Search Results (32,592)

Cryptococcosis often begins in the lungs and may later reach the central nervous system, where it can lead to severe or fatal disease. The course of infection is shaped by changing interactions between host cells, fungal adaptive states, and local tissue environments. Many virulence factors and immune responses have been studied in detail, but the evidence remains divided across organs, cell types, and experimental systems. As a result, pulmonary infection is better understood than later stages, including dissemination, crossing of the blood–brain barrier, CNS involvement, and long-term persistence. In this review, we use a stage-resolved phenomic framework to connect host cell states, fungal adaptive phenotypes, and tissue niches throughout the course of infection. Evidence from multi-omics studies, spatial analyses, cellular experiments, animal models, and clinical cohorts is brought together to show how phenotypic features differ between stages and how uneven the current evidence base remains. The strongest evidence remains concentrated in pulmonary infection, whereas dissemination, crossing of the blood–brain barrier, and CNS disease are supported by more model-dependent data. Evidence for persistence and reactivation is the most limited. By organizing these findings into a disease-course map, this review outlines testable questions for biomarker discovery, host-directed therapy, and risk stratification in cryptococcal infection. Full article

Background and Objectives: Non-small cell lung cancer (NSCLC) comprises biologically distinct histologic subtypes, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We evaluated whether the prognostic association of cyclin-dependent kinase-like 2 (CDKL2) differs by histology. Materials and Methods: TCGA CDKL2 expression was linked to harmonized clinical data. The primary analysis used a pooled multivariable Cox model with continuous standardized CDKL2 expression, histology, and a CDKL2 × histology interaction, adjusted for age, sex, pathologic stage, and smoking. Additional analyses assessed model assumptions, tumor purity, tumor-versus-normal expression, KEGG pathways, the tumor microenvironment, and single-cell RNA sequencing. External evaluation used GSE30219. Results: The primary TCGA cohort included 943 patients (471 LUAD, 472 LUSC; 375 deaths). Higher CDKL2 expression was associated with lower mortality in LUAD (HR per 1 pooled SD = 0.721, 95% CI 0.603–0.862, p < 0.001) but higher mortality in LUSC (HR = 1.237, 95% CI 1.011–1.515, p = 0.039), with a significant interaction (HR = 1.717, p < 0.001) persisting after tumor-purity adjustment. CDKL2-low tumors were enriched for cell-cycle, DNA-replication, proteasome, and DNA-repair programs. Single-cell analyses showed predominant epithelial detection and greater malignant-cell CDKL2 detection in LUAD. In GSE30219, the favorable LUAD association was supported in a median-split-adjusted analysis of 207073_at (HR = 0.473, 95% CI 0.250–0.897, p = 0.022), whereas the corresponding continuous estimate was directionally favorable but nonsignificant; 236331_at was nonsignificant in both models; neither probe supported the adverse LUSC association or histology interaction. Conclusions: Higher CDKL2 expression showed a favorable prognostic association in LUAD, with consistent TCGA sensitivity analyses and limited but suggestive independent-cohort support. The adverse LUSC association remains preliminary, and CDKL2 should be regarded as a candidate prognostically associated marker rather than an established clinical biomarker. Full article

Background/Objectives: Osteoarthritis (OA) is a whole-joint disease, and cellular senescence is one of several processes associated with cartilage degeneration. This study aimed to identify senescence-associated differentially expressed genes in established OA and to examine checkpoint-related candidates without assuming a causal checkpoint-imbalance mechanism. Methods: Five Gene Expression Omnibus (GEO) datasets spanning articular-cartilage tissue and primary cartilage-derived chondrocytes (GSE57218, GSE117999, GSE114007, GSE246425, and GSE169077) were integrated as a training cohort; the meniscus dataset GSE98918 was reserved as an independent cross-tissue validation cohort. OA-associated differentially expressed genes (DEGs) were intersected with CELLAGE genes. Enrichment, protein–protein interaction, transcription-factor, competing endogenous RNA, drug-enrichment, and molecular-docking analyses were performed. CDK6 and WEE1 expression was evaluated in IL-1β-treated human C28/I2 chondrocytes by RT-qPCR and representative Western blotting. Results: Forty-one senescence-associated DEGs were identified, and seven network-central genes (CDKN1A, CDK6, WEE1, NFKB2, ID1, RBL2, and IGFBP7) were prioritized. CDKN1A, CDK6, and WEE1 were reduced in OA-associated meniscal samples in GSE98918; within-dataset ROC analyses yielded AUCs of 0.931, 0.882, and 0.792, respectively. In IL-1β-treated C28/I2 cells, WEE1 mRNA decreased whereas CDK6 mRNA increased; representative immunoblots showed concordant qualitative trends. Berberine- and folic acid-related docking findings were computational only. Conclusions: Checkpoint-related gene expression is associated with senescence-linked transcriptomic changes in established OA. The discordant CDK6 results between clinical tissue datasets and an acute inflammatory cell model do not establish stage-dependent regulation. The present data also do not demonstrate p53-mediated CDKN1A activation, checkpoint failure, cell-cycle arrest, or cellular senescence; these hypotheses require dedicated functional experiments. Full article

Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action—paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs—while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood–brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies—MSCs as adjuncts to gene or enzyme replacement therapy—and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice. Full article

Total flavonoids (TF) from Artemisia argyi, a traditional edible-medicinal Asteraceae herb, were extracted via a food-grade ternary deep eutectic solvent (TDES, Glycerol/Levulinic Acid/Xylitol = 1:1:1 molar ratio, 30% w/w water) under ultrasound assistance. A hybrid response surface methodology–genetic algorithm–artificial neural network (RSM-GA-ANN) model optimized parameters to deliver a maximum TF yield of 107.7 mg/g—1.5–1.8-fold higher than conventional hydroalcoholic extraction. Greenness was quantified by AGREEprep (score = 0.70) and MoGAPI (score = 80/100), confirming the method’s sustainability, with TDES retaining >84% extraction efficiency over three reuse cycles. Molecular dynamics simulations revealed TDES forms a more stable hydrogen bond network with plant cell walls (average H-bond lifetime: 101.279 ps vs. 46.698 ps for 50% ethanol), a finding validated by density functional theory calculations showing TDES establishes 7–9 hydrogen bonds with cellobiose (the cellulose repeating unit), far exceeding ethanol’s 1–2 hydrogen bonds. Purified TF exhibited potent radical-scavenging activity (DPPH IC₅₀: 0.176 mg/mL; ABTS IC₅₀: 0.159 mg/mL) and multipotent enzyme inhibition (α-glucosidase IC₅₀: 55.31 μg/mL; acetylcholinesterase IC₅₀: 0.618 mg/mL; pancreatic lipase IC₅₀: 0.125 mg/mL). TF also suppressed HCT116, A549, and HepG2 proliferation (IC₅₀ ≈ 50 μg/mL) and protected HepG2 cells against H₂O₂-induced oxidative damage. As an in silico probe, the predominant quantified flavonoid eupatilin (3.64 mg/g) docked to xanthine oxidase (−7.78 kcal/mol vs. allopurinol −6.86), offering a structural hypothesis for XO interaction without attributing mixture bioactivity to a single compound. This TDES-based platform offers a scalable, green route to valorize A. argyi for functional food and nutraceutical applications. Full article

Bacterial diseases caused by Flavobacterium covae (Fc), Vibrio harveyi (Vh), Vibrio vulnificus (Vv) and Photobacterium damselae (Pd) seriously constrain Asian seabass aquaculture. Here we dissect the mucosal immune mechanisms engaged by a five-month sequential vaccination strategy that combines nanoemulsion immersion priming with multivalent oral hydrogel boosting. Juvenile seabass were vaccinated, then challenged with F. covae by freshwater immersion and with a Vibrio–Photobacterium (Vh/Vv/Pd) mix by immersion or intraperitoneal injection. Gills were sampled after immersion challenges and intestine after injection, and profiled by RNA sequencing and label-free quantitative proteomics, with selected genes validated by RT-qPCR. Principal component analysis showed clear separation of vaccinated and control fish in all tissues and challenges, indicating a strong and coherent transcriptional reprogramming. Vaccination markedly increased the number of upregulated genes, with Gene Ontology enrichment revealing dominant signatures of ribosome biogenesis, RNA processing, lysosomal organization and immune response. KEGG analysis highlighted cytokine receptor interaction; NOD and Toll-like receptor signaling; oxidative phosphorylation; and phagosome, lysosome and cell adhesion molecule pathways, consistent with heightened antimicrobial readiness. Volcano plots and focused heatmaps showed strong induction of interferon-stimulated genes, cytokines and chemokine receptors, complement components, macrophage mannose receptor, epithelial barrier mediators and numerous immunoglobulin transcripts, with tissue- and challenge-specific patterns. Proteomics corroborated these trends, demonstrating a higher abundance of immunoglobulin heavy chains, complement proteins, cathepsins, heat shock and redox chaperones, ribosomal proteins and cytoskeletal and adhesion regulators in vaccinated mucosae. Integrated pathway mapping linked endothelial adhesion molecules and leukocyte integrins with T cell costimulation networks and an intestinal immune network for immunoglobulin production, including enhanced pIgR-mediated transcytosis. Overall, the sequential vaccination regimen was associated with coordinated transcriptomic and proteomic signatures related to epithelial responses, innate immunity, and humoral immune functions across gill and intestinal tissues. These molecular patterns were accompanied by improved survival following bacterial challenge; however, the present data do not directly demonstrate the functional activity of the inferred immune mechanisms in Asian seabass. Full article

Microplastics and nanoplastics (MNPs) have emerged as widespread environmental contaminants, with increasing evidence suggesting that chronic exposure may adversely affect human health. Experimental and emerging human studies indicate that MNPs can interact with multiple biological systems and trigger a range of mechanisms, including oxidative stress, mitochondrial dysfunction, cellular injury, barrier disruption, and immune and inflammatory responses. These effects may involve direct interactions with tissues and cells as well as indirect pathways, including alterations in gut microbial and intestinal homeostasis. In turn, persistent inflammatory and metabolic disturbances may contribute to tissue dysfunction and the development or progression of chronic diseases. This narrative review summarizes current evidence on the biological effects of MNP exposure, focusing on the mechanisms linking environmental exposure to chronic inflammation and disease. We discuss their potential involvement in cardiovascular, liver, kidney, respiratory, and neurological diseases, while highlighting the emerging role of the gut microbiota and intestinal barrier as potential modulators of these effects. Given the limitations of current human evidence and the heterogeneity of experimental models, we also discuss major knowledge gaps and the need for further mechanistic and epidemiological studies to clarify the clinical relevance of chronic MNPs exposure. Full article

Hepatocellular carcinoma (HCC) remains difficult to control because recurrence, impaired hepatic reserve, and treatment resistance limit durable benefit. Natural products and traditional Chinese medicine (TCM) provide resources that range from drug-lead discovery to adjunctive multicomponent therapy. This review integrates pharmacological and clinical evidence for purified compounds, semisynthetic derivatives, extracts, formulas, and delivery systems. It focuses on metabolic reprogramming and redox homeostasis, stress responses and regulated cell death, tumor cell plasticity and vascular remodeling, and the immune microenvironment and host response. Recent studies have strengthened selected mechanistic claims through chemical probes, functional perturbation, and resistance models. Clinical research has concentrated on recurrence control after surgery or minimally invasive treatment and on combinations with transarterial chemoembolization, targeted agents, and immunotherapy. Randomized trials and prospective cohorts suggest potential benefit in specific settings, although product standardization, external validation, and long-term follow-up remain limited. Major translational barriers include uncertain active constituents, inadequate batch comparability, missing tumor-exposure data, and sparse herb–drug interaction studies. Future development should match target validation, pharmacokinetics, safety assessment, and clinical endpoints to each product class and clarify whether a candidate is best positioned as a drug lead, adjunctive therapy, or supportive intervention. Full article

Immune checkpoint inhibitor-induced immune thrombocytopenia (ICI-ITP) is a rare but severe adverse event that may lead to bleeding complications and may require therapeutic changes or interventions. The clinical condition and interventions are highly complex; there are certainly tumour-type and combination-therapy differences, as well as individual ICI-agent factors that modify the risk of thrombocytopenia. ICI-ITP shares some common features, even though its pathogenesis differs markedly from that of traditional ITP. However, ICI-ITP is a clinically important complication; a deeper analysis of factors related to ICI–platelet interactions is also necessary. White blood cell–lymphocyte and platelet count ratios may have prognostic value in predicting the development of a low platelet count. Platelet counts themselves might influence the effectiveness of ICI-type anticancer interventions by facilitating T-cell-induced neoexpression of PD-1 on platelet surfaces. Baseline platelet counts and immunoglobulin levels may also modify treatment outcomes. Platelet activation can also promote immune-related adverse events. ICI-induced ITP-like syndrome’s prognostic factors are not only experimental facts but also clinically important. The connections among platelet counts, activation, immunoglobulins, and cell ratios are likely important factors influencing ICI-induced ITP risk reduction and the improvement of tumour-directed immune response by tailoring ICI selection to tumour type and specific baseline cellular characteristics. Full article

