Search Results (13,360)

BST2 has emerged as a multifunctional molecule that bridges antiviral defense, membrane architecture, and tumor immunity. Originally characterized as an interferon-inducible restriction factor that tethers virions to the plasma membrane, BST2 is now recognized as an oncogenic driver and immunoregulatory hub in diverse malignancies. In cancer, BST2 expression is frequently upregulated through promoter hypomethylation and transcriptional activation. Functionally, BST2 promotes proliferation, epithelial–mesenchymal transition, anoikis resistance, and chemoresistance, whereas its loss sensitizes tumor cells to proteotoxic and metabolic stresses. Beyond tumor cells, BST2 modulates the tumor microenvironment by promoting M2 macrophage infiltration, dendritic cell exhaustion, and natural killer (NK)-cell resistance, thereby contributing to immune evasion. Elevated BST2 expression correlates with poor prognosis in glioblastoma, breast, nasopharyngeal, and pancreatic cancers, and it serves as a circulating biomarker within small extracellular vesicles. In conclusion, BST2 is a dual-function molecule that integrates oncogenic signaling and immune regulation, making it an attractive diagnostic and therapeutic target for hematological and solid tumors. Full article

Coelomactra antiquata, a marine bivalve of high nutritional and economic value, lacks comprehensive data on its toxic responses and adaptive mechanisms to ammonia nitrogen. This study integrated histophysiology, transcriptomics, and metabolomics to investigate its ammonia tolerance and molecular mechanisms, determining a 48 h LC₅₀ of 99.06 mg/L and a sublethal concentration of 9.91 mg/L. After 48 h of sublethal ammonia stress, SOD, CAT, GLDH, and GS activities in gill and hepatopancreas significantly increased, with notable changes in MDA, Gln, and urea contents, confirming disruption of antioxidant defense and nitrogen metabolism homeostasis. Tissue sections revealed irreversible histopathological damage to key tissues. Omics analyses identified 7823 differentially expressed genes (DEGs) and 737 differentially expressed metabolites (DEMs) in hepatopancreas. DEGs were enriched in metabolic pathways and multiple immune-related signaling pathways (e.g., NF-kappa B, RIG-I-like receptor), while DEMs were primarily involved in processes such as protein digestion/absorption, aminoacyl-tRNA biosynthesis, and amino acid metabolism. Research data indicate that ammonia nitrogen stress primarily regulates the antioxidant function and nitrogen metabolism homeostasis of C. antiquata by activating multiple immune- and metabolism-related pathways. This first systematic multi-omics study elucidates C. antiquata’s tolerance to ammonia nitrogen and its molecular responses, filling a gap in environmental toxicology research for sustainable aquaculture and genomic studies. Full article

Melanin produced in melanocytes contributes to photoprotection, oxidative stress reduction, immune regulation, and epidermal homeostasis, while its dysregulation underlies diverse pigmentary disorders. Natural products modulate melanogenesis by regulating tyrosinase activity, intracellular signaling pathways such as extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and cyclicAMP/protein kinase A/cAMP response element-binding protein (cAMP/PKA/CREB), and cellular redox balance. Anti-melanogenic effects have been reported for various fruit-derived phytochemicals, ginseng-based metabolites, and plant polyphenols, which act through direct enzymatic inhibition, suppression of melanoenic signaling, modulation of melanosome dynamics, and antioxidant or anti-inflammatory activities. Advances in delivery systems, including nano- and microencapsulation platforms, further enhance the stability and topical bioavailability of these compounds. In contrast, certain methoxylated flavonoids and phenolic constituents can stimulate pigmentation by sustaining melanogenic signaling and promoting microphthalmia-associated transcription factor (MITF)-driven transcription, emphasizing the context-dependent and bidirectional influence of natural substances on pigmentation outcomes. Collectively, these findings highlight the therapeutic potential of natural product-based modulators of melanogenesis while underscoring the need for mechanistic clarification, safety evaluation, and translational studies to ensure effective and controlled pigmentation management. This review summarizes the biological functions of melanin and examines natural strategies for regulating pigmentation. Full article

Background: Fatty acid-binding protein 3 (FABP3) is released in circulation following myocardial infarction, and an increased level of circulatory FABP3 has also been reported in peripheral artery disease patients, exposing endothelial cells to higher levels of FABP3. Recently, loss of endothelial FABP3 was shown to protect endothelial cells against inflammation-induced endothelial dysfunction; however, the effect of FABP3 exposure on endothelial cells is unknown. Accordingly, to study the effect of FABP3 exposure on endothelial cells, we performed transcriptomic profiling following recombinant human FABP3 (rhFABP3) treatment of endothelial cells. Methods: Cultured human endothelial cells were treated with either a vehicle or rhFABP3 (50 ng/mL, 6 h); then, RNA sequencing was performed. Gene expression analysis followed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses was performed to identify differentially expressed genes and affected cellular functions and pathways. Results: Differential gene expression analysis revealed kinesin family member 26b (KIF26B) to be the most upregulated and survival of motor neuron 2 (SMN2) to be the most downregulated genes in rhFABP3-treated compared to vehicle-treated endothelial cells. Most of the differentially expressed genes were associated with endothelial cell motility, immune response, and angiogenesis. GO and KEGG analyses indicated that rhFABP3 exposure impacts several crucial pathways, predominantly “Regulation of leukocyte mediated cytotoxicity” and “Natural killer cell mediated cytotoxicity”, suggesting its involvement in endothelial cell physiology and response mechanisms to cardiovascular stress. Conclusions: This is the first study to evaluate rhFABP3-induced transcriptomics in human endothelial cells. Our data reveal novel genes and pathways affected by the exposure of endothelial cells to FABP3. Further research is necessary to validate these findings and fully understand FABP3’s role in endothelial biology and in cardiovascular diseases like myocardial infarction and peripheral artery disease. Full article

Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. This diversity determines whether tissue repair resolves normally or progresses into maladaptive scarring that disrupts myocardial structure and function after injuries. Recent single-cell and spatial transcriptomic studies show that CFs exist in distinct yet interrelated molecular states in murine models and human cardiac tissue with specialized roles in matrix production, angiogenesis, immune signaling, and mechanical sensing. These insights redefine cardiac fibrosis as a dynamic and context-dependent process rather than a uniform cellular response. Although CFs are promising targets for preventing HF progression and enhancing cardiac remodeling, translation into effective therapies remains limited by the unclear heterogeneity of pathological fibroblasts, the lack of distinctive CF markers, and the broad activity of fibrogenic signaling pathways. In this review, we discuss the dynamics of CF activations during the development and progression of HF and assess the underlying pathways and mechanisms contributing to cardiac dysfunction. Additionally, we highlight the potential of targeting CFs for developing therapeutic strategies. These include nonspecific suppression of fibroblast activity and targeted modulation of the signaling pathways and cell populations that sustain chronic remodeling. Furthermore, we assess regenerative approaches that can reprogram fibroblasts or modulate their paracrine functions to restore functional myocardium. Integrating antifibrotic and regenerative strategies with advances in precision drug discovery and gene delivery offers a path toward reversing established fibrosis and achieving recovery in HF. Full article

Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, is increasingly recognized as a key modifier of antitumor immunity and the tumor microenvironment (TME). In preclinical models, autophagy can not only promote ICD by sustaining endoplasmic reticulum (ER) stress, eukaryotic translation initiation factor-2α (eIF2α) phosphorylation, and secretory pathways, but it can also limit ICD by degrading DAMPs, antigenic cargo, and major histocompatibility complex (MHC) molecules. The net outcome is highly context-dependent and determined by the tumor type, the nature and intensity of the stress, and the level at which autophagy is modulated. Herein, we summarize how autophagy affects the three canonical ICD-associated DAMPs, highlight solid-tumor models in which autophagy supports ICD, and contrast them with systems wherein autophagy inhibition is required for immunogenicity. We then focus on hematological malignancies, especially multiple myeloma, where recent reports implicate the autophagy-related protein GABARAP in bortezomib-induced ICD. Finally, we discuss the translational implications, including rational combinations of autophagy modulators with ICD-inducing chemotherapies, targeted drugs, and cellular immunotherapies, and outline the remaining challenges for safely harnessing the autophagy–ICD axis in the clinical setting. Full article

