Effects of Monacolin K in Nondiabetic Patients with NAFLD: A Pilot Study

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver condition with significant risk of progression to steatohepatitis and cirrhosis. Therapeutic strategies in NAFLD include lifestyle changes mainly related to dietary interventions and use of drugs or nutritional components that could improve plasma lipid profiles and insulin sensitivity and decrease the local inflammatory response. In this study, we tested the effects of monacolin K, an inhibitor of HMCoA reductase. In a prospective, uncontrolled, open study, we treated 24 patients with NAFLD and mild hypercholesterolemia with 10 mg/day of monacolin K. At baseline and after 26 weeks, we measured in plasma liver tests, lipids, malondialdehyde, and oxidized glutathione, and assessed biochemical steatosis scores, liver elastography, and body composition with bioimpedance analysis. Monacolin K significantly reduced plasma alanine aminotransferase, cholesterol, triglycerides and the homeostatic model assessment (HOMA) index that indicated improved insulin sensitivity. No significant changes were found in body fat mass and visceral fat, nor in liver elastography, while the fatty liver index (FLI) was significantly decreased. Plasma levels of both malondialdehyde and oxidized glutathione were markedly reduced by monacolin K treatment, suggesting a reduction in oxidative stress and lipid peroxidation. In summary, this pilot study suggests possible benefits of monacolin K use in NAFLD patients that could be linked to a reduction in oxidative stress. This hypothesis should be further investigated in future studies

Control of bulk superconductivity via surface-bound electric fields in ion-gated niobium nitride thin films

Ionic gating is a very popular tool to investigate and control the electric transport and electronic ground state in a wide variety of different materials. This is due to its capability to induce large modulations of the surface charge density by means of the electric-double-layer field-effect transistor (EDL-FET) architecture, often reaching values comparable to those occurring in metallic systems. Despite finding large success in tuning the phase diagram of low-carrier density systems, including cuprates and iron-based superconductors, its applicability to conventional metallic superconductors has received significantly less attention. In my talk, I will present the work which has been carried out in my research group over several years to investigate how ionic gating can tune the properties of metallic superconductor, using niobium nitride (NbN) as an emblematic case. By fabricating EDL-FETs on NbN thin films with thickness ranging between 10 and 40 nm, we observed that small positive and negative shifts in the critical temperature Tc could be induced by changing the gate-voltage polarity, and that the magnitude of these shifts increased upon decreasing the film thickness. These findings indicated that, despite the gate-induced electric field being confined in a thin layer at the surface by electrostatic screening, the perturbation to the superconducting state extends in a region much larger than a single unit cell. Indeed, the dependence of Tc on the gate voltage and thickness could be reconciled with the Eliashberg theory of superconductivity only if this thin surface layer is coupled to the underlying, unperturbed bulk via proximity effect. We also determined that the thickness of this surface layer (i.e. the screening length of the electric field) strongly increases for large gate electric fields, reaching values of the order of 3 nm at the highest doping. Ab-initio DFT calculations reproduced these results and linked this anomalous increase of the screening length to a distortion of the pristine charge density in the material upon the application of sufficiently large electric fields. This proximity-effect-induced transformation of the quasi-2D perturbation to the electron density into a 3D bulk modification of the superconducting properties seems to be a general behavior in gated superconductors that could hinder the possibility to obtain large Tc shifts in films thicker than the screening length. Consequently, we are currently focusing on exploring the tunability of ultrathin (< 5nm-thick) NbN films in order to maximize the gate-induced Tc shift, where we developed a novel technique of self-encapsulation in ultrathin niobium oxide to ensure the full reversibility of the gate modulation in these extremely sensitive devices

SPR Biosensing MUA/Poly-L-lysine platform for the detection of 2,4-Dinitrophenol as small molecule model system

