CN114886912A - 酵母多糖Zymosan-A在肠道辐射损伤防护中的应用 - Google Patents
酵母多糖Zymosan-A在肠道辐射损伤防护中的应用 Download PDFInfo
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Abstract
本发明提供了酵母多糖Zymosan‑A在肠道辐射损伤防护中的应用。经过研究发现酵母多糖Zymosan‑A具有保护生物体遭受电离辐射时的肠道损伤,为生物体的肠道损伤提供了新的治疗方案。
Description
技术领域
本发明涉及医药领域,特别是涉及酵母多糖Zymosan-A在肠道辐射损伤防护中的应用。
背景技术
电离辐射可造成多种类型辐射损伤,其中肠道组织对电离辐射极度敏感,是核与辐射大剂量照射时伤病员常见的病理损伤,受照剂量≥10Gy时可导致受照者肠道组织大量变性坏死、出血等,引发肠型放射病,伤员一般在照后短期内死亡(5-10天),死亡率百分之百。这类损伤不仅在核战争中常见,在平时突发核事故时也屡见不鲜。此外,肠道电离辐射损伤也是腹部肿瘤患者放射治疗中常见的并发症,限制肿瘤病人放疗剂量和疗效。尽管目前国内外在骨髓性放射病防治研究方面取得较大进展,但对大剂量照射所致放射性肠损伤仍无理想的治疗手段,是放射医学领域亟待解决的关键难题之一。
一直以来国内外围绕肠道辐射损伤防护作用和机制进行了大量研究,初步结果提示辐射导致肠道损伤是一个涉及多种细胞凋亡以及炎症激活等多方面机制的复杂过程,最终导致机体死亡的原因主要有肠道消化吸收障碍、水电酸碱平衡被打破、肠道菌群移位等。而在防护手段研究方面,干细胞移植、细胞因子、化学药物等虽然也取得了一定的研究进展(比如:FDA批准上市的防护剂WR2721),但是防护效果还不够理想,且毒副作用较大,主要存在的问题是防护效果的高效与低毒难以兼顾,从而限制了其临床应用。因此,不断开拓新的研究思路,寻找新的高效低毒的肠道辐射损伤防护剂并揭示其作用机制,对于突破肠道辐射损伤防护这一世界性难题具有重大意义。
Zymosan A又称酵母多糖(CAS号:58856-93-2),主要由酵母真菌壁制备,是一类通过β-1,3糖苷键连接的葡聚糖。它也是第一个被发现具有免疫活性的葡聚糖,其来源广泛、价格便宜,毒副作用小。研究发现其具有抗肿瘤活性、抗菌以及免疫调节作用,静脉注射Zymosan A能够增强巨噬细胞吞噬能力10倍以上,具有显著地肿瘤抑制作用。已有研究发现,Zymosan A能够通过TLR2--MYD88--NF-KB--IL-6/G-CSF信号通路发挥对造血系统的辐射损伤防护作用(参见文献:Du J,Cheng Y,Dong S,et al.:Zymosan-a Protects theHematopoietic System from Radiation-Induced Damage by Targeting TLR2Signaling Pathway.Cell Physiol Biochem 2017;43:457-464;Du J,Zhang P,Zhao H,etal.:The Mechanism for the Radioprotective Effects of Zymosan-A on MiceRadiation Injury.J CELL MOL MED.2018Apr;22(4):2413-2421)。但是尚未有文献报道Zymosan A对肠道的辐射损伤防护作用。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供一种酵母多糖Zymosan-A在肠道辐射损伤防护中的应用,用于解决现有技术中对于电离辐射生物体肠道损伤缺乏有效的治疗手段的问题。
本发明一方面提供了Zymosan A或者Zymosan A药学上可接受的盐在制备保护肠道免受电离辐射损伤药物中的用途。
进一步地,所述药物具有至少以下功效之一:
保护小肠绒毛长度和数量,
保护隐窝上皮细胞免受损伤。
进一步地,所述Zymosan A的,其结构式如图3所示。
所述Zymosan A可以通过市购获得,也可以通过本领域技术人员自行制备,例如,本文中所使用的来自invivogen(Z4250)。
进一步地,所述电离辐射可以为放疗引起或者其他意外遭受辐射情况,因此电离辐射可以是生物体全身或者部分肢体遭受电离辐射。
