Search Results (20,476)

Background: Lipoproteins are molecules composed of phospholipids and apolipoproteins that transport triacylglycerol and cholesterol in blood and are implicated in the development of many diseases. Methods: In this study, we fill a knowledge gap by precisely characterizing the apolipoprotein profile (with Bio-Plex Human Apolipoprotein Assay) in three metabolically separate groups of individuals (lean individuals and obese individuals without and with metabolic syndrome) and at four distinct time points (0, 3, 6, and 12 months post bariatric surgery). Results: Obese patients had a higher baseline ApoB/ApoA1 ratio, which returned to the reference level over the follow-up period. The above is of clinical importance, as the ratio is a predictor of adverse cardiovascular events common in obese subjects. Interestingly, plasma concentrations of most of the investigated apolipoproteins appeared to be relatively stable at the onset of the experiment, with changes observed later in time. We detected significant drops in the levels of ApoC3, ApoD, and ApoH that occurred as early as three months post intervention. On the other hand, the levels of ApoA2, ApoE, and ApoJ increased with time. Of the above, ApoE is known to be involved in the removal of TAGs and cholesterol from the blood. Conversely, ApoJ appears to be one of the determinants of the tissues’ responsiveness to insulin. Thus, it may be an indicator of the reduced insulin resistance observed a few months after the surgery. Conclusions: Overall, the investigated proteins have a documented role in the development and progression of vascular pathologies. Hence, our results may be interpreted as a sign of improved cardiovascular fitness of our patients. Full article

Ethanol consumption can modify both drug exposure and drug response. However, the clinical relevance of these interactions depends strongly on the timing and pattern of alcohol intake, the affected pharmacological pathway, the dosage form and organ reserve. This review summarizes current evidence on ethanol–drug interactions, particularly human crossover studies, phenotyping studies, cohort analyses and appropriate case reports. It distinguishes acute ethanol–drug co-exposure, chronic alcohol exposure, drug use during early abstinence after chronic drinking, and pharmacotherapy in alcohol-associated liver disease. Key mechanisms include ADH- and ALDH-dependent ethanol oxidation, acetaldehyde formation, NADH/NAD⁺ redox shift, CYP2E1 induction, carboxylesterase 1 (CES1) modulation, altered intestinal and hepatic first-pass handling, dose dumping from susceptible modified-release products, changes in protein binding in alcohol-associated liver disease, and ALDH inhibition with acetaldehyde accumulation in disulfiram-like reactions. At the molecular level, ethanol may promote acetaldehyde adduct formation with proteins and DNA, CYP2E1-driven reactive oxygen species generation, redox stress, intestinal barrier injury, and CES1-dependent transesterification of selected ester drugs. Acute ethanol intake mainly increases pharmacodynamic toxicity and causes short-term pharmacokinetic disturbances, including enhanced central nervous system depression, delayed gastric emptying, impaired glucose and lactate handling and altered hemodynamic responses. In contrast, chronic exposure, early abstinence and alcohol-associated liver disease are more often associated with hepatic enzyme and transporter remodeling, altered protein binding, reduced hepatic or renal reserve, and greater susceptibility to drug-related organ injury. The highest-risk scenarios involve older adults, polypharmacy, alcohol-associated liver disease, dehydration or acute illness, early abstinence, and the concurrent use of central nervous system depressants, glucose-lowering drugs, NSAIDs, antihypertensives, renally eliminated drugs or warfarin. Hence, ethanol exposure should be treated as a dynamic, context-dependent modifier factor that can acutely exacerbate pharmacodynamic toxicity, alter selected pharmacokinetic pathways and lower organ tolerance to drug-related injury. Full article

