CN113491718B - 一种海葡萄萃取物用于制备缓解糖尿病及预防或治疗生殖障碍医药组合物或保健食品的用途 - Google Patents
一种海葡萄萃取物用于制备缓解糖尿病及预防或治疗生殖障碍医药组合物或保健食品的用途 Download PDFInfo
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Abstract
本发明提供一种海葡萄萃取物用于制备医药组合物或保健食品的用途,该海葡萄萃取物是以热水萃取而得,可以改善空腹血糖、血中胰岛素浓度、口服葡萄糖耐量以缓解糖尿病,可以改善***活动力、***变异、生精小管萎缩以预防或治疗生殖障碍,其中该医药组合物的施予方式包含口服、浸泡、喷洒或注射,该海葡萄萃取物的人体有效剂量为每日40~100mg/kg。
Description
技术领域
本发明系关于一种海葡萄萃取物,特别系关于一种可以缓解糖尿病及预防或治疗生殖障碍的应用。
背景技术
糖尿病,古称"消渴症",是一种由遗传和环境因素相互作用而引起的内分泌疾病,患者胰岛素分泌不足或身体未能有效地运用胰岛素,影响血糖的调节,令血糖过高。
高血糖是糖尿病临床的主要标志。糖尿病因其发病率高、并发症严重,已成为继肿瘤、心脑血管疾病之后,危害人类健康的严重疾病。糖尿病导致的胰岛素绝对或相对分泌不足以及靶组织细胞对胰岛素敏感性降低,可引起蛋白质、脂肪、水和电解质等一系列代谢紊乱综合征,若得不到有效的治疗,最终会引起糖尿病并发症,包括性功能障碍。
根据医学统计,男性糖尿病患者百分之三十到百分之七十以上都有轻重不一的性功能障碍,这是糖尿病重要的并发症之一,医学上认为糖尿病所造成的性功能障碍常是不可逆性,和糖尿病的轻重及病期的长短没有直接的关系,即使血糖一直控制在理想的范围,性功能也不可能完全恢复。
因此如何开发出一种可以同时预防、缓解、或治疗糖尿病及糖尿病引起生殖障碍的新成分是本发明在此欲解决的重要课题。
海葡萄的学名为长茎葡萄蕨藻(Caulerpa lentillifera),是一种可食用的绿藻,命名来自绿色浑圆小巧、有如葡萄串的外观。目前尚没有关于海葡萄可以降血糖方面的研究,更没有其可以治疗糖尿病引起的生殖障碍。
发明内容
有鉴于现有技术的缺失,本发明的目的即在于提供一种海葡萄萃取物用于制备缓解糖尿病医药组合物的用途,其中该海葡萄萃取物是以热水萃取而得,该缓解糖尿病是指治疗或改善糖尿病。
本发明的另一目的在于提供一种包含海葡萄萃取物之保健食品用于减缓糖尿病的用途,其中该海葡萄萃取物是以热水萃取而得,该缓解糖尿病是指治疗或改善糖尿病。
为达前述发明目的,其中该缓解糖尿病是指空腹血糖降低。
为达前述发明目的,其中该缓解糖尿病是指血中胰岛素浓度降低。
为达前述发明目的,其中该缓解糖尿病是指口服葡萄糖耐量改善。
本发明的又一目的在于提供一种海葡萄萃取物用于制备预防或治疗生殖障碍医药组合物的用途,其中该海葡萄萃取物是以热水萃取而得。
本发明的再一目的在于提供一种包含海葡萄萃取物之保健食品用于预防或改善生殖障碍的用途,其中该海葡萄萃取物是以热水萃取而得。
为达前述发明目的,其中该生殖障碍是指糖尿病引起的生殖障碍。
为达前述发明目的,其中该生殖障碍是指***活动力降低或***变异。
为达前述发明目的,其中该生殖障碍是指生精小管萎缩。
为达前述发明目的,其中该医药组合物的施予方式包含口服、浸泡、喷洒或注射。
为达前述发明目的,其中该海葡萄萃取物的人体有效剂量为每日40~100mg/kg。
本发明为其所属技术领域长期存在之糖尿病及生殖障碍问题提供了一个解决方法。本发明所提供的海葡萄萃取物可缓解糖尿病及其生殖障碍并发症,更具体地说,可改善葡萄糖耐量试验中的血糖浓度、空腹血糖、胰岛素、稳态模型评估(HOMA-IR)、炎症因子(IL-1β、TNF-α)以缓解糖尿病,并改善生殖***的睪丸组织萎缩、***型态变异、氧化反应以预防/治疗生殖障碍。本发明所提供的海葡萄萃取物系萃取自天然绿藻,具有天然、不会产生食安问题及对环境伤害疑虑较低的优势。
