Search

Background: Sacubitril/valsartan has been demonstrated to promote left ventricular (LV) reverse remodelling and improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. We aimed to evaluate the effects of sacubitril/valsartan on LV remodelling, myocardial fibrosis and mitochondrial biology in a murine model of non-ischaemic LV dysfunction., Methods: Adult transgenic male mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injections to induce LV systolic dysfunction. After 7 days, mice were randomized to a 2-week treatment with saline (ISO-AS n = 15), valsartan (ISO + V n = 12) or sacubitril/valsartan (ISO + S/V n = 12). Echocardiography was performed at baseline, at day 7, and after each of the 2 weeks of treatment. After sacrifice at day 21, histological and immunochemical assays were performed. A control group of AS mice was also obtained (Ctrl-AS n = 8)., Results: Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement in LVEF (p = 0.009 vs ISO-AS) and fractional shortening (p = 0.032 vs ISO-AS) after 2- week treatment. In both ISO + V and ISO + S/V groups, a trend toward reduction of the cardiac collagen 1/3 expression ratio was detected. ISO + V and ISO + S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation., Conclusion: In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV systolic function, and on cardiac energetics, by improving mitochondrial activity., Competing Interests: Declaration of competing interest The authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To study in vivo the bioactivity of biodegradable magnesium implants and other possible biomaterials, we are proposing a previously unexplored application of PET-CT imaging, using available tracers to follow soft tissue and bone remodelling and immune response in the presence of orthopaedic implants. Female Wistar rats received either implants (Ti6Al7Nb titanium or WE43 magnesium) or corresponding transcortical sham defects into the diaphyseal area of the femurs. Inflammatory response was followed with [ 18 F]FDG and osteogenesis with [ 18 F]NaF, over the period of 1.5 months after surgery. An additional pilot study with [ 68 Ga]NODAGA-RGD tracer specific to α v β 3 integrin expression was performed to follow the angiogenesis for one month. [ 18 F]FDG tracer uptake peaked on day 3 before declining in all groups, with Mg and Ti groups exhibiting overall higher uptake compared to sham. This suggests increased cellular activity and tissue response in the presence of Mg during the initial weeks, with Ti showing a subsequent increase in tracer uptake on day 45, indicating a foreign body reaction. [ 18 F]NaF uptake demonstrated the superior osteogenic potential of Mg compared to Ti, with peak uptake on day 7 for all groups. [ 68 Ga]NODAGA-RGD pilot study revealed differences in tracer uptake trends between groups, particularly the prolonged expression of α v β 3 integrin in the presence of implants. Based on the observed differences in the uptake trends of radiotracers depending on implant material, we suggest that PET-CT is a suitable modality for long-term in vivo assessment of orthopaedic biomaterial biocompatibility and underlying tissue reactions. STATEMENT OF SIGNIFICANCE: The study explores the novel use of positron emission tomography for the assessment of the influence that biomaterials have on the surrounding tissues. Previous related studies have mostly focused on material-related effects such as implant-associated infections or to follow the osseointegration in prosthetics, but the use of PET to evaluate the materials has not been reported before. The approach tests the feasibility of using repeated PET-CT imaging to follow the tissue response over time, potentially improving the methodology for adopting new biomaterials for clinical use., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The gut microbiota has been causally linked to cognitive development. We aimed to identify metabolites mediating its effect on cognitive development, and foods or nutrients related to most promising metabolites. Faeces from 5-year-old children (DORIAN-PISAC cohort, including 90 general population families with infants, 42/48 females/males, born in 2011-2014) were transplanted (FMT) into C57BL/6 germ-free mice. Children and recipient mice were stratified by cognitive phenotype, or based on protective metabolites. Food frequency questionnaires were obtained in children. Cognitive measurements in mice included five Y-maze tests until 23 weeks post-FMT, and (at 23 weeks) PET-CT for brain metabolism and radiodensity, and ultrasound-based carotid vascular indices. Children (faeces, urine) and mice (faeces, plasma) metabolome was measured by 1H NMR spectroscopy, and the faecal microbiota was profiled in mice by 16S rRNA amplicon sequencing. Cognitive scores of children and recipient mice were correlated. FMT-dependent modifications of brain metabolism were observed. Mice receiving FMT from high-cognitive or protective metabolite-enriched children developed superior cognitive-behavioural performance. A panel of metabolites, namely xanthine, hypoxanthine, formate, mannose, tyrosine, phenylalanine, glutamine, was