Search Results (577)

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

Background: Despite more than 30 licenced antiseizure medications (ASMs), approximately one third of people with epilepsy remain drug-resistant, and developmental and epileptic encephalopathies represent one of the greatest unmet needs in epilepsy therapeutics. The past decade has produced a substantial reorientation of ASM discovery, driven by epilepsy genetics, new disease models, advances in drug screening, and innovative therapeutic modalities. Objective: The objective of this study was to review the contemporary clinical-stage pipeline of ASMs with novel or differentiated mechanisms of action, organized by molecular target, while placing recent regulatory successes and instructive failures within the broader transition toward mechanism-based, precision, and potentially disease-modifying therapies. Findings: A 2024 pipeline analysis identified more than 200 epilepsy therapies in preclinical or clinical development; at the cutoff of the present literature search (30 June 2026), over 40 compounds had reached phase II or III, with the majority directed at DEEs. Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial. Several of the efficacy figures summarized here derive from congress presentations, interim analyses, or open-label extensions and await full peer-reviewed publication. Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABA_A modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen). Pre-symptomatic intervention in tuberous sclerosis complex provides an early, single-trial clinical proof of principle for delaying and reducing the incidence of epilepsy in a genetically defined population; this should not yet be equated with established disease prevention. Conclusions: The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent translational gap between early signals and randomized-trial confirmation, and by the preliminary status of much of the supporting evidence. Full article

Genetic background strongly influences the penetrance and phenotypic expression of SMAD4-associated intestinal tumorigenesis, yet the underlying modifier loci remain poorly defined. To investigate the genetic architecture of tumor susceptibility and systemic physiology, we analyzed 260 Smad4⁺/⁻ × Collaborative Cross (CC)-F1 mice derived from 14 CC lines using 11 quantitative traits, including longitudinal body weight, adjusted organ weights, and intestinal polyp counts across anatomical regions. Principal component analysis reduced these traits to seven components explaining more than 85% of total phenotypic variance. PC1 represented a tumor burden–metabolic axis, whereas PC2 captured systemic organ-physiology variation. Genome-wide QTL mapping of principal component scores identified significant loci for PC1 on chromosomes 1 and 4 and a female-specific locus for PC5 on chromosome 10, with additional suggestive loci supporting a polygenic architecture. Founder-effect analysis revealed strong contributions from CAST/EiJ, 129S1/SvImJ, and WSB/EiJ haplotypes. Candidate gene annotation identified biologically relevant coding and noncoding loci, including Galnt7 and Galntl6, as well as regulatory regions with potential enhancer activity. Together, these findings indicate that intestinal tumor susceptibility in Smad4⁺/⁻ × CC-F1 mice is influenced by multiple coding and regulatory genetic modifiers with sex-dependent effects. This study demonstrates that integrating multivariate phenotyping with systems genetics analyses provides an effective framework for identifying the complex genetic networks underlying intestinal tumorigenesis and associated systemic physiological variation in genetically diverse mouse populations. Full article

Global warming-induced temperature increases adversely affect plant growth, exacerbating agricultural risks and threatening global food security. These challenges are particularly acute for important crops like non-heading Chinese cabbage (NHCC; Brassica campestris L. syn. B. rapa), a nutritionally and economically significant leafy vegetable cultivated worldwide. While breeding for thermotolerance has been explored to stabilize summer supplies, these efforts remain insufficient under complex field conditions, necessitating cost-effective and practical alternatives. Here, we demonstrate that biochar derived from enoki mushroom (Flammulina velutipes) spent mushroom substrate (SMS-BC) significantly alleviates heat-induced growth suppression in greenhouse-cultivated NHCC. SMS-BC alters the soil nutrient profile and enhances available phosphorus and potassium through its unique feedstock properties, including its filamentous architecture and surface functional groups. Furthermore, SMS-BC may reshape microbial community composition of NHCC under heat stress. Our findings establish SMS-derived biochar as an effective soil amendment for alleviating heat stress-induced growth suppression in NHCC. Full article

