗效,突变TP53蛋白可能无法激活由wt TP53控制的靶基因,致使对肿瘤的抑制作用受到负面影响以及获得(GOF)效应,从而失去对恶性细胞的持续增殖和存活的正常调控。表皮生长因子受体(EGFR)为ERBB家族受体之一。在肺腺癌肿瘤细胞中,ERBB受体信号传导失调致使癌细胞异常增殖并逃避程序性死亡,增强迁移转移能力。血管内皮生长因子(VEGF)是启动和调节血管生成的重要细胞因子,是最强的血管生成激活剂之一。VEGF-A是VEGF的一个亚型,在缺氧条件下,缺氧诱导因子(HIF-1α)释放VEGF,VEGF过度表达影响支气管细胞的细胞再调节和炎症反应,同时也与内皮细胞功能密切相关,VEGF蛋白是肺组织的维持因子,VEGF的过度表达显著影响了在T辅助性2型细胞介导的炎症反应(TH2)及细胞因子产生和气道重塑。
根据KEGG通路分析相关通路主要包括PI3K-Akt信号通路AGE-RAGE及HIF-1信号通路等。PI3K/AKT通路紊乱常见于肺癌确诊患者,该通路可通过受体酪氨酸激酶的突变激活或扩增以及调控PI3K p85亚基(PIK3R1和PIK3R2)失活,进而影响肺部组织细胞。PI3K-Akt及HIF-1信号通路可参与由缺氧诱导因子(HIFs)激活介导的表皮生长因子(EGFR)与肺组织中VEGF过表达,同时HIF-1转录元件可激活PIK3/AKT通路增加VEGF表达。此外,PI3K-Akt通路还通过内皮细胞一氧化氮信号调控血管生成过程。ANG1(血管生成素1)通过诱导内皮细胞的NOs磷酸化、NO生成和血管生成,激活PI3K通路,促进内皮细胞存活。癌细胞适应更高的葡萄糖摄取并因此持续暴露于主要参与AGE合成的高血糖状况,RAGE除在免疫细胞和肺组织中成型表达外,在癌细胞中也可诱导表达。AGEs与RAGE的结合激活MAPK、ERK 1/2、PI3K-Akt、JAK-STAT等多种信号传导途径,以及与细胞存活、炎症和癌症进展相关的NF-κB。低氧条件促进血管生成、侵袭、转移、耐药性表型,并限制癌症进展期间的凋亡机制。缺氧还诱导AGE-RAGE介导的HIF1α、NF-κB、ERK和Akt信号通路的活化,加快癌症的进展。AGE-RAGE信号传导的激活也产生氧自由基,引起氧化应激,并激活NF-κB,其分泌促炎细胞因子、生长因子和粘附分子如ICAM-1和VCAM-1,最终导致癌症进展。
实施例3治疗肺结节及肺癌的中药组合物的实际临床应用
肺结节病例1:王某,女,52岁,2022年8月20日首诊,诉发现肺部结节5月余。患者2022年3月检查胸部CT提示左肺上叶、右肺中叶小结节影,较大者左肺上叶,直径约7mm,边缘毛糙,同月行左肺上叶结节切除术,病理提示:浸润性肺癌。(2022-7-21)复查胸部CT提示:左肺上叶术后改变,可见条索影,右肺中叶磨玻璃结节影,约5×4mm。患者平素胸闷气短,易汗出、易怒,咽干,失眠多梦,胃胀胃酸,大便不成形,舌淡苔白腻有剥脱。给予本复方制剂加减口服,日一剂,早晚分服,服用本药4周后,患者复诊诉胸闷及胃口不适好转,脾气、睡眠改善,无不良反应。后继予给予本发明中药组合物加减辩证调整,随访2月,患者复查结节消散,(2022-10-27)胸部CT提示:左肺上叶术后改变,下叶可见条索影,余肺野内未见异常明显密度阴影。
肺结节病例2:闫某,女,46岁,2022年3月初首诊。患者诉发现肺结节1月余。患者于2022年2月9日在宁夏医学科大学总医院检查胸部CT发现右肺下叶前基底段小结节,CT提示:双肺多发条索影,结节直径约0.4cm。患者值围绝经期,平素烦躁易怒,易有烘热汗出,常有乏力,偶有咳嗽,入睡困难且失眠多梦较为严重,偶尔心悸伴随胸痛不适,饮食尚可,舌暗苔黄,脉滑数。给予本复方制剂加减口服,日一剂,早晚分服,服用本药4周后,患者复诊诉症状明显改善且无不良反应。后继予本发明中药组合物加减辩证调整,随访2月,患者复查结节消散,(2022-6-4)胸部CT提示:双肺野清晰,未见明确异常。
