CN117018007A - 一种黑果枸杞中活性物质的应用 - Google Patents
一种黑果枸杞中活性物质的应用 Download PDFInfo
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Abstract
本发明公开了一种黑果枸杞中活性物质的应用，涉及天然产物分离技术领域，黑果枸杞中活性物质在糖代谢和脂代谢方面的应用，包括在制备治疗和/或预防糖或脂代谢紊乱相关疾病的产品中的应用以及在制备PPARγ拮抗剂、C/EBPα拮抗剂、FAS抑制剂、ACC抑制剂中的至少一种的应用。本发明发现黑果枸杞中分离出的活性物质norpetanin具有降糖和降脂作用。
Description
技术领域
本发明涉及天然产物分离技术领域，特别是涉及一种黑果枸杞中活性物质的应用。
背景技术
黑果枸杞是近年来在青海柴达木盆地等地被广泛种植的一种药食两用植物。具有较高的营养和食用价值，含有蛋白质、维生素以及矿物质等多种营养成分。其果实也含有丰富的花青素成分，具有抗氧化和抗过敏功能，增强人体免疫力和改善睡眠。
研究表明，黑果枸杞含有多种生物活性成分，其成熟浆果中富含花色苷等多酚类物质，具有抗氧化、潜在预防和治疗心血管系统疾病等作用。其中多酚类物质包括花色苷、黄酮类化合物等通过其较强的抗氧化清除自由基作用，表现出抗炎、保护心血管、抗肿瘤等多种生物活性。
目前对于黑果枸杞的活性物质的研究还比较薄弱，其活性成分的发掘、分离和提取，还有待进一步的研究。若能对黑果枸杞中新的化学成分及其药理作用进行更加深入、细微的研究与活性机制探讨，则有望开发出更多可治疗疾病且安全有效的天然植物来源药物。
发明内容
本发明的目的在于一种黑果枸杞中活性物质的应用，首次发现黑果枸杞中的一种活性物质norpetanin，具有降糖和降脂的作用。
本发明所采用的技术方案是：
一种黑果枸杞中活性物质的应用，所述应用包括所述活性物质以及其药学上可接受的盐、水合物或溶剂合物在改善糖代谢或/和脂代谢中的应用，所述活性物质如通式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
进一步地，所述糖代谢中的应用为在制备治疗和/或预防糖代谢紊乱相关疾病的产品中的应用。
进一步地，所述产品为改善胰岛素抵抗的产品。
进一步地，所述脂代谢中的应用为在制备治疗和/或预防脂代谢紊乱相关疾病的产品中的应用。
进一步地，所述产品为具有降脂作用或抑制脂肪细胞分化的产品。
进一步地，所述产品为抑制细胞内脂滴积累和/或细胞内脂质生成的产品。
进一步地，所述产品为治疗和/或预防肥胖症、高血压、高血脂、心血管疾病、代谢综合征相关疾病产品中的至少一种。
进一步地，所述应用还包括在制备PPARγ拮抗剂、C/EBPα拮抗剂、FAS抑制剂、ACC抑制剂中的至少一种的应用。
进一步地，所述活性物质以及其药学上可接受的盐、水合物或溶剂合物包含如式Ⅱ或式Ⅲ所示的化合物：
进一步地，所述活性物质中式Ⅱ和式Ⅲ所示的化合物的比例为3:1。
本发明的活性物质或其溶剂化物、水合物、药学上可接受的盐或共晶的药物组合物中，可以含有药学上可接受的辅料。
本发明中所述“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。
本发明所述药学上可接受的辅料，是药物中除主药以外的一切附加材料的总称，辅料应当具备如下性质：(1)对人体无毒害作用，几无副作用；(2)化学性质稳定，不易受温度、pH、保存时间等的影响；(3)与主药无配伍禁忌，不影响主药的疗效和质量检查；(4)不与包装材料相互发生作用。本发明中辅料包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包含十二烷基硫酸钠、水或醇等；抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等；乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。上述酸碱为广义的路易斯酸碱。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物同样可以用于注射制剂。其中，所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片，临用时用注射用水溶解，供皮下或肌肉注射之用)。
其中，所述注射用粉剂的中除含有上述化合物外，还至少含有赋形剂。本发明中所述赋形剂，为有意加到药物中的成分，其在所用的量上不应具有药理学特性，但是，赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给药途径递药或有助于稳定性。
