CN114903879A - 3-烃基苯酚衍生物在制备预防或治疗高脂血症及相关代谢性疾病产品中的用途 - Google Patents
3-烃基苯酚衍生物在制备预防或治疗高脂血症及相关代谢性疾病产品中的用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于生物医药领域,具体涉及3-烃基苯酚衍生物在制备AMPK或PPARα激动剂中的用途,另外还涉及3-烃基苯酚衍生物在制备预防或治疗高脂血症及相关代谢性疾病产品中的用途。
背景技术
脂质是人体中一类重要的生物有机分子,包括脂肪酸(FA)、胆固醇(TC)、甘油三酯(TG)以及磷脂、糖脂等类脂成分,在维持机体正常生命活动方面发挥重要作用。脂质代谢是一个复杂过程,包括TG的合成及转运、脂肪酸的合成及β氧化分解以及胆固醇的代谢等。机体脂质代谢网络复杂,受肝脏、肠道、脂肪等多种组织器官调控。当人体内能量的摄入与消耗、合成与分解代谢长期处于不平衡状态时,将导致脂质代谢紊乱。临床上常见的高脂血症,其特点是患者血液中甘油三酯和/或低密度脂蛋白水平升高,部分出现高密度脂蛋白水平降低。高脂血症可引发多种慢性代谢性疾病,例如2型糖尿病、肥胖、非酒精性脂肪性肝病、心血管系统疾病等,严重威胁人类健康。发现安全性高、降血脂效果显著的新型药物或保健品具有重要的实际应用价值。
腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)是由催化的α亚基和调节的β、γ亚基构成的异源三聚体,是细胞能量状态的关键感受器,在人体的肝脏等多种脏器组织细胞中均有较高表达。作为一种重要的蛋白激酶,AMPK在机体脂质代谢过程中发挥重要作用。在细胞能量缺乏状态下,AMPK可通过其α亚基Thr172的磷酸化而激活,进而抑制细胞中的合成代谢并促进分解代谢来维持脂质代谢的平衡。肝脏中的AMPK通过直接磷酸化固醇调节元件结合蛋白1(sterol-regulatory element bindingprotein 1,SREBP1)的Ser372位点,抑制其转录,进而下调SREBP1下游脂肪酸合酶(fattyacid synthase,FAS)的表达,从而减少脂肪酸的从头合成。鉴于AMPK在能量代谢中的重要作用,其已成为防治代谢性疾病如肥胖症、糖尿病、非酒精性脂肪性肝病等的重要药物靶点。
过氧化物酶体増殖物激活受体α(peroxisome proliferators-activatedreceptor alpha,PPARα)属核受体家族中配体激活的转录因子,主要分布在线粒体脂肪酸氧化效率髙的组织,如肝脏、心脏、肾脏、肠等。大量证据表明,PPARα是肝脏脂质代谢调节的重要参与者,参与调控脂肪酸转运和β氧化、甘油三酯和脂滴的形成和分解以及血浆脂蛋白代谢等。PPARα可以被内源性脂肪酸及其代谢产物等天然配体激活,而一些临床上使用的部分降血脂药物如贝特类也属于PPARα激动剂。PPARα经配体激活后,与维甲酸X受体(retinoid X receptor,RXR)形成异二聚体,结合到靶基因启动子区域过氧化物酶体增殖物反应元件(peroxisome proliferator response element,PPRE)上,通过DNA结合依赖途径调控下游靶基因的转录9。在脂肪酸代谢过程中,参与脂肪酸摄取与转运的的一些蛋白如脂肪酸转位酶36(cluster of differentiation 36,CD36),以及脂肪酸β氧化的关键酶如肉毒碱棕榈酰转移酶1(carnitine palmitoyltransferase 1,CPT1)、酰基辅酶A氧化酶1(Acyl-Coenzyme Aoxidase 1,ACOX1)和羟烷基辅酶A脱氢酶(hydroxyacyl-CoenzymeAdehydrogenase,HADHA)均受PPARα调控。PPARα激动剂在高血脂、肥胖、心血管疾病等药物研发中具有广阔的应用前景。
