CN117982482A - 棕榈酰肉碱的制药用途 - Google Patents
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Abstract
本申请涉及棕榈酰肉碱在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用;进一步涉及促进哺乳动物体内棕榈酰肉碱水平增加的化合物在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
Description
技术领域
本申请涉及药理研究领域,具体涉及棕榈酰肉碱在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
背景技术
妊娠期间,母体会发生多种生理变化和代谢适应,任何与正常值的微小偏差都可能导致妊娠期不良后果的风险增加(Chang和Streitman,2012;von Versen-Hoeynck和Powers,2007;Zeng等,2017)。例如,与胎盘相关的高血压疾病使6-8%的妊娠复杂化,其中约2%发展为先兆子痫(Verbeek和Verbeek,2014),而心血管疾病使1-4%的妊娠复杂化(Ramlakhan等,2020),两者都可能导致孕产妇以及胎儿的发病率或死亡率显著增加。尽管多年来全球医疗保健和卫生标准大幅改善,但全球分析估计,每100000名活产婴儿中,仍有1800名新生儿和216名母亲死于各种妊娠并发症(Alkema等,2016;Hug等,2019)。目前诊断不良妊娠并发症的临床方法主要基于超声成像(Bricker andNeilson,2000),临床血液学检测(Liu等,2012)和临床血液生化检测(Larsson等,2008),但很少有能够为预防性干预提供足够早期预测的方法,目前可用的干预疗法更少。这在一定程度上是由于我们对正常妊娠期间母体需要发生的生理适应的基本理解存在分歧。
先前的转录组学研究表明,在小鼠妊娠期间,母体器官和胎盘的代谢相关基因发生了显著变化(Paquette等,2018;Patel等,2011)。此外,已知在妊娠过程中,多个母体器官会发生复杂的代谢相互作用和动态变化(Aasa等,2015;Ellery等,2015;Papacleovoulou等,2017;Saoi等,2020)。尽管啮齿类动物的研究加深了我们对妊娠的基本理解,但由于灵长类动物的器官生理学与啮齿类动物非常不同,尤其是在妊娠期间快速进化的胎盘,因此啮齿类动物的研究并不能完全反映灵长类动物/人类的真实状况(Hemberger等,2020;Sieck,2019)。相比之下,食蟹猴被认为是研究人类生理学高度可靠的灵长类动物模型,因为它们在进化、基因组、结构、生理和代谢方面都具有良好的保守性(Wagner等,2006;Yan等,2011)。此外,它们的生殖特征与人类更为相似,例如卵泡发育、排卵周期、单绒毛膜胎盘结构和生理,甚至也可以在食蟹猴胎盘中检测到猕猴绒毛膜促性腺激素(mCG),类似于人类绒毛膜促性腺激素(hCG)(Buse和Markert,2019;Mihm等,2011;威尔肯等,2002)。与人类相似,食蟹猴也有月经并且可以全年受孕,单产的妊娠周期相对较长(Weinbauer等,2008;Yoshida等,2010),这与多胎啮齿类动物有很大不同。因此,食蟹猴被认为是研究灵长类动物/人类妊娠的生理和病理都最相关的动物模型(Grossmann等,2020)。
对人类正常妊娠母体血液样本进行的多项代谢组学分析研究揭示了血液中的一些代谢变化和候选生物活性分子(等,2021;Liang等,2020;Lindsay等,2015;Orczyk-Pawilowicz等,2016;Wang等,2016)。然而,由于在妊娠期间无法直接获取到母体器官和组织,迄今为止还没有对灵长类动物多个妊娠阶段和多个母体组织的代谢组学变化进行过系统性分析,对正常妊娠期间灵长类母体组织的代谢组学适应仍然知之甚少。在本研究中,我们揭示了灵长类动物妊娠不同阶段23种母体组织的非靶向代谢组学特征,系统地描述和分析了灵长类动物妊娠期间多个母体组织之间代谢耦联的变化,并确定了灵长类动物各个阶段与母体组织相关的新代谢通路和代谢物。此外,我们还进一步地验证了一些差异代谢物与人类多种祖细胞的生物医学相关性。我们的研究为了解灵长类动物在妊娠期间的代谢稳态提供了新的见解,全面的揭示了妊娠母体组织的代谢网络演变、通路适应以及一些关键灵长类代谢物的调节,为更好地了解灵长类动物母体如何适应妊娠带来的代谢挑战奠定了基础。
发明内容
基于上述目的,本申请提供了:
1.棕榈酰肉碱在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
