CN112870182A - 紫苏醇及其衍生物在制备减轻化疗副作用药物中的应用 - Google Patents
紫苏醇及其衍生物在制备减轻化疗副作用药物中的应用 Download PDFInfo
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Abstract
本发明属于生物医药领域,具体涉及紫苏醇及其衍生物在制备减轻化疗副作用药物中的应用。本发明基于临床实验中化疗患者在服用益生菌后进行的代谢组学研究,发现紫苏醇与化疗后认知损伤的发生率、重度口腔溃疡的发生率、严重手足综合征的发生率呈负相关。将紫苏醇应用于化疗的大鼠模型中,经脑损伤相关参数的检测,可知紫苏醇能够减轻海马突触可塑性损伤,降低小胶质细胞和星形胶质细胞的活化水平,且能够改善氧化应激水平,对化疗产生的脑损伤副作用具有积极的效果,在制备减轻化疗副作用药物中具有良好的应用前景。
Description
技术领域
本发明属于生物医药领域,具体涉及紫苏醇及其衍生物在制备减轻化疗药所致副作用的药物中的应用。
背景技术
化疗是一种常用的肿瘤治疗方法,针对于某些肿瘤虽然其治疗效果良好,但是其副作用较大,对脑、皮肤、粘膜产生较大程度的损伤,严重影响了病人的生活质量和对化疗的耐受能力。
针对于化疗对脑、皮肤和粘膜副作用,目前研究发现可行的,提高患者抵抗力的防治方法包括口服维生素B6,佩戴小一码手套,进行冰敷、漱口,或者采用食物疗法等方式,但上述防治方法因患者依从性差或者疗效差而无法达到预期目标,因此,化疗相关副作用的防止是临床的棘手问题。
发明内容
为解决上述技术问题,本发明是基于临床实验中化疗患者在服用益生菌后进行代谢组学研究,发现紫苏醇与化疗后认知损伤的发生率、重度口腔溃疡的发生率、严重手足综合征的发生率呈负相关,将紫苏醇及其衍生物应用于制备减轻化疗副作用药物,通过将紫苏醇用于大鼠化疗脑损伤的保护实验,检测用药后大鼠脑片电生理、突触密度、脑内胶质细胞活化水平、氧自由基水平,得出紫苏醇能够减轻化疗后海马的突触可塑性损伤,减轻化疗诱导脑内胶质细胞活化,以及降低化疗诱导脑内氧化应激水平,针对于化疗引起的副作用具有良好的防治作用。
本发明的目的在于提供山紫苏醇及其衍生物在制备减轻化疗副作用药物中的应用。
基于同一发明构思,本发明还提供了一种减轻化疗副作用药物组合物,所述组合物包含紫苏醇及其衍生物或紫苏醇及其衍生物药学上可接受的盐和/或溶剂化物和/或水合物。
进一步的,所述紫苏醇衍生物为在体内能够代谢获得紫苏醇单质的衍生物,具体包括:紫苏醇与脂肪酸、维A酸酯化形成的酯类化合物;或者紫苏醇与葡萄糖成甘键的糖苷类化合物。
进一步的,所述药物组合物还包括药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物中的至少一种。
进一步的,所述组合物制成固体制剂、注射剂、喷剂、液体制剂、吸入制剂或复方制剂。
其中紫苏醇的结构式为:
有益效果:
(1)本发明通过临床实验,首次发现紫苏醇存在给益生菌后的化疗患者的血浆代谢物中,且根据相关化疗副作用的临床统计,可以得出紫苏醇的浓度与相关认知功能障碍的发生率、口腔溃疡及手足综合征的发生率等化疗副作用呈负相关。
(2)本发明第一次将紫苏醇用于减轻化疗副作用,通过将化疗大鼠给药紫苏醇后,兴奋性突触后电位的标准化斜率(fEPSP)增幅升高,小胶质细胞和星形胶质细胞的活化水平降低,并改善氧化应激水平,对化疗产生的脑损伤的防治具有良好的治疗效果。
(3)紫苏醇作为减轻化疗副作用的药物,提供了一种简单、依从性好、特异性高且疗效确切的防治化疗相关副作用的方法。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明临床实验中分别给与益生菌(Probiotics)和安慰剂(Placebo)后的化疗患者的血浆代谢物。A)化疗前后血浆样本PCA评分;B)两组中存在显著性差异的9种代谢物质;C)具有差异的代谢物和化疗相关认知障碍发生的相关性。
