CN117503836A - 衢枳壳及衢枳壳提取物在预防和治疗肾损伤中的应用 - Google Patents
衢枳壳及衢枳壳提取物在预防和治疗肾损伤中的应用 Download PDFInfo
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Abstract
本发明衢枳壳及衢枳壳提取物在预防和治疗肾损伤中的应用，具体为在制备预防和治疗顺铂等化疗药物诱导的急性肾损伤的产品中的应用。本发明创造性地提出了衢枳壳提取物在肾损伤治疗中的新的治疗用途，开拓了衢枳壳提取物新的药理应用领域。衢枳壳来源丰富，价廉，安全无毒副作用，衢枳壳提取物制备工艺路线简单，生产成本低廉，可制成药品用于抑制顺铂诱导的肾组织氧化应激及凋亡，改善顺铂诱导的肾损伤。
Description
技术领域
本发明属于天然药物应用技术领域，具体涉及到衢枳壳及衢枳壳提取物在预防和治疗肾损伤中的应用。
背景技术
顺铂是临床广泛使用的抗肿瘤药物，广泛用于卵巢癌，乳腺癌，肺癌，睾丸癌等实体器官癌的治疗，然而，在临床使用过程中发现，顺铂的毒副作用如肾毒性，耳毒性，神经毒性等极大地限制了顺铂的临床使用，尤其以肾毒性最为常见和严重，直接影响化疗的效果及预后，顺铂应用于大约10％-20％的癌症患者，其中30％的患者会发生急性肾损伤，急性肾损伤是顺铂在临床使用中发生的严重毒副作用之一。寻找有效预防顺铂诱导的急性肾损伤的药物成为亟需解决的问题。
衢枳壳，是常山胡柚的干燥未成熟果实，于2016年收载于《浙江省中药炮制规范》2015版，2018年入选浙江省新“浙八味”“衢六味”中药材培育品种之一，衢枳壳性寒味苦,具有理气宽胸、行滞消涨、镇咳化痰、清热解毒的功效。衢枳壳主要成分为黄酮类，现代药理学研究发现，衢枳壳中的黄酮成分具有降血脂、降血糖、抗炎、保肝等作用，衢枳壳中的柚皮素和橙皮素能够提高自发性2型糖尿病db/db小鼠自由饮食情况下的血清胰岛素水平，并缓解胰岛细胞损伤。
现有技术中对于衢枳壳提取物的药理研究，大多集中在肝损伤及肺损伤的治疗应用上，而对于由衢枳壳提取物在顺铂诱导的肾损伤的应用，未见有报道。
发明内容
针对现有技术中存在的问题，本发明设计的目的在于提供一种衢枳壳及提取物的新用途，具体为衢枳壳及衢枳壳提取物在制备预防和治疗肾损伤的产品中的应用。
进一步地，肾损伤为在癌症治疗中顺铂诱导的肾功能下降、肾组织急性病理损伤。
进一步地，所述产品能够显著改善顺铂诱导的药源性急性肾损伤，主要包括显著改善急性肾损伤小鼠肾功能和肾脏组织病理学改变。
进一步地，所述产品改善肾损伤的机制与增加肾脏组织中过氧化物酶3和抗凋亡蛋白Bcl2表达有关，提示其能够通过抑制氧化应激和凋亡来保护肾功能、改善肾损伤。
进一步地，衢枳壳提取物采用以下方法制备：
1)取衢枳壳饮片于热水中浸泡后，回流提取，滤过，收集滤液；
2)滤渣加水继续加热回流提取，过滤后合并滤液；
3)将步骤1)和步骤2)的滤液合并后减压回收溶剂至干，再置于真空干燥箱中烘干水分，即得衢枳壳提取物。
步骤1)中衢枳壳饮片与水的质量比为1:8，浸泡时间为2h，回流提取的时间为1.5h。
步骤2)中残渣与水的质量比为1:6，回流提取两次，每次提取时间为1h。
