DNA double-strand breaks (DSBs), caused by various endogenous and exogenous factors, pose a significant threat to genomic stability. Several conserved repair pathways address DSBs, with homologous recombination (HR) being the only mechanism capable of accurately restoring the original DNA sequence. The BRCA1 gene plays a critical role in HR and is involved in maintaining genomic stability, cell cycle regulation, transcription, and tumor angiogenesis. Germline mutations in BRCA1 are strongly associated with increased risks of breast, ovarian, and other cancers. Dysfunction of BRCA1 leads to homologous recombination deficiency (HRD), forcing cells to rely on error-prone repair pathways, which promotes genomic instability and tumorigenesis. Besides hereditary mutations, HRD can also arise in sporadic cancers through epigenetic mechanisms such as promoter hypermethylation and reduced BRCA1 expression. Although BRCA1 deficiency is uncommon in lung cancer, BRCA1 status is considered a potential biomarker for sensitivity to platinum-based chemotherapy and other cytotoxic agents used in lung cancer treatment. However, the impact of BRCA1 on treatment response and prognosis in lung cancer remains controversial and not fully understood. This review summarizes current evidence on the role of BRCA1 in modulating chemotherapy response and disease outcomes in lung cancer patients, highlighting its potential as a biomarker for personalized therapy selection. Thus, in this context, the key unresolved issues critical for the development of personalized treatment strategies for lung cancer associated with BRCA1 alterations include the identification of molecular biomarkers most reliably associated with tumor sensitivity to chemotherapy. In addition, the development of methods for identifying patients with homologous recombination deficiency specifically in lung tumors appears to be of considerable importance, as does a better understanding of how the biological and therapeutic implications of BRCA1-related parameters in lung cancer differ from those observed in other tumor types. Addressing these challenges could substantially improve the efficacy of chemotherapy and patient outcomes, while also expanding the opportunities for a personalized approach to treatment selection in patients with lung cancer.
Neurogenic pulmonary edema (NPE) is a life-threatening complication of acute central nervous system (CNS) injury, characterized by the rapid onset of hypoxemia and pulmonary fluid accumulation in the absence of underlying cardiopulmonary disease. In recent years, emerging integrative frameworks such as the "neuroimmunoaxis" and "brain-lung axis" have provided new perspectives on how CNS injury leads to systemic immune dysregulation and pulmonary dysfunction. However, critical questions remain regarding the interplay between excessive sympathetic activation, immune homeostasis disruption, and lung tissue injury. This narrative review proposes a neurotransmitter-immune-inflammatory model that integrates mechanical, adrenergic, and inflammatory pathways across the spatiotemporal evolution of NPE. We identify four progressive stages involving sympathetic storm initiation due to central autonomic network disinhibition, pulmonary vascular barrier disruption through Piezo channel activation and angiotensin II-norepinephrine synergy, inflammatory amplification from loss of the cholinergic anti-inflammatory reflex, and systemic progression involving gut-lung axis dysregulation. The model generates three testable predictions. Lesions disrupting the nucleus tractus solitarius-ventromedial hypothalamus-intermediolateral column projection should produce more severe NPE. And selective activation of TRPA1+ dorsal root ganglion neurons should attenuate sympathetic outflow and pulmonary edema. Enhancing α7 nicotinic acetylcholine receptor signaling should mitigate systemic inflammation. These predictions offer experimental avenues for validating the hijacking hypothesis. Translational implications include stage-specific interventions, early sympathetic blockade, mid-phase anti-inflammatory and neuro-modulatory strategies, and late-stage lung-protective ventilation. This study aims to offer a comprehensive analysis of NPE by exploring its pathological mechanisms-from central sympathetic signaling to peripheral lung damage. Emphasis is placed on examining the interactions between neural signals, neurotransmitters, and immune responses to uncover the spatiotemporal dynamics of NPE. By identifying potential pathways for early diagnosis and targeted therapies, the research seeks to improve disease management and contribute to better clinical outcomes for affected patients.