Food security faces significant challenges due to the growing threat of insect pests and global climate change, making it essential to adopt sustainable agricultural strategies. Plants possess intrinsic defense systems that are activated in response to herbivore attack, including the emission of specialized volatile organic compounds (VOC) known as herbivore-induced plant volatiles (HIPVs). These volatiles aid the foraging of natural enemies (predators and parasitoids), thereby contributing to biological control of pest populations. Harnessing these chemical defense mechanisms offers a promising avenue for pest management, although natural enemy attraction does not necessarily result in pest suppression or increased crop yield. This review synthesizes plant and insect-derived chemical signaling mechanisms with direct relevance to biological control in crop agroecosystems, including field crops, orchards, vegetable systems, and protected cultivation. We emphasize recent applied research while retaining selected foundational studies that established the principal concepts and mechanisms underlying chemically mediated pest management. Considering the importance of chemical signaling in sustainable agriculture, we propose four key research directions: (1) optimizing plant defense induction mechanisms; (2) integrating HIPVs with natural enemy pheromone-based attractants; (3) combining habitat management with the provision of plant-derived food resources; and (4) harnessing plant defenses through breeding and infochemical-based genetically modified crops. Additionally, we examine the potential impacts of environmental stressors on plant–herbivore chemical communication, underscoring their importance for resilient and environmentally sustainable agricultural systems. Full article

Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with a well- documented prodromal phase during which non-motor symptoms appear years before motor onset. Seborrheic dermatitis (SD) is a chronic inflammatory skin disease that is significantly more prevalent in PD patients than in the general population. The biological mechanisms underlying this association have not been integrated into a single framework. Objectives: This narrative review aims to synthesise the available evidence on the molecular, genetic, and pathophysiological mechanisms linking SD and PD. Methods: A literature search was conducted across PubMed/MEDLINE, Scopus and ScienceDirect, supplemented by manual searches in OMIM and GeneCards. Results: Four major biological links between SD and PD have been proposed. First, alpha-synuclein deposits are detectable in cutaneous nerve fibres and autonomic fibres innervating sebaceous glands in PD patients and their pattern has been associated with disease subtype and progression. Second, dysfunction in ceramide and sphingolipid metabolism, associated with variants in GBA1, LRRK2, and ZNF750, has been linked to impaired lysosomal function and skin barrier integrity in both brain and skin tissue. Third, Malassezia, a commonly associated organism and possible trigger in susceptible hosts, produces metabolites that activate neuroinflammatory pathways relevant to PD and PD patients show altered Malassezia species composition on their skin. Fourth, NLRP3 inflammasome activation, which can be triggered by ceramide accumulation and fungal metabolites, has been proposed as a shared inflammatory mechanism that may operate in both keratinocytes and dopaminergic neurons. Conclusions: SD and PD appear to share overlapping genetic, lipidomic, microbial, and neuroinflammatory features. These associations are consistent with, but do not yet prove, a common pathological basis rather than a coincidental one. SD may therefore represent a potential prodromal feature or risk marker of PD. Future research should examine whether targeted intervention in high-risk SD patients can delay or modify PD onset. Full article

The vaginal microbiome is often interpreted through static taxonomic patterns. Yet microbial composition alone does not explain why some communities resist perturbation, recover after disruption, or transition toward dysbiosis. This narrative review synthesizes evidence that vaginal microbiome stability is shaped by endocrine phase, epithelial substrate availability, microbial functional capacity, mucosal tone and candidate host modifiers. High-estrogen states, particularly pregnancy, are associated with epithelial maturation, glycogen accumulation, low vaginal pH, and Lactobacillus-dominant communities, whereas postpartum, lactational, menopausal, and other hypoestrogenic states are associated with reduced epithelial support and increased vulnerability to diverse anaerobe-rich configurations. We review the linking of the estrogen–glycogen–Lactobacillus axis, focusing on microbial functions involved in glycogen degradation, lactate production and biofilm persistence, and host pathways that may modify mucosal responsiveness. Direct human genotype-to-vaginal-microbiome stability evidence remains limited; therefore, host genetic features are treated as candidate modifiers rather than validated clinical predictors. We propose a conceptual multi-omic hierarchy for organizing endocrine, epithelial, microbial, immune, temporal, and candidate host-modifier domains relevant to vaginal microbiome resilience. This framework is hypothesis-generating and requires longitudinal, phase-resolved human validation before quantitative prediction or clinical application. Full article

