摘要
目的：借助《普济方》数据库管理系统，以及基于此系统创建的中药新功能的发现方法，分析并挖掘黄芩在古代方剂中被大量配伍应用但未被历代本草明确记载的利水消肿等潜在功能,并通过实验研究予以验证和确认。进而为丰富黄芩功能主治奠定坚实基础，并论证一种中药新功能发现方法的科学性。
材料与方法：研究分文献研究和实验研究两部分。文献研究主要借助于先前建立的《普济方》数据库管理系统，运用古代方剂数据库检索技术，以黄芩为关键词，检索其所在复方主治疾病的分布，借以考察黄芩在古方书的应用情况。同时运用古代方药文献整理分析方法，考察历代本草对黄芩功能的论述，综合本草学及古代方书应用情况，可以初步认定黄芩的潜在功能。为了明确黄芩这些潜在功能与国家药典所记是否具有质的差异性，引入数理统计分析方法，对各病种应用黄芩复方的频次进行2*2列联表的卡方检验，借以确认黄芩具有的潜在功能。为了验证本草书和古方书都有论述的黄芩利水消肿功能是否存在，进行实验研究予以验证。实验研究建立大鼠水负荷模型，取SD雄性健康大鼠，用生理盐水2.5ml/kg灌胃后，收集其24h内尿量，以排尿量达到灌胃量的40%以上者入选实验。取预选合格的60只大鼠，随机分为模型对照组（简称模型组）、黄芩高剂量组、黄芩中剂量组、黄芩低剂量组、速尿组、五苓片组。禁食(不禁水)24h后,灌胃给予5ml/100g含被试药物的生理盐水负荷，用手压迫大鼠下腹部使其排尽余尿，模型组给予相应的生理盐水。将大鼠放入代谢笼(每笼1只大鼠)，记录自水负荷开始至大鼠首次排尿的时间，作为排尿潜伏期,每小时收集尿液1次，连续收集5h，记录每小时每只动物的尿量，计算5h总的排尿量，初步探索黄芩水煎液的利尿功效，进而深入探索黄芩水煎液是否对肾炎有治疗作用。按照贾慧等建立MsPGN大鼠模型的具体方法，采用大鼠一侧肾切除、预免疫和免疫相结合的方法，制造MsPGN大鼠模型。造模第5w末，用代谢笼收集大鼠24h尿液，考马斯亮蓝法测定各组大鼠24h尿蛋白的含量，剔除模型不成功大鼠3只，术后及造模过程中共死亡24只，将剩余61只大鼠随机分为模型对照组（简称模型组）、黄芩高剂量组、黄芩中剂量组、黄芩低剂量组、肾炎片组、泼尼松片组，单独饲养没有造模的12只大鼠为正常对照组（简称正常组）。于造模第6w开始给药。同时继续进行免疫。每日1次灌胃给药。连续给药6w。存活大鼠最后一次给药24h后，采集标本进行分析测定。检测大鼠24h尿蛋白含量及血液生化指标，光镜下观察大鼠肾脏组织形态学变化，采用双抗体夹心酶联免疫吸附法（ELISA）测定大鼠血清中细胞因子IL-1、TNF-α、TGF-β1的表达水平，免疫组化法检测大鼠肾组织中MMP-9、NF-κB蛋白的表达，采用RT-PCR法，对肾组织中MMP-9mRNA、NF-ΚBp65-mRNA表达情况进行检测。
结果：
1以黄芩为关键词检索其所在复方主治疾病的分布情况，得到含黄芩复方3737个，用于958种疾病。古方书用黄芩治疗胸腹痛、头痛、身痛、痹痛等，计137方，说明黄芩可能会缓解疼痛，具有止痛功能。黄芩用于惊痫、风痫、一切痫、癫痫、痫、热痫、以及中风的治疗，说明黄芩可能具有息风止痉的功能。黄芩用于治疗小便不通、痈疽大小便不通等病症的治疗，以及黄芩用于乳石发浮肿、诸肿、热肿、阴肿、身体肿胀、水肿、恶核肿、气肿、痢兼肿、湿肿、石水、消渴后成水病、脚气变成水肿等水肿类疾病的治疗，都说明黄芩可能具有利水消肿的功能。以上可以确认古代含黄芩复方所治水肿、疼痛、精神神经疾病、中风、虚劳、眼疾等优势病症现已舍弃不用，将黄芩治疗以上六种疾病的使用频次分别与黄芩安胎的使用频次进行卡方检验，统计结果显示，前六种疾病的使用频次明显高于胎动不安的使用频次，有显著差异（P<0.01）。因此在古代配伍黄芩治疗水肿、疼痛、精神神经疾病、中风、虚劳、眼疾具有非常确定的优势，明显优于2010版中国药典一部医学标准记载的黄芩治疗胎动不安。
