Kansuinine J,a new macrocyclic diterpenoid from the roots of Euphorbia kansui

A new macrocyclic diterpenoid,named kansuinine J（1）,was isolated from the roots of Euphorbia kansui.Its structure was characterized on the basis of spectroscopic analysis.

Studies on the Structure of Kansuinine A from Euphorbia kansui

Kansuinine A is a macrocyclic jatrophane diterpene that was isolated from Euphorbia kansui. Further investigation of the structure was revealed that the benzoyl group located at C-8 and the position of C-3 was the present of an acetyl group by means of HMQC, HMBC spectra.

Elucidating the interaction of kansui and licorice by comparative plasma/tissue metabolomics and a heatmap with relative fold change

Although compatibility is highly advocated in traditional Chinese medicine (TCM), inappropriate combination of some herbs may reduce the therapeutic action and even produce toxic effects. Kansui and licorice, one of TCM “Eighteen Incompatible Medicaments”, are the most representative cases of improper herbal combination, which may still be applied simultaneously under given conditions. However, the potential mechanism of their compatibility and incompatibility is unclear. In the present study, two different ratios of kansui and licorice, representing their compatibility and incompatibility respectively, were designed to elucidate their interaction by comparative plasma/tissue metabolomics and a heatmap with relative fold change. As a result, glycocholic acid, prostaglandin F2a, dihydroceramide and sphinganine were screened out as the principal alternative biomarkers of compatibility group;sphinganine, dihydroceramide, arachidonic acid, leukotriene B4, acetoacetic acid and linoleic acid were those of incompatibility group. Based on the values of biomarkers in each tissue, the liver was identified as the compatible target organ, while the heart, liver, and kidney were the incompatible target organs. Furthermore, important pathways for compatibility and incompatibility were also constructed. These results help us to better understand and utilize the two herbs, and the study was the first to reveal some innate characters of herbs related to TCM “Eighteen Incompatible Medicaments”.

Investigation of the processing technology and mechanism of Kansui radix by licorice based on response surface methodology and integrative pharmacology

Background:The herbs should be processed by different methods before use,and the efficacy and toxicity of Chinese herbal medicines may change,which may enhance efficacy and reduce toxicity after processing.Gansui(Kansui radix)is a common clinical herbal medicine,and there are considerable changes in its toxicity and efficacy after processing.Gaocao(Glycyrrhizae radix et rhizome)has a detoxifying effect.Methods:Using the contents of euphorbiadienol and the alcohol-soluble extract of Glycyrrhizae radix-processed Kansui radix as evaluation indexes,response surface methodology was used to optimize the processing technology of Kansui radix by exploring the effects of Glycyrrhizae radix et rhizoma-addition amount,frying temperature,and frying time on the processing technology of Kansui radix.Meanwhile,response surface software was used to analyze experimental data to determine the processing parameters of Kansui radix by Glycyrrhizae radix et rhizoma.Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine is used to analysis the potential ingredients of Kansui radix and verify the potential ingredients by western blotting.Results:The technology of Glycyrrhizae radix et rhizoma-processed Kansui radix was optimized for the Glycyrrhizae radix et rhizoma-addition amount of 27%,frying temperature of 180℃,and frying time of 11 min.The network pharmacology analysis revealed that Kansui radix could cause kidney,liver,and heart injury by the PI3K/AKT signaling pathway.Kansui radix at high or low dose could decrease the ratio of p-AKT/AKT while Glycyrrhizae radix et rhizoma-processed Kansui could increase it.Conclusion:The model established by response surface methodology is relatively accurate and can predict the contents of euphorbiadienol and alcohol extract of processed Kansui radix.The toxic effects and its mechanism of action of Kansui radix and processed Kansui radix on kidney,liver,and heart,from the perspective of systems biology,have provided scientific evidence to its clinical application.

