CN113215030A - 约氏乳杆菌eu03及其用途 - Google Patents
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- CN113215030A CN113215030A CN202110391018.9A CN202110391018A CN113215030A CN 113215030 A CN113215030 A CN 113215030A CN 202110391018 A CN202110391018 A CN 202110391018A CN 113215030 A CN113215030 A CN 113215030A
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Abstract
本发明属于微生物技术领域,公开了一种约氏乳杆菌EU03(Lactobacillus johnsonii EU03)及其用途。本发明所述约氏乳杆菌具有抗氧化活性,可改善心肌梗死(MI)大鼠血清酶学指标,修复心肌损伤;并可改善MI大鼠心功能指标;使受损心脏恢复正常心肌形态学作用。
Description
技术领域
本发明属于微生物技术领域,具体涉及一种约氏乳杆菌EU03(Lactobacillusjohnsonii EU03)及其用途,尤其是一种能够改善心肌损伤、心功能以及心肌形态学的约氏乳杆菌 EU03及其用途。
背景技术
心血管疾病和相关疾病,如高胆固醇血症、高血压、肥胖、糖尿病,是全世界死亡的主要原因,并且造成了经济损失。心肌梗死(MI)作为引起心血管疾病死亡的重要原 因,已受到广泛关注。目前,治疗MI的药物在开发过程中存在多种问题。临床上早期采 用糖皮质激素类药物治疗MI,随后发现此类药物会增加MI患者心脏破裂的风险4]。非 甾体类抗炎药也曾广泛应用于MI的治疗中。然而,在使用过程中发现此类药物也会增加 不良心血管事件的发生,加剧胃肠道出血。冠状动脉扩张药物如硝酸酯类药物,在使用 过程中会产生耐药性,此外,硝酸酯类药物的持续治疗还会对缺血后的心肌细胞活力产 生负面影响,导致动物心肌梗塞模型中的梗塞面积增加。钙拮抗剂如二氢吡啶类在治疗 时可引起反射性心动过速等不良反应。β受体阻滞剂被报道静脉应用存在一定风险且具有 疲劳,头晕,抑郁和性功能障碍等不良反应。调节血脂他汀类药物近年也被证实可以降 低心血管风险事件的发生,但有文献报道长期的他汀类药物疗法引起的唯一严重不良事 件(即他汀类药物的不良反应)是肌病(定义为肌肉疼痛或无力并伴有血肌酸激酶血药 浓度大幅增加)。综上,当前治疗MI药物都有一定程度的不良反应,因此,开发无副作 用且改善MI的药物还需研究人员进一步探究。
补充益生菌可降低心血管风险且没有副作用。益生菌可能通过不同的机制发挥作用, 包括建立适当的肠道平衡,改善营养吸收和免疫功能,以及抵御病原体。在肠道益生菌中,乳杆菌属(Lactobacillus sp.)是革兰氏阳性菌,被归类为乳酸菌。各种乳杆菌菌株 通过影响脂质胆固醇代谢、免疫炎症反应、氧化应激反应以及涉及的肠道代谢物(包括 氧化三甲胺TMAO、短链脂肪酸SCFAs、脂多糖LPS和胆汁酸BAs)在心血管相关疾病 预防和治疗中得到广泛研究。乳杆菌产生的代谢物,尤其是抗菌物质,可以抑制病原体 的生长,调节肠道菌群(GM)紊乱。多糖是一种类似益生元的代谢物,在心血管相关疾 病的预防和治疗中也发挥着重要作用。它们是GM的保护者,是乳杆菌对心血管相关疾 病的主要贡献者。
