CN114404431B - 甜菊双糖苷在制备防治肠缺血再灌注损伤的组合物中的应用 - Google Patents
甜菊双糖苷在制备防治肠缺血再灌注损伤的组合物中的应用 Download PDFInfo
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- CN114404431B CN114404431B CN202210151189.9A CN202210151189A CN114404431B CN 114404431 B CN114404431 B CN 114404431B CN 202210151189 A CN202210151189 A CN 202210151189A CN 114404431 B CN114404431 B CN 114404431B
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Abstract
本发明涉及生物医疗领域,具体涉及甜菊双糖苷在制备用于防治肠缺血再灌注损伤的组合物中的应用。本发明还涉及含有治疗有效量的甜菊双糖苷的药物组合物在制备用于防治肠缺血再灌注损伤的药物中的应用。该组合物明显改善肠缺血再灌注诱导的肠组织损伤、肝组织损伤以及抑制炎症因子的表达和提高其生存率,效果显著,安全无毒,无副作用,具有广阔的应用前景。
Description
技术领域
本发明涉及生物医疗领域,具体涉及甜菊双糖苷在制备防治肠缺血再灌注损伤的组合物中的应用。
背景技术
肠缺血再灌注损伤在围手术期具有很高的发病率,死亡率。临床上尚未成功开发出有针对性的治疗肠缺血再灌注损伤的有效药物,探索肠I/R损伤的机制及有效的防治策略,是目前临床上亟待解决的问题。
甜叶菊为一种低热值的天然糖料植物,可代替蔗糖和合成甜味剂,具有极高的经济价值。其主要成分为甜菊糖苷(Stevia),甜菊糖苷的甜度约为蔗糖的200~300倍,热值仅为蔗糖的 1/300,可作为代糖用于食品工业中,还具有抗炎、抗氧化、抗肿瘤细胞等多种生物活性,具极为广泛的潜在药用价值。甜菊双糖苷(Steviolbioside)是存在于甜菊叶中的一种罕见的甜菊糖苷衍生物,其结构名称为:(4α)-13-[(2-O-β-D-Glucopyranosyl-β-D-glucopyranosyl)oxy]kaur-16-en-18-oic acid;分子式为:C32H50O13;分子量为:642.73;CAS号为41093-60-1;化学结构如下所示:
甜菊双糖苷具有与甜菊糖苷相同的萜烯分子骨架(内-贝壳杉烯酸,ent-kaurenoic acid),可能同样具有潜在的药用价值,然而,现阶段关于甜菊双糖苷的生物活性报道较少,仅存在其抗肿瘤活性的相关报道。
基于此,有必要进一步探索甜菊双糖苷潜在的生物利用价值。
发明内容
为实现上述目的,特采用以下技术方案:
本发明涉及甜菊双糖苷在制备用于防治肠缺血再灌注损伤的组合物中的应用。
一些实施方式中,所述肠缺血再灌注损伤发生于围手术期。
一些实施方式中,所述肠缺血再灌注损伤包括肠缺血再灌注诱导的肠组织损伤和肠缺血再灌注诱导的肝脏损伤中的至少一种。
一些实施方式中,所述肠缺血再灌注损伤为肠系膜上动脉夹闭导致的围术期肠损伤。
一些实施方式中,所述的组合物为食品、保健品或药物。
一些实施方式中,所述的组合物为液体制剂或固体制剂。
一些实施方式中,所述的组合物为片剂、胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、霜剂、喷雾剂、滴剂或贴剂。
一些实施方式中,所述的组合物中含有有效量的甜菊双糖苷。
一些实施方式中,所述的组合物为药物组合物,受试者为哺乳动物。
一些实施方式中,所述受试者为小鼠或人。
一些实施方式中,所述的组合物在受试者中抑制炎症因子mRNA的表达水平,所述炎症因子mRNA为IL-1β和/或IL-6的mRNA;及/或,
所述的组合物抑制受试者血清中AST和ALT水平。
本发明还涉及含有治疗有效量的上述甜菊双糖苷的药物组合物在制备用于防治上述肠缺血再灌注损伤的药物中的应用。
本发明中,甜菊双糖苷明显改善肠缺血再灌注诱导的肠组织损伤,提高其生存率,并且减轻肝损伤,效果显著,毒性低,副作用小。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是本发明一个实施例中小鼠的生存率的结果图;数据采用Log-rank(Mantel-Cox)test;
图2是本发明一个实施例中小鼠的肠组织HE染色图;其中,A对应假手术组、B对应肠I/R组、C对应肠I/R+甜菊双糖苷组;图片标尺为50μm;
图3是本发明一个实施例中小鼠的肠组织HE染色定量评分结果;
图4是本发明一个实施例中小鼠的肠组织炎症因子mRNA表达水平的条形图;
图5是本发明一个实施例中小鼠的血清中谷丙转氨酶(AST)、谷草转氨酶(ALT)水平的条形图;
上述附图1-5中,图中标注符号每次出现,具有如下含义:Sham指假手术组、I/R指肠 I/R组、I/R+Steviolbioside指肠I/R+甜菊双糖苷组;“*”表示与I/R组比较差异具有统计学意义p<0.05;“**”表示与I/R组比较差异具有统计学意义p<0.01;“***”表示与I/R组比较差异具有统计学意义p<0.001;
