Search Results (328)

Background: Achilles tendon (AT) thickening reflects cumulative low-density lipoprotein cholesterol (LDL-C) exposure. The Japan Atherosclerosis Society (JAS) explicitly includes AT thickness as a diagnostic criterion for familial hypercholesterolemia (FH) in adults, whereas internationally, it is not a standard diagnostic measure. However, the clinical significance of AT thickening in pediatric populations remains unclear. Methods: We conducted a single-center, retrospective, observational study involving pediatric patients (11–18 years old) with suspected FH through standardized universal lipid screening across Kagawa Prefecture, Japan. Genetic testing confirmed FH through pathogenic variants in the LDLR, PCSK9, or APOB genes. The AT thickness was measured using a standardized ultrasonography protocol. We assessed associations between the FH status, cumulative LDL-C levels, and AT thickness. Results: In the pediatric patients, no significant difference in the AT thickness was observed between the FH and non-FH groups (median 4.4 vs. 4.5 mm; p = 0.570). Cumulative LDL-C was higher in the FH group, while no clear association between cumulative LDL-C and AT thickness was apparent in either group. Conclusions: In this single-center, retrospective study of pediatric patients identified through standardized universal lipid screening, no significant differences were found in AT thickness between FH and non-FH groups although cumulative LDL-C levels were higher in the FH group. Given methodological limitations (small sample size, selection bias, and residual confounding related to statin therapy and growth), these findings should be interpreted as exploratory rather than confirmatory. Regardless of genotype, early risk management may be warranted. Full article

Glycosylation, the enzymatic addition of glycans to proteins and lipids, is a critical post-translational modification that influences protein folding, stability, trafficking, immune modulation, and cell signaling. The vast structural diversity of glycans arising from differences in monosaccharide composition, branching, and terminal modifications such as sialylation, fucosylation, and sulfation underpins their functional specificity and regulatory capacity. This review provides a comprehensive overview of glycan biosynthesis, with a focus on N-glycans, O-glycans, glycosaminoglycans (GAGs), and glycolipids. It explores their essential roles in maintaining cellular homeostasis, development, and immune surveillance. In health, glycans mediate cell–cell communication, protein interactions, and immune responses. In disease, however, aberrant glycosylation is increasingly recognized as a hallmark of numerous pathological conditions, including cancer, neurodegenerative disorders, autoimmune diseases, and a wide range of infectious diseases. Glycomic alterations contribute to tumor progression, immune evasion, therapy resistance, neuroinflammation, and synaptic dysfunction. Tumor-associated carbohydrate antigens (TACAs) and disease-specific glycoforms present novel opportunities for biomarker discovery and therapeutic targeting. Moreover, glycan-mediated host–pathogen interactions are central to microbial adhesion, immune escape, and virulence. This review highlights current advances in glycomics technologies, including mass spectrometry, lectin microarrays, and glycoengineering, which have enabled the high-resolution profiling of the glycome. It also highlights the emerging potential of single-cell glycomics and multi-omics integration in precision medicine. Understanding glycome and its dynamic regulation is essential for uncovering the molecular mechanisms of disease and translating glycomic insights into innovative diagnostic and therapeutic strategies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)—an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention. Full article

Sulforaphane, a natural isothiocyanate predominantly found in cruciferous vegetables, has shown potential in preventing and treating Helicobacter pylori infection. However, the underlying metabolic mechanisms remain largely unclear. This study employed high-coverage metabolomics and lipidomics methods to comprehensively investigate the effects of sulforaphane on the serum and liver metabolic profiles of H. pylori-infected mice. Metabolomics and lipidomics analysis revealed that H. pylori infection disrupted multiple metabolic pathways, leading to perturbations in amino acids, fatty acids, bile acids, and various lipid species. Sulforaphane treatment can ameliorate these disruptions, notably reversing alterations in serum glycerophospholipids and restoring hepatic levels of amino acids, bile acids, glycerophospholipids, ceramides, and peptides. Key metabolic pathways implicated included glutathione metabolism and glycine and serine metabolism, which are associated with antioxidant defense and host resistance to pathogenic infections. These findings offer a comprehensive metabolic basis for understanding the therapeutic effects of sulforaphane against H. pylori infection. Full article

