CN108392511A - 一种苦瓜萃取物及其应用 - Google Patents
一种苦瓜萃取物及其应用 Download PDFInfo
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- CN108392511A CN108392511A CN201810464967.3A CN201810464967A CN108392511A CN 108392511 A CN108392511 A CN 108392511A CN 201810464967 A CN201810464967 A CN 201810464967A CN 108392511 A CN108392511 A CN 108392511A
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- balsam pear
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种苦瓜萃取物，及其制备方法，以及该苦瓜萃取物在药用和食用方面的用途；发明人意外发现本发明的苦瓜萃取物可以提高肝细胞中CLOCK、ARNTL及PER2等基因表达，可用于制备治疗或预防与CLOCK、ARNTL及PER2等基因相关的疾病的药物、或是用于调节与前述基因相关的生理机能，尤其是用于调整生理时钟、改善睡眠质量及帮助入睡方面的食物或保健品。
Description
技术领域
本发明涉及一种苦瓜萃取物及其应用，属于天然植物萃取及其药用和食用方面的技术。
背景技术
昼夜节律(circadian rhythm)是由昼夜时钟(circadian clock)所驱动的约以24小时为周期之生命活动(例如动物的摄食、躯体活动、睡眠、觉醒) 的变动。当人体的昼夜节律受到扰乱，会导致人体的生理时钟改变、睡眠质量降低、贺尔蒙分泌失调、及行动能力下降等，使工作效率降低、发生意外的机率增加，并可能引发各种疾病(例如忧郁症)。
目前临床上常用来调节昼夜节律以治疗失眠症、忧郁症等相关疾病的药物有地西泮(Diazepam)及劳拉西泮(Lorazepam)，但患者在使用前述药物后极易产生成瘾性，且可能出现例如嗜睡、恶心、头痛、呕吐、胃肠不适、记忆力障碍、反弹性失眠(rebound insomnia)、精神恍惚、运动失调、呼吸抑制、及╱或梦游等副作用。因此，持续开发可有效调节昼夜节律、且不易产生成瘾性与副作用的药物或方法系有相当的必需性及迫切性。
研究已知，人体的昼夜节律及睡眠周期是由CLOCK(Circadian Locomotor OutputCycles Kaput)、ARNTL(Aryl Hydrocarbon Receptor Nuclear Translocator Like)、及PER2(Period Circadian Clock 2)等基因的表现来调控。因此，若能增加CLOCK基因、ARNTL基因、及PER2基因的表达水平，即可有效调控昼夜节律，有利于调整生理时钟、改善睡眠质量及帮助入睡。
因此，本申请的发明人尝试着开发和筛选能够增加CLOCK基因、ARNTL 基因、及PER2基因的表达水平的天然植物萃取物。
发明内容
为了解决上述技术问题，本发明一方面提供了一种苦瓜萃取物，该苦瓜萃取物采用下述步骤获得：
步骤1)将苦瓜经破壁机处理后与水混合，其中苦瓜：水的重量比为1： 2～1：8；
步骤2)在60～100摄氏度下进行加热萃取，过滤、浓缩后获得所述苦瓜萃取物。
优选的，在所述步骤1)中，所述苦瓜与水的重量比为1:5。
优选的，在所述步骤2)中，在80摄氏度下进行加热萃取，获得一粗萃取液，再以200网目的筛网过滤所述粗萃取液获得一萃取液，再将所述萃取液浓缩四倍后获得所述苦瓜萃取物。
优选的，在所述步骤1)之前，将所述苦瓜进行烘烤预处理，烘烤温度范围为80～200℃。
优选的，所述烘烤预处理是采用阶梯式升温烘烤的方式，其包括第一阶段烘烤处理和第二阶段烘烤处理，其中，所述第一阶段烘烤处理的温度为T1，所述第二阶段烘烤处理的温度为T2，80℃≤T1＜135℃，135℃＜T2≤200℃。
本发明另一方面提供了一种食物组合物，所述食物组合物包含上述的苦瓜萃取物。
本发明再一方面提供了一种药物组合物，所述药物组合物包含上述的苦瓜萃取物。
本发明再一方面提供了上述的苦瓜萃取物或上述食物组合物在用于制备调整生理时钟、改善睡眠质量或帮助入睡的食品或保健品方面的应用。
本发明再一方面提供了上述的苦瓜萃取物或上述的药物组合物在用于制备治疗癌症、酒精性肝损伤、忧郁症、躁郁症、男性不育症、老化、帕金森氏症、血管疾病、代谢症候群或古柯碱成瘾的药物方面的应用。
优选的，癌症包括胃癌、肺癌和卵巢癌。
优选的，代谢症候群包括肥胖、高血压、及糖尿病。
