CN104257651B - 麦冬黄烷酮f的医药用途 - Google Patents
麦冬黄烷酮f的医药用途 Download PDFInfo
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- CN104257651B CN104257651B CN201410476508.9A CN201410476508A CN104257651B CN 104257651 B CN104257651 B CN 104257651B CN 201410476508 A CN201410476508 A CN 201410476508A CN 104257651 B CN104257651 B CN 104257651B
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- ophiopogon
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- hepatocyte
- flavonoid
- ophiopogon flavonoid
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Abstract
本发明涉及医药领域，特别是涉及一种麦冬黄烷酮F的医药用途。本发明的麦冬黄烷酮F可用于制备抗肝细胞损伤的药物。
Description
技术领域
本发明涉及医药领域，特别是涉及一种黄酮类化合物的用途。
背景技术
肝细胞是肝脏中含量最丰富的细胞。各种病因所导致的肝损伤均可引起肝细胞炎症、坏死并继发肝纤维化，进而可能发展为肝硬化并引起严重的并发症如门脉高压、肝衰竭和肝癌等。因此，保护肝细胞、修复损伤的肝细胞可以防止或延缓由于肝细胞损伤、坏死引发的各种肝炎、肝纤维化及其并发症。
肝细胞损伤、坏死后，细胞内的酶可释放进入血液，血清中转氨酶如ALT等水平升高。血清转氨酶的升高在一定程度上反映了肝细胞的损伤、坏死程度，因此ALT活性升高是肝实质细胞损伤、坏死以及修复的标志。此外，肝细胞损伤、坏死后还可引发炎症反应，持续的炎症反应可导致成肝脏疤痕形成，并进展为肝硬化和/或肝癌。
炎症反应是生物体在进化过程中形成的一套复杂的防御体系，其能激发机体适当的应答，是各种肝脏疾病的始发因素。肿瘤坏死因子(Tumor necrosis factor，TNF-α)是急性损伤后最早出现和最强效的宿主反应介质(Lin E,Calvano SE,Lowry SF.Inflammatoycytokines and cell response in surgery[J].Surgery,2000,127:117-126)。TNF-α可参与炎症反应对肝细胞的损害，诱导细胞凋亡和坏死。
活性氧(reactive oxygen species，ROS)自由基的产生与炎症过程密切相关，过量的ROS容易导致氧化应激。各种肝病如肝炎、肝硬化、脂肪肝、肝癌和酒精肝等的发生、发展过程都与自由基损伤密切相关(刘亚锋，氧化应激与肝脏保护，胃肠病学和肝病学杂志，2011；20(7)：594-597)。过氧化氢所导致的肝细胞损伤甚至凋亡是一个经典的肝细胞过氧化损伤模型(Wei L,Ren F,Zhang X,Wen T,Shi H,Zheng S,Zhang J,Chen Y,Han Y,DuanZ,Oxidative stress promotes D-GalN/LPS-induced acute hepatotoxicity byincreasing glycogen synthase kinase 3βactivity.Inflamm Res.2014；63(6):485-94.)。
发明内容
本发明的目的旨在提供一种麦冬黄烷酮F的新用途。
具体地说，本发明提供了麦冬黄烷酮F在制备抗肝细胞损伤的药物中的应用。
在一优选例中，所述的麦冬黄烷酮F是作为唯一的活性成分应用于抗肝细胞损伤的药物的制备中。
在另一优选例中，所述的肝细胞损伤由H2O2和/或TNF-α所引发。
本发明各个方面的细节将在随后的章节中得以详尽描述。通过下文以及权利要求的描述，本发明的特点、目的和优势将更为明显。
附图说明
图1不同浓度麦冬黄烷酮F对H2O2损伤肝细胞活力的影响(##P<0.01vs对照组；*P<0.05vs模型组)。
图2麦冬黄烷酮F不同作用时间对H2O2损伤肝细胞活力的影响(##P<0.01vs对照组；*P<0.05vs模型组)
