Search Results (3,398)

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists are used long term for obesity and diabetes, but their oesophageal safety is uncertain: weight loss may reduce Barrett’s oesophagus and adenocarcinoma risk, whereas delayed gastric emptying may worsen reflux. We performed a genetic assessment of target-mediated oesophageal safety. Methods: Two-sample drug-target Mendelian randomisation used cis-expression quantitative trait loci for both receptors (31,684 participants). Outcomes were European genome-wide association studies of gastro-oesophageal reflux disease and the Barrett’s oesophagus/oesophageal adenocarcinoma axis, with a trans-ancestry squamous cell carcinoma comparator. A prespecified gated workflow required positive-control validation, and target specificity required genetic colocalisation (posterior probability of a shared causal variant ≥ 0.70). Candidate metabolic mediators were examined in two-step analyses, and findings were replicated in an independent Finnish population (FinnGen R12). Results: Genetically proxied GLP-1 receptor expression was not associated with reflux disease (odds ratio 0.97, 95% confidence interval 0.85–1.11), arguing against a substantial target-mediated reflux liability; the GIP receptor estimate was not estimable. For the Barrett’s oesophagus/adenocarcinoma endpoint, estimates were near the null for both receptors (GLP-1R 0.96, 0.47–1.96; GIPR 1.00, 0.42–2.37); colocalisation was uninformative because the outcome loci carried no detectable association signal, and wide intervals did not exclude moderate effects. The null reflux findings were reproduced in FinnGen. Adiposity showed the most consistent pathway association, whereas glycaemic traits did not, including when HbA1c was instrumented from a population-based genome-wide association study providing an order of magnitude more variants. Conclusions: GLP-1 receptor perturbation was not associated with reflux disease, providing cautious genetic reassurance. For the Barrett’s oesophagus/adenocarcinoma axis, no target-specific association was demonstrated, but colocalisation was uninformative because the outcome loci carried no detectable signal, and imprecision precludes firm safety conclusions; larger adenocarcinoma-specific studies are warranted. Full article

Cardiac surgery-associated acute kidney injury (CS-AKI) increases short- and long-term mortality, progression to chronic kidney disease (CKD), and healthcare costs. Its pathogenesis is multifactorial—combining renal hypoperfusion, impaired oxygen delivery, hemodilution, inflammation, ischemia–reperfusion injury, and nephrotoxin exposure—so no single intervention confers universal protection. This narrative review appraises fourteen perioperative prevention strategies, grading each by study design, reproducibility, and concordance with contemporary guidelines. The strongest actionable evidence supports the preservation of renal oxygen delivery during cardiopulmonary bypass through goal-directed perfusion, perioperative amino acid infusion, and biomarker-guided Kidney Disease: Improving Global Outcomes (KDIGO) care bundles. Remote ischemic preconditioning, pulsatile flow, minimally invasive extracorporeal circulation, dexmedetomidine, N-acetylcysteine, levosimendan, hemoadsorption with the oXiris membrane, and natriuretic peptides show variable or subgroup-dependent signals limited by heterogeneous trial design and acute kidney injury (AKI) definitions. Prevention of CS-AKI is, therefore, best conceived as a multimodal, patient-centered process integrating preoperative risk stratification, intraoperative oxygen delivery optimization, patient blood management (PBM), and postoperative nephrotoxin avoidance and surveillance. Full article

