CN114774302B - 植物乳杆菌cqpc02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用 - Google Patents
植物乳杆菌cqpc02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用 Download PDFInfo
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Abstract
本发明公开了植物乳杆菌CQPC02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用,所述植物乳杆菌CQPC02,保藏于中国微生物菌种保藏管理委员会普通微生物中心,其保藏编号为CGMCCNo.14491。本发明通过建立动物模型观察了植物乳杆菌CQPC02对狼疮性肾炎的干预作用。通过检测小鼠血清中相关指标和炎症相关细胞因子水平确实了植物乳杆菌CQPC02对狼疮性肾炎的效果,并进一步采用病理学观察、组织的mRNA和蛋白基因的表达检测深入的阐明了植物乳杆菌CQPC02的作用机理。
Description
技术领域
本发明涉及微生物及生物技术领域,具体涉及植物乳杆菌CQPC02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用。
背景技术
四川泡菜是中国传统的天然发酵蔬菜。它的生产历史大约有两千年。悠久的生产和使用历史使其成为中国的标志性食品。经常食用泡菜的面积超过2000万公顷。四川泡菜营养丰富,富含维生素和矿物质元素等有益物质。除了用作配菜外,它还可以与其他食物一起制作美味佳肴。由于四川盆地的地理环境和多民族混合生活的独特生活习惯,四川天然发酵泡菜具备特殊的品质,特别是自然发酵过程中产生了大量的发酵微生物。研究表明,在自然发酵泡菜中发现的微生物可用于食品工业,它们还表现出多种生物活性,包括肠道保护、减肥、抗炎和抗氧化作用。中国四川天然发酵泡菜中的微生物种类繁多,具有良好的开发利用价值,是潜在的益生菌资源来源。
狼疮性肾炎是一种***性红斑狼疮,是复杂的免疫失调肾炎,肾衰竭常后出现狼疮性肾炎,发病后会表现出肾小球肾炎的症状。狼疮性肾炎会引起免疫力下降、***增生和肾小球肾炎等病变,肾脏组织会发生肾小球硬化或弥漫性增生,造成患者的代谢和排毒功能严重受损,最终导致慢性肾功能衰竭,严重的时候会危及生命。大多数狼疮性肾炎发病后表现出B细胞和T细胞的过度激活,T细胞分化为辅助性T细胞,在免疫仅能起到中间过程的角色的作用,但是益生菌存在的情况下可以使更多的T细胞发育为可以化解炎症的调节性T细胞,直接干预肾炎。益生菌的自身结构成分还可以直接以抗原的方式刺激和激活免疫***,起到排出体内毒性物质,减轻炎症的作用。在实验性研究中降植烷能够成功构建狼疮性肾炎模型,在科学研究中得到普遍的认同,已经被用于检验药物和保健食品对狼疮性肾炎作用,降植烷能够引起炎症和加强免疫反应,使T细胞出现高度活化,同时也能使B细胞的反应性大幅度增高,由此促发动物产生多种自身抗体,从而发生狼疮性肾炎。
发明内容
本发明所要解决的技术问题是:提供植物乳杆菌CQPC02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用。
为解决上述技术问题,采用的技术方案为:植物乳杆菌CQPC02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用,所述产品为药品。
所述的植物乳杆菌,其保藏信息如下:
分类命名:植物乳杆菌;
拉丁文名称:Lactobacillus plantarum;
保藏该生物材料样品的单位全称:中国微生物菌种保藏管理委员会普通微生物中心;
地址:北京市朝阳区北辰西路1号院3号;