2.根据项1所述的应用,其中,所述哺乳动物妊娠期与组织损伤相关的疾病选自下组:妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
3.根据项1-2的任一项所述的应用,其中,所述哺乳动物为人类。
4.根据项1-2的任一项所述的应用,其中,所述哺乳动物来自人类饲养动物;优选选自下组:猪、牛、马、狗、猫、山羊、兔、食蟹猕猴、小鼠、大鼠;最优选为食蟹猕猴。
5.根据项1所述的应用,其中,所述棕榈酰肉碱在妊娠期组织发生损伤时通过促进祖细胞的生长和分化实现组织再生。
6.促进哺乳动物体内棕榈酰肉碱水平增加的化合物在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
7.根据项6所述的应用,其中,所述哺乳动物妊娠期与组织损伤相关的疾病选自下组:妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
8.根据项6-7的任一项所述的应用,其中,所述哺乳动物为人类。
9.根据项6-7的任一项所述的应用,其中,所述哺乳动物来自人类饲养动物;优选选自下组:猪、牛、马、狗、猫、山羊、兔、食蟹猕猴、小鼠、大鼠;最优选为食蟹猕猴。
10.根据项6-7的任一项所述的应用,其中,所述促进哺乳动物体内棕榈酰肉碱水平增加的化合物为棕榈酰肉碱合成促进剂和/或棕榈酰肉碱分解抑制剂;其中,
优选所述棕榈酰肉碱合成促进剂为肉碱棕榈酰转移酶I(CPT-1)激活剂,最优选为黄芩苷或其衍生物;
优选所述棕榈酰肉碱分解抑制剂为肉碱棕榈酰转移酶II(CPT-2)抑制剂,最优选为4-三甲基铵基丁酸盐类。
本申请的技术方案实现的有益技术效果
在本申请中,将棕榈酰肉碱用于制药,出乎预料地促进妊娠期组织祖细胞的生长和分化,成功地治疗妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
附图说明
图1为根据样本的组织来源和系统归类,以及对非妊娠(NP)、妊娠早期(EP)、妊娠中期(MP)、妊娠晚期(LP)等4个时期单个样本的非靶向代谢组学数据进行聚类分析;其中,A和B.t分布-随机近邻嵌入(t-SNE)和偏最小二乘判别分析(PLS-DA)根据样本组织来源对单个样本的代谢组进行聚类;C.PLSDA根据系统归类对单个样本的代谢组进行聚类;D.斯皮尔曼相关系数作为距离度量,分别计算4个时期23种母体组织的3份生物学重复样本每个代谢物的平均强度,对每个时期各组织的代谢组进行分层聚类;E-H.PLS-DA根据妊娠时期对单个样本的代谢组进行聚类;I-L.同一质控(QC)样品和胎盘样品的LC/MS总离子色谱图。
图2为分别对4个时期23种母体组织的代谢组数据进行相关性分析;其中,A-D.相关性热图显示NP、EP、MP和LP等4个时期23种母体组织的代谢偶联;E-H.相关性网络图显示NP、EP、MP和LP等4个时期23种母体组织的代谢偶联;I-L.收集的食蟹猴母体组织和每种组织中代谢物缺失值数量。
图3为MetaboAnalystR里MSEA鉴定的妊娠期间23种母体组织的代谢通路分析;其中,A.热图显示23种母体组织发生显著改变的代谢通路数量(NP、MP和LP vs EP,P<0.05);B.气泡图显示NP、MP和LPvs EP组在半数及以上所检测的母体组织中8条显著改变的代谢通路;C.热图显示除B中8条通路以外,NP、MP和LPvs EP组其它在半数及以上所检测的母体组织中显著改变的代谢通路;D.热图显示除B和C图以外,LPvs EP在半数及以上所检测的母体组织中显著改变的其它代谢通路。
图4为与EP相比,23种母体组织在MP和LP时的差异代谢物数量(差异倍数≥1.5);从外往内,第一环显示组织的类型,不同颜色代表组织起源的器官。第二环显示4个时期23种组织确定的总代谢特征。第三环中的数字显示每种组织中确定的代谢物总数量。第四环中的数字显示每种组织在MP和LP时与EP相比共享的差异代谢物数量。最内环的白色数字显示23种组织在MP和LP时与EP相比共享的差异代谢物数量。
图5妊娠期间23种组织中棕榈酰肉碱代谢丰度倍数变化及其对不同人类祖细胞的功能影响;其中,A.23种母体组织的NP、MP和LP与EP相比,棕榈酰肉碱代谢丰度倍数变化;B.RT-qPCR分析经二甲基亚砜、25和50μM棕榈酰肉碱(PC)处理后的肝祖细胞(LPCs)中Tbx3、Afp、Hnf4a、Hnf1b、FAH、ALB的mRNA表达水平;C.RT-qPCR分析经二甲基亚砜、25和50μM棕榈酰肉碱(PC)处理后的骨骼肌细胞(MCs)中Pax3、Pax7、MyoD1、MyoG、NCAM1、ACTA1的mRNA表达水平;D.RT-qPCR分析经二甲基亚砜、25和50μM棕榈酰肉碱(PC)处理后的心肌细胞(CMs)中NKX2-5、ISL1、Tnnt2的mRNA表达水平;E.RT-qPCR分析经二甲基亚砜、25和50μM棕榈酰肉碱(PC)处理后的胰腺祖细胞(PPCs)中PDX1、RFX6、PAX4的mRNA表达水平。