本发明创造性地提出了衢枳壳提取物在肾损伤治疗中的新的医疗用途，开拓了衢枳壳提取物新的应用领域，衢枳壳来源丰富，价廉，安全无毒副作用，衢枳壳提取物制备工艺路线简单，生产成本低廉，可制成药品用于减轻顺铂诱导的肾组织氧化应激及凋亡，改善顺铂诱导的药源性急性肾损伤。
附图说明
图1为本发明衢枳壳提取物的色谱图；注：A为标准品色谱图；B为样品色谱图；1为芸香柚皮苷；2为柚皮苷；3为橙皮苷；4为新橙皮苷；
图2为本发明衢枳壳提取物对顺铂诱导小鼠急性肾损伤中血清BUN,CREA的影响图；
图3为本发明动物实验中各组小鼠肾脏中H2O2,GSH含量图；
图4为本发明动物实验中各组小鼠肾组织病理学变化图(小鼠肾脏HE染色CDDP模型组肾组织出现大量肾小管上皮细胞损伤，以近曲小管损伤为主，肾小管上皮细胞肿胀，空泡变性，细胞核肿胀，部分细胞核溶解，细胞坏死，与CDDP模型组比较，给予QAF高剂量可明显改善顺铂诱导的肾小管上皮细胞损伤，细胞核溶解，蛋白沉积)；
图5为本发明衢枳壳提取物对顺铂诱导小鼠急性肾损伤模型动物肾组织中过氧化还原酶3(PRDX3)及抗凋亡蛋白表达的影响图。
具体实施方式
以下结合说明书附图对本发明做进一步说明，以便更好地理解本技术方案。
本发明衢枳壳提取物在制备缓解和治疗肾损伤的产品中的应用，具体地，肾损伤为在癌症治疗中顺铂诱导的肾组织氧化应激及凋亡，其中衢枳壳提取物采用以下方法制备：
取衢枳壳饮片470g，加入8倍量水加热后浸泡2h，加热回流提取1.5h，滤过；残渣加6倍量水，继续加热回流提取两次，每次1h；合并续滤液，减压回收溶剂至干，再置真空干燥箱中烘干水分，即得衢枳壳提取物即QAF提取物。
实验例
实验中药物与试剂：QAF提取物；顺铂(Sigama，美国)，过氧化氢含量检测试剂盒，谷胱甘肽含量测定试剂盒(北京索莱宝科技有限公司，中国)，β-actin一抗，PRDX3一抗，Bcl2一抗，KIM1一抗(abcam，美国)，PAGE凝胶快速制备试剂盒(12.5％))上海雅酶生物医药科技有限公司)，SDS-PAGE上样缓冲液(5×)(碧云天生物技术有限公司)。
仪器：EI0001型电泳仪(ThermoFisher,美国)、6000exp化学发光成像系统(上海勤翔)；1658001型垂直电泳槽、170-3932型转移电泳槽(美国Bio-Rad公司)，MB-102震荡恒温金属浴(杭州博日)，7100全自动生化分析仪(日本日立)，80i显微镜(日本尼康)。实验动物：C57小鼠42只，雄性，SPF级，7周龄，体质量22±2g，由北京维通利华实验动物技术有限公司提供，实验动物生产许可证号：SCXK(浙)2019-0002,实验动物许可证号：SYXK(浙)2022-0027。给予自由饮水，12h昼夜节律，室温(22±1℃)。动物实验经浙江省医学科学院安全性评价研究中心实验动物管理和使用委员会(IACUC)审核批准(批准号：KY-2023-019)。
实验方法
1.QAF提取物的鉴定：色谱条件：以Agilent Extend C18(5μm，4.6×250nm)为色谱柱，以乙腈-0.1％甲酸水(18:82，v/v)为流动相等度洗脱；流速为1.0mL/min；检测波长为330nm；柱温为30℃；进样量为10μL。对照品溶液的制备：分别取芸香柚皮苷、柚皮苷、橙皮苷、新橙皮苷对照品适量，精密称定，加50％的甲醇使溶解，配制成约60、150、120、120μg/ml的混合对照品溶液。供试品溶液的制备：取衢枳壳提取物(T230301)，取0.1g，精密称定，置25mL量瓶中，加50％甲醇适量，超声20min，放冷至室温，加50％甲醇至刻度，摇匀，离心，取上清液，即得。QAF提取物的色谱图如图1所示。
