Search Results (1,404)

Successful embryo implantation requires dynamic, bidirectional communication between a developmentally competent blastocyst and a receptive endometrium, integrating hormonal, molecular, and immunologic signals. Increasing evidence indicates that endometrial receptivity is critically dependent on a specialized immune microenvironment that supports trophoblast invasion while maintaining maternal tolerance. This review synthesizes current knowledge on the immunologic regulation of implantation, with emphasis on uterine natural killer (uNK) cells, regulatory T cells (Tregs), macrophages, dendritic cells, and cytokine networks. We further examine intracellular signaling pathways—including JAK/STAT, PI3K/AKT, NF-κB, and MAPK—that integrate immune and decidual responses. The bidirectional embryo–endometrium dialogue is explored through embryo-derived mediators such as human chorionic gonadotropin (hCG), cytokines, growth factors, and extracellular vesicles. The endometrium is increasingly recognized as a biosensor of embryo quality, selectively supporting viable embryos. Disruption of this complex communication network is implicated in recurrent implantation failure and early pregnancy loss. Despite substantial mechanistic advances, clinical translation remains limited. Emerging strategies, including immune profiling, microbiome modulation, and extracellular vesicle-based diagnostics, hold promise for precision reproductive medicine. Full article

Polycythemia vera (PV) is a JAK2V617F-driven myeloproliferative neoplasm characterized by erythroid expansion, increased thrombotic risk, and heterogeneous clinical outcomes. Although prior studies have described key transcriptional abnormalities—including Janus kinase–signal transducer and activator of transcription (JAK–STAT) hyperactivation and chronic myeloinflammation—most have examined single hematopoietic compartments. A multi-compartment approach may reveal conserved and lineage-specific disease-associated transcriptional programs. Here, an integrated, multi-compartment transcriptomic analysis of publicly available microarray datasets was performed, spanning bone marrow (BM) CD34+ progenitors, peripheral blood (PB) CD34+ progenitors, and whole blood from PV patients and healthy controls, with independent validation in neutrophils. Differential gene expression, pathway enrichment, and protein–protein interaction network analyses were used to delineate conserved versus compartment-specific transcriptional programs and to evaluate persistence of progenitor-derived signatures into mature myeloid cells. Across compartments, PV demonstrated consistent enrichment of inflammatory, interferon, and JAK–STAT-associated pathways despite limited overlap at the individual gene level, indicating that core disease processes are maintained through lineage- and differentiation-stage-specific transcriptional reprogramming. Network analysis identified highly connected hub genes, which were used to derive a single-sample gene set enrichment (ssGSEA) signature. This signature showed strong diagnostic performance across cohorts; remained enriched in PV neutrophils; and correlated with platelet count, indolent disease status, and reduced levels in post-splenectomy patients. Together, these findings support a model in which PV is driven by stable, progenitor-derived inflammatory programs that persist across myeloid differentiation while incorporating compartment-specific adaptations, and highlight the value of multi-compartment, network-based approaches for translational biomarker development. Full article

The dental pulp–dentin complex is a dynamic tissue system whose structure and biological functions evolve over time under physiological, molecular, and environmental influences. This study aimed to characterize age-related alterations in apoptotic, inflammatory, and autophagy-associated signaling pathways, alongside nanoscale mechanical changes, and to evaluate their potential impact on pulp tissue homeostasis and cellular adaptive capacity. Materials and Methods: Human teeth (n = 90) were divided into three age groups: young (≤17 years), mature (18–50 years), and old (>51 years). Immunohistochemistry was performed to assess the expression of CD34, BID, Caspase-8, NFκB, STAT3, JAK1, COX-2, LAMP2, and MAP LC3II. Nanoindentation and atomic force microscopy (AFM) were used to measure dentin hardness and modulus of elasticity. Results: BID expression increased with age, whereas Caspase-8 showed a relative decrease (p < 0.05). Anterior teeth exhibited higher marker positivity than molars for BID (p = 0.029), Caspase-8 (p = 0.004), STAT3 (p = 0.001), and JAK1 (p = 0.026). Mechanical analysis revealed the lowest modulus of elasticity in young root dentin and the highest in old coronal dentin, reflecting progressive age-dependent structural changes. Conclusions: Aging of the dentin–pulp complex involves coordinated modulation of apoptotic, autophagic, and inflammatory pathways, closely linked to altered mechanical properties. This interplay likely influences pulp vitality and adaptive cellular responses, highlighting potential targets for age-adapted dental therapeutic strategies. Full article

