CN112168812A - 棕榈油酸用于制备预防或治疗炎症性疾病的组合物的用途 - Google Patents
棕榈油酸用于制备预防或治疗炎症性疾病的组合物的用途 Download PDFInfo
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- CN112168812A CN112168812A CN201910589996.7A CN201910589996A CN112168812A CN 112168812 A CN112168812 A CN 112168812A CN 201910589996 A CN201910589996 A CN 201910589996A CN 112168812 A CN112168812 A CN 112168812A
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- palmitoleic acid
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Abstract
本发明提供了棕榈油酸用于制备预防或治疗炎症性疾病的组合物的用途。本发明还提供了棕榈油酸用于制备预防或治疗自身免疫性疾病的组合物的用途。本发明还提供了棕榈油酸用于制备提高Foxp3表达水平的组合物的用途。本发明还提供了棕榈油酸用于制备降低TNF‑α与IL‑17分泌的组合物的用途。棕榈油酸可以显著提高Foxp3表达水平而增加调节性T细胞的数量及功能，还可以降低TNF‑α与IL‑17的分泌，控制炎症的发生发展，对自身免疫性及炎症性疾病具有治疗或预防的效果。
Description
技术领域
本发明涉及生物医药、食品和保健品领域，具体涉及棕榈油酸和/或棕榈酸用于制备提高Foxp3表达水平、降低或抑制TNF-α和/或IL-17分泌、预防或治疗炎症性疾病、自身免疫性疾病的用途。
背景技术
免疫系统的主要作用是识别和消除外来抗原，当免疫系统错误地攻击自身正常成分，则可能导致自身免疫性疾病(autoimmune diseases)。自身免疫性疾病的是指机体对自身抗原发生免疫应答而导致自身组织、器官甚至系统受损所引起的一类疾病。据估计，全球约有7.6％～9.4％的人群患有各种类型的自身免疫性疾病。在美国，每年治疗这类疾病的费用已超过500亿美元。系统性红斑狼疮和类风湿关节炎作为自身免疫性疾病中的两种典型疾病，在我国，单两种疾病的患病率分别为0.03％～0.04％和0.35％。自身免疫性疾病很难根治，大多数患者需要长期甚至终身服药。而炎症性疾病是机体受到内外致炎因子刺激及局部损伤引起的病理性病症。炎症是多种慢性疾病的发病基础，如肠胃疾病。如果病因没有去除，长期慢性炎症对癌症的诱发、促进、恶性转化、侵袭和转移过程都起到推动作用。
免疫系统紊乱在自身免疫及炎症性疾病中起着重要作用，免疫调节逐渐成为发病的中心环节。越来越多的研究发现，在生理和感染、肿瘤、移植免疫、自身免疫性疾病及炎症性疾病等病理条件下，调节性T细胞(Regulatory T cell，Treg)通过释放细胞因子IL-10和TGF-β，降低炎症细胞因子(例如：肿瘤坏死因子α(Tumor necrosis factorα，简称：TNF-α等)的产生而发挥免疫抑制效应。Foxp3属于转录因子叉头蛋白家族，作为重要的转录因子对调节性T细胞(Treg)的形成及其免疫抑制功能起到至关重要的作用。因此调节Foxp3的表达并影响调节性T细胞(Treg)的数量及功能成为治疗炎症性或自身免疫病的关键靶点及策略。但是，目前，自身免疫及炎症性疾病治疗效果不佳，主要是引起发病的危险因素众多而且药物特异性不强，副作用大。例如，目前临床使用的非甾体抗炎药是治疗类风湿关节炎的一线药物，可缓解症状，但其胃肠副作用大且不能预防关节破坏等并发症，严重影响患者生活质量，也无法对疾病的发展起到阻滞或缓解作用；白介素-2(Interleukin-2，IL-2)可以一定程度上有助于维持调节性T细胞(Treg)和效应T细胞的免疫稳态平衡，但IL-2治疗方案在临床上需静脉滴注且需严格控制剂量，细胞毒性较大，副作用极大，威胁患者生命安全，疗效欠佳。
