CN111212636A - 橄榄裂环烯醚萜用于动脉粥样硬化预防 - Google Patents
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Abstract
公开了橄榄裂环烯醚萜用于通过有效抑制巨噬细胞摄取oxLDL(特别是通过降低巨噬细胞清道夫受体的表达)来抑制泡沫细胞形成过程的用途。根据本发明生产的含橄榄裂环烯醚萜的药物制剂可用于治疗和/或预防动脉粥样硬化，特别是用于预防早期动脉粥样硬化病变。
Description
本发明的目的是橄榄裂环烯醚萜(oleacein)用于通过有效抑制巨噬细胞摄取oxLDL(特别是由于巨噬细胞清道夫受体表达降低的结果)来抑制泡沫细胞形成过程的用途。根据本发明生产的含橄榄裂环烯醚萜的药物制剂可用于治疗和/或预防动脉粥样硬化，特别是用于预防早期动脉粥样硬化病变。
橄榄裂环烯醚萜是式1的化合物，在文献中也称为3,4-DHPEA-EDA，其是用烯酸的二醛衍生物酯化的3,4-二羟基苯基乙醇(羟基酪醇(hydroxytyrosol))。
Czerwińska M.等人，EAS 2012,abstract book 2012-05-29,第1108页公开了关于橄榄裂环烯醚萜对髓过氧化物酶释放(MPO)的影响的研究结果，该研究结果是使用选定的一组细胞(即从健康志愿者的外周血中体外分离的中性粒细胞)进行的。另外，从Czerwińska M.等人,Food Chemistry，第131卷，第3期.2011-09-20，第940-947页已知橄榄裂环烯醚萜对从血液分离的中性粒细胞释放MPO的影响。结果表明橄榄裂环烯醚萜对氧化损伤的保护作用。
动脉粥样硬化是基于内皮功能障碍和慢性炎症的综合征。单核细胞、巨噬细胞和改性的低密度脂蛋白(LDL)(主要是氧化部分(oxLDL))被认为在动脉粥样硬化发病机理中起主要作用。oxLDL对内皮细胞(EC)的损害引发一系列促炎症反应，从而导致粘附分子(ICAM-1，VCAM-1)和趋化因子(M-CSF，MCP-1)的活化。这导致单核细胞向血管内膜的迁移增加。在该位置，单核细胞转化为巨噬细胞，其摄取oxLDL并转化为泡沫细胞。泡沫细胞是动脉粥样硬化斑块的主要结构成分，并且在动脉粥样硬化的发展中起重要作用，其导致中风和/或心肌梗塞和死亡。
巨噬细胞结合oxLDL在摄取过程之前，并涉及清道夫受体(SR)。清道夫受体是蛋白质，并且它们在整个人体的生理和病理过程中起重要作用。它们的功能是在凋亡或坏死阶段结合改性的脂蛋白、聚阴离子和细胞。从SR-A到SR-G，共有7类SR。在脂质沉积物(泡沫细胞)的积累中，主要涉及来自A类–SRA(CD204)，来自B类–CD36和来自E类-LOX-1(凝集素样oxLDL受体)的受体。
波兰专利申请P.399962公开了普通女贞(Ligustrum vulgare L.)用于制备包含橄榄裂环烯醚萜的制剂中的用途，所述制剂用于抑制存在于动脉粥样硬化斑块中的细胞的MMP-9表达，以及用于稳定动脉粥样硬化斑块，特别是用于治疗和预防由动脉粥样硬化斑块的崩解引起的疾病，特别是选自包括以下的组的那些疾病：缺血性中风、心肌衍射和缺血性心脏病。
本发明的目的是提供一种可通过有效抑制巨噬细胞摄取oxLDL(特别是由于巨噬细胞清道夫受体的表达降低的结果)来抑制泡沫细胞形成过程的制剂。这种制剂可以用于治疗和预防动脉粥样硬化，特别是用于预防早期动脉粥样硬化阶段。
令人惊讶地，在本发明中实现了本文提出的目标。
本发明的目的是提供用于体内抑制泡沫细胞形成过程和/或抑制巨噬细胞中的脂质沉积物的形成的用途的橄榄裂环烯醚萜，优选通过有效抑制巨噬细胞摄取oxLDL，特别是由于巨噬细胞上的清道夫受体的表达降低的结果。优选地，橄榄裂环烯醚萜降低选自以下的清道夫受体的表达：CD36、LOX-1和SRA(CD204)。优选地，橄榄裂环烯醚萜旨在用于治疗或预防动脉粥样硬化，特别是用于预防早期动脉粥样硬化阶段。
优选地，使用源自普通女贞(Ligustrum vulgare L.)的橄榄裂环烯醚萜，特别是通过专利申请P.399962中公开的方法分离的橄榄裂环烯醚萜。
已经显示(专利申请P.399962)橄榄裂环烯醚萜对稳定人的动脉粥样硬化斑块的潜在贡献。本发明证明，通过抑制动脉粥样硬化斑块形成之前的过程，橄榄裂环烯醚萜也可以用于预防早期的动脉粥样硬化病变。
实施例1.由普通女贞(Ligustrum vulgare L.)的叶子制备橄榄裂环烯醚萜
橄榄裂环烯醚萜可得自来自油橄榄科(Oleacea family)的各种植物，即橄榄树(油橄榄)和普通女贞(common privet)(Ligustrum vulgare L.)，特别是来自普通女贞的叶子。普通女贞(Ligustrum vulgare L.)是欧洲常见的观赏植物，通常用于种植树篱。使用专利申请P.399962中公开的方法从普通女贞的叶子中分离出橄榄裂环烯醚萜。
