CN116726176A - 一种用于创面修复的药物及其应用 - Google Patents
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Abstract
本发明公开了一种用于创面修复的药物及其应用。本发明公开了己糖激酶2在电离辐射创面修复中发挥重要作用，使用其抑制剂可促进创面愈合。本发明提供了一种创面修复的方法。本发明还提供了一种诊断放射损伤或放射性疾病的方法。
Description
技术领域
本发明属于生物医药领域，具体涉及一种用于创面修复的药物及其应用。
背景技术
创伤愈合是一个复杂有序的过程，涉及造血细胞反应、修复细胞反应和细胞外基质与生长因子反应等过程，其中细胞反应是整个修复过程中的关键环节。大剂量电离辐射作用明显延缓创伤愈合的病理过程主要表现为：造血功能受抑，炎症反应削弱，特别是创伤局部浸润的巨噬细胞和中性粒细胞等炎性细胞显著减少，创伤启动过程延迟；血管损害，内皮细胞变性、坏死，出血较明显；肉芽组织形成和成熟均明显减缓，成纤维细胞数量和功能受损；再上皮化过程延迟，愈合时间延长。近年从分子层面的研究进一步深化了对电离辐射延缓创面愈合机制的认识。研究表明，造血细胞来源减少和射线引起的凋亡增加是导致创伤局部炎性细胞数量减少的重要原因，而射线作用致细胞增殖受抑和凋亡增加是成纤维细胞数量减少的重要原因。与细胞增殖密切相关的增殖性细胞核抗原(proliferate cellnuclear antigen，PCNA)、细胞周期素E(cyclinE)、细胞周期素依赖性激酶4(cyclin-dependent kinase 4，CDK4)等分子表达降低，抑制细胞周期G1期向S期的过渡是造成细胞增殖受抑的重要机制；而bax等促凋亡基因的表达增加和bcl-2等抗凋亡基因的表达下降是造成细胞凋亡增加的重要机制。进一步研究还发现，除细胞数量减少外，细胞功能也受到了明显影响，突出表现为胶原、纤维粘连蛋白等细胞外基质分子和碱性成纤维细胞生长因子、转化生长因子β等生长因子的合成与分泌降低。
己糖激酶2(Hexokinase 2,HK2)是催化糖酵解途径中的第一步反应的关键代谢酶，将葡萄糖磷酸化为6-磷酸葡萄糖，主要定位在线粒体外膜上。HK2在许多肿瘤中都呈现出高表达，在促进Warburg效应产生上起到重要作用。目前还没有研究报道HK2能够促进电离辐射后的创面愈合。
发明内容
本发明的第一目的是提供一种用于创面修复的药物；
本发明的第二目的是提供一种预防或治疗放射损伤的药物；
本发明的第三目的是提供一种预防或治疗放射性疾病的药物；
本发明的第三目的是提供一种诊断放射损伤或放射性疾病的方法。
基于上述目的，本发明采用了如下技术方案：
一方面，本发明提供了如下任一项应用：
(1)己糖激酶2的抑制剂在制备用于创面修复的药物中的应用；
(2)己糖激酶2的抑制剂在制备预防或治疗放射损伤的药物中的应用；
(3)己糖激酶2的抑制剂在制备预防或治疗放射性疾病的药物中的应用。
进一步，所述的放射损伤为电离辐射所致损伤。
进一步，所述的放射性疾病为电离辐射所致疾病。
如本发明所使用的“电离辐射”是指放射治疗(可简称为放疗)时使用放射线而造成的辐射。放射治疗中使用的放射线类型包括α射线、β射线、X射线和γ射线；其中，α射线和β射线是粒子束，X射线和γ射线是电磁波。
进一步，所述电离辐射是指使用60Coγ射线而造成的辐射。
在本发明的实施方式中，所述电离辐射的强度是1-20Gy，具体地包括1Gy、2Gy、3Gy、4Gy、5Gy、6Gy、7Gy、8Gy、9Gy、10Gy、11Gy、12Gy、13Gy、14Gy、15Gy、16Gy、17Gy、18Gy、19Gy、20Gy。在本发明的具体实施例中，所述的电离辐射的强度是5Gy、8Gy。
本发明所述Gy即“Gray”的缩写，是物理量“电离辐射能量吸收剂量”的标准单位。Gray可译作“戈瑞”、“戈雷”、“格雷”，有时简称“戈”，在本发明中以上概念皆代表相同含义，可互换使用。
进一步，所述的用于创面修复的药物为能够促进创面愈合的药物。
创面愈合(Woundhealing)是指由于致伤因子的作用造成组织缺失后，局部组织通过再生、修复、重建，进行修补的一系列病理生理过程。
