CN116077506A - 刺囊酸在制备防治ii型糖尿病或非酒精性脂肪肝的药食中应用 - Google Patents
刺囊酸在制备防治ii型糖尿病或非酒精性脂肪肝的药食中应用 Download PDFInfo
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Abstract
本发明公开了一种刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,属于医药技术领域。本发明实施例证实刺囊酸显著增加小鼠糖吸收,刺囊酸能够预防肥胖导致的二型糖尿病;刺囊酸可以减少肝脏的TG水平,减少肝脏脂质沉积,改善脂肪变性的作用,对非酒精脂肪肝的发生具有预防和治疗的效果。因而证实了刺囊酸可在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。刺囊酸没有细胞活性变化等副作用的产生,从而为有效预防或治疗II型糖尿病或非酒精脂肪肝提供了一种的低毒性天然小分子药物‑刺囊酸。并且,刺囊酸作为一种低毒性天然小分子化合物,价格十分低廉,具有广泛的应用前景。
Description
技术领域
本发明属于医药技术领域,尤其涉及一种刺囊酸(Echinocystic acid,EA)在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。
背景技术
肥胖是由能量摄入和能量消耗长期失衡引起的脂肪过度堆积。近年来,肥胖人数在世界范围内正持续增长,超重或肥胖引起的发病率和死亡率的风险都在增加。肥胖已成为主要的公共健康问题,肥胖会增加糖尿病、脂肪肝、心血管疾病等多种疾病的风险。肥胖不仅只是身材管理问题,更重要的是,肥胖导致患者生活质量降低,更严重的情况还会严重威胁人类健康。
糖尿病分为一型糖尿病(T1DM)和二型糖尿病(T2DM),其中T1DM由遗传因素决定,T2DM和肥胖均是与胰岛素抵抗相关的两种疾病,研究报道约半数的肥胖患者都会发展为糖尿病。糖尿病可导致身体损伤,生理功能障碍和不同器官的衰竭,特别是眼睛,肾脏,神经,心脏,血管和大脑。
肝炎症主要包括病毒性肝炎和脂肪肝炎,其中病毒性肝炎是由机体感染病毒引起的,已成为世界发病率最高的肝疾病,感染者会产生食欲减退、恶心、上腹部不适、肝区痛、乏力为主要表现,部分病人伴有肝功能损害,进一步发展成肝硬化,少数可发展为肝癌,其可通过抑制病毒活性而进行病毒性肝炎治疗。与病毒性肝炎不一样,由过度肥胖会引起的肝脏脂肪沉积被定义为非酒精性脂肪肝(NAFLD),NAFLD是一种肝脏代谢综合征,与肥胖和胰岛素抵抗密切相关。病理学上分为单纯性脂肪肝、脂肪肝炎(NASH)、肝纤维化、肝硬化和肝癌等肝疾病。脂肪肝被定义为存在超过5%的大泡脂肪变性而没有肝细胞损伤的证据,NASH被定义为存在超过5%的肝脂肪变性加上炎症和球囊变性,并伴或不伴纤维化。在全球范围内,脂肪肝是最常见的肝脏疾病之一,成为仅次于病毒性肝炎的第二大肝病,发病率在不断升高,且发病年龄日趋年轻化,其可通过减少脂肪摄入,增加脂肪分解而得到治疗。
高热量的饮食易导致肥胖,肥胖导致机体代谢紊乱,进一步引起肥胖性相关疾病。当前市面上用于减肥的方法多种多样,如手术切除、激素类药物、非激素类减肥药物等,但由于手术减肥会导致术后出血、伤口感染、腹腔积液、肠道功能紊乱、肠梗阻、肥胖复发的可能性等问题。服用激素类药物出现肤色暗沉,发黄长斑,头晕眼花,身体疲乏,出虚汗,甚至是会是神经系统受到影响,表现异常的兴奋或者感觉心慌等。因此急需更安全可靠的减肥方式解决当下肥胖疾病增加的问题。市面上用于减肥降脂的药物种类繁多,研究报道,大多数药物具有毒副作用,药物耐性,所以,使用无毒副作用的天然活性小分子来改善肥胖和非酒精性脂肪肝具有重要意义。
