CN104244937B - 含ramalin的用于预防或治疗肝纤维化和肝硬化的药物组合物 - Google Patents
含ramalin的用于预防或治疗肝纤维化和肝硬化的药物组合物 Download PDFInfo
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- CN104244937B CN104244937B CN201280072479.9A CN201280072479A CN104244937B CN 104244937 B CN104244937 B CN 104244937B CN 201280072479 A CN201280072479 A CN 201280072479A CN 104244937 B CN104244937 B CN 104244937B
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Abstract
提供了ramalin用于预防或治疗肝病的新用途，更具体而言，一种含有ramalin或其药物学上可接受的盐的用于预防或治疗肝纤维化或肝硬化的药物组合物，以及一种含有同样成分的功能性食品。经证实在应用作为根据本发明的来自孔树花的化合物ramalin时，对于动物模型而言，与已知作为肝细胞保护成分的水飞蓟素相比，ramalin可显著地抑制肝纤维化并降低肝硬化水平，而对正常肝细胞没有细胞毒性，从而ramalin可有效地用于预防或治疗肝纤维化和肝硬化。
Description
技术领域
本发明涉及ramalin在预防或治疗肝病方面的新应用，更具体而言，涉及一种含ramalin或其药物学上可接受的盐的用于预防或治疗肝纤维化或肝硬化的药物组合物，以及一种含有同样成分的功能性食品。
背景技术
已知地衣产生与较高等植物的次级代谢物不同的独特次级代谢物(Ingolfsdottir,K.,Phytochemistry,61:729,2002)，地衣产生的大多数次级代谢物属于缩酚酸(depside)、缩酚酸环醚(depsidone)和二苯并呋喃(dibenzfurane)，并且估计这些化合物与地衣的缓慢生长速率相关(Kumar,K.C.S.等,J.Nat.Prod.,62:817,1999；Huneck,S.,Naturwissenschaften,86:559,1999)。此外，通过地衣代谢物的筛选过程，证实了各种生物活性，包括抗生素、抗微细菌、抗病毒、止痛和退热活性等等(Ingolfsdottir,K.,Phytochemistry,61:729,2002；Kumar,K.C.S.et al.,J.Nat.Prod.,62:817,1999)。因而，使用地衣的次级代谢物的药物开发方面的兴趣在增加。
同时，肝脏是在体外物质和体内物质的代谢中起关键作用的组织。酒精性或病毒性肝炎发展成肝硬化或肝癌，但目前还没有针对肝硬化的独特治疗物质。由于在肝纤维化的早期没有疼痛或主观症状，且肝纤维化发现于终末期，故死亡率高，从而造成社会问题。在东北亚和东南亚，包括中国，与病毒性(酒精性)肝硬化和肝癌相关的疾病表现率十分高。在针对病毒性肝炎的治疗剂的情况下，已经积极地进行了新药物的开发，并已经取得市场成功，但除了熊去氧胆酸(ursodeoxycholic acid)和水飞蓟素(silymarin)之外，还没有针对肝硬化的治疗剂。因而，在保证一种能够预防和治疗肝硬化的新物质的情况下，所述新物质将会对未来市场带来显著影响。
因此，本发明者们尝试提供一种能够预防和治疗肝硬化的新物质，并发现ramalin具有预防和治疗肝硬化动物模型中的肝纤维化和肝硬化的效果，由此完成了本发明。
本技术领域中公开的该信息仅用于促进对本发明背景的理解。因而，可能并未包括本发明所属领域技术人员已知的现有技术的信息。
发明内容
本发明的一个目的在于提供一种能够预防和治疗肝硬化的新物质。
根据本发明的一个方面，提供了一种用于预防或治疗肝纤维化或肝硬化的药物组合物，含有由以下化学式1表示的化合物或其药物学上可接受的盐作为活性成分。
化学式
1
根据本发明的另一方面，提供了一种用于预防或治疗肝纤维化或肝硬化的药物组合物的应用，包括由化学式1表示的化合物或其药物学上可接受的盐作为活性成分。
根据本发明的另一方面，提供了一种用于预防或改善肝纤维化或肝硬化的功能性食品，含有由化学式1表示的化合物或其食品学上可接受的盐作为活性成分。
根据本发明的另一方面，提供了一种用于预防或改善肝纤维化或肝硬化的功能性食品的应用，包括由化学式1表示的化合物或其食品学上可接受的盐作为活性成分。
根据本发明的另一方面，提供了一种用于预防或治疗肝纤维化或肝硬化的药物组合物，包括含有由化学式1表示的化合物的孔树花(Ramalina terebrata)提取物作为活性成分。
根据本发明的另一方面，提供了一种用于预防或治疗肝纤维化或肝硬化的药物组合物的应用，包括含有由化学式1表示的化合物或其药物学上可接受的盐的孔树花提取物作为活性成分。
根据本发明的另一方面，提供了一种用于预防或改善肝纤维化或肝硬化 的功能性食品，包括含有由化学式1表示的化合物的孔树花提取物作为活性成分。
根据本发明的另一方面，提供了一种用于预防或治疗肝纤维化或肝硬化的功能性食品的应用，包括含有由化学式1表示的化合物或其药物学上可接受的盐的孔树花提取物作为活性成分。
通过以下详细描述和所附权利要求书，本发明的其他特征和实施方式将变得显而易见。
附图说明
图1A至1C是示出通过细胞活力测试在用ramalin处理肝癌细胞系huh7、Hep3B细胞和张氏肝细胞时测得的细胞毒性(IC50)的图表。
图2是示出在对照组、RM组、SM组、DMN组、RMDM组和SMDM组每种物质中，给药前和给药期间测量的重量变化结果的图表。
图3是示出在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后测量的肝重量和计算的相对肝重量比体重的结果的图表。
图4是示出在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后进行血生化测试的结果的图表。
图5是示出在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后进行MT染色的结果的图表。
图6是示出在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后作为胶原蛋白成分的羟脯氨酸的检测量的图表。
图7是用于证实在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后α-SMA、Nrf-2、NQO-1和HO-1的表达量的照片。
图8是用于证实在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后白细胞介素-6、TNF-α、白细胞介素-4的mRNA是否表达的电泳照片。
图9是用于证实在对照组、RM组、SM组、DMN组、RMDM组和SMDM组中，试验结束后Nrf-2、NQO-1、HO-1、α-SMA、β-肌动蛋白是否表达的电泳照片。
具体实施方式
除非本文中另有定义，本说明书中使用的所有技术和科学术语具有与本发明所属领域技术人员所理解的含义相同的含义。一般来说，本说明书中使用的名称是本领域公知且通用的。
本发明的详细说明中使用的主要术语的定义如下：
如本文所使用的术语“肝硬化”是指一种由肝组织纤维化引起的疾病。这里，“肝纤维化”是指结缔组织的合成和分解过程失去平衡的一种状态，其由肝组织中的结缔组织的过量积累造成并伴随坏死或炎症。特别地，已知用于在肝脏中存储维生素A的肝星形细胞(HSC)在肝功能正常的状态下通过急性或慢性肝损伤转变成肌成纤维细胞样细胞，并通过增加诸如胶原蛋白、蛋白聚糖、透明质酸等的胞外物质的产生和运动而迅速增殖以过量产生结缔组织，使得肝纤维化过程发展。
如本文所使用的术语“地衣提取物”是指通过在溶剂中溶解地衣的机体、组织或细胞而分离的物质，且所述提取物可通过蒸馏或蒸发而浓缩。
一方面，本发明提供了一种用于预防或治疗肝纤维化或肝硬化的药物组合物，含有由以下化学式1表示的化合物或其药物学上可接受的盐作为活性成分。
化学式
1