中国公布的细菌名录包括13种乳酸菌,它们被公认为安全成分,广泛用于食品生产。 国家食品药品监督管理局以公告的形式对名单进行了补充 (http://samr.cfda.gov.cn/WS01/CL1975/228275.html,[2010]65号)包括L.acidophilus,L.casei,L.crispatus,L.delbrueckii,L.fermentum,L.gasseri,L.helveticus,L.johnsonii, L.paracasei,L.plantarum,L.reuteri,L.rhamnosus和L.salivarius。鉴于研究报道对MI 有防治作用的乳杆菌仅有L.rhamnosus,从肠道中筛选和鉴定功能性乳杆菌研究已成为 热点领域。
因此本发明中的约氏乳杆菌具有对MI大鼠的心脏保护作用,改善MI大鼠心脏功能指标,具有开发成功能性食品的潜力,且对MI的临床治疗具有重要的指导意义。
发明内容
有鉴于此,本发明旨在克服上述现有技术中存在的缺陷,提供一种从肠道中分离的 乳杆菌,该乳杆菌可改善心肌损伤、心功能以及心肌形态学。
为达到上述目的,本发明的技术方案是这样实现的:
本发明提供了一种约氏乳杆菌EU03(Lactobacillus johnsonii EU03),于2020年10 月9日保藏于中国微生物菌种保藏管理委员会普通微生物中心(CGMCC),保藏地址为 北京市朝阳区北辰西路1号院3号,保藏编号为CGMCC No.20845,状态为存活。
在一个实施方案中,本案考察了约氏乳杆菌EU03对心肌梗死导致的心肌损伤的改善作用,结果显示,约氏乳杆菌EU03的摄入可使MI大鼠具有抗氧化活性,降低大鼠氧 化应激,改善MI大鼠血清酶学指标,提高SOD含量,降低MDA和LDH含量,起到修 复心肌损伤的作用。
在一个实施方案中,本案考察了约氏乳杆菌EU03对心肌梗死导致的心功能指标下降的改善作用,结果显示,约氏乳杆菌EU03的摄入可使心脏室壁变厚,并增强室壁运 动和收缩能力,提高血流动力学指标。
在一个实施方案中,本案考察了约氏乳杆菌EU03对心肌梗死导致的心肌细胞缺血坏死、心脏形态和胶原纤维遭到破坏的改善作用,结果显示,约氏乳杆菌EU03的摄入 可以降低MI大鼠的梗死面积,降低炎性浸润,改善了心肌间质水肿和纤维化程度。
因此本发明提供了约氏乳杆菌EU03在制备改善心肌损伤、心功能以及心肌形态学的产品中的应用;
其中,所述改善心肌损伤为提高MI大鼠的抗氧化活性和血清酶学指标,降低氧化应 激,提高SOD含量,降低MDA和LDH含量;所述改善心功能为降低Toll样受体(TLR) 的刺激,从而减少心脏重塑标志物MMP9的产生,改善心功能;所述改善心肌形态学为 通过抑制TGF-β蛋白水平及其下游蛋白的表达水平,减少梗死心脏炎症期后伤口重塑中 的胶原沉积,并抑制成肌纤维细胞的数量,改善心肌纤维化。
本发明所述产品包括但不限于药物。
进一步地,本发明提供了含有所述约氏乳杆菌EU03的菌剂。
优选的,所述菌剂中约氏乳杆菌EU03的活菌数大于108CFU/mL。
本发明所书菌剂可以按常规方法制备。
在一些实施方案中,所述菌剂的制备方法为,将约氏乳杆菌EU03按照体积分数2%的接种量接种至MRS液体培养基中,在37℃兼性厌氧条件下培养24h,取出离心,弃 去上清,用灭菌水洗两次后,用灭菌水调整菌液浓度为108CFU/mL。
本发明所书制备方法中,所述离心为在4℃的条件下进行离心操作,离心机转速为10000r/min,离心的时间为10min。