上述附图1-5中,涉及英文,具有如下含义:Precent survival(%)表示生存百分率(%); Time(Hour)表示时间(小时);HE score表示HE评分(即HE染色定量评分);IL-6mRNA expression level表示IL-6mRNA表达水平;IL-1b mRNA expression level表示IL-1b mRNA表达水平;U/L表示单位/升。
具体实施方式
下面结合附图、实施方式和实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书的保护范围。
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实施方式和实施例的目的,不是旨在于限制本发明。
术语:
本文所使用的术语“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列项目中任一个项目,也包括相关所列项目的任意的和所有的组合,所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明书的是,当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时,应当理解,在本申请中,该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案,还毫无疑问地包括均用“逻辑或”连接的技术方案。比如,“A及/或B”包括A、B和A+B三种并列方案。又比如,“A,及/或,B,及/或,C,及/或,D”的技术方案,包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案),也包括A、B、 C、D的任意的和所有的组合,也即包括A、B、C、D中任两项或任三项的组合,还包括A、 B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。
本文中,“优选”、“较佳”、“更佳”等仅为描述效果更好的实施方式或实施例,应当理解,并不构成对本发明防护范围的限制。
本发明中,“第一方面”、“第二方面”、“第三方面”等中,术语“第一”、“第二”、“第三”等仅用于描述目的,不能理解为指示或暗示相对重要性或数量,也不能理解为隐含指明所指示的技术特征的重要性或数量。而且“第一”、“第二”、“第三”等仅起到非穷举式的列举描述目的,应当理解并不构成对数量的封闭式限定。
本发明中,以开放式描述的技术特征中,包括所列举特征组成的封闭式技术方案,也包括包含所列举特征的开放式技术方案。
本发明中,“防治”包括预防、治疗、辅助治疗等概念。
本发明中,“围手术期”(或称围术期)是围绕手术的一个全过程,从病人决定接受手术治疗开始,到手术治疗直至基本康复,包含手术前、手术中及手术后的一段时间,具体是指从确定手术治疗时起,直到与这次手术有关的治疗基本结束为止,时间约在术前5~7天至术后7~12天。
本发明中,“组合物”可以为多种物质的组合,进一步地,可以为组合使用,也可以为组合而成的混合物。
本发明中,“有效量”是指该术语所对应的组分在受试者中实现治疗、预防、减轻和/或缓解特定疾病、病症和/或症状的剂量,本发明中,如无特别限定,指实现治疗、预防、减轻和/或缓解肠缺血再灌注损伤的剂量。
本发明中,“受试者”是动物,优选为哺乳动物,更优选地为人,受试者包括但不限于食品的食用者,保健品的使用者和具有疾病、病症和/或症状的患者。本发明中的受试者优选为哺乳动物。术语“哺乳动物”主要是指温血脊椎类哺乳动物,包括但不限于:如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠(如大鼠、小鼠)、猪、牛、羊、马、人等,优选灵长类动物,更优选为人。以甜菊双糖苷的受试者为例,指接受甜菊双糖苷或其组合物以治疗、预防、减轻和/或缓解疾病、病症、症状的动物。
本发明中,“患者”是指一种动物,优选为哺乳动物,更好的为人。术语“哺乳动物”主要是指温血脊椎类哺乳动物,包括但不限于:如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪、牛、羊、马、人等,优选灵长类动物,更优选为人。
本发明中,“载体”包括但不限于甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠,一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、吐温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁。
本发明中,“药物组合物”指具有药学上预防和/或治疗效果、可用于药物的组合物。
如本文所用,“药物”包括在在体内或体外提供生理和/或药理作用的任何药剂、化合物、组合物或混合物,且往往提供的是有益效果。所述“药物”在体内产生生理和/或药理作用的范围没有特别限制,可以为全身效果,也可以只在局部产生效果。所述“药物”的活性没有特别限制,可以为能与其它物质发生相互作用的活性物质,也可以为不发生相互作用的惰性物质。