图2为本发明实施例提供的紫苏醇干预能减轻化疗后海马的突触可塑性损伤图;a)为化疗药物干预后大鼠给与腹腔注射紫苏醇(MDO)及其溶媒对照处理技术路线图;b)为兴奋性突出电位的标准化斜率(fEPSP)及长时程增强(LTP)改变(左)和LTP定量分析(右);c)为突出素SYN和突触后致密物-95(PSD-95)共聚焦成像及突触素和PSD-95共定位(圈出部分)百分比;
图3为本发明实施例提供的紫苏醇干预能减轻化疗诱导脑内胶质细胞活化图;a)为大鼠海马DG区Iba-1染色显示小胶质细胞形态,以及小胶质细胞活化百分比;b)为大鼠海马DG区GFAP染色显示星形胶质细胞形态,以及小胶质细胞活化比;
图4为本发明实施例提供的紫苏醇干预能减轻化疗诱导脑内氧化应激水平图;a)为化疗药物干预后大鼠给与腹腔注射MDO及其溶酶对照处理技术路线图;b)为第一次化疗药物处理后第10天,SD大鼠海马内活性氧水平的变化倍数。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚,下面将结合附图及具体实施例进行详细描述,但本发明的保护范围并不限于以下具体实施例。
除非另有定义,下文中所使用的所有专业术语与本领域技术人员通常理解含义相同。本文中所使用的专业术语只是为了描述具体实施例的目的,并不是旨在限制本发明的保护范围。
除非另有特别说明,本发明中用到的各种原材料、试剂、仪器和设备等均可通过市场购买得到或者可通过现有方法制备得到。
将临床化疗患者随机分为安慰剂组或益生菌组,益生菌组患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充益生菌;安慰剂组的患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充安慰剂(所使用的安慰剂胶囊含有益生菌胶囊中除益生菌以外的全部辅料,且在形状、大小和气味上均与益生菌胶囊相同)。分别于化疗前(化疗开始前一天)及化疗后(最后一次化疗结束后21天)通过成套认知功能量表、焦虑和抑郁自测量表评估患者认知功能、焦虑和抑郁情况,另根据世界卫生组织(WHO)制定的标准对其皮肤粘膜损伤的发生及严重程度进行分级和记录,并对其生活质量进行测评和记录,并通过代谢组学测定血浆代谢物在化疗过程中的变化。具体步骤如下:
实施例1
对206名女性I-III期乳腺癌患者进行系统筛选和沟通,在征得患者和家属同意后,纳入实验,随机分为安慰剂组或益生菌组;
益生菌组:对益生菌组的患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充益生菌,具体方法为口服益生菌胶囊(双歧三联活菌胶囊)每次3粒(0.84g),每天两次,于餐后半小时后以温水送服。
安慰剂组:对安慰剂组的患者在整个化疗过程中(自第一次化疗开始时至最后一次化疗结束后)予以补充安慰剂,所使用的安慰剂胶囊含有益生菌胶囊中除益生菌以外的全部辅料,且在形状、大小和气味上均与益生菌胶囊相同,具体方法亦为口服安慰剂胶囊每次3粒,每天两次,于餐后半小时后以温水送服。
对上述安慰剂组和益生菌组进行认知评估、化疗后乳腺癌患者各组的口腔溃疡和手足并发症的发生率和严重程度评估以及化疗后各组前后血浆代谢物检测。
其中血浆代谢物检测的步骤为:患者分别于化疗前(化疗开始前一天)及化疗后(最后一个周期化疗结束后21天)对患者的空腹血液标本进行外周静脉血采血。使用含有EDTA-K2抗凝剂的一次性真空采血管收集患者外周静脉血5ml,冰盒保存低温送达实验室处理。