本发明再一方面提供了上述的苦瓜萃取物或上述的药物组合物在用于制备调节肝醣原合成、肺病生理学、骨骼肌的维持与适应、多能干细胞的维持与分化、葡萄糖恒定、葡萄糖代谢、胰岛素释放、脂肪生成、视网膜功能、类固醇合成、肝脏脂质代谢、血管新生、细胞老化过程的自噬作用、骨体积与骨密度的维持、昼夜时钟、昼夜喜好、肝醣代谢、脂质代谢、内皮前驱细胞功能或氧化性损伤的药物方面的应用。
附图说明
图1示出了效果例1的结果，即实施例2的未经烘烤的苦瓜萃取物对细胞的CLOCK、ARNTL及PER2基因表达量的影响；具体的，6小时处理组、 24小时处理组和48小时处理组相对于对照组在CLOCK、ARNTL、及PER2 基因表达量方面的图谱；
图2示出了效果例2的部分结果，即未烘烤处理组、烘烤处理1组至5 组的HepG2细胞的CLOCK基因的相对表达量(相对于对照组)图谱；
图3示出了效果例2的部分结果，即未烘烤处理组、烘烤处理1组至5 组的HepG2细胞的ARNTL基因的相对表达量(相对于对照组)图谱；
图4示出了效果例2的部分结果，即未烘烤处理组、烘烤处理1组至5 组的HepG2细胞的PER2基因的相对表达量(相对于对照组)图谱。
具体实施方式
以下通过具体实施方式对本发明作进一步的说明，但本发明并不限于这些具体实施方式。在不背离本发明精神下，本发明可以多种不同变形方式来实施，不应将本发明保护范围解释为说明书的具体实施方式。
除非文中有另外说明，于本说明书中(尤其是在后述专利申请范围中) 所使用的“一”、“该”及类似用语应理解为包含单数及复数形式；所谓“治疗”，不应被解释为治疗一个体直至完全恢复，而应包括将一个体的疾病进展或症状维持在一实质上静态的程度、增加一个体的恢复速率、改善一具体病况的严重性、或提高一患者的生命质量；所谓“预防”是指抑制或防止一具体病况的发作、或维持敏感个体的良好健康状态或建立该个体对疾病的耐受性；所述“调节”指正向调控(包括诱导、刺激、及增强)或负向调控(包括抑制、及减弱)以使个体朝向所述生理机能的正常状态者；所谓“有效量”，是指投予至个体时，可有效地至少部分改善怀疑个体的病情的物质数量；所谓“个体”是指哺乳动物，该哺乳动物可以为人类或非人动物。
苦瓜(Momordica charantia)，又称凉瓜、半生瓜，是一种葫芦科植物，原产地一般在热带地区，于南亚、东南亚、中国台湾、中国大陆、与加勒比海群岛等地均有广泛的种植，在中国台湾则常见分布于台中、彰化、嘉义及高雄等地。
本申请的发明人意外发现苦瓜萃取物具有调控CLOCK、ARNTL、及PER2 等基因的表达的效果。关于这些基因，已知CLOCK基因系与酒精性肝损伤、癌症、忧郁症、肝醣原合成、肺病生理学、男性不育症、肥胖、以及骨骼肌的维持与适应、多能干细胞的维持与分化之治疗、预防或调节为正向相关。因此，若可提升CLOCK基因的表现，则可治疗或预防该与CLOCK基因相关的疾病、或调节该与CLOCK基因相关的生理机能。有关CLOCK基因与前述疾病或生理机能之关联性，可参见例如：The Molecular Circadian Clock and Alcohol-Induced LiverInjury.Biomolecules.5:2504-2537(2015)、Genetic variation of clock genes andcancer risk:a field synopsis and meta-analysis. Oncotarget.Vol.8,(No.14),pp:23978-23995(2017)、CLOCK is suggested to associate with comorbid alcohol useand depressive disorders.Journal of Circadian Rhythms.8:1(2010)、CLOCKRegulates Circadian Rhythms of Hepatic Glycogen Synthesis throughTranscriptional Activation of Gys2.The journal of biologicalchemistry.Vol.285,No.29,pp.22114–22121(2010)、Circadian molecular clock inlung pathophysiology.Am J Physiol Lung Cell Mol Physiol. 