CN110664850A - 柴达木大肥菇酚酸保护急、慢性缺氧损伤的用途 - Google Patents
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Abstract
本发明公开了柴达木大肥菇酚酸在制备保护急、慢性缺氧损伤的药物、保健品或食品中的用途，经本发明研究表明，柴达木大肥菇酚酸具有延长常压耐缺氧试验缺氧小鼠的死亡时间；在亚硝酸钠中毒试验延长中毒小鼠的存活时间；在急性脑缺血性缺氧试验中延长急性缺氧小鼠喘息时间的作用；可降低缺氧条件下LDH(乳酸脱氢酶)含量、NO(一氧化碳)含量水平，升高ATP(三磷酸腺苷)含量水平，增强机体低氧损伤的耐受能力，提高组织的急性缺氧损伤的代偿能力，保护组织免受缺氧危害，可以将其作为安全可靠的抗缺氧药物、保健品或食品。
Description
技术领域
本发明涉及药用保健品技术领域，具体涉及一种柴达木大肥菇酚酸的抗缺氧用途。
技术背景
高原病(High altitude disease，HAD)是发生于高原低氧环境(一般指海拔3000m以上)的一种特发性疾病，高原低压性缺氧是主要的致病因素。高原病根据发病的急缓可分为急性高原病(acute mountain sickness，AMS)和慢性高原病(Chronic mountainsickness，CMS)二大类：AMS是指由平原进入高原或由高原进入更高海拔地区时，在数小时至数天内发生的各种临床综合征，包括急性轻型高原病、高原肺水肿和高原脑水肿；CMS是指长期生活在高原地区的世居者或移居者，对高原低氧环境逐渐失去习服而导致的临床综合征，包括高原红细胞增多症、高原心脏病、混合型慢性高原病和高原衰退等4个亚型。在急性缺氧情况下，由于缺氧信号的刺激，机体为适应低氧环境会发生呼吸加快、血管收缩、心率增加等一系列的代偿性反应，以保证脑和心脏等重要器官的氧气供应。在缺氧情况下，可促进机体红细胞及血管的生成、增强糖酵解及葡萄糖转运，使机体产生低氧耐受。促进机体在缺氧条件下的调适能力是提高人体低氧耐受性的重要措施。其中，比较有效的手段是进行低氧预适应和摄食耐缺氧的药物或功能食品，低氧预适应需要特定的设备支持、且耗时较长，抗缺氧药物或食品则具有携带方便和作用迅速等特点。LDH是无氧代谢过程关键酶之一，对机体、组织及细胞在缺氧条件下的能量代谢有重要的影响，其活力大小与机体无氧代谢能量的产生及对氧气缺乏的耐受能力有关；在持续缺氧条件下，ATP水平因线粒体氧化磷酸化过程底物NO供给不足而下降，脑组织以提高无氧代谢水平而补充能量。
柴达木大肥菇也称为柴达木双层环伞菌(Agaricus bitorquis(Quél.)SaccChaidamu.)，主要生长于青海柴达木盆地海拔2600～3300m戈壁土层20～70cm之下，富含酚酸等多种抗缺氧活性成分，被当地农牧民作为天然抗缺氧食物广泛采食。目前还未见对柴达木大肥菇酚酸抗缺氧的报道。
发明内容
本发明的目的在于提供一种柴达木大肥菇酚酸的新用途。
具体的，本发明提供了柴达木大肥菇酚酸在制备保护急、慢性缺氧损伤的药物、保健品或食品中的用途。
进一步地，所述保护急、慢性缺氧损伤的药物、保健品或食品是改善高原病患者的低氧耐受能力及急性缺氧人群机体急性缺氧损伤代偿能力的药物、保健品或食品。
其中，所述改善高原病患者的低氧耐受能力及急性缺氧人群机体急性缺氧损伤代偿能力是指降低缺氧人群LDH、NO水平，升高ATP水平。
