A Multi-Omics Approach to Evaluate the Toxicity Mechanisms Associated with Silver Nanoparticles Exposure

Silver nanoparticles (AgNPs) are currently used in many different industrial, commercial and health fields, mainly due to their antibacterial properties. Due to this widespread use, humans and the environment are increasingly exposed to these types of nanoparticles, which is the reason why the evaluation of the potential toxicity associated with AgNPs is of great importance. Although some of the toxic effects induced by AgNPs have already been shown, the elucidation of more complete mechanisms is yet to be achieved. In this sense, and since the integration of metabolomics and transcriptomics approaches constitutes a very useful strategy, in the present study targeted and untargeted metabolomics and DNA microarrays assays have been combined to evaluate the molecular mechanisms involved in the toxicity induced by 10 nm AgNPs. The results have shown that AgNPs induce the synthesis of glutathione as a cellular defense mechanism to face the oxidative environment, while inducing the depletion of relevant molecules implicated in the synthesis of important antioxidants. In addition, it has been observed that AgNPs completely impair the intracellular energetic metabolism, especially affecting the production of adenosine triphosphate (ATP) and disrupting the tricarboxylic acids cycle. It has been demonstrated that AgNPs exposure also affects the glycolysis pathway. The effect on such pathway differs depending on the step of the cycle, which a significant increase in the levels of glucose as way to counterbalance the depleted levels of ATP.Depto. de Química AnalíticaFac. de Ciencias QuímicasTRUEMinisterio de Ciencia, Innovaciónpu

Integrated transcriptomics and metabolomics analysis reveals the biomolecular mechanisms associated to the antitumoral potential of a novel silver‑based core@shell nanosystem

A combination of omics techniques (transcriptomics and metabolomics) has been used to elucidate the mechanisms responsible for the antitumor action of a nanosystem based on a Ag core coated with mesoporous silica on which transferrin has been anchored as a targeting ligand against tumor cells (Ag@MSNs-Tf). Transcriptomics analysis has been carried out by gene microarrays and RT-qPCR, while high-resolution mass spectrometry has been used for metabolomics. This multiomics strategy has enabled the discovery of the effect of this nanosystem on different key molecular pathways including the glycolysis, the pentose phosphate pathway, the oxidative phosphorylation and the synthesis of fatty acids, among others

Mechanistic insights into the antitumoral potential and in vivo antiproliferative efficacy of a silver-based core@shell nanosystem

This study delves into the biomolecular mechanisms underlying the antitumoral efficacy of a hybrid nanosystem, comprised of a silver core@shell (Ag@MSNs) functionalized with transferrin (Tf). Employing a SILAC proteomics strategy, we identified over 150 de-regulated proteins following exposure to the nanosystem. These proteins play pivotal roles in diverse cellular processes, including mitochondrial fission, calcium homeostasis, endoplasmic reticulum (ER) stress, oxidative stress response, migration, invasion, protein synthesis, RNA maturation, chemoresistance, and cellular proliferation. Rigorous validation of key findings substantiates that the nanosystem elicits its antitumoral effects by activating mitochondrial fission, leading to disruptions in calcium homeostasis, as corroborated by RT-qPCR and flow cytometry analyses. Additionally, induction of ER stress was validated through western blotting of ER stress markers. The cytotoxic action of the nanosystem was further affirmed through the generation of cytosolic and mitochondrial reactive oxygen species (ROS). Finally, in vivo experiments using a chicken embryo model not only confirmed the antitumoral capacity of the nanosystem, but also demonstrated its efficacy in reducing cellular proliferation. These comprehensive findings endorse the potential of the designed Ag@MSNs-Tf nanosystem as a roundbreaking chemotherapeutic agent, shedding light on its multifaceted mechanisms and in vivo applicability.Ministerio de Ciencia e InnovaciónEuropean Uniońs through ERC2015-AdG (VERDI) Proposal No. 694160Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu