Battaglini Matteo, Carmignani Alessio, Martinelli Chiara, Colica Jamila, Marino Attilio, Doccini Stefano, Mollo Valentina, Santoro Francesca, Bartolucci Martina, Petretto Andrea, Santorelli Filippo Maria, Ciofani Gianni
Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy.
Sant'Anna School of Advanced Studies, The Biorobotics Institute, Viale Rinaldo Piaggio 34, 56025 Pontedera, Italy.
Biomater Sci. 2022 Jul 12;10(14):3770-3792. doi: 10.1039/d2bm00729k.
Reactive oxygen species (ROS) are active molecules involved in several biological functions. When the production of ROS is not counterbalanced by the action of protective antioxidant mechanisms present in living organisms, a condition of oxidative stress can arise with consequent damage to biological structures. The brain is one of the main ROS-generating organs in the human body, with the consequence that most of the neurological disorders are associated with an overproduction of ROS. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease associated with mutations in the sacsin gene (). At cellular level, ARSACS is characterized by mitochondrial impairments, a reduction in bioenergetic processes, and by both an over-production of and an over-sensitivity to ROS. Several antioxidant molecules have been proposed as a potential treatment for ARSACS, such as idebenone and resveratrol. Polydopamine nanoparticles (PDNPs) gained significant attention in recent years owing to their peculiar physical/chemical properties, and especially because of their antioxidant activity. PDNPs have shown a great ROS scavenging capacity that, combined with their completely organic nature that grants them the ability to be degraded and excreted by living organisms, make them a promising candidate in the treatment of oxidative stress-related disorders. In this work, we assessed the effect of PDNPs on human fibroblasts derived from ARSACS patients in terms of antioxidant properties and protein expression. PDNP interaction with fibroblasts was analyzed in terms of biocompatibility, internalization and uptake pathway, reduction of ROS levels, prevention of ROS-induced apoptosis/necrosis, and protective action upon ROS-induced mitochondrial dysfunctions. Moreover, a complete proteomic analysis was performed. Altogether, our data showed that PDNPs can partially counteract ROS-induced damages in ARSACS patient-derived fibroblasts, making them a potential therapeutic candidate to treat - or at least to ameliorate - the condition of oxidative stress associated with ARSACS.
活性氧（ROS）是参与多种生物学功能的活性分子。当活性氧的产生未被生物体中存在的保护性抗氧化机制的作用所抵消时，就会出现氧化应激状态，从而对生物结构造成损害。大脑是人体中主要产生活性氧的器官之一，因此大多数神经疾病都与活性氧的过量产生有关。常染色体隐性遗传性夏勒沃魁 - 萨格奈痉挛性共济失调（ARSACS）是一种与萨克斯因基因（）突变相关的神经退行性疾病。在细胞水平上，ARSACS的特征是线粒体损伤、生物能量过程减少，以及活性氧的过量产生和对其过度敏感。几种抗氧化分子已被提议作为ARSACS的潜在治疗方法，如艾地苯醌和白藜芦醇。聚多巴胺纳米颗粒（PDNPs）近年来因其独特的物理/化学性质，特别是因其抗氧化活性而备受关注。PDNPs已显示出强大的活性氧清除能力，再加上它们完全有机的性质使其能够被生物体降解和排泄，这使它们成为治疗氧化应激相关疾病的有希望的候选者。在这项工作中，我们从抗氧化特性和蛋白质表达方面评估了PDNPs对源自ARSACS患者的人成纤维细胞的影响。从生物相容性、内化和摄取途径、活性氧水平的降低、活性氧诱导的细胞凋亡/坏死的预防以及对活性氧诱导的线粒体功能障碍的保护作用等方面分析了PDNPs与成纤维细胞的相互作用。此外，还进行了完整的蛋白质组学分析。总之，我们的数据表明，PDNPs可以部分抵消活性氧对源自ARSACS患者的成纤维细胞造成的损伤，使其成为治疗——或至少改善——与ARSACS相关的氧化应激状况的潜在治疗候选者。
