CN113662948A - 磷脂及其衍生物在制备改善系统性红斑狼疮制品中的应用 - Google Patents
磷脂及其衍生物在制备改善系统性红斑狼疮制品中的应用 Download PDFInfo
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Abstract
本发明属于活性物质筛选技术领域,具体涉及一种磷脂在制备改善系统性红斑狼疮制品中的应用。包括磷脂及其糖基化衍生物,如磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酰糖苷和富含DHA的磷脂。本发明通过实验研究,证实了磷脂及其衍生物在改善系统性红斑狼疮方面具有显著的改善作用,使磷脂增加了一种新用途,有产业利用价值,而且该结果可应用于在改善系统性红斑狼疮的医学临床实践,用于开发相关的药品和保健品,具有潜在的经济和社会效益。
Description
技术领域:
本发明属于活性物质筛选技术领域,具体涉及一种磷脂及其衍生物在制备改善系统性红斑狼疮制品中的应用。
背景技术:
系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种严重的慢性、反复发作的弥漫性结缔组织疾病。SLE通过遗传、环境、机体免疫和激素因子等多种因素的相互作用诱发自身抗原激活机体的先天性和适应性免疫应答,诱导自身抗体的产生,并且组织中免疫复合物的沉积导致补体的激活,中性粒细胞、单核细胞以及自身反应性淋巴细胞的增多。SLE可以引起全身多种器官的组织损伤,最常见的是皮肤和肾脏。目前临床上针对系统性红斑狼疮的治疗药物主要包括糖皮质激素、羟氯喹、环磷酰胺等,长时间服用会引起毒副反应,目前临床上尚未有彻底治疗SLE的药物。己有越来越多的研究表明营养干预措施对缓解疾病的重要性,膳食补充功能性成分或者营养补充剂可以改善系统性红斑狼疮。
磷脂是广泛存在于动植物组织中的一类脂质。目前,商业磷脂的主要来源是大豆和卵黄。除陆生生物外,磷脂还在鱼卵、虾、贝等海洋动物以及海洋植物中广泛存在。海洋来源的磷脂具有特殊结构,其sn-2位富含二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。磷脂具有重要的生理作用和营养价值,在食品、医药、化妆品和纺织等行业均有应用。磷脂作为乳化剂在聚合物包装膜、药物及活性物质的运输方面起到重要作用,并且磷脂对肝损伤、心脑血管疾病、急性肾损伤等方面具有改善作用。然而目前尚未有研究关注磷脂及其衍生物对系统性红斑狼疮的改善作用。
发明内容:
本发明要解决的技术问题是目前临床上仍没有研究摄入磷脂及其衍生物对系统性红斑狼疮的作用。
为解决上述问题,本发明通过实验研究,证实了磷脂及其衍生物在改善系统性红斑狼疮方面具有显著的改善作用,使磷脂增加了一种新用途,提高其产业利用价值,而且该结果可应用于在改善系统性红斑狼疮的医学临床实践,用于开发相关的药品和保健品,具有潜在的经济和社会效益。
为达到上述目的,本发明具体通过以下技术方案实现:
磷脂及其衍生物在制备改善系统性红斑狼疮制品中的应用。
进一步的,所述磷脂及其衍生物包括磷脂及其糖基化衍生物,如磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酰糖苷和富含DHA的磷脂,此处DHA也可以是其他海洋来源的n-3多不饱和脂肪酸,如EPA。
进一步的,所述磷脂及其衍生物为从大豆或鱿鱼卵中提取分离出的磷脂及其衍生物,此处鱿鱼卵也可以是其他海洋食品。