血液标本室温直立静置30分钟。
低温离心机(4℃)中以3000转/分钟的速度离心10分钟;取上清液(血浆)保存备用;
应用液相色谱-串联质谱法(LC-MS/MS)分析的方法对两组患者血浆代谢物质水平的进行非靶向检测。具体步骤包括:血浆样品100ul各加入含有1μg/mL内标的甲醇300μL,置于涡旋机上30秒至充分混匀;冰水超声处理10分钟后静置(-40℃)1小时,4℃条件下,以12000rpm的速度离心15分钟后,在取上清液加入液加入进样瓶内,上机开始检测;
上机检测:应用超高效液相色谱仪(Vanquish,Thermo Fisher Scientific),经Waters ACQUITY UPLC BEHAmide(2.1mm×100mm,1.7μm)液相色谱柱来对目标物质进行色谱分离。其中液相色谱的A相为水相(含有乙酸铵25mmol/L和氨水25mmol/L),而B相则为乙腈。按0-0.5分钟,95%B;0.5-7分钟,95%-65%B;7-8分钟,65%-40%B;8-9分钟,40%B;9-9.1分钟,40%-95%B;9.1-12分,95%B来进行梯度洗脱。其进样体积为3μL,样品盘温度为4℃,柱温为25℃,流动相的流速为0.5mL/分。在控制软件(Xcalibur,Thermo)控制下按如下参数:sheath gas flow rate:50Arb,aux gas flow rate:10Arb,capillarytemperature:320℃,full ms resolution:60000,MS/MS resolution:7500,collisionenergy:10/30/60inNCE mode,spray voltage:3.5kV(positive)或-3.2kV(negative)进行一级、二级质谱数据采集。
数据处理:应用ProteoWizard软件将采集到的一级、二级质谱数据转成mzXML格式,在R程序包(内核为XCMS)中进行峰值识别、峰值提取、峰值对齐和积分等的处理,在BiotreeDB(V2.1)二级质谱数据库中经对比找到匹配物质并进行注释,将cutoff值设置为0.3。
根据认知评估统计可知,安慰剂组患者化疗相关认知功能障碍的发生率为81%,益生菌组化疗相关认知功能障碍的总发生率、轻度化疗相关认知功能障碍的发生率以及中度化疗相关认知功能障碍的发生率均显著低于安慰剂组。根据化疗后乳腺癌患者各组的口腔溃疡和手足并发症的发生率和严重程度评估,可知益生菌组能够降低了化疗药物诱导的手足并发症(HFS)和口腔溃疡(OM)的发生率及其严重性。根据各组的血浆代谢物发现,其结果如图1所示,给与益生菌后,化疗组血浆中有9种代谢物质的变化率存在显著性差异,通过对这9种差异代谢物的变化率和肠道微生物改变以及患者是否发生化疗相关认知功能障碍进行相关性发现,紫苏醇(p-entha-1,8-dien-7-ol[P=0.049])的变化率和发生化疗相关认知功能障碍呈负相关。
根据上述研究,将紫苏醇作为减轻化疗副作用的药物,以下动物实验进行进一步的说明。
实施例2
将SD大鼠(8-9周龄,200-250g)随机分为化疗+紫苏醇组(Chemo+MDO)、化疗+溶媒组(Chemo+Solvent)、正常对照组(Control)。化疗+紫苏醇组大鼠尾静脉注射化疗药物阿霉素(1mg/kg,每周一次,连续注射四周),化疗10天后腹腔注射紫苏醇(10mg/kg,一天两次,连续注射10天),化疗+溶媒组大鼠尾静脉注射化疗药物阿霉素(1mg/kg,每周一次,连续注射四周),化疗10天后腹腔注射与紫苏醇同剂量的溶媒,正常对照组注射生理盐水。
实施例3
