CN111888350B - 桑辛素n在制备防治铁死亡相关疾病的产品中的应用 - Google Patents
桑辛素n在制备防治铁死亡相关疾病的产品中的应用 Download PDFInfo
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Abstract
本发明涉及一种桑辛素N或其盐在制备防治铁死亡相关疾病的产品中的应用。本发明首次发现桑辛素N可以有效拮抗铁死亡或谷氨酸引起的谷胱甘肽水平的降低,有效提高细胞内谷胱甘肽的含量水平,可以很好地改善和防治铁死亡或谷氨酸诱导的相关疾病,尤其是神经损伤疾病的作用,活性显著优于神经保护调节剂槲皮素。
Description
技术领域
本发明涉及食品药品领域,特别是涉及一种桑辛素N在制备防治铁死亡相关疾病的产品中的应用。
背景技术
铁死亡,是近年来发现的一种由铁依赖的氧化损伤引起的细胞死亡模式,与凋亡、坏死、自噬等细胞程序性死亡方式不同,铁死亡的特征主要是活性氧产生、脂质过氧化、活性铁累积、细胞体积缩小和线粒体膜密度增加,没有典型的细胞凋亡和坏死表征。谷氨酸,作为哺乳动物大脑内最主要的兴奋性神经递质,在神经元的生长、分化和迁移过程中发挥着重要的作用。大量研究表明,过量谷氨酸是神经细胞损伤的重要原因,主要表现为氧化性毒性和兴奋性毒性。研究还发现,谷氨酸氧化毒性诱导神经细胞死亡形态与铁死亡(ferroptosis)非常相似。
随着现代社会的快速发展,人们的生活压力不断增加。当人们长期生活在高压环境中,会导致记忆衰减或神经性损伤,严重影响人们的学习和生活。神经损伤在神经退行性变的进展中起着重要作用。此外,发生在中枢神经系统中的神经损伤随着年龄的增加而增加,进而导致与年龄相关的神经退行性疾病的发生,如阿兹海默症和帕金森症等。随着全球社会老龄化现象的日益严重,老年痴呆等神经退行性疾病已经成为全球公众健康问题,亟待解决。因此,探索和研究具有改善或治疗与神经损伤相关的功能物质已成为热点和难点。
植物化合物是植物中重要的活性成分,在神经损伤保护中发挥重要作用,具有高效、低毒、副作用小或无副作用等特点。桑辛素N的结构式如式(1)所示,其为桑科植物桑叶中的重要活性成分,可从桑科植物桑叶或其他植物中提取或人工化学合成。目前尚未见桑辛素N在防治铁死亡抑制或改善谷氨酸诱导疾病或改善神经损伤方面的报道。
发明内容
基于此,本发明的目的是提供一种桑辛素N或其盐在制备防治铁死亡相关疾病的产品中的应用。
具体技术方案如下:
桑辛素N或其盐在制备防治铁死亡相关疾病的产品中的应用。
在其中一些实施例中,所述铁死亡相关疾病为铁死亡诱导的神经损伤相关疾病。
在其中一些实施例中,防治铁死亡相关疾病的产品为铁死亡抑制剂。
本发明的另一目的是提供一种桑辛素N或其盐在制备防治谷氨酸诱导疾病的产品中的应用。
在其中一些实施例中,所述谷氨酸诱导疾病为谷氨酸诱导的神经损伤相关疾病。
本发明的另一目的是提供一种桑辛素N或其盐在制备防治神经损伤相关疾病的产品中的应用。
在其中一些实施例中,所述神经损伤相关疾病为铁死亡诱导或者谷氨酸诱导的神经损伤相关疾病。
在其中一些实施例中,所述神经损伤相关疾病为神经退行性疾病。
在其中一些实施例中,所述神经退行性疾病为阿兹海默症或帕金森症。
本发明的另一目的是提供一种桑辛素N或其盐在制备谷胱甘肽生成促进剂中的应用。
本发明的另一目的是提供一种防治铁死亡相关疾病、谷氨酸诱导相关疾病或神经损失相关疾病的产品,其包括桑辛素N或其盐,以及包括其他防治铁死亡相关疾病、谷氨酸诱导相关疾病或神经损失相关疾病的药物或者辅料。
在其中一些实施例中,所述产品为药品或保健品或功能性食品。
