Circulating Extracellular Vesicles Impair Mesenchymal Stromal Cell Differentiation Favoring Adipogenic Rather than Osteogenic Differentiation in Adolescents with Obesity Barbara Peruzzi, Enrica Urciuoli, Michela Mariani, Laura Chioma, Luigi Tomao, et al. International Journal of Molecular Sciences, 2023 Excess body weight has been considered beneficial to bone health because of its anabolic effect on bone formation; however, this results in a poor quality bone structure. In this context, we evaluated the involvement of circulating extracellular vesicles in the impairment of the bone phenotype associated with obesity. Circulating extracellular vesicles were collected from the plasma of participants with normal weight, as well as overweight and obese participants, quantified by flow cytometry analysis and used to treat mesenchymal stromal cells and osteoblasts to assess their effect on cell differentiation and activity. Children with obesity had the highest amount of circulating extracellular vesicles compared to controls. The treatment of mesenchymal stromal cells with extracellular vesicles from obese participants led to an adipogenic differentiation in comparison to vesicles from controls. Mature osteoblasts treated with extracellular vesicles from obese participants showed a reduction in differentiation markers in comparison to controls. Children with obesity who regularly performed physical exercise had a lower circulating extracellular vesicle amount in comparison to those with a sedentary lifestyle. This pilot study demonstrates how the high amount of circulating extracellular vesicles in children with obesity affects the bone phenotype and that physical activity can partially rescue this phenotype.
Relationship between glucose homeostasis and obesity in early life - A study of Italian children and adolescents Zhanna Balkhiyarova, Rosa Luciano, Marika Kaakinen, Anna Ulrich, Aleksey Shmeliov, et al. Human Molecular Genetics, 2022 Epidemic obesity is the most important risk factor for prediabetes and type 2 diabetes (T2D) in youth as it is in adults. Obesity shares pathophysiological mechanisms with T2D and is likely to share part of the genetic background. We aimed to test if weighted genetic risk scores (GRSs) for T2D, fasting glucose (FG) and fasting insulin (FI) predict glycaemic traits and if there is a causal relationship between obesity and impaired glucose metabolism in children and adolescents. Genotyping of 42 SNPs established by genome-wide association studies for T2D, FG and FI was performed in 1660 Italian youths aged between 2 and 19 years. We defined GRS for T2D, FG and FI and tested their effects on glycaemic traits, including FG, FI, indices of insulin resistance/beta cell function and body mass index (BMI). We evaluated causal relationships between obesity and FG/FI using one-sample Mendelian randomization analyses in both directions. GRS-FG was associated with FG (beta = 0.075 mmol/l, SE = 0.011, P = 1.58 × 10−11) and beta cell function (beta = −0.041, SE = 0.0090 P = 5.13 × 10−6). GRS-T2D also demonstrated an association with beta cell function (beta = −0.020, SE = 0.021 P = 0.030). We detected a causal effect of increased BMI on levels of FI in Italian youths (beta = 0.31 ln (pmol/l), 95%CI [0.078, 0.54], P = 0.0085), while there was no effect of FG/FI levels on BMI. Our results demonstrate that the glycaemic and T2D risk genetic variants contribute to higher FG and FI levels and decreased beta cell function in children and adolescents. The causal effects of adiposity on increased insulin resistance are detectable from childhood age.