2完善了古代方药整理分析方法。对具体药物功效的论述上,进行了病名与功能之间的相互转化,明确同病（证、症）异名、同药异名问题，明确相近、相关病（证、症）名问题，对病（证、症）名和药名分门别类处理。
3黄芩利尿实验结果表明，药物干预组排尿潜伏期均不同程度缩短，与模型组比较差异显著（p<0.05），具有统计学意义。与黄芩高剂量组比较，黄芩中剂量组及黄芩低剂量组的排尿潜伏期要长一些，差异显著，（P<0.05），说明黄芩高剂量组的利尿效果要优于其他两组。与正常组比较，药物干预各组的5h尿量都明显增加（P<0.05），黄芩各组间比较，黄芩高剂量组的5h尿量最多（P<0.05），说明黄芩高剂量组的利尿效果最好。4黄芩治疗MsPGN实验结果表明，经过治疗，与模型组比较，用药各组24h尿蛋白含量均明显下降（p<0.05）。黄芩各组间比较，以高剂量组治疗效果好一些。经药物干预后各组大鼠血脂、血肌酐、血尿素氮水平均有所降低，血清总蛋白升高明显，肝功能没有明显变化。肾组织病理形态观察模型组呈现弥漫性肾小球病变，有部分肾小球萎缩，球内细胞数增多，ECM中、重度聚集，系膜区面积增宽，部分肾小球毛细血管腔受压变窄，肾小球基底膜增厚，肾间质有炎性细胞浸润，经过药物治疗后，各组情况有所改善。药物干预各组大鼠血清中IL-1、TNF-α、TGF-β1等多种炎性因子表达与模型组比较明显降低。模型组大鼠肾小球NF-κB p65表达明显增多。药物干预各组大鼠肾小球NF-κB p65的阳性表达主要集中在胞浆，虽比正常对照组高，但较模型组明显减少(P<0.05)。模型组MMP-9的表达较正常组显著增加（p<0.05），具有统计学意义，而且肾组织MMP-9表达并不局限于肾小管内，在肾小球内亦见明显表达。实验用药各组较模型组均可明显降低MMP-9表达水平，p<0.05，黄芩各剂量组比较，黄芩高剂量组MMP-9表达水平最低。RT-PCR法测定肾组织NF-ΚBp65与MMP-9mRNA的表达，实验用药各组较模型组均可明显降低NF-ΚBp65mRNA与MMP-9mRNA表达水平，p<0.05。黄芩各剂量组比较，黄芩高剂量组NF-ΚBp65mRNA与MMP-9mRNA表达水平最低，与肾炎片组比较，数值虽差异，但无统计学意义。
结论：
1黄芩具有治疗水肿、疼痛、精神神经疾病、中风、虚劳、眼疾的潜在功能。
2黄芩水煎剂具有利尿的功能。
3黄芩水煎剂能够降低MsPGN大鼠尿蛋白含量，保护肾功能，减轻肾小球损伤，对MsPGN有一定治疗作用。
4黄芩水煎剂对MsPGN的治疗作用机制，可能是通过抑制炎症因子(IL-1、TNF-α、TGF-β1)的表达，降低NF-κBp65的激活，从而调控MMP-9的过度表达。
Purpose：To analyze and excavate scutellaria potential functions which hasnot been specifically mentioned in ancient herbal but had a large number ofapplications in ancient prescriptions with database management system of “PujiFang”. While they were confirmed by experimental research, then we can clearand rich new features in traditional Chinese medicine. And demonstrated thescientificity and practicality of a new method to find new features oftraditional Chinese medicine.
