IL-1β Inhibition in Cardiovascular Complications Associated to Diabetes Mellitus

Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients

IL-1β inhibition in cardiovascular complications associated to diabetes mellitus

Diabetes mellitus (DM) is a chronic disease that affects nowadays millions of people worldwide. In adults, type 2 diabetes mellitus (T2DM) accounts for the majority of all diagnosed cases of diabetes. The course of the T2DM is characterized by insulin resistance and a progressive loss of β-cell mass. DM is associated with a number of related complications, among which cardiovascular complications and atherosclerosis are the main cause of morbidity and mortality in patients suffering from the disease. DM is acknowledged as a low-grade chronic inflammatory state characterized by the over-secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, which reinforce inflammatory signals thus contributing to the development of complications. In this context, the pharmacological approaches to treat diabetes should not only correct hyperglycaemia, but also attenuate inflammation and prevent the development of metabolic and cardiovascular complications. Over the last years, novel biological drugs have been developed to antagonize the pathophysiological actions of IL-1β. The drugs currently used in clinical practice are anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, the soluble decoy receptor rilonacept and the monoclonal antibodies canakinumab and gevokizumab. This review will summarize the main experimental and clinical findings obtained with pharmacological IL-1β inhibitors in the context of the cardiovascular complications of DM, and discuss the perspectives of IL-1β inhibitors as novel therapeutic tools for treating these patients.This work was supported by grants from Ministerio de Economía y Competitividad (SAF2014-52762-R) and Banco de Santander-Universidad Autónoma de Madrid (CEAL-AL/2015-17

The angiotensin-(1-7)/mas axis counteracts angiotensin II-dependent and -independent pro-inflammatory signaling in human vascular smooth muscle cells

Background and Aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7) is a member of the renin-angiotensin system (RAS) that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7) to counteract human aortic smooth muscle cell (HASMC) inflammation triggered by RAS-dependent and -independent stimuli, such as Ang II or interleukin (IL)-1β. Methods and Results: In cultured HASMC, the expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide were stimulated by both Ang II and IL-1β, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7) in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7), suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and nuclear factor (NF)-κB. Indeed, Ang-(1-7) markedly inhibited the activation of the NADPH oxidase and subsequently of NF-κB, as determined by lucigenin-derived chemiluminescence and electromobility shift assay, respectively. Conclusion: Ang-(1-7) can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7)/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.This work was funded by grants from Ministerio de Economía y Competitividad (SAF2014-52762-R

Postsynthetic Metalated MOFs as Atomically Dispersed Catalysts for Hydroformylation Reactions

A manganese-based metal-organic framework with dipyrazole ligands has been metalated with atomically dispersed Rh and Co species and used as a catalyst for the hydroformylation of styrene. The Rh-based materials exhibited excellent conversion at 80 °C with complete chemoselectivity, high selectivity for the branched aldehyde, high recyclability, and negligible metal leaching

Visfatin Impairs Endothelium-Dependent Relaxation in Rat and Human Mesenteric Microvessels through Nicotinamide Phosphoribosyltransferase Activity

Visfatin, also known as extracellular pre–B-cell colony–enhancing factor (PBEF) and nicotinamide phosphoribosyltransferase (Nampt), is an adipocytokine whose circulating levels are enhanced in metabolic disorders, such as type 2 diabetes mellitus and obesity. Circulating visfatin levels have been positively associated with vascular damage and endothelial dysfunction. Here, we investigated the ability of visfatin to directly impair vascular reactivity in mesenteric microvessels from both male Sprague-Dawley rats and patients undergoing non-urgent, non-septic abdominal surgery. The pre-incubation of rat microvessels with visfatin (50 and 100 ng/mL) did not modify the contractile response to noradrenaline (1 pmol/L to 30 µmol/L), as determined using a small vessel myograph. However, visfatin (10 to 100 ng/mL) concentration-dependently impaired the relaxation to acetylcholine (ACh; 100 pmol/L to 3 µmol/L), without interfering with the endothelium-independent relaxation to sodium nitroprusside (1 nmol/L to 3 µmol/L). In both cultured human umbilical vein endothelial cells and rat microvascular preparations, visfatin (50 ng/mL) stimulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, as determined by lucigenin-derived chemiluminiscence. The relaxation to ACh impaired by visfatin was restored by the NADPH oxidase inhibitor apocynin (10 µmol/L). Additionally, the Nampt inhibitor APO866 (10 mmol/L to 10 µmol/L), but not an insulin receptor-blocking antibody, also prevented the stimulation of NADPH oxidase and the relaxation impairment elicited by visfatin. Accordingly, the product of Nampt activity nicotinamide mononucleotide (100 nmol/L to 1 mmol/L) stimulated endothelial NADPH oxidase activity and concentration-dependently impaired ACh-induced vasorelaxation. In human mesenteric microvessels pre-contracted with 35 mmol/L potassium chloride, the endothelium-dependent vasodilation to bradykinin (1 nmol/L to 3 µmol/L) was equally impaired by visfatin and restored upon co-incubation with APO866. In conclusion, visfatin impairs endothelium-dependent relaxation through a mechanism involving NADPH oxidase stimulation and relying on Nampt enzymatic activity, and therefore arises as a potential new player in the development of endothelial dysfunction

