WO2021147151A1 - 岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用 - Google Patents
岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用 Download PDFInfo
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- the invention belongs to the technical field of pharmaceutical preparations, and specifically relates to the application of fucoidan sulfate in promoting the autophagy decomposition of ox-LDL by foam cells.
- AS Atherosclerosis
- ox-LDL oxidized low density lipoprotein
- the specific process is that monocytes enter the endothelium through the endothelial gap and differentiate into macrophages under the action of inflammatory factors.
- the scavenger receptors of the macrophages recognize and engulf ox-LDL to form foam cells, and a large number of foam cells accumulate Form lipid streaks and even atherosclerotic plaques.
- existing studies have shown that in mice and human atherosclerotic plaques, the autophagy-lysosome system of foam cells is destroyed, so that the over-absorbed ox-LDL cannot be decomposed to accelerate the process of AS.
- Fucoidan sulfate is a kind of sulfated polysaccharide containing a high proportion of L-fucose and organic sulfate, mainly derived from brown algae. Current studies have shown that fucoidan sulfate has anti-inflammatory, anti-tumor, anti-oxidant and hypolipidemic effects, as well as inducing autophagic apoptosis of cancer cells. However, the effect of fucoidan sulfate on foam cells and its mechanism have not been reported.
- One of the objectives of the present invention is to provide the application of fucoidan sulfate in promoting autophagy decomposition of ox-LDL by foam cells.
- the second objective of the present invention is to provide a drug for promoting autophagy decomposition of ox-LDL by foam cells.
- the third objective of the present invention is to provide a pharmaceutical composition for promoting autophagy decomposition of ox-LDL by foam cells.
- the present invention relates to the following technical solutions:
- the first aspect of the present invention provides the use of fucoidan sulfate in promoting autophagy decomposition of ox-LDL by foam cells.
- the second aspect of the present invention provides a medicine for promoting the autophagy decomposition of ox-LDL by foam cells, and the active ingredient in the medicine is fucoidan sulfate.
- the effective dose of the drug is 50 ⁇ g/mL and above, more preferably 800 ⁇ g/mL.
- the medicine also contains one or more pharmaceutically or food acceptable excipients.
- the auxiliary materials used can be solid or liquid.
- Solid form preparations include powders, tablets, dispersed granules, capsules, pills, and suppositories. Powders and tablets may contain from about 0.1% to about 99.9% of the active ingredient.
- Suitable solid excipients can be magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, pills and capsules are solid dosage forms suitable for oral use.
- Liquid form preparations include solutions, suspensions and emulsions, or oral solutions containing sweeteners and contrast agents. In addition, it can also be made into small injection needles, freeze-dried powder injections, large infusions or small infusions.
- the third aspect of the present invention provides a pharmaceutical composition comprising the above-mentioned drug and at least one other drug for promoting autophagy decomposition of ox-LDL by foam cells.
- the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection.
- the pharmaceutical composition is a tablet, a dispersible tablet, an enteric-coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar coating, a granule, a dry powder, an oral solution, a small injection needle for injection, Lyophilized powder injection, large infusion or small infusion.
- Fucoidan sulfate can decompose excessive ox-LDL in foam cells by promoting autophagy, and provide a new direction for foam cells to return to normal macrophages, thereby preventing arteriosclerosis.
- the invention provides a new idea for the application of fucoidan sulfate.
- Figure 1 is a graph showing the effect of ox-LDL on macrophages in the example, A: 0-120 ⁇ g/mL ox-LDL on the survival rate of macrophages RAW264.7; B: 0-120 ⁇ g/mL ox- The content of cholesterol ester/total cholesterol in macrophages after LDL treatment. *, p ⁇ 0.05vs Group 0 ⁇ g/mL; **, p ⁇ 0.01vs Group 0 ⁇ g/mL;
- Figure 2 is an oil red O staining diagram after ox-LDL treatment in the embodiment
- Figure 3 is an experimental diagram of the pharmacological activity of fucoidan sulfate on foam cells in the examples.