本发明中,菌落的计数方法为:将冻存的约氏乳杆菌转移至灭菌的脱脂乳培养基中, 42℃培养4h,反复活化3代,使菌种活力恢复,置于4℃保存备用。将活化的约氏乳杆 菌分别转种至MRS液体培养基中,37℃静置培养16h,以此作为种子液。用灭菌水依 次10倍稀释至106倍稀释液。取100~106倍稀释液50μL分别涂布于MRS琼脂平皿上, 每个稀释度做3个平行,37℃恒温培养24h后,对菌落数在30~300个的平板计数,求 平均值,以CFU/mL为单位,确定其中1μL乳杆菌培养液相当于105CFU活菌数。
在某些实施方案中,所述受试者是指哺乳动物,包括但不限于,人,啮齿类动物(小鼠,大鼠,豚鼠),狗,马,牛,猫,猪,猴,黑猩猩。
在某些优选的实施方案中,所述受试者是人。
本发明还提供了一种发酵食品,以所述约氏乳杆菌EU03作为发酵剂发酵生产的食品。
所述发酵食品为发酵乳制品、发酵豆制品或发酵果蔬制品。
本发明还提供了一种药物制剂,包括有效剂量的约氏乳杆菌EU03和药学上可接受的辅料。
术语解释:
如本文中所使用的,“SOD”是指超氧化物歧化酶又称超氧歧化酶,是一类能催化超氧阴离子自由基(O2-)歧化为H2O2和O2的酶。“MDA”是指丙二醛,是膜脂过氧化最重 要的产物之一,它的产生能加剧膜的损伤。“LDH”是指乳酸脱氢酶,为含锌离子的金属 蛋白,分子量为135-140kD,是糖无氧酵解及糖异生的重要酶系之一,可催化丙酸与L- 乳酸之间的还原与氧化反应,也可催化相关的α-酮酸。“CTn-T”是指心肌肌钙蛋T,是是 心肌肌肉收缩的调节蛋白,CTn-T的大部分是以C-T-I的复合物形式存在于细丝上, 6%—8%以游离的形式存在于心肌细胞浆中。“CK-MB”是指肌酸激酶同工酶,主要分布 于心肌中,当心肌损伤后,CK-MB会释放到血液中。
“LVEF”是指左室射血分数,指每搏输出量占心室舒张末期容积量(即心脏前负荷)的百分比,射血分数与心肌的收缩能力有关,心肌收缩能力越强,则每搏输出量越多, 射血分数也越大。“LVFS”是指左室短轴缩短率,是左心室收缩功能指标参数;若左室短 轴缩短率>25%为左心室收缩功能正常,若左室短轴缩短率<25%为左心室收缩功能受 损。“AVPeak Vel”指流出道血流峰值,“LVID;d”指舒张末期左室内径,“LVID;s”指收缩 末期左室内径,以上超声参数均可作为评价心梗后大鼠心功能指标。
本发明的有益效果在于:
本发明所述约氏乳杆菌EU03可使MI大鼠具有抗氧化活性,降低大鼠氧化应激,改善MI大鼠血清酶学指标,提高SOD含量,降低MDA和LDH含量,起到修复心肌损伤 的作用;且可使心脏室壁变厚,并增强室壁运动和收缩能力,提高血流动力学指标,改 善心功能;并可降低MI大鼠的梗死面积,降低炎性浸润,改善了心肌间质水肿和纤维化 程度,对心肌梗死导致的心肌细胞缺血坏死、心脏形态和胶原纤维遭到破坏的改善作用。 本发明所述的约氏乳杆菌EU03可用于制备改善心肌损伤、心功能以及心肌形态学的药 物,具有广泛的应用前景。
生物保藏说明:
EU03,分类命名:约氏乳杆菌EU03(Lactobacillus johnsonii EU03),其保藏于中国微生物菌种保藏管理委员会普通微生物中心,保藏地址为北京市朝阳区北辰西路1号 院3号,有保藏号为CGMCC No.20845,保藏日期:2020年10月9日,状态为存活。
附图说明
构成本发明的一部分的附图用来提供对本发明的进一步理解,本发明的示意性实施 例及其说明用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1A-E为约氏乳杆菌EU03对MI大鼠SOD、MDA、LDH、CK-MB和CTn-T的 影响;其中对照组为sham,模型组为model,给菌组为LJ,(vs sham#p<0.05,##p<0.01, ###p<0.001;vsmodel*p<0.05,**p<0.01,**p<0.001);
