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Abstract The molecular mechanisms that govern differential T cell development from CD4+CD25-conventional T (Tconv) into CD4+CD25+ forkhead-box-P3+ (FoxP3+) inducible regulatory T (iTreg) cells remain unclear. Herein, we investigated the relative contribution of protein kinase A (PKA) in this process. Mechanistically, we found that PKA controlled the efficiency of human iTreg cell generation through the expression of different FoxP3 splicing variants containing or not the exon 2. We found that transient PKA inhibition reduced the recruitment of cAMP-responsive element-binding protein (CREB) on regulatory regions of the FoxP3 gene, a condition that is associated with an impaired acquisition of their suppressive capacity in vitro. To corroborate our findings in a human model of autoimmunity, we measured CREB phosphorylation and FoxP3 levels in iTreg cells from treatment-naïve relapsing–remitting (RR)-multiple sclerosis (MS) subjects. Interestingly, both phospho-CREB and FoxP3 induction directly correlated and were significantly reduced in RR-MS patients, suggesting a previously unknown mechanism involved in the induction and function of human iTreg cells.

Microplastics (MPs) accumulate in tissues, including kidney tissue, while Bisphenol A (BPA) is a plasticizer of particular concern. At present, the combined effects of MPs and BPA are unexplored in human renal cells. Therefore, we exposed a proximal tubular cell line (PTECs) to polyethylene (PE)-MPs and BPA, both separately and in combination. When co-exposed, cells showed a significantly reduced cell viability (MTT test) and a pronounced pro-oxidant (MDA levels, NRF2 and NOX4 expression by Western blot) and pro-inflammatory response (IL1β, CCL/CCR2 and CCL/CCR5 mRNAs by RT-PCR), compared to those treated with a single compound. In addition, heat shock protein (HSP90), a chaperone involved in multiple cellular functions, was reduced (by Western Blot and immunocytochemistry), while aryl hydrocarbon receptor (AHR) expression, a transcription factor which binds environmental ligands, was increased (RT-PCR and immunofluorescence). Our research can contribute to the study of the nephrotoxic effects of pollutants and MPs and shed new light on the combined effects of BPA and PE-MPs.

Abstract Extracellular vesicles (EVs) are released by all cells and contribute to cell‐to‐cell communication. The capacity of EVs to target specific cells and to efficiently deliver a composite profile of functional molecules have led researchers around the world to hypothesize their potential as therapeutics. While studies of EV treatment in animal models are numerous, their actual clinical benefit in humans has more slowly started to be tested. In this scoping review, we searched PubMed and other databases up to 31 December 2023 and, starting from 13,567 records, we selected 40 pertinent published studies testing EVs as therapeutics in humans. The analysis of those 40 studies shows that they are all small pilot trials with a large heterogeneity in terms of administration route and target disease. Moreover, the absence of a placebo control in most of the studies, the predominant local application of EV formulations and the inconsistent administration dose metric still impede comparison across studies and firm conclusions about EV safety and efficacy. On the other hand, the recording of some promising outcomes strongly calls out for well‐designed larger studies to test EVs as an alternative approach to treat human diseases with no or few therapeutic options.

Mucous membrane pemphigoid (MMP) is an autoimmune-based bullous disease affecting the mucous membranes, mainly oral and ocular. One of the most common clinical manifestations is desquamative gingivitis (DG), characterized by intense symptoms and functional limitations. The dentist is among the first specialists to observe DG and, therefore, must be able to diagnose it. In this regard, the purpose of the present study was to evaluate the efficacy and safety of a clinical protocol for the topical management of patients with DG and MMP buccal lesions. Thirteen patients with clinical and histologic diagnoses of MMP-localized DG in the oral cavity were retrospectively enrolled. Each patient received topical treatment with clobetasol propionate oral gel 0.05%; nicotinamide; oral probiotic (contains Bifidobacterium lactis HN019, Kluyveromyces marxianus fragilis B0399, colostrum, and biotin); and doxycycline. Before and after 3 months of therapy, clinic records were collected for each patient. Seven patients (53.8%) had a complete response to treatment; four patients (30.8%) had a partial response to treatment; and, finally, two patients (15.4%) had no benefit from therapy. Dental management of patients presenting solely with oral manifestations of MMP may involve the use of topical corticosteroids, doxycycline, vitamin supplements, and probiotics and associating professional oral hygiene procedures.