found to mediate the gut-cognitive axis in donor children and recipient mice. Vascular indices partially explained the metabolite-to-phenotype relationships. Children's consumption of legumes, whole-milk yogurt and eggs, and intake of iron, zinc and vitamin D appeared to support protective gut metabolites. Overall, metabolites involved in inflammation, purine metabolism and neurotransmitter synthesis mediate the gut-cognitive axis, and holds promise for screening. The related dietary and nutritional findings offer leads to microbiota-targeted interventions for cognitive protection, with long-lasting effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Obesity is an independent risk factor to develop cardiac functional and structural impairments. Here, we investigated the effects of supplementation of inositols on the electrical, structural, and functional cardiac alterations in the mouse model of high fat diet (HFD) induced obesity. Three groups of C57BL6 mice (n = 16 each) were studied: j) HFD feeding; jj) HFD feeding + inositols from week 9 to 13; jjj) standard diet feeding. Study observation period was 13 weeks. Inositols were administered as mixture of myo-inositol and d-chiro-inositol in the drinking water. Effects of inositols were evaluated based on electrical, structural, and functional cardiac features, autonomic sympatho-vagal balance and arrhythmogenic susceptibility to adrenergic challenge. Heart samples were collected for histological evaluations and transcriptional analyses of genes involved in defining the shape and propagation of the action potential, fatty acid metabolism and oxidative stress. Inositol supplementation significantly restored control values of heart rate and QTc interval on ECG and of sympatho-vagal balance. Moreover, it blunted the increase in left ventricular mass and cardiomyocyte hypertrophy, reversed diastolic dysfunction, reduced the susceptibility to arrhythmic events and restored the expression level of cardiac genes altered by HFD. The present study shows, for the first time, how a short period of supplementation with inositols is able to ameliorate the HFD-induced electrical, structural and functional heart alterations including ventricular remodeling. Results provide a new insight into the cardioprotective effect of inositols, which could pave the way for a novel therapeutic approach to the treatment of HFD obesity-induced heart dysfunction., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Metabolic diseases, such as obesity and type 2 diabetes, are known risk factors for cardiovascular (CV) diseases. Thus, patients with those comorbidities could be at increased risk of experiencing cardiotoxicity related to treatment with Anthracyclines and the other new generation targeted anticancer drugs. However, investigations addressing the mechanisms underlying the development of CV complications and poor outcome in such cohort of patients are still few and controversial. Given the importance of a personalized approach against chemotherapy-induced cardiomyopathy, this review summarizes our current knowledge on the pathophysiology of chemotherapy-induced cardiomyopathy and its association with obesity and type 2 diabetes. Along with clinical evidences, future perspectives of preclinical research around this field and its role in addressing important open questions, including the development of more proactive strategies for prevention, and treatment of cardiotoxicity during and after chemotherapy in the presence of metabolic diseases, is also presented., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Anaplastic thyroid cancer (ATC) is a rare neoplasia with a poor prognosis. Proliferation and apoptosis assays were performed on ATC cell lines (8305C, 8505C) exposed to vinorelbine, lenvatinib, as well as to concomitant combinations. ABCB1, ABCG2 and CSF-1 mRNA expression was evaluated by real time PCR. The relative levels of pospho Akt were investigated as part of a human phospho-kinase array analysis, and CSF-1 and VEGFR-2 protein levels were measured by ELISA. The intracellular concentration of lenvatinib in ATC cells was measured by combined reversed-phase liquid chromatography-tandem mass spectrometry. An ATC subcutaneous xenograft tumor model in nude mice was treated with vinorelbine, lenvatinib, or vinorelbine plus lenvatinib. After treatment with vinorelbine, lenvatinib, a significant antiproliferative effect in ATC cell lines was observed. The concomitant treatment of vinorelbine and lenvatinib revealed synergism for all the fractions of affected cells. A decrease in ABCB1 expression was reported in both ATC cell lines treated with the lenvatinib plus vinorelbine combination, as was an increase in the intracellular concentration of lenvatinib. The combination caused a decrease in Akt, GSK3α/β, PRAS40 and Src phosphorylation, and in both CSF-1 mRNA and protein levels. In the subcutaneous tumor model, the combination reduced the tumor volume during the treatment period. Our results establish the synergistic ATC antitumor activity of a vinorelbine and lenvatinib combination., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests, (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The