Search Results (4,417)

Background: Pyroptosis, a pro-inflammatory programmed cell death process, is a key player in tumor biology, including in triple-negative breast cancer (TNBC). Inhibiting G9a has been proven to exert anticancer effects; however, the molecular mechanism of the effects remains unclear. The study aimed to illustrate whether inhibiting G9a can suppress the process of TNBC cells by promoting pyroptosis and investigate the underlying mechanisms. Methods: MCF-10A, MDA-MB-231 and SUM159PT cell lines were used for in vitro study. CCK8 and EdU staining assay were used to examine the cell proliferation, and flow cytometry assay was performed to evaluate cell death. Inflammatory factors were measured by ELISA kits. The mRNA and protein expression levels were analyzed by qRT-PCR, Western blot, and immunofluorescence staining. Transmission electron microscopy was used to observe the morphological changes in cells. Results: We found that knockdown of G9a suppressed the growth and the abilities of invasion and migration, induced pyroptosis, and increased the expression of RIG-I, p-STAT1, and GSDME of TNBC. Furthermore, a RIG-I inhibition Cyclo (Phe-Pro) partially rescued the activation of pyroptosis enhanced by knockdown of G9a. Conclusions: These findings indicate that inhibiting the function of G9a induces pyroptosis in TNBC cells by the RIG-1/STAT1/GSDME pathway, which provides a new therapeutic target for TNBC treatment. Full article

Skin mast cells (MCs) play a vital role in acute allergic reactions and also contribute to chronic dermatoses partially through cytokine production. Key growth factors (GFs), such as SCF and IL-33, orchestrate MC survival and activity. Whether early responses differ between these factors remains incompletely defined. In the skin, MCs are long-lived and can proliferate outside the body but eventually exit the cell cycle. It remains unclear whether post-mitotic MCs show altered sensitivity to GFs. MCs were isolated from human foreskin and cultured in the presence of SCF + IL-4. GF-deprived cells were stimulated with either SCF or IL-33. Signaling events were determined by immunoblot. Gene expression was studied by RT-qPCR, cytokine release by ELISA, comparing dividing (3–4 weeks) with post-mitotic “aged” MCs (≥6 weeks). SCF strongly induced genes like FOS, EGR1, and NR4A2, while IL-33 was particularly effective at inducing JUN. IL-33 also prompted significant cytokine production (TNF-α, CCL1 and IL-13), whereas the activation of LIF was confined to SCF. SCF favored KIT, ERK, AKT, and STAT5 activation, whereas IL-33 preferentially stimulated JNK and p38 pathways. Although post-mitotic MCs showed diminished overall responsiveness to SCF, and with interesting differences among modules, their cytokine response to SCF remained comparable. Intriguingly, after exiting the cell cycle, MCs showed heightened sensitivity to IL-33, evidenced by increased ERK activation and TNF-α production. Collectively, IL-33 and SCF elicit markedly different early responses in human skin MCs. Chronic exposure to SCF reduces the responsiveness to this GF without eliminating their reactivity, while non-dividing MCs become more sensitive to IL-33, possibly as a compensatory adaptation. Full article

Marrow-isolated adult multilineage inducible (MIAMI) cells are a subpopulation of mesenchymal stem/stromal cells (MSC) with enhanced self-renewal, multilineage plasticity, and anti-inflammatory properties, suggesting that their extracellular vesicles (MIA-EVs) may confer advantages over conventional MSC-EVs. MIAMI cells were transcriptionally profiled and expressed regenerative markers, including PDGFRB, CDX2, and TERT. We report the first successful isolation and characterization of MIA-EVs. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, transmission electron microscopy, flow cytometry, and surface markers. Cargo analysis identified growth factors (IGFBP-1, HGF, VEGF-D) and 19 highly expressed miRNA targeting survival, regenerative, and immune regulatory pathways. MIA-EVs were efficiently internalized, enhanced keratinocyte wound closure and suppressed osteosarcoma proliferation in vitro. Conditioned MIA-EVs reshaped pathway weighting without altering core regulatory identity, as a conserved 15-miRNA backbone persisted across naïve, irradiated, and cytokine-primed states. In contrast, a 9-miRNA core shared with MSC-EVs defined a basal mesenchymal framework, while MIA-EVs expanded regenerative, survival, and immune network connectivity. Similar to embryonic stem cell (ESC)-EVs, both MIA- and cytokine-primed EVs promoted M2 macrophage polarization, selectively upregulating IL1R2 and PPARG/STAT1, respectively. Meanwhile, MSC-EVs induced heterogeneous responses. These findings establish MIA-EVs as a conditioning-resistant, systems-regulated, cell-free platform with regenerative, immunomodulatory, and cytoprotective potential under hostile microenvironments. Full article