Abstract Background Metabolic reprogramming is an important issue in tumor biology. A recently-identified actor in this regard is the molecular chaperone TRAP1, that is considered an oncogene in several cancers for its high expression but an oncosuppressor in others with predominant oxidative metabolism. TRAP1 is mainly localized in mitochondria, where it interacts with respiratory complexes, although alternative localizations have been described, particularly on the endoplasmic reticulum, where it interacts with the translational machinery with relevant roles in protein synthesis regulation. Results Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival. Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A. Conclusions These results shed new light on the molecular mechanisms involved in TRAP1-dependent regulation of cancer cell metabolism and point out a potential novel target for metabolic therapy in ovarian cancer.

Intraoral three-dimensional scanning techniques could be used to improve dental practice, leading to an improved overall quality of the prosthetic devices and improved comfort for the patient. An accurate and precise intraoral scanner allows proper diagnosis, follow-up evaluation, and prosthesis application. The aim of this research is to evaluate the precision of an intraoral scanners (Medit i500, Medit Corp., Seoul, Korea), using open-source software in the digital workflow. The precision was compared through repetitions of the scanning process of the upper dental arch, following superimpositions in the whole 3D arch area. It was possible to display colorimetric maps for qualitative comparison, and the deviations of the values were classified as clinically acceptable. Within the limitation of this study, the clinically acceptable in vivo frequency of points’ deviation, or the precision, was obtained in 98.8% ± 1.4%; therefore, the use of open-source software can be a viable option in the digital workflow, improving patient follow ups with the 3D model superimposition.

Background: An elevated lipoprotein insulin resistance (LP-IR) score corresponds to insulin resistance in adults with overweight and obesity, yet data are lacking regarding the impact of exercise interventions on LP-IR. The purpose of this secondary analysis was to evaluate the effects of a weight loss and weight maintenance intervention on LP-IR score in adults with overweight and obesity. Methods: Thirty sedentary adults with overweight and obesity completed a 10-week OPTIFAST® weight loss program with supervised aerobic exercise to achieve clinical weight loss (CWL) (≥7% from baseline). Aerobic exercise volume increased weekly until 700 MET min/week was reached. Participants who reached CWL were randomized to groups at volumes at either physical activity (PA-REC) or weight maintenance (WM-REC) recommendations (weeks 11–28). Plasma blood samples were analyzed via nuclear magnetic resonance spectroscopy at baseline, after weight loss (week 10), and following weight maintenance (week 28). Results: Following the weight loss phase, on average, participants significantly (p < 0.001) reduced LP-IR score (−12.1 ± 13.5), body weight (−8.9 ± 2.7%), and waist circumference (−7.7 ± 4.1 cm). During the weight maintenance phase, there were no changes in LP-IR score between exercise groups (PA-REC: 4.1 ± 13.6; WM-REC: −2.0 ± 11.2; P = 0.7). The PA-REC group had improvements in LP-IR score from baseline (49.8 ± 24.6 to 36.6 ± 27.6, P < 0.001), yet there were no within-group changes during the weight maintenance phase (P > 0.05). Conclusion: LP-IR score improved during weight loss in adults with overweight and obesity and were sustained during the weight maintenance phase in the PA-REC group. Aerobic exercise at least at minimum guidelines following CWL can preserve LP-IR score improvements and may indicate a reduced T2DM risk in adults with overweight and obesity. [ABSTRACT FROM AUTHOR]