本发明分别从大豆、鱿鱼卵中提取分离以及制备出六种不同磷脂,包括系列物I-ⅤI,系列物Ⅰ到Ⅲ是大豆来源的磷脂和磷脂衍生物,系列物Ⅰ是大豆来源的磷脂酰胆碱,在它的sn-2位脂肪酸主要是亚油酸,其极性头部为磷脂酰胆碱;系列物Ⅱ是大豆来源的磷脂酰糖苷,其极性头部为磷脂酰糖苷;系列物Ⅲ是大豆来源的磷脂酰丝氨酸,其极性头部为磷脂酰丝氨酸。系列物Ⅳ-Ⅵ是鱿鱼卵来源的磷脂,系列物Ⅳ是富含DHA的磷脂酰胆碱,其sn-2位脂肪酸主要是DHA,极性头部为磷脂酰胆碱;系列物Ⅴ是富含DHA的磷脂酰丝氨酸,其极性头部为磷脂酰丝氨酸;系列物Ⅵ是富含DHA的磷脂酰乙醇胺,其极性头部为磷脂酰乙醇胺。六种化合物都具有甘油骨架,脂肪酸和极性头部,虽然均属于磷脂,但结构上存在差异,最终导致它们的生理活性也存在差异。首先磷脂因其来源不同,具有不同的脂肪酸组成。大豆磷脂中C18:2n-6占脂肪酸组成的近50%,海洋来源的磷脂则富含EPA和DHA两种n-3脂肪酸。磷脂的生物活性与其脂肪酸组成密切相关,例如研究发现富含DHA或EPA的磷脂对代谢综合征和急性肾损伤的改善作用优于大豆磷脂。然而磷脂的生物活性有时不仅依赖于脂肪酸组成,磷脂的极性头部也是影响其生物活性的重要因素。磷脂酰胆碱作为胆碱的主要膳食来源,对维持肝脏和肾脏功能、脂质代谢和运输、细胞膜信号传递、细胞组成和修复都起着至关重要的作用;磷脂酰乙醇胺俗称脑磷脂,对维持细胞形态正常、调控细胞代谢、改善神经退行性疾病具有重要的作用。磷脂酰丝氨酸是细胞膜磷脂的重要成分,在神经细胞的修复及细胞代谢的调节过程中具有重要作用。针对本发明来讲,通过膳食干预磷脂及其糖基化衍生物,达到改善系统性红斑狼疮的目的。第一,狼疮肾炎(lupus nephritis,LN)是系统性红斑狼疮患者最常见的严重并发症,LN也是造成SLE患者死亡的主要危险因素,而免疫调节失衡是LN发生发展的重要环节,肾内炎性细胞和炎性因子的大量浸润导致不可逆肾损害是LN的主要原因。因此,寻找调节自身免疫功能潜在方法,通过抑制炎症反应对于开发LN治疗药物至关重要。此外研究表明NF-κB的激活与LN免疫失衡密切相关。NF-κB是关键的炎症启动因子,其激活有赖于IKKβ活性使IκB磷酸化,激活后NF-κB进入细胞核内促进炎症反应。所以本发明通过膳食干预磷脂及其糖基化衍生物,进而选择性抑制NF-κB活性,达到改善LN导致肾损伤的目的。第二,研究表明饮食中胆碱的摄入水平被认为与血清炎症因子水平负相关,PC中存在的胆碱是卵黄PC能够降低炎症反应的可能原因之一。体外实验表明有两种PE分子能够抑制PAF(血小板活化因子,一种参与慢性炎症反应的炎症介质)诱导的血小板聚集。因此通过营养干预PC或PE可以促进肾脏磷脂组成正常化以及降低体内炎症水平,这可能也是富含DHA的PC或者PE效果优于磷脂酰糖苷和PS的原因之一。第三,最新研究结果表明肾脏疾病小鼠脂肪酸组成会发生显著性变化。数据显示小鼠肾脏中亚油酸含量会显著升高,而多不饱和脂肪酸,特别是DHA和EPA含量减少。因此通过膳食补充DHA或者EPA可以提高肾脏疾病小鼠体内缺乏的多不饱和脂肪酸,从而促进肾脏恢复。实验室前期研究表明与普通DHA相比,磷脂形式的DHA可以显著提高组织中DHA、EPA水平。尽管已有研究表明磷脂形式的DHA可以改善药物诱导的急性肾损伤,但急性肾损伤与狼疮肾炎病理机制存在差异。急性肾损伤主要是由肾缺血或肾毒性药物而导致的一类重症疾病,其发病机制主要包括线粒体功能障碍、氧化应激反应及肾小管上皮细胞坏死和凋亡等,而狼疮肾炎主要与肾脏免疫复合物形成与沉积、炎症活化和自噬密切相关。虽然已有研究发现溶血磷脂酰胆碱一种具有良好抗炎活性的活性成分,可以改善多种炎性疾病,如肝炎,但溶血磷脂酰胆碱是氧化型低密度脂蛋白的主要成分,其在体内会激活蛋白激酶C,引起血管平滑肌收缩,导致内皮依赖性收缩;此外它也会破坏纤溶和凝血系统的平衡,调控单核巨噬细胞,淋巴细胞的免疫功能,长期服用有可能促进动脉粥样硬化。而磷脂则具有多种生理活性,膳食补充富含DHA的磷脂不但可以抑制体内炎症,提高机体免疫力,而且可以改善动脉粥样硬化,预防多种神经退行性疾病。我们后续通过测定血清炎症、免疫相关因子和肾脏炎症相关基因分析了磷脂及其衍生物和普通DHA与大豆来源磷脂的复配对系统性红斑狼疮的功效差异。
