CN111134240A - 食蟹猴酒精性肝病模型构建用液体饲料及方法 - Google Patents
食蟹猴酒精性肝病模型构建用液体饲料及方法 Download PDFInfo
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Abstract
本发明涉及一种食蟹猴酒精性肝病模型构建用液体饲料及方法,该液体饲料包括分别含特定组分的液体饲料A和液体饲料B。该食蟹猴酒精性肝病模型构建方法通过依次采用常规固体饲料与液体饲料B相配合、液体饲料B与液体饲料A相配合以及液体饲料A渐进过渡方式进行食蟹猴酒精性肝病造模,更贴合人酒精性肝病疾病发生环境,并可有效避造模动物厌食、脱水、状态差等情况,提高造模成功率。
Description
技术领域
本发明涉及医用动物模型技术领域,尤其涉及一种食蟹猴酒精性肝病模型构建用液体饲料及方法。
背景技术
中国超两成以上人口患有肝病,其中乙肝患者9000万,丙肝患者1000万,非酒精性脂肪肝患者1.73-3.1亿,酒精性肝病患者6200万,肝硬化患者700万,每年新发癌症46万例。肝病在中国的发病率和死亡率较高。
《2018年中国酒精性肝病防治指南》指出:饮酒超过5年,折合乙醇量男性≥40克/日,女性≥20克/日,就可以发生酒精性肝炎;超过10年,可发生酒精性肝硬化。2周内有大量饮酒,折合乙醇量>80克/日,也可发生酒精性肝炎。
在临床上,酒精性肝病的治疗上缺乏有针对性的靶点治疗方法,临床上只能被动的以对症处理为主,用营养支持来防治营养不良和用糖皮质激素来控制炎症。
因此,建立一种更接近人类酒精性肝病的动物模型,尤其是构建具有酒精性肝脏病变进程的动物模型,并利用该动物模型研宄其发生机制,进而发现新的治疗靶点和药物,是具有非常重要的医学基础理论和临床应用价值。
传统酒精性脂肪肝的造模动物主要是鼠,造模方法是用固体高脂饲料配合自行引用酒精水溶液。该自行引用酒精水溶液的方式无法有效控制乙醇的摄入量,还容易导致动物营养不良。
虽然CN 106389394A公开了一种食蟹猴酒精性肝病模型的构建方法,其采用与人体结构更接近的食蟹猴,但是该构建方法中依然采用自行引用酒精水溶液的方式,容易出现营养不足等问题。
虽然CN105901380A公开了一种用于制备酒精性肝病动物模型的鼠饲料,该鼠饲料由酪蛋白、L-胱氨酸、DL-蛋氨酸、麦芽糊精、膳食纤维素、黄原胶、重酒石酸胆碱、矿物质预混料、维生素预混料、胆固醇、胆酸钠、鱼油、酒精和水配制而成。将该液体型的鼠饲料用于制备动物酒精性肝病模型,可逐步造成小鼠酒精性脂肪肝、肝炎和肝纤维化。但是,鼠与人体结构及代谢差异较大,与人酒精性肝病病变进程差距较大。
发明内容
基于此,有必要提供一种食蟹猴酒精性肝病模型构建用液体饲料及方法,更接近人类酒精性肝病的动物模型,便于筛选新药。
本发明解决上述技术问题的技术方案如下:
本发明提供一种食蟹猴酒精性肝病模型构建用液体饲料,包括液体饲料A和液体饲料B:
每升液体饲料A含玉米50-140g、豆粕10-60g、面粉10-60g、麦麸10-100g、鱼粉4-60g、啤酒酵母1-20g、植物油10-100g、磷酸氢钙1-4g、石粉2-6g、食盐0-8g、乙醇20-150g以及余量水;
每升液体饲料B含玉米225-275g、豆粕50-125g、面粉25-75g、麦麸50-175g、鱼粉10-75g、啤酒酵母2.5-25g、植物油25-125g、磷酸氢钙2.5-10g、石粉5-7.5g、食盐0-10g以及余量水。
进一步地,每升液体饲料A中和每升液体饲料B中还均含胆固醇0.5-1.5g。
上述所述食蟹猴酒精性肝病模型构建用液体饲料在构建肝病动物模型中的应用。
本发明还提供一种食蟹猴酒精性肝病模型构建方法,包括如下步骤:
第1周,采用常规固体饲料和上述液体饲料B混合喂养且逐渐提高液体饲料B占比、降低常规固体饲料占比的方式适应性饲喂造模用食蟹猴;
第2-3周,采用上述液体饲料A和液体饲料B混合喂养且逐渐提高液体饲料A占比、降低液体饲料B占比的方式继续饲喂造模用食蟹猴,饲料量标准为每天每公斤体重动物100mL液体饲料;