- AG oil red O staining after fucoidan sulfate treatment
- H the effect of fucoidan sulfate on the survival rate of macrophages Impact
- I The effect of fucoidan sulfate on the content of cholesteryl esters in foam cells, *, p ⁇ 0.05vs Model; **, p ⁇ 0.01vs Model; ***, p ⁇ 0.001vs Model;
- Figure 4 is a graph showing the influence of fucoidan sulfate on foam cell autophagy marker mRNA levels in the examples;
- A LC3B mRNA expression;
- B p62 mRNA expression;
- C TFEB mRNA expression;
- D Lamp1 mRNA expression .
- * p ⁇ 0.05vs Model; **, p ⁇ 0.01vs Model;
- *** p ⁇ 0.001vs Model;
- Figure 5 is a graph showing the influence of fucoidan sulfate on the expression of autophagy marker protein in foam cells in the examples,
- A autophagy marker protein Western blot results
- B ImageJ data processing results.
- Figure 6 is a graph showing the effect of fucoidan on the lipid metabolism of foam cells after 3-MA treatment in the embodiment
- Figure 7 is a diagram showing the effect of fucoidan sulfate on lipid metabolism after Bafilomycin A1 treatment in the embodiment
- Figure 8 shows the cholesterol ester content after autophagy inhibitor treatment in the example.
- A Cholesterol ester content after 5mM 3-MA treatment for 1.5h
- B Cholesterol ester content change after 100nM Bafilomycin A1 treatment for 2h. *, p ⁇ 0.05; **, p ⁇ 0.01; ***, p ⁇ 0.001.
- RAW264.7 with a density of 5 ⁇ 10 4 cells/mL was inoculated on a 24-well plate.
- the experiment was divided into a blank control group and an experimental group. After 24 hours of attachment, the blank control group was given medium, and the experimental group was combined with 80 ⁇ g/mL ox -LDL was incubated together for 24 hours, and then 100, 200, 400, 800 ⁇ g/mL fucoidan sulfate and 342.3 ⁇ g/mL trehalose were given respectively. After 24 hours of treatment, MTT assay was used to detect cell viability, and oil red was used. The O and Cholesterol kits were used for lipid droplet staining and cholesterol ester content determination. It can be seen from Figure 3 that fucoidan sulfate can remove ox-LDL in foam cells.
- Fucoidan sulfate can promote autophagy in foam cells.
- Inoculate RAW264.7 with a density of 5 ⁇ 10 4 cells/mL in a 6-well plate The experiment is divided into a blank control group and an experimental group. After overnight, the blank control group is given medium, and the experimental group is given 80 ⁇ g/mL ox-LDL After treatment for 24 hours, the experimental group was given 200, 400, 800 ⁇ g/mL fucoidan sulfate and 342.3 ⁇ g/mL trehalose, respectively. After treatment for 24 hours, cell lysate and RNA extraction kit were used to extract the cells from the cells. Extract protein and mRNA.
- RAW264.7 with a density of 5 ⁇ 10 4 cells/mL was inoculated on 96-well plate/24-well plate, and the blank control group was given medium after being attached to the wall for 24 hours, and the experimental group was given 80 ⁇ g/mL ox-LDL after 24 hours of treatment
- the autophagy inhibitor 5mM 3-MA(3-Methyladenine) and 100nM Bafilomycin A1 were pretreated for 1.5h and 2h, respectively.
- the blank control group and the model control group were given medium, and the drug treatment group was given 200, 400, 800 ⁇ g/ mL of fucoidan sulfate and 342.3 ⁇ g/mL of trehalose were treated for 24h, and lipid droplet staining and cholesterol ester content determination were performed using oil red O and cholesterol kits, respectively.
- the autophagy inhibitor reversed the scavenging effect of fucoidan sulfate on foam cell ox-LDL.
