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1.
Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions.
Caruso, L, Fields, M, Rimondi, E, Zauli, G, Longo, G, Marcuzzi, A, Previati, M, Gonelli, A, Zauli, E, Milani, D
International journal of molecular sciences. 2024;(4)
Abstract
The human retina is a complex anatomical structure that has no regenerative capacity. The pathogenesis of most retinopathies can be attributed to inflammation, with the activation of the inflammasome protein platform, and to the impact of oxidative stress on the regulation of apoptosis and autophagy/mitophagy in retinal cells. In recent years, new therapeutic approaches to treat retinopathies have been investigated. Experimental data suggest that the secretome of mesenchymal cells could reduce oxidative stress, autophagy, and the apoptosis of retinal cells, and in turn, the secretome of the latter could induce changes in mesenchymal cells. Other studies have evidenced that noncoding (nc)RNAs might be new targets for retinopathy treatment and novel disease biomarkers since a correlation has been found between ncRNA levels and retinopathies. A new field to explore is the interaction observed between the ocular and intestinal microbiota; indeed, recent findings have shown that the alteration of gut microbiota seems to be linked to ocular diseases, suggesting a gut-eye axis. To explore new therapeutical strategies for retinopathies, it is important to use proper models that can mimic the complexity of the retina. In this context, retinal organoids represent a good model for the study of the pathophysiology of the retina.
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2.
The Role of Inflammation in Cardiovascular Disease.
Henein, MY, Vancheri, S, Longo, G, Vancheri, F
International journal of molecular sciences. 2022;23(21)
Abstract
Atherosclerosis is a chronic inflammatory disease, in which the immune system has a prominent role in its development and progression. Inflammation-induced endothelial dysfunction results in an increased permeability to lipoproteins and their subendothelial accumulation, leukocyte recruitment, and platelets activation. Recruited monocytes differentiate into macrophages which develop pro- or anti-inflammatory properties according to their microenvironment. Atheroma progression or healing is determined by the balance between these functional phenotypes. Macrophages and smooth muscle cells secrete inflammatory cytokines including interleukins IL-1β, IL-12, and IL-6. Within the arterial wall, low-density lipoprotein cholesterol undergoes an oxidation. Additionally, triglyceride-rich lipoproteins and remnant lipoproteins exert pro-inflammatory effects. Macrophages catabolize the oxidized lipoproteins and coalesce into a lipid-rich necrotic core, encapsulated by a collagen fibrous cap, leading to the formation of fibro-atheroma. In the conditions of chronic inflammation, macrophages exert a catabolic effect on the fibrous cap, resulting in a thin-cap fibro-atheroma which makes the plaque vulnerable. However, their morphology may change over time, shifting from high-risk lesions to more stable calcified plaques. In addition to conventional cardiovascular risk factors, an exposure to acute and chronic psychological stress may increase the risk of cardiovascular disease through inflammation mediated by an increased sympathetic output which results in the release of inflammatory cytokines. Inflammation is also the link between ageing and cardiovascular disease through increased clones of leukocytes in peripheral blood. Anti-inflammatory interventions specifically blocking the cytokine pathways reduce the risk of myocardial infarction and stroke, although they increase the risk of infections.
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3.
Deep Neck Infections: Decisional Algorithm for Patients with Multiple Spaces Involvement.
Ricciardiello, F, Mazzone, S, Viola, P, Guggino, G, Longo, G, Napolitano, A, Russo, G, Sequino, G, Oliva, F, Salomone, P, et al
Reviews on recent clinical trials. 2022;(1):46-52
Abstract
BACKGROUND Deep Neck Infections (DNIs) spread along fascial planes and involve neck spaces. Recently, their incidence has decreased due to the introduction of antibiotics; nevertheless, complications related to DNIs are often life-threatening. OBJECTIVE The purpose of this article is focused on the identification of predisposing factors of these complications, as well as on the development of a reliable therapeutic algorithm. METHODS Sixty patients with DNIs were enrolled from 2006 to 2019 for a retrospective study. The exclusion criteria for the present study were cellulitis, small abscesses responding to empiric or specific antibiotic therapy, or involvement of only one deep neck space. During the analysis, the following parameters of interest have been evaluated: gender, age, site of origin, pathways of spread, comorbidities, clinical features, bacteriology data, type of surgical approach required, complications, duration of hospitalization and mortality rate. On admission, microbial swab analysis was performed. RESULTS Diabetes Mellitus (DM), Chronic Obstructive Pulmonary Disease (COPD), iron deficiency anemia and the involvement of multiple spaces have been associated with a significantly higher risk of developing complications. Most of our patients had polymicrobial infections. All patients underwent surgical drainage. The complication rate had occurred in 56.6% of patients, while death in 18.3%. CONCLUSION DNIs represent a medical and surgical emergency with potentially serious complications; thus, avoidance of diagnostic delay is mandatory. Our preliminary data suggest the importance of evaluating the extent of infections because the involvement of multiple spaces requires timely surgery due to the higher risk of complications and mortality.
