天南星科有毒中药凝集素蛋白与毒性的相关性研究
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摘要
本学位论文得到两项国家自然科学基金——天南星科有毒中药矾制解毒共性规律研究(NO.30973939)、天南星科有毒中药凝集素蛋白与毒性的相关性和炮制的影响(NO.81173549)以及江苏省普通高校研究生科研创新计划项目(NO.CXZZ11_0786)的资助。
2010版《中国药典》收载的半夏(Pinellia ternata (Thunb.) Breit.)、天南星(Arisaema erubescens (Wall.) Schott)、白附子(Typhonium giganteum Engl)及在市场上作为天南星的代用品广泛使用的掌叶半夏(Pinellia pedatisecta Schott.),均属于天南星科,为临床常用有毒中药,这四种有毒中药临床中毒症状极为相似,误服均出现粘膜及皮肤刺激,口舌肿胀,呼吸缓慢甚至窒息死亡,所以中医临床上均使用炮制品。
论文作者所在课题组在前期研究中提出并证实天南星科四种有毒中药半夏、掌叶半夏、天南星及白附子的刺激性毒性成分均为其所含有的具有特殊晶形的针晶复合物,具有强烈的刺激性毒性,可产生严重的刺激性炎症反应,故课题组称为“毒针晶”。毒针晶主要由草酸钙、蛋白组成,前期研究发现组成毒针晶的草酸钙没有刺激性作用,而组成毒针晶的蛋白可显著加重豚鼠破损皮肤的炎症反应。对半夏毒针晶蛋白研究的结果显示,半夏毒针晶上带有的半夏凝集素蛋白是半夏毒针晶进一步诱发炎症反应的刺激物,凝集素蛋白可显著诱导中性粒细胞迁移,引起大鼠足趾肿胀,可显著加重毒针晶引起的家兔眼结膜水肿,具有强烈的促炎作用。天南星科的掌叶半夏、天南星及白附子,与半夏同属天南星科,刺激性毒性反应相似,毒性物质基础都是块茎中含有的毒针晶,故本论文提出,掌叶半夏、天南星、白附子的毒针晶上也存在与半夏类似的化学刺激物。对天南星科有毒中药凝集素蛋白与毒针晶毒性的相关性研究,除本课题组外,未见有研究报道。
本学位论文以同属天南星科、毒性表现相似的有毒中药掌叶半夏、天南星及白附子的毒针晶为研究对象,以半夏为参照,考察半夏、掌叶半夏、天南星及白附子的毒针晶中是否存在同类的与刺激性毒性相关的化学成分,研究表明四种有毒中药的毒针晶中带有共性的凝集素(lectin)蛋白成分。进一步的研究结果表明四种毒针晶中的凝集素蛋白均具有显著促炎作用,毒针晶的刺激性毒性是凝集素蛋白随毒针晶刺入组织后诱导炎症反应产生严重的炎症刺激性毒性。论文基本阐明了天南星科有毒中药半夏、掌叶半夏、天南星及白附子凝集素蛋白与毒性的相关性,主要工作内容和研究结果包括以下几个方面：
1天南星科有毒中药毒针晶蛋白类成分分析及共性刺激性相关蛋白研究
采用SDS-PAGE (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis,SDS.PAGE)分析,考察半夏、掌叶半夏、天南星及白附子毒针晶的条带,是否存在分子量相同的蛋白条带,结果显示分子量约12kDa处有相同的蛋白条带。继续将毒针晶中约12kDa处的蛋白条带采用混合蛋白胶内酶解后肽段的液相色谱串联质谱联用(1iquid chromatography tandem mass spectrogram,LC-MS-MS)技术分析,结果显示四种毒针晶约12kDa的条带存在共性的凝集素蛋白,分别为半夏凝集素(Pillellia ternata lectin,PTL),掌叶半夏凝集素(Pillellia pedatisecta lectin,PPL),天南星凝集素(Arisaema erubescens lectin,AEL)及白附子凝集素(Typhonium giganteum lectin,TGL)。
2天南星科有毒中药凝集素的提取分离纯化及性质研究
从半夏、掌叶半夏、天南星及白附子新鲜块茎中分离纯化相应的植物凝集素蛋白PTL、PPL、AEL及TGL。提取分离的流程为：半夏、掌叶半夏、天南星及白附子新鲜块茎粗提液经硫酸铵分级沉淀、苯基琼脂糖凝胶(Phenyl FF)疏水柱层析、Tris-HCl(pH=8.0)缓冲体系,收集主峰通过强阴离子(Q FF)交换柱层析,脱盐,冷冻干燥分别得PTL、PPL、AEL及TGL。高效体积排阻色谱(size-exclusion high performance liquid chromatography, SEC-HPLC)及SDS-PAGE电泳分析显示分离所得的PTL、PPL、AEL及TGL均达到色谱纯及电泳纯,测得其分子量约为12kDa。通过不同来源红细胞、温度、pH及糖或糖蛋白考察凝集素蛋白的凝集活性,结果显示：四种凝集素蛋白均能凝集兔、鼠、狗的红细胞,不能凝集鸡及人的红细胞；80℃以下具有凝集活性,50℃以下凝集活性最强,85℃以上凝集活性全部丧失；pH6.0-10.0范围内具有凝集活性,pH6.0-8.0范围内凝集活性保持稳定,pH达到11.0,凝集活性完全丧失；凝集活性不被D-木糖、D-核糖、D-阿拉伯糖、无水葡萄糖、D-半乳糖、D-甘露糖、L-鼠李糖、甲基-α-D-甘露糖苷所抑制,仅被去唾液酸胎球蛋白所抑制。
3天南星科四种有毒中药毒针晶中凝集素蛋白与块茎中凝集素蛋白比对鉴定
为进一步确定毒针晶上带有的凝集素蛋白是否与相应植物块茎中的凝集素蛋白为同一蛋白,采用SDS-PAGE分析,研究表明从植物块茎中分离获得的半夏、掌叶半夏、天南星及白附子的凝集素蛋白与其毒针晶蛋白具有相同的分子量。进一步对块茎中分离的凝集素蛋白进行LC-MS-MS分析鉴定,与美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)数据库进行比对,发现从块茎中提取的凝集素蛋白为对应植物的凝集素蛋白。蛋白免疫印迹Westem blotting结果进一步证实四种毒针晶中含有相应的PTL、PPL、AEL及TGL,即从块茎中提取分离的半夏、掌叶半夏、天南星及白附子凝集素蛋白与相应毒针晶上带有的凝集素蛋白为同一蛋白。
4天南星科有毒中药毒针晶中凝集素蛋白的含量研究
前面的研究结果表明毒针晶上含有凝集素蛋白,采用Western Blotting方法对毒针晶上的凝集素蛋白含量进行半定量分析,结果半夏、掌叶半夏、天南星及白附子毒针晶中的凝集素蛋白占毒针晶蛋白上的含量PTL为19.89%,PPL为24.84%,AEL为15.08%,TGL为11.67%,四种有毒中药凝集素蛋白含量大小顺序为掌叶半夏>半夏>天南星>白附子,该结果与前期课题组研究的四种有毒中药的毒针晶毒性与其蛋白的含量呈相关性的结果一致,表明四种毒针晶的毒性与毒针晶中带有的凝集素蛋白含量呈正相关。
5天南星科四种有毒中药凝集素蛋白的促炎作用研究
采用大鼠腹腔中性粒细胞迁移模型研究PTL、PPL、AEL及TGL的促炎作用。结果显示腹腔注射PTL、PPL、AEL及TGL后,四种有毒中药的凝集素蛋白出现明显的中性粒细胞向腹腔迁移的现象并呈剂量依赖性,腹腔液中炎症介质一氧化氮(Nitric Oxide,NO)、前列腺素E2(Prostaglandin E2, PGE2)及肿瘤坏死因子α (Tumor necrosis factor-alpha, TNF-α)的含量与空白组相比较均显著升高,表明PTL、PPL、AEL及TGL均可诱导炎症介质释放。进一步考察加热对凝集素蛋白致大鼠腹腔中性粒细胞迁移的影响,结果显示加热组与空白组比较无显著性差异,表明加热可导致凝集素蛋白失活,使其促炎作用显著下降。
6天南星科四种有毒中药凝集素蛋白与毒针晶的刺激性协同作用研究
采用家兔眼结膜刺激性模型,家兔破损皮肤刺激性模型和大鼠足趾肿胀模型,考察PTL、PPL、AEL及TGL对毒针晶所致家兔眼刺激性,家兔破损皮肤刺激性及大鼠足趾肿胀的影响以及加热处理对凝集素蛋白及毒针晶诱导炎症反应的影响。结果显示单用毒针晶对家兔眼结膜具有强烈的刺激作用,单用PTL、PPL、AEL及TGL无刺激性,毒针晶中加入一定量的PTL、PPL、AEL及TGL后对家兔眼结膜的刺激性毒性显著增强,与单用毒针晶组相比呈显著性差异,表明PTL、PPL、AEL及TGL需要毒针晶刺入黏膜导致黏膜破损才可诱发炎症反应,即PTL、PPL、AEL及TGL具有协同毒针晶引起强烈的家兔眼结膜刺激性毒性；毒针晶经加热处理后与未处理的毒针晶比较,刺激性明显降低,表明加热可破坏毒针晶蛋白的活性,该结果与凝集素蛋白加热后促炎活性显著降低的结果一致。家兔破损皮肤试验结果表明凝集素蛋白可加重毒针晶对家兔破损皮肤的刺激性,加热处理的凝集素蛋白不增强家兔破损皮肤刺激的作用,呈显著性差异。同时毒针晶加热处理后与未处理的毒针晶比较对家兔破损皮肤的刺激性显著降低。大鼠足趾肿胀试验结果显示单用凝集素蛋白,通过皮下注射进入组织的凝集素蛋白即可引起严重的促炎效应,加热处理后凝集素蛋白组与空白组相比无显著性差异。毒针晶中加入凝集素蛋白可显著增强大鼠足趾肿胀,毒针晶组与毒针晶加入加热处理的凝集素蛋白组比较无显著性差异,表明加热可导致凝集素蛋白失活,使其促炎作用显著下降。同时加热处理的毒针晶组与未处理的毒针晶组比较对大鼠足趾肿胀显著降低,进一步表明毒针晶的刺激性毒性与毒针晶带有的凝集素蛋白密切相关。上述实验结果表明凝集素蛋白只有被带入机体与组织接触才可产生促炎效应,即凝集素蛋白需要随毒针晶刺入组织才可产生促炎效应,而且加热可破坏凝集素蛋白的促炎效应。
7天南星凝集素蛋白炎症刺激性与炎症相关细胞的研究
前述试验证实天南星科四种有毒中药的凝集素蛋白可诱导大鼠中性粒细胞向腹腔迁移,诱发炎症发应,这种作用与机体的炎症相关细胞有何关系?论文采用动物整体试验,腹腔内居留细胞灌洗模型,巯基乙酸盐(Thioglycolate, Tg)刺激大鼠腹腔内巨噬细胞增殖模型,N-甲基-对甲氧基苯乙胺和甲醛的缩合物(Compound48/80N-methyl-p-methoxyphenethylamine with formaldehyde,48/80)致大鼠腹腔内肥大细胞凋亡模型,考察凝集素AEL诱导大鼠中性粒细胞迁移与居留细胞、巨噬细胞及肥大细胞的关系。结果显示AEL诱导大鼠中性粒细胞迁移不依赖于居留细胞,但居留细胞中的巨噬细胞能协同AEL诱导大鼠中性粒细胞迁移,肥大细胞能拮抗AEL诱导大鼠中性粒细胞迁移。
进一步采用体外细胞试验考察四种凝集素蛋白对巨噬细胞的影响,测定炎症介质TNF-α、白细胞介素IL-1β(Interleukin-1β, IL-1β)的含量。体内外试验结果均表明凝集素蛋白的炎症刺激性毒性与游离巨噬细胞并刺激巨噬细胞释放炎症介质有关。
论文研究表明,半夏、掌叶半夏、天南星及白附子毒针晶中均带有相应植物的凝集素蛋白,且是毒针晶蛋白中的主要毒蛋白,是天南星科四种有毒中药毒针晶引起炎症反应产生强烈刺激性毒性的共性化学刺激物。毒针晶产生刺激性毒性的机制在于毒针晶刺入组织后,产生机械刺激性,同时毒针晶上的凝集素蛋白随毒针晶进入组织诱导中性粒细胞向刺入部位迁移,促使巨噬细胞活化,并刺激巨噬细胞释放炎症介质TNF-a及IL-1β,导致严重的组织水肿和炎症反应。
本论文的研究结果揭示了天南星科四种有毒中药半夏、掌叶半夏、天南星及白附子毒针晶产生强烈炎症刺激性的共性机制,基本阐明了天南星科有毒中药凝集素蛋白与其毒性的相关性,为天南星科有毒中药炮制机理的进一步深入研究提供坚实基础,并将为天南星科有毒中药炮制方法的改进与创新提供理论支持。
This work was supported by National Nature Science Fund of China (NO.30973939, No.81173549).2011Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education Institutions (CXZZ11_0786).
Pinellia ternata (Thunb.) Breit, Arisaema erubescens (Wall.) Schott., Typhonium giganteum Engl included in Chinese Pharmacopoeia (2010), and Pinellia pedatisecta Schott widely used in china herbal market as a substitute for arisaematis are all belonged to Araceae family and are important toxic Chinese medicines. It has been reported that the four Araceae plants possess similar toxic properties, such as causing mucous membrane and skin irritation, mouth and lingua pain, even respiration slowing and suffocation, which have seriously restricted the development of its clinical applications. Our previous research had proved that the four Araceae plants demonstrated toxicity due to the components of raphide including calcium oxalate, protein and trace carbohydrates. For the raphides could aggratate the inflammation toxicity, the raphides were called "toxic raphides". Moreover, investigations showed that the toxicity of the P. ternate raphide might closely relate to the protein components. Among the protein components, a lectin was proven to be the main pro-inflammatory component. The lectin of raphides from P. ternate could induce neutrophil migration and aggratate the inflammation such as severe conjunctival edema in rabbit and footpad edema in rat. P. ternate, P. pedatisecta, A. erubescens and T. giganteum belong to the same Araceae family and have the similar irritation. However, the raphides irritation mechanism has not been well illustrated.
The raphides of P. ternata, P. pedatisecta, A. erubescens and T. giganteum were investigated. Analysis of the chemical components of the raphides showed that proteins in the raphides were associated with the irritation. The lectins of the four plants were proved to be the ringleader of inflammation. The irritating effect of the raphides was due to the dual action of the sharp raphides in puncturing soft skin or mucosa and the lectin in bring inflammation. This paper explained the correlation between lectin from Araceae and toxity. Detail researches and findings include the following aspects:
1Analysis and identification of the proteins on the raphides of the four plants
SDS-PAGE showed the raphides from the four plants of same molecular weight at about12kDa. The12kDa bands were soaked in a mixed protease enzyme solution by liquid chromatography tandem mass spectrogram. The result showed that the lectin is the same proteins of the12kDa bands. The lectin of the four plants is P. ternata lectin(PTL), P. pedatisecta lectin(PPL), A. erubescens lectin(AEL) and T. giganteum lectin(TGL)
2Purification and character of the lectin from the tuber of P. pedatisecta, A. erubescens and T. giganteum.