具体实施方式
下面将参照附图更详细地描述本发明的具体实施例。虽然附图中显示了本发明的具体实施例,然而应当理解,可以以各种形式实现本发明而不应被这里阐述的实施例所限制。相反,提供这些实施例是为了能够更透彻地理解本发明,并且能够将本发明的范围完整的传达给本领域的技术人员。
需要说明的是,在说明书及权利要求当中使用了某些词汇来指称特定组件。本领域技术人员应可以理解,技术人员可能会用不同名词来称呼同一个组件。本说明书及权利要求并不以名词的差异来作为区分组件的方式,而是以组件在功能上的差异来作为区分的准则。如在通篇说明书及权利要求当中所提及的“包含”或“包括”为一开放式用语,故应解释成“包含但不限定于”。说明书后续描述为实施本发明的较佳实施方式,然所述描述乃以说明书的一般原则为目的,并非用以限定本发明的范围。本发明的保护范围当视所附权利要求所界定者为准。
如本文所用,就特定组分而言“基本上不含”在本文中用于表示特定组分未被有目的地配制到组合物中和/或仅作为污染物或以痕量存在。因此,由组合物的任何意外污染导致的特定组分的总量低于0.05%,优选低于0.01%。最优选的是其中特定组分的量用标准分析方法检测不到的组合物。
如在本说明书中所使用的,“一”或“一个”可以表示一个或多个。如权利要求中所使用的,当与单词“包含”一起使用时,单词“一”或“一个”可以表示一个或多于一个。
在权利要求中使用术语“或”用于表示“和/或”,除非明确指出仅指代替代方案或者替代方案是相互排斥的,尽管本公开内容支持仅指代替代方案和“和/或”的定义。如本文所用,“另一个”可以表示至少第二个或更多个。
贯穿本申请,术语“约”用于指示值包括装置的误差的固有变化,该方法用于测定该值或存在于研究对象之间的变化。
实施例中描述到的各种生物材料的取得途径仅是提供一种实验获取的途径以达到具体公开的目的,不应成为对本发明生物材料来源的限制。事实上,所用到的生物材料的来源是广泛的,任何不违反法律和道德伦理能够获取的生物材料都可以按照实施例中的提示替换使用。
本申请在第一方面涉及棕榈酰肉碱在药物制备中的应用。
在一个具体实施方式中,提供了棕榈酰肉碱在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
在本说明书的上下文中,“棕榈酰肉碱”具有下述特征:
结构式为:
CAS号为:2364-67-2
英文名称为:PALMITOYL CARNITINE
分子式为:C23H46NO4
在又一具体实施方式中提供了:所述哺乳动物妊娠期与组织损伤相关的疾病选自下组:妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
在本说明书的上下文中,妊娠期心脏病、妊娠期糖尿病、妊娠期肝病符合本技术领域的一般定义。
在怀孕期间或者产后,心脏病的发病率会相应增加,而且围产期心肌病是孕妇死亡的主要原因,占妊娠晚期死亡人数的23%。随着妊娠年龄的延迟,妊娠合并冠状动脉疾病,尤其是急性冠状动脉综合征的比例逐年增加,发病率以及病死率逐年增高;所以,妊娠可以视为心脏病的危险因素;妊娠期出现心脏病,会观察到心肌产生组织损伤。在本申请的实施例中,申请人从ISL1和TNNT2表达的剂量依赖性增加中观察到,棕榈酰肉碱会诱导心肌细胞的特化和分化,这表明它可以促进孕期母体心脏的生长和再生从而修复心肌出现的组织损伤。
妊娠期糖尿病是一类较为特殊的糖尿病,对孕产妇和胎婴儿有较高的危险性。受妊娠期特殊生理机制的影响,此类糖尿病患者血糖水平波动较大,难以控制,若无法及时接受有效治疗,会导致严重不良妊娠结局;而且,对比健康孕妇和妊娠期糖尿病孕妇的预后可知,后者发生糖尿病、心血管疾病等并发症的风险显著提高。据研究,孕前BMI≥25kg/m2、有糖尿病家族史、血清Leptin水平高、血清APN水平低均为妊娠期糖尿病发生的危险因素;妊娠期出现糖尿病,会观察到胰腺产生组织损伤。本申请的实施例证明,棕榈酰肉碱会诱导胰腺β胰岛细胞的特化和终末分化,从PAX4和RFX6表达的增加观察,提示它可以在正常妊娠期间促进母体胰腺β胰岛新生。
