nature-medicine201212-12

来自印第安纳大学的科学家发现了将两种激素分子结合起来治疗疾病的新方法,这将为治疗肥胖及相关疾病的疗法的开发提供帮助。

-2012年12月《自然-医学》


中文翻译


【题目】靶向雌激素的分泌逆转了代谢综合症

【译文】我们报道了可实现多肽介导的核荷尔蒙药理学的选择性组织靶向而在其他组织中清除副作用的新组合方法的开发。尤其是,我们报道了胰高血糖素样肽-1(GLP-1)-雌激素结合的开发,这比单个雌激素具有出众的性别非依赖效能以纠正小鼠肥胖、高血糖症和血脂障碍。 这种治疗效应是通过多效双重荷尔蒙行为驱动以改善能量、葡萄糖和脂类代谢的,正如通过功能丧失性模型和遗传作用分析的那样。值得注意的是,基于多肽的靶向策略也阻止雄性和雌性小鼠中雌激素的标志副作用的发生,例如生殖内分泌毒性和致癌性。总之,GLP-1靶向的组织中雌激素受体的选择性活化产生史无前例的效应以增强GLP-1激动剂的代谢效用。靶向代谢综合症的例子揭示一种新疗法,这种方法通过基于小分子的肽选择性传输实现协同共激动。尽管我们在对糖尿病和肥胖症GLP-1-雌激素结合证实翻译研究中的观察,但多数多肽和小分子其他的可能组合可能为其他疾病提供了同样的希望。

英文原稿


[Title]: Targeted estrogen delivery reverses the metabolic syndrome

[Authors]:Brian Finan,1, 2, 3 Bin Yang,3 Nickki Ottaway,4 Kerstin Stemmer,1, 2 Timo D Müller,1, 2 Chun-Xia Yi,1, 2 Kirk Habegger,4 Sonja C Schriever,1, 2 Cristina García-Cáceres,1, 2 Dhiraj G Kabra,1, 2 Jazzminn Hembree,4 Jenna Holland,4 Christine Raver,4 Randy J Seeley,4 Wolfgang Hans,5 Martin Irmler,5 Johannes Beckers,5, 6 Martin Hrabě de Angelis,5, 6 Joseph P Tiano,7 Franck Mauvais-Jarvis,7 Diego Perez-Tilve,4 Paul Pfluger,1, 2, 4 Lianshan Zhang,8 Vasily Gelfanov,3 Richard D DiMarchi3 & Matthias H Tschöp1, 2, 4 et al.

[Abstract]We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.

原文地址

http://www.nature.com/nm/journal/v18/n12/abs/nm.3009.html

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