本发明的有益效果是：
本发明首次从黑果枸杞中得到一种活性物质norpetanin，发现活性物质norpetanin具有降低血糖和降脂的作用。
本发明中化合物结构式上标注的数字，仅为了便于对化合物的结构进行说明。
附图说明
图1norpetanin的高分辨质谱图；
图2norpetanin的1H NMR图；
图3norpetanin的13C NMR图；
图4norpetanin的HMBC图；
图5norpetanin的HSQC图；
图6norpetanin的COSY图；
图7norpetanin的DEPT图；
图8norpetanin的紫外吸收光谱图；
图9FCM法检测norpetanin处理后3T3-L1脂肪细胞2-NBDG摄取的影响图；
图10norpetanin对3T3-L1脂肪细胞中p-PI3K、p-AKt表达的影响图；
图11norpetanin对3T3-L1细胞脂滴积累的影响图(100×)；
图12norpetanin对3T3-L1细胞TG含量的影响图；
图13norpetanin对3T3-L1细胞成脂转录因子表达的影响图；
图14norpetanin对3T3-L1细胞脂代谢相关蛋白表达的影响图。
具体实施方式
以下对本发明的技术方案进行清晰、完整地描述，显然，此处所描述的实施例仅是本发明中的一部分，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的前提下所获得的所有其他实施例，都属于本发明的保护范围。
实施例1
所述活性物质，结构如通式Ⅱ和Ⅲ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
黑果枸杞中活性物质的核磁共振数据如表1所示。
表1活性物质的核磁共振数据
活性物质：黄色粉末，ESI-MS m/z：809[M-H]-，主要成分分子式为C36H42O21。经HR-ESI-MS测定m/z 809.2140[M-H]-，计算值809.2141，不饱和度为19。其核磁共振谱显示出不同强度的成对信号，表明存在互变异构现象。为了便于结构分析，主要的反式互变异构体的NMR信号优先用于结构阐明。如表1所示，1H NMR(DMSO-d6/CF3COOD(9:1),600MHZ):δH7.53(2H,d,J＝8.5Hz,H-2””/H-6””),6.79(2H,d,J＝8.5Hz,H-3””/H-5””),7.53(1H,d,J＝15.9Hz,H-7””)和6.35(1H,d,J＝15.9Hz,H-8””)处信号显示出一组特征的反式对酰基，δH7.53(1H、s、H-4)处信号显示一个芳香或烯属质子单线态，δH 6.54(1H，d，J＝1.7Hz，H-6)和6.36(1H、d，J＝1.7Hz，H-8)处信号显示有一组1，3，4，5-四取代苯环，δH 5.09(1H(d)，J＝7.3Hz，H-1’)和4.82(1H”)处信号显示两个β-吡喃葡萄糖异头质子，δH 4.61(1H,br s,H-1”)处信号显示α-鼠李糖基异头质子，δH 4.82(1H,t-like,J＝9.6Hz,H-4”)处信号显示一个酰化次甲基三重态，以及上场区显示鼠李糖甲基双重态。13C NMR(DMSO-d6/CF3COOD(9:1),600MHZ):显示共有36个碳共振，包括一组反式对酰基碳，以及可归属于三个糖部分的18个碳信号，而其余未归属的9个共振碳来自糖苷配基母核。上述NMR特征通常与petanin的NMR特征相似，主要区别在于花青素核母核中的环B信号在本化合物中不存在，这使得我们可以推断环B部分应该被氧化和降解，以得到特殊的3,5,7-三氧基取代的香豆素母核。从H-4到C-2[δC 157.6(s)]、C-5[δC 154.5(s))]和C-9[δC 152.1(s)]、从H-6和H-8到C-10[δC103.1(s)]以及从H-1’到C-3[δC 138.0(s)]的HMBC相关性，如图4所示，证实了这一推断。通过仔细分析HSQC、HMBC和1H、1H-COSY相关性，进一步验证了所得结构，如图2、4-6所示。值得注意的是，新化合物是以不可分离的互变异构体的组合物(反式：顺式≈3:1)分离的。因此，活性物质的结构即为式Ⅱ和式Ⅲ所示，并命名为norpetanin。据我们所知，活性物质norpetanin代表了一类罕见的环B花青素。
其DEPT图、紫外吸收光谱图和高分辨质谱图分别如图7、8和1所示。
实施例2
