Alteration of the Mitochondrial Effects of Ceria Nanoparticles by Gold: An Approach for the Mitochondrial Modulation of Cells Based on Nanomedicine

[EN] Ceria nanoparticles are cell compatible antioxidants whose activity can be enhanced by gold deposition and by surface functionalization with positive triphenylphosphonium units to selectively target the mitochondria. The antioxidant properties of these nanoparticles can serve as the basis of a new strategy for the treatment of several disorders exhibiting oxidative stress, such as cancer, diabetes or Alzheimer's disease. However, all of these pathologies require a specific antioxidant according with their mechanism to remove oxidant species excess in cells and diminish their effect on mitochondrial function. The mechanism through which ceria nanoparticles neutralize oxidative stress and their effect on mitochondrial function have not been characterized yet. In the present study, the mitochondria antioxidant effect of ceria and ceria-supported gold nanoparticles, with or without triphenylphosphonium functionalization, was assessed in HeLa cells. The effect caused by ceria nanoparticles on mitochondria function in terms of mitochondrial membrane potential (Delta Psi m), adenosine triphosphate (ATP) production, nuclear respiratory factor 1 (NRF1) and nuclear factor erythroid-2 like 1 (NFE2L1) was reversed by the presence of gold. Furthermore, this effect was enhanced when nanoparticles were functionalized with triphenylphosphonium. Our study illustrates how the mitochondrial antioxidant effect induced by ceria nanoparticles can be modulated by the presence of gold.This research was funded by Carlos III Health Institute and the European Regional Development Fund, grant number CP13/00252 and PI16/1083; the Catalonian Agency for Management of University and Research Grants, grant number 2017SGR1303; the Ministry of Education of the Valencian Regional Government, grant number PROMETEO/2019/027, The Foundation for the Promotion of Health and Biomedical Research of Valencia Region, grant number Nanobetes2.Gutiérrez-Carcedo, P.; Navalón Oltra, S.; Simó, R.; Setoain, X.; Aparicio-Gómez, C.; Abasolo, I.; Victor, VM.... (2020). Alteration of the Mitochondrial Effects of Ceria Nanoparticles by Gold: An Approach for the Mitochondrial Modulation of Cells Based on Nanomedicine. Nanomaterials. 10(4):1-16. https://doi.org/10.3390/nano10040744S11610

Correction: Assessment of gold nanoparticles on human peripheral blood cells by metabolic profiling with 1H-NMR spectroscopy, a novel translational approach on a patient-specific basis.

[This corrects the article DOI: 10.1371/journal.pone.0182985.]

Assessment of gold nanoparticles on human peripheral blood cells by metabolic profiling with ¹H-NMR spectroscopy, a novel translational approach on a patient-specific basis

<div><p>Human peripheral blood cells are relevant ex vivo models for characterizing diseases and evaluating the pharmacological effects of therapeutic interventions, as they provide a close reflection of an individual pathophysiological state. In this work, a new approach to evaluate the impact of nanoparticles on the three main fractions of human peripheral blood cells by nuclear magnetic resonance spectroscopy is shown. Thus, a comprehensive protocol has been set-up including the separation of blood cells, their <i>in vitro</i> treatment with nanoparticles and the extraction and characterization of metabolites by nuclear magnetic resonance. This method was applied to assess the effect of gold nanoparticles, either coated with chitosan or supported on ceria, on peripheral blood cells from healthy individuals. A clear antioxidant effect was observed for chitosan-coated gold nanoparticles by a significant increase in reduced glutathione, that was much less pronounced for gold-cerium nanoparticles. In addition, the analysis revealed significant alterations of several other pathways, which were stronger for gold-cerium nanoparticles. These results are in accordance with the toxicological data previously reported for these materials, confirming the value of the current methodology.</p></div

