中药蛋白酶抑制剂的筛选及防治急性肺损伤作用研究
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摘要
蛋白酶抑制剂(PI)广泛存在于动植物和微生物中,在体内能抑制蛋白水解酶活性,在许多疾病及病理过程中有控制作用,如与炎症、血液凝固、补体级联反应、细胞调亡、激素调节等;现代药理研究表明鱼腥草具有增强机体免疫、抗病毒和抑癌等作用,临床主要用于治疗呼吸系统疾病如治疗肺痈吐脓、痰热喘咳,肺及气管病变(气管炎、肺炎、支气管扩张、百日咳)。急性肺损伤(ALI)是急性呼吸窘迫综合征(ARDS)或多脏器功能衰竭(MOF)的早期阶段,是指由各种肺内、外致病因素导致的急性进行性缺氧性呼吸衰竭。ALI的发病率和死亡率很高,在美国每年大约有10万人发生ARDS,其病死率高达50～70%,是临床上常见的死亡率极高的危重症之一,是目前医学界研究的一个热点。为在中药中寻找出安全有效的植物源蛋白酶抑制剂,并探讨其作用和机理,本研究对60种中药蛋白酶抑制剂的活性进行了筛选,并对鱼腥草蛋白酶抑制剂组分防治急性肺损伤的作用和机理进行了研究,以期为临床用药提供科学依据。本论文的主要研究内容和结果如下:
1具有蛋白酶抑制剂活性的中药筛选
本实验以胰蛋白酶为底物,以大豆胰蛋白酶抑制剂为对照,对临床应用较广的60种中药配方颗粒,大黄、鱼腥草、麻黄、白芍、瓜蒌皮5种药材的水、乙醇提取物的体外蛋白酶的抑制作用以及这5种中药的水提取物进入体内的蛋白酶抑制剂活性进行了研究。研究结果显示:
(1)蛋白酶抑制剂活性较强的中药集中在发散风寒药及清热解毒药中。60种中药配方颗粒中有13种中药在100mg·mL-1时蛋白酶抑制作用较强,依次为三七、麻黄、大黄、白芍、鱼腥草等;有9种中药在50mg·mL-1浓度下蛋白酶抑制作用较强,依次为茯苓、大黄、山豆根、麻黄、白芍、鱼腥草、连翘等;其中麻黄、大黄、鱼腥草、白芍、连翘5种中药在上述两浓度下均表现出蛋白酶抑制作用。
(2)大黄、鱼腥草水提取液,麻黄、白芍的70%乙醇提取液的体外蛋白酶的抑制作用较强。大黄、鱼腥草、麻黄3种中药水提取液和70%乙醇提取液均有较强的蛋白酶抑制作用,瓜蒌皮的蛋白酶抑制作用不明显。
(3)大黄、鱼腥草、麻黄、白芍、瓜蒌皮水提取物大鼠灌胃给药,大黄、鱼腥草的含药血浆对胰蛋白酶的抑制作用较强,瓜蒌皮水提取物对胰蛋白酶的抑制作用不明显。
2鱼腥草蛋白酶抑制剂组分的分离
本实验采用正交试验的方法,考查了影响鱼腥草水提取物蛋白酶抑制活性的因素,确定了最佳提取条件为60℃,加30倍量水,在pH 9下煎煮3h,并以此条件对鱼腥草进行提取,水提液减压浓缩,离心除去沉淀,上清液氯仿萃取,水层过滤除去沉淀后过大孔树脂,分别用水、30%,50%,70%,95%乙醇洗脱大孔树脂,得组分1、2、3、4、5。氯仿层过离子交换树脂,氨水洗脱,得组分6。
经试管法和薄层色谱法定性鉴别,组分1为多糖和苷类物质,组分2、3、4、5为黄酮类物质、组分6为生物碱。测定各组分对蛋白酶活性的抑制,结果表明:蛋白酶抑制剂活性最强的为组分6(生物碱),其次是组分1(多糖类)和组分2、3、4、5(黄酮类)。
3鱼腥草蛋白酶抑制剂防治LPS诱导的大鼠急性肺损伤实验研究
本实验采用LPS诱导的大鼠急性肺损伤(ALI)模型,研究鱼腥草蛋白酶抑制剂对ALI的防治作用。结果显示:鱼腥草蛋白酶抑制剂能减轻LPS诱导的急性肺损伤大鼠肺间质增厚,减少肺间质和肺泡腔内出血、水肿及渗出物,降低肺间质中胶原纤维含量,减轻肺组织纤维性增生,改善肺损伤症状;鱼腥草蛋白酶抑制剂能显著降低ALI大鼠肺泡灌洗液中MDA含量及血清中IL-6、IL-8及TNF-α水平;有显著降低ALI大鼠肺组织中HYP含量的趋势;显著下调ALI大鼠肺组织中MMP-2、MMP-9的含量和蛋白质表达。说明鱼腥草蛋白酶抑制剂对ALI有一定的防治作用,其作用的机理可能是阻止了急性肺损伤的早期阶段脂质过氧化过程,通过减少氧自由基和炎性因子的释放,降低MMPs的活性,减少肺组织的损伤。
4基因芯片技术研究鱼腥草蛋白酶抑制剂对A549细胞基因表达谱的影响
