CN112168819A - 6bio在抗心脏衰老方面的应用 - Google Patents
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Abstract
本发明公开了6BIO在抗心脏衰老方面的应用,6BIO在治疗或预防抗心脏衰老的药物中的应用;所述治疗或预防抗心脏衰老的药物含有治疗有效量的6BIO和药学上可接受的载体。本发明中6BIO能通过抑制mTOR,激活自噬,从而延缓甚至逆转心脏衰老,我们的研究成果为寻找能防止心脏退行性改变的有效药物提供了新的思路,对心脏疾病的预防与治疗具有十分重要的现实意义与临床价值。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及6BIO在抗心脏衰老方面的应用。
背景技术
随着年龄的增长,心脏相关疾病的发生率显著增加,这些心脏衰老相关改变包括心律失常、心脏纤维化、心室顺应性下降、心肌细胞退行性改变等。心脏衰老是影响人类健康的重要问题。近年来,人们对衰老的研究越来越多,也日益深入,实现人为控制衰老的进程指日可待,抗心脏衰老药物的研究也逐渐吸引了大量生物医学领域研究人员的关注。
寻找延缓心脏衰老的有效药物,并探究其抗心脏衰老的作用及作用机制,有利于人类寻找防止退行性心脏疾病发生发展的方法,探究延长人类健康寿命的措施,避免等疾病发生后再逐一治疗衰老相关的病理症状,这对人类心血管疾病的预防与治疗具有十分重要的现实意义与临床价值。
6-Bromoindirubin-3’-oxime(6BIO)是一种新发现的药物,它来源于泰尔紫靛玉红,是Glycogen synthase kinase-3β(GSK-3β)的抑制剂。根据最近的研究报道,6BIO可用于许多衰老相关疾病的治疗,包括糖尿病、神经退行性疾病、白血病、肿瘤等。它能有效地抑制细胞衰老相关的生物分子损伤的积累,缓解细胞衰老进程的发生发展,协调衰老相关的炎症、氧化应激、细胞活力改变、细胞分化、细胞凋亡等。
最近的研究发现,6BIO还是有效的自噬抑制剂,它能上调人类皮肤成纤维细胞的自噬相关蛋白Beclin1,提示它能够上调人类成纤维细胞的自噬水平。还有研究表明,在帕金森模型中,6BIO能激活小鼠中脑多巴胺能神经元细胞的自噬,从而提高该神经元细胞清除毒性蛋白聚合物的能力。同时该研究还表明6BIO能降低ribosomal protein S6 kinaseB1(RPS6KB1)和eukaryotic translation initiation factor 4E binding protein 1(EIF4EBP1)的磷酸化水平,提示其上游mTOR通路被抑制,而mTOR/自噬通路是经典的抗衰老相关通路,提示6BIO可能是一种新的抗衰老良药。
如前文所述,6BIO能用于治疗许多衰老相关疾病,改善衰老相关病变,且能抑制mTOR,能激活自噬。mTOR/自噬通路同时也是抗心脏衰老的重要机制通路之一,抑制心肌细胞的mTOR信号通路能诱导心肌细胞的自噬功能,从而延缓甚至逆转心肌细胞衰老相关的退行性改变。但是,至今没有严谨的科学研究证明6BIO的抗心脏衰老作用。
发明内容
有鉴于此,本发明提供一种6BIO在抗心脏衰老方面的应用。
进一步的,上述6BIO在治疗或预防抗心脏衰老的药物中的应用。
进一步的,上述治疗或预防抗心脏衰老的药物含有治疗有效量的6BIO和药学上可接受的载体。
更进一步的,上述治疗或预防抗心脏衰老的药物制成散剂、片剂、丸剂、胶囊剂、口服液、气雾剂或注射剂。
进一步的,上述6BIO能通过抑制mTOR,激活自噬,从而延缓甚至逆转心脏衰老。
我们最新的研究发现:6BIO能通过抑制mTOR,激活自噬,从而延缓甚至逆转心脏衰老,我们的研究成果为寻找能防止心脏退行性改变的有效药物提供了新的思路,对心脏疾病的预防与治疗具有十分重要的现实意义与临床价值。