Material and method： Research includes literature research andexperimental research. In literature research ancient prescriptions and herbsliterature analysis method was used to investigate ancient herbal expositionsabout scutellariae function, and found that some features of scutellariaeancient herbal said didn’t match with medical standard of2010edition ChinesePharmacopoeia recording. In general, the real records of clinical applicationretained among successive prescriptions. Therefore, with database managementsystem of “Puji Fang”, using the ancient prescription database retrievaltechniques studied the application of scutellariae in ancient books.We confirmedscutellariae function. We introduced mathematical statistical analysis methodin order to confirm the potential function of scutellaria. In order to verifydiuresis and elimination of edema of scutellaria function which the ancientprescriptions and herbs book had discussed, we conducted experimental study.We established water load model in rats with the SD healthy male rats.Mice stomachwere perfused with2.5ml/kg saline, after the collection of urine within24h,the voided volume reached more than40%of the amount of gavage were selected intothe experiment.60qualified rats of pre-selection were randomly divided intomodel control group (referred to as the model group), scutellariae high dosegroup, scutellaria middle dose group, scutellariae low dose group, furosemidegroup, Wuling tablets group. After fasted for24hours but water, gastricperfusion of saline (5ml/100g) was given, mice lower abdomen were oppressed todrained enuresis, model group was given saline. The rats were placed inmetabolic cages (one rat per cage), recorded for the first time urination timesince the water load to rats as urination incubation period. Urine were collectedhourly, collected five hours at a stretch.Recorded per hour per only animal urineoutput and calculated total urinary amount, in order to preliminarily explorediuretic effect of scutellariae decoction, depth explord whether scutellariaedecoction have a therapeutic effect on nephritis. Experimental MsPGN model ofunilateral nephrectomized SD rats were induced with pre-immune and immunecombined method. In Modeling5th weekend using metabolic cages collected24hurine of rats, determined of24h urinary protein content of the rats in eachgroup with coomassie blue method.Excluding three urine protein negative ratsand24death rats in modeling process,the remaining61rats were randomly dividedinto model control group (referred to as the model group), scutellariae highdose group, scutellariae middle dose group, scutellariae low dose group,nephritis tablets group, prednisone tablets group, individually housed12ratswithout model for the control group (referred to as normal group). In Modeling6th weekend started to administrate while continued to carry out immunization.Model rats orally administrated once a day for6weeks.Collection of samplesfor analysis were conducted24hours after the last administration in mice ofeach group.Detected24-hour urinary protein and blood biochemical parameters,Observed the morphological changes of renal tissue in the light microscope,determinated serum levels of IL-1, TGF-β1and TNF-α with ELISA, DetectedMMP-9and NF-κB expression of renal tissue in rat by immunohistochemistry method,detected MMP-9mRNA and NF-ΚBp65mRNA expression of renal tissue by RT-PCR method.