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4.
The Impact of Mental Stress on Cardiovascular Health-Part II.
Henein, MY, Vancheri, S, Longo, G, Vancheri, F
Journal of clinical medicine. 2022;(15)
Abstract
Endothelial dysfunction is one of the earliest manifestations of atherosclerosis, contributing to its development and progression. Mental stress induces endothelial dysfunction through increased activity of the sympathetic nervous system, release of corticotropin-releasing hormone from the hypothalamus, inhibition of nitric oxide (NO) synthesis by cortisol, and increased levels of pro-inflammatory cytokines. Mental-stress-induced increased output of the sympathetic nervous system and concomitant withdrawal of the parasympathetic inflammatory reflex results in systemic inflammation and activation of a neural-hematopoietic-arterial axis. This includes the brainstem and subcortical regions network, bone marrow activation, release of leukocytes into the circulation and their migration to the arterial wall and atherosclerotic plaques. Low-grade, sterile inflammation is involved in all steps of atherogenesis, from coronary plaque formation to destabilisation and rupture. Increased sympathetic tone may cause arterial smooth-muscle-cell proliferation, resulting in vascular hypertrophy, thus contributing to the development of hypertension. Emotional events also cause instability of cardiac repolarisation due to brain lateralised imbalance of cardiac autonomic nervous stimulation, which may lead to asymmetric repolarisation and arrhythmia. Acute emotional stress can also provoke severe catecholamine release, leading to direct myocyte injury due to calcium overload, known as myocytolysis, coronary microvascular vasoconstriction, and an increase in left ventricular afterload. These changes can trigger a heart failure syndrome mimicking acute myocardial infarction, characterised by transient left ventricular dysfunction and apical ballooning, known as stress (Takotsubo) cardiomyopathy. Women are more prone than men to develop mental-stress-induced myocardial ischemia (MSIMI), probably reflecting gender differences in brain activation patterns during mental stress. Although guidelines on CV prevention recognise psychosocial factors as risk modifiers to improve risk prediction and decision making, the evidence that their assessment and treatment will prevent CAD needs further evaluation.
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5.
Time-restricted eating effects on performance, immune function, and body composition in elite cyclists: a randomized controlled trial.
Moro, T, Tinsley, G, Longo, G, Grigoletto, D, Bianco, A, Ferraris, C, Guglielmetti, M, Veneto, A, Tagliabue, A, Marcolin, G, et al
Journal of the International Society of Sports Nutrition. 2020;17(1):65
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Plain language summary
Adequate nutrition is important for elite athletes, as nutrient availability influences energy expenditure, body composition, performance and exercise-induced immune responses. Time-restricted eating (TRE) is a form of intermittent fasting that has received much interest in recent years. Previous research of TRE suggested beneficial effects on performance in untrained individuals, by allowing weight loss whilst maintaining muscle functions. These qualities are of interest for endurance cyclists hence the authors of this study sought to investigate the impact of TRE in elite cyclists. Sixteen under-23 year old, elite cyclists were randomly assigned to eat within a TRE window of 8-hr or 15hr window during a 4-week, high-level endurance training phase. Both groups consumed their full estimated energy needs and markers such as fat and fat-free mass, VO2 max, basal metabolism, blood counts, anabolic hormones and inflammatory markers were measured. As a result, TRE produced weight loss, improved body composition and increased peak power output in relation to body weight without compromising aerobic performance. Furthermore, the TRE pattern proved helpful in mitigating some of the exercise-induced suppressions of the immune system. The authors concluded that TRE could be considered as part of a performance nutrition plan in endurance athletes. Particularly where there is a need to reduce body fat mass or for the management of training-induced depression of the immune system and associated respiratory infection susceptibility. This can be of clinical relevance in the support of endurance athletes.