Mosquito antimicrobial peptides (AMPs) contribute to innate defense against bacteria, fungi, parasites, and, in some experimental contexts, arboviruses. This narrative review evaluates endogenous mosquito AMP families across Aedes, Anopheles, and Culex species and clearly separates them from heterologous peptides introduced into mosquitoes for transmission-blocking studies. The best-supported endogenous families are cecropins, defensins, gambicin, attacin, and diptericin, although gene repertoires vary among mosquito lineages. Mechanistic evidence is strongest for membrane interaction by individual cecropins and defensins. Evidence for intracellular or redox mechanisms is more limited and peptide- and assay-specific; for example, mitochondrial effects have been demonstrated for Anopheles albimanus cecropin 3 in isolated rat cardiac mitochondria, whereas DNA binding and membrane permeabilization have been shown for an Aedes aegypti cecropin A derivative in Pseudomonas aeruginosa. Scorpine, magainin, and human defensin 5 are not mosquito AMPs and are considered separately as heterologous antiplasmodial effectors. Toll and immune deficiency (IMD) pathways regulate mosquito immune genes through NF-κB-family transcription factors, whereas Janus kinase–signal transducer and activator of transcription (JAK–STAT) is a distinct cytokine-signaling pathway. Translational approaches—including transgenic expression, paratransgenesis, Wolbachia-based control, and peptide engineering—remain promising but require cautious interpretation because efficacy, mechanism, ecological safety, horizontal gene transfer, regulatory oversight, and durability have not been resolved uniformly. By distinguishing direct peptide activity from genetic, expression-only, and inferential evidence, this review provides a more rigorous framework for evaluating mosquito AMPs and their potential use in vector-borne disease control. Full article

Endothelial dysfunction is a key mechanism linking obesity, metabolic disturbances, and cardiovascular disease, contributing to the development and progression of atherosclerosis and other vascular complications. This review provides a comprehensive overview of the molecular mechanisms underlying endothelial dysfunction in obesity and discusses current diagnostic approaches and therapeutic strategies aimed at restoring vascular homeostasis. The available evidence indicates that chronic inflammation, oxidative stress, insulin resistance, reduced nitric oxide bioavailability, increased reactive oxygen species production, and dysregulated adipokine signaling play central roles in endothelial impairment. Recent advances in functional vascular assessment, circulating biomarkers, and imaging techniques have improved the early identification of endothelial dysfunction and cardiovascular risk. Current therapeutic strategies include pharmacological agents, such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter 2 inhibitors, metformin, and dipeptidyl peptidase-4 inhibitors, together with lifestyle interventions based on healthy dietary patterns and regular aerobic and resistance exercise. These approaches improve glycemic control, reduce inflammation and oxidative stress, enhance endothelial function, and contribute to cardiovascular protection. Overall, the evidence supports an integrated and personalized management strategy targeting both metabolic and vascular abnormalities to reduce cardiovascular risk and improve long-term clinical outcomes in individuals with obesity. Full article

The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), defined as a tumour’s capacity to be recognised by the immune system and respond to immunotherapy. Tumours with intact antigen presentation pathways are more likely to generate effective antitumour responses, whereas APM defects promote immune escape and therapeutic resistance. Cancer cells frequently evade immune detection through altered antigen processing or reduced expression of major histocompatibility complex (MHC) class I molecules, limiting tumour antigen presentation to cytotoxic T lymphocytes. These alterations are increasingly recognised as determinants of response to immune checkpoint inhibitors and potential predictive biomarkers. APM defects may be reversible or irreversible. Interferon-mediated signalling can restore MHC class I expression and T-cell cytotoxicity in some tumours, whereas permanent genomic alterations affecting human leukocyte antigen (HLA) class I genes, β2-microglobulin (β2-m), or interferon-γ (IFN-γ) pathway components can severely impair antigen presentation. Emerging evidence highlights four mechanistic levels of APM perturbation: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. Each contributes to distinct patterns of immune evasion. This review examines how MHC class I alterations influence CIR and contribute to immune evasion and immunotherapy resistance in gastrointestinal malignancies, while discussing therapeutic strategies to restore or bypass APM deficiencies. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