Surface Plasmon Resonance assays are being developed as alternative biodetection methods for a great number of pesticides and toxins.These substances typically have low molecular weight, making it necessary to perform competitive inhibition immunoassays. In most of the cases, the strategy is to immobilize a protein derivative of the analyte, which usually involves the appearance of nonspecific protein binding which limits the detection range of the assay. In this work we present results of a poly-L-lysine (Au-MUA-PLL) based sensor platform for quantitative determination of 2,4-dinitrophenol as model system for small molecular weight substances detection. The prepared sensor chip was characterized by means of Atomic Force Microscopy, Surface Plasmon Resonance, and Surface Enhanced Raman Spectroscopy. Experiments verified the absence of nonspecific protein adsorption to Au-MUA-PLL surfaces and the improvement of the competitive inhibition assays performance in comparison with single and mixed thiol self-assembled monolayers. The possibility of directly immobilizing 2,4-dinitrophenol to the poly-L-lysine containing platforms leads to an improvement in the detection of the soluble analyte by the competitive inhibition assay avoiding undesirable nonspecific protein adsorption.Therefore, Au-MUA-PLL surfaces constitute a suitable alternative for quantitative detection of small molecules when nonspecific adsorption cannot be avoided.Fil: Daza Millone, Maria Antonieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Ramirez, Eduardo A. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Chain, Cecilia Yamil. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Crivaro, Andrea. Universidad Nacional de la Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Romanin, David Emmanuel. Universidad Nacional de la Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rumbo, Martín. Universidad Nacional de la Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Docena, Guillermo H. Universidad Nacional de la Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cocco, Mauro D. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche, Instituto Balseiro; ArgentinaFil: Pedano, María Laura. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche, Instituto Balseiro; ArgentinaFil: Fainstein, Alejandro. Comisión Nacional de Energía Atómica. Centro Atomico Bariloche, Instituto Balseiro; ArgentinaFil: Montoya, Jorgelina Ceferina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Anguil; ArgentinaFil: Vela, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Salvarezza, Roberto Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentin

SPR Biosensing MUA/Poly-L-lysine Platform for the Detection of 2,4-Dinitrophenol as Small Molecule Model System

Surface Plasmon Resonance assays are being developed as alternative biodetection methods for a great number of pesticides and toxins. These substances typically have low molecular weight, making it necessary to perform competitive inhibition immunoassays. In most of the cases, the strategy is to immobilize a protein derivative of the analyte, which usually involves the appearance of nonspecific protein binding which limits the detection range of the assay. In this work we present results of a poly-L-lysine (Au-MUA-PLL) based sensor platform for quantitative determination of 2,4-dinitrophenol as model system for small molecular weight substances detection. The prepared sensor chip was characterized by means of Atomic Force Microscopy, Surface Plasmon Resonance, and Surface Enhanced Raman Spectroscopy. Experiments verified the absence of nonspecific protein adsorption to Au-MUA-PLL surfaces and the improvement of the competitive inhibition assays performance in comparison with single and mixed thiol self-assembled monolayers. The possibility of directly immobilizing 2,4-dinitrophenol to the poly-L-lysine containing platforms leads to an improvement in the detection of the soluble analyte by the competitive inhibition assay avoiding undesirable nonspecific protein adsorption. Therefore, Au-MUA-PLL surfaces constitute a suitable alternative for quantitative detection of small molecules when nonspecific adsorption cannot be avoided.Instituto de Investigaciones Fisicoquímicas Teóricas y AplicadasInstituto de Estudios Inmunológicos y FisiopatológicosFacultad de Ciencias Exacta

Local treatment with lactate prevents intestinal inflammation in the TNBS-induced colitis model

Lactate has long been considered as a metabolic by-product of cells. Recently, this view has been changed by the observation that lactate can act as a signaling molecule and regulates critical functions of the immune system. We previously identified lactate as the component responsible for the modulation of innate immune epithelial response of fermented milk supernatants in vitro. We have also shown that lactate downregulates proinflammatory responses of macrophages and dendritic cells. So far, in vivo effects of lactate on intestinal inflammation have not been reported. We evaluated the effect of intrarectal administration of lactate in a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The increase in lactate concentration in colon promoted protective effects against TNBS-induced colitis preventing histopathological damage, as well as bacterial translocation and rise of IL-6 levels in serum. Using intestinal epithelial reporter cells, we found that flagellin treatment induced reporter gene expression, which was abrogated by lactate treatment as well as by glycolysis inhibitors. Furthermore, lactate treatment modulated glucose uptake, indicating that high levels of extracellular lactate can impair metabolic reprograming induced by proinflammatory activation. These results suggest that lactate could be a potential beneficial microbiota metabolite and may constitute an overlooked effector with modulatory properties.Centro de Investigación y Desarrollo en Criotecnología de AlimentosInstituto de Estudios Inmunológicos y Fisiopatológico