Abstract
BACKGROUND Although there is substantial interest in intermittent fasting as a dietary approach in active individuals, information regarding its effects in elite endurance athletes is currently unavailable. The present parallel randomized trial investigated the effects of a particular intermittent fasting approach, called time-restricted eating (TRE), during 4 weeks of high-level endurance training. METHODS Sixteen elite under-23 cyclists were randomly assigned either to a TRE group or a control group (ND). The TRE group consumed 100% of its estimated daily energy needs in an 8-h time window (from 10:00 a.m. to 6:00 p.m.) whilst energy intake in the ND group was distributed in 3 meals consumed between 7:00 a.m. and 9:00 p.m. Fat and fat-free mass were estimated by bioelectrical impedance analysis and VO2max and basal metabolism by indirect gas analyzer. In addition, blood counts, anabolic hormones (i.e. free testosterone, IGF-1) and inflammatory markers (i.e. IL-6, TNF-α) were assessed. RESULTS TRE reduced body weight (- 2%; p = 0.04) and fat mass percentage (- 1.1%; p = 0.01) with no change in fat-free mass. Performance tests showed no significant differences between groups, however the peak power output/body weight ratio (PPO/BW) improved in TRE group due to weight loss (p = 0.02). Free testosterone and IGF-1 decreased significantly (p = 0.01 and p = 0.03 respectively) in TRE group. Leucocyte count decreased in ND group (p = 0.02) whilst the neutrophils-to-lymphocytes ratio (NLR) decreased significantly (p = 0.03) in TRE group. CONCLUSIONS Our results suggest that a TRE program with an 8-h feeding window elicits weight loss, improves body composition and increases PPO/BW in elite cyclists. TRE could also be beneficial for reducing inflammation and may have a protective effect on some components of the immune system. Overall, TRE could be considered as a component of a periodized nutrition plan in endurance athletes. TRIAL REGISTRATION This trial was retrospectively registered at clinicaltrials.gov as NCT04320784 on 25 March 2020.
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6.
Coronary Artery Microcalcification: Imaging and Clinical Implications.
Vancheri, F, Longo, G, Vancheri, S, Danial, JSH, Henein, MY
Diagnostics (Basel, Switzerland). 2019;(4)
Abstract
Strategies to prevent acute coronary and cerebrovascular events are based on accurate identification of patients at increased cardiovascular (CV) risk who may benefit from intensive preventive measures. The majority of acute CV events are precipitated by the rupture of the thin cap overlying the necrotic core of an atherosclerotic plaque. Hence, identification of vulnerable coronary lesions is essential for CV prevention. Atherosclerosis is a highly dynamic process involving cell migration, apoptosis, inflammation, osteogenesis, and intimal calcification, progressing from early lesions to advanced plaques. Coronary artery calcification (CAC) is a marker of coronary atherosclerosis, correlates with clinically significant coronary artery disease (CAD), predicts future CV events and improves the risk prediction of conventional risk factors. The relative importance of coronary calcification, whether it has a protective effect as a stabilizing force of high-risk atherosclerotic plaque has been debated until recently. The extent of calcium in coronary arteries has different clinical implications. Extensive plaque calcification is often a feature of advanced and stable atherosclerosis, which only rarely results in rupture. These macroscopic vascular calcifications can be detected by computed tomography (CT). The resulting CAC scoring, although a good marker of overall coronary plaque burden, is not useful to identify vulnerable lesions prone to rupture. Unlike macrocalcifications, spotty microcalcifications assessed by intravascular ultrasound or optical coherence tomography strongly correlate with plaque instability. However, they are below the resolution of CT due to limited spatial resolution. Microcalcifications develop in the earliest stages of coronary intimal calcification and directly contribute to plaque rupture producing local mechanical stress on the plaque surface. They result from a healing response to intense local macrophage inflammatory activity. Most of them show a progressive calcification transforming the early stage high-risk microcalcification into the stable end-stage macroscopic calcification. In recent years, new developments in noninvasive cardiovascular imaging technology have shifted the study of vulnerable plaques from morphology to the assessment of disease activity of the atherosclerotic lesions. Increased disease activity, detected by positron emission tomography (PET) and magnetic resonance (MR), has been shown to be associated with more microcalcification, larger necrotic core and greater rates of events. In this context, the paradox of increased coronary artery calcification observed in statin trials, despite reduced CV events, can be explained by the reduction of coronary inflammation induced by statin which results in more stable macrocalcification.
