Search Results (13,571)

Background/Objectives: Lipedema is a chronic, progressive disorder of the adipo-fascial tissue characterized by abnormal subcutaneous fat accumulation, inflammation, fibrosis, pain, and edema. Despite its considerable impact on patients’ quality of life, it remains underdiagnosed. Recent studies have suggested a potential overlap between lipedema and hypermobility spectrum disorders (HSDs), both involving connective tissue dysfunction. This work explores the shared pathophysiological features of lipedema and HSD, highlighting clinical correlations, comorbidities, and the need for integrated diagnostic and therapeutic approaches. Methods: A cross-sectional observational study was conducted through an online survey targeting individuals with lipedema and a control group with lymphedema. The questionnaire assessed symptoms typically associated with HSD, including musculoskeletal, gastrointestinal, urogynecological, vascular, and neuropsychological manifestations. Descriptive statistics were used to evaluate clinical patterns in both groups. Results: Among the lipedema patients, 44% reported joint hypermobility and 60% recalled being hypermobile during childhood. High rates of pediatric overweight (50%), low muscle tone (55%), and exercise-induced fatigue (70%) were observed. Adult symptoms included joint pain (notably in the ankles, knees, cervical spine, sacrum, and feet), digestive issues (50%), and thyroid disorders (24.4%). Compared with the control group, patients with lipedema showed significantly more connective tissue-related motor deficits and systemic symptoms. Conclusions: Connective tissue laxity may play a critical role in the pathogenesis of lipedema, contributing to multisystemic manifestations through vascular, lymphatic, gastrointestinal, and musculoskeletal involvement. The high prevalence of HSD-like features calls for a paradigm shift in the understanding of lipedema as a systemic disorder. Early identification of connective tissue alterations, especially in children with familial predisposition, could enable timely interventions, potentially mitigating disease progression. A multidisciplinary, evidence-based approach is essential for accurate diagnosis and effective management. Full article

Excessive production of type I interferons (IFNs) underlies the immunopathogenesis of autoimmune disorders, including systemic lupus erythematosus and autoimmune pancreatitis. Whether type I IFNs play pathogenic or protective roles in the development of inflammatory bowel diseases (IBD) has been a matter of debate. The production of type I IFNs is tightly regulated by the conjugation and removal of polyubiquitin chains on or from intracellular signaling molecules. OTU deubiquitinases 3 (OTUD3) and 5 (OTUD5) are enzymes that cleave various polyubiquitin chains from target proteins. OTUD3 and OTUD5 deubiquitinate key critical intracellular molecules of the type I IFN signaling pathways, stimulator of interferon genes (STING), and TNF receptor-associated factor 3 (TRAF3), respectively, and thus regulate the production of type I IFNs by innate immune cells. Recent studies provided evidence that the impaired function of OTUD3 and OTUD5 increases susceptibility to human and experimental IBD owing to the excessive production of type I IFNs caused by the activation of STING and TRAF3, respectively. Collectively, OTUD3 and OTUD5 play protective rather than pathogenic roles in the development of IBD through the negative regulation of type I IFN-mediated signaling pathways. In this review article, we discuss the association between the development of IBD and impaired function of OTUD3 or OTUD5 by focusing on their deubiquitinase activity and type I IFN responses. Full article

Polycystic ovary syndrome (PCOS) is a systemic metabolic and endocrine disorder that significantly disrupts reproductive physiology and endometrial function. In this narrative review, we examine the molecular impact of metabolic and hormonal imbalances on the endometrium of women with PCOS. We investigate the specific mechanisms that delineate how hyperinsulinemia and insulin resistance, chronic low-grade inflammation, and estrogen/progesterone/androgen imbalance contribute to altered epigenetic, transcriptomic, metabolomic, and signaling profiles in a wide array of different cell types within endometrial tissues. The synergistic interplay between upregulated inflammatory cytokines (e.g., IL-1,2,6,8,17,18, and TNF-α), along with key changes in critical molecular pathways associated with hyperinsulinemia and insulin resistance (e.g., PI3K/AKT/MAPK, and Wnt/β-catenin), in addition to aberrant sex steroid hormone signaling (e.g., CYP19A1, COX-2, PGE₂, HOXA10, 11βHSD2), promotes deleterious changes within the endometrial microenvironment. These anomalies underpin a spectrum of clinical manifestations observed in women with PCOS at each stage of the life course, including abnormal uterine bleeding in reproductive-age women, impaired decidualization in pregnancy, and altered postmenopausal endometrial physiology. Clinically, these alterations are associated with abnormal uterine bleeding, subfertility, implantation failure, miscarriage, pregnancy complications, and postmenopausal endometrial hyperplasia and cancer. Overall, our review provides novel insights into the molecular mechanisms linking systemic metabolic and endocrine dysfunction with endometrial pathology in PCOS and has broader implications that apply to all women. Full article

Background/Objectives: Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells used in treating blood and immune disorders. Despite its potential and the availability of public banking systems in Italy, donation rates remain low due to patient misinformation, emotional barriers, and organizational inefficiencies. This study aimed to evaluate the impact of integrating Narrative Medicine (NM) and Lean Management (LM) on UCB donation rates and operational effectiveness at the University Hospital of Alessandria. Methods: This prospective, single-center pre-post study ran from July 2022 to December 2024. Two interventions were introduced: NM training for healthcare staff to enhance empathetic communication, and LM-based reorganization of workflows to improve process efficiency. Outcomes included changes in UCB donation and adherence rates, transplant-eligible unit percentages, and patient satisfaction, assessed through institutional and project-specific surveys (PERLA–SIMeN). Results: Post-intervention, donation rates increased from 0% in early 2022 to 30.8% (2022), 25.8% (2023), and 30.6% (2024), with adherence rates near 40%, far exceeding the national average of ~3%. Patient satisfaction improved, resulting in PERLA certification in February 2025. Conclusions: The integration of NM and LM significantly improved both patient engagement and organizational efficiency. Empathetic communication fostered trust and reduced emotional barriers, while LM optimized workflows and resource use. These results suggest the model is applicable in other hospitals to enhance UCB donation outcomes and overall quality of maternal care. Full article

Background/Objectives: Sweet’s syndrome (SS), also known as acute febrile neutrophilic dermatosis, is a rare inflammatory skin disorder that may also present with extracutaneous manifestations. Liver involvement is thought to result from sterile neutrophilic infiltration, mirroring the skin pathology and highlighting the syndrome’s systemic inflammatory nature. Timely recognition, exclusion of infectious or autoimmune etiologies, and prompt corticosteroid therapy are critical for favorable outcomes. Methods: Herein, we present the case of a 73-year-old man with hyperuricemia who developed both cutaneous and systemic manifestations of SS seven days after initiating allopurinol treatment. His symptoms included fever, conjunctivitis in the right eye, and painful, non-pruritic erythematous plaques, some with pustules, on the lower limbs, palms, and face. Results: Initial laboratory investigations revealed neutrophilic leukocytosis, elevated inflammatory markers, and renal and hepatic dysfunction. Empirical treatment with antibiotics and antivirals failed to improve his condition. The patient discontinued allopurinol and initiated a high-dose corticosteroid regimen, leading to rapid resolution of fever and improvement in skin lesions. Laboratory parameters gradually normalized, except for persistent high liver enzymes. A comprehensive diagnostic workup ruled out infectious, autoimmune, and malignant causes. Imaging studies, including CT, MRI, and MRCP, showed no structural liver abnormalities. Skin biopsy findings were consistent with SS, demonstrating dense neutrophilic infiltrates in the reticular dermis and papillary dermal edema. After his discharge, he was followed up by the Hepatology unit. The patients’ liver enzyme levels normalized within three months with no recurrence or late complications one year later. Conclusions: In the context of drug-induced SS, persistent hepatic abnormalities, although rare, may occur in patients without underlying liver disease. Full article

Adenosine plays a crucial role in various pathophysiological conditions, including neuroinflammation and neurodegeneration. Neuroinflammation can be either beneficial or detrimental to the central nervous system, depending on the intensity and duration of the inflammatory response. Across a wide range of brain disorders, neuroinflammation contributes to both the onset and progression of disease. Notably, neuroinflammation is not limited to conditions primarily classified as neuroinflammatory but is also a key factor in other neurological disorders, including life-threatening neurodegenerative diseases. All four adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃) are implicated, to varying degrees, in these conditions. This review aims to summarize the roles of individual adenosine receptor subtypes in neuroinflammation and neurodegenerative diseases, emphasizing their therapeutic potential. While some therapeutic applications are well-established with clinically approved drugs, others warrant further investigation due to their promising potential. Full article

Ginsenosides, the primary bioactive components of Panax ginseng, have demonstrated significant immunomodulatory potential. While major ginsenosides have been extensively studied, rare ginsenosides produced through deglycosylation, heating, and steaming show enhanced biological activities with improved bioavailability. This review aimed to comprehensively analyze the immunomodulatory mechanisms, structure-activity relationships (SARs), therapeutic applications, and clinical translation strategies of five emerging rare ginsenosides: F1, Rg5, Rk1, Rh1, and Rg2. We conducted a comprehensive literature review examining the production methods, immunological effects, molecular mechanisms, pharmacokinetics, safety profiles, and clinical applications of these five compounds. Analysis focused on chemical structures, immune cell modulation, signaling pathways, disease model efficacy, and bioavailability enhancement strategies. Ginsenoside F1 uniquely demonstrated immunostimulatory effects, enhancing natural killer (NK) cell cytotoxicity and macrophage phagocytosis through mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) activation. Conversely, Rg5, Rk1, Rh1, and Rg2 exhibited anti-inflammatory properties via distinct mechanisms: Rg5 through Toll-like receptor 4 (TLR4)/NF-κB inhibition, Rk1 via triple pathway modulation (NF-κB, p38 MAPK, signal transducer and activator of transcription (STAT)), Rh1 by selective p38 MAPK and STAT1 inhibition, and Rg2 through modulation of both central nervous system (neuroinflammation) and peripheral organ systems. Structure-activity analysis revealed that sugar moiety positions critically determine immunological outcomes. Crucially, advanced delivery systems including nanostructured lipid carriers, self-microemulsifying systems, and specialized liposomes have overcome the major translational barrier of poor bioavailability, achieving up to 2.6-fold improvements and enabling clinical development. Safety assessments demonstrated favorable tolerability profiles across preclinical and clinical studies. These five rare ginsenosides represent promising immunomodulatory agents with distinct therapeutic applications. F1’s unique immunostimulatory properties position it for cancer immunotherapy, while the complementary anti-inflammatory mechanisms of Rg5, Rk1, Rh1, and Rg2 offer opportunities for precision medicine in inflammatory diseases. Advanced formulation technologies and optimized production methods now enable their significant clinical translation potential, providing promising therapeutic options for immune-related disorders pending further development. Full article

Many central nervous system disorders (CNS), including chronic pain and migraine, involve metabolic changes in the brain. These changes are best detected and monitored in cerebrospinal fluid (CSF), which requires lumbar puncture. Blood-based measurements may offer an alternative, if they reflect CSF changes. To assess this, we measured and correlated the concentrations of 39 amino acids, biogenic amines, and other amines in blood and CSF of 95 healthy volunteers and, in addition, correlated the ratios of 741 amines. Amines were measured using a validated UPLC-MS platform. In healthy volunteers, only 4/39 (10.3%) analyzed amine metabolite concentrations had a correlation coefficient ≥ 0.70. Correlations of metabolite ratios were significantly better for 308/741 (41.5%) combinations. Specifically, ratios of amino acids showed high correlations. In addition, amines were investigated in 197 participants with migraine. Six amine metabolite ratios were different in migraineurs versus healthy volunteers. Most blood amine concentrations do not reflect those in CSF, but many of the ratios did correlate between CSF and plasma, showing diagnostic potential. This study improves our understanding of blood-CSF relationships, and our data suggest that ratios of amines may be of relevance to CNS disorders, as we showed for migraine. Full article

Interferons (IFNs) are key cytokines at the intersection of innate and adaptive immunity. While their antiviral and antitumor roles are well recognized, emerging evidence implicates IFNs—particularly types I, II, and III—in the initiation and progression of autoimmune diseases (ADs). This review synthesizes current data on IFN biology, their immunoregulatory and pathogenic mechanisms, and their contributions to distinct AD phenotypes. We conducted a comprehensive review of peer-reviewed literature on IFNs and autoimmune diseases, focusing on publications indexed in PubMed and Scopus. Studies on molecular pathways, immune cell interactions, disease-specific IFN signatures, and clinical correlations were included. Data were extracted and thematically organized by IFN type, signaling pathway, and disease context, with emphasis on rheumatic and systemic autoimmune disorders. Across systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, idiopathic inflammatory myopathies, multiple sclerosis, type 1 diabetes, psoriasis, and inflammatory bowel diseases, IFNs were consistently associated with aberrant activation of pattern recognition receptors, sustained expression of interferon-stimulated genes (ISGs), and dysregulated T cell and B cell responses. Type I IFNs often preceded clinical onset, suggesting a triggering role, whereas type II and III IFNs modulated disease course and severity. Notably, IFNs exhibited dual immunostimulatory and immunosuppressive effects, contingent on tissue context, cytokine milieu, and disease stage. IFNs are central mediators in autoimmune pathogenesis, functioning as both initiators and amplifiers of chronic inflammation. Deciphering the context-dependent effects of IFN signaling may inform targeted therapeutic strategies and advance precision immunomodulation in autoimmune diseases. Full article

The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a crucial role in regulating immune homeostasis, inflammatory responses, and intestinal barrier function. Indole compounds and their derivatives are ligands of AHR, which can activate the AHR signal transduction pathway and show significant regulatory potential in various inflammatory and immune diseases. Cystic fibrosis (CF) is a life-threatening autosomal recessive genetic disorder. Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction affects multiple systems throughout the body. The core of its pathological process is chronic infection, abnormal inflammation, and tissue damage caused by mucus accumulation. Exploring alternative or adjunctive therapeutic strategies targeting pathological pathways downstream of CFTR is of significant importance. The aim of the present study is to explore the multiple beneficial effects that indole compounds may exert in regulating pulmonary infection and inflammation, repairing intestinal barrier function, and regulating immune homeostasis in CF patients by activating the AHR signaling pathway. Additionally, this study discusses the risks and challenges associated with developing indole compounds as CF drugs, offering a novel research approach distinct from traditional CFTR modulators for creating new CF therapeutics. Full article