norpetanin对糖代谢的影响：
1.实验材料与仪器
1.1材料与试剂
受试物：为实验室自制制备所得norpetanin。
3T3-L1小鼠胚胎成纤维细胞购买于中国科学院上海细胞库，实验中所使用的材料与试剂见表2。
表2材料与试剂
主要实验试剂
(1)2-NBDG配制
将2-NBDG粉末用DMSO溶解配制成10mM的母液，使用时用无糖DMEM稀释至终浓度为100μM。
(2)Western blotting工作液的配制如下：
a.10％ SDS
称取10gSDS，加入100mL超纯水，50℃水浴溶解，室温保存。如出现沉淀，水浴溶化后仍可使用。
b.SDS-PAGE电泳液(5×)
称取15.1g Tris，94.0g Glycine，5.0g SDS，加超纯水溶解，定容至100mL，室温保存。使用时可将5×电泳液稀释为1×电泳液，可重复使用2-3次，室温保存。
c.转膜液(10×)
称取15.15g Tris，72.0g Glycine，用时稀释为1×转膜液，方法：量取10×转膜液50mL，加甲醇100mL，用超纯水补至500mL，即10×转膜液：甲醇：水＝1:2:7，可重复使用3-5次，4℃冰箱保存。
d.TBS(10×)
称取12.12g Tris，40.03g NaCl，加超纯水溶解，HCl调pH＝7.6(加HCl大约3.5mL)，定容至500mL，4℃冰箱保存。
1.2仪器和设备
本实验所用的主要仪器和设备见表3。
表3仪器和设备
2实验方法
2.1 3T3-L1脂肪细胞模型的建立
(1)3T3-L1细胞的体外培养与传代
3T3-L1细胞用含10％FBS及1％青链霉素混合液的DMEM高糖培养基中培养。细胞培养箱的温度为37℃、湿度为95％和CO2浓度为5％。在正常培养条件下，3T3-L1细胞需要每隔3天传代一次。当细胞密度达到85％～90％以上时，先用吸泵吸弃原来的培养基，加温浴的PBS洗细胞1～2次，随后立即加入850μL的胰酶消化液，并轻轻晃动培养皿使消化液均匀铺满整个培养皿底。显微镜下观察至细胞变圆并从皿底部脱落时，加入新鲜的培养基，并反复吹打细胞，使细胞从培养皿底部完全脱落并分散成单个细胞。将细胞悬液按照1:5的比例传代至新的培养皿中，并加入适量的DMEM和FBS后放于细胞培养箱中继续培养。
(2)3T3-L1细胞的冻存与复苏
细胞的冻存：选取对数生长期的细胞，快速消化细胞，将消化后的细胞悬液在室温下以1000g离心5min得到细胞团，加入提前配制的细胞冻存液(DMEM:FBS:DMSO＝5:4:1)，每支冻存管中加入1.2mL的细胞悬液，同时在管壁上做好标记(细胞类型、细胞代数、冻存的细胞个数和冻存的时间)，以便能随时查询，最后4℃放置10min，-20℃放置1h，-80℃放置过夜，第二天置于液氮罐中保存。细胞的复苏：从液氮罐中快速取出冻存的细胞株，迅速置于37℃水浴中融化，待细胞完全融化后，快速地将细胞转移至培养液中进行培养，待细胞贴壁后(一般6～8h)更换新鲜培养液。
(3)3T3-L1细胞的计数
细胞计数常用的工具是血球计数板，血球计数板每块计数板由2块H形凹槽，形成高0.10mm的计数池，计数板中有9个大方格，细胞计数的区域为四角的4个大方格。细胞个数确定后然后根据实验需要，调整细胞密度。一般计数的原则，记上不记下，记左不记右。根据实验要求调整细胞计数密度，记录4个大方格的细胞总数，最后按照公式计算细胞个数：
细胞个数＝4个格中的细胞总数/4×104×稀释倍数
(4)胰岛素抵抗模型的建立
采用“鸡尾酒”法对3T3-L1细胞进行诱导分化，按如下方法进行诱导分化：将细胞状态良好的3T3-L1细胞接种于培养板上，铺板密度5×104个/mL，用含10％FBS的高糖DMEM培养液培养至细胞密度达到85％～90％左右时细胞换液，接触抑制两天后弃去完全培养液，加入含有10μg/mL Insulin、0.5mM IBMX和1μM Dex的培养液培养2d(加诱导液时记为第0d，诱I)，随后换成含有10μg/mL Insulin的培养液(诱II)继续培养2d，随后换成正常培养液继续培养4d，隔天换液。在诱导分化成熟后的第8天，向细胞液加入1μM Dex建立IR模型。
2.2norpetanin对3T3-L1细胞2-NBDG摄取的影响
将3T3-L1前脂肪细胞以5×104个/mL的密度接种至12孔板中，待细胞密度长到80％以上时，进行诱导分化，在诱导分化成熟后的第8天，向细胞液加入1μM Dex建立IR模型。分别设置正常组、模型组和药物处理组，除正常组用完全培养基培养之外，其余各组用1μM Dex培养；药物处理组中各加入10μM受试物培养48h后，吸走培养液，用DPBS洗1次，加入500μL胰酶37℃消化1min，加入2mL DPBS吹打均匀，1000g离心6min。弃去上清液，每孔加入1mL含有10μM2-NBDG的无糖培养基37℃孵育30min，用流式在波长488nm，515-545nm检测荧光强度。
