Search Results (4,431)

Background: This study investigated the renoprotective potential of Nano-Cilostazol against cisplatin (CIS)-induced renal injury in male rats and explored its molecular mechanisms. Our results showed that Nano-Cilostazol has a favorable physicochemical characteristic, including a mean particle size of approximately 101 nm, narrow polydispersity, and high stability. FTIR analysis indicated successful drug entrapment, preserving functional groups and enhancing hydrogen bonding. Docking analysis showed that cilostazol had stronger binding affinities than disulfiram against seven acute kidney injury-related targets. Interaction profiling confirmed stable binding through hydrogen bonding, hydrophobic, and π-interactions with BAX, ASC, GSDMD, KIM-1, JAK2, NLRP3, and miRNA-155. In vivo, CIS administration led to marked renal dysfunction, showing up as significant elevations in serum urea, creatinine, cystatin-C, CRP, and NGAL which indicated by severe histopathological damage. Co-treatment with Nano-Cilostazol significantly lessened renal functional impairment biochemically and histopatologically. Nano-Cilostazol markedly reduced lipid peroxidation and oxidized glutathione while also restoring antioxidant defenses like superoxide dismutase and catalase, with total and reduced glutathione. Additionally, Nano-Cilostazol attenuated renal inflammation, inhibiting NF-κB activation, lowering pro-inflammatory cytokines (TNF-α and IL-1β), and downregulating inflammatory and injury-related genes. CIS-triggered apoptotic signaling was also mitigated, shown by increased caspase-3 and BAX expression with downregulation of BCL-2. Nano-Cilostazol significantly inhibited apoptosis and pyroptosis (NLRP3, ASC, GSDMD)-related pathways, modulated JAK2/STAT3 signaling, and downregulated miRNA-155 expression. In conclusion, Nano-Cilostazol offers potent protection against cisplatin-induced nephrotoxicity. Full article

Type I interferons (IFN-I) are pleiotropic cytokines best known for their antiviral impacts. However, they are known to also impact immune responses outside of viral infection through directly signaling many populations of innate and adaptive immune cells. Here, we focus on the complex body of findings from viral, bacterial, and parasitic infection models, cancer and autoimmunity studies, as well as in vitro experiments using human and murine T cells, demonstrating that IFN-I can be directly sensed by CD4 T cells. Such signaling has been shown to influence many central aspects of antigen-specific CD4 T cell responses, including proliferation, apoptosis, effector subset differentiation, and memory formation. These effects are frequently divergent and sometimes opposing, likely reflecting how differences in variables related to the IFN-I signal, overall inflammatory milieu, and the CD4 T cell integrate to shape outcomes. Indeed, we discuss findings supporting a framework in which dynamic engagement of canonical and non-canonical signaling pathways downstream of IFN-I, which are contingent on a cell’s activation state, play a key role in determining whether and how IFN-I promotes, restrains, or otherwise reprograms CD4 T cell fates. Together, these observations highlight the impressive scope of regulation that IFN-I signals to CD4 T cells can exert, parallel to its actions on other immune and non-immune cell types. They also suggest that harnessing such signaling could offer powerful therapeutic strategies to shape CD4 T cell immunity in diverse context-dependent situations. Full article

T-cell lymphomas are a heterogeneous group of lymphoid neoplasms with a variable prognosis. They can be further divided into cutaneous T-cell lymphomas and peripheral T-cell lymphomas. Treatment options are relatively limited for patients with relapsed or refractory disease. Janus kinase (JAK) inhibitors have emerged as promising new drugs for these lymphomas, as increasing evidence supports the JAK and signal transducer and activator of transcription (STAT) pathway as a potential target. The objective of this review is to summarize the current evidence supporting the use of JAK inhibitors in the treatment of T-cell lymphomas and highlight areas for future research. Although many JAK inhibitors have been developed for the treatment of autoimmune conditions, only a subset of these have been tested in T-cell lymphomas and reported in the literature. These include abrocitinib, cerdulatinib, golidocitinib, ruxolitinib, tofacitinib, and upadacitinib. Other drugs are currently being tested in clinicals trials, including pacritinib and ivarmacitinib, but results are not yet available. Most of the published data are for ruxolitinib, which was found to have a clinical benefit rate of up to 53% in patients with PTCL with activating JAK and/or STAT mutations. Response durations are limited, which may be overcome through combination therapies in the future. JAK inhibitors are associated with multiple adverse effects, including cytopenias and infections, and long-term safety data are lacking for newer agents. Future studies will need to clarify long-term safety and efficacy through well-designed clinical trials involving larger groups of patients. Full article

Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system (CNS) and is characterized by poor prognosis and significant resistance to available treatments. Surgery, radiation therapy, and chemotherapy are the standard treatments; however, their efficacy is often limited by resistance. Resveratrol (RES), a naturally occurring polyphenol with antioxidant properties, has shown significant anticancer effects through inhibition of multiple cellular pathways. However, our earlier research revealed that the LN428 cell exhibited resistance, while the U251 cell showed sensitivity to RES monotherapy. Hence, RES and AG490, a JAK2 inhibitor, were used to overcome GBM cell resistance, which might enhance therapeutic efficacy. Methods: Human GBM cell lines LN428 and U251 were used. CCK-8, H&E staining, transwell, wound healing, calcein AM/PI, and flow cytometry assays were performed to evaluate cell proliferation, migration, and apoptosis. Molecular docking was performed to analyze the binding energy. Western blot, immunocytochemistry (ICC), and immunofluorescence (IF) were used to assess protein expression following treatment with RES, AG490, and their combination. Results: The results revealed that U251 cells were more sensitive to RES, AG490, and RES + AG490 than LN428 cells. Additionally, the combination of both compounds significantly reduced cell viability, proliferation, and migration, while increasing apoptosis in the LN428 and U251 cell lines. Moreover, the combination of RES and AG490 led to increased BAX protein expression while decreasing BCL-2 expression in LN428 and U251 cell lines. Notably, the monotherapy administration of RES did not significantly inhibit STAT3 or pSTAT3 protein expression in LN428 cells, while combination therapy significantly inhibited the expression of these proteins in LN428 and U251 cell lines. Conclusion: The concurrent administration of RES and AG490 effectively inhibited the JAK2/STAT3 signalling pathway and enhanced antitumor effects in GBM cells, indicating their potential as a therapeutic strategy. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, necessitating the development of novel multi-targeted therapeutic agents. This study investigates the anticancer effects of Panax notoginseng extract (PNE) against CRC using an integrative approach of network pharmacology and experimental validation. Phytochemical profiling via LC–MS identified major ginsenosides, including Rb1, Rg1, and Rd. Network pharmacology analysis revealed potential targets such as Bcl-xL, STAT3/CDK1, and IL-2, which are associated with apoptosis, cell cycle regulation, and immune modulation, respectively. Experimental results demonstrated that PNE significantly inhibited the proliferation of HCT 116 and HT-29 CRC cells, induced G0/G1 phase arrest by modulating CDK4/6 and p21/p27, and promoted apoptosis by regulating BCL2 family proteins. Furthermore, PNE treatment suppressed tumor growth in a CT26-bearing syngeneic mouse model. These findings highlight that PNE exerts potent anticancer effects through multi-pathway modulation, suggesting its potential as a therapeutic candidate for CRC. Full article

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide, yet only a fraction of smokers develops the disease, suggesting protective mechanisms in resilient individuals. Identifying airway-localized molecular signatures may improve our understanding of disease pathomechanisms and support hypothesis generation for biomarker research. In this pilot study, induced sputum from smokers with COPD (n = 28) and smokers without COPD (n = 16; Global Initiative for Chronic Obstructive Lung Disease (GOLD)-defined pre-COPD) was analyzed by untargeted proteomics, metabolomics, and lipidomics. After quality control, 1180 proteins, 187 metabolites, and 1234 lipids were retained. Analyses included univariate models with false discovery rate adjustment and multivariate analyses (PCA, PLS-DA), followed by pathway enrichment and protein interaction network analysis. While few features remained significant after FDR correction, consistent cross-omics patterns were observed. COPD was characterized by ↑ glutathione, creatine, and L-arginine; ↓ CCDC88A and ↑ STAT3 and SYDE2; and broad lipid remodeling involving phosphatidylcholines, sphingolipids, and eicosanoids. Network analysis highlighted STAT3 as a highly connected node linking COPD-related genes. These findings suggest that the multi-omic profiling of induced sputum can capture coherent airway-localized molecular signatures such as oxidative stress, cytoskeletal remodeling, and Rho-family GTPase signaling. However, the results should be interpreted as exploratory and require validation in functional studies. Full article