其中，所述高原病包括慢性高原病和急性高原病。
进一步地，所述高原病患者为急性缺氧、低氧耐受时机体功能受损的患者。
其中，所述保护急、慢性缺氧损伤的药物、保健品或食品为口服剂型；进一步地，所述口服剂型选自片剂、粉剂、胶囊剂、丸剂、颗粒剂、散剂、浸膏剂或口服。
酚酸纯度为60-95％w/w，进一步为80～95％w/w，更进一步为90～93％w/w。
柴达木大肥菇酚酸采用超声波辅助乙醇提取法制备得到；进一步地，所述超声波辅助乙醇提取法具体操作如下：将柴达木大肥菇粉碎、过筛、去糖后，以超声波辅助加乙醇提取，得酚酸粗提液，以大孔树脂纯化，收集洗脱液，浓缩，干燥，即得到柴达木大肥菇酚酸纯品；更进一步地，提取溶剂乙醇的浓度为85～95％v/v，超声波辅助提取的功率为160～200W，提取温度为56～66℃；更进一步地，提取溶剂乙醇的浓度优选为90±2％v/v，超声波辅助提取的功率优选为180±5W，提取温度优选为61±2℃。
去糖具体操作如下：将柴达木大肥菇粉碎后，过筛，脱脂，采用水提醇沉法，提取后的残渣过滤，挥干溶剂，得去糖的柴达木大肥菇残渣；水提醇沉法去糖的具体操作如下：所得已过筛的柴达木大肥菇粉末，加水溶解，过滤，得滤渣，即为柴达木大肥菇去糖残渣，过滤时滤液加入乙醇至含醇量达到70～90％v/v，静置，待沉淀完全过滤；进一步地，除糖加入乙醇至含醇量至75～85％v/v，优选为80±2％v/v。
通过大孔树脂纯化酚酸粗提液的具体操作如下：预处理D101大孔吸附树脂，粗酚酸上样浓度为10～30mg/mL，上样体积为0.2～0.4BV，洗脱速度0.2～0.4mL/min；进一步地，优选的上样浓度为20±2mg/mL，上样体积为0.3±0.05BV，洗脱速度为0.3±0.05mL/min。
本发明所述柴达木大肥菇酚酸，为柴达木双层环伞菌(Agaricus bitorquis(Quél.)Sacc Chaidamu.)子实体的醇提取物，醇提物中以酚酸为主要成分。本发明具体实施方式中测定表明，醇取物中酚酸含量为91±2％w/w，该酚酸纯度较高，用此纯度下的酚酸进行生物活性实验，其结果能够真实的反映出柴达木大肥菇酚酸的生物活性，有效地避免了其他成分对酚酸活性测定的干扰。在已知酚酸生物活性的基础上，即便是降低酚酸在提取物中的含量，只要适当调节提取物用量，使得酚酸达到相应的起效浓度，同样能够发挥出相同或相似的生物活性。因此，本发明限定，提取物中酚酸含量应为60～95％w/w。
经本发明研究表明，柴达木大肥菇酚酸具有延长常压耐缺氧试验缺氧小鼠的死亡时间；在亚硝酸钠中毒试验延长中毒小鼠的存活时间；在急性脑缺血性缺氧试验中延长急性缺氧小鼠喘息时间的作用；可降低缺氧条件下LDH(乳酸脱氢酶)含量、NO(一氧化碳)含量水平，升高ATP(三磷酸腺苷)含量水平，增强机体低氧损伤的耐受能力，提高组织的急性缺氧损伤的代偿能力，保护组织免受缺氧危害，可以将其作为安全可靠的抗缺氧药物、保健品或食品。
附图说明
图1为小鼠常压耐缺氧试验结果-LDH水平统计图；
图2为小鼠常压耐缺氧试验结果-ATP水平统计图；
图3为小鼠常压耐缺氧试验结果-NO水平统计图。
具体实施方式
下面结合附图通过具体实施例对本发明做进一步说明：
本发明具体实施方式中使用的柴达木大肥菇酚酸采用常规的酚酸提取、纯化方式制备得到，在本发明中具体操作如下：
一、柴达木大肥菇酚酸的制备
1)柴达木大肥菇去糖：分别用子实体粉末与蒸馏水以1:20混合，保持70℃、60min，辅助超声波提取，抽滤，离心得到残渣，提取液过滤后弃去；
