CN115337357B - 皂公二藤汤及其制备方法和应用 - Google Patents
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Abstract
本发明属于中医药技术领域，具体涉及皂公二藤汤及其制备方法和应用。所述皂公二藤汤由以下重量份数的原料药制备而成：皂角刺10‑12份，蒲公英30‑32份，忍冬藤14‑15份，红藤15‑16份，桃仁9‑10份，红花9‑10份，当归10‑12份，香附9‑10份，乌药8‑9份，路路通15‑16份，柴胡9‑10份，白芍12‑13份，鳖甲20‑21份，茯苓14‑15份。本发明的皂公二藤汤对LPS诱导的小鼠子宫内膜炎具有明显的治疗作用，显著提高了患病小鼠的配种率和D8的着床点数，有望成为临床上一种安全、新颖且有效的子宫内膜炎的治疗药物。
Description
技术领域
本发明属于中医药技术领域，具体涉及皂公二藤汤及其制备方法和应用。
背景技术
子宫内膜炎是一种常见的子宫感染性疾病，其会引起雌性哺乳动物子宫分泌脓性炎症粘液。炎症会引起子宫内环境的紊乱，使胚胎无法存活，最终导致不孕。在畜牧业生产中，奶牛患子宫内膜炎会导致产奶量下降，给农场带来巨大的经济损失。子宫内膜炎主要是由病原微生物入侵引起的，入侵子宫的病原微生物单独或联合释放毒力因子，引起子宫组织损伤和炎症反应。这些病原微生物主要是细菌，包括Escherichia coli,Trueperellapyogenes,Clostridium,Streptococcus,or Staphylococcus。脂多糖(LPS)是革兰氏阴性菌细胞壁的主要成分，是引起子宫内膜炎的重要毒力因子，在雌性动物子宫中会引发强烈的炎症反应。因此LPS常被用于制作子宫内膜炎的动物模型。
TLR-4是细胞表面介导天然抗感染免疫的关键受体蛋白之一，其下游的NF-κB信号通路和IRF3信号通路是LPS诱导炎症反应中激活的主要通路。这些信号通路在多种真核细胞中可被LPS、细菌糖蛋白、病毒分子和炎症因子等激活，使NF-κB/P65和IRF3发生磷酸化，从细胞质转移到细胞核促使炎性因子过表达，引发炎症反应。抑制TLR4/NF-κB信号通路，降低LPS诱导的子宫内膜炎，是近年来人们在治疗药物开发中考虑的一个重要策略。
目前抗生素是治疗子宫内膜炎的常用药物；然而，其严重的细菌耐药性和药物残留等方面的缺点限制了其广泛使用。中草药因其安全性好、毒副作用少、无残留、给药方便等优点，已成为临床用药的热点。因此，人们正在努力寻求一种安全有效的治疗子宫内膜炎的中药。
发明内容
为解决上述技术问题，本发明提供了一种皂公二藤汤，由以下重量份数的原料药制备而成：
皂角刺10-12份，蒲公英30-32份，忍冬藤14-15份，红藤15-16份，桃仁9-10份，红花9-10份，当归10-12份，香附9-10份，乌药8-9份，路路通15-16份，柴胡9-10份，白芍12-13份，鳖甲20-21份，茯苓14-15份。
所述皂公二藤汤的制备方法，包括以下步骤：
S1、按重量份数称取各原料药；
S2、将原料药混合后加水浸泡30-40分钟，然后大火加热，水沸腾后，改为小火，煎煮30-35分钟，将煎液与药渣分离；
S3、所得药渣加入80-85℃的水，沸腾后改为小火，煎煮30-35分钟，将煎液与药渣分离；
S4、所得药渣重复S3步骤一次；
S5、将三次的煎液混合，过滤，水浴浓缩至1ml汤药含1.15-2.3g生药，得所述皂公二藤汤。
进一步的，S2和S3中加水量为刚浸没药材为准。
基于同一个发明构思，本发明还提供了所述皂公二藤汤在制备治疗动物子宫内膜炎药物中的应用。