309:L1056–L1075(2015)、Genetic Variation in Circadian Rhythm Genes CLOCK and ARNTL as RiskFactor for Male Infertility.PLoS One.8(3):e59220 (2013)、Altered Clock GeneExpression in Obese Visceral Adipose Tissue Is Associated with MetabolicSyndrome.PLoS One.Nov 3；9(11):e111678(2014)、 Circadian Rhythms,the MolecularClock,and Skeletal Muscle.Curr Top Dev Biol. 96:231–271(2011)、及Role ofcircadian gene Clock during differentiation of mouse pluripotent stemcells.Protein Cell.7(11):820–832(2016)，该等文献之全文并于此处以供参考。
此外，已知ARNTL基因与肥胖、脂肪生成、老化、躁郁症、癌症、葡萄糖恒定、葡萄糖代谢、高血压、胰岛素释放、男性不育症、帕金森氏症、视网膜功能、类固醇合成、第二型糖尿病、及血管疾病的治疗、预防或调节为正向相关。因此，若可提升ARNTL基因的表达，则可治疗或预防该与 ARNTL基因相关的疾病、或调节该与ARNTL基因相关的生理机能。有关ARNTL基因与前述疾病或生理机能之关联性，可参见例如：Obesity in mice with adipocyte-specific deletion of clock component Arntl.Nat Med.18(12): 1768–1777(2012)、Brain and muscle Arnt-like protein-1(BMAL1),a component of the molecularclock,regulates adipogenesis.Proc Natl Acad Sci U S A. 102(34):12071-6(2005)、Early aging and age-related pathologies in mice deficient in BMAL1,the corecomponent of the circadian clock.Genes Dev. 20(14):1868-73(2006)、Suggestiveevidence for association of the circadian genes PERIOD3and ARNTL with bipolardisorder.Am J Med Genet B Neuropsychiatr Genet.141B(3):234–241(2006)、A LargeScale shRNA Barcode Screen Identifies the Circadian Clock Component ARNTL asPutative Regulator of the p53Tumor Suppressor Pathway.PLoS One.4(3):e4798(2009)、BMAL1 and CLOCK,Two Essential Components of the Circadian Clock,AreInvolved in Glucose Homeostasis.PLoS Biol.Nov.2(11):e377(2004)、Global Loss ofBmal1 Expression Alters Adipose Tissue Hormones,Gene Expression and GlucoseMetabolism.PLoS One.Jun 4；8(6):e65255(2013)、Aryl hydrocarbon receptor nucleartranslocator-like(BMAL1)is associated with susceptibility to hypertension andtype 2diabetes.Proc Natl Acad Sci U S A.104(36):14412-7 (2007)、ArylHydrocarbon Receptor Nuclear Translocator/Hypoxiainducible Factor-1βPlays aCritical Role in Maintaining Glucose-stimulated Anaplerosis and InsulinRelease from、Pancreaticβ-Cells.J Biol Chem.286(2):1014-24 (2011)、Geneticvariation in circadian rhythm genes CLOCK and ARNTL as risk factor for maleinfertility.PLoS One.8(3):e59220(2013)、Association of