Search Results (39,417)

Aspartate–glutamate carrier 1 (AGC1) deficiency is a rare neurometabolic disorder caused by biallelic pathogenic variants in SLC25A12. Clinically, it is characterized by early-onset developmental and epileptic encephalopathy, often associated with hypomyelination and reduced brain N-acetylaspartate. AGC1 loss reduces malate–aspartate shuttle flux, limiting cytosolic NAD⁺ regeneration and impairing neuronal redox coupling, ATP supply, and aspartate-dependent biosynthesis during brain development. We integrate human genetics with mechanistic evidence from mammalian, Drosophila melanogaster, and Saccharomyces cerevisiae models to describe conserved transport principles and species-specific regulation underlying selective central nervous system vulnerability. We review the management of AGC1 deficiency, focusing on ketogenic therapy. Published reports show reproducible seizure reduction and, in some patients, improved myelination and N-acetylaspartate. However, these responses are heterogeneous and appear to depend on the timing, duration, and stability of ketosis. Preclinical evidence suggests that β-hydroxybutyrate may contribute to metabolic support in AGC1 deficiency. Prospective studies should test disease modification using standardized endpoints plus MRI/¹H-MRS and ketosis measures. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread condition with a complex pathogenesis. Cell-based models are important tools for studying the mechanisms underlying its development and progression. The aim of this review is to analyze the HepaRG, Huh-7, immortalized human hepatocyte (IHH), and primary human hepatocyte (PHH) cell lines for modeling and studying MASLD. HepaRG represents the most metabolically competent immortalized hepatocyte model with preserved biotransformation activity and a physiological bioenergetic response to lipid loading, making it valuable for pharmacological and toxicological studies. Huh-7 is distinguished by its accessibility and suitability for studying steatosis, lipotoxicity, insulin resistance, and paracrine mechanisms of fibrogenesis; however, its use is limited by its tumor origin, impaired carbohydrate metabolism, and low activity of xenobiotic-metabolizing enzymes. The IHH model occupies an intermediate position because of its non-tumor origin and is of interest for studies of senescence, epigenetic regulation, and signaling pathways involved in steatosis, although interpretation of results requires consideration of immortalization-related effects and specific metabolic limitations. PHH remains the most physiologically relevant platform for MASLD modeling, particularly in three-dimensional (3D) and microphysiological formats; however, its use is limited by high cost, interindividual variability, and the limited duration of the differentiated phenotype. Increasing model complexity—from two-dimensional (2D) monocultures to co-cultures, spheroids, and organ-on-chip systems—enhances physiological relevance and enables reproduction not only of steatosis but also of the inflammatory and fibrogenic components of MASLD progression, yet it reduces reproducibility and complicates standardization. Overall, none of the existing models is universal, and the optimal strategy is to select models according to the specific research question. A key direction for future research is the standardization of steatosis induction protocols and the unification of criteria for evaluating results. Full article

Restless legs syndrome (RLS) is a common sensorimotor disorder with limited treatment options and incompletely understood pathophysiology. Genome-wide association studies have identified numerous risk loci, but translating these findings into causal genes and therapeutic targets remains challenging. We performed a proteome-wide association study (PWAS) integrating RLS genome-wide association study (GWAS) data from FinnGen with two brain pQTL datasets (ROSMAP and Banner). We validated the identified proteins using TWAS, SMR, and colocalization analyses using brain pQTL and eQTL datasets. To further investigate peripheral protein associations, we performed SMR using plasma pQTL data from the UK Biobank Pharma Proteomics Project (UKB-PPP). We also conducted a phenome-wide association study (PheWAS) to screen for potential off-target effects of the prioritized genes, followed by drug prediction using DSigDB and molecular docking. PWAS identified GLO1, along with GRWD1 and MAP2K5, as significantly associated with RLS. GLO1 was identified by brain-based SMR (p = 0.0001), colocalization (PP.H4 = 0.96), TWAS (p = 0.048), and was confirmed by plasma-based SMR (p = 3.16 × 10⁻⁹) as the only protein associated with RLS. PheWAS analysis, without associations for 783 non-RLS phenotypes, confirmed the specificity of GLO1. Among 27 predicted GLO1-targeting compounds, Gambierol had the strongest binding affinity (−8.3 kcal/mol). This proteogenomic study identifies GLO1 as a prioritized causal gene and promising drug target for RLS, combining brain and plasma data to provide new insights into pathogenesis and candidate drug development. Full article

Beyond gas transport, red blood cells (RBCs) have emerging roles regarding innate immunity, regulating blood flow, and participating in nutrient transport, which can be engineered as drug delivery systems since they contribute to maintaining water homeostasis. Following extensive thermoanalytical studies of human blood plasma, our working group investigated the properties of RBCs, examining their role in healthy and in different disease states by using differential scanning calorimetry (DSC) and the deconvolution of the resulting thermal curve. In the first study, guinea pigs were treated with intraperitoneal chemotherapy. Cyclophosphamide treatment showed a dose-dependent difference between the thermal parameters of control and treated samples, indicating that DSC can be used in this area. Following deconvolution of the DSC studies, the changes can be attributed to the damaged compounds. In the second part of our study, a method for the thermal analysis and deconvolution of RBCs in patients with lower limb ischemia during a three-month cilostazol treatment was developed. The control DSC curve showed 5-6 distinct thermal domains, and in contrast to other drug treatments, this remained stable throughout the entire study period. No effects of stiffness or compact were caused by the anticancer drug cyclophosphamide were observed in the structure of RBCs. These preliminary results highlight the uniqueness of thermodynamic studies of RBCs and provide a fingerprint-like identification of a given individual or disease state. Full article

High-density microelectrode arrays (HDMEAs) have become increasingly important tools in neuroscience and biomedical engineering because of their high spatial and temporal resolution for recording and modulating electrical activity across diverse biological systems. Initially developed for in vitro studies of cultured cells, HDMEAs are now being applied to increasingly complex models, including organoids, animal systems, and even human neural systems. These advancements enable a deeper investigation of cellular interactions, network dynamics, and disease mechanisms, as well as providing novel therapeutic and diagnostic tools for neurological disorders. This review explores the evolution of HDMEAs, emphasizing recent innovations in their design, fabrication, and functionalization. We discuss their applications across cellular models, organoid systems, animal studies, and human electrophysiology, and highlight current challenges such as biocompatibility, long-term stability, scalability, and translational deployment. Finally, we outline future directions for advancing HDMEA technologies in both research and clinical settings. Full article

Inflammation plays a key role in the pathogenesis of many diseases, including cardiovascular disease and ischemic stroke. However, despite the existence of known inflammatory genes, the question of estimating their total number and the possibility of discovering new ones remains open. This study sought and analyzed genes involved in inflammation among genes related to cardiovascular disease and ischemic stroke. Human genes associated with ischemic stroke (N = 1177) and cardiovascular disease (N = 1756) were retrieved from the DisGeNET platform. Inflammatory and immune response genes were obtained from the Gene Ontology, NCBI, and Reactome databases. An additional list of 140 inflammatory genes was compiled based on our previously obtained data on the differential gene expression in a rat brain under transient middle cerebral artery occlusion. Genes that occurred simultaneously in both the inflammatory gene lists and gene lists of diseases were selected and considered. The resulting combined gene list included 1285 inflammatory genes. The NFKB1 and RELA genes demonstrated the highest frequencies across the various inflammatory gene selection resources we examined. Using a combination of experimental and bioinformatics approaches, a representative list of inflammatory genes important for the pathogenesis of ischemic stroke was compiled. The identified genes may be crucial for the development of anti-inflammatory therapeutic strategies for this disease. Full article

We present a modular microfluidic platform for constructing miniaturized, compartmentalized cell culture systems that support monoculture, co-culture, and organ-on-a-chip models of human tissues. The devices provide architecturally defined three-dimensional microenvironments in which heterogeneous cell populations can be cultured in close proximity while maintaining precise spatial organization and independent access to each compartment. In vivo-like perfusion into, from, and between adjacent chambers is achieved via micro-engineered porous barriers that act as perfusion microchannels, enabling controlled convective and diffusive transport and recapitulating paracrine signaling between tissue units. As a proof of concept, we implement an adipose–immune co-culture model that reproduces key features of inflamed, insulin-resistant adipose tissue, including altered cytokine secretion and glucose uptake. Together, these features establish a versatile platform for the biofabrication of customizable single-organ and multi-organ in vitro models that more faithfully recapitulate human tissue structure and function for applications in disease modeling, immunometabolic studies, and preclinical drug testing. Full article

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and prominent neuroimmune remodeling, but the contribution of macrophage and myeloid states across disease severity remains incompletely defined. We integrated bulk transcriptomic, single-cell RNA sequencing (RNA-seq), and spatial transcriptomic datasets to characterize AD-associated myeloid immune changes across Braak stage and disease status. Across datasets, M2-like macrophage and myeloid signatures showed progressive enrichment with increasing neuropathological severity and were accompanied by pathway changes related to macrophage proliferation, TGF-β signaling, and myeloid homeostasis. Immune-feature-based classifiers identified macrophage-related variables among the informative features distinguishing AD from controls. CellChat analyses further inferred that M2-like myeloid populations occupied communication-enriched positions in single-cell and spatial interaction networks, including apolipoprotein E (ApoE), CX3C chemokine signaling, and fibronectin 1 (FN1)-associated signaling contexts. Collectively, these findings indicate that M2-like myeloid programs are consistently associated with AD severity and neuroimmune network remodeling. Rather than establishing a causal disease driver, this study highlights M2-like myeloid signatures as candidate neuroimmune components that warrant experimental validation in human-relevant systems. Full article

Avian influenza (AI) remains a serious threat to poultry and public health worldwide due to its zoonotic nature and pandemic potential. This paper develops and analyzes a coupled system of nonlinear ordinary differential equations and an SEIR-SEIR model that describes the transmission dynamics of avian influenza in both human and bird populations. The model incorporates multiple transmission routes (bird-to-bird, bird-to-human, human-to-human), exposed/latent compartments in both hosts, disease-induced mortality, and demographic processes. From a mathematical perspective, we present a rigorous analysis of this eight-dimensional dynamical system. We prove positivity and boundedness of solutions in ${\mathbb{R}}_{+}^8$, characterize the equilibrium points, and derive the basic reproduction numbers $R_0^b$ and $R_0^h$ using the next-generation matrix method. Local asymptotic stability of the disease-free equilibrium is established via the Routh–Hurwitz criterion. A composite Lyapunov function is constructed to prove global asymptotic stability when both reproduction numbers are less than unity—a result that exploits the cascade structure of the system and provides a template for analyzing similar multi-host models. Sensitivity analysis using normalized forward sensitivity indices identifies critical parameters. In addition, we use neural network models to validate both models and provide error analysis. These results emphasize the crucial role of controlling cross-species transmission and improving recovery efforts, which have significant implications for the design of effective intervention and surveillance programs in the context of the One Health framework. Full article

Methylglyoxal (MG) is a reactive dicarbonyl compound generated mainly as a byproduct of glycolysis. Excess accumulation of MG can promote protein glycation and the formation of advanced glycation end-products (AGEs), which have been associated with oxidative stress, inflammation, mitochondrial dysfunction, and cellular damage. These processes are implicated in the development of several chronic conditions, including diabetes, neurodegenerative disorders, cardiovascular disease, and age-related decline. The glyoxalase system, comprising Glyoxalase I (Glo1) and Glyoxalase II (Glo2), serves as a key cellular defense mechanism that detoxifies MG and helps maintain dicarbonyl homeostasis. Among these enzymes, Glo1 catalyzes the conversion of MG into less reactive intermediates in a glutathione (GSH)-dependent manner. A range of natural compounds and dietary phytochemicals, including sulforaphane, resveratrol, α-lipoic acid, selenium, vitamin D3, and N-acetylcysteine, have been reported to modulate Glo1 activity through transcriptional regulation, antioxidant effects, or support of intracellular GSH levels. Evidence from preclinical and limited human studies suggests that these compounds may help reduce MG burden and AGE formation, although their effects are often indirect and context-dependent. However, several challenges remain, including variable bioavailability, dose-dependent responses, disease-specific differences in Glo1 regulation, and the lack of standardized biomarkers and adequate clinical validation. This review examines the MG–Glo1 axis as a mechanistic framework linking metabolic stress to disease and evaluates natural compounds as context-dependent modulators of this pathway. By integrating mechanistic insights with emerging in vivo and clinical evidence, this work highlights the potential, while acknowledging the limitations, of targeting Glo1 as a translational strategy for managing glycation-associated disorders. Full article

Tick-borne encephalitis virus (TBEV) is a major arthropod-borne flavivirus responsible for severe neurological disease in humans across Europe and Asia. It is maintained in nature through complex interactions within ticks and between tick vectors, vertebrate hosts and environmental factors. This review summarizes current knowledge on TBEV–tick interactions, focusing on virus acquisition, dissemination, vector competence, and long-term persistence within tick vectors. TBEV is acquired by ticks during blood feeding on viremic hosts or through co-feeding transmission under experimental conditions. Transovarial transmission has also been reported, as indicated by the detection of infected larvae in nature, although its efficiency appears to be low and variable. Following ingestion, TBEV infects and replicates in the tick midgut before dissemination via the hemolymph to secondary tissues, including the salivary glands and reproductive organs, which are essential for viral persistence and transmission. Vector competence and capacity vary between tick species and are shaped by intrinsic and extrinsic factors. Although transstadial transmission and transovarial transmission contribute to long-term virus maintenance, their efficiency is generally low and variable. In vitro models, including tick cell lines, have provided valuable insights into virus–tick interactions. Nevertheless, important knowledge gaps remain, particularly in understanding early events at the tick–host interface and mechanisms underlying viral dissemination and persistence within ticks. Full article

Schistosomiasis, a neglected tropical disease (NTD), affects humans and leads to considerable clinical morbidity and severe long-term sequelae. Laboratory diagnostics for Schistosoma mansoni are mainly based on microscopic identification of eggs in stool, but sensitivity varies with infection intensity. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is the gold standard for bacterial identification in high-income countries. Here, we first evaluate the capacity of MALDI-TOF MS and our existing ‘in-house helminths’ database for the identification of S. mansoni worms and eggs. A subset of adult worms and egg samples was used to generate MALDI reference spectra, which were added to the database and evaluated by blind-test identification. Subsequently, egg-free human stool was spiked with purified S. mansoni eggs and analyzed by MALDI-TOF MS. Log score values (LSVs) were employed to assess the reliability of identification. A total of 62/90 (68.9%, 95% confidence interval (CI): 58.3–78.2%) adult samples were correctly identified. After database expansion, 90/90 (100%, 95% CI: 96.0–100%) and 59/60 (98.3%, 95% CI: 91.1–100%) were correctly identified for adult worms and purified eggs, respectively. In contrast, the analysis of 35 human stool samples spiked with S. mansoni as eggs did not yield identifiable spectra. MALDI-TOF MS can be applied for the identification of isolated adult S. mansoni worms and eggs. Further investigations and optimization are necessary before potential application to clinical samples (e.g., for egg detection in stool). Full article

Akkermansia muciniphila (A. muciniphila) is a bacterium that breaks down mucus and is studied for its effects on metabolism and the immune system. Studies show that it affects Alzheimer’s disease (AD) by protecting the gut barrier, reducing inflammation, and influencing communication between the immune system, the brain, and mitochondria. This review summarizes mechanistic, preclinical, and translational evidence connecting A. muciniphila to AD, including products such as short-chain fatty acids (SCFAs), and structural or secreted proteins including Amuc_1100 and extracellular vesicles (AmEVs). We also discuss differences between bacterial strains, differences in research methods, and findings that change under different conditions, which make the results harder to interpret. Animal studies suggest neuroprotective effects, but clinical evidence is still limited. Clinical use will need human studies at the strain level, confirmation in humanized models, and early trials using biomarkers to test safety and causal effects. Full article

Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by dominant mutations in the gfap gene, which encodes glial fibrillary acidic protein (GFAP), a major intermediate filament in astrocytes. As a primary astrogliopathy, AxD is marked by white matter abnormalities, the formation of GFAP-containing Rosenthal fibers, astrocyte dysfunction, and progressive neurodegeneration. While GFAP mutations are known to cause toxic gain-of-function effects, the precise mechanisms by which mutant GFAP drives astrocyte dysfunction and central nervous system pathology remain unclear. To address this, we developed a novel rat model of AxD harboring the R237H mutation in the endogenous gfap locus, which mirrors the R239H mutation commonly associated with early-onset AxD in humans. This model recapitulates key AxD pathologies, including GFAP aggregation, widespread astrogliosis, white matter abnormalities, and motor deficits. Using homozygous mutant rats, we dissected the distinct contributions of mutant GFAP and elevated GFAP expression to astrocyte dysfunction and neurodegeneration. Our findings reveal that AxD pathogenesis results from a synergistic interaction between the toxic gain-of-function properties of mutant GFAP and its elevated expression, which together drive GFAP aggregation, proteostatic stress, and astrocyte dysfunction. These insights provide a deeper understanding of AxD mechanisms and a foundation for developing targeted therapies for this devastating disease. Full article