CN112898143A - 高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮及其应用 - Google Patents
高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮及其应用 Download PDFInfo
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Abstract
本发明公开了高良姜中分离5‑羟基‑7‑(4‑羟基‑3‑甲氧基苯基)1‑苯基‑3‑庚酮及其应用,分离方法如下:高良姜42kg粉碎,80%乙醇加热回流3次,每次2h,料液比1:10,合并滤液,浓缩至10L得到;取高良姜浸膏55g,按1:7(硅胶)上柱子,硅胶上样量385g,硅胶保护柱55g。分别接洗脱剂比例为石油醚:乙酸乙酯=(30:1)、(25:1)、(20:1)、(15:1)、(10:1)、(5:1)、(5:3)冲洗来的流分。石油醚:乙酸乙酯=10:1洗脱得到5‑羟基‑7‑(4‑羟基‑3‑甲氧基苯基)1‑苯基‑3‑庚酮单体。高良姜提取物改善IR作用显著。该化合物可上调Nrf2mRNA及下游靶基因的转录水平。
Description
技术领域
本发明涉及天然药物技术领域,特别涉及高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮及其应用。
背景技术
高良姜是姜科山姜属植物高良姜(Alpinia officinarum Hance)的干燥根茎,具有温中散寒,温通止痛,和胃平逆,行气导滞的功效,临床常用于治疗脘腹冷痛、胃寒呕吐等病症。化学研究表明高良姜主要含黄酮类、挥发油和二苯庚烷化合物。药理研究发现,其具有抗糖尿病、抗溃疡、止呕、抗炎等多方面的药理作用。据报道,高良姜提取物具有显著降糖作用。国内亦有研究报道高良姜提取物及二苯庚烷类化合物改善胰岛素抵抗作用显著。但是,目前的报道缺乏更深层次的研究,不能很好的确定高良姜分离提取的5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮对糖尿病的具体影响。
发明内容
本发明的目的在于提供高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮及其应用,通过对高良姜提取物的化学成分研究,从中分离得到多种二苯庚烷成分;5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮呈现不同程度的促进前脂肪细胞的分化的活性;以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:
高良姜中分离的5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,分离方法包括如下步骤;
步骤1:高良姜提取物提取:高良姜42kg粉碎,80%乙醇加热回流3次,每次2h,料液比1:10,合并滤液,浓缩至10L得到;
步骤2:分离纯化制备高良姜浸膏:取少量高良姜水提取物于分液瓶中,加入大量的乙酸乙酯充分振摇后,静置1小时以上,出现明显分层即可取上层液合并旋蒸挥干,得到高良姜浸膏;
步骤3:取高良姜浸膏55g,按1:7(硅胶)上柱子,硅胶上样量385g,硅胶保护柱55g。分别接洗脱剂比例为石油醚:乙酸乙酯=(30:1)、(25:1)、(20:1)、(15:1)、(10:1)、(5:1)、(5:3)冲洗来的流分。石油醚:乙酸乙酯=10:1洗脱得到5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮单体。
进一步地,步骤2的上层液为乙酸乙酯层。
进一步地,包括药物组合物,该药物组合物含有5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮或药学上可接受衍生物及药学上可接受的载体。
进一步地,高良姜中分离的5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮或其药学上可接受衍生物用于制备治疗胰岛素抵抗引发疾病的药物。
进一步地,其中胰岛素抵抗引发疾病包括糖尿病、高尿酸血症、高脂血症、代谢综合征、肥胖病、心血管疾病。
本发明提供的另技术方案:高良姜中分离的5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮在制备抗氧化食品、保健品或药品中的应用。
与现有技术相比,本发明的有益效果是:本发明给予提取物干预后,小鼠的随机血糖水平显著下降,糖耐量得到了明显改善,高良姜提取物改善IR作用显著。所得成分之一5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮对高糖作用下肝脏细胞对Nrf2/ARE通路的影响。5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮可上调Nrf2mRNA及下游靶基因的转录水平。
附图说明
图1为本发明的5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮单体的结构式;
图2为本发明的DH8活性成分对HepG2细胞存活的影响图;
图3为本发明的高糖干预后DH8对HepG2细胞15min内糖消耗情况图;