进一步地,所述药物主要针对的对象为哺乳动物。所述哺乳动物优选为啮齿目动物、偶蹄目动物、奇蹄目动物、兔形目动物、灵长目动物等。所述灵长目动物优选为猴、猿或人。
当所述药物治疗对象为人体时,所述肠道包括不限于大肠、小肠、回肠以及结肠等。所述药物在医生的指导下服用。
药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
进一步地,所述药物可在对象遭受辐射之前、辐射时、或者辐射后服用。
本发明的另一方面提供了一种保护肠道免受电离辐射损伤药物,所述药物包含治疗有效剂量的Zymosan A或者Zymosan A药学上可接受的盐。
进一步地,所述药物具有至少以下功效之一:
保护小肠绒毛长度和数量,
保护隐窝上皮细胞免受损伤。
进一步地,所述药物中还包含人体可接受的辅料或者载体。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、粉剂、及其组合。
本发明的另一方面提供了一种保护肠道免受电离辐射损伤药物组合物,所述药物组合物的有效成分之一为治疗有效剂量的Zymosan A或者Zymosan A药学上可接受的盐。
所述药物或者药物组合物的形式无特殊限制,可以为固体、液体、凝胶、半流质、气雾等各种物质形式。
以药物组合物为例,本发明的组合物可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物,可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。
本发明的药物、制剂或者药物组合物可通过常规的方式施用于所需的对象(如人和非人哺乳动物)。代表性的施用方式包括(但并不限于):口服或注射(包括静脉注射、静脉滴注、肌肉注射或皮下注射等中的一种或多种)等中的一种或多种给药途径。使用药物组合物时,是将安全有效量的药物施用于哺乳动物。当然,具体剂量和方法还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
如上所述,本发明的酵母多糖Zymosan-A在肠道辐射损伤防护中的应用,具有以下有益效果:
经过研究发现酵母多糖Zymosan-A具有保护生物体遭受电离辐射时的肠道损伤,为生物体的肠道损伤提供了新的治疗方案。
附图说明
图1显示为本发明实施例1实验结果图。
图2显示为本发明实施例2实验结果图。
图3显示为Zymosan A的化学结构式。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。须知,下列实施例中未具体注明的工艺设备或装置均采用本领域内的常规设备或装置。此外应理解,本发明中提到的一个或多个方法步骤并不排斥在所述组合步骤前后还可以存在其他方法步骤或在这些明确提到的步骤之间还可以插入其他方法步骤,除非另有说明;还应理解,本发明中提到的一个或多个设备/装置之间的组合连接关系并不排斥在所述组合设备/装置前后还可以存在其他设备/装置或在这些明确提到的两个设备/装置之间还可以插入其他设备/装置,除非另有说明。而且,除非另有说明,各方法步骤的编号仅为鉴别各方法步骤的便利工具,而非为限制各方法步骤的排列次序或限定本发明可实施的范围,其相对关系的改变或调整,在无实质变更技术内容的情况下,当亦视为本发明可实施的范畴。
实施例1 Zymosan A能够显著减轻照后小鼠所受到的肠道辐射损伤
6周龄雄性SPF级C57BL/6小鼠购于上海斯莱克实验动物有限责任公司,体重20克左右,小鼠分为PBS对照组和Zymosan A(invivogen,Z4250)给药组(n=6),给药组照射前24小时和照射前2小时分别予以小鼠腹腔注射Zymosan-A(25mg/kg/次),Zymosan-A用无菌生理盐水溶解,对照组小鼠给予腹腔注射相同体积的无菌生理盐水。随后给予小鼠单次全身60Coγ射线照射,照射剂量为9.0Gy,剂量率为1Gy/min。照射后分别于第4和84小时取小鼠小肠组织用于病理HE染色分析。
病理HE染色操作步骤如下:
1.固定:小鼠颈椎脱臼处死,置于75%酒精缸中浸泡片刻,打开小鼠腹腔,截取靠近胃下小肠的一段,再以纵向剖开,用PBS冲洗3遍,取材长约1CM,厚约5MM,放入4%多聚甲醛溶液中24小时以便固定。
2.脱钙:将固定好的小肠组织放入脱钙液浸泡24小时脱钙。
3.脱水:然后置于包埋盒中流水冲洗30分钟去除固定液,逐步置于由低到高不同浓度(70%、80%、90%、100%)的酒精中进行脱水处理。