Radix Kansui Stir-Fried with Vinegar Reduces Radix Kansui-Related Hepatotoxicity in Mice via Mitochondrial Pathway

Objective To investigate the mechanism of Radix Kansui(RK)stir-fried with vinegar(VRK)decreased hepatotoxicity in mice.Methods According to a random number table,40 mice were randomly divided into negative control group(0.5%carboxymethylcellulose sodium,20 mL/kg),positive control group(0.1%mixture of carbon tetrachloride in soybean oil,20 mL/kg),RK group(the ethyl acetate extracts of RK,250 g crude drug/kg)and VRK group(the ethyl acetate extracts of VRK,250 g crude drug/kg)with 10 mice per group.All mice were administered orally by gavage daily for 7 continuous days.The morphology of liver tissues was examined to assess the liver injury by a transmission electron microscope.Hepatocyte apoptosis in vivo was determined by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nickend labeling(TUNEL)assay.Immunohistochemical technique was adopted to detect the expression of particular antiapoptotic and proapoptotic proteins in the mitochondrial pathways,including B-cell lymphoma(Bcl-2)and caspase-3,as well as the expression of inflammatory mediators,including nuclear factor kappa B(NF-κB)and intercellular adhesion molecule-1(ICAM-1).Results Liver injury and hepatocyte apoptosis were observed in RK mice,and the liver injury were significantly reduced in VRK-treated mice.In immunohistochemistry study,compared with the negative control group,RK inhibited dramatically the Bcl-2 protein expression and significantly increased the expression of caspase-3,NF-κB and ICAM-1(all P<0.01).Compared with the RK group,VRK group induced significant increase on Bcl-2 protein expression,and decreased the caspase-3,NF-κB and ICAM-1 protein expression(P<0.05 or <0.01).Conclusion The mechanism of reduced hepatotoxicity of VRK may be associated with the reduced inflammation,regulation of antiapoptotic and proapoptotic mediators in the mitochondrial pathway.

基于水负荷模型的醋炙前后甘遂的泻水逐饮功效研究

通过建立水负荷动物模型,研究醋炙前后甘遂泻水逐饮功效的改变,从而为甘遂临床治疗腹水疾病提供理论依据。采用代谢笼法,大鼠腹腔注射5 mL生理盐水,同时灌胃给予5 mL生理盐水造成水负荷模型,观察生、醋甘遂对水负荷大鼠在0~2h、2~4 h、4~6h以及6h的总尿量的影响,检测血清中Na^(+)、K^(+)水平,肝脏中AQP9、肾脏中AQP2水平以及肾脏、十二指肠组织形态学观察。与空白组比较,水负荷模型组的大鼠尿量显著增高,肾脏指数、肝AQP9和肾AQP2水平也显著增加;与模型组比较,生甘遂高剂量(SH)可显著升高水负荷模型大鼠的4~6 h尿量和6 h总尿量;醋甘遂高剂量(CH)对2~4 h、4~6 h尿量有显著增加,表现为自水负荷2 h后即有持续利尿作用,且越到后期利尿作用越强。此外,SH组对肾脏球囊间隙增宽和管壁增厚有明显的改善,对十二指肠壁上皮血管扩张充血明显增加;CH组对肠壁化脓液渗出明显减少,且醋甘遂低剂量(CL)组形态与阳对药组极为相似。生、醋甘遂组对水负荷模型大鼠均有显著的利尿作用,后者效果更为持久缓慢。初步判断甘遂可能通过调控水负荷大鼠肾脏中水通道蛋白的下调而影响分泌相关体液,使水重吸收受到抑制,从而有助于发挥排尿作用。在考虑到生、醋甘遂逐水功效相近,对肠壁及肾脏组织副作用更低的角度,推荐临床应用醋炙甘遂。

