Search

Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3β complex in response to insulin, hindering the accumulation of pGSK3βS9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3βS9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.

PurposeThe coronavirus pandemic (COVID-19) significantly impacted the global economy and health. Italy was one of the first and most affected countries. The objective of our study was to assess the impact of the pandemic and the vaccination campaign on the radiological examinations performed in a radiology department of a tertiary center in Southern Italy.Materials and methodsWe analyzed weekly and retrospectively electronic medical records of case volumes performed at the Radiology Department of “Mater Domini” University Hospital of Catanzaro from March 2020 to March 2022, comparing them with the volumes in the same period of the year 2019. We considered the origin of patients (outpatient, inpatient) and the type of examinations carried out (x-ray, mammography, CT, MRI, and ultrasound). A non-parametric test (Wilcoxon Signed Rank test) was applied to evaluate the average volumes.ResultsTotal flows in the pandemic period from COVID-19 were lower than in the same pre-pandemic period with values of 552 (120) vs. 427 (149) median (IQR) (p

Abstract Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder characterized by cognitive and behavioral symptoms, obesity, and sleep disturbance, and no therapy has been developed to alleviate its symptoms or delay disease onset. SMS occurs due to haploinsufficiency of the retinoic acid-induced-1 (RAI1) gene caused by either chromosomal deletion (SMS-del) or RAI1 missense/nonsense mutation. The molecular mechanisms underlying SMS are unknown. Here, we generated and characterized primary cells derived from four SMS patients (two with SMS-del and two carrying RAI1 point mutations) and four control subjects to investigate the pathogenetic processes underlying SMS. By combining transcriptomic and lipidomic analyses, we found altered expression of lipid and lysosomal genes, deregulation of lipid metabolism, accumulation of lipid droplets, and blocked autophagic flux. We also found that SMS cells exhibited increased cell death associated with the mitochondrial pathology and the production of reactive oxygen species. Treatment with N-acetylcysteine reduced cell death and lipid accumulation, which suggests a causative link between metabolic dyshomeostasis and cell viability. Our results highlight the pathological processes in human SMS cells involving lipid metabolism, autophagy defects and mitochondrial dysfunction and suggest new potential therapeutic targets for patient treatment.

Abstract Background Type 1 diabetes (T1D) is frequently associated with autoimmune thyroiditis (AT) and coeliac disease (CD). Whether the coexistence of multiple autoimmune diseases increases cardiovascular risk is uncertain. We evaluated the effects of AT and CD on arterial wall thickening and endothelial function in patients with T1D. Methods This observational study analyzed data from T1D patients regularly followed by the Diabetes Care Centre. Clinical and biochemical characteristics and micro and macrovascular complications were collected from the electronic medical records. All subjects performed Echo-Doppler to evaluate Intima-Media Thickness (IMT) of the common carotid artery (CCA) and endothelial function by the flow-mediated dilation (FMD) technique. The statistical analyses were performed by SPSS for Macintosh. Comparison between means was performed using the t-test for unpaired data and the Mann–Whitney U test. The ANalysis Of VAriance and the Tukey posthoc test were applied to compare patients with and without other autoimmune diseases, and control subjects. The p-value for statistical significance was set at p

Chronic lymphocytic leukemia (CLL) is a widespread type of leukemia that predominantly targets B lymphocytes, undermining the balance between cell proliferation and apoptosis. In healthy B cells, miR-15/16, a tandem of microRNAs, functions as a tumor suppressor, curbing the expression of the antiapoptotic B cell lymphoma 2 protein (Bcl-2). Conversely, in CLL patients, a recurring deletion on chromosome 13q14, home to the miR15-a and miR16-1 genes, results in Bcl-2 overexpression, thereby fostering the onset of the pathology. In the present research, a novel approach utilizing humanized ferritin-based nanoparticles was employed to successfully deliver miR15-a and miR-16-1 into MEG01 cells, a model characterized by the classic CLL deletion and overexpression of the human ferritin receptor (TfR1). The loaded miR15-a and miR16-1, housed within modified HumAfFt, were efficiently internalized via the MEG01 cells and properly directed into the cytoplasm. Impressively, the concurrent application of miR15-a and miR16-1 demonstrated a robust capacity to induce apoptosis through the reduction in Bcl-2 expression levels. This technology, employing RNA-loaded ferritin nanoparticles, hints at promising directions in the battle against CLL, bridging the substantial gap left by traditional transfection agents and indicating a pathway that may offer hope for more effective treatments.