进一步的，所述动物包括小鼠。
本发明的皂公二藤汤的部分原料药的功效如下：
皂角刺作为一种传统的抗炎药物，在临床上已被用作炎性疾病的治疗。皂角刺的水提物可抑制NF-κB的激活和磷酸化，促使IκB-α降解，能有效抑制脂多糖(LPS-)诱导的巨噬细胞中一氧化氮(NO)的产生和诱导型一氧化氮合酶(NOS)的表达，激活HaCaT细胞中趋化因子的表达。蒲公英在临床上也已被广泛用于治疗各种感染性和炎症性疾病，如支气管炎、肺炎、上呼吸道感染、肝炎和乳腺炎等。蒲公英甾醇是蒲公英的主要活性物质，其可通过抑制NF-κB和MAPK信号通路调节促炎细胞因子和中介物的产生，而发挥其抗炎活性。忍冬藤也是一种重要的抗炎草药，其主要活性成分是绿原酸，绿原酸具有抗感染、抗菌和抗氧化等特性，其能抑制JAK/STAT和NF-κB信号通路中关键分子的表达，抑制IL-6介导的炎症反应信号通路的激活，从而减少炎症的发生。
本发明的皂公二藤汤的方解：
以皂角刺、蒲公英为君药，臣以忍冬藤、红藤，辅以桃仁、红花、当归、香附活血化瘀，以乌药理气止痛、行气活血，路路通利水通络，柴胡引药入肝，白芍柔肝止痛，鳖甲软坚散结，茯苓健脾利湿，共奏清热解毒、活血化瘀、软坚散结之功效，对妇科炎症性疾病导致的不孕症有较好疗效。
本发明的附加方面和优点将在以下描述中列出，或通过本项目的实践了解到。
附图说明
图1为各个实验组的小鼠子宫。A.Control；B.LPS；C.LPS+AMC；D.LPS+low ZGETD；E.LPS+high ZGETD；F.Low ZGETD；G.High ZGETD；箭头所示：子宫组织。
图2为小鼠的子宫体重比(×10-3)(N＝10)；*表示与对照组比差异显著；#表示与模型组比差异显著；■表示与阳性组相比差异显著；□表示与LPS+低浓度药物组相比差异显著。
图3为小鼠子宫组织HE染色；A.Control；B.Low ZGETD；C.High ZGETD；D.LPS；E.LPS+AMC；F.LPS+low ZGETD；G.LPS+high ZGETD；图中，a：完整的内膜上皮；b：脱落的上皮细胞；c：损伤的子宫内膜上皮；d：出血区域；e：炎性细胞聚集；f：破坏的腺组织结构。
图4为小鼠子宫组织HE染色；A.LPS+清热解毒方；B.LPS+high ZGETD；双箭头：子宫内膜的厚度。
图5为子宫组织中炎性因子的表达水平(ng/ml)(N＝10)；*表示与对照组比差异显著；#表示与模型组比差异显著；■表示与阳性组相比差异显著；□表示与LPS+低浓度药物组相比差异显著。
图6为小鼠子宫组织中MPO活性(U/mg)(N＝10)；*表示与对照组比差异显著；#表示与模型组比差异显著；■表示与阳性组相比差异显著；□表示与LPS+低浓度药物组相比差异显著。
图7为子宫组织TUNEL染色。阳性细胞：黄绿色。
图8为子宫组织中TUNEL染色的阳性细胞数，*表示与对照组比差异显著；#表示与模型组比差异显著。
图9为趋化因子基因(CXCL5和CXCL8)在子宫组织中的表达；*表示与对照组比差异显著；#表示与模型组比差异显著。
图10为Western blotting检测子宫组织中IRF3,p-IRF3,P65,p-P65和TLR4蛋白的表达。
图11为Image J图像分析软件分析IRF3,p-IRF3,P65,p-P65和TLR4蛋白的相对表达水平；*表示与对照组比差异显著；#表示与模型组比差异显著。
图12为子宫内膜炎治疗后小鼠的配种率统计。
图13为D8怀孕小鼠子宫和LPS注射侧小鼠子宫；A.LPS+清热解毒方；B.LPS+highZGETD；箭头：注射LPS侧子宫角。