刺囊酸(Echinocystic Acid,EA),一种从皂荚植物中提取的天然三萜类物质,其安全性已得到广泛证明,许多亚洲国家的食品和传统中药使用中均报告了EA的安全性。研究发现,EA在急性疾病的抗炎和抗氧化特性方面具有积极作用,例如抑制2,4,6-三硝基苯磺酸(TNBS)诱导的小鼠结肠炎,抑制脂多糖(lipopolysaccharide,LPS)诱导的小鼠急性局部肺炎等。虽然EA对炎症的治疗已有报道,但暂无研究报道EA具有预防肥胖引起二型糖尿病和非酒精性脂肪肝的作用。
发明内容
本发明的目的在于提供一种刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。本发明旨在解决目前缺乏有效预防、治疗II型糖尿病或非酒精性脂肪肝的低毒性天然小分子药物的问题;本发明中的刺囊酸作为天然萜类物质,可直接添加至饮食中进行肥胖治疗,进一步缓解由肥胖引起的非酒精性脂肪肝等代谢性疾病,具有一定的安全性。
本发明的目的通过如下技术方案实现:
刺囊酸在50μM内对肝细胞活性无明显影响,对肝细胞无明显的毒副作用,有药物应用的前景。
体外细胞实验方面,刺囊酸在浓度为40μM和50μM时显著降低HepG2人肝癌细胞脂质沉积;刺囊酸增加胞内甘油三酯的分解,刺囊酸显著抑制脂合成相关基因的表达,促进脂分解相关基因的表达。刺囊酸能够缓解脂质氧化引起的氧化应激。
体外实验方面,刺囊酸具有降低小鼠脂质沉积的作用,且不是因为能量摄入失衡引起。刺囊酸显著增加小鼠糖吸收,刺囊酸能够预防肥胖导致的II型糖尿病;刺囊酸可以减少肝脏的TG水平,减少肝脏脂质沉积,改善脂肪变性的作用,对非酒精脂肪肝的发生具有预防和治疗的效果。
经过本发明实施例中从体外实验和体内实验的结果可知,刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。
所述的防治包括预防、缓解或治疗中的一种或多种。
所述的药食为药物、或食品中的一种。
所述的药物优选为口服制剂药物。
所述的口服制剂药物为胶囊制剂,软胶囊制剂,口服液制剂,滴丸制剂或片剂制剂药物中的一种。
所述的口服制剂药物中还含有药学上可接受的辅料和/或载体。
作为优选的实施方式,所述刺囊酸的用量优选为50mg/kg-100mg/kg。
本发明与现有技术相比具有以下有益效果:
本发明实施例中确认,在体外细胞实验方面,刺囊酸在浓度为40μM和50μM时显著降低HepG2人肝癌细胞脂质沉积;刺囊酸增加胞内甘油三酯的分解,刺囊酸显著抑制脂合成相关基因的表达,促进脂分解相关基因的表达。刺囊酸能够缓解脂质氧化引起的氧化应激。在体外实验方面,刺囊酸具有降低小鼠脂质沉积的作用,且不是因为能量摄入失衡引起;刺囊酸显著增加小鼠糖吸收,刺囊酸能够预防肥胖导致的二型糖尿病;刺囊酸可以减少肝脏的TG水平,减少肝脏脂质沉积,改善脂肪变性的作用,对非酒精脂肪肝的发生具有预防和治疗的效果。因而证实了刺囊酸可在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。刺囊酸没有细胞活性变化等副作用的产生,从而为有效预防或治疗II型糖尿病或非酒精脂肪肝提供了一种的低毒性天然小分子药物-刺囊酸。并且,刺囊酸作为一种低毒性天然小分子化合物,价格十分低廉,具有广泛的应用前景。
附图说明
图1为本发明实施例一中体外实验和体内实验的流程示意图。
图2为不同浓度的刺囊酸对HepG2人肝癌细胞活性的影响结果图。
图3为不同浓度的刺囊酸处理后HepG2人肝癌细胞内TG浓度和甘油含量的检测结果图。
图4为刺囊酸处理后HepG2人肝癌细胞的脂肪酶LPS活性和相关基因mRNA水平的检测结果图。
图5为刺囊酸处理后HepG2人肝癌细胞的ROS水平和SOD水平的检测结果图。
图6为高脂饮食和刺囊酸处理后小鼠体重、脂肪率、附睾组织、小鼠附睾脂重/体重、食物摄取量的检测结果图。