2)柴达木大肥菇酚酸提取：称取步骤1)所得已除糖柴达木大肥菇残渣与90％乙醇混合，超声波辅助提取，离心得到提取液，残渣过滤后弃去；提取液浓缩得到粗酚酸提取液。
二、柴达木大肥菇酚酸的纯化
1)粗酚酸提取液脱色：粗酚酸提取液依次用活性炭脱色、Savege法除去蛋白质，以大孔吸附树脂－D101层析柱，90％乙醇为洗脱液纯化，得到纯化酚酸醇提液。
对本发明方法制备的柴达木大肥菇酚酸以没食子酸为标准品进行测定，其中酚酸含量为90％±2w/w。
三、柴达木大肥菇酚酸保护急、慢性缺氧损伤作用实验
1)抗缺氧评价试验依据：依据中国卫生部2003年公布了《保健食品功能学评价程序和检测方法》，每组雌雄各10只(分笼饲养)，按体重随机分为1个空白对照组、1个阳性(红景天苷)对照组、1个药物(总酚酸)各3个剂量组，共计7组。按每公斤体重日推荐摄入量的10倍为其中一个中等剂量(150mg/kg)，另外2个剂量根据受试物的具体情况如下制定为高剂量(300mg/kg)、低剂量(75mg/kg)。按照试剂盒说明书检测脑组织中ATP、NO、LDH含量。
2)小鼠常压耐缺氧试验：经口连续给药20-30d，于末次给予受试物后1h，将各组小鼠分别放入盛有15g钢石灰的250mL，广口瓶内(每瓶只放1只小鼠)，用凡士林从涂抹瓶口，盖严，使之不漏气，立即计时，以呼吸停止为指标，观察小鼠因缺氧而死亡的时间。
3)亚硝酸钠中毒试验：配置20mL，200％亚硝酸钠溶液，浓度为2000mg/mL，按照每只小鼠体重，小鼠按200～240mg/kg BW，进行灌胃，立即计时，记录小鼠存活时间。
4)急性脑缺血试验：将小鼠快速断头处死，观察小鼠张口喘息情况，以5s内不再张口喘息作为观察指标，记录小鼠喘息时间。
5)柴达木大肥菇酚酸抗缺氧活性评价试验结果
a小鼠常压耐缺氧试验
表1小鼠常压耐缺氧试验结果-死亡时间
(n＝20)
由表1可知：酚酸试验组的低、中、高剂量组均能明显延长缺氧小鼠的死亡时间，与空白对照组、阳性对照组(红景天苷组)比较，常压耐缺氧试验小鼠的死亡时间差异显著(P<0.05)，可判定：柴达木大肥菇酚酸的常压耐缺氧试验结果为阳性。
b亚硝酸钠中毒试验
表2亚硝酸钠中毒试验结果-存活时间
(n＝20)
注：小写字母表示p<0.05显著，以下同。
表2可知：在亚硝酸钠中毒试验中，酚酸试验组均可延长中毒小鼠的存活时间，与空白、阳性(红景天苷)对照组比较，差异显著(P<0.05)，酚酸试验组的低、中、高剂量组，与空白、阳性对照组对比，延长中毒小鼠存活时间效率较高，可判定：柴达木大肥菇酚酸的亚硝酸钠中毒试验结果为阳性。
c急性脑缺血性缺氧试验
表3急性脑缺血性缺氧试验结果-喘息时间(n＝20)
由表3可知：在急性脑缺血性缺氧试验中，各试验组与空白、阳性对照组比较，能明显延长急性缺氧小鼠喘息时间差异显著(P<0.05)，总酚酸试验组与空白、阳性对照组比较，也能延长喘息时间差异显著(P<0.05)。可判定：柴达木大肥菇酚酸的急性脑缺血性缺氧试验结果为阳性。
本发明柴达木大肥菇酚酸各剂量组对常压缺氧试验、亚硝酸钠中毒试验及急性脑缺血性缺氧试验中小鼠的生存时间均有调节延长作用，且呈剂量效应关系，高、中、低剂量组与空白模型组有显著性差异(P<0.05)，即三个判定抗缺氧试验结果均为阳性，故判定柴达木大肥菇酚酸具有抗缺氧活性。且酚酸高剂量组抗缺氧效果明显高于阳性对照(红景天干)组，因此，以柴达木大肥菇酚酸可代替红景天苷，缓解开发抗缺氧药物资源匮乏的问题。