图4为本发明的高糖干预后不同药物对HepG2细胞中糖摄取的影响示意图;
图5为本发明的DH8对IR-HepG2细胞中ROS的影响示意图;
图6为本发明的DH8对IR-HepG2细胞中SOD的影响示意图;
图7为本发明的DH8对核转录因子Nrf2影响示意图;
图8为本发明的DH8对血红素氧合酶-1(HO-1)影响示意图;
图9为本发明的DH8对IRS1蛋白影响示意图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
高良姜中分离的5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,分离方法包括如下步骤;
高良姜提取物提取:高良姜42kg粉碎,80%乙醇加热回流3次,每次2h,料液比1:10,合并滤液,浓缩至10L得到;分离纯化制备高良姜浸膏::取少量高良姜水提取物于分液瓶中,加入大量的乙酸乙酯充分振摇后,静置1小时以上,出现明显分层即可取上层液(乙酸乙酯层)合并旋蒸挥干,得到高良姜浸膏;取高良姜浸膏55g,按1:7(硅胶)上柱子,硅胶上样量385g,硅胶保护柱55g。分别接洗脱剂比例为石油醚:乙酸乙酯=(30:1)、(25:1)、(20:1)、(15:1)、(10:1)、(5:1)、(5:3)冲洗来的流分。石油醚:乙酸乙酯=10:1洗脱得到5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮单体(DH8)。
5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮单体的结构式如图1。
药效学实验证明:
1.DH8对HepG2细胞增殖的影响
如图2所示,与正常对照组相比,DH8浓度1~50μmol/L时,对HepG2细胞的存活率未见明显影响。与5.5mM相比较*:p<0.05,**:p<0.01,***:p<0.001,n=4。
2.DH8对IR-HepG2细胞糖消耗的影响。
如图3所示,与正常对照组相比较,通过高糖诱导产生的IR模型组,细胞对葡萄糖的消耗量显著性降低(p<0.01),表明IR模型诱导成功,该模型组细胞对胰岛素产生抵抗。加入阳性药物-罗格列酮治疗后,与正常对照组相比,葡萄糖消耗量有显著性差异;与模型组相比较,罗格列酮组(p<0.05)的葡萄糖消耗量显著升高,表明阳性药物组具有改善IR-HepG2细胞的糖消耗。
与正常对照组相比较,DH8活性成分均能改善IR-HepG2细胞的糖消耗,当DH8浓度在10uM、20uM和40uM时,与空白组糖消耗量比较无显著性差异,与模型组相比存在显著差异(p<0.05)。表明DH8能有效改善IR-HepG2细胞对葡萄糖的消耗。
图3中,与模型组相比较药物组*:p<0.05,**:p<0.01,***:p<0.001,n=4。与空白组相比,模型组#:p<0.05,##:p<0.01,###:p<0.001,n=4。
3.DH8对IR-HepG2细胞糖消耗的影响
实验中采用2-NBDG荧光探测示踪剂观察DH8药物治疗后细胞对葡萄糖的摄取情况。结果如图4所示,与正常对照组相比较,通过高糖诱导产生的胰岛素抵抗模型组,细胞对葡萄糖的摄取量显著降低(P<0.001),表明成功诱导出了IR模型,该模型组细胞产生了IR。加入阳性药物-罗格列酮治疗后,葡萄糖摄取量与正常对照组比较,无显著差异;与模型组相比较,罗格列酮组(p<0.05)细胞的葡萄糖摄取量显著升高,表明阳性药物能有效改善IR-Hep G2细胞的糖摄取。与模型组相比较,DH8浓度为5μM、25μM和50μM时葡萄糖相对摄取荧光值与模型组存在显著性差异(p<0.001)。表明DH8能有效改善IR-Hep G2细胞对葡萄糖的摄取。图4中,与模型组相比较药物组*:p<0.05,**:p<0.01,***:p<0.001,n=4。与空白组相比,模型组#:p<0.05,##:p<0.01,###:p<0.001,n=4。
4.药物对胰岛素抵抗模型细胞内ROS水平的影响
本实验使用荧光探针DCFH-DA染色后,置于流式细胞仪上检测细胞内ROS水平。经过分析,结果如图5所示,模型组与正常对照组比较,细胞中的ROS水平极显著性升高(P<0.001);与模型组相比较,阳性对照组(与模型组间均存在极显著性差异(P<0.001),当DH8浓度为10uM、20uM和50uM时,与模型组间均有显著性差异(P<0.05)时,与模型组间均存在显著性差异(P<0.05),在浓度为50uM时效果最明显(P<0.001)。DH8显著的降低了IR-Hep G2细胞中的ROS水平,表现出了显著的抗氧化活性。
图5中,与模型组相比较药物组*:p<0.05,**:p<0.01,***:p<0.001,n=4。与空白组相比,模型组#:p<0.05,##:p<0.01,###:p<0.001,n=4。
5.药物对胰岛素抵抗模型细胞内抗氧化酶SOD活性的影响
氧化应激发生时,机体会发生一系列的抗氧化反应来对细胞起到保护作用。SOD是机体中防御自由基损伤的重要抗氧化酶之一,在细胞中,可清除自由基对细胞起到保护作用,其活力的大小可体现细胞清除氧自由基的能力。DH8对IR-Hep G2细胞中SOD活性的影响如图6,结果显示,DH8可促进SOD的释放。与正常对照组相比较,模型组中的SOD活力极显著性降低(P<0.001),罗格列酮组与正常对照组间均无显著性差异,与模型组相比较,当DH8浓度达到5uM、25uM和50uM时,IR-HepG2细胞中SOD活力显著性升高(P<0.05)。