Signal transducer and activator of transcription 3 (STAT3) is a central oncogenic hub in several tumors including the Triple-Negative Breast Cancer (TNBC) subtype, where its constitutive activity supports proliferation, metabolic flexibility, tumor progression, immune evasion, and therapeutic resistance. Therapeutic development has largely focused on canonical STAT3 activation driven by tyrosine 705 phosphorylation (p-Y705), which enables dimerization and transcriptional programs. However, accumulating evidence indicates that phosphorylation at serine 727 (p-S727) defines a functionally distinct STAT3 axis, underpinning non-canonical activities across extranuclear compartments that include mitochondria and endoplasmic reticulum/mitochondria-associated membranes. In TNBC, p-S727 STAT3 is frequently prevalent and may sustain oncogenic signaling when p-Y705 is low or pharmacologically suppressed, contributing to metabolic rewiring, redox control, apoptosis resistance, and metastatic fitness. Here, we review the mechanistic basis and clinical correlations of STAT3 p-S727 across cancers with emphasis on TNBC, and discuss how compartmentalized STAT3 pools may integrate kinase signaling, nutrient sensing, and stress responses. We also summarize emerging therapeutic strategies that modulate p-S727—often in conjunction with p-Y705—highlighting proof-of-concept for dual targeting or specific p-S727 to overcome limitations of Y705-centric approaches. Finally, we propose that integrating p-S727/p-Y705 distribution and activity into patient stratification could improve the efficacy–toxicity balance of STAT3-directed therapies in TNBC. Full article

The ovaries are crucial reproductive organs that regulate the menstrual cycle and support pregnancy through the production of steroid hormones. They are highly susceptible to various environmental pollutants, which can lead to ovarian disorders. Luteal phase defect (LPD) and premature ovarian failure (POF) are common ovarian disorders in women. In this study, we integrate network toxicology with molecular docking and molecular dynamics simulations to elucidate the toxicological mechanisms of Benzo(a)pyrene (BaP), a widespread endocrine disruptor, in LPD and POF. Through systematic data mining of the GeneCards and OMIM databases, we identified 1336 targets associated with LPD and 2066 targets related to POF, as well as 220 BaP targets. Venn diagram analysis revealed 36 potential targets for BaP-induced LPD and 43 for BaP-induced POF. GO and KEGG enrichment analyses suggest that BaP-induced LPD and POF may share toxicological mechanisms. PPI network visualization indicated that EGFR, ESR1, and STAT3 are critical common targets for BaP-induced LPD and POF. Molecular docking and molecular dynamics simulations revealed that BaP exhibits strong binding affinity with all three core genes. In KGN cells modeling LPD and POF phenotypes, cellular experiments confirmed that BaP downregulated EGFR and ESR1 expression while upregulating STAT3 expression, thereby supporting the reliability of these targets in BaP-induced ovarian dysfunction. These findings provide insights into BaP-induced reproductive toxicity and offer a foundation for targeted clinical interventions to mitigate the effects of environmental pollutants on women’s reproductive health. Full article

Interferon-γ (IFNγ), a key inflammatory cytokine that orchestrates immune responses, also emerges as a regulator of cellular metabolism; however, in alveolar epithelial cells its impact on amino acid homeostasis remains poorly defined. Here, we investigated the effects of IFNγ on intracellular amino acid content and transmembrane transport in human alveolar epithelial A549 cells, focusing on the contribution of the JAK/STAT/IRF1 signaling axis. To this end, A549 WT and IRF1 knockout (IRF1 KO) cells were used to investigate IRF1 contribution, and baricitinib to evaluate the role of the JAK/STAT pathway. HPLC analysis reveals that in WT, but not in IRF1 KO cells, IFNγ markedly increases the intracellular concentration of many amino acids, including glutamine, glutamate, and several neutral and cationic amino acids, without affecting the cell volume, thus indicating true metabolic accumulation. The measurement of the transmembrane uptake of specific radiolabeled amino acids demonstrates a concomitant increase in transport Systems ASC, A, L, and y⁺ activity; an upregulation of the related transporters ASCT2, SNAT2, LAT1, and CAT1 has also been observed by means of qPCR analysis. Moreover, conditioned medium from SARS-CoV-2 spike-activated macrophages recapitulates IFNγ-driven amino acid remodeling in a JAK/STAT/IRF1-dependent manner. Overall, our findings identify IFNγ as a potent regulator of intracellular amino acid availability in alveolar epithelial cells through the modulation of the activity of membrane transporters. The observed IFNγ-reprogramming is IRF1 dependent, ascribing a crucial role to this transcription factor in linking inflammation and amino acid metabolism. Full article

