Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet needed for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the b-adrenergic (cyclic nucleotide PDEs) and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca²⁺]_i and inositol triphosphate (IP₃) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent re-contraction of ASM after b-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiologic activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

中文翻译：

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生姜代谢物和代谢物启发的合成产品调节细胞内钙和放松气道平滑肌

哮喘影响全世界数百万人，其患病率正在增加。它的特点是慢性气道炎症、气道重塑和病理性支气管收缩，并且由于很少有新疗法可用，它对持续的治疗提出了挑战。因此，许多哮喘患者转向以植物为基础的补充产品，包括生姜，以更好地控制症状，这表明新疗法的需求尚未得到满足。之前，我们证明了姜的主要生物活性成分 6-shogaol (6S) 可能通过抑制β-肾上腺素能（环核苷酸 PDE）和毒蕈碱（磷脂酶 C）中的磷酸二酯酶 (PDE) 来放松人气道平滑肌 (hASM)。 , PLC) 受体通路。然而，口服 6S 被广泛代谢，并且不知道由此产生的代谢物是否保持生物活性。在这里，我们筛选了 6S 的所有已知人类代谢物和几种基于代谢物的合成衍生物，以更好地了解它们的作用机制和结构-功能关系。我们证明了几种代谢物和基于代谢物的合成衍生物能够阻止 Gq 耦合刺激细胞内钙 [Ca²⁺ ] _i和肌醇三磷酸 (IP ₃ ) 通过抑制 PLC 合成，类似于母体化合物 6S。我们还表明，这些化合物可能通过抑制 PDE 来防止 b-激动剂松弛后 ASM 的再收缩。此外，它们增强了异丙肾上腺素诱导的松弛。重要的是，除了基于细胞的检测之外，代谢物还保留了在上（人）和下（鼠）气道中放松 Gq 耦合收缩的功能能力。目前的研究表明，虽然口服生姜可能代谢迅速，但它通过其代谢物保留了生理活性。此外，我们能够利用自然发生的代谢物作为灵感来开发针对支气管收缩性疾病的新疗法。