CN113893238A - 乳酸及其盐的应用 - Google Patents
乳酸及其盐的应用 Download PDFInfo
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- CN113893238A CN113893238A CN202010648092.XA CN202010648092A CN113893238A CN 113893238 A CN113893238 A CN 113893238A CN 202010648092 A CN202010648092 A CN 202010648092A CN 113893238 A CN113893238 A CN 113893238A
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- lactic acid
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- claudin
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Abstract
本发明公开了乳酸及其盐的应用,乳酸及其盐应用于制备预防或者治疗乙醇诱导的胃黏膜损伤药物中,盐为药学上可接受的盐。乳酸能减少胃黏膜损伤时不受控制的局部炎症反应,并通过下调Bax和Caspase‑3基因的表达来干预胃黏膜细胞的凋亡;此外,乳酸能够上调胃组织中编码Occludin、Claudin‑1和Claudin‑5等紧密连接蛋白基因的表达,最终显著减轻乙醇诱导的胃黏膜损伤的严重程度。
Description
技术领域
本发明涉及医药技术领域,尤其指的是乳酸及其盐的应用。
背景技术
胃黏膜损伤(gastric mucosal injury,GMI)是一种常见的癌前状态,在包括中国在内的许多亚洲国家中,其与胃癌的高发病率有关。GMI被认为是一种主要由胃黏膜局部炎症反应强烈引起的疾病,目前已证实炎性细胞因子如IL-1β、TNF-α和IL-6的过度表达均参与GMI的损伤进程。此外,细胞凋亡是导致胃黏膜损伤的另一个关键机制。Bax是一种能渗透线粒体外膜的胞浆蛋白,是内源性凋亡途径的核心调节因子之一。Caspase-3是凋亡Caspases级联反应的关键执行蛋白,它可以与Caspase-8和Caspase-9相互作用。已有研究证实了胃黏膜损伤中Bax和Caspase-3表达上调。GMI的愈合是多种损伤因子与黏膜修复同时存在的复杂过程,由于发病机制中过分强调致病因子的作用,忽略胃黏膜屏障这个十分重要的环节,临床上针对GMI的治疗策略主要集中在防止胃黏膜酸蚀,而缺乏修复受损黏膜的治疗手段,因此,如何切实有效地促进胃黏膜的修复,提高愈合质量,仍亟待解决。
多项研究报道了益生菌乳酸杆菌对胃黏膜有保护作用;然而,其潜在机制尚未完全阐明。乳酸是乳酸杆菌的主要代谢产物之一,并且其作为一种常见的食品添加剂,可以安全地应用于人类。有学者于体外和体内的疾病模型中,均发现乳酸能够通过GPR81信号途径减轻肠道炎症,但乳酸对GMI是否具有类似的效应目前仍未见报道。
发明内容
本发明所要解决的技术问题是针对现有技术的现状,提供乳酸及其药学上能接受的盐在制备预防或者治疗乙醇诱导的胃黏膜损伤药物中的应用。
本发明解决上述技术问题所采用的技术方案为:
乳酸及其盐应用于制备预防或者治疗乙醇诱导的胃黏膜损伤药物中,盐为药学上能接受的盐。
优化的技术措施还包括:
上述的盐为乳酸纳。
上述的药物还包括与所述乳酸或其药学上能接受的盐相配伍的其他药类以及药学上可接受的载体和/或辅料。