2.3norpetanin对3T3-L1细胞AKt磷酸化的影响
将3T3-L1前脂肪细胞以5×104个/mL的密度接种至6孔板中，待细胞密度长到80％以上时，进行诱导分化，在诱导分化成熟后的第8天，向细胞培养液中加入1μMDex来建立IR模型。分别设置正常组、模型组和药物处理组，除正常组用完全培养基培养之外，其余各组用1μM Dex培养，药物处理组中各加入10μM norpetanin培养48h后，吸走培养液，收集细胞，并用Western blotting检测PI3K和AKt蛋白的表达水平。
2.4Western blot分析
将处理得到细胞样品进行蛋白提取，其具体操作方法如下：(1)将RIPA裂解液与PMSF按100:1的比例混合均匀(如分析磷酸化蛋白时，需加入磷酸酶抑制剂)，配制成细胞裂解液。将6孔板中的细胞用冷的PBS洗3次，每孔加入100μL细胞裂解液，放于冰上裂解5min，随后用细胞刮子刮取细胞，收集到1.5mL离心管，再次放入4℃冰箱充分裂解30min。最后在12000g，4℃，15min的条件下离心肝组织匀浆液和细胞裂解液，取上清液蛋白于新的EP管。
(2)BCA法测定蛋白质含量：取出适量蛋白样品，根据BCA蛋白定量试剂盒说明书的要求，将蛋白标准品用PBS缓冲液稀释为0.5mg/mL，按50:1的比例将试剂A：试剂B混匀配制成工作液。按表4所示将标准品和PBS加入96孔板中，每孔20μL，一般每个浓度设3个复孔，用来绘制标准曲线。蛋白样品1μL加到96孔板中，加PBS补到20μL。每孔加入200μLBCA工作液充分混匀，上述样品在微孔板孵育振荡器37℃振荡孵育30min，于酶标仪562nm处测吸光度值，根据标准曲线计算出样品的蛋白浓度。配好的蛋白样品于100℃加热10min，使蛋白完全变性。蛋白上样前，样品离心混合均匀后使用。
表4 BCA法蛋白定量表
| 编号 | 蛋白标准液(μL) | PBS缓冲液(μL) | BCA工作液(μL) | 蛋白含量(μg) |
| 1 | 0 | 20 | 200 | 0 |
| 2 | 1 | 19 | 200 | 0.5 |
| 3 | 2 | 18 | 200 | 1 |
| 4 | 4 | 16 | 200 | 2 |
| 5 | 8 | 12 | 200 | 4 |
| 6 | 12 | 8 | 200 | 6 |
| 7 | 16 | 4 | 200 | 8 |
| 8 | 20 | 0 | 200 | 10 |
(3)SDS-PAGE电泳：根据目标蛋白的分子量大小选择合适的分离胶浓度(如表5所示)，配制合适的溶液体系(下层胶)，待下层胶在室温放置40min以上使至完全凝固，再配制5％的浓缩胶(上层胶)，并插入大小合适的梳子。待浓缩胶凝固后，将胶板放入电泳槽中，往两块板之间加满电泳液后拔出梳子，上蛋白样品和marker后进行跑胶。电泳条件：S1阶段，80V，30min；S2阶段，120V，大约60～90min，直至缓冲液中溴酚蓝跑到分离胶最下端时结束电泳。
(4)转膜：待到蛋白电泳结束后立即进行转膜，根据marker条带按照分子量切下目标蛋白所在的位置。取出PVDF膜剪裁成与胶相同的大小，将剪裁好的膜放置甲醇溶液活化1min后放入转膜液中。按照转印夹黑板-滤纸-胶PVDF-滤纸-转印夹白板顺序夹紧电转夹，黑板对着槽的黑面，放入电泳槽，加满转膜液至整个槽中，通电后将转膜仪置于冰水混合物中。转膜的条件为恒流250mA，时间90min。
表5不同浓度的SDS-PAGE分离胶的最佳分离范围
| 聚丙烯酰胺浓度(％) | 最佳分离范围(KDa) |
| 6 | 50-150 |
| 8 | 30-90 |
| 10 | 20-80 |
| 12 | 12-60 |
| 15 | 10-40 |
(5)封闭：转膜结束后，将PVDF膜快速从转膜板中用镊子轻轻拿出，放于TBST缓冲液中漂洗5min，随后立刻用含5％脱脂奶粉的TBST在室温摇床上封闭1h。
(6)一抗孵育：封闭结束后，将PVDF膜放入稀释好的一抗溶液中，在4℃条件下置于水平摇床上慢摇孵育过夜。
(7)二抗孵育：一抗孵育结束后，TBST洗膜三次，一次8min。随后将PVDF膜置于含有HRP标记的鼠二抗或兔二抗溶液中室温慢摇孵育1h。
