CN111567725A - 木犀草素作为抑制赭曲霉毒素a肾毒性的食物营养素的应用 - Google Patents
木犀草素作为抑制赭曲霉毒素a肾毒性的食物营养素的应用 Download PDFInfo
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Abstract
木犀草素作为抑制赭曲霉毒素A肾毒性的食物营养素的应用。LUT通过恢复细胞活力和阻止LDH释放而发挥其预防作用。它通过减少ROS积累，改善线粒体膜电位降低，使抗氧化酶活性恢复到对照水平，从而减轻OTA诱导的氧化应激和脂质过氧化。通过细胞免疫荧光实验、报告基因质粒转染实验和荧光定量PCR反应分析和评价Nrf2和HIF‑1α在此过程中的调控作用。结果表明，LUT激活了Nrf2途径，提高了细胞对抗OTA所致氧化性损伤的防御能力。此外，LUT还通过调节HIF‑1α通路，启动血管生成和上皮修复过程，从而促进细胞进行损伤后修复。本发明揭示了LUT作为黄酮类膳食补充剂在抑制OTA以及其它真菌毒素方面具有较好的应用潜力，可开发为抑制OTA肾毒性的食物营养素，从而拓展LUT的用途。
Description
技术领域
本发明涉及生物医药，具体涉及木犀草素作为抑制赭曲霉毒素A肾毒性的食物营养素的应用。
背景技术
赭曲霉毒素A(ochratoxin A,OTA)这一真菌毒素污染物，具有严重的肾毒性，是国际社会普遍关注的食品安全问题。木犀草素(luteolin,LUT)作为一种广泛存在于天然植物或食品中的营养素，因其显著的抗氧化能力，越来越受到科学家的关注。
发明内容
发明人经过大量实验研究发现食物营养素LUT通过中和ROS累积发挥抑制OTA所致肾细胞毒性的作用。LUT激活Nrf2通路增加了细胞抗氧化损伤的能力；同时LUT还通过调控HIF-1α通路从而启动损伤后的修复过程。OTA诱导ROS累积在0-24h内呈现先上升后下降再上升的过程，且在1h和24h存在2个峰值。表明LUT可开发为抑制OTA肾毒性的食物营养素。
与现有技术相比，本发明的有益效果：LUT作为黄酮类膳食补充剂在抑制OTA以及其它真菌毒素方面具有较好的应用潜力，可开发为作为抑制OTA肾毒性的食物营养素，从而拓展LUT的用途。
附图说明
图1木犀草素(LUT)对赭曲霉毒素A(OTA)所致肾细胞毒性的抑制作用实验；
图2木犀草素(LUT)对赭曲霉毒素A(OTA)所致细胞膜的完整性(A-F)和细胞上清乳酸脱氢酶(LDH)渗漏(G)的影响实验；
图3赭曲霉毒素A(OTA)所致ROS累积的时间关系图，OTA浓度为50μM，作用时间为(A)0h，(B)1h，(C)3h，(D)6h，(E)12h，(F)24h；
图4木犀草素(LUT)对赭曲霉毒素A(OTA)所致ROS累积的抑制作用实验，(a)0.1％DMSO，(b)50μM OTA，(c)50μM OTA+100μM LUT，(d)100μM LUT。作用时间分别为(A)1h和(B)24h；
图5木犀草素(LUT)抑制赭曲霉毒素A(OTA)所致的线粒体膜电位下降，(A)0.1％DMSO组，(B)50μM OTA组，(C)50μM OTA+100μM LUT组，(D)100μM LUT组，作用时间为24h；左列代表线粒体膜电位较高，JC-1形成聚合物，呈红色荧光；中间列代表线粒体膜电位较低，JC-1为单体，呈绿色荧光；右列为左中列重叠后得到；
图6木犀草素(LUT)对赭曲霉毒素A(OTA)所致(A-D)Nrf2核转位和(E)ARE抑制的保护作用实验，实验分为4组，(A)为0.1％DMSO组，(B)50μM OTA组，(C)50μM OTA+100μM LUT组，(D)100μM LUT组，作用时间为24h。细胞用Nrf2一抗孵育后用荧光二抗孵育，细胞核用DAPI染色，然后置于荧光显微镜下观察拍照。(E)采用lipofectamine 8000转染p-ARE质粒24h后进行药物孵育，24h后依据荧光素酶报告基因检测试剂盒进行检测，ARE激活用RLU表示；
图7木犀草素(LUT)对赭曲霉毒素A(OTA)所致(A-D)HIF-1α核转位激活的调控作用实验，实验分为4组，(A)为0.1％DMSO组，(B)50μM OTA组，(C)50μM OTA+100μM LUT组，(D)100μM LUT组，作用时间为24h。细胞用HIF-1α一抗孵育后用荧光二抗孵育，细胞核用DAPI染色，然后置于荧光显微镜下观察拍照；