本实验采用肺泡上皮来源的A549癌细胞株替代肺泡Ⅱ型上皮细胞,用基因芯片技术检测了鱼腥草蛋白酶抑制剂对A549细胞基因表达谱的影响。结果表明:有明显差异表达的基因共有204条,占总检测基因数的1.3 %。其中上调的基因有139条,表达下调的基因有65条;与凋亡相关的基因上调的有25条,下调的有7条。在表达上调的基因中与细胞凋亡相关的基因其主要功能以下列形式出现:信号转导、肿瘤抑制、蛋白表边转录因子、细胞分裂/细胞凋亡、细胞骨架/运动蛋白、新陈代谢/蛋白质水解、细胞因子/化学因子、膜蛋白、转录相关蛋白和蛋白酶抑制剂等。在表达下调的基因中与细胞凋亡相关的基因其主要功能以下列形式出现:细胞分裂/细胞凋亡、信号转导、细胞周期和癌基因等。说明鱼腥草蛋白酶抑制剂对细胞结构和功能基因、细胞信号转导相关基因、细胞代谢基因、转录和转录因子类基因以及蛋白质翻译合成类相关基因有调节作用。
结论:蛋白酶抑制剂活性较强的中药集中在发散风寒药及清热解毒药,其中作用明显的有:三七、大黄、鱼腥草、麻黄、白芍、茯苓、山豆根、连翘等;鱼腥草含有蛋白酶抑制剂活性组分,蛋白酶抑制剂活性最强的为生物碱,其次是多糖或糖苷,极性强的黄酮类成分,蛋白酶抑制剂活性较强,弱极性的黄酮类化合物,蛋白酶抑制剂活性相对较弱;鱼腥草蛋白酶抑制剂能降低急性肺损伤大鼠肺组织脂质过氧化水平,增强抗氧化能力,减少氧自由基和炎性因子的释放,降低肺组织中MMP-2、MMP-9的活性,从而对急性肺损伤有一定的防治作用;鱼腥草蛋白酶抑制剂对肺泡上皮细胞来源的A549细胞的细胞结构和功能基因、细胞信号转导相关基因、细胞代谢基因、转录和转录因子类基因以及蛋白质翻译合成类相关基因有调节作用。
Proteinase inhibitors are ubiquitously distributed in the animal, plant and microorganism kingdoms, and could bind with relevant target proteinase to form specific protein-protein complex, cause competitive inhibiting effect, decrease enzyme activity, form a certain dynamic balance, play key regulatory roles in many biological processes, including the blood coagulation system, the complement cascade ,apoptosis and the hormone processing pathways. According to modern pharmacological research, Herba houttuyniae could strengthen immune function, resist virus, and inhibit cancer;it was mainly clinically applicable to treat respiratory diseases, such as pulmonary abscess, premises, hot sputum, asthma cough, bronchitis, pneumonia, bronchiectasis, and pertussis. Acute lung injury (ALI) was early stage of Acute Respiratory Distress Syndrome (ARDS) or Multisystem Organs Failure (MOF), and was the acute progressive anoxic respiratory failure caused by various factors inside and outside the lung. ALI was of very high morbidity rate and mortality rate, and ARDS occurred annually in about 100,000 American people with a mortality rate of up to 50～70%, and was a focus of recent medical research.