甘遂醋炙减毒机制的主要途径及靶点预测

目的研究甘遂醋炙减毒机制的主要途径及靶点。方法取24只SPF级SD大鼠,随机分为空白组、生甘遂组(850 mg/kg)、醋甘遂组(850 mg/kg),每组8只。空白组灌胃0.5%羧甲基纤维素钠溶液,生甘遂组、醋甘遂组给予相应的供试品药液,连续给药20 d,第20天收集大鼠12 h尿液。采用超高效液相色谱串联四极杆静电场轨道阱高分辨质谱(UPLC-Q-Exactive-MS)技术分析尿液样本。经Compound Discoverer 3.0软件进行数据前处理,经BioCyc、HMDB等数据库进行代谢物结构鉴定,应用主成分分析(PCA)、正交偏最小二乘法-判别分析(OPLS-DA)等多种方法观察不同组别是否呈现各自聚类现象;基于MetaboAnalyst进行通路分析,对甘遂醋炙减毒机制潜在靶点进行预测。结果鉴定出20个有显著性差异的内源性代谢物,其中有N-乙酰基-L-天冬氨酸、3-磷酸羟基丙酮酸等10个目标生物标志物为醋甘遂减毒机制作用靶点,参与的主要代谢通路包括精氨酸生物合成,丙氨酸、天冬氨酸和谷氨酸代谢,半胱氨酸和蛋氨酸代谢及精氨酸和D-鸟氨酸代谢。对通路中所有相关代谢物的生物学意义进行分析推测,甘遂醋炙后可能通过降低N-乙酰基-L-天冬氨酸水平缓解神经毒性,通过升高L-高精氨酸水平对心脑血管系统存在保护作用等。结论甘遂经醋炙后,可对机体的神经系统、心脑血管系统、免疫系统及能量代谢等方面的不利因素有明显改善,其发挥减毒机制的最集中相关的代谢通路为精氨酸生物合成。

中药甘遂在急性胰腺炎肠道菌群中的研究进展

急性胰腺炎(AP)诱发的全身炎症反应可导致肠道菌群紊乱、肠道屏障功能和肠道免疫功能受损。Ap发病机制与肠道微生物密切相关,并与重症急性胰腺炎(SAP)的高病死率相关。近年来,肠道菌群失调被认为是当前中医药治疗AP的重要潜在靶点,其中中药甘遂在治疗SAP中发挥了重要功效。本文结合最新研究成果,从肠道菌群的角度对中药甘遂治疗AP的有关作用机制进行综述,以期为中药甘遂治疗AP提供更多的基础研究参考和临床参考。

甘遂与甘草合用对大鼠肝药酶CYP1A2、CYP2C19和CYP2E1的影响

“十八反”则告诫人们,甘遂（Euphorbia kansui,EK）与甘草（Glycyrrhiza uralensis,GU）相对立不宜伍用.但有学者认为,反药同用能相反相成,产生较强的功效.故一直以来,甘遂与甘草组合在临床上仍有广泛的应用[1-3].近年来,中药用药的安全性问题越来越受到重视,阐明“反”的机制,已成为中医药理论自身发展的必然要求.药物相互作用中最常见的原因是CYP450的诱导和抑制[4-5].

腹针疗法联合脐水消外敷神阙治疗肝癌腹水的临床研究

目的观察腹针疗法联合脐水消外敷神阙治疗肝癌腹水的疗效。方法40例原发性肝癌腹水患者,非随机化分为治疗组和对照组,各20例。对照组给予常规西医对症治疗,治疗组则在对照组基础上给予腹针联合脐水消外敷神阙治疗。比较两组腹水疗效、中医症状积分改善情况、Karnofsky功能状态评分量表(KPS)评分改善情况、不良反应发生情况。结果治疗后,治疗组腹水治疗总有效率为90%,高于对照组的45%,差异有统计学意义(P<0.05)。治疗后,治疗组中医症状积分改善总有效率为90%,高于对照组的35%,差异有统计学意义(P<0.05)。治疗后,治疗组KPS评分改善总有效率为40%,与对照组的15%比较,差异无统计学意义(P>0.05)。两组均未见严重不良反应。结论腹针联合脐水消外敷神阙能短期内改善肝癌腹水患者相关临床症状,减慢腹水生成,但在生活质量方面并未显示出优势。

煨甘遂炮制的历史沿革及质量标准研究进展

目的研究煨甘遂炮制的历史沿革及质量标准研究进展。方法通过查阅有关煨甘遂文献,从历史沿革、质量标准研究两个方面对煨甘遂炮制的研究进展进行分析。结果总结了煨甘遂的历史沿革及质量标准,优化了薄层鉴别实验方法。结论整理了煨甘遂历史沿革,总结分析了煨甘遂的质量标准,为进一步系统研究煨甘遂的质量标准提供参考。