Global food trade exposes sharp differences in food safety regulation, especially between the EU and the US. The EU follows a precautionary, hazard-based model, allowing intervention under scientific uncertainty to protect consumers, maintain public trust, and avoid long-term risks. The US applies a science-based, proof-of-harm approach, requiring clearer evidence of risk before limiting market access, supporting innovation and regulatory efficiency. These contrasting philosophies create trade tensions and non-tariff barriers, as seen in disputes over hormone-treated beef, genetically modified organisms, and chlorine-washed poultry. Beyond the transatlantic context, countries adopt precautionary, science-based, or hybrid systems depending on domestic priorities, institutional capacity, and trade commitments. Hybrid models in India, China, and parts of Africa combine precautionary safeguards with evidence-based risk assessment to balance consumer protection and market access. International bodies such as Codex Alimentarius, the WHO, and the WTO help manage regulatory divergence through standards, guidance, and dispute resolution, while recognising precaution under uncertainty. Recent EU agreements with Mercosur and India show pragmatic cooperation through transparency, safeguards, and sanitary and phytosanitary commitments. Overall, effective global food governance depends on hybrid, coordinated, and adaptive approaches that reconcile health protection, trade facilitation, and innovation. Full article

Calcium alginate is an anionic polysaccharide that forms an ionically crosslinked hydrogel network with encapsulation properties to nucleic acids and nutrients for the amelioration of osmotic stress, ion toxicity and nutrient imbalance in saline–alkali soils. Traditional soil reclamation methods, including salt leaching, incorporation of organic matter, and gypsum application, are water-intensive under a changing climate, ultimately necessitating transformative bio-based solutions for food security. Calcium alginate-based biohydrogel represents a versatile platform with a tunable macromolecular architecture, ionic crosslinking via an “egg box” mechanism and potentially promising to deliver engineered co-encapsulated nutrients and genetically modified cargoes. The mannuronic (M) and guluronic (G) acid (M/G) ratios govern ion exchange capacity, rheological behavior and release kinetics in saline- and alkali-stressed environments. Recent studies on alginate-based nutrient encapsulation showed reduced oxidative damage and a 15–50% increase in plant-available water. The irrigation intervals extended from 7 to 14 days and yield gains by 24% in wheat, with comparable improvements in maize, tomato, rice and cotton. Calcium alginate hydrogels encapsulated salt tolerance genes (HKT1, SOS1, AVP1) encoding proteins mainly involved in Na⁺ retrieval from xylem, Na⁺ extrusion from root cells and vacuolar Na⁺ sequestration, which have achieved yield gains of 40 to 75% across wheat, rice and maize. Future research should focus on optimizing mechanical strength, crosslinking chemistry and smart bioencapsulation strategies for sustainable development so that crops are capable of withstanding variable climate stresses. Full article