LINC01270 is a long intergenic noncoding RNA implicated in the progression of various cancers. In our previous study, we demonstrated that LINC01270 plays a role in regulating the pro-inflammatory response in the THP-1 monocytic cell line, partly through modulation of NF-κB activation. Given the multifaceted nature of inflammation and the ability of noncoding RNAs to influence this process at multiple levels, we further investigated the potential role of LINC01270 in modulating additional inflammatory signaling pathways in lipopolysaccharide (LPS)-stimulated THP-1 cells. We found that attenuation of LINC01270 levels led to increased transcription and phosphorylation of STAT1, accompanied by elevated expression of the genes under STAT1 regulation. Further investigation revealed that LINC01270 regulates STAT1 expression via the miR-326/leucine zipper downregulated in cancer 1 (LDOC1) axis. Notably, inhibition of the interaction between LINC01270 and miR-326 effectively reversed the effects of LINC01270 knockdown on STAT1 expression and its downstream targets. Interestingly, both gain- and loss-of-function experiments with LDOC1 resulted in a consistent upregulation of STAT1 transcription. Taken together, our findings highlight a pleiotropic role of the LINC01270 in regulating the pro-inflammatory response through modulation of STAT1 signaling, in addition to its previously established role in NF-κB regulation. Furthermore, this study uncovers a novel function of the LDOC1 in inflammation through its regulation of STAT1. These findings provide new mechanistic insights into lncRNA–microRNA–protein interactions in inflammatory signaling and may open avenues for developing novel therapeutic strategies targeting chronic inflammatory diseases. Full article

Oncogenic kinase pathways, including PI3K/AKT, RAS/ERK/MAPK and JAK/STAT, are central drivers of cancer cell proliferation, survival and metastatic potential. However, excessive activation of these pathways imposes intrinsic cellular stresses, such as oncogene-induced senescence, DNA damage responses and apoptosis. Recent evidence reveals that cancer cells mimic immunoregulatory programs to mitigate these stresses by ectopically expressing inhibitory receptors traditionally found on hematopoietic cells. These receptors recruit phosphatases such as DUSPs, SHP1, SHIP1 and PP2A, which directly counteract hyperactivated kinases. Acting as dynamic homeostatic buffers, these phosphatases attenuate oncogenic signaling intensity, maintaining a balance that permits continued proliferation while preventing the activation of fail-safe tumor-suppressive mechanisms. This mechanism appears particularly relevant in metastasizing cancer populations, where elevated co-expression of inhibitory receptors and phosphatases correlates with survival advantage and adaptation under selective pressures. Understanding the dual roles of phosphatases, not only as classical tumor suppressors but also as modulators of signaling homeostasis, provides insight into cancer cell adaptation to oncogenic stress. Targeting the phosphatase–inhibitory receptor axis may selectively destabilize this balance, exposing vulnerabilities in aggressive, resistant or metastatic cancer cells. This review highlights emerging evidence for the phosphatase-mediated buffering of oncogenic kinase signaling, the molecular mechanisms underlying inhibitory receptor engagement and the clinical implications for tumor progression and therapy resistance. Full article

MicroRNAs (miRNAs) are essential post-transcriptional regulators of gene expression and have emerged as key modulators of host–pathogen interactions during bacterial infection. In this narrative review, we synthesize recent experimental and mechanistic evidence on how infection-responsive miRNAs shape innate and adaptive immunity, focusing on four representative pathogens: Salmonella, Listeria monocytogenes, Mycobacterium tuberculosis, and Helicobacter pylori. We highlight major miRNA-regulated signaling modules, including TLR/NF-κB, JAK–STAT, autophagy, immunometabolic reprogramming, and extracellular vesicle mediated intercellular communication, and summarize experimentally validated miRNA–target interactions that calibrate immune activation thresholds and inflammatory outcomes. Accumulating evidence indicates that miRNAs not only fine-tune host defense programs by controlling immune-related gene expression and immune cell activation, but can also be exploited by bacterial pathogens to suppress antimicrobial signaling and promote intracellular survival or persistent colonization. Collectively, these findings position miRNAs as a critical regulatory layer linking immune signaling networks to infection outcomes and underscore their translational potential as biomarkers and host directed therapeutic targets, while remaining grounded in current experimental evidence. Full article