Methyltransferase-like 9 (METTL9) has been implicated in tumor progression, yet its clinical significance, functional roles, and immunoregulatory functions in lung adenocarcinoma (LUAD) remain unclear. This study aimed to integrate multi-omics datasets and experimental evidence to systematically evaluate the expression profile, prognostic value, molecular mechanisms, and tumor microenvironment (TME)-related functions of METTL9 in LUAD. Transcriptome and clinical data for LUAD and METTL9 protein expression were obtained from public databases. Survival analysis was performed using Kaplan-Meier analysis and Cox proportional hazards models. METTL9-related differentially expressed genes (DEGs) were screened, followed by functional annotation and pathway enrichment analysis. A protein-protein interaction (PPI) network associated with METTL9 was constructed using STRING. METTL9 gene mutations and promoter methylation levels were analyzed via cBioPortal and UALCAN. Immune infiltration was evaluated through gene set variation analysis (GSVA) and the TIMER platform. The role of METTL9 depletion in regulating transforming growth factor-β (TGF-β)/Smad signaling, epithelial-mesenchymal transition (EMT), as well as the behavior of A549 and H1975 cells was investigated. METTL9 was markedly elevated in LUAD, which was confirmed in external datasets and immunohistochemistry. Increased METTL9 expression showed a strong association with advanced TNM stage, unfavorable clinicopathological parameters, and poor survival outcomes in univariate analysis. Receiver operating characteristic (ROC) analysis indicated that METTL9 showed moderate diagnostic utility for LUAD, with an Area Under the Curve (AUC) of 0.704 (95% Confidence Interval [CI]: 0.650-0.758) in the The Cancer Genome Atlas (TCGA) dataset and 0.815 (95% CI: 0.758-0.872) in the GSE31210 dataset. Moreover, high METTL9 expression was significantly correlated with poor survival outcomes (Hazard Ratio [HR] = 1.349, 95% CI: 1.010-1.802, p = 0.043). METTL9 interacted with multiple oncogenic proteins in the PPI network and showed significant correlations with cuproptosis-related genes. Immune infiltration analysis further demonstrated that METTL9 expression showed significantly associated with immune cell infiltration and the tumor immune microenvironment in LUAD. METTL9 knockdown suppressed LUAD cell proliferation, migration, invasion, and EMT, while promoting apoptosis and reducing the expression of B-cell lymphoma 2 (Bcl-2), phosphorylated Smad2 (p-smad2), and phosphorylated Smad3 (p-smad3). METTL9 is upregulated in LUAD and correlates with an unfavorable prognosis. Our results indicate that METTL9 may contribute to LUAD progression and EMT, potentially in relation to the TGF-β/Smad signaling pathway.
Scientific research relies on transparent dissemination of data and its associated interpretations, including raw data, metadata, experimental design, and data processing details. Production and handling of research data represents an ongoing challenge, extending beyond publication into individual facilities, institutes and research groups, often termed Research Data Management (RDM). It is foundational to scientific discovery and aligned with the FAIR principles. Although the majority of peer-reviewed journals require raw data deposition in public repositories in alignment with FAIR principles, metadata frequently lacks standardization, hindering effective utilization and sharing of research findings. Here we present FRED, a generalized toolkit for FAIR metadata management in omics research based on a flexible, machine-readable YAML format. FRED enables (i) guided, dialog-based creation of metadata files, (ii) structured semantic validation, (iii) logical cross-file search, (iv) API-based integration with external systems, and (v) self-hosted web deployment. We demonstrate the utility of FRED through a complete annotation workflow applied to a published single-nucleus RNA-seq dataset, covering metadata generation, validation, repository-based discovery, and export to NCBI GEO submission format. FRED is designed for non-computational scientists and specialized facilities alike, and integrates into existing RDM infrastructure without requiring dedicated IT resources.