进一步的,所述制品包括特医食品、保健品、药品或者生物制剂,及相关制品,如乳剂等。
进一步的,所述制品包含有药理有效浓度(1%-100%)的所述的权利要求1所述的磷脂及其衍生物。
进一步的,所述磷脂及其衍生物的制备方法包括以下步骤:
(1)将鱿鱼卵或大豆冻干,然后粉碎处理,用15倍体积的氯仿/甲醇(2∶1,V/V)混合液浸提24h,抽滤,浸提3次;然后加入氯化钠溶液,摇匀并静止过夜,收集下层氯仿层,经减压浓缩得到鱿鱼卵或者大豆脂质粗提取物;
(2)将脂质粗提物采用正相硅胶柱层析法分离,三氯甲烷和甲醇(90∶10→60∶40→0∶100,V/V)梯度洗脱,分步收集洗脱液,减压浓缩,采用TLC法初步检测收集物成分,合并Rf值相同的组分,减压浓缩至干,得到磷脂酰胆碱和磷脂酰乙醇胺(系列物Ⅰ或系列物Ⅳ、系列物Ⅵ);
(3)配制pH=5.6醋酸钠缓冲溶液,添加6%果糖、1.5%Lipozyme435溶于缓冲液中作为水相,20%步骤(2)得到的大豆来源磷脂酰胆碱溶于甲醇中作为有机相,将水相和有机相充分混合,水相与有机相比为1:4;混合物37℃搅拌反应10h,收集有机相层,将有机溶剂除去即得到磷脂酰糖苷(系列物Ⅱ);
(4)将醋酸/醋酸钠溶液缓冲液放入集热式恒温加热磁力搅拌器中预热,将L-丝氨酸溶于其中,加入上述步骤(2)中的不同来源的磷脂酰胆碱,最后加入磷脂酶D,在40℃下搅拌反应48h,加入盐酸,灭活酶,反应终止,用正己烷-异丙醇提取反应产物,即得到大豆磷脂酰丝氨酸(系列物Ⅲ)和DHA磷脂酰丝氨酸(系列物Ⅴ)。
本发明的有益效果如下:
(1)通过动物实验发现了磷脂及其衍生物在改善系统性红斑狼疮中的显著作用,为系统性红斑狼疮的预防与治疗提供了新的理论途径。
(2)为磷脂及其衍生物在改善系统性红斑狼疮制品的应用给出了合理的指导,具有广阔的市场前景。
附图说明
图1为实施例2系统性红斑狼疮小鼠干预磷脂及其衍生物后的皮肤损害的结果图;
图2为实施例2磷脂及其衍生物对系统性红斑狼疮小鼠干预磷脂及其衍生物后的血清生化指标影响的结果图;
图3为实施例2磷脂及其衍生物对系统性红斑狼疮小鼠干预磷脂及其衍生物后的脾脏重量结果图;
图4为实施例2磷脂及其衍生物对系统性红斑狼疮小鼠干预磷脂及其衍生物后的血清炎症和免疫因子结果图;
图5为实施例2磷脂及其衍生物对系统性红斑狼疮小鼠干预磷脂及其衍生物后的肾脏多个RNA表达结果图;
图6为实施例2磷脂及其衍生物对系统性红斑狼疮小鼠干预磷脂及其衍生物后的肾脏NF-κB蛋白表达结果图。
具体实施方式:
为使本发明实施例的目的、技术方案和优点更加清楚,下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:磷脂及其衍生物的制备
(1)将鱿鱼卵或大豆冻干,然后粉碎处理,用15倍体积的氯仿/甲醇(2∶1,V/V)混合液浸提24h,抽滤,浸提3次;然后加入氯化钠溶液,摇匀并静止过夜,收集下层氯仿层,经减压浓缩得到鱿鱼卵或者大豆脂质粗提取物;
(2)将脂质粗提物采用正相硅胶柱层析法分离,三氯甲烷和甲醇(90∶10→60∶40→0∶100,V/V)梯度洗脱,分步收集洗脱液,减压浓缩,采用TLC法初步检测收集物成分,合并Rf值相同的组分,减压浓缩至干,得到磷脂酰胆碱和磷脂酰乙醇胺;
(3)配制pH=5.6醋酸钠缓冲溶液,添加6%果糖、1.5%Lipozyme435溶于缓冲液中作为水相,20%大豆磷脂酰胆碱溶于甲醇中作为有机相,将水相和有机相充分混合,水相与有机相比为1:4;混合物37℃搅拌反应10h,收集有机相层,将有机溶剂除去即得到磷脂酰糖苷;