The greater amberjack (Seriola dumerili) is an economically important marine species that is prone to bacterial infections, resulting in high mortality rates and substantial economic losses. In this study, a virulent bacterial strain, Vh-2, was isolated from diseased greater amberjack and identified as Vibrio harveyi. Experimental infections caused high mortality and severe splenic damage characterized by tissue necrosis, abnormal pigment deposition, cellular disintegration, and extensive immune cell infiltration. A virulence gene analysis revealed that Vh-2 harbored multiple virulence-associated genes such as toxR, toxS, vhpA, vhpB, vhhA, vhhB, luxR, and pap6. Antibiotic susceptibility testing demonstrated ampicillin resistance but sensitivity to ceftriaxone, florfenicol, and meropenem. Transcriptomic profiling of infected spleens identified 396 differentially expressed genes (DEGs) compared to the control group, of which 293 were upregulated and 103 were downregulated. A functional enrichment analysis indicated that these genes were primarily involved in cell cycle regulation, DNA repair, metabolic processes, and immune-related pathways. These findings enhance our understanding of V. harveyi pathogenesis and immune responses of S. dumerili and provide new insights into the prevention and control of V. harveyi infections in marine fish. Full article

Atherosclerosis is a chronic, multifactorial vascular disease and the leading global cause of cardiovascular morbidity. Its development reflects interconnected disturbances in lipid metabolism, endothelial function, inflammation, smooth muscle cell (SMC) phenotypic switching, and extracellular matrix remodeling. Genetic predisposition, including monogenic disorders such as familial hypercholesterolemia and polygenic risk variants, modulates disease susceptibility by altering lipid homeostasis as well as inflammatory and thrombotic pathways. Epigenetic regulators and noncoding RNAs, such as histone modifications, microRNAs, and long noncoding RNAs, further shape gene expression and link environmental cues to vascular pathology. Endothelial injury promotes lipoprotein retention and oxidation, triggering monocyte recruitment and macrophage-driven foam cell formation, cytokine secretion, and necrotic core development. Persistent inflammation, macrophage heterogeneity, and SMC plasticity collectively drive plaque growth and destabilization. Emerging insights into immune cell metabolism, intracellular signaling networks, and novel regulatory RNAs are expanding therapeutic possibilities beyond lipid-lowering. Current and evolving treatments include statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, anti-inflammatory agents targeting interleukin-1 beta (IL-1β) or NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and advanced approaches such as gene editing, siRNA, and nanoparticle-based delivery. Integrating multi-omics, biomarker-guided therapy, and precision medicine promises improved risk stratification and next-generation targeted interventions. This review summarizes recent molecular advances and highlights translational opportunities for enhancing atherosclerosis prevention and treatment. Full article

Autoinflammatory diseases involve recurrent systemic inflammation caused by dysregulated innate immunity, arising from genetic or multifactorial mechanisms, as seen in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. About 10% of PFAPA patients show autosomal dominant inheritance. We describe a three-generation family with a PFAPA-like recurrent fever syndrome displaying clear autosomal dominant transmission. All affected individuals tested negative on a diagnostic panel of 13 known autoinflammatory genes. Whole-exome sequencing was performed in two distantly related affected members, followed by variant filtering, segregation analysis, and phenotype-based prioritization. A single heterozygous missense variant in RXFP1, c.154G>A p.(Asp52Asn), co-segregated with disease in all affected relatives. This variant is extremely rare in population databases, absent from ClinVar, present in COSMIC, and predicted as damaging by REVEL and CADD. RXFP1, not previously implicated in autoinflammatory or innate immune disorders, encodes the relaxin family peptide receptor 1, a G protein–coupled receptor involved in extracellular matrix regulation, anti-fibrotic pathways, and modulation of inflammatory cytokine production. Protein network analysis showed interactions with RLXN1-3, inflammatory mediators, PTGDR, ADORA2B, and C1QTNF8, supporting an immunomodulatory function. This is the first report linking RXFP1 variation to a hereditary recurrent fever syndrome, identifying relaxin signalling as a potential immune regulatory pathway. Full article

The enteric nervous system (ENS) constitutes a highly organized and intricate neuronal network comprising two principal plexuses: myenteric and submucosal. These plexuses consist of neurons and enteric glial cells (EGCs). Neurons ensure innervation throughout the intestinal wall, whereas EGCs, distributed within the mucosa, contribute to epithelial barrier integrity and modulation of local inflammatory responses. The ENS orchestrates essential gastrointestinal functions, including motility, secretion, absorption, vascular regulation, and immune interactions with gut microbiota. Under physiological conditions, intestinal homeostasis involves moderate generation of reactive oxygen species (ROS) through endogenous processes such as mitochondrial oxidative phosphorylation. Cellular antioxidant systems maintain redox equilibrium; however, excessive ROS production induces oxidative stress, promoting EGCs activation toward a reactive phenotype characterized by pro-inflammatory cytokine release. This disrupts neuron–glia communication, predisposing to enteric neuroinflammation and neurodegeneration. Obesity, associated with hyperglycemia, hyperlipidemia, and micronutrient deficiencies, enhances ROS generation and inflammatory cascades, thereby impairing ENS integrity. Nevertheless, non-pharmacological strategies—including synthetic and natural antioxidants, bioactive dietary compounds, probiotics, and prebiotics—attenuate oxidative and inflammatory damage. This review summarizes preclinical and clinical evidence elucidating the interplay among the ENS, obesity-induced oxidative stress, inflammation, and the modulatory effects of antioxidant interventions. Full article

Background/Objectives: The gut microbiome influences melanoma biology and response to immune checkpoint inhibitors. Dietary fiber is a key modifiable factor that shapes the microbial composition and metabolite production. This review summarizes mechanistic, preclinical, and clinical evidence describing how fiber and fiber-responsive taxa may affect melanoma immunity and treatment outcomes. Methods: A literature search of MEDLINE, Embase, and Scopus identified studies published within the past five years examining dietary fiber, gut microbiome interactions, immune modulation, or melanoma outcomes. After screening 491 unique records, 49 peer-reviewed mechanistic, preclinical, observational, and interventional studies were synthesized qualitatively in this narrative review. Results: Fiber fermentation produces short-chain fatty acids that regulate dendritic cell activation, T-cell priming, and cytokine signaling. Preclinical melanoma models show that fibers such as inulin and β-glucan enhance IFN-γ-driven antitumor immunity, increase CD8⁺ infiltration, and improve checkpoint blockade efficacy in a microbiota-dependent manner. In humans, fiber-rich diets and enrichment of taxa such as Bifidobacterium, Faecalibacterium, and Akkermansia are associated with improved PD-1 inhibitor responses, longer progression-free survival, and possible reductions in ICI-related colitis. Although epidemiologic studies suggest no clear association between fiber intake and melanoma incidence, dietary fiber intake appears to correlate strongly with treatment-related outcomes. Conclusions: Dietary fiber represents a potentially safe and plausible adjunct to melanoma immunotherapy. However, study variability and emerging counterevidence highlight the need for controlled trials to clarify causality and define optimal fiber-based interventions. Full article

The success of cancer vaccines relies on the ability of dendritic cells (DCs) to efficiently prime cytotoxic CD8 T cell responses against tumors. However, in solid tumors this process is often undermined by tumor-driven immunosuppression and intrinsic defects in DC activation. Among the signaling pathways implicated in DC dysfunction, β-catenin signaling has emerged as a key regulator of immune tolerance in DCs. In parallel, inhibitory receptors such as PD-L1 and TIM-3 on DCs have been recognized as critical DC-intrinsic brakes on CD8 T cell priming and on responses to immune checkpoint blockade (ICB). Recent work has identified a DC-intrinsic immunoregulatory circuit in which β-catenin activation in DCs—particularly in cross-presenting cDC1s—induces expression of TIM-3, thereby suppressing CD8 T cell cross-priming and limiting anti-tumor CD8 T cell immunity. This β-catenin–TIM-3 axis represents a previously underappreciated layer of negative regulation that may help explain, at least in part, the limited efficacy of many current DC-based cancer vaccines. In this review, we examine how β-catenin activation in DCs, particularly in cDC1s, induces TIM-3 and related inhibitory programs that suppress cross-priming of tumor antigen-specific CD8 T cells and constrain the efficacy of DC-based vaccines. We further discuss how selectively targeting this β-catenin–TIM-3 checkpoint axis—alone or together with PD-L1 and other β-catenin–linked receptors—could restore DC function and inform rational combinations of DC-based vaccination with ICB and other T cell-based immunotherapies. Full article