PPL, AEL and TGL were respectively purified from tuber of Pinellia pedatisecta, Arisaema erubescens and Typhonium giganteum in the sequence of processing steps. Hydrophobic interaction, ion exchange and desalting chromatographic steps were applied to the purification of PPL, AEL and TGL. A single peak on size-exclusion high performance liquid chromatography (SEC-HPLC) and a single band of about12kDa on SDS-PAGE were observed, suggesting that the purity of isolated PPL, AEL and TGL was fairly good. The haemagglutination activities of PTL, PPL, AEL and TGL were investigated by different erythrocytes, temperatures, pH and sugars. PTL, PPL, AEL and TGL could agglutinate rabbit, mice and dog erythrocytes and could not agglutinate chicken erythrocytes and human red blood cells. PTL, PPL, AEL and TGL are stable up to50℃for20min without any loss of activity and is not markedly affected by pH in the range of6.0～10.0. The haemagglutination activity of PTL, PPL, AEL and TGL is inhibited by asialofetuin only, while monosaccharide is not react.
3Identification of PPL, AEL and TGL from the tuber and raphides of P. pedatisecta, A. erubescens and T. giganteum.
SDS-PAGE analysis showed that the gel of PPL, AEL and TGL from the tuber and raphides of P. pedatisecta, A. erubescens and T. giganteum have the same bands. LC-MS-MS identification showed that12kDa protein bands from PPL, AEL and TGL from the tuber of P. pedatisecta, A. erubescens and T. giganteum was corresponding lectin protein respectively. The result of western blotting also showed that PPL, AEL and TGL were on the raphides of P. pedatisecta, A. erubescens and T. giganteum. All these results demonstrated that the purified PPL, AEL and TGL from the tuber and raphides of P. pedatisecta, A. erubescens and T. giganteum are the same protein respectively.
4The content of PTL, PPL, AEL, TGL from the raphide protein
It is important that the content of the lectins which are the stimulation of raphide and are decreased by heating posses to the raphide protein. Western Blotting analysis showed that the content of PTL, PPL, AEL and TGL from the raphide protein is19.89%,24.84%,15.08%and11.67%respectively. The results indicated that lectin is the main protein of the raphide protein.
5Pro-inflammatory effect of PTL, PPL, AEL and TGL
The in vivo model of neutrophil migration was used to study the inflammatory activity of lectin. PTL, PPL, AEL and TGL (100,200and300μg/mL/cavity) could induce significant and dose-dependent neutrophil migration in the rat peritoneal cavities. Besides, PTL, PPL, AEL and TGL at doses ranging from100to300μg/mL/cavity could significantly increase the concentration of nitric oxide (NO), prostaglandin E2(PGE2) and tumor necrosis factor alpha (TNF-a) in peritoneal fluid. Compared with control animals, heated PTL, PPL, AEL and TGL did not reduce neutrophil migration. This result indicated that the irritation effects of lectins were decreased by heated.
6Synergistic effect of inflammation stimulated by PTL, PPL, AEL and TGL and raphides of P. ternate, P. pedatisecta, A. erubescens and T. giganteum.
The models of Draize rabbit eye test, rabbit's damaged skin test and rat paw edema test were used to study the role of the PTL, PPL, AEL and TGL and raphides of P. ternate, P. pedatisecta, A. erubescens and T. giganteum on inflammatory response. The results showed that the pro-inflammtation effect of PTL, PPL, AEL and TGL could work only when the raphides pierce into the organization, and PTL, PPL, AEL and TGL enhanced the inflammation induced by raphides, and heating could decrease the lectin of the pro-inflammation effect.
7Pro-inflammatory effect of PTL, PPL, AEL, TGL and relative study of resident cells
The role of resident cells on the PTL, PPL, AEL and TGL effect was evaluated using three strategies:(a) reducing the total resident cell population by lavage of rat cavities with saline;(b) increasing macrophage population by treating rats with Tg.;(c) depleting mast cell population by subchronic treatment of rats with compound48/80. This results indicate that PTL, PPL, AEL, TGL-induced neutrophil migration is independent on resident cells. However, macrophages could synergize PTL, PPL, AEL, TGL-induced neutrophil migration, while mast cells could antagonize the process. The pro-inflammation effect of lectin with macrophages was determinating TNF-a, Interleukin-1β (IL-1β) in vitro. These results indicated that PTL, PPL, AEL and TGL-induced neutrophil migration was dependent on macrophages which release TNF-α, IL-1β in vivo and in vitro.
Through the researches above, we concluded that the irritation induced by raphides is due to the dual action of the sharp raphides in puncturing and the PTL, PPL, AEL, and TGL in causing inflammation. The pro-inflammation effect of lectin was related to the macrophage which release TNF-α, IL-1β.
These findings illustrated the reason why raphides could induce severe inflammation. The researches above could provide the way of studies on the toxic components and detoxification processing skills and mechanism of other poisonous medicines from Araceae.
2010版《中国药典》收载的半夏(Pinellia ternata (Thunb.) Breit.)、天南星(Arisaema erubescens (Wall.) Schott)、白附子(Typhonium giganteum Engl)及在市场上作为天南星的代用品广泛使用的掌叶半夏(Pinellia pedatisecta Schott.),均属于天南星科,为临床常用有毒中药,这四种有毒中药临床中毒症状极为相似,误服均出现粘膜及皮肤刺激,口舌肿胀,呼吸缓慢甚至窒息死亡,所以中医临床上均使用炮制品。
论文作者所在课题组在前期研究中提出并证实天南星科四种有毒中药半夏、掌叶半夏、天南星及白附子的刺激性毒性成分均为其所含有的具有特殊晶形的针晶复合物,具有强烈的刺激性毒性,可产生严重的刺激性炎症反应,故课题组称为“毒针晶”。毒针晶主要由草酸钙、蛋白组成,前期研究发现组成毒针晶的草酸钙没有刺激性作用,而组成毒针晶的蛋白可显著加重豚鼠破损皮肤的炎症反应。对半夏毒针晶蛋白研究的结果显示,半夏毒针晶上带有的半夏凝集素蛋白是半夏毒针晶进一步诱发炎症反应的刺激物,凝集素蛋白可显著诱导中性粒细胞迁移,引起大鼠足趾肿胀,可显著加重毒针晶引起的家兔眼结膜水肿,具有强烈的促炎作用。天南星科的掌叶半夏、天南星及白附子,与半夏同属天南星科,刺激性毒性反应相似,毒性物质基础都是块茎中含有的毒针晶,故本论文提出,掌叶半夏、天南星、白附子的毒针晶上也存在与半夏类似的化学刺激物。对天南星科有毒中药凝集素蛋白与毒针晶毒性的相关性研究,除本课题组外,未见有研究报道。
本学位论文以同属天南星科、毒性表现相似的有毒中药掌叶半夏、天南星及白附子的毒针晶为研究对象,以半夏为参照,考察半夏、掌叶半夏、天南星及白附子的毒针晶中是否存在同类的与刺激性毒性相关的化学成分,研究表明四种有毒中药的毒针晶中带有共性的凝集素(lectin)蛋白成分。进一步的研究结果表明四种毒针晶中的凝集素蛋白均具有显著促炎作用,毒针晶的刺激性毒性是凝集素蛋白随毒针晶刺入组织后诱导炎症反应产生严重的炎症刺激性毒性。论文基本阐明了天南星科有毒中药半夏、掌叶半夏、天南星及白附子凝集素蛋白与毒性的相关性,主要工作内容和研究结果包括以下几个方面：
1天南星科有毒中药毒针晶蛋白类成分分析及共性刺激性相关蛋白研究
采用SDS-PAGE (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis,SDS.PAGE)分析,考察半夏、掌叶半夏、天南星及白附子毒针晶的条带,是否存在分子量相同的蛋白条带,结果显示分子量约12kDa处有相同的蛋白条带。继续将毒针晶中约12kDa处的蛋白条带采用混合蛋白胶内酶解后肽段的液相色谱串联质谱联用(1iquid chromatography tandem mass spectrogram,LC-MS-MS)技术分析,结果显示四种毒针晶约12kDa的条带存在共性的凝集素蛋白,分别为半夏凝集素(Pillellia ternata lectin,PTL),掌叶半夏凝集素(Pillellia pedatisecta lectin,PPL),天南星凝集素(Arisaema erubescens lectin,AEL)及白附子凝集素(Typhonium giganteum lectin,TGL)。
2天南星科有毒中药凝集素的提取分离纯化及性质研究
从半夏、掌叶半夏、天南星及白附子新鲜块茎中分离纯化相应的植物凝集素蛋白PTL、PPL、AEL及TGL。提取分离的流程为：半夏、掌叶半夏、天南星及白附子新鲜块茎粗提液经硫酸铵分级沉淀、苯基琼脂糖凝胶(Phenyl FF)疏水柱层析、Tris-HCl(pH=8.0)缓冲体系,收集主峰通过强阴离子(Q FF)交换柱层析,脱盐,冷冻干燥分别得PTL、PPL、AEL及TGL。高效体积排阻色谱(size-exclusion high performance liquid chromatography, SEC-HPLC)及SDS-PAGE电泳分析显示分离所得的PTL、PPL、AEL及TGL均达到色谱纯及电泳纯,测得其分子量约为12kDa。通过不同来源红细胞、温度、pH及糖或糖蛋白考察凝集素蛋白的凝集活性,结果显示：四种凝集素蛋白均能凝集兔、鼠、狗的红细胞,不能凝集鸡及人的红细胞；80℃以下具有凝集活性,50℃以下凝集活性最强,85℃以上凝集活性全部丧失；pH6.0-10.0范围内具有凝集活性,pH6.0-8.0范围内凝集活性保持稳定,pH达到11.0,凝集活性完全丧失；凝集活性不被D-木糖、D-核糖、D-阿拉伯糖、无水葡萄糖、D-半乳糖、D-甘露糖、L-鼠李糖、甲基-α-D-甘露糖苷所抑制,仅被去唾液酸胎球蛋白所抑制。
3天南星科四种有毒中药毒针晶中凝集素蛋白与块茎中凝集素蛋白比对鉴定
为进一步确定毒针晶上带有的凝集素蛋白是否与相应植物块茎中的凝集素蛋白为同一蛋白,采用SDS-PAGE分析,研究表明从植物块茎中分离获得的半夏、掌叶半夏、天南星及白附子的凝集素蛋白与其毒针晶蛋白具有相同的分子量。进一步对块茎中分离的凝集素蛋白进行LC-MS-MS分析鉴定,与美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)数据库进行比对,发现从块茎中提取的凝集素蛋白为对应植物的凝集素蛋白。蛋白免疫印迹Westem blotting结果进一步证实四种毒针晶中含有相应的PTL、PPL、AEL及TGL,即从块茎中提取分离的半夏、掌叶半夏、天南星及白附子凝集素蛋白与相应毒针晶上带有的凝集素蛋白为同一蛋白。
4天南星科有毒中药毒针晶中凝集素蛋白的含量研究
前面的研究结果表明毒针晶上含有凝集素蛋白,采用Western Blotting方法对毒针晶上的凝集素蛋白含量进行半定量分析,结果半夏、掌叶半夏、天南星及白附子毒针晶中的凝集素蛋白占毒针晶蛋白上的含量PTL为19.89%,PPL为24.84%,AEL为15.08%,TGL为11.67%,四种有毒中药凝集素蛋白含量大小顺序为掌叶半夏>半夏>天南星>白附子,该结果与前期课题组研究的四种有毒中药的毒针晶毒性与其蛋白的含量呈相关性的结果一致,表明四种毒针晶的毒性与毒针晶中带有的凝集素蛋白含量呈正相关。
5天南星科四种有毒中药凝集素蛋白的促炎作用研究
采用大鼠腹腔中性粒细胞迁移模型研究PTL、PPL、AEL及TGL的促炎作用。结果显示腹腔注射PTL、PPL、AEL及TGL后,四种有毒中药的凝集素蛋白出现明显的中性粒细胞向腹腔迁移的现象并呈剂量依赖性,腹腔液中炎症介质一氧化氮(Nitric Oxide,NO)、前列腺素E2(Prostaglandin E2, PGE2)及肿瘤坏死因子α (Tumor necrosis factor-alpha, TNF-α)的含量与空白组相比较均显著升高,表明PTL、PPL、AEL及TGL均可诱导炎症介质释放。进一步考察加热对凝集素蛋白致大鼠腹腔中性粒细胞迁移的影响,结果显示加热组与空白组比较无显著性差异,表明加热可导致凝集素蛋白失活,使其促炎作用显著下降。
6天南星科四种有毒中药凝集素蛋白与毒针晶的刺激性协同作用研究
采用家兔眼结膜刺激性模型,家兔破损皮肤刺激性模型和大鼠足趾肿胀模型,考察PTL、PPL、AEL及TGL对毒针晶所致家兔眼刺激性,家兔破损皮肤刺激性及大鼠足趾肿胀的影响以及加热处理对凝集素蛋白及毒针晶诱导炎症反应的影响。结果显示单用毒针晶对家兔眼结膜具有强烈的刺激作用,单用PTL、PPL、AEL及TGL无刺激性,毒针晶中加入一定量的PTL、PPL、AEL及TGL后对家兔眼结膜的刺激性毒性显著增强,与单用毒针晶组相比呈显著性差异,表明PTL、PPL、AEL及TGL需要毒针晶刺入黏膜导致黏膜破损才可诱发炎症反应,即PTL、PPL、AEL及TGL具有协同毒针晶引起强烈的家兔眼结膜刺激性毒性；毒针晶经加热处理后与未处理的毒针晶比较,刺激性明显降低,表明加热可破坏毒针晶蛋白的活性,该结果与凝集素蛋白加热后促炎活性显著降低的结果一致。家兔破损皮肤试验结果表明凝集素蛋白可加重毒针晶对家兔破损皮肤的刺激性,加热处理的凝集素蛋白不增强家兔破损皮肤刺激的作用,呈显著性差异。同时毒针晶加热处理后与未处理的毒针晶比较对家兔破损皮肤的刺激性显著降低。大鼠足趾肿胀试验结果显示单用凝集素蛋白,通过皮下注射进入组织的凝集素蛋白即可引起严重的促炎效应,加热处理后凝集素蛋白组与空白组相比无显著性差异。毒针晶中加入凝集素蛋白可显著增强大鼠足趾肿胀,毒针晶组与毒针晶加入加热处理的凝集素蛋白组比较无显著性差异,表明加热可导致凝集素蛋白失活,使其促炎作用显著下降。同时加热处理的毒针晶组与未处理的毒针晶组比较对大鼠足趾肿胀显著降低,进一步表明毒针晶的刺激性毒性与毒针晶带有的凝集素蛋白密切相关。上述实验结果表明凝集素蛋白只有被带入机体与组织接触才可产生促炎效应,即凝集素蛋白需要随毒针晶刺入组织才可产生促炎效应,而且加热可破坏凝集素蛋白的促炎效应。
7天南星凝集素蛋白炎症刺激性与炎症相关细胞的研究
前述试验证实天南星科四种有毒中药的凝集素蛋白可诱导大鼠中性粒细胞向腹腔迁移,诱发炎症发应,这种作用与机体的炎症相关细胞有何关系?论文采用动物整体试验,腹腔内居留细胞灌洗模型,巯基乙酸盐(Thioglycolate, Tg)刺激大鼠腹腔内巨噬细胞增殖模型,N-甲基-对甲氧基苯乙胺和甲醛的缩合物(Compound48/80N-methyl-p-methoxyphenethylamine with formaldehyde,48/80)致大鼠腹腔内肥大细胞凋亡模型,考察凝集素AEL诱导大鼠中性粒细胞迁移与居留细胞、巨噬细胞及肥大细胞的关系。结果显示AEL诱导大鼠中性粒细胞迁移不依赖于居留细胞,但居留细胞中的巨噬细胞能协同AEL诱导大鼠中性粒细胞迁移,肥大细胞能拮抗AEL诱导大鼠中性粒细胞迁移。
进一步采用体外细胞试验考察四种凝集素蛋白对巨噬细胞的影响,测定炎症介质TNF-α、白细胞介素IL-1β(Interleukin-1β, IL-1β)的含量。体内外试验结果均表明凝集素蛋白的炎症刺激性毒性与游离巨噬细胞并刺激巨噬细胞释放炎症介质有关。
论文研究表明,半夏、掌叶半夏、天南星及白附子毒针晶中均带有相应植物的凝集素蛋白,且是毒针晶蛋白中的主要毒蛋白,是天南星科四种有毒中药毒针晶引起炎症反应产生强烈刺激性毒性的共性化学刺激物。毒针晶产生刺激性毒性的机制在于毒针晶刺入组织后,产生机械刺激性,同时毒针晶上的凝集素蛋白随毒针晶进入组织诱导中性粒细胞向刺入部位迁移,促使巨噬细胞活化,并刺激巨噬细胞释放炎症介质TNF-a及IL-1β,导致严重的组织水肿和炎症反应。
本论文的研究结果揭示了天南星科四种有毒中药半夏、掌叶半夏、天南星及白附子毒针晶产生强烈炎症刺激性的共性机制,基本阐明了天南星科有毒中药凝集素蛋白与其毒性的相关性,为天南星科有毒中药炮制机理的进一步深入研究提供坚实基础,并将为天南星科有毒中药炮制方法的改进与创新提供理论支持。
This work was supported by National Nature Science Fund of China (NO.30973939, No.81173549).2011Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education Institutions (CXZZ11_0786).
