Search Results (1,761)

Interferons (IFNs) are a family of cytokines which serve as the first line of defense against pathogen infections while also exerting critical immunomodulatory roles. IFNs can induce hundreds of IFN-stimulated genes (ISGs) with cell-specificity, yet a high-resolution comparison of time-serial ISG induction across cell types is lacking. By using RNA sequencing, we conducted a comparative transcriptomic profiling during time-serial IFN-γ stimulation for up to 24 h in HeLa and HEK293T cells, the two most widely used immortalized human cell lines. We uncovered remarkably stronger IFN responses in HeLa cells, regarding the global transcriptomic dynamics, the number of induced ISGs, and the level of ISG expression. Both cell lines share a core set of ISGs associated with canonical JAK-STAT signaling, yet HeLa uniquely activates additional inflammatory and adaptive immunity-related pathways. Despite the much weaker IFN response in HEK293T cells, we also identified a few HEK293T-specific ISGs, including several with crucial immune-related functions. Notably, transposable elements—including many adjacent to ISGs—are also highly up-regulated in HeLa cells, implying their potential links to ISG induction. Collectively, this study provides a high-resolution temporal atlas of IFN-γ-stimulated transcriptomic dynamics in HeLa and HEK293T cells, revealing the shared core module and cell-specific patterns of their interferon responses. Full article

Background: The specific mechanisms underlying the antihypertensive actions of corosolic acid (CA) have not been systematically elucidated. Methods: Evidence was categorized according to major signaling and physiological pathways, including the renin–angiotensin system (RAS), oxidative and inflammatory responses, endothelial and smooth muscle regulation (NO/cGMP and H₂S/K_ATP), and kinase-mediated signaling (AMPK, NF-κB, JAK/STAT, PKC). Results: Consistent with in vitro and animal studies, CA has been reported to attenuate pro-hypertensive signaling through multiple pathways: (i) downregulating renin–angiotensin system-related cascades; (ii) reduction in reactive oxygen species and inflammatory mediators through activation of AMPK and inhibition of NF-κB and JAK/STAT pathways; (iii) improved vascular tone by enhancing NO/cGMP signaling, partly involving the H₂S/K_ATP pathway, and inhibiting PKC. CA may indirectly contribute to blood pressure reduction by improving glucose and lipid metabolism and adipose tissue inflammation, thereby affecting metabolic risk factors. The existing evidence gaps include: lack of direct studies on voltage-gated, receptor-gated and store-regulated calcium channels; the specific effects on the isoforms of nitric oxide synthase (eNOS/iNOS/nNOS) and PKC are not known; limited human data on the antihypertensive efficacy, dose effect and safety of CA in humans are available. Conclusions: CA may have multi-targeted blood-pressure-lowering potential. Its clinical efficacy and safety require further confirmation. Full article

Background: Atopic dermatitis (AD) is a persistent and recurring skin disease characterized by epidermal barrier dysfunction, immune dysregulation, and elevated expression of proinflammatory mediators. We investigated the anti-inflammatory potential of polynucleotides (PN), highly purified DNA biopolymers isolated from salmonid gonads, in keratinocyte and macrophage activation models. Methods: RAW 264.7 macrophages were stimulated with lipopolysaccharide (LPS), whereas HaCaT keratinocytes were stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). The effects of PN treatment on the production or expression of inflammatory mediators, cytokines, and chemokines were evaluated. Changes in the phosphorylation of mitogen-activated protein kinases (MAPKs) and Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and in the nuclear localization of nuclear factor-κB (NF-κB) were also assessed. Results: In LPS-activated RAW 264.7 macrophages, PN treatment significantly suppressed nitric oxide production and downregulated the expression of inducible nitric oxide synthase (iNOS), TNF-α, IL-1β, and IL-8, accompanied by reduced NF-κB nuclear translocation. In TNF-α/IFN-γ-stimulated HaCaT keratinocytes, PN treatment markedly decreased the secretion levels of IL-6, IL-1β, and thymic stromal lymphopoietin. Moreover, PN treatment markedly reduced T-cell-recruiting chemokines, including MDC/CCL22, TARC/CCL17, RANTES/CCL5, and IL-8. Signaling analyses demonstrated that PN treatment attenuated the phosphorylation of key MAPKs (ERK, JNK, and p38) and the JAK1/STAT3 axis. Furthermore, PN treatment markedly reduced NF-κB nuclear translocation. Conclusions: These in vitro findings indicate that the anti-inflammatory effects of PN are associated with reduced activation of multiple core signaling pathways governing cytokine and chemokine responses, supporting further investigation of PN in AD and other chronic inflammatory skin diseases. Full article

