CN114008062A - 源自西瓜的新化合物和使用该新化合物的组合物 - Google Patents
源自西瓜的新化合物和使用该新化合物的组合物 Download PDFInfo
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Abstract
本发明提供一种西瓜幼果中所含的具有抗氧化作用的新化合物。西瓜幼果中所含的式(1)或式(2)表示的新化合物具有抗氧化作用，还具有抗皮肤老化作用。由于这些化合物是来自原本可食用的植物的提取物，因此对人类的安全性非常高。因此，以这些化合物作为有效成分的抗氧化用药物组合物、抗氧化用加工食品组合物、抗皮肤老化用组合物作为安全性高的组合物具有高利用价值。
Description
技术领域
本发明涉及源自西瓜的具有抗氧化作用的新化合物及使用该新化合物的药物组合物、加工食品组合物和抗皮肤老化用组合物。
背景技术
在生物体内，活性氧是产生能量、及攻击入侵异物、传递细胞信息所必需的物质。但是，超氧化物自由基等也被称为活性氧，在生物体内可能成为毒性物质。自由基是未配对的电子，是一种强氧化剂。此外，已知它会诱发脂质、蛋白质、核酸和碳水化合物等生物物质的氧化，并对生物体产生各种各样的影响。
例如，据说它对特应性疾病、癌症、高血压、心肌梗塞、动脉硬化、风湿病、白内障、帕金森病等各种慢性病的进展有许多影响，还作为削弱免疫系统功能的主要因素而起作用。
另一方面，在生物体内，有抗坏血酸和谷胱甘肽等抗氧化物质、及超氧化物歧化酶和过氧化氢酶等修复由活性氧引起的损害的抗氧化酶，它们作为生物体内防御系统来对抗活性氧。
但是，已知由于吸烟、压力会产生过量的活性氧，对辅助生物体内防御系统的抗氧化剂的需求越来越大。特别是，可以食用并具有实际成效的食物(天然物)中所含的物质因为其安全性已得到一定程度的确认，所以适合用作为上述抗氧化剂。
专利文件1公开了一种新化合物，其为源自黑加仑叶的新物质，具有α-葡萄糖苷酶等糖尿病调节剂的抑制作用、抑制自由基生成的作用及LDL的抗氧化作用、抑制酪氨酸酶活性的作用等药理活性。
此外，专利文献2公开了一种通过对橄榄叶提取物进行酶处理而得的抗氧化物质。此外，专利文件3公开了一种能用于抑制乳腺癌、肝癌、前列腺癌肿瘤细胞生长的樟芝的环己酮提取物。
此外，具有抗氧化性的物质有时具有抗皮肤老化特性。抗皮肤老化特性是指能够预防和改善皮肤产生的皱纹的特性。皱纹中，被称为光皮肤老化的现象是由于皮肤被紫外线照射而形成皱纹。
更详细地说，光皮肤老化是指由于UV照射，导致纤维细胞的细胞膜上存在的单次跨膜丝氨酸/苏氨酸内置受体转化生长因子-β受体II型(TβRII)的表达被下调，促进作为胶原蛋白前体的I型前胶原的合成的转化生长因子-β(TGF-β)信号通路减弱，胶原蛋白的表达减少、或由于下述的胶原蛋白非交联键等，造成皮肤产生皱纹或松弛的现象。
胶原蛋白非交联键形成的机理被认为如下所述。在皮肤的脂腺及口腔、肠胃等中栖息的痤疮丙酸杆菌(P.acnes)通过将谷氨酸转化为氨基乙酰丙酸的C5途径，最终产生光敏物质原卟啉IV。该光敏物质原卟啉IV通过吸收照射在皮肤上的UV，产生单线态氧(1O2)，将作为胶原蛋白的构成氨基酸之一的组氨酸氧化。
其结果是形成胶原蛋白非交联键，皮肤的弹性降低，导致皱纹等皮肤老化。此外，生物体内的卟啉等光敏物质不仅有单线态氧(1O2)，还产生作为其他活性氧(reactiveoxygen species，以下记为ROS)的超氧化物(·O2 -)、羟基自由基(OH)。
这些ROS激活氧化应激反应性丝裂原活化蛋白3激酶(MAP3K)的细胞凋亡信号调节激酶1(ASK-1)，过量产生炎性细胞因子肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)等，引起皮肤炎症反应。