TNF-α和白介素17(Interleukin-17，简称：IL-17)等炎症细胞因子是参与全身炎症和自身免疫性疾病的关键细胞因子。目前的研究发现，很多自身免疫及炎症性疾病都会伴随着TNF-α和/或IL-17的异常上调或紊乱表达，拮抗TNF-α和/或IL-17可以有效调控自身免疫及炎症性疾病的转归。因此，TNF-α和/或IL-17是大量炎症性疾病及自身免疫性疾病的关键治疗靶点。目前，靶向TNF-α和/或IL-17的治疗在自身免疫及炎症性疾病取得了显著的进展。如获得FDA批准的阿达木单抗可以有效缓解类风湿患者的关节损伤。但近年部分研究指出，TNF-α靶向药物长期使用，将导致表达TNF-α的细胞凋亡，从而产生严重并发感染、结核、全血细胞减少、肺纤维化等不良反应。而且TNF-α靶向药的生产成本高，价格昂贵。因此，发现新的靶向Foxp3、TNF-α和/或IL-17等全身炎症和自身免疫性疾病的关键因子的治疗技术，研发更为安全有效、经济、毒副作用小、给药方式更方便的药物或治疗技术刻不容缓。
棕榈油酸(Palmitoleic acid)和/或其前体棕榈酸作为一种ω-7单不饱和脂肪酸，存在于植物、海洋生物或细菌等微生物及其代谢物中，在营养、医药和工业上具有重要的应用价值。据报道，棕榈油酸增加细胞膜的流动性，降低血液中低密度脂蛋白胆固醇含量，减少血管中粥样硬化、斑块形成而造成的阻塞血管，从而防止心律失常和降低高血压等。另外，棕榈油酸已被证明能提高人体对胰岛素的敏感性，对糖尿病、代谢综合征有效，且没有明显的副作用。同时，棕榈油酸作为一种可以直接从饮食摄取的天然小分子，来源广泛，相比于药物注射，棕榈油酸在临床上更容易被接受，且患者耐受性、依从性会更好。但是，目前没有棕榈油酸用于预防或治疗炎症或自身免疫性疾病的相关应用的报道。
发明内容
本发明所要解决的技术问题是针对目前免疫系统紊乱中Treg相对功能不足的难题，提供一种能够提高Foxp3表达水平、降低或抑制TNF-α和/或IL-17的分泌、预防和/或治疗自身免疫性及炎症性疾病的技术方案。
为了实现上述目的，本发明提供了棕榈油酸和/或棕榈酸用于制备预防或治疗炎症性疾病的组合物的用途。
优选地，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
本发明所公开的化合物棕榈油酸(Palmitoleic acid)cas号：373-49-9，分子式：C16H30O2，结构如式(Ⅰ)所示：
优选地，所述棕榈油酸包括棕榈油酸的前体或其衍生物，所述棕榈油酸衍生物为以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
所述药学上可接受的盐包括酸式或碱式无机盐或有机盐。所述酸式无机盐包括盐酸盐、硫酸盐、磷酸盐、硝酸盐、碳酸盐、硼酸盐、氨基磺酸盐或氢溴酸盐。所述碱式盐包括钠盐、钾盐、锂盐、镁盐、钙盐或铵盐。所述有机盐包括乙酸盐、丙酸盐、丁酸盐、酒石酸盐、马来酸盐、羟基马来酸盐、富马酸盐、柠檬酸盐、乳酸盐、黏液酸盐、葡萄糖酸盐、苯甲酸盐、琥珀酸盐、草酸盐、苯乙酸盐、甲基磺酸盐、对甲苯磺酸盐、苯磺酸盐、对氨基水杨酸盐、天门冬氨酸盐，谷氨酸盐、依地酸盐、硬脂酸盐、棕榈酸盐、油酸盐、月桂酸盐、鞣酸盐、抗坏血酸盐、戊酸盐或烷铵盐。