ARNTL and PER1geneswith Parkinson's disease:a case-control study of Han Chinese. Sci Rep.5:15891(2015)、Intrinsic circadian clock of the mammalian retina: importance forretinal processing of visual information.Cell.130(4):730-41 (2007)、Impairedsteroidogenesis and implantation failure in Bmal1-/-mice. Endocrinology.Apr；150(4):1879-85(2009)、Aryl hydrocarbon receptor nuclear translocator-like(BMAL1)is associated with susceptibility to hypertension and type2diabetes.Proc Natl Acad Sci U S A.Sep 4；104(36):14412-7(2007)、及 Vasculardisease in mice with a dysfunctional circadian clock.Circulation. 119(11):1510-7(2009)，该等文献之全文并于此处以供参考。
再者，已知PER2基因则与肝脏脂质代谢、代谢症候群(metabolic syndrome)、血管新生、细胞老化过程的自噬作用、骨体积与骨密度、老化、昼夜时钟、古柯碱成瘾、糖尿病、昼夜喜好、内皮前驱细胞功能、胃癌、肝醣代谢、肺癌、卵巢癌、及氧化损伤的治疗、预防或调节为正向相关。因此，若可提升PER2基因的表现，则可治疗或预防该与PER2基因相关的疾病、或调节该与PER2基因相关的生理机能。有关PER2基因与前述疾病或生理机能之关联性，可参见例如：KSRP is critical in governing hepatic lipid metabolism throughcontrolling Per2expression.J Lipid Res.56(2):227-40. (2015)、NPAS2and PER2arelinked to risk factors of the metabolic syndrome.J Circadian Rhythms.26；7:5.(2009)、Period 2is essential to maintain early endothelial progenitor cellfunction in vitro and angiogenesis after myocardial infarction in mice.J CellMol Med.18(5):907-18(2014)、Crosstalk of clock gene expression and autophagyin aging.Aging(Albany NY).8(9):1876-1895(2016)、 Decreased Bone Volume andBone Mineral Density in the Tibial Trabecular Bone Is Associated withPer2Gene by 405nm Laser Stimulation.Int J Mol Sci. 16(11):27401-10(2015)、Negative reciprocal regulation between Sirt1and Per2 modulates the circadianclock and aging.Sci Rep.6:28633.(2016)、Repeat variation in the human PER2geneas a new genetic marker associated with cocaine addiction and brain dopamineD2receptor availability.Transl Psychiatry. 2:e86.(2012)、Per2mutationrecapitulates the vascular phenotype of diabetes in the retina and bonemarrow.Diabetes.62(1):273-82.(2013)、PER2Variation is Associated with DiurnalPreference in a Korean Young Population.Behav Genet. 41(2):273-7.