Pinellia ternata (Thunb.) Breit, Arisaema erubescens (Wall.) Schott., Typhonium giganteum Engl included in Chinese Pharmacopoeia (2010), and Pinellia pedatisecta Schott widely used in china herbal market as a substitute for arisaematis are all belonged to Araceae family and are important toxic Chinese medicines. It has been reported that the four Araceae plants possess similar toxic properties, such as causing mucous membrane and skin irritation, mouth and lingua pain, even respiration slowing and suffocation, which have seriously restricted the development of its clinical applications. Our previous research had proved that the four Araceae plants demonstrated toxicity due to the components of raphide including calcium oxalate, protein and trace carbohydrates. For the raphides could aggratate the inflammation toxicity, the raphides were called "toxic raphides". Moreover, investigations showed that the toxicity of the P. ternate raphide might closely relate to the protein components. Among the protein components, a lectin was proven to be the main pro-inflammatory component. The lectin of raphides from P. ternate could induce neutrophil migration and aggratate the inflammation such as severe conjunctival edema in rabbit and footpad edema in rat. P. ternate, P. pedatisecta, A. erubescens and T. giganteum belong to the same Araceae family and have the similar irritation. However, the raphides irritation mechanism has not been well illustrated.
The raphides of P. ternata, P. pedatisecta, A. erubescens and T. giganteum were investigated. Analysis of the chemical components of the raphides showed that proteins in the raphides were associated with the irritation. The lectins of the four plants were proved to be the ringleader of inflammation. The irritating effect of the raphides was due to the dual action of the sharp raphides in puncturing soft skin or mucosa and the lectin in bring inflammation. This paper explained the correlation between lectin from Araceae and toxity. Detail researches and findings include the following aspects:
1Analysis and identification of the proteins on the raphides of the four plants
SDS-PAGE showed the raphides from the four plants of same molecular weight at about12kDa. The12kDa bands were soaked in a mixed protease enzyme solution by liquid chromatography tandem mass spectrogram. The result showed that the lectin is the same proteins of the12kDa bands. The lectin of the four plants is P. ternata lectin(PTL), P. pedatisecta lectin(PPL), A. erubescens lectin(AEL) and T. giganteum lectin(TGL)
2Purification and character of the lectin from the tuber of P. pedatisecta, A. erubescens and T. giganteum.
PPL, AEL and TGL were respectively purified from tuber of Pinellia pedatisecta, Arisaema erubescens and Typhonium giganteum in the sequence of processing steps. Hydrophobic interaction, ion exchange and desalting chromatographic steps were applied to the purification of PPL, AEL and TGL. A single peak on size-exclusion high performance liquid chromatography (SEC-HPLC) and a single band of about12kDa on SDS-PAGE were observed, suggesting that the purity of isolated PPL, AEL and TGL was fairly good. The haemagglutination activities of PTL, PPL, AEL and TGL were investigated by different erythrocytes, temperatures, pH and sugars. PTL, PPL, AEL and TGL could agglutinate rabbit, mice and dog erythrocytes and could not agglutinate chicken erythrocytes and human red blood cells. PTL, PPL, AEL and TGL are stable up to50℃for20min without any loss of activity and is not markedly affected by pH in the range of6.0～10.0. The haemagglutination activity of PTL, PPL, AEL and TGL is inhibited by asialofetuin only, while monosaccharide is not react.
3Identification of PPL, AEL and TGL from the tuber and raphides of P. pedatisecta, A. erubescens and T. giganteum.
SDS-PAGE analysis showed that the gel of PPL, AEL and TGL from the tuber and raphides of P. pedatisecta, A. erubescens and T. giganteum have the same bands. LC-MS-MS identification showed that12kDa protein bands from PPL, AEL and TGL from the tuber of P. pedatisecta, A. erubescens and T. giganteum was corresponding lectin protein respectively. The result of western blotting also showed that PPL, AEL and TGL were on the raphides of P. pedatisecta, A. erubescens and T. giganteum. All these results demonstrated that the purified PPL, AEL and TGL from the tuber and raphides of P. pedatisecta, A. erubescens and T. giganteum are the same protein respectively.
4The content of PTL, PPL, AEL, TGL from the raphide protein
It is important that the content of the lectins which are the stimulation of raphide and are decreased by heating posses to the raphide protein. Western Blotting analysis showed that the content of PTL, PPL, AEL and TGL from the raphide protein is19.89%,24.84%,15.08%and11.67%respectively. The results indicated that lectin is the main protein of the raphide protein.
5Pro-inflammatory effect of PTL, PPL, AEL and TGL
The in vivo model of neutrophil migration was used to study the inflammatory activity of lectin. PTL, PPL, AEL and TGL (100,200and300μg/mL/cavity) could induce significant and dose-dependent neutrophil migration in the rat peritoneal cavities. Besides, PTL, PPL, AEL and TGL at doses ranging from100to300μg/mL/cavity could significantly increase the concentration of nitric oxide (NO), prostaglandin E2(PGE2) and tumor necrosis factor alpha (TNF-a) in peritoneal fluid. Compared with control animals, heated PTL, PPL, AEL and TGL did not reduce neutrophil migration. This result indicated that the irritation effects of lectins were decreased by heated.
6Synergistic effect of inflammation stimulated by PTL, PPL, AEL and TGL and raphides of P. ternate, P. pedatisecta, A. erubescens and T. giganteum.
The models of Draize rabbit eye test, rabbit's damaged skin test and rat paw edema test were used to study the role of the PTL, PPL, AEL and TGL and raphides of P. ternate, P. pedatisecta, A. erubescens and T. giganteum on inflammatory response. The results showed that the pro-inflammtation effect of PTL, PPL, AEL and TGL could work only when the raphides pierce into the organization, and PTL, PPL, AEL and TGL enhanced the inflammation induced by raphides, and heating could decrease the lectin of the pro-inflammation effect.
7Pro-inflammatory effect of PTL, PPL, AEL, TGL and relative study of resident cells
The role of resident cells on the PTL, PPL, AEL and TGL effect was evaluated using three strategies:(a) reducing the total resident cell population by lavage of rat cavities with saline;(b) increasing macrophage population by treating rats with Tg.;(c) depleting mast cell population by subchronic treatment of rats with compound48/80. This results indicate that PTL, PPL, AEL, TGL-induced neutrophil migration is independent on resident cells. However, macrophages could synergize PTL, PPL, AEL, TGL-induced neutrophil migration, while mast cells could antagonize the process. The pro-inflammation effect of lectin with macrophages was determinating TNF-a, Interleukin-1β (IL-1β) in vitro. These results indicated that PTL, PPL, AEL and TGL-induced neutrophil migration was dependent on macrophages which release TNF-α, IL-1β in vivo and in vitro.
Through the researches above, we concluded that the irritation induced by raphides is due to the dual action of the sharp raphides in puncturing and the PTL, PPL, AEL, and TGL in causing inflammation. The pro-inflammation effect of lectin was related to the macrophage which release TNF-α, IL-1β.
These findings illustrated the reason why raphides could induce severe inflammation. The researches above could provide the way of studies on the toxic components and detoxification processing skills and mechanism of other poisonous medicines from Araceae.
引文
[1]Sasayama S, Matsumori A, Kihara Y. New insights into the pathophysiological role of cytokines in heart failure [J]. Cardiovasc Res,1999,42:557-564.
[2]Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease[J]. J Clin Invest, 2008,118 (11):3546-3556.
[3]曾剑儿,何炳斌.不同时期肺纤维化兔全肺灌洗液中炎症细胞及细胞因子研究[J].江西医药,2010,45(12)：1183-1185.
[4]徐少华,王伟,邵红艳,等.超短波治疗对COPD患者诱导痰中炎症细胞及IL-8和TNF-α的影响[J].中华物理医学与康复杂志,2005,27(3)：171-173.
[5]Sarir H, Henricks PA, Van Houwelingen AH, et al. Cells, mediators and Toll-like receptors in COPD[J]. Eur J Pharmacol,2008,585:346-353.
[6]周伟.氨溴索对慢性阻塞性肺疾病患者血.清细胞因子与肺功能的影响[J].中国药业,2011,20(19)：14-15.
[7]张弛,林如平,刘洪,等.鱼腥草注射液对慢性阻塞性肺疾病患者炎症细胞因子与肺功能的影响[J].中国中医药科技,2006,13(5)：294-295.
[8]廖文生,李卫青,陈世伟,等.参附注射液对慢性阻塞性肺疾病急性加重期患者炎症细胞因子和肺功能的影响[J].中国中西医结合急救杂志,2008,15(3)：149-151.
[9]陈卫熹,邓永超.中西医结合对慢性阻塞性肺疾病患者炎症细胞因子及肺功能的影响[J].中医药导报,2011,17(8)：28-29.
[10]胡华元,王捷鹏,张寿山,等.吸入药物治疗对稳定期COPD肺功能及炎症细胞因子的影响[J].中国现代医生,2010,48(34)：19-20.
[11]李春盛,何新华,桂培春.大黄对急性肺损伤大鼠血浆和支气管肺泡灌洗液中炎症细胞因子表达的影响[J].中国中西医结合急救杂志,2005,12(5)：306-308.
[12]汪春彦,吴常青,江勤,等.金荞麦对克雷伯杆菌肺炎大鼠心肌损伤中炎症细胞因子表达的影响[J].安徽医科大学学报,2011,46(1)：44-48.
[13]刘凤,石增立,于小玲,等.肾缺血再灌注损伤时血清及肾组织中促炎症细胞因子的变化与意义[J].中国临床医学,2005,12(1)：174-176.
[14]Kennedy JA, Clements WD, Kirk SJ, et al. Characterization of the kupffer cell response to exogenous endotoxinin a rodent model of obstructive jaundice[J]. Br J Surg.1999,86(5):628-633.
[15]王昱澍,李杰.肝硬化患者细胞因子TNF-α、IL-8检测的意义[J].中国医学工程,2011,19(8)：61-63.
[16]林佑武,张诗军,陈泽雄,等.运脾通络方治疗非酒精性脂肪性肝炎疗效观察[J].中药材,2011,34(7)：1158-1162.
[17]郝晓利,赵良中.玉竹提取物A对免疫性肝损伤小鼠促炎症细胞因子的影响[J].光明中医,2009,24(12)：2266-2267.
[18]钱玲妃,倪淑红.阿托伐他汀对不稳定型心绞痛患者血脂和血浆炎症细胞因子的影响[J].中国药房,2011,22(48)：4568-4569.
[19]冯学斌,刘凤,傅振荣,等.促炎症细胞因子、T细胞亚群在小儿过敏性紫癜不同病期的变化[J].中国病理生理杂志,1999,15(2)：1124-1126.
[20]雷宁玉,石增立,刘凤.败血症大鼠促炎症细胞因子变化及其干预研究[J].中国临床医学,2003,10(5)：685-687.
[21]吴洪华,杨成,石增立,等.川芎嗪对缺氧缺血性脑损伤炎症细胞因子作用的实验研究[J].滨州医学院学报,2007,30(3)：161-163.
[22]汪明灯,高修仁.炎症细胞因子与慢性心力衰竭[J].新医学,2006,37(3)：200-202.
[23]张敏莉,李昭屏,肖晗,等.不同类型心脏肥大大鼠模型心肌中炎症细胞因子表达差异[J].北京大学学报(医学版),2007.39(6)：570-575.
[24]Sasayama S, Matsumori A, Kihara Y. New insights into the pathophysiological role of cytokines in heart failure [J]. Cardiovasc Res,1999,42:557-564.
[25]罗永姣,刘红英,李双杰.小鼠柯萨奇B3病毒性心肌炎心脏炎症细胞因子基因和蛋白表达及黄芪甲甙干预研究[J].中国动脉硬化杂志,2009,17(2)：122-124.
[26]刘英,程翔,廖玉华.心肌钙反常模型细胞因子的表达及地尔硫卓的干预作用[J].中国药理学通 报,2010,26(3)：309-311.
[27]张金盈,程翔,廖玉华,等.大鼠急性心肌梗死后心脏炎症细胞因子基因和蛋白表达及辛伐他汀干预研究[J].中华老年心脑血管病杂志,2005,7(5)：344-346.
[28]Pugin J, Ricou B, Steinberg K P, et al. Proinflammatory activity in brochoalveolar lavage fluids from patients with a prominent role of interleukin-1[J]. Am J Respir Crit Care Med,1996,153:1850-1856.
[29]陈乾坤,姜格宁,丁嘉安,等.大鼠肺缺血再灌注损伤后前炎症细胞因子IL-1β mRNA的表达分析[J].复旦学报(医学版),2008,35(4)：560-563,596.