Parton Showers since LEP

We briefly discuss the development of Monte Carlo event generators over the lastfifteen years. During this period there has been a revolutionary transformationin the accuracy of these programs as matching to higher-multiplicity matrixelements and next-to-leading order calculations has become standard with thefirst next-to-next-to-leading order processes now available. Finally theprospects for future improvements are discussed. Monte Carlo Simulations at LEPMonte Carlo event generators came of age at LEP where for the first time acombination of better understanding of QCD and increased computing powerprovided simulated events which were in good quantitative agreement with theexperimental results. These simulations used: • a leading-order matrix elementfor e + e − → qq; • a parton shower simulation for the evolution from the hardscale of the partonic collision to the infrared cutoff including the correcttreatment of colour coherence; • hadronization using either the non-perturbativestring or cluster models. The main programs used by the end of the LEP programmewere PYTHIA 6[1] and HERWIG 6[2]. These simulations also included the matchingof the hardest gluon emission for processes with a single colour line, forexample e + e − → qq, Deep inelastic scattering and Drell-Yan, which effectivelygave for e + e − → qq, apart from the trivial normalisation by a K-factor anext-to-leading order (NLO) simulation of the hard process. * The alternativedipole shower of ARIADNE (together with the string hadronization model) oftenprovide the best agreement with the data [4]. From LEP to the LHC Starting inthe early 2000's there was a major programme to develop better Monte Carlosimulations in order to describe the data from the energy frontier hadroncolliders, first the Tevatron and now the LHC. This started with the developmentof the first viable approach allowing multiple hard emissions to be describedcorrectly at leading order together with a parton shower simulation of soft andcolinear radiation (CKKW)[5]. This was first used to describe the production offour jet events in e + e − collisions where it gave quantitative improvements.However the main success of the approach was in hadron-hadron collisions whereit allowed the accurate description of multiple jet production, for example inassociation with electroweak vector bosons, for the first time

¹H-NMR spectra of erythrocytes, PMNs and PBMCs.

<p>Polar (a) and non polar (b) ¹H-NMR metabolomic profiles of extracts of the main types of peripheral blood cells. Metabolite assignments are indicated with the following numbers: 1) 2-hydroxybutyrate, 2) leucine, 3) valine, 4) ethanol, 5) lactate, 6) 2-aminoisobutyrate, 7) alanine, 8) lysine, 9) acetate, 10) glutamate, 11) reduced glutathione (GSH), 12) oxidized glutathione (GSSG), 13) pyroglutamate, 14) pyruvate, 15) succinate, 16) glutamine, 17) creatine, 18) phosphocreatine, 19) malonate, 20) spermidine/spermine, 21) phosphocholine (PC), 22) glycerophosphocholine (GPC), 23) carnitine, 24) betaine, 25) taurine, 26) methanol, 27) proline, 28) glycine, 29) glycerol, 30) ascorbate, 31) guanidino/guanido acetate, 32) 6-phosphogluconate 33) glycolate, 34) phosphoethanolamine, 35) ATP, 37) AMP, 38) NAD+, 39) NADP+, 40) trehalose, 41) phosphoenolpyruvate, 42) UDP-glucose, 43) UDP-NAG, 43) NADH, 44) uracil/tryptophane, 45) GDP, 46) GTP, 47) NADPH, 48) CTP, 49) fumarate, 50) tyrosine, 51) histidine/histamine, 52) tryptophane, 53) phenylalanine, 54) guanosine, 55) xanthine, 56) guanine, 57) hypoxanthine, 58) CTP, 59) CDP, 60) ADP, 61) formate, 62) methionine, 63) aspartate, 64) malate, 65) glucose, 66) isoleucine, 67) acetoacetate, 68) methylacetoacetate, 69) sarcosine, 71) thymidine, 72) hydroquinone, 73) pyridoxamine, 74) 4-pyridoxate, 75) nicotinamide, 76) N-Methyl-a-aminoisobutyric acid, 80) cholesterol, 81) lipid CH₃-, 82) lipid -CH₂-, 83) fatty ester -CH₂CH₂COO-, 84) polyinsaturated fatty acids (PUFA), 85) monoinsaturated fatty acids (MUFA), 86) phosphatidylethanolamine, 87) phosphatidycholine, 88) acylglycerophosphoserine, 89) phospholipids, 90) TAG, 91) spingosine, 92) fatty ester—CH₂OCO-.</p

¹H NMR spectra of the aqueous extracts of RBCs, PMNs and PBMCs after treatment with nanoparticles.

