Fröjdö Sara, Durand Christine, Pirola Luciano
INSERM, U870, IFR62, Lyon, France.
Curr Aging Sci. 2008 Dec;1(3):145-51. doi: 10.2174/1874609810801030145.
Resveratrol, a polyphenol found in several vegetal sources, has been shown to possess lifespan-promoting properties in yeast and metazoans, including small mammals. While in yeast and low metazoans resveratrol acts mainly by activating the histone deacetylase Sir2, in mammals it appears to target - besides the Sir2 homolog SIRT1 - several crucial pathways for the control of metabolism, including the AMPK and the insulin-IGF1 receptors axis. The action of resveratrol on these pathways has been linked to its capability to i) prolong lifespan following chronic administration to mice and ii) protect from the development of diet-induced obesity and obesity-dependent metabolic disorders. Here we summarise the current understanding on how resveratrol displays its remarkable properties by acting on the control of insulin secretion and by modulation of insulin action in pheripheral insulin-responsive tissues. Since resveratrol has the potential for pharmacological exploitation to prevent the establishment of insulin-resistance and thus postpone - or even prevent - the onset of type 2 diabetes, toxicologic and pharmacodynamics studies in humans have been initiated. These studies show that resveratrol is non-toxic and easily absorbed by humans. As a drawback, its bioavailability is very limited due to the fast metabolic alterations to which it is subjected in the plasma. Therefore, we also review here the efforts that have been made - in the drug discovery field - to identify new molecules endowed with resveratrol-like pharmacological properties but with better bioavailability, which could prove to possess therapeutic potential.
白藜芦醇是一种存在于多种植物中的多酚，已被证明在酵母和后生动物（包括小型哺乳动物）中具有延长寿命的特性。在酵母和低等后生动物中，白藜芦醇主要通过激活组蛋白脱乙酰酶Sir2发挥作用，而在哺乳动物中，除了Sir2同源物SIRT1外，它似乎还靶向控制新陈代谢的几个关键途径，包括AMPK和胰岛素 - IGF1受体轴。白藜芦醇对这些途径的作用与其以下能力有关：i）长期给小鼠服用后可延长寿命；ii）预防饮食诱导的肥胖症及肥胖相关代谢紊乱的发生。在此，我们总结了目前对于白藜芦醇如何通过控制胰岛素分泌以及调节外周胰岛素反应性组织中的胰岛素作用来展现其显著特性的理解。由于白藜芦醇具有进行药物开发以预防胰岛素抵抗的建立从而推迟甚至预防2型糖尿病发病的潜力，因此已经启动了人体毒理学和药效学研究。这些研究表明，白藜芦醇对人体无毒且易于吸收。然而，其生物利用度非常有限，因为它在血浆中会迅速发生代谢变化。因此，我们在此还回顾了在药物研发领域为鉴定具有白藜芦醇样药理特性但生物利用度更好的新分子所做的努力，这些新分子可能具有治疗潜力。