妊娠期适应性的生理变化会导致肝脏脆性增加,缓冲能力削弱,病程进展加快。妊娠期的肝脏疾病一直是导致孕产妇死亡的独立影响因素;在怀孕期间,有3%至9%的孕妇受到某种形式肝病的影响,其中一些问题对于母子来说是致命的;它们大致可以分为三种类型:一是与妊娠直接相关的肝病,其可以在怀孕期间的特定时期发生;二是与妊娠无关的肝病,可以在任何时间发生,例如病毒或者药物诱导的肝炎;三是怀孕发生在既往患有肝病的女性身上;由于孕产本身的病理生理特异性、肝脏自身强大的代偿能力和疾病早期的隐蔽性,妊娠相关肝病在早期容易被产科医生忽略,而一旦出现显著性的临床症状,肝脏已经出现严重损伤,甚至出现肝衰竭;综上,妊娠期出现肝病,会观察到肝脏出现组织损伤。在本申请的实施例中可以看到,对于肝祖细胞,棕榈酰肉碱可显著诱导肝祖细胞终末分化为表达ALB的肝细胞,如从ALB表达的剂量依赖性增加所观察到的那样,这表明它可以加速母体肝损伤后的组织再生。
在又一具体实施方式中,所述哺乳动物为人类。
在再一具体实施方式中,所述哺乳动物来自人类饲养动物;优选选自下组:猪、牛、马、狗、猫、山羊、兔、食蟹猕猴、小鼠、大鼠;最优选为食蟹猕猴。
在一个具体实施方式中,所述棕榈酰肉碱在妊娠期组织发生损伤时通过促进祖细胞的生长和分化实现组织再生。
在本说明书的上下文中,“祖细胞(Progenitor cell)”是指存在于成体组织中的、具有较为明确分化目标的干细胞。细胞在彻底分化前,能转化成某种中间细胞(intermediate cell),这种中间细胞被称作祖细胞或前体细胞(precursor cell)。祖细胞属于成体干细胞,是未分化的多能或专能干细胞。与干细胞不同,祖细胞的分化具有更多的明确性,也就是说,只能分化为一些目标细胞。它们另外一个最重要的区别是:干细胞可以无限增殖,而祖细胞分裂的次数是有限的。祖细胞分别存在于生物的各种成体组织中,负责组织损伤后的修复再生过程。在损伤发生后,祖细胞可以被动员激活,大量增殖并迁移到受损部位,分化成成熟的细胞,替换受损的组织。在人体的多种组织器官中都已鉴定到相应的祖细胞,例如:血液祖细胞、皮肤祖细胞、小肠祖细胞、肺脏祖细胞等。本申请的实施例示出了棕榈酰肉碱对于肝脏祖细胞、心肌祖细胞以及胰腺祖细胞的作用。
本申请在第二方面涉及促进哺乳动物体内棕榈酰肉碱水平增加的化合物的应用。
在一个具体实施方式中,提供了促进哺乳动物体内棕榈酰肉碱水平增加的化合物在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
在又一具体实施方式中,所述哺乳动物妊娠期与组织损伤相关的疾病选自下组:妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
在再一具体实施方式中,所述哺乳动物为人类。
在一个具体实施方式中,所述哺乳动物来自人类饲养动物;优选选自下组:猪、牛、马、狗、猫、山羊、兔、食蟹猕猴、小鼠、大鼠;最优选为食蟹猕猴。
在又一具体实施方式中,所述促进哺乳动物体内棕榈酰肉碱水平增加的化合物为棕榈酰肉碱合成促进剂和/或棕榈酰肉碱分解抑制剂;其中,
优选所述棕榈酰肉碱合成促进剂为肉碱棕榈酰转移酶I(CPT-1)激活剂,最优选为黄芩苷或其衍生物;
优选所述棕榈酰肉碱分解抑制剂为肉碱棕榈酰转移酶II(CPT-2)抑制剂,最优选为4-三甲基铵基丁酸盐类。
在本说明书的上下文中,“黄芩苷”具有下述特征:
结构式为:
CAS号为:21967-41-9
英文名称为:Baicailin
分子式为:C21H18O11
在本说明书的上下文中,“4-三甲基铵基丁酸盐类”具有下述结构特征:
其中
A1是O或键,
m选自3、4、5、6、7、8、9和10,
n选自1、2、3、4和5,
R1是选自苯基和萘基的芳基,所述芳基是未取代的或被1、2、3、4或5个基团取代的,所述基团选自由低级烷基、卤素、低级卤代烷基和苯基组成的组,或者
选自由吡啶基、噻吩基和噻唑基组成的组的杂芳基,所述杂芳基是未取代的或被1、2或3个基团取代的,所述基团选自低级烷基、卤素、低级卤代烷基、低级氧烷基和苯基,
其中“低级”指由1至7个碳原子组成的基团,
及其药用盐。
实施例部分
实验方法:
动物伦理声明
所有的实验都符合非人灵长类动物伦理治疗原则并事先得到动物研究所(中国科学院)机构动物护理和使用委员会的批准(IOZ-IACUC-2021-184)。
动物样本采集
健康雌性食蟹猴与健康雄性食蟹猴交配,并在交配期间通过肉眼或阴道涂片中存在精子来确认性交。B超确定妊娠时期,包括妊娠早期(EP,5-8周,N=3),妊娠中期(MP,12-15周,N=3),妊娠晚期(LP,18-20周,N=3)。总共有9只自然妊娠和3只非妊娠的雌性食蟹猴(5-8岁,体重2.5-6.0公斤)在已获得实验动物护理认证的协尔鑫生物资源研究所(中国北京)圈养。所有动物都被安置在保持23±3℃,并使用12小时光照/12小时黑暗循环的房间内。在兽医的持续监督下,每天喂一次水果和蔬菜,给予2次自来水。在实验之前,没有一只猴子具有影响生理代谢的临床疾病史或其它实验史。收集样本之前,猴子用盐酸氯胺酮麻醉,剂量为10-12mg/kg。由专业兽医进行B超检测再次确认妊娠时期。从股静脉获得全血样品并分装到非肝素化管中并使其凝结30分钟,然后在4℃离心机以2000g离心10分钟以收集血清样本。在确保动物完全处于深度麻醉后,通过大腿动脉放血以诱导安乐死。血清和另外22种组织被获取后均立即在液氮中速冻并储存在-80℃冰箱直至进行代谢组学检测。
