Search Results (371)

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health challenge characterized by complex adipose–liver interactions mediated by adipokines and hepatokines. Despite rapid field evolution, a comprehensive understanding of research trends and translational advances remains fragmented. This study systematically maps the scientific landscape through bibliometric analysis, identifying emerging domains and future clinical translation directions. Methods: A comprehensive bibliometric analysis of 1002 publications from 2004 to 2025 was performed using thematic mapping, temporal trend evaluation, and network analysis. Analysis included geographical and institutional distributions, thematic cluster identification, and research paradigm evolution assessment, focusing specifically on adipokine–hepatokine signaling mechanisms and clinical implications. Results: The United States and China are at the forefront of research output, whereas European institutions significantly contribute to mechanistic discoveries. The thematic map analysis reveals the motor/basic themes residing at the heart of the field, such as insulin resistance, fatty liver, metabolic syndrome, steatosis, fetuin-A, and other related factors that drive innovation. Basic clusters include metabolic foundations (obesity, adipose tissue, FGF21) and adipokine-centered subjects (adiponectin, leptin, NASH). New themes focus on inflammation, oxidative stress, gut microbiota, lipid metabolism, and hepatic stellate cells. Niche areas show targeted fronts such as exercise therapies, pediatric/novel adipokines (chemerin, vaspin, omentin-1), and advanced molecular processes that focus on AMPK and endoplasmic-reticulum stress. Temporal analysis shows a shift from single liver studies to whole models that include the gut microbiota, mitochondrial dysfunction, and interactions between other metabolic systems. The network analysis identifies nine major clusters: cardiovascular–metabolic links, adipokine–inflammatory pathways, hepatokine control, and new therapeutic domains such as microbiome interventions and cellular stress responses. Conclusions: In summary, this study delineates current trends and emerging areas within the field and elucidates connections between mechanistic research and clinical translation to provide guidance for future research and development in this rapidly evolving area. Full article

Xylosyltransferase-I (XT-I) plays a crucial role in skeletal development and cartilage integrity. An XT-I deficiency is linked to severe bone disorders, such as Desbuquois dysplasia type 2. While animal models have provided insights into XT-I’s role during skeletal development, its specific effects on adult bone homeostasis, particularly in human mesenchymal stem cell (hMSC) differentiation, remain unclear. This study investigates how XT-I deficiency impacts the differentiation of hMSCs into chondrocytes, osteoblasts, and adipocytes—key processes in bone formation and repair. The aim of this study was to elucidate for the first time the molecular mechanisms by which XT-I deficiency leads to impaired bone homeostasis. Using CRISPR-Cas9-mediated gene editing, we generated XYLT1 knockdown (KD) hMSCs to assess their differentiation potential. Our findings revealed significant disruption in the chondrogenic differentiation in KD hMSCs, characterized by the altered expression of regulatory factors and extracellular matrix components, suggesting premature chondrocyte hypertrophy. Despite the presence of perilipin-coated lipid droplets in the adipogenic pathway, the overall leptin mRNA and protein expression was reduced in KD hMSCs, indicating a compromised lipid metabolism. Conversely, osteogenic differentiation was largely unaffected, with KD and wild-type hMSCs exhibiting comparable mineralization processes, indicating that critical aspects of osteogenesis were preserved despite the XYLT1 deficiency. In summary, these results underscore XT-I’s pivotal role in regulating differentiation pathways within the bone marrow niche, influencing cellular functions critical for skeletal health. A deeper insight into bone biology may pave the way for the development of innovative therapeutic approaches to improve bone health and treat skeletal disorders. Full article

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α). Full article

Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood. Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model. Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis. Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies. Full article

African swine fever virus (ASFV) causes global swine outbreaks, but its cellular pathogenesis is poorly understood. Using single-cell RNA data from ASFV-infected pig spleens across four timepoints, we identified macrophages as the primary viral reservoir, with infection driving lymphoid depletion and myeloid expansion. We characterized four functionally distinct macrophage subsets, including a metabolically reprogrammed SusceptibleMac population serving as the major viral niche and an AntiviralMac subset rapidly depleted during infection. Viral gene expression analysis revealed E165R as a central hub in viral replication networks, while host transcriptomics uncovered disruption of Netrin signaling pathways that may facilitate immune evasion. Pseudotime analysis revealed dynamic macrophage state transitions during infection. These findings provide a high-resolution cellular atlas of ASFV pathogenesis, revealing macrophage subset-specific responses that shape disease outcomes and identifying potential targets for therapeutic intervention. Full article