Factor Xa (FXa) remains an important target in the development of anticoagulant and antithrombotic agents. In this study, twenty isosteviol-derived oxime ether analogs previously reported as FXa inhibitors were used to develop a predictive QSAR model. The compounds were geometry-optimized at the B3LYP/6-311++G(d,p) level, and Dragon molecular descriptors were calculated from the optimized structures. After descriptor filtering, Random Forest-based supervised preselection and correlation-based pruning were applied. Several models of increasing complexity were evaluated, including multiple linear regression, additive MARSplines, and constrained second-order MARSplines models. The final model employed four active basis functions involving R6p+, C-025, ATSC7e, and Mor31p and demonstrated excellent calibration and cross-validated predictive ability (R² = 0.929 and Q²_LOO = 0.865). Based on this model, twenty new isosteviol-derived analogs were designed and their activities were predicted after DFT optimization and descriptor calculation. Eight representative compounds were subsequently subjected to molecular docking against human factor Xa (PDB ID: 2P16), molecular dynamics simulations, MM/GBSA binding free energy calculations, and preliminary SwissADME/pkCSM profiling. Docking protocol validation yielded a redocking RMSD of 0.953 Å. Although ISV-M20 was the highest-ranked compound according to the QSAR model, subsequent receptor-based analyses identified ISV-M19, ISV-M04, and ISV-M06 as the derivatives with the most favorable combination of structural stability, persistent protein–ligand interactions, and binding free energies. The ADMET/toxicity screen further refined this prioritization: ISV-M19, ISV-M04, and ISV-M06 showed the most favorable preliminary toxicity balance among the prioritized derivatives, whereas ISV-M20 displayed additional developability liabilities, including very high lipophilicity, poor predicted solubility, P-gp substrate status, and a predicted hERG II alert. Overall, the results demonstrate that integrating interpretable QSAR modeling with receptor-based simulations and early ADMET/toxicity filtering provides a more balanced strategy for the rational design and prioritization of novel isosteviol-derived FXa inhibitors than any single computational approach alone. Full article

Impaired wound healing is often caused by persistent inflammation, bacterial infection, and insufficient extracellular matrix remodeling. Natural polymer-based hydrogels represent ideal wound dressings but often struggle to balance structural stability and biological activity. Herein, we report a dual-functional network regulation strategy enabled by highly soluble mussel foot protein (HMFP) that acts simultaneously as a structural crosslinking regulator and bioactive effector to fabricate synergistic hydrogels (CS-SH-H) from β-chitosan (CS) and sodium hyaluronate (SH). HMFP homogenizes the porous microstructure, strengthens intermolecular interactions, and significantly improves thermal and structural stability via multivalent non-covalent bonding. In vitro, CS-SH-H shows excellent cytocompatibility, significantly promotes fibroblast proliferation and migration, and exerts potent antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In a mouse full-thickness skin defect model, the hydrogel dramatically accelerates wound closure, reducing the residual wound area to 25% on day 7, outperforming the control groups. Immunohistochemistry confirms that HMFP suppresses TNF-α-mediated inflammation and enhances Ki-67-positive cell proliferation, leading to accelerated re-epithelialization and collagen deposition. This study establishes HMFP as a promising marine-derived dual-functional network regulator for designing high-performance hydrogel dressings. This strategy is scalable and translatable for treating infected and inflammatory wounds. Full article

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and end-stage kidney disease worldwide, imposing a major clinical and economic burden. Conventional diagnostic markers, including albuminuria and estimated glomerular filtration rate (eGFR), have limited sensitivity and specificity for early disease detection and for accurately predicting progression. Increasing evidence suggests that DKD involves complex glomerular, tubular, inflammatory, fibrotic, and oxidative stress pathways that precede overt clinical manifestations. Consequently, considerable attention has focused on identifying novel noninvasive biomarkers, particularly urinary biomarkers, alongside selected circulating biomarkers and emerging multi-omics signatures. Proteins, peptides, extracellular vesicles, and RNA-based biomarkers have demonstrated promising diagnostic and prognostic potential for detecting early renal injury, improving risk stratification, and monitoring therapeutic response. This review summarizes recent advances in biomarker research for DKD, highlighting emerging molecular and omics-based signatures that may complement conventional markers in improving early detection, prognostic assessment, and disease phenotyping. While numerous biomarkers have shown promising associations with renal outcomes and disease progression, the majority remain investigational. Their translation into routine clinical practice will depend on rigorous external validation, standardized analytical methods, and demonstration of added value beyond established clinical measures. Full article

Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16, is a major driver of HPV-associated cancers; however, strategies for treating established HPV-induced tumors remain scarce. Here, we developed a DNA-based vaccine linking the SARS-CoV-2 spike (S) protein with an HPV16 E7 epitope (aa 49-57) to simultaneously induce antiviral humoral immunity and antitumor cellular responses. We generated 2 constructs, S-E7 and S-RE7, with the latter incorporating a furin cleavage site (R) to enhance antigen processing. In vitro, S-RE7 significantly enhanced E7-specific CD8⁺ T cell activation compared to S-E7, highlighting the importance of the furin sequence. In vivo, both S-linked vaccines elicited robust E7-specific CD8⁺ T cell responses and provided complete protection against TC-1 tumor challenge in a prophylactic murine model, with long-lasting immunity upon tumor rechallenge. In therapeutic settings, vaccination with S-E7 or S-RE7 significantly suppressed tumor growth, extended survival, and reduced circulating myeloid-derived suppressor cells (MDSCs), indicating alleviation of systemic immunosuppression. Notably, S-RE7 demonstrated faster antitumor effects overall in early tumor progression. In addition to cellular immunity, both constructs induced high levels of anti-spike antibodies, with S-RE7 eliciting approximately fourfold higher responses than S-E7. Furthermore, S-RE7 effectively boosted pre-existing anti-spike immunity in mice that were previously vaccinated. This “two-in-one” strategy represents a promising and versatile platform for the prevention and treatment of HPV-associated cancers while maintaining preparedness against potential SARS-CoV-2. Full article