图8赭曲酶毒素A(OTA)对(A)Nrf2通路相关基因，包括Nrf2,HO-1,γ-GCS,TGF-β在mRNA水平表达量的影响和(B)HIF-1α通路相关基因，包括HIF-1α,VEGF,EPO,TGF-β在mRNA水平表达量的影响。作用时间分别为0，3，6，12，24h；
图9木犀草素(LUT)调控(A,C)Nrf-2和(B,D)HIF-1α通路相关基因的表达抑制赭曲酶毒素A(OTA)所致的肾细胞氧化性损伤实验，实验分为4组，0.1％DMSO，50μM OTA，50μMOTA+100μM LUT，100μM LUT组，作用时间为(A,B)3h，(C,D)24h。
具体实施方式：
下面将结合附图和具体实施例，对本发明的技术方案进行清楚、完整地描述。显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：
一、选用的材料、设备和研究方法
1 细胞培养
NRK-52E细胞购买自中国科学院细胞生物所，来源于正常大鼠的肾皮质上皮细胞，培养液为DMEM，含有4mM谷氨酸盐、1.5g/L碳酸氢钠、4.5g/L葡萄糖、10％的小牛血清、100U/ml的青霉素和链霉素，培养条件为37℃、5％CO2。
2 MTT法测定细胞活力
将大鼠肾细胞NRK-52E铺于96孔板，细胞密度为2×104cells/ml，置于37℃、5％CO2环境中培养24h后给药。赭曲霉毒素A(OTA)的浓度为0，1.25，2.5，5，10，20，50μM，0.1％的DMSO作为溶剂对照。木犀草素(LUT)的浓度为0，5，25，50，100，200，300μM。药物作用时间为24，48和72h。结束后，每孔加入20μL MTT(5mg/mL PBS)继续孵育4h。孵育完成后，取出96孔细胞培养板，1500rpm离心10min，用移液器轻轻弃掉上清，每孔加入150μL DMSO，室温震荡10min直到蓝色结晶全部溶解，读取570nm处的吸光度值。细胞活(％)＝100×(Atreatment-Ablank)/(Avehicle-Ablank)。
经上述实验过程筛选到合适的OTA和LUT浓度后，细胞按照上述步骤重新铺板，24h后，OTA和LUT同时给药。OTA浓度为50μM，LUT浓度分别为50，100，200μM。药物作用24h后，按照上述步骤进行检测和数据统计。
3 乳酸脱氢酶(LDH)测定
将大鼠肾细胞NRK-52E铺于96孔板，细胞密度为2×104cells/ml，置于37℃、5％CO2环境中培养24h后给药。OTA浓度为50μM，LUT浓度为50，100，200μM。药物作用48h后，取出培养板，600g离心10min，吸取上清用于LDH活性测定。试剂盒为南京建成生物科技中心。LDH活性表示为U/L。
4 流式细胞术测定ROS累积
首先为了获得OTA诱导ROS产生的时间趋势曲线，NRK-52E细胞铺板于6孔板，密度为1×105cells/ml。孵育24h后，OTA给药浓度为50μM，给药时间为0，1，3，6，12，24h。为了进一步研究LUT对OTA所致ROS累积的抑制作用，选择100μM浓度研究。OTA(50μM)和LUT(100μM)同时给药，1h和24h后，收取细胞，用10μM的DCFH-DA进行染色30min，清洗干净后上机分析，每个样品分析10000个细胞。
5 线粒体膜电位测定
细胞处理和给药参考2.4。OTA(50μM)和LUT(100μM)同时给药，24h后，倒掉培养液，清洗细胞，然后用JC-1染料(10μM)于37℃染色30分钟，用荧光显微镜分别观察红色和绿色荧光强度。
6 丙二醛(MDA),超氧化物歧化酶(SOD)和还原性谷胱甘肽(GSH)水平测定
细胞处理和给药参考2.4。OTA(50μM)和LUT(100μM)同时给药，24h后收集细胞，PBS清洗一遍后置于超声波裂解器裂解，10000rpm离心收取上清，采用南京建成的MDA，SOD，GSH试剂盒测定。
7 荧光定量PCR(RT-qPCR)
细胞处理和给药参考2.4。6孔板的每个孔加入1ml的Trizol试剂提取RNA。定量后取1μg的RNA用于制备cDNA。采用美国Applied Biosystems公司的ABI StepOnePlusTMReal-Time PCR系统进行分析。条件为：94℃预变性2min，95℃变性15s，60℃延申30s，40个循环。溶解曲线为：95℃ 15s，60℃ 1min，95℃ 15s。所用引物列在下表：
表1 荧光定量PCR所需的基因引物序列
8 Nrf2和HIF-1α核转位水平测定
NRK-52E细胞铺板于置于6孔板的多聚赖氨酸处理过的载玻片，24h后，细胞用0.1％DMSO，50μM的OTA，50μM OTA+100μM LUT，100μM LUT处理24h。0.1％的Triton X-100处理后，用碧云天封闭缓冲液封闭(QuickBlockTM,P0260)，然后用Nrf2抗体(Proteintech，16396-1-AP)或者是HIF-1α抗体(Affinity Biosciences，AF1009)于4℃封闭过夜，抗体用碧云天一抗稀释液(P0262)稀释。次日除去一抗后加入Alexa Fluor 488标记的羊抗兔IgG抗体，细胞核用DAPI染色，最后将载玻片取出置于荧光显微镜观察荧光强度。
9 报告基因质粒pARE-luc转染
p-ARE-luc报告基因质粒(D2112)和Lipofectamine 8000转染试剂购买自碧云天。细胞铺板于24孔板，密度为4×104cells/ml(0.5ml/well)。24h后，采用Lipofectamine8000转染试剂转染p-ARE-luc质粒，8h后，吸除含有转染试剂和质粒的完全培养基，并更换新的完全培养基。16h后，加入0.1％DMSO，50μM的OTA，50μM OTA+100μM LUT或100μM LUT处理24h。然后用碧云天荧光素酶报告基因检测试剂盒检测荧光素酶的表达强度，用RLU表示。
10 统计分析
所有的数据用Mean±SD表示。采用SPSS 18.0进行统计分析，one-way ANOVA和Tukey’s test用于差异分析，two-tailed Pearson’s test和student test用于相关性分析。
二、LUT对OTA所致肾细胞毒性的抑制作用
1 LUT对OTA所致的细胞活力抑制具有保护作用
首先采用MTT筛选OTA的有效浓度和LUT的最大无作用浓度。
图1所示的是木犀草素(LUT)对赭曲霉毒素A(OTA)所致肾细胞毒性具有抑制作用。(A)MTT法明确OTA对NRK-52E细胞活力抑制的时间和剂量趋势。OTA浓度为0，1.25，2.5，5，10，20，50μM，孵育时间为24，48，72h。结果用％细胞活力表示。(B)MTT法筛选LUT对NRK-52E细胞没有毒性的剂量和时间。LUT浓度为0，5，25，50，100，200，300μM，孵育时间为24，48，72h。结果用％细胞活力表示。(C)LUT对OTA所致肾细胞活力抑制的保护作用，OTA浓度为50μM，LUT浓度为50，100，200μM。细胞活力表示为Mean±SD(n＝4)。*P<0.05代表和对照组相比差异显著。
图1A结果显示，OTA在20和50μM浓度显著抑制NRK-52E细胞活力，且呈剂量和时间依赖性，经过Prism计算显示，OTA作用24h对NRK-52E细胞活力抑制率为50％的剂量(IC50)为38.43μM，95％的置信区间为33.98-44.22μM，因此选择50μM作为后续研究的剂量。
图1B结果显示LUT在300μM浓度时显著抑制细胞活力，而5，25，50，100，200μM浓度则无显著作用，因此选择没有毒性反应的较高的三个剂量50，100，200μM进行后续的研究。
图1C结果显示，单独给于50μM的OTA，细胞活力显著下降，但是同时给于50，100或200μM的LUT均能减轻OTA所致的肾细胞活力下降，尤其是100μM的LUT组差异具有统计学意义。
2 LUT对OTA所致细胞上清乳酸脱氢酶(LDH)渗漏的抑制作用
正常细胞的LDH存在于细胞内，一旦细胞受到损伤，细胞内容物LDH渗漏到上清中，因此测定细胞上清中LDH活力可分析细胞受损伤的程度。
图2所示为木犀草素(LUT)对赭曲霉毒素A(OTA)所致细胞膜的完整性(A-F)和细胞上清乳酸脱氢酶(LDH)渗漏(G)的影响实验。NRK-52E细胞用(A)0.1％DMSO，(B)50μM OTA，(C)50μM OTA+50μM LUT,(D)50μM OTA+100μM LUT,(E)50μM OTA+200μM LUT,(F)200μM LUT处理24h。孵育完成后，细胞培养板置于倒置显微镜观察并拍照。(G)不同处理组细胞上清LDH渗漏的水平，结果表示为Mean±SD(n＝4)。不同字母代表差异显著，显著性水平为P<0.05。