<p>Changes observed in the metabolomic profile of the main peripheral blood cells after 3h of treatment with vehicle, AuChi and AuCeO₂ nanoparticles.</p

Significant changes in PBMCs.

<p>Significant changes in PBMCs.</p

A Translational In Vivo and In Vitro Metabolomic Study Reveals Altered Metabolic Pathways in Red Blood Cells of Type 2 Diabetes

Clinical parameters used in type 2 diabetes mellitus (T2D) diagnosis and monitoring such as glycosylated haemoglobin (HbA1c) are often unable to capture important information related to diabetic control and chronic complications. In order to search for additional biomarkers, we performed a pilot study comparing T2D patients with healthy controls matched by age, gender, and weight. By using 1 H-nuclear magnetic resonance (NMR) based metabolomics profiling of red blood cells (RBCs), we found that the metabolic signature of RBCs in T2D subjects differed significantly from non-diabetic controls. Affected metabolites included glutathione, 2,3-bisphophoglycerate, inosinic acid, lactate, 6-phosphogluconate, creatine and adenosine triphosphate (ATP) and several amino acids such as leucine, glycine, alanine, lysine, aspartate, phenylalanine and tyrosine. These results were validated by an independent cohort of T2D and control patients. An analysis of the pathways in which these metabolites were involved showed that energetic and redox metabolism in RBCs were altered in T2D, as well as metabolites transported by RBCs. Taken together, our results revealed that the metabolic profile of RBCs can discriminate healthy controls from T2D patients. Further research is needed to determine whether metabolic fingerprint in RBC could be useful to complement the information obtained from HbA1c and glycemic variability as well as its potential role in the diabetes managemen

Glutamate interactions with obesity, insulin resistance, cognition and gut microbiota composition

[Aims]: To investigate the interactions among fecal and plasma glutamate levels, insulin resistance cognition and gut microbiota composition in obese and non-obese subjects.[Methods]: Gut microbiota composition (shotgun) and plasma and fecal glutamate, glutamine and acetate (NMR) were analyzed in a pilot study of obese and non-obese subjects (n = 35). Neuropsychological tests [Trail making test A (TMT-A) and Trail making test B (TMT-B)] scores measured cognitive information about processing speed, mental flexibility and executive function.[Results]: Trail-making test score was significantly altered in obese compared with non-obese subjects. Fecal glutamate and glutamate/glutamine ratio tended to be lower among obese subjects while fecal glutamate/acetate ratio was negatively associated with BMI and TMT-A scores. Plasma glutamate/acetate ratio was negatively associated with TMT-B. The relative abundance (RA) of some bacterial families influenced glutamate levels, given the positive association of fecal glutamate/glutamine ratio with Corynebacteriaceae, Coriobacteriaceae and Burkholderiaceae RA. In contrast, Streptococaceae RA, that was significantly higher in obese subjects, negatively correlated with fecal glutamate/glutamine ratio. To close the circle, Coriobacteriaceae/Streptococaceae ratio and Corynebacteriaceae/Streptococaceae ratio were associated both with TMT-A scores and fecal glutamate/glutamine ratio.[Conclusions]: Gut microbiota composition is associated with processing speed and mental flexibility in part through changes in fecal and plasma glutamate metabolism.This work was supported by FIS Grant (PI15/01934), FIS Grant (PI16/02064) from the National Institute of Health Carlos III and by ERDF (European Regional Development Fund).Peer reviewe