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Abstract
本发明公开了岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用,属于药物制剂技术领域,岩藻聚糖硫酸酯可以通过促进细胞自噬分解泡沫细胞内过多的ox-LDL,为泡沫细胞恢复成正常巨噬细胞提供了新的方向,为岩藻聚糖硫酸酯的应用提供了新的思路。
Description
本发明属于药物制剂技术领域,具体涉及岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用。
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
随着社会老龄化和城市化进程的加快,居民不健康生活方式的流行,心脑血管疾病(Cardiovascular disease,CVD)的发病率不断上升,已经成为一个世界性难题。而动脉粥样硬化(Atherosclerosis,AS)是心肌梗死和脑梗死等心脑血管事件发病的共同基础,且AS的机制复杂、病程漫长。
在AS的病理学机制中,脂质代谢异常是重要的组成部分。过量的氧化型低密度脂蛋白(oxidized low density lipoprotein,ox-LDL)是使巨噬细胞转变成泡沫细胞的关键。具体过程为单核细胞透过内皮间隙进入内皮,在炎症因子等的作用下分化为巨噬细胞,巨噬细胞的清道夫受体识别并大量吞噬ox-LDL形成泡沫细胞,泡沫细胞的大量堆积形成脂质条纹乃至粥样斑块。且已有研究表明,在小鼠和人类动脉粥样硬化斑块中,泡沫细胞的自噬-溶酶体系统被破坏,致使被过度吸收的的ox-LDL无法被分解从而加速AS的进程。
岩藻聚糖硫酸酯是一种含有高比例L-岩藻糖和有机硫酸酯的硫酸多糖,主要来源于褐藻。目前的研究表明,岩藻聚糖硫酸酯具有抗炎、抗肿瘤、抗氧化和降血脂以及诱导癌细胞自噬性凋亡的作用。但是岩藻聚糖硫酸酯对于泡沫细胞的作用及其作用机制未有报道。
发明内容
为了解决现有技术中存在的问题,发明人经过长期的技术研究和实践探索,发现岩藻聚糖硫酸酯可以促进泡沫细胞中的ox-LDL的清除。这一新发现有可能为防治动脉粥样硬化提供新的解决方案,为心脑血管疾病治疗提供新的药物。
本发明的目的之一在于提供岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用。
本发明的目的之二在于提供一种促进泡沫细胞自噬分解ox-LDL的药物。
本发明的目的之三在于提供一种促进泡沫细胞自噬分解ox-LDL的药物组合物。
为实现上述目的,本发明涉及以下技术方案:
本发明的第一个方面,提供岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用。
经过试验验证,岩藻聚糖硫酸酯对泡沫细胞中ox-LDL的清除具有较好的促进作用,清除机制确定为促进细胞自噬,进而可以有效防治动脉粥样硬化。
本发明的第二个方面,提供一种促进泡沫细胞自噬分解ox-LDL的药物,所述药物中的活性成分为岩藻聚糖硫酸酯。
在一些实施例中,所述药物用药的有效剂量为50μg/mL及以上,进一步优选为800μg/mL。
进一步的,所述药物还包含一种或多种药学上或食品学上可接受的辅料。所用辅料可为固态或液态。固态形式的制剂包括粉剂、片剂、分散颗粒、胶囊、药丸及栓剂。粉剂及片剂可包含约0.1%至约99.9%的活性成分。适当的固体辅料可以是碳酸镁、硬脂酸镁、滑石粉、糖或者乳糖。片剂、粉剂、药丸及胶囊为适于口服用的固态剂型。液态形式的制剂包括溶液、悬浮液及乳液,或添加 甜味剂及造影剂的口服溶液。此外,还可制成注射用小水针、注射用冻干粉针、大输液或小输液。
本发明的第三个方面,提供一种药物组合物,所述药物组合物包括上述药物与其他至少一种用于促进泡沫细胞自噬分解ox-LDL的药物。