Autoimmune ocular surface diseases represent a complex group of disorders in which systemic immune dysregulation triggers chronic inflammation, epithelial dysfunction, and progressive tissue fibrosis. Systemic lupus erythematosus, primary Sjögren’s syndrome, and ocular cicatricial pemphigoid are the principal entities linking systemic autoimmunity to ocular surface pathology. These conditions share convergent mechanisms—including dysregulated cytokine signaling (IFN-I, IL-6, and IL-17), complement activation, and epithelial–mesenchymal transition—culminating in tear film instability and visual impairment. Recent advances in molecular immunology and omics profiling have elucidated disease-specific pathways and identified actionable therapeutic targets. Conventional immunosuppressants such as corticosteroids and cyclosporine remain fundamental, yet emerging biologics targeting BAFF, IFNAR, and JAK/STAT signaling—alongside regenerative strategies employing mesenchymal and induced pluripotent stem cells—are transforming disease management. Parallel innovations in amniotic membrane transplantation, keratoprosthesis, and bioengineered corneal scaffolds integrate structural reconstruction with immune modulation. Furthermore, the convergence of multi-omics analytics, artificial intelligence-assisted diagnostics, and microbiome-based immunomodulation heralds a new era of precision ophthalmology. This review synthesizes current molecular insights, clinical observations, and translational advances that collectively redefine autoimmune ocular surface diseases—from chronic inflammatory disorders into a targetable, regenerative, and potentially reversible spectrum of conditions. Full article

Background: Chronic periodontitis is a prevalent inflammatory disease. It goes beyond the oral cavity, exerting systemic immunomodulatory effects through continuous low-grade inflammation, microbial dysbiosis, and cytokine spillover. Accumulating evidence suggests that the immunological consequences of periodontitis may influence systemic immune homeostasis and alter responses to cancer immunotherapies, specifically checkpoint blockade. Objectives: This narrative review describes how periodontal inflammation induces systemic immune reprogramming. It also investigates possible effects on the efficacy of immunotherapy. Methods: The paper synthesizes current findings on molecular and cellular mechanisms linking periodontitis to immune dysfunction. It underscores the mutual signaling pathways NF-κB, STAT3, and PD-1/PD-L1 that connect oral and systemic immunity. Results: Chronic periodontal inflammation reprograms innate and adaptive immune responses. It elevates proinflammatory mediators, such as IL-1β, IL-6, and TNF-α. It alters T-cell polarization and promotes myeloid cell “training”. This process may lead to immune exhaustion, impaired antigen presentation, and treatment resistance. Preclinical and new clinical data suggest that controlling periodontal inflammation may partially reduce systemic inflammatory burden, although clinical evidence in immunotherapy-treated cancer cohorts remains limited. Conclusions: Periodontal health should be considered in the management of immunotherapy. This can facilitate new studies that integrate oral and systemic immunology. Understanding the two-way link between periodontal inflammation and systemic immune reprogramming may offer fresh opportunities for personalized immunomodulation and combined interventions. Full article

Interleukin-37 (IL-37) is an anti-inflammatory cytokine with an undefined role in chronic endometritis (CE). This study aims to explore its therapeutic mechanism in CE, focusing on epithelial-mesenchymal transition (EMT) and macrophage polarization. A CE model was induced in Sprague-Dawley rats using lipopolysaccharide (LPS), followed by intervention with TAT-fused recombinant IL-37. Histological damage and fibrosis were evaluated through H&E and Masson staining. Immunofluorescence staining was performed to assess the expression of IL-37 and EMT markers (E-cadherin and vimentin) and macrophage phenotypes (M1: CD86⁺; M2: CD206⁺). In vitro, transwell, qPCR, Western blot, and flow cytometry analyses were performed to determine the effects of IL-37 on EMT and macrophage polarization. The activity of the STAT6 and Smad3 pathways was evaluated using Western blotting, dual-luciferase assays, and immunofluorescence staining. The results revealed that IL-37 accumulated in the injured uterus, alleviating inflammation, tissue damage, and collagen deposition. IL-37 reduced epithelial migration and reversed abnormal EMT by upregulating E-cadherin expression and downregulating vimentin expression. It also suppressed M1 macrophage infiltration and promoted M2 polarization. Mechanistically, IL-37 coactivated the STAT6 and Smad3 pathways, thereby increasing their phosphorylation and nuclear translocation and elevating ARG1 expression. In conclusion, IL-37 mitigates CE by suppressing EMT and promoting M2 macrophage polarization via coordinated STAT6/Smad3 activation, highlighting its therapeutic potential for CE. Full article