优选地，所述炎症性疾病是以下的一种或多种疾病：急性或慢性器官移植排斥、移植物抗宿主病、炎性肠病、克罗恩氏病、炎症性皮肤病、多发性硬化症、胰腺炎、急性支气管炎、慢性支气管炎、急性毛细支气管炎、哮喘、慢性毛细支气管炎、骨关节炎、痛风、脊柱关节病、赖特尔综合征、银屑病性关节病毛囊炎、新生儿早产伴随的局部或系统性炎症及由细菌、真菌、病毒、微生物、病原体、寄生虫感染和/或其引起和/或伴随的炎症。
本发明还提供了棕榈油酸和/或其前体和/或其衍生物用于制备预防或治疗自身免疫性疾病的组合物的用途。
优选地，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
优选地，所述棕榈油酸包括棕榈油酸的前体和/或其衍生物，所述棕榈油酸衍生物为以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
所述药学上可接受的盐包括酸式或碱式无机盐或有机盐。所述酸式无机盐包括盐酸盐、硫酸盐、磷酸盐、硝酸盐、碳酸盐、硼酸盐、氨基磺酸盐或氢溴酸盐。所述碱式盐包括钠盐、钾盐、锂盐、镁盐、钙盐或铵盐。所述有机盐包括乙酸盐、丙酸盐、丁酸盐、酒石酸盐、马来酸盐、羟基马来酸盐、富马酸盐、柠檬酸盐、乳酸盐、黏液酸盐、葡萄糖酸盐、苯甲酸盐、琥珀酸盐、草酸盐、苯乙酸盐、甲基磺酸盐、对甲苯磺酸盐、苯磺酸盐、对氨基水杨酸盐、天门冬氨酸盐，谷氨酸盐、依地酸盐、硬脂酸盐、棕榈酸盐、油酸盐、月桂酸盐、鞣酸盐、抗坏血酸盐、戊酸盐或烷铵盐。
优选地，所述自身免疫性疾病为由于调节性T细胞相对功能不足引起的的自身免疫性疾病。更优选地，所述自身免疫性疾病是以下的一种或多种疾病：红斑狼疮、甲状腺功能亢进、IgA肾炎、Ⅰ型或Ⅱ型糖尿病及其并发症、口眼干燥综合征、类风湿性关节炎、单纯性肥胖、强直性脊柱炎、支气管哮喘、神经性皮炎、溃疡性结肠炎、口腔溃疡、银屑病、白癜风、白塞氏病、自身免疫性眼虹膜睫状体炎、自身免疫性湿疹、自身免疫性葡萄膜炎、自身免疫性结膜炎、自身免疫性干眼症、自身免疫性青光眼、自身免疫性白内障、过敏性鼻炎、肠易激综合征、皮肤瘙痒。
本发明还提供了棕榈油酸用于制备提高Foxp3表达水平的组合物的用途。
优选地，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
优选地，所述棕榈油酸包括棕榈油酸的前体和/或其衍生物，所述棕榈油酸衍生物为以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
所述药学上可接受的盐包括酸式或碱式无机盐或有机盐。所述酸式无机盐包括盐酸盐、硫酸盐、磷酸盐、硝酸盐、碳酸盐、硼酸盐、氨基磺酸盐或氢溴酸盐。所述碱式盐包括钠盐、钾盐、锂盐、镁盐、钙盐或铵盐。所述有机盐包括乙酸盐、丙酸盐、丁酸盐、酒石酸盐、马来酸盐、羟基马来酸盐、富马酸盐、柠檬酸盐、乳酸盐、黏液酸盐、葡萄糖酸盐、苯甲酸盐、琥珀酸盐、草酸盐、苯乙酸盐、甲基磺酸盐、对甲苯磺酸盐、苯磺酸盐、对氨基水杨酸盐、天门冬氨酸盐，谷氨酸盐、依地酸盐、硬脂酸盐、棕榈酸盐、油酸盐、月桂酸盐、鞣酸盐、抗坏血酸盐、戊酸盐或烷铵盐。
本发明还提供了棕榈油酸用于制备降低TNF-α和/或IL-17分泌的组合物的用途。
优选地，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
优选地，所述棕榈油酸包括棕榈油酸的前体和/或其衍生物，所述棕榈油酸衍生物为以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
所述药学上可接受的盐包括酸式或碱式无机盐或有机盐。所述酸式无机盐包括盐酸盐、硫酸盐、磷酸盐、硝酸盐、碳酸盐、硼酸盐、氨基磺酸盐或氢溴酸盐。所述碱式盐包括钠盐、钾盐、锂盐、镁盐、钙盐或铵盐。所述有机盐包括乙酸盐、丙酸盐、丁酸盐、酒石酸盐、马来酸盐、羟基马来酸盐、富马酸盐、柠檬酸盐、乳酸盐、黏液酸盐、葡萄糖酸盐、苯甲酸盐、琥珀酸盐、草酸盐、苯乙酸盐、甲基磺酸盐、对甲苯磺酸盐、苯磺酸盐、对氨基水杨酸盐、天门冬氨酸盐，谷氨酸盐、依地酸盐、硬脂酸盐、棕榈酸盐、油酸盐、月桂酸盐、鞣酸盐、抗坏血酸盐、戊酸盐或烷铵盐。