图3麦冬黄烷酮F对H2O2损伤肝细胞增殖的影响。
图4麦冬黄烷酮F对H2O2损伤肝细胞早期凋亡和坏死的影响。
图5麦冬黄烷酮F对H2O2损伤肝细胞内ROS含量的动态变化的影响(#P<0.05，##P<0.01vs0h；*P<0.05,**P<0.05vs相同时间点模型组)。
图6麦冬黄烷酮F对H2O2损伤肝细胞内蛋白质羰基化动态变化的影响。
图7肝脏HE染色结果。
具体实施方式
本发明的问世是基于这样一个意外发现：黄酮类化合物麦冬黄烷酮F在体内/体外均具有良好的抗肝细胞损伤的作用。因此，麦冬黄烷酮F有望开发成为一种抗肝细胞损伤的药物。
进而，本发明的第一方面是提供了麦冬黄烷酮F在制备抗肝细胞损伤的药物中的应用。
较优选地，所述的麦冬黄烷酮F是作为唯一的活性成分应用于抗肝细胞损伤的药物的制备中。
较优选地，所述的肝细胞损伤由H2O2和/或TNF-α所引发。
如本发明所用，本发明的化合物麦冬黄烷酮F，化学名5，8-dimethoxy-6-methyl-7-hydroxy-3-3(2-hydroxy-4-methoxybenzyl)chroman-4-one(简写：58-F)是麦冬中提取的一种单体成分，分子量374.38，分子式C20H22O7，CAS号：4477336-79-1，结构式如下：
如本领域的普通技术人员所知，本发明的化合物麦冬黄烷酮F可通过商业途径购买获得，亦可用本领域的常规方法从百合科植物如麦冬(Ophiopogon japonicus)等中提取获得。其纯度均符合药用标准。
本发明的麦冬黄烷酮F可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成分的本发明的麦冬黄烷酮F及可药用载体。较佳地，本发明的药物组合物含有0.1～99.9％重量百分比的作为活性成分的本发明的麦冬黄烷酮F。“可药用载体”不会破坏本发明的麦冬黄烷酮F的药学活性，同时其有效用量，即能发挥药物载体作用时的用量对人体无毒。
所述可药用载体包括但不限于：软磷脂、硬脂酸铝、氧化铝、离子交换材料、自乳化药物传递系统、吐温或其他表面活化剂、血清蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅酸镁、饱和脂肪酸部分甘油酯混合物等。
其他常用的药物辅料如粘合剂(如微晶纤维素)、填充剂(如淀粉、葡萄糖、无水乳糖和乳糖珠粒)、崩解剂(如交联PVP、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素)、润滑剂(如硬脂酸镁)以及吸收促进剂、吸附载体、香味剂、甜味剂、赋形剂、稀释剂、润湿剂等。
本发明的麦冬黄烷酮F以及其药物组合物可按本领域常规方法制备并可以通过肠道或非肠道或局部途径给药。口服制剂包括胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等；非肠道给药制剂包括注射液等；局部给药制剂包括霜剂、贴剂、软膏剂、喷雾剂等。优选为口服制剂。
本发明的麦冬黄烷酮F以及其药物组合物的给药途径可以为口服、舌下、经皮、经肌肉或皮下、皮肤粘膜、静脉、尿道、阴道等。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本专利说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
实施例麦冬黄烷酮F在体内外的保肝作用研究
一、实验目的
观察麦冬黄烷酮F在体内、体外保护肝细胞的作用
二、实验材料
1.药物：麦冬黄烷酮F购自上海一林生物科技有限公司。
2.试剂：四氯化碳(CCl4)和橄榄油(国药集团)，谷丙氨酸转移酶(ALT)检测试剂盒(南京建成科技有限公司，#20140419)，肿瘤坏死因子(TNF-α)Elisa检测试剂盒(上海威奥生物科技有限公司，货号：EM0213)，Cell Counting Kit-8细胞增殖与活性检测试剂盒(SCK0105)购自上海生博医学生物工程科技有限公司；BrdU(BU20a)Mouse mAb,
Cell signaling(#5292)；Hoechst 33342,Cell signaling(#4082)；Annexin V-FITC Apoptosis Detection Kit I,BD Biosciences(#556547)；OxyBlotTM ProteinOxidation Detection Kit,(#S7150)Millipore。
三、体外实验