6)柴达木大肥菇酚酸对相关生化指标的影响如图1-3所示。
本发明柴达木大肥菇酚酸各剂量组对常压缺氧试验、亚硝酸钠中毒试验及急性脑缺血性缺氧试验中LDH、NO水平均有调节降低作用，对ATP水平有调节上升作用，且呈剂量效应关系，高剂量组与模型组有显著性差异(p＜0.05)。
以上已将本发明做一详细说明，以上所述，仅为本发明之较佳实施例而已，当不能限定本发明实施范围，即凡依本申请范围所作均等变化与修饰，皆应仍属本发明涵盖范围内。
Claims (11)
1.柴达木大肥菇酚酸在制备保护急、慢性缺氧损伤的药物、保健品或食品中的用途。
2.根据权利要求1所述的用途，其特征在于：所述保护急、慢性缺氧损伤的药物、保健品或食品是改善高原病患者的低氧耐受能力及急性缺氧人群机体急性缺氧损伤代偿能力的药物、保健品或食品。
3.根据权利要求1或2所述的用途，其特征在于：所述改善高原病患者的低氧耐受能力及急性缺氧人群机体急性缺氧损伤代偿能力是指降低缺氧人群LDH、NO水平，升高ATP水平。
4.根据权利要求2所述的用途，其特征在于：所述高原病包括慢性高原病和急性高原病。
5.根据权利要求2所述的用途，其特征在于：所述高原病患者为急性缺氧、低氧耐受时机体功能受损的患者。
6.根据权利要求1～5任意一项所述的用途，其特征在于：所述保护急、慢性缺氧损伤的药物、保健品或食品为口服剂型；进一步地，所述口服剂型选自片剂、粉剂、胶囊剂、丸剂、颗粒剂、散剂、浸膏剂或口服。
7.根据权利要求1所述的用途，其特征在于：酚酸纯度为60-95％w/w，进一步为80～95％w/w，更进一步为90～93％w/w。
8.根据权利要求1～7任意一项所述的用途，其特征在于：柴达木大肥菇酚酸采用超声波辅助乙醇提取法制备得到；进一步地，所述超声波辅助乙醇提取法具体操作如下：将柴达木大肥菇粉碎、过筛、去糖后，以超声波辅助加乙醇提取，得酚酸粗提液，以大孔树脂纯化，收集洗脱液，浓缩，干燥，即得到柴达木大肥菇酚酸纯品；更进一步地，提取溶剂乙醇的浓度为85～95％v/v，超声波辅助提取的功率为160～200W，提取温度为56～66℃；更进一步地，提取溶剂乙醇的浓度优选为90±2％v/v，超声波辅助提取的功率优选为180±5W，提取温度优选为61±2℃。
9.根据权利要求8所述的用途，其特征在于：去糖具体操作如下：将柴达木大肥菇粉碎后，过筛，脱脂，采用水提醇沉法，提取后的残渣过滤，挥干溶剂，得去糖的柴达木大肥菇残渣；水提醇沉法去糖的具体操作如下：所得已过筛的柴达木大肥菇粉末，加水溶解，过滤，得滤渣，即为柴达木大肥菇去糖残渣，过滤时滤液加入乙醇至含醇量达到70～90％v/v，静置，待沉淀完全过滤；进一步地，除糖加入乙醇至含醇量至75～85％v/v，优选为80±2％v/v。
10.根据权利要求8所述的用途，其特征在于：通过大孔树脂纯化酚酸粗提液的具体操作如下：预处理D101大孔吸附树脂，粗酚酸上样浓度为10～30mg/mL，上样体积为0.2～0.4BV，洗脱速度0.2～0.4mL/min；进一步地，优选的上样浓度为20±2mg/mL，上样体积为0.3±0.05BV，洗脱速度为0.3±0.05mL/min。
11.根据权利要求1～10任意一项所述的用途，其特征在于：柴达木大肥菇为柴达木双层环伞菌子实体。
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