This test aimed to find out safe effective vegetable proteinase inhibitor from TCM materials, and explore its effect and mechanism. It screened the activity of 60 TCM proteinase inhibitors, and studied the effect and mechanism of Herba houttuyniae proteinase inhibitor (HHPI) compositions for ALI prevention & treatment, so as to provide scientific basis for clinical drug application. Its main research contents and results were summarized as follows:
1. Screen TCM materials with activity of proteinase inhibitor
This test studied the in vitro trypsin inhibiting effect of water and 70% ethanol extract of 60 decoction-free TCM materials granule and 5 TCM materials (Rhubarb, Herba houttuyniae, Ephedra, White peony, and Mongolian snakegourd peel), and the in vivo trypsin inhibitor activity of these 5 TCM materials through the substrate of trypsin and the control of soybean trypsin inhibitor. All these test
TCM materials granules and TCM materials were of wider clinical application.
(1) TCM materials of stronger proteinase inhibitor activity mainly occurred in wind/cold-dispersing drugs and heat/toxin clearing drugs. Among 60 test TCM materials granules, trypsin inhibiting effect was stronger at 100mg/mL dose in 13 TCM materials (i.e. pseudo-ginseng, Ephedra, Rhubarb, white peony, and Herba houttuyniae from strongest to weakest effect), stronger at 50mg/mL dose in 9 TCM materials (i.e. Tuckahoe, Rhubarb, subprostrate sophora, Ephedra, white peony, Herba houttuyniae, and Forsythia from stronger to weaker effect), and evident at both above concentrations in 5 TCM materials (i.e. Ephedra, Rhubarb, Herba houttuyniae, white peony, and Forsythia).
(2) In vitro trypsin inhibiting effect was stronger in water extract of Rhubarb/Herba houttuyniae and 70% ethanol extract of Ephedra/white peony, stronger in both extracts of Rhubarb/Herba houttuyniae/Ephedra, and not evident in Mongolian snakegourd peel.
(3) After the gavage of their water extract in rats, compared with that in Ephedra and White peony, trypsin inhibiting effect was stronger in vitro plasma containing Rhubarb and Herba houttuyniae, and not evident in water extract of Mongolian snakegourd peel.
2. Separate HHPI compositions
This test studied, through orthogonal test, the effect of Herba houttuyniae water extract on proteinase inhibiting activity under 4 extracting conditions (i.e. extracting temperature, decoction time, solution volume, and solution pH), and finally found out optimal extraction conditions (i.e. 60℃, water addition by 30 times, 3h decoction, and pH9). Extract Herba houttuyniae under this optimal condition, concentrate water extract at reduced pressure, centrifuge, remove sediment, extract supernatant with chloroform, filter water layer, remove sediment, pass through macroporous resin, elute with deionized water until no sediment with 95% ethanol in elution, concentrate elution at reduced pressure, add 95% ethanol until 75% alcohol content, freeze for overnight, filter, elute sediment repeatedly with ethanol and acetone until colorless elution, dry at low temperature, and obtain Composition 1. Elute macroporous resin with 30%, 50%, 70% and 95% ethanol respectively until colorless elution, recover ethanol at reduced pressure, dry concentrated solution at reduced pressure and vacuum state, and obtain Composition 2, 3, 4, and 5 respectively. Pass chloroform layer through ion exchange resin, elute with ammonia water, collect elution, concentrate at reduced pressure, dry at vacuum state, and obtain Composition 6.
By assaying qualitatively through test tube method and TLC, Composition 1 was polysaccharides and glycosides, Composition 2, 3, 4 and 5 were flavones, and Composition 6 was alkaloids. As shown by assaying the inhibition of 1mg/mL crude extract of each composition on trypsin activity, the proteinase inhibitor activity occurred in Composition 6 (alkaloid), Composition 1 (polysaccharide), and Composition 2, 3, 4 and 5 (flavones) respectively in the order from strongest activity to weakest activity.