Osteoarthritis (OA) is a degenerative joint disorder characterized by progressive articular cartilage degradation, leading to pain, stiffness, and impaired mobility. This study investigated the anti-osteoarthritic effects of Lindera obtusiloba (LO) leaf extract in primary cultured chondrocytes and a mouse model of destabilization of the medial meniscus (DMM)-induced OA. Mouse primary chondrocytes were treated with IL-1β and various concentrations of LO leaf extract (50–150 μg/mL), and analyzed by RT-PCR, Western blotting, and ELISA. For the in vivo experiments, male C57BL/6 mice underwent DMM surgery and were administered LO leaf extract (50–200 mg/kg/day) for eight weeks, followed by micro-CT, histological, and immunohistochemical analyses. LO leaf extract exhibited no cytotoxicity in chondrocytes. In interleukin-1β-induced inflammatory chondrocytes, LO leaf extract significantly suppressed the expression of OA-associated catabolic factors, including cyclooxygenase-2 (Cox-2), matrix metalloproteinases (MMP3 and MMP13), and phosphorylated nuclear factor-kappa B (NF-κB). It also reduced the production of destructive mediators, such as prostaglandin E₂ (PGE₂) and collagenase, in a dose-dependent manner. In vivo, LO leaf extract-treated mice demonstrated significant reductions in articular cartilage degradation, subchondral bone sclerosis, and the expression of catabolic and inflammatory mediators. Additionally, LO leaf extract administration significantly decreased systemic pro-inflammatory cytokine levels in DMM-induced mice. Collectively, these findings indicate that LO leaf extract attenuates OA progression by suppressing both local and systemic inflammatory responses, supporting its potential as a natural therapeutic agent for the prevention and treatment of OA. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder characterized by systemic deposition of amyloid fibrils, leading to peripheral neuropathy and multisystemic involvement. Peripheral nerve ultrasound is a promising tool for detecting structural nerve changes, yet its use in Latin American populations is limited. This study aimed to characterize nerve ultrasound findings in Brazilian patients with ATTRv. Methods: We conducted a cross-sectional study of 72 genetically confirmed ATTRv individuals from two Brazilian centers. Participants were classified into symptomatic patients with polyneuropathy (n = 31) and asymptomatic TTR variant carriers (n = 41). All participants underwent a standardized neurological examination, and nerve ultrasound was used to assess the median nerve, brachial plexus, and C6 root. Cross-sectional areas (CSAs) from the right side were used for analysis and compared to reference values. Conclusions: Symptomatic patients showed increased CSAs in the median nerve (wrist: 10.17 mm², arm: 9.8 mm²), C6 root (8.55 mm²), and brachial plexus (70.82 mm²; all p < 0.05), but not in the forearm. Notably, asymptomatic carriers exhibited nerve enlargement in the median nerve at the wrist, the C6 root, and the brachial plexus, despite lacking clinical signs of neuropathy. Peripheral nerve enlargement in ATTRv affects both symptomatic patients and asymptomatic carriers, with a predilection for proximal and entrapment sites. These findings support the utility of nerve ultrasound as a non-invasive biomarker for early nerve involvement in ATTRv. Further studies are warranted to validate its role in disease monitoring and guide therapeutic interventions, especially in genetically at-risk populations. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Accurate assessment of sleep architecture is critical for diagnosing and managing sleep disorders, which significantly impact global health and well-being. While polysomnography (PSG) remains the clinical gold standard, its inherent intrusiveness, high cost, and logistical complexity limit its utility for routine or home-based monitoring. Recent advances highlight that subtle variations in respiratory dynamics, such as respiratory rate and cycle regularity, exhibit meaningful correlations with distinct sleep stages and could serve as valuable non-invasive biomarkers. In this work, we propose a framework for estimating sleep stage distribution—specifically Wake, Light (N1+N2), Deep (N3), and REM—based on respiratory audio captured over a single sleep episode. The framework comprises three principal components: (1) a segmentation module that identifies distinct respiratory cycles in respiratory sounds using a fine-tuned Transformer-based architecture; (2) a feature extraction module that derives a suite of statistical, spectral, and distributional descriptors from these segmented respiratory patterns; and (3) stage-specific regression models that predict the proportion of time spent in each sleep stage. Experiments on the public PSG-Audio dataset (287 subjects; mean 5.3 h per subject), using subject-wise cross-validation, demonstrate the efficacy of the proposed approach. The segmentation model achieved lower RMSE and MAE in predicting respiratory rate and cycle duration, outperforming classical signal-processing baselines. For sleep stage proportion prediction, the proposed method yielded favorable RMSE and MAE across all stages, with the TabPFN model consistently delivering the best results. By quantifying interpretable respiratory features and intentionally avoiding black-box end-to-end modeling, our system may support transparent, contact-free sleep monitoring using passive audio. Full article