CN115252630B - 黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用 - Google Patents
黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用 Download PDFInfo
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Abstract
本发明涉及黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用。本发明创造性地发现黄柏酮可以作为预防、改善或治疗非酒精性脂肪肝的药物进行使用,其能够显著降低肝细胞内的脂质堆积,降低肝脏细胞内的甘油三酯含量。本发明为研究非酒精性脂肪肝的治疗策略提供了理论依据,为制备新的治疗非酒精性脂肪肝的药物提供了一个嵌入点。
Description
技术领域
本发明属于生物医药技术领域,涉及一种非酒精性脂肪肝的新的预防或治疗方式,具体涉及黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用。
背景技术
非酒精性脂肪肝病(NAFLD)是指除酒精和其他明确损伤肝的因素所导致的肝细胞内脂肪过度沉积的临床病理综合征。包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化。随着肥胖及其相关代谢综合征的流行,非酒精性脂肪性肝病现已成为慢性肝病的重要病因,普通成人NAFLD患病率10%-30%,其中10%-20%为NASH,后者10年内肝硬化发生率高达25%。非酒精性脂肪性肝病除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外,还可影响其他慢性肝病的进展。
非酒精性脂肪性肝病危害人类健康,其发病机制复杂,目前尚无有效的治疗非酒精性脂肪肝的药物,大多数患者只能通过改变生活习惯、多运动。但是对于进展为NASH或发生肝硬化的患者来说,单纯干预生活方式无法起到缓解病情的作用。因此探究非酒精性脂肪肝新的药物靶点对于NAFLD的诊断和防治具有重要意义。
黄柏酮(Obacunone)主要来源于黄柏、白鲜皮等植物,为柠檬苦素类三萜化合物,具有多样药理活性。现代药理研究表面,黄柏酮有以下作用:(1)使昆虫产生拒食行为;(2)微管抑制增效作用:能增强具有抑制微管作用的抗肿瘤药的细胞毒性,其本身没有细胞毒性。而对其他抗肿瘤药物如RNA合成抑制剂、烷化剂因子、胸苷酸合成酶抑制剂等没有显示出明显的增效作用;(3)保护神经活性:白鲜根皮的甲醇提取物对神经有保护作用。包括黄柏酮在内的醇提物在0.1μmol/L浓度时,对原始培养的老鼠皮质细胞表现出很强的神经保护活性(抗谷氨酸盐诱导的神经毒性);(4)柠檬苦素类似物具有抗肿瘤、抗病毒、镇痛、抗炎、催眠等多种生物活性。
有研究报道:黄柏酮通过调节肠道微生物群、减弱TLR4/NF-κB信号级联反应和改善受损的上皮屏障来预防小鼠溃疡性结肠炎;黄柏酮引起MKP-1的持续表达,从而使p38MAPK失活,通过细胞内MIF抑制促炎介质;黄柏酮通过增强GPx-4的抗氧化作用和抑制EMT来减轻肝纤维化;黄柏酮和黄柏酮糖苷通过诱导凋亡抑制人结肠癌(SW480)细胞;通过TGR5和PPARγ途径,饮食补充黄柏酮刺激肌肉肥大,抑制高血糖和肥胖;对22RV1前列腺癌细胞凋亡有很强的促进作用;通过抑制GSK-3β活性减轻高糖诱导的NRK-52E细胞氧化损伤;通过抑制MCF-7人乳腺癌细胞中的p38 MAPK信号通路,黄柏酮在体外表现出抗增殖和抗芳香化酶活性;通过激活NRF2延缓常染色体显性多囊肾病患者的肾囊肿发展;减少慢性炎症诱导的结肠直肠癌小鼠的炎症信号和肿瘤发生。
目前还未有黄柏酮具有改善非酒精性脂肪肝功效的相关报道。
发明内容
针对现有技术的不足,本发明的目的在于提供一种非酒精性脂肪肝的新的预防或治疗方式,具体涉及黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用。
本发明创造性地发现黄柏酮可以作为预防、改善或治疗非酒精性脂肪肝的药物进行使用,其能够显著降低肝细胞内的脂质堆积,降低肝脏细胞内的甘油三酯含量。本发明为研究非酒精性脂肪肝的治疗策略提供了理论依据,为制备新的治疗非酒精性脂肪肝的药物提供了一个嵌入点。
优选地,所述黄柏酮降低肝脏细胞内的脂质堆积。
优选地,所述黄柏酮降低肝脏细胞内的甘油三酯含量。
优选地,所述非酒精性脂肪肝包括单纯性脂肪肝、非酒精性脂肪性肝炎或相关肝硬化。
第二方面,本发明提供黄柏酮在制备降低肝脏细胞内脂质堆积的药物中的应用。
第三方面,本发明提供黄柏酮在以非疾病诊断和/或治疗为目的的制备降低肝脏细胞内脂质堆积的制剂中的应用。
根据本发明的研究结果,黄柏酮具有显著地降低肝脏细胞内脂质堆积的作用,因此,该结果表明黄柏酮可以作为一种制剂,用于科研领域,例如研究更多的肝脏细胞代谢机制或行为、筛选治疗非酒精性脂肪性肝病的药物等等。
第四方面,本发明提供黄柏酮在制备降低肝脏细胞内甘油三酯含量的药物中的应用。
第五方面,本发明提供黄柏酮在以非疾病诊断和/或治疗为目的的制备降低肝脏细胞内甘油三酯含量的制剂中的应用。
根据本发明的研究结果,黄柏酮具有显著地降低肝脏细胞内甘油三酯含量的作用,因此,该结果表明黄柏酮可以作为一种制剂,用于科研领域,例如研究更多的肝脏细胞代谢机制或行为、筛选治疗非酒精性脂肪性肝病的药物等等。
优选地,上述药物还包括药学上可接受的辅料;所述药学上可接受的辅料包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。
所述至少两种的组合例如填充剂和粘合剂的组合、乳化剂和助溶剂的组合、渗透压调节剂和表面活性剂的组合、pH调节剂和抗氧剂的组合等,其他任意的组合方式均可选择,在此便不再一一赘述。
第六方面,本发明提供一种预防、改善或治疗非酒精性脂肪肝的联合用药物组合物,所述联合用药物组合物包括黄柏酮和阿托伐他汀。
本发明还创造性地发现将黄柏酮与阿托伐他汀进行联合使用在预防、改善或治疗非酒精性脂肪肝方面具有比单一的黄柏酮或阿托伐他汀更好的效果,本发明为非酒精性脂肪肝病的治疗提供了有效的药物联用策略,具有十分显著的意义。
优选地,所述联合用药物组合物还包括药学上可接受的辅料;所述药学上可接受的辅料包括载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。
优选地,所述联合用药物组合物为单一的复方制剂或两种单独的制剂的组合。
优选地,所述联合用药物组合物为两种单独的制剂的组合,两种单独的制剂同时施用或依次施用。
所述联合用药物组合物可以为单一的复方制剂形式,也可以为两种单独的制剂的组合;当为两种单独的制剂的组合时,其用药方式可以为同时施用,也可以为交叉施用或依次施用。
优选地,所述制剂为药剂学上可接受的任意一种剂型,例如片剂、散剂、混悬剂、颗粒剂、胶囊剂、溶液剂、灌肠剂、乳剂等。
第七方面,本发明提供根据第六方面所述的联合用药物组合物在制备降低肝脏细胞内脂质堆积的药物中的应用。
第八方面,本发明提供根据第六方面所述的联合用药物组合物在以非疾病诊断和/或治疗为目的的制备降低肝脏细胞内脂质堆积的制剂中的应用。
根据本发明的研究结果,上述联合用药物组合物具有显著地降低肝脏细胞内脂质堆积的作用,因此,该结果表明该联合用药物组合物可以作为一种制剂,用于科研领域,例如研究更多的肝脏细胞代谢机制或行为、筛选治疗非酒精性脂肪性肝病的药物等等。
第九方面,本发明提供根据第六方面所述的联合用药物组合物在制备降低肝脏细胞内甘油三酯含量的药物中的应用。
第十方面,本发明提供根据第六方面所述的联合用药物组合物在以非疾病诊断和/或治疗为目的的制备降低肝脏细胞内甘油三酯含量的制剂中的应用。
根据本发明的研究结果,上述联合用药物组合物具有显著地降低肝脏细胞内甘油三酯含量的作用,因此,该结果表明该联合用药物组合物可以作为一种制剂,用于科研领域,例如研究更多的肝脏细胞代谢机制或行为、筛选治疗非酒精性脂肪性肝病的药物等等。
相对于现有技术,本发明具有以下有益效果:
本发明创造性地发现黄柏酮可以作为预防、改善或治疗非酒精性脂肪肝的药物进行使用,其能够显著降低肝细胞内的脂质堆积,降低肝脏细胞内的甘油三酯含量。本发明为研究非酒精性脂肪肝的治疗策略提供了理论依据,为制备新的治疗非酒精性脂肪肝的药物提供了一个嵌入点。