通过这种炎症反应，表皮细胞膜上存在的6次跨膜离子通道型受体瞬时受体电位香草素1型(TRPV1)的表达上调，流入细胞内的Ca2+量增加，诱导分解胶原蛋白的基质金属蛋白酶-1(matrix metallo proteinase-1，以下记为MMP-1)的表达。
其结果是胶原蛋白发生分解，皮肤出现皱纹或松弛等皮肤老化症状。
此外，MMP-1的胶原蛋白分解所生成的胶原蛋白片段通过激活整合素家族的玻连蛋白受体(αVβ3)，抑制由作为低分子三磷酸鸟苷(GTP)结合蛋白质之一的Ras同源激酶(ROCK)引起的丝切蛋白的磷酸化，从而减弱其向下游的磷酸化的丝裂原活化蛋白激酶(MAPK)家族的细胞外信号调节激酶1/2(ERK1/2)和转录因子ELK-1的信号通路，降低透明质酸合酶2(HAS2)的表达。
其结果是，具有皮肤的保水能力的透明质酸的合成受到抑制，皮肤出现皱纹或松弛等皮肤老化。另外，作为通过抑制MMP而发挥抗皱效果的发明，可例举专利文献4。
现有技术文献
专利文献
专利文献1：日本专利特开2016-020338号公报
专利文献2：日本专利特开2011-021025号公报
专利文献3：日本专利特开2008-169194号公报
专利文献4：日本专利特开2020-002053号公报
发明内容
发明所要解决的技术问题
如上所述，从保护生物体的观点来看，具有抗氧化性和安全性得到确保的物质可以预期对各种疾病和健康维持有效。发明人对西瓜有多年的经验和生产实验，以提供源自西瓜的抗氧化剂作为课题进行研究。
解决技术问题所采用的技术方案
鉴于上述技术问题，通过对西瓜幼果中所含物质进行提取而得到一种以前未知的新化合物，通过确认其具有抗氧化作用而完成了本发明。
更具体而言，本发明的抗氧化化合物(新化合物)由式(1)或式(2)表示。
[化学式1]
[化学式2]
发明效果
式(1)和式(2)的化合物是从西瓜幼果提取的新物质，安全性高、且具有抗氧化作用。因此，可以期待应用于除去生物体内的自由基的药物组合物和加工食品组合物等。更具体而言，可以期待总体上对预防老化有效，可期待对预防或改善动脉硬化、癌症等与生活习惯相关的疾病、预防或改善白发、色斑、皱纹等皮肤老化等有效。
特别是抗氧化药物组合物、抗氧化用加工食品组合物、抗皮肤老化用组合物确认具有具体的效果。
附图的简要说明
图1是从西瓜幼果中获得提取物的溶剂分配流程图。
图2是显示求出从幼西瓜中提取和分离的两种新化合物的自由基清除率的结果的图表以及拍摄微孔板的状态的照片。
图3是显示研究MMP-1的表达抑制的(a)蛋白质印迹的结果和(b)实时PCR的基因表达率的图表。
图4是显示研究信号分子的活化性的(a)蛋白质印迹和(b)光密度分析的结果的图表。
图5是研究AP-1转录活性的图表。
图6是研究对细胞内活性氧(ROS)量的影响的图表。
图7是显示研究对羰基化蛋白质产生的影响的(a)蛋白质印迹的结果和(b)光密度分析的结果的图表。
具体实施方式
下面示出实施例对本发明的化合物、含有该化合物作为有效成分的药物组合物、加工食品组合物和抗皮肤老化用组合物进行说明。另外，以下说明仅例示本发明的一个实施方式和一个实施例，本发明不限于以下说明。以下说明可以在不超出本发明主旨的范围内进行改变。
本发明的化合物的特征是由式(1)或式(2)表示。
[化学式3]
[化学式4]
式(1)的化合物为2-咖啡酰基-3-羟基-3-甲基丁酸4’-β-D-吡喃葡萄糖基氧基-3’-羟基苄基酯(2-Caffeoyl-3-hydroxy-3-methylbutyric4’-β-D-glucopyranosyloxy-3’-hydroxybenzyl ester)，简称4G3HBE，别名为“Citrulluside H”。以下称为4G3HBE。
此外，式(2)的化合物为2-咖啡酰基-3-羟基-3-甲基丁酸4’-β-D-吡喃葡萄糖氧基苄基酯(2-Caffeoyl-3-hydroxy-3-methylbutyric 4’-β-D-glucopyranosyloxyben zylester)，简称4GBE，别名为“Citrulluside T”。以下称为4GBE。