Background/Objectives: Burn wound infections present significant clinical challenges due to multidrug-resistant pathogens and the limitations of traditional antimicrobials. While antimicrobial peptides (AMPs) have broad-spectrum effectiveness, their instability in wound environments limits their use. This study compares properties of AMP-decorated nanostructured lipid carriers (NLCs) to free AMPs, focusing on their dermal penetration, retention, and antimicrobial efficacy in simulated ex vivo burn wound models. Methods: AMP-decorated NLCs (smart-AMPs) were produced by electrostatic and hydrophobic surface adsorption and characterized regarding their size, zeta potential, and physical short-term stability. The distribution of AMPs within the wounds was evaluated using an ex vivo porcine ear model with various wound types. The antimicrobial efficacy was assessed by monitoring the bioluminescence of Aliivibrio fischeri as a live bacterial marker for 24 h. Results: The size and zeta potential measurements confirmed the successful formation of smart-AMPs. The dermal penetration of AMPs was influenced by the type of wound and the type of AMP formulation (free AMPs vs. smart-AMPs). In the chronically infected burn wounds, which were characterized by the formation of a biofilm in a protein-rich wound fluid, the smart-AMPs resulted in a 1.5-fold higher and deeper penetration of the AMPs, and the antimicrobial activity was 6-fold higher compared to the free AMPs. Conclusions: smart-AMPs present an innovative approach for treating chronic, biofilm-associated wounds more efficiently than the current treatment options. Full article

Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G>A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries and the development of abnormal collateral networks. Recent evidence suggests that RNF213 variants are also enriched in non-moyamoya intracranial arteriopathies, such as large-artery atherosclerotic stroke and intracranial arterial stenosis/occlusion (ICASO), particularly in east Asian individuals with early-onset or cryptogenic stroke. This expanded phenotypic spectrum, termed RNF213-related vasculopathy (RRV), represents a distinct pathogenic entity that may involve unique pathogenic processes separate from traditional atherosclerosis. In this review, we synthesize current genetic, clinical, radiological, and experimental findings that delineate the unique features of RRV. Patients with RRV typically exhibit a lower burden of traditional vascular risk factors, negative vascular remodeling in the absence of atheromatous plaques, and an increased propensity for disease progression. RNF213 variants may compromise vascular resilience by impairing adaptive responses to hemodynamic stress. Furthermore, emerging cellular and animal model data indicate that RNF213 influences angiogenesis, lipid metabolism, and stress responses, offering mechanistic insights into its role in maintaining vascular integrity. Recognizing RRV as a distinct clinical entity has important implications for diagnosis, risk stratification, and the development of genome-informed therapeutic strategies. Full article

Invasive candidiasis (IC), characterized by the most common clinical manifestation of candidemia, is a fungal infection with a high mortality rate and a significant impact on global public health. It is estimated that each year there are between 227,000 and 250,000 hospitalizations related to IC, with more than 100,000 associated deaths. In Latin America and the Caribbean (LA&C), the absence of a standardized surveillance system has led to multicenter studies documenting incidences ranging from 0.74 to 6.0 cases per 1000 hospital admissions, equivalent to 50,000–60,000 hospitalizations annually, with mortality rates of up to 60% in certain high-risk groups. Armed conflicts and structural violence in LA&C cause forced displacement, the collapse of health systems, and poor living conditions—such as overcrowding, malnutrition, and lack of sanitation—which increase vulnerability to opportunistic infections, such as IC. Insufficient specialized laboratories, diagnostic technology, and trained personnel impede pathogen identification and delay timely initiation of antifungal therapy. Furthermore, the empirical use of broad-spectrum antibiotics and the limited availability of echinocandins and lipid formulations of amphotericin B have promoted the emergence of resistant non-albicans strains, such as Candida tropicalis, Candida parapsilosis, and, in recent outbreaks, Candidozyma auris. Full article

Root rot, mainly caused by Fusarium oxysporum, is one of the most destructive diseases and leads to significant economic loss of Astragalus membranaceus. To develop an effective strategy for the management of this serious disease, a bacterial strain 2-12 was screened from A. membranaceus rhizosphere soil and identified as Bacillus paralicheniformis based on the phylogenetic analyses of gyrase subunit B gene (gyrB) and RNA polymerase gene (rpoB) sequences. Interestingly, the volatile organic compounds (VOCs) produced by B. paralicheniformis 2-12 exhibited potent antifungal activities against F. oxysporum, as well as fifteen other plant pathogens. Under scanning electron microscopy observation, hyphae treated with the VOCs exhibited abnormal variation such as distortion, twist, and vesiculation, leading to distinctive protoplasm shrinkage. After treatment with B. paralicheniformis 2-12 VOCs, the lesion diameter and disease incidence both reduced significantly compared to control (p < 0.05), thus demonstrating prominent biological efficiency. Moreover, B. paralicheniformis 2-12 VOCs were composed of 17 VOCs, including 9 alkanes, 3 alcohols, 3 acids and esters, 1 aromatic compound, and 1 alkyne compound. A total of 1945 DEGs, including 1001 up-regulated and 944 down-regulated genes, were screened via transcriptome analysis. These DEGs were mainly associated with membranes and membrane parts, amino acid metabolism, and lipid metabolism. The findings in this work strongly suggested that B. paralicheniformis 2-12 VOCs could be applied as a new candidate for the control of A. membranaceus root rot. Full article

Background: Aortic stenosis (AS) has long been considered a degenerative disease and is typically diagnosed in older men at an advanced stage. However, accumulating evidence has highlighted the similarities between AS and atherosclerosis, particularly regarding shared risk factors and overlapping pathophysiological mechanisms. This connection has led to a paradigm shift, suggesting that AS may be preventable in its early stages. Methods: This narrative review synthesizes the existing literature exploring the parallels between AS and atherosclerosis, focusing on common risk factors, pathogenic pathways, and evolving therapeutic strategies. Clinical trials and translational studies were examined to assess the effectiveness of atherosclerosis-based treatments for AS. Results: Multiple studies have confirmed the shared inflammatory, lipid-mediated, and calcific mechanisms of AS and atherosclerosis. Despite these similarities, therapeutic strategies effective in atherosclerosis, such as statin therapy, have not consistently shown benefits in AS. New medical approaches aim to delay aortic valve replacement and reduce the associated morbidity. The partially overlapping pathogenesis continues to guide future research. Conclusions: While AS and atherosclerosis share several pathogenic features, their clinical courses and treatment responses diverge. Understanding the limits and potential of their overlap may inform future preventive and therapeutic strategies. Earlier detection and targeted intervention in AS remain key goals, drawing on insights from cardiovascular disease management. Full article

Advanced glycation end-products (AGEs) are formed by the non-enzymatic glycation of proteins, lipids, and nucleic acids due to the consumption of high-carbohydrate diets; their production is also promoted by a sedentary lifestyle as well as cigarette smoking. Elevated levels of AGEs in the circulatory system and internal organs of the body are commonly observed in a number of cardiovascular diseases such as hypertension, diabetes, atherosclerosis, coronary artery disease, aortic aneurysm, atrial fibrillation, myocardial infarction, and heart failure, which are associated with the development of oxidative stress and myocardial inflammation. The adverse effects of AGEs on the cardiovascular system are elicited by both non-receptor mechanisms involving the cross-linking of extracellular and intracellular proteins, and by receptor-mediated mechanisms involving the binding of AGEs with advanced glycation end-product receptors (RAGEs) on the cell membrane. AGE–RAGE interactions along with the cross-linking of proteins promote the generation of oxidative stress, the production of inflammation, the occurrence of intracellular Ca²⁺-overload, and alterations in the extracellular matrix leading to the development of cardiovascular dysfunction. AGEs also bind with two other protein receptors in the circulatory system: soluble RAGEs (sRAGEs) are released upon the proteolysis of RAGEs due to the activation of matrix metalloproteinase, and endogenous secretory RAGEs (esRAGEs) are secreted as a spliced variant of endogenous RAGEs. While the AGE–RAGE signal transduction axis serves as a pathogenic mechanism, both sRAGEs and esRAGEs serve as cytoprotective interventions. The serum levels of sRAGEs are decreased in ischemic heart disease, vascular disease, and heart failure, as well as in other cardiovascular diseases, but are increased in chronic diabetes and renal disease. Several interventions which can reduce the formation of AGEs, block the AGE–RAGE axis, or increase the levels of circulating sRAGEs have been shown to exert beneficial effects in diverse cardiovascular diseases. These observations support the view that the AGE–RAGE axis not only plays a critical role in pathogenesis, but is also an excellent target for the treatment of cardiovascular disease. Full article

Phenylketonuria (PKU) is a monogenic disorder caused by pathogenic variants in the gene encoding phenylalanine hydroxylase (PAH), an enzyme essential for phenylalanine (Phe) metabolism. It is characterized by elevated Phe levels, leading to a wide spectrum of clinical phenotypes. These phenotypes are characterized by varying Phe accumulation, dietary tolerance, and heterogeneous cognitive and neurological outcomes, but current monitoring methods, focused primarily on blood Phe levels, are limited in capturing this variability. In this study, we applied mass spectrometry-based advanced quantitative amino acid analyses, untargeted metabolomics, and lipidomics analyses. We examined the plasma metabolite and lipid profiles in a total of 73 individuals with various PKU phenotypes against healthy controls to see how the metabolome and lipidome of the patients change in different phenotypes. We investigated whether novel markers could be associated with metabolic control status. By elucidating the metabolic and lipid fingerprints of PKU’s phenotypic variability, our findings may provide novel insights that could inform the refinement of dietary and pharmacological interventions, thereby supporting the development of more personalized treatment strategies. Full article

Oxidized phospholipids (OxPLs) are increasingly recognized as biologically active lipids involved in various pathologies. Both exposure to pathogenic factors and the efficacy of protective mechanisms are critical to disease development. In this study, we characterized an immunoassay that quantified the total capacity of the plasma to degrade or mask OxPLs, thereby preventing their interaction with cells and soluble proteins. OxLDL-coated plates were first incubated with human blood plasma or a control vehicle, followed by an ELISA using a monoclonal antibody specific to oxidized phosphatidylethanolamine. Pretreatment with the diluted blood plasma markedly inhibited mAb binding. The masking assay was optimized by evaluating the buffer composition, the compatibility with various anticoagulants, potential interfering compounds, the kinetic parameters, pre-analytical stability, statistical robustness, and intra- and inter-individual variability. We propose that this masking assay provides a simple immunological approach to assessing protective mechanisms against lipid peroxidation products. Establishing this robust and reproducible method is essential for conducting clinical association studies that explore masking activity as a potential biomarker of the predisposition to a broad range of lipid-peroxidation-related diseases. Full article

Respiratory syncytial virus (RSV) is a major human respiratory pathogen, particularly affecting infants, the elderly, and immunocompromised individuals. RSV exists in both spherical and filamentous forms, with the filamentous morphology associated with enhanced infectivity and cell-to-cell spread. Here, we demonstrate that RhoA, a small GTPase involved in cytoskeletal regulation, is essential for filamentous RSV morphogenesis through its role in organizing lipid raft microdomains. Rhosin, a selective RhoA inhibitor developed through structure-guided screening, disrupts GEF–RhoA interactions to block RhoA activation. The pharmacological inhibition of RhoA with Rhosin significantly reduced filamentous virion formation, disrupted RSV fusion (F) protein colocalization with lipid rafts, and diminished cell-to-cell fusion, without affecting overall viral replication. Scanning electron microscopy revealed that Rhosin-treated infected HEp-2 cells exhibited fewer and shorter filamentous projections compared to the extensive filament formation seen in untreated cells. β-galactosidase-based fusion assays confirmed that reduced filamentation corresponded with decreased cell-to-cell fusion. The biophysical separation of RSV spherical and filamentous particles by sucrose gradient velocity sedimentation, coupled with fluorescence and transmission electron microscopy, showed that Rhosin treatment shifted virion morphology toward spherical forms. This suggests that RhoA activity is critical for filamentous virion assembly, which may enhance viral spread. Immunofluorescence microscopy using lipid raft-selective dyes (DiIC₁₆) and fusion protein-specific antibodies revealed the strong co-localization of RSV proteins with lipid rafts. Importantly, the pharmacological inhibition of RhoA with Rhosin disrupted F protein partitioning into raft domains, underscoring the requirement for intact lipid rafts in assembly. These findings highlight a novel role for host RhoA signaling in regulating viral assembly through raft microdomain organization, offering a potential target for host-directed antiviral intervention aimed at altering RSV structural phenotypes and limiting pathogenesis. Full article

