CN111228279A - 一种新型枇杷叶倍半萜苷在减轻肝细胞脂质沉积上的应用 - Google Patents
一种新型枇杷叶倍半萜苷在减轻肝细胞脂质沉积上的应用 Download PDFInfo
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Abstract
本发明公开了一种新型枇杷叶倍半萜苷在减轻肝细胞脂质沉积中的应用；及用于制备预防或治疗非酒精性脂肪肝的药物、保健食品上的应用。该倍半萜苷名称为：nerolidol‑3‑O‑α‑L‑arabinopyranosyl‑(1→4)‑α‑L‑rhamnopyranosyl‑(1→2)‑[α‑L‑rhamnopyranosyl‑(1→6)]‑β‑D‑glucopyranoside。
Description
技术领域
本发明涉及医药领域，具体涉及一种天然提取的新型倍半萜苷化合物，通过降低肝细胞脂质沉积防治非酒精性脂肪肝。
背景技术
随着经济的发展，人们膳食结构与生活方式的改变，出现营养摄入不合理、能量过剩等现象，造成非酒精性脂肪肝(nonalcoholic fatty liver disease，NAFLD)发病率大幅增加。非酒精性脂肪肝是指排除酒精因素外造成的以肝细胞内脂肪过度沉积为主要特征的临床病理综合征，是代谢综合征在肝脏的主要病理表现，包括单纯性脂肪肝和更危险的非酒精性脂肪肝炎(nonalcoholic steatohepatitis，NASH)，非酒精性脂肪肝炎可进一步发展为肝硬化和肝衰竭，对患者生命健康造成严重影响。近年来，NAFLD的发病率在全世界大幅增加。近期流行病学调查显示，全球非酒精性脂肪患病率已超过24％。目前在全球范围内，NAFLD/NASH都被视为最常见的慢性肝脏疾病。临床上关于NAFLD的治疗多采用化学合成药物，合成药物治疗存在一定的局限性和不良反应，因此，从药用植物(中草药)中寻找高效低毒的防治NAFLD的天然产物越来越受到重视。
枇杷叶是蔷薇科(Rosaceae)枇杷属植物枇杷Eriobotrya japonica(Thunb.)Lindl.的干燥叶，是我国卫生部批准的食品原料，枇杷叶制成的枇杷茶也被应用于日常饮用。研究表明，枇杷叶中主要包括三萜、倍半萜苷、挥发油、黄酮等化合物，具有抗炎、抗氧化、降血糖、肝脏保护等多种药理作用。目前针对其具有的肝脏保护作用尚未研究完全。
发明内容
本发明的目的是为了提供一种用于预防或治疗非酒精性脂肪肝的新药物或保健食品。
为了实现上述目的，本发明提供了一种枇杷叶倍半萜苷D(nerolidol-3-O-α-L-arabinopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside，橙花叔醇-3-O-α-L-吡喃阿拉伯糖基(1→4)-α-L-吡喃鼠李糖基(1→2)-[α-L-吡喃鼠李糖基(1→6)]-β-D-吡喃葡萄糖苷)，该化合物为首次发现，其在制药上的用途也为首次发现。
该制药用途，具体体现在制备治疗肥胖症或其并发症的药物或保健品上的应用。
进一步的，枇杷叶倍半萜苷D在降低肝细胞脂质沉积的应用的改进：用于制备预防或治疗非酒精性脂肪肝的药物、保健品上的应用。
本发明相比现有技术具有以下优点：
本发明通过对单体化合物枇杷叶倍半萜苷D的药理研究，明确了其具有减轻肝细胞脂质沉积的作用，为后续的药效研究、进一步临床研究及指导用药奠定了基础，拓展了非酒精性脂肪肝治疗药物的种类。
附图说明
图1为本发明实施例1中新型枇杷叶倍半萜苷(枇杷叶倍半萜苷D)的结构图；
图2为本发明枇杷叶倍半萜苷D的1H-NMR谱；
图3为本发明枇杷叶倍半萜苷D的13C-NMR谱；
图4为本发明枇杷叶倍半萜苷D的HMBC谱；
图5为本发明枇杷叶倍半萜苷D的HMQC谱；
图6为本发明枇杷叶倍半萜苷D的COSY谱；
图7为本发明枇杷叶倍半萜苷D的NOESY谱；
图8为本发明实施例2中不同浓度的枇杷叶倍半萜苷D作用24h对HepG2细胞活力的比较；
图9为本发明实施例2中各组HepG2细胞油红染色的变化对比图；
图10为本发明实施例2中各组HepG2细胞TC的变化对比图；
图11为本发明实施例2中各组HepG2细胞TG的变化对比图。
图9中，正常对照组(Control)：在正常低糖DMEM培养液中培养的HepG2细胞；棕榈酸模型组(PA)：250μM PA处理组；药物处理组(SGD)：250μM PA+10μM枇杷叶倍半萜苷D(SGD)处理组。
