基于整合药理学分析丁香柿蒂汤降逆止呃的分子机制
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摘要
目的:探讨经典名方丁香柿蒂汤降逆止呃的分子作用机制,为该方的后续研究与开发具有提供参考。方法:利用中药整合药理学平台,从多成分、多靶标的维度揭示丁香柿蒂汤降逆止呃的潜在分子机制。结果:丁香柿蒂汤降逆止呃作用主要与89个化学成分相关,共有靶标1个[大麻素受体1(CNR1)],CNR1一方面通过抑制γ-氨基丁酸(GABA),多巴胺和5-羟色胺(5-HT)的释放而抑制呃逆的发生;另一方面,CNR1激活可抑制胃肠动力、延迟胃排空,推测可能是通过脑-肠轴发挥调节胃肠运动的作用。同时,丁香柿蒂汤降逆止呃作用可能与神经系统、核苷酸代谢相关。结论:丁香柿蒂汤可能是通过影响神经递质的释放、线粒体能量代谢等调节胃肠运动,基于多靶标、多通路共同干预实现其降逆止呃的作用。
Objective: The classical formula of Dingxiang Shiditang can be used for hiccup and vomit which caused by many reasons,its molecular mechanism of this formula was investigated. Method: Based on the integrated pharmacology platform of traditional Chinese medicine,the potential molecular mechanism of Dingxiang Shiditang was revealed from the dimensions of multi-components and multi-targets. Result: There were 89 compounds related to hiccup and vomit of Dingxiang Shiditang,and there was 1 common target [cannabinoid receptor 1( CNR1) ]. On the one hand,CNR1 could inhibit the occurrence of hiccup and vomit by inhibiting the release of γ-aminobutyric acid( GABA),dopamine,5-hydroxytryptamine( 5-HT); on the other hand,CNR1 could inhibit gastrointestinal motility and delay gastric emptying,and it was speculated that CNR1 may play a role in regulating gastrointestinal motility through brain-gut axis. Meanwhile,the mechanism of Dingxiang Shiditang may be related to nucleotide metabolism and nervous system. Conclusion: Dingxiang Shiditang may regulate gastrointestinal motility by affecting the release of neurotransmitters, mitochondrial energy metabolism, and achieve its effect on hiccup and vomit based on the joint intervention of multiple targets and multiple pathways.
Objective: The classical formula of Dingxiang Shiditang can be used for hiccup and vomit which caused by many reasons,its molecular mechanism of this formula was investigated. Method: Based on the integrated pharmacology platform of traditional Chinese medicine,the potential molecular mechanism of Dingxiang Shiditang was revealed from the dimensions of multi-components and multi-targets. Result: There were 89 compounds related to hiccup and vomit of Dingxiang Shiditang,and there was 1 common target [cannabinoid receptor 1( CNR1) ]. On the one hand,CNR1 could inhibit the occurrence of hiccup and vomit by inhibiting the release of γ-aminobutyric acid( GABA),dopamine,5-hydroxytryptamine( 5-HT); on the other hand,CNR1 could inhibit gastrointestinal motility and delay gastric emptying,and it was speculated that CNR1 may play a role in regulating gastrointestinal motility through brain-gut axis. Meanwhile,the mechanism of Dingxiang Shiditang may be related to nucleotide metabolism and nervous system. Conclusion: Dingxiang Shiditang may regulate gastrointestinal motility by affecting the release of neurotransmitters, mitochondrial energy metabolism, and achieve its effect on hiccup and vomit based on the joint intervention of multiple targets and multiple pathways.
引文
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[8]闻彬.丁香柿蒂汤、穴位注射联合多潘立酮治疗肿瘤致顽固性呃逆随机平行对照研究[J].实用中医内科杂志,2015,29(11):120-121.
[9]秦岭,闫宏建,王艳,等.丁香柿蒂汤治疗顽固呃逆66例[J].陕西中医,2013,34(7):875-876.
[10]薛潇春,胡晋红.网络药理学的研究方法与应用进展[J].药学实践杂志,2015,33(5):401-405.
[11] ZHANG Y Q,GUO Q Y,LI Q Y,et al. Main active constituent identification in Guanxinjing capsule,a traditional Chinese medicine,for the treatment of coronary heart disease complicated with depression[J].Acta Pharmacol Sin, 2017, doi:10. 1038/aps. 2017. 117.
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[13] YU G,ZHANG Y,REN W,et al. Network pharmacologybased identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis[J]. Int J Chron Obstruct Pulmon Dis,2016,12:85-94.
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[16] Musumeci A,Cristofori L,Bricolo A. Persistent hiccup as presenting symptom in medulla oblongata cavernoma:a case report and review of the literature[J]. Clin Neurol Neurosurg,2000,102(1):13-17.
[17]顾佩菲,吴春福.内源性大麻素样物质的可能作用机制[J].中国药理学通报,2003,19(11):1223-1226.
[18] Landi M,Croci T,Rinaldi-camona M,et al. Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB1receptors[J]. Eur J Pharmacol,2002,450(1):77-83.
[19] Nicola M, Izza A A, Aiessia L, et al. The endocannabinoid system and the molecular basis of paralytic ileus in mice[J]. FASEB J,2002,16(14):1973-1975.
[20] Pertwee R G. Cannabinoid and the gastrointestinal tract[J]. Gut,2001,48(6):859-867.
[21]宋晓冬,划谶安,孙丰润,等.中药胃肠舒对胃肠平滑肌细胞ATP生成的影晌[J].世界华人消化杂志,2007,15(30):3159-3162.
[22] HUANG M,Camara A K,Stowe D F, et al.Mitochondrial inner membrane electrophysiology assessed by rhodamine-123 transport and fluorescence[J]. Ann Biomed Eng,2007,35(7):1276-1285.
[23] Hosoya R,Uesawa Y,Ishii-Nozawa R,et al. Analysis of factors associated with hiccups based on the Japanese Adverse Drug Event Report database[J]. PLo S One,2017,12(2):e0172057.
[24] Nausheen F,Mohsin H,Lakhan S E. Neurotransmitters in hiccups[J]. Springerplus,2016,doi:10. 1186/s40064-016-3034-3.
[25]李振洲,郎森阳.呃逆与脑血管病[J].国际脑血管病杂志,2004,12(3):198-200.
[26]金晓仙,高旸.顽固性呃逆研究进展[J].河南中医,2014,34(5):987-989.
[27]孙卫国.丁香柿蒂汤治疗腹部手术后并发顽固性呃逆疗效观察[J].中医学报,2010,9(5):941-942.
[28]何海涛,孙婷,崔佳乐,等.嘌呤核苷酸补偿对吗啡依赖大鼠嘌呤核苷酸分解代谢的影响[J].中国药理学通报,2008,24(8):1081-1083.
[29]何海涛,李鸿梅,李昆,等.嘌呤核苷酸补偿对海洛因依赖大鼠脑中嘌呤核苷酸含量的影响及机制研究[J].中国实验诊断学,2009,13(11):1512-1514.
[30]吴海芬,朱春辉,郭建友.人参皂苷Rg1对抑郁症模型大鼠行为学及海马氨基酸的影响[J].中国中药杂志,2012,37(20):3117-3121.
[31]黄倩,楚世峰,连晓媛,等.人参皂苷Rg1的抗抑郁作用及其作用机制[J].神经药理学报,2013,3(1):1-11.
[32]毛晶晶,张彤,王冰,等. 20(S)-原人参二醇的药理作用研究进展[J].中国实验方剂学杂志,2011,17(24):274-277.
[33]贾士奇,王军,张红霞,等.生姜对局灶性脑缺血大鼠海马神经细胞凋亡及相关蛋白表达的影响[J].中国实验方剂学杂志,2011,17(3):163-166.
[34]王军,黄启福,刘惠霞,等.生姜水提物对全脑缺血再灌注大鼠脑组织氨基酸递质的影响[J].中国实验方剂学杂志,2011,17(21):184-187.
[35]吴培俊.丁香柿蒂汤对功能性消化不良患者胃运动功能影响的临床观察[J].中国中医药科技,2011,18(1):9.
[36]谢金东,涂春香,陈继承,等.丁香柿蒂汤及其拆方对小鼠离体小肠收缩活动的影响[J].福建中医学院学报,2010,20(4):36-37.
[37]赵庆华.柿蒂提取物抑制大鼠离体膈肌收缩的作用机制及其有效部位的研究[D].石家庄:河北医科大学,2005.
[38]任骏.齐墩果酸对前列腺素及环核苷酸的影响[J].中国药理学通报,1991,7(3):179-181.
[39]张晓凯.柿蒂活性成分的研究[D].武汉:湖北中医学院,2008.
[40] Sanchez M,Theoduloz C,Schmeda-Hirschmann G,et al.Gastroprotective and ulcer-healing activity of oleanolic acid derivatives:in vitro-in vivo relationships[J]. Life Sci,2006,79(14):1349-1356.
[41]胡洪波,钱长苏.丁香柿蒂在呃逆中的应用[J].实用中医内科杂志,2007,21(1):84.
[42]洪天国,钟海岩,黄光胜,等.丁香超微粉对离体大鼠肠活动影响的量效关系研究[J].时珍国医国药,2011,22(11):2647-2648.
[43]赵怀舟.丁香郁金配伍应用的理论探讨及其对小鼠胃排空影响的实验研究[D].武汉:湖北中医学院,2004.