上述的药物为药学上可接受的剂型。
上述的剂型为粉剂、注射剂、胶囊、片剂或者口服液。
本发明为乳酸及其盐的应用,其在制备预防或者治疗乙醇诱导的胃黏膜损伤药物中,能减少胃黏膜损伤时不受控制的局部炎症反应,并通过下调Bax和Caspase-3基因的表达来干预胃黏膜细胞的凋亡;此外,乳酸能够上调胃组织中编码Occludin、Claudin-1和Claudin-5等紧密连接蛋白基因的表达,最终显著减轻乙醇诱导的胃黏膜损伤的严重程度。
附图说明
图1是本发明实验中乳酸对乙醇诱导的小鼠胃黏膜损伤模型的影响对比图;
图2是乳酸对乙醇诱导型急性胃黏膜损伤小鼠的组织病理学评价图;
图3是乳酸对乙醇诱导型GMI小鼠胃组织中IL-1β、TNF-α和IL-6表达影响图;
图4是乳酸对乙醇诱导型GMI小鼠胃组织中Bax和Caspase-3的表达影响图;
图5是乳酸对乙醇诱导型GMI小鼠胃组织中Occludin、Claudin-1和Claudin-5等紧密连接蛋白表达影响图。
具体实施方式
以下结合附图实施例对本发明作进一步详细描述。
乳酸及其盐的应用,所述的乳酸及其盐应用于制备预防或者治疗乙醇诱导的胃黏膜损伤药物中,所述的盐为药学上能接受的盐。
实施例中,盐为乳酸纳。
实施例中,药物还包括与所述乳酸或其药学上能接受的盐相配伍的其他药类以及药学上可接受的载体和/或辅料。
实施例中,药物为药学上可接受的剂型。
实施例中,剂型为粉剂、注射剂、胶囊、片剂或者口服液。
下面通过实验说明乳酸及其盐能够减轻由乙醇诱导的胃黏膜损伤。
我们采用乙醇诱导的小鼠急性GMI模型,检测胃黏膜的病理变化、炎性因子表达情况、细胞凋亡参数以及紧密连接蛋白的表达量来观察乳酸对GMI的作用及其机制。
材料和方法
药物和试剂:
无水乙醇,L-乳酸钠(Sigma-Aldrich公司),BCA蛋白测定和Trizol(中国南通碧云天生物技术研究所),IL-1β、TNF-α和IL-6的ELISA试剂盒(中国上海西唐生物科技有限公司),逆转录试剂盒和SYBR-Green(TaKaRa公司),Bax抗体(北京生物合成生物技术有限公司),Caspase-3抗体(武汉Proteintech集团有限公司)。
动物和分组:
健康ICR雄性小鼠,体重为20-30g,由温州医科大学实验动物中心提供。实验期间提供标准饲料,自由饮水,环境温度控制在20-25℃。本研究经温州医科大学动物保护与伦理委员会批准(伦理批准文号:wydy2012-0109)。所有实验均按照动物使用和护理委员会的准则和条例进行。
将50只ICR小鼠随机分为5组(n=10/组):正常对照组,模型组和乳酸预处理组,其中乳酸预处理组分为乳酸高(3g/kg)、中(2g/kg)、低剂量(1g/kg)组。乳酸预处理各组在造模前30min以相应的乳酸钠剂量灌胃;正常对照组以相同体积的生理盐水处理;将等量的NaHCO3溶液预先调整至与乳酸溶液相同的pH值,以口服方式给予模型组的动物。
乙醇诱导建立胃黏膜损伤模型:
小鼠禁食24h,在GMI建立前只给予自由饮水。将0.1ml/g的无水乙醇口服给模型组和乳酸预处理组的小鼠进行GMI建模。给药1h后处死动物,收集胃组织标本。
胃黏膜损伤指数评估:
用数码相机(4928×3264像素;日本东京尼康D7000)对胃内表面的GMI进行视觉检查和成像。用Image Pro-Plus(IPP)6.0软件对图像进行分析,计算出血性病变面积和损伤抑制百分率。
胃组织病理学分析:
将胃组织标本用4%多聚甲醛固定后,进行石蜡包埋,然后制成5μm的病理切片。用苏木精-伊红(HE)对损伤组织进行染色,在光学显微镜下观察。