angiopoietin signal transduction system is a complex of vascular-specific kinase pathways that plays a crucial role in angiogenesis and maintenance of vascular homeostasis. Angiopoietin1 (Ang1) and 2 (Ang2), the ligand proteins of the pathway, belong to a family of glycoproteins that signal primarily through the transmembrane Tyrosine-kinase-2 receptor. Despite a considerable sequence homology, Ang1 and Ang2 manifest antagonistic effects in pathophysiological conditions. While Ang1 promotes the activation of survival pathways and the stabilization of the normal mature vessels, Ang2 can either favor vessel destabilization and leakage or promote abnormal EC proliferation in a context-dependent manner. Altered Ang1/Ang2 balance has been reported in various pathological conditions in association with inflammation and deregulated angiogenesis. In particular, increased Ang2 levels have been documented in human cancer and cardiovascular disease (CVD), including ischemic myocardial injury, heart failure and other cardiovascular complications secondary to diabetes, chronic renal damage and hypertension. Despite the obvious phenotypic differences, CVD and cancer share some common Ang2-dependent etiopathological mechanisms such as inflammation, epithelial (or endothelial) to mesenchymal transition, and adverse vascular network remodeling. Interestingly, both cancer and CVD are negatively affected by thyroid hormone dyshomeostasis. This review provides an overview of the complex Ang2-dependent signaling involved in CVD and cancer, as well as a survey of the related clinical literature. Moreover, on the basis of recent molecular acquisitions in an experimental model of post ischemic cardiac disease, the putative novel role of the thyroid hormone in the regulation of Ang1/Ang2 balance is also briefly discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Pulse wave velocity (PWV) is considered as a surrogate marker of arterial stiffness and could be useful for characterizing cardiovascular disease progression even in mouse models. Aim of this study was to develop an image process algorithm for assessing arterial PWV in mice using ultrasound images only and test it on the evaluation of age-associated differences in abdominal aorta PWV., Methods: Ultrasound scans were obtained from ten adult (mean age: 5.5 months) and nine old (mean age: 15.5 months) wild type male mice (strain C57BL6) under gaseous anesthesia. For each mouse, instantaneous values of diameter and flow velocity were obtained from abdominal aorta B-mode and PW-Doppler, respectively. Single-beat mean diameter and velocity were calculated providing the velocity-diameter (lnD-V) loop. PWV values for both the early systolic phase (aaPWV) and the late systolic one (aaPWVls) were obtained from the slope of the corresponding linear parts of the loop. Relative distension (relD) was calculated from the mean diameter signal., Results: aaPWV values for adult mice (1.91 ± 0.44 m/s) were significantly lower (p < 0.01) than those obtained for older ones (2.71 ± 0.63 m/s) and the same result was found for aaPWVls (2.68 ± 0.68 vs 3.67 ± 0.95 m/s; p < 0.05). relD measurements were significantly higher (p < 0.01) in adult (22.7% ± 5.2%) compared with older animal evaluations (15.8% ± 3.9%)., Conclusions: The proposed system discriminates well between age groups and supplies a non-invasive evaluation of anatomical and functional parameters of the mouse abdominal aorta. Since it provides a non-invasive PWV assessment from ultrasound (US) images only, it may offer a simple and useful system for evaluation of local vascular stiffness at other arterial site in the mouse, such as the carotid artery., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We examined mechanisms by which L-4F reduces obesity and diabetes in obese (ob) diabetic mice. We hypothesized that L-4F reduces adiposity via increased pAMPK, pAKT, HO-1, and increased insulin receptor phosphorylation in ob mice. Obese and lean mice were divided into five groups: lean, lean-L-4F-treated, ob, ob-L-4F-treated, and ob-L-4F-LY294002. Food intake, insulin, glucose adipocyte stem cells, pAMPK, pAKT, CB1, and insulin receptor phosphorylation were determined. Subcutaneous (SAT) and visceral adipose tissue (VAT) were determined by MRI and hepatic lipid content by magnetic resonance spectroscopy. SAT and VAT volumes decreased in ob-L-4F-treated animals compared with control. L-4F treatment decreased hepatic lipid content and increased the numbers of small adipocytes (P < 0.05) and phosphorylation of insulin receptors. L-4F decreased CB1 in SAT and VAT and increased pAKT and pAMPK in endothelium. L-4F-mediated improvement in endothelium was prevented by LY294002. Inhibition of pAKT and pAMPK by LY294002 was associated with an increase in glucose levels. Upregulation of HO-1 by L-4F produced adipose remodeling and increased the number of small differentiated adipocytes. The anti-obesity effects of L-4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, pAMPK, pAKT, and phosphorylation of insulin receptors with improved insulin sensitivity.