This scientific article proposal explores the potential benefits of using artificial intelligence (AI) in prosthodontic restoration to achieve predictable and safer dental outcomes. Prosthodontic restoration involves designing, fabricating, and placing dental prostheses to restore oral function and aesthetics. Although traditional prosthodontic techniques have evolved significantly, incorporating AI into the workflow can revolutionize the field by enhancing accuracy, efficiency, and patient satisfaction. The proposed study aims to investigate the integration of AI algorithms and techniques into various stages of prosthodontic restoration, including treatment planning, digital impression acquisition, prosthesis design, and fabrication. By leveraging machine learning algorithms and image processing, AI can assist in diagnosing dental conditions, predicting treatment outcomes, and optimizing prosthesis design to ensure optimal fit and function. This technology can also aid in identifying potential challenges and risks before proceeding with the restorative procedures, minimizing errors, and improving patient safety. Furthermore, AI-powered systems can facilitate real-time assessment and feedback during fabrication, ensuring precise milling or 3D printing of prosthetic materials. These advancements have the potential to streamline workflows, reduce human error, and shorten treatment times, ultimately leading to enhanced treatment outcomes and increased patient satisfaction. The proposed research methodology includes a comprehensive literature review, an analysis of existing AI applications in prosthodontic restoration, and the development of a prototype AI-assisted system for prosthesis design and fabrication. The evaluation of this prototype will involve quantitative and qualitative assessments, comparing its performance with traditional methods. Overall, this article proposal seeks to highlight the transformative role of AI in prosthodontic restoration, emphasizing its potential to revolutionize traditional approaches and deliver predictable and safer dentistry. The findings from this research can contribute to advancing dental technology, fostering innovation, and improving patient care in prosthodontics.

Abstract Gene expression, lipidomic and growth impairment findings suggest that the natural history of celiac disease (CD) starts before the gluten-induced immune response. Gluten intake in the first years of life is a controversial risk factor. We aimed to estimate the risk of developing CD associated with the amount of gluten intake and the serum inflammatory profile in genetically predisposed infants. From an Italian cohort of children at risk for CD, we enrolled 27 children who developed CD (cases) and 56 controls matched by sex and age. A dietary interview at 9, 12, 18, 24 and 36 months was performed. Serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10 IL12p70, IL17, and TNFα) were analysed at 4 and 36 months. Infants who developed CD by 6 years showed an increase in serum cytokines (INFγ, IL1β, IL2, IL6, IL10, IL12p70 and TNFα) at 4 months of age before gluten introduction. CD cases ate significantly more gluten in the second year of life than controls, and gluten intake in the second year of life was strongly correlated with serum cytokines (INFγ, IL2, IL4, IL12p70, IL17) at 36 months only in CD cases. The dietary pattern of infants who developed CD was characterized by high consumption of biscuits and fruit juices and low intake of milk products, legumes, vegetables and fruits. Genetically predisposed infants who developed CD showed a unique serum cytokine profile at 4 months before gluten consumption. The amount of gluten was strongly correlated with an inflammatory profile in serum cytokines at 36 months only in infants who developed CD.

Programmed cell death‐1 (PD‐1) signaling downregulates the T‐cell response, promoting an exhausted state in tumor‐infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin‐related protein‐1 (Drp1)‐dependent mitochondrial fission plays a crucial role in sustaining T‐cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD‐1 in tumor‐infiltrating T cells. Here, we show that PD‐1pos CD8+ T cells infiltrating an MC38 (murine adenocarcinoma)‐derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD‐1neg counterparts. Also, PD‐1pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp1. Mechanistically, PD‐1 signaling directly prevents mitochondrial fragmentation following T‐cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor‐infiltrating PD‐1pos CD8+ T cells seems to be a mechanism exploited by PD‐1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor‐infiltrating T cells may become a valuable target to ameliorate the anticancer immune response in future immunotherapy approaches.

Background: The aim of this work is to evaluate changes following rapid maxillary expansion (RME) on breathing function in two groups of patients: mouth breathers and nasal breathers. Materials and methods: Twenty-five oral breather patients (12 male, 13 female, mean age 15.2 ± 1.3), and 25 nasal breather patients (14 male, 11 female, mean age 15.3 ± 1.6) were treated with RME. Breathing function was evaluated by computerized spirometry. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), Tiffenau index (FEV1/ FVC ratio, IT%), forced expiratory flow at 25–75% of vital capacity (FEF 25–75%), and Tidal volume (TV) were assessed. Breathing function analysis was performed before RME and 6 and 12 months after RME during follow-up appointments. The Shapiro–Wilk test was used to assess whether data were normally distributed. As data were not normally distributed, Mann–Whitney U and Friedman tests were used to perform comparisons between treatment groups and within group comparisons, respectively. Results: Oral breathers and nasal breathers showed statistically significant differences in FVC, FEF 25–75%, and TV at T0. They did not present any statistically significant difference in FEV1 and IT% at the same time point.Statistically significant differences were noticed for all indices in the oral breather group after maxillary expansion, while the nasal breather group showed statistically significant differences only in FCV, FEF 25–75%, and TV after treatment.There were no statistically significant differences in all indices 12 months after maxillary expansion between the oral breather and nasal breather groups. Conclusions: RME appeared to improve breathing function in both groups. Forced vital capacity (FVC), forced expiratory flow at 25–75% of vital capacity (FEF 25–75), and Tidal volume (TV) reached similar values in both groups after treatment with RME.

