title: Active components of ginger potentiate β-agonist-induced relaxation of airway smooth muscle by modulating cytoskeletal regulatory proteins.
abstract: β-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate β-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with β-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 μM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C β enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C β activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate β-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with β-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.
authors: 1 Department of Anesthesiology, Columbia University, New York, New York; and.
authors: Elizabeth A
authors: EA
authors: Townsend
authors: Yi
authors: Y
authors: Zhang
authors: Carrie
authors: C
authors: Xu
authors: Ryo
authors: R
authors: Wakita
authors: Charles W
authors: CW
authors: Emala
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology; D002460:Cell Line; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005233:Fatty Alcohols / Q000494:pharmacology; D020939:Zingiber officinale / Q000737:chemistry*; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors / Q000378:metabolism; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D002396:Catechols; D003598:Cytoskeletal Proteins; D005233:Fatty Alcohols; D050886:HSP20 Heat-Shock Proteins; C494382:HSPB6 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D018994:Myosin Light Chains; C107507:PPP1R14A protein, human; D010716:Phosphatidylinositols; D010936:Plant Extracts; D015221:Potassium Channels; C066737:RHOA protein, human; C040115:shogaol; C007845:gingerol; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D054799:Phospholipase C beta; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; D020742:rhoA GTP-Binding Protein; C534464:8-gingerol
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