附图说明
图1是油红O染色观察细胞内脂质堆积试验中各组样品的染色结果图。
图2是油红O染色观察细胞内脂质堆积试验中各组样品的染色结果OD490值统计图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。各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。
除非另有说明,本说明书中使用的全部专业术语和科学用语的含义均与本发明所属技术领域的技术人员一般理解的含义相同。但如有冲突,以包含定义的本说明书为准。
下述实施例所涉及的药物黄柏酮、诺米林、柠檬苦素以及阿托伐他汀由Selleck公司提供。
HepG2细胞来自于上海联迈生物工程有限公司。
实施例1
甘油三酯(TG)含量检测试验:
(1)取数量为1×106对数生长期的HepG2细胞株接种于六孔板,待细胞贴壁后,吸去培养基并更换无血清DMEM培养基处理24小时。试验共分为(1.1)对照组:用DMEM培养基(含1%牛血清白蛋白)处理HepG2细胞;(1.2)模型组(PO组):由含有油酸钠和棕榈酸钠的造模培养基诱导HepG2细胞成为NAFLD细胞模型,诱导方式为用终浓度为1mM的油酸钠与棕榈酸钠(2:1)处理HepG2细胞24小时,造模培养基的配方为DMEM培养基(含1%牛血清白蛋白)加入1mM油酸钠与棕榈酸钠(2:1);(1.3)黄柏酮处理组:用含有油酸钠和棕榈酸钠的造模培养基和100μM黄柏酮同时处理HepG2细胞24小时;(1.4)柠檬苦素处理组:用含有油酸钠和棕榈酸钠的造模培养基和100μM柠檬苦素同时处理HepG2细胞24小时;(1.5)诺米林处理组:用含有油酸钠和棕榈酸钠的造模培养基和100μM诺米林同时处理HepG2细胞24小时;(1.6)黄柏酮+阿托伐他汀共处理组:用含有油酸钠和棕榈酸钠的造模培养基和100μM黄柏酮加10μM阿托伐他汀同时处理HepG2细胞24小时;
(2)诱导24小时后,吸弃孔内原有培养基,用PBS洗涤两次。
(3)按照甘油三酯检测试剂盒(E1013,北京普利莱基因技术有限公司)说明书进行操作。按比例每1×106个细胞加入0.1mL裂解液,混匀后25℃静置10min。
(4)取适量上清液转移到1.5mL离心管中用BCA法进行蛋白定量,余下样品70℃加热10min,组织量多时可能出现絮状沉淀。
(5)甘油三酯(TG)样品25℃2000rpm离心5min,上层清液即可用于酶学测定。
(6)利用甘油三酯(TG)含量测试盒进行检测,工作溶液配制:按4:1比例,取4mL试剂R1与1mL试剂R2混合即可,立即使用或4℃保存<1天,变色弃去。
(7)用与样品缓冲液一致的液体,将4mM甘油标准品倍比稀释为1000、500、250、125、62.5、31.25、15.625、7.8125μmol/L,通常取其中4~6管即可,注意设置0浓度对照反应管。
(8)在96孔板中每孔加入190μL工作液后,每孔分别加入10uL对应的样品,37℃反应15min。反应平衡后颜色在60min内稳定。
(9)用酶标仪测反应液在550nm波长的吸收光。
(10)绘制标准曲线并计算甘油三酯浓度。
(11)用于BCA法进行蛋白定量的样品先12000rpm离心五分钟以分离蛋白,细胞碎片和油脂。
(12)利用BCA蛋白定量试剂盒进行检测。工作溶液配制:按50:1比例,取5mL试剂A与0.1mL试剂B混合即可。
(13)用与样品缓冲液一致的液体,将2mg/mL蛋白标准品倍比稀释为1000、500、250、125、62.5、31.25、15.625、7.8125ug/mL,通常取其中4~6管即可,注意设置0浓度对照反应管。
(14)在96孔板中每孔加入190μL工作液后,每孔分别加入10uL对应的样品(中间无色层),37℃反应15min。
(15)用酶标仪测反应液在560nm处的吸收光。
(16)绘制标准曲线并计算蛋白浓度。
(17)将样品甘油三酯浓度与对应蛋白浓度相除,得到每组甘油三酯的相对值。
结果如表1所示(每组样品分别平行测定2次,取平均值):
表1
组别 | 甘油三酯含量(μmol/g protein) |