保藏日期:2017年08月04日保藏中心收到,并登记入册;经保藏中心于2017年08月04日检测,结果:存活;
保藏编号:CGMCC No.14491。
有益效果:植物乳杆菌CQPC02是本研究团队从四川红原采集到的藏族牧民家庭自制自然发酵酸乳中分离鉴定的一株乳酸菌,其基本体外抗性较好,在pH=3.0人工胃液中的存活率超过90%,在0.3%胆盐中的生长效率接近70%。
本申请通过建立动物模型观察了植物乳杆菌CQPC02对狼疮性肾炎的干预作用。通过检测小鼠血清中相关指标和炎症相关细胞因子水平确实了植物乳杆菌CQPC02对狼疮性肾炎的效果,并进一步采用病理学观察、组织的mRNA和蛋白基因的表达检测深入的阐明了植物乳杆菌CQPC02的作用机理。
附图说明
图1小鼠肾脏组织的H&E染色切片;
图2小鼠肾组织中的mRNA表达。
具体实施方式
下面结合实施例对本发明的方法予以进一步地说明,但并不因此而限制本发明。
一种植物乳杆菌的分离纯化方法,其步骤包括:分别取1mL泡菜水样品,用无菌生理盐水进行10倍梯度稀释至10-6,然后取10-4、10-5、10-6,3个梯度的菌液100μL进行平板涂布,37℃培养24-48h,观察并记录菌落形态;挑取平板上不同形态的菌落进行划线分离,经37℃培养48h后,再次挑取平板上不同形态的单菌落进行划线分离,如此重复2至3次,直至得到形态一致的纯的单菌落。
1材料与方法
1.1材料与试剂
植物乳杆菌CQPC02分离鉴定于重庆南岸区的家庭自然发酵泡菜,菌种保藏于中国微生物菌种保藏管理委员会普通微生物中心,专利保藏号为CGMCC No.14491。
SPF级六周龄的雌性C57BL/J6小鼠,体重为23±2g,购于重庆医科大学实验动物中心,生产许可证号为SCXK(渝)2018-0003。本研究中的动物实验经重庆市功能性食品协同创新中动物实验伦理委员会批准,批准号为2021050007B。
降植烷上海麦克林生化科技有限公司;总蛋白(TP)、血清肌酐(SCr)、尿素氮(BUN)、总胆固醇(TC)、甘油三酯(TG)、白蛋白(ALB)测定试剂盒南京建成生物工程研究所;辣根过氧化物酶美国Sigma公司;IL-6、IL-12、TNF-α和IFN-γ检测试剂盒上海酶联生物科技有限公司;TRIzol试剂美国Invitrogen公司;SYBR Green PCRMaster Mix、qPCR引物、SDS-PAGE预制胶、一抗、二抗美国Thermo Fisher Scientific公司;蛋白浓度测定试剂盒美国Bio-Rad公司;其余试剂均为国产分析纯。
1.2仪器与设备
BX43显微镜日本奥林巴斯公司;Varioskan LUX多功能酶标仪、StoponePlus定量PCR仪、iBright成像***美国Thermo Fisher Scientific公司。
1.3方法
1.3.1动物实验
C57BL/J6小鼠饲养在温度为20±1℃和湿度为30%~40%的环境下,实验小鼠可自由采食和饮水,小鼠适应性喂养7d后正式开始进行实验。50只小鼠随机分为5组,每组10只,分别为正常组、模型组、药物阳性对照组、LP-CQPC02低浓度处理(LP-CQPC02-L)组和LP-CQPC02高浓度处理(LP-CQPC02-H)组。实验正式开始后第一天正常组小鼠一次性腹腔注射生理盐水溶液,其余各组小鼠次性腹腔注射0.5mL降植烷。药物阳性对照组小鼠每日按计量10mg/kg灌胃***溶液,LP-CQPC02-L组和LP-CQPC02-H组小鼠每日按108CFU/kg和109CFU/kg的计量灌胃LP-CQPC02,***和LP-CQPC02的灌胃持续12周。12周后对小鼠实施断颈处死后,解剖取小鼠心脏血和内脏待测。
1.3.2尿蛋白检验
实验开始后,每两周将小鼠饲养在代谢笼中,收集小鼠在1日中的排尿,采用总蛋白试剂盒(考马斯亮蓝法)测定24h内小鼠尿液中的蛋白量。
1.3.3血清和组织炎症细胞因子测定
