CN113244246A - 一种微生物源缩醛磷脂在治疗结肠癌中的应用 - Google Patents
一种微生物源缩醛磷脂在治疗结肠癌中的应用 Download PDFInfo
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Abstract
本发明公开了一种微生物源缩醛磷脂在治疗结肠癌中的应用，属于生物医药及微生物技术领域。为了提供一种改善结肠癌的方法。本发明提供了一种微生物源缩醛磷脂在制备治疗结肠癌的应用，微生物源缩醛磷脂是从厌氧微生物乳酸菌、双歧杆菌、丁酸梭菌和消化链球菌中的任意一种或多种混合提取出来的。微生物源缩醛磷脂能够从分子水平上降低结肠癌相关细胞因子的表达，并抑制结肠癌细胞的增殖、降低结肠癌患者的结肠腺瘤的数量与体积，可以作为预防和治疗结肠癌的有效营养策略，为确定肠道微生物来源的缩醛磷脂的高效利用提供理论支持。
Description
技术领域
本发明涉及一种微生物源缩醛磷脂在治疗结肠癌中的应用，属于生物医药及微生物技术领域。
背景技术
结肠癌是一种针对结肠组织的遗传性疾病，是由特定基因发生的突变引起的，这些突变可以使一个细胞比它附近的细胞更具优势。在某些基因中发生足够的突变后，细胞可能会发生癌变并不受控制地分裂，从而形成肿瘤。目前结肠癌已经是世界上第二大最常见的癌症死亡原因。风险因素包括：家史。炎症性肠病、糖尿病、低纤维和高脂肪饮食、癌症的放射治疗、遗传性结肠癌综合症等。目前其预防与改善的方法仍受限，而使用毒性更小、更天然的方法，结合目前的治疗方法，以更成功地治疗结肠癌，是目前的研究与产业趋势。
缩醛磷脂是一类甘油磷脂，其独特结构在于sn-1位上具有烯醚键的长链烯醇，广泛存在于动物组织、厌氧微生物中。值得注意的是，结肠细胞中缩醛磷脂比例最高，约占总磷脂的35％。人体细胞中缩醛磷脂的缺乏可导致慢性阻塞性肺病等多种炎症和神经疾病的产生。
外源性缩醛磷脂也已被证明具有多种生物活性，可以改善氧化应激水平以及神经炎症，但在结肠癌症方面目前仍无研究。微生物源缩醛磷脂作为改善结肠癌症的策略亟待研究，在更好地保护患者的整体健康上具有巨大的潜力。
发明内容
本发明的目的是为了提供一种改善结肠癌的方法，解决了治疗结肠癌治疗局限性的问题。本发明提供了微生物源缩醛磷脂在制备治疗结肠癌的药品中的应用，所述微生物源缩醛磷脂来源于厌氧微生物。
在一个实施方式中，所述微生物源缩醛磷脂作为治疗结肠癌的药品的有效成分的最小剂量为5mg/kg.BW
在一个实施方式中，所述厌氧微生物为乳酸菌、双歧杆菌、丁酸梭菌和消化链球菌中的任意一种或多种混合。
在一个实施方式中，所述厌氧微生物为长双歧杆菌和丁酸梭菌。
在一个实施方式中，所述微生物源缩醛磷脂的成分由158.3mg/g缩醛磷脂酰胆碱(PlsCho)、241.8mg/g缩醛磷脂酰乙醇胺(PlsEtn)、11.0mg/g缩醛磷脂酰丝氨酸(PlsSer)、367.1mg/g缩醛磷脂酰甘油(PlsGly)和181.0mg/g缩醛磷脂酸(PlsOH)组成。
在一个实施方式中，所述微生物源缩醛磷脂的纯度大于90％。
在一个实施方式中，所述的药品的剂型为片剂、胶囊剂、颗粒剂、散剂、液体制剂中的任意一种。
在一个实施方式中，所述治疗结肠癌是指降低结肠癌相关的细胞因子IL-6、TNFα和COX2的表达、降低结肠腺瘤的数量、减小结肠腺瘤的体积或者抑制结肠癌细胞增殖。
本发明还提供了一种微生物源缩醛磷脂在制备缓解结肠癌的症状的保健品中的应用，所述微生物源缩醛磷脂的最小剂量为5mg/kg.BW。
本发明还提供了一种微生物源缩醛磷脂在制备缓解结肠癌的症状的食品中的应用，所述微生物源缩醛磷脂的最小剂量为5mg/kg.BW。
在一个实施方式中，微生物源缩醛磷脂是肠内营养制剂、膳食补充剂、兽药或者饲料添加剂的有效成分。
有益效果：微生物源缩醛磷脂能够从分子水平上降低结肠癌相关细胞因子的表达，并抑制结肠癌细胞的增殖、降低结肠癌患者的结肠腺瘤的数量与体积，可以作为治疗和缓解结肠癌的有效营养策略，为确定肠道微生物来源的缩醛磷脂的高效利用提供理论支持。