在本发明的实施例中，在慢性肝硬化诱导的动物模型中用于比较从孔树花(Ramalina terebrata)提取物中分离的ramalin与已知具有保护肝细胞效果的水飞蓟素(silymarin)的试验中证实，ramalin具有优异的预防和治疗肝硬化和肝纤维化的效果。也就是说，证实在使用二甲基亚硝胺(DMN)在大鼠中诱导肝组织的纤维化的情况下，指示肝硬化的AST、ALT和ALP值在血清中显著增加，且由于纤维化而引起肝硬化。然而，证实在用ramalin治疗的组中，与作为阳性对照组的用水飞蓟素治疗的组相比，抑制肝纤维化的效果是显著优异的，且胶原蛋白的形成显著降低，指示肝硬化的值也降低。此外，通过 免疫组织学测试和用于证实NADPH醌氧化还原酶-1(NQO-1)、血红素加氧酶-1(HO-1)以及类似物的蛋白表达的测试，证实了ramalin的抗氧化效果，所述NADPH醌氧化还原酶-1(NQO-1)、血红素加氧酶-1(HO-1)以及类似物是与对应于抗氧化指示物的抗氧化反应元件(ARE)和核因子E2相关因子2(nuclear erythroid 2-related factor-2,Nrf-2)相关的基因。
此外，根据本发明的ramalin分离自孔树花提取物，显然含有ramalin的孔树花提取物自身具有预防和治疗肝硬化和肝纤维化的效果。因而，另一方面，本发明涉及一种用于预防或治疗肝纤维化或肝硬化的组合物，所述组合物含有包含ramalin的孔树花提取物作为活性成分。
同时，本发明中使用的化学式1的Ramalin可以呈药物学上可接受的盐的形式。本发明中的药物学上可接受的盐可以通过本领域中使用的通用方法来制备。例如，ramalin可以与诸如盐酸、溴化氢、硫酸、硫酸氢钠、磷酸、碳酸等的无机酸，或诸如甲酸、乙酸、草酸、苯甲酸、柠檬酸、酒石酸、葡萄糖酸、龙胆酸、富马酸、乳糖酸、水杨酸或乙酰水杨酸(阿司匹林)的有机酸形成药物学上可接受的盐。此外，ramalin可以与诸如钠离子或钾离子的碱金属离子反应形成其金属盐，或与铵离子反应形成另一形式的药物学上可接受的盐。
含有根据本发明的化合物的药物学组合物、其药物学上可接受的盐、或包括该化合物的孔树花提取物可以以用于口服、外用、栓剂和无菌注射液的形式来配制和使用，所述口服形式例如粉剂、颗粒、片剂、胶囊、悬液、乳液、糖浆、气雾剂或类似形式。作为含所述化合物的组合物中包含的载体、赋形剂和稀释剂，有乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藻糖醇、麦芽糖醇、淀粉、阿拉伯胶橡胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯比咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物质油。
在配制药物组合物的情况下，可以使用通常使用的稀释剂或赋形剂，例如填料、增量剂、粘合剂、润湿剂、崩解剂、表面活性剂等。用于口服的固体制剂包括片剂、丸剂、粉剂、颗粒、胶囊等，可以通过将化合物与诸如淀粉、碳酸钙、蔗糖或乳糖、明胶等的至少一种赋形剂混合来制备用于口服的固体制剂。进一步，除了简单的赋形剂，可使用诸如硬脂酸镁或滑石之类的润滑剂。用于口服的液体制剂包括悬液、溶液、乳液、糖浆等，并且可含有各种赋形剂，例如润湿剂、甜味剂、调味剂、防腐剂等，且可以包含作为通常使用的简单稀释剂的水和液体石蜡。用于肠胃外给药的制剂包括无菌水溶液、非水溶剂、悬液、乳液、冻干制剂和栓剂。在非水溶剂或悬液中，可以使用丙二醇、聚乙二醇、诸如橄榄油之类的植物油、诸如油酸乙酯之类的可注射脂类。作为栓剂的基体，可以使用Witepsol、Macrogol、Tween 60、可可油脂(cacao butter)、laurinum、甘油明胶或类似物。
润滑剂。用于口服的液体制剂包括悬液、溶液、乳液、糖浆等，并且可含有各种赋形剂，例如润湿剂、甜味剂、调味剂、防腐剂等，且可以包含作为通常使用的简单稀释剂的水和液体石蜡。用于肠胃外给药的制剂包括无菌水溶液、非水溶剂、悬液、乳液、冻干制剂和栓剂。在非水溶剂或悬液中，可以使用丙二醇、聚乙二醇、诸如橄榄油之类的植物油、诸如油酸乙酯之类的可注射脂类。作为栓剂的基体，可以使用Witepsol、Macrogol、Tween 60、可可油脂(cacao butter)、laurinum、甘油明胶或类似物。