Background: Atrial fibrillation (AF) is associated with atrial remodelling, hemodynamic stress, and complex cardiopulmonary interactions. While natriuretic peptides and echocardiographic abnormalities are established markers of AF-related substrate, the contribution of spirometry changes, as a landmark of pulmonary impairment, remains less clearly defined. This study evaluated whether AF is associated with an integrated cardiopulmonary profile characterized by altered spirometry, increased NT-proBNP, and conventional echocardiographic markers of left atrial structure and function. Methods: We performed a retrospective, single-center observational study based on an existing clinical database of adult patients referred for 24 h 12-lead Holter ECG monitoring because of palpitations and/or chest pain. None of the included patients had a previously documented diagnosis of atrial fibrillation before Holter monitoring. Because a single 24 h Holter recording cannot establish spontaneous termination or long-term temporal pattern with certainty, AF documented for the first time during this recording is referred to throughout as “newly detected AF” rather than “paroxysmal AF”. During Holter monitoring, no ECG changes suggestive of myocardial ischemia were detected. From 536 records of patients without previously known AF who underwent 24 h 12-lead Holter ECG monitoring for palpitations and/or chest pain, 164 patients were retained for the main comparison, including 48 with newly detected paroxysmal AF and 116 without AF. Demographic, biochemical, spirometric, and echocardiographic variables were analyzed. The main respiratory parameters were forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and peak expiratory flow (PEF). NT-proBNP was the primary biomarker, while conventional left atrial structural and functional variables were used for echocardiographic assessment. Results: NT-proBNP was markedly higher in the AF group (684.5 vs. 62.3 pg/mL, p = 0.001), even when accounting for confounders like age, CKD, or CPD, showing by far the largest between-group difference among the biomarkers assessed (formal discrimination statistics such as ROC/AUC were not computed). The exploratory inflammatory markers assessed (hs-CRP, neutrophil/lymphocyte ratio, homocysteine) showed only modest, non-significant differences. Conventional echocardiographic parameters did not differ significantly between groups. In the strict complete-case comparison, spirometric indices did not reach statistical significance; however, preliminary project-level analysis showed lower FVC, FEV1, and PEF in AF patients, but without supporting the COPD diagnosis, and exploratory correlations suggested a relationship between spirometric performance and left atrial function. Conclusions: In this cohort, AF was most strongly associated with NT-proBNP, while the respiratory signal was weaker but directionally consistent with a broader cardiopulmonary phenotype. These findings do not support spirometry or NT-proBNP as stand-alone diagnostic tools for AF. However, when interpreted alongside traditional AF risk factors and symptoms, elevated NT-proBNP with concordant spirometric impairment may represent a hypothesis-generating additive signal supporting longer or repeated rhythm monitoring beyond 24 h in selected patients with suspected AF; this additive value was not formally tested against clinical models alone and requires prospective confirmation. Full article

Bioactive peptides are an important source of therapeutic molecules and molecular scaffolds involved in defense, signaling, and immune regulation. Despite the extraordinary diversity of Coleoptera, the structural landscape of beetle-derived bioactive peptides remains largely unexplored, limiting our understanding of their evolutionary diversity and biotechnological potential. Here, we performed a large-scale structural survey of predicted toxin-like peptide scaffolds across publicly available Coleoptera transcriptomes by integrating transcriptome mining, peptide maturation prediction, physicochemical characterization, AlphaFold 3 structural modeling, structural similarity analyses, and interpretable machine learning. We identified 291 candidate peptides, of which 155 contained canonical signal peptides and 273 produced mature peptides within the expected size range of known bioactive peptides. Structural analyses revealed that, despite extensive sequence diversity, many candidates were organized into a comparatively restricted repertoire of compact cysteine-rich architectures, indicating that structural similarity is retained across peptides exhibiting substantial primary-sequence variation. Comparative structural analyses further identified recurrent protein architectures shared across multiple beetle lineages, while machine learning prioritization integrated structural and biochemical descriptors to identify high-confidence candidates for future functional characterization. These analyses establish the first structural atlas of predicted toxin-like peptides across Coleoptera and demonstrate that structure-guided transcriptome mining provides a powerful framework for uncovering recurrent bioactive peptide scaffolds that would remain largely undetected using sequence-based approaches alone. Beyond expanding our understanding of peptide evolution in beetles, this resource is a foundation for future structural, functional, and biotechnological exploration of bioactive peptides in underexplored animal groups. Full article

Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence. Full article

Although flaviviruses, including DENV, ZIKV and JEV, remain important causes of febrile, congenital, and neurological diseases, treatment options remain largely supportive, with limited availability of virus-specific antiviral therapies. Marine organisms and marine-derived microorganisms produce chemically distinct antiviral materials, including sulfated polysaccharides, terpenoids, alkaloids, peptides, cyclodepsipeptides, and polyketides. However, their activities range from preliminary extract-level inhibition to direct biochemical target validation, making mechanistic comparison difficult. This review critically evaluates marine-derived anti-flaviviral agents using two complementary dimensions, the infection stage implicated by experimental assays and the strength of evidence supporting that assignment. DENV evidence is dominated by sulfated algal macromolecules that interfere with adsorption or internalization, whereas ZIKV studies encompass lipophilic algal metabolites, fungal alkaloids, cyclodepsipeptides, and a few target-oriented candidates. Across the field, most reports remain stage-associated rather than target-validated. Cross-study potency comparisons are constrained by differences in virus strains, cell models, assay formats, and treatment schedules. JEV-specific evidence is particularly sparse. Based on the DENV and ZIKV evidence map, we propose concise priorities for JEV-oriented discovery: early compound-level dereplication, parallel cytotoxicity testing, orthogonal confirmation of productive infection, stage-resolved assays, and biochemical or genetic validation of conserved flaviviral targets. This evidence-based framework can help distinguish promising chemical candidate scaffolds from preliminary antiviral signals and guide mechanism-informed development of marine-derived natural products against flaviviruses. Full article

Plant cell walls play a crucial role in plant development and evolution. This structure is primarily composed of proteins and polysaccharides, including cellulose, hemicellulose, and pectins. Homogalacturonan (HG), the most abundant pectin in the primary cell wall, is synthesized by α -1,4-D-GALACTURONOSYLTRANSFERASE (GAUT) enzymes, methylesterified, and subsequently secreted into the apoplast. The dynamics of pectin methylesterification is regulated by enzymes such as PECTIN METHYLESTERASES (PMEs) and PECTIN METHYLESTERASE INHIBITORS (PMEIs). Across plant evolution and development, different cell types display distinct domains of pectin methylesterification. The binding of de-methylesterified pectins to the Catharanthus roseus RECEPTOR-LIKE KINASE 1-LIKE (CrRLK1L) proteins and RAPID ALKALINIZATION FACTOR (RALF) peptides is involved in pectin signaling and cell wall integrity maintenance during developmental processes. While phylogenetic studies highlight molecular innovations in pectin metabolism, functional studies remain scarce outside of angiosperms. Furthermore, the explicit role of de-methylesterified pectin in coupling cell wall structure to intracellular signaling has only been demonstrated in angiosperms. Comparative functional studies addressing key evolutionary transitions will ultimately reveal how pectin metabolism has contributed to morphological innovations across plant evolution. Full article

Verticillium wilt, caused by Verticillium dahliae, is a major constraint on cotton production. The GASA (Gibberellic Acid-Stimulated in Arabidopsis) proteins are cysteine-rich peptides induced by gibberellin signaling; however, their systemic role in upland cotton (Gossypium hirsutum) resistance to Verticillium wilt remains elusive. Here, we identified 40 GhGASA members from the G. hirsutum genome, which were clustered into three subfamilies. All members possessed a typical gibberellin-regulated domain, and segmental duplication was the primary driver of family expansion. Transcriptomic analyses revealed tissue-specific expression, with high abundance in pistils and roots, and distinct responsive patterns to salt, drought, and cold stresses. Quantitative real-time PCR (qRT-PCR) showed that multiple GhGASA genes were significantly upregulated following V. dahliae inoculation, with transcript levels being much higher in roots and stems than in leaves. Notably, GhGASA17, harboring ethylene-responsive elements, was identified as a key candidate involved in the defense response. Overall, this study provides a comprehensive characterization of the GhGASA gene family, offering a theoretical foundation for understanding its regulatory functions in Verticillium wilt resistance and delivering potential genetic resources for molecular breeding in cotton. Full article

Hydraulic perturbations are among the earliest plant-wide consequences of drought, salinity and wounding, yet they are often treated as passive outcomes rather than as biologically interpreted inputs. This review distinguishes hydraulic state, hydraulic perturbation and hydraulic signal, and evaluates how organ-scale pressure and water-potential changes are converted into local membrane tension, wall strain, turgor and water-flux cues. We propose, as a testable model rather than an established mechanism, a distributed architecture comprising OSCA/TMEM63 and other mechanosensitive channels, cell-wall integrity pathways, aquaporin-mediated conductance control and vacuolar buffering. Evidence for the individual components is substantial, but evidence that they act together within a single physiological event is still limited. These layers are reciprocally coupled to Ca²⁺, ROS, electrical, hormonal and peptide networks. Hydraulic cues are fast, and they differ in amplitude, direction, rise time, duration, recovery and anatomical route, so they are not informationally inert. Specificity nevertheless appears to emerge from the integration of the hydraulic waveform with tissue state and coincident ionic, electrical and biochemical inputs rather than from any single variable. We compare drought, salinity and wounding; clarify the roles of roots, vasculature, bundle sheath, mesophyll and guard cells; and outline experiments that combine calibrated physical perturbations with live reporters, tissue-specific genetics and hydromechanical modeling. The key frontier is no longer to document that pressure changes occur. It is to identify the variables directly sensed, to separate instructive from permissive roles, and to test whether dynamic decoding traits improve crop resilience at acceptable carbon and growth cost. Full article

Glutamine peptides not only serve as delivery vehicles for supplemental glutamine but also frequently possess unique biological activities that surpass glutamine itself, playing a crucial role in maintaining intestinal health. Corn gluten meal, as a major byproduct of corn processing with substantial production volume, is rich in glutamine, making it an ideal raw material for preparing glutamine peptides. This study aims to establish an enzymatic hydrolysis process for the efficient release of glutamine peptides from corn gluten meal and to identify glutamine peptides with gut health-maintaining effects. The results indicate that stepwise enzymatic hydrolysis of corn gluten meal using Protamex and Trypsin yields a glutamine-rich corn protein hydrolysate (GRCH). A total of 175 glutamine peptides were further identified from the low-molecular-weight fraction of GRCH. Through physicochemical property analysis and molecular docking technology, five glutamine peptides with potential inhibitory activity against the JAK2/STAT3 signaling pathway were screened, among which QFSLP demonstrated outstanding performance. In vitro experiments demonstrate that QFSLP is fully absorbed by intestinal epithelial cells and effectively alleviates LPS-induced inflammatory responses in intestinal cells. Following QFSLP intervention, the levels of proinflammatory factors TNF-α, IL-1β, and IL-8 in cells were significantly reduced (p < 0.05), while the level of the anti-inflammatory factor IL-10 was significantly increased (p < 0.05). The findings of this study contribute to the industrial-scale production of glutamine peptides and provide experimental evidence for their development in gut health-related products. Full article

Cellular inhibitor of apoptosis protein 1 (cIAP1) plays a crucial role in the apoptotic process. This study involved gene cloning, protein expression, bioinformatics analysis, and the preparation of a specific polyclonal antibody. First, the coding sequence of the duck cIAP1 was amplified by PCR and sequenced. Bioinformatics prediction indicated that this protein is a stable hydrophilic protein with no signal peptides and transmembrane domains. It contains characteristic BIR (bacterial IAP repeat) domains. The secondary structure consists of 43% random coils, 28% α-helix, and 8% β-strand, and its 3D structure is highly conserved compared with human and mouse cIAP1. Subsequently, the cIAP1 was cloned into the pET-28a vector. The recombinant His-tagged cIAP1 protein was successfully expressed in Escherichia coli BL21(DE3) upon induction and subsequently purified. Immunization of BALB/c mice with the purified protein emulsified in Freund’s adjuvant generated polyclonal antibodies. Indirect ELISA confirmed that the antibody titer exceeded 1:2,048,000. Additionally, Western blotting and immunofluorescence staining demonstrated that the antibody specifically recognized native duck cIAP1 protein without non-specific reactions with negative serum. This study successfully achieved prokaryotic expression of duck cIAP1 and produced a high-titer, highly specific mouse polyclonal antibody. This antibody is suitable for experiments such as Western blotting and immunofluorescence, providing important biological materials and a theoretical basis for further investigation of the anti-apoptotic mechanism of cIAP1 in major diseases of ducks. Full article