ELISA法检测胃组织细胞因子:
为了评估胃黏膜损伤程度,我们采用双抗体夹心ABC-ELISA法检测胃组织中IL-1β、TNF-α和IL-6等炎症因子的表达量,按照所用试剂盒的说明书如下进行:
1.配制标本稀释液(1% BSA-碳酸盐缓冲液)和洗涤液(0.02mol/L pH=7.4 Tris-HCl-Tween20溶液),再将标准品(HBsAg纯品)稀释成合适的一系列梯度浓度;
2.加样:每孔各加入标准品和胃组织匀浆(按匀浆液:生理盐水=2:3稀释)100μl,将反应板充分混匀后置37℃ 40min;
3.洗板:用洗涤液将反应板充分洗涤5次,向滤纸上印干;
4.每孔加入蒸馏水和第一抗体工作液(生物素化单克隆抗体)各50μl (空白除外);将反应板充分混匀后置37℃ 20min。并按与步骤3相同的步骤再次进行洗板;
5.每孔加入酶标抗体工作液100μl,将反应板置37℃ 10min。并按与步骤3相同的步骤再次进行洗板;
6.每孔加入底物工作液(TMB溶液)100μl,置37℃暗处反应15分钟。然后每孔加入100μl终止液(0.1mol/L H2SO4溶液)混匀;
7.用酶标仪在450nm处测吸光度。根据一系列浓度的标准品吸光度制作标准曲线,然后进行单位重量组织内IL-1β、TNF-α和IL-6的含量计算。
免疫组化检测Bax:
对Bax进行免疫组化检测,一抗浓度通过预实验,确定一抗浓度为1:250,具体操作步骤如下:
1.烤片:
将玻片放到65℃的烘箱中烤片1.5h;
2.脱蜡:
1) 二甲苯 (Ⅰ):10min;
2) 二甲苯 (Ⅱ):10min;
3.复水:
1) 100%乙醇:5min;
2) 95%乙醇:5min;
3) 80%乙醇:5min;
4) 70%乙醇:5min;
5) 50%乙醇:5min;
6) 纯水孵化:5min;
4.抗原修复:
将玻片放入0.01mol/L的枸橼酸盐缓冲液中,然后放入高压锅中加热至沸腾后再保持10min,取出放有玻片的枸橼酸盐缓冲液;
5.免疫反应:
1) 玻片上滴加3%的H2O2放入湿盒中孵育15min;
2) PBS冲洗3次,每次3min;
3) 滴加一抗工作液,室温孵育1.5h;
4) PBS冲洗3次,每次3min;
5) 滴加二抗于组织,室温孵育30min;
6) PBS冲洗3次,每次5min;
7) 滴加现配的DAB工作液,室温孵育,在显微镜下观察,当出现特异性显色时用蒸馏水终止反应;
8) 苏木素复染10s左右;
9) PBS返蓝;
6.脱水:
1) 50%乙醇:5min;
2) 70%乙醇:5min;
3) 80%乙醇:5min;
4) 95%乙醇:5min;
5) 100%乙醇:5min;
7.透明:
1) 二甲苯 (Ⅰ):3min;
2) 二甲苯 (Ⅱ):3min;
3) 二甲苯 (Ⅲ):3min;
8.封固:
中性树脂封片;
9.结果判断:用Image-Pro Plus6.0软件进行图像半定量分析,每张切片选取5个高倍镜视野(×400),测定各组小鼠胃黏膜Bax阳性目标积分吸光度。
BCA分析、SDS-PAGE和蛋白印迹分析:
1.提取总蛋白:
组织样本:取EP管,分别称重标记,把组织剪切成小块装入EP管中,称重。按每20mg组织加200-400μl的比例加入裂解液(如裂解不完全,可以适当增加裂解液的用量;如需要的蛋白样品浓度较高,可以适当减少裂解液的用量)。用手握式电动组织细胞匀浆器匀浆约1min或直至充分裂解。经12000转离心10min后,取上清,于-80℃保存。
2.BCA定量分析蛋白浓度:
使用碧云天BCA蛋白测定试剂盒操作说明书:
1) 用蛋白标准配制液溶解蛋白标准品,并用PBS稀释使蛋白标准品终浓度为0.5 mg/ml;
2) 根据蛋白数量,按50:1的BCA试剂A与B配置BCA工作液,室温放置24 h;
3) 将标准品按照0、1、2、4、8、12、16、20μl体积加入到96孔酶标板中,并加标准品稀释液补足到20μl;
4) 在96孔酶标板中加入2μl待测蛋白样品,并加标准品稀释液补足到20μl;
5) 向个孔中加入200μL BCA工作液,每组样品设置3个复孔,37℃放置30 min;
6) 酶标仪检测562 nm处吸光度值,即OD值;
7) 以标准品浓度为横坐标,以标准品OD值为纵坐标绘制的标准曲线计算出样品蛋白浓度。
3.制备SDS-PAGE胶:
1) 将灌胶玻璃板洗净,晾干固定,确定灌制分离胶液面标志线(距样品梳子底部约0.5-1.0cm处);
2) 配制10%分离胶4ml(见下表),快速灌入凝胶玻璃槽中,使其液面至标志线位置(避免产生气泡);
3) 立即用去离子水覆盖胶面(隔绝空气,有助于凝胶聚合),室温放置约40min至分离胶凝固;
4) 配制4%浓缩胶2ml(见下表);
分离胶 | 浓缩胶 | |
10% | 4% | |
ddH<sub>2</sub>O | 1.576ml | 1.2ml |
30%Acrylamide(4℃避光) | 1.36ml | 0.27ml |
1.5M Tris-HCl(pH8.8) | 1.00ml | ------ |
0.5 M Tris-HCl(pH6.8) | ------ | 0.5ml |
10%SDS | 40μl | 20μl |
10%APS(后加) | 40μl | 20μl |
TEMED(后加) | 2.0μl | 2μl |
ToTal | 4ml | 2ml |
5) 倒掉去离子水覆盖液,并用吸水纸吸掉残留的液体。将凝胶板重新垂直放置,轻轻加入4%浓缩胶液(注意避免产生气泡),插入样品梳,室温凝胶约40min;
6) 轻轻拔去梳子,将玻璃夹板“凹”面贴紧电泳槽,两侧用夹子很好的固定在电泳槽上。
4.蛋白样品变性、电泳:
1) 由-80℃冰箱取出提取的总蛋白样品,立即插入冰中(减少蛋白降解)待其融化;
2) 根据蛋白定量结果,加入相应体积的总蛋白样品与5×蛋白质凝胶电泳上样缓冲液,轻轻混合,95℃变性10min,立即插入冰中待用;
3) 将样品轻轻加至凝胶孔中,电泳仪设置成稳压状态,接通电源,将电压调至80V 使样品通过浓缩胶与分离胶(电压约8V/cm)。电泳使染料至分离胶适当位置,结束电泳。
5.凝胶转膜及其检测:
凝胶电泳结束后,将凝胶上分离到的蛋白条带通过转移电泳方式转印至固相支持物上,然后分别用非标记一抗及辣根过氧化物酶标记的二抗对其进行孵育、检测。用于Western印迹法的固相支持物有多种,本实验采用PVDF膜作为固相支持物。本实验采用半干转的转膜方式。
1) PVDF膜的预处理:先置于100%甲醇中浸泡2-3min,水、电转液依次漂洗2min×2次,置于电转液中备用;
2) 剪裁与胶同样大小的6 层滤纸,用转移缓冲液浸泡后待用;
3) 取下电泳板,将其平置(使“凹”面玻璃板在下),小心取出夹板中的垫片及去掉上层玻璃板,切除多余凝胶,将含样品胶用电转液漂洗一次;
4) 将样品胶与膜装入标有正、负极的转膜夹板中:由阴极侧开始,依次为海绵垫片→3层滤纸→样品胶→PVDF膜→三层滤纸(注意:排除气泡)→海绵垫片,扣紧转膜夹板,放入含有转膜缓冲液的转移电泳槽中;
5) 正确连接转移电泳连线,保证电荷由负极向正极流动(转膜条件:电流130mA,电压20v左右,转膜时间为30min);