Myocardial ischemia–reperfusion injury remains a major unresolved challenge in cardiovascular medicine. Although timely restoration of blood flow is essential to limit ischemic damage, reperfusion triggers a complex network of maladaptive biological responses, including oxidative stress, calcium overload, mitochondrial dysfunction, metabolic impairment, and sterile inflammation. These processes converge on cardiomyocyte death, adverse ventricular remodeling, and long-term functional deterioration. Mesenchymal stem cells have been widely investigated as cardioprotective agents; however, accumulating evidence indicates that their beneficial effects are predominantly mediated by paracrine mechanisms. Among these, extracellular vesicles released by mesenchymal stem cells have emerged as key biological effectors. Experimental studies demonstrate that mesenchymal stem cell–derived extracellular vesicles modulate multiple signaling pathways involved in ischemia–reperfusion injury, including activation of the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB) axis, regulation of signal transducer and activator of transcription 3 (STAT3) signaling in a cell-specific manner, suppression of nuclear factor kappa B (NF-κB)-driven inflammatory responses, and stabilization of hypoxia-inducible factor-1α (HIF-1α)–dependent adaptive programs. At the subcellular level, these vesicles preserve mitochondrial structure and function, support energy metabolism, regulate mitophagy, and limit oxidative damage. Their molecular cargo, comprising regulatory microRNAs, metabolic enzymes, and stress-response proteins, enables coordinated modulation of survival, inflammatory, and reparative pathways rather than single-target effects. This review synthesizes current experimental evidence on the mechanistic basis of mesenchymal stem cell–derived extracellular vesicle–mediated cardioprotection and discusses their potential as cell-free, mechanism-based therapeutic strategies to limit myocardial ischemia–reperfusion injury. Full article

Cinnamomum cassia essential oil production generates substantial waste, and the therapeutic potential of non-volatile constituents from cinnamomum cassia leaves in ulcerative colitis (UC) has not been fully explored. This research focused on identifying the principal components of cinnamomum cassia leaf extract (CCLE) through ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS), and its anti-inflammatory potential was verified in vitro. A lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage model was employed, with assessments performed through cell viability assays, Griess assay, fluorescent probe detection, wound healing, and Transwell migration assays. Network pharmacology analysis combined with molecular docking revealed that CCLE exerts therapeutic effects against UC by targeting key molecules including TNF, TLR4, STAT3, SRC, PTGS2, NFKB1, MMP9, EGFR, BCL2, and AKT1, with high binding affinity between these targets and CCLE components (especially Quercetin, Catechin, Naringenin, 3′,4′-dimethoxyflavonol, Procyanidin Bl, and Caffeic acid). Enrichment analysis indicated that the therapeutic effect of CCLE on UC was significantly associated with the PI3K-Akt signaling pathway, B cell receptor signaling pathway, NF-κB signaling pathway, TNF signaling pathway, and JAK-STAT signaling pathway. The experimental results demonstrated that CCLE markedly reduced the production of nitric oxide (NO) and reactive oxygen species (ROS) (* p < 0.05) and inhibited macrophage migration (* p < 0.05). In conclusion, CCLE appears to ameliorate UC via a multi-target regulatory mechanism involving inflammatory signaling pathways. These outcomes offer a scientific foundation for the further development of CCLE. Full article

Chronic rhinosinusitis with nasal polyps (CRSwNP) comprises multiple molecular endotypes that only partly align with the clinical phenotype, which complicates target selection and interpretation of treatment effects. Human omics and biomarker studies define candidate pathways, but causal attribution of specific nodes to lesion formation and remodeling requires perturbable in vivo systems. Here, we present a “module-first” framework that links murine induction paradigms to epithelial–immune–stromal circuits and to a minimal, module-matched endpoint set for reproducible causal inference. We summarize commonly used CRSwNP-like protocols (allergen/protease ± SEB, aeroallergen + SEB, innate trigger-enriched paradigms, and modifier layers), emphasize operational pathology terminology (“polyp-like lesion” versus “true polyp”), and propose a uniform causal template for validated pathway modules (alarmins/IL-33–NF-κB, type 2/ILC2–eosinophil, IL-17A/neutrophil, Wnt/EMT remodeling, and JAK/STAT kinase convergence). Finally, we organize chemical and molecular interventions by leverage point and propose an ARRIVE-aligned Minimum Reporting Set to standardize model anchoring, target engagement, and cross-study comparability. This module-first roadmap is intended to accelerate mechanism-linked discovery and preclinical validation of tractable drug targets in CRSwNP. Importantly, this module-first roadmap is intended as a heuristic organizing principle rather than an exhaustive taxonomy, because pathway modules can overlap and shift dynamically across time and tissue compartments in vivo. Full article

The carapace of the Chinese soft-shelled turtle (Pelodiscus sinensis) is rich in collagen and stands as a crucial economic trait for assessing its quality, as well as a key indicator for selective breeding. However, current studies on the mechanisms underlying collagen deposition in the carapace remain severely limited, significantly hindering progress in selective breeding. Here, the Col1a2 gene of P. sinensis was molecularly characterized for the first time. Analysis of gene structure, phylogenetic tree, and amino acid sequence homology revealed that Col1a2 is relatively conserved among tetrapods but divergent from fishes. Collinearity analysis identified the BET1-COL1A2-CASD1-SGCE gene block shared across all 14 representative vertebrates and found that the Col1a2 is located on the Z chromosome of Thamnophis elegans. Tissue expression analysis showed that Col1a1 was highly expressed in the heart, gonad, and lung. Additionally, Col1a1 expression levels markedly increased during carapace development, exhibiting a strongly positive correlation with the changes in collagen content of the carapace. In situ hybridization results revealed strong signal for the Col1a2 transcripts in fibroblasts of the dermal layer of P. sinensis carapace. Knockdown of the Col1a2 gene in the carapace cells of P. sinensis significantly reduced collagen content. Transcriptome analysis following Col1a2 knockdown identified several differentially expressed genes associated with collagen deposition, including Fbln2, IL-11, and Rspo4, as well as significantly enriched pathways such as the JAK-STAT signaling pathway, the apelin signaling pathway, and the Hippo signaling pathway. Our findings offer a molecular basis for elucidating the mechanisms of collagen deposition in the carapace of P. sinensis, while also supplying a potential target for the selective breeding of collagen-rich strains of P. sinensis. Full article

Dendrobium officinale exhibits hepatoprotective potential against acetaminophen-induced liver injury (AILI). Fermentation has been proposed as a strategy to enhance the utilization and efficacy of herbal medicines. However, whether yeast fermentation improves the hepatoprotective effects of D. officinale remains unclear. This study investigated whether fermentation of D. officinale flower extract with Saccharomyces cerevisiae (1002S) enhances its protective effects against AILI, compared with a nonfermented extract (DOFE). Hepatoprotective efficacy was evaluated in male C57BL/6 mice, which received 1002S or DOFE (500 mg/kg, oral gavage) for 7 days before an acute acetaminophen challenge. Untargeted metabolomics and network pharmacology analyses were used to characterize fermentation-associated metabolic alterations and to explore potential pathways related to the observed effects. Metabolomic profiling revealed distinct metabolic differences between 1002S and DOFE. Network pharmacology analysis indicated predicted targets of fermentation-associated metabolites were associated with the phosphoinositide 3-kinase (PI3K)/ protein kinase B (Akt) and Janus kinase (JAK)/signal transducer and activator of transcription proteins (STAT) signaling pathways. In vivo, 1002S more effectively alleviated hepatocellular necrosis and significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was observed in liver tissues. Molecular docking suggested hemsleyanoside may contribute to these effects. Collectively, S. cerevisiae fermentation enhanced the antioxidant and hepatoprotective efficacy of D. officinale flower extract, supporting its potential development for AILI prevention. Full article

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