Bone is a preferred site for disseminated tumor cells, yet the molecular mechanisms that prepare the skeletal microenvironment for metastatic colonization are only beginning to be understood. At the heart of this process are extracellular vesicles (EVs), nano-sized, lipid-encapsulated particles secreted by cancer cells and stromal components. This review consolidates current findings that position EVs as key architects of the bone-metastatic niche. We detail the biogenesis of EVs and their organotropic distribution, focusing on how integrin patterns and bone-specific ligands guide vesicle homing to mineralized tissues. We then outline the sequential establishment of the pre-metastatic niche, driven by EV-mediated processes including fibronectin deposition, stromal cell reprogramming, angiogenesis, neurogenesis, metabolic reconfiguration, and immune modulation, specifically, the expansion of myeloid-derived suppressor cells and impaired lymphocyte function. Within the bone microenvironment, tumor-derived EVs carrying microRNAs and proteins shift the balance toward osteoclastogenesis, inhibit osteoblast differentiation, and disrupt osteocyte signaling. These alterations promote osteolytic destruction or aberrant bone formation depending on tumor type. We also highlight cutting-edge imaging modalities and single-EV omics technologies that resolve EV heterogeneity and identify potential biomarkers detectable in plasma and urine. Finally, we explore therapeutic approaches targeting EVs, such as inhibition of nSMase2 or Rab27A, extracorporeal EV clearance, and delivery of engineered, bone-targeted vesicles, while addressing translational challenges and regulatory considerations. This review offers a roadmap for leveraging EV biology in predicting, preventing, and treating skeletal metastases by integrating advances across basic biology, bioengineering, and translational science. Full article

Background: Metabolic-associated fatty liver disease (MAFLD) is characterized by metabolic syndrome and immune infiltration, with glycolysis pathway activation emerging as a pivotal contributor. This study aims to identify glycolysis-associated key genes driving MAFLD progression and elucidate their crosstalk with immune infiltration through bioinformatics analysis and experimental validation. Methods: Integrative multi-omics analysis was performed on bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic datasets from MAFLD patients and controls. Differential expression analysis and WGCNA were employed to pinpoint glycolysis-correlated key genes. The relationship with immune infiltration was analyzed using single-cell and spatial transcriptomics technologies. Machine learning was applied to identify feature genes for matching shared TFs and miRNAs. External cohort validation and in vivo experiments (methionine choline-deficient diet murine models) were conducted for biological confirmation. Results: Five glycolysis-associated key genes (ALDH3A1, CDK1, DEPDC1, HKDC1, SOX9) were identified and validated as MAFLD discriminators. Single-cell analysis revealed that the hepatocyte–fibroblast–macrophage axis constitutes the predominant glycolysis-active niche. Spatial transcriptomics showed that CDK1, SOX9, and HKDC1 were colocalized with the monocyte-derived macrophage marker CCR2. Using four machine learning models, four feature genes were identified, along with their common transcription factors YY1 and FOXC1, and the miRNA “hsa-miR-590-3p”. External datasets and experimental validation confirmed that the key genes were upregulated in MAFLD samples. Conclusions: In this study, we identified five glycolysis-related key genes in MAFLD and explored their relationship with immune infiltration, providing new insights for diagnosis and metabolism-directed immunomodulation strategies in MAFLD. Full article

Three-dimensional (3D) scaffold systems have proven instrumental in advancing our understanding of polymicrobial biofilm dynamics and probiotic interactions within the oral environment. Among oral probiotics, Streptococcus salivarius K12 (Ssk12) has shown considerable promise in modulating microbial homeostasis; however, its long-term therapeutic benefits are contingent upon successful and sustained colonization of the oral mucosa. Despite its clinical relevance, the molecular mechanisms underlying the adhesion, persistence, and integration of Ssk12 into the native oral microbiome/biofilm remain inadequately characterized. In this pilot study, we explored the temporal colonization dynamics of Ssk12 and its impact on the structure and functional profiles of salivary-derived biofilms cultivated on melt-electrowritten poly(ε-caprolactone) (MEW-mPCL) scaffolds, which emulate the native oral niche. Colonization was monitored via fluorescence in situ hybridization (smFISH), confocal microscopy, and RT-qPCR, while shifts in community composition and function were assessed using 16S rRNA sequencing and meta-transcriptomics. A single administration of Ssk12 exhibited transient colonization lasting up to 7 days, with detectable presence diminishing by day 10. This was accompanied by short-term increases in Lactobacillus and Bifidobacterium populations. Functional analyses revealed increased transcriptional signatures linked to oxidative stress resistance and metabolic adaptation. These findings suggest that even short-term probiotic colonization induces significant functional changes, underscoring the need for strategies to enhance probiotic persistence. Full article