液相色谱-质谱(LC-MS)代谢组学
代谢物提取方案基于Shyh-Chang等的方案(Shyh-Chang等,2013)。简而言之,样本的质量和体积被测量之后与相同体积的80%(v/v)甲醇-水在-78℃结合。将混合物在TissuePrep 24均质机中用经-78°预冷过的316不锈钢珠(Gering,北京,中国)处理,然后在100Hz的振动频率下在液氮中浸泡1-5分钟。匀浆后裂解物以5000g离心15分钟,收集上清液用于LC-MS分析。
A cquity I级超高效液相色谱(UPLC)系统与Xevo G2-XS高分辨率四极杆飞行时间混合质谱仪(Waters)相结合,用于非靶向代谢物分析。使用T3色谱柱(A cquityUPLC HSST3,长2.1×100mm,粒径1.7μm)进行反相色谱分离,使用以下溶剂:流动相A(100%水)和B(100%乙腈)均含0.1%甲酸,采用以下洗脱梯度:0min 95%A;8.5min 50%A;12min2%A;16min 95%A。流速为0.4ml/min,上样量为2μl。
质谱仪在正负ESI模式下使用UPLC/MS E进行数据采集,允许在一次进样中采集母离子和子离子数据。前体离子最大强度的典型源条件如下:毛细管电压,2.5kV正模式和2.0kV负模式;样品锥,40V;源温度,120℃;去溶剂化温度,20℃;锥体气体流量,30L/h;去溶剂化气体(N2)流速,800L/h。所有分析均使用lockspray进行,确保了准确性和可重复性。亮氨酸-脑啡肽(5ng/ml)用作产生参考离子(正离子模式:m/z 556.2771;负离子模式:m/z554.2615)的锁定质量,并通过锁定喷雾以10μl/min的速度引入,以获取准确的质量数。MS数据是使用MSE获得的,它有两个独立的扫描,具有独立的碰撞能量。扫描1(低能量):50-1200质量扫描范围;0.2秒扫描时间;6eV碰撞能量;扫描2(高能量):50-1200质量扫描范围;0.2秒扫描时间;碰撞能量坡为10-40eV。以这种方式采集MS数据可以分析母离子和碎片离子。使用Progenesis QI软件(Nonlinear Dynamics,Waters)进行MS数据处理。将原始数据导入Progenesis QI进行峰对齐和峰拾取并根据准确的电荷质量数(m/z)高分辨率MSE数据进行匹配。
代谢组学数据的质量评估
为了进一步分析,原始代谢组学数据通过强度总和与对数转换方法进行归一化,并使用MetaboAnalystR进行偏最小二乘判别分析(PLS-DA)(Pang等,2021)(https://github.com/xia-lab/MetaboAnalystR)。在我们的分析中,任何一个样品中缺失的代谢物值都使用零代替。总共在23个组织中检测到11852个代谢特征。T分布随机邻域嵌入(t-SNE)(Melit Devassy et al.,2020)对原始数据进行无监督聚类,上述分析使用了Rtsne和ggplot2软件包(图1A)。
斯皮尔曼(Spearman)相关性分析
我们对每个样本的所有已识别代谢物的强度计算平均值并使用Spearman相关系数作为MetaboAnalystR中的距离范数度量和完整链接构建了一个层次聚类树状图。为进一步确定代谢相关性,在每个组织之间我们构建了跨越四个阶段的23种组织的相关矩阵,并在R环境中使用相关性热图和网络图将它们可视化,数据定义的阈值为0.185。相关性热图由pheatmap包绘制,相关性网络图由qgraph包生成(Epskamp等,2012)。
通路富集分析
我们利用MetaboAnalystR对NP、MP和LP的23种组织中所有已鉴定的代谢物进行代谢物富集分析(MSEA)(Xia and Wishart,2010),以EP作为比较的基线。为了量化通路活性,我们统计了显著变化的代谢通路的数量(P<0.05),并用pheatmap包可视化制图。此外,我们还使用ggplot2包制作气泡图和热图一起可视化在妊娠至少一个阶段时跨半数及以上我们所检测组织中显著改变的重要代谢通路。
鉴定显著改变的代谢物
使用MetaboAnalystR进行倍数变化(FC)分析,该分析是基于特定组织中所有代谢物丰度的平均值相对于EP的比值计算得出。为了量化结果,我们统计了MP和LP中相对于每个组织中EP有显著变化(FC≥1.5)的代谢物数量,使用tidyverse和viridis软件包将它们绘制在圆形堆叠条形图上,并使用UpSetR包可视化维恩图以显示交集代谢物的个数(Conway等,2017)。
细胞培养