附图说明
图1A-图1C系海葡萄萃取物对细胞安全性试验结果图;其中图1A系MTT分析,图1B是一氧化碳浓度,图1C是硝基蓝四唑浓度;
图2系海葡萄萃取物对糖尿病小鼠口服葡萄糖耐性试验的影响结果图;
图3A-图3C系海葡萄萃取物对糖尿病小鼠空腹血糖(图3A)、胰岛素(图3B)、稳态模型评估(图3C)的影响结果图;
图4A-图4B系海葡萄萃取物对糖尿病小鼠糖尿病炎性反应的影响结果图,图4A系IL-1β,图4B系TNF-α;
图5系海葡萄萃取物对糖尿病小鼠睪丸型态及生精小管的影响结果图,图5中A系对照组小鼠,图5中B系糖尿病小鼠(DM组),图5中C系摄取二甲双胍的糖尿病小鼠(阳性对照组),图5中D系摄取600mg/kg海葡萄萃取物的糖尿病小鼠(CL1组)、图5中E系摄取1000mg/kg海葡萄萃取物的糖尿病小鼠(CL2组);
图6A-图6D系海葡萄萃取物对糖尿病小鼠***活动的影响结果图,图6A系放大倍数为20的显微镜下***型态,图6B系***总数,图6C系***异常率,图6D系***活动力;
图7A-图7E系海葡萄萃取物对糖尿病小鼠睪丸、***氧化程度的影响结果图,图7A系***的一氧化碳含量,图7B系睪丸的一氧化碳含量,图7C系***的硝基蓝四唑浓度,图7D系***的脂质过氧化值,图7E系睪丸的图7D系***的脂质过氧化值。
具体实施方式
本发明之新颖技术特征,包含特定特征,系揭示于申请专利范围,针对本发明之技术特征,较佳之理解兹配合说明书、依据本发明原理之实施例、和图式将本发明较佳之实施例详细说明。
本发明所述组合物适合之施予途径系包含但不限于浸泡、喷洒、药浴、口服或注射。
本发明实施例所使用之海葡萄或蕨藻系指但不限于长茎葡萄蕨藻(Caulerpalentillifera),可从市面上购得,本发明所属技术领域中具有通常知识者亦可从天然海域取得本发明所指之海葡萄。本发明实施例中用于验证功效之细胞皆可于市面上购得或依据本发明所属技术领域的通常知识从相对应的组织中分离而得。另外,除非另有说明,本发明所用之材料皆市售易于取得。
本发明系以下面的实施例予以示范阐明,但本发明不受下述实施例所限制。
实施例一、海葡萄萃取物制备
将新鲜的海葡萄(Caulerpa lentillifera)清洗干净后,把藻体研磨打碎利用热水萃取法进行萃取,离心取上清液进行冷冻干燥及可得到海葡萄萃取物(简称CL);于高压灭菌釜内进行热水萃取,其中热水萃取的温度为100~130℃,较佳的热水萃取的温度为118~124℃;热水萃取的萃取时间为45~80分钟,较佳的萃取时间为55~65分钟,其中热水萃取的萃取压力为1~1.25kg/cm2,较佳的萃取压力为1.20~1.22kg/cm 2。
实施例二、细胞安全性试验
选用的细胞为莱氏细胞(Leydig cell-540),莱氏细胞为睪丸间质内细胞,会分泌睪固酮,影响生殖细胞的分化与成熟。
二-(1)、细胞存活率试验
使用MTT比色法细胞存活率试验测定萃取物对细胞是否有毒性,将细胞培养在96孔盘内并加入不同浓度的海葡萄萃取物(简称CL,1500、1000、500、250和125μg/mL),培养24小时,之后每孔加入100μL的MTT(1mg/mL),反应4小时,加入100μL的DMSO,震荡10分钟,测量540nm的吸光值;由图1A结果可看出通过MTT比色法,不同浓度的萃取物没有任何显著差异,表示海葡萄萃取物对莱氏细胞不具细胞毒性。
二-(2)、硝基蓝四唑(Nitro Blue Tetrazolium,NBT)测定