Stem-cell behavior is governed not solely by intrinsic genetic programs but by highly specialized microenvironments—or niches—that integrate structural, biochemical, and mechanical cues to regulate quiescence, self-renewal, and differentiation. This review traces the evolution of stem-cell niche biology from foundational embryological discoveries to its current role as a central determinant in tissue regeneration and disease. We describe the cellular and extracellular matrix architectures that define adult stem-cell niches across diverse organs and dissect conserved signaling axes—including Wnt, BMP, and Notch—that orchestrate lineage commitment. Emphasis is placed on how aging, inflammation, fibrosis, and metabolic stress disrupt niche function, converting supportive environments into autonomous drivers of pathology. We then examine emerging therapeutic strategies that shift the regenerative paradigm from a stem-cell-centric to a niche-centric model. These include stromal targeting (e.g., FAP inhibition), which are engineered scaffolds that replicate native niche mechanics, extracellular vesicles that deliver paracrine cues, and composite constructs that preserve endogenous cell–matrix interactions. Particular attention is given to cardiac, hematopoietic, reproductive, and neurogenic niches, where clinical failures often reflect niche misalignment rather than intrinsic stem-cell deficits. We argue that successful regenerative interventions must treat stem cells and their microenvironment as an inseparable therapeutic unit. Future advances will depend on high-resolution niche mapping, mechanobiologically informed scaffold design, and niche-targeted clinical trials. Re-programming pathological niches may unlock regenerative outcomes that surpass classical cell therapies, marking a new era of microenvironmentally integrated medicine. Full article

Pre-metastatic niche (PMN) formation is a critical step in metastatic progression. However, the biological effects of subtherapeutic doses of ionizing radiation (SDIRs) following radiotherapy on this process remain unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIRs (3 × 0.3 Gy) on lung PMN development and metastasis upon SDIR exposure on days 8–10 post-tumor injection, followed by mastectomy and analyzed on day 24. SDIRs significantly increased the total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, the SDIR acted as an early catalyst for niche priming, upregulating Bv8 expression, enhancing neutrophil recruitment, and increasing MMP9, S100A8, and Il6 production in the PMN by day 11. Moreover, SDIR drives metastasis through distinct mechanisms. Proteomic analysis revealed SDIR-driven metabolic reprogramming, with a shift away from fatty acid metabolism toward glycolysis and lipid accumulation within the PMN. This shift contributes to extracellular matrix (ECM) remodeling, immune modulation, and the upregulation of adhesion-related pathways, shaping a microenvironment that accelerates metastatic outgrowth. By reprogramming the pre-metastatic lung, the SDIR highlights the need to integrate organ-specific radiation exposure into metastasis models. Metabolic and immune-stromal pathways emerge as potential therapeutic targets, underscoring the importance of refining radiotherapy strategies to mitigate unintended pro-metastatic effects. Full article

Bacterial natural ecological niches are characterized by variations in the availability of nutrients, resulting in a complex metabolism. Their impressive ability to adapt to changeable nutrient conditions is possible through the utilization of large amounts of substrates. Recent discoveries in bacterial metabolism have suggested the importance of polyamine metabolism in bacteria, particularly in those of the order Actinomycetales, in enabling them to survive in their natural habitats. This makes such enzymes promising targets to inhibit their growth. Since the polyamine metabolisms of soil bacteria of the genus Streptomyces and the human pathogenic Mycobacteria are surprisingly similar, target-based drug development in Streptomyces and Mycobacterium spp. is an alternative approach to the classical search for antibiotics. The recent development of drugs to treat epidemic diseases like tuberculosis (TB) has gained attention due to the occurrence of multidrug-resistant strains. In addition, drug repurposing plays a crucial role in the treatment of various complex diseases, such as malaria. With that notion, the treatment of TB could also benefit from this approach. For example, molecular chaperones, proteins that help other proteins to fold properly, are found in almost all living organisms, including the causative agents of TB. Therefore, targeting these molecules could help in the treatment of TB. We aim to summarize our knowledge of the nitrogen and carbon metabolism of the two closely related actinobacterial genera, Streptomyces and Mycobacterium, and of the identification of new potential drug targets. Full article

