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Francesca Cinti,* Simona Moffa,* Flavia Impronta,* Chiara MA Cefalo, Vinsin A Sun, Gian Pio Sorice, Teresa Mezza, Andrea Giaccari Center for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy *These authors contributed equally to this work Abstract: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and β-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients. Keywords: antidiabetic drugs, glycosylated hemoglobin, glycemic control, sodium-glucose cotransporter 2 inhibitors, precision medicine, type 1 diabetes mellitus, type 2 diabetes mellitus, weight reduction

Giovanna Aquino,1 Enzo Iuliano,1 Alessandra di Cagno,2 Angela Vardaro,3 Giovanni Fiorilli,1 Stefano Moffa,1 Alfonso Di Costanzo,1 Giuseppe De Simone,3 Giuseppe Calcagno1 1Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, Campobasso, 2Department of Health Science, University ForoItalico, Rome, 3“Villa Margherita”, Benevento, Italy Aim: The aim of this study was to investigate the effects of high-intensity aerobic training (AT) and high-intensity aerobic training combined with resistance training (ie, combined training [CT]) on cognitive function in patients with COPD. Methods: Twenty-eight Caucasian male patients (68.35±9.64 years; mean ± SD) with COPD were recruited and randomized into two groups, AT and CT. Both groups performed physical reconditioning for 4 weeks, with a frequency of five training sessions per week. The CT group completed two daily sessions of 30 minutes: one aerobic session and one strength session, respectively; The AT group performed two 30-minute aerobic endurance exercise sessions on treadmill. Physical and cognitive function tests were performed before and after the training intervention performances. Results: Exercise training improved the following cognitive functions: long-term memory, verbal fluency, attentional capacity, apraxia, and reasoning skills (P

Humans exposed to altitude hypoxia experience dysfunctions of the urinary system. As a non-invasive, easily manageable and informative biological sample, urine represents a relevant matrix for detecting clinical impairments of urinary system, as well as alterations of other systems and extracellular vesicles (EVs) biology during high-altitude expeditions. Nevertheless, gaps exist in the comprehensive assessment of dysfunction, molecular burden and EVs biology due to high-altitude acute exposure. This study aimed to find a biophysical and biochemical signature of urinary EVs for hypoxia-induced changes in urinary function, putatively accompanied by an oxinflammatory burden. Urine samples of 15 participants were sampled at low and high-altitude during an Alpine project (7 women and 8 men, aged 24-to-63 years and with BMI 17.93-to-30.76 kg/m 2 ) and analysed for: creatinin and albumin, lipid peroxidation, IL6, NO derivatives; atomic force microscopy and Raman spectroscopy were carried out after urinary EVs were isolated through sucrose-gradient ultracentrifugation. Albumin-to-creatinin ratio increased at high altitude, as did IL6 and 8-isoprostane. AFM showed a globular and flattened shape of EVs, although several samples were characterized by a lot of contaminants and EVs lost their prototypal spherical shape; EVs comprehensively maintained their morphology at high altitude. Raman spectroscopy revealed some typical phospholipidic-like pattern, often masked by contaminants of spectra that most often refer to high-altitude samples. Collectively, short-term exposure to altitude hypoxia increased renal concentrating ability, produced non-pathological impairment or renal function, and triggered an oxyinflammatory burden with heterogeneous response of NO system. The combination of AFM and Raman spectroscopy revealed that EVs collected at high altitude more likely are fused together and incorporated into a sediment matrix, and contain contaminants peaks that make the purification process less efficient. The combination of analytical procedures as in the present study offers novel possibilities to detect the biological and clinical effects of high altitude on renal system., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Regenerative medicine and tissue engineering aim to restore or replace impaired organs and tissues using cell transplantation supported by scaffolds. Recently scientists are focusing on developing new biomaterials that optimize cellular attachment, migration, proliferation, and differentiation. Nanoparticles, such as graphene oxide (GO), have emerged as versatile materials due to their high surface-to-volume ratio and unique chemical properties, such as electrical conductivity and flexibility. However, GO faces challenges such as cytotoxicity at high concentrations, a negative surface charge, and potential inflammatory responses; for these reasons, variations in synthesis have been studied. A GO derivative, Graphene Oxide-Polyethylenimine (GO-PEI), shows controlled porosity and structural definition, potentially offering better support for cell growth. Human amniotic fluid stem cells (hAFSCs) are a promising candidate for regenerative medicine due to their ability to differentiate into mesodermic and ectodermic lineages, their non-immunogenic nature, and ease of isolation. This study investigates the effects of GO and GO-PEI on hAFSCs, focusing on the effects on adhesion, proliferation, and metabolic features. Results indicate that GO-PEI restores cell proliferation and mitochondrial activity to control levels, with respect to GO that appeared less biocompatible. Both materials also influence the miRNA cargo of hAFSC-derived microvesicles, potentially influencing also cell-to-cell communication.

Aims: Chronic pancreatitis (CP) is - along with acute pancreatitis - the most frequent cause of diabetes of the exocrine pancreas (DEP). Although insulin deficiency is widely accepted as the major feature of DEP, it is still unclear whether diabetes associated with CP is characterized by additional or different functional defects of the insulin secretory machinery. To identify possible functional defects specifically induced by CP, we performed a cross-sectional study in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM) comparing patients with and without CP (CP vs. NCP)., Methods: We administered an oral glucose tolerance test (OGTT) to all participants and, according to their glucose tolerance, classified them as NGT, IGT and DM. Insulin sensitivity and beta-cell functional parameters were derived from OGTT, hyperglycemic clamp and hyperinsulinemic euglycemic clamp., Results: Studying 146 subjects, we found that beta-cell function and insulin secretion were significantly lower in CP compared to NCP patients. However, when we classified the subjects according to OGTT-derived glucose tolerance, we found no differences in beta-cell function or in insulin sensitivity between CP and NCP with the same glucose tolerance status. Of note, we found that arginine-stimulated insulin secretion is reduced only in subjects with CP and DM compared to NCP subjects with DM., Conclusions: Patients with CP had no specific alterations in insulin secretion and beta-cell function. However, in patients diagnosed with diabetes, we found a lower arginine-stimulated insulin secretion, a marker of reduced functional mass., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Physical exercise is a key component in the treatment of type 2 diabetes and plays an important role in maintaining a healthy glucose metabolism even in healthy subjects. To date, no studies have investigated the effect of a single bout of aerobic physical exercise on glucose metabolism in young, moderately active, healthy adults., Methods: We performed an OGTT 7 days before and 24 h after a single bout of physical exercise, to evaluate 1-hour post-load plasma glucose and surrogate indexes of insulin sensitivity and insulin secretion., Results: Glucose levels were significantly reduced after exercise at baseline and one hour after glucose load; similarly, insulin was significantly lower 1 h after glucose load. We found a significant increase in the Matsuda index, confirmed by OGIS index, QUICKI index, and by significant reduction in HOMA-IR. Conversely, we observed a trend to increase in HOMA-B., Conclusion: This is the first study to evaluate the effect of a single bout of exercise on 1-hour glucose levels following OGTT. We found a significant reduction in 1-hour glucose levels following OGTT together with an increased insulin sensitivity. A single 30-minute bout of aerobic exercise also seemed to improve the insulin secretion pattern. Modifications in beta cell secretory capacity during exercise are likely secondary to an improvement in insulin action in insulin dependent tissues., (© 2024. The Author(s).)