图2G显示，0.1％DMSO，OTA和LUT组细胞上清LDH活力分别为136.80，193.55，106.10U/L，说明OTA导致细胞损伤。而50，100，200μM的LUT和OTA同时给药后，细胞上清LDH活力下降，尤其是100μM的LUT作用最为显著。同时，我们通过倒置显微镜观察细胞形态，结果显示50μM的OTA组细胞死亡较多，而100和200μM的LUT显著改善了OTA的细胞毒性(图2D，E)。综合以上实验结果，选择100μM的LUT研究其对OTA所致氧化性损伤的分子机制。
3 LUT对OTA所致氧化性损伤的影响
3.1 LUT降低OTA所致ROS的累积
首先分析OTA所致ROS累积的时间趋势。图3结果显示50μM的OTA作用NRK-52E细胞1h和24h后，细胞内ROS累积显著上升，因此选择1h和24h研究LUT对OTA所致ROS累积的抑制作用。
图4所示是LUT对OTA所致ROS累积的抑制作用实验。图4结果显示100μM的LUT和50μM的LUT联合作用后细胞内ROS累积水平相比OTA单独给药组显著下降(图4Ab,Bb)，且1h和24h两个时间点作用水平均有显著性差异。此外，LUT单独给药组细胞内ROS累积水平在相同时间点的组内均是最低水平(图4Ad,Bd)，说明LUT显著抑制OTA所致的ROS累积。
ROS累积水平增加常伴随着线粒体膜电位下降，图5结果显示，50μM的OTA组(图5B)相比0.1％的DMSO组(图5A)绿色荧光水平增加，线粒体膜电位下降，而100μM的LUT组和50μMOTA+100μM LUT联合给药组几乎看不到绿色荧光，说明LUT对OTA所致的线粒体膜电位下降具有保护作用。
3.2 LUT降低OTA所致线粒体膜电位的降低
ROS累积水平增加常伴随着线粒体膜电位下降，图5结果显示，50μM的OTA组(图5B)相比0.1％的DMSO组(图5A)绿色荧光水平增加，线粒体膜电位下降，而100μM的LUT组和50μMOTA+100μM LUT联合给药组几乎看不到绿色荧光，说明LUT对OTA所致的线粒体膜电位下降具有保护作用。
3.3 LUT抑制OTA所致的脂质过氧化水平
如表2所示，50μM的OTA组MDA水平相比对照组显著增加，而SOD和GSH水平则显著下降。但是LUT和OTA联合给药后，细胞内MDA，SOD，GSH相比OTA组均有被逆转的趋势，但是没有统计学差异，说明LUT对OTA所致的脂质过氧化具有抑制作用。
表2木犀草素(LUT)抑制赭曲霉毒素A(OTA)所致的脂质过氧化水平。NRK-52E细胞分别给于0.1％DMSO，50μM OTA，50μM OTA+100μM LUT，100μM LUT，作用时间为24h。细胞裂解后检测细胞内丙二醛(MDA)，超氧化物歧化酶(SOD)和还原性谷胱甘肽(GSH)水平。MDA活力用nmol/mg protein表示，SOD活力表示方法为1U为50％抑制pyragallol自氧化所需的酶的量，GSH表示方法为μmol GSH/g protein。
4 LUT调节Nrf2和HIF-1α通路抑制OTA所致的肾细胞毒性
4.1 LUT调节Nrf2和HIF-1α的核转位水平
首先采用免疫荧光法分析OTA对Nrf2和HIF-1α核转位的影响。图6结果显示，100μM的LUT单独给药组(图6D)相比对照组(图6A)细胞核内Nrf2的表达量显著上调。而OTA单独给药组细胞核内Nrf2的表达量显著降低，说明OTA显著抑制Nrf2的核转位水平而LUT显著激活Nrf2的核转位水平。此外，LUT和OTA联合给药组(图6C)相比OTA组Nrf2核转位水平明显上调，说明LUT通过激活Nrf2的核转位从而逆转OTA所致的Nrf2核转位抑制，从而达到抑制OTA所致的过氧化损伤。
同时，采用细胞内转染抗氧化元件(ARE)质粒的方法研究OTA和LUT对ARE的抑制或者是激活。图6E结果显示LUT显著激活ARE的表达，相反OTA显著抑制ARE的表达。LUT和OTA同时给药组细胞内ARE活力则是OTA组的7.6倍，是对照组的2.1倍，说明LUT完全逆转了OTA所致的ARE抑制，且恢复到了正常水平。
