基于苦味受体的现代药理学研究挖掘“苦入心”的科学内涵
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摘要
中医药五味理论认为:"药有酸、咸、甘、苦、辛五味"。传统的归经理论认为:"酸入肝,辛入肺,苦入心,咸入肾,甘入脾",即传统中医认为具有苦味及其特性的中药对治疗心血管有好的疗效。现代药理学研究发现,苦味中药确实具有治疗心血管疾病的潜力,并且苦味中药中的特定化合物能激活味蕾细胞上的苦味受体TAS2Rs(bitter taste receptors),从而让人们感知到苦味,同时TAS2Rs在心血管系统中也有表达。这暗示苦味中药和心之间的联系可能由TAS2Rs作为桥梁。本文通过综述TAS2Rs的研究进展,以期利用现代药理学知识来阐述中医理论中"苦入心"的理论,进而探讨苦味中药通过TAS2R改善心血管功能的作用机制。
The five flavour theory of Chinese medicine is: "medicine has sour, salty, sweet, bitter, and spicy five tastes". The traditional attribution theory holds that "sour into the liver, pungent into the lung, bitter into the heart, salty into the kidney, and sweet into the spleen." In short, traditional Chinese medicine believe that Chinese medicine with bitter taste and its characteristics have a good effect on cardiovascular disease. A large number of modern pharmacological studies found that many bitter Chinese medicines did have the potential to treat cardiovascular diseases. Based on modern genetic studies, specific compounds of bitter Chinese medicines can activate the bitter taste receptor(TAS2Rs) on taste bud cells and allow people to perceive bitter taste. TAS2 Rs can express in the cardiovascular system. Therefore, the relationship between bitter Chinese medicine and the heart may be bridged by TAS2 Rs. This article reviews the research progress of bitter receptors, explains the conception of "bitter into heart" in TCM theory with modern pharmacological knowledge, and then discusses the mechanism of bitter Chinese medicine improving cardiovascular function by activating TAS2 Rs.
The five flavour theory of Chinese medicine is: "medicine has sour, salty, sweet, bitter, and spicy five tastes". The traditional attribution theory holds that "sour into the liver, pungent into the lung, bitter into the heart, salty into the kidney, and sweet into the spleen." In short, traditional Chinese medicine believe that Chinese medicine with bitter taste and its characteristics have a good effect on cardiovascular disease. A large number of modern pharmacological studies found that many bitter Chinese medicines did have the potential to treat cardiovascular diseases. Based on modern genetic studies, specific compounds of bitter Chinese medicines can activate the bitter taste receptor(TAS2Rs) on taste bud cells and allow people to perceive bitter taste. TAS2 Rs can express in the cardiovascular system. Therefore, the relationship between bitter Chinese medicine and the heart may be bridged by TAS2 Rs. This article reviews the research progress of bitter receptors, explains the conception of "bitter into heart" in TCM theory with modern pharmacological knowledge, and then discusses the mechanism of bitter Chinese medicine improving cardiovascular function by activating TAS2 Rs.
引文
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[5]杨超.黄芩苷对支气管哮喘的药效学及其对苦味受体作用机制研究[D].河北医科大学,2013.
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[19]Gu, Q.D., D.S. Joe, and C.A. Gilbert, Activation of bitter taste receptors in pulmonary nociceptors sensitizes TRPV1 channels through the PLC and PKC signaling pathway[J]. Am J Physiol Lung Cell Mol Physiol,2017,312(3):L326-l333.
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[21]Kim, D., et al.Coupling of Airway Smooth Muscle Bitter Taste Receptors to Intracellular Signaling and Relaxation Is via Galphai1,2,3[J]. Am J Respir Cell Mol Biol,2017,56(6):762-771.
[22]Prandi, S., et al. Expression profiling of Tas2r genes reveals a complex pattern along the mouse GI tract and the presence of Tas2r131 in a subset of intestinal Paneth cells[J]. Cell Mol Life Sci,2018,75(1):49-65.
[23]Yamaki, M., et al.Genotyping Analysis of Bitter-Taste Receptor Genes TAS2R38 and TAS2R46 in Japanese Patients with Gastrointestinal Cancers[J]. J Nutr Sci Vitaminol(Tokyo), 2017,63(2):148-154.
[24]Chen, J.G., et al. The expression of bitter taste receptors in mesenteric,cerebral and omental arteries. Life Sci, 2017,170:16-24.
[25]Zheng, K., et al. Bitter taste receptors as targets for tocolytics in preterm labor therapy[J]. Faseb j, 2017,31(9):4037-4052.
[26]Wolfle, U., et al. Expression and Functional Activity of the Human Bitter Taste Receptor TAS2R38 in Human Placental Tissues and JEG-3 Cells[J].Molecules, 2016,21(3):306.
[27]Xu, J., et al. Functional characterization of bitter-taste receptors expressed in mammalian testis[J]. Mol Hum Reprod,2013,19(1):17-28.
[28]Foster, S.R., et al. Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart[J]. PLoS One,2013,8(5):e64579.
[29]Foster, S.R., et al.Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart[J]. FASEB J, 2014,28(10):4497-508.
[30]Foster,S.R.,etal.BittertastereceptoragonistselicitG-proteindependentnegativeinotropyinthemurineheart[J].Faseb Journal,2014,28(10):4497-4508.
[31]Foster, S.R., et al.Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation[J].Naunyn-Schmiedeberg’s archives of pharmacology,2015,388(10):1009.
[32]Chen, J.G., et al.The expression of bitter taste receptors in mesenteric,cerebral and omental arteries[J]. Life Sciences,2017,170:16-24.