400g接地的原料用于分离。在第一阶段，普通女贞叶使用超声清洗器在30℃下用蒸馏水萃取四次，每次30分钟。以1∶10的原料：溶剂比例进行萃取。通过棉絮过滤水性萃取物并合并。通过冻干将获得的水性萃取物浓缩至约1L的最终体积。为了进一步纯化萃取物并提高所需化合物分离过程的效率，使用二乙醚代替乙酸乙酯。如先前的分析所示，用乙酸乙酯制备的萃取物包含更多的化学化合物，因此在橄榄裂环烯醚萜的分离过程中产生困难。然后将浓缩的水性萃取物用二乙醚以1∶1的溶剂：萃取物比例萃取5次。在减压下于35℃下将乙醚萃取物在旋转蒸发仪上进行浓缩。获得约5克的醚萃取物。
通过使用氯仿和乙酸乙酯的混合物(85:15)在等度模式下通过在硅胶柱(PF-30SIHP/80G PuriFlash)上的快速色谱法分离乙醚萃取物持续60分钟(20mL/min)。总共获得9个级分，并选择级分3和4进行进一步分离。将这些级分在硅胶柱(PF-30 SIHP/80GPuriFlash)上使用甲苯、乙酸甲酯和甲醇(84：11：5)的混合物在等度模式下进行进一步分离持续60分钟(20mL/min)。总共获得5个馏分。将级分3加载至Sephadex柱上，并使用氯仿和甲醇(9∶1)的混合物从其中分离出橄榄裂环烯醚萜。获得总计1.289g的化合物。通过NMR和HPLC-DAD-MS/MS方法确认化合物的身份。
实施例2.橄榄裂环烯醚萜作为抑制动脉粥样硬化发展过程中由人巨噬细胞形成泡沫细胞的化合物。
所有实验均使用从人外周血分离的巨噬细胞进行。将巨噬细胞与oxLDL和浓度为20μmol/L和50μmol/L的橄榄裂环烯醚萜孵育72小时。所使用的橄榄裂环烯醚萜剂量显示对巨噬细胞没有细胞毒性。使用流式细胞仪(flow cytometer)确定清道夫受体的表达。巨噬细胞(泡沫细胞)中的脂质沉积物的可视化是通过使用众所周知的红油O染色方法进行的。
获得的结果如图1所示。使用流式细胞仪测定了橄榄裂环烯醚萜对泡沫细胞中清道夫受体即SRA(A)、CD36(B)和LOX-1(C)表达的影响，并显示为直方图。在直方图中，在用oxLDL刺激巨噬细胞的情况下，M1标志物显示SRA、CD36和LOX-1受体的最大表达。对照-无刺激的细胞，OC-用橄榄裂环烯醚萜(50μmol/L)孵育的细胞，OC+oxLDL-用橄榄裂环烯醚萜(50μmol/L)和oxLDL(50μg/mL)孵育的细胞，oxLDL-用oxLDL(50μg/mL)刺激的细胞-经刺激的对照。
评估橄榄裂环烯醚萜对泡沫细胞中清道夫受体(CD36，SRA和LOX-1)表达的影响的实验结果总结在图2中。使用以下标记：#-对50μg/mL的浓度下的oxLDL刺激的细胞(刺激对照)，OC20+oxLDL-用20μmol/L的橄榄裂环烯醚萜和50μg/mL的oxLDL孵育的巨噬细胞，OC50+oxLDL-用50μmol/L的橄榄裂环烯醚萜和50μg/mL的oxLDL孵育的巨噬细胞确定统计显著性(*-p<0.05,**-p<0.001)。
总之，获得的结果证明，橄榄裂环烯醚萜明显降低了巨噬细胞清道夫受体的表达。证明的橄榄裂环烯醚萜活性取决于所用剂量。报告了CD36受体活性下降最大(从约23％至约84％，p<0.001)，而注意到LOX-1下降最小(从约8％至约25％，p<0.05)。另一方面，报告了对于SRA受体活性下降约20％和约75％(p<0.05；p<0.001)。
此外，图3显示了使用红油O在巨噬泡沫细胞中观察到的脂质沉积物的可视化。图像是使用荧光显微镜Nikon TS100F采集的。D–对照，无刺激的细胞，E–用橄榄裂环烯醚萜(50μmol/L)孵育的细胞，F–用oxLDL(50μg/ml)刺激的细胞–经刺激的对照，G–用橄榄裂环烯醚萜(50μmol/L)和oxLDL(50μg/mL)孵育的细胞。
迄今为止，橄榄裂环烯醚萜是唯一显示出对泡沫细胞和脂质沉积物的形成具有抑制作用的天然物质。
Claims (7)
1.用于体内抑制泡沫细胞形成过程和/或抑制巨噬细胞中的脂质沉积物形成的用途的橄榄裂环烯醚萜。
2.权利要求1所述的用于所述用途的橄榄裂环烯醚萜，特征在于其旨在抑制通过巨噬细胞摄取oxLDL。
3.权利要求1所述的用于所述用途的橄榄裂环烯醚萜，特征在于其旨在减少巨噬细胞清道夫受体的表达。
4.权利要求1所述的用于所述用途的橄榄裂环烯醚萜，特征在于其旨在减少选自以下的巨噬细胞清道夫受体的表达：CD36、LOX-1和SRA(CD204)。
5.权利要求1所述的用于所述用途的橄榄裂环烯醚萜，特征在于其旨在用于动脉粥样硬化治疗和/或预防。
6.权利要求1所述的用于所述用途的橄榄裂环烯醚萜，特征在于其旨在用于预防早期的动脉硬化性病变。
7.权利要求1所述的用于所述用途的橄榄裂环烯醚萜，特征在于其由普通女贞(Ligustrum vulgare L.)制成。
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| Application Number | Priority Date | Filing Date | Title |
