Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes,ACS Pharmacology & Translational Science

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Rosmarinic Acid Potently Detoxifies Amylin Amyloid and Ameliorates Diabetic Pathology in a Transgenic Rat Model of Type 2 Diabetes
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-07-21 , DOI: 10.1021/acsptsci.1c00028
Ling Wu _{1,

2} , Paul Velander ₁ , Anne M Brown _{1,

1} , Yao Wang ₁ , Dongmin Liu _{1,

1} , David R Bevan _{1,

1,

1} , Shijun Zhang ₃ , Bin Xu _{1,

1,

1,

2,

4}

Affiliation

Protein aggregation is associated with a large number of human protein-misfolding diseases, yet FDA-approved drugs are currently not available. Amylin amyloid and plaque depositions in the pancreas are hallmark features of type 2 diabetes. Moreover, these amyloid deposits are implicated in the pathogenesis of diabetic complications such as neurodegeneration. We recently discovered that catechols and redox-related quinones/anthraquinones represent a broad class of protein aggregation inhibitors. Further screening of a targeted library of natural compounds in complementary medicine that were enriched with catechol-containing compounds identified rosmarinic acid (RA) as a potent inhibitor of amylin aggregation (estimated inhibitory concentration IC₅₀ = 200–300 nM). Structure–function relationship analysis of RA showed the additive effects of the two catechol-containing components of the RA molecule. We further showed that RA does not reverse fibrillation back to monomeric amylin but rather lead to nontoxic, remodeled protein aggregates. RA has significant ex vivo efficacy in reducing human amylin oligomer levels in HIP rat sera as well as in sera from diabetic patients. In vivo efficacy studies of RA treatment with the diabetic HIP rat model demonstrated significant reduction in amyloid islet deposition and strong mitigation of diabetic pathology. Our work provides new in vitro molecular mechanisms and in vivo efficacy insights for a model nutraceutical agent against type 2 diabetes and other aging-related protein-misfolding diseases.

中文翻译：

迷迭香酸可有效解毒胰淀素淀粉样蛋白并改善 2 型糖尿病转基因大鼠模型中的糖尿病病理学

蛋白质聚集与大量人类蛋白质错误折叠疾病有关，但目前尚无 FDA 批准的药物。胰岛淀粉样蛋白和斑块沉积在胰腺中是 2 型糖尿病的标志性特征。此外，这些淀粉样蛋白沉积物与神经变性等糖尿病并发症的发病机制有关。我们最近发现儿茶酚和氧化还原相关的醌/蒽醌代表了一类广泛的蛋白质聚集抑制剂。对补充医学中富含含儿茶酚化合物的天然化合物目标库进行进一步筛选，发现迷迭香酸 (RA) 是胰淀素聚集的有效抑制剂（估计抑制浓度 IC ₅₀ = 200–300 nM）。 RA 的结构-功能关系分析显示了 RA 分子中两种含儿茶酚成分的相加效应。我们进一步表明，RA 不会将纤维颤动逆转回单体胰淀素，而是导致无毒的重构蛋白质聚集体。 RA 在降低 HIP 大鼠血清以及糖尿病患者血清中的人胰岛淀粉样多肽寡聚物水平方面具有显着的离体功效。用糖尿病 HIP 大鼠模型进行 RA 治疗的体内疗效研究表明，淀粉样蛋白胰岛沉积显着减少，糖尿病病理得到强烈缓解。我们的工作为对抗 2 型糖尿病和其他与衰老相关的蛋白质错误折叠疾病的模型营养药物提供了新的体外分子机制和体内功效见解。

更新日期：2021-08-13

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