在本研究中,我们研究了小鼠模型在正常衰老过程中的变化以及H2O2诱导的心肌细胞衰老所引起的变化,包括组织病理学变化、衰老标记物含量变化和分子生物学变化。我们的结果表明,正常老化导致细胞衰老标志物的显著改变,并加重心肌纤维化。心肌的分子生物学状态对年龄的增长很敏感,这在一定程度上解释了老年人心血管疾病的流行。这些老化相关标志物的变化也表明,衰老模型已经成功建立,这些标志物可以用来评估候选药物的抗衰老作用。此外,观察到的一些蛋白表达水平的变化暗示了一些可能的机制与心脏衰老有关。这些发现表明,自噬、氧化应激、mTOR途径和GSK3肾通道均参与了衰老过程中心脏状况的恶化。
本研究表明,6BIO对心脏抗衰老效果体内和体外以及雷帕霉素的一个最有前途的抗衰老剂,特点是与年龄相关的变化的改进包括衰减纤维化,细胞衰老标记的改良,诱导自噬,减轻氧化应激。虽然6BIO的心脏抗衰老作用机制尚需进一步研究,但我们的研究提示,在衰老的心脏中,6BIO可能通过抑制GSK3的氧化抑制和mTOR信号通路,诱导自噬,减轻氧化应激,延缓衰老过程。
从上述的技术方案可以看出,本发明的优点是:
1.6BIO的抗心脏衰老作用及作用机制至今没有严谨的科学研究证实,且无可靠证据表明6BIO是通过激活自噬从而延缓衰老进程的,该实验首次对该药物在心血管领域及抗衰老方面的作用进行深入的研究,具有很高的创新性。
2.前人对心脏衰老的研究以及各种抗衰老药物的研究中,尤其缺乏运用自然衰老模型的相关实验研究。本实验的动物模型采用了自然衰老模型进行实验,更接近于临床上衰老的实际情况,更具有现实意义与临床参考价值;
3.6BIO(6-Bromoindirubin-3’-oxime)能用于抵抗心脏衰老,且能通过延缓心脏衰老起到对心脏退行性疾病的预防和改善作用。
除了上面所描述的目的、特征和优点之外,本发明还有其它的目的、特征和优点。下面将参照图,对本发明作进一步详细的说明。
附图说明
图1为典型的心肌显微照片(×200和×400)。
图2为衰老标记和mTOR/S6K通路。
图3为GSK3分子通路和自噬活性。
图4为心肌组织中抗氧化剂(A)SOD和(B)GSH的水平。
图5为与衰老相关的β-gal染色(×200)的和(B)与衰老相关的β-gal活性测定评价的代表性图片。
图6为衰老标志物与自噬活性。
图7为H9C2细胞中ROS生成的测定。
图8为mTOR和GSK3的增强信号分析。
图9为自噬通量分析。
图10为与衰老相关的β-gal染色(×200)的和(B)与衰老相关的β-gal活性测定评价的代表性图片。
具体实施方式
以下对本发明的实施例进行详细说明,但是本发明可以由权利要求限定和覆盖的多种不同方式实施。
实施例
6BIO在抗心脏衰老方面的应用
材料和方法
1、动物和处理
我们从中国人民解放军第四军医大学实验动物中心获得雄性幼龄(2个月)和老龄(18个月)C57BL/6J小鼠。所有小鼠被放置在特定的无病原体(SPF)环境中,有光和温度控制,并可以自由地获得食物和水。我们实验小鼠分为以下四组,每组八个老鼠:
(1)幼龄雄鼠每天腹腔注射0.9%氯化钠(10毫升/公斤);
(2)老龄雄性小鼠每天腹腔注射0.9%氯化钠(10毫升/公斤);
(3)雷帕霉素处理衰老雄性小鼠,每天腹腔注射雷帕霉素(4mg/kg)10ml/kg生理盐水;
(4)用6BIO处理老龄雄性小鼠,每日腹腔注射6BIO(10mg/kg)10ml/kg生理盐水;其中,由于有报道雷帕霉素逆转年龄相关性心功能障碍,我们采用雷帕霉素治疗作为阳性对照,通过促进mter调控的自噬。
两周后,小鼠被处死,将心脏标本切成两部分,一部分保存在-80℃备用,另一部分在4%多聚甲醛中固定48小时,石蜡包埋。所有动物实验均由上海交通大学附属第六人民医院动物实验伦理委员会按照上海交通大学机构动物护理与使用委员会(IACUC)的指导方针批准。
2、试验分析
(1)抗氧化酶活性和脂质过氧化的测定
将心脏组织切碎,浸入9体积的冷磷酸盐缓冲生理盐水(PBS)匀浆。在4℃条件下,3000rpm离心15分钟,得到用于估计氧化应激标志物的上清液。根据从南京建成生物技术研究所购买的商用检测试剂盒说明书,测定超氧化物歧化酶(SOD)和谷胱甘肽(GSH)的活性。
(2)Masson染色