[30]赵曙光,李强,王景杰,等.姜黄素诱导Nrf2核转位对脂多糖引起库普弗细胞分泌炎症细胞因子的影响[J].现代生物医学进展,2011,11(17)：3204-3207.
[31]王非,张长志,李晓娟,等.清瘟败毒饮对急性肺损伤大鼠促炎症和抗炎症因子水平的影响[J].江中医药大学学报,2011,35(3)：391-394.
[32]梅雪,李建生,张艳霞.毒素清对肺炎痰热证大鼠肺组织炎症细胞因子的影响[J].中国实验方剂学杂志,2011,17(5)：153-156.
[33]陈洁,曾耀英,曾慧兰,等.补阳还五汤预先干预对大鼠脑死亡后心肺炎症细胞因子表达的抑制作用[J].中草药,2010,41(5)：757-761.
[34]冯兵,杨旭,叶自林,等.MG-132对慢性肾衰竭大鼠主动脉及循环炎症细胞因子表达的抑制作用[J].解放军医学杂志,2008,33(7)：857-860.
[35]梁永会,韩继媛,邱红根.肿瘤坏死因子-α及白细胞介素-1p在大鼠肾缺血后处理中的变化及意义[J].广东医学,2011,32(14)：1809-1811.
[36]万涛,潘忠良,贺亚东,等.急性胰腺炎时肝损伤与血清炎症细胞因子关系的实验研究[J].浙江医学,2008,30(1)：34-37.
[37]郑飞霞,李光乾.反复热性惊厥大鼠体内促炎症细胞因子水平的变化[J].温州医学院学报,2007,37(6)：529-532.
[38]潘芙蓉,蔡强军,潘平,等.阿托伐他汀影响原发性高血压患者循环血单个核细胞炎症因子表达的临床研究[J].中国药学杂志,2010,45(2)：140-143.
[39]曾灶吕.阿维A联合窄谱中波紫外线对银屑病患者炎症细胞因子的影响[J].中国药业,2009,18(12)：41-43.
[40]Corrigall VM, Panayi GS. Autoantigens and immune pathways in rheumatoid arthritis [J]. Crit Rev Immunol,2002,22 (4):281-293.
[41]韦叶生,黄瑞雅,蓝艳,等.白细胞介素-1α基因启动子-889C/T和白细胞1受体拮抗剂第2内含子VNTR基因多态性与脑梗死关系的研究[J].中国老年学杂志,2005,25(2)：126-128.
[42]罗小星,赵永华,赵锋利.复苏饮对重症脑出血患者炎症细胞因子的影响[J].中国中医急症,2004,13(2)：70-71.
[43]傅晨,张允岭,常富业,等.利开灵对脑出血大鼠内毒素血症炎症效应的影响[J].环球中医药.2011.4(5)：340-343,347.
[44]朱参胜,冯清华,于曰祥,等.大骨节病患者血清促炎症细胞因子水平的检测[J].细胞与分子免疫学杂志,2006,22(1)：84-85.
[45]徐雅,李澎涛,陈杰,等.安宫清开灵对自发性高血压大鼠脑出血模型前炎症细胞因子与黏附分子含量的影响[J].世界科学技术——中医药现代化,2007,9(2)：45-49,72.
[46]陈锐,刘伟,刘建平,等EGCG通过ERKl/2途径抑制LPS诱导人单核细胞产生前炎性细胞因子[J].中国现代医生,2011,49(9)：5-6,9.
[47]丁青,尤昭玲.三七复合有效成分对子宫内膜炎症细胞NF-KB p65及TNF-α、IL-1β变化的影响[J].中国中医药科技,2007,14(2)：113-115.
[48]吴俊,梁维邦,倪红斌,等.促红细胞生成素对大鼠急性脊髓损伤后核因子-κB及炎症因子表达的影响[J].江苏医药,2011,37(4)：381-383.
[49]李新纯,何明大.脑灵汤对阿尔茨海默病患者MMSE及血清促炎症细胞因子的影响[J].实用预防医学,2010,17(5)：959-961.
[50]王慧玲,董克礼.益智健脑颗粒对阿尔茨海默病患者脑内促炎症细胞因子的影响[J].湖南中医药大学学报,2008,28(2)：54-56.
[51]沈晓明,韩宁,马云枝,等.舒郁颗粒对卒中后抑郁大鼠模型海马单胺类神经递质及炎症细胞因子的影响[J].中国实验方剂学杂志,2011,17(19)：177-180.
[52]朱光明.异丙酚麻醉对肝叶切除术患者肝功能与炎症细胞因子的影响[J].中国药业,2011,20(17)：17-18.
[53]李静,陈长勋,高阳,等.鱼腥草素抗炎与抗动脉硬化作用的探索[J].中成药,2010,32(1)：26-30.
[54]Fonseca-Camarillo G, Villeda-Ramirez M, Sanchez-Munoz F, et al. IL-6 and TNF-a gene expression in the rectal mucosal of patients with chronic idiopathic ulcerative colitis and controls[J]. Rev Gastroenterol Mex,2009,74(4):334-340.
[55]Jones S A. Directing transition from innate to acquired immunity:defining a role for IL-6[J]. J Immunol, 2005,175(6):3463-3468.
[56]廖玉华.心血管疾病免疫学研究进展[J].郑州大学学报(医学版),2005,40(2)：181-183.
[57]苏慧敏.阿托伐他汀对重度慢性充血性心力衰竭患者心功能及相关炎症细胞因子的影响[J].中国误诊学杂志,2007,7(23),5478-5479.
[58]欧阳迎春,刘加勉,刘应才.卡维地洛对慢性心力衰竭患者核因子-κB活化和炎症细胞因子表达的影响[J].中国现代医学杂志,2008,18(18)：2628-2631.
[59]姚淮芳,胡业彬,程晓昱,等.温肾益心丹对充血.性心力衰竭炎症细胞因子水平的影响[J].中国中西医结合急救杂志,2005.12(3)：149-152.
[60]刘洪,张弛,陈云凤.慢性阻塞性肺疾病炎症细胞因子与肺通气功能变化相关分析[J].实用医院临床杂志,2007,4(1)：52-53.
[61]Chaouat A, Savale L, Chouaid C, et al. Role for interleukin-6 in COPD-related pulmonary hypertension[J]. Chest,2009,136:678-687.
[62]曹奇峰.吸入舒利迭对慢性阻塞性肺疾病患者血浆炎症细胞因子和肺功能的影响[J].中国现代医生,2011,49(26)：60-61.
[63]冯学斌,刘德尧,刘凤,等.柴桂合剂对反复呼吸道感染患儿血浆促炎症细胞因子、IgG亚类的影响[J].中国临床医学,2005,12(5)：893-895.
[64]刘凤,于小玲,董晓青,等.油酸型急性呼吸窘迫综合征血清及肺组织促炎症细胞因子变化及山莨菪碱干预的实验研究[J].中国病理生理杂志,2002,18(8)：959-961.
[65]吴建魏,耿智隆,刘东,等.远隔预处理对兔肺缺血再灌注后炎症细胞因子和呼吸指数的影响[J].解放军医学杂志,2009,34(8)：989-991,996.
[66]李岑,杨红英.原发性高血压病患者血清细胞因子水平变化的检测及临床意义分析[J].中国分子心脏病学杂志,2006,6(6)：316-318.
[67]姚祖培,陈建新,喻海忠.化瘀复元胶囊对高血压病病人血清炎症细胞因子的影响[J].中西医结合心脑血管病杂志,2008,6(1)：5-6.
[68]唐可倩,刘玉文,唐伟,等.替米沙坦对高血压冠心病患者血浆炎症细胞因子的调节作用[J].海峡药学,2010,22(8)：168-169.
[69]刘时武,王喜玉,马建林.高胆固醇血症患者炎症细胞因子与颈动脉内膜中层厚度及血管内皮依赖性舒张功能的相关性[J].海南医学,2010,21(10)：4-5.
[70]陈昕琳,顾仁樾,章怡袆.丹参多酚酸B对动脉粥样硬化大鼠炎症细胞因子的影响[J].上海中医药大学学报,2011,25(1)：63-67.
[71]刘时武,王喜玉,马建林,等.瑞舒伐他汀对高胆固醇血症患者炎症细胞因子的影响[J].实用医学杂志,2010,26(13)：2419-2421.
[72]曾平,符秀琼,王启瑞,等.加味补阳还五汤对动脉粥样硬化斑块形成及炎症细胞因子表达谱的影响[J].中药药理与临床,2009,25(6)：11-13.
[73]李顺宁.脉复生对动脉硬化闭塞症患者血脂及炎症细胞因子的影响[J].云南中医中药杂志,2011,32(11)：19-21.
[74]戴建明,谭美娟,黄波.亚低温治疗对中度脑外伤患者炎症细胞因子的影响[J].实用心脑肺血.管病杂志,2009,17(4)：250-251.
[75]陈芳洁,黄宏春,王永亮.肝硬化腹水患者前炎症细胞因子的改变[J].医药论坛杂志,2009,30(24)：27-28.
[76]李林,王茂材,罗赤苗,等.大柴胡汤联合运动对阻塞性黄疸大鼠肝脏炎症细胞因子的影响[J].中国运动医学杂志,2011,30(9)：836-844.
[77]Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis[J]. Circulation,2002,105:1135-1143.
[78]杨帆,刘开俊,曾叶,等.雷公藤多苷对内毒素激活小鼠腹腔巨噬细胞分泌促炎症细胞因子的影响[J].中国免疫学杂志,2006,22(11)：1021-1024.
[79]Mizutani H, Ohmoto Y, Mizutani M, et al. Role of increased production of monocyte TNF-alpha, IL-a-beta and IL-6 in psoriasis:relation to focal infection disease activity and responses to treatments[J]. J Dermatol Sci,1997,14(2):145-153
[80]张静,崔苏扬,汪小海,等.氟比洛芬酯注射液对消化道肿瘤手术后炎症细胞因子表达的影响[J].临床麻麻醉学杂志,2007,23(5)：383-384.
[81]包长顺,陈礼刚,顾应江,等.高压氧对重型脑创伤大鼠血清中炎症细胞因子水平的影响[J].泸江医学院学报,2007,30(6)：480-482.
[82]Rice GE. Cytokines and the initiation o f parturition[J]. Front Horm Res,2001,27:113-146.
[83]武春梅.早产及正常妊娠孕妇IL-6与IL-10含量相关性分析[J].中国实验诊断学,2011,15(7)：1170-1171.
[84]Pooran N, Indaram A, Singh P, et al. Cytokines (IL-6, IL-8, TNF):early and reliable predictors of severe acute pancreatitis[J]. J Clin Gastroenterol,2003,37(3):263-266.
[85]谌剑飞.糖尿病缺血性中风中医证型与血清炎症细胞因子关系的研究[J].中国中西医结合急救杂志,2000,7(3)：147-149.
[86]高书荣,建宏,朱良争.芪连汤与降糖药联合干预2型糖尿病胰岛素抵抗及对相关炎症细胞因子的影响[J].中国中西医结合杂志,2004,24(7)：593-595.
[87]吕玉宏,张再高,李家承.慢性前列腺炎患者治疗前后血清IL-8、IL-1p和TNF-a检测的临床意义[J].放射免疫学杂志,2009,22(6)：593-594.
[88]徐巧萍,王砚,唐法娣,等.1,8-桉油精对卵白蛋白致哮喘豚鼠的气道高反应性和炎症的抑制作用[J].中国药理学与毒理学杂志,2010,24(1)：35-43.
[89]何文一,覃数,张冬颖.白细胞介素-8与冠状动脉病变程度的关系[J].重庆医学,2010,39(1)：31-33.
[90]魏天辉,赵施竹.冠心病急性心肌梗死患者血浆心肌营养素和血清白介素18的变化[J].中国心血管病研究杂志,2010,8(4)：271-274.
[91]李巧汶,李志梁,邱健,等.冠心病患者血浆组织因子、组织因子途径抑制物、白介素18、白介素10水平的变化及其关系[J].中华老年多器官疾病杂志,2010,9(3)：252-255,260.
[92]Netea MG, Azam T, Ferwerda G, et al. IL-32 synergizes with nucleotide oligomerization domain (NOD) land (NOD) 2 ligands for IL-1(3 and IL-6 production through acaspase 1-dependent mechanism [J]. Proc Natl Acad Sci USA,2005,102(45):16309-16314.
[93]雷光文,衡爱萍.IL-32在HBV感染者检测中的诊断价值[J].放射免疫学杂志,2011,24(2)：230-231.
[94]王娟,姜艳芳.IL-33在感染性疾病中的研究进展[J].中国免疫学杂志,2011,27(12)：1129-1131.
[95]Xian Qiong Liu, Hao Wu, Hong Li Yu, et al. Purification of a Lectin from Arisaema erubescens (Wall.) Schott and its Pro-Inflammatory Effect [J]. Molecules.2011,16,9480-9494.
[1]孙册.凝集素(Lectin)研究进展[J].生物化学与生物物理学进展,1981,3(1)：15-17.
[2]王志斌,张秀梅,郭三堆.在转基因植物中利用植物凝集素防治害虫的研究[J].植物学通报,2000,17(2)：108-113.
[3]Dhuna, V, Bains, J.S, Kamboj, S.S, et al. Purification and characterization of a lectin from Arisaema tortuosum schott having in-vitro anticancer activity against human cancer cell lines[J]. J. Biochem. Mol. Biol. 2005,38,526-532.
[4]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[5]Takano Y, Teranishi Y, Terashimas, et al. Lymphnode metastasis related carbohydrate epitopes of gastric cancer with submucosal invasion[J]. Surg Today,2000,30(12):1073-1082.
[6]Kawaguchi T, Takazawa H, Imai S, et al. Expression of vicia villosa agglutinin(VVA)-binding glycoprotein in primary breastcancer cells in relation to lymphatic metastasis is atypical MUC1 bearing Tn antigen a receptor of WA[J]. Breast Cancer Res Treat,2006,98(1):31-43.
[7]Remani P, Pillai K R, Haseenabeevi V M, et al. Lectin cytochemistry in the exfoliative cytology of uterine cervix[J]. Neoplasma,1994,41 (1):39-42.
[8]Gercel-Taylor C, Bazzett LB, Taylor DD. Presence of aberrant tumor-reactive immunoglobulins in the circulation of patients with ovarian cancer[J]. Gynecol Oncol,2001,81(1):71-76.
[9]项锋钢,杨梅怀,张岩峰,等.原发性肺癌的凝集素定位研究[J].临床与实验病理学杂志,1994,10(3)：186-189.
[10]侯学文,吴伯良,曾仲奎,等.海芋凝集素的鉴定及性质研究[J].暨南大学学报,1998,19(3)：89-93.
[11]Nakanishi K, Kawai T, Suzuki M, et al. Lectin binding and expression of blood group related antigens in carcinoma in situ and invasive carcinoma of urinary bladder[J]. Histopathology.1993,23 (2):153-158.
[12]罗旭,沈寅初,李春明.五种凝集素受体在膀胱癌中的分布及意义[J].遵义学院学报,2000,23(2)：99-101.
[13]张十文,葛根,金伯涛.膀胱癌增殖细胞核抗原与麦胚凝集素受体的相关关系[J].肿瘤学杂志,2001,7(2)：98-100.