Responsiveness of liposomes to external stimuli, such as light, should allow a precise spatial and temporal control of release of therapeutic agents or ion transmembrane transport. Here, some aryl-azo derivatives of thymol are synthesized and embedded into liposomes from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine to obtain light-sensitive membranes whose photo-responsiveness, release behaviour, and permeability towards Cl - ions are investigated. The hybrid systems are in-depth characterized by dynamic light scattering, atomic force microscopy and Raman spectroscopy. In liposomal bilayer the selected guests undergo reversible photoinduced isomerization upon irradiation with UV and visible light, alternately. Non-irradiated hybrid liposomes retain entrapped 5(6)-carboxyfluorescein (CF), slowing its spontaneous leakage, whereas UV-irradiation promotes CF release, due to guest trans-to-cis isomerization. Photoisomerization also influences membrane permeability towards Cl - ions. Data processing, according to first-order kinetics, demonstrates that Cl - transmembrane transport is enhanced by switching the guest from trans to cis but restored by back-switching the guest from cis to trans upon illumination with blue light. Finally, the passage of Cl - ions across the bilayer can be fine-tuned by irradiation with light of longer λ and different light-exposure times. Fine-tuning the photo-induced structural response of the liposomal membrane upon isomerization is a promising step towards effective photo-dynamic therapy., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lynch syndrome (LS) is a genetic disease with increased risk of colorectal cancer and other malignancies. There are few reported cases of thyroid cancer in LS patients. The aim of this study is to investigate the presence of thyroid nodules in LS patients and to explore their association with the genetic features of the disease., Methods: A retrospective and descriptive analysis was conducted to include all LS patients followed at the CEMAD (Centro Malattie Apparato Digerente) of Fondazione Policlinico Universitario A. Gemelli IRCCS. The characteristics of LS disease, gene mutations, and previous history of thyroid disease were evaluated. Majority of patients underwent thyroid ultrasound (US), and nodule cytology was performed when needed., Results: Of a total of 139 patients with LS, 110 patients were included in the study. A total of 103 patients (74%) underwent thyroid ultrasound examinations, and 7 patients (5%) had a previous history of thyroid disease (cancer or multinodular goiter). The mean age was 51.9 years. Thyroid nodules were found in 62 patients (60%) who underwent US, and 9 of them (14%) had suspicious features of malignancy, inducing a fine-needle aspiration biopsy. A cytologic analysis classified 7 of 9 cases (78%) as TIR2 and 2 (22%) as TIR3a. Between patients with nodular thyroid disease (single nodule, multinodular goiter, and cancer), most of them (25 patients, 36% of total) were carriers of the MSH6 mutation, while 22 (32%), 17 (24%), and 5 (7%) had MSH2, MLH1, and PMS2 mutations, respectively., Conclusions: A high prevalence of thyroid nodules was found in patients with LS, especially in MSH6-carrying patients. Performing at least one thyroid ultrasound examination is suggested for the detection of nodular thyroid disease in LS patients. Systematic investigations are needed to estimate their prevalence, features, and risk of malignant transformation.

Exposure to high altitude might cause the body to adapt with negative energy and fluid balance that compromise body composition and physical performance. In this field study involving 12 healthy adults, sex-balanced, and aged 29 ± 4 years with a body mass index of 21.6 ± 1.8 kg/m 2 , we investigated the effects of a 4-day trekking up to 4556 m a.s.l. on Monte Rosa (Alps, Italy). The food intake was recorded using food diaries and nutrient averages were calculated. The bio-impedance analysis was performed at low and high altitudes, and a wearable biosensor (Swemax) was used to track hydro-saline losses in two participants. Daily total energy intake was 3348 ± 386 kcal for males and 2804 ± 415 kcal for females (13%-14% protein, 35% fat, 44%-46% carbohydrates). Although there was a significant body weight loss (65.0 ± 9.3 vs. 64.2 ± 9.10 kg, p  < 0.001, d  = 1.398), no significant changes in body composition parameter were found but a trend in the increase of the bioelectrical phase angle in males ( p  = 0.059, d = -0.991). Body water percentage significantly changed ( p  = 0.026, η 2 p   = 0.440), but the absolute water did not, suggesting that the weight loss was not due to water loss. Salivary and urinary osmolality did not change. A reduction in sweat rate at higher altitudes was observed in both participants. Interestingly, salivary leptin increased ( p  = 0.014, η 2 p   = 0.510), and salivary ghrelin decreased ( p  = 0.036, η 2 p  = 0.403). Therefore, the 4-day trekking at altitude of hypoxia exposure induced changes in satiety and appetite hormones. High altitude expeditions require more specific nutritional guidance, and using multiplex analysis could help in monitoring fluid balance and body composition., Competing Interests: Matteo Beccatelli, Pierluigi Lodi Rizzini, Davide Seletti, Rocco Mecca, and Tommaso Beccatelli were employee or collaborators of the company Biometrica S.r.l., Parma, Italy (which provided the device SWEMAX and the technical assistance) while engaged in the research project. The other authors declare there are no competing interests.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO)., Aim: To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR., Methods: Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells., Results: Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group (p = 0.043)., Conclusions: In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population., Trial Registration: EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752., (© 2023. The Author(s).)

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose-lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose-lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose-lowering agents on NAFLD and may represent the key to NAFLD treatment., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual β-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and β-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on β-cell function.