图7为高脂饮食和刺囊酸处理后小鼠GTT检测、葡萄糖吸收检测的结果图。
图8为高脂饮食和刺囊酸处理后小鼠肝脏的拍照结果图。
图9为高脂饮食和刺囊酸处理后小鼠肝脏进行油红O染色的结果图。
图10为高脂饮食和刺囊酸处理后小鼠肝脏进行TG检测的结果图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
目前,目前缺少有效缓解肥胖和非酒精性脂肪肝的低毒性天然小分子药物。为了解决上述技术问题,本发明提出了一种刺囊酸在制备防治或非酒精性脂肪肝的药食中的应用。
实施例一
技术方案:如图1所示,通过对体内外进行试验验证,即进行活体以及细胞试验,探究EA对高脂引起的脂质代谢紊乱缓解作用。活体水平:6周龄C57BL/6J小鼠经两周适应性培养之后,进行随机分组,每组10只,以纯度为10%的刺囊酸治疗普通组和高脂饮食祖,分别包括:普通饮食组(NC,10% Kcal脂肪)、低浓度EA治疗普通饮食组(NC-50,10% Kcal,50mg/kg EA/体重)、高浓度EA治疗普通饮食组(NC-10,10% Kcal脂肪,100mg/kg EA/体重)、高脂饮食组(HFD,60% Kcal脂肪)、低浓度EA治疗高脂饮食组(HFD-50,60%Kcal脂肪,50mg/kg EA/体重)、高浓度EA治疗高脂饮食组(HFD-100,60% Kcal脂肪,100mg/kg EA/体重),模型治疗时长为12周,期间分时间段追踪小鼠各项生理指标,对小鼠肝脏进行脂质代谢相关研究。体外水平:通过200μM油酸/50μM棕榈酸(OA/PA)诱导HepG2人肝癌细胞构建脂肪堆积模型的同时添加纯度为98%的EA 50μM处理细胞24小时后测定糖脂代谢相关指标。
试验方法方面,通过下述六方面进行相关的试验检测:
1.确定并验证EA对HepG2人肝癌细胞活性的影响,细胞经不同浓度刺囊酸诱导24小时后,进行CCK8细胞活性检测。
2.确定并验证EA对HepG2人肝癌细胞脂代谢进行调控,测定测胞内TG和脂肪酶(Lipase,LPS)等变化,对细胞进行油红O染色以观察细胞脂质积累的变化情况,测定脂代谢相关基因的表达。
3.确定并验证EA对HepG2人肝癌细胞氧化应激的影响,测细胞ROS,SOD和MDA氧化方面指标变化。
4.确定并验证EA对小鼠体重影响。在诱导治疗期间,每一周检测小鼠采食量,每两周进行一次小鼠体重监测,同时进行小鼠脂肪率的测定、第12周使用小鼠CT进行小鼠脂肪分布检测、随即对小鼠进行脱颈椎处死,取脂肪组织,测定组织重量并进行切片染色。
5.确定并验证EA对小鼠葡萄糖耐受性的影响,在小鼠治疗第7周进行小鼠葡萄糖耐量GTT实验,测定EA是否改善高脂饮食引起的血糖紊乱。
6.确定并验证EA对小鼠肝脏脂质沉积的影响,取得组织后,随即对其进行组织甘油三酯测定,并以蛋白含量进行甘油三酯标准化。
实验结果
1.EA对HepG2人肝癌细胞活性无明显影响
如图2所示,EA在最高浓度50μM时对HepG2人肝癌细胞活性无明显影响。
2.EA调控HepG2人肝癌细胞脂质代谢
如图3所示,EA在浓度为40μM和50μM时显著降低HepG2人肝癌细胞脂质沉积,且在50μM时最为显著,所以后续细胞水平研究均以50μM为试验浓度。图4还包含甘油含量检测结果,图4为脂肪酶活性检测,说明EA增加胞内甘油三酯的分解,图4为脂质合成和分解相关基因的表达量,结果显示,EA显著抑制脂合成相关基因的表达,促进脂分解相关基因的表达。
3.EA增加HepG2人肝癌细胞的抗氧化能力
氧化应激(oxidative stress)是因为机体活性氧水平和内源性抗氧化能力之间失去了平衡,导致细胞抗氧化能力不足,细胞内毒性活性氧(ROS)增加,产生氧自由基(O2-,.OH,H2O2),使生物大分子受到攻击,从而引起的细胞和组织损伤。为探究EA对脂质氧化损伤的影响,我们检测ROS,过氧化物歧化酶SOD的含量,结果如图5所示,EA降低活性氧ROS的含量,增加超氧化物歧化酶SOD的含量,表明EA缓解脂质氧化引起的氧化应激。