[14]司维可,李仕敏,罗朝学,等.伴刀豆球蛋白A识别正常与肝癌谷氨酰转移酶的实验观察[J].第三军医大学学报,2000,22(3)：294-295.
[15]Carr BI, Kanke F, Wise M, et al. Clinical evaluation of lens culi-naris agglutinin-reactive alpha-fetoprotein and desgammacarboxy prothrombin in histologically proven hepatocellular carcinoma in the United States[J].Dig Dis Sci,2007,52(3):776-782.
[16]王海燕,白晓春,罗深秋.植物凝集素与医学应用[J].生命的化学,2003,23(3)：224-226.
[17]Litynska A, Przybylo M, Pochec E, et al. Comparison of the lectin-binding pattern in different human melanoma celllines[J]. Melanoma Res,2001,11(3):205-212.
[18]Thies A, Berlin A, Brunner G, et al. Glycoconjugate profiling of primary melanoma and its sentinel node and distant metastases:implications for diagnosis and pathophysiology of metastases[J].Cancer Lett,2007, 248(1):68-80.
[19]Shimizu K, Nakamura K, Kobatake S, et al. The clinical utility of Lens culinaris agglutinin-reactive thyroglobulin ratio in serum for distinguishing benign from malignant conditions of the thyroid[J]. Clin Chim Acta,2007,379(1-2):101-104.
[20]Inagaki Y, Tang W, Guo Q, et al. Sialogy coconjugate expression in primary colorectal cancer and metastatic lymph node tissues[J]. Hepatogastro enterology,2007,54(73):53-57.
[21]张红宇,吴先军,唐克轩,等.半夏凝集素基因导入水稻及其表达的初步研究[J].遗传学报,2003,30(11)：1013-1019.
[22]王逸群,赵仁贵,王玉兰,等.豌豆凝集素基因转化单倍体烟草[J].吉林农业大学学报,2001,23(2)：21-23.
[23]黄大防,潘映红,张淑香,等.从掌叶半夏和半夏中发现对几种蚜虫有致死活性的蛋白[J].中国农业科学,1997,30(2)：94-96.
[24]李润植,高武军,季道藩,等.朝鲜天南星凝集素的分离及抗棉蚜效应分析[J].棉花学报,2000,12(1)：54-56.
[25]潘科,侯学文,黄炳球.海芋凝集素对豆蚜的抗生作用研究[J].华南农业大学学报,2004,25(3)：51-54.
[26]Zhu YR, Wang J, Huang BQ, et al. Molecular cloning of a lectin cDNA from Alocasia macrorrhiza and prediction of its characteristics [J]. J Plant Physiol Mol Biol,2006,32(6):634-642.
[27]潘映红,张淑香,曹景萍,等.掌叶半夏凝集素的分离纯化及抗蚜活性研究[J].自然科学进展,1998,8(4)：502-505.
[28]王逸群,荆玉祥.豆科植物凝集素及其对根瘤菌的识别作用[J].植物学通报,2000,17(2)：127-132.
[29]熊维全,万群.植物凝集素及其在生物固氮中的作用[J].热带农业科技,2005,28(2)：21-26.
[30]高莹,瞿礼嘉.植物凝集素的分子生物学研究[J].生物技术通报,2000,(5)：18-22.
[31]张成省,李多川,孔凡玉.凝集素的分离纯化、基因克隆及功能研究进展[J].山东科学,2003,16(2)：11-17.
[32]宋海珊,闫明,李娟,等.凝集素染色法在真菌性角膜溃疡病原菌检查中的作用[J].中国实用眼科杂志,2003,21(4)：296-298.
[33]刘慧慧,李太武,苏秀榕.植物凝集素及其在生殖细胞表面糖复合物检测中的应用[J].自然杂志,2003,25(6)：323-32.
[34]段淑红,刘凯,尹海燕,等.凝集素受体WGA、RCA和ECL在过量维甲酸致昆明小鼠腭裂发生中的作用[J].山东大学学报(医学版),2009,47(6)：47-50,54.
[35]王敏康,王吕梅,张丽芬.植物凝集素在避孕与预防性传播疾病中的应用前景[J].生殖与避孕,2009,29(10)：670-675.
[36]肖智雄.人精细胞膜表面白附子凝集素受体的研究[J].四川大学学报,1987,24(3)：329-335.
[37]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa lectin induces paw edema with leukocyte infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[38]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem. Cell Biol. 2003,35,1674-1681.
[39]Alencar, V.B.M.; Alencar, N.M.N.; Assreuy, A.M.S.; et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[40]Andrade, J.L.; Arruda, S.; Barbosa, T.; et al. Lectin-induced Nitric Oxide production [J]. Cell. Immunol. 1999,194,98-102.
[41]施玉棉.王文萍.张辉.等.半夏凝集素在脂双层形成的阳离子通道[J].生理学报,1992,44(2)：142-148.
[42]孙光星,丁声颂,钱瑶君.掌叶半夏凝集素A的分离纯化及分析[J].上海医科大学学报,1995,22(4)：299-302.
[43]Shangary, S.; Singh, J.; Kamboj, S.S.; et al. Purification and properties of four monocot lectins from the family Araceae[J]. Phytochemistry,1995,40,449-455.
[44]肖智雄.白附子凝集素的亲和纯化及其理化性质的研究[J].四川大学学报,1986,4,135-141.
[45]吴皓,葛秀允,郁红礼,等.天南星科4种有毒中药针晶的晶型结构和其毒性的比较[J].中国中药杂志,2010,35(9)：1152-1155.
[1]郁红礼,朱法根,吴皓.半夏及掌叶半夏毒针晶中共性毒蛋白的研究[J].中华中医药杂志,2011,26(5)：1037-1042.
[2]葛秀允,吴皓.天南星科有毒中药毒针晶的组成成分分析[J].药物分析杂志,2010,30(2)：190-193.
[3]朱涛,吴昭,张琳,等.禹白附刺激性毒性成分的初步研究[J].南京中医药大学学报,2008,24(2)：97-100.
[4]吴皓,郁红礼,史闰均,等.凝集素：半夏及掌叶半夏毒针晶中的化学刺激性毒性成分[C].2010中药炮制技术、学术交流暨产业发展高峰论坛.2010,161-173.
[5]Bento, CAM.; Cavada, BS.; Oliveira, JTA.; et al. Rat paw edema and leukocyte immigration induced by plant lectins[J]. Agents Actions.1993,38,48-54.
[6]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[7]Andrade, J.L.; Arruda, S.; Barbosa, T.; et al. Lectin-induced Nitric Oxide production[J]. Cell. Immunol. 1999,194,98-102.
[1]郁红礼,朱法根,吴皓.半夏及掌叶半夏毒针晶中共性毒蛋白的研究[J].中华中医药杂志,2011,26(5)：1037-1042.
[2]Bento, C.A.M.; Cavada, B.S.; Oliveira, J.T.A.; et al. Rat paw edema and leukocyte immigration induced by plant lectins[J]. Agents Actions.1993,38,48-54.
[3]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[4]Andrade, J.L.; Arruda, S.; Barbosa, T.; et al. Lectin-induced Nitric Oxide production [J]. Cell. Immunol. 1999,194,98-102.
[5]孙光星,丁卢颂,钱瑶君.掌叶半夏凝集素A的分离纯化及分析[J].上海医科大学学报,1995,22(4)：299-302.
[6]Shangary, S.; Singh, J.; Kamboj, S.S.; et al. Purification and properties of four monocot lectins from the family Araceae[J]. Phytochemistry.1995,40,449-455.
[7]肖智雄.白附子凝集素的亲和纯化及其理化性质的研究[J].四川大学学报,1986,4,135-141.
[8]刘先琼,吴皓,郁红礼,等.半夏、掌叶半夏、禹白附凝集素蛋白的刺激性研究[J].中国实验方剂学杂 志,2011,17(18)：244-247.
[9]Xian Qiong Liu, Hao Wu, Hong Li Yu, et al. Purification of a Lectin from Arisaema erubescens (Wall.) Schott and its Pro-Inflammatory Effect[J]. Molecules.2011,16,9480-9494.
[10]苏凤云.微量雷帕霉素对缺血性脑损伤的保护作用及机制研究[D].第二军医大学学位论文,2011.
[11]吴皓,郁红礼,史闰均,等.凝集素：半夏及掌叶半夏毒针晶中的化学刺激性毒性成分[C].2010中药炮制技术、学术交流暨产业发展高峰论坛.2010,161-173.
[12]郭敦明.人膝骨性关节炎关节软骨差异表达蛋白质组学研究[D].南京医科大学学位论文,2007.
[13]Chelius D, Zhang T, Wang G, et al. Global protein identification and quantification technology using two-dimensional liquid chromatography nanospray mass spectrometry[J]. Anal Chem.2003, 75(23):6658-6665.
[14]Xiao F, Chen D, Lu Y, et al. analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy[J]. Brain Res. Proteomic.2009,1255 (19):180-189.
[15]Zhang L, Lun Y, Yan D, et al. Proteomic analysis of macrophages:A new way to identify novel cell-surface antigens[J]. Journal of Immunological Methods.2007,321(1-2):80-85.
[16]Dhuna, V., Bains, J.S., Kamboj, S.S., et al. Purification and Characterization of a Lectin from Arisaema tortuosum Schott Having in-vitro Anticancer Activity against Human Cancer Cell Lines[J]. J. Biochem Mol. Biol.2005,38,526-532.
[17]Herre, J.; Willment, J.A.; Gordon, S.; et al. The role of Dectin-1 in antifungal immunity[J]. Crit. Rev. Immunol.2004,24,193-203.
[18]Balzarini, J.; Neyts, J.; Schols, D.; et al. The mannose-specific plant lectins from Cymbidium hybrid and Epipactis helleborine and the (N-acetylglucosamine)n-specific plant lectin from Urtica dioica are potent and selective inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro[J]. Antiviral Res.1992,18,191-207.
[19]Hilder, V.A.; Powell, K.S.; Gatehouse, A.M.R.; et al. Expression of snowdrop lectin in transgenic tobacco plants results in added protection against aphids[J]. Transgenic Res.1995,4,18-25.
[20]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa Lectin Induces Paw Edema with Leukocyte Infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[21]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem Cell B. 2003,35,1674-1681.
[1]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa lectin induces paw edema with leukocyte infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[2]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem. Cell Biol., 2003,35,1674-1681.
[3]Alencar, V.B.M.; Alencar, N.M.N.; Assreuy, A.M.S.; et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[4]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[5]郁红礼,朱法根,吴皓.半夏及掌叶半夏毒针晶中共性毒蛋白的研究[J].中华中医药杂志,2011,26(5)：1037-1042.
[6]Shangary, S.; Singh, J.; Kamboj, S.S.; et al. Purification and properties of four monocot lectins from the family Araceae[J]. Phytochemistry,1995,40,449-455.
[7]Oda, Y.; Minami, K. Isolation and characterization of a lectin from tulip bulbs, Tulipa gesneriana[J]. Eur. J. Biochem.1986,159,239-245.
[8]宋玉娟.三种海藻凝集素的分离、纯化及其部分性质的研究[D].大连水产学院,2001.
[9]林玉满,苏爱华.牛舌菌凝集素的分离、性质及细胞凝集活性[J].天然产物研究与开发,2004,16(5)：420-425.
[10]Dhuna, V.; Bains, J.S.; Kamboj, S.S.; et al. Purification and characterization of a lectin from Arisaema tortuosum schott having in-vitro anticancer activity against human cancer cell lines[J]. J. Biochem. Mol. Biol. 2005,38,526-532.
[11]王幸,马秋枝,刘强.大豆凝集素的分离纯化和血凝活性研究[J].家畜生态学报,2006,27(6)：57-60.
[12]肖静,刘跟成.4种软体动物凝集素粗提物的凝集活性初探[J].海洋水产研究,2006,27(3)：32-36.
[13]林玉满,苏爱华.斑玉蕈Hypsizygus marmorers凝集素的部分性质和细胞凝集活性分析[J].菌物学报,2006,25(2)：284-291.
[1]Bruchas MR, Macey TA, Lowe JD, et al.. Kappa Opioid Receptor Activation of p38 MAPK Is GRK3-and Arrestin-dependent in Neurons and Astrocytes[J]. J Biol Chem.2006,281(26):18081-18089.
[1]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa lectin induces paw edema with leukocyte infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[2]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism [J]. Int. J. Biochem. Cell Biol. 2003,35,1674-1681.
[3]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[4]Alencar, V.B.M.; Alencar, N.M.N.; Assreuy, A.M.S.; et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[5]葛秀允,吴皓.天南星科有毒中药毒针晶的组成成分分析[J].药物分析杂志,2010,30(2)：190-193.
[6]朱欣佚,奚肇庆,张文曦.复方薤白胶囊抗内皮细胞凋亡与信号转导通路的研究[J].南京中医药大学学报,2010,26(5)：359-361.
[1]吴皓,葛秀允,郁红礼,等.天南星科4种有毒中药针晶的晶型结构和其毒性的比较[J].中国中药杂志,2010,35(9)：1152-1155.
[2]葛秀允,吴皓.天南星科有毒中药毒针晶的组成成分分析[J].药物分析杂志,2010,30(2)：190-193.
[3]Alencar, N.M.N., Assreuy, A.M.S., Criddle, D.N., et al. Vatairea Macrocarpa Lectin Induces Paw Edema with Leukocyte Infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[4]Bento, C.A.M., Cavada, B.S., Oliveira, J.T.A., et al. Rat paw edema and leukocyte immigration induced by plant lectins[J]. Agents Actions.1993,38,48-54.
[5]Alencar, V.B.M., Alencar, N.M.N., Assreuy, A.M.S, et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[6]Alencar, V.B.M., Assreuy, A.M.S., Alencar, N.M.N., et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[7]Alencar, N.M.N., Assreuy, A.M.S., Alencar, V.B.M., et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem Cell B. 2003,35,1674-1681.
[8]Andrade J.L., Arruda S., Barbosa T., et al. Lectin-induced Nitric Oxide production[J]. Cell. Immunol. 1999,194,98-102.
[9]Higuchi M., Higashi N., Taki H., et al. Cytolytic mechanisms of activated macrophages, tumor necrosis factor and L-arginine-dependent mechanisms act synergistically as the major cytolytic mechanisms of activated macrophages [J]. J. Immunol.1990,144,1425-1431.
[10]Barral-Netto M., Barral, A. A simple method for assessing the binding of concanavalin A to mononuclear cell surfaces:NO interference of visceral leishmaniasis serum on this binding[J]. Mem. Inst. Oswaldo Cruz.1986,81,343-345.
[11]Schultz R.M., Pavlidis N.A., Stylos W.A., et al. Regulation of macrophage tumoricidal function:a role for prostaglandins of the E series[J]. Science.1978,202,320-321.
[12]Locksley R.M., Killeen N., Lenardo M.J. The TNF and TNF receptor superfamilies:Integrating mammalian biology [J]. Cell.2001,104,487-501.
[13]Souza G.E.P., Ferreira S.H. Blockade by anti-macrophages serum of the migration of PMN neutrophils into the inflamed peritoneal cavity[J]. Agents Actions.1985,17,97-103.