Acute ischemic stroke (AIS) is a leading cause of long-term disability and death. The genetic, epigenetic, and molecular mechanisms underlying AIS in young adults require further investigation. Inflammatory pathways, such as the programmed death-ligand 1 (PD-L1) and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway, are implicated in promoting post-ischemic neuroinflammation and neuronal apoptosis. While miR-155 and miR-216a are mediators of inflammation, apoptosis, and tissue repair following AIS. This exploratory study aimed to analyze the expression of the JAK2/STAT3, miR-155, and miR-216a genes in young AIS patients (mean age: 39.4 ± 11.9 years) versus the healthy population (HP). Peripheral blood samples were collected, and gene and miRNA expressions were measured using quantitative real-time PCR. Our results showed that stroke patients exhibited overexpression of all genes (p < 0.001), except for miRNA-216a (p = 0.061), compared to HP. These findings suggest that JAK2, STAT3, and miR-155 could be potential biomarkers for patients with AIS. Full article

Background: The tumor microenvironment (TME) is a dynamic ecosystem that critically shapes tumor progression, immune escape, and therapeutic responses. Hedyotis diffusa Willd (HDW) has long been used in East Asian medicine for conditions associated with inflammation and malignancy, yet its immunological and microenvironmental mechanisms have not been systematically synthesized. Methods: A scoping review of preclinical studies (2016–2025) was conducted following the Arksey-O’Malley framework and PRISMA-ScR guidance to systematically map experimental evidence on the antitumor, immune-related, and TME-associated effects of HDW. To complement and interpret these heterogeneous experimental findings at a systems level, a network pharmacology analysis was performed to identify bioactive compounds, predict their putative protein targets, and assess their convergence on immune- and microenvironment-related signaling networks through protein-protein interaction and pathway enrichment analyses. Results: Fifty-nine studies met eligibility criteria, encompassing in vitro and in vivo models across diverse cancer types. Experimental evidence from preclinical models showed that HDW extracts and bioactive fractions consistently suppressed proliferation, induced apoptosis and ferroptosis, inhibited epithelial-mesenchymal transition (EMT) and angiogenesis, and enhanced cytotoxic lymphocyte activity, while attenuating tumor-associated inflammation. In parallel, in silico network analysis identified 94 intersecting immune- and TME-related targets and revealed a densely connected interaction network centered on PI3K-Akt, STAT3, EGFR, and SRC. Enrichment analyses highlighted receptor tyrosine kinase signaling, inflammatory pathways, metabolic regulation, and focal adhesion as dominant functional themes. Conclusions: HDW acts as a multi-target botanical agent that integrates direct cytotoxicity with immune activation and TME remodeling. Network-in-formed interpretation indicates that the modulation of PI3K-Akt-STAT3 signaling is a common mechanistic axis linking experimental observations. Full article

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and remains a leading cause of cancer-related mortality worldwide. Despite recent advances in immunotherapy and targeted agents, treatment efficacy is frequently limited by tumor heterogeneity, drug resistance, and systemic toxicity. Natural products, particularly carotenoid-derived compounds, have emerged as promising multi-target anticancer agents. Xanthophylls, a class of oxygenated carotenoids, exhibit pleiotropic biological activities that are relevant to cancer therapy; however, their potential against HCC remains incompletely explored. This study aimed to systematically evaluate the anti-HCC potential of xanthophyll-rich extracts from Garcinia dulcis pulp using integrated metabolomic, in silico, and in vitro approaches. Methods: Xanthophyll-rich extracts from G. dulcis pulp were prepared using microwave-assisted extraction. Phytochemical profiling was performed using UHPLC–ESI–MS/MS. In silico analyses included bioactivity prediction, ADMET profiling, target identification, network pharmacology, pathway enrichment, and molecular docking against key HCC-related proteins (EGFR, BCL-2, and mTOR). In vitro antiproliferative activity was assessed using MTT assays on HepG2 and Huh7 hepatocellular carcinoma cell lines, with THLE-2 normal hepatocytes used as controls. Results: Metabolomic analysis revealed a xanthophyll-dominated profile, with zeaxanthin and lutein as the major constituents, alongside fucoxanthin, astaxanthin, β-cryptoxanthin, β-carotene, and canthaxanthin. In silico predictions demonstrated high antineoplastic and pro-apoptotic activities, with strong involvement in the HIF-1, EGFR, PD-1/PD-L1, JAK–STAT, and mTOR signaling pathways. Molecular docking confirmed stable and high-affinity interactions of xanthophylls with EGFR, BCL-2, and mTOR. In vitro assays showed selective cytotoxicity against HCC cells, with IC₅₀ values of 42.8 ± 3.6 µg/mL (HepG2) and 58.4 ± 4.9 µg/mL (Huh7), while exhibiting significantly lower toxicity toward normal hepatocytes. Conclusions: Xanthophyll-rich extracts from Garcinia dulcis pulp exhibit potent and selective anti-hepatocellular carcinoma activity through multi-target mechanisms involving oncogenic signaling, apoptosis regulation, and tumor metabolism. These findings support the translational potential of G. dulcis xanthophylls as promising natural candidates for further development in HCC therapy. Full article