图2A为术后大鼠超声心动图(包括(1)切面图;(2)运动曲线图;(3)血流显 像图;(4)多普勒频谱图;其中对照组为sham,模型组为model,给菌组为LJ);
图2B-F为术后大鼠超声心功能参数变化(包括(B)EF%;(C)FS%;(D)AV; (E)LVID:d;(F)LVID:S;其中对照组为sham,模型组为model,给菌组为LJ,(vs sham#p<0.05,##p<0.01,###p<0.001;vs model*p<0.05,**p<0.01,**p<0.001));
图3A-B为术后各组大鼠心肌左室部位细胞形态化(包括(A)HE染色图;(B) Masson染色图;其中对照组为sham,模型组为model,给菌组为LJ)。
具体实施方式
下面将结合实施例对本申请的实施方案进行详细描述,但是本领域技术人员将理解, 下列实施例仅用于说明本申请,而不是对本申请的范围的限定。根据优选实施方案的下 列详细描述,本申请的各种目的和有利方面对于本领域技术人员来说将变得显然。
为了进一步理解本发明,下面将结合实施例对本发明的实施方案进行详细描述,但 是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂 或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1:约氏乳杆菌EU03具有抗氧化活性,改善MI后大鼠心肌损伤指标作用
如表1所示,实验共分三组,对照组(4周)、模型组(4周)和给菌组(4周), 分别以三组实验大鼠的血清作为检测样品。
模型组(4周):大鼠适应性饲养一周,术前禁食12h,自由饮水。造模前对大鼠 称重,并以现用现配5%的水合氯醛按照0.6mL/100g体重腹腔注射麻醉大鼠。麻醉后 的大鼠胸部备皮,仰卧位固定,用酒精或碘伏进行胸前皮肤的消毒,沿左侧第四肋间(或 心脏搏动最明显处)剪开,用止血钳逐层分离皮下组织,少量钝性分离胸肌。在心脏搏 动最明显处用止血钳撑开胸廓,暴露心脏。剥开心包膜,轻压右胸,将心脏轻轻挤压出 胸壁外,持无创缝合针丝线,于肺动脉圆锥与左心耳之间,在离左冠状动脉前降支(LAD) 起始部2-3mm处进针。以5/0无损伤丝线结扎冠状动脉前降支,将心脏放回胸腔,抽 空胸腔内空气,关闭胸腔,以2/0无损伤丝线分别缝合肌层及皮肤,假手术组仅在相应 冠脉位置穿线,在MI后24小时,使用MS-250、16.0–21.0MHZ成像传感器评估左 心室功能,该传感器连接到超声心动图***,专门设计对小动物来说。麻醉下刮除大鼠 胸部,进行二维超声心动图检查。通过室间隔和左室后壁的鉴别获得图像。超声心动图 自动计算左室缩短率(FS,%)和射血分数(EF,%)左心室射血分数符合(30-45%) 的大鼠予以保留,不符合的条件的大鼠视为不成模,剔除。模型组给予同体积的液体培 基。每天定期喂养每只大鼠,连续喂养4周。
给菌组(4周):造模后约氏乳杆菌灌胃组剂量为108CFU/mL,按每100g体重灌服1mL菌体计算,大鼠每天称重1次,根据体重变化及时调整给菌体积,连续喂养4周。
对照组(4周):假手术组给予同体积的液体培基。每天定期喂养每只大鼠,连续喂养4周。饲料满足SPF级饲养和营养需要。
表1.约氏乳杆菌动物实验分组及剂量
指标检测原理:
SOD检测原理:通过黄嘌呤及黄嘌呤氧化酶反应***产生超氧阴离子(O2-),O2-可还 原氮蓝四唑生成蓝色甲臜,后者在560nm处有吸收;SOD可清除O2-,从而抑制了甲臜 的形成;反应液蓝色越深,说明SOD活性愈低,反之活性越高。