(4)将醋酸/醋酸钠溶液缓冲液放入集热式恒温加热磁力搅拌器中预热,将L-丝氨酸溶于其中,加入上述步骤(2)中的Soy-PC或DHA-PC,最后加入磷脂酶D,在40℃下搅拌反应48h,加入盐酸,灭活酶,反应终止,用正己烷-异丙醇提取反应产物,即得到大豆磷脂酰丝氨酸(Soy-PS)和DHA磷脂酰丝氨酸(DHA-PS)。
实施例2:动物实验
(1)实验设计
六周龄MRL/lpr雌性小鼠随机分为9组:模型对照组(M)、系列物Ⅰ大豆来源的磷脂酰胆碱组(Soy-PC),系列物Ⅱ大豆来源的磷脂酰糖苷组(Soy-PG),系列物Ⅲ大豆来源的磷脂酰丝氨酸组(Soy-PS),DHA与大豆来源的磷脂酰胆碱复配组(DHA+PC),DHA与大豆来源的磷脂酰丝氨酸复配组(DHA+PS),系列物Ⅳ富含DHA的磷脂酰胆碱组(DHA-PC),系列物Ⅴ富含DHA的磷脂酰丝氨酸组(DHA-PS),系列物Ⅵ富含DHA的磷脂酰乙醇胺组(DHA-PE),同周龄的C57BL6雌性小鼠作为正常对照组(N)。小鼠喂食改良AIN-93G啮齿动物饲料。MRL/lpr小鼠每日喂食添加1%磷脂的饲料。期间记录小鼠生长情况以及生存状态。连续干预十四周后,小鼠禁食过夜,收集血液等样本,用于后续生化指标检测。
(2)统计学处理
实验数据以x±SEM表示,采用SPSS 18.0软件进行Student’s t test和Tukey’stest分析,以P<0.05为有显著差异。
(3)实验结果
磷脂及其衍生物在改善系统性红斑狼疮中的效果如图1-6所示。喂养期间,MRL/lpr小鼠在十六周龄时皮肤表面会生成典型的红斑,如图1所示,表明小鼠患有系统性红斑狼疮。随着小鼠周龄的增加,患有红斑的小鼠数量显著增加,但各组之间存在显著差异。富含DHA的磷脂酰胆碱组红斑小鼠数量显著低于模型组,且皮肤损害程度低于模型组;富含DHA的磷脂酰丝氨酸和乙醇胺相似,这两组红斑小鼠数量呈降低的趋势,但效果逊于富含DHA的磷脂酰胆碱组。复配组红斑小鼠的数量低于富含DHA的磷脂组;预干预DHA和大豆磷脂酰胆碱也可以抑制模型小鼠的红斑生成,且效果优于大豆磷脂酰丝氨酸和大豆磷脂酰糖苷。血清生化指标结果如图2所示,与正常组相比较,模型组小鼠血清中抗dsDNA和抗ANA水平提高了约4倍,进一步表明小鼠患有典型的系统性红斑狼疮。而干预不同的磷脂或复配物均可以降低系统性红斑狼疮小鼠血清中异常增加的抗dsDNA和抗ANA水平。富含DHA的PC、PS和PE可以显著减少小鼠血清中异常升高的dsDNA和ANA抗体含量,且DHA-PC效果最为突出,该组小鼠上述生化参数约恢复至正常水平;DHA与大豆磷脂的复配可以显著抑制小鼠血清中dsDNA和ANA抗体的增加,但效果不如富含DHA的磷脂组;大豆来源三种磷脂组小鼠可以显著降低血清中ANA抗体含量,但未能显著降低抗dsDNA含量。脾脏是机体的重要免疫器官,脏器指数结果如图3所示:模型小鼠的脾脏指数显著增加,而干预富含DHA的磷脂酰胆碱可以抑制小鼠脾脏水肿,且效果优于其他化合物。此外小鼠血清中多个炎症因子IL-6、IL-1β、MCP-1和TNF-α水平明显高于其他组(图4),而干预不同磷脂和DHA可以抑制炎症因子水平,且DHA-PC效果最为显著,DHA-PS和DHA-PE也可以降低血清中炎症因子水平,且抑制作用优于大豆来源磷脂和复配组。此外,血清免疫因子结果显示DHA与大豆磷脂的复配和富含DHA的磷脂均能提高小鼠体内免疫因子IgG和IgM的含量,改善系统性红斑狼疮小鼠体内的免疫紊乱,且富含DHA的磷脂的效果优于复配,大豆来源的磷脂有提高机体免疫力的趋势(图4)。