从多能WA07人ESC(WiCell,美国)中诱导人肝脏、肌肉、心脏和胰腺祖细胞,所有细胞都按照之前文献中所述的详细步骤进行培养(Ang等,2018;Chua等,2019;Koh等,2016;Martin等,2020)。传代1天后,在培养基中添加25或50μM棕榈酰肉碱(PC)或二甲基亚砜,将所有细胞再继续培养2天后进行RNA提取。
定量实时PCR分析
按照FastPure Cell/Tissue Total RNA Isolation Kit V2(RC112)说明书提取细胞总RNA,并使用HiScript III All-in-one RT SuperMix Perfect for qPCR kit(R333-01)将1μg总RNA逆转录为cDNA。然后使用LightCycler 480System Real Time PCRSystem(Roche,LC-480,USA)和SYBR Premix Ex Taq II(TakaraBio)进行实时定量聚合酶链式反应(qRT-PCR)。使用ΔΔCT方法计算mRNA的表达水平,并以GAPDH作为内部对照。每种基因至少进行三次重复,并以条形图表示结果。使用t检验进行统计分析,误差线表示平均值±SEM。
关键资源列表
关键商业试剂盒
软件
实施例1妊娠食蟹猴不同阶段母体组织代谢组学分析
为了研究灵长类动物妊娠期间母体组织的代谢适应,我们选择分析来自不同妊娠阶段的食蟹猴母体组织,构建对应于人类妊娠的三个时期妊娠早期、中期和晚期的成年食蟹猴模型,每组各三只。采集了来自9只妊娠和3只非妊娠食蟹猴的10个器官系统的23种母体组织,包括子宫、卵巢、胎盘、乳腺、胸腺、心尖部、左心室、左心房、右心室、右心房、胰头、胰颈、胰体、胰尾、肝脏、肾脏、肾上腺、脊髓、腓肠肌、股四头肌、腹部皮肤、头部皮肤和血清(图2I)。与非妊娠相比,子宫胎盘系统的总重量及其脏器系数在整个妊娠期间增加(Mayhew,2006),而胸腺的总重量及其脏器系数在妊娠中期和晚期阶段减少(图2J和2K),这可能与调节母体免疫系统的关键适应性机制有关(Dixit等,2003)。然而心脏、肝脏、肾脏和胰腺的重量并没有显著变化(图2J和2K)。通过液相色谱-质谱(LC-MS)共分析了273个样品的非靶向代谢组学。数据经峰对齐、过滤、质量控制和归一化预处理之后(图1A),显示23种组织在四个阶段共鉴定了11852个代谢特征。其中,在所有组织中都检测到并注释的有1468个特征(图2L)。T分布随机邻域嵌入(t-SNE)和偏最小二乘判别分析(PLS-DA)均显示样本可以根据组织来源进行区分(图1A和1B),这确定了我们的代谢组学分析方案质量的可靠性(图1A和1B)。另PLS-DA还显示组织样本也可以根据其器官系统起源很好地聚集在一起(图1C),进一步证实了我们的LC-MS代谢组学数据的可靠性。总之,这些结果表明母体组织之间存在代谢相关性。为了阐明每种组织之间的层次关系,我们创建了每种组织在所有阶段的树状图(图1D)。有趣的是,我们发现23种母体组织可以被分成三个簇,它们是以支持相同组织类型器官之间代谢相似性的方式显现。第一个簇包含富含脂质的血清、头部皮肤、腹部皮肤和胸腺。第二个簇包含许多具有内分泌功能的器官,包括肝脏、肾脏、肾上腺和胰腺组织。第三个簇包含腓肠肌和股四头肌、心脏组织、子宫、乳腺、脊髓、胎盘和卵巢。除此之外,PLS-DA还显示样本也可以根据妊娠阶段区分,有趣的是妊娠早期(EP)与非妊娠(NP)的距离最远(图1E-1H)。总之,这些结果表明代谢耦联存在于器官系统中,且它们在食蟹猴妊娠期间存在着动态进化。
实施例2食蟹猴妊娠期间母体组织之间代谢耦联的演变
为了揭示4个阶段23种母体组织之间代谢耦联是如何演变的,我们进行了Spearman相关分析,并使用相关性热图和网络图来可视化结果(图2)。相关性热图显示,每种组织的3份生物学重复样本之间的相关性都非常高,进一步证实了我们的代谢组学数据的可靠性(图2A-2D)。此外,我们发现心脏和胰腺内的各个部分在四个阶段都具有高度相似性,腓肠肌和股四头肌,或腹部皮肤和头部皮肤也是如此,这又进一步证明了我们从采样、数据预处理和代谢组学数据分析整个流程的可靠性(图2A-2D)。有趣的是,相关性热图还显示,在4个阶段肝脏与肾脏代谢组都存在较高的相关性(图2A-2D),表明这两个代谢活跃的器官之间存在代谢耦联。
此外,相关性热图表明有15个组织之间的代谢耦联在不同阶段存在动态演变。例如,腓肠肌和股四头肌的代谢组在非妊娠状态下与心肌组织高度相关,但在妊娠早期和中期向肾上腺转移(图2A-2C)。到妊娠晚期,两种骨骼肌与脊髓的相关性更高,表明神经肌肉的协调性增加(图2D)。以上结果表明,骨骼肌和各种组织之间的代谢耦联在妊娠过程中发生了显著变化。