进一步，所述的创面愈合为电离辐射后的创面愈合。
在本发明中，术语“抑制剂”是指分子或物质或化合物或组合物或药剂或任何组合，其能够抑制和/或降低所述靶分子的活性或表达水平。
进一步，所述的抑制剂包括核酸抑制剂、蛋白抑制剂、蛋白水解酶、蛋白结合分子、化合物。
进一步，所述的抑制剂为化合物。
进一步，所述的抑制剂为3-BP或其立体异构体、药学上可接受的盐、溶剂化物或其水合物。
进一步，所述的抑制剂能够促进电离辐射后的创面修复。
进一步，所述的药物还包括药学上可接受的载体。
如本文所用，“药学上可接受的”的成分是适用于人和/或哺乳动物而无过度不良副反应(如毒性、刺激和变态反应)的，即具有合理的效益/风险比的物质。术语“药学上可接受的载体”指用于治疗剂给药的载体。
进一步，所述的药学上可接受的载体包括稀释剂、缓冲剂、混悬剂、乳剂、颗粒剂、包囊剂、赋形剂、填充剂、粘合剂、喷雾剂、透皮吸收剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、着色剂、矫味剂或吸附载体。
另一方面，本发明提供了检测受试者样本中己糖激酶2的表达量的试剂在制备用于诊断放射损伤或放射性疾病的产品中的应用。
本发明中，所述受试者为哺乳动物。例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物。
术语“样本”被定义为在本文中所述的分析或实验方法中要被测试的任何材料。样本通常从本文中所述的受试者获得。在一些实施方案中，样本是经由非侵入性方法获得(例如是非侵入性样本)。示例性非侵入性方法包括但不限于被动收集体液或无伤害的刮擦从外部环境可接近的(例如表皮或嘴的)组织。示例性非侵入性样本包括但不限于唾液、痰液、粘液、汗液、尿液、粪便、精液、子宫颈阴道分泌物、母乳、发炎性分泌物、泪液或脸颊上皮拭子。在一些实施方案中，样本是经由微侵入性方法获得。示例性微侵入性方法包括但不限于毛细管收集、静脉穿刺、胸腔穿刺、羊膜穿刺、针吸或洗胃。示例性微侵入性样本包括但不限于血液或血液级分(例如血浆或PBMC制品)、组织间液、胆汁、胃液和羊水。在一些实施方案中，样本是经由活检获得。示例性活检样本包括但不限于皮肤活检样本(例如通过穿孔、刮剃、碟形手术、楔入、切开或切除活检获得)、骨髓样本(例如通过抽吸活检获得)、淋巴结或乳房活检(例如通过细针抽吸、芯针活检、真空辅助活检或图像引导活检获得)、手术活检样本(例如通过切除或切开活检获得内部器官的样本)，或嘴、胃肠道、肺、膀胱或尿道活检样本(例如通过内镜检查获得)。
进一步，所述的放射损伤为电离辐射所致损伤。
进一步，所述的放射性疾病为电离辐射所致疾病。
进一步，所述的电离辐射所致疾病包括辐射所致恶性肿瘤、辐射所致退行性疾病。
在本发明中，辐射所致恶性肿瘤包括但不限于白血病，外照射引起的皮肤癌、甲状腺癌、骨恶性肿瘤，内照射引起的肺癌、骨恶性肿瘤、肝和胆道系统的恶性肿瘤及甲状腺癌。
在本发明中，辐射所致退行性疾病包括但不限于白内障，再生障碍性贫血，骨坏疽，骨质疏松症，其它身体局部的纤维化。
进一步，所述的试剂包括通过数字成像技术、蛋白免疫技术、染料技术、核酸测序技术、核酸杂交技术、色谱技术、质谱技术检测己糖激酶2的表达量的试剂。
进一步，所述的试剂包括引物、探针、蛋白结合剂。
“引物”是指寡核苷酸，它与靶核酸中的序列(“引物结合位点”)杂交并且能够用作在适用于合成的条件下沿着核酸的互补链启动该合成的点。
除非另有指出，术语“探针”通常指能通过互补碱基配对与另一多核苷酸(往往称为“靶多核苷酸”)结合的多核苷酸探针。根据杂交条件的严格性，探针能和与该探针缺乏完全序列互补性的靶多核苷酸结合。探针可作直接或间接的标记。杂交方式，包括，但不限于：溶液相、固相、混合相或原位杂交测定法。
蛋白结合剂是例如蛋白质的受体、结合蛋白质的凝集素、针对蛋白质的抗体、针对蛋白质的肽抗体(peptidebody)、双特异性双重结合剂或双特异性抗体形式。
进一步，所述的产品包括芯片、试剂盒或核酸膜条。