Influenza virus infection remains a major global health burden, with severe disease outcomes driven not only by viral replication but also by excessive host inflammatory responses. Current antiviral therapies predominantly target viral components and fail to adequately control virus-induced hyperinflammation. In this study, we report a dual-target therapeutic strategy integrating direct antiviral activity with host-directed immunomodulation. Using a molecular hybridization approach, we designed and synthesized several dual-target inhibitors simultaneously targeting the influenza virus PB2 cap-binding subunit and host JAK2 kinase. Among them, PB05 emerged as the most promising candidate and was systematically evaluated in vitro and in vivo. PB05 exhibited potent broad-spectrum antiviral activity against influenza A viruses, with nanomolar EC₅₀ values. Mechanistic studies demonstrated that PB05 directly binds to the PB2 cap-binding domain, thereby disrupting viral cap-snatching and RNA synthesis. In parallel, PB05 inhibited JAK–STAT signaling by suppressing STAT2 phosphorylation and downstream ISRE-mediated transcription, leading to a marked reduction in pro-inflammatory cytokine production, including IL-6, IL-1β, and IFN-β, in infected or stimulated immune cells. In a lethal influenza A/PR/8/34 (H1N1) mouse model, oral administration of PB05 at 100 mg/kg (twice daily) markedly decreased lung viral titers, attenuated pulmonary tissue damage and edema, and moderated excessive inflammatory responses. Collectively, these findings identify PB05 as a dual PB2/JAK2 inhibitor that effectively couples antiviral efficacy with immunomodulatory activity, promoting a therapeutic strategy for the treatment of severe influenza and other viral diseases associated with excessive inflammation. Full article

Despite significant advances in oncology, current cancer therapies remain constrained by toxicity, resistance, and limited selectivity. Endophytic fungi symbiotic microorganisms inhabiting plant tissues represent a sustainable and underexplored source of structurally diverse anticancer metabolites. These include alkaloids, terpenoids, polyketides, and peptides that disrupt microtubule dynamics, interfere with DNA replication, and induce mitochondrial-mediated apoptosis. They also modulate key oncogenic signalling pathways such as nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), thereby enhancing the efficacy of existing chemotherapies. Endophyte derived compounds further inhibit angiogenesis, suppress metastasis, and stimulate immune responses, offering multi-target mechanisms with reduced toxicity. This review examines strategies that enhance the discovery and yield of these bioactive metabolites, including One Strain Many Compounds (OSMAC), microbial co-culture, epigenetic activation, genome mining, and synthetic biology. A comparative assessment of endophyte-derived versus conventional anticancer agents highlights their potential for scalable, eco-sustainable production. Collectively, endophytic fungi are positioned as promising contributors to the next generation of accessible, cost-effective, and environmentally responsible anticancer therapies. Full article

Radiotherapy is a mainstay in the management of locally advanced lung cancer; however, intrinsic and acquired radioresistance contribute to poor prognosis. S6K1, a serine/threonine kinase, regulates cell growth, protein synthesis, and survival, and is increased in tumors, which is linked to enhanced survival under therapeutic stress, including radiation. The mechanisms, however, are not fully understood. This study investigates the role of S6K1 in lung cancer radioresistance and the mechanisms involved. Intrinsic radioresistance in lung cancer cells was associated with increased S6K1 activation. Pharmacologic inhibition or genetic deletion of S6K1 enhanced radiosensitivity both in vitro and in vivo, highlighting the therapeutic potential of targeting S6K1. Transcriptomic analysis revealed that S6K1 deletion significantly downregulated STAT3 expression, a transcription factor that promotes radioresistance. S6K1 deletion reduced STAT3 phosphorylation and transcriptional activity, thereby sensitizing lung cancer to radiation. Additionally, radiation exposure or overexpression of a constitutively active S6K1 isoform restored STAT3 activation in S6K1 knockout cells, underscoring the regulatory role of S6K1 in STAT3 signaling. Together, these findings establish a novel S6K1–STAT3 axis that drives radioresistance in lung cancer and suggest that targeting this pathway may enhance radiotherapy efficacy. Full article