文献研究显示，过氧化水平的增加常伴随着HIF-1α表达量的增加，因此我们进一步研究OTA LUT单独给药或联合给药对HIF-1α核转位的影响。结果如图7B显示，与Nrf2的变化结果相反，OTA显著激活HIF-1α的核转位。有意思的是LUT也激活HIF-1α的核转位，但是激活的效果并不强烈。同时LUT和OTA同时给药后细胞核内HIF-1α的表达水平相比对照组和OTA组均上升，结果表明LUT也可通过调控HIF-1α通路抑制OTA的过氧化损伤。
4.2 LUT调节Nrf2和HIF-1α下游相关基因的转录
Nrf2和HIF-1α的核转位分别激活HO-1，γ-GCS，Gpx-1和VEGF，EPO，TGF-β在mRNA水平的表达。因此我们继续研究LUT和OTA单独或联合给药对这些下游基因的转录。我们首先通过表达量时间关系曲线筛选OTA的有效作用时间。如图8A所示，OTA对Nrf2的表达呈现0-6h先抑制6-24h后促进的作用。HO-1和γ-GCS的表达量在3h和6h相比对照组显著下降，但是12h和24h后反而上升。而Gpx-1则在给药后6，12，24h均显著上升。HIF-1α的表达量趋势和Nrf2类似，图8B所示，HIF-1α在mRNA水平的表达量3h和6h显著下降，但是12和24h显著上升。VEGF和EPO的表达量趋势与HIF-1α一致，即3h显著下降，24h显著上升。但是TGF-β的表达量只在12和24h显著上升。综合考虑，我们选择3h和24h研究LUT对OTA所致肾毒性的抑制作用。如图9A所示，OTA和LUT联合给药后3h Nrf2，HO-1，γ-GCS，Gpx-1的表达量相比OTA组均上升，但是不具有统计学差异；24h后，只有Gpx-1的表达量相比OTA组显著上升(图9C)。图9B显示，LUT和OTA联合作用3h后HIF-1α和VEGF表达量相比OTA组显著上升；24h后，VEGF和EPO的表达量相比OTA组显著上升(图9D)。
本发明以NRK-52E大鼠肾细胞为模型，研究LUT对OTA诱导的肾细胞氧化应激损伤的保护作用及其分子机制。结果表明，LUT通过恢复细胞活力和阻止LDH释放而发挥其预防作用。它通过减少ROS积累，改善线粒体膜电位降低，使抗氧化酶活性恢复到对照水平，从而减轻OTA诱导的氧化应激和脂质过氧化。通过细胞免疫荧光实验、报告基因质粒转染实验和荧光定量PCR反应(RT-qPCR)分析和评价Nrf2和HIF-1α在此过程中的调控作用。结果表明，LUT激活了Nrf2途径，提高了细胞对抗OTA所致氧化性损伤的防御能力。此外，LUT还通过调节HIF-1α通路，启动血管生成和上皮修复过程，从而促进细胞进行损伤后修复。本发明揭示了LUT作为黄酮类膳食补充剂在抑制OTA以及其它真菌毒素方面具有较好的应用潜力，可开发为抑制OTA肾毒性的食物营养素，从而拓展LUT的用途。
Claims (4)
1.木犀草素作为真菌毒素毒性抑制物的应用。
2.根据权利要求1所述的应用，其特征在于，所述真菌毒素为赭曲霉毒素A。
3.根据权利要求1所述的应用，其特征在于，所述真菌毒素毒性为真菌毒素所致的肾毒性。
4.根据权利要求1所述的应用，其特征在于，所述抑制物为食物营养素。
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| CN105188729A (zh) * | 2013-05-07 | 2015-12-23 | 默克专利股份有限公司 | 用于针对肾毒性活性物质进行保护的缀合物 |
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| HENNICKE G.KAMP等: "Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats", 《MOLECULAR NUTRITION AND FOOD RESEARCH》 * |
| 陈洪忠等: "木犀草素对EA.hy926细胞Nrf2信号通路的激活作用及H_2O_2致氧化损伤的保护作用", 《山东大学学报(医学版)》 * |
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