准备人工脑脊液(冰水混合状态):2mM KCL,12mM MgSO4,1.3mM NaH2PO4,0.2mMCaCl2,26mM NaHCO3,10mM D-glucose,220mM蔗糖;持续通入混合氧气(95%O2和5%CO2)达饱和状态;
将实施例1获得的各组处理后的大鼠腹腔注射深度麻醉后断头取脑,迅速将脑组织放入事先冰冻好的人工脑脊液中进行震荡切片,切片厚度300μm。
脑片在34℃孵育30min,接着室温(25±1℃)下,在电生理记录用人工脑脊液(126mM NaCl,2.5mM KCl,1.25mM NaH2PO42.0mM CaCl21.0mM MgSO426mM NaHCO3和10mM葡萄糖,持续通入混合氧气)中再孵育2-8h。
兴奋性突触后场电位(fEPSPs)记录:将孵育好的完整脑切片放置在32-34℃的记录用人工脑脊液灌流的记录槽中,以3ml/min灌流脑片。
用双同心双极刺激电极(FHC,USA)刺激Schaffer侧支(SC),在CA1辐射层诱发场兴奋性突触后电位(fEPSPs)。
通过AxonMultiClamp 700B双探头膜片钳放大器(美国Molecular Devices公司),玻璃微电极(2–5MΩ)内充灌recording aCSF,在电流钳模式下记录诱发反应。
场电位记录:切片放置在用32-34℃的recording aCSF灌流的记录槽中,以3ml/min灌流脑片。用双同心双极刺激电极(FHC,USA)刺激Schaffer侧支(SC),在CA1辐射层诱发场兴奋性突触后电位(fEPSPs)。通过Axon MultiClamp 700B双探头膜片钳放大器(美国Molecular Devices公司),玻璃微电极(2–5MΩ)内充灌recording aCSF,在电流钳模式下记录诱发反应。测试刺激为单相100μs脉冲,频率0.033hz,恒定电流(调整刺激强度以产生25%的最大响应)。通过测量初始(10–60%上升相)fEPSP斜率来确定突触传递强度。用一系列高频刺激(测试刺激强度,100HZ,持续1s)诱发长时程增强(LTP)。根据LTP汇总图最后30min的平均EPSC值,计算LTP的大小。所有电生理实验均在盲法条件下进行分析。
实施例4
将实施例1获得各组处理后的大鼠腹腔注射麻醉后,经心内灌注生理盐水清除血液,然后用4%多聚甲醛固定组织;解剖取脑组织,并在4%多聚甲醛中固定过夜。
将脑组织依次置于4℃的15%和30%的蔗糖溶液(0.01MPBS配制)中进行脱水;脱水后的脑组织包埋在OCT胶中速冻,并使用冰冻切片机(Leica CM1950,Wetzlar,Germanny)连续切片。选择相同部位的脑组织切片,0.01M PBS洗涤10分钟3次后,在封闭液(0.01M PBS中的5%山羊血清)中避光室温孵育1小时。
一抗孵育(兔抗-SYN,1:100,Abcam;鼠抗PSD-95,1:100,Millipore;兔抗Iba-1,1:1000,Wako Chemical;兔抗-GFAP,1:200,Abclonal),在4℃过夜;二抗孵育:脑组织切片用0.01M PBS清洗3次,然后在二抗中孵育(1:200,Jacksonimmunoresearch),室温放置2小时。
用PBS洗涤三遍后,将切片用含DAPI的Vectamount封固剂(Vectorlabs H-1000)盖上盖子。所有图像均使用LSM800共聚焦显微镜和Zen 2009图像采集软件(Carl Zeiss,德国)采集。
3D成像:突触素和PSD95覆盖了10个图像(每个图像1μm),IBA1和GA\FAPfugai了20个图像(每个图像1μm)。定量分析齿状回颗粒细胞层中线周围50μm*50μm区域内共定位点的数目以及突触素和PSD95的阳性面积;ZEN对3D图像进行了分析,以确定共定位斑点的数量。然后将共定位斑点的数量除以图像堆栈的总面积。