Computational clearing (CC) enhances widefield (WF) fluorescence microscopy by suppressing out-of-focus haze and autofluorescence, yielding semi-confocal quality images suitable for segmentation and image-based phenotyping. Here, we propose an “image tracing” workflow for inflammatory mouse intestinal organoids (mIOs) using paired CC and WF images to generate a differential signal (CC − WF). mIOs were derived from intestinal crypts of Lgr5-EGFP stem cell reporter mice and expanded under epidermal growth factor, Noggin, and R-spondin (ENR) conditions. Inflammation was induced by dextran sulfate sodium (DSS) treatment. CC processing enhanced phalloidin-stained apical F-actin and improved EGFP signals by reducing background noise, enabling robust segmentation and quantitative extraction of image morphometrics including area, circularity, and perimeter. CC-WF vectors derived from three-dimensional area–perimeter–circularity plots sensitively captured DSS-induced epithelial disruption analogous to a leaky-epithelium phenotype. Transcriptomic analysis by RNA-seq of DSS-treated mIOs revealed upregulation of inflammatory pathways including TNF-α signaling via NF-κB and IL-6/JAK/STAT3, aligning with microscopy findings. In a proof-of-concept demonstration using phalloidin-stained fluorescence images, ROC analysis of the CC-WF workflow achieved an AUC = 0.95 with 87.5% sensitivity and 92.9% specificity in distinguishing intact from injured mIOs. Full article

Insects represent powerful experimental systems for investigating host–microorganism interactions, providing valuable insights into bacterial pathogenicity, immune regulation, symbiosis, and antimicrobial discovery. This review examines the complex relationships between insects and bacteria, focusing on the mechanisms that control infection, immune activation, and microbial adaptation. Particular attention is given to the routes of pathogen entry and to the conserved innate immune pathways that coordinate host defenses, including the Toll, Imd, Duox, and Jak/Stat signaling cascades. The review illustrates how bacterial pathogens exploit toxins, immune evasion strategies, and metabolic adaptation to overcome host defenses, while insects rely on tightly regulated cellular and humoral responses, antimicrobial peptides, melanization, and microbiota-mediated homeostasis. Interactions between pathogenic and commensal bacteria in the insect gut are discussed in the context of immune tolerance, dysbiosis, and ecological adaptation. The dual role of bacterial virulence factors in both pathogenesis and symbiosis is highlighted through examples involving entomopathogenic bacteria such as Photorhabdus spp., Xenorhabdus spp., and Bacillus thuringiensis. In addition, the review summarizes the use of insect models, including Drosophila melanogaster, Galleria mellonella, Bombyx mori, and Apis mellifera, in experimental infections aimed at studying virulence mechanisms, host immune responses, and antimicrobial efficacy. Finally, multi-omic approaches, including transcriptomics, metabolomics, epigenomics, and single-cell technologies are discussed as transformative tools for dissecting host–microbe interactions at molecular and systems levels. Overall, insect–bacteria interactions emerge as dynamic and evolutionarily shaped systems in which immunity, metabolism, microbiota composition, and environmental factors are closely interconnected, offering important perspectives for both basic research and the development of sustainable biocontrol and antimicrobial strategies. Full article