Self-Assembly of Oriented Antibody-Decorated Metal–Organic Framework Nanocrystals for Active-Targeting Applications

Antibody (Ab)-targeted nanoparticles are becoming increasingly important for precision medicine. By controlling the Ab orientation, targeting properties can be enhanced; however, to afford such an ordered configuration, cumbersome chemical functionalization protocols are usually required. This aspect limits the progress of Abs-nanoparticles toward nanomedicine translation. Herein, a novel one-step synthesis of oriented monoclonal Ab-decorated metal–organic framework (MOF) nanocrystals is presented. The crystallization of a zinc-based MOF, Zn2(mIM)2(CO3), from a solution of Zn2+ and 2-methylimida-zole (mIM), is triggered by the fragment crystallizable (Fc) region of the Ab. This selective growth yields biocomposites with oriented Abs on the MOF nanocrystals (MOF*Ab): the Fc regions are partially inserted within the MOF surface and the antibody-binding regions protrude from the MOF surface toward the target. This ordered configuration imparts antibody–antigen rec-ognition properties to the biocomposite and shows preserved target binding when compared to the parental antibodies. Next, the biosensing performance of the system is tested by loading MOF*Ab with luminescent quantum dots (QD). The targeting efficiency of the QD-containing MOF*Ab is again, fully preserved. The present work represents a simple self-assembly approach for the fabrication of antibody-decorated MOF nanocrystals with broad potential for sensing, diagnostic imaging, and targeted drug delivery

Metallicities on the Double Main Sequence of omega Centauri Imply Large Helium Enhancement

Having shown in a recent paper that the main sequence of omega Centauri is split into two distinct branches, we now present spectroscopic results showing that the bluer sequence is_less_ metal-poor. We have carefully combined GIRAFFE@VLT spectra of 17 stars on each side of the split into a single spectrum for each branch, with adequate S/N to show clearly that the stars of the blue main sequence are less metal poor by 0.3 dex than those of the dominant red one. From an analysis of the individual spectra, we could not detect any abundance spread among the blue main sequence stars, while the red main sequence stars show a 0.2 dex spread in metallicity. We use stellar-structure models to show that only greatly enhanced helium can explain the color difference between the two main sequences, and we discuss ways in which this enhancement could have arisen.Comment: 24 pages, 7 figures, The Astrophysical Journal, accepted 30 Nov. 200

Partial Discharges detection in 1 MV power supplies in MITICA experiment, the ITER Heating Neutral Beam Injector prototype

MITICA (Megavolt ITER Injector & Concept Advancement), the full scale prototype of ITER Heating Neutral Beam, is under realization at the Neutral Beam Test Facility (Padova, Italy). It is designed to deliver 16.5 MW to ITER plasma, obtained by accelerating negative Deuterium ions up to 1 MeV for a total ion current of 40 A and then neutralized. MITICA Acceleration Power Supply is composed of several non-standard equipment, beyond industrial standard for insulation voltage level (-1 MVdc) and dimensions. Voltage withstand tests (up to 1.265 MVdc) have been performed in five subsequent steps (from 2018 to 2019), according to the installation progress, after connecting equipment belonging to different procurements. During integrated commissioning, started in 2021, two breakdowns occurred in a position of the HV plant not still identified, so they could be occurred either in air or in SF6. To identify the locations of possible weak insulation points, the existing diagnostics for partial discharge detection (the precursor of breakdowns) as a first step have been improved on air-insulated parts by consisting in a set of instrumentation, like capacitive probes and off-the-shelf instruments for AC application (acoustic and electromagnetic sensors). The paper deals with the instruments qualification to assess their suitability for DC usage and then with the investigation performed in MITICA, in particular: 1) sensitivity assessment campaign, with artificially produced corona effect to identify the minimum threshold of each diagnostics 2) voltage application to MITICA plant, moving the instrumentation around equipment and increasing progressively the voltage looking for corona phenomena to identify possible weak insulation points.Comment: Nine pages, twelve figures, accepted manuscript of a paper published in Fusion Engineering and Desig

Correction to: Effects of immune suppression for transplantation on inflammatory colorectal cancer progression (Oncogenesis, (2018), 7, 6, (46), 10.1038/s41389-018-0055-5)

At the time of publication, the html version of this paper contained an error; the authors Imerio Angriman and Lucrezia Furian were not tagged as equally contributing authors. This has now been fixed in the html version of the paper, the PDF was correct at the time of publication. Erratum for Effects of immune suppression for transplantation on inflammatory colorectal cancer progression. [Oncogenesis. 2018