丁郁柿蒂汤调控5-HT、5-HT3R干预急性CINV的机制研究
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摘要
目的:从蛋白定量分析和基因表达水平探讨丁郁柿蒂汤治疗急性化疗性恶心呕吐(CINV)的作用机制,并通过观察大鼠症状并检测相关指标证明丁香配伍郁金治疗急性CINV的可行性。方法:采取慢性束缚法+顺铂注射法复制急性CINV大鼠异食癖模型;造模组分别用丁香柿蒂汤、郁金单方、丁郁柿蒂汤、昂丹司琼和蒸馏水干预;用ELISA法和RT-q PCR法观察5-HT和5-HT3R的表达情况。结果:急性CINV造模后23～24 h模型组大鼠的糖水偏爱度较低,急性CINV造模后12～24 h高岭土摄食量显著升高,血清和回肠组织中5-HT的合成显著升高,5-HT的代谢率显著降低,回肠和延髓组织中5-HT3R的基因表达显著升高。丁郁柿蒂汤可降低血清和回肠组织中5-HT的合成,升高5-HT的代谢率,降低回肠和延髓组织中5-HT3R的基因表达。结论:丁郁柿蒂汤能够通过降低血液和回肠组织中5-HT的合成,并加速其代谢来降低5-HT的含量。再通过抑制5-HT3R的表达,有效阻滞神经冲动的传导,在急性CINV时显著减少传入呕吐中枢的信号,起到良好的止呕效果。丁郁柿蒂汤中用丁香和郁金相伍,不仅能大大降低郁金在急性CINV时表现出来的毒性,而且能增加丁香柿蒂汤的药效,具有减毒增效的效果。
Objective: To study the mechanism of Dingxiang Shidi Decoction treating acute CINV from the perspective of protein quantitative analysis and gene expression,and to prove the feasibility of the therapy in treating acute CINV by observing the symptoms of rats and detecting related indexes. Methods: The model of acute CINV with pica was established in rats by adopting the method of chronic restraint combined with the Cisplatin injection. The rats after sucessful modeling were respectively intervened by Dingxiang Shidi Deoction,Yujin Deoction,Dingyu Shidi Decoction,ondansetron hydrochloride,and distilled water. The expressions of 5-HT and 5-HT3 R were observed by the methods of ELISA and RT-q PCR. Results: The sugar water preference of the model group was lower than that of the blank group 23-24 h after modeling; the intake of kaoline was significantly increased 12-24 h after modeling. The synthesis of 5-HT in serum and ileum increased significantly,the metabolic rate of 5-HT decreased significantly,and the gene expressions of 5-HT3 R in ileum and medulla oblongata increased significantly after modeling. Dingyu Shidi Decoction could decrease the synthesis of 5-HT in serum and ileum,increase metabolic rate of 5-HT,and reduce gene expression of 5-HT3 R in ileum and medulla oblongata. Conclusion: Dingyu Shidi Decoction can reduce the level of 5-HT by reducing its synthesis and speed up its metabolism. By inhibiting the expression of 5-HT3 R,it can effectively block the conduction of the nerve impulse,and significantly reduce the signal of the vomiting center in acute CINV rats,therefore it plays a good antiemetic effect. The compatibility of Dingxiang and Yujin in Dingyu Shidi Decoction can not only greatly reduce the toxicity of Yujin in acute CINV,but also increase the efficacy of Dingxiang Shidi Decoction,possessing the function of reducing toxicity and increasing efficiency.
Objective: To study the mechanism of Dingxiang Shidi Decoction treating acute CINV from the perspective of protein quantitative analysis and gene expression,and to prove the feasibility of the therapy in treating acute CINV by observing the symptoms of rats and detecting related indexes. Methods: The model of acute CINV with pica was established in rats by adopting the method of chronic restraint combined with the Cisplatin injection. The rats after sucessful modeling were respectively intervened by Dingxiang Shidi Deoction,Yujin Deoction,Dingyu Shidi Decoction,ondansetron hydrochloride,and distilled water. The expressions of 5-HT and 5-HT3 R were observed by the methods of ELISA and RT-q PCR. Results: The sugar water preference of the model group was lower than that of the blank group 23-24 h after modeling; the intake of kaoline was significantly increased 12-24 h after modeling. The synthesis of 5-HT in serum and ileum increased significantly,the metabolic rate of 5-HT decreased significantly,and the gene expressions of 5-HT3 R in ileum and medulla oblongata increased significantly after modeling. Dingyu Shidi Decoction could decrease the synthesis of 5-HT in serum and ileum,increase metabolic rate of 5-HT,and reduce gene expression of 5-HT3 R in ileum and medulla oblongata. Conclusion: Dingyu Shidi Decoction can reduce the level of 5-HT by reducing its synthesis and speed up its metabolism. By inhibiting the expression of 5-HT3 R,it can effectively block the conduction of the nerve impulse,and significantly reduce the signal of the vomiting center in acute CINV rats,therefore it plays a good antiemetic effect. The compatibility of Dingxiang and Yujin in Dingyu Shidi Decoction can not only greatly reduce the toxicity of Yujin in acute CINV,but also increase the efficacy of Dingxiang Shidi Decoction,possessing the function of reducing toxicity and increasing efficiency.