4G3HBE和4GBE可从西瓜幼果获得。西瓜(学名：Citrullus lanatus)是葫芦科一年生藤本植物的果实。幼果是指从结果后到成熟需要10～20天的果实。种类没有特别限定，可优选使用红肉系大球品种、无籽红肉系品种、黑皮系品种、长形品种、黄肉系品种、橙色品种等品种。
图1显示西瓜幼果提取物的溶剂分配流程图。作为提取方法，将西瓜幼果洗净、粉碎后，将粉碎物浸入乙醇中，得到乙醇提取物。将乙醇提取物在己烷(己烷Fr.)、乙酸乙酯(乙酸乙酯Fr.)、丁醇(丁醇Fr.)和蒸馏水溶解物(水Fr.)中进行溶剂分配，以制备级分。然后，将乙酸乙酯提取物通过柱分级进行分离得到上述两种新化合物。
本发明的药物组合物是通过发现4G3HBE和4GBE具有抗氧化作用而想到的。因此，本发明的药物组合物是抗氧化用药物组合物，含有4G3HBE和4GBE中的至少一种，这些化合物可以通过在水、甲醇、乙醇和丙酮等溶剂中与药学上允许的酸混合，从而转换成盐。作为药学上允许的酸，可例举例如盐酸、氢溴酸、硫酸、磷酸、硝酸等无机酸、或乙酸、丙酸、草酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、马来酸、富马酸、甲磺酸、对甲苯磺酸、抗坏血酸等有机酸。
此外，这些化合物也可以口服或肠胃外(例如，静脉内、皮下或肌肉内注射、局部、经直肠、经皮或鼻内)给药。
作为用于口服给药的药物组合物，可以通过添加药学上允许的常用的赋形剂、粘合剂、润滑剂、崩解剂、表面活性剂、流动性促进剂等来制备。作为赋形剂，例如可以使用乳糖、果糖、葡萄糖、玉米淀粉、山梨糖醇、结晶纤维素等。
此外，作为粘合剂，可以使用甲基纤维素、乙基纤维素、阿拉伯树胶、明胶、羟丙基纤维素、聚乙烯吡咯烷酮等。此外，作为润滑剂，可以优选使用滑石、硬脂酸镁、聚乙二醇、硬化植物油等。
此外，作为崩解剂，可以使用淀粉、海藻酸钠、明胶、碳酸钙、柠檬酸钙、糊精、碳酸镁、合成硅酸镁等。此外，作为表面活性剂，可以使用月桂基硫酸钠、大豆卵磷脂、蔗糖脂肪酸酯、聚山梨醇酯80等。
此外，作为流动性促进剂，可以使用轻质无水硅酸、干燥氢氧化铝凝胶、合成硅酸铝、硅酸镁等。此外，作为其他添加剂，也可以使用糖浆、凡士林、甘油、乙醇、丙二醇、柠檬酸、氯化钠、亚硝酸钠、磷酸钠等。
此外，可根据给药形式制成相应的剂型，可以配制成胶囊剂、片剂、颗粒剂、散剂、丸剂、细颗粒剂等口服给药剂，或注射剂、直肠给药剂、油性栓剂、水性栓剂等非肠道给药剂等各种制剂。此外，本发明的药物组合物除本发明的上述化合物外还可包含其他药理活性成分。
本发明的抗氧化用药物组合物可以用作据称通过抗氧化活性得到改善的已知症状的治疗药。例如，可例举心血管疾病、特应性疾病、癌症、风湿病、白内障、帕金森病等。
本发明的化合物也可以作为加工食品组合物提供。本发明的加工食品组合物也可以称为抗氧化用加工食品组合物。作为加工食品组合物，不仅有包含糖果、口香糖、果冻、饼干、曲奇、煎饼、面包、面条、鱼肉畜肉酱制品、茶、清凉饮料、咖啡饮料、乳饮料、乳清饮料、乳酸菌饮料、酸奶、冰淇淋、布丁等嗜好食品或健康食品的一般加工食品，还包括日本厚生劳动省的保健功能食品制度所规定的特定保健用食品或营养功能食品等保健功能食品，还可进一步包含在营养辅助食品(补充剂)、饲料、食品添加物等加工食品组合物中。
此外，本发明的化合物也可以作为抗皮肤老化用组合物提供。作为抗皮肤老化用组合物，可以直接使用本发明化合物的至少一种，或者除了通常的有效成分之外还可以添加用于外用药物的成分。另外，不妨碍与上述的药物组合物的情况重复。
作为其他成分，作为可优选使用的其他成分，可例举高分子、蛋白质及其水解物、粘多糖类等。作为高分子，可例示羧乙烯基聚合物、黄原胶、海藻酸钠等，但并不限定于此。
作为蛋白质及其水解物，可例举胶原蛋白、弹性蛋白、角蛋白、酪蛋白、它们的水解物、水解物的盐、水解物的酯或酶处理物，特别优选胶原蛋白。这是因为胶原蛋白的生成受到紫外线的抑制。