The rapid proliferation of genetically modified (GM) crops and the uncontrolled distribution of GM-based food and feed have become a growing global concern, posing new challenges for regulatory oversight and traceability. The traditional PCR detection method cannot simultaneously meet the needs of high-throughput, high-specificity and high-sensitivity detection of transgenic organisms. In this study, a multiplex fluorescence PCR-capillary electrophoresis platform was developed by labeling primers of endogenous and exogenous genes with different fluorescent groups. The system enabled the simultaneous detection of 27 GM-related genes and events in a single analytical workflow. The results demonstrated accurate identification of all seven GM maize events, with correct detection achieved for each individual strain. In addition, the method enabled precise discrimination of a mixed sample containing five GM maize varieties. The assay also achieved a detection sensitivity of 0.1% in gradient mixtures with different GM contents. Our platform integrates a larger number of targets into a single PCR reaction, thereby simplifying the detection workflow while maintaining high analytical performance. Furthermore, the combination of multicolor fluorescence labeling and capillary electrophoresis provides high-resolution fragment discrimination and robust multiplex detection capability. This platform provides a novel and effective tool for rapid detection in food safety of transgenic crops and related areas, and can be applied in import/export inspection, quarantine, and biosafety surveillance. Full article

The interindividual phenotypic heterogeneity in Alpha-1 Antitrypsin Deficiency (AATD), despite a shared genetic etiology (the Z-allele of SERPINA1), is explained by the interaction of dual pathogenic mechanisms (gain-of-function vs. loss-of-function), additional genetic modifiers, and environmental or metabolic factors. Building on recent evidence suggesting divergent disease trajectories, we investigated whether pulmonary and hepatic impairments represent coupled manifestations or independent clinical dimensions within a large European cohort. Methods: This international multicenter study utilized the European Alpha-1 Research Collaboration (EARCO) registry (n = 1217). Pulmonary and hepatic severities were quantified using concurrent 0.0–10.0 composite indices. Independence was evaluated via partial Spearman correlations, multivariable multinomial regression, and geometric mapping across a continuous phenotypic space. Results: Cross-domain correlations between respiratory metrics and liver stiffness were near zero (r = −0.03), demonstrating statistical independence. Phenotypic dominance classification isolated distinct profiles; the lung-dominant group exhibited a higher age (57.0 vs. 54.0 years; p < 0.001) and tobacco exposure, while the liver-dominant group registered a higher body mass index (25.8 vs. 24.4 kg/m²; p < 0.001). Multivariable models identified age (OR 1.03; 95% CI 1.02–1.05) and smoking as independent predictors of lung dominance, whereas body mass index was independently associated with liver dominance (OR 1.04; 95% CI 1.01–1.07). Geometric mapping revealed advanced disease clusters at orthogonal margins rather than forming a systemic continuum. Conclusions: Hepatic and pulmonary impairments in AATD operate as independent clinical dimensions modulated by distinct metabolic and environmental factors. Risk stratification must transition toward organ-specific prognostic models. Full article

African soils face increasing levels of metal pollution due to industrialization, artisanal mining activities, improper waste management, and enhanced agricultural productivity. However, unlike many organic pollutants, heavy metals do not degrade naturally and therefore persist in environmental systems for prolonged periods. Heavy metals accumulate over many decades in the soil and bioaccumulate through the food chain causing severe health complications such as cancer, kidney problems, and neurological impairment. This paper reviews the current literature on the origin, prevalence, and behavior of the main pollutants Pb, Cd, Cr, As, Hg, and Cu. The major phytoremediation methods including phytoextraction, rhizofiltration, phytostabilization, and phytovolatilization are highlighted alongside in planta screening methods for hyperaccumulating plants including Berkheya coddii (Ni) and Haumaniastrum robertii (Co). The paper evaluates various enhancement techniques such as the use of chelators, Rhizobium inoculations, and genetic modifications. The significance of these approaches in tropical and subtropical climates is discussed. The paper suggests a holistic framework involving empirical kinetic modeling, geospatial machine learning (random forest, kriging), and molecular omics in prediction modeling. Major hurdles in such predictions include lack of field-based verification of the models, biotechnology safety of genetically modified (GM) organisms, and inadequate regulations. Future perspectives emphasize community-driven phytomining, biomass recycling, and resilient phytoremediation solutions. Full article

