Search Results (11,938)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques, neurofibrillary tau tangles, neuroinflammation, and progressive cognitive decline. Beyond these classical pathological features, emerging evidence implicates microbial dysbiosis as a contributing factor, with the gut and oral microbiomes currently providing the strongest evidence for microbiome AD associations. In contrast, the ocular microbiome represents a biologically plausible but largely unexplored candidate whose potential contribution to AD pathogenesis remains hypothetical and requires rigorous investigation. The ocular surface shares embryological, anatomical, and functional connections with the central nervous system, and the retina has emerged as a non-invasive window into neurodegenerative brain changes. Bacterial taxa detected in ocular specimens, including Cutibacterium acnes and Acinetobacter johnsonii, overlap with those reported in some studies of AD brain tissue, prompting speculation about an ocular–brain microbial interface. However, this overlap does not establish microbial trafficking, and no direct evidence currently supports the proposition that ocular microorganisms translocate to, colonize, or contribute causally to AD brain pathology. This review critically appraises the existing evidence, graded by methodological rigor and evidence strength, across gut, oral, nasal, ear, and ocular microbiome compartments. We address the substantial methodological challenges inherent in low-biomass microbiome research, emphasize the importance of distinguishing contamination artifacts from biological signals, and delineate the evidence gaps that separate association from causation. We conclude by proposing a research framework that places the ocular microbiome as an emerging hypothesis warranting experimental validation, rather than an established contributor to AD. Full article

Oral diseases represent a major global health burden, and non-coding RNAs (ncRNAs) have emerged as pivotal regulators in their pathogenesis, offering new avenues for diagnosis and therapy. This review synthesizes current knowledge on ncRNAs—including miRNAs, lncRNAs, and circRNAs—across a spectrum of oral conditions, encompassing periodontitis, oral squamous cell carcinoma, oral submucous fibrosis, oral lichen planus, oral leukoplakia, and chronic orofacial pain. Mechanistically, ncRNAs function through competing endogenous RNA networks, immune–inflammatory cascades, metabolic reprogramming, and fibroblast activation; notably, recent discoveries have revealed that certain circRNAs and lncRNAs encode functional micropeptides, adding an additional layer of regulatory complexity in oral pathology. On the translational front, salivary and circulating ncRNAs have shown promise as non-invasive biomarkers. However, major bottlenecks remain, including insufficient longitudinal validation, marked technical heterogeneity across studies, and delivery challenges specific to the oral microenvironment. By critically evaluating mechanistic insights alongside these translational barriers, this review identifies critical knowledge gaps and proposes prioritized strategies to facilitate the clinical integration of ncRNA-based precision dentistry. Full article

Exosomes are nanoscale, double-membrane extracellular vesicles of endocytic origin that are released by diverse cell types under both physiological and pathological conditions. They have emerged as critical mediators of intercellular communication and immune regulation during homeostasis and infection. Accumulating evidence indicates that pathogen-infected mammalian cells actively secrete exosomes enriched with host- and pathogen-derived components, including proteins, lipids, DNA, and regulatory RNAs such as microRNA (miRNA) and circular RNA (circRNA). In the context of infection, exosomes exhibit dual and often opposing functions, contributing to both host defense and disease progression. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis and a leading cause of mortality from infectious diseases worldwide, has been shown to modulate exosome biogenesis and alter cargo composition in exosomes when secreted by macrophages. These exosomes carry mycobacterial antigens and immunomodulatory molecules that can influence host immune responses, thereby shaping disease outcomes. This review summarizes current insights into the biogenesis and functional roles of exosomes during Mtb infection, highlighting their contributions to host–pathogen interactions, immune modulation, and disease pathogenesis. We further discuss the potential of exosomes as biomarkers and therapeutic targets in tuberculosis, emphasizing their dual roles in mediating protective and detrimental effects. Full article

Endothelial dysfunction and impaired mitophagy represent core pathological drivers of atherosclerosis progression, yet upstream molecular regulators governing this process in vascular endothelium remain largely uncharacterized. This study delineated the functional role and mechanistic basis of filamin C (FLNC) in atherosclerosis-related endothelial injury. We profiled FLNC expression in 20 paired human carotid plaque and adjacent normal vascular tissues collected from patients undergoing carotid endarterectomy. In vitro, CRISPRa/CRISPRi-stable HUVEC lines were challenged with ox-LDL, with pharmacological (Mdivi-1) and genetic (si-PINK1/si-Parkin) rescue assays used to verify causal signaling. In vivo, Tie2-driven endothelial-specific FLNC-overexpressing ApoE^−/− mice were fed a high-fat diet to induce atherosclerotic lesions. FLNC was significantly downregulated in human plaques, ox-LDL-treated HUVECs, and atherosclerotic mouse aortas. FLNC overexpression attenuated endothelial apoptosis and oxidative stress, while its knockdown exacerbated these injuries. Mechanistically, FLNC activated PINK1/Parkin-mediated mitophagy to restrict cytosolic mtDNA leakage and suppress subsequent activation of the cGAS-STING inflammatory cascade. Mitophagy inhibition or PINK1/Parkin silencing fully abrogated FLNC’s cytoprotection, and endothelial FLNC overexpression retarded plaque progression in vivo. Collectively, our findings identify FLNC as a novel endogenous endothelial mitophagy regulator, revealing an unreported regulatory mechanism and supporting FLNC as a promising therapeutic target for atherosclerotic disease. Full article

Hyperuricemia (HUA) is a metabolic disorder caused by excessive uric acid (UA) production and/or insufficient UA excretion. Brassica rapa L. (turnip) is a traditional medicinal and edible plant in northwestern China. In this study, the urate-lowering effects of B. rapa L. ethanol extract (BrEE) and associated underlying mechanisms were investigated using a hypoxanthine/potassium oxonate-induced HUA mouse model and UA-stimulated HK-2 cells. BrEE was prepared and characterized; quercetin-3-glucuronide was the most abundant compound in BrEE, with a relative abundance of 22.04%. BrEE significantly lowered serum UA levels and improved renal function in mice. Key UA-producing enzymes, xanthine oxidase (XOD) and adenosine deaminase (ADA), were suppressed and renal UA transporters were modulated to enhance excretion: URAT1 and GLUT9 were downregulated and ABCG2 was upregulated. These results indicated that BrEE’s protective effects were associated with its regulatory effects on UA transport-related protein expression. BrEE also alleviated oxidative stress, and reduced inflammation and renal pathology. Meanwhile, molecular docking predicted favorable binding between the major BrEE constituents and XOD or URAT1, providing preliminary support for their potential interactions with these targets. Thus, BrEE exerted multi-target urate-lowering and kidney-protective effects, providing preliminary evidence for the potential of B. rapa L. as a plant-derived resource for further investigation in the development of functional food ingredients to regulate urate metabolism. Full article

Background/Objectives: Fecal incontinence (FI) is an underrecognized complication of inflammatory bowel disease (IBD) and colorectal neoplasia that substantially impairs quality of life. This study translated, culturally adapted, and validated the Arabic Vaizey Incontinence Score while evaluating the burden of FI among Egyptian patients. Methods: In this multicenter cross-sectional study, 287 adults with histopathologically confirmed diagnoses were enrolled, including colorectal cancer/precancerous lesions (n = 54), IBD (n = 55), and other/no significant colorectal pathology (n = 178). The questionnaire underwent standardized translation and cultural adaptation. Internal consistency was assessed using McDonald’s omega. Structural validity was evaluated using exploratory factor analysis (EFA; n = 143) and confirmatory factor analysis (CFA; n = 144). Results: Patients with IBD had the greatest fecal incontinence burden, with the highest mean Vaizey score (9.24 ± 6.77) compared with patients with colorectal neoplasia (7.28 ± 6.03) and those with other or no significant colorectal pathology (6.68 ± 4.79). Continence-related quality of life was also poorest in IBD (median 8.0 [IQR 4–10] vs. 2.0 [IQR 1–3] and 2.5 [IQR 1–6]). EFA supported a two-factor solution explaining 48.1% of the variance (KMO = 0.691; Bartlett’s χ² = 298.61, p < 0.001). The inability-to-defer-defecation item showed negligible loading and was excluded. CFA confirmed a refined six-item model with excellent fit (CFI = 0.992, TLI = 0.985, RMSEA = 0.088, SRMR = 0.087). McDonald’s omega was 0.825 for Leakage Severity and Management and 0.869 for Functional Impact, with average variance exceeding 0.50 for both domains. Conclusions: The refined six-item Arabic Vaizey Incontinence Score demonstrated good reliability and construct validity. FI score was significantly higher among patients with IBD, supporting routine assessment using this validated instrument across Egyptian patients with colorectal diseases. Full article

Introduction: Catheter-associated urinary tract infections (CAUTIs) caused by multidrug-resistant (MDR) uropathogens pose a management challenge due to bacterial biofilm formation and crystalline encrustation, especially those associated with Proteus mirabilis, which result in persistent infections and catheter obstructions. Current catheter surface coatings against CAUTIs target either the initial stages or later phases of such pathologies separately. Aim: We report the design and characterization of a novel polyfunctional coating comprised of polydopamine (PDA), genipin-crosslinked chitosan (GCS), and ZnO nanoparticles capable of blocking bacterial attachment, biofilm formation, and mineral encrustation. Methods: PDA-coated silicon surfaces were functionalized with genipin-crosslinked GCS/ZnO nanocomposites and studied by means of TEM, XRD, FTIR, SEM, AFM, water contact angle measurements, and zinc ion release tests. Antibacterial, antibiofilm, anti-encrustation, and hemocompatibility activities were then assessed. Results: ZnO nanoparticles were spherical, with an average particle size of 34.6 ± 8.2 nm and a highly crystalline hexagonal wurtzite structure. Coatings containing ZnO nanoparticles retained hydrophilic surface properties and released Zn²⁺ ions steadily. The G5 coating (containing 0.2% ZnO) demonstrated an ability to decrease bacterial adherence by >4 log₁₀ CFU, lower biofilm biomass by 80–90% (p < 0.001), prevent mineral deposition by 67–70% caused by Proteus mirabilis, and keep catheter patency for 14 days. Hemolysis was within the ISO 10993-4 acceptance criteria. Conclusions: A rationally designed combination of PDA, genipin-crosslinked GCS, and ZnO nanoparticles provided a multifunctional coating with potent antibacterial, antibiofilm, anti-encrustation, and initial hemocompatibility activity, serving as a proof-of-concept platform for further cytotoxicity assessment, mechanical durability studies, and preclinical evaluations prior to clinical implementation. Full article

Efficient cutaneous wound healing relies on the phenotypic transition of macrophages toward an anti-inflammatory, pro-reparative M2-like state. Non-healing chronic wounds are pathologically characterized by the breakdown of this polarization balance. In this review, we synthesize recent research on biomaterials fabricated from naturally occurring polysaccharides with intrinsic immunomodulatory activity, mainly represented by hydrogels that modulate macrophage phenotypic transitions. We first dissect the immune microenvironment of wound healing and elaborate on the core regulatory networks governing M1/M2 polarization, with a particular focus on signaling pathways and metabolic reprogramming. On this basis, we classify pro-M2 natural polysaccharides into mannose-containing and mannose-free categories according to their core structural motifs that mediate immunomodulatory activity, and detail their molecular mechanisms, including pattern recognition receptor engagement (MR, Dectin-1, CD44, etc.) and downstream signaling cascades (STAT6, PI3K/Akt, NF-κB, etc.). Representative polysaccharides such as konjac glucomannan (KGM), Ganoderma lucidum polysaccharide (GLP), chitosan (CS) and hyaluronic acid (HA) are discussed with a clarified structure–activity relationship (SAR). Finally, we highlight emerging design strategies for multi-functional immunomodulatory hydrogels, including mechano-biochemical coupling platforms and spatiotemporally controlled delivery systems, and analyze ongoing controversies and translational bottlenecks in this field. The relationship between material structure and function enables the rational design of purpose-built polysaccharide dressings that regulate immunity. This review highlights these materials as promising preclinical platforms for chronic wound management, although their clinical translation requires further validation. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of late-life dementia. As pathology spreads through the brain, affected individuals experience devastating cognitive decline, linguistic impairments, mood changes, and behavioral issues. Developing effective disease-modifying therapies remains a persistent challenge because diagnosis typically occurs at a late stage, long after extensive, irreversible neuronal and synaptic loss has taken place. To overcome these diagnostic and therapeutic bottlenecks, attention has shifted to microRNAs (miRNAs), the most prominent class of abundant, small non-coding RNAs that post-transcriptionally regulate eukaryotic gene expression networks. This review delineates the critical functions of specific miRNAs in orchestrating the three primary pathological pillars of AD: amyloid-β (Aβ) buildup, chronic neuroinflammation, and systemic oxidative stress. Unraveling these complex epigenetic interactions contributes fundamentally to understanding AD’s pathology, offering highly sensitive avenues for early blood-based biomarker discovery and highlighting promising targets for innovative, RNA-targeted clinical therapeutics. Full article

Hip disorders—including hip osteoarthritis (OA), greater trochanteric pain syndrome (GTPS) with gluteal tendinopathy, femoroacetabular impingement syndrome (FAIS) with associated labral pathology, and osteonecrosis of the femoral head (ONFH)—are common causes of pain and functional loss, and several are refractory to conventional non-operative care. Platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) are the two most widely used autologous orthobiologics, yet a comparative appraisal of these agents across the full spectrum of hip pathology is lacking. This narrative review is based on structured searches of MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus for clinical studies—randomized controlled trials (RCTs), comparative studies, and prospective series—and evidence syntheses evaluating PRP or BMAC in hip disorders; studies were synthesized narratively by biologic type and by disorder, and no formal systematic-review or scoping-review reporting protocol was applied. Society guidelines and consensus documents were additionally examined, and PRP formulation subgroups (leukocyte-rich [LR-PRP] versus leukocyte-poor [LP-PRP]) were considered, including a numerically larger, but methodologically heterogeneous and comparator-sensitive evidence base for hip disorders, supported by several RCTs and pooled analyses in hip OA and in gluteal tendinopathy; however, findings are heterogeneous, effect sizes are modest, a network meta-analysis found intra-articular saline to be statistically indistinguishable from PRP for hip OA pain, and the only adequately powered placebo-controlled RCT in GTPS was negative. BMAC evidence in the hip is concentrated almost entirely in surgical augmentation of core decompression for ONFH, where results are stage-dependent and include a negative double-blind RCT in post-collapse disease; intra-articular BMAC for hip OA rests on small uncontrolled cohorts, and no standalone hip BMAC RCT has been published. No RCT directly compares PRP with BMAC for any hip disorder; the closest evidence is a knee OA meta-analysis, in which both biologics outperformed hyaluronic acid with no clear separation between the two. Current society guidance advises strongly against PRP for hip OA, and no guideline currently incorporates BMAC for hip indications. Neither biologic is established as superior. The search for standardized, hip-specific, adequately powered head-to-head RCTs incorporating biologic characterization, structural (imaging) endpoints, and longer follow-up, represents the most important research priority in this field. Full article

Circulating tumor cell (CTC) clustering is a key driver of metastatic progression in non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms remain largely unknown. Here, we performed single-cell proteomic sequencing on CTC clusters and individual CTCs isolated from lung cancer patients, identifying 912 proteins in total, of which 246 were significantly upregulated in clusters versus single CTCs. Enrichment analyses revealed a prominent involvement of lipid and cholesterol metabolism pathways. Apolipoprotein E (APOE) emerged as a central hub, exhibiting marked upregulation in CTC clusters. Functional experiments showed that cholesterol supplementation promoted cluster formation in NSCLC cell lines and accelerated metastatic dissemination in vivo, whereas APOE depletion impaired clustering capacity. Mechanistically, we identified USF2 as a potential transcriptional regulator of APOE through direct binding to the promoter, as supported by Chromatin Immunoprecipitation (ChIP) and reporter assays. Clinical validation in a cohort of 75 lung cancer patients demonstrated that elevated APOE expression was strongly associated with advanced pathological grade, distant metastasis, and poor survival. Taken together, these findings establish a novel USF2–APOE–cholesterol axis that governs CTC clustering and metastatic progression, positioning APOE as both a prognostic biomarker and a potential therapeutic target for NSCLC metastasis. Full article

Background: Intracellular Ca²⁺ dysregulation and neurovascular dysfunction are increasingly recognized as important mechanisms underlying neurodegenerative disorders, including Alzheimer’s disease (AD). Restoration of pathological Ca²⁺ imbalance has therefore emerged as a potential therapeutic strategy. Although ginsenoside compound K (CK) has demonstrated neuroprotective and anti-inflammatory properties, its role in Ca²⁺ homeostasis remains unclear. Methods: SH-SY5Y neuronal cells, U373 astrocytes, BV2 microglia, bEND brain endothelial cells, and MOVAS vascular smooth muscle cells were exposed to trimethyltin chloride (TMT, 5 μM, 24 h). Cell viability, real-time cell confluence, intracellular Ca²⁺ influx, and endoplasmic reticulum (ER) Ca²⁺ store release were evaluated. Ca²⁺ dynamics were analyzed using Fura-2 fluorescence, and signaling associated with CK-mediated Ca²⁺ regulation was investigated using pharmacological inhibitors. Orai1 protein expression was evaluated by Western blot analysis in SH-SY5Y and U373 cells. Results: TMT increased store-operated Ca²⁺ entry (SOCE)-mediated Ca²⁺ influx in SH-SY5Y neuronal cells without significant cytotoxicity. In contrast, TMT reduced both Ca²⁺ influx and cell viability in U373 astrocytes, BV2 microglia, and MOVAS cells, whereas bEND cells showed minimal changes. CK restored abnormal Ca²⁺ responses in a cell type-specific manner, reducing elevated Ca²⁺ influx in neuronal cells while restoring suppressed Ca²⁺ signaling in astrocytes. Consistent with these functional findings, Orai1 protein expression was increased by TMT in SH-SY5Y cells and attenuated by CK, whereas TMT reduced Orai1 expression in U373 cells, which was restored by CK. Pharmacological analyses suggested involvement of PKA- and LTCC-associated signaling in neuronal cells and PLC- and PLD-associated signaling in astrocytes. In both cell types, CK-associated Ca²⁺ responses were sensitive to NAC and the SOCE inhibitor BTP2, supporting ROS- and SOCE-associated mechanisms. Additional controls showed no significant inhibitor effects under control or CK-only conditions, strengthening the pharmacological interpretation of responses under TMT-containing conditions. Conclusions: TMT-induced Ca²⁺ dysregulation differed markedly by cell type. CK restored disrupted Ca²⁺ homeostasis in association with distinct pharmacological signaling profiles in neuronal and astrocytic cells. These findings suggest that CK may function as a cell type-specific Ca²⁺ homeostatic regulator under neurotoxic stress conditions and highlight the importance of differential Ca²⁺ regulation in neurodegenerative disease models. Full article

Inter-organelle membrane contact sites (MCSs) enable direct communication between organelles, and this communication is fundamental to cellular homeostasis, coordinated calcium (Ca²⁺) signaling, lipid metabolism, energy production, and stress responses. While MCSs are evolutionarily conserved, emerging evidence indicates that their organization and function are highly context dependent. In the brain, neurons and glial cells differ markedly in their physiological roles, morphologies, and metabolic demands, suggesting that inter-organelle contact networks might be specialized in a cell-type-dependent manner. Although much of the existing literature focuses on neurons, growing evidence indicates that these contact sites also play important roles in glial cells. Here, we review recent advances in our understanding of MCSs in the nervous system, focusing on cell-type-specific differences between neurons and glial cells. We highlight the spatial specialization of MCSs within neurons, emphasizing how subcellular localization shapes their functional output. Our analysis of the current literature suggests that neuronal MCSs are primarily optimized for rapid Ca²⁺ signaling and metabolic adaptation, whereas glial MCSs preferentially coordinate lipid metabolism, inflammatory signaling, and tissue homeostasis. We also review the context-dependent and disease-driven remodeling of MCSs in the brain, reflecting alterations in contact-site composition and function rather than simply increased or decreased organelle proximity. Furthermore, we discuss emerging therapeutic perspectives aimed at modulating inter-organelle communication in multiple neurological diseases and outline key unresolved questions and future directions necessary to elucidate how inter-organelle contact sites shape brain physiology and disease. Collectively, the evidence reviewed here indicates that MCSs serve as dynamic signaling platforms, with their specific physiological and pathological functions varying according to cell type, subcellular localization, and molecular composition. Full article

The bidirectional transfer of biological information between insulin and neurotrophin-3 (NT-3) in hemodialysis patients (end-stage renal disease—ESRD) with type 2 diabetes mellitus (T2DM) is extremely poorly studied. Why was NT-3 chosen? Because, of all the nerve growth factors, this one also exhibits specific actions at the nephron level. The authors of this manuscript also conducted the first study on the serum behavior of NT-3 in this category of patients. Even though the results have already been published, the way in which an endocrine compound (insulin) interacts at the renal level with a growth factor with predominantly autocrine and paracrine action (NT-3), under both normal and pathological conditions, has not been thoroughly studied. This paper will address the following topics: 1. that insulin synthesis and release involve the same molecules that also exert important actions at the renal level; 2. involvement of insulin deficiency/resistance in the development of diabetic nephropathy and end-stage renal disease vs. kidney influences on serum glucose and insulin levels; 3. actions of NT-3 under normal conditions vs. diabetes mellitus; 4. aspects highlighted by personal studies performed on hemodialysis patients with T2DM. Taking an original approach, the functional link between insulin and NT-3 in hemodialysis patients, especially those with T2DM, will be presented. Finally, new therapeutic possibilities and directions for patient monitoring will be proposed, as well as topics for further research. Full article

Background rhythmic activity in routine EEG recordings of epilepsy patients contains extensive information about brain function under pathological conditions, far exceeding the duration of epileptiform and interictal discharges. However, clinical interpretation remains predominantly focused on detecting conspicuous pathological patterns, such as seizures and interictal events, which is labor-intensive and requires expert evaluation. Recent advances in rhythmic EEG analysis combined with machine learning (ML) have enabled reliable differentiation between healthy individuals and epilepsy patients. Building on this momentum, the present study introduces a novel ML framework for the automated analysis and localization of cortical hyperexcitability foci, using only background EEG oscillations in the absence of detectable interictal discharges or seizure events. Leveraging publicly available EEG data, we demonstrate that Random Forest and CatBoost algorithms can effectively predict the approximate localization of interictal discharge foci at the level of major cortical regions. In a cohort of 48 patients (782 one-minute background epochs, five localization classes), Random Forest achieved an accuracy of 0.92 with a macro F1-score of 0.90 under patient-wise cross-validation. These findings establish background EEG activity as a promising clinically relevant biomarker for focal epilepsy diagnosis and highlight the feasibility of developing automated, expert-independent localization tools, addressing a critical unmet need in clinical neurophysiology. Full article