作为粘多糖，可例举硫酸软骨素、透明质酸、硫酸皮肤素、硫酸乙酰肝素、硫酸粘蛋白、肝素及其衍生物、以及它们的盐等，并且特别优选硫酸软骨素、透明质酸和它们的钠盐。特别是透明质酸会抑制合成，因此希望与抗皮肤老化用组合物一起使用。
此外，在不损害作为抗皮肤老化用组合物的效果的范围内，可以添加保湿剂、水溶性高分子、油成分、着色剂、抗氧化剂、金属螯合剂、防腐剂、pH调节剂、清爽剂、香料、紫外线吸收和散射剂等。
另外，抗皮肤老化用组合物也可以作为抗皮肤老化用药物组合物、抗皮肤老化用加工食品组合物提供。
实施例
＜化合物的提取方法＞
将2kg(湿重)的西瓜CS种的幼果(结果后15天)粉碎，在该粉碎物中加入5L乙醇，一边搅拌一边在常温下制备乙醇洗脱液。
对于乙醇洗脱液，使用己烷、乙酸乙酯、丁醇依次通过溶剂分配法制备各洗脱液级分和蒸馏水溶解物。通过用色谱柱纯化乙酸乙酯层，得到多个级分。从其中的两个级分得到两种新化合物。
＜物质的鉴定＞
提取的两种新物质通过NMR来确定结构。
2-咖啡酰基-3-羟基-3-甲基丁酸4’-β-D-吡喃葡萄糖基氧基-3’-羟基苄基酯(2-Caffeoyl-3-hydroxy-3-methylbutyric 4’-β-D-glucopyranosyloxy-3’-hydroxybenzylester)：
1H NMR(400MHz,丙酮-d6):δ7.63(1H,d,J＝15.6Hz,H-γ”),7.16(1H,d,J＝1.8Hz,H-2”),7.12(1H,d,J＝8.2Hz,H-5’),7.03(1H,dd,J＝8.2和1.8Hz,H-6”),6.91(1H,d,J＝2.3Hz,H-2’),6.85(1H,d,J＝7.8Hz,H-5”),6.80(1H,d,J＝8.2和2.3Hz,H-6’),6.35(1H,d,J＝16.0Hz,H-β”),5.07(2H,s,H-α’),4.85(1H,s,H-2),4.74(1H,d,J＝7.3Hz,H-1”’),3.92-3.84(1H,m,H-6α”’),3.73-3.68(1H,m,H-6β”’),3.52-3.43(4H,m,H-2”’,H-3”’,H-4”’,和H-5”’),1.31(3H,s,H-4),1.30(3H,s,H-5)；13C NMR(100MHz,丙酮-d6):δ168.5,166.3,148.3,147.9,146.1,145.6,145.3,131.9,126.6,122.0,119.6,118.4,116.0,115.6,114.5,113.8,103.4,79.3,77.2,76.6,73.9,70.5,70.4,66.1,61.7,25.8(2C):HRESITOFMS:m/z603.1678[M+Na]+(对C27H32O14Na计算,603.1690)。
以上是式(1)的4G3HBE。
2-咖啡酰基-3-羟基-3-甲基丁酸4’-β-D-吡喃葡萄糖氧基苄基酯(2-Caffeoyl-3-hydroxy-3-methylbutyric 4’-β-D-glucopyranosyloxybenzyl ester)：
1H NMR(400MHz,丙酮-d6):δ7.63(1H,d,J＝16.0Hz,H-γ”),7.31(2H,d,J＝8.7Hz,H-2’和H-6’),7.16(1H,d,J＝1.8Hz,H-2”),7.05-7.00(3H,m,H-3’,H-5’,和H-6”),6.85(1H,d,J＝8.3Hz,H-5”),6.35(1H,d,J＝16.0Hz,H-β”),5.11(2H,s,H-α’),4.94(1H,d,J＝7.8Hz,H-1”’),4.84(1H,s,H-2),3.89-3.84(1H,m,H-6α”’),3.72-3.65(1H,m,H-6β”’),3.53-3.42(4H,m,H-2”’,H-3”’,H-4”’,和H-5”’),1.30(3H,s,H-4),1.28(3H,s,H-5)；13CNMR(100MHz,丙酮-d6):δ168.5,166.3,157.9,148.3,146.2,145.6,129.8(2C),129.6,126.6,122.0,116.4(2C),115.6,114.5,113.8,100.9,79.3,77.1,76.9,73.8,70.5,70.4,66.0,61.8,25.7(2C)；HRESITOFMS:m/z 587.1716[M+Na]+(对C27H32O13Na计算,587.1741)。