心脏组织在4%多聚甲醛中固定48小时,然后用梯度酒精脱水,二甲苯玻璃化,石蜡包埋。然后,将心脏样本切成5μm厚的的切片。按照标准方案进行Masson三色染色,所有切片均在×200和×400放大倍数的显微镜下观察。
(3)细胞培养和处理
H9C2,心室成肌细胞细胞系来源于胚胎,来自American Type CultureCollection(Manassas,VA,USA)和在Dulbecco’s modified Eagle’s medium(Invitrogen,Carlsbad,CA,USA)以10%牛胎儿血清,2mM l-谷氨酰胺,0.1mM非必需氨基酸,10单位/ml青霉素,100μg/ml链霉素,37℃,5%二氧化碳(CO2)湿化培养箱进行人工培养。24小时培养后,细胞附着在培养皿上,并在所需的实验条件下进行处理:(1)用PBS处理的对照组;(2)用过氧化氢(150μM)处理24小时的老龄组;(3)用H2O2(150μM)雷帕霉素(100nM)处理24小时的石墨霉素对照组;(4)用H2O2(150μM)和6BIO(10μM)处理24小时的生物治疗治疗组;(5)用H2O2(150μM)+CQ(50μM)处理24小时的H2O2和CQ组;(6)用H2O2(150μM)+CQ(50μM)+6BIO(10μM)处理24小时的H2O2+CQ+6BIO组。处理后,收集细胞进行进一步分析。
(4)西方墨点法
心脏组织和H9C2细胞均质并用裂解缓冲液(蛋白酶和磷酸酶抑制剂RIPA)裂解。使用bicinchoninic acid蛋白检测试剂盒(生物技术,中国)测定总蛋白浓度。蛋白质样品用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,并转移到聚偏二氟乙烯膜(PVDF)上。在室温下用5%脱脂牛奶封闭1小时,用适量的抗体在4℃孵育过夜,然后用辣根过氧化物酶标记的二抗(1:50000;(美国BIO-Rad公司)在室温下放置1小时。最后,使用电化学发光溶液(Millipore,美国)和ImageJ(NIH,美国)分析系统,用增强化学发光方法观察抗原-抗体条带。
(5)活性氧(ROS)测定
PBS洗涤后,将收集到的心肌细胞与5μM 5-(和6-)-氯甲基-20,70-二氯二氢荧光素二醋酸乙酰酯(DCFDA)在37℃孵育30分钟。流式细胞仪检测细胞内ROS水平作为DCF的荧光,其激发波长为480nm,发射波长为535nm。通过显示在细胞背景染色下生成的样品的对数荧光来获得示踪。
(6)衰老的β-半乳糖苷酶染色
使用衰老细胞β-半乳糖苷酶染色试剂盒(Cell Signaling Technology,USA)按照制造商的协议测定衰老细胞β-半乳糖苷酶水平。在分别进行干预后,细胞在37℃的乙醇染色液中孵育过夜。在Olympus IX51倒置显微镜下,蓝染细胞为衰老心肌细胞。
(7)串联RFP-GFP-LC3荧光显微镜
自噬通量分析采用串联荧光标记的RFP-GFP-LC3腺病毒(上海Asia-Vector生物技术,中国)感染H9C2细胞。RFP-GFP-LC3腺病毒孵育24小时后,细胞再接受相应的处理24小时。4%多聚甲醛固定细胞,DAPI染色可见细胞核。代表性图像在1000倍放大的荧光显微镜下采集。自噬体标记为绿色和红色斑点,自噬溶酶体标记为红色斑点。使用ImageJ(NIH,美国)软件进行图像分析。
(8)统计分析
使用GraphPad Prism 7.0软件进行统计分析。结果以均数±标准差(SD)表示。采用单因素方差分析和Tukey事后分析评估统计学意义;p值小于0.05为有统计学意义。
结果与分析:
(1)6BIO和雷帕霉素可减弱年龄相关性心肌纤维化
由图1可以看出,与幼龄组相比,老龄组出现明显的纤维化,6BIO或雷帕霉素治疗改善了以较少纤维化为特征的衰老心脏组织的组织病理学改变,而6BIO的效果是显著的。
(2)6BIO和雷帕霉素可改善衰老小鼠的年龄相关标志物水平
如图2所示,与幼龄对照组相比,老龄组心肌组织中p53含量较少,而p16和β-gal水平较高。雷帕霉素作为一种有效的抗衰老药物,在衰老小鼠中显著提高p53水平,降低p16和β-gal水平。与未处理的衰老小鼠相比,6BIO处理的衰老小鼠中p53水平显著升高,p16和β-gal含量显著降低。
