Search Results (734)

Background: Cardiac involvement is common in Fabry disease (FD) and typically manifests with left ventricular hypertrophy (LVH). Patients with FD are frequently misdiagnosed, and this is mainly related to the lack of disease awareness among clinicians. The aim of this study was to determine whether providing a targeted educational intervention on FD may enhance FD diagnosis. Methods. This research was designed as a single-arm before-and-after intervention study and evaluated the impact of providing a specific training on FD to cardiologists from different Italian centers, without experience in rare diseases. In the 12-month period after the educational intervention, the rate of FD screening and diagnosis was assessed and compared with those conducted in the two years preceding the study initiation. Results: Fifteen cardiologists participated to this study, receiving a theoretical and practical training on FD. In the two previous two years, they conducted 12 FD screening (6/year), and they did not detect any cases of FD. After the training, they performed 45 FD screenings, with an eight-fold rise in the annual screening rate. The screened population (age: 61 ± 11 years, men: 82%) was mainly composed of patients with unexplained LVH (n = 43). There were four new FD diagnoses and, among of them, three had a late-onset GLA variant. After the cascade genetic screening, 11 affected relatives and 8 heterozygous carriers were also detected. Conclusions: A targeted educational intervention for cardiologists allowed the identification of four new families with FD. Enhancing FD awareness is helpful to reduce the diagnostic and therapeutic delay. Full article

Oxysterols such as 7-ketocholesterol (7KCh) contribute to the pathogenesis of autoimmune and chronic inflammatory diseases by inducing oxidative stress and promoting pro-inflammatory immune cell activation. Dendritic cells (DCs) play a central role in maintaining immune tolerance, and their dysregulation is a key driver of autoimmunity. Targeting DCs by using natural compounds offers a promising strategy to restore redox balance and suppress aberrant immune responses. This study investigated the immunomodulatory and antioxidant properties of Lupeol, a natural triterpenoid, in human monocyte-derived DCs exposed to 7KCh. Flow cytometry and cytokine profiling demonstrated that Lupeol preserved the immature, tolerogenic phenotype of DCs by promoting a dose-dependent increase in the anti-inflammatory cytokine IL-10. Lupeol also inhibited the 7KCh-induced upregulation of maturation markers (CD83, CD86) and suppressed the release of pro-inflammatory cytokines IL-1β and IL-12p70. Functionally, Lupeol-treated DCs directed T cell polarization toward an anti-inflammatory and regulatory profile while dampening the inflammatory responses triggered by 7KCh. This immunoregulatory effect was further supported by the decreased secretion of the pro-inflammatory cytokines IL-1β and IL-12p70 in DC culture supernatants. Mechanistic analyses using immunofluorescence showed that Lupeol alone significantly increased nuclear NRF2 levels and upregulated HO-1 expression. Western blot analysis further confirmed Lupeol’s ability to activate the KEAP1-NRF2 signaling pathway, as evidenced by increased expression of NRF2 and its downstream target, NQO1. The use of ML385, a selective NRF2 inhibitor, in ROS and cytokine assays supported the involvement of NRF2 in mediating the Lupeol antioxidant and anti-inflammatory effects in DCs. Notably, the oxidative burden induced by 7KCh limited the full activation of NRF2 signaling triggered by Lupeol. Furthermore, docking and MM/PBSA analyses revealed the specific interactions of Lupeol with the kelch domain of KEAP1. These findings suggest that Lupeol may serve as a promising orally available immunomodulatory agent capable of promoting tolerogenic DCs, offering potential applications in autoimmune and other chronic inflammatory diseases. Full article