6) 封闭:小心取出转移膜置于封闭液中,室温、摇床上缓慢摇动状态下封闭1h;
7) 一抗反应:用Bax、Caspase-3、β-肌动蛋白和GAPDH的一抗(抗体稀释度均为1:1000)孵育,4℃反应过夜;
8) 洗膜:将反应膜放入平皿中,用1×TBST 洗涤三次,(室温下缓慢摇动洗涤)每次10min,洗净未结合的一抗;
9) 二抗反应:将洗涤后的一抗反应膜放入二抗工作液(1:3000)中,室温、避光缓慢摇动作用60min;
10) 洗膜:用1×TBST洗膜,方法同(8),洗去游离二抗;
11) 曝光及洗片;
12) 用增强化学发光法检测条带,并用ChemiDoc-MP成像系统进行可视化。
RNA提取与实时定量PCR:
1.RNA提取
TRIzol,用匀浆仪进行匀浆处理。样品体积不应超过TRIzol体积10%。 1) 将组织在液氮中磨碎,每50-100mg组织加入1ml
2) 每1ml Trizol加入0.2ml氯仿,剧烈振荡15s,室温放置5min。
3) 每1ml Trizol加入0.2ml氯仿,剧烈振荡15s,室温放置5min。
10000×g离心15min。样品分为三层。RNA主要在水相中,水相体积约为所用Trizol试剂的60%。 4) 2-8℃
5) 把水相转移到新的EP管中加入等体积的异丙醇,室温放置10min。
6) 2-8℃ 10000×g离心10min,离心前看不出RNA沉淀,离心后在管侧和管底出现胶状白色沉淀。弃上清进行下一步操作。
7) 用75%冰预冷的乙醇洗涤RNA沉淀。每使用1ml Trizol至少加1ml 75%乙醇。2-8℃不超过7500×g离心5min,弃上清。
8) 超净台中风干大约5-10min。
2.实时定量PCR
1) 利用核酸蛋白分析仪器检测所提RNA的浓度及纯度。
2) 按照逆转录试剂盒说明书提示合成样品cDNA。
在反应条件为95℃预变性30s;95℃变性5s;60℃退火30s后采集荧光信号,重复40个循环的条件下以合成的cDNA为模板。按荧光定量PCR试剂盒说明书,在25µl体系内进行PCR扩增。引物序列如表1,并以GAPDH为内参,用所得各炎症因子的Ct计算出其相对表达量。
实验结果:
图1是本发明实验中乳酸对乙醇诱导的小鼠胃黏膜损伤模型的影响对比图。如图1所示:图1A为小鼠胃黏膜大体形态变化;图1B为乙醇诱导的胃黏膜损伤面积的数据分析。50只小鼠平均分为5组。将小鼠饥饿24小时,然后造模前30min给予不同剂量的乳酸钠进行预处理。造模1h后处死小鼠,对胃黏膜大体形态变化评价。C:正常对照组;D:疾病模型组;L1-3分别代表给予1g/kg、2g/kg和3g/kg剂量的乳酸预处理组。
在口服0.1ml/g无水乙醇的小鼠中观察到胃黏膜广泛出血性损伤(图1A)。对照组胃黏膜未见明显病变(图1A)。在定性(图1A)和定量(图1B)图像分析下,观察乳酸处理组,可知乳酸以剂量依赖的方式显著降低GMI的严重程度。
图2是乳酸对乙醇诱导型急性胃黏膜损伤小鼠的组织病理学评价图。胃组织切片(n =6/组)进行常规脱水,苏木精-伊红(HE)染色后,显微镜下观察,A:×200,B:×400。C:正常对照组 D:模型组 L:3g/kg乳酸预处理组。
鉴于高剂量的乳酸表现出最强的胃黏膜保护作用,因此我们使用经3g/kg乳酸预处理的动物胃组织进行详细的组织病理学检查。从组织学进一步评价乳酸对GMI模型的影响,如图2所示,与正常对照组比较,GMI模型组胃黏膜存在广泛损伤;经乳酸预处理的动物胃样本的黏膜坏死损伤较少,局部黏膜脱离较少,白细胞浸润较少,这与大体形态学变化相一致,表明乳酸可以减弱胃黏膜损伤的严重程度。