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7.
Nanomotion detection based on atomic force microscopy cantilevers.
Kohler, AC, Venturelli, L, Longo, G, Dietler, G, Kasas, S
Cell surface (Amsterdam, Netherlands). 2019;:100021
Abstract
Atomic force microscopes (AFM) or low-noise in-house dedicated devices can highlight nanomotion oscillations. The method consists of attaching the organism of interest onto a silicon-based sensor and following its nano-scale motion as a function of time. The nanometric scale oscillations exerted by biological specimens last as long the organism is viable and reflect the status of the microorganism metabolism upon exposure to different chemical or physical stimuli. During the last couple of years, the nanomotion pattern of several types of bacteria, yeasts and mammalian cells has been determined. This article reviews this technique in details, presents results obtained with dozens of different microorganisms and discusses the potential applications of nanomotion in fundamental research, medical microbiology and space exploration.
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8.
Maternal Haplotypes in DHFR Promoter and MTHFR Gene in Tuning Childhood Acute Lymphoblastic Leukemia Onset-Latency: Genetic/Epigenetic Mother/Child Dyad Study (GEMCDS).
Tisato, V, Muggeo, P, Lupiano, T, Longo, G, Serino, ML, Grassi, M, Arcamone, E, Secchiero, P, Zauli, G, Santoro, N, et al
Genes. 2019;(9)
Abstract
Childhood acute lymphoblastic leukemia (ALL) peaks around age 2-4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role in determining ALL onset age and survival. Pyrosequence of DHFR 19bp ins/del (rs70991108; W/D), MTHFR C677T (rs1801133; C>T), and MTHFR A1298C (rs1801131; A>C) was assessed in children and in 72% of mothers for dyad-analysis comparison. DHFR DD-children had delayed ALL onset compared to WW-children (7.5 ± 4.8 vs. 5.2 ± 3.7 years; P = 0.002) as well as MTHFR 1298 CC-children compared to AA-children (8.03 ± 4.8 vs. 5.78 ± 4.1 years; P = 0.006), and according to the strong linkage disequilibrium between MTHFR 677 T-allele and 1298C-allele, MTHFR TT-children showed early mean age of onset though not significant. Offspring of MTHFR 677 TT-mothers had earlier ALL onset compared to offspring of 677 CC-mothers (5.4 ± 3.3 vs. 7 ± 5.3 years; P = 0.017). DHFR/MTHFR 677 polymorphism combination influenced onset age by comparing DD/CC vs. WW/TT children (8.1 ± 5.7 vs. 4.7 ± 2.1 years; P = 0.017). Moreover, mother-child genotype combination gave 5.5-years delayed onset age in favor of DD-offspring of 677 CC-mothers vs. WW-offspring of 677 TT-mothers, and it was further confirmed including any D-carrier children and any 677 T-carrier mothers (P = 0.00052). Correction for multiple comparisons maintained statistical significance for DHFR ins/del and MTHFR A1298C polymorphisms. Unexpectedly, among the very-early onset group (<2.89 years; 25th), DD-genotype inversely clustered in children and mothers (4.8% vs. 23.8% respectively), and accordingly ALL offspring of homozygous DD-mothers had increased risk to have early-onset (adjusted OR (odds ratio) = 3.08; 1.1-8.6; P = 0.03). The opposite effect DHFR promoter variant has in tuning ALL onset-time depending on who is the carrier (i.e., mother or child) might suggest a parent-origin-effect of the D-allele or a two-faced epigenetic role driven by unbalanced folate isoform availability during the in-utero leukemogenesis responsible for the wide postnatal childhood ALL latency.
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9.
Gene-gene interactions among coding genes of iron-homeostasis proteins and APOE-alleles in cognitive impairment diseases.