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| PL423146A PL423146A1 (pl) | 2017-10-12 | 2017-10-12 | Oleaceina do zastosowanie w prewencji miażdżycy |
| PLP.423146 | 2017-10-12 | ||
| PCT/PL2018/050023 WO2019074383A1 (en) | 2017-10-12 | 2018-05-30 | OLEACEIN FOR USE IN THE PREVENTION OF ATHEROSCLEROSIS |
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| US (1) | US20200237703A1 (zh) |
| EP (1) | EP3470069A1 (zh) |
| JP (1) | JP2020536964A (zh) |
| CN (1) | CN111212636A (zh) |
| CA (1) | CA3078910A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014012871A1 (en) * | 2012-07-14 | 2014-01-23 | Warszawski Uniwersytet Medyczny | Oleacein for treating or preventing diseases resulting from atherosclerotic plaques |
| CN106794213A (zh) * | 2014-10-16 | 2017-05-31 | 三得利控股株式会社 | 含有橄榄果实提取物的Tie2活化剂 |
-
2017
- 2017-10-12 PL PL423146A patent/PL423146A1/pl unknown
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2018
- 2018-05-30 EP EP18461563.1A patent/EP3470069A1/en not_active Withdrawn
- 2018-05-30 CA CA3078910A patent/CA3078910A1/en not_active Abandoned
- 2018-05-30 US US16/755,346 patent/US20200237703A1/en not_active Abandoned
- 2018-05-30 JP JP2020541638A patent/JP2020536964A/ja active Pending
- 2018-05-30 WO PCT/PL2018/050023 patent/WO2019074383A1/en active Application Filing
- 2018-05-30 CN CN201880066501.6A patent/CN111212636A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014012871A1 (en) * | 2012-07-14 | 2014-01-23 | Warszawski Uniwersytet Medyczny | Oleacein for treating or preventing diseases resulting from atherosclerotic plaques |
| CN106794213A (zh) * | 2014-10-16 | 2017-05-31 | 三得利控股株式会社 | 含有橄榄果实提取物的Tie2活化剂 |
Non-Patent Citations (1)
| Title |
|---|
| MAREK NARUSZEWICZ等: "Oleacein. Translation from Mediterranean Diet to Potential Antiatherosclerotic Drug", 《CURRENT PHARMACEUTICAL DESIGN》 * |
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| Publication number | Publication date |
|---|---|
| WO2019074383A1 (en) | 2019-04-18 |
| CA3078910A1 (en) | 2019-04-18 |
| PL423146A1 (pl) | 2019-04-23 |
| EP3470069A1 (en) | 2019-04-17 |
| US20200237703A1 (en) | 2020-07-30 |
| JP2020536964A (ja) | 2020-12-17 |
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