进一步分析了肾脏NF-κB通路的多个炎症相关基因的表达,结果如图5所示,模型小鼠体内NF-κB通路多个促炎因子基因表达上调,如MCP-1,IL-1β,IL-6,TNF-α和p65;长期饮食摄入富含DHA的磷脂,特别是DHA-PC可以显著抑制体内炎症反应;DHA-PE和DHA-PS抑炎活性次之,大豆来源的PC、PS和PG也可以抑制炎症因子表达,但效果逊于复配。最后肾脏NF-κB蛋白表达结果显示富含DHA的磷脂可以显著抑制NF-κB的激活(图6),从而抑制反应,且DHA-PC和DHA-PS效果最为显著,优于DHA-PE;此外大豆来源的磷脂酰胆碱与DHA复配也可以抑制NF-κB的表达,从而抑制NF-κB信号通路。综上实验结果表明:富含DHA的磷脂对系统性红斑狼疮的改善效果优于大豆磷脂与DHA的复配和大豆磷脂,富含DHA的磷脂酰胆碱的改善作用优于富含DHA的磷脂酰丝氨酸和磷脂酰乙醇胺,大豆来源的磷脂酰胆碱的改善效果与磷脂酰丝氨酸和磷脂酰糖苷效果相似。这可能与磷脂及其衍生物改善系统性红斑狼疮小鼠的皮肤、肾脏损伤有关,进一步机制研究表明磷脂及其衍生物可以抑制体内NF-κB的激活,进而抑制促炎因子的激活,从而抑制系统性红斑狼疮小鼠体内的炎症反应,同时恢复机体免疫平衡,进而改善系统性红斑狼疮。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (9)
1.磷脂及其衍生物在制备改善系统性红斑狼疮制品中的应用。
2.如权利要求1所述的应用,其特征在于:所述磷脂及其衍生物包括磷脂及其糖基化衍生物。
3.如权利要求1或2所述的应用,其特征在于:所述磷脂及其衍生物为磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺、磷脂酰糖苷和富含DHA的磷脂中的一种或一种以上的混合物。
4.如权利要求1或2所述的应用,其特征在于:所述磷脂及其衍生物为从大豆或鱿鱼卵中提取分离出的磷脂及其衍生物。
5.如权利要求1所述的应用,其特征在于:所述制品包括特医食品、保健品、药品或者生物制剂,及相关制品。
6.如权利要求1所述的应用,其特征在于:所述制品包含有药理有效浓度的所述的权利要求1所述的磷脂及其衍生物。
7.一种权利要求4中的磷脂及其衍生物的制备方法,其特征在于包括以下步骤:(1)将鱿鱼卵或大豆冻干,然后粉碎处理,用15倍体积的氯仿/甲醇(2∶1,V/V)混合液浸提24h,抽滤,浸提3次;然后加入氯化钠溶液,摇匀并静止过夜,收集下层氯仿层,经减压浓缩得到鱿鱼卵或者大豆脂质粗提取物;
(2)将脂质粗提物采用正相硅胶柱层析法分离,三氯甲烷和甲醇(90∶10→60∶40→0∶100,V/V)梯度洗脱,分步收集洗脱液,减压浓缩,采用TLC法初步检测收集物成分,合并Rf值相同的组分,减压浓缩至干,得到磷脂酰胆碱和磷脂酰乙醇胺。
8.一种权利要求7中的磷脂及其衍生物的制备方法,其特征在于:配制pH=5.6醋酸钠缓冲溶液,添加6%果糖、1.5%Lipozyme435溶于缓冲液中作为水相,20%步骤(2)得到的大豆来源磷脂酰胆碱溶于甲醇中作为有机相,将水相和有机相充分混合,水相与有机相比为1:4;混合物37℃搅拌反应10h,收集有机相层,将有机溶剂除去即得到磷脂酰糖苷。
9.一种权利要求7中的磷脂及其衍生物的制备方法,其特征在于:将醋酸/醋酸钠溶液缓冲液放入集热式恒温加热磁力搅拌器中预热,将L-丝氨酸溶于其中,加入上述步骤(2)中的鱿鱼卵来源的磷脂酰胆碱,最后加入磷脂酶D,在40℃下搅拌反应48h,加入盐酸,灭活酶,反应终止,用正己烷-异丙醇提取反应产物,即得到大豆磷脂酰丝氨酸和DHA磷脂酰丝氨酸。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0516034A1 (en) * | 1991-05-28 | 1992-12-02 | FIDIA S.p.A. | Pharmaceutical compositions with immunosuppresive properties |
