CN117653619A - 紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用 - Google Patents
紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P3/06—Antihyperlipidemics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明公开了一种紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用。所述脂质代谢异常相关性疾病为非酒精性脂肪性肝炎。本发明首次发现紫铆因具有改善肝脏脂质沉积和炎症反应的作用，可用于预防和/或治疗非酒精性脂肪性肝炎。
Description
技术领域
本发明涉及一种紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用，属于医药领域。
背景技术
非酒精性脂肪性肝病(NAFLD)是世界范围内慢性肝病的主要原因，影响着全球约四分之一的人口。NAFLD的范围从简单的良性脂肪变性到非酒精性脂肪性肝炎NASH，其特征是肝脏坏死炎症和肝细胞气球样变性，导致肝纤维化，最终进展为肝癌和肝硬化。到2030年，NAFLD引起的终末期肝病预计将增加2～3倍。
NAFLD的一般治疗包括改变饮食和运动等生活方式、改善心血管疾病的危险因素等，此外有减肥手术和药物治疗，但是治疗药物的选择非常有限，尚无获批的特异性药物用于NAFLD的治疗。美国肝病研究协会推荐不伴有糖尿病的NASH患者可每天服用维生素E 800国际单位，连续服用2年，但长期大剂量使用维生素E的安全性尚无定论。我国治疗指南尚未明确推荐治疗NASH尤其是肝脏纤维化的药物，而目前临床中广泛应用的保肝药物如水飞蓟素(宾)、双环醇、多烯磷脂酰胆碱、甘草酸二胺、还原型谷胱甘肽、S-腺苷甲硫氨酸、熊去氧胆酸等对NASH和肝纤维化的疗效还需进一步证实。由此可见，NAFLD的治疗是亟待解决的临床难题。
紫铆因(Butein)是一种从多种天然植物中提取的类黄酮，如肉豆蔻、苏木、皂荚和鬼针草。
发明内容
发明目的：本发明的第一目的是提供了一种紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用。本发明的第二目的是提供一种预防和/或治疗脂肪肝的药物组合物。
技术方案：本发明提供了紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用。
其中，紫铆因的化学结构式如下：
其中，所述脂质代谢异常相关性疾病为非酒精性脂肪性肝炎。
其中，所述紫铆因能降低甘油三酯、总胆固醇、脂质合成因子和脂质氧化因子的含量。
其中，所述脂质合成因子包括SREBP1c、Fas、SCD1中的一种或多种。
其中，所述脂质氧化因子包括PPARa、CPT1a、Mlycd中的一种或多种。
其中，所述炎症因子包括TNF-α或MCP-1。
其中，所述紫铆因的有效浓度为5～10μM。
本发明还提供了一种预防和/或治疗脂肪肝的药物组合物，所述药物组合物中的活性物质为紫铆因。
其中，所述药物组合物还包括其他药学上可接受的辅料。
有益效果：与现有技术相比，本发明具有如下突出的显著优点：本发明首次发现紫铆因具有改善肝脏脂质沉积和炎症反应的作用，可用于预防和/或治疗非酒精性脂肪性肝炎。
附图说明
图1为紫铆因对HepG2细胞毒性测定结果；
图2为尼罗红染色结果图；
图3为TG含量检测结果；
图4为脂质合成因子基因含量检测结果；
图5为脂质氧化因子基因含量检测结果；
图6为炎症因子基因含量检测结果；
图7为脂质代谢和炎症相关蛋白表达结果；
图8为NASH小鼠肝脏H&E染色结果；
图9为NASH小鼠肝脏脂肪含量检测结果；
图10为NASH小鼠肝脏脂质氧化和炎症相关蛋白表达结果；
其中，上图中*P<0.05,**P<0.01,***P<0.001。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
实施例1验证紫铆因性质的体外实验
1.细胞培养
用含有10％ FBS、1％双抗的DMEM培养基，于37℃、5％ CO2的细胞培养箱中培养HepG2细胞。待细胞密度生长达80％～90％时进行传代以及后续实验。
2.紫铆因对HepG2细胞毒性测定
将6组不同浓度的紫铆因(1、3、6、12、25、50μM，成都普菲德生物技术有限公司，批号：JOT-12044)分别作用于HepG2细胞24h，另设置加入DMSO为溶剂对照组；紫铆因/DMSO 1:1000稀释使用，采用CCK-8法(CCK-8试剂盒购自上海东仁化学科技有限公司，CK04)检测细胞生存率。
结果如图1所示，细胞增殖和毒性实验(CCK–8法)结果显示，与DMSO溶剂对照组相比，当紫铆因浓度大于12μM时，紫铆因对HepG2细胞生长具有抑制作用，差异具有统计学意义(P<0.05)。因此，选择5μM、10μM分别作为紫铆因低剂量处理浓度、高剂量处理浓度。