图14为D8怀孕小鼠子宫和LPS注射侧小鼠子宫着床点统计；*表示与清热解毒方治疗组相比差异显著。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明，但不应理解为本发明的限制。如未特殊说明，下述实施例中所用的技术手段为本领域技术人员所熟知的常规手段，下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1：皂公二藤汤(Zaogong Erteng Decoction,ZGETD)的制备
所有的药材购自中国北京同仁堂。称取皂角刺12克，蒲公英30g，忍冬藤15克，红藤15克，桃仁9g，红花9g，当归12克，香附9克，乌药9g，路路通15g，柴胡9g，白芍12g，鳖甲21g，茯苓15克。干燥、粉碎成粉后置于砂锅内，加水浸泡30分钟，然后大火加热，水沸腾后，改为小火，煎煮30分钟，将煎液与药渣分离；所得药渣加入80℃的水，沸腾后改为小火，煎煮30分钟，将煎液与药渣分离；所得药渣重复前步骤一次，将三次的煎液混合，过滤(4层纱布过滤)，滤液置于烧杯中80℃水浴浓缩至1ml汤药含2.3g生药材作为高浓度皂公二藤汤，1ml汤药含1.15g生药材作为低浓度皂公二藤汤。含有皂角刺、蒲公英、忍冬藤、红藤、柴胡、鳖甲、茯苓的清热解毒方剂为1ml汤药含1.4g生药材。4℃冷藏备用。
皂公二藤汤由清热解毒方和活血化瘀方两个方剂的中药组成，其中皂角刺、蒲公英、忍冬藤、红藤、柴胡、鳖甲、茯苓属于清热解毒方，具有清热解毒、软坚散结之功效；乌药、路路通、桃仁、红花、当归、香附、白芍属于活血化瘀方，具有行气活血、利水通络、活血化瘀的作用。
实施例2：皂公二藤汤对LPS诱导的子宫内膜炎的治疗
1材料与方法
1.1实验动物
试验采用性成熟的体重35～40g的3月龄昆明品系雌性小鼠，购自吉林省长春市亿斯实验动物技术有限责任公司。小鼠生活在温控的房间(21±2℃)，12h光照/12h黑暗的光照周期。自由饮水和采食。小鼠的处理方法经吉林医药学院伦理委员会同意。
1.2动物处理
性成熟的130只雌性小鼠被随机分为七组，分别是对照组(n＝10)、模型组(LPSgroup)(n＝10)，阿莫西林治疗组(LPS+AMC group)(n＝10)、低浓度皂公二藤汤治疗组(LPS+低浓度ZGETD group)(n＝10)、高浓度皂公二藤汤治疗组(LPS+高浓度ZGETD group)(n＝30)、清热解毒方治疗组(LPS+清热解毒方剂)(n＝20)、低浓度皂公二藤汤组(低浓度ZGETDgroup)(n＝10)、高浓度皂公二藤汤组(高浓度ZGETD group)(n＝30)。
对照组、低浓度ZGETD group和高浓度ZGETD group的雌鼠单侧子宫注射无菌的PBS，LPS group、LPS+AMC group、LPS+低浓度ZGETD group、LPS+高浓度ZGETD group和LPS+清热解毒方剂group的雌鼠单侧子宫注射2.5mg/ml LPS 20ul(L2755，Sigma,St.Louis,MO,USA)；24h后，正常组和模型组雌鼠灌胃无菌的PBS,LPS+AMC group雌鼠灌胃500mg/kg的阿莫西林(国药准字H21023908，四川援健药业有限公司)，低浓度ZGETD group和LPS+低浓度ZGETD group组雌鼠灌胃11.2g/kgZGETD，高浓度ZGETD group和LPS+高浓度ZGETD group组雌鼠灌胃22.4g/kg ZGETD，LPS+清热解毒方剂group雌鼠灌胃13.63g/kg清热解毒方剂，每天灌胃一次，6天后，颈椎脱臼处死小鼠，收集小鼠子宫样本，剔除周围的脂肪组织，称量小鼠子宫的重量，并拍照记录小鼠子宫的形态。高浓度ZGETD治疗组和清热解毒方治疗组6天治疗后，各取20只治疗鼠与雄鼠1:1配种，第二天早上检查阴道栓，见栓当天为怀孕D1，怀孕D4收集并固定子宫组织(n＝10),怀孕D8收集子宫组织，计数着床点的数量并统计怀孕率(n＝10)。