[1]吴皓,郁红礼,史闰均,等.凝集素：半夏及掌叶半夏毒针晶中的化学刺激性毒性成分[C].2010中药炮制技术、学术交流暨产业发展高峰论坛.2010,161-173.
[2]钟凌云,吴皓,王倩茹,等.生半夏中草酸钙针晶对家兔眼结膜的刺激性研究[J].中国中药杂志,2006,31(20)：1706-1710.
[3]朱涛.禹白附和虎掌南星刺激性毒性成分研究[D].南京中医药大学学位论文,2008.
[4]国家药品监督管理局注册司.新药毒理学研究指导原则[S].1999,205-207.
[1]Rabinowich, H. Integrins as signal transducing receptors on NK Cells[J]. Methods.1996,9,362-369.
[2]Hogan, A. D., Schwartz, L. B. Markers of mast cell degranulation[J]. Methods.1997,13,43-52.
[3]Alencar, V.B.M., Alencar, N.M.N., Assreuy, A.M.S, et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[4]Alencar, V.B.M., Assreuy, A.M.S., Alencar, N.M.N., et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[5]Faccioli, L H.; Souza, G E P; Cunha, F Q., et al. Recombinant interleukin 1 and tumor necrosis factor induce neutrophil migration in vivo by indirect mechanisms [J]. Agents Actions.1990,30,344-349.
[6]刘先琼,吴皓,郁红礼,等.半夏、掌叶半夏、禹白附凝集素蛋白的刺激性研究[J].中国实验方剂学杂志,2011,17(18)：244-247.
[7]Ribeiro, R A.; Souza Filho, M V P.; Souza, M H L P; et al. Role of resident mast cells and macrophages in the neutrophil migration induced by LTB4, fMLP and C5a dearg[J]. Int Arch Allergy Immunol.1997,112, 27-35.
[8]Ribeiro, R A; Flores, C A; Cunha, F Q; et al. IL 8 in vivo neutrophil migration by a cell dependent mechanism [J]. Immunology.1991,73,472-477.
[9]Di Rosa, M; Giround, J P; Willoughby, D A. Studies of the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine[J]. J Pathol.1971,104,15-29.
[10]Rankin, J A; Sylvester, I; Smith, S; et al. Macrophages cultured in vitro release leukotriene B4 and neutrophil attractant activation protein (interleukin 8) sequentially in response to stimulation with lipopolysaccharide and zymosan[J]. J. Clin. Invest.1990,80,1554-1564.
[11]沈祥春,支娜,许立,等.大蝎子草乙酸乙脂部位对脂多糖诱导巨噬细胞炎症介质表达的影响[J].中华中医药杂志,2010,25(9)：1397-1400.
[12]田维毅,杨娟,王平,等.四物汤等复方多糖组分对小鼠腹腔巨噬细胞释放细胞因子的影响[J].中华中医药杂志,2009,24(4)：515-517.
[13]赵平,董蕾,罗金燕,等.胞大细胞和胃肠激素在TNBS所致大鼠溃疡性结肠炎模型中的变化[J].南方医科大学学报,2009,29(7)：1359-1363.
[14]Alencar, N M N; Assreuy, A M S; Alencar, V B M; et al. The galactose binding lectin from Vataire a macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem. Cell Biol. 2003,35,1674-1681.
[1]Del Zoppo G, Ginis I, Hallenbeck JM, et al. Inflammation and stroke:putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia[J]. B rain Pathol.2000,10(1):95-112.
[2]Sasayama S, Matsumori A, Kihara Y. New insights into the pathophysiological role of cytokines in heart failure[J]. Cardiovasc Res.1999,42:557-564.
[3]Fonseca-Camarillo G, Villeda-Ramirez M, Sanchez-Munoz F, et al. IL-6 and TNF-a gene expression in the rectal mucosal of patients with chronic idiopathic ulcerative colitis and controls [J]. Rev Gastroenterol Mex.2009,74(4):334-340.
[4]马永杰.炎症介质TNF-α、IFN-γ、TGF-β1对RAW264.7巨噬细胞株中类固醇激素合成急性调节蛋白的影响[D].复旦大学学位论文,2006.
[5]洪敏,余黎,华永庆,等.雌二醇对巨噬细胞的激活作用[J].中国病理生理杂志,2004,20(4)：566-570.
[6]Braun C, Hamacher J, Morel DR, et al. Dichotomal role of TNF in experiment a pulmonary edema reabsorption[J]. J Immunol.2005,175(5):3402-3408.
[2]Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease[J]. J Clin Invest, 2008,118 (11):3546-3556.
[3]曾剑儿,何炳斌.不同时期肺纤维化兔全肺灌洗液中炎症细胞及细胞因子研究[J].江西医药,2010,45(12)：1183-1185.
[4]徐少华,王伟,邵红艳,等.超短波治疗对COPD患者诱导痰中炎症细胞及IL-8和TNF-α的影响[J].中华物理医学与康复杂志,2005,27(3)：171-173.
[5]Sarir H, Henricks PA, Van Houwelingen AH, et al. Cells, mediators and Toll-like receptors in COPD[J]. Eur J Pharmacol,2008,585:346-353.
[6]周伟.氨溴索对慢性阻塞性肺疾病患者血.清细胞因子与肺功能的影响[J].中国药业,2011,20(19)：14-15.
[7]张弛,林如平,刘洪,等.鱼腥草注射液对慢性阻塞性肺疾病患者炎症细胞因子与肺功能的影响[J].中国中医药科技,2006,13(5)：294-295.
[8]廖文生,李卫青,陈世伟,等.参附注射液对慢性阻塞性肺疾病急性加重期患者炎症细胞因子和肺功能的影响[J].中国中西医结合急救杂志,2008,15(3)：149-151.
[9]陈卫熹,邓永超.中西医结合对慢性阻塞性肺疾病患者炎症细胞因子及肺功能的影响[J].中医药导报,2011,17(8)：28-29.
[10]胡华元,王捷鹏,张寿山,等.吸入药物治疗对稳定期COPD肺功能及炎症细胞因子的影响[J].中国现代医生,2010,48(34)：19-20.
[11]李春盛,何新华,桂培春.大黄对急性肺损伤大鼠血浆和支气管肺泡灌洗液中炎症细胞因子表达的影响[J].中国中西医结合急救杂志,2005,12(5)：306-308.
[12]汪春彦,吴常青,江勤,等.金荞麦对克雷伯杆菌肺炎大鼠心肌损伤中炎症细胞因子表达的影响[J].安徽医科大学学报,2011,46(1)：44-48.
[13]刘凤,石增立,于小玲,等.肾缺血再灌注损伤时血清及肾组织中促炎症细胞因子的变化与意义[J].中国临床医学,2005,12(1)：174-176.
[14]Kennedy JA, Clements WD, Kirk SJ, et al. Characterization of the kupffer cell response to exogenous endotoxinin a rodent model of obstructive jaundice[J]. Br J Surg.1999,86(5):628-633.
[15]王昱澍,李杰.肝硬化患者细胞因子TNF-α、IL-8检测的意义[J].中国医学工程,2011,19(8)：61-63.
[16]林佑武,张诗军,陈泽雄,等.运脾通络方治疗非酒精性脂肪性肝炎疗效观察[J].中药材,2011,34(7)：1158-1162.
[17]郝晓利,赵良中.玉竹提取物A对免疫性肝损伤小鼠促炎症细胞因子的影响[J].光明中医,2009,24(12)：2266-2267.
[18]钱玲妃,倪淑红.阿托伐他汀对不稳定型心绞痛患者血脂和血浆炎症细胞因子的影响[J].中国药房,2011,22(48)：4568-4569.
[19]冯学斌,刘凤,傅振荣,等.促炎症细胞因子、T细胞亚群在小儿过敏性紫癜不同病期的变化[J].中国病理生理杂志,1999,15(2)：1124-1126.
[20]雷宁玉,石增立,刘凤.败血症大鼠促炎症细胞因子变化及其干预研究[J].中国临床医学,2003,10(5)：685-687.
[21]吴洪华,杨成,石增立,等.川芎嗪对缺氧缺血性脑损伤炎症细胞因子作用的实验研究[J].滨州医学院学报,2007,30(3)：161-163.
[22]汪明灯,高修仁.炎症细胞因子与慢性心力衰竭[J].新医学,2006,37(3)：200-202.
[23]张敏莉,李昭屏,肖晗,等.不同类型心脏肥大大鼠模型心肌中炎症细胞因子表达差异[J].北京大学学报(医学版),2007.39(6)：570-575.
[24]Sasayama S, Matsumori A, Kihara Y. New insights into the pathophysiological role of cytokines in heart failure [J]. Cardiovasc Res,1999,42:557-564.
[25]罗永姣,刘红英,李双杰.小鼠柯萨奇B3病毒性心肌炎心脏炎症细胞因子基因和蛋白表达及黄芪甲甙干预研究[J].中国动脉硬化杂志,2009,17(2)：122-124.
[26]刘英,程翔,廖玉华.心肌钙反常模型细胞因子的表达及地尔硫卓的干预作用[J].中国药理学通 报,2010,26(3)：309-311.
[27]张金盈,程翔,廖玉华,等.大鼠急性心肌梗死后心脏炎症细胞因子基因和蛋白表达及辛伐他汀干预研究[J].中华老年心脑血管病杂志,2005,7(5)：344-346.
[28]Pugin J, Ricou B, Steinberg K P, et al. Proinflammatory activity in brochoalveolar lavage fluids from patients with a prominent role of interleukin-1[J]. Am J Respir Crit Care Med,1996,153:1850-1856.
[29]陈乾坤,姜格宁,丁嘉安,等.大鼠肺缺血再灌注损伤后前炎症细胞因子IL-1β mRNA的表达分析[J].复旦学报(医学版),2008,35(4)：560-563,596.
[30]赵曙光,李强,王景杰,等.姜黄素诱导Nrf2核转位对脂多糖引起库普弗细胞分泌炎症细胞因子的影响[J].现代生物医学进展,2011,11(17)：3204-3207.
[31]王非,张长志,李晓娟,等.清瘟败毒饮对急性肺损伤大鼠促炎症和抗炎症因子水平的影响[J].江中医药大学学报,2011,35(3)：391-394.
[32]梅雪,李建生,张艳霞.毒素清对肺炎痰热证大鼠肺组织炎症细胞因子的影响[J].中国实验方剂学杂志,2011,17(5)：153-156.
[33]陈洁,曾耀英,曾慧兰,等.补阳还五汤预先干预对大鼠脑死亡后心肺炎症细胞因子表达的抑制作用[J].中草药,2010,41(5)：757-761.
[34]冯兵,杨旭,叶自林,等.MG-132对慢性肾衰竭大鼠主动脉及循环炎症细胞因子表达的抑制作用[J].解放军医学杂志,2008,33(7)：857-860.
[35]梁永会,韩继媛,邱红根.肿瘤坏死因子-α及白细胞介素-1p在大鼠肾缺血后处理中的变化及意义[J].广东医学,2011,32(14)：1809-1811.
[36]万涛,潘忠良,贺亚东,等.急性胰腺炎时肝损伤与血清炎症细胞因子关系的实验研究[J].浙江医学,2008,30(1)：34-37.
[37]郑飞霞,李光乾.反复热性惊厥大鼠体内促炎症细胞因子水平的变化[J].温州医学院学报,2007,37(6)：529-532.
[38]潘芙蓉,蔡强军,潘平,等.阿托伐他汀影响原发性高血压患者循环血单个核细胞炎症因子表达的临床研究[J].中国药学杂志,2010,45(2)：140-143.
[39]曾灶吕.阿维A联合窄谱中波紫外线对银屑病患者炎症细胞因子的影响[J].中国药业,2009,18(12)：41-43.
[40]Corrigall VM, Panayi GS. Autoantigens and immune pathways in rheumatoid arthritis [J]. Crit Rev Immunol,2002,22 (4):281-293.
[41]韦叶生,黄瑞雅,蓝艳,等.白细胞介素-1α基因启动子-889C/T和白细胞1受体拮抗剂第2内含子VNTR基因多态性与脑梗死关系的研究[J].中国老年学杂志,2005,25(2)：126-128.
[42]罗小星,赵永华,赵锋利.复苏饮对重症脑出血患者炎症细胞因子的影响[J].中国中医急症,2004,13(2)：70-71.
[43]傅晨,张允岭,常富业,等.利开灵对脑出血大鼠内毒素血症炎症效应的影响[J].环球中医药.2011.4(5)：340-343,347.
[44]朱参胜,冯清华,于曰祥,等.大骨节病患者血清促炎症细胞因子水平的检测[J].细胞与分子免疫学杂志,2006,22(1)：84-85.
[45]徐雅,李澎涛,陈杰,等.安宫清开灵对自发性高血压大鼠脑出血模型前炎症细胞因子与黏附分子含量的影响[J].世界科学技术——中医药现代化,2007,9(2)：45-49,72.
[46]陈锐,刘伟,刘建平,等EGCG通过ERKl/2途径抑制LPS诱导人单核细胞产生前炎性细胞因子[J].中国现代医生,2011,49(9)：5-6,9.
[47]丁青,尤昭玲.三七复合有效成分对子宫内膜炎症细胞NF-KB p65及TNF-α、IL-1β变化的影响[J].中国中医药科技,2007,14(2)：113-115.
[48]吴俊,梁维邦,倪红斌,等.促红细胞生成素对大鼠急性脊髓损伤后核因子-κB及炎症因子表达的影响[J].江苏医药,2011,37(4)：381-383.
[49]李新纯,何明大.脑灵汤对阿尔茨海默病患者MMSE及血清促炎症细胞因子的影响[J].实用预防医学,2010,17(5)：959-961.
[50]王慧玲,董克礼.益智健脑颗粒对阿尔茨海默病患者脑内促炎症细胞因子的影响[J].湖南中医药大学学报,2008,28(2)：54-56.
[51]沈晓明,韩宁,马云枝,等.舒郁颗粒对卒中后抑郁大鼠模型海马单胺类神经递质及炎症细胞因子的影响[J].中国实验方剂学杂志,2011,17(19)：177-180.
[52]朱光明.异丙酚麻醉对肝叶切除术患者肝功能与炎症细胞因子的影响[J].中国药业,2011,20(17)：17-18.
[53]李静,陈长勋,高阳,等.鱼腥草素抗炎与抗动脉硬化作用的探索[J].中成药,2010,32(1)：26-30.
[54]Fonseca-Camarillo G, Villeda-Ramirez M, Sanchez-Munoz F, et al. IL-6 and TNF-a gene expression in the rectal mucosal of patients with chronic idiopathic ulcerative colitis and controls[J]. Rev Gastroenterol Mex,2009,74(4):334-340.
[55]Jones S A. Directing transition from innate to acquired immunity:defining a role for IL-6[J]. J Immunol, 2005,175(6):3463-3468.
[56]廖玉华.心血管疾病免疫学研究进展[J].郑州大学学报(医学版),2005,40(2)：181-183.
[57]苏慧敏.阿托伐他汀对重度慢性充血性心力衰竭患者心功能及相关炎症细胞因子的影响[J].中国误诊学杂志,2007,7(23),5478-5479.