(2011)、Period 2is essential to maintain early endothelial progenitor cell functionin vitro and angiogenesis after myocardial infarction in mice.J Cell MolMed.18(5):907-18.(2014)、Prognostic relevance of Period1(Per1)and Period2(Per2)expression in human gastric cancer.Int J Clin Exp Pathol. 15；7(2):619-30.(2014)、PER2promotes glucose storage to liver glycogen during feeding andacute fasting by inducing Gys2PTG and G L expression.Mol Metab. 2(3):292-305.(2013)、PER2controls lipid metabolism by direct regulation of PPARγ.CellMetab.12(5):509-20.(2010)、Aberrant expression of Per1,Per2and Per3and theirprognostic relevance in non-small cell lung cancer.Int J Clin Exp Pathol.7(11):7863-71(2014)、Effects of Per2overexpression on growth inhibition andmetastasis,and on MTA1,nm23-H1and the autophagy-associated PI3K/PKB signalingpathway in nude mice xenograft models of ovarian cancer. Mol Med Rep.13(6):4561-8.(2016)、The Mammalian circadian clock gene per2 modulates cell death inresponse to oxidative stress.Front Neurol.5:289.(2015)、及Loss of corepressorPER2under hypoxia up-regulates OCT1-mediated EMT gene expression and enhancestumor malignancy.Proc Natl Acad Sci U S A. 110(30):12331-6(2013)，该等文献的全文并于此处以供参考。
因此，本发明一方面提供一种使用苦瓜萃取物于制备一药剂的用途，其中该药剂用于提高以下基因中至少其中一种的表达：CLOCK、ARNTL、及 PER2。较佳地，该药剂用于治疗或预防与前述基因相关的疾病、或用于调节与前述基因相关的生理机能。
其中，与CLOCK基因、ARNTL基因、及/或PER2基因相关的疾病是指以下的至少一种：癌症(包含胃癌、肺癌、及卵巢癌)、酒精性肝损伤、忧郁症、躁郁症、男性不育症、老化、帕金森氏症、血管疾病、代谢症候群(包含肥胖、高血压、及糖尿病)、及古柯碱成瘾。
其中，与CLOCK基因、ARNTL基因、及/或PER2基因相关的生理机能指以下的至少一种：肝醣原合成、肺病生理学、骨骼肌的维持与适应、多能干细胞的维持与分化、葡萄糖恒定、葡萄糖代谢、胰岛素释放、脂肪生成、视网膜功能、类固醇合成、肝脏脂质代谢、血管新生、细胞老化过程的自噬作用、骨体积与骨密度的维持、昼夜时钟、昼夜喜好、肝醣代谢、脂质代谢、内皮前驱细胞功能、及氧化性损伤。
此外，本申请的发明人发现，本发明的经烘烤处理后获得的苦瓜萃取物 (即，在进行萃取操作之前，先对苦瓜进行一烘烤处理)，则可进一步改善关于提高CLOCK基因、ARNTL基因、及/或PER2基因表达方面的效果。因此，较佳地，在前述用途中，采用经烘烤处理后获得的苦瓜萃取物。
因此，本发明也提供一种增进苦瓜萃取物效果的方法，其中，在进行萃取操作之前，先对苦瓜进行一烘烤处理。较佳地，该烘烤处理为一高温烘烤处理，例如，于80至200℃的温度下进行的烘烤处理。更佳地，该烘烤处理系包括阶梯式升温处理。例如，包含一于温度T1进行的第一阶段烘烤以及一于第一阶段烘烤之后、在温度T2进行的第二阶段烘烤的至少二阶段的阶梯式升温处理，其中，T1<T2；较佳地，T1<T2，且80℃≤T1＜200℃， 80℃＜T2≤200℃；更佳地，T1<T2，且80℃≤T1≤135℃，135℃<T2≤200℃。