另一个有趣的组织是胎盘,当它在妊娠早期首次出现时,它与子宫高度相关(图2B),这可能与妊娠期间胎盘和子宫形成用来相互交换营养物质和代谢物的绒毛有关。子宫在非妊娠状态下与心脏组织代谢组相关性较高(图2A),但在妊娠早期和中期与胎盘和胰腺组织有着更高的耦联度(图2B-2C)。然而到了妊娠晚期,胎盘与肝脏和心脏组织的代谢组耦联度更高,而子宫与头部皮肤的耦联度更高(图2D)。这些结果表明,子宫和胎盘组织的代谢功能在妊娠过程中也发生了显著变化。除此之外,卵巢在非妊娠状态下与头部皮肤和腹部皮肤高度相关(图2A),可能是由于它们都富含上皮组织。然而,随着妊娠的进展,它们相关性变弱,卵巢与胎盘的耦联度更高,尤其是在妊娠中期和晚期(图2C-2D)。此外,我们还进一步为每个阶段23种组织的代谢组构建了相关性网络图,更清楚地显示了皮肤(左)、胎盘(上)、心脏组织(右)、子宫和卵巢(下)之间的代谢耦联在妊娠期间发生的显著变化。与高度耦联的非妊娠状态相比,组织之间的代谢耦联总量在整个妊娠期间显著减少(图2E-2H),到妊娠晚期达到高度解耦的状态(图2H)。相关性网络图还更清楚地显示了胎盘的出现如何与整体代谢耦联的相变同时发生,以及胎盘如何从妊娠早期与子宫、皮肤和许多其他组织的代谢耦联转到妊娠中期和晚期与卵巢和心脏组织代谢耦联(图2F-2H)。以上结果表明,妊娠期间组织之间的相互代谢耦联和平衡稳态的基础模式被严重破坏,并且多个母体组织中的代谢耦联模式在妊娠期间以高度协调的方式演变。
实施例3妊娠期间23种母体组织中的代谢途径发生变化
为了进一步研究23种母体组织中代谢重编程的程度和确切的代谢通路变化,我们首先分析了11852个注释特征中有哪些在妊娠的每个阶段发生了显著变化。考虑到胎盘对于维持妊娠的重要性,但只存在于妊娠早期,我们使用妊娠早期作为所有比较的基线。MetaboanalystR参考小分子途径数据库(SMPDB)分析了富含显著变化代谢物的代谢通路(Jewison等,2014;Pang等,2021)。为量化23种母体组织中代谢通路重编程的程度,我们统计了在每个妊娠阶段发生显著变化代谢通路的数量(P<0.05)(图3A)。结果表明,在非妊娠和妊娠早期之间,胰颈、子宫、心尖部、卵巢、左心房和胸腺的代谢通路比其他组织发生了更显著的变化(图3A)。在妊娠早期和中期之间,子宫、胰颈、胰头、卵巢、脊髓、肾脏和头部皮肤比其他组织的代谢通路发生了更显著的变化(图3A)。在妊娠早期和晚期之间,子宫、胎盘、心脏组织、乳腺、肾上腺、胰腺组织、肝脏和腹部皮肤比其他组织的代谢通路发生了更显著的变化(图3A)。平均而言,胰腺组织、生殖组织(子宫、胎盘、卵巢)和心脏组织似乎在妊娠期间表现出更高程度的代谢重编程。
为进一步揭示各妊娠期母体组织代谢通路发生的大规模变化,我们统计了98个映射的SMPDB通路中的每一个发生显著变化的组织数量(P<0.05)。结果表明,与妊娠早期相比,我们发现在妊娠的每个阶段检测的半数及更多种母体组织中有8种代谢通路发生了显著变化(图3B)。在这8种代谢通路中,众所周知,类固醇生成在妊娠期间发挥着关键作用(Noyola-Martínez等,2019),而胆汁酸生物合成和花生四烯酸(一种omega-6脂肪酸)代谢在维持妊娠方面也是必不可少的途径(Jadoon等,2014;McIlvride等,2017),从而确定了我们研究结果的有效性。此外,我们还观察到嘧啶代谢、谷氨酸代谢、嘌呤代谢、酪氨酸代谢和卟啉代谢在妊娠期间可能也很重要。
除了上述8种在妊娠不同时期都共享的显著改变的代谢通路外,我们的研究结果还揭示了每个妊娠阶段中半数及以上所检测组织共享的显著改变的其它代谢通路(图3C和3D)。从非妊娠到妊娠早期发生显著变化的代谢通路中(图3C,左热图),已知鞘脂代谢异常与人类流产有关(Mizugishi等,2007),并且鞘脂类正在成为先兆子痫(PE)潜在的妊娠早期生物标志物(Dobierzewska等,2017)。此外,我们还观察到从妊娠早期到中期,胰腺组织中的类固醇生物合成通路发生了显著变化(图3C,中间热图),这可能与人类妊娠期间的胰岛素抵抗和胰岛功能有关(Vejrazkova等,2014)。我们还观察到母体组织中的许多类固醇途径从妊娠早期到晚期发生了显著变化,例如:雄激素和雌激素代谢、雌酮代谢、类固醇生物合成等(图3C,右热图)。有趣的是,许多脂肪酸代谢通路在妊娠早期到晚期的多个母亲组织中也发生了显著变化(图3C,右热图)。胎盘在妊娠晚期表现出最多的代谢通路变化(图3A),进一步证实了我们的观察,即胎盘是妊娠期代谢最活跃的器官之一。综上,我们的通路富集分析揭示了每种母体组织中与妊娠相关的许多重要代谢途径,包括某些已知的和以前未知的。
实施例4妊娠期间多个母体组织共享的显著变化代谢物