所述药物组合物可以是药学上可行的任一种或多种剂型，包括但不限于为片剂、胶囊剂、口服液或冻干粉剂。
优选地，上述的药物组合物中，所述药学上可接受的载体为脱脂奶、乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、海藻糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油中的一种或多种的混合物。
经实验研究发现，棕榈油酸在免疫系统紊乱时，可显著提高Foxp3表达而增加调节性T细胞的比例，还可以降低炎症因子TNF-α和/或IL-17等的分泌，控制炎症的发生发展，对自身免疫及炎症性疾病具有预防和/或治疗和/或辅助治疗的效果。
附图说明
图1为棕榈油酸处理后小鼠Foxp3蛋白表达水平上western blot对比图。
图2为棕榈油酸处理后小鼠流式细胞分析图，其中右象限为CD4+Foxp3+(既表达CD4又表达Foxp3)占总体CD4+T细胞的百分比。
图3为棕榈油酸处理小鼠后血清中炎症因子TNF-α的表达量统计图。
图4为棕榈油酸处理小鼠后血清中炎症因子IL-17的表达量统计图。
图5为棕榈油酸处理后人PBMC培养上清中TNF-α的表达量统计图。
图6为棕榈油酸处理后人PBMC培养上清中IL-17的表达量统计图。
图7为口服棕榈油酸治疗卡介苗急性感染所致肺部炎症肺病理对比图。
图8为口服棕榈油酸治疗实验性自身免疫性脑脊髓炎(EAE)后小鼠的EAE病变分析统计对比图。
具体实施方式
下面将结合具体实施例对本发明作进一步说明。需要指出的是，由本发明中的用于治疗和/或预防自身免疫及炎症性疾病的棕榈油酸及棕榈油酸的前体和/或其衍生物或含有本发明的棕榈油酸的药物组合物、食品、保健品及食品添加剂中在施用于受试者后，都可以应用于上文所述的适应症并展现出上文所述的功能，在本发明范围内的所有剂型均已测试，下文中，仅仅是为说明，只在实施例中描述了其中一小部分，然而不应将其理解为对本发明的限制。
本发明所指的棕榈油酸及其衍生物包括但不限于以下中的任意一种或多种：棕榈油酸、棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
所述疾病是自身免疫性疾病，例如但不限于系统性红斑狼疮、甲状腺功能亢进、IgA肾炎、Ⅰ型或Ⅱ型糖尿病及其并发症、口眼干燥综合征、类风湿性关节炎、单纯性肥胖、强直性脊柱炎、支气管哮喘、神经性皮炎、溃疡性结肠炎、口腔溃疡、银屑病、白癜风、白塞氏病、自身免疫性眼虹膜睫状体炎、自身免疫性湿疹、自身免疫性葡萄膜炎、自身免疫性结膜炎、自身免疫性干眼症、自身免疫性青光眼、自身免疫性白内障、过敏性鼻炎、肠易激综合征、皮肤瘙痒中的一种或多种疾病。
所述疾病是炎症性疾病，例如但不限于由急性或慢性器官移植排斥、移植物抗宿主病、炎性肠病、克罗恩氏病、炎症性皮肤病、多发性硬化症、胰腺炎、急性支气管炎、慢性支气管炎、急性毛细支气管炎、慢性毛细支气管炎、骨关节炎、痛风、脊柱关节病、赖特尔综合征、银屑病性关节病、毛囊炎、新生儿早产伴随的局部或系统性炎症及细菌、真菌、病毒、病原体、微生物、寄生虫感染和/或其引起和/或伴随的炎症组合的群中的一种或多种疾病。
所述药物组合物包括但不限于为片剂、胶囊剂或口服液。所述药学上可接受的载体包括但不限于为脱脂奶、乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、海藻糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油中的一种或多种。