The red-spotted grouper nervous necrosis virus (RGNNV) exhibits high pathogenicity in larval C. sonnerati, yet the immune molecular mechanism remains unclear. Non-coding RNAs (ncRNAs) are vital in the host’s immune responses during viral infection. However, there has been no study on ncRNA research for this species to date. We systematically identified 105 DE microRNAs (miRNAs), 157 DE long non-coding RNAs (lncRNAs) and 31 DE circular RNAs between the infection group and control group. Functional enrichment analysis revealed that these differentially expressed genes were significantly enriched in pathways associated with innate immune defense, inflammatory, and cell death, such as JAK-STAT signaling pathway, NF-κB signaling pathway, apoptosis, and necroptosis. Furthermore, the lncRNA–miRNA–mRNA interaction network involving miR-93 was constructed, which may represent a promising candidate therapy target for future investigations. This study presents the first comprehensive ncRNA transcriptome dataset of C. sonnerati infected with RGNNV, identifies key antiviral defense and cell death-related genes and hub pathways, and thereby identifies miR-93-involved lncRNA–miRNA–mRNA network and key targeted genes (STAT1, TRIM25, UNC93B, IL12RB1, IRF8, CDKN1A, FCGR1A) as hub molecular regulators in immune response of this species. Full article

Background: Ankylosing Spondylitis (AS) and inflammatory bowel disease (IBD) exhibit substantial pathophysiological overlap, including dysregulated innate immunity, barrier dysfunction, and Th17-mediated inflammation. However, whether Na⁺ overload-related genes (NRGs) exhibit shared transcriptional alterations in IBD and AS remains unclear. This study aimed to characterize the expression patterns of NRGs across IBD and AS and to identify candidate genes associated with both diseases. Methods: Differential expression analysis was performed to identify differentially expressed NRGs (DE-NRGs) in diseased tissues relative to normal tissues. Shared DE-NRGs between IBD and AS were screened and defined as common differentially expressed NRGs (Co-DE-NRGs). We then analyzed the correlations of these Co-DE-NRGs and explored their relationships with immune cell infiltration in target tissues. Four machine learning algorithms were applied to screen key NRGs associated with both IBD and AS. Potential therapeutic agents targeting these core biomarkers were predicted using drug–gene interaction databases, and molecular docking was conducted for further validation. Results: A total of 32 shared Co-DE-NRGs were identified for IBD and AS, with nine key regulatory NRGs recognized: CALR, CD63, CYBA, DYSF, HYOU1, IL1B, JAK1, MMP9, and STAT3. Exploratory MR analysis identified disease-specific associations between genetically predicted expression of NRGs and CD, UC, and AS. Genetically predicted STAT3 expression showed positive associations with CD and UC but an inverse association with AS and therefore did not represent a consistent risk factor across the three diseases. Furthermore, transcriptome-based drug-response analysis identified four candidate agents shared between AS and at least one IBD dataset: ciclosporin, BCL-LZH-4, BRD-K79669418, and CID-5951923. Exploratory molecular docking generated STAT3 binding poses for BCL-LZH-4 and CID-5951923, with DOCK Grid Scores of −35.321896 and −28.361128, respectively. CID-5951923 was selected for representative visualization of its predicted interaction with STAT3. Single-cell RNA-sequencing analysis identified tissue- and cell-type-specific STAT3 mRNA expression patterns in the analyzed IBD colonic and AS peripheral-blood datasets, with monocytes representing a major cell population exhibiting detected STAT3 expression in the AS dataset. Conclusions: These findings identify shared NRG-related transcriptional alterations in IBD and AS, with STAT3 emerging as a candidate gene associated with both diseases. Further experimental studies are required to determine whether these alterations reflect the involvement of NECSO and to evaluate their potential diagnostic or therapeutic relevance. Full article