于根据本发明的提升苦瓜萃取物效果的方法中，可视需要调整烘烤的时间，只要可以降低苦瓜的含水量即可。于本发明的部分具体实施方案中，是采用二阶段的阶梯式升温处理，于90至120℃的环境下对苦瓜进行第一阶段烘烤，历时2至24小时，接着，于150至180℃的环境下对苦瓜进行第二阶段烘烤，历时20至100分钟。
根据本发明所提供的药物组合物可以以任何合适的形式呈现，并无特殊限制，可以根据其用途来设计对应的合适的剂型。举例来说，但不以此为限，该药物可以适于口服或非经口服(例如：经皮肤给药、经鼻腔给药、皮下注射、静脉注射、肌肉注射、腹腔注射、皮下植入、或组织间植入)的给药方式施用至有需要的个体上。其中，根据所使用的形式及用途而定，可选用合适的药用载体，只要该药用载体对本发明的苦瓜萃取物的效果没有不利的影响即可。举例来说，该载剂可为例如：赋形剂、稀释剂、辅助剂、安定剂、吸收延迟剂、崩散剂、增溶剂、乳化剂、抗氧化剂、黏合剂、结合剂、增黏剂、分散剂、悬浮化剂、润滑剂、吸湿剂等，但不以此为限。
以适于口服给药的剂型为例，该药用载体的例子包括，但不限于，水、食盐水、葡萄糖(dextrose)、甘油、乙醇或其类似物、纤维素、淀粉、糖膨润土(sugar bentonite)、及前述的组合。可采用任何合适的方法，以适于口服给药的剂型提供该药物，例如固体形式的片剂、丸剂、胶囊剂、颗粒剂、散剂等、或是液体形式的口服液、糖浆剂、醑剂(spirit)、酏剂(elixir)、酊剂等，但不以此为限。
有关适于皮下、静脉内、肌肉、或腹腔注射的针剂或点滴剂，则可于根据本发明所提供的药剂中含有一或多种例如等张溶液、盐类缓冲液(如磷酸盐缓冲液或柠檬酸盐缓冲液)、增溶剂、乳化剂、5％糖溶液、以及其他载剂等成分，以静脉输注液、乳剂静脉输注液、干粉注射剂、悬液注射剂、或干粉悬液注射剂等剂型提供该药剂。或者，将该药剂制备成一注射前固体，以可溶于其他溶液或悬浮液中的剂型、或可乳化的剂型提供该注射前固体，并给药至有需要的个体之前，将该注射前固体溶于其他溶液或悬浮液中或将其乳化，提供所需要的注射剂。此外，适于经鼻腔或经皮肤给药的外用剂型，则例如涂抹剂(例如乳液、乳霜、凝胶、分散膏、软膏)、喷剂、贴剂、或溶液(例如洗液、悬浮液)。
于根据本发明应用所提供的药剂中，可视实际应用需求，调整药剂中的苦瓜萃取物的含量比例。
视需要地，可于根据本发明所提供的药剂中另含有合宜用量的添加剂，例如可提高该药剂于服用时的口适感及视觉感受之调味剂、调色剂、着色剂等，以及可改善该药剂的稳定性及储存性之缓冲剂、保存剂、防腐剂、抗菌剂、抗真菌剂等。此外，该药剂可视需要另含一或多种其他活性成分，或者与含该一或多种其他活性成分之药物并用，以进一步加强该药剂之功效或增加制剂配方的运用灵活性与调配度，只要该其他活性成分对苦瓜萃取物之所欲效益没有不利的影响即可。
根据本发明所提供之药剂可以一日一次、一日多次、或数日一次等不同投药频率施用，端视投予个体之需求、年龄、体重、及健康况状而异。
如前述，本案发明人发现苦瓜萃取物具有调控CLOCK、ARNTL、及PER2 等基因的表现的效果，故可用于调整生理时钟、改善睡眠质量及帮助入睡。因此，本发明亦提供一种使用经苦瓜萃取物于制造一食品之用途，其中该食品系用于调整生理时钟、改善睡眠质量及帮助入睡之至少一者。
根据本发明所提供之食品可以是保健食品、营养补充食品或特殊营养食品，且可以制成例如乳制品、肉类加工品、面包类、面食品、饼干、口含锭、胶囊、果汁类、茶类、运动饮料、营养饮料等产品，但不以此为限。较佳地，根据本发明之应用的食品系以保健食品的型式提供。
根据本发明所提供之保健食品、营养补充食品、及特殊营养食品系可以一日一次、一日多次、或数日一次等不同频率食用，端视投予个体之年龄、体重、及健康状况而异。亦可针对特定族群调整根据本发明所提供之保健食品、营养补充食品及特殊营养食品中苦瓜萃取物的含量，较佳为调整至每日应服用的量。
可于本发明保健食品、营养补充食品及/或特殊营养食品之外包装标示建议使用量、特定族群(例如失眠症、生理时钟失调等)的使用标准及条件、或与其他食品或医药共同服用的建议事项，以利用户在无医师、药师或相关执事人员指导下可在家自行服用而无安全疑虑。于根据本发明所提供之食品中，有关该苦瓜萃取物之态样、适用剂量、以及相关之应用，均如上述之说明。
本发明亦提供一种用于提升CLOCK基因、ARNTL基因、及/或PER2 基因之表现的方法，其系包含对一有需要之个体投予一有效量之苦瓜萃取物。有关该苦瓜萃取物之态样、投予途径、投予形式、施用频率、以及相关之应用，均如上述之说明。
以下通过实施例对本发明作进一步的说明，但本发明并不限于这些实施例。
实施例1
苦瓜萃取物的制备(苦瓜经过烘烤)
将苦瓜清洗后分为五组，并分别以下表1之条件进行烘烤(仪器：OV-80 烘箱，购自Firstek公司)：
表1
| 组别 | 烘烤条件 |