在本发明中，“芯片”也称为“阵列”，指包含连接的核酸或肽探针的固体支持物。阵列通常包含按照不同的已知位置连接至基底表面的多种不同的核酸或肽探针。这些阵列，也称为“微阵列”，通常可以利用机械合成方法或光引导合成方法来产生这些阵列，所述光引导合成方法合并了光刻方法和固相合成方法的组合。阵列可以包含平坦的表面，或者可以是珠子、凝胶、聚合物表面、诸如光纤的纤维、玻璃或任何其它合适的基底上的核酸或肽。可以以一定的方式来包装阵列，从而允许进行全功能装置的诊断或其它方式的操纵。
“微阵列”是杂交阵列原件有序排列在基质上，所述杂交阵列原件诸如聚核苷酸探针(例如寡核苷酸)或结合剂(例如抗体)。所述基质可以是固体基质，例如，玻璃或二氧化硅玻片、珠、纤维光学粘结剂或半固态基质，例如硝酸纤维素膜。核苷酸序列可以是DNA、RNA或其中的任何排列。
进一步，所述试剂盒包括基因检测试剂盒、蛋白检测试剂盒。
进一步，所述的试剂盒还包括下组的一种或多种物质：容器、使用说明书、阳性对照物、阴性对照物、缓冲剂、助剂或溶剂。
另一方面，本发明还提供了一种检测表皮干细胞是否受到电离辐射的方法，所述的方法包括检测表皮干细胞中己糖激酶2的表达量。
另一方面，本发明还提供了一种抑制表皮干细胞发生细胞凋亡的方法，所述的方法包括抑制表皮干细胞中己糖激酶2的表达量。
进一步，所述的抑制表皮干细胞中己糖激酶2的表达量包括使用己糖激酶2的抑制剂处理表皮干细胞。
进一步，所述的抑制剂包括核酸抑制剂、蛋白抑制剂、蛋白水解酶、蛋白结合分子、化合物。
进一步，所述的抑制剂为化合物。
进一步，所述的抑制剂为3-BP或其立体异构体、药学上可接受的盐、溶剂化物或其水合物。
本发明的有益效果：
本发明首次公开了人表皮干细胞在电离辐射处理后48h，细胞中己糖激酶2的蛋白水平显著增多。本发明进一步通过动物实验验证使用HK2其抑制剂可促进创面愈合。本发明为促进创面愈合提供了新方法，具有良好的临床应用前景。
附图说明
图1是免疫印迹法检测电离辐射后人表皮干细胞中γH2A的蛋白水平的结果图，
图2是ROS检测电离辐射后人表皮干细胞中活性氧的结果图，
图3是Tunel检测电离辐射后人表皮干细胞的凋亡水平的结果图，
图4是免疫印迹法检测电离辐射后人表皮干细胞中HK2的蛋白水平，
图5是Tunel检测经3-BP处理后人表皮干细胞的凋亡水平的结果图，图6为证明3-BP促进电离辐射后创面愈合的结果图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例己糖激酶2(Hexokinase2,HK2)在创面修复中的作用
一、实验材料
1.人表皮干细胞系，实验室保存的(最早购自公司)；
2.电离辐射源：军事医学研究院60Coγ射线源；
3.小鼠：为C57BL/6J背景，饲养于室温(23℃)，12小时昼夜周期并且可以自由摄食和饮水，购于斯贝福(北京)生物技术有限公司；
4.HK2的抑制剂3-BP(小化合物)购自selleck公司；
5.ROS检测试剂盒、凋亡检测试剂盒购自碧云天公司。
二、实验方法
1.建立电离辐射(Ionizingradiation,IR)损伤细胞模型及评价
使用人表皮干细胞建立电离损伤细胞模型，表皮干细胞经胰酶消化后制成单细胞悬液，平铺于细胞培养板中；次日细胞贴壁，将细胞板置于60Coγ射线下照射，剂量选择5Gy，照射剂量为79cGy/min；照射时间6min左右，而后置于培养箱中，在12h、D2等不同时间点收集样品，进行后续检测。
电离辐射后急性期DNA发生损伤，而γH2AX是DNA双链断裂密切相关，是DNA损伤的标志物，指示电离辐射细胞模型是否成功。
2.ROS检测、细胞凋亡检测
参考试剂盒说明书，分别使用ROS试剂盒、Tunel试剂盒(碧云天)分析细胞内活性氧、细胞凋亡情况。
3.小鼠电离辐射损伤模型
雄性C57BL/6J小鼠随机分为4组，Ctrl、Ctrl+3-BP、IR、IR+3-BP，用2％三溴乙醇麻醉后(腹腔给药，10ul/g)，剃去其背部毛发后，用打孔器打出直径为1cm左右的圆形皮肤缺损创面，在60Coγ射线下局部照射，剂量选择8Gy，照射前涂抹小化合物3-BP(3％甲基纤维素为溶剂配制)，记录创面愈合情况。
三、实验结果
1.成功建立人表皮干细胞电离辐射模型
如图1所示，人表皮干细胞(EpSC)在电离辐射(5Gy)后0.5h，γH2A的蛋白水平显著升高，指示细胞发生DNA损伤，电离辐射细胞模型成功。