[58]欧阳迎春,刘加勉,刘应才.卡维地洛对慢性心力衰竭患者核因子-κB活化和炎症细胞因子表达的影响[J].中国现代医学杂志,2008,18(18)：2628-2631.
[59]姚淮芳,胡业彬,程晓昱,等.温肾益心丹对充血.性心力衰竭炎症细胞因子水平的影响[J].中国中西医结合急救杂志,2005.12(3)：149-152.
[60]刘洪,张弛,陈云凤.慢性阻塞性肺疾病炎症细胞因子与肺通气功能变化相关分析[J].实用医院临床杂志,2007,4(1)：52-53.
[61]Chaouat A, Savale L, Chouaid C, et al. Role for interleukin-6 in COPD-related pulmonary hypertension[J]. Chest,2009,136:678-687.
[62]曹奇峰.吸入舒利迭对慢性阻塞性肺疾病患者血浆炎症细胞因子和肺功能的影响[J].中国现代医生,2011,49(26)：60-61.
[63]冯学斌,刘德尧,刘凤,等.柴桂合剂对反复呼吸道感染患儿血浆促炎症细胞因子、IgG亚类的影响[J].中国临床医学,2005,12(5)：893-895.
[64]刘凤,于小玲,董晓青,等.油酸型急性呼吸窘迫综合征血清及肺组织促炎症细胞因子变化及山莨菪碱干预的实验研究[J].中国病理生理杂志,2002,18(8)：959-961.
[65]吴建魏,耿智隆,刘东,等.远隔预处理对兔肺缺血再灌注后炎症细胞因子和呼吸指数的影响[J].解放军医学杂志,2009,34(8)：989-991,996.
[66]李岑,杨红英.原发性高血压病患者血清细胞因子水平变化的检测及临床意义分析[J].中国分子心脏病学杂志,2006,6(6)：316-318.
[67]姚祖培,陈建新,喻海忠.化瘀复元胶囊对高血压病病人血清炎症细胞因子的影响[J].中西医结合心脑血管病杂志,2008,6(1)：5-6.
[68]唐可倩,刘玉文,唐伟,等.替米沙坦对高血压冠心病患者血浆炎症细胞因子的调节作用[J].海峡药学,2010,22(8)：168-169.
[69]刘时武,王喜玉,马建林.高胆固醇血症患者炎症细胞因子与颈动脉内膜中层厚度及血管内皮依赖性舒张功能的相关性[J].海南医学,2010,21(10)：4-5.
[70]陈昕琳,顾仁樾,章怡袆.丹参多酚酸B对动脉粥样硬化大鼠炎症细胞因子的影响[J].上海中医药大学学报,2011,25(1)：63-67.
[71]刘时武,王喜玉,马建林,等.瑞舒伐他汀对高胆固醇血症患者炎症细胞因子的影响[J].实用医学杂志,2010,26(13)：2419-2421.
[72]曾平,符秀琼,王启瑞,等.加味补阳还五汤对动脉粥样硬化斑块形成及炎症细胞因子表达谱的影响[J].中药药理与临床,2009,25(6)：11-13.
[73]李顺宁.脉复生对动脉硬化闭塞症患者血脂及炎症细胞因子的影响[J].云南中医中药杂志,2011,32(11)：19-21.
[74]戴建明,谭美娟,黄波.亚低温治疗对中度脑外伤患者炎症细胞因子的影响[J].实用心脑肺血.管病杂志,2009,17(4)：250-251.
[75]陈芳洁,黄宏春,王永亮.肝硬化腹水患者前炎症细胞因子的改变[J].医药论坛杂志,2009,30(24)：27-28.
[76]李林,王茂材,罗赤苗,等.大柴胡汤联合运动对阻塞性黄疸大鼠肝脏炎症细胞因子的影响[J].中国运动医学杂志,2011,30(9)：836-844.
[77]Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis[J]. Circulation,2002,105:1135-1143.
[78]杨帆,刘开俊,曾叶,等.雷公藤多苷对内毒素激活小鼠腹腔巨噬细胞分泌促炎症细胞因子的影响[J].中国免疫学杂志,2006,22(11)：1021-1024.
[79]Mizutani H, Ohmoto Y, Mizutani M, et al. Role of increased production of monocyte TNF-alpha, IL-a-beta and IL-6 in psoriasis:relation to focal infection disease activity and responses to treatments[J]. J Dermatol Sci,1997,14(2):145-153
[80]张静,崔苏扬,汪小海,等.氟比洛芬酯注射液对消化道肿瘤手术后炎症细胞因子表达的影响[J].临床麻麻醉学杂志,2007,23(5)：383-384.
[81]包长顺,陈礼刚,顾应江,等.高压氧对重型脑创伤大鼠血清中炎症细胞因子水平的影响[J].泸江医学院学报,2007,30(6)：480-482.
[82]Rice GE. Cytokines and the initiation o f parturition[J]. Front Horm Res,2001,27:113-146.
[83]武春梅.早产及正常妊娠孕妇IL-6与IL-10含量相关性分析[J].中国实验诊断学,2011,15(7)：1170-1171.
[84]Pooran N, Indaram A, Singh P, et al. Cytokines (IL-6, IL-8, TNF):early and reliable predictors of severe acute pancreatitis[J]. J Clin Gastroenterol,2003,37(3):263-266.
[85]谌剑飞.糖尿病缺血性中风中医证型与血清炎症细胞因子关系的研究[J].中国中西医结合急救杂志,2000,7(3)：147-149.
[86]高书荣,建宏,朱良争.芪连汤与降糖药联合干预2型糖尿病胰岛素抵抗及对相关炎症细胞因子的影响[J].中国中西医结合杂志,2004,24(7)：593-595.
[87]吕玉宏,张再高,李家承.慢性前列腺炎患者治疗前后血清IL-8、IL-1p和TNF-a检测的临床意义[J].放射免疫学杂志,2009,22(6)：593-594.
[88]徐巧萍,王砚,唐法娣,等.1,8-桉油精对卵白蛋白致哮喘豚鼠的气道高反应性和炎症的抑制作用[J].中国药理学与毒理学杂志,2010,24(1)：35-43.
[89]何文一,覃数,张冬颖.白细胞介素-8与冠状动脉病变程度的关系[J].重庆医学,2010,39(1)：31-33.
[90]魏天辉,赵施竹.冠心病急性心肌梗死患者血浆心肌营养素和血清白介素18的变化[J].中国心血管病研究杂志,2010,8(4)：271-274.
[91]李巧汶,李志梁,邱健,等.冠心病患者血浆组织因子、组织因子途径抑制物、白介素18、白介素10水平的变化及其关系[J].中华老年多器官疾病杂志,2010,9(3)：252-255,260.
[92]Netea MG, Azam T, Ferwerda G, et al. IL-32 synergizes with nucleotide oligomerization domain (NOD) land (NOD) 2 ligands for IL-1(3 and IL-6 production through acaspase 1-dependent mechanism [J]. Proc Natl Acad Sci USA,2005,102(45):16309-16314.
[93]雷光文,衡爱萍.IL-32在HBV感染者检测中的诊断价值[J].放射免疫学杂志,2011,24(2)：230-231.
[94]王娟,姜艳芳.IL-33在感染性疾病中的研究进展[J].中国免疫学杂志,2011,27(12)：1129-1131.
[95]Xian Qiong Liu, Hao Wu, Hong Li Yu, et al. Purification of a Lectin from Arisaema erubescens (Wall.) Schott and its Pro-Inflammatory Effect [J]. Molecules.2011,16,9480-9494.
[1]孙册.凝集素(Lectin)研究进展[J].生物化学与生物物理学进展,1981,3(1)：15-17.
[2]王志斌,张秀梅,郭三堆.在转基因植物中利用植物凝集素防治害虫的研究[J].植物学通报,2000,17(2)：108-113.
[3]Dhuna, V, Bains, J.S, Kamboj, S.S, et al. Purification and characterization of a lectin from Arisaema tortuosum schott having in-vitro anticancer activity against human cancer cell lines[J]. J. Biochem. Mol. Biol. 2005,38,526-532.
[4]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[5]Takano Y, Teranishi Y, Terashimas, et al. Lymphnode metastasis related carbohydrate epitopes of gastric cancer with submucosal invasion[J]. Surg Today,2000,30(12):1073-1082.
[6]Kawaguchi T, Takazawa H, Imai S, et al. Expression of vicia villosa agglutinin(VVA)-binding glycoprotein in primary breastcancer cells in relation to lymphatic metastasis is atypical MUC1 bearing Tn antigen a receptor of WA[J]. Breast Cancer Res Treat,2006,98(1):31-43.
[7]Remani P, Pillai K R, Haseenabeevi V M, et al. Lectin cytochemistry in the exfoliative cytology of uterine cervix[J]. Neoplasma,1994,41 (1):39-42.
[8]Gercel-Taylor C, Bazzett LB, Taylor DD. Presence of aberrant tumor-reactive immunoglobulins in the circulation of patients with ovarian cancer[J]. Gynecol Oncol,2001,81(1):71-76.
[9]项锋钢,杨梅怀,张岩峰,等.原发性肺癌的凝集素定位研究[J].临床与实验病理学杂志,1994,10(3)：186-189.
[10]侯学文,吴伯良,曾仲奎,等.海芋凝集素的鉴定及性质研究[J].暨南大学学报,1998,19(3)：89-93.
[11]Nakanishi K, Kawai T, Suzuki M, et al. Lectin binding and expression of blood group related antigens in carcinoma in situ and invasive carcinoma of urinary bladder[J]. Histopathology.1993,23 (2):153-158.
[12]罗旭,沈寅初,李春明.五种凝集素受体在膀胱癌中的分布及意义[J].遵义学院学报,2000,23(2)：99-101.
[13]张十文,葛根,金伯涛.膀胱癌增殖细胞核抗原与麦胚凝集素受体的相关关系[J].肿瘤学杂志,2001,7(2)：98-100.
[14]司维可,李仕敏,罗朝学,等.伴刀豆球蛋白A识别正常与肝癌谷氨酰转移酶的实验观察[J].第三军医大学学报,2000,22(3)：294-295.
[15]Carr BI, Kanke F, Wise M, et al. Clinical evaluation of lens culi-naris agglutinin-reactive alpha-fetoprotein and desgammacarboxy prothrombin in histologically proven hepatocellular carcinoma in the United States[J].Dig Dis Sci,2007,52(3):776-782.
[16]王海燕,白晓春,罗深秋.植物凝集素与医学应用[J].生命的化学,2003,23(3)：224-226.
[17]Litynska A, Przybylo M, Pochec E, et al. Comparison of the lectin-binding pattern in different human melanoma celllines[J]. Melanoma Res,2001,11(3):205-212.
[18]Thies A, Berlin A, Brunner G, et al. Glycoconjugate profiling of primary melanoma and its sentinel node and distant metastases:implications for diagnosis and pathophysiology of metastases[J].Cancer Lett,2007, 248(1):68-80.
[19]Shimizu K, Nakamura K, Kobatake S, et al. The clinical utility of Lens culinaris agglutinin-reactive thyroglobulin ratio in serum for distinguishing benign from malignant conditions of the thyroid[J]. Clin Chim Acta,2007,379(1-2):101-104.
[20]Inagaki Y, Tang W, Guo Q, et al. Sialogy coconjugate expression in primary colorectal cancer and metastatic lymph node tissues[J]. Hepatogastro enterology,2007,54(73):53-57.
[21]张红宇,吴先军,唐克轩,等.半夏凝集素基因导入水稻及其表达的初步研究[J].遗传学报,2003,30(11)：1013-1019.
[22]王逸群,赵仁贵,王玉兰,等.豌豆凝集素基因转化单倍体烟草[J].吉林农业大学学报,2001,23(2)：21-23.
[23]黄大防,潘映红,张淑香,等.从掌叶半夏和半夏中发现对几种蚜虫有致死活性的蛋白[J].中国农业科学,1997,30(2)：94-96.
[24]李润植,高武军,季道藩,等.朝鲜天南星凝集素的分离及抗棉蚜效应分析[J].棉花学报,2000,12(1)：54-56.
[25]潘科,侯学文,黄炳球.海芋凝集素对豆蚜的抗生作用研究[J].华南农业大学学报,2004,25(3)：51-54.
[26]Zhu YR, Wang J, Huang BQ, et al. Molecular cloning of a lectin cDNA from Alocasia macrorrhiza and prediction of its characteristics [J]. J Plant Physiol Mol Biol,2006,32(6):634-642.
[27]潘映红,张淑香,曹景萍,等.掌叶半夏凝集素的分离纯化及抗蚜活性研究[J].自然科学进展,1998,8(4)：502-505.
[28]王逸群,荆玉祥.豆科植物凝集素及其对根瘤菌的识别作用[J].植物学通报,2000,17(2)：127-132.
[29]熊维全,万群.植物凝集素及其在生物固氮中的作用[J].热带农业科技,2005,28(2)：21-26.
[30]高莹,瞿礼嘉.植物凝集素的分子生物学研究[J].生物技术通报,2000,(5)：18-22.
[31]张成省,李多川,孔凡玉.凝集素的分离纯化、基因克隆及功能研究进展[J].山东科学,2003,16(2)：11-17.
[32]宋海珊,闫明,李娟,等.凝集素染色法在真菌性角膜溃疡病原菌检查中的作用[J].中国实用眼科杂志,2003,21(4)：296-298.
[33]刘慧慧,李太武,苏秀榕.植物凝集素及其在生殖细胞表面糖复合物检测中的应用[J].自然杂志,2003,25(6)：323-32.
[34]段淑红,刘凯,尹海燕,等.凝集素受体WGA、RCA和ECL在过量维甲酸致昆明小鼠腭裂发生中的作用[J].山东大学学报(医学版),2009,47(6)：47-50,54.
[35]王敏康,王吕梅,张丽芬.植物凝集素在避孕与预防性传播疾病中的应用前景[J].生殖与避孕,2009,29(10)：670-675.
[36]肖智雄.人精细胞膜表面白附子凝集素受体的研究[J].四川大学学报,1987,24(3)：329-335.
[37]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa lectin induces paw edema with leukocyte infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[38]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem. Cell Biol. 2003,35,1674-1681.
[39]Alencar, V.B.M.; Alencar, N.M.N.; Assreuy, A.M.S.; et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[40]Andrade, J.L.; Arruda, S.; Barbosa, T.; et al. Lectin-induced Nitric Oxide production [J]. Cell. Immunol. 1999,194,98-102.
[41]施玉棉.王文萍.张辉.等.半夏凝集素在脂双层形成的阳离子通道[J].生理学报,1992,44(2)：142-148.
[42]孙光星,丁声颂,钱瑶君.掌叶半夏凝集素A的分离纯化及分析[J].上海医科大学学报,1995,22(4)：299-302.
[43]Shangary, S.; Singh, J.; Kamboj, S.S.; et al. Purification and properties of four monocot lectins from the family Araceae[J]. Phytochemistry,1995,40,449-455.
[44]肖智雄.白附子凝集素的亲和纯化及其理化性质的研究[J].四川大学学报,1986,4,135-141.