Tuberculous meningitis (TBM) is a severe form of tuberculosis. We report the development of fatal TBM in a 2-year-old previously healthy child, suggesting that TBM must be evaluated in children of all ages with non-specific symptoms of central nervous involvement because a diagnostic delay induces a negative prognosis.

Optical coherence tomography angiography (OCTA) is an innovative and reliable technique detecting the early preclinical retinal vascular change in patients with diabetes. We have designed our study to evaluate whether an independent relationship exists between continuous glucose monitoring (CGM)-derived glucose metrics and OCTA parameters in young adult patients with type 1 diabetes without diabetic retinopathy (DR). Inclusion criteria were age≥18 years, diagnosis of type 1 diabetes from≥1 year, stable insulin treatment in the last three months, use of real-time CGM, and CGM wear time≥70%. Each patient underwent dilated slit lamp fundus biomicroscopy to exclude the presence of DR. A skilled operator performed OCTA scans in the morning to avoid possible diurnal variation. CGM-derived glucose metrics from the last 2 weeks were collected through the dedicated software during OCTA. Forty-nine patients with type 1 diabetes (age 29 [18; 39] years, HbA1c 7.7±1.0%) and 34 control subjects participated in the study. Vessel density (VD) of the whole image and parafoveal retina in the superficial (SCP) and deep capillary plexus (DCP) was significantly lower in patients with type 1 diabetes compared to controls. The coefficient of variation of average daily glucose, evaluated by CGM, significantly correlated with foveal and parafoveal VD in SCP and with foveal VD in DCP. High glucose variability might be responsible for the early increase of VD in these areas. Prospective studies may help understand if this pattern precedes DR. The difference we detected between patients with and without diabetes confirms that OCTA is a reliable tool for detecting early retinal abnormalities.

Lung cancer is a very aggressive tumor that often forms brain metastases. We show that lung cancer cells motility, fundamental for the formation of metastases, is controlled by amino acids such as serine and glycine, abundant in brain microenvironment.

Cesare Tripolino,1 Concetta Irace,2 Antonio Cutruzzolà,2 Martina Parise,1 Milena Barone,1 Caterina Scicchitano,1 Claudio Cortese,3 Agostino Gnasso1 1Metabolic Diseases Unit, Department of Clinical and Experimental Medicine, University Magna Graecia, Catanzaro, Italy; 2Department of Health Science, University Magna Graecia, Catanzaro, Italy; 3Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, ItalyCorrespondence: Agostino GnassoMetabolic Diseases Unit, Department of Clinical and Experimental Medicine, Mater Domini Hospital, Magna Græcia University, Catanzaro, ItalyTel +39 9613697039Fax +39 9613697250Email gnasso@unicz.itIntroduction: Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of complications in type 1 diabetes (T1DM) patients. To date, several biochemical indexes of NAFLD have been developed. Among these, hepatic steatosis index (HSI) strongly relates with the results of magnetic resonance.Aim: The aim of the present study was to evaluate the possible association between HSI and complications in T1DM.Methods: Medical records of patients with T1DM were evaluated. Macro- and micro-vascular complications were evaluated by a combination of instrumental (ECG, carotid artery echo-Doppler, fundus examination, vibration threshold at biothesiometry) and laboratory examination. HSI was calculated based on gender, body mass index and transaminases level.Results: Of the 124 patients evaluated, 71 were free of complications and 53 had at least one complication. The prevalence of diabetes complications was: 27% for retinopathy, 15% for carotid atherosclerosis, 16% for neuropathy. HSI was directly correlated with age, disease duration, triglycerides, total daily insulin and inversely with HDL and eGFR. In logistic regression analysis, HSI was independently associated with diabetic complications.Conclusion: These findings show that HSI is independently associated with the presence of complications in subjects with T1DM. This can be of clinical utility, allowing a better diagnostic classification of the patient and possibly guiding the therapeutic choice.Keywords: fatty liver, type 1 diabetes, diabetes complications