Repeated exposure to subinhibitory concentrations of antiseptics may lead to reduced susceptibility or resistance and potentially promote cross-resistance to antibiotics. However, the underlying molecular mechanisms remain incompletely understood. This study investigated whether antiseptic-adapted Escherichia coli strains exhibit altered protein expression profiles compared with wild-type (WT) E. coli. Protein expression was analysed in E. coli strains previously adapted over ten passages to subinhibitory concentrations of chlorhexidine (CHX), cetylpyridinium chloride (CPC), and benzalkonium chloride (BAC). WT bacteria were exposed to sub-minimum inhibitory concentrations (sub-MICs) of antiseptics for 3 h to induce stress. Untreated WT and heat-shocked WT E. coli (42 °C, 2 h) served as controls. Protein expression profiles were assessed using SDS-PAGE and Western blotting targeting stress-associated proteins. SDS-PAGE demonstrated altered protein expression patterns in antiseptic-adapted strains, including differences in band intensities and additional protein bands. Western blot analysis showed increased DnaK and GroEL expression with reduced LexA levels in heat-shocked WT bacteria, whereas RecA remained largely unchanged. Antiseptic-adapted strains exhibited increased DnaK, GroEL, and OmpF expression together with reduced LexA and RecA expression. These findings indicate that adaptation to antiseptics involves complex mechanisms among multiple proteins rather than a single adaptive mechanism. Full article

This article proposes three possible explanations that relate to the process of eukaryotic translation initiation. These explanations suggest mechanisms as to how concentrations of initiation factors (by mass or by posttranslational modification) can influence start site selection, how regulation of translation by 4E-BP (an inhibitor of m⁷G cap-dependent translation) can be explained by “eIF4F disassembly” and how the scanning mechanism might involve initiation factor binding at the 5′ end of the mRNA to provide for apparent unidirectional Brownian movement to locate the initiating AUG. These represent testable models, although the experiments would not be simple. It is hoped that the insights provided will assist researchers in defining the precise steps and mechanisms of the complex initiation process. It is noted that the better this process is understood, the easier it will be to understand how this process is regulated under a wide variety of biological situations, such as nutritional deprivation, heat shock, cell growth, or disease. Additionally, as initiation is the rate-limiting step in translation, a better understanding of this process should also suggest new avenues to treat various diseases, especially conditions of unrestricted growth. Full article

Hepatitis B virus (HBV) infection remains a major global health burden, with chronic infection leading to severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). HBV-encoded X protein (HBx) plays a critical role in viral replication and pathogenesis by modulating host cellular processes, including autophagy and lysosomal function. However, the molecular mechanisms by which HBx disrupts lysosomal biogenesis and autophagic degradation remain elusive. In this study, we show that HBx downregulates the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, which leading to impaired lysosomal acidification and autophagosome–lysosome fusion. Mechanistically, HBx-mediated TFEB downregulation involves the CUL4A (Cullin 4A)/CUL4B (Cullin 4B)-DDB1 (DNA damage-binding protein 1) E3 ubiquitin ligase complex and is dependent on the DDB1-interacting motif in HBx. HBx mutants defective in DDB1 binding (HBx^R96E and HBx^ΔDBD) fail to downregulate TFEB or impair lysosomal function. Collectively, our findings identify a pathway by which HBx disrupts lysosomal function via CUL4A/CUL4B–DDB1-dependent TFEB downregulation, providing insights into HBV-associated liver pathogenesis and highlighting potential targets for therapeutic intervention. Full article