由图1知：提取所得样品量179.6g，得率38.2％，含量测定结果：芸香柚皮苷、柚皮苷、橙皮苷、新橙皮苷含量分别为13.07、141.05、7.38、91.27mg/g。
2.动物分组、造模及给药
42只雄性C57小鼠，按照体重随机分为7组，每组6只，实验动物分为对照组(control)，QAF给药组(2.5g/kg,QAF),顺铂模型组(CDDP，15mg/kg)，顺铂+地塞米松组(5mg/kg，CDDP+Dex)，顺铂+QAF低剂量组(0.625g/kg QAF,CDDP+LQAF)，顺铂+QAF中剂量组(1.25g/kg,CDDP+MQAF),顺铂QAF高剂量组(2.5g/kg，CDDP+HQAF)。连续灌胃7天QAF水溶液，每天两次，在灌胃第5天时，顺铂模型组，顺铂+QAF低、中、高剂量组腹腔注射顺铂(15mg/kg)造模，顺铂+Dex组在造模前一小时腹腔注射Dex(5mg/kg)；对照组，QAF组腹腔注射等量生理盐水。动物采集组织及血液样本保存。造模72h后，提前12h禁食不禁水，0.5％戊巴比妥钠麻醉，腹主动脉取血，分离血清，分离肾脏并称双肾重量，-80℃保存。
血清生化指标监测：全自动生化仪检测小鼠血清中BUN,CREA含量，QAF提取物对顺铂诱导小鼠急性肾损伤中血清BUN，CREA的影响如图2所示，由图2可知：小鼠肾脏BUN水平与对照组比较，CDDP模型组BUN水平显著升高，与模型组比较，CDDP+HQAF(2.5g/kg)BUN水平显著降低，**P＜0.05，##P＜0.05；小鼠肾脏CREA水平与对照组比较，CDDP模型组CREA水平显著升高,与模型组比较，CDDP+HQAF(2.5g/kg)CREA水平显著降低，**P＜0.05，##P＜0.05。
肾组织匀浆指标监测：按照试剂盒说明检测肾组织匀浆中H2O2,GSH含量。结果如图3所示，由图3可知：小鼠肾脏H2O2含量与对照组相比，CDDP模型组H2O2含量显著升高，与CDDP模型组比较，CDDP+HQAF(2.5g/kg)组H2O2含量显著显著下降，**P＜0.05；小鼠肾脏GSH含量与对照组比较，CDDP模型组GSH含量显著升高，与CDDP模型组比较，CDDP+HQAF(2.5g/kg)组GSH含量显著显著下降，**P＜0.05。
肾组织病理学观察：以10％甲醛溶液固定肾脏组织，石蜡包埋，切片，苏木精-伊红(hematoxylineosin,HE)染色，观察。结果见图4，从图4可以看出：HE染色结果表明，空白对照组与单独给药组肾组织皮质及髓质比例正常，肾小球与肾小管排列正常，结构清晰，无肿胀、变性、坏死等异常变化；CDDP模型组皮质及髓质重度蛋白管型，肾小管弥漫性变性、坏死，正常肾小管几乎不见，肾小管上皮细胞核肿胀、碎裂、溶解，胞浆崩解；QAF低剂量组皮质及髓质中度蛋白管型，肾小管大面积坏死，肾小管上皮细胞核肿胀、碎裂、溶解，胞浆崩解，但可见少量相对正常的肾小管；QAF中剂量组皮质轻度蛋白管型，多灶性的肾小管坏死，肾小管上皮细胞坏死、脱落，细胞核固缩、核碎裂、核溶解，局部可见较多正常肾小管存在；QAF高剂量组与Dex阳性对照组皮质轻度蛋白管型，局灶性肾小管坏死，坏死的面积较中、低剂量要小，正常肾小管的数量增多。