Diabetes mellitus results from insulin resistance, progressive pancreatic β-cell dysfunction, dysregulated hepatic and adipose metabolism, oxidative stress, and inflammation. Plant-derived compounds can modulate several of these processes, yet pharmacological breadth does not necessarily produce a reproducible therapy. This critical narrative review links phytochemical identity and product composition to intestinal carbohydrate digestion, insulin secretion, hepatic glucose production, GLUT4 trafficking, AMPK and PPARγ signaling, the incretin–DPP-4 axis, renal glucose handling, and diabetic organ injury. Alkaloids, flavonoids, phenolic acids, tannins, saponins, and polysaccharides are considered alongside evidence concerning nephropathy, neuropathy, ocular disease, hepatopathy, and cardiomyopathy. Controlled human studies provide product-specific signals, particularly for chemically defined berberine preparations and mulberry alkaloids, whereas most other interventions remain supported by small, short, or chemically undercharacterized trials. The strongest candidates are those for which defined chemistry, plausible exposure, mechanism, and controlled clinical findings converge. Progress requires authenticated raw material, validated analytical fingerprints, pharmacokinetic and toxicological characterization, herb–drug interaction testing, and trials using the same standardized product. These interventions should remain supervised adjuncts or drug-discovery leads rather than substitutes for established diabetes treatment. Full article

Industrial fermentation relies on mechanically agitated submerged culture, in which impeller-driven mixing improves oxygen and nutrient transfer but imposes an energy penalty and a hydrodynamic shear field that stresses cells. Solid supports offer an agitation-free alternative, yet their surface is typically ill-defined and only a single polymer and a single organism have been examined. Here we treat the support material as a controllable process variable. Using an identical scaffold geometry 3D-printed by fused-deposition modeling in four thermoplastics—ABS, TPU, PLA, and PETG—we compared static cultivation of a model yeast (Saccharomyces cerevisiae) and a model lactic acid bacterium (Lactobacillus plantarum) against shaken and static controls, and related the outcomes to polymer surface wettability. For S. cerevisiae, embedding a matrix in static medium nearly doubled biomass relative to the static control and drove glucose to near-complete assimilation, raising ethanol titres ~1.7–1.8-fold to shaken-culture levels without any agitation. For L. plantarum, three of the four matrices (PLA, ABS, PETG) exceeded both the static and the aerated shaking controls in biomass (by ~15–21%) and in lactic acid production, while the elastomeric TPU behaved like the controls. Because L. plantarum is microaerophilic, these results suggest that factors other than improved aeration, including interactions at the scaffold–liquid interface, contribute to the observed enhancement. The polymer type thus emerges as a tunable parameter for scaffold-assisted cultivation, enabling fermentation without mechanical agitation while achieving performance comparable to, and in some cases greater than, that of shaken culture. The polymer type thus emerges as a tunable determinant of performance, defining an agitation-free cultivation strategy in which the interface—rather than bulk flow—is engineered to achieve, and in some cases surpass, the productivity of conventional stirred culture. Full article

Fusarium sacchari is one of the major pathogenic fungi that cause sugarcane Pokkah Boeng disease (PBD). Effectors play pivotal roles in F. sacchari–sugarcane interaction; thus, characterizing these effectors is essential for elucidating the molecular mechanisms underlying F. sacchari pathogenicity and for developing effective strategies to control PBD. However, only a limited number of effectors have been functionally validated to date. Here, we report FsRGAE1, a candidate effector protein from F. sacchari predicted to encode a rhamnogalacturonan acetylesterase (RGAE). FsRGAE1 exhibits high expression during the early stages of infection and maintains relatively elevated expression levels throughout the F. sacchari–sugarcane interaction. Targeted deletion of the FsRGAE1 gene in F. sacchari had no discernible impact on mycelial growth, conidiation, or carbon-source utilization, yet it significantly attenuated fungal virulence. FsRGAE1 possesses both a signal peptide conferring secretory capacity and a transit peptide enabling its translocation into the host cytoplasm and nucleus. Using the Agrobacterium tumefaciens-mediated transient expression system in Nicotiana benthamiana, FsRGAE1 was confirmed to suppress cell death induced by Bcl-2-associated X protein (BAX), as well as ROS accumulation and callose deposition, and its nuclear localization is indispensable for this immunosuppressive activity. Collectively, these findings indicate that FsRGAE1 promotes F. sacchari virulence by suppressing host immune responses in a nuclear localization-dependent manner, providing new insights into effector-mediated F. sacchari pathogenesis and potential target for resistance breeding in sugarcane. Full article