3. Test on prevention & treatment of LPS-induced ALI with HHPI compositions in rats
This test studied the prevention & treatment effect of HHPI compositions on ALI through LPS-induced ALI rat model. As shown by the test results, HHPI could alleviate pulmonary mesenchyme thickening, reduce hemorrhage/ edema/exudates in pulmonary mesenchyme and alveolar cavity, decrease collagen fiber content in pulmonary mesenchyme, alleviate fibrous proliferation of lung tissue, improve lung injury symptoms, decrease significantly MDA content in bronchoalveolar lavage fluid and IL-6, IL-8 and TNF-αlevel in serum, tend to significantly decrease HYP content in lung tissue, and down-regulate MMP-2 and MMP-9 content and protein expression in lung tissue. Thus, HHPI had a certain effect of ALI prevention & treatment, possibly by blocking the lipid peroxidation process at early stage of ALI, reducing the release of oxygen free radical and inflammatory factor, decreasing MMPs activity, and reducing injury of lung tissue.
4. Test of HHPI effect on gene expression spectrum of A549 cells (gene chip technique)
This test detected the effect of HHPI compositions on gene expression spectrum of A549 cells through gene chip technique by replacing Type II alveolar epithelial cells with A549 cancer cells strain in alveolar epithelium. As shown by the test results, among all 15552 detected genes, there were 204 genes (1.3%) of significantly different expression (including 139 up-regulated ones and 65 down-regulated ones);and among apoptosis-related genes, there were 25 up-regulated ones and 7 down-regulated ones. Apoptosis-related genes at up-regulated expression mainly existed in the following functional types: signal transduction, tumor inhibition, protein transcription factor, cell division/cell apoptosis, cell skeleton/movement protein, body defense/heat shock protein, DNA injury/repair, metabolism/proteolysis, cell factor/chemical factor, membrane protein, enzyme/cancer gene/cell cycle, transcription-related protein, and proteinase inhibitor. Apoptosis-related genes at down-regulated expression mainly existed in the following functional types: cell division/cell apoptosis, signal transduction, cell division, cell cycle, and cancer gene. HHPI could regulate various genes related to cell structure/function, cell signal transduction, cell metabolism, transcription, transcription factor, and protein translation/synthesis.
To sum up, TCM materials of stronger proteinase inhibitor activity mainly occurred in wind/cold-dispersing drugs and heat/toxin clearing drugs. (i.e.pseudo-ginseng, Ephedra, Rhubarb, white peony, Herba houttuyniae ,Tuckahoe, subprostrate sophora, and Forsythia). As shown by assaying the inhibition of each composition on trypsin activity, the Herba houttuyniae proteinase inhibitor activity occurred in alkaloid, polysaccharide, and flavones respectively in the order from strongest activity to weakest activity. HHPI had a certain effect of ALI prevention & treatment, possibly by blocking the lipid peroxidation process at early stage of ALI, reducing the release of oxygen free radical and inflammatory factor, decreasing MMPs activity, and reducing injury of lung tissue. HHPI could regulate various genes related to cell structure/function, cell signal transduction, cell metabolism, transcription, transcription factor, and protein translation/synthesis.
1具有蛋白酶抑制剂活性的中药筛选
本实验以胰蛋白酶为底物,以大豆胰蛋白酶抑制剂为对照,对临床应用较广的60种中药配方颗粒,大黄、鱼腥草、麻黄、白芍、瓜蒌皮5种药材的水、乙醇提取物的体外蛋白酶的抑制作用以及这5种中药的水提取物进入体内的蛋白酶抑制剂活性进行了研究。研究结果显示:
(1)蛋白酶抑制剂活性较强的中药集中在发散风寒药及清热解毒药中。60种中药配方颗粒中有13种中药在100mg·mL-1时蛋白酶抑制作用较强,依次为三七、麻黄、大黄、白芍、鱼腥草等;有9种中药在50mg·mL-1浓度下蛋白酶抑制作用较强,依次为茯苓、大黄、山豆根、麻黄、白芍、鱼腥草、连翘等;其中麻黄、大黄、鱼腥草、白芍、连翘5种中药在上述两浓度下均表现出蛋白酶抑制作用。
(2)大黄、鱼腥草水提取液,麻黄、白芍的70%乙醇提取液的体外蛋白酶的抑制作用较强。大黄、鱼腥草、麻黄3种中药水提取液和70%乙醇提取液均有较强的蛋白酶抑制作用,瓜蒌皮的蛋白酶抑制作用不明显。
(3)大黄、鱼腥草、麻黄、白芍、瓜蒌皮水提取物大鼠灌胃给药,大黄、鱼腥草的含药血浆对胰蛋白酶的抑制作用较强,瓜蒌皮水提取物对胰蛋白酶的抑制作用不明显。
2鱼腥草蛋白酶抑制剂组分的分离
本实验采用正交试验的方法,考查了影响鱼腥草水提取物蛋白酶抑制活性的因素,确定了最佳提取条件为60℃,加30倍量水,在pH 9下煎煮3h,并以此条件对鱼腥草进行提取,水提液减压浓缩,离心除去沉淀,上清液氯仿萃取,水层过滤除去沉淀后过大孔树脂,分别用水、30%,50%,70%,95%乙醇洗脱大孔树脂,得组分1、2、3、4、5。氯仿层过离子交换树脂,氨水洗脱,得组分6。
经试管法和薄层色谱法定性鉴别,组分1为多糖和苷类物质,组分2、3、4、5为黄酮类物质、组分6为生物碱。测定各组分对蛋白酶活性的抑制,结果表明:蛋白酶抑制剂活性最强的为组分6(生物碱),其次是组分1(多糖类)和组分2、3、4、5(黄酮类)。
3鱼腥草蛋白酶抑制剂防治LPS诱导的大鼠急性肺损伤实验研究
本实验采用LPS诱导的大鼠急性肺损伤(ALI)模型,研究鱼腥草蛋白酶抑制剂对ALI的防治作用。结果显示:鱼腥草蛋白酶抑制剂能减轻LPS诱导的急性肺损伤大鼠肺间质增厚,减少肺间质和肺泡腔内出血、水肿及渗出物,降低肺间质中胶原纤维含量,减轻肺组织纤维性增生,改善肺损伤症状;鱼腥草蛋白酶抑制剂能显著降低ALI大鼠肺泡灌洗液中MDA含量及血清中IL-6、IL-8及TNF-α水平;有显著降低ALI大鼠肺组织中HYP含量的趋势;显著下调ALI大鼠肺组织中MMP-2、MMP-9的含量和蛋白质表达。说明鱼腥草蛋白酶抑制剂对ALI有一定的防治作用,其作用的机理可能是阻止了急性肺损伤的早期阶段脂质过氧化过程,通过减少氧自由基和炎性因子的释放,降低MMPs的活性,减少肺组织的损伤。
4基因芯片技术研究鱼腥草蛋白酶抑制剂对A549细胞基因表达谱的影响
本实验采用肺泡上皮来源的A549癌细胞株替代肺泡Ⅱ型上皮细胞,用基因芯片技术检测了鱼腥草蛋白酶抑制剂对A549细胞基因表达谱的影响。结果表明:有明显差异表达的基因共有204条,占总检测基因数的1.3 %。其中上调的基因有139条,表达下调的基因有65条;与凋亡相关的基因上调的有25条,下调的有7条。在表达上调的基因中与细胞凋亡相关的基因其主要功能以下列形式出现:信号转导、肿瘤抑制、蛋白表边转录因子、细胞分裂/细胞凋亡、细胞骨架/运动蛋白、新陈代谢/蛋白质水解、细胞因子/化学因子、膜蛋白、转录相关蛋白和蛋白酶抑制剂等。在表达下调的基因中与细胞凋亡相关的基因其主要功能以下列形式出现:细胞分裂/细胞凋亡、信号转导、细胞周期和癌基因等。说明鱼腥草蛋白酶抑制剂对细胞结构和功能基因、细胞信号转导相关基因、细胞代谢基因、转录和转录因子类基因以及蛋白质翻译合成类相关基因有调节作用。
结论:蛋白酶抑制剂活性较强的中药集中在发散风寒药及清热解毒药,其中作用明显的有:三七、大黄、鱼腥草、麻黄、白芍、茯苓、山豆根、连翘等;鱼腥草含有蛋白酶抑制剂活性组分,蛋白酶抑制剂活性最强的为生物碱,其次是多糖或糖苷,极性强的黄酮类成分,蛋白酶抑制剂活性较强,弱极性的黄酮类化合物,蛋白酶抑制剂活性相对较弱;鱼腥草蛋白酶抑制剂能降低急性肺损伤大鼠肺组织脂质过氧化水平,增强抗氧化能力,减少氧自由基和炎性因子的释放,降低肺组织中MMP-2、MMP-9的活性,从而对急性肺损伤有一定的防治作用;鱼腥草蛋白酶抑制剂对肺泡上皮细胞来源的A549细胞的细胞结构和功能基因、细胞信号转导相关基因、细胞代谢基因、转录和转录因子类基因以及蛋白质翻译合成类相关基因有调节作用。
Proteinase inhibitors are ubiquitously distributed in the animal, plant and microorganism kingdoms, and could bind with relevant target proteinase to form specific protein-protein complex, cause competitive inhibiting effect, decrease enzyme activity, form a certain dynamic balance, play key regulatory roles in many biological processes, including the blood coagulation system, the complement cascade ,apoptosis and the hormone processing pathways. According to modern pharmacological research, Herba houttuyniae could strengthen immune function, resist virus, and inhibit cancer;it was mainly clinically applicable to treat respiratory diseases, such as pulmonary abscess, premises, hot sputum, asthma cough, bronchitis, pneumonia, bronchiectasis, and pertussis. Acute lung injury (ALI) was early stage of Acute Respiratory Distress Syndrome (ARDS) or Multisystem Organs Failure (MOF), and was the acute progressive anoxic respiratory failure caused by various factors inside and outside the lung. ALI was of very high morbidity rate and mortality rate, and ARDS occurred annually in about 100,000 American people with a mortality rate of up to 50～70%, and was a focus of recent medical research.
This test aimed to find out safe effective vegetable proteinase inhibitor from TCM materials, and explore its effect and mechanism. It screened the activity of 60 TCM proteinase inhibitors, and studied the effect and mechanism of Herba houttuyniae proteinase inhibitor (HHPI) compositions for ALI prevention & treatment, so as to provide scientific basis for clinical drug application. Its main research contents and results were summarized as follows:
1. Screen TCM materials with activity of proteinase inhibitor
This test studied the in vitro trypsin inhibiting effect of water and 70% ethanol extract of 60 decoction-free TCM materials granule and 5 TCM materials (Rhubarb, Herba houttuyniae, Ephedra, White peony, and Mongolian snakegourd peel), and the in vivo trypsin inhibitor activity of these 5 TCM materials through the substrate of trypsin and the control of soybean trypsin inhibitor. All these test
TCM materials granules and TCM materials were of wider clinical application.
(1) TCM materials of stronger proteinase inhibitor activity mainly occurred in wind/cold-dispersing drugs and heat/toxin clearing drugs. Among 60 test TCM materials granules, trypsin inhibiting effect was stronger at 100mg/mL dose in 13 TCM materials (i.e. pseudo-ginseng, Ephedra, Rhubarb, white peony, and Herba houttuyniae from strongest to weakest effect), stronger at 50mg/mL dose in 9 TCM materials (i.e. Tuckahoe, Rhubarb, subprostrate sophora, Ephedra, white peony, Herba houttuyniae, and Forsythia from stronger to weaker effect), and evident at both above concentrations in 5 TCM materials (i.e. Ephedra, Rhubarb, Herba houttuyniae, white peony, and Forsythia).
(2) In vitro trypsin inhibiting effect was stronger in water extract of Rhubarb/Herba houttuyniae and 70% ethanol extract of Ephedra/white peony, stronger in both extracts of Rhubarb/Herba houttuyniae/Ephedra, and not evident in Mongolian snakegourd peel.
(3) After the gavage of their water extract in rats, compared with that in Ephedra and White peony, trypsin inhibiting effect was stronger in vitro plasma containing Rhubarb and Herba houttuyniae, and not evident in water extract of Mongolian snakegourd peel.
