CN110548020B - 亚精胺在制备治疗主动脉瘤药物方面的应用 - Google Patents
亚精胺在制备治疗主动脉瘤药物方面的应用 Download PDFInfo
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Abstract
本发明公开了亚精胺在制备治疗主动脉瘤药物方面的应用。本发明的有益效果是,亚精胺可以作为一种延缓腹主动脉瘤进展药物,该药物在动物实验中取得良好治疗效果,毒理药理较为明确,安全性较高,毒副作用弱。
Description
技术领域
本发明涉及亚精胺在制备治疗主动脉瘤药物方面的应用,属于主动脉瘤药物技术领域。
背景技术
动脉瘤的定义是指动脉管壁永久性局限性扩张超过正常血管直径的50%。腹主动脉瘤是动脉瘤中最为常见的一种,最常见于腹主动脉肾动脉下段。腹主动脉瘤是一种与年龄相关的动脉退行性病变,其发生与很多流行病学因素有关, 如年龄、吸烟、性别、种族、家族史等。随着我国人口老龄化以及并发的高血压、动脉硬化等高危因素, 腹主动脉瘤的发病人数也随之增多。
腹主动脉瘤临床表现为腹主动脉渐进且持续性的瘤样扩张,最终破裂死亡。目前腹主动脉瘤的治疗的主要取决于直径大小,目前指南建议对于动脉瘤直径男性≥5.5cm、女性≥5cm的病人需要手术干预,但是对于未达到手术标准的小腹主动脉瘤尚无药物能延缓腹主动脉瘤疾病的进展。因此,研发腹主动脉瘤(简称AAA)的有效干预药物,实现从微创到无创的跨越,具有重要的临床意义。
针对腹主动脉瘤的发病机制,目前的研究表明腹主动脉瘤组织病理学主要表现为炎性细胞浸润、血管平滑肌细胞凋亡、动脉壁胶原纤维和弹性纤维的降解,进而导致动脉全层变薄扩张,其中炎性细胞浸润在腹主动脉瘤进展中发挥关键作用。近期研究表明,自噬功能紊乱参与了腹主动脉瘤疾病的发生,在动脉瘤病变部位发现了自噬功能改变的证据,同时自噬功能的缺失可以加重腹主动脉瘤模型的病变程度。
主动脉瘤不同于肿瘤,动脉瘤是由于动脉壁损伤,形成动脉壁局限性或弥漫性的瘤样扩张表现,是一个形态学上的描述。而肿瘤的是正常细胞变性以后,成为一个肿瘤细胞,进而形成局部组织细胞增生。
亚精胺的CAS号:124-20-9。现有技术中有关于其减肥(CN 109820844A)、治疗神经细胞损伤(CN107929270A)的药用报道,但未涉及动脉瘤相关的应用。
发明内容
本发明解决的技术问题是,目前腹主动脉瘤主要通过手术治疗,暂无治疗主动脉瘤的疗效的相关药物报道。
本发明提供亚精胺在制备治疗主动脉瘤药物方面的应用。另外,还可使用亚精胺在药学上可接受的盐制备治疗主动脉瘤药物。
本发明还提供将上述亚精胺和/或亚精胺在药学上可接受的盐与其他药物配合,制备治疗主动脉瘤药物的组合物。
在亚精胺制备的治疗主动脉瘤药物的组合物中,亚精胺属于药物的活性成分。
亚精胺是一种广泛存在于蔬菜、谷物、豆类等日常饮食中的天然多胺,主要在小肠吸收迅速入血进而提升其血浆浓度,并通过肾脏代谢排泄。虽然目前还未有已批准的亚精胺相关药物进入临床治疗,但是已有临床实验证明了其安全性和耐受性。亚精胺是一种阳离子胺,能与带负电荷的DNA、RNA、蛋白质等生物大分子相互作用,在细胞的生长、发育及分化中发挥着重要作用。亚精胺作为组蛋白乙酰转移酶抑制剂,可以诱导细胞多种蛋白质脱乙酰化,参与稳定DNA结构、转录、翻译、凋亡、自噬等多项生物学进程。
流行病学研究表明高亚精胺饮食与人动脉粥样硬化等心血管疾病发生率降低相关。以往研究表明,亚精胺可以通过自噬依赖方式延长多种模式生物寿命,发挥多种心血管保护作用。在小鼠中,外源性补充亚精胺可以增加一氧化氮生物利用度,减少氧化应激和增强自噬来逆转动脉衰老。多项动物模型实验表明,亚精胺能够靶向抑制NF-κB通路从而降低促炎因子水平和巨噬细胞活化、抑制中性粒细胞和巨噬细胞募集、抑制循环肿瘤坏死因子、减少氧化应激,从而发挥抗炎作用。
腹主动脉瘤是一种与衰老密切相关的动脉退行性变,炎症在其进展中起到关键作用,同时伴有自噬功能紊乱。亚精胺作为一种抗衰老物质,其抗炎和促进自噬的双重作用在腹主动脉瘤的治疗中有着重要意义。
本发明的有益效果是,亚精胺可以作为一种延缓腹主动脉瘤进展药物。该药物在动物实验中取得良好治疗效果,毒理药理较为明确,安全性较高,毒副作用弱。
附图说明
图1表示对照组(空白)和亚精胺组在诱导小鼠腹主动脉瘤模型造模时(0天)以及成瘤后(14天)的解剖图片。图示为对照组和亚精胺组腹主动脉瘤外观特征,其中箭头长短标记为腹主动脉瘤直径大小。
图2表示图1的两组腹主动脉瘤直径统计结果。