以上是式(2)的4GBE。
＜抗氧化作用＞
为了对分离的两种新化合物进行抗氧化能力的评价，作为试剂，制备了用50％乙醇溶解的200μM的DPPH(1,1-二苯基-2-三硝基苯肼)。试剂的制备步骤是，首先用乙醇溶解DPPH后，添加等量的MilliQ水。然后，通过用0.45μm的注射器过滤器进行过滤，除去未溶解物。
将150μL样品溶液和150μL的200μM的DPPH乙醇溶液在96孔板中充分混合，静置30分钟，然后用酶标仪(赛默飞世尔科技公司，Multiscan-LUX)测定520nm处的吸光度。通过式(F1)求出自由基清除率。
[数学式1]
这里，RD(％)表示自由基清除率(％)。此外，ODblank520nm是在试剂(DPPH)中不添加各样品溶液的状态下的520nm处的吸收，ODsample520nm是在试剂(DPPH)中添加混合各样品溶液、并静置30分钟后的520nm处的吸收。
结果示于图2。图2是显示结果的图表和对微孔板的状态进行拍照的照片。此外，图2的图表中，横轴是样品溶液种类及其浓度(μM)，纵轴表示自由基清除率(记作自由基清除活性(％))。
样品溶液种类中，4G3HBE是2-咖啡酰基-3-羟基-3-甲基丁酸4’-β-D-吡喃葡萄糖基氧基-3’-羟基苄基酯，4GBE是2-咖啡酰基-3-羟基-3-甲基丁酸4’-β-D-吡喃葡萄糖氧基苄基酯。
L-AsA是L-抗坏血酸。L-抗坏血酸(维生素C)被认为是具有抗氧化作用的物质。
4G3HBE和4GBE虽然抗氧化能力是抗氧化能力高的维生素C的一半左右，但是具有抗氧化活性。
＜抗皮肤老化作用＞
对于4G3HBE和4GBE的抗皮肤老化作用，通过以下5个项目进行验证。
(1)MMP-1的表达抑制
(2)对有助于产生MMPs的p38MAP和SAPK/JNK或NK-κB的信号分子的激活(磷酸化)
(3)位于其信号通路下游的AP-1转录活性
(4)对细胞内活性氧(ROS)量的影响
(5)对产生羰基化蛋白质的影响
[MMP-1的表达抑制]
由于对皮肤的UV照射使皮肤产生炎症反应，其结果是分解胶原蛋白的MMP-1(基质金属蛋白酶)的表达向上调节，出现皮肤老化的现象。因此，研究了本发明的4G3HBE和4GBE抑制MMP-1表达的能力。
将人新生儿正常皮肤成纤维细胞(NHDF：Normal Human Dermal Fibroblast-Neo，以下简称为“NHDF细胞”)调整至1×105个细胞/mL，在12孔多孔板中各接种1mL，培养直至汇合。然后，添加供试样品(终浓度为50和100μM(各溶剂级分)(各分离的物质))，并预培养24小时。然后，用PBS进行两次清洗，以25mJ/cm2的照度照射UV-B。
对紫外线照射后24小时后的细胞进行SDS-PAGE后，将细胞转移到聚偏二氟乙烯(PVDF)上，进行蛋白质印迹，检测MMP-1的蛋白表达。
此外，对与上述同样地培养NHDF细胞后的细胞以25mJ/cm2的照度照射UV-B后，从细胞提取总RNA(总RNA溶液)，使用高容量RNA-to-cDNA试剂盒(应用生物系统(AppliedBiosystems),赛默飞世尔科技)并用具有表1所示组成的逆转录酶溶液逆转录成cDNA。表1中，“total RNA solution”是总RNA溶液。
[表1]
| 试剂 | 量(μL) |
| 2×RT缓冲液混合物 | 10 |
| 20×酶混合物 | 1 |
| total RNA solution | 1 |
| 无核酸酶的水 | 8 |