将细胞培养在96孔盘内并加入不同浓度的海葡萄萃取物(简称CL,1500、1000、500、250和125μg/mL),培养24小时后,移除培养液,再加入250μL胰蛋白酶作用3分钟再加250μL终止溶液,液体移至Eppendorf,以800xg离心15分钟,然后移除上清液,再添加0.3mL硝基蓝四唑溶液(13.8mL细胞培养基、450μL DMSO、750μL FBS及1.5mg NBT)培养1小时,以1500xg离心15分钟,移除上清液,然后添加0.2mL DMSO,放入超音波振荡器5分钟后测量570nm的吸光值(Absorbance,简称A),以下列公式计算抑制百分比:
「(Acontrol–Asample)/Acontrol×100」。
由图1B可看出通过硝基蓝四唑检测超氧化物(O2-)的含量来测定的潜在的超氧化物,不同浓度的萃取物没有任何显著差异,表示海葡萄萃取物不刺激氧化反应。
二-(3)、一氧化氮(Nitric Oxide,NO)测定
将细胞(1*104cells/mL)培养在96孔盘内并加入不同浓度的海葡萄萃取物(简称CL,1500、1000、500、250和125μg/mL)共培养24小时,取50μL上清液,移至平板中的另一个孔中。然后,各加入50μL 100pM亚硝酸盐标准液、5.80mM磺胺试剂及3.85mM NED试剂,混合均匀,避光保持10分钟,并用测定540nm的吸光值;由图1C可看出通过Griess试剂检测一氧化氮(NO)的含量来测定潜在的自由基,结果表明,不同浓度的萃取物没有任何显著差异。表示海葡萄萃取物不刺激氧化反应。
实施例三、糖尿病模式小鼠分析
将六周大的雄性BALB/c小鼠作为模式动物,将小鼠分为5组(每组5只小鼠):对照组小鼠喂食商业饲料;高脂饮食(High Fat Diet,HFD)组(20只小鼠)喂食含有猪油的高脂饲料,会注射链脲佐菌素(streptozotocin,STZ,30mg/kg)诱导糖尿病发生,共分为4个处理组:糖尿病组(Diabetes Mellitus,DM)、阳性对照组(二甲双胍(Metformin),200mg/kg)、CL1组(海葡萄萃取物,600mg/kg)及CL2组(海葡萄萃取物,1000mg/kg),投喂6周处死后,将组织样品保存在-80℃进行后续生化分析。
三-(1)、口服葡萄糖耐量试验(Oral Glucose Tolerance Test,OGTT)
进行口服葡萄糖耐量试验(OGTT)以了解葡萄糖摄取变化。小鼠在试验前一天禁食10-12小时,通过口服管饲法给予葡萄糖(2g/kg BW)。在0、30、60和120分钟内从小鼠的眼睛中抽血,并放入Eppendorf(含抗凝剂),取血后15分钟内以3000rpm、4℃的条件离心,使用Randox Laboratory的血糖试剂盒进行检测。由图2结果表明,DM组(糖尿病组)在0、30、60和120分钟时的血糖水平显著高于对照组。在海葡萄萃取物CL1(600mg/kg)、CL2(1000mg/kg)或二甲双胍(metformin)治疗6周后,血糖水平显著改善。
三-(2)、血浆生化分析
三-(2)-A、葡萄糖浓度
使用RandoxLaboratory的GLUC试剂盒测定血糖,取2μL标准液或样品,然后将200μL检测试剂加入96孔板中,在15-25℃下培养25分钟或在37℃下孵育10分钟后,测量500nm的吸亮度并以下列公式进行计算:
葡萄糖浓度(mg/dl)=Asample/Astandard×102
由图3A结果可看出用海葡萄萃取物处理6周后空腹血糖(fasting bloodglucose,简称FBG)在糖尿病小鼠中的数值。DM组(糖尿病组)由于胰岛素水平的不平衡而观察到葡萄糖升高,与DM组(糖尿病组)相比,摄取海葡萄萃取物的糖尿病小鼠(DM+CL组)的空腹血糖水平降低,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2组)的空腹血糖数值都较DM组(糖尿病组)显著降低,空腹血糖数值几乎和对照组小鼠相同。