图3是乳酸对乙醇诱导型GMI小鼠胃组织中IL-1β、TNF-α和IL-6表达影响图。通过胃组织匀浆ELISA实验测定炎症因子水平,将胃组织中的细胞因子水平用蛋白量标准化。C:正常对照组 D:模型组 L:3g/kg乳酸预处理组。
通过检测匀浆胃组织中炎症因子IL-1β、TNF-α和IL-6的水平来明确乳酸的抗炎作用。与未经治疗的对照组相比,乙醇会导致胃组织中以上三种促炎细胞因子的过度产生(图3A)。在乙醇诱导GMI之前用乳酸对动物进行预处理能够显著减轻这些促炎因子的过度产生(与模型组相比,p<0.01,图3A)。实时定量PCR结果进一步证实了这一点,其结果显示,在乙醇诱导的GMI模型的胃组织中,IL-1β、TNF-α和IL-6基因过度表达而乳酸预处理能使这些基因的表达显著下降(图3B)。
图4是乳酸对乙醇诱导型GMI小鼠胃组织中Bax,Caspase-3的影响图。图4A为Bax的免疫组化染色:胃标本固定和切片,经Bax的抗体做组化染色,细胞中的棕色颗粒明显存在。图4B和图4C分别为Bax和Caspase-3的实时定量和蛋白印迹图。C:正常对照组 D:模型组 L:3g/kg乳酸预处理组。
免疫组化分析结果显示,与正常对照组相比,经乙醇处理的小鼠胃黏膜中的凋亡调节因子Bax水平显著升高,而用乳酸进行预处理可以抵消这种变化(图4A)。与免疫组化分析结果一致,蛋白质印迹法结果同样支持在GMI诱导前用乳酸预处理能够降低Bax和Caspase-3的表达(图4B和图4C)。实时定量PCR证实了上述发现,其结果显示乳酸能够使Bax和Caspase-3的表达下调(图4B和图4C)。
图5是乳酸对乙醇诱导型GMI小鼠胃组织中紧密连接蛋白Occludin、Claudin-1、Claudin-5、Claudin-18、ZO-1和TJP2的表达影响图。提取RNA,并进行实时定量PCR检测紧密连接蛋白表达水平。C:正常对照组 D:模型组 L:3g/kg乳酸预处理组。
紧密连接蛋白如Occludin、Claudin-1、Claudin-5、Claudin-18、ZO-1和TJP2,是维持胃上皮屏障完整性的关键。用实时定量PCR检测乳酸是否能够调节紧密连接的完整性,结果显示乳酸能够刺激编码紧密连接蛋白的基因Occludin、 Claudin-1和Claudin-5在胃组织中的表达上调,而对Claudin-18、ZO-1和TJP2的表达无影响。
本发明的实验表明,乳酸钠作为乳酸药学上能接受的盐,在乙醇诱导的胃黏膜损伤中,对胃黏膜的病理变化、炎性因子表达、细胞凋亡以及紧密连接蛋白的表达具有正性疗效。因此,乳酸及其药学上能接受的盐对乙醇诱导的胃黏膜损伤具有预防和治疗作用。
本发明的最佳实施例已阐明,由本领域普通技术人员做出的各种变化或改型都不会脱离本发明的范围。
Claims (5)
1.乳酸及其盐的应用,其特征是:所述的乳酸及其盐应用于制备预防或者治疗乙醇诱导的胃黏膜损伤药物中,所述的盐为药学上能接受的盐。
2.根据权利要求1所述的乳酸及其盐的应用,其特征是:所述的盐为乳酸纳。
3.根据权利要求2所述的乳酸及其盐的应用,其特征是:所述的药物还包括与所述乳酸或其药学上能接受的盐相配伍的其他药类以及药学上可接受的载体和/或辅料。
4.根据权利要求3所述的乳酸及其盐的应用,其特征是:所述的药物为药学上可接受的剂型。
5.根据权利要求4所述的乳酸及其盐的应用,其特征是:所述的剂型为粉剂、注射剂、胶囊、片剂或者口服液。
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