The respiratory system is directly exposed to various environmental factors, and specifically allergens and environmental pollutants, which are ligands/agonists of the aryl hydrocarbon receptor (AhR) and promote chronic lung diseases in humans. AhR, a ligand-activated transcription factor, is involved in the metabolism of xenobiotics, assigning their carcinogenic and toxic effects, and is also involved in normal homeostasis, organogenesis, and immune system function. Exogenous and endogenous AhR ligands are both high-molecular-weight compounds with a planar structure and low-molecular-weight compounds of diverse chemical structures. After entering the cell, the ligands bind to AhR and induce the activation of signaling cascades. The lung immune system responds to pathogens and environmental toxins first with a pro-inflammatory innate immune response, and then with an anti-inflammatory adaptive immune response. An imbalance between these immune systems may have an effect on the course of the disease. Activation of AhR by exogenous or endogenous ligands can affect this balance and lead to dysregulation of the immune response, leading to inflammatory complications in the lungs. Individual features of AhR expression or components of the AhR-dependent signaling pathway may also play a role in the superposition of the functions of these two links of immunity. This review summarizes advances in the comprehension of AhR's role in immunomodulation and inflammatory responses in the lungs following data in experimental rodent models, in vitro studies utilizing lung structural cells and isolated immune cell lines, and humans. The molecular mechanisms of AhR's regulation of immunity and inflammation and the potential of AhR as a therapeutic target for inflammatory lung disease are also considered.
Pectolinarigenin (PEC), a naturally occurring flavonoid, exhibits anti-inflammatory and antioxidant activities in various experimental models. However, its protective effects against lipopolysaccharide (LPS)-induced lung inflammation and the underlying molecular mechanisms remain unclear. This study investigated the protective effects of PEC using LPS-treated MLE12 cells and RAW264.7 macrophages, as well as a prophylactic mouse model in which PEC was administered before LPS exposure. In LPS-treated MLE12 cells and RAW264.7 macrophages, PEC reduced inflammatory responses and cellular injury, accompanied by decreased reactive oxygen species production and modulation of the histone deacetylase 3 (HDAC3)/nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) signaling. Consistent with these findings, PEC pretreatment attenuated pulmonary edema, inflammatory cell infiltration, pro-inflammatory cytokine production, oxidative stress, pyroptosis-associated signaling, and histopathological lung injury in LPS-exposed mice. These protective effects were accompanied by reduced HDAC3 expression and nuclear localization, together with reduced NF-kB/NLRP3 signaling in lung tissues. Overall, PEC attenuated LPS-induced lung inflammation and injury, accompanied by reduced oxidative stress and modulation of HDAC3/NF-κB/NLRP3 signaling. These findings support the potential of PEC as a preventive agent against excessive pulmonary inflammation.
Lung cancer remains a leading cause of cancer-related mortality worldwide, with metastatic disease accounting for ∼90% of deaths. While p53 gene therapy offers promise for restoring tumor suppressor function, its clinical translation has been hindered by inefficient delivery systems and pulmonary administration challenges. Here, we developed redox-responsive thiolated chitosan nanoparticles (TCS NPs) as the first inhalable nanotherapeutic platform for tumor-selective p53 gene delivery to treat metastatic lung cancer. Our system exploits elevated glutathione levels in cancer cells to trigger selective gene release, while mucoadhesive properties ensure prolonged pulmonary retention. The p53 DNA-loaded TCS NPs demonstrated exceptional cancer selectivity, exhibiting significant cytotoxicity against lung cancer cells while maintaining biocompatibility with normal tissues. Treatment restored p53-mediated pathways, upregulating metastasis suppressors (KLF6 and E-cadherin) and apoptotic factors (Bax and cleaved caspase-3), thereby inhibiting migration, invasion, and metastatic progression. In vivo studies using ectopic xenograft and experimental metastasis models confirmed robust therapeutic efficacy, with inhaled TCS@p53 NPs achieving significant tumor suppression and reduced metastatic nodule formation while maintaining excellent safety profiles. This work presents a transformative inhalable gene therapy platform that overcomes traditional delivery limitations through tumor-selective targeting.
