CN113116873B - 芦荟大黄素作为抗肥大细胞活化剂的新用途 - Google Patents
芦荟大黄素作为抗肥大细胞活化剂的新用途 Download PDFInfo
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Abstract
本发明属于医药技术领域,公开了芦荟大黄素(英文名:aloe‑emodin;CAS号:481‑72‑1)作为抗肥大细胞活化剂的新用途。体外药效学实验结果表明:芦荟大黄素在不影响细胞活力(无毒)的前提下,能显著减少肥大细胞致敏物质的释放,稳定肥大细胞膜,具有强大而显著的抗肥大细胞活化作用。动物实验结果表明:芦荟大黄素能够显著提高过敏性休克小鼠生存率,具有明显的保护作用。因此,本发明提出了芦荟大黄素可作为抗肥大细胞活化剂的新用途,可用于制备与过敏性休克相关病症的药品。
Description
技术领域
本发明属于医药技术领域,具体涉及芦荟大黄素作为抗肥大细胞活化剂的用途。
背景技术
肥大细胞(Mast cells)是一类重要的免疫细胞,起源于骨髓CD13+34+CD117+造血祖细胞。肥大细胞能在干细胞生长因子或其他调节发育的细胞因子诱导下分化,广泛分布于皮肤、黏膜、气道等部位,以及时应对环境中的变应原作出免疫应答。当机体受到不同的外界刺激时,会引起肥大细胞活化,合成并释放颗粒中的多种生物活性介质和细胞因子,如β-己糖胺酶、组胺、5-HT、类胰蛋白酶、白三烯、前列腺素等,进而导致一系列病理变化。由此可见,肥大细胞的活化是其发挥作用的前提条件。目前已知的诱导肥大细胞活化的途径主要包括 IgE-FcεRI途径、基础促分泌素(如Compound48/80等)介导的Mrg受体途径、补体及其受体途径、细胞因子及其受体途径等。而与肥大细胞活化密切相关的病理现象或病症则包括IgE 介导的I型过敏反应,IgG介导速发型超敏反应,Mrg受体介导的非免疫型速发型超敏反应(国内也称之为类过敏反应),如过敏性哮喘、春季卡他性结膜炎、过敏性鼻炎、过敏性结膜炎、过敏性皮炎、过敏性休克、过敏性紫癜、变异性咳嗽、过敏性支气管炎、肥大细胞增多症等。
芦荟大黄素为蒽醌类化合物,分子式为C15H10O5,化学名为:1.8-二羟基-3-羟甲基蒽醌 (1.8-Dihydroxy-3-[hydroxymethyl]-anthraquinone),CAS号为481-72-1,结构式如下(式I):
芦荟大黄素是芦荟根茎中含量较高生物活性成分之一,也是中药大黄的重要活性成分。现有的药理学研究表明,芦荟大黄素具有抗炎、抗菌、抗肿瘤、降血脂等多种活性,还能预防与治疗心肌缺血以及心律失常,改善非酒精性脂肪性肝,但目前暂未发现公开芦荟大黄素作为抗肥大细胞活化剂的现有技术。
发明内容
本发明的目的在于,提供式I所示的芦荟大黄素作为唯一活性成分用于制备抗肥大细胞活化剂的应用。
本发明所述的抗肥大细胞活化剂是指含有式I化合物的组合物,例如药品。
本发明所述抗肥大细胞活化剂可用于预防、缓解或治疗过敏性休克。
优选地本发明所述抗肥大细胞活化剂为含有式I化合物的药品,所述药品可以根据实际需求选择任何制剂类型;例如:片剂、口含剂、气雾剂、混悬剂、注射剂、胶囊剂、颗粒剂、散剂、酊剂、口服液。
附图说明
图1为本发明中芦荟大黄素抑制Compound48/80诱导的人肥大细胞株LAD2上清中β-己糖胺酶释放的分析图。其中,##P<0.01vs.正常对照组;*P<0.05和**P<0.01vs.模型组(Compound48/80 only)。
图2为本发明中芦荟大黄素抑制Compound48/80诱导的原代小鼠腹腔肥大细胞上清中β-己糖胺酶释放的分析图。其中,##P<0.01vs.正常对照组;*P<0.05和**P<0.01vs.模型组 (Compound48/80 only)。