(3)6BIO和雷帕霉素在体内负调控mTOR信号通路
如图2所示,与之前的研究一致,随着年龄的增长,mTOR的磷酸化被抑制,而雷帕霉素作为mTOR的有效抑制剂,如预期的那样显著下调了mTOR的磷酸化。我们发现,6BIO也显著降低了衰老心脏中磷酸化mTOR的水平。为了进一步评估mTOR信号通路,我们检测了mTOR下游靶点p70S6K的磷酸化状态。我们发现,如图2所示,与年轻对照组相比,老龄组磷酸化的p70S6K有所增加。在6BIO或雷帕霉素处理的衰老小鼠中,衰老心脏中p70S6K的磷酸化水平显著下降。这些结果表明,mTOR/p70S6K信号通路受到6BIO或雷帕霉素的负调控。
(4)GSK3细胞在体内被6BIO抑制,雷帕霉素诱导
由于6BIO被报道为GSK3蛋白的有效抑制剂,我们使用Western blot方法检测GSK3蛋白的磷酸化水平。如图3所示,与年轻组相比,未处理的老龄组磷酸化GSK3蛋白的表达水平明显升高。6BIO处理可显著降低衰老小鼠心脏p-GSK3蛋白的表达。然而,雷帕霉素对GSK3蛋白磷酸化的影响却恰恰相反。然后我们进一步检测了AKT的磷酸化,这被认为是GSK3的磷酸化或mTOR的上游。衰老心脏中p-AKT水平显著升高,而6BIO和雷帕霉素处理后p-AKT水平略有升高,但差异不显著。
(5)6BIO和雷帕霉素治疗可增强心脏自噬
大多数研究表明,自噬在包括心脏衰老在内的衰老过程中发挥着关键作用。因此,我们通过分析p62、Beclin-1和LC3的水平来估计自噬活性。如图3所示,Western blot分析显示,正常衰老过程中,p62含量显著增加,Beclin-1和LC3II/I比值显著降低,表明随着衰老,自噬水平降低。6BIO和雷帕霉素处理后,p62显著降低,Beclin-1水平和LC3II/I比值升高,证实了给药后诱导自噬。
(6)小鼠心脏的氧化应激几乎不能用6BIO或雷帕霉素替代
已有文献表明,氧化应激是心脏衰老的重要机制。通过SOD和GSH水平检测心肌组织氧化应激损伤。从图4可以看出,与年轻组相比,老龄组的SOD和GSH活性明显降低。然而,雷帕霉素和6BIO都不能交替老化小鼠心脏的氧化应激。与未处理衰老组相比,6BIO处理小鼠的SOD和GSH浓度略有升高,但差异无统计学意义。
(7)6BIO和雷帕霉素在体外逆转H2O2诱导的衰老
为了进一步研究6BIO对心肌细胞的影响,我们对H9C2细胞进行了研究。衰老相关的β-gal染色用于测定细胞系的衰老。如图5所示,与PBS处理组相比,H2O2处理组中出现了更多与衰老相关的β-gal阳性细胞,说明H2O2引起了细胞衰老。而在H2O2处理的培养物中,6BIO和雷帕霉素处理明显减少了可见的蓝色色素细胞,表明心肌衰老逆转。
然后我们利用Western blot对一些衰老标志物的浓度进行分析,发现H2O2明显降低了P53的含量,增加了P16和β-gal的浓度,6BIO和雷帕霉素处理逆转了H2O2对这些蛋白表达水平的影响。这些结果表明,6BIO和雷帕霉素可以逆转H2O2诱导的心肌细胞衰老(图6)。
(8)6BIO和雷帕霉素在体外诱导自噬
接下来,我们使用Western blot检测自噬特异性标志物来评估自噬改变。如图6所示,H2O2处理的H9C2细胞中,p62表达水平明显升高,Beclin-1浓度和LC3II/I比值明显降低,说明自噬受到抑制。与单纯H2O2处理组相比,6BIO和雷帕霉素处理组p62含量升高,Beclin-1水平和LC3II/I比值降低,提示体外诱导自噬,这与之前的动物实验结果一致。
(9)6BIO处理和雷帕霉素处理抑制了ROS的积累
已经证实,ROS参与氧化应激并影响细胞状态。如图7所示,与对照组相比,H2O2处理的心肌细胞中出现了ROS的积累,而6BIO和雷帕霉素处理抑制了H2O2诱导的ROS的积累。
(10)6BIO抑制心肌细胞中mTOR和GSK3的细胞凋亡