Results:1. We get scutellaria compound3737which were used to958kinds ofdiseases by retrieving. In ancient prescription books scutellaria was used totreat thoracic and abdominal pain, headache, body pain, and so on, we speculatedthat scutellaria may relieve pain. The scutellaria for panic epilepsy, epilepsywind, all epileptic seizures, epilepsy, hot epilepsy, as well as the treatmentof stroke, scutellaria may have function of calm the wind and stop the spasms.Scutellaria for the treatment of difficulty in urination and scutellaria foredema, all swollen, scutellaria may have the benefits of water swelling. Insummary we confirmed that ancient compound of containing scutellaria foredema,pain, neuropsychiatric disorders, stroke, consumption, all eye diseaseshad been discarded. Chi-square test statistics showed that ancient scutellariacompound treating edema,pain, neuropsychiatric disorders, stroke, consumption,all eye diseases had a very definite advantage, superior to scutellaria treatmentof fetal irritability which was recorded by medical standard of the2010editionChinese Pharmacopoeia.
2. Improved the methods of arrange and analysis about ancient recipe.
3.Scutellaria diuretic experimental results showed that urination incubationperiod of the drug treatment group had shortened to varying degrees, which wassignificantly different (p<0.05)comparing with the normal group, with astatistically significant. Comparing with scutellaria high dose group,urination incubation period of the scutellaria middle dose group and scutellarialow dose group were longer, significant differences (P<0.05), explained thatthe diuretic effect of scutellaria high dose group was superior to the othertwo groups. Comparing with the normal group, drug intervention groups5h urineoutput were significantly increased (P<0.05),5h urine output of scutellariahigh dose group were most, explained that diuretic effect of scutellaria highdose group was best.
4. Experimental results of scutellaria treating MsPGN showed that24h urinary protein levels of the medication groups were significantly decreased(p<0.05)comparing with the model group. Among the three groups, the therapeuticeffect of scutellaria high dose group was best. After drug intervening, bloodfat, serum creatinine, blood urea nitrogen levels of all groups were reducedsignificantly, serum total protein was elevated, liver function did not changesignificantly. Kidney tissue pathological observation of model group showeddiffuse glomerular lesions and partial glomerular atrophy, an increasing thenumber of cells in the glomerular, the ECM severed gathered, widened mesangialarea, glomerular capillary cavity pressure change narrow, glomerular basementmembrane thickening, renal interstitial infiltration of inflammatory cellswhile all groups improved after drug treatment. Comparing with model group serumIL-1, TNF-α, TGF-β1expression of drug intervention groups decreasedsignificantly. NF-κB-p65expression of the model rats in the glomerular wassignificantly increased, and most of the brown particles had entered the nucleus,and had high expression in the nucleus. NF-κBp65of drug intervention groupspositively expressed mainly in the cytoplasm, although higher than the normalcontrol group, but significantly reduced (P<0.05)comparing with the model group.Comparing with the normal group the expression of MMP-9in the model group(p<0.05)significantly increased, and MMP-9expression of kidney tissue was notlimited to the tubular, expressed significantly in the glomerular also.Comparing with the model group, the drug intervention groups could decrease theexpression level of MMP-9, p<0.05, the expression level of MMP-9was the lowestin the scutellaria high dose group. Comparing with the model group, the drugintervention groups can significantly reduced the expression levels of NF-ΚBp65mRNA and MMP-9mRNA. Expression levels of NF-ΚBp65mRNA and MMP-9mRNA werelowest in scutellaria high dose group.
Conclusion：
1. Scutellaria has the potential function to treat edema, pain,neuropsychiatric disorders, stroke, consumption, all eye diseases.
2. The scutellaria decoction benefits of water swelling.
3. The scutellaria decoction can reduce the urine protein content of MsPGN rats,protect the renal function, reduce glomerular injury, has a certain therapeuticeffect on MsPGN rats. The therapeutic mechanisms of scutellaria decoction forMsPGN rats may reduce the activation of NF-κBp65by inhibiting the expressionof inflammatory cytokines (IL-1, TNF-α, TGF-β1), thereby regulating theexpression of MMP-9.
4. With database management system of “Puji Fang”, relying on ancientprescription database retrieval technology, combining with logical analysis andmodern statistical methods, then be confirmed by the experimental study, wefound that the method has scientific feasibility.
引文
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