Background/Objectives: We conducted the first pharmacogenetic investigation of atopic dermatitis in a cohort of 43 Greek patients, focusing on key variants within the IL6/JAK/STAT signaling axis, a pathway central to inflammation and therapeutic targeting. Methods: Patients receiving dupilumab, JAK inhibitors, or topical corticosteroids were prospectively evaluated, with treatment response assessed by changes in the Eczema Area and Severity Index over four months. Targeted genotyping of IL6R rs2228145 A>C, JAK1 rs2780815 T>G, and TRAF3 rs12147254 G>A were performed using PCR-RFLP. Results: Across the full cohort, no robust pharmacogenetic effects were detected, while baseline disease severity was the strongest predictor of absolute clinical improvement. However, stratified analyses revealed a significant association between the IL6R rs2228145 minor allele and reduced upadacitinib response (p-value = 0.026). Consistently, the same variant demonstrated a nominal association with reduced likelihood of achieving ≥75% improvement (p = 0.065). Conclusions: Although limited by sample size, these findings suggest potential treatment-specific pharmacogenetic effects within the IL6 pathway, supporting further investigation in larger cohorts to inform personalized therapeutic strategies in eczema. Full article

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF), a fatal and highly contagious disease, resulting in enormous losses to the global swine industry. No licensed vaccines or effective therapeutics are currently available to control ASFV infection. Interferons (IFNs) serve as key mediators of host antiviral immunity by inducing interferon-stimulated genes (ISGs), but the specific mechanisms by which individual ISGs restrict ASFV replication remain unclear. Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3, also called ISG60) has been shown to exhibit antiviral activity against various viruses, but its role in ASFV infection has not been previously studied. Here, we used porcine alveolar macrophages (PAMs), the primary target cells of ASFV, to investigate IFIT3’s function in ASFV replication. We found that overexpression of IFIT3 inhibited ASFV replication, while its knockdown enhanced viral propagation. Mechanistically, IFIT3 directly blocked ASFV adsorption to host cells, thereby suppressing all subsequent stages of the viral cycle. IFIT3 also specifically interacted with ASFV F334L, an early viral gene product that encodes the small subunit of ribonucleotide reductase, a key enzyme for viral DNA synthesis. Additionally, IFIT3 positively regulated the STAT1/TBK1/IRF3 signaling axis: its overexpression increased phosphorylation of TBK1 and IRF3, as well as the protein level of STAT1, while IFIT3 knockdown attenuated activation of these molecules. Transcriptomic analysis of IFIT3-knockout PAMs revealed significant suppression of innate immune pathways, including type I interferon, JAK-STAT, and RIG-I-like receptor pathways, along with downregulated expression of core antiviral molecules such as ISG15, MX1, and STAT1. Conversely, pathways related to viral adsorption, endocytosis, and cytoskeleton were activated, and pathways involved in protein translation initiation, endoplasmic reticulum stress, and autophagy were dysregulated, creating a favorable intracellular environment for ASFV replication. In conclusion, IFIT3 restricts ASFV replication possibly by inhibiting viral adsorption and promoting innate immune signaling, identifying it as a potential therapeutic target against ASFV. This study’s limitation is its in vitro PAM model; future work will validate IFIT3’s role in vivo and develop targeted inhibitors. Full article

Background/Objectives: Excessive dietary inorganic phosphate (Pi) as a food additive poses potential health risks. Methods: This study investigated the impact of excessive dietary inorganic phosphate on intestinal and immune homeostasis in mice using gradient Pi exposure combined with an inflammatory model. Results: Pi overload induced atrophy in the thymus, spleen, and kidney; damaged the intestinal barrier; reduced the villus height-to-crypt-depth ratio; and decreased goblet cell numbers. Altered levels of serum sIgA and IgE, as well as intestinal IgA, IgG, IgE, and IgM, together with decreased IFN-α, indicated altered levels of immunoglobulins and cytokines under Pi treatment. Proteomic analysis revealed differential expression of key proteins, including CNTFR and Bcl2l1 in the JAK/STAT pathway and metabolic regulators CPT1α and IDH1, when comparing Pi-treated mice with the control group. Conclusions: These preliminary findings suggest that Pi may affect intestinal mucosal barrier function and systemic immune response through immune regulation and mitochondrial metabolic pathways, providing preliminary insight into the potential health implications of Pi overconsumption in humans. Full article