[44]贾颖,赵怀舟,王红梅,等.丁香配伍郁金对小鼠胃排空影响的实验研究[J].中华中医药杂志,2006,21(11):2647-2648.
[45]黄燕琼,秦华珍,李世阳,等.丁香3种提取物对寒证大鼠脑内神经递质及环磷酸腺苷、环磷酸鸟苷的影响[J].中国实验方剂学杂志,2010,16(10):153-155.
[46]秦华珍,李世阳,黄燕琼,等.干姜、高良姜、丁香3种提取物对寒证大鼠交感神经-肾上腺机能的影响[J].中国实验方剂学杂志,2010,16(14):124-127.
[47]宋齐.人参化学成分和药理作用研究进展[J].人参研究,2017,29(2):47-54.
[48]何平平,钟凌云.干姜、生姜及其炮制辅料姜汁的研究进展[J].中国实验方剂学杂志,2016,22(6):219-223.
[49] Matsuki M. Mechansmsof cytotoxic drug-induced emesis and its prevention[J]. Yakugaku Zasshi,1996,116(9):710-718.
[2]许海玉,刘振明,杨洪军,等.中药整合药理学计算平台的开发与应用[J].中国中药杂志,2017,42(18):3633-3638.
[3]许海玉,黄璐琦,卢鹏,等.基于体内ADME过程和网络药理学的中药现代研究思路[J].中国中药杂志,2012,37(2):142-145.
[4]韦明婵,林江,莫明月,等.网络方剂学特征的研究进展[J].中国实验方剂学杂志,2016,22(11):218-224.
[5]邓中甲.方剂学[M].北京:中国中医药出版社,2017:10.
[6]温长路.实用方剂歌诀[M].北京:中国中医药出版社,2014:11.
[7]耿明.丁香柿蒂汤治疗肿瘤致顽固性呃逆的临床效果分析[J].中国医药指南,2017,15(5):195-196.
[8]闻彬.丁香柿蒂汤、穴位注射联合多潘立酮治疗肿瘤致顽固性呃逆随机平行对照研究[J].实用中医内科杂志,2015,29(11):120-121.
[9]秦岭,闫宏建,王艳,等.丁香柿蒂汤治疗顽固呃逆66例[J].陕西中医,2013,34(7):875-876.
[10]薛潇春,胡晋红.网络药理学的研究方法与应用进展[J].药学实践杂志,2015,33(5):401-405.
[11] ZHANG Y Q,GUO Q Y,LI Q Y,et al. Main active constituent identification in Guanxinjing capsule,a traditional Chinese medicine,for the treatment of coronary heart disease complicated with depression[J].Acta Pharmacol Sin, 2017, doi:10. 1038/aps. 2017. 117.
[12] ZHANG Y Q,MAO X,SU J,et al. A network pharmacology based strategy deciphers the underlying molecular mechanisms of Qixuehe capsule in the treatment of menstrual disorders[J]. Chin Med,2017,doi:10. 1186/s13020-017-0145-x.
[13] YU G,ZHANG Y,REN W,et al. Network pharmacologybased identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis[J]. Int J Chron Obstruct Pulmon Dis,2016,12:85-94.
[14]孙广仁.中医基础理论[M].北京:中国中医药出版社,2007:131-132.
[15]陆永利,刘长金,李从德.大麻素在神经系统中的作用[J].生理科学进展,2008,39(2):179-181.
[16] Musumeci A,Cristofori L,Bricolo A. Persistent hiccup as presenting symptom in medulla oblongata cavernoma:a case report and review of the literature[J]. Clin Neurol Neurosurg,2000,102(1):13-17.
[17]顾佩菲,吴春福.内源性大麻素样物质的可能作用机制[J].中国药理学通报,2003,19(11):1223-1226.
[18] Landi M,Croci T,Rinaldi-camona M,et al. Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB1receptors[J]. Eur J Pharmacol,2002,450(1):77-83.
[19] Nicola M, Izza A A, Aiessia L, et al. The endocannabinoid system and the molecular basis of paralytic ileus in mice[J]. FASEB J,2002,16(14):1973-1975.
[20] Pertwee R G. Cannabinoid and the gastrointestinal tract[J]. Gut,2001,48(6):859-867.
[21]宋晓冬,划谶安,孙丰润,等.中药胃肠舒对胃肠平滑肌细胞ATP生成的影晌[J].世界华人消化杂志,2007,15(30):3159-3162.
[22] HUANG M,Camara A K,Stowe D F, et al.Mitochondrial inner membrane electrophysiology assessed by rhodamine-123 transport and fluorescence[J]. Ann Biomed Eng,2007,35(7):1276-1285.