1.3子宫组织HE染色
子宫组织切片置于10％福尔马林溶液中，固定24小时后，将子宫组织常规脱水、二甲苯处理、石蜡包埋，用切片机切成5μm的石蜡切片(德国莱卡切片机)。然后，将子宫切片进行脱蜡和梯度乙醇处理，苏木精染色6min和伊红染色30s；梯度乙醇脱水和二甲苯透明，中性树脂封片待镜检拍照。
1.4酶联免疫吸附法(ELISA)
利用酶联免疫吸附法(ELISA)检测了小鼠子宫组织中肿瘤坏死因子(TNF-α)、小鼠白介素1β(IL-1β)和小鼠白介素6(IL-6)等炎症因子的表达。TNF-α(BPE20220)、IL-1β(BPE20533)和IL-6(BPE20012)检测的试剂盒均购自上海朗顿生物科技有限公司。具体检测方法如下：取小鼠子宫组织称重，匀浆离心获得上清。在组织上清中加入生物素标记抗原工作液，37℃培养箱中孵育30min，洗涤后，加入亲和素放置37℃培养箱中孵育30min，洗涤，加入显色剂，37℃避光显色10min，检测OD450值。
1.5髓过氧化物酶(MPO)活性检测
利用MPO可以使过氧化氢还原，产生的化合物与供氢体邻联茴香胺反应生成黄色的化合物，在460nm处通过比色测定黄色化合物的生成量。MPO检测试剂盒(A044-1-1)购自南京建成生物工程研究所。具体方法如下：准确称取子宫组织，制备成5％的组织匀浆液，37℃水浴15分钟后，加入过氧化氢，
混匀，37℃水浴30分钟后，加入邻联茴香胺，60℃水浴10分钟，检测OD460值。
1.6TUNEL assay
利用末端脱氧核糖核酸转移酶(Terminal deoxynucleotidyl Transferase)将地高辛标记的dUTP(DIG-dUTP)标记至DNA断点部位的3’-OH末端，通过生物素化抗地高辛抗体(Anti-DIG-Biotin)反应，再结合荧光素FITC标记的链酶亲和素(SABC-FITC)。凋亡的细胞在荧光显微镜下呈明亮的黄绿色。TUNEL检测的试剂盒(MK1019)购自武汉博士德生物工程有限公司。具体检测方法如下：常规石蜡切片至5μm，二甲苯中脱蜡，蛋白酶K消化，在标本片添加1ul TdT和18ul DIG-d-UTP 37℃反应2h。利用生物素化抗地高辛抗体与样本37℃反应30分钟，TBS洗3次，SABC-FITC对样本37℃标记30分钟，Hochest33342染细胞核，水溶性封片剂封片。每个实验组使用5只小鼠，每只小鼠制作3张子宫组织切片，Olympus IX-53的正置显微镜下观察，利用显微图像采集系统(CellSens Dimension)对每张组织切片随机选取3个靠近子宫腔的视野(×200)进行拍摄，计数呈现黄绿色荧光的凋亡细胞的数量。
1.7qRT-PCR assay
将小鼠子宫组织利用Plus RNA Purification Kit(12183-555，Invitrogen)提取RNA，并使用SuperScriptTMIII First-Strand Synthesis SuperMix forqRT-PCR(11752-050，Invitrogen)将mRNA转录成cDNA。使用Quantstudio多重实时荧光定量PCR仪(美国life technologies公司)、利用Power/>Green PCR Master Mix(4913914001，Roche)通过定量实时PCR对趋化因子基因(CXCL5和CXCL8)的表达进行分析。PCR的产物通过琼脂糖凝胶电泳确认。管家基因，β-actin被用来作为实验的内参。使用2-△△Ct方法计算目的基因相对表达水平。