采取心脏取血收集小鼠全血后在1500rpm和4℃下进行离心分离10min,去上层血清进行实验。另外称取0.1g肾脏组织,在肾脏组织中加入0.9mL生理盐水,然后在4℃下进行对肾脏组织进行均质,离心后(4000rpm、10min)取上清液进行实验。最后按检测试剂盒方法测定血清和组织中的IL-6、IL-12、TNF-α和IFN-γ炎症细胞因子水平。
1.3.4血清SCr、BUN、TC、TG和ALB水平测定
采取1.3.3方法收集小鼠血清,按检测试剂盒方法测定小鼠血清的SCr、BUN、TC、TG和ALB水平。
1.3.5抗dsDNA抗体测定
实验开始后每两周采用眼眶取血收集小鼠血液,然后按1.3.3方法制备小鼠血清后使用微滴度板和间接免疫荧光试验测定对抗dsDNA抗体进行测定。
1.3.6组织切片观察
解剖小鼠后,取小鼠的肾脏组织用10%的***固定。脱水48h后,用石蜡包埋组织样品,再进行切片,最后用苏木精-伊红(H&E)燃料进行染色后采用光学显微镜观察组织病理变化。
1.3.7qPCR实验
在0.1g的小鼠肾脏组织中加入0.9mL的生理盐水,然后对组织混合液进行匀浆。然后在使用RNAzol(1.0mL)提取小鼠肾脏组织中的RNA。在260nm和280nm处测定提取到RNA的吸光度值,计算RNA纯度和浓度,并将RNA浓度调整为1μg/μL。进行反转录生成cDNA后,将1μLcDNA、10μL SYBR Green PCR Master Mix、7μL无菌蒸馏水和各1μL的上下游引物溶液混合配制成反应体系溶液。接着在95℃持续60s;95℃持续15s,进行40个循环;55℃持续30s;72℃持续35s;95℃持续30s;55℃持续35s的条件下进行反应,并使用2-ΔΔCt法对其相关基因进行定量分析,实验中使用GAPDH作为内参(表1)。
表1本实验中使用的引物序列
1.4统计学分析
动物实验结束后对所有指标进行三次平行测定,测定得到的结果以平均值表示,同时标注出标准偏差(平均值±标准偏差)。然后采用单因素方差分析得到的各组指标值在P<0.05上是否具有显著差异。
2结果与分析
2.1小鼠尿液中蛋白量
在实验过程中,正常组小鼠的尿液中蛋白量没有明显变化,但其他组小鼠的尿蛋白随着时间的延长而增加。2周后,在LP-CQPC02-L、LP-CQPC02-H和***作用下下,有7、5和4只小鼠出现蛋白尿,模型组小鼠均出现蛋白尿。12周后,狼疮性肾炎小鼠(模型组)的尿蛋白含量高于LP-CQPC02和***处理小鼠和正常组小鼠(表2)。用高浓度LP-CQPC02和***处理的小鼠的尿蛋白输出量与正常小鼠最接近,LP-CQPC02-H小组小鼠的尿蛋白仅高于***组小鼠。
表2实验过程中各组小鼠尿蛋白含量
注:不同字母表示各组之间在P<0.05水平上具有显著差异,相同字母表示无显著差异,下同。
2.2小鼠血清和肾脏组织中IL-6、IL-12、TNF-α和IFN-γ细胞因子水平
由表3和表4所示,正常组小鼠血清和肾组织的IL-6、IL-12、TNF-α和IFN-γ细胞因子水平显著低于其他各组(P<0.05)。相对模型组小鼠,LP-CQPC02和***作用后,狼疮性肾炎小鼠(模型组)的IL-6、IL-12、TNF-α和IFN-γ细胞因子水平被显著下调(P<0.05),且高浓度LP-CQPC02(LP-CQPC02-H)和***下调这些细胞因子水平的能力更强。
表3小鼠血清IL-6、IL-12、TNF-α和IFN-γ水平
表4小鼠肾脏组织IL-6、IL-12、TNF-α和IFN-γ水平
2.3小鼠血清SCr、BUN、TC、TG、TP和ALB水平
模型组小鼠的血清SCr、BUN、TC和TG水平高于其他组,而正常小鼠的血清SCr、BUN、TC和TG水平最低(P<0.05,表5)。与模型组小鼠相比,经LP-CQPC02和***处理小鼠的SCr、BUN、TC和TG水平也有所降低,但任高于正常小鼠。LP-CQPC02可使肾炎小鼠的SCr、BUN、TC和TG水平接近正常水平。另外,TP和ALB血清水平呈相反趋势,各组水平由高到低依次为正常组、***组、LP-CQPC02-H组、LP-CQPC02-H组和对照组。