图10～11中，正常对照组(Control)：在正常低糖DMEM培养液中培养的HepG2细胞；PA模型组(PA)：250μM PA处理组；低浓度药物处理组(SGD1)：250μM PA+5μM枇杷叶倍半萜苷D(SGD)处理组；高浓度药物处理组(SGD2)：250μM PA+10μM枇杷叶倍半萜苷D(SGD)处理组。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1
枇杷叶倍半萜苷D的制备实施例
取干燥枇杷叶1kg，粉碎，用质量百分比浓度为80％的乙醇溶液10L室温浸泡提取3次，合并提取液，过滤，减压浓缩至有沉淀析出，3000转/分钟离心15分钟，取上清液备用；
将上述上清液缓缓流过XAD16大孔吸附树脂柱，用水-乙醇梯度洗脱，经高效液相检测分析后合并乙醇浓度为60-80％之间的流分，减压浓缩，备用。
上述浓缩液进一步流过经处理后的聚酰胺(200目，200g)柱，用水-甲醇梯度洗脱，经高效液相检测分析后合并甲醇浓度为0-20％之间的流分，减压浓缩，浓缩液进一步经反向ODS柱层析，水-甲醇梯度洗脱，经高效液相检测分析后合并甲醇浓度为50-80％之间的流分，减压浓缩得到总倍半萜苷提取物。将总倍半萜苷提取物上制备型高效液相色谱(岛津LC-6AD)纯化，得到本发明枇杷叶倍半萜苷D。制备型高效液相色谱条件如下：Agilent RP-C18柱，规格为5μm,9.4×250mm，流动相A相为甲醇，B相为水，采用等度洗脱程序：0-40min，65％A，流速为8mL/min，柱温为25℃，检测波长为210nm。
制备得到的化合物为白色粉末，易溶于甲醇。HR-ESI-TOF/MS显示[M-H]-准分子离子m/z 807.5577，确定其分子式为C38H64O18，理化性质和波谱特征表明其为倍半萜苷类化合物。在1H NMR图谱(如表1、图2所示)中，δ5.21(H-1a,1H)，5.17(H-1b,1H)，5.76(H-2,1H)，5.08(H-6,1H)和5.07(H-10,1H)为乙烯基质子信号。单峰δ1.56(H-12,3H)和1.63(H-15,3H)为连接在烯碳上的偕二甲基信号。单峰δ1.54(H-14,3H)对应一个甲基信号，并与双键相连。另一个单峰δ1.27(H-13,3H)也为甲基信号，且与季碳相连。四个多重峰δ1.46(H-4)，1.92(H-5)，1.94(H-8)和2.01(H-9)，都为对应的亚甲基信号。在13C NMR图谱(表1、图3所示)中，δ116.08(C-1)，143.44(C-2)，124.68(C-6)，134.66(C-7)，124.61(C-10)和131.05(C-11)对应3对烯碳信号。δ79.98(C-3)为氧取代碳信号。分析以上数据，可知化合物的苷元为橙花叔醇。
在糖信号区域，氧取代的碳信号δ79.98(C-3)表现出低场位移，说明成苷位置在C-3位。此外可看到4个质子信号δ4.25(H-1',1H)，5.13(H-1",1H)，4.32(H-1"',1H)，和4.56(H-1””,1H)，其分别与糖的4个异头碳δ96.90(C-1')，100.24(C-1”)，106.16(C-1”')和101.29(C-1””)相连。通过GC分析衍生化后化合物的单糖，并与对照品比对，可知化合物所含单糖为D-葡萄糖、L-鼠李糖和L-阿拉伯糖(比率为1:2:1)。由葡萄糖端基H的较大耦合常数JH-1',H-2'(7.6Hz)可以推定葡萄糖为β端基构型，鼠李糖的C-3(δ70.95,71.09)和C-5(δ66.79,68.79)共振信号比对应的β异构体出现在更高场，表明其为α端基构型，而由JH-1”',H-2”'(7.5Hz)可确定阿拉伯糖也为α端基构型。糖的连接顺序信息可由HMBC谱中相关信号获得：阿拉伯糖的H-1"'(δ4.32)与鼠李糖的C-4”(δ83.72)相关，而鼠李糖的H-1”(δ5.13)又与葡萄糖的C-2'(δ78.47)相关，另一个鼠李糖的H-1””(δ4.56)与葡萄糖的C-6'(δ67.45)相关，同时葡萄糖的H-1'(δ4.25)与苷元C-3(δ79.98)相关。如图5至图7所示。综合以上信息，化合物鉴定为橙花叔醇-3-O-α-L-吡喃阿拉伯糖基(1→4)-α-L-吡喃鼠李糖基(1→2)-[α-L-吡喃鼠李糖基(1→6)]-β-D-吡喃葡萄糖苷，化学结构式如图1所示。