| 计 | 20 |
然后，通过实时PCR考察了基因(MMP-1和MMP-3)的表达量。使用的引物如表2所示。此外，实时PCR反应液的组成如表3所示。对照使用管家基因(GAPDH)。
[表2]
[表3]
| 试剂 | 量(μL) |
| 主混合物 | 10 |
| 无核酸酶的水 | 6.4 |
| 引物(正向) | 0.8 |
| 引物(反向) | 0.8 |
| cDNA样品 | 2 |
| 计 | 20 |
结果示于图3。图3(a)是蛋白质印迹的照片，图3(b)表示基因表达率的图表。
参照图3(a)，照片上部的两栏中，上栏表示有无UV照射(有为“+”，无为“-”)，下栏表示样品(无为“-”，4G3HBE和4GBE)。此外，照片左方的纵向上表示检测目标(MMP-1和β-Actin)。β-Actin作为对照进行测定。
4G3HBE和4GBE对MMP-1的检测影浅，明显抑制了MMP-1的表达。
图3(b)中，横轴表示有无UV照射和样品，纵轴是算出的基因(MMP-1和MMP-3的总和)相对于管家基因(GAPDH)的表达率(Gene/GAPDH)。
通过UV照射，MMP-1相对于管家基因的表达为4.8倍左右，相对于此，4G3HBE和4GBE抑制到约1.8～2.2倍左右。由此也可以确认4G3HBE和4GBE抑制MMP-1的表达。
[信号分子的激活]
由于p38MAP激酶和SAPK/JNK及参与炎症反应的NF-κB激活与在UV-B照射后诱导产生的MMP密切相关，因此通过蛋白质印迹法对这些信号分子的激活(磷酸化)进行了研究。
更具体而言，与上述同样地预培养24小时，用PBS洗涤两次，并对用UV-B以25mJ/cm2的照度照射后的NHDF细胞进行蛋白质印迹，研究了p38MAP、SAPK/JNK和NF-κB的磷酸化。
结果示于图4。图4(a)为蛋白质印迹的印迹图像，图4(b)表示对磷酸化前后的变化进行光密度分析的结果。数据以平均值±标准误差(n＝3)示出。多组之间的比较通过Tukey-Kramer法进行检验(p＜0.05)。
参照图4(a)，照片上部的3栏自上而下表示有无UB的照射(有为“+”，无为“-”)、有无4G3HBE(有为“+”，无为“-”)、有无4GBE(有为“+”，无为“-”)。
此外，结果的照片中，“p38”表示p38MAP，“JNK:”表示SAPK/JNK，“NF-κB”表示NF-κB。此外，“p-p38”、“p-JNK”、“p-NF-κB”是各自的磷酸化物。同时测定β-Actin作为对照。
参照图4(b)。图表的横轴表示样品的状态，表示有无UB的照射(有为“+”、无为“-”)、有无4G3HBE(有为“+”、无为“-”)、有无4GBE(有为“+”、无为“-”)。此外，纵轴表示磷酸化的变化，表示磷酸化活性的相对比率。参照图4(b)时，通过UV-B的照射，p38MAP、SAPK/JNK、磷酸化NF-κB增高，但由于4G3HBE或4GBE的存在，信号分子的表达受到了抑制。
由上可知，在用4G3HBE和4GBE处理的细胞中，p38MAP激酶和SAPK/JNK、NF-κB的激活显著下调。
[AP-1转录活性]
由于表明照射UV-B后p38MAP激酶和SAPK/JNK及参与炎症反应的NF-κB激活因4G3HBE和4GBE处理而被减弱，所以以下通过荧光素酶报告基因检测对下游的激活蛋白-1(AP-1)的转录活性进行研究。
将pRL-SV40(海肾萤光素酶)和pGL4.44[Luc2P/AP-1-RE/Hygro]一起导入NHDF细胞后，加入4G3HBE和4GBE使各自终浓度为50μM，培养24小时。培养后，以25mJ/cm2的照度照射UV-B，然后培养12小时。
将该细胞溶解，用光度计测定掺入pRL-SV40的海肾萤光素酶的发光强度。结果示于图5。
参照图5，横轴是样品的状态，纵轴是相对于对照的AP-1转录比。样品的状态表示有无UB的照射(有为“+”、无为“-”)、有无4G3HBE(有为“+”、无为“-”)、有无4GBE(有为“+”、无为“-”)。对照是无UB的照射、无4G3HBE、无4GBE的情况，将该状态的AP-1转录比设为1。