Calibrated automated thrombogram values in infants with cardiac surgery before and after cardiopulmonary bypass Alessandra Rizza, Giovina Di Felice, Rosa Luciano, Ottavia Porzio, Ombretta Panizzon, et al. Thrombosis Research, 2017 INTRODUCTION Impaired thrombin generation has been associated to increase bleeding after cardiac surgery with cardiopulmonary bypass (CPB), especially in children. The aim of this study was to evaluate standard coagulation assay, thrombin generation by calibrated automated thrombogram (CAT), thromboelastography (TEG) and procoagulant phospholipids (PPL) activity in infants undergoing cardiac surgery with CPB. MATERIALS AND METHODS Prospective observational study performed in children aged <24months undergoing cardiac surgery with CPB. Exclusion criteria were preoperative coagulopathy or anticoagulant therapy. Coagulation was evaluated by standard coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen level, platelet count), TEG, CAT and PPL at anaesthesia induction (T1) and after 12h (T2). Perioperative bleeding management was performed according to the institutional guidelines. RESULTS Forty-nine children aged <24months were enrolled. At T1 ETP and peak height evaluated by CAT were significantly lower in infants aged <6months. Standard coagulation tests, TEG and PPL did not correlate with age. At T2 platelet count, plasmatic fibrinogen level, all TEG parameters, ETP and peak height by CAT were significantly impaired compared to baseline values (T1), despite allogeneic blood product transfusions. CONCLUSIONS Thrombin generation is significantly impaired in children affected by congenital heart disease, compared to healthy children and adults. CAT parameters resulted age-dependent, and thrombin generation is lower in infants aged <6months. After cardiac surgery with CPB, a coaugulopathy, revealed by CAT, TEG, but not by PT and aPTT assays, is persistent 12h after surgery despite transfusions of blood products.
A new index to simplify the screening of hypertension in overweight or obese youth P. Di Bonito, G. Valerio, L. Pacifico, C. Chiesa, C. Invitti, et al. Nutrition Metabolism and Cardiovascular Diseases, 2017 BACKGROUND AND AIMS Hypertension (HTH) is a frequent complication in pediatric obesity. To simplify the screening of HTH in overweight/obese (Ow/Ob) youth, we compared the performance of a new index (High Blood Pressure index, HBPi) with respect to the standard criteria of the IV Report [systolic BP (SBP) and/or diastolic BP (DBP) ≥95th percentile for age, gender and height]. We also compared the performance of HBPi with other simplified indices such as the BP/height ratio and the absolute height-specific BP thresholds. Ten pediatrics' outpatient centers participating in the "CARdiometabolic risk factors in ITALY study" provided medical records of 4225 Ow/Ob children and adolescents (age 6-16 years). METHODS AND RESULTS Centers were divided into two groups: training set (TS) (n = 2204 participants) and validation set (VS) (n = 2021 participants). The simplified HBPi (mmHg) was: (SBP/2 + DBP/10) - age + (1 × female gender). In the TS, a HBPi value ≥57 mmHg in both children and adolescents had high sensitivity (0.89), specificity (0.97), positive (0.89) and negative (0.97) predictive values in classifying youth at high risk of HTN compared with the IV Report. In the VS, the HBPi showed a better performance than high levels of BP/height ratio and height-specific BP thresholds in classifying individuals at risk of HTN: area under curves 0.95 (0.93-0.96), 0.80 (0.78-0.82), 0.76 (0.74-0.79), respectively; specificities 0.95 (0.94-0.96), 0.69 (0.67-0.72), 0.60 (0.57-0.62), respectively. CONCLUSIONS HBPi, combining SBP and DBP, gender and age, may help pediatricians to implement HTN screening in Ow/Ob youth.
Inside out the Ragbag of Glucose Intolerance in Obese Adolescents Claudia Brufani, Andrea Tura, Giorgio Bedogni, Rosa Luciano, Stefano Sbrignadello, et al. Hormone Research in Paediatrics, 2017 Background/Aims: The prevalence of impaired glucose tolerance (IGT) is rising among obese adolescents in parallel with epidemic obesity. In some cases, IGT reverts to normal glucose tolerance (NGT) by the end of puberty. The aims of the present study were to investigate metabolic factors determining changes over time of glucose at 120 min (Glu120) following an oral glucose tolerance test (OGTT), and to verify whether preserved β-cell glucose sensitivity (βCGS) protects against persistent IGT. Methods: We performed a cohort study of 153 severely obese children and adolescents evaluated with a 5-point OGTT at baseline and at follow-up with measurements of glucose, insulin, and C-peptide to estimate several empirical parameters of insulin sensitivity (includ ing oral glucose insulin sensitivity [OGIS] and OGTT-derived glucose effectiveness) and secretion. Results: At follow-up (range 0.9–4.8 year), 113 (73.9%) patients remained with NGT, 9 (5.9%) had IGT, and 28 (18.3%) had reverted to NGT; 3 NGT patients had developed IGT. In multivariable models, change in loge(βCGS) was inversely associated with time-related change in loge(Glu120), with (model 2) and without (model 1) correction for the change in loge(OGIS). Model 2 was more strongly associated with change in loge(Glu120). Conclusions: Changes in βCGS and insulin sensitivity were inversely associated with changes in Glu120 at follow-up, contributing a likely explanation for the reversal of IGT to NGT.