如本文所用,“治疗有效量”是指针对疾病、病症和/或症状,将引起个体的生物学或医学响应的药物活性成分的量,例如为个体带来生理和/或药理上积极效果的本发明化合物的量,所述生理和/或药理上积极效果包括但不限于降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等。
本发明中,“药学上可接受的”指在合理医学判断范围内适于施用患者且与合理益处/风险比相称的那些配体、材料、组合物和/或剂型。
本发明中,“药学上可接受的载体”指药学上可接受的材料、组合物或媒剂,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。如本文所用,语言“药学上可接受的载体”包括与药物施用相容的缓冲剂、注射用无菌水、溶剂、分散介质、包衣、抗细菌剂及抗真菌剂、等渗剂及吸收延迟剂及诸如此类。在与配制物中其他成分兼容且对患者无害的意义上,每种体必须为“药学上可接受的”。合适的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉、马铃薯淀粉及经取代或未经取代的β-环糊精;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;(4)粉状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油类,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯类,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液;(19)乙醇;(20)磷酸盐缓冲液;及(21)药物配制物中所采用的其他无毒兼容物质。
肠缺血再灌注损伤(I/R)是外科常见的病理变化,是发生于肠道组织的再灌注损伤,被证实在严重感染、创伤休克的致死性疾病发生与进展中起到重要作用,研究其防治策略,有利于逆转疾病进程,降低死亡风险。现阶段研究表明,细胞凋亡是小肠缺血再灌注损伤的主要机制,其诱导机制包括:氧自由基直接损伤,或炎症递质释放、细菌移位的间接促进作用。本发明中,发明人推测,甜菊双糖苷在本申请中用于防治肠缺血再灌注损伤可能是基于如下的作用机理:通过促进肠紧密连接蛋白的表达,维持肠粘膜屏障,同时促进肠干细胞增殖修复肠粘膜,减少细菌移位,同时,减少细胞凋亡水平及炎症反应,减轻肠损伤。
本发明的第一方面,涉及甜菊双糖苷在制备用于防治肠缺血再灌注损伤的组合物中的应用。甜菊双糖苷少量存在于甜叶菊中,甜度强度比0.5%和10%蔗糖溶液分别高44倍和18.51 倍,与现已广泛用于甜味剂的甜菊糖苷相比,甜味更加明显而不具有苦涩味(Physico-chemical and sensory characteristics of steviolbioside synthesizedfrom stevioside and its application in fruit drinks and food.J Food SciTechnol.2017,54(1):185-195.)。甜菊双糖苷还对人肝癌细胞Hep3B、人乳腺癌细胞MDA-MB-231和人胰腺癌细胞BxPC-3有明显的抑制作用,具有潜在的药用价值(Production of abioactive sweetener steviolbioside via specific hydrolyzing ester linkage ofstevioside with a,β-galactosidase.Food Chem.2016Apr 1;196:155-160)。然而,目前关于甜菊双糖苷的应用报道很少,特别是在缺血再灌注损伤中的作用目前尚无报道。
一些实施方式中,所述肠缺血再灌注损伤发生于围手术期。
一些实施方式中,所述肠缺血再灌注损伤包括肠缺血再灌注诱导的肠组织损伤和肠缺血再灌注诱导的肝脏损伤中的至少一种。一些实施例中,所述肠缺血再灌注损伤为肠缺血再灌注诱导的肠组织损伤。一些实施例中,所述肠缺血再灌注损伤为肠缺血再灌注诱导的肝脏损伤。一些实施例中,所述肠缺血再灌注损伤为肠缺血再灌注诱导的肠组织损伤和肠缺血再灌注诱导的肝脏损伤。
一些实施方式中,所述肠缺血再灌注损伤为肠系膜上动脉夹闭导致的围术期肠损伤。
一些实施方式中,所述的组合物为食品、保健品或药物。
一些实施方式中,所述的组合物为食品。一些实施方式中,所述食品选自饮料、酸奶、果汁、冰淇淋、面包、饼干、谷类、健康棒和酱。一些实施方式中,食品包含选自燕麦片粥、乳酸发酵食物、抗性淀粉、饮食纤维、糖类、蛋白质和糖基化蛋白质的载体材料。
一些实施方式中,所述的组合物为液体制剂或固体制剂。
一些实施方式中,所述的组合物为片剂、胶囊剂、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、霜剂、喷雾剂、滴剂或贴剂。
一些实施方式中,所述的组合物中含有有效量的甜菊双糖苷。