Tisato, V, Zuliani, G, Vigliano, M, Longo, G, Franchini, E, Secchiero, P, Zauli, G, Paraboschi, EM, Vikram Singh, A, Serino, ML, et al
PloS one. 2018;(3):e0193867
Abstract
Cognitive impairments of different aetiology share alterations in iron and lipid homeostasis with mutual relationships. Since iron and cholesterol accumulation impact on neurodegenerative disease, the associated gene variants are appealing candidate targets for risk and disease progression assessment. In this light, we explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes and in the main lipoprotein transporter gene (APOE) in a cohort of 765 patients with dementia of different origin: Alzheimer's disease (AD) n = 276; vascular dementia (VaD), n = 255; mild cognitive impairment (MCI), n = 234; and in normal controls (n = 1086). In details, four genes of iron homeostasis (Hemochromatosis (HFE: C282Y, H63D), Ferroportin (FPN1: -8CG), Hepcidin (HAMP: -582AG), Transferrin (TF: P570S)), and the three major alleles of APOE (APOE2, APOE3, APOE4) were analyzed to explore causative interactions and synergies. In single analysis, HFE 282Y allele yielded a 3-fold risk reduction in the whole cohort of patients (P<0.0001), confirmed in AD and VaD, reaching a 5-fold risk reduction in MCI (P = 0.0019). The other iron SNPs slightly associated with risk reduction whereas APOE4 allele resulted in increased risk, reaching more than 7-fold increased risk in AD homozygotes (P = 0.001), confirmed to a lower extent in VaD and MCI (P = 0.038 and P = 0.013 respectively) as well as in the whole group (P<0.0001). Comparisons of Mini Mental State Examination (MMSE) among AD showed appreciable lowering in APOE4 carriers (P = 0.038), confirmed in the whole cohort of patients (P = 0.018). In interaction analysis, the HFE 282Y allele completely extinguished the APOE4 allele associated risk. Conversely, the coexistence in patients of a substantial number of iron SNPs accrued the APOE4 detrimental effect on MMSE. Overall, the analysis highlighted how a specific iron-allele burden, defined as different combinations of iron gene variants, might have different effects on cognitive impairment and might modulate the effects of established genetic risk factors such as APOE4. Our results suggest that established genetic risk factors might be affected by specific genetic backgrounds, making patients differently suited to manage iron accumulation adding new genetic insights in neurodegeneration. The recently recognized interconnections between iron and lipids, suggest that these pathways might share more than expected. We therefore extended to additional iron gene variants the newly proposed influencing mechanisms that HFE gene has on cholesterol metabolism. Our results have a strong translational potential promoting new pharmacogenetics studies on therapeutic target identification aimed at optimally tuning brain iron levels.
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10.
Behavior of ligand binding assays with crowded surfaces: Molecular model of antigen capture by antibody-conjugated nanoparticles.
Malaspina, DC, Longo, G, Szleifer, I
PloS one. 2017;(9):e0185518
Abstract
Ligand-receptor binding is of utmost importance in several biologically related disciplines. Ligand binding assays (LBA) use the high specificity and high affinity of ligands to detect, target or measure a specific receptors. One particular example of ligand binding assays are Antibody conjugated Nanoparticles (AcNPs), edge-cutting technologies that are present in several novel biomedical approaches for imaging, detection and treatment of diseases. However, the nano-confinement in AcNPs and LBA nanostructures introduces extra complexity in the analysis of ligand-receptor equilibriums. Because antibodies are large voluminous ligands, the effective affinity in AcNPs is often determined by antibody orientation and surface coverage. Moreover, antibodies have two binding sites introducing an extra ligand-receptor binding equilibrium. As consequence of all this, experimental or theoretical studies providing a guidelines for the prediction of the binding behavior in AcNPs are scarce. In this work, we present a set of theoretical calculations to shed light into the complex binding behavior of AcNPs and its implications in biomedical applications. To investigate the ligand-receptor binding on AcNPs, we have used a molecular theory that predicts the probability of different molecular conformations of the system depending on the local environment. We have considered two different pathways for designing these devices: covalently conjugated antibodies and streptavidin-biotin conjugated antibodies. We also explore the effects of surface coverage, bulk concentrations, nanoparticle size and antibody-antigen affinity. Overall, this work offers a series of theoretical predictions that can be used as a guide in the design of antibody conjugated nanoparticles for different applications.