附图说明
图1为微生物源缩醛磷脂对结肠腺瘤数量与肿瘤体积的影响，其中，A是微生物源缩醛磷脂对结肠腺瘤体积的影响，横坐标是组别，纵坐标是肿瘤体积；B是微生物源缩醛磷脂对结肠腺瘤数量的影响，横坐标是组别，纵坐标是肿瘤数量；**代表P<0.01；
图2为微生物源缩醛磷脂对结肠癌小鼠的结肠中与结肠癌相关的炎症因子表达量的影响，其中，A是微生物源缩醛磷脂对IL-6的mRNA表达量的影响，横坐标是组别，纵坐标是表达量；B是微生物源缩醛磷脂对TNF-α的mRNA表达量的影响，横坐标是组别，纵坐标是表达量；C是微生物源缩醛磷脂对Cox-2的mRNA表达量的影响，横坐标是组别，纵坐标是表达量；**代表P<0.01；
图3为微生物源缩醛磷脂对结肠癌细胞系生长抑制情况，其中，横坐标是组别，纵坐标是细胞的生存率；**代表P<0.01。
具体实施方式
人结肠癌细胞株HT-29来源于ATCC细胞库；小鼠购买自维通利华生物有限公司。
长双歧杆菌(Bifidobacterium longum)购自中国工业微生物菌种保藏管理中心，保藏编号为CICC 24632。
丁酸梭菌(Clostridium butyricum)购自明舟生物有限公司，货号为246167。
实施例1.
一、获取微生物源缩醛磷脂
微生物源缩醛磷脂的菌株来源为厌氧微生物，包括乳酸菌(Lactobacillaceae)、双歧杆菌(Bifidobacterium)、丁酸梭菌(Clostridium butyricum)、消化链球菌(Peptostreptococcus Kluyver and van Niel)、韦荣氏球菌(Veillonella)等缩醛磷脂阳性微生物(即含缩醛磷脂的微生物)，一种缩醛磷脂阳性微生物菌株或缩醛磷脂阳性微生物的微生物菌株组合；
1)分别培养长双歧杆菌(Bifidobacterium longum)和丁酸梭菌(Clostridiumbutyricum)，接种量均为0.1％，分别于MRS液体培养基中培养24小时，分别收集长双歧杆菌与丁酸梭菌培养液，3500rpm/min进行离心并收集菌体。两种微生物的缩醛磷脂组成见表1，组成检测方法采用液质联用技术，即样品用异丙醇提取脂质，使用ACQUITY UPLC液相系统和TripleTOF 5600质谱进行脂质组成测定，BEH C18柱(50×2.1mm；1.7μm)进行分离，柱温45℃，流速为0.3mL/min。参数为碰撞能量：40eV；碰撞能量扩散：15eV；循环时间：1300ms；温度:300℃(-)，组成比例单位为峰面积，经过计算得到产物的组成含量。
表1为长双歧杆菌与丁酸梭菌的缩醛磷脂
2)按照1:1比例合并长双歧杆菌与丁酸梭菌的菌体，冷冻真空干燥后经粉粹得到含脂量15.9％的粉末；
3)将粉末通过亚临界萃取得到磷脂复合物，具体操作参数为溶料比1:1-1.5:1；萃取罐工作压力：0.3-0.8MPa；萃取温度：30-50℃；萃取时间：30-60分钟；分离罐温度：50-70℃；
4)磷脂复合物用正己烷溶解，控制底物浓度2g/mL，加酶量(磷脂酶A1，LectiaseUltra)4％，加水量10％，反应温度45℃，于集热式搅拌器中(200r/min)反应20h，反应液经离心(4000r/min)和旋转蒸发30min，得到酶解磷脂；
5)将酶解磷脂装料50g，密封后升温升压到预定的萃取条件：萃取温度为50℃，萃取压力为35MPa，乙醇量3kg/h，萃取时间为5h。
收集得到的缩醛磷脂为sn-1位脂肪酸与甘油骨架以烯醚键相连，且含奇数或偶数链脂肪酸的缩醛磷脂混合物，主要包括缩醛磷脂酰胆碱(PlsCho)、缩醛磷脂酰乙醇胺(PlsEtn)、缩醛磷脂酰丝氨酸(PlsSer)、缩醛磷脂酰甘油(PlsGly)、缩醛磷脂酸(PlsOH)的一种或多种混合。
收集得到高纯度的微生物来源的缩醛磷脂，成分如表2中所示，其纯度为95.84％，并用于功能评价。
表2为微生物源缩醛磷脂的组成分析
二、动物分组与处理：
1.建模