4.透明与包埋:将小肠组织置于透明剂二甲苯I和II中进行透明处理,处理完毕后放置于熔化的石蜡中,再放入熔蜡箱保温。等到石蜡完全浸入小肠组织后进行包埋,石蜡经过冷却凝固成块。
5.切片、烤片与脱蜡:将包埋好并冷却凝固的石蜡组织块固定在切片机上切成薄片5~8um厚。薄片放到热水中烫平后贴到载玻片上,恒温烘箱(45℃)烘干,再用二甲苯脱去薄片中的石蜡以备染色。
6.染色与封片:将切片用苏木精和伊红染液染色完成后用纯酒精脱水,再经二甲苯透明化后滴上树胶封片。
7.观察记录:切片晾干后即可用显微镜观察拍照,根据需要选择合适的放大倍数。
如图1,通过观察病理切片发现:与给药组相比,对照组小肠绒毛断裂变短和数目减少,形态异常,黏膜变薄,隐窝上皮细胞减少。这说明Zymosan-A能够显著减轻小鼠小肠所受到的辐射损伤。
实施例2 Zymosan A能够有效促进小鼠小肠类器官照后的增殖与分化
6周龄雄性SPF级C57BL/6小鼠购于上海斯莱克实验动物有限责任公司,体重20克左右。照射前12小时取小鼠肠隐窝进行类器官培养,并给予类器官Zymosan-A(10μg/ml)刺激,对照组给予等体积的生理盐水。随后给予类器官6.0Gy的60Coγ射线照射,照后继续培养类器官7天,并对类器官的大小及出芽情况做统计学分析。
小肠类器官培养操作步骤如下:
1.小鼠颈椎脱臼处死,75%酒精浸泡后无菌条件下取小肠组织15cm,剪成3~5cm长的小段,用1ml移液枪吸取含三抗的冷PBS从小肠两端反复冲洗肠腔,然后纵向剪开,将里面的内容物彻底冲洗干净。
2.将小段小肠组织垂直剪成米粒大小于六孔板中,吸管移入50ml离心管,加入15ml含三抗的冷PBS,用吸管反复3次吹打冲洗去上清。
3.小肠组织加入15ml PBS–EDTA,冰浴摇床2000rpm快速摇1小时,期间每过半小时用漩涡振荡器剧烈震荡3次,每次持续1分钟,间隔2分钟。
4.小肠组织悬浊液用70nm小滤器过滤,滤液移入15ml离心管中,4℃条件下290G离心5分钟取沉淀。
5.细胞沉淀中加入10ml含三抗的冷PBS重悬,4℃条件下200G离心5分钟,反复清洗两次,离心后的下层沉淀即为小肠隐窝细胞。
6.24孔板置于细胞培养箱预热,按照S1:S2:C=1:1:18的比例配制完全培养基备用,然后按照完全培养基:基质胶=1:1的比例配制混合培养基。
7.按照小肠隐窝细胞:混合培养基=1:50的比例混匀,然后在预热的24孔板中每孔中心加入50ul混合细胞液,放置30分钟待培养基凝固后每孔加入0.5ml完全培养基,置于细胞培养箱进行小肠类器官的培养。
如图2,通过观察小肠类器官培养情况,发现Zymosan-A可以提高受照小鼠隐窝形成类器官能力,表现为Zymosan-A给药组较对照组,其隐窝形成类器官数目增多,单个类器官出芽数目增多、体积更大。这表明Zymosan-A对小肠类器官具有辐射损伤防护作用,能够有效促进小鼠小肠类器官照后的增殖与分化。
以上的实施例是为了说明本发明公开的实施方案,并不能理解为对本发明的限制。此外,本文所列出的各种修改以及发明中方法、组合物的变化,在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对本发明进行了具体的描述,但应当理解,本发明不应仅限于这些具体实施例。事实上,各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。
Claims (6)
1.Zymosan A或者Zymosan A药学上可接受的盐在制备保护肠道免受电离辐射损伤药物中的用途。
2.根据权利要求1所述的用途,其特征在于,药物具有至少以下功效之一:
保护小肠绒毛长度和数量,
保护隐窝上皮细胞免受损伤。
3.一种保护肠道免受电离辐射损伤药物,其特征在于,所述药物包含治疗有效剂量的Zymosan A或者Zymosan A药学上可接受的盐。
4.根据权利要求4所述的药物,其特征在于,所述药物具有至少以下功效之一:
保护小肠绒毛长度和数量,
保护隐窝上皮细胞免受损伤。
5.根据权利要求4所述的药物,其特征在于:所述药物中还包含人体可接受的辅料或者载体。
6.一种保护肠道免受电离辐射损伤药物组合物,其特征在于:所述药物组合物的有效成分之一为治疗有效剂量的Zymosan A或者Zymosan A药学上可接受的盐。
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