Percentiles of serum uric acid and cardiometabolic abnormalities in obese Italian children and adolescents Rosa Luciano, Blegina Shashaj, MariaRita Spreghini, Andrea Del Fattore, Carmela Rustico, et al. Italian Journal of Pediatrics, 2017 BackgroundTo investigate the association of serum uric acid (SUA) with cardiometabolic abnormalities in Caucasian overweight/obese children (<10 years of age) versus adolescents (≥10 years of age) by drawing age and gender specific percentiles of uric acid.MethodsCross-sectional evaluation of 1364 Caucasian overweight/obese patients (age 4.1–17.9 years; 726 males, 53%; 560 children, 41%).ResultsSUA levels were significantly lower in children than in adolescents (4.74 ± 1.05 vs. 5.52 ± 1.49 mg/dl, p < 0.001) and peaked in 12–14 years-old boys and 10–12 years-old girls.In children with levels of SUA in the highest quartile (N = 75, 13%), OR for high triglycerides was 4.145, 95% CI 1.506–11.407 (p = 0.009). In adolescents with SUA in the highest quartile (N = 274, 34%), ORs for insulin resistance was 2.399 (95%CI 1.4–4.113; p < 0.001); for impaired fasting glucose 2.184 (95% CI 0.877–5.441; p = 0.07); for impaired glucose tolerance 2.390 (95% CI 1.405–4.063; p = 0.001); and for high triglycerides 1.8, (95%CI 0.950–3.420; p = 0.05). Multivariable random-effect linear regression models demonstrated that waist circumference and age (p < 0.0001 for both) are the variables most significantly predicting SUA levels, followed by triglycerides (p = 0.005) and 2 h glucose (p = 0.03) while HOMA-IR and BMI z-score did not predict SUA.ConclusionsHigh uric acid is associated with metabolic abnormalities and particularly with waist circumference very early in childhood.
New perspectives in Glioblastoma: Nanoparticles-based approaches Rosa Luciano, Giulia Battafarano, Rossana Saracino, Michela Rossi, Antonio Perrotta, et al. Current Cancer Drug Targets, 2016 Glioblastoma multiforme represents one of the most aggressive tumor of central nervous system. Current therapy includes surgery, radiation and chemotherapy. These treatments are rarely curative and glioma are associated with a poor prognosis. Nanomedicine represents the most innovative branch of medicine since many studies demonstrated great advantage in the diagnosis and therapy of several diseases. In this review we will summarize the results obtained by the use of nanoparticles and extracellular vesicles in glioblastoma. A great interest is raising from these studies that underlined the efficacy and specificity of this treatment for glioma, reducing side-effects associated with conventional therapies.