表5小鼠血清SCr、BUN、TC、TG、TP和ALB水平
2.4dsDNA阳性率
在治疗后第2、第4、第6、第7、第10和第12周,通过间接免疫荧光法检测自身抗体dsDNA。结果表明,从第6周末开始,模型组所有小鼠均呈阳性,狼疮性肾炎诱导均成功。LP-CQPC02-L组小鼠在第8周末检测为阳性,LP-CQPC02-H组和***组小鼠均在第10周末检测为阳性,这意味着LP-CQPC02和***减慢了小鼠患上狼疮性肾炎的速度,且LP-CQPC02和***的效果接近(表6)。
表6各组狼疮性肾炎小鼠的dsDNA阳性率
2.5肾脏组织病理学观察
由图1所示,模型组小鼠肾脏组织出现较为严重的病变,大量的肾小球现实出形态不规则,部分肾小球出现破裂现象,组织间出现严重的炎症细胞浸润现象。正常组小鼠肾小球和细胞结构完整,LP-CQPC02和***都能够减轻狼疮性肾炎导致的肾组织病变,减轻肾脏组损伤。同时,高浓的LP-CQPC02(LP-CQPC02-H)和***的效果较好,都能够促进肾组织的组织形态接近正常组。
2.6小鼠肾组织的mRNA表达
如图2所示,正常组小鼠肾组织中NF-κB、TGF-β1、VEGF、ICAM-1和VCAM-1的mRNA表达最弱,IκB-α的表达最强。而模型组IκB-α表达最弱,NF-κB、TGF-β1、VEGF、ICAM-1和VCAM-1表达最强。与模型组相比,LP-CQPC02和***能显著上调模型组肾组织IκB-α的表达,下调NF-κB、TGF-β1、VEGF、ICAM-1和VCAM-1的表达(P<0.05),高浓度LP-CQPC02(LP-CQPC02-H)和***的作用强于低浓度LP-CQPC02(LP-CQPC02-L)。
尿蛋白在肾脏病的发生和发展中表现出重要的作用,复杂的综合型肾病中大量蛋白尿是主要病症之一,狼疮性肾炎的临床主要表现就是出现蛋白尿。本研究中建模成果的狼疮性肾炎小鼠也表现出蛋白尿,而LP-CQPC02和***均能够降低狼疮性肾炎小鼠尿液中的蛋白量,起到缓解狼疮性肾炎的作用,且随着浓度的升高,LP-CQPC02的效果也随之增加。血清肌酐和尿素氮是含氮有机化合物,是蛋白质代谢的最终产物。当肾功能正常时,这些小分子从肾小球滤过。当肾脏受损时,肾小球的过滤能力降低,血清肌酐和尿素氮含量增加,因此血清肌酐和尿素氮水平的升高可作为临床诊断肾损伤的指标。过多的胆固醇和甘油三酯是导致高脂血症的原因,当肾病恶化到一定程度时,高钾血症的特征将并存。因此,胆固醇和甘油三酯也可被视为肾功能减退和肾损害的指标。肾病综合征患者因为长期蛋白尿的原因导致血清中的总蛋白显著降低。白蛋白是血清中最常见的蛋白质,白蛋白常用于治疗严重疾病,包括在临床上用于治疗肾病引起的水肿,肾功能不良的情况下总蛋白和白蛋白含量的降低。由此可见,保持血清总蛋白和白蛋白的含量是维持肾功能正常的重要途径。本研究中LP-CQPC02和***也体现出抑制狼疮性肾炎导致血清肌酐、尿素氮、胆固醇、甘油三酯升高和总蛋白、白蛋白降低的能力,通过调节这些肾病相关指标起到保护肾脏的作用。
IL-12在狼疮性肾炎自身免疫反应中起重要作用,狼疮性肾炎发病期IL-12水平升高。狼疮性肾炎的特征之一是出现大量自身抗体,IL-12可以促进细胞直接产生这种自身抗体,IL-12水平的提高进一步导致这种自身抗体的大量产生,加重病症。IFN-γ作为一种炎症介质,参与了肾炎的整个免疫炎症过程,临床上显示肾小球肾炎患者的IFN-γ水平显著升高。肾炎发生后,与炎症相关的细胞因子发生变化,血液中与炎症相关的细胞因子,如IL-6、IL-12、TNF-α和IFN-γ的含量也会明显增加。本研究中狼疮性肾炎小鼠的炎症细胞因子IL-6、IL-12、TNF-α和IFN-γ水平均大幅度上升,而LP-CQPC02和***能够显著抑制这种变化。