图3表示图1的两组腹主动脉瘤成瘤率差异。
图4表示两组小鼠成瘤后,动脉瘤组织切片的病理组织学评价。图示为两组腹主动脉瘤切片的EVG、Masson、SMA染色结果,箭头方向表示阳性染色细胞。
图5表示两组小鼠成瘤后,动脉瘤组织切片的免疫组织学评价。图示为两组腹主动脉瘤切片的CD3、CD68、CD31的免疫组化染色结果,箭头方向表示阳性染色细胞。
图6表示两组小鼠成瘤后,利用流式细胞术检测两组小鼠动脉瘤组织炎性细胞比例,右图为细胞比例的量化统计。
图7表示两组小鼠成瘤后,利用流式细胞术检测两组小鼠血液白细胞中炎性单核细胞比例,右图为细胞比例的量化统计。
图8表示两组小鼠成瘤后,动脉瘤组织自噬相关蛋白标志物的表达水平。图示为通过蛋白免疫印迹检测两组小鼠动脉瘤组织匀浆的p-mTOR/mTOR、p62、GAPDH、LC3I/II的表达。
图9表示图8中两组蛋白表达水平的统计结果,其中NS表示无显著差异性。
具体实施方式
实施例1
模型的建立:胰蛋白酶灌注法诱导小鼠腹主动脉瘤,可以模拟人腹主动脉瘤形成中的病理生理学机制,同时还可以反映细胞外基质降解、平滑肌细胞凋亡、炎症反应、氧化应激等病变,其术后存活率约90%,存活后成瘤率100%,是一种被广泛认可的经典腹主动脉瘤模型。
我们将40只8-10周龄的雄性C57小鼠随机分为2组,每组20只,对照组正常饮食,实验组于饮水在添加亚精胺(浓度3mmol/L)。造模第14天后腹主动脉瘤形成,开腹测量动脉瘤的直径并与初始直径比较(图1),当扩张50%以上时定义为成瘤。测出动脉瘤直径数据后,我们通过比较两组动脉瘤直径及成瘤率的差异来评估亚精胺干预效果。实验结果显示,亚精胺能有效减少腹主动脉瘤的直径(1.27±0.07mm vs. 1.67±0.40mm, P<0.05)(图2)和成瘤率(77.2% vs. 100%, P<0.05)(图3),提示亚精胺对腹主动脉瘤有良好的治疗效果。
实施例2
病理组织学评价
为了进一步评估亚精胺的治疗水平,我们利用切片染色在组织病理学层面评价血管的病变程度,进而评估亚精胺的治疗效果。
两组老鼠成瘤后,我们取动脉瘤标本分别进行石蜡包埋固定切片,并利用染色技术进行组织病理学评价。我们利用EVG染色观察血管的弹力纤维的染色情况、利用Masson染色观察血管的胶原纤维和肌纤维的染色情况、利用SMA染色观察血管平滑肌的染色情况(图4)。实验结果显示,亚精胺能够显著改善腹主动脉瘤的弹力纤降解、肌纤维和胶原纤维破坏、和平滑肌细胞减少。提示亚精胺改善了腹主动脉瘤的组织病理学破坏。
进一步,我们通过免疫组化评价亚精胺对腹主动脉瘤炎性浸润的影响。我们利用免疫组化染色对小鼠腹主动脉瘤切面进行CD3染色以观察T淋巴细胞、CD68染色以观察巨噬细胞、CD31染色以观察新生血管(图5)。实验结果显示亚精胺可以抑制T细胞、巨噬细胞的浸润、减少血管新生(均P<0.05)(图5),提示亚精胺可以减少腹主动脉瘤的炎性浸润。
实施例3
流式细胞术评价
为了进一步验证亚精胺对动脉瘤组织中炎性细胞浸润的影响,我们利用流式细胞术来评估主动脉组织中炎性细胞的比例。我们先利用消化酶将主动脉组织消化为单个悬浮细胞,然后利用荧光抗体标记相应的细胞,最后利用流式细胞仪进行分析量化。我们发现在亚精胺处理组,动脉瘤组织中白细胞细胞的比例明显降低(CD45+)(P<0.05)(图6),这提示亚精胺减轻了腹主动脉瘤的炎性细胞浸润。
由于小鼠血液中炎性单核细胞是腹主动脉瘤中单核细胞和巨噬细胞等炎性细胞的前体细胞,我们还对小鼠循环中炎性单核细胞做了评估,发现亚精胺减少了小鼠循环炎性单核细胞的水平(CD11b+Ly6Chi)(P<0.05)(图7),提示亚精胺有助于其整体炎症水平的降低。
实施例4
自噬功能评价
由于亚精胺是一种经典的自噬诱导剂,我们对亚精胺干预后腹主动脉瘤组织的自噬功能进行评价。我们将动脉瘤组织进行均浆以提取蛋白质,然后利用Westernblot技术对自噬相关蛋白进行检测。我们发现亚精胺降低了p62蛋白水平,同时减少了mTOR的磷酸化(P<0.05)(图8、图9),这提示亚精胺增强了小鼠的自噬水平,并且mTOR通路可能在其中发挥作用。
通过以上实验,我们发现口服亚精胺可以延缓腹主动脉瘤扩张,这可能与亚精胺有助于保持腹主动脉瘤动脉壁结构完整,炎性浸润,增强自噬水平有关。
Claims (1)
1.亚精胺及其在药学上可接受的盐在制备治疗腹主动脉瘤药物方面的应用。
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