图3为本发明中芦荟大黄素抑制IgE介导的大鼠嗜碱细胞株RBL-2H3上清中β-己糖胺酶释放的分析图。其中,##P<0.01vs.正常对照组;*P<0.05和**P<0.01vs.模型组(Compound48/80 only)。
图4为本发明中芦荟大黄素抑制致敏小鼠腹腔肥大细胞上清中β-己糖胺酶释放的分析图。其中,##P<0.01vs.正常对照组;*P<0.05和**P<0.01vs.模型组(Compound48/80only)。
具体实施方式
实施例1芦荟大黄素对Compound48/80诱导的过敏性休克小鼠死亡率的影响。
(1)实验材料:
芦荟大黄素(Adamas Reagent Co.,Ltd.,纯度>99%),富马酸酮替芬(CAS号:34580-14-8, M.W.425.5,梯希爱上海化成工业发展有限公司,纯度>98%),色甘酸钠(CAS号:15826-37-6, M.W.512.33,上海源叶生物科技有限公司,纯度>98%),Compound48/80(Sigma-Aldrich, CatNo.C2313);SPF级雄性Balb/c小鼠(18g-20g,北京维通利华实验动物技术有限公司);无菌生理盐水,一次性无菌注射器。
(2)实验方法:
将小鼠按体重随机分为正常对照组,模型组,阳性药酮替芬组,阳性药色甘酸钠组,芦荟大黄素大中小三个剂量组(12.5mg/kg,25mg/kg和50mg/kg),每组15只。实验时,各组小鼠分别腹腔注射相应的受试物,正常对照组腹腔注射无菌生理盐水,0.3ml/只。30min后,除正常对照组给予等体积无菌生理盐水之外,其余每组小鼠均按8mg/kg腹腔注射Compound48/80(可直接溶于无菌生理盐水)。观察一小时之内小鼠的生存情况。
(3)实验结果:
如表1所示,腹腔注射8mg/kgCompound48/80可致小鼠100%死亡,而提前30min给予各受试物,均能起不同程度保护作用。
表1芦荟大黄素对Compound48/80引起过敏性休克小鼠生存率的影响。
实施例2芦荟大黄素对Compound48/80诱导人肥大细胞株LAD2释放β-己糖胺酶的影响。
(1)实验材料:
芦荟大黄素(Adamas Reagent Co.,Ltd.,纯度>99%),富马酸酮替芬(CAS号:34580-14-8, M.W.425.5,梯希爱上海化成工业发展有限公司,纯度>98%),色甘酸钠(CAS号:15826-37-6, M.W.512.33,上海源叶生物科技有限公司,纯度>98%),Compound48/80(Sigma-Aldrich, CatNo.C2313),4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖(Sigma-Aldrich,CatNo.69585);人肥大细胞株LAD2来源于美国NIH。
(2)实验方法:
将处于对数生长期的LAD2细胞按6×104个/孔均匀加在96孔板中,给药孔加入不同浓度受试物(50μM阳性药或5μM-20μM芦荟大黄素),阴性对照孔加入等体积的Hank’s液(NaCl 8.0g,KH2PO4 0.06g,KCl 0.4g,NaHCO3 0.35g,Na2HPO4·H2O 0.06g,用三蒸水溶解定容至1L)。30min后,除阴性对照孔加入等体积Hank’s液之外,其余各孔加入终浓度为10μg/ml的Compound48/80。1.5h后,每孔取30μl细胞上清液加入50μl荧光底物工作液[0.57 mg/ml 4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖,用pH 4.3枸橼酸钠溶液(含133mM枸橼酸钠和133mM氯化钠,pH 4.3)配制],25℃避光孵育2h,每孔加入180μl终止液(含 50mM甘氨酸和5mM EDTA.4Na,pH 10.5),于λex 355nm and λem 460nm测定荧光强度。