基于物质基础探析十八反中“藻戟遂芫俱战草”配伍禁忌

目的基于物质基础探析十八反中“藻戟遂芫俱战草”配伍禁忌,为完善中药配伍禁忌理论和指导临床应用提供依据。方法通过检索近年来国内外文献,从物质基础角度分析“藻戟遂芫俱战草”甘草组反药组合配伍前后物质基础变化和其对毒效作用的影响。结果海藻、大戟、甘遂、芫花与甘草配伍对反药组合的毒、效成分溶出有影响,配伍后,可能通过促进毒性成分溶出、抑制毒性成分代谢、抑制有效成分溶出、产生新的物质、破坏物质结构等途径产生增毒减效的“毒”或增效减毒的“效”作用。结论甘草组反药组合并非绝对的配伍禁忌,还需继续基于物质基础,结合药物毒理基因组学和代谢组学等方法及高效技术进行研究。

甘遂的现代研究进展

甘遂为大戟科大戟属植物甘遂(Euphorbia kansui T.N.Liou ex T.P.Wang)的干燥块根,味苦,寒,有毒,归肺、肾、大肠经。具有泄水逐饮,消肿散结的功效。其中含有三萜类、二萜类、甾体类及有机酸等成分,能治疗重症胰腺炎、晚期肝硬化腹水与肠梗阻等疾病,同时还具有利尿作用,在治疗恶性疾病也有显著的疗效。文章综述了近年来甘遂的本草考证、化学成分、药理作用、毒性以及减毒增效的研究。以期对甘遂的临床应用、质量标准与制剂开发研究提供参考。

甘遂醋炙前后对脾淋巴细胞活力和腹腔巨噬细胞释放NO的量效关系比较研究

目的比较甘遂醋炙前后对脾淋巴细胞活力和腹腔巨噬细胞释放NO的量效关系,初步探讨甘遂醋炙减毒机制。方法采用MTT法分析脾淋巴细胞活力和Griess法分析大鼠腹腔巨噬细胞NO释放情况,比较甘遂生品、清炒品、醋润品和醋炙品的致炎毒性及量效关系比较。结果在9.5～4750 mg·L-1浓度范围内,甘遂生品组与阴性对照组比较,能够促进脾淋巴细胞增殖和腹腔巨噬细胞NO的释放(P<0.01),药物作用呈现一定的量效关系;甘遂清炒组、醋润组和醋炙组与甘遂生品组比较,均能抑制脾淋巴细胞增殖和腹腔巨噬细胞NO释放(P<0.05),其抑制顺序为醋炙品>醋润品>清炒品,且抑制作用呈现一定的量效关系。结论在9.5～4 750 mg·L-1浓度范围内,甘遂清炒品、醋润品和醋炙品均能降低甘遂的致炎毒性,且降低毒性作用呈现一定的量效关系,并提示在甘遂醋炙过程中加热和醋润两个炮制程序能够起到降低甘遂致炎毒性的协同作用,从而为探讨甘遂醋炙减毒机制提供了一定的依据。

炮制对甘遂、牛膝、苦杏仁特殊毒性及药效的影响

炮制前后毒理学研究表明，经炮制可降低甘遂、牛膝、苦杏仁对ＥＢ病毒早期抗原的激活作用，降低甘遂的皮肤刺激作用、二阶段皮肤肿瘤促进作用及峻泻作用。减毒同时可保留药效或增效。

甘遂炮制前后各部位刺激性和泻下作用研究

目的比较生甘遂和醋甘遂各极性部位的刺激性和泻下作用。方法以家兔皮肤刺激和眼刺激的评分标准为依据,观察各受试物组的刺激性。以黑色炭末为指示剂,以正常小鼠首次排黑便时间和数量为指标,观察各受试物组的泻下作用。结果与对照组相比,生品乙酸乙酯部位和二萜部位具有明显刺激性,醋制后刺激性显著下降,生品石油醚部位有轻度刺激,醋制后稍有下降,正丁醇部位刺激性不明显。甘遂各部位组均能缩短小鼠第一次排黑便时间,使排黑便粒数增加。其中生品石油醚和二萜部位,与对照组相比具有极显著性差异(P<0.01),生品乙酸乙酯部位与对照组相比具有显著性差异(P<0.05),醋制后各组作用皆有所降低。结论甘遂的刺激性成分主要集中在乙酸乙酯和二萜部位,泻下成分主要集中在石油醚和二萜部位,炮制后作用均显著下降。