The application of biomaterials on immune regenerative strategies to deal with unsolved pathologies is getting attention in the field of tissue engineering. In this context, graphene oxide (GO) has been proposed as an immune-mimetic material largely used for developing stem cell-based regenerative therapies, since it has shown to influence stem cell behavior and modulate their immune response. Similarly, amniotic epithelial stem cells (AECs) are getting an increasing clinical interest as source of stem cells due to their great plasticity and immunomodulatory paracrine activities, even though GO bio-mimetic effects still remain unknown. To this aim, GO-functionalized glass coverslips have been used for AECs culture. The results demonstrated how GO-coating is able to induce and accelerate the Epithelial-Mesenchymal Transition (EMT), in a process mediated by the intracellular activation of TGFβ1-SMAD2/3 signaling pathway. The trans -differentiation towards mesenchymal phenotype provides AECs of migratory ability and substantially changes the pattern of cytokines secretion upon inflammatory stimulus. Indeed, GO-exposed AECs enhance their pro-inflammatory interleukins production thus inducing a more efficient activation of macrophages and, at the same time, by slightly reducing their inhibitory action on peripheral blood mononuclear cells proliferation. Therefore, the adhesion of AECs on GO-functionalized surfaces might contribute to the generation of a tailored microenvironment useful to face both the phases of the inflammation, thereby fostering the regenerative process., Competing Interests: 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., (© 2023 The Authors. Published by Elsevier Ltd.)

Next-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale pathogenic variants, the copy number variations (CNVs) represent the underlying molecular defects in approximately 10% of FH cases. Here, we reported a novel large deletion in the LDLR gene involving exons 4-18, identified by the bioinformatic analysis of NGS data in an Italian family. A long PCR strategy was employed for the breakpoint region analysis where an insertion of six nucleotides (TTCACT) was found. Two Alu sequences, identified within intron 3 and exon 18, could underlie the identified rearrangement by a nonallelic homologous recombination (NAHR) mechanism. NGS proved to be an effective tool suitable for the identification of CNVs, together with small-scale alterations in the FH-related genes. For this purpose, the use and implementation of this cost-effective, efficient molecular approach meets the clinical need for personalized diagnosis in FH cases.

Background: Anti-PCSK9 monoclonal antibodies are effective in reducing LDL-C and cardiovascular events by neutralizing circulating PCSK9. PCSK9, however, is also expressed in tissues, including the pancreas, and studies on PCSK9 KO mice have shown impaired insulin secretion. Statin treatment is already known to affect insulin secretion. Our aim was to conduct a pilot study to evaluate the effect of anti-PCSK9 mAb on glucose metabolism and β-cell function in humans., Methods: Fifteen non-diabetic subjects, candidates for anti-PCSK9 mAb therapy, were enrolled. All underwent OGTT at baseline and after 6 months of therapy. During OGTT, insulin secretion parameters were derived from C-peptide by deconvolution (β cell glucose sensitivity). Surrogate insulin sensitivity indices were also obtained from OGTT (Matsuda)., Results: Glucose levels during OGTT were unchanged after 6 months of anti-PCSK9 mAb treatment, as well as insulin and C-peptide levels. The Matsuda index remained unchanged, while β-cell glucose sensitivity improved post-therapy (before: 85.3 ± 65.4; after: 118.6 ± 70.9 pmol min -1 m -2 mM -1 ; p<0.05). Using linear regression, we found a significant correlation between βCGS changes and BMI (p=0.004). Thus, we compared subjects with values above and below the median (27.6 kg/m 2 ) and found that those with higher BMI had a greater increase in βCGS after therapy (before: 85.37 ± 24.73; after: 118.62 ± 26.83 pmol min -1 m -2 mM -1 ; p=0.007). There was also a significant correlation between βCGS change and Matsuda index through linear regression (p=0.04), so we analyzed subjects who had values above and below the median (3.8). This subgroup analysis showed a slight though not significant improvement in βCGS in more insulin resistant patients, (before: 131.4 ± 69.8; after: 170.8 ± 92.7 pmol min -1 m -2 mM -1 ; p=0.066)., Conclusions: Our pilot study demonstrates that six-month treatment with anti-PCSK9 mAb improves β-cell function, and does not alter glucose tolerance. This improvement is more evident in patients with greater insulin-resistance (low Matsuda) and higher BMI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Moffa, Mezza, Ferraro, Di Giuseppe, Cefalo, Cinti, Impronta, Capece, Ciccarelli, Mari, Pontecorvi and Giaccari.)