Autophagy is a crucial mechanism in the host response to intracellular bacterial pathogens during which microorganisms may undergo direct degradation in autophagolysosomes. As a highly virulent intracellular pathogen, Francisella tularensis has developed survival strategies to escape from the phagosome, replicate in the cytosol of mononuclear cells, and avoid degradation within the double-membrane vacuole during the autophagy-mediated response. The aim of this study was to investigate the role of the ATG5 autophagy protein in the host immune response to Francisella tularensis subsp. holarctica, live vaccine strain (LVS), since ATG5 plays an important role in autophagosome formation during canonical autophagy. In vitro experiments were conducted on immortalized bone marrow macrophages subjected to starvation-induced autophagy. Transgenic mice deficient in ATG5 of cells of the myeloid lineage (monocytes/macrophages and granulocytes) were used to analyze the immunological responses after intradermal infection. Cytokine levels were analyzed using Luminex, RT-qPCR, and ELISA, while inflammatory cell infiltration in the lung was analyzed by immunohistochemistry. Our results demonstrate that induced autophagy decreased bacterial replication in vitro. However, ATG5 deficiency in myeloid cells in vivo significantly diminished levels of pro-inflammatory cytokine IFN-γ in the sera, spleen, liver, and lung during Francisella infection. The attenuated pro-inflammatory response also led to significantly reduced macrophage and T cell infiltration in the lung tissue. Our findings also reveal that neutralization of IL-1β in myeloid ATG5ΔMye mice increased susceptibility to tularemia by increasing bacterial burden in organs.
Chronic obstructive pulmonary disease (COPD) remains a major global health challenge. This study explored the therapeutic mechanisms of Huangjing (Polygonati Rhizoma) and Gegen (Puerariae Lobatae Radix), two food-medicine homologous herbs with potential in COPD management. Integrating network pharmacology, serum pharmacochemistry, molecular docking, and experimental validation, we identified 239 shared targets and the PI3K/AKT pathway as a potential key mechanism. UHPLC Q-Exactive Orbitrap MS revealed 66 compounds, 14 of which were absorbed into circulation. In vivo, Huangjing-Gegen appeared to improve lung function (PaO2 increased by 28.3%, PaCO2 decreased by 22.7%), alleviate pathology, and reduce inflammation through downregulating TNF-α (by 21.4%), IL-6 (by 30.7%), and IL-1β (by 29.3%) and suppressing the EGFR-PI3K/AKT pathway. Molecular docking provided supportive evidence for strong binding between absorbed puerarin derivatives and core targets. These findings suggest that the PI3K/AKT pathway may play a central role in the therapeutic effects of Huangjing-Gegen against COPD.
HERC4 is a well-known HERC family ubiquitin ligase in several types of cancer but its role in lung cancer remains elusive. In the present study, we found that HERC4 is highly dysregulated in lung adenocarcinoma (LUAD) and promotes LUAD cell growth. Mechanically, HERC4 interacts with translation-related proteins and specifically stabilizes RPS15, a component of 40S ribosomal subunit, by promoting its deubiquitination in a manner independent of E3 ligase activity. HERC4 collaborates with USP16, a deubiquitinase that also interacts with translation-related proteins, to stabilize RPS15 by preventing its K48-linked ubiquitination. Further studies revealed that the interaction between HERC4 and USP16 is important to regulate RPS15 and to promote LUAD cell proliferation. Knockdown of HERC4 or USP16 prevents the recruitment of translation-related proteins to ribosomes, increases their nuclear retention and reduces global translational efficacy. Overexpression of RPS15 partially rescues reduced protein translation efficiency and cell survival triggered by HERC4/USP16 knockdown. Moreover, knockdown of HERC4 or USP16 upregulates p53 and downregulates p38 via RPS15 dysregulation. In conclusion, the present study reveals a novel ubiquitination modulation on ribosomal stability and protein translation. HERC4 synergizes with USP16 to deubiquitinate and stabilize RPS15, thereby potentiating global protein translation and promoting LUAD growth. The HERC4/USP16-RPS15 axis may represent a potential therapeutic target for LUAD treatment.