(3)实验结果:
如图1所示,Compound48/80能显著诱导人肥大细胞株LAD2脱颗粒(上清中β-己糖胺酶含量明显增多),两个阳性药(酮替芬和色甘酸钠)均能显著减少该细胞β-己糖胺酶的释放;而芦荟大黄素在低于两个阳性药的无毒剂量下,能够显著抑制LAD2细胞β-己糖胺酶的释放,表现出强大的稳定人肥大细胞膜的作用。
实施例3芦荟大黄素对Compound48/80诱导原代小鼠腹腔肥大细胞释放β-己糖胺酶的影响。
(1)实验材料:
芦荟大黄素(Adamas Reagent Co.,Ltd.,纯度>99%),富马酸酮替芬(CAS号:34580-14-8, M.W.425.5,梯希爱上海化成工业发展有限公司,纯度>98%),色甘酸钠(CAS号:15826-37-6, M.W.512.33,上海源叶生物科技有限公司,纯度>98%),Compound48/80(Sigma-Aldrich, CatNo.C2313),4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖(Sigma-Aldrich,CatNo.69585); SPF级雄性Balb/c小鼠(18g-20g,北京维通利华实验动物技术有限公司);无菌生理盐水,一次性无菌注射器。
(2)实验方法:
a)原代小鼠腹腔肥大细胞的获得:
脱颈处死小鼠,用冰冷的PBS液洗小鼠腹腔,反复轻揉3-5min后,吸出腹腔液,500g离心10min后,沉淀的细胞团块即为已致敏的小鼠腹腔肥大细胞。
b)Compound48/80诱导小鼠腹腔肥大细胞释放β-己糖胺酶的测定:.
将小鼠腹腔肥大细胞均匀加在96孔板中,给药孔加入不同浓度受试物(50μM阳性药或 5μM-20μM芦荟大黄素),阴性对照孔加入等体积的Hank’s液(NaCl 8.0g,KH2PO40.06g, KCl 0.4g,NaHCO3 0.35g,Na2HPO4·H2O 0.06g,用三蒸水溶解定容至1L)。30min后,除阴性对照孔加入等体积Hank’s液之外,其余各孔加入终浓度为10μg/ml的Compound48/80。 1.5h后,每孔取30μl细胞上清液加入50μl荧光底物工作液[0.57mg/ml 4-甲基伞形酮基N- 乙酰基-β-D-氨基葡萄糖,用pH 4.3枸橼酸钠溶液(含133mM枸橼酸钠和133mM氯化钠,pH 4.3)配制],25℃避光孵育2h,每孔加入180μl终止液(含50mM甘氨酸和5mM EDTA.4Na,pH10.5),于λex 355nm and λem 460nm测定荧光强度。
(3)实验结果:
如图2所示,Compound48/80能显著诱导原代小鼠腹腔肥大细胞脱颗粒(上清中β-己糖胺酶含量明显增多),两个阳性药(酮替芬和色甘酸钠)均能显著减少该细胞β-己糖胺酶的释放;而芦荟大黄素在低于两个阳性药的无毒剂量下,能够显著抑制细胞β-己糖胺酶的释放,表现出强大的稳定小鼠肥大细胞膜的作用。
实施例4芦荟大黄素对FcεRI-IgE介导的大鼠嗜碱细胞株RBL-2H3释放β-己糖胺酶的影响。
(1)实验材料:
芦荟大黄素(Adamas Reagent Co.,Ltd.,纯度>99%),富马酸酮替芬(CAS号:34580-14-8, M.W.425.5,梯希爱上海化成工业发展有限公司,纯度>98%),色甘酸钠(CAS号:15826-37-6, M.W.512.33,上海源叶生物科技有限公司,纯度>98%);虾总蛋白(为本实验室自制,制备方法见下);铝佐剂(美国General Chemical公司)、4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖(Sigma-Aldrich,Cat No.69585);大鼠嗜碱粒细胞株RBL-2H3来源于中国科学院上海生命科学研究院细胞资源中心;SPF级雄性Balb/c小鼠(18g-20g,北京维通利华实验动物技术有限公司);无菌生理盐水,一次性无菌注射器。
(2)实验方法:
a)虾总蛋白的制备:
购买新鲜基围虾,用研钵将虾肉捣碎后,用匀浆机匀浆,浸入0.1M PBS(pH7.4)中,充分搅拌,于4℃静置8h。10,000转/min离心10min,取上清,将沉淀重溶于0.1M pH 7.4 PBS中,搅拌后静止12h,10,000转/min再次离心,合并上清液。边搅拌边缓慢加入硫酸铵粉末,使其终浓度为60%,混匀后于4℃静置20min,1500转/min离心15min,弃沉淀,取上清。于上清液中再缓慢加入硫酸铵粉末,使其终浓度为90%,混匀后于4℃静置20min,1500转 /min离心15min,弃上清,取沉淀。将沉淀复溶于0.01M pH 7.4 PBS中,对蒸馏水透析24h 以上去盐。将透析好的液体冻干,即得虾总蛋白粉末,存于-20℃备用。
b)虾总蛋白致敏血清的制备:
用无菌生理盐水将虾总蛋白配制成0.6mg/ml溶液。致敏Balb/c小鼠时,混合等体积的铝佐剂,摇匀,腹腔注射200μl混合液。每7天致敏一次,共致敏5周。末次致敏7天后,取全血,于4℃放置过夜,2000g离心10min,取上清,即为虾总蛋白致敏血清。
c)FcεRI-IgE介导的RBL-2H3细胞释放β-己糖胺酶的测定:
将处于对数生长期的RBL-2H3细胞按3×105个/孔均匀加在48孔板中,同时加入虾总蛋白致敏血清(终浓度为1%),贴壁过夜。次日,于给药孔中加入不同浓度受试物(50μM阳性药或5μM-20μM芦荟大黄素),阴性对照孔和模型孔加入等体积的Hank’s液(NaCl 8.0g,KH2PO4 0.06g,KCl 0.4g,NaHCO3 0.35g,Na2HPO4.H2O 0.06g,用三蒸水溶解定容至1L)。30min后,除阴性对照孔加入等体积Hank’s液之外,其余各孔加入终浓度为10μg/ml的Compound48/80。1.5h后,每孔取30μl细胞上清液加入50μl荧光底物工作液[0.57mg/ml 4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖,用pH 4.3枸橼酸钠溶液(含133mM枸橼酸钠和133mM氯化钠,pH 4.3)配制],25℃避光孵育2h,每孔加入180μl终止液(含50mM甘氨酸和5mMEDTA.4Na,pH 10.5),于λex 355nm and λem 460nm测定荧光强度。
(3)实验结果:
如图3所示,在经过虾总蛋白致敏血清致敏后的RBL-2H3细胞上,再用虾总蛋白攻击,能显著诱导原代小鼠腹腔肥大细胞脱颗粒(上清中β-己糖胺酶含量明显增多);两个阳性药(酮替芬和色甘酸钠)均能显著减少该细胞β-己糖胺酶的释放;而芦荟大黄素在低于两个阳性药的无毒剂量下,能够显著抑制细胞β-己糖胺酶的释放,表现出抑制FcεRI-IgE介导肥大细胞脱颗粒的作用。
实施例5芦荟大黄素对已致敏小鼠腹腔肥大细胞释放β-己糖胺酶的影响。
(1)实验材料:
芦荟大黄素(Adamas Reagent Co.,Ltd.,纯度>99%),富马酸酮替芬(CAS号:34580-14-8, M.W.425.5,梯希爱上海化成工业发展有限公司,纯度>98%),色甘酸钠(CAS号:15826-37-6, M.W.512.33,上海源叶生物科技有限公司,纯度>98%);虾总蛋白(为本实验室自制,制备方法见下);铝佐剂(美国General Chemical公司)、4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖(Sigma-Aldrich,Cat No.69585);SPF级雄性Balb/c小鼠(18g-20g,北京维通利华实验动物技术有限公司);无菌生理盐水,一次性无菌注射器。
(2)实验方法:
a)虾总蛋白的制备:
购买新鲜基围虾,用研钵将虾肉捣碎后,用匀浆机匀浆,浸入0.1M PBS(pH7.4)中,充分搅拌,于4℃静置8h。10,000转/min离心10min,取上清,将沉淀重溶于0.1M pH 7.4PBS中,搅拌后静止12h,10,000转/min再次离心,合并上清液。边搅拌边缓慢加入硫酸铵粉末,使其终浓度为60%,混匀后于4℃静置20min,1500转/min离心15min,弃沉淀,取上清。于上清液中再缓慢加入硫酸铵粉末,使其终浓度为90%,混匀后于4℃静置20min,1500转 /min离心15min,弃上清,取沉淀。将沉淀复溶于0.01M pH 7.4 PBS中,对蒸馏水透析24h 以上去盐。将透析好的液体冻干,即得虾总蛋白粉末,存于-20℃备用。
b)已致敏小鼠腹腔肥大细胞的获得:
用无菌生理盐水将虾总蛋白配制成0.6mg/ml溶液。致敏Balb/c小鼠时,混合等体积的铝佐剂,摇匀,腹腔注射200μl混合液。每7天致敏一次,共致敏5周。末次致敏7天后,脱颈处死小鼠,用冰冷的PBS液洗小鼠腹腔,反复轻揉3-5min后,吸出腹腔液,500g离心 10min后,沉淀的细胞团块即为已致敏的小鼠腹腔肥大细胞。
c)已致敏小鼠腹腔肥大细胞释放β-己糖胺酶的测定:
将已致敏的小鼠腹腔肥大细胞均匀加在96孔板中,给药孔加入不同浓度受试物(50μM 阳性药或5μM-20μM芦荟大黄素),阴性对照孔和模型孔加入等体积的Hank’s液(NaCl8.0 g,KH2PO4 0.06g,KCl 0.4g,NaHCO3 0.35g,Na2HPO4·H2O 0.06g,用三蒸水溶解定容至1L)。30min后,除阴性对照孔加入等体积Hank’s液之外,其余各孔加入终浓度为20ng/ml 的虾总蛋白。1.5h后,每孔取30μl细胞上清液加入50μl荧光底物工作液[0.57mg/ml 4-甲基伞形酮基N-乙酰基-β-D-氨基葡萄糖,用pH 4.3枸橼酸钠溶液(含133mM枸橼酸钠和133 mM氯化钠,pH 4.3)配制],25℃避光孵育2h,每孔加入180μl终止液(含50mM甘氨酸和5mMEDTA.4Na,pH 10.5),于λex 355nm and λem 460nm测定荧光强度。
(3)实验结果:
与实施例4中,用虾总蛋白致敏血清直接致敏RBL-2H3细胞的不同之处在于,本实验的致敏过程为体内过程,而将已致敏小鼠的腹腔肥大细胞取出进行实验,实为离体实验。结果如图4所示,在已致敏小鼠的腹腔肥大细胞上,再用虾总蛋白攻击,能显著诱导细胞脱颗粒 (上清中β-己糖胺酶含量明显增多);两个阳性药(酮替芬和色甘酸钠)均能显著减少该细胞β-己糖胺酶的释放;而芦荟大黄素在低于两个阳性药的无毒剂量下,能够显著抑制细胞β-己糖胺酶的释放,再次表现出抑制FcεRI-IgE介导肥大细胞脱颗粒的作用。
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