本发明的棕榈油酸还可以被制成食品、保健品及食品添加剂等。所述食品、保健品及食品添加剂均含有包含棕榈油酸，包括以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。这些食品、保健品或皮肤护理用品(如化妆品)均可用于治疗和/或预防自身免疫及炎症性疾病。
以上内容是结合本发明创造的优选实施方式对所提供技术方案所作的进一步详细说明，不能认定本发明创造具体实施只局限于上述这些说明，对于本发明创造所属技术领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明创造的保护范围。
实施例1棕榈油酸提高Foxp3及TNF-α、IL-17等炎症因子表达水平的小鼠实验
1.棕榈油酸的配制
实施案例以棕榈油酸(Palmitoleic acid)为例，但不仅限于棕榈油酸，还包括以下中的任意一种或多种棕榈油酸的前体和/或其衍生物：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
步骤1：取101.6mg棕榈油酸(购自Sigma公司)溶于4mlNaOH(0.1M)，配制成100mM棕榈油酸原液；
步骤2：将100mM原液加纯净水稀释成0.36mM棕榈油酸工作液，0.22μm过滤，便于后续动物实验；
2、棕榈油酸提高Foxp3表达水平及降低TNF-α、IL-17等炎症因子分泌的小鼠实验
实验动物：14只C57BL/6小鼠3～4周，精神状态良好，购自广东省实验动物中心。小鼠然后经皮下免疫注射人髓鞘少突胶质细胞糖蛋白(MOG)35-36多肽，然后将小鼠随机分成2组，每组7只，2组分别为对照组、棕榈油酸组(0.36mM)，2组小鼠分别给纯水、棕榈油酸工作液(0.36mM)，连续饮用2周。2周后处死小鼠，分别收集脾脏细胞，使用western blot检测其Foxp3蛋白的表达量，利用核内因子染色及流式细胞术检测分析脾脏细胞中表达Foxp3的CD4+T细胞的量，同时用细胞因子微球(Cytometric Bead Array,CBA)检测技术检测小鼠血清中TNF-α、IL-17A(IL-17A是IL-17的主要形式。本发明利用分析IL-17A来分析IL-17的含量)等炎症因子的含量。
实施例2棕榈油酸控制风湿性关节炎患者的TNF-α、IL-17等炎症因子分泌的实验
1、棕榈油酸的配制
配制方法同实施例1
2、棕榈油酸控制风湿性关节炎患者的TNF-α、IL-17等炎症因子分泌的实验
分离5个未治疗的风湿性关节炎患者的外周血单个核细胞(Peripheral bloodmononuclear cell，PBMC)，将PBMC铺板于96孔板中，每孔1x106个PBMC，每个病人的PBMC分两组，分别为培养基组，棕榈油酸组(0.0036mM)，培养5天后，取培养上清100μl用细胞因子微球(Cytometric Bead Array,CBA)就流式细胞检测技术检测培养上清中TNF-α、IL-17A等炎症因子的含量。
实施例3棕榈油酸控制小鼠急性炎症的实验
1、棕榈油酸的配制
配制方法同实施例1
2、棕榈油酸控制小鼠肺部急性炎症的实验
实验动物：14只C57BL/6小鼠3～4周，精神状态良好，购自广东省实验动物中心。将小鼠随机分成2组，每组7只，2组分别为对照组、棕榈油酸组(0.36mM)。随后分别用卡介苗感染两组老鼠，感染方式为滴鼻，剂量为1x107CFU/每只。2组小鼠分别给纯水、棕榈油酸工作液(0.36mM)，连续饮用2周。2周后处死小鼠，取小鼠肺组织做病理切片，苏木素-伊红(HE)染色分析肺部的炎症浸润及病损病变。
实施例4棕榈油酸控制小鼠实验性自身免疫性脑脊髓炎(EAE)的实验
1.棕榈油酸的配制
配制方法同实施例1
2.棕榈油酸控制小鼠自身免疫性脊髓炎(EAE)的实验