免疫印迹法检测肾组织PRDX3,Bcl2，KIM1蛋白表达：小鼠肾组织加入到Western及IP细胞裂解液中匀浆，提取蛋白，经十二烷基硫酸钠-聚丙烯酰氨凝胶电泳(sodiumdodecylsulphate-polyacrylamide gel electrophoresis,SDS-PAGE)分离，转印至聚偏二氟乙烯(polyvinylidenefluoride,PVDF)膜，常温封闭后加入一抗(稀释比例：1∶1 000),4℃孵育过夜。清洗后加入二抗(抗兔Ig G和抗鼠Ig G，稀释比例：1∶1000)，常温摇床孵育1h，清洗后以增强型化学发光(enhanced chemiluminescence,ECL)显色液显色，凝胶成像仪拍摄条带。采用Image J软件进行统计分析，目的蛋白相对表达量以目的蛋白的灰度值除以内参蛋白的灰度值计算。
衢枳壳提取物对顺铂诱导小鼠急性肾损伤中肾组织能够抗氧化蛋白与抗凋亡蛋白表达的影响如图5所示，从图5可以看出：小鼠肾脏Bcl2，PRDX3蛋白表达与对照组比较，DDP模型组Bc2，PRDX3表达显著降低，与CDDP模型组比较，CDDP+HQAF(2.5g/kg)组Bcl2，PRDX3表达显著在升高，**p<0.05。
本发明QAF干预能够显著改善顺铂诱导的急性肾损伤小鼠肾功能，包括降低顺铂诱导的血清肌酐，尿素氮水平的升高，改善肾脏组织病理学改变，增加肾脏组织中过氧化物酶3(PRDX3)，抗凋亡蛋白Bcl2表达，提示QAF具有改善顺铂诱导的急性肾损伤作用。本发明实验结果表明，在顺铂诱导的急性肾损伤中，QAF可以通过抑制氧化应激和凋亡来保护肾功能，为QAF防止顺铂诱导急性肾损伤的潜在机制提供方向。
Claims (7)
1.衢枳壳及衢枳壳提取物在制备预防和治疗肾损伤的产品中的应用。
2.如权利要求1所述的应用，其特征在于所述肾损伤为在癌症治疗中顺铂诱导的肾功能下降、肾组织急性病理损伤。
3.如权利要求1所述的应用，其特征在于所述衢枳壳提取物采用以下方法制备：
1)取衢枳壳饮片于热水中浸泡后，回流提取，滤过，收集滤液；
2)滤渣加水继续加热回流提取，过滤后合并滤液；
3)将步骤1)和步骤2)的滤液合并后减压回收溶剂至干，再置于真空干燥箱中烘干水分，即得衢枳壳提取物。
4.如权利要求3所述的应用，其特征在于步骤1)中衢枳壳饮片与水的质量比为1:8，浸泡时间为2h，回流提取的时间为1.5h。
5.如权利要求3所述的应用，其特征在于步骤2)中残渣与水的质量比为1:6，回流提取两次，每次提取时间为1h。
6.如权利要求1所述的应用，其特征在于所述产品能够显著改善顺铂诱导的药源性急性肾损伤，主要包括显著改善急性肾损伤小鼠肾功能和肾脏组织病理学改变。
7.如权利要求6所述的应用，其特征在于所述产品改善肾损伤的机制与增加肾脏组织中过氧化物酶3和抗凋亡蛋白Bcl2表达有关，提示其能够通过抑制氧化应激和凋亡来保护肾功能、改善肾损伤。
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