title: Screening and identification of Caulis Sinomenii bioactive ingredients with dual-target NF-κB inhibition and β2-AR agonizing activities.
abstract: Caulis Sinomenii (CS) is a valuable traditional medicine in China. Its extract can act as an anti-inflammatory agent and a vascular smooth muscle relaxant. However, the underlying mechanisms remain unknown. In this study, we developed a simple dual-target method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-target bioactive screening assay for anti-inflammatory and antispasmodic activities to characterize the chemical structure of various bioactive compounds of CS rapidly. Seven potential NF-κB inhibitors were identified, including laudanosoline-1-O-xylopyranose, 6-O-methyl-laudanosoline-1-O-glucopyranoside, menisperine, sinomenine, laurifoline, magnoflorine and norsinoacutin. Furthermore, IL-6 and IL-8 assays confirmed the anti-inflammatory effects of these potential NF-κB inhibitors, in which laudanosoline-1-O-d-xylopyranose and menisperine were revealed as novel NF-κB inhibitors. Among the seven identified alkaloids, three potential β2-adrenergic receptor agonists, including sinomenine, magnoflorine and laurifoline, were characterized using a luciferase reporter system to measure for the activity of β2-adrenergic receptor agonists. Finally, sinomenine, magnoflorine and laurifoline were identified not only as potential NF-κB inhibitors but also as potential β2-adrenegic receptor agonists, which is the first time this has been reported. Molecular dynamic simulation and docking results suggest that the three dual-bioactive constituents could not only inhibit Pseudomonas aeruginosa PAK strain-induced inflammatory responses via a negative regulation of the Braf protein that participates in MAPK signaling pathway but also activate the β2-adrenegic receptor. These results suggest that CS extract has dual signaling activities with potential clinical application as a novel drug for asthma.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Traditional Chinese Medicine, Tianjin Institute of Pharmaceutical Research Co. Ltd, Tianjin, People's Republic of China.
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
authors.forename: Zengyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
authors.forename: Xiaoyao
authors.initials: X
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, People's Republic of China. houyy@nankai.edu.cn.|Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China. houyy@nankai.edu.cn.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, People's Republic of China.|Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Bai
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D013058:Mass Spectrometry; D008813:Mice, Inbred ICR; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009465:Neuromuscular Agents / Q000737:chemistry / Q000494:pharmacology; D010276:Parasympatholytics / Q000737:chemistry* / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D032841:Sinomenium / Q000737:chemistry*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D009465:Neuromuscular Agents; D010276:Parasympatholytics
keywords: Braf protein; Caulis Sinomenii; MAPK signaling pathway; anti-inflammation; antispasmodic; β2-adrenegic receptor agonist