甘遂不同提取物对斑马鱼急性毒性的初步观察

目的评价甘遂不同提取物对模式生物斑马鱼的急性毒性。方法采用回流提取方法制备甘遂水提物、醇提物、先醇提后水提物;将甘遂不同提取物按几何级数设置浓度梯度,添加到鱼只生活的水中,观察给药后96h鱼只的死亡情况,以此为判断待测药物毒性大小的依据,采用SPSS 13.0软件计算各药物对斑马鱼的半数致死浓度(LC50)。结果斑马鱼对甘遂不同提取物均表现出急性毒性反应,并呈现出明显的量-毒关系;甘遂水提物LC50为31.00μg/mL,甘遂醇提物LC50为6.89μg/mL,甘遂先醇提后水提物LC50为4.26μg/mL。结论以斑马鱼作为实验动物,发现甘遂先醇提后水提物急性毒性最强,水提物毒性最弱,为进一步认识与评价甘遂的毒性作用提供了依据。

甘草甘遂伍用对大鼠心肝肾功能及形态的影响

目的 观察中药十八反中甘草与甘遂同用时对Wistar大鼠心、肝、肾功能及形态的影响。方法 单味药甘草及单味药甘遂各 1 0 0g分别加水 2 0 0ml,煎煮浓缩至 5 0ml药液 ,配伍组将甘草及甘遂各 1 0 0g加水 40 0ml,煎煮浓缩至 5 0ml药液。共 2 0只大鼠分成甘草组、甘遂组、甘草 +甘遂组及对照组 4组 ,每组各 5只大鼠 ,采用灌胃法 ,药物剂量按 0 .2ml/ 1 0g大鼠计算 ,每日灌胃一次 ,连续 7d ,对照组灌服生理盐水。观察大鼠心、肝、肾功能及形态的变化。结果 配伍组对大鼠心、肝、肾功能有明显影响 ,而对肾功能无影响 ,对大鼠心、肝、肾组织形态有较轻微影响 ,但属可逆性改变。结论 甘草、甘遂同用后有一定的副作用 ,临床尚需谨慎使用。

甘遂不同炮制品中二萜类成分的变化研究

目的比较甘遂炮制前后各炮制品中二萜类成分甘遂萜酯B和甘遂萜酯A含有量的变化,以期揭示上述成分与甘遂醋炙减毒作用的关联性。方法采用HPLC法测定甘遂各炮制品中二萜类成分甘遂萜酯A、甘遂萜酯B,以X TerreRP C18色谱柱(4.6 mm×150 mm,5μm)为固定相;流动相为甲醇(A)-水(B)二元梯度洗脱,体积流量1.0 mL/min,检测波长235 nm,柱温38℃。结果假白榄烷型二萜类成分甘遂萜酯A和甘遂萜酯B经炮制后均有所降低,其质量分数高低顺序为生品>清炒品>醋润品>醋炙品。结论甘遂醋炙前后甘遂萜酯A与甘遂萜酯B的含有量变化与甘遂醋炙减毒有一定的关联性。

甘遂炮制前后整体化学成分变化的研究

目的:研究甘遂在炮制前后化学成分的整体变化,以揭示炮制减毒、增效的物质基础。方法:取甘遂生品和炮制品,分别用水和甲醇提取,提取液进行高效液相色谱分析。比较甘遂生品及醋制品醇提取液和水提取液的色谱图。结果:甘遂经过炮制后水煎液中,有7个原有成分消失,产生了4个新成分,同时有4个成分的含量显著下降。甘遂炮制后的醇提取液中原有的2个成分消失了,有1个新成分生成,同时有1个成分的含量下降,6个成分的含量显著上升。结论:甘遂炮制增效、减毒的物质基础可能是有毒成分的消失或含量减少,这些消失或含量减少的成分转变成了新成分或者在水中溶解度小而在醇中溶解度大的成分。