[33]Manson, M.L., et al.Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle[J]. European Journal of Pharmac ology,2014,740(6):302-311.
[2]孙玉信.黄帝内经·素问[M]. 2005:第二军医大学出版社.
[3]Zhou, Y., et al.Inotropic effects and mechanisms of matrine, a main alkaloid from Sophora flavescens AIT[J]. Biological&Pharmaceutical Bulletin,2008,31(11):2057-62.
[4]Zhang, C.Y. and B.K. Tan.Hypotensive activity of aqueous extract of Andrographis paniculata in rats[J]. Clinical&Experimental Pharmacology&Physiology,1996,23(8):675.
[5]杨超.黄芩苷对支气管哮喘的药效学及其对苦味受体作用机制研究[D].河北医科大学,2013.
[6]
[7]
[8]Zhang, M., et al.Tetramethylpyrazine promotes the proliferation and migration of brain endothelial cells[J]. Mol Med Rep, 2014,10(1):29-32.
[9]Chandrashekar,J.,etal.T2Rsfunctionasbittertastereceptors[J].Cell,2000,100(6):703-11.
[10]Levit, A., et al.The bitter pill:clinical drugs that activate the human bitter taste receptor TAS2R14[J]. Faseb j,2014,28(3):1181-97.
[11]Ji, M., et al. Identification of novel compounds for human bitter taste receptors[J].Chem Biol Drug Des, 2014,84(1):63-74.
[12]Meyerhof, W., et al.The molecular receptive ranges of human TAS2R bitter taste receptors[J]. Chem Senses, 2010,35(2):157-70.
[13]Jaggupilli, A., et al.Analysis of the expression of human bitter taste receptors in extraoral tissues[J]. Molecular&Cellular Biochemistry,2016,426(1):1-11.
[14]Behrens, M., et al.The human bitter taste receptor hTAS2R50 is activated by the two natural bitter terpenoids andrographolide and amarogentin[J]. J Agric Food Chem,2009,57(21):9860-6.
[15]Behrens, M., et al.Bitter substances from plants used in traditional Chinese medicine exert biased activation of human bitter taste receptors[J].Chem Biol Drug Des,2018,91(2):422-433.
[16]Yu, Y., et al.Berberine induces GLP-1 secretion through activation of bitter taste receptor pathways[J]. Biochemical Pharmacology,2015,97(2):173-177.
[17]Yue, X., et al.Berberine activates bitter taste responses of enteroendocrine STC-1 cells[J]. Molecular&Cellular Biochemistry,2018:1-12.
[18]Behrens, M., et al.Bitter substances from plants used in traditional Chinese medicine exert biased activation of human bitter taste receptors[J].Chemical Biology&Drug Design,2018. 91(2):422.
[19]Gu, Q.D., D.S. Joe, and C.A. Gilbert, Activation of bitter taste receptors in pulmonary nociceptors sensitizes TRPV1 channels through the PLC and PKC signaling pathway[J]. Am J Physiol Lung Cell Mol Physiol,2017,312(3):L326-l333.
[20]Liu, S., et al.Members of Bitter Taste Receptor Cluster Tas2r143/Tas2r135/Tas2r126 Are Expressed in the Epithelium of Murine Airways and Other Non-gustatory Tissues[J].Front Physiol,2017,8:849.
[21]Kim, D., et al.Coupling of Airway Smooth Muscle Bitter Taste Receptors to Intracellular Signaling and Relaxation Is via Galphai1,2,3[J]. Am J Respir Cell Mol Biol,2017,56(6):762-771.
[22]Prandi, S., et al. Expression profiling of Tas2r genes reveals a complex pattern along the mouse GI tract and the presence of Tas2r131 in a subset of intestinal Paneth cells[J]. Cell Mol Life Sci,2018,75(1):49-65.
[23]Yamaki, M., et al.Genotyping Analysis of Bitter-Taste Receptor Genes TAS2R38 and TAS2R46 in Japanese Patients with Gastrointestinal Cancers[J]. J Nutr Sci Vitaminol(Tokyo), 2017,63(2):148-154.
[24]Chen, J.G., et al. The expression of bitter taste receptors in mesenteric,cerebral and omental arteries. Life Sci, 2017,170:16-24.
[25]Zheng, K., et al. Bitter taste receptors as targets for tocolytics in preterm labor therapy[J]. Faseb j, 2017,31(9):4037-4052.
[26]Wolfle, U., et al. Expression and Functional Activity of the Human Bitter Taste Receptor TAS2R38 in Human Placental Tissues and JEG-3 Cells[J].Molecules, 2016,21(3):306.
[27]Xu, J., et al. Functional characterization of bitter-taste receptors expressed in mammalian testis[J]. Mol Hum Reprod,2013,19(1):17-28.
[28]Foster, S.R., et al. Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart[J]. PLoS One,2013,8(5):e64579.
[29]Foster, S.R., et al.Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart[J]. FASEB J, 2014,28(10):4497-508.
[30]Foster,S.R.,etal.BittertastereceptoragonistselicitG-proteindependentnegativeinotropyinthemurineheart[J].Faseb Journal,2014,28(10):4497-4508.
[31]Foster, S.R., et al.Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation[J].Naunyn-Schmiedeberg’s archives of pharmacology,2015,388(10):1009.
[32]Chen, J.G., et al.The expression of bitter taste receptors in mesenteric,cerebral and omental arteries[J]. Life Sciences,2017,170:16-24.
[33]Manson, M.L., et al.Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle[J]. European Journal of Pharmac ology,2014,740(6):302-311.