(8)显影：二抗孵育结束后，TBST洗膜三次，一次8min。洗膜结束后，将混合好的ECL显影液滴加在PVDF膜上，并用凝胶成像系统进行拍照。
(9)结果分析：目标蛋白和内参蛋白的灰度值用Image J软件进行定量分析，蛋白的相对表达量为目标蛋白与内参蛋白的比值(磷酸化与非磷酸化蛋白的比值)。
2.5统计分析
使用GraphPad Prism7软件进行作图和统计学分析，两组间均数的比较采用独立样本t检验，多组数据之间均数的相互比较采用单因素方差分析(one-way ANOVA)，统计数据以平均值±标准差(x±s)表示，*或者#表示P<0.05说明具有统计学意义，**或者##表示P<0.01说明其差异具有极显著统计学意义。
3实验结果
3.1norpetanin对3T3-L1细胞2-NBDG摄取的影响
如图9所示，采用荧光标记的葡萄糖类似物2-NBDG检测3T3-L1脂肪细胞对葡萄糖的摄取。荧光探针2-NBDG(2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-ylamino]-2-deoxyglucose)是一种2-脱氧葡萄糖荧光类似物，能特异性结合胞内的葡萄糖，检测时有较高的灵敏性。通常胰岛素抵抗的细胞或机体中2-NBDG的荧光强度极弱，处于本底值，说明细胞或机体对葡萄糖的摄取能力弱。实验结果显示，正常组中2-NBDG的摄取能力高于胰岛素抵抗模型组中的葡萄糖摄取能力，模型组中细胞对葡萄糖的摄取能力较弱，与正常组中胰岛素刺激后的细胞的葡萄糖摄取能力差异较明显。活性物质norpetanin干预后，能促进胰岛素刺激下脂肪细胞对2-NBDG的摄取，活性物质norpetanin具有改善胰岛素抵抗的潜力。
注：与正常组相比，#P<0.05，##P<0.01；与模型组相比，*P<0.05，**P<0.01
3.2norpetanin对3T3-L1细胞PI3K和AKt磷酸化的影响
AKt又称为蛋白激酶B(PKB)，是一种丝氨酸/苏氨酸蛋白激酶，该蛋白在细胞进程中扮演着重要的角色，如葡萄糖代谢、细胞凋亡、细胞增殖、细胞转运等多方面。在葡萄糖代谢过程中活化的AKt通过磷酸化途径而激活胰岛素信号通路中的多种酶、激酶和转录因子等下游因子，进而调节细胞功能和胰岛素信号的传递。通常活化的AKt通过激活其下游的磷脂酰肌醇激酶3(PI3K)而促使葡萄糖转运蛋白从胞浆转位到细胞膜上，加快葡萄糖的吸收利用，从而发挥胰岛素信号传递的作用。本实验通过检测黑果枸杞中活性物质norpetanin对细胞中p-AKt和p-PI3K表达的影响，考察其是否具有促进细胞吸收利用葡萄糖，增强胰岛素信号传递过程，改善胰岛素抵抗的作用。其实验结果如图10所示，与正常组相比，模型组p-AKt和p-PI3K蛋白表达水平降低。活性物质norpetanin处理后，能提高3T3-L1脂肪细胞中p-AKt和p-PI3K的表达水平，从而促进3T3-L1脂肪细胞细胞对葡萄糖摄取、增强胰岛素敏感性。
3.3小结
利用3T3-L1脂肪细胞建立了胰岛素抵抗模型研究黑果枸杞中活性物质norpetanin的降糖作用，借助FCM检测化合物对处于胰岛素抵抗状态下的脂肪细胞对葡萄糖类似物的摄取情况，同时采用Western blotting检测3T3-L1脂肪细胞中PI3K和AKt的磷酸化水平，实验结果表明黑果枸杞活性物质norpetanin干预后，能促进胰岛素刺激下脂肪细胞对2-NBDG的摄取，具有改善胰岛素抵抗的潜力。从Western blotting实验结果可以看出，活性物质norpetanin也能提高3T3-L1脂肪细胞中p-PI3K和p-AKt表达水平。
本研究中黑果枸杞活性物质norpetanin能提高3T3-L1脂肪细胞中p-AKt和p-PI3K表达水平，其暗示着黑果枸杞中活性物质norpetanin能促进胰岛素靶组织对葡萄糖的摄取，提高对胰岛素的敏感性，具有改善胰岛素抵抗的潜力，为开发利用黑果枸杞治疗II型糖尿病提供更多的科学依据。
实施例3
norpetanin对脂代谢的影响：
1实验材料与仪器
1.1材料与试剂
受试物：为实验室分离制备得到的norpetanin。
3T3-L1小鼠胚胎成纤维细胞购买于中国科学院上海细胞库，实验中所使用的材料与试剂见表6。
表6材料与试剂
1.2仪器和设备
本实验所用的主要仪器和设备见表7。
表7仪器和设备
| 仪器和设备 | 生产厂家 |
| Haier HYCD-205冷藏冷冻冰箱 | 青岛海尔股份有限公司 |
| Micro 21R高速冷冻离心机 | Thermo Fisher Scientific Inc. |
| LS-750液氮罐 | 四川成都金凤液氮容器有限公司 |