实验动物为14只C57BL/6小鼠3～4周，精神状态良好，购自广东省实验动物中心。小鼠然后经皮下免疫注射人髓鞘少突胶质细胞糖蛋白(MOG)35-36多肽，然后每只小鼠继续经腹腔注射200ng的百日咳毒素两次，隔1天各注射1次，然后将小鼠随机分成2组，每组7只，2组分别为喝水对照组、棕榈油酸组(0.36mM)。三周后，观察小鼠的EAE病变情况。
小鼠EAE的病变情况采用如下的打分方法：0分：无病变；1分：尾部瘫痪；2分：步伐受损和/或翻正反应受损；3分：部分的前后肢瘫痪；4分：完全的前肢或后肢瘫痪；5分：前肢瘫痪及完全的后肢瘫痪；6分：垂死或死亡。因此，打分越高说明小鼠的EAE病变越严重。
结果分析：
为分析棕榈油酸对Foxp3表达的影响，我们首先利用western blot技术分析小鼠经棕榈油酸处理后体内Foxp3表达的影响。图1为棕榈油酸处理后小鼠脾脏细胞的Foxp3蛋白水平上western blot对比图，观察到棕榈油酸组的小鼠脾脏细胞中Foxp3蛋白的表达量高于喝水的对照组小鼠。这说明，棕榈油酸可以显著提高Foxp3表达水平。为验证westernblot的发现，我们进一步利用流式细胞技术分析经棕榈油酸处理后Foxp3+T细胞的数量及比例的变化。图2为棕榈油酸处理后小鼠的流式细胞分析图，可以观察到，棕榈油酸显著增强了CD4+T细胞中Foxp3的表达，CD4+Foxp3+T细胞占脾脏总体CD4+T细胞的比例高达12.27％，而喝水对照组只有约6.45％左右；图3、图4分别为棕榈油酸处理小鼠后血清中炎症因子TNF-α、IL-17的表达量统计图。从图3、图4可以清楚地观察到，棕榈油酸处理小鼠后小鼠体内的TNF-α、IL-17的表达量均显著下降(***表示p<0.001，具有统计学差异意义)。
我们更进一步验证了TNF-α与IL-17对自身免疫性病人的的TNF-α与IL-17的表达量的调节功能。如实施例2所述，图5为棕榈油酸处理其中一例病人PBMC后培养上清中TNF-α表达量的CBA与流式细胞分析对比图。图6为棕榈油酸处理其中一例病人PBMC后培养上清中IL-17表达量的CBA与流式细胞分析对比图。从图5、图6可以观察到棕榈油酸处理后TNF-α与IL-17的荧光团(如图中黑色矩形标识)均显著分别向左迁移，其余4例病人均获得了如涂、图6相似的的结果，棕榈油酸处理均可以有效降低病人PBMC的TNF-α与IL-17的表达量。这些结果说明，说明棕榈油酸处理可显著降低例如风湿性关节炎等自身免疫性病人的PBMC中炎症因子TNF-α与IL-17的分泌或表达。
鉴于增加FoxP3的表达而增加FoxP3+调节性T细胞的数量比例以及抑制TNF-α与IL-17的分泌是控制炎症及自身免疫病及炎症的关键免疫学机制，我们进一步分析棕榈油酸是否可以有助于抑制自身免疫性疾病及(或)炎症性疾病。
为此，建立一个细菌感染小鼠诱导的肺部炎症模型并对小鼠进行棕榈油酸处理。图7为棕榈油酸治疗卡介苗急性感染的小鼠后肺病理对比图(中间2.5X图为顶层图片中的矩形区域所示的放大图，下层10X图为中间图内矩形区域所示放大图)。从图7中，我们可以看出，喝水的对照组小鼠会出现大面积的炎症渗出、出血，肺间质内可见大量炎性细胞浸润；但相较于对照组，棕榈油酸组的小鼠，炎症减轻，出血灶减少，肺泡结构完整。对比可以说明，棕榈油酸可以高效控制炎症发生发展的过程。
更进一步，分析棕榈油酸对控制自身免疫病的作用。如图8所示，小鼠在经喝棕榈油酸后，小鼠的自身免疫性脑脊髓炎的病变病损得分显著减少(***表示p<0.001，具有统计学差异意义，EAE得分越高说明病变越严重)。这说明棕榈油酸可以提高Foxp3的表达，控制炎症因子TNF-α、IL-17等的表达从而控制EAE(自身免疫性脑脊髓炎)等自身免疫病。
以上结果表明，棕榈油酸可以显著提高Foxp3表达水平而增加调节性T细胞的数量及功能，还可以降低TNF-α的分泌，控制炎症的发生发展，对自身免疫性疾病及(或)炎症性疾病具有治疗、预防及(或)辅助治疗的效果。