Goose blood has anticancer properties and was recorded in ancient China, but the specific molecular mechanisms underlying this effect still require further exploration. In this study, SW1990 cells were treated with goose serum or plasma, and transcriptome analysis was performed to explore the function of goose blood on cancer cells. Metabolomic profiling was also performed on goose serum, goose plasma, chicken serum, and chicken plasma to identify the bioactive substances responsible for the anticancer effect. The study examined the effects of goose plasma and serum on SW1990 cells and compared the metabolites between goose and chicken blood. Wound scratch, CCK-8, and Annexin V-PI assays showed that goose plasma and serum inhibited SW1990 cell proliferation at 24 and 48 h. Both treatments reduced cell viability, with serum inducing early and late apoptosis and plasma inducing late apoptosis. RNA sequencing (RNA-seq) identified 2259 (1418 upregulated, 841 downregulated) and 2731 (1844 upregulated, 887 downregulated) differentially expressed genes (DEGs) in the plasma and serum groups versus the negative control (NC), respectively, and 689 DEGs between the plasma and serum groups. Gene Ontology (GO) and KEGG pathway analyses revealed that the DEGs were enriched in processes such as lipid metabolism, JAK-STAT, and IL-17 pathways. Untargeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis identified distinct metabolites in goose and chicken blood, with unique metabolites and differential ones between groups. In SW1990 cells, four metabolite subclusters matched the plasma and serum effects. In summary, goose blood can suppress cancer cells by regulating gene expression to affect the key signaling pathways involved in cancer cell apoptosis and autophagy. Certain metabolites present at high concentrations in goose blood, such as cucurbitacin D and Oleoyl-L-carnitine, may also contribute to the inhibition of cancer cell proliferation and migration. These findings suggest that goose blood holds broad application prospects as a future auxiliary drug for cancer treatment, and this study provides a theoretical basis for the further application of goose products. Full article

Suppressors of cytokine signaling (SOCSs) are negative feedback regulators of the JAK-STAT pathway and are often exploited by viruses to evade host antiviral immunity. Unlike other SOCS members, the role of SOCS2 in viral infection remains poorly understood. Here, we report that overexpression of silkworm SOCS2 isoforms, SOCS2L and SOCS2S, promotes Bombyx mori nucleopolyhedrovirus (BmNPV) replication at multiple stages, including viral DNA replication, late gene (VP39) transcription, and virion egress, while their knockdown suppresses these processes. Overexpression of SH2 domain mutants (R123Q in SOCS2S, R142Q in SOCS2L) reduced viral DNA replication to baseline and VP39 expression below baseline, drastically decreased infectious progeny titers, but unexpectedly increased viral DNA release to wild-type levels, suggesting that the SH2 domain may differentially regulate distinct steps of viral replication. Furthermore, SOCS2 isoforms, alone or cooperatively with BmNPV, modulate the mRNA levels of SOCS-STAT network members in an isoform-, dose-, and target-specific manner. Collectively, this study reveals for the first time the multiple proviral functions of silkworm SOCS2 isoforms, with differential effects on distinct stages of the viral life cycle, and highlights their potential as transcriptional modulators exploited by viruses for immune evasion. Full article