| LX71倒置显微镜 | OLYMPUS |
| BE-9008型微孔板恒温振荡器 | 上海言和仪器设备有限公司 |
| Tanon520凝胶成像系统 | 上海天能科技有限公司 |
| 多功能酶标仪 | Molecular Devices Corporation |
| 超声波清洗器 | 江苏省定山湖仪器厂 |
| 电泳仪 | Bio-Rad公司 |
| HH-2数显恒温水浴锅 | 金坛市科兴仪器厂 |
| 不同大小规格的移液枪 | Eppendorf |
| LDZM-80KCS立式压力蒸汽灭菌锅 | 上海申安医疗器械厂 |
| SW-CJ-2FD型双人单面净化工作台 | 苏州净化设备有限公司 |
| 恒温二氧化碳培养箱 | SANYO |
2实验方法
2.1 3T3-L1脂肪细胞模型的建立
(1)3T3-L1细胞的体外培养与传代
3T3-L1细胞用含10％FBS及1％青链霉素混合液的DMEM高糖培养基中培养。细胞培养箱的温度为37℃、湿度为95％和CO2浓度为5％。在正常培养条件下，3T3-L1细胞需要每隔3天传代一次。当细胞密度达到85％～90％以上时，先用吸泵吸弃原来的培养基，加温浴的PBS洗细胞1～2次，随后立即加入850μL的胰酶消化液，并轻轻晃动培养皿使消化液均匀铺满整个培养皿底。显微镜下观察至细胞变圆并从皿底部脱落时，加入新鲜的培养基，并反复吹打细胞，使细胞从培养皿底部完全脱落并分散成单个细胞。将细胞悬液按照1:5的比例传代至新的培养皿中，并加入适量的DMEM和FBS后放于细胞培养箱中继续培养。
(2)3T3-L1细胞的冻存与复苏
细胞的冻存：选取对数生长期的细胞，快速消化细胞，将消化后的细胞悬液在室温下以1000g离心5min得到细胞团，加入提前配制的细胞冻存液(DMEM:FBS:DMSO＝5:4:1)，每支冻存管中加入1.2mL的细胞悬液，同时在管壁上做好标记(细胞类型、细胞代数、冻存的细胞个数和冻存的时间)，以便能随时查询，最后4℃放置10min，-20℃放置1h，-80℃放置过夜，第二天置于液氮罐中保存。细胞的复苏：从液氮罐中快速取出冻存的细胞株，迅速置于37℃水浴中融化，待细胞完全融化后，快速地将细胞转移至培养液中进行培养，待细胞贴壁后(一般6～8h)更换新鲜培养液。
(3)3T3-L1细胞的计数
细胞计数常用的工具是血球计数板，血球计数板每块计数板由2块H形凹槽，形成高0.10mm的计数池，计数板中有9个大方格，细胞计数的区域为四角的4个大方格。细胞个数确定后然后根据实验需要，调整细胞密度。一般计数的原则，记上不记下，记左不记右。根据实验要求调整细胞计数密度，记录4个大方格的细胞总数，最后按照公式计算细胞个数：
细胞个数＝4个格中的细胞总数/4×104×稀释倍数
(4)3T3-L1细胞诱导分化
采用“鸡尾酒”法对3T3-L1细胞进行诱导分化，按如下方法进行诱导分化：将细胞状态良好的3T3-L1细胞接种于培养板上，铺板密度5×104个/mL，用含10％FBS的高糖DMEM培养液培养至细胞密度达到85％～90％左右时细胞换液，接触抑制两天后弃去完全培养液，加入含有10μg/mL Insulin、0.5mM IBMX和1μM Dex的培养液培养2d(加诱导液时记为第0d，诱I)，随后换成含有10μg/mL Insulin的培养液(诱II)继续培养2d，随后换成正常培养液继续培养4d，隔天换液。在诱导的第8d时，可观察细胞内85％以上的细胞呈现出成熟脂肪细胞的形态，具有大小不一的脂滴，脂滴呈“戎环样”。
2.2油红O染色
将细胞状态良好的3T3-L1细胞接种于6孔板上，铺板密度5×104个/mL，用含10％FBS的高糖DMEM培养液培养至细胞密度达到85％～90％左右时细胞换液，接触抑制两天后弃去完全培养液，加入含有10μg/mL Insulin、0.5mM IBMX和1μMDex的培养液培养2d(加诱导液时记为第0d，诱I)，随后换成含有10μg/mL Insulin的培养液(诱II)继续培养2d，随后换成正常培养液加10μM的norpetanin共同孵育，隔天换液。诱导结束后，用4％中性甲醛固定细胞30min，待细胞固定结束后加入提前配制的油红O工作液染于细胞表面，避光静置60min。待染色结束后用70％乙醇洗涤细胞，弃去多余的染料，再用超纯水洗涤3～4次，最后置于显微镜下观察并拍照。
2.3TG含量测定
将3T3-L1细胞以5×104个/mL的密度接种于6孔板中，待细胞密度达到85％～90％左右进行诱导分化，在诱导的第8d进行TG含量的测定，其具体方法如下：
(1)细胞前处理：在诱导的第8d，将细胞培养液吸走，冷PBS洗两次后加入胰酶消化液进行消化细胞。