Vernal keratoconjunctivitis (VKC) is a chronic pediatric ocular allergy that can progress from seasonal to persistent inflammation with vision-threatening complications. Although Th2-associated mechanisms have been implicated, the immune correlates of disease severity are not well defined. Tear samples from VKC patients (moderate intermittent and moderate persistent) and healthy controls were collected using Schirmer’s strips. Cytokine profiling was performed using the OLINK^® Target 48 Cytokine Panel. Differential expression, correlation with clinical features, and pathway enrichment analyses were performed. Compared to control, IL-15, CXCL11, CXCL9, MMP12, and CCL13 were significantly elevated in VKC, with higher levels in the persistent phenotype. These cytokines correlated with symptom duration, limbal involvement, and papillary hypertrophy. Pathway analysis revealed enrichment of IL-17, JAK–STAT, and chemokine signaling pathways. VKC severity is associated with distinct tear cytokine signatures, with the persistent phenotype showing enhanced chronic inflammatory signaling. These findings identify candidate tear-based markers of disease severity that require validation in larger, independent, and longitudinal cohorts. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated premalignant state defined by somatic mutations in hematopoietic cells at a variant allele frequency (VAF) ≥2% in the absence of overt hematologic malignancy. Among CHIP-associated mutations, JAK2 V617F is of particular interest because it occupies a dual biological and clinical role: it is both the principal driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs) and a clonal hematopoiesis variant conferring approximately 12-fold cardiovascular risk in selected cohorts, exceeding that reported for common DTA CHIP variants. Quantitative assessment of JAK2 V617F allele burden is therefore clinically relevant across the full disease continuum—from subclinical clonal expansion to MPN diagnosis, prognostic stratification, and therapeutic monitoring—as VAF thresholds correlate with disease phenotype, thrombotic risk, molecular response, and fibrotic progression. Digital PCR platforms, including droplet digital PCR (ddPCR) and chip-based digital PCR, have emerged as highly sensitive and reproducible methods for absolute JAK2 V617F quantification without the need for standard curves, with reported limits of detection as low as 0.01%. In this review, we synthesize current evidence on the molecular biology of JAK2-driven clonal hematopoiesis, the clinical significance of allele burden quantification, and the analytical performance of digital PCR compared with quantitative PCR and next-generation sequencing. We interpret these findings through a systems biology lens that draws together JAK-STAT signaling networks and thrombo-inflammatory pathways including inflammasome-dependent IL-1 signaling, clonal architecture, and bone marrow microenvironmental remodeling. We also discuss published quantitative models in which JAK2 V617F allele burden is treated as a dynamic state variable, while emphasizing that the present review offers a conceptual synthesis rather than a new computational model. We provide a structured comparative synthesis of published digital PCR analytical performance data, a stage-adapted proposal for clinical monitoring, and schematic models to guide future implementation. Overall, the evidence supports digital PCR as a precision tool for monitoring JAK2 V617F clonal dynamics across the CHIP–MPN spectrum, and points to several priorities: assay standardization, harmonized reporting, external quality assessment, and prospective clinical validation. Full article

Chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis, and chronic bronchitis, are characterized by persistent airway inflammation and mucus hypersecretion, leading to airway remodeling and progressive pulmonary dysfunction. Although current therapies improve disease control, they often fail to adequately target the complex molecular mechanisms underlying chronic airway diseases and may cause adverse effects during long-term use. Natural products have therefore emerged as promising multitarget therapeutic agents because they simultaneously regulate oxidative stress, inflammatory signaling, epithelial dysfunction, and mucus production. Recent evidence demonstrates that marine-derived bioactive compounds and plant-derived phytochemicals modulate key signaling pathways, including nuclear factor-kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (JAK/STAT), the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby suppressing airway inflammation, oxidative stress, goblet cell differentiation, and MUC5AC overexpression. Advances in nanoformulation, pulmonary drug delivery, multi-omics, artificial intelligence-assisted drug discovery, and network pharmacology are expected to accelerate clinical translation. Collectively, natural products represent promising candidates for the development of evidence-based functional foods, nutraceuticals, and novel therapeutic strategies for chronic respiratory diseases. Full article