MDA检测原理:MDA与硫代巴比妥酸(thiobarbituric acid,TBA)缩合,生成红色产物,在532nm有最大吸收峰,进行比色后可估测样品中过氧化脂质的含量;同时测定600nm下的吸光度,利用532nm与600nm下的吸光度的差值计算MDA的含量。
LDH检测原理:在乳酸脱氢酶的作用下,NAD+被还原生成NADH,NADH和INT (2-p-iodophenyl-3-nitrophenyl tetrazolium chloride)被硫辛酰胺脱氢酶(diaphorase)催化 反应生成NAD+和强生色物甲臜(formazan),在490nm波长下产生吸收峰,从而可以 通过比色来定量乳酸脱氢酶的活性。
CK-MB、CTn-T含量测定原理:采用ELISA法测定,CK-MB、CTn-T抗体包被 于96孔微孔板中,制成固相载体,向微孔中分别加入标准品或样品,其中的CK-MB、 CTn-T与连接于固相载体上的抗体结合,然后加入生物素化的CK-MB、CTn-T抗体,将 未结合的生物素化抗体洗净后,加入HRP标记的亲和素,再次彻底洗涤后加入TMB底 物显色。TMB在过氧化物酶的催化下转化成蓝色,并在酸的作用下转化成最终的黄色。 颜色的深浅和样品中的CK-MB、CTn-T呈正相关。用酶标仪在450nm波长下测定吸 光度(OD值),计算样品浓度。
酶联免疫吸附测定(ELISA)法测定CK-MB、CTn-T的水平,具体操作如下溶液的 制备:20X洗涤缓冲液用蒸馏水按1:20比例稀释。
(1)试剂盒室温平衡20min,从铝箔袋中取出所需板条。
(2)设置空白孔、标准品孔和样本孔,标准品孔中加不同浓度的标准样品50μL, 样本孔先加入待测样品10μL,再加样品稀释液40μL。
(3)除空白孔外,向孔中加入辣根过氧化物酶(HRP)标记的检测抗体100μL, 将反应孔用封板膜盖住封口,37℃恒温孵育60min。
(4)弃去液体,在吸水纸上拍干,每空加满洗涤液,静置1min,甩去洗涤液, 吸水纸拍干,重复洗板5次。
(5)每孔加入底物A、B各50μL,37℃避光孵育15min。每孔加入终止液50μL, 15min内,在450nm波长检测各孔OD值。
实验结果:
图1A显示,与对照组相比,模型组SOD水平较低,且与模型组相比,给菌组大鼠 组织中的SOD水平显著升高(P<0.05)。图1B显示,MI术后给药28天时,与对照组 相比,模型组大鼠组织MDA水平显著升高(P<0.001)。给菌后,MDA水平显著降低 (P<0.01)。此外,与对照组相比,模型组LDH、CK-MB、CTn-T水平均较高,且给菌 后有一定程度降低,说明给菌组有向假手术组回调的趋势(图1C-E)。
本领域,氧化程度越高心肌受损越严重,SOD较高,MDA较低,LDH较低,说明 抗氧化活性高,氧化应激可以通过多种机制引起细胞凋亡或坏死,CK-MB和CTn-T是心 肌损伤的标志物,越高表明受损越严重,可以推测氧化程度高,心肌损伤严重,从而使 CK-MB和CTn-T升高。
综上,给菌组具有抗氧化活性,可改善MI大鼠血清酶学指标,修复心肌损伤。其抗氧化活性源于益生菌具有自己的抗氧化酶***,可以产生各种抗氧化代谢物,增加抗氧 化剂水平,抵抗ROS,包括过氧化物自由基,超氧阴离子和羟基自由基。同时益生菌还 可以刺激宿主的抗氧化***,刺激Nrf2-Keap1-ARE等抗氧化信号通路,同时也可调节肠 道菌群,降低氧化应激。
实施例2:约氏乳杆菌EU03改善MI大鼠心功能作用