| 第1组 | 于120℃下烘烤2小时后，再于150℃下烘烤80分钟 |
| 第2组 | 于120℃下烘烤2小时后，再于150℃下烘烤100分钟 |
| 第3组 | 于120℃下烘烤2小时，再于180℃下烘烤40分钟 |
| 第4组 | 于120℃下烘烤2小时，再于180℃下烘烤60分钟 |
| 第5组 | 于90℃下烘烤1天，再于180℃下烘烤20分钟 |
以约1：5(苦瓜：水)的重量比将烘烤后的苦瓜(烘烤后的苦瓜经破壁机处理后)浸泡于水中，并置于80℃下加热进行萃取(历时30分钟)，以获得一粗萃取液。接着，以200网目的筛网过滤该粗萃取液，获得一萃取液。最后，将萃取液浓缩四倍，以提供一萃取物(以下称“经烘烤的苦瓜萃取物”)，实施例1中获得了5组经烘烤的苦瓜萃取物(分别对应表1中的5组烘烤条件)。
实施例2
苦瓜萃取物的制备(苦瓜未经过烘烤)
将苦瓜清洗后，以约1：5(苦瓜：水)的重量比将苦瓜(经破壁机处理后)浸泡于水中，并置于80℃下加热进行萃取(历时30分钟)，以获得一粗萃取液。接着，以200网目的筛网过滤该粗萃取液，获得一萃取液。最后，将萃取液浓缩四倍，以提供一萃取物(以下称“未经烘烤的苦瓜萃取物”)。
细胞处理
将HepG2细胞(由美国典型培养物保藏中心(American Type CultureCollection，ATCC)提供；编号HB-8065)培养于含有10％胎牛血清 (购自Gibco公司)的杜氏改良Eagle培养基(DMEM，购自Gibco公司) 中24小时后，供后续实验使用。
检测实施例1和实施例2的苦瓜萃取物对细胞的CLOCK、ARNTL及PER2 基因表达量的影响
(1-1)未经烘烤的苦瓜萃取物的效果(效果例1)
取上述培养好的HepG2细胞，将其分为四组，并于5％CO2、37℃的条件下进行以下处理：
对照组：将细胞培养于含有10％胎牛血清的DMEM培养基中(即，不含苦瓜萃取物的培养液)中，历时48小时；
6小时处理组：与上述的对照组的操作基本相同，但于培养42小时之后，加入实施例2的未经烘烤的苦瓜萃取物，使其于培养液中的最终浓度为2毫克/毫升，继续培养6小时；
24小时处理组：与上述的对照组的操作基本相同，但于培养24小时之后，加入实施例2的未经烘烤的苦瓜萃取物，使其于培养液中的最终浓度为 2毫克/毫升，继续培养24小时；以及
48小时处理组：于含有10％胎牛血清之DMEM培养基中加入实施例2 的未经烘烤的苦瓜萃取物，使其于培养液中的最终浓度为2毫克/毫升，以进行培养，历时48小时。
其后，收集上述各组细胞，以RNA Lysis buffer(购自Geneaid公司)进行RNA萃取，再以SuperScriptTM Reverse Transcriptase kit(购自Invitrogen 公司)将RNA转录为cDNA。接着，以ABI StepOnePlusTM系统(购自Applied Biosystems)对前述cDNA进行实时定量聚合酶链锁反应(Q-PCR)，以测定各组细胞CLOCK、PER2、ARNTL、RPLP0基因的表达量，并以RPLP0基因的表达量为基准作为参考基因标准化其他基因表达量。最后，再以控制组的基因表达量为基准以标准化各组的基因表达量。结果参见图1。
从图1可以看出，相较于对照组细胞(基因表达量设定为1倍)，48小时处理组的细胞的CLOCK基因表达量为控制组的1.35倍，ARNTL基因表达量为控制组的4.36倍，PER2基因表达量则为控制组的2.83倍。这些结果说明，苦瓜萃取物可显助提升肝细胞CLOCK、ARNTL及PER2基因的表达，故可用于调节人体生理时钟及昼夜节律。
(1-2)经烘烤的苦瓜萃取物的效果(效果例2)
取上述培养好的HepG2细胞，将其分为六大组，并于5％CO2、37 ℃之条件下进行以下处理：
未烘烤处理组：将其中一组细胞进一步分为三小组，分别于含有10％胎牛血清的DMEM培养基中培养24小时之后，加入实施例2的未经烘烤的苦瓜萃取物，使其于培养液中的最终浓度为2毫克/毫升，分别继续培养6小时、24小时及48小时；
烘烤处理1组：如未烘烤处理组的操作基本相同，将其中一组细胞进一步分为三小组，分别于含有10％胎牛血清的DMEM培养基中培养24小时之后，加入实施例1的经烘烤的苦瓜萃取物(第1组经烘烤的苦瓜萃取物)，使其于培养液中的最终浓度为2毫克/毫升，分别继续培养6小时、24小时及 48小时；
烘烤处理2组～5组的操作与烘烤处理1组完全相同，只是加入的萃取物分别为实施例1的第2组～第5组经烘烤的苦瓜萃取物。
收集上述各组的细胞，依序进行上述(1-1)中的RNA萃取、cDNA制备、以及实时定量聚合酶链锁反应(Q-PCR)，以测定各组细胞CLOCK、PER2、 ARNTL之表现量。结果参见图2至图4，其中也示出了对照组(即，未经苦瓜萃取物处理的细胞)的基因表达量为基准进行标准化的结果。