The immune system is a critical system in evolutionary biology, shaped by coevolution between hosts and pathogens. The frog Xenopus is a valuable model organism for studying this process, offering insights into amphibian development, immunity, and the evolutionary dynamics of the interferon (IFN) response and viral interactions. The role of Xenopus IFN and the viral mimics introduced during the development of the immune system is discussed in this review, and the roles they played in the study of host–pathogen interactions and in the replication of genes that allowed the development and complexity of the immune system are reflected. We discussed the molecular mechanisms of Xenopus IFN signaling and the emergence of viral mimics in evolutionary biology. This review offers insight into how immune systems evolve under the pressure of pathogens, and the understanding of Xenopus IFN, its viral mimics, and that of other leading players in the vertebrate immune system may have further applications in medicine and biotechnology. Xenopus is a good model for studying the evolutionary dynamics of immune systems. In conclusion, this review posits that further elucidation of vertebrate immune adaptation mechanisms—particularly the evolutionary refinement of IFN-mediated antiviral restriction pathways, as demonstrated by Xenopus IFNs counteracting viral molecular mimics—will critically inform the rational design of next-generation antiviral pharmacotherapies, structure-guided vaccine adjuvants, and targeted immunomodulatory biologics. Full article

Background/Objectives: Adenomyosis is a chronic gynecological disorder characterized by the presence of endometrial tissue within the myometrium, causing pelvic pain, abnormal uterine bleeding, and infertility. Despite its high prevalence, the molecular mechanisms underlying disease initiation and progression remain incompletely understood. Current evidence implicates disruption of the endometrial–myometrial interface, epithelial–mesenchymal transition, and progesterone resistance in driving tissue invasion and remodeling. Diagnosis relies mainly on imaging modalities, while reliable non-invasive biomarkers are lacking. MicroRNAs, as stable post-transcriptional regulators of gene expression, have emerged as key modulators of proliferation, inflammation, and hormonal signaling, and represent promising candidates for novel diagnostic strategies. Methods: A systematic review was conducted in accordance with PRISMA guidelines and registered with PROSPERO (CRD42025637752). A comprehensive search of the Medline, Embase, Scopus, and Cochrane databases was performed in April 2025. Studies investigating miRNA expression in patients with adenomyosis compared with controls were included. The quality of the studies and the risk of bias were assessed using the Newcastle–Ottawa scale. Two reviewers independently performed study selection, data extraction, and quality assessment. Results: Twenty-seven studies published between 2015 and 2025 met the inclusion criteria. Thirty-nine distinct miRNAs were reported as significantly dysregulated in adenomyosis. Recurrently altered miRNAs included let-7a, miR-145, miR-10b, miR-30c-5p, miR-141-3p, miR-143, and miR-191. Functional analyses have consistently implicated miRNAs in key pathogenic pathways, including Hippo-YAP, PI3K/AKT, MAPK/ERK, JAK/STAT, and Wnt/β-catenin signaling. These alterations were associated with enhanced epithelial–mesenchymal transition, increased cellular proliferation and migration, progesterone resistance, chronic inflammation, and immune modulation. Emerging evidence highlights exosomal and circulating miRNAs as promising non-invasive biomarkers, with a few studies already demonstrating diagnostic potential using serum, plasma, or urine samples. However, substantial heterogeneity in tissue types, sampling timing, and analytical methods precluded meta-analysis. Conclusions: MiRNAs play a central role in the molecular pathogenesis of adenomyosis and show strong potential as non-invasive diagnostic biomarkers. However, large-scale validation studies and standardized methodologies are required before clinical implementation. Full article