三-(2)-B、胰岛素测定
使用Taiclone Biotechnology Corporation的ELISA试剂盒检测胰岛素的含量,取100μL样品或标准品至涂有抗体的孔板中,并于37℃培养1.5小时,然后,加入100μL生物素化检测抗体,在37℃下培养1小时后,清洗并添加100μL与辣根过氧化物酶(HRP)偶联的抗生蛋白链菌素,并在37℃下培养30分钟,清洗后添加100μL四甲基联苯胺溶液(TMB),并在37℃下培养15分钟,最后加入100μL终止液,检测450nm的吸光值;由图3B结果可看出用海葡萄萃取物处理6周后胰岛素在糖尿病小鼠中的数值,DM组(糖尿病组)的胰岛素浓度显著升高,与DM(糖尿病组)组相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)的糖尿病小鼠胰岛素浓度显著降低。
三-(2)-C、稳态模型评估(HOMA)测试
稳态模型评估(Homeostatic model assessment-Insulin resistance,简称HOMA-IR)测试可根据空腹血糖和胰岛素浓度评估胰岛素敏感性;由图3C结果可看出用海葡萄萃取物处理6周后糖尿病小鼠的HOMA-IR数值,DM组(糖尿病组)的HOMA-IR数值显著增加,与DM(糖尿病组)组相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)的糖尿病小鼠HOMA-IR数值降低,DM组(糖尿病组)的数值明显高于对照组及摄取海葡萄萃取物的CL处理组,表明摄取海葡萄萃取物可以使糖尿病患者从糖尿病状态恢复。
三-(3)、细胞因子分析
使用Arigo Biolaboratories所的ELISA试剂盒检测肿瘤坏死因子α(tumornecrosis factor-alpha,简称TNFα)和白介素(interleukin-1β,简称IL-1β),取100μL样品或标准品到涂有抗体的孔板中,并于37℃培养1.5小时后,清洗并添加100μL偶联的抗体,在37℃下培养1小时后,清洗并添加100μL与辣根过氧化物酶(HRP)偶联的链霉亲和素,在37℃培养30分钟后,清洗并添加100μL四甲基联苯胺溶液(TMB),并在37℃下培养15分钟后,最后添加100μL终止液并检测450nm的吸光值;由图4A和图4B结果可看出,DM组(糖尿病组)的IL-1β的表达较对照组显著升高,与DM(糖尿病组)组相比,摄取海葡萄萃取物1000mg/kg(CL2)的IL-1β的表达有明显降低;DM组(糖尿病组)的TNF-α表达较对照组显著升高,与DM组(糖尿病组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)糖尿病小鼠的IL-1β的TNF-α表达明显降低。
三-(4)、睪丸及***分析
三-(4)-A、睪丸组织学分析
睾丸用10%***固定,包埋在石蜡中,用苏木精和曙红(H&E)染色,使用光学显微镜观察测量生精小管(ST);睪丸来自对照组小鼠(图5中A图)、糖尿病小鼠(DM组,图5中B图)、摄取二甲双胍的糖尿病小鼠(阳性对照组,图5中C图)、摄取600mg/kg海葡萄萃取物的糖尿病小鼠(CL1组,图5中D图)、摄取1000mg/kg海葡萄萃取物的糖尿病小鼠(CL2组,图5中E图),实验小鼠的睾丸切片均用苏木精和曙红(H&E)染色(放大倍数20x)用来评估睾丸结构和生精小管的形态;由图5结果可看出DM组生精小管结构较其他组分离,糖尿病组有萎缩的生精小管,生殖细胞很少,反应糖尿病引起的微循环损伤,睾丸结构崩溃和凋亡细胞数量增加,与DM组(糖尿病组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)糖尿病小鼠的生精小管形态较紧密,推测海葡萄萃取物可以回复糖尿病引起的微循环损伤。