表1：本发明倍半萜苷化合物D的1H NMR和13C NMR的数据归属(DMSO-d6,δ,ppm,J/Hz)
实施例2
效果实施例
实验一：枇杷叶倍半萜苷D对HepG2细胞的作用
HepG2细胞用10％胎牛血清的DMEM培养液培养于37℃，5％CO2的细胞培养箱中，按照按1×106/mL的密度接种于96孔板中。按照空白对照组、50、100、150、200、250μM枇杷叶倍半萜苷D进行分组，每组重复8孔，培养24h后，去除培养液，缓冲液(PBS)清洗两遍。每孔加入100μL 10倍稀释的CCK-8溶液，培养1h后，使用酶标仪于450mM测定其吸光度值。
细胞增殖活性(100％)＝实验孔OD值/空白对照孔OD值*100％。
如图8所示，通过CCK-8实验，当枇杷叶倍半萜苷D浓度在0-200μM时，处理24h后，细胞活力没有明显差异，在达到250μM时，细胞活力显著下降。一次，在0-200μM浓度范围内，枇杷叶倍半萜苷D处于安全范围。
实验二：枇杷叶倍半萜苷D作用24h后对PA诱导的HepG2细胞内脂肪沉积的影响
细胞用含10％胎牛血清的DMEM培养液培养于37℃，5％CO2的细胞培养箱中，按1×106/mL的密度接种于6孔板中。正常对照组细胞使用DMEM低糖培养液培养，模型组及药物干预组先使用250μM的PA预处理24h建立高脂细胞模型，随后模型组细胞继续使用250μM的PA，枇杷叶倍半萜苷干预组(SGD)使用250μM的PA+10μM SGD继续处理24h，处理后的HepG2细胞去除培养液，PBS清洗3遍，油红染色15min，60％异丙醇洗净染液后用苏木素复染，光学显微镜下观察结果。
根据图9可知，PA处理可诱导HepG2细胞脂肪堆积，脂滴增加，而枇杷叶倍半萜苷D可显著降低HepG2细胞脂肪堆积。
实验三：枇杷叶倍半萜苷D对PA诱导的HepG2细胞内总胆固醇(TC)与甘油三酯(TG)含量的影响
细胞用含10％胎牛血清的DMEM培养液培养于37℃，5％CO2的细胞培养箱中，按1×106/mL的密度接种于6孔板中。正常对照组细胞使用DMEM低糖培养液培养，模型组及药物干预组先使用250μM的PA预处理24h建立高脂细胞模型，随后模型组细胞继续使用250μM的PA，枇杷叶倍半萜苷D低剂量组(SGD1)使用250μM的PA+5μM SGD，枇杷叶倍半萜苷D高剂量组(SGD2)使用250μM的PA+10μM SGD继续处理24h，处理后的HepG2细胞去除培养液，使用裂解液裂解获得细胞液，按照TC、TG检测试剂盒方法测定细胞内TC、TG含量。
根据图10、图11可知，PA可诱导HepG2细胞内TC、TG含量显著增加，加入枇杷叶倍半萜苷D处理后，细胞内TC、TG含量显著降低，说明枇杷叶倍半萜苷D可显著改善肝细胞脂质沉积，且以低剂量组SGD1改善效果更佳，在后续的使用研究中可以SGD浓度5μM作为优选浓度进行考虑。
Claims (4)
1.一种新型枇杷叶倍半萜苷在制药上的应用，该新型枇杷叶倍半萜苷为nerolidol-3-O-α-L-arabinopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside。
2.一种新型枇杷叶倍半萜苷在降低肝细胞脂质沉积上的应用，该新型枇杷叶倍半萜苷为nerolidol-3-O-α-L-arabinopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside。
3.一种新型枇杷叶倍半萜苷在制备预防或治疗非酒精性脂肪肝的药物、保健食品上的应用，该新型枇杷叶倍半萜苷为nerolidol-3-O-α-L-arabinopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside。
4.一种新型枇杷叶倍半萜苷在制备治疗肥胖症或其并发症的药物、保健食品上的应用，该新型枇杷叶倍半萜苷为nerolidol-3-O-α-L-arabinopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→6)]-β-D-glucopyranoside。
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