Expanded newborn screening (NBS) is a preventive program that allows for the early identification of over 40 congenital endocrine-metabolic diseases by analyzing dried blood spot samples collected from the newborn's heel within 48-72 h of birth. The determination of amino acids and acyl-carnitines by Flow Injection Analysis Tandem Mass Spectrometry (FIA-MS/MS) may also highlight metabolic alterations resulting from external factors, such as maternal nutrition. In the present study, we developed a questionnaire to investigate the eating habits of 109 women during pregnancy and statistically correlated the results from the investigation on dietary habits with the data obtained by the NBS laboratory of Abruzzo region (Italy). Parameters such as smoking, physical activity, and the intake of iodized salt, drugs, and supplements were analyzed. This study aimed to highlight how maternal lifestyle, diet, and drug intake during pregnancy may affect the neonatal metabolic profile, possibly generating false positive or false negative results in the NBS test. The results pointed out how the knowledge of maternal nutrition and lifestyle may also be precious in preventing misinterpretations of the neonatal metabolic profile, thereby reducing unnecessary stress for newborns and their parents and limiting costs for the health system.

Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with β cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual β cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on β cell secretion., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The development of novel three-dimensional (3D) nanomaterials combining high biocompatibility, precise mechanical characteristics, electrical conductivity, and controlled pore size to enable cell and nutrient permeation is highly sought after for cardiac tissue engineering applications including repair of damaged heart tissues following myocardial infarction and heart failure. Such unique characteristics can collectively be found in hybrid, highly porous tridimensional scaffolds based on chemically functionalized graphene oxide (GO). By exploiting the rich reactivity of the GO's basal epoxydic and edge carboxylate moieties when interacting, respectively, with NH 2 and NH 3 groups of linear polyethylenimines (PEIs), 3D architectures with variable thickness and porosity can be manufactured, making use of the layer-by-layer technique through the subsequent dipping in GO and PEI aqueous solutions, thereby attaining enhanced compositional and structural control. The elasticity modulus of the hybrid material is found to depend on scaffold's thickness, with the lowest value of 13 GPa obtained in samples containing the highest number of alternating layers. Thanks to the amino-rich composition of the hybrid and the established biocompatibility of GO, the scaffolds do not exhibit cytotoxicity; they promote cardiac muscle HL-1 cell adhesion and growth without interfering with the cell morphology and increasing cardiac markers such as Connexin-43 and Nkx 2.5. Our novel strategy for scaffold preparation thus overcomes the drawbacks associated with the limited processability of pristine graphene and low GO conductivity, and it enables the production of biocompatible 3D GO scaffolds covalently functionalized with amino-based spacers, which is advantageous for cardiac tissue engineering applications. In particular, they displayed a significant increase in the number of gap junctions compared to HL-1 cultured on CTRL substrates, which render them key components for repairing damaged heart tissues as well as being used for 3D in vitro cardiac modeling investigations.+ groups of linear polyethylenimines (PEIs), 3D architectures with variable thickness and porosity can be manufactured, making use of the layer-by-layer technique through the subsequent dipping in GO and PEI aqueous solutions, thereby attaining enhanced compositional and structural control. The elasticity modulus of the hybrid material is found to depend on scaffold's thickness, with the lowest value of 13 GPa obtained in samples containing the highest number of alternating layers. Thanks to the amino-rich composition of the hybrid and the established biocompatibility of GO, the scaffolds do not exhibit cytotoxicity; they promote cardiac muscle HL-1 cell adhesion and growth without interfering with the cell morphology and increasing cardiac markers such as Connexin-43 and Nkx 2.5. Our novel strategy for scaffold preparation thus overcomes the drawbacks associated with the limited processability of pristine graphene and low GO conductivity, and it enables the production of biocompatible 3D GO scaffolds covalently functionalized with amino-based spacers, which is advantageous for cardiac tissue engineering applications. In particular, they displayed a significant increase in the number of gap junctions compared to HL-1 cultured on CTRL substrates, which render them key components for repairing damaged heart tissues as well as being used for 3D in vitro cardiac modeling investigations.