三-(4)-B、***活动分析
利用上泳法收集***,将附睾放入RPMI培养基中,保存在37℃,然后在shaker上以120rpm的转速在10分钟内切开附睾,再以190xg离心5分钟,然后在37℃下培养30分钟。取在中间的液体(透明)并放入Eppendorf,取10μL在显微镜下分析,并用以下公式计算:
***总数(***/mL)=细胞数×104×稀释度
运动力(%)=(运动***数量/总***数量)×100
异常率(%)=(***异常数/***总数)×100。
通过***的形态分析了海葡萄萃取物对生殖的影响。在放大倍数为20的显微镜下观察***分析,以评估***衰竭与糖尿病之间的相关性;图6A是放大倍数为20的显微镜下***型态;图6B结果显示,与对照组相比,糖尿病组(DM组)小鼠的***总数(total sperm)较少;图6C结果显示,糖尿病组(DM组)小鼠***异常率(Abnormality)较高,与糖尿病组(DM组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)使***异常率明显降低,推测海葡萄萃取物可以回复糖尿病引起的***异常;图6D结果显示,糖尿病组(DM组)小鼠***运动力(Motility)较差,与糖尿病组(DM组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)使***运动力明显提高,且有浓度相关性,推测海葡萄萃取物可以回复糖尿病引起的***运动力降低。
结果证明,糖尿病组(DM组)中***变异最多且***数少,异常形态高,摄取海葡萄萃取物(CL组)改善了糖尿病对***的影响。
三-(4)-C、睪丸及***氧化分析
用海葡萄萃取物处理6周后,对小鼠***和睾丸的氧化反应(NBT、一氧化氮、脂质过氧化)进行研究,因氧化反应会影响***生成、睾丸DNA损伤和生殖细胞受损;将睪丸或***样本秤重,以组织重量(g):PBS(mL)=1:9的比例下,透过冻融循环(在-20℃下储存24小时,然后在-4℃下反复冻溶),以均质机均质,再以5000xg离心5分钟以得到上清液。
三-(4)-C-1、一氧化氮(Nitric Oxide,NO)测定
取50μL样本上清液至孔盘中,各加入50μL 100pM亚硝酸盐标准液、5.80mM磺胺试剂及3.85mM NED试剂,混合均匀,避光保持10分钟,并用测定540nm的吸光值;图7A(***)、图7B(睪丸)结果显示糖尿病组(DM组)小鼠***、睪丸样本的一氧化氮含量较高,与糖尿病组(DM组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)使***和睾丸中一氧化氮含量显著下降。
三-(4)-C-2、Nitro Blue Tetrazolium(NBT)测定
取***细胞添加0.2mL NBT溶液(0.1mg/mL NBT,以5%FBS及3%DMSO溶解),在37℃下以10mL RPMI培养基内培养1小时,以500xg离心10分钟,移除上清液并用PBS清洗,然后添加0.2mL DMSO,放入超音波振荡器5分钟后测量570nm的吸光值,在以下列公式计算抑制百分比:
(Acontrol–Asample)/Acontrol×100
图7C结果显示糖尿病组(DM组)小鼠***样本的NBT含量较高,与糖尿病组(DM组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)使一氧化氮含量降低,但无明显变化。