从图2至图4的结果可以看出，未经烘烤苦瓜萃取物或经烘烤苦瓜萃取物对肝细胞的CLOCK、ARNTL及PER2等基因的调控，皆以48小时的处理时间效果为最佳。
此外，CLOCK、ARNTL及PER2等基因的表达量也随苦瓜的烘烤条件不同而有不同趋势变化。如图2所示，相较于未烘烤组，烘烤处理1组至烘烤处理5组的细胞的CLOCK基因表达量皆显著提升。以处理48小时的结果为例，未烘烤组细胞的CLOCK表现量为控制组的1.35倍，烘烤处理1组至烘烤处理5组的细胞的CLOCK基因表达量则依序为控制组的2.12、2.26、1.50、1.60及2.07倍。
如第3图所示，以处理48小时的结果为例，未烘烤组细胞的ARNTL基因表达为控制组的4.36倍，烘烤条件1组至烘烤条件5组的细胞的ARNTL 基因表达量则依序为控制组的7.24、8.41、6.61、6.01及8.19倍。
如图4所示，以处理48小时的结果为例，未烘烤组细胞的PER2基因表达为控制组的2.83倍，烘烤处理1组至烘烤处理5组的细胞的PER2基因表达则依序为控制组的3.14、3.62、2.24、2.06及2.27倍。
上述结果显示，将较于未经烘烤苦瓜萃取物，经烘烤苦瓜萃取物于提升肝细胞中CLOCK、ARNTL及PER2等基因表达的效果更为优异，更可用于治疗或预防与CLOCK、ARNTL及PER2等基因相关的疾病、或是调节与前述基因相关的生理机能，尤其是用于调整生理时钟、改善睡眠质量及帮助入睡。
应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施方式中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。
上文所列出的一系列的详细说明仅仅是针对本发明的可行性实施方式的具体说明，它们并非用以限制本发明的保护范围，凡未脱离本发明技艺精神所作的等效实施方式或变更均应包含在本发明的保护范围之内。
Claims (10)
1.一种苦瓜萃取物，其特征在于：该苦瓜萃取物采用下述步骤获得：
步骤1)将苦瓜经破壁机处理后与水混合，其中苦瓜：水的重量比为1：2～1：8；
步骤2)在60～100摄氏度下进行加热萃取，过滤、浓缩后获得所述苦瓜萃取物。
2.如权利要求1所述苦瓜萃取物，其特征在于：
在所述步骤1)中，所述苦瓜与水的重量比为1:5。
3.如权利要求1所述苦瓜萃取物，其特征在于：
在所述步骤2)中，在80摄氏度下进行加热萃取，获得一粗萃取液，再以200网目的筛网过滤所述粗萃取液获得一萃取液，再将所述萃取液浓缩四倍后获得所述苦瓜萃取物。
4.如权利要求1至3中任意一项所述苦瓜萃取物，其特征在于：
在所述步骤1)之前，将所述苦瓜进行烘烤预处理，烘烤温度范围为80～200℃。
5.如权利要求4所述苦瓜萃取物，其特征在于：
所述烘烤预处理是采用阶梯式升温烘烤的方式，其包括第一阶段烘烤处理和第二阶段烘烤处理，其中，所述第一阶段烘烤处理的温度为T1，所述第二阶段烘烤处理的温度为T2，80℃≤T1＜135℃，135℃＜T2≤200℃。
6.如权利要求5所述苦瓜萃取物，其特征在于：
所述第一阶段烘烤处理的T1为90～120℃，持续时间为2～24小时；
所述第二阶段烘烤处理的T2为150～180℃，持续时间为20～100分钟。
7.一种食物组合物，其特征在于：所述食物组合物包含如权利要求1所述的苦瓜萃取物。
8.一种药物组合物，其特征在于：所述药物组合物包含如权利要求1所述的苦瓜萃取物。
9.如权利要求1至6中任意一项所述的苦瓜萃取物或如权利要求7所述食物组合物在用于制备调整生理时钟、改善睡眠质量或帮助入睡的食品或保健品方面的应用。
10.如权利要求1至6中任意一项所述的苦瓜萃取物或如权利要求8所述的药物组合物在用于制备治疗或预防癌症、酒精性肝损伤、忧郁症、躁郁症、男性不育症、老化、帕金森氏症、血管疾病、代谢症候群或古柯碱成瘾的药物方面的应用，或者用于制备调节肝醣原合成、肺病生理学、骨骼肌的维持与适应、多能干细胞的维持与分化、葡萄糖恒定、葡萄糖代谢、胰岛素释放、脂肪生成、视网膜功能、类固醇合成、肝脏脂质代谢、血管新生、细胞老化过程的自噬作用、骨体积与骨密度的维持、昼夜时钟、昼夜喜好、肝醣代谢、脂质代谢、内皮前驱细胞功能或氧化性损伤的药物方面的应用。
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| TW201800102A (zh) * | 2016-06-21 | 2018-01-01 | 大江生醫股份有限公司 | 用於提升clock基因、arntl基因、及／或per2基因之表現的苦瓜萃取物及其應用 |
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