Search Results (7,204)

Salinity is an important environmental factor affecting the physiological homeostasis of freshwater fish, yet the underlying mechanisms in grass carp (Ctenopharyngodon idella) gills remain unclear. Therefore, grass carp were exposed to different salinity levels for 60 days, and gill responses were evaluated using histopathological, ion regulatory, antioxidant, transcriptomic, and metabolomic analyses. Histological observations showed that high salinity (8 g/L) caused marked structural damage to the gill lamellae. Specifically, Na⁺ and Ca²⁺ concentrations and Na⁺/K⁺-ATPase activity significantly decreased, while K⁺ concentration and Ca²⁺-ATPase activity increased, revealing disrupted ion homeostasis. Salinity exposure also led to decreased antioxidant enzyme activities. Integrated omics analysis further demonstrated that a total of 2447 differentially expressed genes and 268 differentially expressed metabolites were identified, with significant enrichment in pathways related to biosynthesis of amino acids, arachidonic acid metabolism, glutathione metabolism, PPAR signaling, and calcium signaling. Notably, the PPAR and calcium signaling pathways showed positive enrichment under salinity stress, suggesting their potential involvement in the regulation of lipid metabolism, energy allocation, and cellular stress responses. Our findings indicated amino acid biosynthesis and arachidonic acid metabolism as key pathways involved in the adaptation of grass carp gills to salinity stress. Overall, chronic salinity exposure caused structural alterations, disrupted ion regulation, altered antioxidant status, and marked transcriptomic and metabolomic changes in grass carp gills, offering new insight into salinity adaptation in freshwater fish. Full article

Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones that transport fatty acids and other hydrophobic molecules, playing essential roles in cellular lipid metabolism, signaling, and brain function. Within the central nervous system, FABP3, FABP5, and FABP7 facilitate the trafficking of long-chain polyunsaturated fatty acids and endocannabinoids, thereby modulating key regulatory pathways including the endocannabinoid system (ECS), peroxisome proliferator-activated receptor (PPAR) signaling, and dopaminergic neurotransmission. Peripherally, FABP1 and FABP4 contribute to hepatic drug metabolism, kidney excretion, and inflammatory processes in both tissues, with implications for the pharmacokinetics of substances of abuse. This narrative review synthesizes the current literature on FABPs and their involvement in substance use and addiction-related behaviors. Evidence from transgenic knockout models, pharmacological inhibition studies, and adeno-associated virus vector approaches demonstrates that manipulation of FABP subtypes can alter reward-related behaviors across multiple substances, including THC, ethanol, nicotine, and cocaine. Reduction or knockout of FABP7 alters THC metabolite levels in a sex-dependent manner. FABP3 shows involvement with dopamine receptor expression; however, interaction between FABP3 modulation and specific substances has sparsely been investigated. FABP5 has vastly diverging interactions with addictive behavior and appears to be substance dependent, as downregulation reduces cocaine self-administration, but knockout enhances nicotine conditioned place preference (CPP) and increases brain uptake of THC. Combined deletion of FABP5 and 7 additionally reduces cocaine CPP and reinstatement, while showing promising decreases in ethanol consumption paradigms. FABPs may be a potential therapeutic target for treating substance use disorders and underlying reward deficiency mechanisms underlying addiction and further research is required to elucidate specific mechanistic effects and eliminate potential adverse consequences of chronic FABP modulation. Full article