优选的,所述药物组合物为固体口服制剂、液体口服制剂或注射剂。
进一步优选的,所述药物组合物为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
本发明的有益效果是:
岩藻聚糖硫酸酯可以通过促进细胞自噬分解泡沫细胞内过多的ox-LDL,为泡沫细胞恢复成正常巨噬细胞提供了新的方向,从而起到防治动脉硬化的效果。本发明为岩藻聚糖硫酸酯的应用提供了新的思路。
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为实施例中ox-LDL对巨噬细胞的影响图,A:0-120μg/mL的ox-LDL对巨噬细胞RAW264.7存活率的影响;B:0-120μg/mL的ox-LDL处理后巨噬细胞中胆固醇酯/总胆固醇的含量。*,p<0.05vs Group 0μg/mL;**,p<0.01vs Group 0μg/mL;
图2为实施例中ox-LDL处理后油红O染色图;
图3为实施例中岩藻聚糖硫酸酯对泡沫细胞药理活性试验图,A-G:岩藻聚糖硫酸酯处理后油红O染色;H:岩藻聚糖硫酸酯对巨噬细胞存活率的影响;I:岩藻聚糖硫酸酯对泡沫细胞内胆固醇酯含量的影响,*,p<0.05vs Model; **,p<0.01vs Model;***,p<0.001vs Model;
图4为实施例中岩藻聚糖硫酸酯对泡沫细胞自噬标志蛋白mRNA水平的影响图;A:LC3B mRNA表达量;B:p62mRNA表达量;C:TFEB mRNA表达量;D:Lamp1mRNA表达量。*,p<0.05vs Model;**,p<0.01vs Model;***,p<0.001vs Model;
图5为为实施例中岩藻聚糖硫酸酯对泡沫细胞自噬标志蛋白表达量的影响图,(A)自噬标志蛋白Western blot结果(B)ImageJ数据处理结果。*,p<0.05vs Model;**,p<0.01vs Model;***,p<0.001vs Model;#,p<0.05vs Control;**,p<0.01vs Control;***,p<0.001vs Control;
图6为实施例中3-MA处理后岩藻聚糖对泡沫细胞脂质代谢的影响图;
图7为实施例中Bafilomycin A1处理后岩藻聚糖硫酸酯对脂质代谢的影响图;
图8为实施例中自噬抑制剂处理后胆固醇酯含量,A:5mM 3-MA处理1.5h后胆固醇酯含量;B:100nM Bafilomycin A1处理2h后胆固醇酯含量变化。*,p<0.05;**,p<0.01;***,p<0.001。
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本发明的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
实施例
使用巨噬细胞RAW264.7构建泡沫细胞模型:
将密度为5×10
4个/mL的RAW264.7接种于96孔板/24孔板,贴壁24h后给与0、20、40、80、100、120μg/mL的ox-LDL,共同孵育24h后,使用油红O和胆固醇试剂盒分别进行脂滴染色以及胆固醇酯的含量测定,由图1和图2确定泡沫细胞适宜的造模浓度为80μg/mL。
岩藻聚糖硫酸酯(市售sigma公司)对泡沫细胞的药理活性试验:
将密度为5×10
4个/mL的RAW264.7接种于24孔板,实验分为空白对照组和实验组,贴壁24h后,空白对照组给与培养基,实验组与80μg/mL ox-LDL共同孵育24h,然后分别给与100、200、400、800μg/mL的岩藻聚糖硫酸酯和342.3μg/mL的海藻糖,处理24h后,MTT实验检测细胞存活率,并使用油红O和胆固醇试剂盒分别进行脂滴染色以及胆固醇酯的含量测定,由图3可知,岩藻聚糖硫酸酯可以清除泡沫细胞内的ox-LDL。