由于UV-B的照射，AP-1的转录比率增高7倍左右，由于4G3HBE或4GBE的存在而被抑制为3～4倍左右。即、用4G3HBE和4GBE处理的细胞中，AP-1的转录活性显著降低。
[对细胞内活性氧(ROS)量的影响]
<抗氧化作用>的讨论中，4G3HBE和4GBE的能力是维生素C的能力的一半左右，但确认了抗氧化活性。另一方面，从[MMP-1的表达抑制]和[信号分子的激活]来看，认为由4G3HBE和4GBE本身的抗氧化能力消除UV-B照射产生的ROS可能是诱导了氧化应激信号的衰减。因此，使用作为ROS指示剂的CM-H2DCFDA测定了细胞内活性氧(ROS)的量。
将NHDF细胞(1.0×105细胞/mL)培养至汇合。然后，添加4G3HBE和4GBE至终浓度为50μM，进行24小时预培养。在照射紫外线前1小时，添加细胞透过性的活性氧指示剂CM-H2DCFDA，使其终浓度为10μM。然后，以25mJ/cm2的照度照射UV-B，在恒温箱内培养1小时。然后，使用多模式酶标仪Varioscan LUX、在495nm的激发波长和530nm的荧光波长下进行荧光测定。
结果示于图6。参照图6，横轴是样品的状态，表示有无UV-B的照射(有为“+”、无为“-”)、有无4G3HBE(有为“+”、无为“-”)、有无4GBE(有为“+”、无为“-”)。纵轴表示细胞内ROS水平(％)。
通过照射UV-B，细胞内的ROS量从1％增加至1.7％左右。但是，由于4G3HBE或4GBE的存在，被抑制在1.4％左右。
由上可知，4G3HBE或4GBE可以显著降低UV-B照射后的细胞内的ROS水平。
[对产生羰基化蛋白质的影响]
细胞或组织中产生的活性氧(ROS)将附近存在的蛋白质非特异地氧化。作为蛋白质的氧化修饰剂，众所周知的是羰基化蛋白质。更具体而言，羰基化蛋白质是蛋白质中的脯氨酸、精氨酸、赖氨酸、苏氨酸等氨基酸被ROS氧化修饰而成为羰基衍生物的蛋白质的总称。羰基衍生物是化学稳定的。
皮肤的变黄，尤其是年龄增大引起的变黄(黄色暗沉)是皮肤问题之一，最近的研究表明，过氧化物等引起的真皮蛋白质羰基化是导致变黄的主要因素。因此，研究了现在从西瓜幼果中分离出的4G3HBE和4GBE表现的抗氧化能力是否对这种“黄色暗沉”也有效。这种变黄也是皮肤老化的现象之一。
更具体而言，将NHDF细胞(1.0×105个细胞/mL)培养至汇合，加入4G3HBE和4GBE至终浓度为50μM和100μM，并预培养24小时。然后以25mJ/cm2的照度照射UV-B，根据MilliporeOxyBlotTM蛋白质氧化检测试剂盒进行评估。
结果示于图7。图7(a)是样品状态下的蛋白质印迹的印迹图像。纵轴表示kDa。此外，图7(b)是光密度分析的结果。参照图7(b)，横轴表示样品的状态，纵轴表示羰基化蛋白质相对于对照的比率。
将对照设为无UV-B照射、无4G3HBE、无4GBE时，对照的羰基化蛋白质的生成比为1％，相对于此，通过照射UV-B，羰基化蛋白质上升至约1.5％。另一方面，由于4G3HBE或4GBE的存在，羰基化蛋白质被抑制到约1.1％～1.2％左右。结果，用4G3HBE和4GBE处理的细胞中羰基化蛋白质的量显著减少。
如上所述，含有新物质4G3HBE和4GBE中的至少一种的药物组合物可以称为抗氧化用药物组合物，含有新物质4G3HBE和4GBE中的至少一种的加工食品组合物可以称为抗氧化用加工食品组合物。此外，如果包含新物质4G3HBE和4GBE中的至少一种，则可以构成抗皮肤老化用组合物。
产业上利用的可能性
本发明的源自西瓜的新化合物4G3HBE和4GBE是具有抗氧化作用的化合物，通过去除活性氧，可以期待在各方面有效地维持生物体。
序列表
<110> 株式会社萩原农场生产研究所(Hagihara Farm Production Institute Co.,Ltd.)