It is important to block SARS-CoV-2 infection immediately with early therapies, such as monoclonal antibodies (MonoAbs). Also, several studies show that obesity is associated with a high risk of severe COVID-19 disease. We enrolled 32 SARS-CoV-2 infected patients who received MonoAbs, all patients were not vaccinated for SARS-CoV-2, and they received therapy after 7 ± 2 days from the onset of COVID-19 symptoms. In the days following administration, patients followed home therapy with Pidotimod 800 mg bid for 10 days and cholecalciferol 2000 UI for 20 days, prescribed the same day they received MonoAbs therapy. Our study found that there are no differences in the therapeutic response between obese and nonobese patients with SARS-CoV-2 infection undergoing MonoAbs therapy, in fact, none of them underwent hospitalization. Furthermore, the effect of the immunostimulant Pidotimod and cholecalciferol may have contributed to the resolution of COVID-19 symptoms in these patients., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Background: Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein-cholesterol levels and it is primarily caused by pathogenic/likely pathogenic variants (P/LPVs) in LDLR, APOB or PCSK9 genes. Next generation sequencing (NGS) technology allows the evaluation of more genes simultaneously, rising the diagnostic throughput of genomics laboratories., Materials and Methods: We report a Ukrainian 37-year-old woman hypercholesterolemic since 2010. Despite a suggestive family history, FH was suspected only when the patient referred to the Endocrine and Metabolic Diseases Center of the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. After specialist advice, genetic testing was offered to the patient at our Molecular and Genomic Diagnostics Unit., Results: A targeted NGS-based pipeline highlighted a novel out-of-frame deletion in the LDLR gene. This variant has a clear deleterious effect on the LDLR protein and it can be classified as PV., Conclusions: The ideal model of care for FH is an evidence-based system aimed to provide the highest-quality health services to all FH patients. In fact, this study reports that the integrated care pathway adopted in our hospital for FH patients led successfully to the discovery of a novel LDLR PV in an Ukrainian patient. The finding of this LDLR variant allowed the clinical FH diagnosis in this patient and in her family, expanding the knowledge of FH-related genetic variants in the Ukrainian population., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

An amphiphilic calix[6]arene, alone or complexed with an axle to form a pseudo-rotaxane, has been embedded into liposomes prepared from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and the permeability of the membrane-doped liposomes towards Cl - ions has been evaluated by using lucigenin as the fluorescent probe. The pseudo-rotaxane promotes transmembrane transport of Cl - ions more than calix[6]arene does. Surprisingly, the quenching of lucigenin was very fast for liposomes doped with the positively charged axle alone. Molecular dynamics (MD) simulations and quantum-chemical calculations were also carried out for providing a semi-quantitative support to the experimental results., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder whose rising incidence suggests the epidemic proportions of the disease. Impaired fasting glucose (IFG) and Impaired Glucose Tolerance (IGT) - alone or combined - represent two intermediate metabolic condition between Normal Glucose Tolerance (NGT) and overt T2DM., Evidence Acquisition: Databases were systematically screened using the following MeSH terms combination as follows: 1. prediabetes, 2. prediabetic state, 3. prevention, 4. lifestyle, 5. diet, 6. nutrition, 7. pharmacotherapy, 8. metformin, 9. thiazolidinediones, 10. sodium glucose cotransporter 2 inhibitors, 11. GLP 1 receptor agonists, 12. alpha glucosidase inhibitors, 13. insulin, 14. DPP IV inhibitors., Evidence Synthesis: Several studies have demonstrated that insulin resistance and beta-cell impairment can be identified even in normoglycemic prediabetic individuals. Worsening of these two conditions may lead to progression of IGT and/or IFG status to overt diabetes. Starting from these assumptions, it seems logical to suppose that interventions aimed at improving metabolic conditions, even in prediabetes, could represent an effective target to halt transition from IGT/IFG to manifest T2DM. Starting from pathophysiological knowledge, in this review we evaluate two possible interventions (lifestyle modifications and pharmacological agents) eligible as prediabetes therapy since they have been demonstrated to improve insulin resistance and beta-cell impairment., Conclusions: Detecting high-risk people and treating them could represent an effective strategy to slow down progression to overt diabetes, normalize glucose tolerance, and even prevent micro- and macrovascular complications.