1.8Western blotting analysis
将子宫组织放入RIPA强裂解液(含1％PMSF)(P0013B和P1006,Beyotime)提取蛋白。利用BCA蛋白检测试剂盒(P0012S,Beyotime)测定总蛋白浓度。将等量的蛋白质在12％SDS-PAGE上进行分离，将蛋白转移到PVDF膜(IPVH00010，Millipore)上，5％脱脂奶粉封闭1h。对PVDF膜进行IRF3(ab68481,Abcam)、p-IRF3(ab76493,Abcam)、P65(ab32536,Abcam)、p-P65(ab76302,Abcam)、TLR4(ab13556,Abcam)和β-actin(ab8226,Abcam)一抗孵育，4℃过夜。PBST洗膜后，膜在山羊抗兔HRP标记的二抗(31210,Thermo Scientific Pierce)中室温孵育2h，然后进行增强的化学发光显色，使用ChemiDOC XRS+imaging systems(Bio-RadLaboratories,Hercules,CA,USA)对膜进行扫描。重复3次后用Image J图像分析软件分析IRF3、p-IRF3、P65、p-P65和TLR4的相对表达水平。
1.9数据分析
采用SPSS 17.0软件对试验数据进行统计学分析，数据表示为平均值±标准差(SD)。采用单因素方差分析(one-way ANOVA)的LSD post hoc检测方法进行多组间差异比较，P<0.05为差异显著。
2结果
2.1皂公二藤汤对LPS刺激的小鼠子宫发育的影响
LPS(2.5mg/ml，20ul)诱导小鼠子宫内膜炎24h后，分别利用PBS、阿莫西林、低浓度皂公二藤汤和高浓度皂公二藤汤灌胃6天，获取小鼠子宫(图1)。正常组、LPS+高浓度ZGETD组、低浓度ZGETD组和高浓度ZGETD组的小鼠子宫较细，血管分布正常，各组之间的子宫/体重比值没有显著差异(p>0.05)(图2)。而在LPS组和LPS+AMC组，子宫组织出现水肿，充血现象，小鼠的子宫/体重比值显著高于对照组(p<0.05)(图2)；LPS+低浓度ZGETD组小鼠子宫组织出现水肿现象，但充血不明显，小鼠的子宫/体重比值显著高于对照组(p<0.05)，但显著低于LPS组(p<0.05)，与LPS+AMC组没有显著差异(p>0.05)(Fig.2)；LPS+高浓度ZGETD组小鼠子宫/体重比值显著低于LPS组、LPS+AMC组和LPS+低浓度ZGETD组(p<0.05)(图2)，高浓度ZGETD对LPS诱导的小鼠子宫水肿和充血的现象有明显的缓解作用。
2.2皂公二藤汤缓解了子宫内膜炎的病理变化
对各组的小鼠子宫组织进行HE染色，结果如图3所示。模型组小鼠的子宫内膜损伤严重，子宫内膜上皮细胞大量脱落，多个区域出血，子宫腺体的结构被破坏；LPS+AMC组子宫内膜上皮受损，内膜中出现出血区域，发生大量的炎性细胞聚集；而在正常组、低浓度ZGETD组、高浓度ZGETD组、LPS+低浓度ZGETD组和LPS+高浓度ZGETD组小鼠子宫腔上皮表面平滑、完整，子宫腺体结构正常，未见出血区域和炎性细胞聚集的现象。ZGETD明显缓解了脂多糖诱导的子宫内膜炎病理性改变。