Reference ranges of HOMA-IR in normal-weight and obese young Caucasians Blegina Shashaj, Rosa Luciano, Benedetta Contoli, Giuseppe Stefano Morino, Maria Rita Spreghini, et al. Acta Diabetologica, 2016 AimsInsulin resistance (IR) may develop very early in life being associated with occurrence of cardiometabolic risk factors (CMRFs). Aim of the present study was to identify in young Caucasians normative values of IR as estimated by the homeostasis model assessment (HOMA-IR) and cutoffs diagnostic of CMRFs.MethodsAnthropometrics and biochemical parameters were assessed in 2753 Caucasians (age 2–17.8 years; 1204 F). Reference ranges of HOMA-IR were defined for the whole population and for samples of normal-weight and overweight/obese individuals. The receiver operator characteristic analysis was used to find cutoffs of HOMA-IR accurately identifying individuals with any CMRF among total cholesterol and/or triglycerides higher than the 95th percentile and/or HDL cholesterol lower than the 5th for age and sex, impaired glucose tolerance, and alanine aminotransferase levels ≥40 U/l.ResultsOverweight/obese individuals had higher HOMA-IR levels compared with normal-weight peers (p < 0.0001) at any age. HOMA-IR index rose progressively with age, plateaued between age 13 and 15 years and started decreasing afterward. HOMA-IR peaked at age 13 years in girls and at 15 years in boys. The 75th percentile of HOMA-IR in the whole population (3.02; AUROC = 0.73, 95 % CI = 0.70–0.75), in normal-weight (1.68; AUROC = 0.76, 95 % CI = 0.74–0.79), and obese (3.42; AUROC = 0.71, 95 % CI = 0.69–0.72) individuals identified the cutoffs best classifying individuals with any CMRF.ConclusionsPercentiles of HOMA-IR varied significantly in young Caucasians depending on sex, age, and BMI category. The 75th percentile may represent an accurate cutoff point to suspect the occurrence of one or more CMRFs among high total cholesterol and triglycerides, low HDL cholesterol, and ALT ≥ 40 UI/l.
Nanoparticles-based treatment for bone metastasis Rossana Saracino, Rosa Luciano, Giulia Battafarano, Antonio Perrotta, Maurizio Muraca, et al. Current Drug Targets, 2016 Bone is the principal site of metastasis for many carcinomas, including prostate. Once bone metastases are established, the chances of survival dramatically drop. Bone metastases place patients at increased risk of skeletal-related events, including pathologic fractures, bone pain and hypercalcemia. Indeed, skeletal metastases represent the prevalent cause of morbidity and mortality for many tumors. They are the result of interactions among tumour cells, bone marrow environment and bone cells (vicious cycle). In the last few years many efforts were undertaken to identify new therapeutic approaches for bone metastasis. Current therapies target the several players of bone vicious cycle. However many adverse effects are associated with these treatments. This review will focus on the new emerging sector of nanomedicine, that could be important to identify more specific and safe treatments for bone metastasis.
Biomarkers of Alzheimer disease, insulin resistance, and obesity in childhood R. Luciano, G. M. Barraco, M. Muraca, S. Ottino, M. R. Spreghini, et al. Pediatrics, 2015 OBJECTIVE: To answer the question of whether onset of insulin resistance (IR) early in life enhances the risk of developing dementia and Alzheimer disease (AD), serum levels of 2 molecules that are likely associated with development of AD, the amyloid β-protein 42 (Aβ42) and presenilin 1 (PSEN1), were estimated in 101 preschoolers and 309 adolescents of various BMI. METHODS: Participants (215 boys; 48.8%) were normal weight (n = 176; 40%), overweight (n = 135; 30.7%), and obese (n = 129; 29.3%). The HOmeostasis Model of IR (HOMA-IR), HOMA percent β-cell function (HOMA-β) and QUantitative Insulin-sensitivity Check Index (QUICKI) were calculated. RESULTS: Obese adolescents had values of Aβ42 higher than overweight and normal-weight peers (190.2 ± 9.16 vs 125.9 ± 7.38 vs 129.5 ± 7.65 pg/mL; P < .0001) as well as higher levels of PSEN1 (2.34 ± 0.20 vs 1.95 ± 0.20 vs 1.65 ± 0.26 ng/mL; P < .0001). Concentrations of Aβ42 were significantly correlated with BMI (ρ = 0.262; P < .0001), HOMA-IR (ρ = 0.261; P < .0001) and QUICKI (ρ = −0.220; P < .0001). PSEN1 levels were correlated with BMI (ρ = 0.248; P < .0001), HOMA-IR (ρ = 0.242; P < .0001), and QUICKI (ρ = −0.256; P < .0001). Western blot analysis confirmed that PSEN1 assays measured the full-length protein. CONCLUSION: Obese adolescents with IR present higher levels of circulating molecules that might be associated with increased risk of developing later in elderly cognitive impairment, dementia, and AD.
Endocrine autoimmunity in Turner syndrome Armando Grossi, Antonino Crinò, Rosa Luciano, Antonietta Lombardo, Marco Cappa, et al. Italian Journal of Pediatrics, 2013