Background: Preeclampsia (PE) is a pregnancy-specific disease and hypertensive disorder with a multifactorial pathogenesis involving complex molecular regulatory networks. Recent studies highlight the critical role of non-coding RNAs, particularly miRNAs and lncRNAs, in PE development. This study investigates the molecular interaction between miR-7151-5p and the lncRNA KCNQ1OT1 and their functional contributions to PE pathogenesis. Methods: An integrative approach combining RNAhybrid-based bioinformatics, dual-luciferase reporter assays, qRT-PCR, Transwell migration and invasion assays, and RNA sequencing was employed to characterize the binding between miR-7151-5p and KCNQ1OT1 and assess their influence on trophoblast cell function and gene expression. Results: A bioinformatic analysis predicted a stable binding site between miR-7151-5p and KCNQ1OT1 (minimum free energy: –37.3 kcal/mol). The dual-luciferase reporter assay demonstrated that miR-7151-5p directly targets KCNQ1OT1, leading to suppressed transcriptional activity. In HTR8/SVneo cells, miR-7151-5p overexpression significantly downregulated both KCNQ1OT1 and Notch1 mRNA, whereas its inhibition showed no significant changes, suggesting additional regulatory mechanisms of Notch1 expression. Transwell assays indicated that miR-7151-5p overexpression suppressed trophoblast cell migration and invasion, whereas its inhibition enhanced these cellular behaviors. RNA-seq analysis further revealed that miR-7151-5p overexpression altered key signaling pathways, notably the TGF-β pathway, and significantly modulates PE-associated genes, including PLAC1, ANGPTL6, HIRA, GLA, HSF1, and BAG6. Conclusions: The regulatory effect of miR-7151-5p on KCNQ1OT1, along with its influence on trophoblast cell dynamics via Notch1 and TGF-β signaling pathways, highlights its role in PE pathogenesis and supports its potential as a biomarker in early PE screening. Full article

Semi-flexible pavement (SFP) is a durable and cost-effective alternative to conventional rigid and flexible pavement and is formed by permeating an open-graded asphalt (OGA) layer with high-fluidity cement grout. The degradation of SFP mattresses due to fuel oil spills can result in significant maintenance costs. Incorporating glass waste (GW) into the construction of SFPs offers an eco-friendly solution, helping to reduce repair costs and environmental impact by conserving natural resources and minimizing landfill waste. The main objective of this research is to investigate the mechanical performance and fuel oil resistance of SFP composites containing different levels of glass aggregate (GlaSFlex composites). Fine glass aggregate (FGA) was replaced with fine virgin aggregate at levels of 0%, 20%, 40%, 60%, 80%, and 100% by mass. The results indicated the feasibility of utilizing FGA as a total replacement (100%) for fine aggregate in the OGA structural layer of SFPs. At 100% FGA, the composite exhibited excellent mechanical performance and durability, including a compressive strength of 8.93 MPa, a Marshall stability exceeding 38 kN, and a stiffness modulus of 19,091 MPa. Furthermore, the composite demonstrated minimal permanent deformation (0.04 mm), a high residual stability of 94.7%, a residual compressive strength of 83.3%, and strong resistance to fuel spillage with a mass loss rate of less than 1%, indicating excellent durability. Full article

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, resulting in a deficient activity of the enzyme α-galactosidase A (α-Gal A). This deficiency leads to the progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (Lyso-Gb3), in various tissues, contributing to a broad spectrum of clinical manifestations. Recent evidence highlights the crucial role of inflammation in the pathophysiology of FD, influencing disease progression and clinical outcomes. This review provides a comprehensive overview of the relationship between inflammation and FD, with a particular focus on the impact of inflammatory processes on disease progression and complications. Full article

Penicillium expansum is an acidogenic fungal species that belongs to the phylum Ascomycota. During the infection and colonization of host fruits, P. expansum can efficiently express glucose oxidase (GOX) and oxidize β-D-glucose to generate gluconic acid (GLA). In this study, the bioinformatics analysis method was employed to predict and analyze the function of the GOX protein. In addition, a comprehensive assessment was conducted on the P. expansum GOX coding gene GOX2, and the expression response rules of GOX2 under different external stress environments were explored. The results show that GOX is an unstable hydrophilic protein. It is either an integrated membrane protein (such as a receptor or channel) that is directly anchored to the membrane through a transmembrane structure or a non-classical secreted protein that is secreted extracellularly. RNA-seq data analysis shows that the GOX2 gene is regulated by multiple environmental factors, including pH, temperature, carbon base, and chemical fungicides. The expression level of GOX2 reaches its maximum value under alkaline conditions (pH 8–10) and at approximately 10 °C. Using starch as the carbon source and adding sodium propionate or potassium sorbate has the effect of inhibiting the expression of the GOX2 gene. The analysis of the function of the GOX protein and the characteristics of the GOX2 gene in P. expansum provides new insights into the glucose oxidase-encoding gene GOX2. The research results provide significant value for the subsequent development of new disease resistance strategies by targeting the GOX2 gene and reducing post-harvest disease losses in fruits. Full article

This study introduces and validates a comparative experiment-based method for determining the effective thickness of composite glass, including polymeric laminated glass (with polyvinyl butyral (PVB) and SentryGlas^® (SGP) interlayers) and vacuum glazing. This method employs comparative four-point bending tests, defining effective thickness by equating the bending stress of a composite specimen to that of a reference monolithic glass specimen under identical loading and boundary conditions. Specimens with varying configurations (glass thicknesses of 5 mm, 6 mm and 8 mm) were tested using non-destructive four-point bending tests under a multi-stage loading protocol (100 N–1000 N). Strain rosettes measured maximum strains at each loading stage to calculate bending stress. Analysis of the bending stress state revealed that vacuum glazing and SGP laminated glass exhibit superior load-bearing capacity compared to PVB laminated glass. The proposed method successfully determined the effective thickness for both laminated glass and vacuum glazing. Furthermore, results demonstrate that employing a 12 mm monolithic reference glass provides the highest accuracy for effective thickness determination. Theoretical bending stress calculations using the effective thickness derived from the 12 mm reference glass showed less than 10% deviation from experimental values. Conversely, compared to established standards and empirical formulas, the proposed method offers superior accuracy, particularly for vacuum glazing. Additionally, the mechanical properties of the viscoelastic interlayers (PVB and SGP) were investigated through static tensile tests and dynamic thermomechanical analysis (DMA). Distinct tensile behaviors and differing time-dependent shear transfer capacities between the two interlayer materials are found out. Key factors influencing the reliability of the method are also discussed and analyzed. This study provides a universally practical and applicable solution for accurate and effective thickness estimation in composite glass design. Full article

Periodontitis (PD), is a chronic inflammatory disease of the periodontal system, which includes gingiva, periodontal ligament, alveolar bone, and tooth cement. It is becoming increasingly prevalent globally, and its implications for oral health are profound. The Nrf2 signaling pathway is crucial in managing the relationship between inflammation and oxidative stress, making it vital for understanding this disease. Nrf2 interacts with key redox-sensitive inflammatory pathways, playing a vital role in the development of periodontitis. Acknowledging these dynamics underscores the importance of proactively addressing the complex aspects of periodontal disease. This review emphasizes its intricate interactions with redox-sensitive transcription factors vital for sustaining the self-perpetuating inflammatory processes underlying the disease. Additionally, it explores promising therapeutic strategies aimed at Nrf2 activation and encourages more effective management of PD. Full article

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, resulting in α-galactosidase A (α-Gal A) deficiency and progressive accumulation of globotriaosylceramide (Gb3). Current therapies, such as enzyme replacement and chaperone therapy, have limitations, including incomplete biodistribution and mutation-specific efficacy. Gene therapy using adeno-associated virus (AAV) vectors presents a promising alternative. Methods: In this study, we assessed the dose-dependent effects of AAV8 and AAV9 vectors encoding human GLA in Gla knockout (Gla^−/y) mice by measuring α-Gal A activity and monitoring safety. To evaluate therapeutic efficacy, symptomatic Fabry mice (G3S^Tg/+Gla^−/y) were used. Results: AAV9-GLA produced significantly higher and more sustained enzyme activity than AAV8-GLA across plasma, liver, heart, and kidney. In symptomatic mice, AAV9-GLA achieved superior reductions in serum Gb3 and lyso-Gb3 levels, greater Gb3 clearance in heart and kidney tissues, and improved proteinuria. Anti-GLA IgG titers remained below threshold for the first four weeks and increased modestly by week eight, indicating a limited humoral immune response. No significant clinical signs or weight loss were observed in Gla^−/y mice over the 3.5-month study period, supporting the favorable safety profile of AAV-mediated gene therapy. Conclusions: These findings demonstrate that AAV9 provides enhanced biodistribution and therapeutic efficacy compared to AAV8, supporting its potential for the treatment of Fabry disease. Full article

Lysosomal storage diseases are caused by defective lysosomal function, such as impaired lysosomal enzyme activities, which include more than 70 different diseases. Although biomarkers and therapies have been developed to date for some of them, many others remain challenging to diagnose and treat. In this study, an elevated level of Globotriaosylsphingosine (Lyso-Gb3), an already known biomarker for Fabry disease, was confirmed in the knock-out cells of the GLA, GNPTAB, and PSAP genes and models for Fabry, mucolipidosis II/III (ML II/III), and combined saposin deficiency, respectively. Lyso-Gb3 was high in ML II/III patient skin fibroblasts compared with normal cells and was decreased after total lysosomal enzyme supplementation. There have been no useful biomarkers reported in ML II/III until now. This study shows that Lyso-Gb3 is elevated in ML II/III patient cells and is decreased by treatment, indicating that Lyso-Gb3 is a potential biomarker for ML II/III. Full article

Glufosinate-ammonium (GLA) is a broad-spectrum herbicide widely used for weed control. However, its potential toxic effects on non-target aquatic organisms, especially in freshwater ecosystems, are of growing concern. This study investigates the toxic effects of GLA on Biomphalaria glabrata, a freshwater snail highly sensitive to environmental pollutants and commonly used as a model organism in toxicological studies. Acute toxicity tests revealed that the 96-h LC50 of GLA for adult snails was 3.77 mg/L, indicating moderate toxicity, while the LC50 for embryos was 0.01576 mg/L, indicating extremely high toxicity. Chronic exposure experiments further showed that at high concentrations (0.5 mg/L), the shell diameter and body weight of the snails not only failed to increase but also decreased, and they ceased to lay eggs. Moreover, their hepatopancreas and gonads suffered significant damage. Even at an environmentally relevant concentration of 0.05 mg/L, the body length, body weight, and reproductive capacity of the snails were inhibited, and damage to the hepatopancreas and gonads was observed. These findings provide important data for assessing the potential risks of GLA to aquatic ecosystems and offer a scientific basis for formulating environmental protection policies and optimizing herbicide usage standards. Full article

This study aims to explore the pathogenic mechanism of H-type hypertension. A rat model of H-type hypertension was established through high-methionine dietary intervention, with subsequent folic acid administration. Untargeted serum metabolomic profiling identified a significant reduction in arachidonic acid (AA) levels in the methionine-enriched group, which were effectively normalized following folic acid supplementation. Transcriptomic analysis revealed methionine-induced upregulation of AA pathway-associated genes Cyp1a1 and Gpr75. In contrast, after the intervention with folic acid, a downregulation of these genes was observed. These findings were corroborated through Western blotting and RT-qPCR validation. In vitro studies using EA.hy926 endothelial cells demonstrated that methionine exposure significantly elevated CYP1A1 expression. Furthermore, methionine stimulation induced marked upregulation of GPR75 and its downstream signaling components (NRAS, MEK1, and ERK1). Population-level evidence from the U.S. NHANES database substantiated significant correlations between essential fatty acids (AA, LA, and GLA) and H-type hypertension prevalence. Our research findings suggest that the CYP1A1/20-HETE/GPR75 axis-mediated dysregulation of AA metabolism may be one of the key pathological mechanisms of H-type hypertension. The research results provide clues for the discovery of new therapeutic targets for H-type hypertension. Full article

Fabry disease (FD) is a lysosomal storage disorder caused by pathogenic variants in the gene encoding alpha-galactosidase A (GLA). Deficiency of GLA results in the progressive accumulation of glycosphingolipids in virtually all organs, resulting in a progressive multisystem disease. Due to multi-organ involvement in FD, a comprehensive, multidisciplinary approach to diagnosis and treatment with regular follow-ups is essential. The Pusan National University Yangsan Hospital (PNUYH) multidisciplinary care model of FD aims to provide detailed practice guidelines and evidence-based recommendations for the diagnosis, screening, and treatment of FD according to specialty. This guideline focuses on the “quarterback” type of multidisciplinary team (MDT) operation and is limited in its applicability to the Korean insurance system. However, it reflects our team’s extensive experience and insights into optimizing MDT operations within these constraints and is expected to be highly beneficial for centers initiating MDTs for the effective treatment of FD. Full article

Newborn screening laboratories are increasingly adding lysosomal storage disorders (LSDs), such as Mucopolysaccharidosis I (MPS I) and Pompe disease, to their screening panels. Without newborn screening, LSDs are frequently diagnosed only after the onset of symptoms; late detection can lead to profound and irreversible organ damage and mortality. While screening of these disorders has accelerated over the past five years, there is little published information regarding the potential correlation of demographic variables (age at sample collection, birthweight, gestational age, gender, etc.) with lysosomal enzyme activity. The Missouri State Public Health Laboratory prospectively screened more than 475,000 newborns for MPS I, Pompe disease, Gaucher disease, and Fabry disease between 15 January 2013 and 15 May 2018. This report investigates trends between several demographic variables and activities of four lysosomal enzymes: α-L-iduronidase (IDUA), acid α-glucosidase (GAA), acid β-glucocerebrosidase (GBA), and acid α-galactosidase (GLA). This information provides a valuable resource to newborn screening laboratories for the implementation of screening for lysosomal storage disorders and the establishment of screening cutoffs. Full article