1.细胞：BNL.CL2小鼠肝细胞(中科院细胞库目录，GNM22，ATCC号：TIB-73TM)购自中科院上海市细胞库。10％FBS-DMEM培养液培养。
2.实验方法：
2.1.CCK-8细胞活力实验细胞接种于96孔培养版，添加不同浓度或不同作用时间的麦冬黄烷酮F作用24h，添加H2O2作用2h，于检测前加入10μl cck-8，酶标仪450nm波长检测。
2.2.细胞增殖能力检测细胞接种于96孔培养版，添加麦冬黄烷酮F作用24h。Brdu处理24小时后4％PFA固定细胞，加一抗，4℃过夜PBS洗涤，二抗室温30min，PBS洗涤，Hoechst染核，加抗淬灭剂30ul拍照。
2.3.流式细胞检测将细胞接种在φ60mm培养皿中，药物组加添加麦冬黄烷酮F分别作用不同时间，经H2O2作用2h后，PBS洗细胞，将各组细胞用0.25％胰酶消化，预冷的PBS洗涤细胞，将细胞重悬在1×bingding buffer中，加入AnnexinⅤ和PI，室温避光孵育15分钟，置冰上，轻轻混匀，1小时内上机检测。
2.4.细胞内ROS检测细胞接种于96孔培养板，添加麦冬黄烷酮F作用不同时间，经H2O2作用后，去除细胞培养液，无血清培养液洗3次，加入50mM的DCFH-DA，37℃细胞培养箱内孵育30分钟，无血清细胞培养液洗涤细胞3次，加入2％TRITON X-100室温孵育10分钟，酶标仪激发波长485nm，发射波长530nm检测。
2.5.细胞内羰基化蛋白检测细胞接种于φ100mm培养皿中，添加麦冬黄烷酮F作用不同时间，收取细胞。5μl(10ug)样品加入5μl 12％SDS，使蛋白质变性，加入10μl1×DNPH，室温孵育15min，加入7.5μl中和溶液混匀，经12％SDS-PAGE电泳、转膜后，5％BSA室温封闭1h。PBST洗涤。加入多克隆抗体兔抗一DNP，4℃过夜。PBST洗涤，然后加入羊抗兔HRP，室温孵育1～2h，PBS洗涤加入ECL，扫描仪扫描并保存图片。
3.实验结果
3.1.不同浓度的麦冬黄烷酮F对H2O2损伤的肝细胞活力影响
细胞经H2O2作用损伤后活力下降48.72％(p<0.01)，对肝细胞有明显的损伤作用，麦冬黄烷酮F的作用浓度从0.1μM到200μM设6个组，其中0.1μM和10μM组对细胞活力无明显影响，10μM、50μM和100μM三个组有显著改善细胞活力的作用(P<0.05)，200μM组细胞活力进一步下降，显示一定的细胞毒性(见图1)。
3.2.麦冬黄烷酮F不同作用时间对H2O2损伤的肝细胞活力影响
根据麦冬黄烷酮F的浓度作用结果，选取50μM的麦冬黄烷酮F温育细胞，分别检测6h、12h、24h、36h、48h和72h 6个作用时间点，观察麦冬黄烷酮F对H2O2损伤肝细胞的保护作用，结果显示，H2O2作用后细胞活力显著降低(p<0.01)，麦冬黄烷酮F作用6h对细胞活力无显著影响，12h及以后的各时间点对细胞都有显著的提高(P<0.01或P<0.05)(图2)。
3.3.麦冬黄烷酮F对H2O2损伤的肝细胞增殖的影响
Brdu参入正在DNA合成的细胞，而Hoechst可与核染色，共定位结果可见：H2O2作用24h后，增殖的肝细胞明显较正常对照组细胞减少，而麦冬黄烷酮F可明显增加肝细胞的增殖(图3)。
4.麦冬黄烷酮F对H2O2损伤肝细胞死亡的影响
H2O2损伤后，早期凋亡的肝细胞上升到3.72％，而对照组只有0.45％，细胞膜破裂，正在发生坏死的细胞更是上升到了19.38％(对照组3.98％)，麦冬黄烷酮F作用12小时和36小时，早期凋亡的细胞分别下降到1.34％和0.96％；正在坏死的细胞分别下降到8.43％和8.97％。显示麦冬黄烷酮F可明显降低早期凋亡和坏死的肝细胞(图4)。
5.麦冬黄烷酮F对H2O2损伤肝细胞内ROS水平的影响
麦冬黄烷酮F作用不同时间，观察H2O2对肝细胞内ROS含量动态变化的影响，发现随着H2O2的作用，细胞内ROS含量在4h达到高峰，随后即下降，24h后。而麦冬黄烷酮F各时间点均可显著降低细胞内ROS的含量(图5)。
6.麦冬黄烷酮F对H2O2损伤肝细胞内羰基化蛋白的影响
H2O2作用0.5h后肝细胞内的蛋白质发生了明显的羰基化损伤，此后一直到24h都维持在高水平，而麦冬黄烷酮F则在0.5h即显著降低细胞内蛋白质的羰基化，24h接近正常对照组水平(图6)。
四、体内实验
1.实验动物：上海斯莱克公司雄性Babl/c小鼠饲养于上海中医药大学实验动物中心。许可证号：SCXK(沪)2012-0002，所有小鼠饲养于上海中医药大学实验动物中心，自由饮食。
2.分组：Babl/c小鼠随机分为正常对照组(CON)10只，模型对照组(H2O2)10只，58-F干预组10只。
3.模型制备及给药：模型组和58-F干预组给予5％CCl4腹腔注射一次(10ul/g体重)，正常对照组给予橄榄油(10ul/g体重)腹腔注射和生理盐水灌胃，模型组给予生理盐水灌胃。58-F干预组于模型开始前3天按15mg/kg体重灌胃，至模型第四天处死小鼠。
4.实验方法：
4.1血清ALT检测按照南京建成检测试剂盒说明操作。即37℃预热基质液，取血清5μl，2,4-二硝基苯肼25μl，0.4M NaOH250ul混匀，室温静置15分钟，510nm波长，酶标仪检测各孔吸光度值。做标准曲线，查得样品ALT活性(卡门单位)。
4.2血清TNF-a检测根据威奥公司试剂说明操作。即将血清样品稀释10倍，待测。将稀释好的各组血清样本100ul加入包被好TNF-a抗体的96孔酶标板，37℃温箱静置90分钟，加TNF-a抗体工作液100ul(1:50)，37℃温箱，60分钟，PBS洗涤；加入预热的ABC工作液100ul，37℃温箱，30分钟，PBS洗涤；加入900ul TMB显色液，避光37℃温箱，30分钟；加入100ul TMB终止液；酶标仪450nm检测各孔吸光度值。做标准曲线，计算样品TNF-a浓度。
4.3.肝脏HE染色取0.5×0.5×0.3cm3大小肝组织1块，放入包埋框，10％甲醛溶液固定，24h后逐级酒精脱水，二甲苯透明，60℃石蜡包埋。4μM的切片经60℃烤片60min，二甲苯I 10min，二甲苯II 10min，无水乙醇I 5min，无水乙醇II 2min，95％乙醇2min，85％乙醇2min，70％乙醇2min，自来水漂洗6次(约5-6分钟)，苏木素染液15min，自来水漂洗6次，盐酸酒精分化3s，自来水漂洗至核呈蓝色(镜检)，伊红4s，95％乙醇I 1min，95％乙醇II 1min，无水乙醇I 1min，无水乙醇II 1min，二甲苯I 1min，二甲苯一下，中性树胶封片。
5.结果
5.1.麦冬黄烷酮F对小鼠血清ALT的影响
CCl4模型组小鼠血清ALT较正常对照组显著升高(P<0.01)，而麦冬黄烷酮F组小鼠血清显著下降(P<0.05)(表1)。
表1.小鼠血清ALT活性(卡门单位)
注：##P<0.01VS CON；*P<0.05vs Model
5.2.麦冬黄烷酮F对小鼠血清TNF-α含量的影响
CCl4模型组小鼠血清TNF-α含量较正常对照组显著升高(P<0.01)，而麦冬黄烷酮F组小鼠血清显著下降(P<0.01)(表2)。
表2.小鼠血清TNF-α含量(pg/ml)
注：##P<0.01VS CON；**P<0.01vs Model
5.3.麦冬黄烷酮F对小鼠肝组织的影响(HE染色)(图7)
如图7所示，正常组肝细胞排列整齐，未见脂质空泡形成，中央静脉区未见肝细胞坏死及炎症细胞浸润；模型组可见中央静脉区大面积肝细胞坏死、少量炎症细胞浸润。58-F用药组中央静脉区坏死细胞明显减少，显示坏死区的肝细胞正在得到修复。
五、实验结论
麦冬黄烷酮F具有修复损伤肝细胞的作用，其作用机制如下：
一、清除损伤肝细胞内的过氧化自由基和损伤的蛋白质(羰基化蛋白质)，提高肝细胞的活力和增殖能力；
二、体内通过保护肝细胞损伤，避免肝细胞内的酶如ALT进入血液，降低血清中ALT转氨酶活性；
三、具有抗炎作用，TNF-α主要由炎症细胞产生，麦冬黄烷酮F通过降低TNF-α的含量降低炎症反应，减少肝细胞的损伤；
鉴于各种肝脏疾病如肝炎、脂肪性肝病(FLD)包括酒精性肝病(ALD)和非酒精性脂肪性肝病(NAFLD)以及肝纤维化的发生发展均与氧化损伤和炎症反应有关，麦冬黄烷酮F通过抗过氧化损伤和抗炎作用，保护修复损伤的肝细胞，从而具有潜在的临床应用前景。
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明精神之前提下，本领域专业人员可对其进行等同改变和修饰，所述改变和修饰同样落入本申请所附权利要求的覆盖范围。
Claims (3)
1.麦冬黄烷酮F在制备抗肝细胞损伤的药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述的麦冬黄烷酮F是作为唯一的活性成分应用于抗肝细胞损伤的药物的制备中。
3.如权利要求1所述的应用，其特征在于，所述的肝细胞损伤由H2O2和/或TNF-α所引发。
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