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease defined by persistent synovial inflammation, progressive cartilage and bone erosion, and extra-articular manifestations. Current treatments, such as disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs), control disease activity but are limited by toxicity, reduced response over time, and are expensive, demonstrating the need for safer and more effective adjuncts. The marine environment is a rich, largely untapped source of structurally diverse bioactive molecules that could be used to develop new therapeutics. This review compiles current evidence on anti-inflammatory and immunomodulatory compounds from marine organisms relevant to RA, including macroalgae, true marine microalgae, marine microorganisms (bacteria and fungi, including deep-sea taxa), sea cucumbers, sponges, mussels, corals, and jellyfish. Recurring mechanisms of action include inhibition of the NF-κB, MAPK, and JAK/STAT signalling cascades; suppression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); reduced production of tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6; and activation of the Nrf2 antioxidant response. Particular attention is given to functional lipids (eicosapentaenoic and docosahexaenoic acids, prostaglandin-like oxylipins) and pigments (astaxanthin, fucoxanthin, β-carotene) from marine microalgae and heterotrophic protists, which recent literature identifies as the most clinically advanced marine leads. To clarify translational status, compounds are grouped by their development stage (marketed nutraceutical, clinical trial, or preclinical) and summarised in a dedicated table. Some compounds, such as green-lipped mussel extract, microalgal omega-3 oils, and astaxanthin, have reached the stage of randomised controlled trials for arthritis. However, most other potential treatments are still in the early, preclinical phase. It is worth noting that ocean-derived compounds appear generally safe, but more thorough studies, especially in living organisms and in clinical settings, are needed to confirm their effectiveness for rheumatoid arthritis before any claims can be made about their therapeutic benefits. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with a five-year survival rate of less than 12%. Oncolytic viruses are considered a promising immunotherapeutic approach, but their effectiveness is often limited by the innate interferon response, which is the main antiviral barrier in resistant tumors. A combination of an oncolytic virus with JAK/STAT pathway inhibitors has been proposed to overcome this resistance. Methods: In this study, we investigated the oncolytic and immunotherapeutic potential of the attenuated yellow fever vaccine strain YFV 17D in combination with the JAK1/JAK2 inhibitor ruxolitinib in a panel of six PDAC cell lines with diverse genetic profiles and JAK/STAT signaling activities and in a syngeneic immunocompetent PAN02 mouse model. Results: In vitro, we identified three distinct response patterns: synergistic enhancement of viral replication and cytopathic effect, lack of synergism due to absent interferon signaling, and increased viral replication without cytopathic effect. Despite different cell mutation profiles, the cell response patterns were determined by the basal JAK/STAT activity of each cell line rather than by specific KRAS or TP53 mutation. In vivo, the combination therapy significantly extended median survival compared to YFV 17D monotherapy and the control group and induced tumor regression in 62.5% of animals. Since no difference in intratumoral viral RNA was detected between the combination and monotherapy groups, we suggest that the antitumor effect in vivo was mediated not by enhanced viral replication, but by activation of adaptive immunity. This is indirectly suggested by increased intratumoral IL-12, a fourfold increase in CD8⁺ T cell infiltration, a reduction in CD4⁺ cells, and the generation of virus-neutralizing antibodies. No systemic cytokine surge, neurovirulence, or viral dissemination was observed, suggesting the safety of the proposed regimen. Conclusions: These findings clarify the immune mechanisms determining the efficacy of YFV 17D combined with ruxolitinib and establish the basis for personalized patient stratification by tumor interferon signaling status. Full article