一些实施方式中,所述组合物包括:(a)甜菊双糖苷;和(b)辅料和/或载体。一些实施方式中,所述组合物包括:甜菊双糖苷和辅料。一些实施方式中,所述组合物包括甜菊双糖苷和载体。一些实施方式中,所述组合物包括甜菊双糖苷、辅料和载体。
一些实施方式中,所述的组合物为药物组合物。进一步地,药物组合物包括:(a)甜菊双糖苷;和(b)药学上可接受的载体。一些实施例中,药物组合物包括甜菊双糖苷和载体。进一步地,载体为1~3mg/mL的磷酸缓冲盐溶液(phosphate buffer saline,PBS)。一些实施例中,药物组合物构成如下:甜菊双糖苷在甜菊双糖苷和PBS磷酸缓冲盐溶液混合物中的浓度为3~5mg/mL,举例的浓度如,3mg/mL、3.5mg/mL、4mg/mL、4.5mg/mL、5mg/mL,等。
一些实施方式中,药物组合物中甜菊双糖苷的含量为3~5mg/mL,举例的浓度如,3mg/mL、3.5mg/mL、4mg/mL、4.5mg/mL、5mg/mL,等。
一些实施方式中,所述的组合物为药物组合物,受试者为哺乳动物。进一步地,所述受试者为小鼠或人。一些实施方式中,所述受试者为小鼠。一些实施方式中,所述受试者为人。
一些实施方式中,所述的组合物在受试者中抑制炎症因子mRNA的表达水平。进一步地,所述炎症因子mRNA为IL-1β和/或IL-6的mRNA。一些实施方式中,所述的组合物在受试者中抑制炎症因子IL-1βmRNA的表达水平。一些实施方式中,所述的组合物在受试者中抑制炎症因子IL-6mRNA的表达水平。一些实施方式中,所述的组合物在受试者中抑制炎症因子IL-1βmRNA的表达水平和IL-6mRNA的表达水平。一些实施方式中,受试者中炎症因子 IL-1βmRNA的表达水平为1.05~1.2,举例如1.05、1.1、1.103、1.12、1.15、1.18、1.2,等。一些实施方式中,受试者中抑制炎症因子IL-6mRNA的表达水平为41~42,举例如41、41.1、 41.3、41.5、41.6、41.687、41.8、42,等。一些实施方式中,受试者中炎症因子IL-1βmRNA 的表达水平为1.1~1.2,IL-6mRNA的表达水平为41~42。一些实施方式中,受试者中炎症因子IL-1βmRNA的表达水平为1.103,IL-6mRNA的表达水平为41.687。
受试者血清转氨酶水平可用于评估肝脏功能或肝损伤,常用的血清转氨酶检测有丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)。ALT与AST主要分布在肝细胞内,如果肝脏受损或损坏,肝细胞中的转氨酶便进入血液,显示ALT和AST水平异常升高。一些实施方式中,所述的组合物抑制受试者血清中AST和ALT水平。一些实施方式中,受试者中AST的表达水平为62~63,举例如62、62.1、62.3、62.5、62.616、62.8、63,等。一些实施方式中,受试者血清中ALT的表达水平为43.5~44.5,举例如43.5、43.6、43.8、43.994、44.1、44.5,等。一些实施方式中,受试者血清中AST的表达水平为62~63,ALT的表达水平为43.5~44.5。一些实施方式中,受试者血清中AST的表达水平为62.616,ALT的表达水平为43.994。
本发明还涉及含有治疗有效量的上述甜菊双糖苷的药物组合物在制备用于防治上述肠缺血再灌注损伤的药物中的应用。
“药物组合物”、“药物”、“肠缺血再灌注损伤”等的定义与前文一致。
一些实施方式中,治疗有效量为3~5mg/剂,举例的有效量如,3mg/剂、3.5mg/剂、4mg/ 剂、4.5mg/剂、5mg/剂,等。
一些实施方式中,所述的药物组合物含有3~5mg的甜菊双糖苷,举例如,3mg、3.5mg、 4mg、4.5mg、5mg,等。
根据上述应用,本发明还提供了一种肠缺血再灌注损伤的预防或治疗方法,包括给予所需患者治疗有效量的甜菊双糖苷。也即,使患者施用治疗有效量的甜菊双糖苷。
施用方式
本发明的化合物(甜菊双糖苷)或其药物组合物的剂型和施用方式没有特别限制。
代表性的施用方式包括但并不限于:口服、直肠、肠胃外(静脉内、肌肉内或皮下)注射、和局部给药、吸入。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,具体例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。如悬浮液可包含悬浮剂,具体例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水或非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。由活性成分在无菌条件下与药学上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合而成。