This study systematically investigated the effects of dietary tea polyphenols (TPs, major bioactive polyphenols from Camellia sinensis with potent antioxidant and anti-inflammatory properties) on the growth performance and intestinal health of hybrid crucian carp HCC2 under chronic crowding stress. A low-density control group (44.4 fish/m³, basal diet without TPs) and four high-density crowding stress groups (222.2 fish/m³) were established, one fed the basal diet without TPs (CS) and three fed basal diets supplemented with 100 (CSLTP), 200 (CSMTP), or 400 (CSHTP) mg/kg TPs. We analyzed the impacts of TPs on growth performance, serum biochemical parameters, antioxidant capacity, expression of lipid metabolism-related genes, and intestinal microbiota composition. The results demonstrated that chronic crowding stress significantly suppressed the final body weight, weight gain rate, and specific growth rate of HCC2, while increasing serum lactate LDH, TG, and ALB and decreasing GLU, LDL-C, ALT, AST, and ALP levels. Dietary TPs supplementation enhanced antioxidant capacity (T-AOC, SOD, CAT, and GSH) and alleviated lipid metabolic disorders by activating the Nrf2/Keap1 and PPARα signaling pathways, thereby upregulating the expression of liver antioxidant genes (CAT and SOD) and fatty acid oxidation genes (CPT1 and acox1). Furthermore, intestinal microbiota analysis revealed that chronic crowding stress significantly increased the abundance of Proteobacteria and decreased the proportion of Firmicutes compared to the low-density control. Dietary TPs intervention, particularly at higher doses, partially restored the Firmicutes abundance and reduced the enrichment of potential pathogenic bacteria associated with stress. This study is the first to comprehensively elucidate the mechanism by which TPs alleviate crowding stress through enhanced antioxidant capacity, metabolic regulation, and microbiota remodeling, providing robust theoretical support for the application of plant-based additives in aquaculture. Full article

Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) serves as a tethering factor that interacts with various proteins and recruits these proteins to the ER surface, exerting multiple functions, such as organelle membrane tethering, lipid transfer between organelles, regulation of calcium homeostasis, autophagy, and the unfolded protein response (UPR). Its interaction is often mediated by its MSP (major sperm) domain, which binds with FFAT (two phenylalanines in an acidic tract)-motif-containing proteins. However, pathogenic variations, such as P56S, P56H, and T46I, in the VAPB MSP domain lead to the familial form of amyotrophic lateral sclerosis (ALS8). Still, the underlying pathophysiology of ALS8 due to pathogenic variations in the VAPB MSP domain remains elusive. In this study, we conducted molecular dynamics (MD) simulations to understand the pathogenic-variant-derived changes in the structural dynamics of the VAPB MSP domain. We found that pathogenic variants altered the fluctuations and conformational dynamics of the VAPB protein. Analyzing the organizations of the secondary structure revealed that pathogenic variants changed the composition of secondary structure elements, especially increasing the proportion of α-helix while reducing β-sheet formation, which might affect the organelle tethering and other functions of VAPB, as well as VAPB homodimer and heterodimer formation. Taken together, these findings can be further investigated through in vivo and/or in vitro studies to not only clarify the pathophysiology of ALS8 resulting from VAPB MSP domain pathogenic variants but also develop novel therapeutics for the disease that restore the native structural organizations as well as fluctuations and motions. Full article