未经证实:糖尿病是世界范围内主要的代谢疾病之一。尽管是一个复杂的系统病理学,胰岛淀粉样多肽(IAPP)的聚集和沉积,或者胰淀素,是该疾病公认的组织病理学标志物。尽管IAPP蛋白毒性是β细胞功能障碍和最终死亡的重要触发因素,它作为治疗工具的开发仍然不发达。(多)酚对抑制病理性蛋白质聚集的生物活性是众所周知的,然而,大多数已鉴定的分子具有有限的生物利用度。
未经评估:使用计算机组合策略,无细胞和细胞研究,我们仔细检查了一个独特的内部收集的(多)酚代谢产物,预测在(多)酚摄入后会出现在人体循环中。
UASSIGNED:我们确定尿石素B是IAPP聚集的有效抑制剂和细胞稳态途径的有效调节剂。显示尿蛋白B影响IAPP聚集模式,延缓淀粉样纤维的形成并改变其大小和形态。尿石素B介导的保护作用的分子机制包括蛋白质清除途径,线粒体功能,和细胞周期最终挽救IAPP介导的细胞功能障碍和死亡。
未经评估:简而言之,我们的研究发现尿石素B是一种靶向IAPP病理聚集的新型小分子,有可能被用作减轻糖尿病细胞功能障碍的治疗工具.膳食鞣花酸在人体内的结肠代谢,尿石素B的生物活性有潜力在营养领域被探索,营养食品,和药理学观点。
Diabetes is one of the major metabolic diseases worldwide. Despite being a complex systemic pathology, the aggregation and deposition of Islet Amyloid Polypeptide (
IAPP), or amylin, is a recognized histopathological marker of the disease. Although
IAPP proteotoxicity represents an important trigger of β-cell dysfunction and ultimately death, its exploitation as a therapeutic tool remains underdeveloped. The bioactivity of (poly)phenols towards inhibition of pathological protein aggregation is well known, however, most of the identified molecules have limited bioavailability.
Using a strategy combining in silico, cell-free and cell studies, we scrutinized a unique in-house collection of (poly)phenol metabolites predicted to appear in the human circulation after (poly)phenols ingestion.
We identified urolithin B as a potent inhibitor of
IAPP aggregation and a powerful modulator of cell homeostasis pathways. Urolithin B was shown to affect
IAPP aggregation pattern, delaying the formation of amyloid fibrils and altering their size and morphology. The molecular mechanisms underlying urolithin B-mediated protection include protein clearance pathways, mitochondrial function, and cell cycle ultimately rescuing IAPP-mediated cell dysfunction and death.
In brief, our study uncovered urolithin B as a novel small molecule targeting
IAPP pathological aggregation with potential to be exploited as a therapeutic tool for mitigating cellular dysfunction in diabetes. Resulting from the colonic metabolism of dietary ellagic acid in the human body, urolithin B bioactivity has the potential to be explored in nutritional, nutraceutical, and pharmacological perspectives.