另一方面，本发明提供了一种用于预防或治疗肝纤维化或肝硬化的药物组合物的应用，包括由化学式1表示的化合物或其药物学上可接受的盐作为活性成分。
根据本发明的组合物的优选剂量可以根据患者的状态和体重、疾病程度、药物配方以及给药途径和持续时间来改变，但可以由本领域技术人员来适当选择。然而，为了获得优选的效果，根据本发明的化合物可以以每天0.1到1000mg/kg的剂量，优选1到100mg/kg的剂量给药。一份剂量可以每天一次给药，或者可以分成几份剂量再给药。本发明的范围并不限于该剂量。
作为根据本发明的功能性食品，例如，有食品、糖果、巧克力、饮料、口香糖、茶、复合维生素、保健食品(health supplement food)等，且功能性食品可以以粉剂、颗粒、片剂、胶囊或饮料的形式使用。
根据本发明的化合物、其食品学上可接受的盐(例如：其钠盐或类似物)、或包括该化合物的孔树花提取物可以添加到食品或饮料中，以预防肝硬化或肝纤维化。在此情况下，该化合物在食品或饮料中的含量如下。一般来说，根据本发明的热的功能性食品组合物的含量可以为基于食品总重量的0.01到50wt％，优选0.1到20wt％，根据本发明的健康饮料组合物的含量可以为基于100ml健康饮料的0.02到10g，优选0.3到1g。
根据本发明的健康饮料组合物的液体成分没有特别的限制，只要该健康饮料组合物以所描述的比例含有根据本发明的化合物作为必要成分，且与普通饮料类似，该健康饮料组合可进一步含有各种调味剂、天然碳水化合物或类似物作为附加成分。天然碳水化合物的例子包括普通糖类，例如单糖类如葡萄糖、果糖和类似物，二糖类如麦芽糖、蔗糖和类似物，多糖类如糊精、环糊精和类似物，糖醇类，例如木糖醇、山梨糖醇、赤藻糖醇和类似物。作 为调味剂，可有利地使用天然调味剂(索马甜(thaumatin)、甜叶菊提取物(例如莱苞迪苷A(rebaudioside A)、甘草酸苷(glycyrrhizin)和类似物))和合成调味剂(糖精、阿斯巴甜和类似物)。天然碳水化合物在根据本发明的组合物中的含量为基于100ml所述组合物的大约1到20g，优选大约5到15g。除了如上所述的的附加成分之外，根据本发明的功能性食品还可包含各种营养物、维生素、矿物质(电解质)、诸如合成食用调味剂和天然食用调味剂的食用调味剂、着色剂和改善剂(奶酪、巧克力和类似物)、果胶酸及其盐、褐藻酸及其盐、有机酸、保护性胶体增稠剂、pH控制剂、稳定剂、防腐剂、甘油、醇类、碳酸饮料中使用的碳酸化剂等。此外，根据本发明的功能性食品可包含用于制备天然水果汁、水果汁饮料和蔬菜饮料的水果果肉。这些成分可单独使用或组合使用。尽管这些添加剂的含量不是特别重要，但通常选择在基于100重量份根据本发明的组合物的0到20重量份范围内。
下面，将通过实施例详细描述本发明。然而，这些实施例仅用于示例本发明，本领域技术人员将理解这些实施例并不被认为对本发明范围的限制。
实施例1：Ramalin的分离
1-1：孔树花提取物的制备和Ramalin的分离
作为天然成群地生长在南极洲乔治王岛的地衣植株孔树花(Ramalina terebrata)可以采集自乔治王岛。
将672g完全冻干的地面地衣孔树花样品用甲醇和水的混合溶液(5L,80:20v/v)重复提取三次，然后冻干，由此获得83g粗提取物。将粗提取物溶解在1L的蒸馏水中并用1L正己烷和氯仿(CHCl3)提取，从而获得12.7g正己烷、9.1g氯仿(CHCl3)和61.0g水溶性提取物。该水溶性提取物表现出对2,2-二苯基-苦基苯肼(2,2-diphenyl-1-picryl-hydrazyl-hydrate,DPPH)的高活性(IC50＝9μg/ml)。采用0％、20％、40％、60％、80％和100％的甲醇水溶液的逐步梯度溶剂体系对一部分(5g)水溶性提取物进行自动中低压液相色谱(MPLC)。在0％的甲醇水溶液中洗脱的提取物表现出对DPPH自由基的高活性(IC50＝8μg/ml)，且采用C18ODS柱(250cmx10cm)通过半制备反向HPLC分析其一部分(100mg)。所使用的溶剂体系是含有0.1％甲酸的0％的甲醇水溶液(超过10min)，20％的甲醇(超过20min)和100％的甲醇(超过30min)。 流速为2mL/min，并在280nm下进行检测。