Bisphenol A (BPA) is a non-persistent industrial chemical widely used in the production of polycarbonate plastics and epoxy resins. Due to its mass production and versatility, BPA is ubiquitous in environmental matrices, leading to human exposure through ingestion, dermal contact, and inhalation. As a known endocrine-disrupting chemical (EDC) with estrogenic activity, BPA exposure has been associated with reproductive, metabolic, immune, oncogenic, and developmental effects. Mechanistically, BPA is reported to exert its toxic effects via multiple pathways, including alterations in epigenetic microRNA (miRNA) expression. miRNAs are endogenous non-coding RNA molecules that regulate gene expression by targeting mRNAs, thereby influencing a wide range of cellular and metabolic pathways involved in development and disease. Importantly, this review consolidates evidence suggesting that the biological effects of BPA may, in part, be mediated through miRNA-driven epigenetic modifications, affecting numerous downstream proteins and signaling pathways. Altered miRNA expression induced by BPA exposure is implicated in diverse health outcomes, including reproductive dysfunction, oncogenesis, metabolic disorders, and neurodevelopmental abnormalities. Notably, BPA exposure predominantly results in the upregulation of specific miRNAs, such as miR-21 and miR-146a, although tissue-specific and sex-dependent variations are evident. In this review, we provide a comprehensive overview of human, in vivo, and in vitro studies investigating BPA-induced miRNA dysregulation and its associated biological effects. Full article

Wound healing is a dynamic and highly coordinated process that involves inflammation, cell proliferation, angiogenesis, re-epithelialization, extracellular matrix remodeling, and tissue maturation. The altered expression of important signaling pathways, such as transforming growth factor-β (TGF-β)/Smad, nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and Wnt/β-catenin, may be responsible for slower wound healing, chronic inflammation, excessive fibrosis, and impaired tissue regeneration. Multifunctional nanomaterials are a promising strategy for tuning these highly coordinated processes due to their tunable physicochemical properties, high surface area, and the ability to deliver cargo, as well as the integration of antimicrobial, antioxidant, anti-inflammatory, and pro-angiogenic properties. The aim of current review is to summarize the potential of multifunctional nanomaterials to promote wound healing, with a focus on mechanisms of action and modulation of key cellular signaling pathways. A systematic review of the literature was conducted using PubMed, Scopus, Web of Science, and Google Scholar, searching for publications from 1996 to June 2026, and representative experimental, mechanistic, preclinical, and translational studies were critically evaluated. In this review, the authors discuss the role of nanomaterial properties, therapeutic payload, molecular targets, modulation of cellular signaling pathways, and regenerative effects. These platforms have been shown in in vitro and animal studies to influence inflammatory signaling, oxidative stress, angiogenesis, collagen remodeling, re-epithelialization, cellular proliferation, and migration. However, the modulation of these pathways are dose-responsive, time-dependent, and cell- and wound-stage-specific. Despite the promising therapeutic potential of nanomaterial-based wound care strategies, the available evidence remains predominantly preclinical, with relatively limited clinical data supporting their use in humans. Concerns regarding long-term toxicity, biodistribution, batch-to-batch reproducibility, sterilization, scalable manufacturing, regulatory approval, and commercial feasibility further challenge translation into clinical practice. Multifunctional nanomaterials may offer a promising approach for pathway-specific and multimodal wound management; however, comprehensive mechanistic studies, long-term safety and biodistribution assessments, and well-designed clinically relevant investigations are required to establish their efficacy, safety, and true translational potential. Full article

Foam cells are central to atherosclerotic plaque development, but their pathological significance in advanced lesions extends beyond lipid accumulation. Under chronic exposure to oxidized lipoproteins, cholesterol crystals, inflammatory cytokines, hypoxia, lysosomal stress, and mitochondrial injury, lipid-loaded foam cells of macrophage and vascular smooth muscle cell (VSMC) origin may acquire maladaptive stress phenotypes. In this focused review, we propose a redox-threshold model, defined as the transition point at which mitochondrial antioxidant and metabolic buffering capacity is exceeded, allowing lipid peroxide accumulation to shift senescence-like foam cells toward ferroptosis susceptibility and defective plaque resolution. Progressive mitochondrial reactive oxygen species (ROS) accumulation, impaired NADPH-dependent antioxidant buffering, defective glutathione and thioredoxin recycling, mitophagy impairment, and reduced GPX4-mediated lipid peroxide detoxification may converge to promote iron-dependent lipid peroxidation. If lipid-peroxidized or dying foam cells are not efficiently cleared, oxidized lipids, cellular debris, and inflammatory signals accumulate, promoting secondary necrosis, necrotic core expansion, plaque non-resolution, and instability. We explicitly distinguish established processes from mechanistically supported inferences and hypothesis-generating links, emphasizing that the complete senescence-like stress-to-ferroptosis-to-non-resolution sequence remains a testable framework rather than an established linear pathway. This focused framework suggests that advanced plaque stabilization may require strategies that preserve mitochondrial redox resilience, limit ferroptotic lipid peroxidation, and enhance efferocytosis-mediated resolution. Full article

Leucine-rich repeat kinase 2 (LRRK2) has emerged as a central molecular node linking genetic risk, membrane trafficking, lysosomal homeostasis, and immune signalling in Parkinson’s disease (PD). Rather than functioning as a conventional protein kinase, LRRK2 operates as a conformationally regulated, Rab-directed signalling machine whose activity is governed by long-range interdomain communication, membrane recruitment, and cooperative interactions with small GTPases. Converging advances in cryo-electron microscopy, quantitative phosphoproteomics, and human genetics indicate that pathogenic mutations, lysosomal stress, and pharmacological inhibitors do not simply alter catalytic output, but reshape the conformational landscape of LRRK2, biasing it toward distinct structural states with divergent cellular consequences. A defining feature of this system is the selective phosphorylation of Rab GTPases at low stoichiometry—most prominently Rab8 and Rab10—yet with disproportionate functional impact on vesicle trafficking, ciliogenesis, autophagy, and organelle positioning. The identification of Rab-directed phosphatases, particularly PPM1H, further establishes that LRRK2 signalling is governed by a dynamically balanced kinase–phosphatase circuit operating in space and time. These observations, together with emerging evidence linking LRRK2 activation to lysosomal damage and immune pathways, support a unifying hypothesis: PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis, rather than from kinase hyperactivity alone. In this review, we integrate structural, biochemical, and cellular evidence to advance this framework and discuss its implications for disease mechanisms and therapy. We highlight key unresolved challenges—including conformation-selective drug targeting, spatial control of Rab phosphorylation, and context-dependent immune–neuronal crosstalk—and propose that restoring physiological regulation of LRRK2, rather than simply inhibiting its activity, will be essential for achieving mechanism-based disease modification in Parkinson’s disease. Full article

Objective: Self-assembling peptide nanomaterials are increasingly investigated as modular platforms for vaccine delivery and immune modulation. However, their structure-dependent interactions with immune cells remain insufficiently defined, limiting their early evaluation as peptide nanomaterial. This study evaluated the physicochemical properties and immunological effects of three Sup35 G7-derived self-assembling peptide nanomaterials, G7, G7d, and G7d(PEG)HER2, with particular attention to innate immune compatibility and macrophage responses. Methods: The morphology and surface charge of the peptides were characterized by transmission electron microscopy and zeta-potential analysis. Their cytocompatibility was assessed in THP-1 macrophages, Jurkat T cells, and IM-9 B cells. Transcriptomic and proteomic analyses were integrated to identify immune-cell-specific molecular responses. Cellular uptake, apoptosis, cytokine secretion, and intracellular reactive oxygen species production were further examined in macrophages. In vivo immunization in BALB/c mice was conducted to assess systemic immunoglobulin responses. Results: G7 and G7d assembled into large crystalline aggregates with limited dispersibility, whereas PEGylated G7d(PEG)HER2 formed more uniform nanofibers. All three materials showed positive zeta potentials and relatively low cytotoxicity across the tested immune cell models. Among these cells, macrophages displayed the strongest molecular responses. Integrated transcriptomic and proteomic analyses revealed coordinated alterations mainly involving metabolic remodeling, redox homeostasis, proteasome activity, and mitochondrial-associated pathways, rather than predominant activation of classical pro-inflammatory signaling. Ultrastructural analysis confirmed intracellular uptake of assembled peptides and mitochondrial morphological changes without detectable apoptosis. Cytokine profiling showed reduced secretion of multiple cytokines and chemokines, while G7 induced higher intracellular reactive oxygen species than G7d and G7d(PEG)HER2. In vivo, G7d administration was associated with increased serum IgG levels, whereas G7 showed a moderate effect and G7d(PEG)HER2 exhibited minimal changes; IgM levels remained unchanged. Conclusions: Sup35 G7 based self-assembling peptides exhibit low acute toxicity but induce structure-dependent modulation of macrophage function. Differences in assembly morphology and surface modification may influence systemic humoral responses. These findings support the importance of physicochemical design in evaluating immune compatibility of peptide nanomaterial scaffolds. Full article

Intercellular communication across cancer cells and the tumor microenvironment (TME) is essential for tumor growth, invasion, metastasis, and therapeutic resistance. Traditionally, these interactions have been viewed through the lens of diffusible signaling molecules and extracellular vesicles. However, growing evidence supports an additional paradigm in which specialized cytoskeleton-based membrane extensions, like tunneling nanotubes (TNTs), tumor microtubes (TMs), and cytonemes, mediate direct, contact-dependent communication between cells. This review examines the emerging roles of these cellular extensions in cancer biology, with a particular emphasis on cytonemes, long specialized signaling filopodia that facilitate transport and reception of signaling ligands and receptors. Cytonemes are interwoven with developmental signaling pathways, which are frequently reactivated in cancer, promoting tumor progression. We discuss cytoneme pathology in cancer, with specific examples in growth, stemness, invasion, and microenvironmental remodeling. These extensions represent an unexplored facet of tumor biology and a promising avenue for therapeutic intervention. Full article

Feed efficiency traits are increasingly important in pig production for improving profitability and environmental sustainability. Understanding their genetic basis is crucial for uncovering underlying biological mechanisms and informing selection strategies. In this study, we analyzed residual feed intake (RFI), feed conversion ratio (FCR), and average daily feed intake (ADFI) in 201 animals. Three separate Bayesian GWASs were conducted using 29,844 SNPs in a case–control design, with the lowest and highest 15% of the phenotypic distribution selected as controls and cases (N = 30 per group), respectively, for each trait. The results confirmed the polygenic nature of the traits, identifying 4 SNPs for RFI on Sus scrofa chromosomes (SSC) 3, 13, and 15 with high posterior probability for the direction of their effects; 4 SNPs for FCR on SSC 8, 14, and 17; and 8 SNPs for ADFI on SSC 1, 2, 6, 8, and 11. A candidate gene search identified 41 potential genes involved in diverse biological processes, including feed efficiency, intestinal development, tissue remodeling and integrity, nutrient transport and absorption, metabolic homeostasis, cellular signaling, energy sensing, and neurological regulation. These genes formed a highly interconnected network, highlighting the complexity of feed efficiency and the interplay among multiple physiological, metabolic, and regulatory pathways. Full article

Respiratory RNA viruses extensively reprogram host regulatory networks, thereby influencing viral replication, immune evasion, and disease severity. This review examines microRNAs (miRNAs) as regulatory interfaces in host–virus interactions, focusing on influenza A virus as a paradigmatic model while integrating evidence from other respiratory RNA viruses as SARS-CoV-2 and respiratory syncytial virus. After outlining canonical miRNA biogenesis and its manipulation during infection, we discuss how respiratory RNA viruses converge on shared miRNA-regulated pathways, including interferon and NF-κB signaling, apoptosis, autophagy, cellular metabolism, and redox homeostasis. Within these networks, host miRNAs can directly target viral RNAs and modulate antiviral defenses and inflammation, whereas viruses can reshape miRNA expression to facilitate replication, influencing immunopathology. The possibility that RNA viruses encode authentic miRNAs is also critically evaluated; current evidence indicates that manipulating host miRNA biogenesis machinery and remodeling miRNA networks are more prevalent than producing canonical viral miRNAs. Finally, the potential of circulating miRNAs as diagnostic and prognostic biomarkers is considered, as well as the capability of miRNA mimics and antagomiRs to function as host-directed therapeutic strategies. Their clinical translation, however, will require standardized validation, cell- and time-resolved studies, efficient delivery systems, and a careful assessment of specificity, safety, and context-dependent effects. Full article

Interactions among molecular recognition systems, neuronal activity, and glial regulation transform early neuronal connectivity into precise functional circuits during brain development. The cerebellum is a powerful model for studying these mechanisms due to its stereotyped and accessible circuitry. Two major excitatory afferent pathways—climbing fibers (CFs), which convey error-related signals to Purkinje cells (PCs), and mossy fibers (MFs), which transmit sensorimotor information via granule cells (GCs) and parallel fibers (PFs)—undergo strengthening, competition, and refinement during postnatal development. Synaptic specificity is established by general and pathway-specific organizers. The neurexin–neuroligin system broadly regulates synapse formation, while the neurexin–CBLN1–GluD2 complex specifies PF–PC synapses and C1qL1–BAI3 signaling stabilizes the dominant CF input during competitive refinement. CF–PC synapse elimination serves as a classic model of activity-dependent competition, where weaker inputs are removed through calcium-dependent mechanisms. In parallel, glial cells regulate synaptic maturation: microglia shape inhibitory environments, and Bergmann glia support glutamate homeostasis, dendritic organization, and synapse stability. PCs integrate CF and PF inputs and provide inhibitory output to the cerebellar nuclei, where convergent excitatory collaterals from CFs and MFs are combined with PC inhibition to generate cerebellar output. Together, these coordinated molecular, cellular, and circuit-level mechanisms establish the synaptic architecture underlying cerebellar computation, motor coordination, and adaptive learning, which are the central focus of this review. Full article

Adult hematopoietic stem cells (HSCs) and bone marrow (BM) mesenchymal stem/stromal cells (MSCs) are essential for lifelong hematopoiesis, skeletal homeostasis, immune competence, and tissue regeneration. The use of electronic cigarettes (E-cigs) among women of reproductive age continues to rise, raising concerns about potential adverse developmental effects; however, the long-term consequences of maternal E-cig vaping on offspring BM stem cell function and hematopoietic homeostasis remain incompletely understood. Here, using a rat model of maternal E-cig exposure (containing nicotine) during gestation, combined with longitudinal in vivo analyses and complementary ex vivo studies of human cells, we show that prenatal E-cig exposure is associated with persistent alterations in offspring BM stem cell function and lineage commitment. Gestational E-cig exposure was associated with expansion of the CD11b/c⁺ myeloid-enriched compartment, increased CD90⁺ stromal cells, and impaired osteogenic differentiation in rat offspring. Complementary experiments using primary human cells showed that nicotine exposure was associated with reduced T-cell proliferation and impaired cytotoxic activity in a proof-of-principle co-culture assay. Mechanistically, transcriptomic profiling followed by Gene Ontology and pathway enrichment analyses identified alterations in molecular programs associated with KLF4–Notch1 signaling, mitochondrial biogenesis, inflammation, and stem cell regulation in the BM of E-cig-exposed rat offspring. Changes in CCL11, FTO, and RUNX2 were additionally associated with an inflammatory and aging-related molecular phenotype that persisted from early life into adulthood, although these findings do not establish a causal CCL11–FTO–RUNX2 signaling axis or direct cellular senescence. Collectively, our study provides a phenotypic and mechanistic framework for understanding how maternal E-cig exposure may influence long-term offspring hematopoietic, skeletal, and immune health while highlighting the need for further studies to establish causal molecular mechanisms and determine their relevance to maternal E-cig use in humans. Full article

Coronary artery disease is a leading cause of morbidity and mortality in modern medicine. In contrast, surgical myocardial revascularization via coronary artery bypass grafting (CABG) remains the gold standard of treatment for complex multivessel disease. The great saphenous vein remains the most frequently used conduit due to its availability and technical simplicity, but its long-term patency is significantly inferior to that of arterial grafts. The primary pathological process responsible for vein graft failure is intimal hyperplasia, which represents a complex response of the vascular wall to surgical trauma, vein arterialization, inflammation, and hemodynamic stress. This process is characterized by endothelial dysfunction, inflammatory cell activation, proliferation and migration of vascular smooth muscle cells, and extracellular matrix remodeling. Underpinning these alterations are numerous molecular pathways, including NF-κB, MAPK, PI3K/Akt, TGF-β, and mTOR signaling, as well as substantial contributions from oxidative stress, cytokines, growth factors, and microRNAs. Contemporary research indicates that the phenotypic transformation of vascular smooth muscle cells constitutes the central event in the development of intimal hyperplasia. Understanding the cellular and molecular mechanisms underlying this disease’s onset enables the development of novel therapeutic strategies to preserve long-term graft patency. This review paper aims to provide a systematic overview of current knowledge regarding the molecular and cellular mechanisms of intimal hyperplasia development in vein grafts following CABG. Full article

Bone remodeling is a dynamic and tightly regulated process that maintains skeletal homeostasis through a balance between bone formation by osteoblasts and bone resorption by osteoclasts. Disruption of this balance contributes to the development of bone-related disorders, particularly osteopenia, osteoporosis and osteogenesis imperfecta, which weaken, deform, or cause fractures. Increasing evidence indicates that oxidative stress and chronic inflammation impair osteoblast functions while promoting osteoclast differentiation and activity. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with cytoprotective, antioxidant, and anti-inflammatory properties. Besides its primary role in cellular defense against oxidative stress and inflammatory damage, HO-1 has been shown to be involved in both osteoblast differentiation and osteoclastogenesis. Through its interaction with key regulatory systems, including the receptor activator of nuclear factor κB (RANK)–receptor activator of nuclear factor κB ligand (RANKL)–osteoprotegerin axis and redox-sensitive signaling pathways, HO-1 contributes to maintenance of optimal bone remodeling. The enzyme also plays a role in modulating metabolic processes in the bone. This review highlights the role of HO-1 in bone formation, bone resorption, and related pathophysiologic conditions. Furthermore, the therapeutic potential of HO-1 as a target for bone disorders is discussed. Full article

Chlorogenic acid (CGA) exhibits anticancer activity in colorectal cancer (CRC), but its clinical application is limited by low lipophilicity. To improve its physicochemical properties, four CGA esters (methyl, ethyl, n-propyl, and n-butyl chlorogenates) were synthesized and evaluated. Physicochemical properties were characterized in silico, and their biological activity was assessed in SW480, HT-29, and non-tumoral NCM460 cell lines using viability assays and flow cytometry. Molecular docking studies were performed to investigate the interactions of CGA and its esters with proteins involved in cell-proliferation-related signaling pathways. In silico analysis showed a progressive increase in LogP values across ester derivatives. All esters complied with Lipinski’s rule of five, whereas none met Veber’s rule due to their predicted topological polar surface area (TPSA) values. The esters induced dose- and time-dependent reductions in cell viability, with n-butyl chlorogenate exhibiting the strongest cytotoxic activity and a significantly lower IC₅₀ value within the tested concentration range. This derivative showed preferential cytotoxic activity toward SW480 cells while exhibiting only limited effects in non-tumoral NCM460 cells. In addition, n-butyl chlorogenate induced changes in mitochondrial oxidative status and phosphatidylserine externalization, consistent with apoptosis-associated cellular changes. Overall, these findings demonstrate that esterification modifies the physicochemical profile of CGA ester derivatives and is associated with enhanced cytotoxic activity. Increased lipophilicity was associated with enhanced cytotoxic activity, supporting further optimization of these compounds for CRC research. Full article