可以理解的是,本发明实施例的药物可以添加不同的药物学可以接受的辅料从而制备成合适的临床剂型,这些临床剂型包括但不限于上文所述剂型。这些药物学可以接受的辅料包括但不限于稀释剂、润湿剂、黏合剂、崩解剂、润滑剂、色香味调节剂、溶剂、增溶剂、助溶剂、乳化剂、抗氧剂、金属络合剂、惰性气体、防腐剂、局部止痛剂、pH调节剂、等渗或等张调节剂等。进一步地:稀释剂,如淀粉、蔗糖、纤维素类、无机盐类等;润湿剂,如水、乙醇等;黏合剂,如淀粉浆、糊精、糖、纤维素衍生物、明胶、聚维酮、聚乙二醇等;崩解剂,如淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、联羧甲基纤维素钠、交联聚维酮、表面活性剂、跑腾崩解剂等;润滑剂,如滑石粉、硬脂酸钙、硬脂酸镁、十二烷基硫酸镁、微粉硅胶、聚乙二醇等;色香味调节剂,如色素、香料、甜味剂、胶浆剂、矫臭剂等,具体如品红、木糖醇;溶剂,如水、油、乙醇、甘油、丙二醇、聚乙二醇、二甲基亚砜、液体石蜡、脂肪油、乙酸乙酯等;增溶剂,如吐温类、卖泽类、聚氧乙烯脂肪醇醚类、肥皂类、硫酸化物、磺酸化物等;助溶剂,如有机酸(如枸橼酸)及其盐类、酰胺及胺类化合物、无机盐、聚乙二醇、聚维酮以、甘油等;乳化剂,如司盘类、吐温类、卖泽类、苄泽类、甘油脂肪酸酯、高级脂肪酸盐、硫酸化物、磺酸化物、阿拉伯胶、西黄耆胶、明胶、果胶、磷脂、琼脂、海藻酸钠、氢氧化物、二氧化硅、皂土等;助悬剂,如甘油、糖浆、阿拉伯胶、西黄耆胶、琼脂、海藻酸钠、纤维素衍生物、聚维酮、卡波普、聚乙烯醇、触变胶等;抗氧剂,如亚硫酸盐、焦亚硫酸盐、亚硫酸氢盐、抗坏血酸、没食子酸及其酯类等;金属络合剂,如乙二胺四乙酸二钠、多羧酸化合物等;惰性气体,如氮气、二氧化碳等;防腐剂,如尼泊金类、有机酸及其盐(如苯甲酸钠)、季铵类化合物、醋酸氯己定、醇类、酚类以及挥发油等;局部止痛剂,如苯甲醇、三氯叔丁醇、利多卡因以及普鲁卡因等;pH调节剂,如盐酸、硫酸、磷酸、酒石酸、醋酸、氢氧化钠、碳酸氢钠、乙二胺、葡甲胺、磷酸盐、醋酸盐、枸橼酸、枸橼酸盐等;等渗或等张调节剂,如葡萄糖、氯化钠、枸橼酸钠、山梨醇以及木糖醇等。可以理解的是,本发明实施例所述的稀释剂也可以叫填充剂,在药物制剂中发挥作用相同;本发明实施例所述的水为满足药剂要求的水,例如注射用水、纯化水等,油为注射用油;本发明实施例所述的防腐剂也可以称作抗菌剂,在制剂中发挥抑制微生物生长、延长保质期等作用;本发明实施例的润滑剂含有助流剂、抗黏剂等;本发明实施例所述的糖可以是糖粉或者是糖浆,糖的种类也不限于葡萄糖;本发明实施例所述的香料包括但不限于香精。
在一些实施方式中,甜菊双糖苷的剂量为10~50mg/kg,进一步可以选自10~20mg/kg、 20~40mg/kg、30~50mg/kg,等,举例如10mg/kg、20mg/kg、30mg/kg、40mg/kg、50mg/kg,等。
在一些实施方式中,给药频次为至少1次/日,举例如1次/日,等。
在一些实施方式中,甜菊双糖苷的施用方式为注射。进一步地,在一些实施例中,注射部位为腹腔注射。
在一些实施方式中,施用剂量为:腹腔注射40mg/kg甜菊双糖苷溶液(将甜菊双糖苷标准品加入PBS磷酸缓冲盐溶液,按照4mg/mL配制,震荡、常温溶解制得)。
在一些实施方式中,所述液体制剂选自口服溶液、混悬液、乳液和糖浆剂。
在一些实施方式中,患者为人或鼠。
在一些实施方式中,患者为人。
在一些实施方式中,患者为小鼠。
以下为一些具体实施例。
以下具体实施例中未写明的实验参数,优先参考本申请文件中给出的指引,还可以参考本领域的实验手册或本领域已知的其它实验方法,或者参考厂商推荐的实验条件。
以下具体实施例中涉及的原料和试剂,可以通过市售得到,或者本领域技术人员能够根据已知手段制备。
以下实施例中,甜菊双糖苷购买自成都德思特生物技术有限公司,批号:DST201107-057,纯度:HPLC≥98%,在4℃下保存。
实施例1甜菊双糖苷能够提高小鼠肠缺血再灌注损伤的生存率
1实验材料
1.1实验动物
实验选取6-8周龄雄性C57BL/6J小鼠60只,体重16~22g,购买于南方医院动物中心,饲养地点为南方医科大学南方医院SPF级动物实验部,动物饲养过程中涉及的操作均通过伦理委员会批准,符合动物伦理要求。
1.2试剂和仪器
甜菊双糖苷(成都德思特生物技术有限公司);异氟烷(瑞沃德生命科技有限公司);微血管动脉夹(成都北美佳瑞生物技术有限公司);无菌丝线(宁波医用缝针有限公司);生理盐水(石家庄四药有限公司);磷酸缓冲盐溶液(phosphate buffer saline,PBS)pH 7.4 缓存液(Gibco);1mL无菌注射器(北京索莱宝科技有限公司);无菌纱布、无菌棉签(广州卓升生物科技有限公司);外科手术器械(上海碧云天生物技术有限公司);氯化钠生理盐水(广东光华科技股份有限公司)。
2实验方法与结果
2.1甜菊双糖苷配制:将甜菊双糖苷标准品加入PBS磷酸缓冲盐溶液,按照4mg/mL配制,震荡、常温溶解。
2.2动物实验
2.2.1小鼠肠系膜上动脉I/R模型的建立(肠缺血再灌注动物模型为经典的肠系膜上动脉夹闭构建的围术期肠损伤模型):手术前禁食12h,自由饮水,异氟烷吸入麻醉小鼠,用无创性微血管动脉夹夹闭肠系膜上动脉,阻断血流。肠缺血持续60min后,松开动脉夹恢复供血,实行肠道再灌注,经检查腹腔内无出血后,用无菌丝线逐层缝合腹膜、肌肉和皮肤。阻断后和再灌注时经皮下注射37℃左右的温生理盐水0.5mL进行液体复苏,观察并记录小鼠的生存灌注时间。
2.2.2实验分组:
将6-8周60只C57BL/6小鼠随机均分为假手术组(Sham)、肠I/R组(I/R)和肠I/R 组+甜菊双糖苷(I/R+Steviolbioside)。