Seamounts are distributed globally across the oceans and are generally considered oases of biomass abundance as well as hotspots of species richness. Diverse microbial communities are essential for biogeochemical cycling, yet their functional partitioning among seamounts with geographic features remains poorly investigated. Through metagenomic sequencing and genome-resolved analysis, we revealed that Proteobacteria (33.18–40.35%) dominated the bacterial communities, while Thaumarchaeota (5.98–10.86%) were the predominant archaea. Metagenome-assembled genomes uncovered 117 medium-quality genomes, 81.91% of which lacked species-level annotation, highlighting uncultured diversity. In the Nazuna seamount, which is located in the Marcus-Wake seamount region, microbiomes exhibited heightened autotrophic potential via the 3-hydroxypropionate cycle and dissimilatory nitrate reduction, whereas in the Magellan seamounts regions, nitrification and organic nitrogen metabolism were prioritized. Sulfur oxidation genes dominated Nazuna seamount microbes, with 33 MAGs coupling denitrification to sulfur redox pathways. Metal resistance genes for tellurium, mercury, and copper were prevalent, alongside habitat-specific iron transport systems. Cross-feeding interactions mediated by manganese, reduced ferredoxin, and sulfur–metal integration suggested adaptive detoxification strategies. This study elucidates how deep-sea microbes partition metabolic roles and evolve metal resilience mechanisms across geographical niches. It also supports the view that microbial community structure and metabolic function across seamount regions are likely influenced by the geomorphological features of the seamounts. Full article

Estuarine ecosystems, characterized by dynamic salinity gradients and complex physicochemical interactions, serve as critical transition zones between freshwater and marine environments. This study investigates the spatial evolution of sediment microbial communities across a freshwater–seawater continuum and their correlations with water quality parameters. Five sampling zones (upstream, midstream, downstream, transition zone, and ocean) were established in a typical estuary (Kuiyu Park, China). High-throughput 16S rRNA sequencing revealed significant shifts in microbial composition, with dominant phyla including Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Alpha diversity decreased from freshwater to the transition zone but rebounded in seawater, suggesting habitat filtering and niche differentiation. Redundancy analysis identified salinity, dissolved oxygen, nutrients, and heavy metals as key drivers of microbial community structure. Functional predictions highlighted metabolic adaptations such as methanogenesis, sulfur oxidation, and aerobic chemoheterotrophy across zones. This study explores how sediment microorganisms adapt to water quality variations during the freshwater–seawater transition, offering insights into estuarine resilience under global change. These findings elucidate microbial assembly rules in estuarine ecosystems and provide insights for ecological management under global environmental change. Full article

The Portuguese coast forms a key biogeographic transition zone where co-occurring kelp species show limited vertical overlap. This study aimed to understand whether temperature and light responses help explain the vertical niche differentiation of Laminaria ochroleuca, Saccorhiza polyschides, and Phyllariopsis brevipes. Results revealed that P. brevipes, despite occupying the southernmost range, showed a low thermal tolerance: 27 °C significantly increased respiration rates, indicating metabolic stress, and exposition at 30 °C caused physiological stress. In contrast, L. ochroleuca and S. polyschides exhibited a greater thermal resilience but displayed high light requirements, with evident stress at 30 °C. These results suggest that light availability may play a key role in shaping vertical zonation in a climate warming scenario, with species adapted to low light occupying deeper subtidal zones. S. polyschides, a high light-requiring species, dominates the shallow subtidal region, while L. ochroleuca, also high light-requiring and temperature-tolerant, is abundant in both intertidal pools and shallow subtidal habitats. These findings raise new hypotheses regarding future distribution patterns under climate change: while L. ochroleuca may continue expanding polewards and potentially replace other Laminaria spp. at shallow depths, low-light-adapted, cold-water species may retain a competitive advantage in deeper zones. Full article

Neutrophils, accounting for 50–70% of circulating leukocytes, exhibit remarkable plasticity in tumor biology. Depending on tumor type and microenvironmental cues, they can exert either anti-tumor or pro-tumor effects. During tumor initiation, neutrophils exposed to chronic inflammation secrete cytokines and oncogenic microRNAs that promote genomic instability and malignant transformation. In tumor progression, neutrophils adopt context-dependent phenotypes and execute diverse functions, including polarization into anti-tumor (N1) or pro-tumor (N2) subsets; secretion of inflammatory and angiogenic mediators; formation of neutrophil extracellular traps (NETs); production of reactive oxygen and nitrogen species (e.g., H₂O₂ and nitric oxide); and modulation of immune cell infiltration and function within the tumor microenvironment. During metastasis, neutrophils facilitate cancer dissemination through three principal mechanisms: (1) promoting epithelial–mesenchymal transition (EMT) via inflammatory signaling, adhesion molecule interactions, and lipid metabolic support; (2) establishing pre-metastatic niches by remodeling distant organ stroma through NETs and matrix metalloproteinases; and (3) reactivating dormant tumor cells in response to chronic inflammation, viral infection, or stress hormones. Collectively, neutrophils function as central regulators across all stages of tumor evolution, influencing cancer growth, immune evasion, and metastatic progression. This review aims to provide a comprehensive synthesis of neutrophil-mediated mechanisms in the tumor microenvironment and highlight emerging strategies for neutrophil-targeted cancer therapy. Full article