This study investigated the role of peptidylprolyl isomerase A (PPIA) in lung adenocarcinoma (LUAD) using bioinformatics approaches and experimental validation. This study began by assessing PPIA expression and its prognostic significance in LUAD. We then performed functional enrichment analyses and examined CNVs, DNA methylation, DNMT activity, RNA modification, immune cell infiltration, and drug therapy efficacy. Cellular experiments were performed to confirm the role of PPIA in DNA damage repair. PPIA was overexpressed in LUAD tissues and was associated with poor prognosis, including shorter overall survival and progression-free interval. PPIA expression was correlated with CNVs, DNA methylation, DNMT activity, and RNA modification-related genes. It was also negatively associated with immune cell infiltration and immune-related gene expression, suggesting a potential immunosuppressive role. Drug sensitivity analysis indicated that PPIA may serve as a predictive biomarker for therapeutic efficacy in LUAD. In addition, PPIA expression was associated with DNA damage repair-related genes. Cellular experiments show that PPIA knockdown increases radiosensitivity and γ-H2AX foci formation, whereas PPIA overexpression exerts the opposite effects. This study highlights the potential of PPIA as a prognostic biomarker and target in LUAD, particularly in the regulation of DNA damage repair and tumor immune microenvironment remodeling.
Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted.
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is one of the most severe extra-articular manifestations of rheumatoid arthritis (RA), requiring reliable biomarkers for early detection. This scoping review synthesized current evidence regarding the diagnostic performance and clinical associations of anti-mutated citrullinated vimentin (anti-MCV) antibodies in patients with RA-ILD. A comprehensive literature search was conducted across PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library. Following systematic screening, two observational studies met the predefined inclusion criteria. Both included studies reported significantly higher anti-MCV positivity rates and/or serum levels in patients with RA-ILD compared with RA patients without pulmonary involvement. Specifically, one study identified an independent association between anti-MCV positivity and RA-ILD, while the other demonstrated significant correlations between anti-MCV titers and pulmonary function impairment, as well as disease activity markers. However, substantial heterogeneity was observed across the studies regarding assay platforms, positivity thresholds, and diagnostic cut-offs, which limits the direct comparability of results. While anti-MCV antibodies represent promising candidate biomarkers for RA-ILD, current evidence remains limited and is insufficient to establish definitive diagnostic, prognostic, or pathogenic significance. Consequently, larger, prospective, and multi-center studies utilizing standardized anti-MCV assay protocols are necessary to rigorously evaluate the clinical utility of these antibodies in the management of RA-ILD.
Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to multi-organ dysfunction. Toll-like receptor signaling via MYD88- and TRIF-dependent pathways plays a central role in this process; however, its temporal and tissue-specific dynamics remain incompletely understood. The aim of this study was to investigate time-dependent transcriptional changes in MYD88- and TRIF-dependent signaling pathways across multiple organs in a murine model of sepsis. mRNA expression of MYD88, IRAK1, IRAK4, NF-kB, CCL4, CCL20, CCR2, IFN-β, IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-18, Klotho, KLF4, HOXA5, NANOG and HIF1α was quantified using qRT-PCR in intestinal, kidney, liver and lung tissues at 24, 48, and 72 h following cecal ligation and puncture-induced sepsis in male C57BL/6J mice. Significant upregulation of innate immune signaling molecules, cytokines, chemokines, and interferon-related genes was observed in all tissues compared with controls. Genes associated with hypoxia and cellular regulation were also increased. These responses were tissue-specific and progressively intensified over time. Sepsis represents a dynamic, time-dependent, and tissue-specific process characterized by sustained activation of immune and hypoxic pathways, providing potential targets for time-stratified therapeutic strategies.
[This corrects the article DOI: 10.3389/fimmu.2026.1732852.].