3.紫铆因性质测试
3.1细胞分组和处理
将HepG2细胞以1×106个/孔接种于6孔板中，过夜贴壁后，根据不同处理将细胞分为四组，分别为：溶剂对照组(DMSO组，原培养基中加入含1‰DMSO的溶剂处理24h)，模型组(FFA组，原培养基中加入1mM，OA油酸：PA棕榈酸＝2：1处理24h，溶剂为1‰DMSO)，紫铆因低浓度组(用模型组处理过的细胞，再加入以1‰DMSO为溶剂配制的5μM紫铆因处理24h)，紫铆因高浓度组(用模型组处理过的细胞，再加入以1‰DMSO为溶剂配制的10μM紫铆因处理24h)。
3.2尼罗红染色
细胞经过3.1分组处理后，去掉培养基，用PBS清洗3次，4％多聚甲醛室温固定30min，PBS清洗3次，用0.5μg/ml尼罗红室温、避光染色30min，最后PBS洗3次，于荧光显微镜下拍照分析。
尼罗红可以将中性脂肪染色，而中性脂肪主要是甘油三酯TG。与溶剂对照组相比，模型组细胞在FFA的处理下，细胞中红色荧光增强，提示脂质含量增加；而用紫铆因处理，两个浓度下细胞中红色荧光均减弱，说明紫铆因可降低HepG2细胞内脂肪沉积，结果见图2。
3.3TG含量测定
收集3.1分组处理好的细胞，制备细胞悬液，按照试剂盒(甘油三酯试剂盒购自南京建成生物工程研究所，A110-1-1)提供的操作方法，采用GPO-PAP法测定细胞内TG浓度。
与溶剂对照组相比，模型组在FFA处理下显著增加细胞内TG含量，差异有统计学意义(P<0.05)；与FFA组相比，2个浓度下的紫铆因处理组TG含量均显著降低，差异有统计学意义(P<0.05)。结果见图3。
3.4测定细胞脂质代谢和炎症因子相关基因表达
收集3.1分组处理好的细胞，根据试剂说明书，使用TRIzol试剂(购自南京诺唯赞生物科技股份有限公司，R401-01)从细胞中提取总RNA。再用试剂盒(购自南京诺唯赞生物科技股份有限公司，R201-01)Hiscript II逆转录酶平衡RNA浓度并逆转录为cDNA，最后采用SYBRgreen荧光定量PCR检测基因表达水平。检测脂质合成相关基因Srebp1c/Fas/SCD1、脂质氧化相关基因PPARa/CPT1a/Mlycd以及炎症因子TNF-α/Mcp1的mRNA表达水平。表达水平用GAPDH校准。实验中使用的人源引物序列见表1。
表1用于实时定量PCR的基因特异性引物的核苷酸序列
所用AceQ qPCR SYBR Green Master Mix扩增试剂盒购自南京诺唯赞生物科技股份有限公司，批号Q111-02。具体PCR反应体系为：4μl的5×HiScript II Buffer、1μl的dNTPMix(10mM each)、1μl的HiScript II Reverse Transcriptase(200U/μl)、1μl的RNaseinhibitor(40U/μl)、1μl的Oligo(dT)23VN(50μM)、1μl的Random hexamers(50ng/μl)、1μg的总RNA，最后用RNase-free ddH2O补至20μl。PCR反应程序为25℃5min，50℃15min，85℃2min。
与FFA组相比，高浓度紫铆因处理组显著增高PPARa、Mlycd的mRNA表达水平，两种浓度紫铆因处理组均能显著增高CPT1a的mRNA表达水平，差异有统计学意义(P<0.05)。结果见图4。
与FFA组相比，高浓度紫铆因处理组细胞内Srebp1c、Fas、SCD1的mRNA表达水平显著降低，差异有统计学意义(P<0.05)，结果见图5。
与FFA组相比，高浓度紫铆因处理组TNF-α、Mcp1的mRNA表达水平显著降低，差异有统计学意义(P<0.05)。结果见图6。
3.5检测脂质代谢和炎症相关蛋白表达
采用Western blot方法检测细胞内Srebp1c，PPARa，Mcp1，β-actin的蛋白表达水平。收集3.1分组处理好的细胞，提取总蛋白，取各组蛋白在SDS-PAGE胶中电泳分离各蛋白，转膜，封闭，一抗(1：1000稀释抗体)4℃孵育过夜，TBST清洗3次，每次10min，然后加入二抗(1：5000稀释抗体)，室温摇床孵育1h，TBST清洗3次，每次15min，化学发光进行显影，拍照分析。所用试剂盒均购自南京诺唯赞生物科技股份有限公司：Srebp1c(批号：A15586)，PPARa(批号：A4331)，Mcp1(批号：A7277)，β-actin(批号：AC004)。
与FFA诱导组相比，高浓度紫铆因组Srebp1c、Mcp1蛋白的表达水平显著降低，PPARa蛋白的表达水平显著增加。结果见图7。
实施例2验证紫铆因性质的动物实验
1.动物分组与处理