第4周及以后,仅采用液体饲料A继续饲喂造模用食蟹猴,直至酒精性肝病造模成功。
优选地,所述逐渐提高液体饲料B占比、降低常规固体饲料占比的方式是将液体饲料B和常规固体饲料按照0%:100%、20%:80%、40%:60%、60%:40%、80%:20%和100%:0%的比例逐渐变换。
优选地,所述逐渐提高液体饲料A占比、降低液体饲料B占比的方式是将液体饲料A和液体饲料B按照(30%-35%):(65%-70%)到(65%-70%):(30%-35%)的比例逐渐变换。
优选地,在整个食蟹猴酒精性肝病模型的构建过程中,还包括按常规饲养方式喂水的步骤。
优选地,在判断酒精性肝病造模成功的过程中,采用经肝穿肝脏活检、肝组织用HE染色判断肝病模型进展。
由上述食蟹猴酒精性肝病模型构建方法构建获得的食蟹猴酒精性肝病模型。
上述食蟹猴酒精性肝病模型在肝病药物筛选中的应用。
本发明的有益效果是:
采用本发明食蟹猴酒精性肝病模型构建用液体饲料造模,通过特定组成的液体饲料A、液体饲料B和常规固体饲料相配合应用,解决动物血酒浓度问题,能够实现过渡渐进式酒精性肝病造模,有效避造模动物厌食、脱水、状态差等情况,提高造模成功率,也更贴合人酒精性肝病疾病发生环境。尤其是液体饲料B作为对照饲料是按照美国推荐的人群营养素摄入量设计的,碳水化合物、蛋白质和脂肪分别提供的热量在47%,18%和35%附近,能够有效保证动物的营养需求。
附图说明
图1为实施例3中第20周末的肝组织染色图(放大200倍);
图2为实施例3中第40周末的肝组织染色图(放大200倍);
图3为正常食蟹猴的肝组织染色图(放大200倍)。
具体实施方式
以下对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
实施例1
本实施例提供一种食蟹猴酒精性肝病模型构建用液体饲料,包括液体饲料A和液体饲料B。
其中,每升液体饲料A含玉米100±20g、豆粕30±10g、面粉35±10g、麦麸45±20g、鱼粉30±20g、啤酒酵母10±5g、植物油50±20g、磷酸氢钙2.5±1.5g、石粉4.5±1.5g、食盐4±4g、乙醇75±20g以及余量水。
其中,每升液体饲料B含玉米250±25g、豆粕90±35g、面粉50±20g、麦麸100±30g、鱼粉40±20g、啤酒酵母10±5g、植物油70±20g、磷酸氢钙6±4g、石粉6g、食盐4±4g以及余量水。
实施例2
本实施例提供一种食蟹猴酒精性肝病模型构建用液体饲料,其组成与实施例1基本相同,区别在于:每升液体饲料A中和每升液体饲料B中还均含胆固醇1±0.5g。
实施例3
本实施例提供一种食蟹猴酒精性肝病模型构建方法,包括如下步骤:
(1)取3-5kg体重雌性食蟹猴12只,并准备实施例2的食蟹猴酒精性肝病模型构建用液体饲料以及常规饲喂食蟹猴的固体饲料(猴维持饲料,北京科澳协力饲料有限公司)。
(2)第1周,采用常规固体饲料和实施例2中的液体饲料B混合喂养且逐渐提高液体饲料B占比、降低常规固体饲料占比的方式适应性饲喂造模用食蟹猴。
在该步骤中,该逐渐提高液体饲料B占比、降低常规固体饲料占比的方式是将液体饲料B和常规固体饲料按照0%:100%、20%:80%、40%:60%、60%:40%、80%:20%和100%:0%的比例逐渐变换。
(3)第2-3周,采用上述液体饲料A和液体饲料B混合喂养且逐渐提高液体饲料A占比、降低液体饲料B占比的方式继续饲喂造模用食蟹猴,饲料量标准为每天每公斤体重动物100mL液体饲料。
在该步骤中,该逐渐提高液体饲料A占比、降低液体饲料B占比的方式是将液体饲料A和液体饲料B按照1:2到2:1的比例逐渐变换。
(4)第4周及以后,仅采用液体饲料A继续饲喂造模用食蟹猴进行造模,并采用经肝穿肝脏活检、肝组织用HE染色判断造模情况。
另外,在整个食蟹猴酒精性肝病模型的构建过程中,根据动物的饮用量,采用大小适当的动物饮水瓶自由饮食,按常规瓶装饲养方式喂水,自由饮水。