3-烃基苯酚是酚类脂质,其结构特点为苯酚的3位连接不同长度的烃基侧链,并且部分结构在侧链上有1或多个不饱和双键。天然来源的3-烃基苯酚类成分在腰果壳、银杏以及蒲桃属植物中含量丰富,被报道具有抗菌、抗氧化、抗突变以及抗肿瘤等活性,然而关于该类成分对AMPK和PPARα的调节作用尚无相关报道。肝脏是机体脂质代谢重要器官,因此研究3-烃基苯酚类成分对肝脏细胞AMPK和PPARα的调节作用将为揭示该类成分的生物学功能奠定实验基础,对于推动其在预防或治疗高脂血症及相关代谢性疾病的药物及保健品中的应用具有积极意义。
发明内容
本发明的目的在于提供3-烃基苯酚衍生物在制备AMPK或PPARα激动剂中的用途,本发明的目的还在于提供3-烃基苯酚衍生物在预防或治疗高脂血症及相关代谢性疾病产品中的用途。
具体地,通过以下几个方面的技术方案实现了本发明:
在第一个方面中,本发明提供了一种具有激动AMPK或PPARα信号通路作用的3-烃基苯酚衍生物,其结构通式为式I所示化合物:
其中,R为含有9~26个碳的烷烃或烯烃侧链。
作为可选的方式,在上述3-烃基苯酚衍生物中,R为C9-C26直链烃基,R上的双键选自0~3个。
作为可选的方式,在上述3-烃基苯酚衍生物中,R为C12-C20直链烃基,R上的双键为2个或3个。
作为可选的方式,在上述3-烃基苯酚衍生物中,所述式I化合物选自以下:
3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚或
3-(8′Z,11′Z-十七烷二烯基)-苯酚。
在第二个方面中,本发明提供了上述第一个方面所述的3-烃基苯酚衍生物的制备方法,所述制备方法包括以下步骤:
选用新鲜蒲桃果实,切片后脱水干燥,干燥的蒲桃果实薄片直接用90%乙醇室温提取3次,提取液过滤后减压浓缩干燥得乙醇提取物,乙醇提取物用水溶解后,采用乙酸乙酯萃取,乙酸乙酯萃取液减压浓缩干燥得乙酸乙酯提取物,乙酸乙酯提取物经小孔树脂柱层析,采用甲醇/水梯度洗脱,分别得到100%水洗脱组分、20%甲醇洗脱组分、40%甲醇洗脱组分、60%甲醇洗脱组分、80%甲醇洗脱组分以及100%甲醇洗脱组分,其中100%甲醇洗脱组分经Sephadex LH-20凝胶柱层析,100%甲醇洗脱,经TLC显色合并相似组分,最后经反相ODS柱色谱进一步纯化,得到所述3-烃基苯酚衍生物样品。
作为可选的方式,在上述制备方法中,所述反相ODS柱色谱的洗脱条件为甲醇/水梯度洗脱,80%甲醇→90%甲醇→100%甲醇。
在第三个方面中,本发明提供了上述第一个方面所述的3-烃基苯酚衍生物或者采用上述第二个方面所述的制备方法制备得到的3-烃基苯酚衍生物在制备AMPK或PPARα激动剂中的用途。
作为可选的方式,在上述用途中,所述AMPK或PPARα激动剂可以用于制备药物、体内或体外科学研究工具药或者诊断试剂。
在第四个方面中,本发明提供了上述第一个方面所述的3-烃基苯酚衍生物或者采用上述第二个方面所述的制备方法制备得到的3-烃基苯酚衍生物在制备预防或治疗高脂血症或相关代谢性疾病产品中的用途。
作为可选的方式,在上述用途中,所述相关代谢性疾病选自以下:糖尿病、肥胖或非酒精性脂肪性肝病。
作为可选的方式,在上述用途中,所述产品选自药物、保健品或功能性食品。
作为可选的方式,在上述用途中,所述产品中还包含药物、保健品或功能性食品领域可接受的载体和/或赋形剂。
本发明相对于现有技术,具有以下有益效果:
(1)本发明提供了式I所示化合物及其在制备AMPK和/或PPARα激动剂产品中的用途。另外,本发明提供了式I所示的化合物及其在制备预防和治疗高脂血症及其相关代谢性疾病产品中的用途。
(2)实验结果表明,式I所示的3-烃基苯酚衍生物可显著降低油酸处理的HepG2细胞甘油三酯水平,改善肝脏细胞脂质代谢紊乱,可激活肝脏细胞AMPK及PPARα信号通路,促进AMPK的α亚基Thr172的磷酸化,增强PPARα的转录活性,改善肝脏细胞脂质代谢紊乱,可改善高脂肪饮食导致的小鼠肝脏脂质异常沉积,缓解小鼠非酒精性脂肪性肝病的病理状态。
附图说明
图1:油酸处理对HepG2细胞甘油三酯(TG)含量的影响。