为了进一步研究6BIO的抗衰老作用的潜在途径,我们分析了总和磷酸化的mTOR、AKT和GSK3蛋白的含量。如图8所示,H2O2处理显著增强了mTOR、AKT和GSK3的磷酸化水平。6BIO和雷帕霉素抑制H2O2诱导的mTOR磷酸化。p-AKT在6BIO和雷帕霉素处理后表达水平无显著差异。6BIO明显抑制GSK3蛋白的磷酸化,而雷帕霉素对GSK3蛋白的磷酸化无显著影响。
(11)6BIO通过诱导自噬对心肌细胞发挥抗衰老作用
为了进一步证明自噬在6BIO抗衰老作用中的作用,我们使用氯喹(chloroquine,CQ)通过阻断自噬体和溶酶体融合来抑制自噬,并观察其变化。同时,我们进一步检测了基于RFP和GFP强度的自噬通量。
RFP是酸不敏感的,而GFP是酸敏感的,在酸性自噬溶酶体中被淬灭。因此,可以在荧光显微镜下观察自噬体到自噬溶酶体的过程。如图9a-b所示,与对照组相比,自噬体和自噬溶酶体总量明显减少,说明自噬早期受到抑制。CQ共处理组中GFP与RFP的比例增加,证实CQ阻断了自溶酶体的形成。6BIO共处理组RFP和GFP的数量以及GFP与RFP的比值明显增加,提示自噬通量升高。与H2O2+CQ组相比,H2O2+6BIO+CQ组自噬空泡总量更多,进一步证实6BIO增加了自噬通量。同时,我们使用Westernblot技术确认自噬改变。如图9C-D所示,H2O2处理下调了自噬,而6BIO处理上调了自噬,与荧光结果一致。CQ在后期阻断了自噬,导致LC3-II积累。与H2O2+CQ处理组相比,H2O2、6BIO、CQ共处理组P62含量明显降低,LC3-II/I比值较高,证实6BIO显著增加自噬通量,CQ在后期抑制了自噬。然后我们进行了衰老相关的β-gal染色来检测细胞系的衰老。如图10A-B所示,H2O2处理诱导了更多衰老相关的半乳糖苷酶的表达,而6BIO共处理降低了衰老相关的半乳糖苷酶的表达。CQ阻断了自噬,消除了6BIO的作用。这些结果表明,6BIO通过诱导心肌细胞自噬来延缓衰老。
以上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 (5)
1.6BIO在抗心脏衰老方面的应用。
2.根据权利要求1所述的应用,其特征在于,所述6BIO在治疗或预防抗心脏衰老的药物中的应用。
3.根据权利要求2所述的应用,其特征在于,所述治疗或预防抗心脏衰老的药物含有治疗有效量的6BIO和药学上可接受的载体。
4.根据权利要求2所述的应用,其特征在于,所述治疗或预防抗心脏衰老的药物制成散剂、片剂、丸剂、胶囊剂、口服液、气雾剂或注射剂。
5.根据权利要求1所述的应用,其特征在于,所述6BIO能通过抑制mTOR,激活自噬,从而延缓甚至逆转心脏衰老。
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Title |
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DONGHAO GUO等: "6-Bromoindirubin-3′-Oxime (6BIO) Suppresses the mTOR Pathway, Promotes Autophagy, and Exerts Anti-aging Effects in Rodent Liver", 《FRONT. PHARMACOL.》 * |
ELENI N. TSAKIRI等: "The Indirubin Derivative 6-Bromoindirubin-3"-Oxime Activates Proteostatic Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effec", 《ANTIOXIDANTS & REDOX SIGNALING》 * |
SHIGEKI MIYAMOTO: "Autophagy and cardiac aging", 《CELL DEATH & DIFFERENTIATION》 * |
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