BACKGROUNDThe appearance of hyperglycemia is due to insulin resistance, functional deficits in the secretion of insulin, and a reduction of β cell mass. There is a long-standing debate as to the relative contribution of these factors to clinically manifesting β cell dysfunction. The aim of this study was to verify the acute effect of one of these factors, the reduction of β cell mass, on the subsequent development of hyperglycemia.METHODSTo pursue this aim, nondiabetic patients, scheduled for identical pancreaticoduodenectomy surgery, underwent oral glucose tolerance tests (OGTT) and hyperglycemic clamp (HC) procedures, followed by arginine stimulation before and after surgery. Based on postsurgery OGTT, subjects were divided into 3 groups depending on glucose tolerance: normal glucose tolerance (post-NGT), impaired glucose tolerance (post-IGT), or having diabetes mellitus (post-DM).RESULTSAt baseline, the 3 groups showed similar fasting glucose and insulin levels; however, examining the various parameters, we found that reduced first-phase insulin secretion, reduced glucose sensitivity, and rate sensitivity were predictors of eventual postsurgery development of IGT and diabetes.CONCLUSIONDespite comparable functional mass and fasting glucose and insulin levels at baseline and the very same 50% mass reduction, only reduced first-phase insulin secretion and glucose sensitivity predicted the appearance of hyperglycemia. These functional alterations could be pivotal to the pathogenesis of type 2 diabetes (T2DM).TRIAL REGISTRATIONClinicalTrials.gov NCT02175459.FUNDINGUniversità Cattolica del Sacro Cuore; Italian Ministry of Education, University and Research; European Foundation for the Study of Diabetes.

Recent events in prisons during the COVID-19 pandemic showed how the health situation and overcrowding in prisons are a source of high risk to the health and physical and mental well-being of the prison population and how this has become an important medical problem. The original purpose of this study, which was initially planned to last 6 months, was to examine the effects of a training program on cardio-respiratory capacity, resistance to dynamic strength of the upper and lower body and muscle mass. Following the COVID-19 pandemic, the purpose was subsequently modified by highlighting whether and which deficiencies occurred as a result of the absence of physical activity. Forty adult men between 35 and 55 years of age with more than 1 year of detention were selected and randomly divided into two groups: the experimental group and control group. The fitness training protocol of the experimental group consisted of three weekly sessions lasting 90 min, while control group subjects followed a walk of 30-60 min three days a week without running or resistance training. The unpaired and paired t-tests revealed significant effects of both health status and fitness level ( p < 0.05; p < 0.01) on group training. The results of this research show that prisoners can improve their fitness and health through participation in physical education programs. This conclusion is especially important for prisoners who have to serve very long prison sentences and who are at great risk of showing poor physical condition levels.

Hoverboards are always more popular among children. Hoverboards are to them like a game or a mean of transport, but they could be used as a valid and useful instrument in children's training programs to improve their performance. In this study, we compared the athletic performance of two groups of 12 children. A total of 24 children aged between 8 and 11 years followed a similar training program for five months, but the first group used a hoverboard (Hb+ group: Age: Standard Deviation (SD) = 1.15 Mean = 9.66; Weight: SD = 5.90 Mean = 32; Height: SD = 7.64 Mean = 135.08) for some of the training time, differently from the second group (Hb- group: Age: SD = 1.15 Mean = 9.66; Weight: SD = 5.82 Mean = 31.16; Height: SD = 7.66 Mean = 136.16), which never used it. All of the children were asked to complete three tests (one leg test, stork test and balance beam walking test) before starting their own training program and after five months, to evaluate how their performances changed in terms of time. Comparing the recorded time difference between T0 and T1 of the Hb+ group with the same difference measured in Hb- group, it was found that there was a statistically significant difference ( p value < 0.05) between these data for all three tests. Children who used the hoverboard in their training program achieved better result than children who did not use it. In the future, the hoverboard could help athletes to improve their performances, possibly applying it not only in football training, but even in other sports.

Introduction: Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). Targeted Next Generation Sequencing (NGS) is a new opportunity to expand the existing pathogenic variants (PVs) spectrum associated to FH. Our aim was to report a diagnostic NGS-based approach to detect variants associated to FH., Methods: We report two patients: a 48-year-old Asian woman, without known history of hypercholesterolemia and a 46-year-old Caucasian man, with childhood hypercholesterolemia., Results: An effective NGS-based pipeline, FH-Devyser kit/Amplicon Suite, beginning from sequencing to data analysis, did not identify known PVs in the LDLR, APOB, APOE, LDLRAP1, STAP1 and PCSK9 genes, but revealed two novel LDLR variants (c.1564A>T, p.Ile522Phe and c.1688C>T, p.Pro563Leu)., Discussion and Conclusions: This study showed that an effective NGS-based pipeline led to a definitive diagnosis in two FH families, allowing to plan their therapeutic treatment. Although the functional consequence of the two LDLR variants needs to be assessed in vitro, the in silico analysis and high preservation of the two amino acid positions observed in the LDLR protein, across different animal species, suggest that both variants are deleterious.