Since the first approval of CTLA-4 blockade for melanoma, immune checkpoint inhibitors (ICIs) have expanded into a major class of cancer therapy, with more than 100 FDA-approved oncological indications across metastatic and earlier-stage disease settings, including use as monotherapy and in combination regimens. Preclinical research has largely focused on myocarditis and atherosclerosis, but a wider set of phenotypes, such as non-inflammatory left ventricular dysfunction (NILVD), arrhythmias, and vasculitis, can be observed, and they are rarely connected within a single mechanistic model. We aim to build a systems-oriented, mechanistic framework of the most widely studied biological processes; it will link the main checkpoint pathways to relevant cardiac and vascular cell types, molecular pathways, immune synapses, and candidate biomarkers. We searched PubMed, Scopus, and Web of Science using combinations of terms for immune checkpoint inhibition and cardiovascular-immune-related adverse events that provide mechanistic insight into cardiac-immune-related adverse reactions (irAEs). An AI-assisted semantic clustering approach was used only to organize the included literature. The integrated framework identifies PD-1/PD-L1 as the dominant mechanistic hub linking T-cell activation, endothelial recruitment, myocardial injury, and vascular inflammation. Across phenotypes, a shared immune core involving checkpoint pathways, cytokine signaling, and leukocyte trafficking coexists with phenotype-restricted mediators that may bias injury toward myocarditis, vascular inflammation, conduction-system disease, or NILVD. KEGG analyses support the enrichment of T-cell receptor signaling, Th17 differentiation, JAK-STAT signaling, cytokine–cytokine receptor interaction, and lipid and atherosclerosis pathways. Candidate biomarkers emerging from the reviewed literature include troponin, IL-6, CXCL9/CXCL10/CXCL13, S100A family proteins, ROCK2, HLA-linked susceptibility signals, and T-cell receptor clonality markers. The AI-assisted clustering broadly recapitulated the expert-defined thematic structure while identifying finer semantic neighborhoods within the literature. This framework provides a support map for further hypotheses about toxicity patterns with current and next-generation checkpoint strategies on the cardiac system, while AI-assisted clustering provides a complementary method for organizing the literature rather than an independent source of biological inference. Full article

Objectives: This study aimed to elucidate the multi-target therapeutic mechanisms of Camellia sinensis phytochemicals in periodontitis using an integrative multi-scale molecular modeling strategy. Methods: An integrated in silico strategy was employed, incorporating network-based pharmacological analysis, protein interaction network evaluation, molecular docking assessment, density functional theory (DFT) computations, molecular dynamics (MD) trajectory analysis, MM/PBSA-derived binding energy estimation, and residue-level energetic contribution profiling. Overlapping targets between C. sinensis and periodontitis-associated genes were identified, followed by topological screening to determine crucial hub proteins. The most promising target was subjected to detailed structural and energetic evaluation. Results: Intersection analysis identified 23 common targets, with AKT1, myeloperoxidase (MPO), MMP2, MMP3, MMP9, STAT1, IL2, BCL2, ESR1, and SERPINE1 emerging as central hubs. Functional enrichment highlighted AGE–RAGE and JAK–STAT signaling pathways and extracellular matrix remodeling processes. Docking revealed MPO as the most favorable core target. Gallate-containing catechins, particularly (−)-gallocatechin gallate (−9.63 kcal/mol) and gallocatechin 3-O-gallate (−9.52 kcal/mol), exhibited more favorable binding affinities than the standard inhibitor 4-ABAH (−6.02 kcal/mol). DFT analysis demonstrated moderate HOMO–LUMO gaps (4.31–4.78 eV) and favorable dipole moments supporting electronic stability and reactivity. MD simulations confirmed stable complex formation over 100 ns, with persistent hydrogen bonding and consistent ligand retention. MM/PBSA calculations further validated a favorable binding of (−)-gallocatechin gallate (−27.66 ± 7.53 kcal/mol) and gallocatechin 3-O-gallate (−26.09 ± 8.96 kcal/mol), comparable to or exceeding 4-ABAH (−25.88 ± 4.44 kcal/mol). Conclusions: C. sinensis phytochemicals, particularly gallate-containing catechins, exhibit stable, energetically favorable interactions with MPO, supporting their potential as competitive inhibitors that modulate oxidative stress and inflammatory pathways in periodontitis. Full article