Globally, chronic kidney disease (CKD) is an increasingly prevalent public health challenge. The current kidney function tests, which include serum creatinine, estimated glomerular filtration rate (eGFR), and proteinuria, are highly useful in clinical practice. Nevertheless, they are characterized by substantial limitations that prevent the early detection of CKD. In contrast, urinary extracellular vesicles (uEVs) may offer an effective alternative for the diagnosis and monitoring of chronic kidney disease if successfully translated. Urinary extracellular vesicles are a wide range of nanosized membrane vesicles that are excreted by cells that line the nephron and urinary tract. These uEVs contain proteins, lipids, and nucleic acids that reflect the pathophysiological state of their cells of origin. This review summarizes the biological evidence for uEV biomarkers in major CKD entities, including diabetic kidney disease, FSGS, IgA nephropathy, ADPKD, and lupus nephritis. From a clinical laboratory perspective, we critically examine pre-analytical variables, analytical factors and validation requirements aligned with ISO 15189 accreditation. We discuss regulatory pathways and the balance between laboratory-developed tests and commercial IVD platforms. Moreover, we conclude that there is an essential need for reference materials, internal quality control, and external quality assessment. Finally, we outline a practical implementation pathway for transitioning uEV assays from research use to routine diagnostics. If successfully translated, uEV-based assays could facilitate earlier detection of CKD, more precise phenotyping, and personalized therapeutic monitoring. Full article

Cardiovascular diseases remain the top cause of death worldwide, with atherosclerosis as a key underlying factor. Natural bioactive ingredients from functional foods are increasingly sought after for preventing chronic metabolic and heart conditions due to their safety and suitability for long-term use. Octacosanol is a naturally occurring long-chain fatty alcohol primarily isolated from plant waxes, including rice bran wax and sugarcane wax. Emerging evidence indicates that octacosanol exhibits promising antioxidant properties and may exert protective effects against atherosclerosis through modulation of lipid metabolism and endothelial function. Unlike statins, which can cause side effects over time, octacosanol works gently through several pathways: it protects blood vessel lining by clearing reactive oxygen species and activating endothelial nitric oxide synthase (eNOS); reduces vascular inflammation by blocking nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling; moderates lipid metabolism by lowering 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression; and suppresses excessive platelet aggregation to reduce thrombotic risk. When taken alongside statins, it boosts lipid control while easing statin-related side effects. With its excellent safety profile, octacosanol is an ideal natural ingredient for functional foods, offering a novel multi-target dietary approach to support long-term cardiovascular health. Full article

Vegan and vegetarian dietary patterns have moved from minority dietary choices to central elements of contemporary nutritional guidance, supported by observational cohorts, short-term randomised trials, and umbrella-level evidence (i.e., syntheses of multiple systematic reviews) reporting favourable associations with body weight, blood lipids, blood pressure, glycaemic control, and inflammatory markers. Recent direct comparisons against healthy omnivorous comparators—including the OMNIVEG controlled crossover transitioning from a traditional to a vegan Mediterranean diet and the Landry identical-twin trial—indicate that well-formulated plant-based patterns can produce additional short-term improvements in selected cardiometabolic markers even when the comparator is not the modern Western diet. Interpretation of the broader evidence base is nonetheless constrained by comparator quality, residual confounding, exposure misclassification, reliance on intermediate biomarkers, and limited follow-up. This critical narrative review integrates clinical, methodological, nutritional, and physiological evidence to compare vegan, vegetarian, and omnivorous dietary patterns, and argues that the dominant explanatory axis of long-term outcomes is dietary pattern quality—minimally processed plant-rich composition, nutrient adequacy, low ultra-processed food intake, and adherence—rather than the binary inclusion or exclusion of animal-source foods. Well-planned vegan and vegetarian patterns are valid dietary expressions that require systematic attention to vitamin B12, iodine, iron, zinc, calcium, vitamin D, EPA/DHA, and protein quality. Public health messaging should prioritise food quality, processing level, nutrient adequacy, adherence, and outcome hierarchy over binary dietary identities. Full article

Endothelial dysfunction is a defining feature of diabetic vascular disease and is characterized by impaired nitric oxide signaling, inflammatory activation, altered mechanotransduction, and disturbed angiogenic responses. The present study investigated whether hyperglycemia modulates endothelial phenotype in a model-dependent manner under distinct structural and mechanical culture conditions. EA.hy926 endothelial cells were cultured for 7 days under normoglycemic (5.5 mM) or high-glucose (25 mM) conditions as static monolayers (G-force = 1 g), adherent clinorotated cells, multicellular spheroids (MCSs) generated during clinorotation, and Matrigel-derived endothelial structures. Gene expression was assessed by qPCR using marker panels related to nitric oxide signaling, PI3K CA-AKT-mTOR signaling, inflammatory adhesion, angiogenesis, and structural adhesion, whereas protein abundance and spatial distribution of eNOS, AKT1, VCAM1, vinculin, and VEGFA together with CDH5/VE-cadherin were analyzed by Western blotting and confocal microscopy. Clinorotation generated both adherent endothelial cells and MCSs. High glucose reduced eNOS-related expression in most models, with the strongest decreases in adherent clinorotated cells and MCSs, whereas Matrigel cultures showed a divergent transcriptional response. PI3K CA expression was markedly suppressed by high glucose in clinostat-derived populations, while mTOR was differentially regulated in spheroids and Matrigel cultures. VCAM1 expression was most prominent in MCSs, whereas ICAM1 was highest in Matrigel cultures. VEGF-related signaling differed substantially among models, and Matrigel cultures showed the strongest VEGFA-associated protein signal and the clearest angiogenic organization under normoglycemic conditions, which became less distinct under high glucose. Vinculin protein abundance was highest in MCSs and Matrigel cultures, reflecting pronounced differences in structural organization. Overall, these findings show that endothelial responses to hyperglycemia are strongly shaped by mechanical and structural context and support the use of complementary in vitro models for studying diabetic endothelial dysfunction. Full article