结果，第五馏分(45mg；tR＝18.88min)表现出对DPPH自由基最高的活性(IC50＝1μg/ml)，该馏分是采用C18ODS柱(250cmx10cm)通过半制备反向HPLC重复纯化的。梯度溶剂体系为含0.1％甲酸的10-30％的乙腈水溶液(超过50min)，流速为2mL/min。结果在8.26min获得了30mg对DPPH自由基的活性为IC50＝0.99μg/mL的以下化学式1的ramalin。
化学式
1
实施例2：细胞毒性评估
使用肝癌细胞系的huh7和Hep3B细胞(Korean Cell Line Bank，韩国)和正常肝细胞的张氏肝细胞(ATCC，美国)来证实ramalin的细胞毒性评估。即，接种Hep3B细胞和Huh7细胞，在96孔板中培养24小时，然后用按照预定浓度的ramalin处理。在培养所述细胞3天之后，去除培养基，并用培养基洗涤所述细胞。然后通过细胞活力测试测定细胞毒性(IC50)。使用与上述相同的方法通过细胞活力测试测定在正常肝细胞(人张氏肝细胞)中的细胞毒性(IC50)。
表1
[表1]
| 细胞系 | IC50(μg/mL) |
| 张氏肝细胞 | 118.30 |
| Hep 3B | 23.77 |
| Huh 7 | 2.11 |
如表1和图1所示，作为ramalin的细胞毒性结果，肝癌细胞系的Hep3B和Huh7细胞中的IC50值为23.77μg/mL和2.11μg/mL，而张氏肝细胞(正常肝细胞)中IC50值为118.3μg/mL，因此ramalin特异性地作用于肝癌细胞系， 而在正常肝细胞系中几乎无毒性。
实施例3：在疾病动物模型中的效果测试
3-1：慢性肝硬化动物模型的建立
为建立慢性肝硬化动物模型，使用驯化周期后的8周龄的SD大鼠(Orientbio Inc.,Gapyenong Center，韩国)，以1mL/kg体重的剂量一周三次(周一、周二和周三)腹腔注射1％的二甲基亚硝胺(DMN)四周(28天)，从而建立慢性肝硬化模型。
3-2:测试组的构成
测试组的总数为6，更具体而言，测试组的构成如下：
1)在对照组中，不给药任何物质(n＝6)，或者对其它给药MCT油(n＝3)。
2)在ramalin(RM)组中，以20mg/kg一周三次给药(周一、周三和周五)(n＝8)。
3)在水飞蓟素(SM)组中，以100mg/kg一周三次给药(周一、周三和周五)(n＝6)。
4)在DMN组中，以1mL/kg体重的剂量一周三次(周一、周二和周三)腹腔注射1％的二甲基亚硝胺(DMN)4周(28天)。
5)在RMDM组中，以1mL/kg体重的剂量一周三次(周一、周二和周三)腹腔注射1％的二甲基亚硝胺(DMN)4周，并同时以20mg/kg一周三次给药ramalin(周一、周三和周五)。
6)在SMDM组中，以1mL/kg体重的剂量一周三次(周一、周二和周三)腹腔注射1％的二甲基亚硝胺(DMN)4周，并同时以100mg/kg一周三次给药水飞蓟素(周一、周三和周五)。
在此案例中，ramalin是通过就在给药前即时以20mg/kg的剂量溶解于饮用水中来制备，并直接将制备的ramalin口服给药，而对应于阳性对照组的水飞蓟素通过在给药前即时以100mg/kg的剂量溶解于MCT油来制备，并直接将制备的水飞蓟素口服给药。
3-3:死亡与临床症状观察及体重与肝重测定
首先，在给药期期间且直到所有动物中的血液采集结束时，观察动物是否死亡或濒临死亡，并观察动物的临床症状。结果，在测试期间，在对照组、RM组、SM组和RMDM组中，没有观察到死亡或濒临死亡的动物，但在DMN和SMDM组中，观察到了死亡或濒临死亡的动物(分别n＝1)。
此外，在驯化期后，在给药前即时测定体重，并在将动物分组后，一周测定2到3次体重。结果，如图2中所示，在RM和SM组中，与对照组类似，体重没有下降，而是增加。然而，在DMN处理的组中(DMN组、RMDM组和SMDM组)，与DMN未处理组相比，体重增加速率显著变慢。与对照组相比，在DMN组中，体重下降了32％，在RMDM组中，体重下降了25％，而在SMDM组中，体重降低了38％。
进一步，在试验结束后，提取肝脏并用磷酸盐缓冲液(PBS)洗涤以去除血块。然后测定重量，计算相对肝重量比体重。结果，如图3所示，在DMN和SMDN组中，实验结束后的相对肝重量比体重低，而在RMDM组中，相对肝重量比体重与对照组中的相对肝重量比体重类似。
3-4:血液生化测试
在给药结束后，麻醉动物，从每个动物中采集血液并在4℃和3000rpm下离心10min，由此采集上清血清并用作样品。通过Samkwang医学实验室(Samkwang Medical Laboratories)测定血清样品中的谷丙转氨酶(ALT)、天冬氨酸转氨酶(AST)、白蛋白、总蛋白质、碱性磷酸酶(ALP)、总胆红素(T-胆红素)、直接胆红素(D-胆红素)等。
结果，如图4所示，证实在该组中，T-胆红素、D-胆红素、ALP、AST和ALT值明显升高(正常值的两倍或更多倍)，表明在DMN组中发生肝硬化，而在未给药DMN的RM和SM组中，结果与对照组类似。证实在RMDM组中，ALT值增加为正常值的大约1.5倍，但与DMN组相比显著要低。在SMDM组中，获得类似于DMN组的值。
3-5:通过MT染色证实是否形成硬化
在给药结束后，麻醉动物，并从每个动物中提取肝组织。然后，测定肝组织的重量并拍照，然后将该组织于10％的中性福尔马林缓冲液中固定。将 经固定的组织以预定的厚度剪切，进行通常的组织处理过程，并包埋在石蜡中，从而制成组织切片(4-5μm)。之后，为观察在肝硬化时的纤维化，进行马松三色(Masson’s trichrome,MT)染色，以便证实纤维化程度，经证实在给药ramalin时，纤维化降低。
结果证实，在DMN处理的组(DMN组、RMDM组和SMDM组)中，如图5所示，纤维化位点以网形状染成蓝色，且形成大量胶原蛋白。然而，在RMDM组中，与DMN和SMDM组相比，纤维化形成显著降低。
3-6:羟脯氨酸分析
为测定组织中的胶原蛋白量，测定作为胶原蛋白成分的羟脯氨酸。将1ml6M的HCl加入100mg试验实施例中提取的肝组织并均匀化，然后在120℃下煮20min。将所得物离心，采集上清液并在50℃下离心36到48小时。在向其中加入1mM HCl以再次分散经浓缩的所得物之后，离心经分散的所得物，采集50μL上清液。向其中加入450μL氯胺T溶液，进行氧化反应25min，然后向其中加入Ehrich试剂并在65℃下反应20min。之后，在558nm下测定UV吸光度。
结果，如图6所示，在RMDM组中，羟脯氨酸的量比DMN组显著低。该结果意味着形成了少量的胶原蛋白。证实在RM和SM组中，羟脯氨酸的量与对照组中的量类似。
3-7:免疫组织化学测试
在通过将石蜡块切成厚度为4μm来制备石蜡切片并干燥该切片的石蜡块之后，使用有机溶剂(此处为Histosolve，ThermoShandon)进行去石蜡化。通过将过氧化氢加入乙醇获得的试剂抑制组织中存在的内源性过氧化物酶，并通过酸性醇抑制内源性碱性磷酸酶。使用蛋白阻断溶液以便抑制能够非特异性结合于初级抗体的蛋白质。在处理初级抗体之后，使用磷酸盐缓冲液(PBS,pH 7.4)进行洗涤，并在处理二抗之后，也使用PBS溶液洗涤。在初级抗体测试中，类似使用Western印迹法的蛋白质测试，测试Nrf-2(1:200,Santa Cruz Biotechnology，美国)NQO-1(1μg/mL,Abcam，英国)和HO-1(1:250,Enzo Life Science，美国)。
结果，如图7所示，在肝纤维化增加时，α-SMA的表达量高，而作为肝组织染色的结果，在DMN组中，表达量最高。在RMDM组中，α-SMA的表达量小于DMN组中的表达量。作为抗氧化指示物的Nrf-2在RM和SM组中表达，而在DMN和SMDM组中很难表达Nrf-2。在RMDM组中，证实Nrf-2表达。作为证实NQO-1和HO-1表达的结果，所述NQO-1和HO-1为ARE承载基因，NQO-1在RM、SM、RMDM和SMDM组中高表达，而HO-1在RM和RMDM组中表达。
3-8:肝组织中白细胞介素(IL)-6、TNF-α和白细胞介素-4的mRNA表达的证实
在mRNA水平证实作为介导炎症应答的信号分子的IL-6、TNF-α和IL-4。采集粗制的肝组织，使用Trizol(invitrogen)从中分离RNA并转录成逆转录体系(Promega)。然后使用聚合酶反应(PCR)证实IL-6、IL-4和TNF-α的表达，并使用GAPDH作为对照组。