2.2.2.1假手术组(Sham):仅行开腹,分离肠系膜上动脉但不夹闭血管,其余操作同正常I/R模型;
2.2.2.2肠I/R组(I/R):正常建立肠I/R模型;
2.2.2.3肠I/R组+甜菊双糖苷(I/R+Steviolbioside):术前1h,小鼠腹腔注射40mg/kg 的甜菊双糖苷溶液(溶剂为PBS溶液),建立肠I/R模型。
2.3实验结果
图1的数据结果显示,肠I/R组小鼠的死亡率为50%,肠I/R组+甜菊双糖苷组小鼠的死亡率我23.8%,说明和肠I/R组相比,肠I/R组+甜菊双糖苷组小鼠的生存率显著提高。
实施例2:甜菊双糖苷减缓小鼠肠缺血再灌注诱导的肠组织病理形态学损伤
1实验材料
1.1实验动物
实验选取6-8周龄雄性C57BL/6J小鼠60只,体重16~22g,购买于南方医院动物中心,饲养地点为南方医科大学南方医院SPF级动物实验部,动物饲养过程中涉及的操作均通过伦理委员会批准,符合动物伦理要求。
1.2试剂和仪器
甜菊双糖苷(成都德思特生物技术有限公司);异氟烷(瑞沃德生命科技有限公司);微血管动脉夹(成都北美佳瑞生物技术有限公司);无菌丝线(宁波医用缝针有限公司);生理盐水(石家庄四药有限公司);磷酸缓冲盐溶液(phosphate buffer saline,PBS)pH7.4缓存液(Gibco);1ml无菌注射器(北京索莱宝科技有限公司);无菌纱布、无菌棉签(广州卓升生物科技有限公司);外科手术器械(上海碧云天生物技术有限公司);氯化钠生理盐水(广东光华科技股份有限公司);苏木精-伊红染色(北京雷根生物公司);无水乙醇(广东光华科技股份有限公司);二甲苯(广东光华科技股份有限公司);石蜡(莱卡);4%多聚甲醛(北京索莱宝科技有限公司);中性树胶(Solarbio);甘油(Sigma);全自动荧光显微镜(奥林巴斯)。
2实验方法与结果
2.1甜菊双糖苷配制:将甜菊双糖苷标准品加入PBS磷酸缓冲盐溶液,按照4mg/ml配制,震荡、常温溶解。
2.2动物实验
2.2.1小鼠肠系膜上动脉I/R模型的建立(肠缺血再灌注动物模型为经典的肠系膜上动脉夹闭构建的围术期肠损伤模型):手术前禁食12h,自由饮水,异氟烷吸入麻醉小鼠,用无创性微血管动脉夹夹闭肠系膜上动脉,阻断血流。肠缺血持续60min后,松开动脉夹恢复供血,实行肠道再灌注,经检查腹腔内无出血后,用无菌丝线逐层缝合腹膜、肌肉和皮肤。阻断后和再灌注时经皮下注射37℃左右的温生理盐水0.5ml进行液体复苏,灌注2小时后,取小鼠肠组织进行待检。
2.2.2实验分组:
将6-8周24只C57BL/6小鼠随机均分为假手术组(Sham)、肠I/R组(I/R)和肠I/R 组+甜菊双糖苷(I/R+Steviolbioside)。
2.2.2.1假手术组(Sham):建立I/R模型时,仅行开腹,分离肠系膜上动脉但不夹闭,其余操作一致;
2.2.2.2肠I/R组(I/R):正常建立肠I/R模型;
2.2.2.3肠I/R组+甜菊双糖苷(I/R+Steviolbioside):术前1h,小鼠腹腔注射40mg/kg 的甜菊双糖苷溶液(溶剂为PBS溶液),建立肠I/R模型。
2.3肠组织病理形态学变化检测
将新鲜的肠组织放入4%多聚甲醛浸泡固定24h,之后进行脱水、包埋、切片,然后进行苏木精-伊红染色,用中性树胶进行封片,在全自动荧光显微镜下观察肠组织病理形态学变化,之后用改良Chiu氏法对肠粘膜损伤进行分级评分。
2.4实验结果
如图2和图3,从HE染色的组织切片观察,假手术组小鼠的肠粘膜上皮完整,杯状细胞清晰可见(图2,A;评分见图3,Sham)。而肠I/R组小鼠的小肠在再灌注60min时顶部肠绒毛脱落,毛细血管扩张(图2,B;评分见图3,I/R))。肠I/R组+甜菊双糖苷组小鼠的小肠在再灌注60min时与I/R造模组相比,出血有显著改善(图2,C;评分见图3, I/R+Steviolbioside)。图2为各组处理小鼠的组织学损伤Chiu’s评分。数据表示为均数±标准差(n=6)。说明给予甜菊双糖苷处理之后小鼠肠组织上述病变显著改善。
实施例3:甜菊双糖苷抑制肠缺血再灌注模型小鼠肠组织中炎症因子的表达
1实验材料
1.1实验动物
实验选取6-8周龄雄性C57BL/6J小鼠24只,体重16~22g,购买于南方医院动物中心,饲养地点为南方医科大学南方医院SPF级动物实验部,动物饲养过程中涉及的操作均通过伦理委员会批准,符合动物伦理要求。
1.2试剂和仪器
甜菊双糖苷(成都德思特生物技术有限公司);异氟烷(瑞沃德生命科技有限公司);微血管动脉夹(成都北美佳瑞生物技术有限公司);无菌丝线(宁波医用缝针有限公司);生理盐水(石家庄四药有限公司);磷酸缓冲盐溶液(phosphate buffer saline,PBS)pH7.4缓存液(Gibco);1ml无菌注射器(北京索莱宝科技有限公司);无菌纱布、无菌棉签(广州卓升生物科技有限公司);外科手术器械(上海碧云天生物技术有限公司);氯化钠生理盐水(广东光华科技股份有限公司);TRIZOL裂解液(Invitrogen);氯仿(广东光华);异丙醇(广东光华);无水乙醇(广东光华);DEPC水(Sigma);SYBR Green荧光染料(东洋纺);ReverTra Ace qPCR RT Kit(东洋纺);PCR仪(德国Eppendorf公司);荧光定量 PCR仪(美国应用生物系统AB公司)。