24只雄性C57BL/6J小鼠(购自扬州大学医学院购)，体重18～22g，鼠龄8周，在湿度为50～60％带有适量木屑的笼子里，昼夜12h循环，自由饮食饮水的条件下饲养一周，适应饲养环境后随机分为4组，每组n＝6。根据不同饮食方法，4个组别分别是：正常饮食组(Normal diet，ND组)，模型组(MCD diet，MCD组)，紫铆因低剂量组(MCD diet+100mg·kg- 1d-1紫铆因灌胃)，紫铆因高剂量组(MCD diet+200mg·kg-1d-1紫铆因灌胃)。蛋氨酸和胆碱缺乏饮食(MCD)能成功诱导NASH组织学特征的动物模型，使肝脏组织容易从单纯脂肪变性转变为脂肪性肝炎，并且可以达到纤维化阶段，造模周期较短。蛋氨酸胆碱缺乏饲料购自南通特洛菲饲料科技有限公司。
2.离体肝组织制备
每组小鼠饲养4周后，禁食8h，不同组别小鼠脱臼处死，取出肝脏，分为3部分保存。其中一部分生理盐水清洗后，浸泡在福尔马林＞72h。其它两部分在液氮中速冻，保存于-80℃。
3.肝组织切片H&E染色
保存在福尔马林的肝组织经脱水，清洗，石蜡包埋，切片，苏木精和伊红染色(H&E)，肝切片在显微镜下观察分析。
和ND组相比，NASH模型组(MCD)小鼠肝组织出现明显脂质堆积以及炎症细胞的浸润；与NASH模型组相比，紫铆因处理组小鼠肝脏的脂质堆积明显减少，炎性细胞的浸润也明显减少。结果见图8。
4.TG和TC含量测定
取肝脏组织，按照试剂盒(购自南京建成生物工程研究所，TG批号：A110-1-1；TC批号：A111-1-1)提供的操作方法，采用GPO-PAP法测定肝脏组织的甘油三酯TG、总胆固醇TC浓度。
与NASH模型组相比，紫铆因处理组肝组织的TG和TC含量显著降低，差异有统计学意义(P<0.05)。结果见图9。
5.检测脂质代谢和炎症相关蛋白表达
采用Western blot方法检测小鼠肝脏组织内PPARa、ACOX1、Mcp1、TNF-α蛋白表达水平。取冻存的肝脏组织，取各组蛋白在SDS-PAGE胶中电泳分离各蛋白，转膜，封闭，一抗(1：1000稀释抗体)4℃孵育过夜，TBST清洗3次，每次10min，然后加入二抗(1：5000稀释抗体)，室温摇床孵育1h，TBST清洗3次,每次15min，化学发光进行显影，拍照分析。所用试剂盒均购自南京诺唯赞生物科技股份有限公司：PPARa(批号：A4331)，Mcp1(批号：A7277)，ACOX1(批号：A21217)，TNF-α(批号：A11534)。
与NASH模型组相比，紫铆因处理组脂质氧化相关蛋白PPARa、ACOX1表达显著增加，炎症因子Mcp1、TNF-α蛋白的表达显著降低。见图10。
从上述的细胞实验和动物实验结果均能看出，紫铆因具有改善NASH疾病肝脏脂质沉积和炎症反应的作用，作用机制与增强脂质氧化相关因子表达、减弱脂质合成相关因子表达、改善小鼠肝脏的病理改变有关。
Claims (9)
1.紫铆因在制备降低炎症因子、预防和/或治疗脂质代谢异常相关性疾病药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述脂质代谢异常相关性疾病为非酒精性脂肪性肝炎。
3.根据权利要求1所述的应用，其特征在于，所述紫铆因能降低甘油三酯、总胆固醇、脂质合成因子和增加脂质氧化因子的含量。
4.根据权利要求3所述的应用，其特征在于，所述脂质合成因子包括SREBP1c、Fas、SCD1中的一种或多种。
5.根据权利要求3所述的应用，其特征在于，所述脂质氧化因子包括PPARa、CPT1a、Mlycd中的一种或多种。
6.根据权利要求3所述的应用，其特征在于，所述炎症因子包括TNF-α或MCP-1。
7.根据权利要求1所述的应用，其特征在于，所述紫铆因的有效浓度为5～10μM。
8.一种预防和/或治疗脂肪肝的药物组合物，其特征在于，所述药物组合物中的活性物质为紫铆因。
9.根据权利要求8所述的预防和/或治疗脂肪肝的药物组合物，所述药物组合物还包括其他药学上可接受的辅料。
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Citations (2)
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| CN101336909A (zh) * | 2008-06-02 | 2009-01-07 | 华东师范大学 | 紫铆因在制备抑制血管新生药物中的应用 |
| KR20130040663A (ko) * | 2011-10-14 | 2013-04-24 | (주)생명의나무 | 옻나무 추출물을 함유하는 고지혈증 및 지방간 개선 및 예방용 조성물 |
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| CN101336909A (zh) * | 2008-06-02 | 2009-01-07 | 华东师范大学 | 紫铆因在制备抑制血管新生药物中的应用 |
| KR20130040663A (ko) * | 2011-10-14 | 2013-04-24 | (주)생명의나무 | 옻나무 추출물을 함유하는 고지혈증 및 지방간 개선 및 예방용 조성물 |
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