Human microbiota, a complex consortium of microorganisms co-evolved with the host, profoundly influences tissue development, immune regulation, and disease progression. Growing evidence shows that microbial metabolites and signaling molecules modulate key stem cell pathways—such as Hedgehog, Wnt/β-catenin, and Notch—thereby reprogramming stem cell fate toward tumor-suppressive or tumor-promoting outcomes. Specific taxa within oral, intestinal, and urogenital niches have been linked to cancer initiation, therapy resistance, and recurrence. In parallel, clinical studies reveal that microbiota composition affects infection dynamics: bacterial isolates from symptomatic urinary tract infections inhibit commensal growth more strongly than the reverse, with Gram-positive and Gram-negative strains displaying distinct interaction profiles. Collectively, these findings highlight microbiota’s dual role in regulating cellular plasticity and pathogenicity. Elucidating host–microbe and microbe–microbe mechanisms may guide microbiota-targeted interventions to improve cancer and infectious disease management. Full article

Forkhead box protein O1 (Foxo1) is an insulin-suppressed transcription factor that governs multiple biological processes, including cell proliferation, apoptosis, autophagy, mitochondrial function, and energy metabolism. Over the past 25 years, Foxo1 has evolved from a liner insulin effector to a pleiotropic integrator of systemic metabolic stress during obesity and aging. Foxo1 integrates hormonal signals with energy balance and plays a central role in glucose and lipid metabolism, organ homeostasis, and immune responses. Given its pleiotropic functions, therapeutic targeting of Foxo1 pathway will require a nuanced, context-specific approach. Here, we reviewed key advances in Foxo1 studies over the past 25 years, including multi-hormonal control of Foxo1 activity, Foxo1-mediated inter-organ crosstalk, immune modulation, and contributions to aging-associated pathologies. Understanding the regulation of Foxo1 and its pleiotropic function across multiple tissues will advance insight into the pathogenesis of metabolic diseases and promote the translation potential of Foxo1 signaling manipulation for the treatment of metabolic disorders, including insulin resistance and type 2 diabetes. Full article

(1) Background: Zinc is an essential micronutrient involved in immune regulation, epithelial barrier integrity, and the host response to bacterial infections. However, the clinical benefits of zinc supplementation across different age groups remain uncertain, with heterogeneous findings and variable dosing strategies reported in the literature. (2) Objectives: To map and summarize randomized controlled trials (RCTs) evaluating zinc supplementation (either as treatment or prophylaxis) for bacterial infection outcomes in neonates, children, and adults, and to identify gaps requiring further research, including the use of zinc-based nanoparticles. (3) Eligibility Criteria: We included English-language RCTs that evaluated zinc supplementation and reported clinical outcomes related to bacterial infections. Observational studies, trials without infection-related outcomes, and studies not involving human participants were excluded. (4) Sources of Evidence: A MEDLINE (PubMed) search was conducted from 2000 to 1 November 2025 using predefined keywords related to zinc supplementation, neonates, children, adults, and bacterial infections. Reference lists of eligible articles were screened to identify additional studies. (5) Charting Methods: Data were charted for each included study, including population characteristics, zinc dosing and regimen, type of supplementation (therapeutic or prophylactic), main infection-related outcomes, and key findings. Data charting was performed independently and verified within the research team. (6) Results: A total of 51 RCTs were included: 10 in neonates, 32 in children, and 9 in adults. In neonates, therapeutic zinc supplementation as an adjunct to antibiotics showed heterogeneous results, with some studies reporting reductions in morbidity, inflammatory markers or mortality, while others found no significant differences in clinical outcomes. In children, zinc supplementation consistently reduced the duration and severity of diarrheal episodes and, in several trials, improved the resolution of respiratory infections. In adults, the evidence was limited but suggested potential benefits in selected populations, such as burn patients or those with zinc deficiency or immunologic dysfunction. Variability in zinc dosage, treatment duration, and outcome definitions limits direct comparison across studies. (7) Conclusions: Zinc supplementation appears to provide benefits in neonates and children, whereas evidence in adults remains mixed and inconclusive. Standardized, well-powered RCTs are needed to define optimal dosing strategies, identify populations most likely to benefit, and clarify the mechanisms underlying zinc’s anti-infective effects. Future research should consider the use of zinc oxide nanoparticles (ZnO-NPs) demonstrated broad-spectrum antimicrobial activity and potential synergy with antibiotics, although clinical data remain still limited. Full article