2实验方法与结果
2.1甜菊双糖苷配制:将甜菊双糖苷标准品加入PBS磷酸缓冲盐溶液,按照4mg/ml配制,震荡、常温溶解。
2.2动物实验
2.2.1小鼠肠系膜上动脉I/R模型的建立(肠缺血再灌注动物模型为经典的肠系膜上动脉夹闭构建的围术期肠损伤模型):手术前禁食12h,自由饮水,异氟烷吸入麻醉小鼠,用无创性微血管动脉夹夹闭肠系膜上动脉,阻断血流。肠缺血持续60min后,松开动脉夹恢复供血,实行肠道再灌注,经检查腹腔内无出血后,用无菌丝线逐层缝合腹膜、肌肉和皮肤。阻断后和再灌注时经皮下注射37℃左右的温生理盐水0.5ml进行液体复苏,灌注2小时后,取小鼠肠组织进行待检。
2.2.2实验分组:
将6-8周24只C57BL/6小鼠随机均分为假手术组(Sham)、肠I/R组(I/R)和肠I/R 组+甜菊双糖苷(I/R+Steviolbioside)。
2.2.2.1假手术组(Sham):建立I/R模型时,仅行开腹,分离肠系膜上动脉但不夹闭,其余操作一致;
2.2.2.2肠I/R组(I/R):正常建立肠I/R模型;
2.2.2.3肠I/R组+甜菊双糖苷(I/R+Steviolbioside):术前1h,小鼠腹腔注射40mg/kg的甜菊双糖苷溶液(溶剂为PBS溶液),建立肠I/R模型。
2.3炎症因子mRNA表达
2.3.1 RNA提取方法:
2.3.1.1取20-50mg的肠组织置于2ml无RNA酶EP管中,加入500μl TRIZOL裂解液后匀浆。
2.3.1.2匀浆液中加入100μl的氯仿,摇晃15-20次,室温静置1-2min。
2.3.1.3 12,000rpm,4℃离心15min,吸取上层水相至新的无RNA酶的1.5ml EP管中。
2.3.1.4加入等体积的异丙醇,摇匀15-20次,室温静置10min。
2.3.1.5 12,000rpm,4℃离心10min,弃上清,加入1ml 80%乙醇(用DEPC水配制),摇晃振荡之后7500rpm,4℃离心5min。
2.3.1.6弃上清,7500rpm,4℃离心1min,吸干残留的乙醇,室温放置5-10min,加入50-100μl的DEPC水重悬。RNA产物置于-80℃冰箱保存备用。
2.3.2提取的RNA进行逆转录反应:
2.3.2.1取1μl提取的RNA加入到6μl的Nuclease-freeWater中,在PCR扩增仪上65℃变性5min。
2.3.2.2变性后立即取出冰上冷却,向反应体系中加入5×reaction buffer 2μl、RT Enzyme mix 0.5μl、Prime mix 0.5μL,轻微震荡后离心3-5s。
2.3.2.3将反应体系置于PCR扩增仪上,37℃15min逆转录,98℃5min使酶失活。
2.3.2.4反应结束后加入190μl的无菌水,得到cDNA溶液。
2.3.3 Real-time PCR反应:
2.3.3.1反应体系中加入6μl SYBR Green、1μl炎症因子引物及5μl cDNA溶液后置于荧光定量PCR仪中。
2.3.3.2 Real-time PCR反应条件:Cycling:stage 95℃15s;60℃1min,40个循环;Melt cure stage:95℃15s;60℃1min;95℃30s;60℃15s。
2.4实验结果
如图4,数据显示I/R+Steviolbioside组肠组织中炎症因子IL-1β、IL-6mRNA的表达水平与I/R组相比明显下调(p<0.05),其中,Sham组IL-1β、IL-6mRNA的表达水平分别为1.00, 1.00;I/R组IL-1β、IL-6mRNA的表达水平分别为1.900,120.307;I/R+Steviolbioside组IL-1β、 IL-6mRNA的表达水平分别为1.103,41.687;实验结果说明甜菊双糖苷抑制肠缺血再灌注模型小鼠肠组织中炎症因子的表达。
实施例4:甜菊双糖苷抑制肠缺血再灌注模型小鼠肝脏损伤
1实验材料
1.1实验动物
实验选取6-8周龄雄性C57BL/6J小鼠24只,体重16~22g,购买于南方医院动物中心,饲养地点为南方医科大学南方医院SPF级动物实验部,动物饲养过程中涉及的操作均通过伦理委员会批准,符合动物伦理要求。
1.2试剂和仪器
甜菊双糖苷(成都德思特生物技术有限公司);异氟烷(瑞沃德生命科技有限公司);微血管动脉夹(成都北美佳瑞生物技术有限公司);无菌丝线(宁波医用缝针有限公司);生理盐水(石家庄四药有限公司);磷酸缓冲盐溶液(phosphate buffer saline,PBS)pH 7.4缓存液(Gibco);1mL无菌注射器(北京索莱宝科技有限公司);无菌纱布、无菌棉签(广州卓升生物科技有限公司);外科手术器械(上海碧云天生物技术有限公司);氯化钠生理盐水(广东光华科技股份有限公司);天门冬氨酸氨基转移酶(GOT/AST)测试盒、丙氨酸氨基转移酶(谷丙转氨酶/ALT/GPT)测试盒(南京建成生物工程研究所),台式低温高速离心机(美国THERMO公司)。
2实验方法与结果