结果如图8所示，证实在DMN组中，IL-6、IL-4和TNF-α的表达增加，而在RMDM组中，其表达下降。
3-9：肝组织中抗氧化酶和α-SMA的表达量证实
在试验结束后，采集粗制的肝组织，使用提取缓冲液来提取蛋白质并量化。然后通过Western印迹证实抗氧化酶的表达。蛋白质的量为40μg，使用β-肌动蛋白作为对照组。
结果，如图9所示，在蛋白质水平证实作为抗氧化指示物的Nrf-2和作为ARE承载基因的NQO-1和HO-1。在DMN和SDMD组中没有表达Nrf-2、NQO-1和HO-1，但在RMDM组中证实了Nrf-2、NQO-1和HO-1的表达。在DMN、RMDM和SMDM组中均证实了α-SMA的表达。在RM和SM组与对照组之间没有显著差异。
根据Lee-CG等人(Lee-CG et al.,Gastroenterology,DOI:
http://dx.doi.org/10.1053/j.gastro.2012.01.007)，已知被称为miR-199a-3p的微小RNA抑制参与肝细胞的抗氧化和抗癌机制的LKB1，从而损害肝细胞。如上所述的试验结果表明，根据本发明的ramalin具有预防和治疗肝纤维化和 肝硬化的效果。
工业实用性
如上面所列出，经证实在应用作为根据本发明的来自孔树花的化合物ramalin时，对于动物模型而言，与已知作为肝细胞保护成分的水飞蓟素相比，ramalin可显著地抑制肝纤维化并降低肝硬化水平，而对正常肝细胞没有细胞毒性，从而ramalin可有效地用于预防或治疗肝纤维化和肝硬化。
尽管本发明已经基于具体特征详细地进行了描述，但对本领域技术人员显然的是，这些具体技术仅仅是优选地实施方式，因而本发明的范围并不限于所述实施方式。因此，本发明的实质范围由所附权利要求书及其等同方式所限定。
Claims (4)
1.由以下化学式1表示的化合物或其药物学上可接受的盐在制备用于预防或治疗肝纤维化或肝硬化的药物组合物中的应用：
化学式1
2.由以下化学式1表示的化合物或其食品学上可接受的盐在制备用于预防或改善肝纤维化或肝硬化的功能性食品中的应用：
化学式1
3.含有由以下化学式1表示的化合物的孔树花提取物在制备用于预防或改善肝纤维化或肝硬化的药物组合物中的应用：
化学式1
4.含有由以下化学式1表示的化合物的孔树花提取物在制备用于预防或改善肝纤维化或肝硬化的功能性食品中的应用：
化学式1
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| KR20110132938A (ko) * | 2010-06-03 | 2011-12-09 | 한국해양연구원 | 라말린을 함유하는 염증질환 또는 면역질환의 예방 또는 치료용 약학 조성물 |
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| KR20110132938A (ko) * | 2010-06-03 | 2011-12-09 | 한국해양연구원 | 라말린을 함유하는 염증질환 또는 면역질환의 예방 또는 치료용 약학 조성물 |
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| US9364452B2 (en) | 2016-06-14 |
| EP2821068B1 (en) | 2016-10-05 |
| EP2821068A4 (en) | 2015-12-02 |
| KR20130098745A (ko) | 2013-09-05 |
| EP2821068A1 (en) | 2015-01-07 |
| CN104244937A (zh) | 2014-12-24 |
| US20150031771A1 (en) | 2015-01-29 |
| WO2013129714A1 (ko) | 2013-09-06 |
| KR101326256B1 (ko) | 2013-11-11 |
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