对照组 | 0.15 |
模型组 | 0.58 |
黄柏酮处理组 | 0.45 |
诺米林处理组 | 0.50 |
柠檬苦素处理组 | 0.52 |
黄柏酮+阿托伐他汀处理组 | 0.40 |
由表1数据可知:黄柏酮可降低脂肪变性的肝细胞内的甘油三酯含量,效果优于诺米林和柠檬苦素,其与阿托伐他汀联用效果更好。
实施例2
油红O染色观察细胞内脂质堆积试验:
(1)取数量为1×106个对数生长期的HepG2细胞株接种于六孔板。待细胞贴壁后,吸去培养基并更换无血清DMEM培养基处理24小时。试验共分为(1.1)对照组:用DMEM培养基(含1%牛血清白蛋白)处理HepG2细胞;(1.2)模型组:由含有油酸钠造模培养基诱导HepG2细胞成为NAFLD细胞模型,诱导方式为终浓度0.5μM的油酸钠处理HepG2细胞24小时,造模培养基的配方为用无水乙醇配置油酸钠母液至250mM,再向含有1%牛血清白蛋白的DMEM培养基中加入油酸钠母液至终浓度0.5μM(如向2mL培养基中加入4μL油酸钠母液);(1.3)黄柏酮处理组:用含有油酸钠的造模培养基和100μM黄柏酮同时处理HepG2细胞;(1.4)柠檬苦素处理组:用含有油酸钠的造模培养基和100μM柠檬苦素同时处理HepG2细胞;(1.5)诺米林处理组:用含有油酸钠的造模培养基和100μM诺米林同时处理HepG2细胞;(1.6)阿托伐他汀处理组:用含有油酸钠的造模培养基和10μM阿托伐他汀同时处理HepG2细胞。
(2)移除细胞培养基,用PBS洗两次,加入油红O固定液固定30min。
(3)弃去固定液,用蒸馏水洗2次。
(4)加入60%异丙醇浸洗30s。
(5)弃去60%异丙醇后加入新配置好的油红O染色液(B1:B2=3:2,若产生沉淀过滤后使用),浸染20min。
(6)弃去染色液,用60%异丙醇漂洗30s至间质清晰。水洗2-5次直到无多余染液。
(7)加入油红O缓冲液1min,弃去。
(8)加入蒸馏水覆盖细胞并在显微镜下观察并拍照记录。
(9)弃去蒸馏水,加入异丙醇震荡5min以溶解细胞内脂肪,可观察到油红O标记的脂肪溶解到异丙醇中。
(10)取100μL在检测490nm处吸收值,数值越高代表细胞油脂含量越高。
结果如图1和图2所示,由图1、2可知:模型组(OA)细胞的红色代表的脂肪含量显著增加,说明NAFLD细胞模型构建成功。在造模的基础上用黄柏酮(Obacunone)处理细胞之后,可以看到细胞内脂肪堆积含量显著减少。与此同时,柠檬苦素(Limonin)、诺米林(Nomilin)和阿托伐他汀(Atorvastatin)组效果较弱。
申请人声明,本发明通过上述实施例来说明本发明的黄柏酮在制备预防、改善或治疗非酒精性脂肪肝的药物中的应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (7)
1.黄柏酮在制备预防、改善或治疗单纯性脂肪肝的药物中的应用,所述预防、改善或治疗单纯性脂肪肝为降低肝脏细胞内的脂质堆积或降低肝脏细胞内的甘油三酯含量。
2.一种预防、改善或治疗单纯性脂肪肝的联合用药物组合物,其特征在于,所述联合用药物组合物的活性成分由黄柏酮和阿托伐他汀组成。
3.根据权利要求2所述的联合用药物组合物,其特征在于,所述联合用药物组合物还包括药学上可接受的辅料,所述药学上可接受的辅料包括填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂中的任意一种或至少两种的组合。
4.根据权利要求3所述的所述联合用药物组合物,其特征在于,所述联合用药物组合物为单一的复方制剂或两种单独的制剂的组合。
5.根据权利要求3所述的所述联合用药物组合物,其特征在于,所述联合用药物组合物为两种单独的制剂的组合。
6.根据权利要求3所述的所述联合用药物组合物,其特征在于,药物组合物剂型为药剂学上可接受的任意一种剂型。
7.根据权利要求2或3所述的联合用药物组合物在制备治疗单纯性脂肪肝的药物中的应用,所述治疗单纯性脂肪肝为降低肝脏细胞内脂质堆积或降低肝脏细胞内的甘油三酯含量。
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