The rapid global transition toward sustainable food systems has intensified interest in alternative protein ingredients derived from both terrestrial plants and blue foods. However, a critical bottleneck in the commercialization of these proteins is the stabilization of flavor profiles during dehydration. Drying technologies ranging from conventional hot-air and heat pump drying to microwave and vacuum freeze-drying inevitably induce structural reorganization and oxidative modifications. These transformations fundamentally modulate how volatile flavor compounds are bound, retained, and released within the food matrix. This review proposes a comprehensive structure–process–function framework that mechanistically connects intrinsic protein architectures, drying-induced denaturation, and flavor-binding behavior. The review first contrasts globular plant proteins (e.g., soy, pea, and emerging tropical crops) with fibrous marine myofibrillar and collagenous proteins, emphasizing their distinct hierarchies, amino acid compositions, and oxidative vulnerabilities. It then critically evaluates how varying drying modalities drive protein unfolding, aggregation, and carbonylation, and how these transformations alter binding pocket accessibility, surface hydrophobicity, and lipid–protein–flavor crosstalk. Furthermore, it highlights the emerging role of hybrid plant–marine protein matrices as a strategy to optimize techno-functionality. By integrating structural biophysics with computational approaches such as molecular docking and structure-based modeling, this review provides a predictive conceptual map for designing flavor–protein interactions under specific dehydration histories. Ultimately, the proposed framework offers practical design principles for selecting protein sources and tailoring drying strategies to produce high-quality, sensorially superior, and sustainable next-generation food products. Full article

The Powassan virus (POWV) is a neurovirulent tick-borne virus that causes age-associated lethality and long-term neurologic sequelae in 50% of survivors. In aged mice the POWV strain LI9 mirrors human lethality and neuropathology; however, an avirulent POWV mutant, LI9-D308N, fails to enter the CNS or cause lethal disease. The D308N mutation is present in an envelope protein domain associated with cell attachment, yet the role of D308N mutations in cell tropism and neuroinvasion remains to be resolved. Here, we engineered fluorescent mScarlet3 and mNeonGreen reporter genes into WT LI9, and avirulent LI9-D308N viruses and assessed their ability to infect CNS cells in vitro. In addition, we generated replication-defective reporter POWVs that only replicate in NS1-expressing cells by replacing NS1 with fluorescent genes. Similar to WT LI9, fluorescent reporter POWVs spread focally and nonlytically, are stable following passage and reach high titers 2–5 dpi. In NS1-expressing VeroE6 cells, LI9-ΔNS1-FL reporters exhibited robust fluorescence 24 h post-infection (hpi), while fluorescence from LI9-reporter infections was first observed ~32 hpi. Comparing LI9-mScarlet3 and avirulent LI9-D308N-mScarlet3 viruses revealed no difference in their ability to infect human brain microvascular endothelial cells, pericytes, astrocytes, microglia or neuronal cells in vitro. Notably, LI9-mScarlet3 viruses productively and persistently infected differentiated, neuron-like, SH-SY5Y cells without apparent cytotoxicity. These findings indicate that LI9-D308N is capable of infecting blood–brain-barrier and CNS cells, and suggest that neuroinvasion is restricted prior to LI9-D308N engaging CNS cells. These results are consistent with clearance of LI9-D308N from the blood, or the D308N mutation interfering with potential routes of POWV neuroinvasion. Collectively, fluorescent POWV reporter viruses provide insight into the mechanism of POWV neuroinvasion, permit analysis of replication-defective POWVs as vaccines and provide a means of analyzing POWV cell tropism, antivirals and cell-to-cell spread in BSL2 and BSL3 settings.: Full article