The biological fate of lipid-based nanocarriers (LBNs) is shaped at the interface. Whereas core architecture governs cargo loading, protection, and baseline release, surface architecture mediates the carrier’s initial interactions with proteins, cells, extracellular matrices, and tissue barriers, thereby influencing colloidal stability, immune recognition, targeting, biodistribution, barrier transport, and release initiation. Layer-by-layer (LbL) engineering provides a modular strategy for programming this interface through sequentially assembled coatings in which functional components are spatially separated yet mechanistically coordinated. By integrating polymers, biomolecules—including peptides and nucleic acids—and stimuli-responsive materials, LbL systems can decouple functions that are difficult to regulate independently within conventional single-layer or compositionally mixed surface architectures. This review examines recent advances in LbL-engineered LBNs (LbL-LBNs), focusing on how multilayer surface architecture reshapes physicochemical properties, cargo localization and release, biological identity, cellular interactions, and transport across physiological barriers. Particular attention is given to the multilayer interface as a dynamic biointerfacial bridge between a cargo-specific core architecture and the surrounding biological environment, including its capacity for stimuli-responsive switching in pathological microenvironments. The discussion further extends to biomimetic hybrid interfaces and establishes a framework for translating hierarchical surface architectures into reproducible, clinically tractable platforms for precision therapeutic delivery. Full article

Nonylphenol (NP) is a chemical compound belonging to the class of alkylphenols (APs), known for its widespread environmental distribution and endocrine-disrupting properties. It is commonly used in the production of detergents, pesticides, and plastic materials and, owing to these properties, it can accumulate in both aquatic and terrestrial ecosystems. As a xenoestrogenic compound, NP can bind steroid receptors, including estrogen receptors (ERs), thereby activating ER-dependent pathways. In this work, we investigated the effects of NP alone and in combination with the endogenous hormones 17β-oestradiol (E2) and/or testosterone (T) on a human non-tumoral prostate cell line (PNT1A). Cell viability and migration assays, together with analysis of ER expression and localization, were carried out to assess the xenoestrogenic activity of NP, particularly in the presence of E2 and T. Our results showed that NP retained its endocrine-disrupting features in the mixtures, positively affecting cell viability, except for the NP+E2 mixture, in which cell viability did not significantly differ from control, suggesting an antagonistic interaction between NP and E2. The mixtures also interfered with steroid receptor dynamics, affecting receptor expression and delaying receptor localization and activation kinetics. Moreover, all mixtures negatively affected cell migration compared with treatment with endogenous hormones alone. In conclusion, our results demonstrate that NP retains its xenoestrogenic behavior in mixture, inducing a significant alteration in prostate cell homeostasis. Full article

Specific niche signals play a vital role in supporting the proliferation and differentiation of neural stem cells (NSCs) throughout neural development and neural regeneration. Glial cells, including astrocytes and microglia, are key components of the stem cell niche. However, their interactions with NSCs remain poorly understood. To explore these interactions, primary NSCs isolated from rat embryos were cultured in either glial cell-derived conditioned medium (CM) or co-cultured with mixed glial cells via Transwell inserts. NSC viability, proliferation, differentiation, and the underlying mechanism involving BMP4 signaling were evaluated. Results showed that microglia and astrocytes were closely localized with NSCs in the subventricular zone (SVZ) of rat brains at postnatal day 14. After being cultured with CM or glial co-culture, NSC viability and astrocytic differentiation were significantly enhanced, while cell proliferation and neuronal differentiation were reduced. BMP4 secretion by both astrocytes and microglia as well as Smad1/5/8 and Stat3 phosphorylation in NSCs was also elevated, indicating that the BMP4–Smad1/5/8 signaling pathway was involved in the effects of the glial cell niche on NSC behaviors. These findings suggest that glial cells regulate NSCs’ fate through BMP4-mediated signaling, providing potential targets for future therapeutic strategies in neurogenesis and regeneration. Full article