比较了高浓度ZGETD治疗组和清热解毒方治疗组小鼠子宫内膜的发育，如图4所示。清热解毒方中缺少了行气活血、利水通络、活血化瘀等中药成分，子宫内膜基质细胞致密，腺体数量少，腺腔小，子宫内膜的厚度比含有活血化瘀方中药的ZGETD明显变薄。皂公二藤汤除了具有抗菌消炎的功效，还有活血化瘀成分的中药，刺激了子宫内膜的发育和蜕膜化，提高了子宫内膜的容受性。
2.3皂公二藤汤降低了炎性因子和髓过氧化物酶(myeloperoxidase,MPO)的表达
炎性细胞因子直接参与了子宫内膜炎的发生和发展过程，其能激活中性粒细胞和淋巴细胞，引起组织细胞的损伤和坏死。ELISA法检测各组小鼠子宫组织中炎性因子TNF-α、IL-1β和IL-6的表达(图5)。模型组小鼠子宫组织中炎性因子TNF-α、IL-1β和IL-6的表达较对照组显著升高(p<0.05)，LPS诱导小鼠子宫内膜炎性因子的表达增强。阿莫西林和ZGETD显著降低了LPS引起的这些炎性因子的表达(p<0.05)，且高浓度ZGETD较阿莫西林和低浓度ZGETD更显著地降低了LPS诱导的这些炎性因子的表达(p<0.05)。高浓度ZGETD具有较好的抑制LPS诱导炎性因子表达的作用。
髓过氧化物酶(myeloperoxidase,MPO),是一种血红素蛋白，富含于中性粒细胞中,组织中MPO的含量可以预测中性粒细胞的数量，反映组织炎性反应的程度和组织的损伤程度[11]。分光光度法测定小鼠子宫中MPO的活性(图6)，与对照组相比，LPS显著升高了小鼠子宫组织中MPO活性(p<0.05)。LPS+AMC组、LPS+低浓度ZGETD组和LPS+高浓度ZGETD组MPO活性显著低于LPS组(p<0.05)，且LPS+高浓度ZGETD组MPO活性更显著地低于LPS+AMC组和LPS+低浓度ZGETD组(p<0.05)。高浓度ZGETD可以更好的抑制LPS诱导的MPO活性增加。
从以上实验结果得知，高浓度ZGETD具有较好的抗炎效果，且其对子宫的发育无不良的影响。因此，我们选择高浓度ZGETD参与后续的实验研究。
2.4皂公二藤汤减少了LPS诱导的子宫内膜细胞的凋亡
TUNEL染色检测小鼠子宫组织中细胞的凋亡，凋亡是与炎症相关的细胞程序性死亡。如图7所示，凋亡的细胞被染成黄绿色。对照组的子宫组织发现少量的TUNEL阳性细胞，而在LPS诱导的子宫内膜炎模型组小鼠子宫组织中TUNEL阳性细胞数较对照组显著增多(p<0.05)(图8)，高浓度ZGETD显著降低了LPS处理的小鼠子宫组织中TUNEL阳性细胞的数量(p<0.05)(Fig.6B)。高浓度ZGETD减少了LPS处理小鼠子宫内膜细胞凋亡。
2.5皂公二藤汤降低了LPS诱导的子宫组织中趋化因子的表达
趋化因子在招募巨噬细胞进入子宫内膜组织的过程中起着重要作用。CXCL5和CXCL8均是CXC型促炎趋化因子，在炎性因子的刺激下它们被释放，释放后它们能够吸引免疫细胞到炎症部位，从而参与子宫组织的生理和病理过程。利用qRT-PCR测定子宫组织中趋化因子CXCL5和CXCL8的基因表达水平。与对照组相比，LPS显著提高了子宫组织中的CXCL5和CXCL8的基因表达(p<0.05)(图9)，高浓度ZGETD显著降低了LPS处理的小鼠子宫组织中CXCL5和CXCL8的基因表达(p<0.05)(图9)，但LPS+高浓度ZGETD组子宫组织中CXCL5和CXCL8基因的表达仍显著高于对照组(p<0.05)(Fig.7)。高浓度ZGETD降低了LPS处理小鼠子宫组织中趋化因子CXCL5和CXCL8的基因表达水平。
2.6皂公二藤汤下调了LPS处理小鼠子宫中TLR4/IRF3和TLR4/NF-κB信号通路蛋白的表达