Background: The pathobiological mechanisms by which Hcy can promote atherothrombosis are not completely understood. Many observations suggest that oxidative consequences of hyperhomocysteinemia have a distinct role in the development of occlusive vascular disease. The aim of this work was to investigate whether sensitivity of erythrocytes to chemically induced oxidative stress in both healthy subjects and patients with clinically ascertained atherosclerosis was modified during the transient increase in homocysteine driven by methionine load., Methods: Erythrocyte sensitivity to oxidative stress during transient hyperhomocysteinemia was assessed by cumene hydroperoxide-induced alpha-tocopherol consumption before and after methionine load in 31 healthy subjects and 23 patients with coronary artery disease., Results: Decreased sensitivity to oxidative challenge ("Type-1" response) after methionine load was more frequent in healthy subjects (35% vs 13% in patients), while increased sensitivity ("Type-2" response) was more frequent in patients (22% vs 6% in healthy subjects). No variation in sensitivity to oxidative challenge throughout the loading test ("Non-variant" response) was detected in either group (58% in healthy subjects and 65% in patients). The distribution of these responses was significantly different between healthy subjects and patients and independent of basal and post-load increase in homocysteine. Plasma lipoperoxides, erythrocyte alpha-tocopherol and glutathione content before methionine load were significantly different between patients and healthy subjects; however only the redox potential of the GSSG/GSH couple was significantly different in the different groups of response., Conclusions: The higher frequency of "Type-2" response in patients with respect to healthy subjects suggests that methionine load reveals individual factors that may contribute to the pathogenesis of atherosclerosis.

Intracellular recordings from 103 photoreceptors in the excised pineal body of adult trouts were obtained by using single electrode current- and voltage-clamp techniques. The photoresponses to brief flashes showed the same polarity but a slower time course than those previously recorded from retinal photoreceptors of lower vertebrates. Pineal photoreceptors showed spectral sensitivity peaks at about 495 and 521 nm and absolute sensitivity comparable to retinal cone cells of the same species. The photoreceptor membrane conductance, measured under voltage clamp during moderate illumination was about 10% lower than in the dark, and the extrapolated reversal potential of the response was at 60 mV above the dark membrane potential. The addition of 3-isobutyl-1-methylxanthine (IBMX) to the perfusate was followed by a receptor depolarization in the dark and by a slow-down of the response kinetic. Pineal receptor cells produce constant amplitude responses during steady illumination, without displaying the delayed slow depolarization typically associated with light adaptation of retinal photoreceptors. Photoresponses to brief flashes superimposed on a steady illumination are decreased in amplitude by an amount directly related to the background intensity. Increase of the background intensity leads to threshold increments without significant changes of the saturation intensity, resulting in a gradual compression of the cell dynamic range. These results were discussed relative to light adaptation in retinal photoreceptors. The conclusion can be drawn that the response properties of pineal photoreceptors during steady illumination are part of an unknown, self-regulating mechanism to lock the rate of metabolism and secretion of indolamines to the absolute level of diurnal light.