BackgroundTelemedicine use in chronic disease management has markedly increased during health emergencies due to COVID-19. Diabetes and technologies supporting diabetes care, including glucose monitoring devices, software analyzing glucose data, and insulin delivering systems, would facilitate remote and structured disease management. Indeed, most of the currently available technologies to store and transfer web-based data to be shared with health care providers. ObjectiveDuring the COVID-19 pandemic, we provided our patients the opportunity to manage their diabetes remotely by implementing technology. Therefore, this study aimed to evaluate the effectiveness of 2 virtual visits on glycemic control parameters among patients with type 1 diabetes (T1D) during the lockdown period. MethodsThis prospective observational study included T1D patients who completed 2 virtual visits during the lockdown period. The glucose outcomes that reflected the benefits of the virtual consultation were time in range (TIR), time above range, time below range, mean daily glucose, glucose management indicator (GMI), and glycemic variability. This metric was generated using specific computer programs that automatically upload data from the devices used to monitor blood or interstitial glucose levels. If needed, we changed the ongoing treatment at the first virtual visit. ResultsAmong 209 eligible patients with T1D, 166 completed 2 virtual visits, 35 failed to download glucose data, and 8 declined the visit. Among the patients not included in the study, we observed a significantly lower proportion of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) users (n=7/43, 16% vs n=155/166, 93.4% and n=9/43, 21% vs n=128/166, 77.1%, respectively; P

Benign prostatic hyperplasia (BPH) is a common cause of male lower urinary tract symptoms (LUTS) that can reduce quality of life. Even if several drugs can be used in its treatment, the development of adverse drug reactions (ADRs) represents the most common cause of low adherence. In the present study, we evaluate both the efficacy and the safety of a new nutrient fixed combination of Pollen Extract plus Teupolioside, named Xipag®, in patients with LUTS. We conduct a pilot single center open label clinical study between 1 March 2020 and 30 June 2020 in patients with BPH referred to general practitioner’s ambulatories. Male patients > 45 years, sexually active, with clinical symptoms of LUTS and with a diagnosis of HPB were enrolled and received one tablet/day of Xipag® (T0), for three months (T1: end of treatment). The IPSS and IIEF-5 questionnaires were carried out at T0 and T1 and represent the first end point, whereas the primary safety end point was considered the absence of ADR or of drug–drug interactions related to Xipag® administration. During the study period, 25 subjects aged 43 to 76 years (mean 62.7 ± 9) were enrolled and completed the study. The clinical evaluation in T1 documented that Xipag® induced a statistically significant improvement (p < 0.01) in symptoms, as documented by the IPSS questionnaire (range 22.7–88.9; mean 55.2 ± 23.6), without the development of ADRs. In conclusion, this is the first real-world study that showed the efficacy and the safety of Xipag® in the BPH patients with LUTS.

Abstract Background Cardiovascular protection following empagliflozin therapy is not entirely attributable to the glucose lowering effect. Increased hematocrit might influence the shear stress that is the main force acting on the endothelium, regulating its anti-atherogenic function. Objective We designed the study with the aim of investigating the effect of empagliflozin on blood viscosity and shear stress in the carotid arteries. A secondary endpoint was the effect of empagliflozin on carotid artery wall thickness. Methods The study was a non-randomized, open, prospective cohort study including 35 type 2 diabetic outpatients who were offered empagliflozin or incretin-based therapy (7 liraglutide, 8 sitagliptin) in combination with insulin and metformin. Blood viscosity, shear stress and carotid wall thickness were measured at baseline and at 1 and 3 months of treatment. Blood viscosity was measured with a viscometer, and shear stress was calculated using a validated formula. Intima-media thickness (IMT) of the carotid artery was detected by ultrasound and was measured with dedicated software. Results Blood viscosity (4.87 ± 0.57 vs 5.32 ± 0.66 cP, p

Aims: Individuals with type 1 diabetes (T1D) do not appear to have an elevated risk of severe Coronavirus Disease 19 (COVID‐19). Pre‐existing immune reactivity to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) in unexposed individuals may serve as a protective factor. Hence, our study was designed to evaluate the existence of T cells with reactivity against SARS‐CoV‐2 antigens in unexposed patients with T1D. Materials and methods: Peripheral blood mononuclear cells (PBMCs) were collected from SARS‐CoV‐2 unexposed patients with T1D and healthy control subjects. SARS‐CoV‐2 specific T cells were identified in PBMCs by ex‐vivo interferon (IFN)γ‐ELISpot and flow cytometric assays. The epitope specificity of T cells in T1D was inferred through T Cell Receptor sequencing and GLIPH2 clustering analysis. Results: T1D patients unexposed to SARS‐CoV‐2 exhibited higher rates of virus‐specific T cells than controls. The T cells primarily responded to peptides from the ORF7/8, ORF3a, and nucleocapsid proteins. Nucleocapsid peptides predominantly indicated a CD4+ response, whereas ORF3a and ORF7/8 peptides elicited both CD4+ and CD8+ responses. The GLIPH2 clustering analysis of TCRβ sequences suggested that TCRβ clusters, associated with the autoantigens proinsulin and Zinc transporter 8 (ZnT‐8), might share specificity towards ORF7b and ORF3a viral epitopes. Notably, PBMCs from three T1D patients exhibited T cell reactivity against both ORF7b/ORF3a viral epitopes and proinsulin/ZnT‐8 autoantigens. Conclusions: The increased frequency of SAR‐CoV‐2‐ reactive T cells in T1D patients might protect against severe COVID‐19 and overt infections. These results emphasise the long‐standing association between viral infections and T1D. [ABSTRACT FROM AUTHOR]