Background/Objectives: Chronic exposure to endocrine-disrupting chemicals has been increasingly recognized as a potential contributor to cancer progression. Monobutyl phthalate (MBP), a major metabolite of dibutyl phthalate, is widely detected in human biological samples, yet its long-term impact on anaplastic thyroid cancer (ATC) has not been systematically investigated. Methods: CAL-62 cells were continuously exposed to an environmentally relevant concentration of MBP (10 nM) over 3 months to establish a chronic exposure model that mimics long-term environmental exposure. Transcriptomic profiling was integrated with network toxicology to identify key molecular pathways and hub genes, followed by molecular docking and Western blot validation. Results: Chronic MBP exposure significantly enhanced cell viability, proliferation, colony formation, and tumorsphere formation, indicating promotion of malignant phenotypes. Transcriptomic profiling revealed extensive molecular remodeling characterized by activation of inflammation-associated pathways, including cytokine–cytokine receptor interaction, IL-17, TNF, and JAK–STAT signaling, accompanied by suppression of p53- and mTOR-related pathways. Integrated analysis identified 57 overlapping KEGG pathways, with IL6 and CSF2 emerging as central hub genes. Molecular docking demonstrated favorable binding affinities between MBP and representative target proteins, including IL6, TP53, CASP3, BCL2, and PPARG. Western blot analysis further confirmed increased IL6 and BCL2 expression together with decreased TP53, CASP3, and PPARG expression following chronic MBP exposure. Conclusions: Chronic environmentally relevant MBP exposure promotes ATC malignant progression through coordinated inflammation-associated molecular network remodeling accompanied by suppression of apoptosis-related signaling. Integrating network toxicology with transcriptomic profiling provides an effective systems-level strategy for identifying biologically relevant molecular networks underlying chronic environmental toxicant exposure. Full article

While glucose-driven mitochondrial dysfunction has been proposed to promote vascular dysfunction responsible for saphenous vein graft failure (VGF) following bypass surgery, the impact of type 2 diabetes mellitus (T2DM) on mitochondrial function in human saphenous vein smooth muscle cells (HSVSMCs) responsible for maladaptive remodelling is unknown. Our aim was to identify signalling pathways that mediate any mitochondrial dysfunction in HSVSMCs in vitro and assess the impact of T2DM. HSVSMCs explanted from surplus HSV tissues from consenting T2DM and non-diabetic patients undergoing coronary artery bypass graft surgery were treated with known activators and inhibitors of the JAK/STAT and MAPK/ERK pathways. Following this, real-time oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measures of mitochondrial function were then determined. Our findings revealed that both IL-6/sIL-6Rα trans-signalling complexes and platelet-derived growth factor-BB (PDGF-BB) significantly increased OCR in HSVSMCs from T2DM patients but not non-diabetic controls. Meanwhile, only PDGF-BB increased ECAR in HSVSMCs from T2DM patients but not in non-diabetic controls. The observed increases in OCR and ECAR were abolished by JAK1/2-selective inhibitor ruxolitinib. Furthermore, thrombin caused a significant increase in OCR, specifically in HSVSMCs from T2DM patients, and this effect was abolished by the MEK1/2-selective inhibitor trametinib. Both ruxolitinib and trametinib significantly reduced basal OCR and ECAR in HSVSMCs from both T2DM and non-diabetic patients. Together, these findings demonstrate a JAK/STAT- and MAPK/ERK-mediated regulation of mitochondrial function in HSVSMCs. As such, they represent potential targets for regulation of HSVSMC function that can be explored for drug development to limit saphenous VGF in T2DM. Full article

Bactrocera dorsalis (Diptera: Tephritidae) ranks among the most serious quarantine pests threatening global fruit and crop production. Irradiation has been adopted worldwide as an eco-friendly phytosanitary treatment strategy, yet how B. dorsalis responds to irradiation is not fully understood. To investigate the transcriptional response to irradiation, third-instar B. dorsalis larvae were exposed to two X-ray doses: a sub-effective dose of 15 Gy and a phytosanitary dose of 120 Gy. Comparative transcriptomic profiling revealed a clear dose-dependent escalation in the number of differentially expressed gene (DEGs). While 15 Gy primarily disrupted basic metabolism and cuticle integrity, 120 Gy induced a systemic metabolic collapse coupled with severe genotoxic stress, activating DNA repair, lysosomal degradation, and the JAK-STAT signaling pathway. Notably, we identified nine dose-specific candidate biomarker genes that are exclusively regulated at the phytosanitary dose. These findings elucidate the molecular network mediating radiation-induced mortality and provide rapid molecular diagnostic tools for validating phytosanitary irradiation efficacy and optimizing pest management strategies. Full article