与现有技术相比,本发明具有以下有益效果:
本发明首次发现桑辛素N可以有效拮抗铁死亡或谷氨酸引起的谷胱甘肽水平的降低,有效提高细胞内谷胱甘肽的含量水平,可以很好地改善和防治铁死亡或谷氨酸诱导的相关疾病,尤其是神经细胞损伤相关疾病,活性显著优于神经保护调节剂槲皮素。
附图说明
图1是桑辛素N对铁死亡诱导剂erastin或RSL3诱导HT22细胞中谷胱甘肽含量水平的影响;
图2是桑辛素N对谷氨酸诱导HT22细胞中谷胱甘肽含量水平的影响。
具体实施方式
本发明下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂,均为市售产品。
除非另有定义,本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不用于限制本发明。
本发明的术语“包括”和“具有”以及它们任何变形,意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块,而是可选地还包括没有列出的步骤,或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”,描述关联对象的关联关系,表示可以存在三种关系,例如,A和/或B,可以表示:单独存在A,同时存在A和B,单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本实施方式提供一种桑辛素N或其盐在制备防治铁死亡相关疾病的产品中的应用。
其中,在一些实施方式中,所述铁死亡相关疾病为铁死亡诱导的神经损伤相关疾病。
其中,在一些实施方式中,所述防治铁死亡相关疾病的产品为铁死亡抑制剂。
本实施方式还提供一种桑辛素N或其盐在制备防治谷氨酸诱导疾病的产品中的应用。
在一些实施方式中,所述谷氨酸诱导疾病为谷氨酸诱导的神经损伤相关疾病。
本实施方式还提供一种桑辛素N或其盐在制备防治神经损伤相关疾病的产品中的应用。
在一些实施方式中,所述神经损伤相关疾病,包括神经退行性疾病,也可以是其他的神经损伤疾病。其中的神经退行性疾病包括但不限于阿兹海默症或帕金森症。
本实施方式还提供一种桑辛素N或其盐在制备谷胱甘肽生成促进剂中的应用
本实施方式还提供一种防治铁死亡相关疾病、谷氨酸诱导相关疾病或神经损失相关疾病的产品,其包括桑辛素N或其盐,以及包括其他防治铁死亡相关疾病、防治谷氨酸诱导相关疾病或防治神经损失相关疾病的药物或者辅料。
其中,所述产品可以为药品或保健品或功能性食品。
本发明所述的产品不限制其剂型,即可以为任意常规的剂型。例如为药品时,可以为口服液、胶囊剂、片剂、颗粒剂、注射剂、丸剂、糖浆剂、散剂、膏剂、乳液或悬浮液等任意常规药品剂型。为保健品时可以为口服液、胶囊剂、片剂、颗粒剂、丸剂、糖浆剂、散剂、膏剂等任意常规保健品剂型。为功能性食品时可以为饮料、胶囊、片剂、颗粒剂、糖浆剂等口服剂型。
本发明产品中所述的辅料为制备药品、保健品以及功能性食品中可接受的任意辅料,如选自载体、赋形剂、填料、增容剂、粘合剂、保湿剂、崩解剂、缓溶剂、吸收加速剂、吸附剂、稀释剂、增溶剂、乳化剂、润滑剂、润湿剂、悬浮剂、矫味剂和香料中的任意一种或多种。
本发明产品中的桑辛素N或其盐可以与其他防治铁死亡相关疾病、谷氨酸诱导相关疾病或神经损失相关疾病的药物组合,所述其他防治铁死亡相关疾病、谷氨酸诱导相关疾病或神经损失相关疾病的药物不限于常规的神经损伤保护剂、铁死亡抑制剂。
在其中一些实施例中,本发明所述化合物桑辛素N的盐指的是通过桑辛素N和碱反应形成的桑辛素N的常规无毒盐。例如,得自无机碱的盐包括钙盐、镁盐、钾盐和钠盐等。
