Correia da Silva Daniela, Valentão Patrícia, Andrade Paula B, Pereira David M
REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Front Pharmacol. 2022 Jul 22;13:956154. doi: 10.3389/fphar.2022.956154. eCollection 2022.
The homeostasis of eukaryotic cells is inseverable of that of the endoplasmic reticulum (ER). The main function of this organelle is the synthesis and folding of a significant portion of cellular proteins, while it is also the major calcium reservoir of the cell. Upon unresolved ER stress, a set of stress response signaling pathways that are collectively labeled as the unfolded protein response (UPR) is activated. Prolonged or intense activation of this molecular machinery may be deleterious. It is known that compromised ER homeostasis, and consequent UPR activation, characterizes the pathogenesis of neurodegenerative diseases. In an effort to discover new small molecules capable of countering ER stress, we subjected a panel of over 100 natural molecules to a battery of assays designed to evaluate several hallmarks of ER stress. The protective potential of these compounds against ER stress was evaluated at the levels of calcium homeostasis, key gene and protein expression, and levels of protein aggregation in fibroblasts. The most promising compounds were subsequently tested in neuronal cells. This framework resulted in the identification of several bioactive molecules capable of countering ER stress and deleterious events associated to it. Delphinidin stands out as the most promising candidate against neurodegeneration. This compound significantly inhibited the expression of UPR biomarkers, and displayed a strong potential to inhibit protein aggregation in the two aforementioned cell models. Our results indicate that natural products may be a valuable resource in the development of an effective therapeutic strategy against ER stress-related diseases.
真核细胞的稳态与内质网（ER）的稳态密不可分。该细胞器的主要功能是合成和折叠细胞内相当一部分蛋白质，同时它也是细胞的主要钙库。当内质网应激得不到解决时，一组统称为未折叠蛋白反应（UPR）的应激反应信号通路就会被激活。这种分子机制的长期或强烈激活可能是有害的。已知内质网稳态受损以及随之而来的UPR激活是神经退行性疾病发病机制的特征。为了发现能够对抗内质网应激的新小分子，我们对100多种天然分子进行了一系列旨在评估内质网应激几个标志的检测。在成纤维细胞中，从钙稳态、关键基因和蛋白质表达以及蛋白质聚集水平等方面评估了这些化合物对抗内质网应激的保护潜力。随后在神经元细胞中测试了最有前景的化合物。这一框架导致鉴定出几种能够对抗内质网应激及其相关有害事件的生物活性分子。飞燕草素是对抗神经退行性变最有前景的候选物。该化合物显著抑制了UPR生物标志物的表达，并在上述两种细胞模型中显示出强大的抑制蛋白质聚集的潜力。我们的结果表明，天然产物可能是开发针对内质网应激相关疾病的有效治疗策略的宝贵资源。
