Searching for synergistic bronchodilators and novel therapeutic regimens for chronic lung diseases from a traditional Chinese medicine, Qingfei Xiaoyan Wan.
Classical Chinese pharmacopeias describe numerous excellent herbal formulations, and each prescription is an outstanding pool of effective compounds for drug discovery. Clarifying the bioactivity of the combined mechanisms of the ingredients in complex traditional Chinese medicine formulas is challenging. A classical formula known as Qingfei Xiaoyan Wan, used clinically as a treatment for prevalent chronic lung disease, was investigated in this work. A mutually enhanced bioactivity-guided ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) characterization system was proposed, coupled with a dual-luciferase reporter assay for β2AR-agonist cofactor screening. Arctiin, arctigenin, descurainoside and descurainolide B, four lignin compounds that showed synergistic bronchodilation effects with ephedrine, were revealed. The synergistic mechanism of arctigenin with the β2ARagonist involved with the reduction of free Ca2+ was clarified by a dual-luciferase reporter assay for intracellular calcium and the Ca2+ indicator fluo-4/AM to monitor changes in the fluorescence. The relaxant and contractile responses of airway smooth muscle are regulated by crosstalk between the intracellular cAMP and calcium signaling pathways. Our data indicated the non-selective βAR agonist ephedrine as the principal bronchodilator of the formula, whereas the lignin ingredients served as adjuvant ingredients. A greater understanding of the mechanisms governing the control of these pathways, based on conventional wisdom, could lead to the identification of novel therapeutic targets or new agents for the treatment of asthma and COPD.
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Yuanyuan
Y
Hou
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Binfeng
B
Cheng
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Mengge
M
Zhou
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Runping
R
Fang
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Min
M
Jiang
Tianjin Engineering Laboratory of Quality Control Techniques for TCM, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
Wenbin
W
Hou
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Gang
G
Bai
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D004195:Disease Models, Animal; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*; D004809:Ephedrine / Q000494:pharmacology / Q000627:therapeutic use; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D005663:Furans / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D005960:Glucosides / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006801:Humans; D007783:Lactones / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D017705:Lignans / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D008171:Lung Diseases / Q000188:drug therapy*; D008516:Medicine, Chinese Traditional; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D005663:Furans; D005960:Glucosides; D007783:Lactones; D017705:Lignans; C499869:descurainolide B; C505648:descurainoside B; D004809:Ephedrine; D002118:Calcium; C077992:arctiin; C071942:arctigenin