(2)细胞收集：细胞消化后，加入PBS重悬细胞后在1000g的条件下离心5min，收集细胞沉淀团。
(3)超声破碎：向收集的沉淀团中加入适量的PBS后进行超声破碎(3min)。
(4)测定：在96孔板中每孔加入2μL细胞破碎悬液，空白孔中加入2μL蒸馏水，标准孔中加入2μL标准品，然后每孔中加入200μL的测定液，混匀，37℃孵育10min后，在510nm处读取吸光值。借助BCA法测定待测样品中蛋白浓度，进行校正，最后根据公式计算TG的含量。
TG含量＝(OD样品-OD空白)/(OD校样-OD空白)×校准品浓度(mM)/待测样品蛋白浓度(gprot/L)
2.4Western blot分析
将处理得到细胞样品进行蛋白提取，其具体操作方法如下：
(1)将RIPA裂解液与PMSF按100:1的比例混合均匀(如分析磷酸化蛋白时，需加入磷酸酶抑制剂)，配制成细胞裂解液。将6孔板中的细胞用冷的PBS洗3次，每孔加入100μL细胞裂解液，放于冰上裂解5min，随后用细胞刮子刮取细胞，收集到1.5mL离心管，再次放入4℃冰箱充分裂解30min。最后在12000g，4℃，15min的条件下离心肝组织匀浆液和细胞裂解液，取上清液蛋白于新的EP管。
(2)BCA法测定蛋白质含量：取出适量蛋白样品，根据BCA蛋白定量试剂盒说明书的要求，将蛋白标准品用PBS缓冲液稀释为0.5mg/mL，按50:1的比例将试剂A：试剂B混匀配制成工作液。按表8所示将标准品和PBS加入96孔板中，每孔20μL，一般每个浓度设3个复孔，用来绘制标准曲线。蛋白样品1μL加到96孔板中，加PBS补到20μL。每孔加入200μLBCA工作液充分混匀，上述样品在微孔板孵育振荡器37℃振荡孵育30min，于酶标仪562nm处测吸光度值，根据标准曲线计算出样品的蛋白浓度。配好的蛋白样品于100℃加热10min，使蛋白完全变性。蛋白上样前，样品离心混合均匀后使用。
表8 BCA法蛋白定量表
| 编号 | 蛋白标准液(μL) | PBS缓冲液(μL) | BCA工作液(μL) | 蛋白含量(μg) |
| 1 | 0 | 20 | 200 | 0 |
| 2 | 1 | 19 | 200 | 0.5 |
| 3 | 2 | 18 | 200 | 1 |
| 4 | 4 | 16 | 200 | 2 |
| 5 | 8 | 12 | 200 | 4 |
| 6 | 12 | 8 | 200 | 6 |
| 7 | 16 | 4 | 200 | 8 |
| 8 | 20 | 0 | 200 | 10 |
(3)SDS-PAGE电泳：根据目标蛋白的分子量大小选择合适的分离胶浓度(如表9所示)，配制合适的溶液体系(下层胶)，待下层胶在室温放置40min以上使至完全凝固，再配制5％的浓缩胶(上层胶)，并插入大小合适的梳子。待浓缩胶凝固后，将胶板放入电泳槽中，往两块板之间加满电泳液后拔出梳子，上蛋白样品和marker后进行跑胶。电泳条件：S1阶段，80V，30min；S2阶段，120V，大约60～90min，直至缓冲液中溴酚蓝跑到分离胶最下端时结束电泳。
(4)转膜：待到蛋白电泳结束后立即进行转膜，根据marker条带按照分子量切下目标蛋白所在的位置。取出PVDF膜剪裁成与胶相同的大小，将剪裁好的膜放置甲醇溶液活化1min后放入转膜液中。按照转印夹黑板-滤纸-胶PVDF-滤纸-转印夹白板顺序夹紧电转夹，黑板对着槽的黑面，放入电泳槽，加满转膜液至整个槽中，通电后将转膜仪置于冰水混合物中。转膜的条件为恒流250mA，时间90min。
表9不同浓度的SDS-PAGE分离胶的最佳分离范围
| 聚丙烯酰胺浓度(％) | 最佳分离范围(KDa) |
| 6 | 50-150 |
| 8 | 30-90 |
| 10 | 20-80 |
| 12 | 12-60 |
| 15 | 10-40 |
(5)封闭：转膜结束后，将PVDF膜快速从转膜板中用镊子轻轻拿出，放于TBST缓冲液中漂洗5min，随后立刻用含5％脱脂奶粉的TBST在室温摇床上封闭1h。
(6)一抗孵育：封闭结束后，将PVDF膜放入稀释好的一抗溶液中，在4℃条件下置于水平摇床上慢摇孵育过夜。
(7)二抗孵育：一抗孵育结束后，TBST洗膜三次，一次8min。随后将PVDF膜置于含有HRP标记的鼠二抗或兔二抗溶液中室温慢摇孵育1h。
(8)显影：二抗孵育结束后，TBST洗膜三次，一次8min。洗膜结束后，将混合好的ECL显影液滴加在PVDF膜上，并用凝胶成像系统进行拍照。
