Breder-Bonk Christina, Docter Dominic, Barz Matthias, Strieth Sebastian, Knauer Shirley K, Gül Désirée, Stauber Roland H
Molecular and Cellular Oncology, University Medical Center Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.
Leiden Academic Center for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Nanomaterials (Basel). 2023 Sep 12;13(18):2546. doi: 10.3390/nano13182546.
Exposure to nanoparticles is inevitable as they become widely used in industry, cosmetics, and foods. However, knowledge of their (patho)physiological effects on biological entry routes of the human body and their underlying molecular mechanisms is still fragmented. Here, we examined the molecular effects of amorphous silica nanoparticles (aSiNPs) on cell lines mimicking the alveolar-capillary barrier of the lung. After state-of-the-art characterization of the used aSiNPs and the cell model, we performed cell viability-based assays and a protein analysis to determine the aSiNP-induced cell toxicity and underlying signaling mechanisms. We revealed that aSiNPs induce apoptosis in a dose-, time-, and size-dependent manner. aSiNP-induced toxicity involves the inhibition of pro-survival pathways, such as PI3K/AKT and ERK signaling, correlating with reduced expression of the anti-apoptotic protein Survivin on the protein and transcriptional levels. Furthermore, induced Survivin overexpression mediated resistance against aSiNP-toxicity. Thus, we present the first experimental evidence suggesting Survivin as a critical cytoprotective resistor against silica-based nanotoxicity, which may also play a role in responses to other NPs. Although Survivin's relevance as a biomarker for nanotoxicity needs to be demonstrated in vivo, our data give general impetus to investigate the pharmacological modulation of Survivin`s functions to attenuate the harmful effects of acute or chronic inhalative NP exposure.
随着纳米颗粒在工业、化妆品和食品中的广泛应用，接触纳米颗粒已不可避免。然而，关于它们对人体生物进入途径的（病理）生理影响及其潜在分子机制的了解仍然支离破碎。在此，我们研究了无定形二氧化硅纳米颗粒（aSiNPs）对模拟肺肺泡 - 毛细血管屏障的细胞系的分子影响。在用最先进的技术对所用的aSiNPs和细胞模型进行表征后，我们进行了基于细胞活力的测定和蛋白质分析，以确定aSiNP诱导的细胞毒性和潜在的信号传导机制。我们发现aSiNPs以剂量、时间和大小依赖性方式诱导细胞凋亡。aSiNP诱导的毒性涉及抑制促生存途径，如PI3K/AKT和ERK信号传导，这与抗凋亡蛋白Survivin在蛋白质和转录水平上的表达降低相关。此外，诱导的Survivin过表达介导了对aSiNP毒性的抗性。因此，我们提供了首个实验证据，表明Survivin是针对基于二氧化硅的纳米毒性的关键细胞保护抵抗因子，它可能在对其他纳米颗粒的反应中也起作用。尽管Survivin作为纳米毒性生物标志物的相关性需要在体内得到证实，但我们的数据为研究Survivin功能的药理学调节以减轻急性或慢性吸入性纳米颗粒暴露的有害影响提供了总体动力。