肺结节病例3:刘某,男,44岁,2022年6月25日首诊。患者诉发现肺结节1年余。平素常胸闷气短、乏力,咽干咽痛,时有咳嗽咳痰,痰黄有血丝,脾气急易生气,胃胀,舌黯苔白腻。既往冠心病2年余,浅表性胃炎多年。胸部CT提示(2022-3-8):右肺上叶后段混合磨玻璃结节,直径约0.9cm。给予本复方制剂加减口服,日一剂,早晚分服,服用本药4周后,患者复诊诉胸闷憋气乏力等症状好转,咳嗽咳痰明显减轻,一般情况均见改善且无不良反应。后继予本发明中药组合物加减辩证调整,随访2月余,患者复查结节减小,(2022-10-11)胸部CT提示:右肺上叶磨玻璃小结节,直径07mm,边缘模糊,建议3-6个月复查。
肺癌病例1:芦某,男,62岁,2020年8月就诊,确诊小细胞肺癌中晚期,胸部CT示:右肺上叶肿物影55×40mm,分叶状伴毛刺,牵拉胸膜。患者平素干咳,偶有胸闷气短,乏力,纳眠差,小便可,大便秘结。患者规律进行抗癌与中药经验清肺方加减口服治疗,天葵子12g白毛藤20g红景天10g莪术10g白花蛇舌草30g桔梗10g牛膝10预知子10g山慈菇20g浙贝母15g半夏10g天花粉15g生地10g麦冬10g海浮石30g旋覆花10g北沙参20g党参15g黄芪15g陈皮12g木香10g砂仁6g枳实10g厚朴10g柏子仁10g酸枣仁15g火麻仁15g五味子5g炙甘草6g,日一剂,早晚分服,服用本药4周后,患者病情稳定,症状均见好转,无不良反应。后继予经验清肺方加减辩证调整,定期随访,患者定期复查,2021-12-29胸部CT提示:右肺叶高密度影较前略显缩小,余大致同前。
肺癌病例2:李某,女,64岁,肺腺癌晚期并继发脑转移。患者2011年确诊并规律治疗,于2020年5月因病情进展就诊于我院,2020-7查胸部CT发现右肺上叶7×6mm高密度结节影,双肺纤维索条影,右肺下叶条片状高密度影。患者干咳,间断头晕、乏力,右侧肢体麻木、活动不利伴关节疼痛,时有反酸烧心,纳差,小便可,大便秘结,舌黯苔白腻,脉弦涩。予经验清肺方加减口服,天葵子10g白毛藤15g红景天15g莪术10g白花蛇舌草30g桔梗10g牛膝10预知子10g山慈菇15g浙贝母12g生地15g熟地15g海浮石15g旋覆花10g党参15g黄芪30g五味子5g半夏12g天花粉15g蒲公英30g羌活12g独活12g白芍12g当归15g桃仁10g红花6g地龙10g酒黄芩10g酒大黄6g黄连5g麦冬10g陈皮10g炙甘草6g,日一剂,早晚分服,服用本药4周后,患者复诊诉症状稍改善,现病情相对平稳且无不良反应。后继予清肺散结方加减辩证调整,定期随访,患者坚持服药,期间规律复查,至2022-3-21仍病情稳定,胸部CT提示:双肺纤维索条影,右肺下叶条片状高密度影,右肺上叶7×6mm高密度结节影。病情稳定。