狼疮性肾炎中自身反应性抗体的必要过程是通过突变和类别转换为IgG。血浆中IgG抗dsDNA抗体和免疫复合物等物质在肾小球中的大量沉积导致肾脏损伤,进而引起炎症造成炎症细胞的侵润。另外,高浓度的dsDNA抗体被发现几乎只出现于狼疮性肾炎中,dsDNA抗体对狼疮性肾炎显示出特异性,因此可以作为诊断***性狼疮性肾炎的指标。临床上狼疮性肾炎患者的肾脏组织多出现肾小球细胞增殖改变和肾小球中性粒细胞浸润等现象。本研究的实验性指标也印证了这些表现,LP-CQPC02和***均能标志性的抑制dsDNA抗体的出现和保护肾脏组织的病理变化。
NF-κB信号转导途径参与多种病理过程,因此其信号通路已成为药物或生物活性物质干预的潜在靶点。NF-κB是一种重要的转录因子,激活后,它激活多种免疫和炎症相关基因,包括TNF、IL-1、IL-2、IL-6、IL-8、IL-10、粘附分子(ICAM-1、VCAM-1)。NF-κB参与多种生理病理过程和肾脏疾病的发病机制。在肾炎中,身体的炎症反应太强烈,导致肾脏自身组织受损。在治疗中,抑制NF-κB的活性可以减少炎症损伤。NF-κB的活性与IκB-α密切相关。当IκB-α表达减弱时,NF-κB与IκB-α分离,起到促进炎症、损伤细胞和组织的作用;当IκB-α表达增加时,解离的NF-κB会迅速结合到新合成的IκB上,从而降低NF-κB的活性,保护机体。NF-κB的激活可引起包括TGF-β1在内的炎症生长因子,TGF-β1可作为调节产物通过正反馈途径激活NF-κB。TGF-β1是机体中最要的促纤维化因子且与包括肾脏在内的脏器纤维化有关,在肾脏疾病中TGF-β1常发生异常表达。肾脏中的TGF-β1是由足细胞和肾小球系膜细胞(GMCs)分泌产生的,足细胞通过与内皮细胞之前的相关作用分泌TGF-β1,而GMCs则是在免疫球蛋白(IgA)的刺激分泌TGF-β1。在肾脏出现损害后肾小球内皮细胞能够通过VEGF的刺激进行TGF-β1的分泌。TGF-β1和VEGF的表达出现异常是狼疮性肾炎发病后的典型表现,因此调节这两个表达可以有效的控制狼疮性肾炎,对IL-6、IL-12、TNF-α和IFN-γ等炎症细胞因子起到抑制作用。NF-κB激活进入细胞核并与靶序列结合,并调节相关基因的转录活性,如ICAM-1、VCAM-1、TNF-α、IL-6等。这些因子基因的增强和启动包含NF-κB的结合位点。ICAM-1和VCAM-1是两种粘附因子,均属于免疫球蛋白超家族。ICAM-1和VCAM-1通过结合白细胞表面的受体和随后白细胞跨内皮细胞转移,介导白细胞与内皮细胞的粘附。白细胞的积累会阻塞毛细血管,激活的白细胞会释放大量有毒物质,损伤神经元和胶质细胞,从而加重组织损伤,加重肾炎。此外,白细胞还会释放一些炎症介质和细胞因子,加剧炎症反应,吸引更多白细胞进入组织,形成恶性循环。
本研究观察了一株从自然发酵泡菜中新发现的植物乳杆菌LP-CQPC02,通过动物模型验证了LP-CQPC02对狼疮性肾炎的干预作用。实验结果显示LP-CQPC02能够缓解狼疮性肾炎造成的小鼠血清和组织炎症病变,特别是LP-CQPC02能够调节狼疮性肾炎的标志性表达TGF-β1。现在临床上使用的狼疮性肾炎治疗药物普遍有一定的副作用,本研究中***作为一种副作用小的药物被作为药物阳性对照,通过对比也发现LP-CQPC02的作用能够接近***,可以更健康的干预狼疮性肾炎。由此可见,LP-CQPC02具有作为益生菌起到干预狼疮性肾炎的作用。
Claims (2)
1.一种植物乳杆菌CQPC02在制备用于预防和/或治疗狼疮性肾炎的产品中的应用,其特征在于,所述植物乳杆菌CQPC02保藏于中国微生物菌种保藏管理委员会普通微生物中心,其保藏编号为CGMCCNo.14491。
2.如权利要求1所述的应用,其特征在于:所述产品为药品。
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