Cannabis-derived compounds are increasingly used as adjuncts in cancer therapy due to their reported antiproliferative and pro-apoptotic effects. However, potential drug–herb interactions with standard anticancer agents—namely sorafenib—remain unclear. This study investigated the interaction between cannabis and sorafenib, together with transcriptomic alterations in human hepatoma HepG2 cells. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the Combenefit program. RNA sequencing was performed to characterize gene expression changes across treatment groups. Combination analysis demonstrated concentration-dependent synergistic effects at intermediate doses. Transcriptomic profiling revealed that the combination treatment induced a broader and more distinct set of differentially expressed genes compared with single treatments. Integrated enrichment analyses showed consistent activation of stress- and inflammation-related pathways, including tumor necrosis factor-α via nuclear factor-kappaB (TNF/NF-κB), mitogen-activated protein kinase (MAPK), janus kinase/signal transducers and activators of transcription (JAK–STAT), oxidative stress, and p53-mediated apoptosis, alongside suppression of metabolic and proliferative processes. While several pathways were shared across treatments, the combination group exhibited a more coordinated transcriptional response, including enrichment of integrated stress response, cytokine signaling, endoplasmic reticulum stress, and epigenetic regulation. These findings were supported by increased reactive oxygen species production and apoptosis, particularly in the combination group. Overall, cannabis may potentiate sorafenib activity through enhanced cellular stress and anti-proliferative signaling. Full article

Signal transducers and activators of transcription (STAT) proteins, which operate via canonical and non-canonical mechanisms, are critically implicated in thyroid tumorigenesis. This review integrates their multifaceted roles in thyroid cancer. STAT3 acts as a “double-edged sword”: hyperactive STAT3 drives metastasis and BRAF inhibitor resistance in advanced carcinomas, yet paradoxically acts as a tumor suppressor by restraining the Warburg effect via non-canonical mitochondrial localization. Clinically, preserved nuclear STAT3 independently predicts a favorable prognosis and is inversely correlated with TERT promoter mutations, offering a biological modifier for clinical risk stratification. Furthermore, STAT1 regulates differentiation via the IGF2BP2-m⁶A axis, STAT5 drives proliferation upon release from TRβ suppression, and STAT6 confers chemoresistance. While novel direct STAT3 inhibitors (e.g., TTI-101) and rational combinations with immune checkpoint inhibitors or STING agonists show promise in overcoming refractory disease, the intricate dual functionality of STAT family proteins demands rigorous biomarker-guided precision medicine approaches. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), are increasingly recognized as key drivers of hepatocellular carcinoma (HCC). Unlike HCC caused by viral infections or alcohol, MASLD/MASH-related liver cancer develops within a chronic immunometabolic environment characterized by lipotoxicity, sterile inflammation, fibrogenesis, and remodeling of the microenvironment. In this setting, interleukin-10 (IL-10) has attracted growing attention due to its complex, context-dependent roles in immune regulation and tumor immune tolerance. This review explores IL-10 biology and its connection to MASLD/MASH-associated HCC, emphasizing the paradox that IL-10 may diminish harmful inflammation in early stages while promoting immunosuppressive conditions in advanced disease. To supplement existing research, we performed an exploratory reanalysis of publicly available bulk liver RNA-seq data from a mouse model that progresses from MASLD/MASH to HCC. The reanalysis revealed a receptor- and effector-specific rewiring of the IL-10 pathway: while the expression of canonical signaling genes (Stat3, Jak1, Jak2, Tyk2, Socs3) showed minimal changes across stages, receptor subunits (Il10ra, Il10rb) and IL-10-responsive effectors (such as Scd2, related to lipid metabolism, and Ddit4, involved in mTOR and glycolysis regulation) displayed strong stage-dependent induction. This was accompanied by a decrease in hepatocyte signature profiles and an increase in stromal and immune signatures. These results generate new hypotheses and raise key questions—particularly whether a large portion of IL-10 modulation originates from peripheral or non-parenchymal sources, and whether the transcriptional patterns observed reflect protein-level changes—that will require stage-specific, cell-focused human studies incorporating proteomic and cytokine measurements. Full article