肺癌病例3:吴某,女,44岁,2019年9月确诊肺腺癌,规律治疗。2020年6月因病情进展于我院就诊,症见咳嗽咳痰,痰白质黏,乏力,间断恶心呕吐,纳眠差,二便尚可,舌淡黯苔白腻,脉濡细。胸部CT提示(2020-6-30):右侧胸腔大量也行密度影,左肺下叶背段团片状高密度影,相邻胸膜增厚,左肺下叶条索状高密度影。予经验清肺方加减口服,天葵子10g白毛藤20g红景天10g莪术10g白花蛇舌草30g桔梗10g牛膝10预知子10g山慈菇20g浙贝母15g柴胡12g黄芩10g枳壳10g陈皮10半夏12g款冬花15g海浮石15g旋覆花10g黄芪30g党参15g五味子5g陈皮15g,木香10g,砂仁5g,日一剂,早晚分服,服用本药2周后,患者诉病情改善且无不良反应,胸部CT提示:右肺肿块较前似略有缩小。后继予经验清肺方加减辩证调整,随访月余,患者2020-12-23胸部CT提示:右肺肿块较前明显缩小,左肺下叶残存纤维条索。病情好转。
肺癌病例4:王某,女,52岁,2022年8月就诊,发现肺部结节5月余。患者2022年3月检查胸部CT提示左肺上叶、右肺中叶小结节影,较大者左肺上叶,直径约7mm,边缘毛糙,同月行左肺上叶结节切除术,病理提示:浸润性肺癌。(2022-7-21)复查胸部CT提示:左肺上叶术后改变,可见条索影,右肺中叶磨玻璃结节影,约5×4mm。患者平素胸闷气短,易汗出、易怒,咽干,失眠多梦,胃胀胃酸,大便不成形,舌淡苔白腻有剥脱。予经验清肺方加减口服,天葵子10g白毛藤10g红景天15g莪术10g白花蛇舌草30g桔梗10g牛膝10预知子10g山慈菇10g浙贝母20g半夏10g天花粉15g海浮石30g旋覆花10g黄芪30g陈皮10g木香10g砂仁3g枳实10g薤白10g柴胡10g桃仁10g黄芩10g五味子5g,日一剂,早晚分服,服用本药4周后,患者复诊诉胸闷及胃口不适好转,脾气、睡眠改善,无不良反应。后继予清肺散结方加减辩证调整,随访2月,患者复查结节消散,(2022-10-27)胸部CT提示:左肺上叶术后改变,下叶可见条索影,余肺野内未见异常明显密度阴影。
虽然在实施例中已经通过一般性说明、具体实施方式及试验对本发明作出了详尽的描述,但在不偏离本发明核心的基础上,仍可以作出的修改或改进,均属于本发明要求保护的范围。
Claims (7)
1.一种治疗肺结节及肺癌的中药组合物,其特征在于,所述中药组合物由如下重量份的原料药组成:天葵子5-25份、白英5-25份、红景天5-25份、莪术10-20份、白花蛇舌草10-30份、桔梗5-15份、牛膝5-25份、预知子10-30份、山慈菇10-30份、浙贝母10-30份、半夏5-15份、天花粉10-30份。
2.根据权利要求1所述的治疗肺结节及肺癌的中药组合物,其特征在于,所述中药组合物由如下重量份的原料药组成:天葵子10份、白英10份、红景天12份、莪术10份、白花蛇舌草30份、桔梗6份、牛膝10份、预知子10份、山慈菇10份、浙贝母20份、半夏9份、天花粉15份。
3.一种治疗肺结节及肺癌的中药制剂,其特征在于,所述中药制剂由权利要求1-2任一项所述的治疗肺结节及肺癌的中药组合物制备得到。
4.根据权利要求3所述的治疗肺结节及肺癌的中药制剂,其特征在于,所述中药制剂为汤剂,所述汤剂按照如下步骤制备得到:
(1)按照重量份称取原料药,加入5-10倍重量份的水浸泡30-120分钟;
(2)将浸泡后的原料药连水一同加热煎煮,过滤,收集滤液;
(3)将滤渣重新加入5-10倍重量份的水,煎煮,过滤,收集滤液;
(4)将两次煎煮后过滤得到的滤液合并,加热浓缩,即得汤剂。
5.根据权利要求4所述的治疗肺结节及肺癌的中药制剂,其特征在于,两次煎煮的时间均为30-60分钟。
6.根据权利要求4所述的治疗肺结节及肺癌的中药制剂,其特征在于,滤液合并后加热浓缩至原体积的10%-20%。
7.根据权利要求1-2任一项所述的治疗肺结节及肺癌的中药组合物在制备治疗肺结节及肺癌的药物中的应用。
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