The gut microbiota is increasingly examined as a therapeutic target because it contributes to epithelial barrier integrity, microbial metabolite production, bile acid transformation, immune regulation, and communication between the gut and distant organs. This structured narrative review synthesizes evidence on microbiota involvement in metabolic, gastrointestinal, hepatic, cancer, and neuroimmune conditions, including MASLD/MASH, inflammatory bowel disease, irritable bowel syndrome, obesity, type 2 diabetes, hypertension, colorectal cancer, Parkinson’s disease, and autism spectrum disorder. Across these conditions, microbiome findings are biologically plausible but heterogeneous. Many associations are shaped by diet, geography, medication exposure, host genetics, disease stage, sampling methods, and analytical pipelines. Microbial alterations should therefore be interpreted as context-dependent signals and candidate modifiers rather than universal causal markers. Conventional microbiota targeted strategies include diet, physical activity, prebiotics, probiotics, synbiotics, postbiotics, and fecal microbiota transplantation. These approaches are clinically familiar, but their effects are often broad, host specific, strain dependent, and difficult to assign to one mechanism. Fecal microbiota transplantation has the clearest clinical role in recurrent Clostridioides difficile infection, while evidence for most other indications remains inconsistent. Engineered microbial therapeutics offer greater experimental precision through signal sensing, payload delivery, metabolic modulation, and genetic circuit design. However, most evidence remains preclinical or early translational. Progress requires stronger human trials, standardized methods, mechanistic validation, safety monitoring, ecological containment, transparent reporting, and proportionate regulation. Full article

Umbilical cord mesenchymal stromal cells (UC-MSCs) are a key element of regenerative medicine due to their ability to secrete growth factors that stimulate proliferation and angiogenesis, and modulate the inflammatory response. Despite their widespread use, the influence of the perinatal microenvironment on their biological properties remains poorly understood. The aim of this study was to assess the influence of pH and blood gas parameters in umbilical cord blood on the global transcriptomic profile of UC-MSCs and to analyze the correlation between the metabolic status of the newborn and the expression of key trophic factors: EGF, FGF2, FGFR1, FGFR3, GDNF, HGF, IGF1, NES, NGF, and PGF. Methods: The study was conducted in two stages. In the first phase, transcriptomic screening was performed using Affymetrix HuGene 2.0 ST microarray on cells isolated from three environmental groups defined by cord blood pH: acidic (pH < 7.35), physiological (7.35–7.39), and alkaline (pH ≥ 7.4). In the second phase, the results were validated using qPCR on an expanded study group (N = 50). Gene expression levels (RQ) were related to blood gas parameters (pH, pCO₂, pO₂, cHCO₃) and the presence of clinical features of threatened neonatal asphyxia. Results: Microarray analysis revealed that environmental pH acts as a molecular phenotypic switch. Under low pH conditions (<7.35), a shift in cell profile from proliferative to structural–migratory was observed. Significant overexpression of genes responsible for extracellular matrix (ECM) organization and adhesion (e.g., COMP, DCN, LUM, FMOD) was observed, while pathways related to cell cycle and cell division (↓CDK1, AURKA, TOP2A) were downregulated. qPCR validation confirmed these observations, demonstrating a strong positive correlation between blood pH and the expression of regenerative mediators: FGFR1 (r = 0.28), EGF (r = 0.30), NGF (r = 0.39), and IGF1 (r = 0.30). A negative correlation was also found between carbon dioxide pressure (pCO₂) and the expression of NGF, FGFR1, and EGF. A significant clinical finding was that in newborns diagnosed with threatened asphyxia, EGF, FGFR1, and NGF gene expression was significantly reduced, indicating impaired trophic potential of the cells in response to metabolic stress. Conclusions: These results indicate that cord blood gas parameters are critical regulators of the genetic activity of UC-MSCs. Metabolic and respiratory acidosis not only inhibit the cells’ proliferative potential but also force them into a matrix remodeling mode, permanently modifying their transcriptomic profile. This suggests that the neonatal acid–base status may serve as an objective indicator of the “biological quality” of isolated stromal cells, which has significant implications for their future applications in cell therapies. Full article