Claims (14)
1.棕榈油酸用于制备预防或治疗炎症性疾病的组合物的用途。
2.根据权利要求1所述的用途，其特征在于，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
3.根据权利要求1所述的用途，其特征在于，所述棕榈油酸包括棕榈油酸衍生物，所述棕榈油酸衍生物选自以下中的任意一种或多种：棕榈油酸的前体、立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐、前药或者化学修饰物或改性物。
4.根据权利要求1所述的用途，其特征在于，所述炎症性疾病选自以下的一种或多种疾病：急性或慢性器官移植排斥、移植物抗宿主病、炎性肠病、克罗恩氏病、炎症性皮肤病、多发性硬化症、胰腺炎、急性支气管炎、慢性支气管炎、急性毛细支气管炎、哮喘、慢性毛细支气管炎、骨关节炎、痛风、脊柱关节病、赖特尔综合征、银屑病性关节病、毛囊炎、新生儿早产伴随的局部或系统性炎症及由细菌、真菌、病毒、病原体、微生物、寄生虫感染和/或其引起和/或伴随的炎症。
5.棕榈油酸和/或棕榈酸用于制备预防或治疗自身免疫性疾病的组合物的用途。
6.根据权利要求5所述的用途，其特征在于，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
7.根据权利要求5所述的用途，其特征在于，所述棕榈油酸包括棕榈油酸的前体和/或其衍生物，所述棕榈油酸衍生物选自以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
8.根据权利要求5所述的用途，其特征在于，所述自身免疫性疾病选自以下的一种或多种疾病：系统性红斑狼疮和/或其并发症、甲状腺功能亢进、IgA肾炎、Ⅰ型或Ⅱ型糖尿病和/或其并发症、口眼干燥综合征、类风湿性关节炎、单纯性肥胖、强直性脊柱炎、支气管哮喘、神经性皮炎、溃疡性结肠炎、口腔溃疡、银屑病、白癜风、白塞氏病、自身免疫性眼虹膜睫状体炎、自身免疫性湿疹、自身免疫性葡萄膜炎、自身免疫性结膜炎、自身免疫性干眼症、自身免疫性青光眼、自身免疫性白内障、过敏性鼻炎、肠易激综合征、皮肤瘙痒。
9.棕榈油酸和/或棕榈酸用于制备提高Foxp3表达水平和/或表达Foxp3的调节性T细胞的数量及功能的组合物的用途。
10.根据权利要求9所述的用途，其特征在于，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
11.根据权利要求9所述的用途，其特征在于，所述棕榈油酸包括棕榈油酸的前体和/或其衍生物，所述棕榈油酸衍生物选自以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
12.棕榈油酸和/或棕榈酸用于制备降低或抑制TNF-α和/或IL-17分泌的组合物的用途。
13.根据权利要求12所述的用途，其特征在于，所述组合物是药物组合物、食品、保健品、皮肤护理用品或食品添加剂中的任何一种。
14.根据权利要求12所述的应用，其特征在于，所述棕榈油酸包括棕榈油酸的前体和/或其衍生物，所述棕榈油酸衍生物为以下中的任意一种或多种：棕榈油酸的立体异构体、互变异构体、几何异构体、氮氧化合物、水合物、溶剂化物、代谢产物、药学上可接受的盐或者前药。
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| WO2021000417A1 (zh) | 2021-01-07 |
| CN112168812B (zh) | 2022-07-08 |
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