CN114939121A - 毛冬青皂苷a在制备电离辐射防护药物中的应用 - Google Patents
毛冬青皂苷a在制备电离辐射防护药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域，提供了毛冬青皂苷A在制备电离辐射防护药物中的应用。经过细胞及动物的电离辐射防护实验，证明：毛冬青皂苷A在1.25‑80μg/mL浓度范围内对小鼠肺成纤维细胞MLG2908无毒性；在1.25‑20μg/mL对X射线导致的MLG2908细胞活力丧失呈剂量依赖的抑制作用；正常小鼠的胸腺组织中p65在胞浆分布，辐射后被激活并进行核转移，毛冬青皂苷A10mg/kg组，明显抑制p65激活，抑制其核转位；给予毛冬青皂苷A能够能够改善小鼠肺和肝的病理学变化，减轻辐射造成的损伤；肺组织被辐射后caspase3被剪切激活，cleaved‑caspase3的产物增多，毛冬青皂苷A干预组，明显下调caspase3的激活产物，抑制caspase3的激活。说明毛冬青皂苷A具有电离辐射防护的药用活性。为开发新的口服途径给药的电离辐射防护药物奠定了坚实的基础。
Description
技术领域
本发明涉及毛冬青皂苷A(毛冬青皂苷甲,ilexsaponin A1，ilexsaponina A)在电离辐射防护中的应用，属于医药技术领域。
背景技术
电离辐射不仅应用在医疗领域，同时在民用工业、农业和军事等领域的也有广泛的应用，电离辐射充斥在人们的日常生活中，从大气中自带的射线、到人们日常接触到的光源、手机、电脑、电视等仪器的辐射作用，人们无时不刻不生活在辐射的环境中，长时间大剂量的辐射对人们的身体健康会造成很大的伤害。因此在有效地使用电离辐射给生活带去便利的同时如何保证人们的健康和安全成为全球范围内非常棘手的一个问题。如何研发出高效低毒的辐射防护剂成为人们迫切需要解决的问题。中药具有来源广、毒副作用小、价格低、易于获得等特点，人们开始关注中药有效成分的抗辐射研究，目前研究发现，中药有效成分：多糖类、黄酮类、多酚类、生物碱类、皂苷类等，具有较好的辐射防护作用。
中药毛冬青是冬青科、冬青属毛冬青的干燥根，是一种在在中国南方地区广泛分布的常用中药材。中药毛冬青在《本草纲目》、《中药大辞典》、《新编中医学概要》等中草药著作中都有收载，含有多种化学成分，毛冬青皂苷A是其有效成分之一，具有抗炎及抗凋亡等作用。据报道，毛冬青皂苷A具有可降低缺氧/复氧心肌细胞的凋亡指数，减小心肌缺血/再灌注大鼠的心肌梗死面积的作用，其机制可能是毛冬青皂苷A可以调节凋亡信号通路—PI3K/Akt信号通路抑制细胞凋亡的进程起到抗凋亡的作用[Ilexsaponin A attenuatesischemia-reperfusion-induced myocardial injury through anti-apoptoticpathway,PLoS One. 2017,12(2):e0170984]。ilexsaponinA1可减轻高脂饮食诱导的非酒精性脂肪肝小鼠的肝脏炎症并改善肠道屏障功能[The combination of IlexhainanosideD and ilexsaponin A1 reduces liver inflammation and improves intestinalbarrier function in mice with high-fat diet-induced non-alcoholic fatty liverdisease，Phytomedicine，63(2019)153039]。据报道，毛冬青皂苷A具有在体外刺激人脐静脉内皮细胞增殖、迁移、侵袭和管状形成，并在利用血管内皮生长因子酪氨酸激酶抑制剂II诱导的血管不足斑马鱼体内发挥促血管生成作用，其机制可能是毛冬青皂苷A通过调控Akt/mTOR、 MAPK/ERK和Src-FAK依赖信号通路起到促血管生成作用。