造模检测结果:
请结合图1,在第20周末,经肝穿肝脏活检,肝组织用HE染色,有10只食蟹猴表现明显的肝细胞膜破裂、浸润的肝炎症状。
请结合图2,第40周末,经肝穿肝脏活检,肝组织用HE染色,有9只食蟹猴表现出肝纤维化症状。
经大量研究发现,当该食蟹猴酒精性肝病模型构建方法通过采用特定组成的液体饲料A(每升液体饲料A含玉米50-140g、豆粕10-60g、面粉10-60g、麦麸10-100g、鱼粉4-60g、啤酒酵母1-20g、植物油10-100g、磷酸氢钙1-4g、石粉2-6g、食盐0-8g、乙醇20-150g以及余量水)、液体饲料B(每升液体饲料B含玉米225-275g、豆粕50-125g、面粉25-75g、麦麸50-175g、鱼粉10-75g、啤酒酵母2.5-25g、植物油25-125g、磷酸氢钙2.5-10g、石粉5-7.5g、食盐0-10g以及余量水)与常规固体饲料相配合应用,能够实现过渡渐进式酒精性肝病造模,更贴合人酒精性肝病疾病发生环境,成功率可达80%以上。
该食蟹猴酒精性肝病模型构建方法构建而成的酒精性肝病模型可用于肝病药物筛选。
以上实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种食蟹猴酒精性肝病模型构建用液体饲料,其特征在于,包括液体饲料A和液体饲料B:
每升液体饲料A含玉米50-140g、豆粕10-60g、面粉10-60g、麦麸10-100g、鱼粉4-60g、啤酒酵母1-20g、植物油10-100g、磷酸氢钙1-4g、石粉2-6g、食盐0-8g、乙醇20-150g以及余量水;
每升液体饲料B含玉米225-275g、豆粕50-125g、面粉25-75g、麦麸50-175g、鱼粉10-75g、啤酒酵母2.5-25g、植物油25-125g、磷酸氢钙2.5-10g、石粉5-7.5g、食盐0-10g以及余量水。
2.根据权利要求1所述的食蟹猴酒精性肝病模型构建用液体饲料,其特征在于,每升液体饲料A中和每升液体饲料B中还均含胆固醇0.5-1.5g。
3.权利要求1或2所述的食蟹猴酒精性肝病模型构建用液体饲料在构建肝病动物模型中的应用。
4.一种食蟹猴酒精性肝病模型构建方法,其特征在于,包括如下步骤:
第1周,采用常规固体饲料和权利要求1或2中液体饲料B混合喂养且逐渐提高液体饲料B占比、降低常规固体饲料占比的方式适应性饲喂造模用食蟹猴;
第2-3周,采用权利要求1或2中液体饲料A和液体饲料B混合喂养且逐渐提高液体饲料A占比、降低液体饲料B占比的方式继续饲喂造模用食蟹猴,饲料量标准为每天每公斤体重动物100mL液体饲料;
第4周及以后,仅采用液体饲料A继续饲喂造模用食蟹猴,直至酒精性肝病造模成功。
5.根据权利要求4所述的食蟹猴酒精性肝病模型构建方法,其特征在于,所述逐渐提高液体饲料B占比、降低常规固体饲料占比的方式是将液体饲料B和常规固体饲料按照0%:100%、20%:80%、40%:60%、60%:40%、80%:20%和100%:0%的比例逐渐变换。
6.根据权利要求4所述的食蟹猴酒精性肝病模型构建方法,其特征在于,所述逐渐提高液体饲料A占比、降低液体饲料B占比的方式是将液体饲料A和液体饲料B按照(30%-35%):(65%-70%)到(65%-70%):(30%-35%)的比例逐渐变换。
7.根据权利要求4至6任一项所述的食蟹猴酒精性肝病模型构建方法,其特征在于,在整个食蟹猴酒精性肝病模型的构建过程中,还包括按常规饲养方式喂水的步骤。
8.根据权利要求4至6任一项所述的食蟹猴酒精性肝病模型构建方法,其特征在于,在判断酒精性肝病造模成功的过程中,采用经肝穿肝脏活检、肝组织用HE染色判断肝病模型进展。
9.由权利要求4至8任一项所述的食蟹猴酒精性肝病模型构建方法构建获得的食蟹猴酒精性肝病模型。
10.权利要求9所述的食蟹猴酒精性肝病模型在肝病药物筛选中的应用。
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