图2:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯基)-苯酚对油酸诱导HepG2细胞存活率的影响。
图3:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(图3A)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(图3B)对油酸诱导HepG2细胞TG含量的影响。
图4:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11'Z-十七烷二烯基)-苯酚对油酸诱导HepG2细胞脂滴聚集的影响。
图5:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯基)-苯酚对油酸诱导HepG2细胞中AMPK信号通路中p-AMPK,FAS,SREBP-1蛋白表达的影响。
图6:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚对si-AMPK干预后油酸诱导HepG2细胞中AMPK信号通路相关蛋白表达的影响。
图7:3-(8′Z,11′Z-十七烷二烯)-苯酚对si-AMPK干预后油酸诱导HepG2细胞中AMPK信号通路相关蛋白表达的影响。
图8:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯)-苯酚对油酸诱导HepG2细胞中PPARα及其下游靶基因表达的影响。
图9:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯)-苯酚对PPARα转录激活活性的影响。
具体实施方式
下面参照具体的实施例对本发明做进一步说明。应当理解,此处所描述的具体实施例仅用于解释本发明,并不用于限定本发明的范围。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为市售产品。
制备实施例:
下述实施例中的3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚以及3-(8′Z,11′Z-十七烷二烯基)-苯酚由以下方法制备:
选用新鲜蒲桃果实,切片后脱水干燥。干燥的蒲桃果实薄片直接用90%乙醇室温提取3次(料液比1:10),每次24小时。提取液过滤后40℃减压浓缩干燥得乙醇提取物。乙醇提取物用水溶解后,采用乙酸乙酯萃取。乙酸乙酯萃取液40℃减压浓缩干燥得乙酸乙酯提取物。乙酸乙酯提取物经MCI CHP-20P小孔树脂柱层析,采用甲醇/水梯度洗脱,分别得到100%水洗脱组分、20%甲醇洗脱组分、40%甲醇洗脱组分、60%甲醇洗脱组分、80%甲醇洗脱组分以及100%甲醇洗脱组分。其中100%甲醇洗脱组分经Sephadex LH-20凝胶柱层析,100%甲醇洗脱,经TLC显色合并相似组分,最后经反相ODS柱色谱(甲醇/水梯度洗脱,80%甲醇→90%甲醇→100%甲醇)进一步纯化,得到3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯)-苯酚样品。其化合物结构式如下,1H-和13C-NMR确定化合物结构。
3-(8′Z,11′Z,14'Z-十七烷三烯基)-苯酚
3-(8'Z,11'Z-十七烷二烯基)-苯酚
效果实施例:
实施例1:建立油酸诱导脂质累积HepG2细胞模型
1.油酸配置:15μL油酸溶于100μL无水乙醇中,混合均匀,然后将此混合液加入到5mL 10%牛血清白蛋白(BSA)中充分溶解,得到10mM油酸母液。4℃保存备用。使用前用无血清DMEM培养基稀释至终浓度200μM。
2.细胞处理:取对数生长期HepG2细胞,按1×105细胞/孔接种于6孔板。待细胞贴壁生长后,使用含终浓度200μM油酸的无血清DMEM培养基继续培养24h。