[Pro-angiogeniceffects of Ilexsaponin A1 on human umbilical vein endothelial cells in vitroand zebrafish in vivo. Phytomedicine.2017,36:229-237.]电离辐射通过直接或间接的作用于机体引发机体非特异性反应，导致细胞损伤、机体功能发生异常、组织器官发生器质性改变甚至死亡。射线直接或间接作用于细胞，会引起细胞内DNA的结构和稳定性发生改变以及产生大量的ROS，从而激活细胞内多种凋亡信号分子，导致细胞凋亡。基于毛冬青皂苷A的抗炎、抗凋亡特性，本发明提供了毛冬青皂苷A的电离辐射防护新用途，现有技术未见报道。
发明内容
本发明的目的在于提供毛冬青皂苷A预防及治疗电离辐射损伤的新用途。
本发明通过细胞、动物水平对毛冬青皂苷A的抗电离辐射活性进行反复验证，实验结果表明毛冬青皂苷A可以抑制X射线照射导致的小鼠肺成纤维细胞MLG2908细胞活力丧失，改善辐射后小鼠肝脏和肺组织的病理学改变，抑制胸腺中炎症相关分子p65的激活，抑制肺组织中凋亡相关分子caspase3的激活，从而完成了本发明。
毛冬青皂苷A可与药学上可接受的载体按本领域已知方法制备成各种药物组合物，如片剂、胶囊剂、颗粒剂、注射剂等各种固体、液体制剂等；或和其他中药有效成分组合制成各种不同的剂型，通过不同的给药途径用于预防及治疗电离辐射损伤。
本发明的优点：
1.发现了毛冬青皂苷A新的医疗用途。
2.毛冬青皂苷A来源广，毒副作用小、价格低、易于获得，药用前景广阔。
3.本发明将成为高效低毒抗电离辐射药物的有益补充。
附图说明
图1毛冬青皂苷A对MLG2908细胞的细胞毒性
图2毛冬青皂苷A对6Gy X射线照射的MLG2908细胞活力的影响
图3毛冬青皂苷A对6Gy X射线照射的小鼠胸腺中p65激活的影响
图4毛冬青皂苷A对6Gy X射线照射的C57小鼠肝和肺组织病理学改变的影响
图5毛冬青皂苷A对6Gy X射线照射的C57小鼠肺组织中凋亡因子Caspase3的影响
具体实施方式
下面结合实施案例对本发明作进一步的说明：
[实施例1]毛冬青皂苷A对MLG2908细胞的毒性检测
MLG2908细胞：复苏MLG2908细胞，将细胞悬液接种于DMEM培养液中(含10％胎牛血清、10万单位青霉素钠、10万单位硫酸链霉素)，于37℃、5％CO2恒温无菌培养箱中培养1-2天。待细胞程度达到培养瓶底面积80％左右，用胰酶消化细胞，用DMEM培养液调整细胞密度5×105/mL备用。
药物准备：将毛冬青皂苷A用RPMI 1640培养液溶解，超声助溶，配置储存浓度1mg/mL 母液备用。
毒性检测：取MLG2908细胞悬液，细胞(5×105个/mL)接种于96孔培养板，100μL/孔，每孔药物100μL，使终浓度为1.25、2.5、5、10、20、40、80、160、320μg/mL(简称药物组)，每浓度5孔，另设空白对照组细胞悬液。于药物作用48h后，更换细胞培养液为100μL/每孔，每孔加入CCK-8溶液10uL，继续培养1h，于多功能酶标仪450nm处测定各孔吸光值。细胞存活率％＝实验组/正常组×100％，数据用spss 22.0进行统计分析，与正常组相比，#，P<0.01。表明，毛冬青皂苷A在1.25-80mg/L对MLG2908细胞无明显细胞毒性。(见附图1)
[实施例2]毛冬青皂苷A对X射线导致的MLG2908细胞活力丧失的保护作用