In the CNS, the chemokine CX3CL1 (fractalkine) is expressed on neurons while its specific receptor CX3CR1 is expressed on microglia and macrophages. Microglia play an important role in health and disease through CX3CL1/CX3CR1 signaling, and in many neurodegenerative disorders, microglia dysregulation has been associated with neuro-inflammation. We have previously shown that CX3CL1 has neuroprotective effects against cerebral ischemia injury. Here, we investigated the involvement of CX3CL1 in the modulation of microglia phenotype and the underlying neuroprotective effect on ischemia injury. The expression profiles of anti- and pro-inflammatory genes showed that CX3CL1 markedly inhibited microglial activation both in vitro and in vivo after permanent middle cerebral artery occlusion (pMCAO), accompanied by an increase in the expression of anti-inflammatory genes. Moreover, CX3CL1 induces a metabolic switch in microglial cells with an increase in the expression of genes related to the oxidative pathway and a reduction in those related to the glycolytic pathway, which is the metabolic state associated to the pro-inflammatory phenotype for energy production. The data reported in this paper suggest that CX3CL1 protects against cerebral ischemia modulating the activation state of microglia and its metabolism in order to restrain inflammation and organize a neuroprotective response against the ischemic insult.

GGDEF-containing proteins respond to different environmental cues to finely modulate cyclic diguanylate (c-di-GMP) levels in time and space, making the allosteric control a distinctive trait of the corresponding proteins. The diguanylate cyclase mechanism is emblematic of this control: two GGDEF domains, each binding one GTP molecule, must dimerize to enter catalysis and yield c-di-GMP. The need for dimerization makes the GGDEF domain an ideal conformational switch in multidomain proteins. A re-evaluation of the kinetic profile of previously characterized GGDEF domains indicated that they are also able to convert GTP to GMP: this unexpected reactivity occurs when conformational issues hamper the cyclase activity. These results create new questions regarding the characterization and engineering of these proteins for in solution or structural studies.

Gab2 is a scaffolding protein, overexpressed in many types of cancers, that plays a key role in the formation of signaling complexes involved in cellular proliferation, migration, and differentiation. The interaction between Gab2 and the C-terminal SH3 domain of the protein Grb2 is crucial for the activation of the proliferation-signaling pathway Ras/Erk, thus representing a potential pharmacological target. In this study, we identified, by virtual screening, seven potential inhibitor molecules that were experimentally tested through kinetic and equilibrium binding experiments. One compound showed a remarkable effect in lowering the affinity of the C-SH3 domain for Gab2. This inhibitory effect was subsequently validated in cellula by using lung cancer cell lines A549 and H1299. Our results are discussed under the light of previous works on the C-SH3:Gab2 interaction.

INTRODUCTION:Intensive treatment aimed at achieving optimal metabolic control to prevent the development of chronic diabetic complications is often associated with an increased rate of hypoglycemic events. Hypoglycemia is believed to be responsible for acute fatal and nonfatal cardiovascular events likely as a consequence of the activation of pro-inflammatory and pro-atherothrombotic pathways. Hypoglycemia has been reported to influence the development of preclinical atherosclerosis. The present study was designed to prospectively evaluate whether hypoglycemia influences the function and the morphology of the arteries in subjects with type 2 diabetes without complications and uncontrolled diabetes. MATERIAL AND METHODS:Seventy-six subjects underwent a noninvasive evaluation of carotid wall thickness and brachial artery function at baseline and after one year of treatment with the intent of obtaining optimal glycemic control. At the end of the observation time, subjects were divided in two groups: with hypoglycemia (H-group) or without hypoglycemia (C-group). RESULTS:Baseline characteristic were comparable between groups. HbA1c significantly decreased in both groups, and fasting plasma glucose was only significant in the H-group. Subjects with hypoglycemia showed a significant reduction of carotid wall thickness after one-year of treatment (H-groups: right baseline 834±141 vs. 1-year 770±132 μ p