2. Separate HHPI compositions
This test studied, through orthogonal test, the effect of Herba houttuyniae water extract on proteinase inhibiting activity under 4 extracting conditions (i.e. extracting temperature, decoction time, solution volume, and solution pH), and finally found out optimal extraction conditions (i.e. 60℃, water addition by 30 times, 3h decoction, and pH9). Extract Herba houttuyniae under this optimal condition, concentrate water extract at reduced pressure, centrifuge, remove sediment, extract supernatant with chloroform, filter water layer, remove sediment, pass through macroporous resin, elute with deionized water until no sediment with 95% ethanol in elution, concentrate elution at reduced pressure, add 95% ethanol until 75% alcohol content, freeze for overnight, filter, elute sediment repeatedly with ethanol and acetone until colorless elution, dry at low temperature, and obtain Composition 1. Elute macroporous resin with 30%, 50%, 70% and 95% ethanol respectively until colorless elution, recover ethanol at reduced pressure, dry concentrated solution at reduced pressure and vacuum state, and obtain Composition 2, 3, 4, and 5 respectively. Pass chloroform layer through ion exchange resin, elute with ammonia water, collect elution, concentrate at reduced pressure, dry at vacuum state, and obtain Composition 6.
By assaying qualitatively through test tube method and TLC, Composition 1 was polysaccharides and glycosides, Composition 2, 3, 4 and 5 were flavones, and Composition 6 was alkaloids. As shown by assaying the inhibition of 1mg/mL crude extract of each composition on trypsin activity, the proteinase inhibitor activity occurred in Composition 6 (alkaloid), Composition 1 (polysaccharide), and Composition 2, 3, 4 and 5 (flavones) respectively in the order from strongest activity to weakest activity.
3. Test on prevention & treatment of LPS-induced ALI with HHPI compositions in rats
This test studied the prevention & treatment effect of HHPI compositions on ALI through LPS-induced ALI rat model. As shown by the test results, HHPI could alleviate pulmonary mesenchyme thickening, reduce hemorrhage/ edema/exudates in pulmonary mesenchyme and alveolar cavity, decrease collagen fiber content in pulmonary mesenchyme, alleviate fibrous proliferation of lung tissue, improve lung injury symptoms, decrease significantly MDA content in bronchoalveolar lavage fluid and IL-6, IL-8 and TNF-αlevel in serum, tend to significantly decrease HYP content in lung tissue, and down-regulate MMP-2 and MMP-9 content and protein expression in lung tissue. Thus, HHPI had a certain effect of ALI prevention & treatment, possibly by blocking the lipid peroxidation process at early stage of ALI, reducing the release of oxygen free radical and inflammatory factor, decreasing MMPs activity, and reducing injury of lung tissue.
4. Test of HHPI effect on gene expression spectrum of A549 cells (gene chip technique)
This test detected the effect of HHPI compositions on gene expression spectrum of A549 cells through gene chip technique by replacing Type II alveolar epithelial cells with A549 cancer cells strain in alveolar epithelium. As shown by the test results, among all 15552 detected genes, there were 204 genes (1.3%) of significantly different expression (including 139 up-regulated ones and 65 down-regulated ones);and among apoptosis-related genes, there were 25 up-regulated ones and 7 down-regulated ones. Apoptosis-related genes at up-regulated expression mainly existed in the following functional types: signal transduction, tumor inhibition, protein transcription factor, cell division/cell apoptosis, cell skeleton/movement protein, body defense/heat shock protein, DNA injury/repair, metabolism/proteolysis, cell factor/chemical factor, membrane protein, enzyme/cancer gene/cell cycle, transcription-related protein, and proteinase inhibitor. Apoptosis-related genes at down-regulated expression mainly existed in the following functional types: cell division/cell apoptosis, signal transduction, cell division, cell cycle, and cancer gene. HHPI could regulate various genes related to cell structure/function, cell signal transduction, cell metabolism, transcription, transcription factor, and protein translation/synthesis.
To sum up, TCM materials of stronger proteinase inhibitor activity mainly occurred in wind/cold-dispersing drugs and heat/toxin clearing drugs. (i.e.pseudo-ginseng, Ephedra, Rhubarb, white peony, Herba houttuyniae ,Tuckahoe, subprostrate sophora, and Forsythia). As shown by assaying the inhibition of each composition on trypsin activity, the Herba houttuyniae proteinase inhibitor activity occurred in alkaloid, polysaccharide, and flavones respectively in the order from strongest activity to weakest activity. HHPI had a certain effect of ALI prevention & treatment, possibly by blocking the lipid peroxidation process at early stage of ALI, reducing the release of oxygen free radical and inflammatory factor, decreasing MMPs activity, and reducing injury of lung tissue. HHPI could regulate various genes related to cell structure/function, cell signal transduction, cell metabolism, transcription, transcription factor, and protein translation/synthesis.
引文
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