How Does Immunomodulatory Nanoceria Work? ROS and Immunometabolism

Immunemetabolism; Metabolism; NanoceriaInmunometabolismo; Metabolismo; NanoceriaImmunemetabolisme; Metabolisme; NanocèriaDysregulation of the immune system is associated with an overproduction of metabolic reactive oxygen species (ROS) and consequent oxidative stress. By buffering excess ROS, cerium oxide (CeO2) nanoparticles (NPs) (nanoceria) not only protect from oxidative stress consequence of inflammation but also modulate the immune response towards inflammation resolution. Immunomodulation is the modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and it is part of immunotherapy, in which immune responses are induced, amplified, attenuated, or prevented according to therapeutic goals. For decades, it has been observed that immune cells transform from relative metabolic quiescence to a highly active metabolic state during activation(1). These changes in metabolism affect fate and function over a broad range of timescales and cell types, always correlated to metabolic changes closely associated with mitochondria number and morphology. The question is how to control the immunochemical potential, thereby regulating the immune response, by administering cellular power supply. In this regard, immune cells show different general catabolic modes relative to their activation status, linked to their specific functions (maintenance, scavenging, defense, resolution, and repair) that can be correlated to different ROS requirements and production. Properly formulated, nanoceria is highly soluble, safe, and potentially biodegradable, and it may overcome current antioxidant substances limitations and thus open a new era for human health management

The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective

Inflamació; Immunitat innata; NanopartículesInflamación; Inmunidad innata; NanopartículasInflammation; Innate immunity; NanoparticlesThe immune system contributes to maintaining the body’s functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.This research was funded by the EU Commission H2020 project PANDORA (GA 671881; to D.B., P.I. and V.P.). Additional funds were provided by the EU Commission H2020 project ENDONANO (GA 812661; to P.I. and D.B.), the Italian MIUR InterOmics Flagship projects MEMORAT and MAME (to D.B. and P.I.), the Italian MIUR/PRIN-20173ZECCM (to P.I.), the CAS President’s International Fellowship Programme (PIFI; award 2020VBA0028; to D.B.), Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER, UE), and Generalitat de Catalunya (2017-SGR-1431) (V.P.)

Nanoceria dissolution at acidic pH by breaking off the catalytic loop

Nanoceria; Cerium oxide nanoparticlesNanoceria; Nanopartículas de óxido de cerioNanoceria; Nanopartícules d'òxid de ceriThis manuscript proves the reproducibility and robustness of cerium oxide nanoparticles, nanoceria, employed as a chemical reagent with oxidizing capacity (as an electron sink) at acidic pH. Unlike nanoceria multi-enzyme-mimetic capabilities at neutral or high pH, nanoceria can behave as a stoichiometric reagent at low pH where insoluble Ce4+ ions transform into soluble Ce3+ in the nanocrystal that finally dissolves. This behaviour can be interpreted as enzyme-like when nanoceria is in excess with respect to the substrate. Under these conditions, the Ce3+/Ce4+ ratio in the NPs can easily be estimated by titration with ferrocyanide. This procedure could become a rapid assessment tool for evaluating nanoceria capacity in liquid environments.N. Sabaté would like to acknowledge the financial support received from ERC Consolidator Grant (SUPERCELL – GA.648518). N. G. B and V. P. acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) (RTI2018-099965-B-I00, AEI/FEDER,UE) proyectos de I + D + i de programación conjunta internacional MCIN/AEI (CONCORD, PCI2019-103436) cofunded by the European Union and Generalitat de Catalunya (2017-SGR-1431). ICN2 is supported by the Severo Ochoa program from Spanish MINECO (SEV-2017-0706) and is funded by the CERCA Programme/Generalitat de Catalunya. Dmitry Galyamin thanks the doctoral program “Electroquímica. Ciència i Tecnologia” of the Universitat Autònoma de Barcelona (UAB)

FGF23: Possible kidney clearance role and time-course of the effects in phosphate homeostasis

Curs 2015-2016Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates renal phosphate reabsorption by decreasing the expression of NaPi-IIa cotransporter in the brush border membrane (BBM) of renal proximal tubules, taking part in a hormonal axis which include vitamin D and parathyroid hormone (PTH) to maintain phosphate and calcium homeostasis. Several studies demonstrated a significant increase in plasma FGF23 levels in diseases which involve kidney failure or in renal nephrectomy, indicating a key role of the kidney in direct or indirect FGF23 clearance. Here we try to demonstrate: 1) if the kidney can directly clear FGF23 and 2) the time-course of the FGF23 effect in phosphate handling. For the first goal, we injected recombinant human FGF23 (rhFGF23) in normal rats and analyzed by immunofluorescence techniques whether we could detect it in kidney: no FGF23 was detected in renal cells, neither at 2 nor at 12 hours post administration probably at least in part of technical issues. For the second objective, blood, urine and kidneys were collected at several intervals after rhFGF23 administration. rhFGF23 showed a peak in plasma 2 h after injection, decreasing to less than a half after 6 h and to almost background levels after18 h. rhFGF23 was not detected in urine at any time point. After 6 h of FGF23 injection a decrease in NaPi-IIa (mRNA and protein) was observed in the kidney, in parallel with an enhanced urinary phosphate excretion. Although NaPi-IIa protein remained reduced 18 h post administration, its mRNA levels as well as urinary excretion of phosphate tended to return to their basal levels. No alterations in plasma phosphate levels were found in any of the groups. Furthermore, vitamin D receptor (VDR) protein expression was transiently decreased in the kidney, whereas no alterations in 24-hydroxylase (CYP24a1) were found. Measurements of FGF23 protein abundance in kidney were not valid, due to technical reasons. Thus, our findings are not conclusive regarding the possibility that FGF23 is filtered in the kidney and excreted in the urine. On the other hand, they indicate that the major action of FGF23 on phosphate excretion and NaPi-IIa expression takes place 6 h after injection, with urinary phosphate but not NaPi-IIa recovering to basal levels after 18 h