3.细胞中甘油三酯(TG)含量测定:弃去培养基,使用细胞裂解液(RIPA裂解液:磷酸酶抑制剂:蛋白酶抑制剂=100:1:1)冰上裂解细胞。取部分裂解后样本,选择南京建成甘油三酯测定试剂盒,按照试剂盒操作说明书测定细胞中TG含量。实验重复三次,取三次数值的平均值作为最终的TG含量。
4.结果如图1所示,与未加油酸处理的HepG2细胞相比,200μM油酸处理HepG2细胞,其TG含量增加了8.2倍,表明油酸诱导脂质累积HepG2细胞模型建立成功。
实施例2:MTT法考察3-(8'Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8'Z,11'Z-十七烷二烯基)-苯酚对HepG2细胞增殖的影响
1.药物配置:3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8'Z,11′Z-十七烷二烯)-苯酚(化合物2)用DMSO溶解,分别配置成100mM母液,4℃保存。使用前用无血清DMEM培养基稀释,使化合物终浓度分别为10、20、40、60以及80μM;或者用含200μM油酸的无血清DMEM培养基稀释,使化合物终浓度分别为10、20、40、60以及80μM。DMSO浓度小于1%。
2.药物处理:取对数生长期HepG2细胞,按8×103细胞/孔接种于96孔板,CO2细胞培养箱孵育过夜。弃去旧培养基,空白组(CON组)更换为无血清DMEM培养基(100μL);药物处理组细胞换用含不同浓度药物(10、20、40、60、80μM)的无血清DMEM培养基(100μL);油酸对照组(OA组)换用含200μM油酸的无血清DMEM培养;药物+油酸处理组细胞换用含有200μM油酸以及不同浓度药物(10、20、40、60、80μM)的无血清DMEM培养基(100μL)。培养24h之后,每孔加入20μL浓度为5mg/mL的MTT溶液,在培养箱中继续孵育4h。弃去上清,每孔加入150μL的DMSO,室温条件下置于水平摇床10min充分溶解。用酶标仪在波长490nm处检测吸光值。实验独立重复三次。
3.结果如图2所示,3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8'Z,11′Z-十七烷二烯)-苯酚(化合物2)在10-40μM的浓度范围内对油酸诱导的HepG2细胞增殖无显著性影响。
实施例3:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯基)-苯酚对油酸处理HepG2细胞中甘油三酯含量的影响
1.药物处理:取对数生长期HepG2细胞,按1×105细胞/孔接种于6孔板。待细胞贴壁生长后,使用含有200μM油酸以及不同浓度3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯)-苯酚(化合物2)(终浓度分别为10、20和40μM)的无血清DMEM培养基继续培养24h。罗格列酮为阳性药。
2.HepG2细胞中甘油三酯含量测定:按照实施例1中步骤3进行。实验重复三次,取三次数值的平均值作为最终的TG含量。
3.结果如图3所示,相比于CON组,OA组细胞内TG含量显著升高。与OA组相比,3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)可显著降低细胞内的TG含量,且在所测定浓度下呈现剂量依赖性。3-(8′Z,11′Z-十七烷二烯基)-苯酚在40μM浓度时降低TG的效果优于阳性药罗格列酮(100μM)。
实施例4:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8'Z,11′Z-十七烷二烯基)-苯酚对油酸处理HepG2细胞中脂滴聚集的影响
1.细胞培养:12孔板底部加入100μL DMEM培养基,然后将0.14mm专用圆片吸附在12孔板底部。调整细胞悬液浓度为5×104细胞/孔,每孔加入1mL细胞悬液,恒温培养箱中继续培养24h。
2.药物处理:向孔中分别加入含有200μM油酸以及不同浓度3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)(终浓度分别为10、20和40μM)的无血清DMEM培养基,恒温培养箱中继续培养。罗格列酮为阳性对照(终浓度为100μM)。
3.油红O染色:药物处理24h后,弃去培养基并用PBS缓冲液洗涤细胞,后每孔加入4%多聚甲醛溶液室温固定30min。之后每孔加入60%异丙醇溶液室温孵育5min。弃去异丙醇溶液,每孔加入1mL油红O工作液室温孵育20min。PBS漂洗后用苏木素染液复染,甘油明胶封片。显微镜下观察细胞内部脂滴积累情况。
4.结果如图4所示,未经油酸处理的CON组细胞边缘清晰、状态良好,脂滴数目少且无明显聚集现象。与CON组相比,OA组细胞内沉积了大量的红色脂滴,并存在脂滴融合现象。与OA组相比,3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)处理后细胞中红色脂滴的大小和数量均有所降低,说明3-(8′Z,11′Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8'Z,11'Z-十七烷二烯基)-苯酚(化合物2)可以有效地改善油酸诱导的HepG2细胞内脂质积累。
实施例5:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯基)-苯酚对HepG2细胞AMPK及下游靶蛋白表达的影响
1.药物处理:同实施例3中的步骤1。
2.Western blot实验:使用裂解液(细胞裂解液:蛋白酶抑制剂:磷酸酶抑制剂=100:1:1)裂解细胞,100℃金属浴10min使蛋白样品变性。利用BCA法测定蛋白浓度,利用SDS-PAGE凝胶电泳进行蛋白分离,GAPDH为内参。电泳结束后,将蛋白转至PVDF膜,5%脱脂牛奶封闭1h。之后在目标蛋白相应的一抗溶液中4℃分别孵育过夜,然后在目标蛋白对应的二抗中室温孵育1h。利用ECL发光液显影,通过凝胶图像分析系统获得目标条带。AMPK、p-AMPK、FAS、SREBP-1抗体均购置于Cell Sigaling Technology。
3.siRNA转染实验:取对数生长期HepG2细胞,按1×105细胞/孔接种于6孔板,培养过夜。待细胞贴壁生长后,利用Rfect转染试剂将siRNA-AMPK转染细胞,敲低AMPK在HepG2细胞中的表达,siRNA-CON作为对照组。将转染siRNA-AMPK的细胞进一步分为OA组和给药组。给药组分别给予3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8'Z,11'Z-十七烷二烯基)-苯酚(化合物2)(终浓度40μM)处理,OA组和给药组血清中均添加OA(终浓度200μM),5%CO2恒温培养箱中继续孵育24h。按步骤2进行Western blot实验,检测AMPK、FAS、SREBP-1蛋白表达情况。
4.结果如图5所示,HepG2细胞经油酸处理后,p-AMPK表达水平显著降低。而3-(8′Z,11'Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)可显著逆转油酸诱导的HepG2细胞p-AMPK蛋白表达水平的降低,使之恢复正常水平且其作用呈剂量依赖性。此外,3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)干预降低了油酸处理HepG2细胞中FAS和SREBP-1等两个AMPK下游与脂质合成相关蛋白的表达。而利用siRNA转染敲低AMPK在HepG2细胞中的表达后,如附图6和7所述,3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)下调细胞中SREBP-1和FAS表达的作用显著降低。因此3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)可作为AMPK激动剂调控AMPK的激活及其下游蛋白的表达而发挥作用。