Akt regulates L-type Ca2+ channel activity by modulating Cavα1 protein stability

The insulin IGF-1–PI3K–Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca2+ channel (LTCC) protein density. The pore-forming channel subunit Cavα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Cavα1 protein levels. Our findings show that Akt-dependent phosphorylation of Cavβ2, the LTCC chaperone for Cavα1, antagonizes Cavα1 protein degradation by preventing Cavα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myocyte Ca2+ entry, Ca2+ handling, and contractility

Single-channel properties of a stretch-sensitive chloride channel in the human mast cell line HMC-1

A stretch-activated (SA) Cl− channel in the plasma membrane of the human mast cell line HMC-1 was identified in outside-out patch-clamp experiments. SA currents, induced by pressure applied to the pipette, exhibited voltage dependence with strong outward rectification (55.1 pS at +100 mV and an about tenfold lower conductance at −100 mV). The probability of the SA channel being open (Po) also showed steep outward rectification and pressure dependence. The open-time distribution was fitted with three components with time constants of τ1o = 755.1 ms, τ2o = 166.4 ms, and τ3o = 16.5 ms at +60 mV. The closed-time distribution also required three components with time constants of τ1c = 661.6 ms, τ2c = 253.2 ms, and τ3c = 5.6 ms at +60 mV. Lowering extracellular Cl− concentration reduced the conductance, shifted the reversal potential toward chloride reversal potential, and decreased the Po at positive potentials. The SA Cl− currents were reversibly blocked by the chloride channel blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) but not by (Z)-1-(p-dimethylaminoethoxyphenyl)-1,2-diphenyl-1-butene (tamoxifen). Furthermore, in HMC-1 cells swelling due to osmotic stress, DIDS could inhibit the increase in intracellular [Ca2+] and degranulation. We conclude that in the HMC-1 cell line, the SA outward currents are mediated by Cl− influx. The SA Cl− channel might contribute to mast cell degranulation caused by mechanical stimuli or accelerate membrane fusion during the degranulation process

SPR Biosensing MUA/Poly-L-lysine Platform for the Detection of 2,4-Dinitrophenol as Small Molecule Model System

Surface Plasmon Resonance assays are being developed as alternative biodetection methods for a great number of pesticides and toxins. These substances typically have low molecular weight, making it necessary to perform competitive inhibition immunoassays. In most of the cases, the strategy is to immobilize a protein derivative of the analyte, which usually involves the appearance of nonspecific protein binding which limits the detection range of the assay. In this work we present results of a poly-L-lysine (Au-MUA-PLL) based sensor platform for quantitative determination of 2,4-dinitrophenol as model system for small molecular weight substances detection. The prepared sensor chip was characterized by means of Atomic Force Microscopy, Surface Plasmon Resonance, and Surface Enhanced Raman Spectroscopy. Experiments verified the absence of nonspecific protein adsorption to Au-MUA-PLL surfaces and the improvement of the competitive inhibition assays performance in comparison with single and mixed thiol self-assembled monolayers. The possibility of directly immobilizing 2,4-dinitrophenol to the poly-L-lysine containing platforms leads to an improvement in the detection of the soluble analyte by the competitive inhibition assay avoiding undesirable nonspecific protein adsorption. Therefore, Au-MUA-PLL surfaces constitute a suitable alternative for quantitative detection of small molecules when nonspecific adsorption cannot be avoided.Instituto de Investigaciones Fisicoquímicas Teóricas y AplicadasInstituto de Estudios Inmunológicos y FisiopatológicosFacultad de Ciencias Exacta

Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores ((Formula presented.) and (Formula presented.)). By applying a logistic regression with both IPGS, ((Formula presented.) (or indifferently (Formula presented.)) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%