给药4周后进行大鼠心功能检测。大鼠经5%水合氯醛腹腔注射麻醉后脱毛膏脱毛。 Vevo2100超高分辨率小动物超声实时影像仪(加拿大)开机后待用,将探头MS-250固定,升降台调节探头高度,旋转调节探头方向。超声采用异氟烷麻醉(完全麻醉:1%氧 气+5%异氟烷于麻醉盒内麻醉;持续麻醉:1%氧气+2%异氟烷)。用胶带将大鼠腹部 向上固定于操作台,设置温度为37℃;在大鼠胸部均匀涂抹一层超声耦合剂,将操作 台向右下倾斜30-45°,并通过X、Y微调操作台位置。胸骨旁长轴,B-型超声长轴切面 (二维成像),可见左心室,主动脉弓和二尖瓣瓣叶,获得图像;M-型超声长轴切面, 获得M-Mode图像,取样线位于最大腔径处(与***肌相切)。通过对大鼠收缩期和舒 张期进行测量,获得相关心脏参数,以此评价约氏乳杆菌对MI心功能指标的改善作用。
实验结果:
MI大鼠超声M-Mode结果显示(图2A),与对照组相比,模型组左心室室腔相较 于Sham组呈现出左室容积扩张,室壁变薄,室壁运动减弱,收缩力降低。给菌组与模 型组相比能明显改善左心室的损伤,提示约氏乳杆菌EU03在一定程度上可改善MI的损 伤。统计出超声结果(图2B-F)来看,急性MI模型的射血分数(EF)、心室短轴缩短 率(FS)、流出道血流峰值(AV Peak Vel)、舒张末期左室内径(LVID;d)、左室收缩 末期内径(LVID;s)与对照组相比具有明显的显著性,给菌组与模型组相比能提高EF、 FS、降低LVID;d、LVID;s,AV PeakVel有上升趋势,但无显著性差异,提示约氏乳杆 菌EU03可改善MI大鼠心功能指标。
研究表明心梗后的不良心输出量会导致肠缺血,水肿和炎症,通常称为肠屏障的“渗 漏”,会引起肠道来源的菌群和有害代谢物移位,如革兰氏阴性菌细胞壁的脂多糖(LPS), 产生“代谢性内毒素血症”进而触发全身炎症。LPS可以和Toll样受体(TLR)结合,刺激先天免疫***,引起代谢紊乱,而益生菌可以使TLR刺激下降,从而减少心脏重塑标 志物MMP9的产生,改善心功能。除此之外,给菌后产生的有益代谢物可以恢复肠屏障 功能,影响宿主心脏代谢功能。
实施例3:约氏乳杆菌EU03可使MI大鼠恢复正常心肌形态学作用
MI发生后,心脏功能发生障碍,导致心肌细胞缺血坏死,心脏形态和胶原纤维遭到破坏。受损的心脏为维持结构的完整性,病理性改善胶原代谢,形成胶原与心肌共存的 病理学形态特征。本实验选择苏木精-伊红染色法(hematoxylin-eosin staining,HE)和Masson染色对心肌病变程度进行比较,从而观察约氏乳杆菌EU03对MI大鼠心肌形态 学的影响。
取固定于10%甲醛溶液中至少48h的心脏组织,改刀切取厚约2-3mm的组织, 按照以下顺序进行处理:75%乙醇1h→95%乙醇过夜→100%乙醇I1h→100%乙醇II 4 h→二甲苯I15min→二甲苯II 45min→软蜡30min→硬蜡1h。随后进行包埋,将提前 熔化的石蜡倒入包埋框,立即把浸入硬蜡的组织块同方向放入,待蜡块凝固后,固定于 石蜡切片机上,切出5μm厚的石蜡组织切片,温水(50℃)中展片、分片、捞片,最 后于电热干燥箱中(60℃)烤片4-6h。冷却后室温保存。
苏木精-伊红染色(HE染色)方法:
(1)脱蜡:将石蜡切片放于烤箱60℃10min;
(2)水化:将脱蜡后的切片取出,于二甲苯溶液Ⅰ、Ⅱ中各浸泡10min,再于无 水乙醇Ⅰ、无水乙醇Ⅱ、95%、75%梯度乙醇中各浸泡5min,流水冲洗5min;
(3)伊红染胞质及脱水透明:l%伊红溶液染色1-2min,流水冲洗15-30sec;75%乙醇浸泡3min,95%乙醇浸泡3min,无水乙醇Ⅰ、无水乙醇Ⅱ各浸泡3-5min,上行 梯度脱水;于二甲苯溶液Ⅰ、Ⅱ中各浸泡5min进行透明;
(4)封片:中性树胶滴加玻片组织周围,后用盖玻片覆盖封片;
(5)观察:光镜显微镜下观察并拍照、记录。
Masson染色:
胶原纤维被苏木素染成蓝紫色,观察蓝紫色视野相对比例大致判断心脏组织纤维化 程度。具体步骤:
(1)石蜡切片脱蜡至水。
(2)铬化处理或去汞盐沉淀(甲醛固定的组织此步可略)。
(3)依次自来水和蒸馏水洗。
(4)用Regaud苏木精染液或Weigert苏木***染核5-10min。
(5)充分水洗,如过染可盐酸酒精分化。
(6)蒸馏水洗。
(7)用Masson丽春红酸性复红液5-10min。
(8)以2%冰醋酸水溶液浸洗片刻。
(9)1%磷钼酸水溶液分化3-5min。
(10)不经水洗,直接用苯胺蓝或光绿液染5min。
(11)以0.2%冰醋酸水溶液浸洗片刻。
(12)95%酒精、无水酒精、二甲苯透明、中性树胶封固。
实验结果:
心肌组织经HE染色后,于显微镜下拍照,观察28天各组大鼠心肌组织的病理改变。如图3所示,对照组大鼠心肌纤维完整、紧密、整齐,无明显炎性细胞浸润和水肿, 细胞核居中,胞质着色均匀,心外膜、心内膜无明显病理异常。模型组大鼠心肌坏死灶 呈片状分布,病变累及心壁全层,肌纤维发生肿胀、断裂,心肌间质可见粘液变及炎细 胞浸润伴有间质水肿,心外膜细胞死亡,呈现空泡样。给菌组病变面积明显缩小,降低 了炎性浸润程度,改善了心肌间质水肿度程度。心肌细胞Masson染色结果显示假手术对 照组心肌细胞排列整齐,模型组梗死灶周围均可见蓝染的胶原纤维,心肌纤维发生明显 的断裂,排列紊乱。给菌组可明显减少胶原纤维产生,改善心肌纤维化。
研究结果显示,约氏乳杆菌EU03可以降低MI大鼠的梗死面积,降低炎性浸润,改善了心肌间质水肿和纤维化程度。研究表明,抑制TGF-β可以减少梗死心脏炎症期后伤 口重塑中的胶原沉积并抑制成肌纤维细胞的数量,由此可推测给菌组可能通过降低 TGF-β蛋白水平及其下游蛋白的表达水平,改善心肌纤维化,在一定阶段内对MI大鼠的 心脏具有保护作用。
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、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种约氏乳杆菌EU03(Lactobacillus johnsonii EU03),保藏在中国微生物菌种保藏管理委员会普通微生物中心,保藏编号为CGMCC No.20845。
2.权利要求1所述约氏乳杆菌EU03在制备改善心肌损伤、心功能以及心肌形态学的产品中的应用。
3.根据权利要求2所述的应用,其特征在于,所述产品为药物。
4.含有权利要求1所述的约氏乳杆菌EU03的菌剂。
5.根据权利要求4所述的菌剂,其特征在于,所述约氏乳杆菌EU03的活菌数大于108CFU/mL。
6.权利要求4所述菌剂的制备方法,其特征在于,将约氏乳杆菌EU03按照体积分数2%的接种量接种至MRS液体培养基中,在37℃兼性厌氧条件下培养24h,取出离心,弃去上清,用灭菌水洗两次后,用灭菌水调整菌液浓度为108CFU/mL。
7.根据权利要求4所述的菌剂的制备方法,其特征在于,所述离心为在4℃的条件下进行离心操作,离心机转速为10000r/min,离心的时间为10min。
8.一种发酵食品,其特征在于,以权利要求1所述约氏乳杆菌EU03作为发酵剂发酵生产的食品。
9.根据权利要求8所述的发酵食品,其特征在于,所述发酵食品为发酵乳制品、发酵豆制品或发酵果蔬制品。
10.一种药物制剂,其特征在于,包括有效剂量的权利要求1所述的约氏乳杆菌EU03和药学上可接受的辅料。
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