接下来,我们分析了在妊娠各阶段持续变化的代谢物,可以作为未来潜在的生物标志物和功能性代谢物。我们选择妊娠早期作为基线,因为在非妊娠状态下没有胎盘,并且每个妊娠阶段彼此之间更具可比性。为了量化结果,我们统计了每种组织在妊娠中期和晚期相对于妊娠早期(倍数变化≥1.5)的差异代谢物数量,并使用UpSetR维恩图和圆形堆叠条形图可视化妊娠中期和晚期出现的差异代谢物数量(图4)。令我们惊讶的是,我们检测的每种组织都有超过3000种差异代谢物,这些代谢物在妊娠中期和晚期时相对于妊娠早期都在持续变化(图4)。然而有趣的是,妊娠期间23种组织仅共享97种差异代谢物(图4),这可能与妊娠晚期导致的代谢解耦有关(图2H)。
在这97种差异代谢物中,我们发现妊娠中期相比于早期,心尖、右心房、左心房、胰尾、肝脏、肾脏、肾上腺和胸腺中棕榈酰肉碱(一种众所周知的脂肪酸氧化中间产物)的水平均增加(等,1996)(图5A)。
实施例5棕榈酰肉碱对人类祖细胞的功能影响
本申请的候选代谢物棕榈酰肉碱不仅可以作为脂肪酸氧化的中间体,还可以调节免疫反应(Trinchese等,2018)。鉴于其在妊娠早期和中期的许多组织中持续增加,但在妊娠晚期普遍减少(图5A),我们决定进一步研究这种代谢物是否也介导母体器官的适应。为了解决这个问题,我们诱导人类胚胎干细胞(hESCs)定向分化为胰腺、肝脏、心脏和肌肉祖细胞(Ang等,2018;Chua等,2019;Koh等,2019;Martin等,2020),然后经棕榈酰肉碱处理后细胞继续增殖或分化。对于肝祖细胞,棕榈酰肉碱可显著诱导肝祖细胞终末分化为表达ALB的肝细胞,且ALB的表达呈现剂量依赖性增加,然而并不影响肝祖细胞的特定因子,这表明它可能有加速母体肝脏损伤后再生的作用(图5B)。对于肌肉祖细胞,棕榈酰肉碱降低了成肌细胞转录因子PAX3的水平,并以剂量依赖性方式增加分化的肌细胞转录因子MYOG,表明它可以调节母体肌肉在应激和损伤时的生长和分化(图5C)。从ISL1和TNNT2表达的剂量依赖性增加中观察到,棕榈酰肉碱还可以诱导心肌细胞的特化和分化(图5D),表明它可以促进孕期母体心脏的生长。此外,棕榈酰肉碱还可以诱导胰腺β胰岛细胞的特化和终末分化,这可以从PAX4和RFX6表达的增加中观察到(图5E),提示它可以在正常妊娠期间促进母体胰腺β胰岛细胞再生。综上,这些结果表明,在妊娠早期和中期,许多组织中棕榈酰肉碱的持续增加可能在调节母体器官生长和再生过程中发挥功能性作用,而棕榈酰肉碱的效应在妊娠后期逐渐减弱。
尽管以上结合附图对本发明的实施方案进行了描述,但本发明并不局限于上述的具体实施方案和应用领域,上述的具体实施方案仅仅是示意性的、指导性的,而不是限制性的。本领域的普通技术人员在本说明书的启示下和在不脱离本发明权利要求所保护的范围的情况下,还可以做出很多种的形式,这些均属于本发明保护之列。
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Claims (10)
1.棕榈酰肉碱在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
2.根据权利要求1所述的应用,其中,所述哺乳动物妊娠期与组织损伤相关的疾病选自下组:妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
3.根据权利要求1-2的任一项所述的应用,其中,所述哺乳动物为人类。
4.根据权利要求1-2的任一项所述的应用,其中,所述哺乳动物来自人类饲养动物;优选选自下组:猪、牛、马、狗、猫、山羊、兔、食蟹猕猴、小鼠、大鼠;最优选为食蟹猕猴。
5.根据权利要求1所述的应用,其中,所述棕榈酰肉碱在妊娠期组织发生损伤时通过促进祖细胞的生长和分化实现组织再生。
6.促进哺乳动物体内棕榈酰肉碱水平增加的化合物在制备预防和治疗哺乳动物妊娠期与组织损伤相关的疾病的药物中的应用。
7.根据权利要求6所述的应用,其中,所述哺乳动物妊娠期与组织损伤相关的疾病选自下组:妊娠期心脏病、妊娠期糖尿病、妊娠期肝病。
8.根据权利要求6-7的任一项所述的应用,其中,所述哺乳动物为人类。
9.根据权利要求6-7的任一项所述的应用,其中,所述哺乳动物来自人类饲养动物;优选选自下组:猪、牛、马、狗、猫、山羊、兔、食蟹猕猴、小鼠、大鼠;最优选为食蟹猕猴。
10.根据权利要求6-7的任一项所述的应用,其中,所述促进哺乳动物体内棕榈酰肉碱水平增加的化合物为棕榈酰肉碱合成促进剂和/或棕榈酰肉碱分解抑制剂;其中,
优选所述棕榈酰肉碱合成促进剂为肉碱棕榈酰转移酶I(CPT-1)激活剂,最优选为黄芩苷或其衍生物;
优选所述棕榈酰肉碱分解抑制剂为肉碱棕榈酰转移酶II(CPT-2)抑制剂,最优选为4-三甲基铵基丁酸盐类。
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