[23] Hosoya R,Uesawa Y,Ishii-Nozawa R,et al. Analysis of factors associated with hiccups based on the Japanese Adverse Drug Event Report database[J]. PLo S One,2017,12(2):e0172057.
[24] Nausheen F,Mohsin H,Lakhan S E. Neurotransmitters in hiccups[J]. Springerplus,2016,doi:10. 1186/s40064-016-3034-3.
[25]李振洲,郎森阳.呃逆与脑血管病[J].国际脑血管病杂志,2004,12(3):198-200.
[26]金晓仙,高旸.顽固性呃逆研究进展[J].河南中医,2014,34(5):987-989.
[27]孙卫国.丁香柿蒂汤治疗腹部手术后并发顽固性呃逆疗效观察[J].中医学报,2010,9(5):941-942.
[28]何海涛,孙婷,崔佳乐,等.嘌呤核苷酸补偿对吗啡依赖大鼠嘌呤核苷酸分解代谢的影响[J].中国药理学通报,2008,24(8):1081-1083.
[29]何海涛,李鸿梅,李昆,等.嘌呤核苷酸补偿对海洛因依赖大鼠脑中嘌呤核苷酸含量的影响及机制研究[J].中国实验诊断学,2009,13(11):1512-1514.
[30]吴海芬,朱春辉,郭建友.人参皂苷Rg1对抑郁症模型大鼠行为学及海马氨基酸的影响[J].中国中药杂志,2012,37(20):3117-3121.
[31]黄倩,楚世峰,连晓媛,等.人参皂苷Rg1的抗抑郁作用及其作用机制[J].神经药理学报,2013,3(1):1-11.
[32]毛晶晶,张彤,王冰,等. 20(S)-原人参二醇的药理作用研究进展[J].中国实验方剂学杂志,2011,17(24):274-277.
[33]贾士奇,王军,张红霞,等.生姜对局灶性脑缺血大鼠海马神经细胞凋亡及相关蛋白表达的影响[J].中国实验方剂学杂志,2011,17(3):163-166.
[34]王军,黄启福,刘惠霞,等.生姜水提物对全脑缺血再灌注大鼠脑组织氨基酸递质的影响[J].中国实验方剂学杂志,2011,17(21):184-187.
[35]吴培俊.丁香柿蒂汤对功能性消化不良患者胃运动功能影响的临床观察[J].中国中医药科技,2011,18(1):9.
[36]谢金东,涂春香,陈继承,等.丁香柿蒂汤及其拆方对小鼠离体小肠收缩活动的影响[J].福建中医学院学报,2010,20(4):36-37.
[37]赵庆华.柿蒂提取物抑制大鼠离体膈肌收缩的作用机制及其有效部位的研究[D].石家庄:河北医科大学,2005.
[38]任骏.齐墩果酸对前列腺素及环核苷酸的影响[J].中国药理学通报,1991,7(3):179-181.
[39]张晓凯.柿蒂活性成分的研究[D].武汉:湖北中医学院,2008.
[40] Sanchez M,Theoduloz C,Schmeda-Hirschmann G,et al.Gastroprotective and ulcer-healing activity of oleanolic acid derivatives:in vitro-in vivo relationships[J]. Life Sci,2006,79(14):1349-1356.
[41]胡洪波,钱长苏.丁香柿蒂在呃逆中的应用[J].实用中医内科杂志,2007,21(1):84.
[42]洪天国,钟海岩,黄光胜,等.丁香超微粉对离体大鼠肠活动影响的量效关系研究[J].时珍国医国药,2011,22(11):2647-2648.
[43]赵怀舟.丁香郁金配伍应用的理论探讨及其对小鼠胃排空影响的实验研究[D].武汉:湖北中医学院,2004.
[44]贾颖,赵怀舟,王红梅,等.丁香配伍郁金对小鼠胃排空影响的实验研究[J].中华中医药杂志,2006,21(11):2647-2648.
[45]黄燕琼,秦华珍,李世阳,等.丁香3种提取物对寒证大鼠脑内神经递质及环磷酸腺苷、环磷酸鸟苷的影响[J].中国实验方剂学杂志,2010,16(10):153-155.
[46]秦华珍,李世阳,黄燕琼,等.干姜、高良姜、丁香3种提取物对寒证大鼠交感神经-肾上腺机能的影响[J].中国实验方剂学杂志,2010,16(14):124-127.
[47]宋齐.人参化学成分和药理作用研究进展[J].人参研究,2017,29(2):47-54.
[48]何平平,钟凌云.干姜、生姜及其炮制辅料姜汁的研究进展[J].中国实验方剂学杂志,2016,22(6):219-223.
[49] Matsuki M. Mechansmsof cytotoxic drug-induced emesis and its prevention[J]. Yakugaku Zasshi,1996,116(9):710-718.