本发明对于推动桑叶的深加工利用,提升桑叶产品附加值,促进该行业的可持续发展具有重要的意义。
以下结合具体实施例对本发明作进一步详细的说明。
本发明具体实施方式中所使用的桑辛素N从桑叶中经分离纯化所得。分离纯化方法为:室温条件下,将干燥桑叶粉(8.9kg)用三倍量的95%乙醇(25L)浸提5天。提取液减压浓缩后得到深绿色膏状物。再将所得的膏状物(1200g)用水复溶后依次用石油醚和乙酸乙酯进行萃取,分别得到石油醚萃取物(230g)和乙酸乙酯萃取物(72.4g)。将乙酸乙酯萃取物用硅胶柱(100-200目,2.0kg)进行分离,洗脱剂为氯仿-甲醇(99:1-80:20),共得到12个组分(1-12),其中组分8采用反相C18ODS柱进行分离纯化(洗脱液为35%~80%甲醇水溶液)得到14个组分(8-1~8-14),组分8-12进一步采用Silgreen C18柱进行半制备分离(流动相为65%甲醇水溶液),得到化合物8-12-3。
经测定,化合物8-12-3的纯度在95%以上,其结构鉴定结果与CAS No:135248-05-4所示结构一致;所使用的槲皮素购于Sigma-Aldrich,纯度≥95%(HPLC),货号为Q4951-10G。在进行细胞实验时将桑辛素N和槲皮素分别采用二甲基亚砜(DMSO)配置为100mM的母液,冻存于-20℃备用。
实施例1:桑辛素N对铁死亡诱导剂所诱导神经细胞死亡的抑制作用
1、采用Erastin作为铁死亡诱导剂
Erastin(CAS No:571203-78-6)是常见的铁死亡诱导剂之一,通过直接抑
-制半胱氨酸/谷氨酸反向转运系统(Xc)活性,激活内质网应激,从而降低谷胱甘肽含量,进而诱导细胞铁死亡。
测试方法细节如下:样品为桑辛素N和槲皮素。
HT22细胞系是小鼠海马神经元细胞系。HT22细胞采用Dulbecco's ModifiedEagle's medium(DMEM)培养,其中加入10%胎牛血清,50units/mL青霉素和50μg/mL链霉素。细胞在37℃的二氧化碳(5%的CO2)中进行培养。传代三次后,进行铁死亡诱导实验。采用96孔板培养细胞,细胞浓度为3000个细胞/孔。细胞首先进行培养24h,然后换取含0.4μM的erastin和不同浓度的待测化合物(桑辛素N或槲皮素,终浓度为0.25、0.5、1、2、5、10μM)的培养基进行共培养12h后,采用Cell Counting Kit-8(CCK8)试剂盒检测细胞活力。
CCK8试剂盒,是一种基于2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐(WST-8)而广泛应用于细胞增殖和细胞毒性的快速、高灵敏度检测的试剂盒。在电子耦合试剂存在的情况下,WST-8可以被线粒体内的一些脱氢酶还原生成水溶性的橙黄色结晶甲瓒(formazan)。当细胞增殖越多越快,其颜色越深;细胞毒性越大,其颜色越浅。采用酶联免疫检测仪测定其在450nm下吸光值,可间接反映活细胞数量。在一定细胞数范围内,吸光值与细胞数目呈线性关系。
Erastin和活性化合物作用12h后,弃掉旧培养基,加入110μL含CKK8溶液的DMEM培养基(CKK8溶液:DMEM培养基=1:10),37℃下避光孵育2h后,采用酶标仪检测450nm下吸光值,计算细胞活力。实验重复三次。
其中:A对照表示仅加入0.5%DMSO培养基处理的细胞;A样品表示加入桑辛素N或槲皮素或0.5%DMSO与erastin共处理的细胞。
2、采用RSL3作为铁死亡诱导剂
RSL3(CAS No:1219810-16-8)是一种谷胱甘肽过氧化物酶4(GPx4)的抑制剂,也是重要的铁死亡激动剂之一,可通过降低GPx4的表达,抑制谷胱甘肽的生成,从而诱导细胞铁死亡。