引文
[1]董爽.化疗所致恶心呕吐现状调查[D].武汉:华中科技大学,2013:1-54.
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[4]燕晓茹,张培彤.癌症相关性抑郁的中医药临床研究进展[J].环球中医药,2016,9(12):1571-1574.
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[6]杨琴,杜青,赵洪庆,等.百合疏肝安神汤对焦虑性抑郁症模型大鼠前额叶-边缘结构及GR/BDNF/NPY表达的影响[J].中国临床药理学与治疗学,2017,22(10):1090-1098.
[7]万光升,孙珏.化疗后恶心呕吐反应及其中医药治疗进展[J].辽宁中医药大学学报,2009,11(8):76-78.
[8]张晓静,张频.肿瘤化疗所致恶心呕吐的发生机制和药物治疗的研究进展[J].癌症进展,2006,4(4):348-354.
[9]于功昌,张勇,聂克.小半夏汤对急性化疗性异食癖模型大鼠5-HT合成与代谢的影响[J].山东中医药大学学报,2015,39(3):277-280.
[10]陈文强,黄小波,李宗信.四君子汤对脾虚大鼠不同脑区单胺类神经递质含量的影响[J].天津中医药,2009,26(2):137-138.
[11]赵燕玲,夏天.鼠脾虚证与胃窦及十二指肠组织5-HT及其受体的关系[J].第四军医大学学报,2000,21(5):87-89.
[12]赵燕玲,张仲海,夏天,等.脾虚大鼠胃窦、十二指肠组织5-HT细胞的变化及意义[J].安徽中医学院学报,2001,20(3):41-42.
[2]张玲凤.恶性肿瘤病人发生抑郁的相关因素研究[J].内蒙古医科大学学报,2013,35(s2):557-559.
[3]于世英,印季良,秦叔逵,等.肿瘤治疗相关呕吐防治指南[J].临床肿瘤学杂志,2014,19(3):263-273.
[4]燕晓茹,张培彤.癌症相关性抑郁的中医药临床研究进展[J].环球中医药,2016,9(12):1571-1574.
[5]徐云浩,赵博.从“百病生于气”解析抑郁症五脏病机[J].中医药信息,2018,35(4):84-87.
[6]杨琴,杜青,赵洪庆,等.百合疏肝安神汤对焦虑性抑郁症模型大鼠前额叶-边缘结构及GR/BDNF/NPY表达的影响[J].中国临床药理学与治疗学,2017,22(10):1090-1098.
[7]万光升,孙珏.化疗后恶心呕吐反应及其中医药治疗进展[J].辽宁中医药大学学报,2009,11(8):76-78.
[8]张晓静,张频.肿瘤化疗所致恶心呕吐的发生机制和药物治疗的研究进展[J].癌症进展,2006,4(4):348-354.
[9]于功昌,张勇,聂克.小半夏汤对急性化疗性异食癖模型大鼠5-HT合成与代谢的影响[J].山东中医药大学学报,2015,39(3):277-280.
[10]陈文强,黄小波,李宗信.四君子汤对脾虚大鼠不同脑区单胺类神经递质含量的影响[J].天津中医药,2009,26(2):137-138.
[11]赵燕玲,夏天.鼠脾虚证与胃窦及十二指肠组织5-HT及其受体的关系[J].第四军医大学学报,2000,21(5):87-89.
[12]赵燕玲,张仲海,夏天,等.脾虚大鼠胃窦、十二指肠组织5-HT细胞的变化及意义[J].安徽中医学院学报,2001,20(3):41-42.