TLR4(Toll-like receptor 4，TLR4)，是介导天然抗感染免疫反应细胞表面的关键受体蛋白。LPS可识别并结合TLR4，激活TLR4介导的IRF3和NF-κB下游信号通路，引起炎性因子释放。我们采用western blotting方法检测了IRF3、p-IRF3、P65、p-P65和TLR4蛋白的表达，结果如图10和11所示，与对照组比，LPS显著提高子宫组织中p-IRF3、p-P65和TLR4蛋白的表达(p<0.05)，对IRF3和P65蛋白的表达没有显著影响(p>0.05)。高浓度ZGETD显著降低了LPS处理的子宫组织中p-IRF3、p-P65和TLR4蛋白的表达，对LPS激活的TLR4/IRF3和TLR4/NF-κB信号通路具有下调作用。
2.7皂公二藤汤对治疗后雌鼠生育能力的影响
比较了高浓度皂公二藤汤治疗组和清热解毒方治疗组小鼠的配种率和注射LPS侧子宫角D8着床点数，结果发现如图12、图13和图14所示，利用高浓度皂公二藤汤和清热解毒方治疗后，高浓度皂公二藤汤治疗组小鼠2个发情周期的配种率显著高于清热解毒方治疗组，且高浓度皂公二藤汤治疗组LPS侧子宫角D8着床点数也显著多于清热解毒方治疗组小鼠，高浓度皂公二藤汤相对于清热解毒方，显著提高了雌鼠的受孕能力和胚胎的着床率，是治疗子宫内膜炎的理想复方中药。
综上，本发明首次确定了皂公二藤汤对LPS诱导小鼠子宫内膜炎治疗作用。其下调了TLR4蛋白的表达，抑制了TLR4/NF-κB和TLR4/IRF3信号通路的激活，影响了炎症因子分泌和趋化因子分泌，降低了MPO的活性，对LPS引起的子宫内膜组织的病理学改变具有明显的缓解作用。且避免了抗生素使用过程出现的细菌耐药性和药物残留等缺陷，有望成为临床上一种安全、新颖且有效的子宫内膜炎治疗药物。
需要说明的是，本发明权利要求书中涉及数值范围时，应理解为每个数值范围的两个端点以及两个端点之间任何一个数值均可选用，为了防止赘述，本发明描述了优选的实施例。
尽管已描述了本发明的优选实施例，但本领域内的技术人员一旦得知了基本创造性概念，则可对这些实施例作出另外的变更和修改。所以，所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (5)
1.一种治疗动物子宫内膜炎的皂公二藤汤，其特征在于，由以下重量份数的原料药制备而成：
皂角刺10-12份，蒲公英30-32份，忍冬藤14-15份，红藤15-16份，桃仁9-10份，红花9-10份，当归10-12份，香附9-10份，乌药8-9份，路路通15-16份，柴胡9-10份，白芍12-13份，鳖甲20-21份，茯苓14-15份。
2.权利要求1所述皂公二藤汤的制备方法，其特征在于，包括以下步骤：
S1、按重量份数称取各原料药；
S2、将原料药混合后加水浸泡30-40分钟，然后大火加热，水沸腾后，改为小火，煎煮30-35分钟，将煎液与药渣分离；
S3、所得药渣加入80-85℃的水，沸腾后改为小火，煎煮30-35分钟，将煎液与药渣分离；
S4、所得药渣重复S3步骤一次；
S5、将三次的煎液混合，过滤，水浴浓缩至1ml汤药含1.15-2.3g生药，得所述皂公二藤汤。
3.根据权利要求2所述皂公二藤汤的制备方法，其特征在于，S2和S3中加水量为刚浸没药材为准。
4.权利要求1所述皂公二藤汤在制备治疗动物子宫内膜炎药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述动物包括小鼠。
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