(9)结果分析：目标蛋白和内参蛋白的灰度值用Image J软件进行定量分析，蛋白的相对表达量为目标蛋白与内参蛋白的比值(磷酸化与非磷酸化蛋白的比值)。
2.5统计分析
使用GraphPad Prism7软件进行作图和统计学分析，两组间均数的比较采用独立样本t检验，多组数据之间均数的相互比较采用单因素方差分析(one-way ANOVA)，统计数据以平均值±标准差(x±s)表示，*或者#表示P<0.05说明具有统计学意义，**或者##表示P<0.01说明其差异具有极显著统计学意义。
3实验结果
3.1norpetanin对3T3-L1细胞脂滴积累的影响：
通过油红O染色观察norpetanin对3T3-L1细胞脂滴积累的影响，其结果如图11所示，未分化的细胞内无脂滴的积累，分化的细胞内含有大量的脂滴。经过norpetanin处理后，胞内脂滴显著减少。
3.2norpetanin对3T3-L1细胞脂质含量的影响：
norpetanin对TG含量的影响结果如图12所示，与未分化的细胞相比，分化的细胞内TG含量显著增加(P<0.01)。与分化的细胞相比，norpetanin处理后TG含量降低且均具有极显著差异P<0.01)。
3.3norpetanin对3T3-L1细胞脂代谢蛋白表达的影响：
(1)norpetanin对3T3-L1细胞成脂转录因子表达的影响
通过Western blot分析norpetanin对3T3-L1细胞成脂转录因子表达的影响，其结果如图13所示。未诱导分化的3T3-L1细胞中PPARγ、C/EBPα蛋白表达水平较低。而在诱导分化的细胞中PPARγ、C/EBPα蛋白表达水平较高。与分化组相比，norpetanin处理能在一定程度上降低PPARγ、C/EBPα转录因子的蛋白表达水平。
(2)norpetanin对3T3-L1细胞脂质生成相关蛋白表达的影响
通过Western blot分析norpetanin对3T3-L1细胞脂质生成相关蛋白表达水平的影响，其结果如图14所示。未诱导分化的3T3-L1细胞中FAS、ACC蛋白表达水平较低。而在诱导分化的细胞中FAS、ACC蛋白表达水平显著升高。与分化组相比，化合物处理后能显著降低FAS、ACC蛋白的表达水平。基于以上的结果，发现norpetanin通过抑制成脂转录因子和脂质生成相关蛋白的表达而减少胞内脂滴的积累。
3.4小结
在细胞水平上探究了norpetanin对3T3-L1细胞脂质生成的影响。3T3-L1细胞从前脂肪细胞分化为成熟的脂肪细胞时会受转录因子和成脂蛋白的调控，并且细胞形态也会发生变化如最终出现“戎环样”。norpetanin能抑制3T3-L1细胞内脂滴的积累，降低细胞内TG含量。本实验结果也表明norpetanin也能通过抑制转录因子如PPARγ、C/EBPα等表达水平而抑制3T3-L1脂肪细胞的分化，降低胞内脂滴的积累。同时通过抑制FAS、ACC蛋白的表达水平从而抑制脂质生成来改善细胞的脂代谢水平。
Claims (10)
1.一种黑果枸杞中活性物质的应用，其特征在于，所述应用包括所述活性物质以及其药学上可接受的盐、水合物或溶剂合物在制备改善糖代谢或/和脂代谢产品中的应用；所述活性物质选自如通式Ⅰ所示的化合物或其各光学异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
2.根据权利要求1所述的应用，其特征在于，所述糖代谢中的应用为在制备治疗和/或预防糖代谢紊乱相关疾病的产品中的应用。
3.根据权利要求2所述的应用，其特征在于，所述产品为改善胰岛素抵抗的产品。
4.根据权利要求1所述的应用，其特征在于，所述脂代谢中的应用为在制备治疗和/或预防脂代谢紊乱相关疾病的产品中的应用。
5.根据权利要求4所述的应用，其特征在于，所述产品为具有降脂作用、或抑制脂肪细胞分化的产品。
6.根据权利要求4所述的应用，其特征在于，所述产品为抑制细胞内脂滴积累和/或细胞内脂质生成的产品。
7.根据权利要求4所述的应用，其特征在于，所述产品为治疗和/或预防肥胖症、高血压、高血脂、心血管疾病、代谢综合征相关疾病产品中的至少一种。
8.根据权利要求1所述的应用，其特征在于，所述应用还包括在制备PPARγ拮抗剂、C/EBPα拮抗剂、FAS抑制剂、ACC抑制剂中的至少一种的应用。
9.根据权利要求1-8任一项所述应用，其特征在于，所述活性物质以及其药学上可接受的盐、水合物或溶剂合物包含如式Ⅱ或式Ⅲ所示的化合物：
10.根据权利要求9所述的应用，其特征在于，所述活性物质中式Ⅱ和式Ⅲ所示的化合物的比例为3:1。
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