US20110177159A1 (en) * | 2010-01-20 | 2011-07-21 | Henry Wu | Custom-formulated phospholipid microbubbles and methods and uses thereof |
CN103509047A (zh) * | 2012-06-22 | 2014-01-15 | 上海傲硕生物科技有限公司 | 一种南极磷虾来源的磷脂酰胆碱的提取工艺和磷脂酰丝氨酸的制备方法 |
CN108159421A (zh) * | 2018-02-05 | 2018-06-15 | 苏州大学 | 磷脂酰丝氨酸阻断剂在制备治疗血小板数量减少相关疾病药物中的用途 |
CN108276438A (zh) * | 2018-02-02 | 2018-07-13 | 中国海洋大学 | 一种epa缩醛磷脂的制备方法及其应用 |
CN108309991A (zh) * | 2018-05-03 | 2018-07-24 | 中国海洋大学 | 富含dha的磷脂在改善急性肾损伤制品中的应用 |
CN111621535A (zh) * | 2020-05-18 | 2020-09-04 | 中国海洋大学 | 一种磷脂酰糖苷的制备方法及其应用 |
-
2021
- 2021-09-10 CN CN202111061808.7A patent/CN113662948B/zh active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0516034A1 (en) * | 1991-05-28 | 1992-12-02 | FIDIA S.p.A. | Pharmaceutical compositions with immunosuppresive properties |
US20110177159A1 (en) * | 2010-01-20 | 2011-07-21 | Henry Wu | Custom-formulated phospholipid microbubbles and methods and uses thereof |
CN103509047A (zh) * | 2012-06-22 | 2014-01-15 | 上海傲硕生物科技有限公司 | 一种南极磷虾来源的磷脂酰胆碱的提取工艺和磷脂酰丝氨酸的制备方法 |
CN108276438A (zh) * | 2018-02-02 | 2018-07-13 | 中国海洋大学 | 一种epa缩醛磷脂的制备方法及其应用 |
CN108159421A (zh) * | 2018-02-05 | 2018-06-15 | 苏州大学 | 磷脂酰丝氨酸阻断剂在制备治疗血小板数量减少相关疾病药物中的用途 |
CN108309991A (zh) * | 2018-05-03 | 2018-07-24 | 中国海洋大学 | 富含dha的磷脂在改善急性肾损伤制品中的应用 |
CN111621535A (zh) * | 2020-05-18 | 2020-09-04 | 中国海洋大学 | 一种磷脂酰糖苷的制备方法及其应用 |
Non-Patent Citations (2)
Title |
---|
姜洪池等: "营养与免疫", 《临床外科杂志》 * |
张道雷等: "浅议DHA、EPA及其应用", 《中国调味品》 * |
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