三-(4)-C-3、脂质过氧化测定
脂质过氧化的值与生殖功能障碍有关,取50μL的样本、H2O(空白组)及丙二醛溶液(MDA,0.2mL HCl、1.44g TCA、0.036g TBA及9.4mL H2O,用做标准品)至Eppendorf,再添加100μL MDA溶液,在100℃下水浴15分钟后,在室温冷却。再添加150μL丁醇,以3000rpm的转速离心10分钟,取上清液检测532nm的吸光值,并代入以下公式:
MDA浓度(mmol/mL)=(Asample–Ablank)/(Astandard–Ablank)×5
图7D结果显示,***中的脂质过氧化作用不明显;图7E结果显示,糖尿病组(DM组)小鼠睾丸中的脂质过氧化作用较高,与糖尿病组(DM组)相比,摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)使摄取海葡萄萃取物600mg/kg(CL1)或1000mg/kg(CL2)使脂质过氧化作用明显降低。
结果显示,摄取海葡萄萃取物可以回复糖尿病引起的氧化反应,避免因氧化反应会影响***生成、睾丸DNA损伤和生殖细胞受损。
综上所述,本发明提供了一种海葡萄萃取物用于缓解糖尿病及预防或治疗生殖障碍的用途。由本发明之实施例可看出,本发明所提供的海葡萄萃取物不具有细胞毒性,海葡萄萃取物透过改善糖尿病小鼠在葡萄糖耐量试验中的血糖浓度、空腹血糖、胰岛素、稳态模型评估(HOMA-IR)、炎症因子(IL-1β、TNF-α)以缓解糖尿病,对由糖尿病引起睪丸组织萎缩、***型态变异、氧化反应也有改善的效果,以预防或治疗生殖障碍。
海葡萄萃取物投予剂量之计算方式:由于人体与实验动物的代谢速率不一,因此须将试验动物的投予剂量换算为人体剂量。依据美国食品药物管理局在2005年提出的「Guidance for Industry Estimating the Maximum Safe Starting Dose in InitialClinical Trials for Therapeutics in Adult Healthy Volunteers」规范,人体与小鼠之换算系数为12.3倍,故本发明实验例中小鼠一天给予600mg/kg之海葡萄萃取物,经系数换算后人体的剂量为48.8mg/kg,发明实验例中小鼠一天给予1000mg/kg之海葡萄萃取物,经系数换算后人体的剂量为81.3mg/kg,因此推测人体的安全有效剂量为40~100mg/kg。
于本说明书较佳实施例揭示之内容,本发明所属领域具有通常知识者可明显得知前述实施例仅为例示;具本发明所属技术领域通常知识者可藉由诸多变换、替换而实施,而不与本发明之技术特征有所差异。依据说明书实施例,本发明可有多种变换仍无碍于实施。本说明书提供之请求项界定本发明之范围,该范围涵盖前述方法与结构及与其相等之发明。
Claims (5)
1.一种海葡萄萃取物用于制备预防或治疗生殖障碍医药组合物的用途,其特征在于,该海葡萄萃取物是于高压下以热水萃取而得,其中,该生殖障碍是指睾丸组织萎缩、***活动力降低或***变异,其中,该热水萃取的温度为100~130℃,热水萃取的萃取时间为45~80分钟。
2.根据权利要求1所述的用途,其特征在于,该生殖障碍是指糖尿病引起的生殖障碍。
3.根据权利要求1所述的用途,其特征在于,该生殖障碍是指生精小管萎缩。
4.根据权利要求1所述的用途,其特征在于,该医药组合物的施予方式包含口服、浸泡、喷洒或注射。
5.根据权利要求1-4任一项所述的用途,其特征在于,该海葡萄萃取物的人体有效剂量为每日40~100mg/kg。
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