实施例6:3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚和3-(8′Z,11′Z-十七烷二烯基)-苯酚对HepG2细胞PPARα激活的影响
1.药物处理:同实施例3中的步骤1。PPARα激动剂WY14643作为阳性对照。
2.总RNA提取:利用Trizol试剂在冰上裂解细胞,在裂解液中加入氯仿(VTrizol:V氯仿=5:1)后离心,吸取上清,加入等体积预冷的异丙醇,混合均匀并离心。弃去上清,75%乙醇洗涤沉淀,室温下晾干,即得总RNA。
3.逆转录合成cDNA:根据反转录试剂盒操作说明书合成单链cDNA。按照RNA(1μL)、Primer Mix(2μL)、dNTP Mix(4μL)、DTT(2μL)、RT Buffer(4μL)、HiFiScript(1μL)和RNase-Free Water(6μL)配置反应体系,总体积为20μL。在PCR仪中42℃反应15min,85℃孵育5min,即得cDNA。
4.Real time-PCR:以合成的cDNA为模板,利用上下游引物扩增目的基因片段。PCR反应体系如下:UltraSYBR Mixture(High Rox)(5μL),forward primer(1μL),reverseprimer(1μL),cDNA(0.125μL),ddH2O(2.875μL),总体积为10μL。反应程序:95℃预变性10min;然后95℃,10s;60℃,20s;72℃,20s,循环数44。以2-ΔΔCt表示实验组目的基因的表达相对于对照组目的基因表达的倍数。PPARα、ACOX1、CPT1A、CD36、HADHA以及管家基因β-actin的引物序列见表1。
表1引物序列
5.结果如图8所示,OA组PPARα及其下游靶基因ACOX1、CPT1A、CD36、HADHA的表达水平显著低于CON组。与OA组相比,3-(8′Z,11′Z,14′Z-十七烷三烯基)-苯酚(化合物1)和3-(8′Z,11′Z-十七烷二烯基)-苯酚(化合物2)能显著升高OA处理的HepG2细胞中PPARα、ACOX1、CPT1A、CD36、HADHA等基因的表达水平,且呈现出剂量依赖性(10-40μM)。
6.PPRE双荧光酶素报告实验:取对数生长期HepG2细胞,按3×105细胞/孔接种于6孔板。培养过夜,按照说明书利用转染试剂Lipo 3000将PPRE荧光素酶基因报告质粒PPRE-Luc转染到HepG2细胞。转染48h后,分别加入40μM的3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8'Z,11'Z-十七烷二烯基)-苯酚(化合物2)处理细胞8h。利用Promega双荧光素酶报告分析试剂盒和酶标仪检测细胞中荧光强度,计算荧光素酶活性。
7.结果如图9所示,转染PPRE-Luc质粒后,与CON组相比,3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚(化合物1)和3-(8'Z,11'Z-十七烷二烯基)-苯酚(化合物2)处理显著增强了HepG2细胞中的荧光素酶活性,表明3-(8'Z,11'Z,14'Z-十七烷三烯基)-苯酚和3-(8'Z,11'Z-十七烷二烯基)-苯酚可作为PPARα的激动剂,增强PPARα对其下游靶基因的转录。
实施例7:3-(8'Z,11'Z-十七烷二烯基)-苯酚改善高脂饮食诱导非酒精性脂肪肝小鼠肝脏脂质异常沉积
1.动物造模及给药:4周龄C57BL/6小鼠饲养于恒温恒湿的标准动物房中,自由饮水和进食。适应环境饲养一周后,将小鼠随机分为3组,每组8只。标准饮食组(SD)给予基础饲料,高脂饮食组(HFD)给予60%Kcal高脂饲料,高脂饮食+3-(8'Z,11'Z-十七烷二烯基)-苯酚组(HFD+P)饲喂高脂饲料并每天灌胃给药一次(250mg/kg/d),SD组和HFD组灌胃同等体积的蒸馏水。持续干预11周。之后小鼠用异氟烷麻醉状态下处死,取小鼠肝脏组织。