将HT22细胞(3000个细胞/孔)种植于96孔细胞培养板中培养。37℃下孵育24h后,分别加入含0.1μM的RSL3和不同浓度的待测化合物(桑辛素N或槲皮素,终浓度为0.25、0.5、1、2、5、10μM)的培养基进行共培养12h后,弃掉旧培养基,加入110μL含CKK8溶液的DMEM培养基(CKK8溶液:DMEM培养基=1:10),37℃下避光孵育2h后,采用酶标仪检测450nm下吸光值,根据式1计算细胞活力。其中A对照表示仅加入0.5%DMSO培养基处理的细胞;A样品表示加入桑辛素N或槲皮素或0.5%DMSO与RSL3共处理的细胞。
*表示样品组与模型组比较p<0.05;**表示样品组与模型组比较p<0.001。
**表示样品组与模型组比较p<0.001。
统计结果如表1和表2所示。结果表明桑辛素N和槲皮素均可抑制铁死亡诱导剂erastin和RSL3所诱导的HT22细胞死亡;在相同浓度范围内,桑辛素N的抑制作用明显高于槲皮素,说明桑辛素N是活性很高的铁死亡抑制剂,其抑制erastin和RSL3诱导铁死亡的活性明显高于槲皮素。
实施例2:桑辛素N对谷氨酸所诱导神经细胞死亡的抑制作用
将HT22细胞以3000个细胞/孔的密度种植于96孔细胞培养板培。37℃下培养24h后,分别加入终浓度为6mM的谷氨酸和不同浓度的待测化合物(桑辛素N或槲皮素,终浓度为0.25、0.5、1、2、5、10μM)的培养基进行孵育。12h后,弃掉旧培养基,加入110μL含CKK8溶液的DMEM培养基(CKK8溶液:DMEM培养基=1:10),37℃下避光孵育2h后,采用酶标仪测定450nm下吸光值,根据式1计算细胞活力。其中A对照表示仅加入0.5%DMSO培养基处理的细胞;A样品表示加入桑辛素N或槲皮素或0.5%DMSO与谷氨酸共处理的细胞。实验重复三次,统计结果如表3所示,表明桑辛素N在测定浓度范围内可以抑制谷氨酸诱导的HT22细胞死亡,在相同浓度范围内,桑辛素N的抑制作用明显高于槲皮素,说明桑辛素N的抑制活性很好。
*表示样品组与模型组比较p<0.05;**表示样品组与模型组比较p<0.001。
实施例3:桑辛素N对神经细胞内GSH水平的影响
将HT22细胞以4×104个细胞/孔的密度接种于12孔细胞培养板中,贴壁24h后,分别加入含不同浓度的桑辛素N(0,0.25、0.5、1μM)以及铁死亡诱导剂(0.4μM erastin或0.15μM RSL3)或6mM谷氨酸培养基进行处理。药物处理12h后,弃掉含药培养基,磷酸盐缓冲液(PBS)冲洗2遍后,加入含Monobromobimane(终浓度为10μM)无血清DMEM培养基,37℃下孵育25min后收集细胞,PBS清洗3遍后,将细胞重悬于Hank's平衡盐溶液并接种到黑色96孔板。采用多功能酶标仪检测荧光变化(激发波长为380nm,发射波长为450nm)。将对照组的荧光水平标准化,并以百分比计算。
结果如图1和图2所示(control组为对照组),表明在铁死亡诱导剂(erastin或RSL3)或谷氨酸的作用下,HT22细胞中GSH的含量显著降低,而桑辛素N处理可有效逆转胞内GSH含量的降低,有效提高HT22细胞中GSH的含量,并且桑辛素N的效果呈剂量依赖性。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (1)
1.桑辛素N或其盐在制备防治阿兹海默症或帕金森症的产品中的应用。
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