2.电离辐射后人表皮干细胞中活性氧增加，细胞发生凋亡
ROS检测结果显示，人表皮干细胞在电离辐射处理后2天，细胞内活性氧含量显著升高，细胞损伤。(如图2所示)
Tunel检测结果显示，人表皮干细胞在电离辐射处理后3天，Tunel阳性细胞数相对明显增加，表明，IR后细胞发生凋亡。(如图3所示)
3.电离辐射后急性期，表皮干细胞中HK2表达量升高
如图4所示，WB检测结果显示，人表皮干细胞在电离辐射处理后48h，细胞中糖代谢关键限速酶HK2的蛋白水平显著增多，暗示IR后细胞糖代谢发生紊乱，代谢关键酶HK2异常增多，可能参与IR后细胞损伤。
4.添加HK2抑制剂3-BP可以减少表皮干细胞发生细胞凋亡
如图5所示，Tunel检测结果显示，人表皮干细胞在电离辐射处理后，Tunel阳性细胞数相对明显增加，使用HK2抑制剂3-BP处理后，细胞凋亡情况减轻。
5.提前涂抹HK2抑制剂3-BP可以促进电离辐射后创面愈合
建立小鼠电离辐射皮肤损伤模型，IR前涂抹HK2抑制剂3-bp，检测伤口愈合情况，结果显示：如图6所示，照射12天后，IR组小鼠伤口还未愈合，ctrl和ctrl+抑制剂组伤口愈合较好。这表明HK2在电离辐射创面修复中发挥重要作用，使用其抑制剂可促进创面愈合。
尽管本发明的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公开的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (10)
1.如下任一项应用：
(1)己糖激酶2的抑制剂在制备用于创面修复的药物中的应用；
(2)己糖激酶2的抑制剂在制备预防或治疗放射损伤的药物中的应用；
(3)己糖激酶2的抑制剂在制备预防或治疗放射性疾病的药物中的应用；
优选的，所述的放射损伤为电离辐射所致损伤，
优选的，所述的放射性疾病为电离辐射所致疾病。
2.根据权利要求1所述的应用，其特征在于，所述的用于创面修复的药物为能够促进创面愈合的药物，
优选的，所述的创面愈合为电离辐射后的创面愈合。
3.根据权利要求1所述的应用，其特征在于，所述的抑制剂包括核酸抑制剂、蛋白抑制剂、蛋白水解酶、蛋白结合分子、化合物，
优选的，所述的抑制剂为化合物，
优选的，所述的抑制剂为3-BP或其立体异构体、药学上可接受的盐、溶剂化物或其水合物，
优选的，所述的抑制剂能够促进电离辐射后的创面修复。
4.根据权利要求1所述的应用，其特征在于，所述的药物还包括药学上可接受的载体，
优选的，所述的药学上可接受的载体包括稀释剂、缓冲剂、混悬剂、乳剂、颗粒剂、包囊剂、赋形剂、填充剂、粘合剂、喷雾剂、透皮吸收剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、着色剂、矫味剂或吸附载体。
5.检测受试者样本中己糖激酶2的表达量的试剂在制备用于诊断放射损伤或放射性疾病的产品中的应用，
优选的，所述的放射损伤为电离辐射所致损伤，
优选的，所述的放射性疾病为电离辐射所致疾病。
6.根据权利要求5所述的应用，其特征在于，所述的试剂包括通过数字成像技术、蛋白免疫技术、染料技术、核酸测序技术、核酸杂交技术、色谱技术、质谱技术检测己糖激酶2的表达量的试剂。
7.根据权利要求5所述的应用，其特征在于，所述的试剂包括引物、探针、蛋白结合剂。
8.根据权利要求5所述的应用，其特征在于，所述的产品包括芯片、试剂盒或核酸膜条，
优选的，所述试剂盒包括基因检测试剂盒、蛋白检测试剂盒。
9.一种检测表皮干细胞是否受到电离辐射的方法，其特征在于，所述的方法包括检测表皮干细胞中己糖激酶2的表达量。
10.一种抑制表皮干细胞发生细胞凋亡的方法，其特征在于，所述的方法包括抑制表皮干细胞中己糖激酶2的表达量。
优选的，所述的抑制表皮干细胞中己糖激酶2的表达量包括使用己糖激酶2的抑制剂处理表皮干细胞，
优选的，所述的抑制剂包括核酸抑制剂、蛋白抑制剂、蛋白水解酶、蛋白结合分子、化合物，
优选的，所述的抑制剂为化合物，
优选的，所述的抑制剂为3-BP或其立体异构体、药学上可接受的盐、溶剂化物或其水合物。
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