[45]吴皓,葛秀允,郁红礼,等.天南星科4种有毒中药针晶的晶型结构和其毒性的比较[J].中国中药杂志,2010,35(9)：1152-1155.
[1]郁红礼,朱法根,吴皓.半夏及掌叶半夏毒针晶中共性毒蛋白的研究[J].中华中医药杂志,2011,26(5)：1037-1042.
[2]葛秀允,吴皓.天南星科有毒中药毒针晶的组成成分分析[J].药物分析杂志,2010,30(2)：190-193.
[3]朱涛,吴昭,张琳,等.禹白附刺激性毒性成分的初步研究[J].南京中医药大学学报,2008,24(2)：97-100.
[4]吴皓,郁红礼,史闰均,等.凝集素：半夏及掌叶半夏毒针晶中的化学刺激性毒性成分[C].2010中药炮制技术、学术交流暨产业发展高峰论坛.2010,161-173.
[5]Bento, CAM.; Cavada, BS.; Oliveira, JTA.; et al. Rat paw edema and leukocyte immigration induced by plant lectins[J]. Agents Actions.1993,38,48-54.
[6]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[7]Andrade, J.L.; Arruda, S.; Barbosa, T.; et al. Lectin-induced Nitric Oxide production[J]. Cell. Immunol. 1999,194,98-102.
[1]郁红礼,朱法根,吴皓.半夏及掌叶半夏毒针晶中共性毒蛋白的研究[J].中华中医药杂志,2011,26(5)：1037-1042.
[2]Bento, C.A.M.; Cavada, B.S.; Oliveira, J.T.A.; et al. Rat paw edema and leukocyte immigration induced by plant lectins[J]. Agents Actions.1993,38,48-54.
[3]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[4]Andrade, J.L.; Arruda, S.; Barbosa, T.; et al. Lectin-induced Nitric Oxide production [J]. Cell. Immunol. 1999,194,98-102.
[5]孙光星,丁卢颂,钱瑶君.掌叶半夏凝集素A的分离纯化及分析[J].上海医科大学学报,1995,22(4)：299-302.
[6]Shangary, S.; Singh, J.; Kamboj, S.S.; et al. Purification and properties of four monocot lectins from the family Araceae[J]. Phytochemistry.1995,40,449-455.
[7]肖智雄.白附子凝集素的亲和纯化及其理化性质的研究[J].四川大学学报,1986,4,135-141.
[8]刘先琼,吴皓,郁红礼,等.半夏、掌叶半夏、禹白附凝集素蛋白的刺激性研究[J].中国实验方剂学杂 志,2011,17(18)：244-247.
[9]Xian Qiong Liu, Hao Wu, Hong Li Yu, et al. Purification of a Lectin from Arisaema erubescens (Wall.) Schott and its Pro-Inflammatory Effect[J]. Molecules.2011,16,9480-9494.
[10]苏凤云.微量雷帕霉素对缺血性脑损伤的保护作用及机制研究[D].第二军医大学学位论文,2011.
[11]吴皓,郁红礼,史闰均,等.凝集素：半夏及掌叶半夏毒针晶中的化学刺激性毒性成分[C].2010中药炮制技术、学术交流暨产业发展高峰论坛.2010,161-173.
[12]郭敦明.人膝骨性关节炎关节软骨差异表达蛋白质组学研究[D].南京医科大学学位论文,2007.
[13]Chelius D, Zhang T, Wang G, et al. Global protein identification and quantification technology using two-dimensional liquid chromatography nanospray mass spectrometry[J]. Anal Chem.2003, 75(23):6658-6665.
[14]Xiao F, Chen D, Lu Y, et al. analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy[J]. Brain Res. Proteomic.2009,1255 (19):180-189.
[15]Zhang L, Lun Y, Yan D, et al. Proteomic analysis of macrophages:A new way to identify novel cell-surface antigens[J]. Journal of Immunological Methods.2007,321(1-2):80-85.
[16]Dhuna, V., Bains, J.S., Kamboj, S.S., et al. Purification and Characterization of a Lectin from Arisaema tortuosum Schott Having in-vitro Anticancer Activity against Human Cancer Cell Lines[J]. J. Biochem Mol. Biol.2005,38,526-532.
[17]Herre, J.; Willment, J.A.; Gordon, S.; et al. The role of Dectin-1 in antifungal immunity[J]. Crit. Rev. Immunol.2004,24,193-203.
[18]Balzarini, J.; Neyts, J.; Schols, D.; et al. The mannose-specific plant lectins from Cymbidium hybrid and Epipactis helleborine and the (N-acetylglucosamine)n-specific plant lectin from Urtica dioica are potent and selective inhibitors of human immunodeficiency virus and cytomegalovirus replication in vitro[J]. Antiviral Res.1992,18,191-207.
[19]Hilder, V.A.; Powell, K.S.; Gatehouse, A.M.R.; et al. Expression of snowdrop lectin in transgenic tobacco plants results in added protection against aphids[J]. Transgenic Res.1995,4,18-25.
[20]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa Lectin Induces Paw Edema with Leukocyte Infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[21]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem Cell B. 2003,35,1674-1681.
[1]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa lectin induces paw edema with leukocyte infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[2]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem. Cell Biol., 2003,35,1674-1681.
[3]Alencar, V.B.M.; Alencar, N.M.N.; Assreuy, A.M.S.; et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[4]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[5]郁红礼,朱法根,吴皓.半夏及掌叶半夏毒针晶中共性毒蛋白的研究[J].中华中医药杂志,2011,26(5)：1037-1042.
[6]Shangary, S.; Singh, J.; Kamboj, S.S.; et al. Purification and properties of four monocot lectins from the family Araceae[J]. Phytochemistry,1995,40,449-455.
[7]Oda, Y.; Minami, K. Isolation and characterization of a lectin from tulip bulbs, Tulipa gesneriana[J]. Eur. J. Biochem.1986,159,239-245.
[8]宋玉娟.三种海藻凝集素的分离、纯化及其部分性质的研究[D].大连水产学院,2001.
[9]林玉满,苏爱华.牛舌菌凝集素的分离、性质及细胞凝集活性[J].天然产物研究与开发,2004,16(5)：420-425.
[10]Dhuna, V.; Bains, J.S.; Kamboj, S.S.; et al. Purification and characterization of a lectin from Arisaema tortuosum schott having in-vitro anticancer activity against human cancer cell lines[J]. J. Biochem. Mol. Biol. 2005,38,526-532.
[11]王幸,马秋枝,刘强.大豆凝集素的分离纯化和血凝活性研究[J].家畜生态学报,2006,27(6)：57-60.
[12]肖静,刘跟成.4种软体动物凝集素粗提物的凝集活性初探[J].海洋水产研究,2006,27(3)：32-36.
[13]林玉满,苏爱华.斑玉蕈Hypsizygus marmorers凝集素的部分性质和细胞凝集活性分析[J].菌物学报,2006,25(2)：284-291.
[1]Bruchas MR, Macey TA, Lowe JD, et al.. Kappa Opioid Receptor Activation of p38 MAPK Is GRK3-and Arrestin-dependent in Neurons and Astrocytes[J]. J Biol Chem.2006,281(26):18081-18089.
[1]Alencar, N.M.N.; Assreuy, A.M.S.; Criddle, D.N.; et al. Vatairea Macrocarpa lectin induces paw edema with leukocyte infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[2]Alencar, N.M.N.; Assreuy, A.M.S.; Alencar, V.B.M.; et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism [J]. Int. J. Biochem. Cell Biol. 2003,35,1674-1681.
[3]Alencar, V.B.M.; Assreuy, A.M.S.; Alencar, N.M.N.; et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[4]Alencar, V.B.M.; Alencar, N.M.N.; Assreuy, A.M.S.; et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[5]葛秀允,吴皓.天南星科有毒中药毒针晶的组成成分分析[J].药物分析杂志,2010,30(2)：190-193.
[6]朱欣佚,奚肇庆,张文曦.复方薤白胶囊抗内皮细胞凋亡与信号转导通路的研究[J].南京中医药大学学报,2010,26(5)：359-361.
[1]吴皓,葛秀允,郁红礼,等.天南星科4种有毒中药针晶的晶型结构和其毒性的比较[J].中国中药杂志,2010,35(9)：1152-1155.
[2]葛秀允,吴皓.天南星科有毒中药毒针晶的组成成分分析[J].药物分析杂志,2010,30(2)：190-193.
[3]Alencar, N.M.N., Assreuy, A.M.S., Criddle, D.N., et al. Vatairea Macrocarpa Lectin Induces Paw Edema with Leukocyte Infiltration[J]. Protein Peptide Lett.2004,11,195-200.
[4]Bento, C.A.M., Cavada, B.S., Oliveira, J.T.A., et al. Rat paw edema and leukocyte immigration induced by plant lectins[J]. Agents Actions.1993,38,48-54.
[5]Alencar, V.B.M., Alencar, N.M.N., Assreuy, A.M.S, et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[6]Alencar, V.B.M., Assreuy, A.M.S., Alencar, N.M.N., et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[7]Alencar, N.M.N., Assreuy, A.M.S., Alencar, V.B.M., et al. The galactose-binding lectin from Vatairea macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem Cell B. 2003,35,1674-1681.
[8]Andrade J.L., Arruda S., Barbosa T., et al. Lectin-induced Nitric Oxide production[J]. Cell. Immunol. 1999,194,98-102.
[9]Higuchi M., Higashi N., Taki H., et al. Cytolytic mechanisms of activated macrophages, tumor necrosis factor and L-arginine-dependent mechanisms act synergistically as the major cytolytic mechanisms of activated macrophages [J]. J. Immunol.1990,144,1425-1431.
[10]Barral-Netto M., Barral, A. A simple method for assessing the binding of concanavalin A to mononuclear cell surfaces:NO interference of visceral leishmaniasis serum on this binding[J]. Mem. Inst. Oswaldo Cruz.1986,81,343-345.
[11]Schultz R.M., Pavlidis N.A., Stylos W.A., et al. Regulation of macrophage tumoricidal function:a role for prostaglandins of the E series[J]. Science.1978,202,320-321.
[12]Locksley R.M., Killeen N., Lenardo M.J. The TNF and TNF receptor superfamilies:Integrating mammalian biology [J]. Cell.2001,104,487-501.
[13]Souza G.E.P., Ferreira S.H. Blockade by anti-macrophages serum of the migration of PMN neutrophils into the inflamed peritoneal cavity[J]. Agents Actions.1985,17,97-103.
[1]吴皓,郁红礼,史闰均,等.凝集素：半夏及掌叶半夏毒针晶中的化学刺激性毒性成分[C].2010中药炮制技术、学术交流暨产业发展高峰论坛.2010,161-173.
[2]钟凌云,吴皓,王倩茹,等.生半夏中草酸钙针晶对家兔眼结膜的刺激性研究[J].中国中药杂志,2006,31(20)：1706-1710.
[3]朱涛.禹白附和虎掌南星刺激性毒性成分研究[D].南京中医药大学学位论文,2008.
[4]国家药品监督管理局注册司.新药毒理学研究指导原则[S].1999,205-207.
[1]Rabinowich, H. Integrins as signal transducing receptors on NK Cells[J]. Methods.1996,9,362-369.
[2]Hogan, A. D., Schwartz, L. B. Markers of mast cell degranulation[J]. Methods.1997,13,43-52.
[3]Alencar, V.B.M., Alencar, N.M.N., Assreuy, A.M.S, et al. Pro-inflammatory effect of Arum maculatum lectin and role of resident cells[J]. Int. J. Biochem. Cell Biol.2005,37,1805-1814.
[4]Alencar, V.B.M., Assreuy, A.M.S., Alencar, N.M.N., et al. Lectin of Pisum arvense seeds induces in-vivo and in-vitro neutrophil migration[J]. J. Pharm. Pharmacol.2005,57,375-381.
[5]Faccioli, L H.; Souza, G E P; Cunha, F Q., et al. Recombinant interleukin 1 and tumor necrosis factor induce neutrophil migration in vivo by indirect mechanisms [J]. Agents Actions.1990,30,344-349.
[6]刘先琼,吴皓,郁红礼,等.半夏、掌叶半夏、禹白附凝集素蛋白的刺激性研究[J].中国实验方剂学杂志,2011,17(18)：244-247.
[7]Ribeiro, R A.; Souza Filho, M V P.; Souza, M H L P; et al. Role of resident mast cells and macrophages in the neutrophil migration induced by LTB4, fMLP and C5a dearg[J]. Int Arch Allergy Immunol.1997,112, 27-35.
[8]Ribeiro, R A; Flores, C A; Cunha, F Q; et al. IL 8 in vivo neutrophil migration by a cell dependent mechanism [J]. Immunology.1991,73,472-477.
[9]Di Rosa, M; Giround, J P; Willoughby, D A. Studies of the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine[J]. J Pathol.1971,104,15-29.
[10]Rankin, J A; Sylvester, I; Smith, S; et al. Macrophages cultured in vitro release leukotriene B4 and neutrophil attractant activation protein (interleukin 8) sequentially in response to stimulation with lipopolysaccharide and zymosan[J]. J. Clin. Invest.1990,80,1554-1564.
[11]沈祥春,支娜,许立,等.大蝎子草乙酸乙脂部位对脂多糖诱导巨噬细胞炎症介质表达的影响[J].中华中医药杂志,2010,25(9)：1397-1400.
[12]田维毅,杨娟,王平,等.四物汤等复方多糖组分对小鼠腹腔巨噬细胞释放细胞因子的影响[J].中华中医药杂志,2009,24(4)：515-517.
[13]赵平,董蕾,罗金燕,等.胞大细胞和胃肠激素在TNBS所致大鼠溃疡性结肠炎模型中的变化[J].南方医科大学学报,2009,29(7)：1359-1363.
[14]Alencar, N M N; Assreuy, A M S; Alencar, V B M; et al. The galactose binding lectin from Vataire a macrocarpa seeds induces in vivo neutrophil migration by indirect mechanism[J]. Int. J. Biochem. Cell Biol. 2003,35,1674-1681.
[1]Del Zoppo G, Ginis I, Hallenbeck JM, et al. Inflammation and stroke:putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia[J]. B rain Pathol.2000,10(1):95-112.
[2]Sasayama S, Matsumori A, Kihara Y. New insights into the pathophysiological role of cytokines in heart failure[J]. Cardiovasc Res.1999,42:557-564.
[3]Fonseca-Camarillo G, Villeda-Ramirez M, Sanchez-Munoz F, et al. IL-6 and TNF-a gene expression in the rectal mucosal of patients with chronic idiopathic ulcerative colitis and controls [J]. Rev Gastroenterol Mex.2009,74(4):334-340.
[4]马永杰.炎症介质TNF-α、IFN-γ、TGF-β1对RAW264.7巨噬细胞株中类固醇激素合成急性调节蛋白的影响[D].复旦大学学位论文,2006.
[5]洪敏,余黎,华永庆,等.雌二醇对巨噬细胞的激活作用[J].中国病理生理杂志,2004,20(4)：566-570.
[6]Braun C, Hamacher J, Morel DR, et al. Dichotomal role of TNF in experiment a pulmonary edema reabsorption[J]. J Immunol.2005,175(5):3402-3408.