2.1甜菊双糖苷配制:将甜菊双糖苷标准品加入PBS磷酸缓冲盐溶液,按照4mg/mL配制,震荡、常温溶解。
2.2动物实验
2.2.1小鼠肠系膜上动脉I/R模型的建立(肠缺血再灌注动物模型为经典的肠系膜上动脉夹闭构建的围术期肠损伤模型):手术前禁食12h,自由饮水,异氟烷吸入麻醉小鼠,用无创性微血管动脉夹夹闭肠系膜上动脉,阻断血流。肠缺血持续60min后,松开动脉夹恢复供血,实行肠道再灌注,经检查腹腔内无出血后,用无菌丝线逐层缝合腹膜、肌肉和皮肤。阻断后和再灌注时经皮下注射37℃左右的温生理盐水0.5mL进行液体复苏,灌注2小时后,取小鼠肠组织进行待检。
2.2.2实验分组:
将6-8周24只C57BL/6小鼠随机均分为假手术组(Sham)、肠I/R组(I/R)和肠I/R 组+甜菊双糖苷(I/R+Steviolbioside)。
2.2.2.1假手术组(Sham):建立I/R模型时,仅行开腹,分离肠系膜上动脉但不夹闭,其余操作一致;
2.2.2.2肠I/R组(I/R):正常建立肠I/R模型;
2.2.2.3肠I/R组+甜菊双糖苷(I/R+Steviolbioside):术前1h,小鼠腹腔注射40mg/kg的甜菊双糖苷溶液(溶剂为PBS溶液),建立肠I/R模型。
2.3血清中ALT、AST水平
2.3.1小鼠心脏采血及血清制备
2.3.1.1在麻醉状态下,仰卧位固定小鼠,沿剑突至两侧腋窝下剪开胸腔暴露心脏,直视下针尖朝向小鼠右心室,直接由小鼠右心室进针抽血,直至无明显血液流出。
2.3.1.2将抽出的血液转移至1.5mL抗凝离心管中,12000rpm 4℃15min离心。
2.3.1.3取上清,置于-20℃保存。
2.3.2根据天门冬氨酸氨基转移酶(GOT/AST)测试盒、丙氨酸氨基转移酶(谷丙转氨酶 /ALT/GPT)测试盒说明书,分别对血清中的AST、ALT水平进行检测。
2.4实验结果
图5数据显示I/R+Steviolbioside组血清中的AST、ALT水平与I/R相比明显下调(p<0.05),其中,Sham组水平分别为22.014,25.498;I/R组AST、ALT水平分别为89.591,65.208; I/R+Steviolbioside组AST、ALT水平分别为62.616,43.994;实验结果说明甜菊双糖苷减轻肠缺血再灌注模型小鼠的肝损伤。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。除非和本申请的发明目的和/或技术方案相冲突,否则,本发明涉及的引用文献以全部内容、全部目的被引用。本发明中涉及引用文献时,相关技术特征、术语、名词、短语等在引用文献中的定义也一并被引用。本发明中涉及引用文献时,被引用的相关技术特征的举例、优选方式也可作为参考纳入本申请中,但以能够实施本发明为限。应当理解,当引用内容与本申请中的描述相冲突时,以本申请为准或者适应性地根据本申请的描述进行修正。
以上所述实施方式和实施例的各技术特征可以进行任意合适方式的组合,为使描述简洁,未对上述实施方式和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,都应当认为在本说明书记载的范围中。
以上所述实施例仅表达了本发明的几种实施方式,但并不能因此理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,得到的等价形式同样落于本发明的保护范围。还应当理解,本领域技术人员在本发明提供的技术方案的基础上,通过合乎逻辑的分析、推理或者有限的试验得到的技术方案,均在本发明所附权利要求的保护范围内。因此,本发明专利的保护范围应以所附权利要求为准,说明书和附图可用于解释权利要求的内容。
Claims (10)
1.甜菊双糖苷在制备用于防治肠缺血再灌注损伤的组合物中的应用,其特征在于,所述肠缺血再灌注损伤是肠缺血再灌注诱导的肠组织损伤和肝脏损伤。
2.根据权利要求1所述的应用,其特征在于,所述肠缺血再灌注损伤发生于围手术期。
3.根据权利要求1所述的应用,其特征在于,所述肠缺血再灌注损伤为肠系膜上动脉夹闭导致的围术期肠损伤。
4.根据权利要求1所述的应用,其特征在于,所述的组合物为药物。
5.根据权利要求4所述的应用,其特征在于,所述的组合物为液体制剂或固体制剂。
6.根据权利要求4所述的应用,其特征在于,所述的组合物的剂型选自如下任意的组或其合适组合:
(1)片剂、胶囊剂、颗粒剂、粉剂、散剂、丸剂、丹剂、膏剂、霜剂、混悬剂或溶液剂;
(2)口服液、口含剂、注射剂、栓剂、喷雾剂、滴剂或贴剂。
7.根据权利要求1所述的应用,其特征在于,所述的组合物中含有有效量的甜菊双糖苷。
8.根据权利要求1所述的应用,其特征在于,所述的组合物为药物组合物,受试者为哺乳动物。
9.根据权利要求8所述的应用,其特征在于,所述受试者为小鼠或人。
10.根据权利要求1~9中任一项所述的应用,其特征在于,所述的组合物在受试者中抑制炎症因子mRNA的表达水平,所述炎症因子mRNA为IL-1β和/或IL-6的mRNA;及/或,
所述的组合物抑制受试者血清中AST和ALT水平。
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