Abstract The autoimmune immunopathology occurring in multiple sclerosis (MS) is sustained by myelin-specific and -nonspecific CD8+ T cells. We have previously shown that, in MS, activated T cells undergoing apoptosis induce a CD8+ T cell response directed against antigens that are unveiled during the apoptotic process, namely caspase-cleaved structural proteins such as non-muscle myosin and vimentin. Here, we have explored in vivo the development and the function of the immune responses to cryptic apoptosis-associated epitopes (AEs) in a well-established mouse model of MS, experimental autoimmune encephalomyelitis (EAE), through a combination of immunization approaches, multiparametric flow cytometry, and functional assays. First, we confirmed that this model recapitulated the main findings observed in MS patients, namely that apoptotic T cells and effector/memory AE-specific CD8+ T cells accumulate in the central nervous system of mice with EAE, positively correlating with disease severity. Interestingly, we found that AE-specific CD8+ T cells were present also in the lymphoid organs of unprimed mice, proliferated under peptide stimulation in vitro, but failed to respond to peptide immunization in vivo, suggesting a physiological control of this response. However, when mice were immunized with AEs along with EAE induction, AE-specific CD8+ T cells with an effector/memory phenotype accumulated in the central nervous system, and the disease severity was exacerbated. In conclusion, we demonstrate that AE-specific autoimmunity may contribute to immunopathology in neuroinflammation.

(1) Background: Delirious mania is a neuropsychiatric condition characterized by the rapid onset of delirium, psychosis, and mania. Due to the presence of catatonic signs and symptoms, some authors considered this syndrome to be a specific excited catatonia subtype. Usually, delirious mania is responsive to intravenous benzodiazepines (BZDs) or to electroconvulsive therapy (ECT). (2) Methods: In the present study, we describe the case of a 64-year-old woman with a diagnosis of recurrent major depressive disorder. We assessed the severity of the clinical picture and the response to ECT treatment with the Bush–Francis Catatonia Rating Scale (BFCRS). (3) Results: After eleven sessions of ECT, the patient presented a reduced BFCRS total score, with a resolution of the autonomic abnormalities (temperature, respiratory, and heart rate). (4) Conclusions: These data demonstrate how important it is to diagnose this syndrome as soon as possible to set up an effective therapy, avoiding the use of antipsychotic drugs and preventing potentially fatal complications. The initial administration of BZDs IV and the subsequent ECT application, associated with intensive care of life-threatening general medical conditions, guaranteed us a good level of efficacy in obtaining a complete resolution of the clinical picture.

Patients with cardiovascular disease (CVD) and periodontitis (PT) show shared risk factors as result of the altered molecular mechanisms associated with pathological conditions. The aim of our study was to evaluate if the plasma biomarkers associated with endothelial dysfunction may also be related to alterations in the inflammatory status in peripheral blood mononuclear cells (PBMC). Patients with PT, coronary heart disease (CHD), or both diseases as well as controls were enrolled. Plasma levels of coenzyme Q10 (CoQ10), 3-nitrotyrosine (NT), and asymmetric dimethylarginine (ADMA) were assessed using HPLC. mRNA levels of caspase-1 (CASP1), NLR family pyrin domain containing 3 (NLRP3), and tumor necrosis factor-α (TNF-α) in PBMC from the recruited subjects were quantified using real-time PCR. Patients with PT + CHD showed lower CoQ10 plasma levels and increased concentrations of NT in comparison to healthy subjects. ADMA levels were higher in CHD and PT + CHD patients compared to controls. Transcript levels of CASP1, NLRP3, and TNF-α were up-regulated in PBMC from all patient groups when compared to healthy subjects. Our results suggest a possible causal link between oxidative stress, high levels of NT and ADMA, and inflammasome activation, which may be involved in the endothelial inflammatory dysfunction leading to the pathogenesis and progression of CHD in PT patients.