国立大学法人三重大学(MIE UNIVERSITY)
国立大学法人东海国立大学机构（NATIONAL UNIVERSITY CORPORATION TOKAINATIONAL HIGHER EDUCATION AND RESEARCH SYSTEM）
<120> 源自西瓜的新化合物和使用该新化合物的组合物
<130> HNMIGF22003
<150> JP/2019-111654
<151> 2019-06-17
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> MMP-1正向引物
<400> 1
ccaaatgggc ttgaagctg 19
<210> 2
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> MMP-1反向引物
<400> 2
ggtatccgtg tagcacattc tgtc 24
<210> 3
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> MMP-3正向引物
<400> 3
tttccaggga ttgactcaaa ga 22
<210> 4
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> MMP-3反向引物
<400> 4
aagtgcccat attgtgcctt c 21
<210> 5
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> GAPDH正向引物
<400> 5
gcaccgtcaa ggctgagaac 20
<210> 6
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> GAPDH反向引物
<400> 6
tggtgaagac gccagtgga 19
Claims (4)
1.由式(1)或式(2)表示的化合物，
[化学式101]
[化学式102]
2.包含由式(1)或式(2)表示的化合物的至少任一种的抗皮肤老化用组合物，
[化学式103]
[化学式104]
3.包含由式(1)或式(2)表示的化合物的至少任一种的药物组合物，
[化学式105]
[化学式106]
4.包含由式(1)或式(2)表示的化合物的至少任一种的加工食品组合物，
[化学式107]
[化学式108]
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2019-111654 | 2019-06-17 | ||
| JP2019111654 | 2019-06-17 | ||
| PCT/JP2020/023685 WO2020255989A1 (ja) | 2019-06-17 | 2020-06-17 | スイカ由来の新規化合物とそれを用いた組成物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114008062A true CN114008062A (zh) | 2022-02-01 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080043738.XA Pending CN114008062A (zh) | 2019-06-17 | 2020-06-17 | 源自西瓜的新化合物和使用该新化合物的组合物 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20220298196A1 (zh) |
| JP (1) | JP2020203885A (zh) |
| CN (1) | CN114008062A (zh) |
| WO (1) | WO2020255989A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024062966A1 (ja) * | 2022-09-21 | 2024-03-28 | 株式会社萩原農場生産研究所 | スイカ由来の化合物を有効成分とする抗炎症剤 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004051492A (ja) * | 2002-07-16 | 2004-02-19 | Kose Corp | 老化防止剤又は細胞賦活剤及びこれを含有する皮膚外用剤 |
| US20070218150A1 (en) * | 2004-04-30 | 2007-09-20 | Kinya Akashi | Active Oxygen Scavenging Agent and Moisturizing Agent Containing Wild Watermelon Extract |
| JP2012106955A (ja) * | 2010-11-18 | 2012-06-07 | Akita Univ | 生理活性組成物、高血圧予防食品及び薬剤、並びにそれらの製造方法 |
| JP2016175861A (ja) * | 2015-03-19 | 2016-10-06 | 株式会社ユーグレナ | 表皮ターンオーバー促進剤、皮膚コラーゲン産生促進剤及び皮膚化粧料 |
| KR20180010743A (ko) * | 2016-07-22 | 2018-01-31 | 경남대학교 산학협력단 | 수박 과피 착즙액을 유효성분으로 함유하는 피부의 노화 방지용 화장료 조성물 |
-
2020
- 2020-06-17 US US17/619,081 patent/US20220298196A1/en active Pending
- 2020-06-17 JP JP2020104153A patent/JP2020203885A/ja active Pending
- 2020-06-17 WO PCT/JP2020/023685 patent/WO2020255989A1/ja active Application Filing
- 2020-06-17 CN CN202080043738.XA patent/CN114008062A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004051492A (ja) * | 2002-07-16 | 2004-02-19 | Kose Corp | 老化防止剤又は細胞賦活剤及びこれを含有する皮膚外用剤 |
| US20070218150A1 (en) * | 2004-04-30 | 2007-09-20 | Kinya Akashi | Active Oxygen Scavenging Agent and Moisturizing Agent Containing Wild Watermelon Extract |
| JP2012106955A (ja) * | 2010-11-18 | 2012-06-07 | Akita Univ | 生理活性組成物、高血圧予防食品及び薬剤、並びにそれらの製造方法 |
| JP2016175861A (ja) * | 2015-03-19 | 2016-10-06 | 株式会社ユーグレナ | 表皮ターンオーバー促進剤、皮膚コラーゲン産生促進剤及び皮膚化粧料 |
| KR20180010743A (ko) * | 2016-07-22 | 2018-01-31 | 경남대학교 산학협력단 | 수박 과피 착즙액을 유효성분으로 함유하는 피부의 노화 방지용 화장료 조성물 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2020255989A1 (ja) | 2020-12-24 |
| JP2020203885A (ja) | 2020-12-24 |
| US20220298196A1 (en) | 2022-09-22 |
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