2.肝脏组织油红O染色:非酒精性脂肪肝的重要病理特征是肝脏脂质异常沉积。通过肝脏组织油红O染色考察3-(8'Z,11′Z-十七烷二烯基)-苯酚对非酒精性脂肪肝小鼠肝脏脂质异常沉积的改善作用。取适宜的小鼠肝脏组织,OCT包埋后冰冻切片,厚度为8μm。将切片放入4%多聚甲醛中固定,用蒸馏水以及60%异丙醇漂洗。之后将固定好的切片放入油红O工作液中进行染色。染色结束后利用60%异丙醇使背景分化至无色;后将切片放入苏木素中染色,流水反蓝;最后用甘油明胶封片,显微镜下观察。
3.肝脏组织H/E染色:高脂饮食会引起肝脏脂质异常蓄积,出现非酒精性脂肪肝样病变。肝脏中蓄积的油脂被二甲苯溶解后,出现大量空泡,并出现炎症浸润现象。通过H/E染色后组织病理学观察考察3-(8'Z,11'Z-十七烷二烯基)-苯酚对非酒精性脂肪肝小鼠肝脏脂质异常沉积的改善作用。肝脏组织切块,大小为10mm×10mm×2mm,放入4%的多聚甲醛中固定。然后使用不同浓度梯度的乙醇依次进行脱水,脱水步骤为70%乙醇→80%乙醇→90%乙醇→95%乙醇→100%乙醇。然后将组织放入二甲苯中,透明。之后将组织块放入软蜡和硬蜡中进行包埋,再用石蜡切片机把包埋的肝脏组织块切片,厚度5μm。将石蜡切片依次放入二甲苯和不同浓度的乙醇(100%乙醇→95%乙醇→90%乙醇→80%乙醇→70%乙醇)中进行脱蜡处理,然后利用苏木素染液进行染色。染色结束后,将石蜡切片放入1%盐酸酒精中分化,然后再利用伊红原液染色。结束后,将石蜡切片依次利用95%和100%乙醇脱水,二甲苯透明。最后用中性树胶封片,显微镜下观察。
4.实验结果表明,3-(8'Z,11′Z-十七烷二烯基)-苯酚可改善高脂肪饮食导致的小鼠肝脏脂质异常沉积,缓解小鼠非酒精性脂肪性肝病的病理状态。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
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2.根据权利要求1所述的3-烃基苯酚衍生物,其特征在于:R为C9-C26直链烃基,R上的双键选自0~3个。
3.根据权利要求1或权利要求2所述的3-烃基苯酚衍生物,其特征在于:R为C12-C20直链烃基,R上的双键为2个或3个。
5.权利要求1至4中所述的3-烃基苯酚衍生物的制备方法,其特征在于:所述制备方法包括以下步骤:
选用新鲜蒲桃果实,切片后脱水干燥,干燥的蒲桃果实薄片直接用90%乙醇室温提取3次,提取液过滤后减压浓缩干燥得乙醇提取物,乙醇提取物用水溶解后,采用乙酸乙酯萃取,乙酸乙酯萃取液减压浓缩干燥得乙酸乙酯提取物,乙酸乙酯提取物经小孔树脂柱层析,采用甲醇/水梯度洗脱,分别得到100%水洗脱组分、20%甲醇洗脱组分、40%甲醇洗脱组分、60%甲醇洗脱组分、80%甲醇洗脱组分以及100%甲醇洗脱组分,其中100%甲醇洗脱组分经Sephadex LH-20凝胶柱层析,100%甲醇洗脱,经TLC显色合并相似组分,最后经反相ODS柱色谱进一步纯化,得到所述3-烃基苯酚衍生物样品。
6.根据权利要求5所述的制备方法,其特征在于:所述反相ODS柱色谱的洗脱条件为甲醇/水梯度洗脱,80%甲醇→90%甲醇→100%甲醇。
7.权利要求1至3中任一项所述的3-烃基苯酚衍生物或者采用权利要求5或权利要求6所述的制备方法制备得到的3-烃基苯酚衍生物在制备AMPK或PPARα激动剂中的用途。
8.权利要求1至3中任一项所述的3-烃基苯酚衍生物或者采用权利要求5或权利要求6所述的制备方法制备得到的3-烃基苯酚衍生物在制备预防或治疗高脂血症或相关代谢性疾病产品中的用途。
9.根据权利要求8所述的用途,其特征在于:所述相关代谢性疾病选自以下:糖尿病、肥胖、非酒精性脂肪性肝病、高血压或动脉粥样硬化。
10.根据权利要求8所述的用途,其特征在于:所述产品选自药物、保健品或功能性食品。
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