45只6周龄C57BL/6J雄性小鼠，体重20-22g，平均分成三组，溶剂对照组、模型组与微生物源缩醛磷脂组；
微生物源缩醛磷脂组：结肠癌造模动物单次腹腔注射氧化偶氮甲烷AOM(10mg/kg.BW)一次，一周后给予含3％葡聚糖硫酸钠溶液连续饮用7天，之后给与正常饮用水连续饮用7天，14天为一个循环，共循环3次；
溶剂对照组第一天腹腔注射与AOM同体积生理盐水，并给与正常饮用水周期与样品组一样；
2.处理
微生物源缩醛磷脂组每天经口给予步骤一得到的微生物源缩醛磷脂灌胃(1.0mg/kg.BW)，共6周。
溶剂对照组每天给予1.0mg/kg.BW的生理盐水，共六周。干预结束后，小鼠CO2处死，心脏缺血并取动物脾脏称量并记录脏器系数。取由肛门至盲肠末端的全部结直肠，沿结肠带垂直剖开直结肠，用生理盐水冲洗后观察肠道内病变情况，计数肿瘤形成个数。
结果：AOM/DSS模型诱导小鼠肠粘膜出现不同程度的增厚皱襞紊乱，可观察到个数不等大小不一的结直肠肿瘤生长，说明建模成功，如图1所示，微生物源缩醛磷脂组相对于溶剂对照组则显著降低结肠肿瘤的数目与体积，分别下降72.4％、61.9％(P<0.01；P<0.01)。
结果如图2所示，通过QtPCR检测结肠组织中多种细胞炎症因子的mRNA表达水平，发现微生物源缩醛磷脂组中结肠细胞因子IL-6(P<0.01)、TNFα(P<0.01)、COX2(P<0.01)的mRNA表达水平显著下降。
三、HT-29结肠癌细胞实验
人结肠癌细胞株HT-29生长于含10％胎牛血清的DMEM培养基中，温度37℃，5％CO2饱和湿度的细胞培养箱中进行培养，每2-3天更换培养液一次，取对数生长期的细胞用于实验。体外培养人结肠癌细胞株HT-29，以上述步骤一得到的微生物源缩醛磷脂干预细胞，即将细胞接种于96孔板中，每孔约5×103个细胞，在恒温培养箱中培养，待细胞贴壁后，加入浓度为100μmol/L微生物源缩醛磷脂(用DMSO溶解)，对照组加入相同体积的DMSO(5μL)，培养24h后，MTT法检测细胞增殖情况。
结果如图3所示微生物源缩醛磷脂抑制结肠癌细胞HT-29增殖水平，其水平下降67.6％(P<0.01)
综上结果显示，微生物源缩醛磷脂具有改善和治疗结肠癌的功效。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.微生物源缩醛磷脂在制备治疗结肠癌的药品中的应用，其特征在于，所述微生物源缩醛磷脂来源于厌氧微生物。
2.根据权利要求1所述的应用，其特征在于，所述微生物源缩醛磷脂的最小剂量为5mg/kg.BW。
3.根据权利要求1所述的应用，其特征在于，所述厌氧微生物为乳酸菌、双歧杆菌、丁酸梭菌和消化链球菌中的任意一种或多种混合。
4.根据权利要求3所述的应用，其特征在于，所述厌氧微生物为长双歧杆菌和丁酸梭菌。
5.根据权利要求1-4任意一项所述的应用，其特征在于，所述微生物源缩醛磷脂的成分由158.3mg/g缩醛磷脂酰胆碱、241.8mg/g缩醛磷脂酰乙醇胺、11.0mg/g缩醛磷脂酰丝氨酸、367.1mg/g缩醛磷脂酰甘油和181.0mg/g缩醛磷脂酸组成。
6.根据权利要求1-4任意一项所述的应用，其特征在于，所述微生物源缩醛磷脂的纯度大于90％。
7.根据权利要求1所述的应用，其特征在于，所述的药品的剂型为片剂、胶囊剂、颗粒剂、散剂、液体制剂中的任意一种。
8.根据权利要求1所述的应用，其特征在于，所述治疗结肠癌是指降低结肠癌相关的细胞因子IL-6、TNFα和COX2的表达、降低结肠腺瘤的数量、减小结肠腺瘤的体积或者抑制结肠癌细胞增殖。
9.微生物源缩醛磷脂在制备缓解结肠癌的症状的保健品中的应用，其特征在于，所述微生物源缩醛磷脂的最小剂量为5mg/kg.BW。
10.微生物源缩醛磷脂在制备缓解结肠癌的症状的食品中的应用，其特征在于，所述微生物源缩醛磷脂的最小剂量为5mg/kg.BW。
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