取MLG(5×105个/mL)接种于96孔培养板，100μL/孔，每孔药物100μL，使终浓度为40、 20、10、5、2.5、1.25μg/mL，每浓度5孔，另设空白对照组细胞悬液、辐照组细胞悬液。于药物作用2h后6Gy辐照，照后24h于每孔中加入cck8溶液20μL，继续培养1h，于多功能酶标仪450nm处测定各孔吸光值。与辐照组相比：#，P<0.05。结果表明，毛冬青皂苷A 在1.25-20μg/mL对X射线6Gy照射的MLG2908细胞活力丧失呈剂量依赖的保护作用，对 MLG2908细胞电离辐射防护的最优浓度为20μg/mL。(见附图2)
[实施例3]毛冬青皂苷A对X射线6Gy照射的小鼠胸腺中p65激活的影响
将雄性C57BL/6J小鼠适应环境后根据需要分为正常组、照射组、药物组，每组10只。正常组和照射组灌胃给予蒸馏水，用药组照前灌胃给予毛冬青皂苷A，连续4天，剂量10mg/kg，给药后全身一次性照射，剂量为6Gy，照后3天，取组织进行免疫荧光分析。结果表明，p65是炎症相关分子，正常小鼠的胸腺组织中p65在胞浆分布，辐射后被激活并进行核转移，毛冬青皂苷A10 mg/kg组，明显抑制p65激活，抑制其核转位。(见附图3)
[实施例4]毛冬青皂苷A对6Gy X射线照射的C57小鼠肝和肺组织病理学改变的影响
将雄性C57BL/6J小鼠适应环境后根据需要分为正常组、照射组、药物组，每组10只。正常组和照射组灌胃给予蒸馏水，用药组照前灌胃给予毛冬青皂苷A，连续4天，剂量10mg/kg，给药后全身一次性照射，剂量为6Gy，照后6天，取组织进行石蜡切片，HE染色分析。结果表明，未经辐射的小鼠肺组织呈现为肺泡轮廓清晰，肺泡上皮细胞排列紧密，组织学形态完整；辐射后6d，只辐射但没有经过药物干预的小鼠的肺组织，其完整性遭到严重破坏，小鼠的肺泡间质明显增多，肺泡由于挤压肺泡体积明显变小；给予毛冬青皂苷A能够减轻辐射造成的损伤，能够改善小鼠肺的病理学变化。辐射小鼠肝细胞广泛肿胀，细胞坏死严重，坏死的细胞核浓缩、碎裂、溶解，大量炎细胞浸润毛冬青皂苷A组坏死细胞少，形态接近正常，血管边缘细胞呈现出较好的放射状排列，肝细胞呈轻微的颗粒变性，细胞坏死程度不明显。实验结果提示，毛冬青皂苷A能够明显改善辐射小鼠肝脏的病理学变化。(见附图4) [实施例5]毛冬青皂苷A对6Gy X射线照射的C57小鼠肺组织中凋亡因子caspase3的影响
将雄性C57BL/6J小鼠适应环境后根据需要分为正常组、照射组、药物组，每组10只。正常组和照射组灌胃给予蒸馏水，用药组照前灌胃给予毛冬青皂苷A，连续4天，剂量10mg/kg，给药后全身一次性照射，剂量为6Gy，照后4天，取肺组织，提取总蛋白，BCA法定量，按照Western blot的步骤检测caspase3蛋白的表达和剪切激活情况。结果表明，肺组织被辐射后caspase3被剪切激活，cleaved-caspase3的产物增多，毛冬青皂苷A干预组，明显下调caspase3的激活产物，抑制caspase3的激活(见附图5) 。
Claims (6)
1.毛冬青皂苷A在制备细胞及动物电离辐射防护药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述药物用于细胞电离辐射防护时，毛冬青皂苷A的有效剂量为1.25-20μg/mL。
3.根据权利要求1所述的应用，其特征在于：所述药物用于动物电离辐射防护时，毛冬青皂苷A的有效剂量为10mg/kg。
4.根据权利要求3所述的应用，其特征在于：所述药物是由毛冬青皂苷A和一种或多种符合药典规定的其它药用成分及药用赋形剂制成的制剂。
5.根据权利要求4所述的应用，其特征在于：所述制剂为含有1％～99％的毛冬青皂苷A和99％～1％的药用赋形剂及其它可组方的口服制剂。
6.根据权利要求5所述的应用，其特征在于：所述口服制剂包括片剂，丸剂，胶囊剂，软胶囊剂，颗粒剂，混悬剂，滴丸的任何一种。
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