岩藻聚糖硫酸酯可以促进泡沫细胞自噬。
将密度为5×10
4个/mL的RAW264.7接种于6孔板,实验分为空白对照组和实验组,过夜后空白对照组给与培养基,实验组给予80μg/mL的ox-LDL,处理24h后,实验组分别给与200、400、800μg/mL的岩藻聚糖硫酸酯和342.3μg/mL的海藻糖,处理24h后,分别使用细胞裂解液和RNA提取试剂盒从细胞中提取蛋白质和mRNA。
使用RevertAid
TM First Strand cDNA Synthesis Kit将分离的mRNA逆转录成互补cDNA,再使用qRT-PCR进行自噬标志物p62、LC3B、Lamp1和TFEB的表达水平测定,从基因水平确定岩藻聚糖硫酸酯对泡沫细胞自噬的影响。使用Western-Blot对提取的蛋白质进行自噬标志物LC3B、p62、TFEB、Atg4B、 Atg5、Atg16等蛋白表达量的测定,从蛋白质水平确定岩藻聚糖硫酸酯对泡沫细胞自噬的影响。由图4和图5可知,岩藻聚糖硫酸酯可以促进泡沫细胞自噬。
将密度为5×10
4个/mL的RAW264.7接种于96孔板/24孔板,贴壁24h后空白对照组给与培养基,实验组给予80μg/mL的ox-LDL,处理24h后分别用自噬抑制剂5mM 3-MA(3-Methyladenine)、100nM Bafilomycin A1预处理1.5h和2h,空白对照组和模型对照组给与培养基,药物处理组分别给与200、400、800μg/mL的岩藻聚糖硫酸酯和342.3μg/mL的海藻糖处理24h,使用油红O和胆固醇试剂盒分别进行脂滴染色以及胆固醇酯的含量测定。如图6、图7和图8所示,自噬抑制剂逆转了岩藻聚糖硫酸酯对泡沫细胞ox-LDL的清除效果。
结论和意义:试验利用ox-LDL成功构建泡沫细胞模型,通过油红O染色和胆固醇酯的含量测定证明了岩藻聚糖硫酸酯可以分解泡沫细胞内过多的ox-LDL。此外,通过对岩藻聚糖硫酸酯处理后泡沫细胞内自噬标志物的mRNA和蛋白质表达水平,确定了岩藻聚糖硫酸酯的ox-LDL消除作用是通过促进细胞自噬实现的,并通过自噬抑制剂进一步验证。以上结果为泡沫细胞恢复成正常巨噬细胞提供了新的方向,为岩藻聚糖硫酸酯的应用提供了新的思路。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
- 岩藻聚糖硫酸酯在促进泡沫细胞自噬分解ox-LDL中的应用。
- 一种促进泡沫细胞自噬分解ox-LDL的药物,其特征在于:所述药物中的活性成分为岩藻聚糖硫酸酯。
- 根据权利要求2所述的药物,其特征在于:所述药物用药的有效剂量为50μg/mL及以上,优选为800μg/mL。
- 根据权利要求2所述的药物,其特征在于:所述药物还包含一种或多种药学上或食品学上可接受的辅料。
- 根据权利要求4所述的药物,其特征在于:所用辅料可为固态或液态。
- 根据权利要求5所述的药物,其特征在于:固态形式的制剂包括粉剂、片剂、分散颗粒、胶囊、药丸及栓剂;粉剂及片剂可包含约0.1%至约99.9%的活性成分。
- 根据权利要求6所述的药物,其特征在于:固体辅料是碳酸镁、硬脂酸镁、滑石粉、糖或者乳糖;液态形式的制剂包括溶液、悬浮液及乳液。
- 一种药物组合物,其特征在于:所述药物组合物包括上述药物与其他至少一种用于促进泡沫细胞自噬分解ox-LDL的药物。
- 根据权利要求8所述的药物组合物,其特征在于:所述药物组合物为固体口服制剂、液体口服制剂或注射剂。
- 根据权利要求8所述的药物组合物,其特征在于:所述药物组合物为片剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小水针、注射用冻干粉针、大输液或小输液。
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