4.EA显著降低高脂饮食诱导的肥胖小鼠体重
如图6所示,体外水平结果显示EA显著降低OA/PA诱导引起的脂质沉积,为验证EA在活体脂质代谢中的影响,我们以60%Kcal脂肪诱导肥胖模型,并在高脂饮食中添加不同量的EA进行治疗,结果发现,高脂饮食小鼠的体重显著高于普通饮食组,且EA以剂量依赖性的方式显著降低高脂饮食引起的体重增加,经小动物体成分分析发现,EA显著降低脂肪率;图6还包括小鼠附睾脂组织图及附睾脂肪与体重比结果图,结果表明EA显著降低小鼠附睾脂堆积。为探究小鼠体重降低是否因饮食减少引起,测定日均采食量,结果显示相较于普通饮食组,高脂饮食组采食量降低,且添加EA的采食量均无变化,说明EA具有降低小鼠脂质沉积的作用,且不是因为能量摄入失衡引起。
5.EA改善肥胖引起的葡萄糖耐量异常
肥胖会导致二型糖尿病的发生,进而引起葡萄糖耐量受损,脂肪葡萄糖摄取量减少,胰岛素敏感性降低的问题,为研究显著预防脂质沉积的EA是否改善肥胖导致的二型糖尿病,我们进行了葡萄糖耐量测试及细胞糖吸收检测,结果如图7所示,EA显著增加小鼠糖吸收,且增加OA/PA诱导的HepG2肝癌细胞的糖吸收,表明刺囊酸具有预防肥胖导致的二型糖尿病的作用。
6.EA缓解肥胖引起的肝脂肪沉积及肝损伤
肝脏是机体最大的代谢器官,高脂饮食易引起肝脏脂肪沉积,从而导致肝脏变性,会形成非酒精性脂肪肝(NAFLD),严重者会引发肝纤维化甚至肝癌。小鼠在实验结束时进行组织取样,并对小鼠肝脏大小及形态进行拍照记录,结果如图8所示,高脂饮食使得小鼠肝脏堆积脂肪颗粒,组织颜色泛白,经EA治疗后,肝脏颜色恢复正常,进一步将小鼠肝脏进行TG检测以、油红O染色和H&E染色,结果如图9和图10所示,发现EA可以减少肝脏的TG水平,减少肝脏脂质沉积。表明刺囊酸具有改善脂肪变性作用。
综上实验结果,本发明实施例中从体外实验和体内实验两方面显示:
刺囊酸在50μM内对肝细胞活性无明显影响,对肝细胞无明显的毒副作用,有药物应用的前景。
体外细胞实验方面,刺囊酸在浓度为40μM和50μM时显著降低HepG2人肝癌细胞脂质沉积;刺囊酸增加胞内甘油三酯的分解,刺囊酸显著抑制脂合成相关基因的表达,促进脂分解相关基因的表达;刺囊酸能够缓解脂质氧化引起的氧化应激。
体外实验方面,刺囊酸具有预防小鼠脂质沉积的作用,且不是因为能量摄入失衡引起。刺囊酸显著增加小鼠糖吸收,刺囊酸能够预防肥胖导致的II型糖尿病;刺囊酸可以减少肝脏的TG水平,减少肝脏脂质沉积,改善脂肪变性的作用,对非酒精脂肪肝的发生具有预防和治疗的效果。
经过本发明实施例中从体外实验和体内实验的结果可知,刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。
所述的防治包括预防、缓解或治疗中的一种或多种。
所述的药食为药物、或食品中的一种。
所述的药物优选为口服制剂药物。
所述的口服制剂药物为胶囊制剂,软胶囊制剂,口服液制剂,滴丸制剂或片剂制剂药物中的一种。
所述的口服制剂药物中还含有药学上可接受的辅料和/或载体。
作为优选的实施方式,所述刺囊酸的用量优选为50mg/kg-100mg/kg。
本发明与现有技术相比具有以下有益效果:
本发明实施例中确认,在体外细胞实验方面,刺囊酸在浓度为40μM和50μM时显著降低HepG2人肝癌细胞脂质沉积;刺囊酸增加胞内甘油三酯的分解,刺囊酸显著抑制脂合成相关基因的表达,促进脂分解相关基因的表达。刺囊酸能够缓解脂质氧化引起的氧化应激。在体外实验方面,刺囊酸具有减缓小鼠脂质沉积的作用,且不是因为能量摄入失衡引起;刺囊酸显著增加小鼠糖吸收,刺囊酸能够预防肥胖导致的二型糖尿病;刺囊酸可以减少肝脏的TG水平,减少肝脏脂质沉积,改善脂肪变性的作用,对非酒精脂肪肝的发生具有预防和治疗的效果。因而证实了刺囊酸可在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。刺囊酸没有细胞活性变化等副作用的产生,从而为有效预防或治疗II型糖尿病或非酒精脂肪肝提供了一种的低毒性天然小分子药物-刺囊酸。并且,刺囊酸作为一种低毒性天然小分子化合物,价格十分低廉,具有广泛的应用前景。
以上所述仅为本发明的较佳实施例而已,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、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (7)
1.刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用。
2.根据权利要求1所述的刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,其特征在于:所述的防治包括预防、缓解或治疗中的一种或多种。
3.根据权利要求1所述的刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,其特征在于:所述的药食为药物、或食品中的一种。
4.根据权利要求3所述的刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,其特征在于:所述的药物为口服制剂药物。
5.根据权利要求4所述的刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,其特征在于:所述的口服制剂药物为胶囊制剂,软胶囊制剂,口服液制剂,滴丸制剂或片剂制剂药物中的一种。
6.根据权利要求4所述的刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,其特征在于:所述的口服制剂药物中还含有药学上可接受的辅料和/或载体。
7.根据权利要求1所述的刺囊酸在制备防治II型糖尿病或非酒精性脂肪肝的药食中应用,其特征在于:所述刺囊酸的用量为50mg/kg-100mg/kg。
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KR20150097442A (ko) * | 2015-07-27 | 2015-08-26 | 경희대학교 산학협력단 | 발효 더덕 추출물 또는 더덕으로부터 분리된 화합물을 포함하는 비만 또는 비만 관련 질환의 예방, 개선 또는 치료용 조성물 |
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CN101919901A (zh) * | 2009-06-10 | 2010-12-22 | 赵全成 | 皂角总苷元及刺囊酸在制备α-葡萄糖苷酶抑制剂的药物中的应用 |
KR20150097175A (ko) * | 2014-02-18 | 2015-08-26 | 경희대학교 산학협력단 | 발효 더덕 추출물 또는 더덕으로부터 분리된 화합물을 포함하는 비만 또는 비만 관련 질환의 예방, 개선 또는 치료용 조성물 |
KR20150097442A (ko) * | 2015-07-27 | 2015-08-26 | 경희대학교 산학협력단 | 발효 더덕 추출물 또는 더덕으로부터 분리된 화합물을 포함하는 비만 또는 비만 관련 질환의 예방, 개선 또는 치료용 조성물 |
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