Departamento de Química Inorgánica, Orgánica y Bioquímica, CRIB, Universidad de Castilla-La Mancha, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Ciencias y Tecnologías Químicas, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain.
Departamento de Química Inorgánica, Orgánica y Bioquímica, CRIB, Universidad de Castilla-La Mancha, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Ciencias y Tecnologías Químicas, Avenida Camilo José Cela 10, 13071, Ciudad Real, Spain; Facultad de Medicina de Ciudad Real, Camino Moledores s/n, 13071, Ciudad Real, Spain.
Free Radic Biol Med. 2019 May 1;135:261-273. doi: 10.1016/j.freeradbiomed.2019.03.019. Epub 2019 Mar 18.
Resveratrol (RSV) is a natural polyphenolic antioxidant with a proven protective role in several human diseases involving oxidative stress, although the molecular mechanism underlying this effect remains unclear. The present work tried to elucidate the molecular mechanism of RSV's role on signal transduction modulation. Our biochemical analysis, including radioligand binding, real time PCR, western blotting and adenylyl cyclase activity, and computational studies provide insights into the RSV binding pathway, kinetics and the most favored binding pose involving adenosine receptors, mainly A subtype. In this study, we show that RSV target adenosine receptors (AdoRs), affecting gene expression, receptor levels, and the downstream adenylyl cyclase (AC)/PKA pathway. Our data demonstrate that RSV activates AdoRs. Moreover, RSV activate A receptors by directly binding to the classical orthosteric binding site. Intriguingly, RSV-induced receptor activation can stimulate or inhibit AC activity depending on concentration and exposure time. Such subtle and multifaceted regulation of the AdoRs/AC/PKA pathway might contribute to the protective role of RSV. Our findings suggest that RSV molecular action is mediated, at least in part, by activation of adenosine receptors and create the opportunity to interrogate the therapeutic use of RSV in pathological conditions involving AdoRs, such as Alzheimer.
白藜芦醇（RSV）是一种天然多酚抗氧化剂，已被证明在涉及氧化应激的多种人类疾病中具有保护作用，尽管其作用的分子机制尚不清楚。本研究试图阐明 RSV 对信号转导调节作用的分子机制。我们的生化分析，包括放射性配体结合、实时 PCR、western blot 和腺苷酸环化酶活性以及计算研究，深入了解了 RSV 与涉及腺苷受体（主要是 A 亚型）的结合途径、动力学和最有利的结合构象。在这项研究中，我们表明 RSV 靶向腺苷受体（AdoRs），影响基因表达、受体水平以及下游的腺苷酸环化酶（AC）/蛋白激酶 A（PKA）途径。我们的数据表明 RSV 激活了 AdoRs。此外，RSV 通过直接与经典的正位结合位点结合来激活 A 受体。有趣的是，RSV 诱导的受体激活可以根据浓度和暴露时间刺激或抑制 AC 活性。AdoRs/AC/PKA 途径的这种微妙和多方面的调节可能有助于 RSV 的保护作用。我们的研究结果表明，RSV 的分子作用至少部分是通过激活腺苷受体介导的，并为在涉及 AdoRs 的病理情况下（如阿尔茨海默病）探索 RSV 的治疗用途提供了机会。
