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新型锌金属有机化合物对脂肪生成信号的胰岛素样活性评价。

Evaluation of Insulin-Like Activity of Novel Zinc Metal-Organics toward Adipogenesis Signaling.

机构信息

Laboratory of Inorganic Chemistry and Advanced Materials, School of Chemical Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.

Center for Research of the Structure of Matter, Magnetic Resonance Laboratory, School of Chemical Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.

出版信息

Int J Mol Sci. 2021 Jun 23;22(13):6757. doi: 10.3390/ijms22136757.

Abstract

Diabetes mellitus is a debilitating disease, plaguing a significant number of people around the globe. Attempts to develop new drugs on well-defined atoxic metalloforms, which are capable of influencing fundamental cellular processes overcoming insulin resistance, has triggered an upsurge in molecular research linked to zinc metallodrugs. To that end, meticulous efforts were launched toward the design and synthesis of materials with insulin mimetic potential. Henceforth, trigonelline and N-(2-hydroxyethyl)-iminodiacetic acid (HEIDAH) were selected as organic substrates seeking binding to zinc (Zn(II)), with new crystalline compounds characterized by elemental analysis, FT-IR, X-rays, thermogravimetry (TGA), luminescence, NMR, and ESI-MS spectrometry. Physicochemical characterization was followed by in vitro biochemical experiments, in which three out of the five zinc compounds emerged as atoxic, exhibiting bio-activity profiles reflecting enhanced adipogenic potential. Concurrently, well-defined qualitative-quantitative experiments provided links to genetic loci responsible for the observed effects, thereby unraveling their key involvement in signaling pathways in adipocyte tissue and insulin mimetic behavior. The collective results (a) signify the quintessential role of molecular studies in unearthing unknown facets of pathophysiological events in diabetes mellitus II, (b) reflect the close associations of properly configured molecular zincoforms to well-defined biological profiles, and (c) set the stage for further physicochemical-based development of efficient zinc antidiabetic metallodrugs.

摘要

糖尿病是一种使人虚弱的疾病,困扰着全球大量的人。为了开发能够影响胰岛素抵抗的基本细胞过程的新型无毒金属配合物药物,人们对与锌金属药物相关的分子研究产生了浓厚的兴趣。为此,人们精心设计和合成了具有胰岛素模拟潜力的材料。此后,选用瓜氨酸和 N-(2-羟乙基)亚氨基二乙酸(HEIDAH)作为与锌(Zn(II))结合的有机底物,通过元素分析、傅里叶变换红外光谱(FT-IR)、X 射线、热重分析(TGA)、发光、核磁共振(NMR)和电喷雾质谱(ESI-MS)对新的结晶化合物进行了表征。在进行物理化学特性表征之后,进行了体外生化实验,其中五种锌化合物中的三种被证明是无毒的,具有增强的脂肪生成潜力的生物活性谱。同时,明确的定性定量实验提供了与观察到的效应相关的遗传基因座之间的联系,从而揭示了它们在脂肪细胞组织中的信号通路和胰岛素模拟行为中的关键作用。总的来说,(a)这些结果表明分子研究在揭示 II 型糖尿病中病理生理事件的未知方面具有重要作用,(b)反映了适当配置的分子锌配合物与明确的生物学谱之间的密切关联,(c)为进一步基于物理化学的高效锌抗糖尿病金属药物的开发奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72a/8268141/eaca52357ed0/ijms-22-06757-sch001.jpg

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