实施例5
活性氧(ROS)包括超氧自由基,过氧化氢,及其下游产物,本实验采用迄今最常用最灵敏的细胞内活性氧检测探针DCFH-DA(2,7-二氯荧光黄双乙酸盐),对各组海马组织的活性氧水平进行检测,方法如下:
将实施例1处理后的大鼠麻醉断头后,取海马组织,立即放入预冷的PBS中漂洗;加入酶消化液,37℃恒温水浴下消化20~30分钟;收集过滤细胞,离心后去上清,并用PBS洗1~2次,重悬制备成单细胞悬液(1×106细胞/ml)。
在单细胞悬液中加入DCFH-DA(最终浓度:1μm),37℃闭光孵育30分钟;收集孵育(探针标记)后的单细胞悬液,离心收集细胞沉淀物,并用PBS重悬;应用BioTekEpoch分光分光光度计进行检测(激发波长485nm/发射波长535nm)。
结果分析:
如图2所示,刺激DG区海马进行检测,给与高频刺激后,统计场兴奋性突触后电位fEPSP增幅发现,化疗组大鼠fEPSP增幅显著低于对照组,而给予腹腔注射紫苏醇后,fEPSP增幅升高(P<0.001)(图2b);各组海马DG区突触素(SYN)和突触后致密物-95(PSD-95)的表达如下:正常组大鼠海马神经元CA1区内SYN,PSD-95的免疫产物分布密集,排列规律;与正常组比较,化疗组的DG区的SYN和PSD-95阳性表达呈减少趋势(P<0.0001[psd95];P=0.604[syn]);共定位斑点的数量/图像堆栈的总面积比例显著降低(P<0.0001);而与单纯化疗组相比,给与紫苏醇后,SYN,PSD-95蛋白在海马DG区的分布增多;共定位斑点比值增加(图2c);由此可知化疗药物可以损伤海马突触可塑性,而给与紫苏醇可以减轻这一损伤。
各组的胶质细胞活化水平如图3所示,可知:和对照组相比,化疗组的小胶质细胞(P=0.0004)(图3a)和星形胶质细胞显著活化(P=0.0012)(图3b),而给与腹腔注射紫苏醇则可降低小胶质细胞和星形胶质细胞的活化水平,进一步说明紫苏醇干预可以改善化疗后的脑损伤。
如图4所示,脑内氧自由基水平增高可以导致认知损伤,我们的实验发现,同对照组相比,化疗组大鼠海马区氧化应激水平增高(P<0.0001)(图4b);而腹腔给与紫苏醇可以改善氧化应激水平。
由上述结果可知,紫苏醇能够减轻海马突触可塑性损伤,降低小胶质细胞和星形胶质细胞的活化水平,且能够改善氧化应激水平,对化疗产生的脑损伤副作用具有积极的效果,应当理解的是,本发明还可以采用紫苏醇衍生物进行化疗副作用,其中的紫苏醇衍生物为在体内能够代谢获得紫苏醇单质的衍生物,具体包括:紫苏醇与脂肪酸、维A酸酯化形成的酯类化合物;或者紫苏醇与葡萄糖成甘键的糖苷类化合物。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.紫苏醇及其衍生物在制备减轻化疗副作用的药物中的应用。
2.一种减轻化疗副作用的药物组合物,其特征在于,所述组合物包含紫苏醇及其衍生物或紫苏醇及其衍生物药学上可接受的盐和/或溶剂化物和/或水合物。
3.根据权利要求2所述的减轻化疗副作用药物组合物,其特征在于,所述紫苏醇衍生物为在体内能够代谢获得紫苏醇单质的衍生物,具体包括:
紫苏醇与脂肪酸、维A酸酯化形成的酯类化合物;或者
紫苏醇与葡萄糖成甘键的糖苷类化合物。
4.根据权利要求2所述的药物组合物,其特征在于,所述药物组合物还包括药学上可接受的载体、赋形剂、稀释剂、辅剂和媒介物中的至少一种。
5.根据权利要求2所述的药物组合物,其特征在于,所述组合物制成固体制剂、注射剂、喷剂、液体制剂、吸入制剂或复方制剂。
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