图6中,与模型组相比较药物组*:p<0.05,**:p<0.01,***:p<0.001,n=4,与空白组相比,模型组#:p<0.05,##:p<0.01,###:p<0.001,n=4。
葡萄糖消耗实验研究表明,DH8均能升高IR-HepG2细胞的糖消耗量,对IR-HepG2细胞的糖代谢具有更好的改善作用。DH8可有效降低模型中的ROS,提高抗氧化物质的活力。
6.DH8活化Nrf2/ARE信号通路实验
(1)核转录因子Nrf2具有抗氧化应激的作用,DH8给药后,Nrf2的蛋白表达量显著性升高,说明DH8可通过激活Nrf2起到抗氧化应激作用,从而改善由高糖引起的胰岛素抵抗。
图7中,各组间比较采用单因素方差分析,P<0.05认为差异有统计学意义。与空白组比较,#p<0.05,##p<0.01,###p<0.001;与模型组相比,*p<0.05,**p<0.01,***p<0.001。
(2)血红素氧合酶-1(HO-1),是Nrf2下游相关的蛋白,HO-1路径是典型的细胞对抗氧化应激的防御系统,给药后,HO-1蛋白表达量显著升高,表明DH8可通过激活Nrf2的下游HO-1蛋白起到抗氧化应激作用,从而改善由高糖引起的胰岛素抵抗,结果如图8。
(3)当糖代谢紊乱时,使得胰岛素受体第五磷酸化水平提高,导致IRS1被泛素化蛋白酶系统降解,加重胰岛素抵抗。实验结果表明给药后,IRS1的蛋白表达量增加,意味着提高了IRS1的生物活性,改善了葡萄糖摄取与利用,并且减轻胰岛素抵抗,结果如图9。
高良姜提取物,特别是总二苯庚烷对糖尿病前期具有显著的治疗作用,尤其是发现总二苯庚烷改善胰岛素抵抗的作用显著,在前人的基础上取得新的进展。研究发现高良姜5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮的改善胰岛素抵抗作用(IR)与激活Nrf2/ARE通路密切相关,观察所得成分5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮对高糖作用下肝脏细胞对Nrf2/ARE通路的影响。发现5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮可上调Nrf2mRNA及下游靶基因的转录水平。
基于氧化应激建立胰岛素抵抗的HepG2细胞模型(IR-HepG2细胞),并利用此模型研究5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮改善胰岛素抵抗作用的具体机制和作用的信号途径。研究高良姜的活性成分DHs是否能通过Nrf2-AER信号改善IR-HepG2细胞中的氧化应激和糖代谢,阐明高良姜活性成分通过Nrf2-AER、JNK和IRS-1/PIK/AKt信号通路改善胰岛素抵抗作用的网络药理机制,为开发改善胰岛素抵抗的高良姜成分药物提供帮助。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明披露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (6)
1.高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,其特征在于,分离方法包括如下步骤:
步骤1:高良姜提取物提取:高良姜42kg粉碎,80%乙醇加热回流3次,每次2h,料液比1:10,合并滤液,浓缩至10L得到;
步骤2:分离纯化制备高良姜浸膏::取少量高良姜水提取物于分液瓶中,加入大量的乙酸乙酯充分振摇后,静置1小时以上,出现明显分层即可取上层液合并旋蒸挥干,得到高良姜浸膏;
步骤3:取高良姜浸膏55g,按1:7(硅胶)上柱子,硅胶上样量385g,硅胶保护柱55g,分别接洗脱剂比例为石油醚:乙酸乙酯=(30:1)、(25:1)、(20:1)、(15:1)、(10:1)、(5:1)、(5:3)冲洗来的流分,石油醚:乙酸乙酯=10:1洗脱得到5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮单体。
2.如权利要求1所述的高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,其特征在于,步骤2的上层液为乙酸乙酯层。
3.如权利要求1所述的高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,其特征在于,包括药物组合物,该药物组合物含有5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮或药学上可接受衍生物及药学上可接受的载体。
4.如权利要求3所述的高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮或其药学上可接受衍生物用于制备治疗胰岛素抵抗引发疾病的药物。
5.如权利要求4所述的高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮,其特征在于,其中胰岛素抵抗引发疾病包括糖尿病、高尿酸血症、高脂血症、代谢综合征、肥胖病、心血管疾病。
6.如权利要求1所述的高良姜中分离5-羟基-7-(4-羟基-3-甲氧基苯基)1-苯基-3-庚酮在制备抗氧化食品、保健品或药品中的应用。
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