Cigarette smoke leads to pulmonary inflammatory injury. Relevant studies confirm it also disturbs gut microbiota and metabolism, but few time-course experiments are performed on juvenile rats. This study investigated intestinal microbial and metabolic alterations under CSE-induced lung injury. Male Wistar rats were randomly assigned to 3 groups: Control, 4-week CSE exposure (CSE 4 W), and 8-week CSE exposure (CSE 8 W). A modified intranasal instillation method was used to establish a lung injury model. Pulmonary function tests and histopathological evaluations were conducted to verify model establishment. Fecal samples were collected for 16S rRNA sequencing to profile the gut microbiota and for gas chromatography-mass spectrometry (GC-MS) to quantify SCFAs levels. Compared with the Control group, CSE 8 W group exhibited significantly impaired pulmonary function and elevated histopathological scores. Both α- and β-diversity of the gut microbiota were markedly altered. Concurrently, fecal concentrations of butyric acid and caproic acid were significantly decreased in the CSE 8 W group. CSE exposure induces progressive gut microbial dysbiosis and perturbs SCFA metabolism in juvenile rats. These findings provide experimental evidence linking CSE-exposure to intestinal alterations, suggesting further investigation into the potential mechanisms. CSE exposure in juvenile rats causes progressive lung injury, time-dependent gut dysbiosis, and disrupted SCFA metabolism, simulating smoking's harm to children's gut homeostasis. It links pulmonary damage to declines in beneficial SCFA producers (e.g., Blautia) and reduced SCFA via systematic time-course analysis. Lung-derived inflammation may disrupt gut homeostasis, reduce beneficial SCFA production, and form a vicious cycle. It underscores the need for understanding the crosstalk between CSE-exposed lungs and intestinal injury, identifying specific taxa and metabolites as potential biomarkers or intervention targets for pediatric tobacco harm mitigation.
Acute respiratory distress syndrome (ARDS) and subsequent pulmonary fibrosis are associated with high mortality and limited treatment options. Periostin (POSTN) is a profibrotic mediator predicted to be regulated by microRNA-19a-3p (miR-19a-3p), but the relevance of this axis in ARDS-associated pulmonary fibrosis remains unclear. Honokiol (HKL), a phytochemical derived from Magnolia officinalis, possesses antioxidant and anti-inflammatory properties. This study investigated whether HKL modulates the miR-19a-3p/POSTN axis in ARDS-associated lung injury and fibrosis. Serum POSTN and miR-19a-3p levels were measured in patients with ARDS and correlated with severity. Mechanistic studies were performed using a lipopolysaccharide (LPS)-induced lung injury mouse model and macrophage-epithelial and macrophage-fibroblast co-culture systems. Patients with ARDS exhibited elevated serum POSTN and reduced miR-19a-3p, which were inversely correlated and associated with indices of disease severity. HKL attenuated LPS-induced lung injury and fibrotic responses, accompanied by reduced POSTN expression and preserved miR-19a-3p levels. Dual-luciferase reporter assays supported a regulatory interaction between miR-19a-3p and POSTN. HKL was associated with alterations in macrophage phenotype and reduced macrophage-associated POSTN expression. In co-culture systems, manipulation of miR-19a-3p in macrophages modulated epithelial apoptotic signalling and fibroblast activation. In vitro loss-of-function experiments suggested that miR-19a-3p contributes, at least in part, to HKL-associated protective effects. The miR-19a-3p/POSTN axis may represent a regulatory pathway associated with ARDS-related lung injury and fibrosis. HKL attenuated experimental injury and fibrotic responses in association with this axis. These findings support further pharmacological investigation of HKL in ARDS-associated lung injury and fibrosis.
Resistance to 5-fluorouracil (5-FU) necessitates its administration in combination with other drugs to enhance the clinical outcome. Oxymatrine (OMT) exhibits antitumor and anti-inflammatory activities. This study aimed to investigate the synergistic antitumor effect of OMT with 5-FU in A549 cells. The knockout of human Apurinic/Apyrimidinic Endonuclease 1 (APE1) in A549 cells was achieved using shRNA. The level of APE1 protein was determined via Western blotting. The levels of IL-2, IL-6, and IL-8 were detected using ELISA. The level of intracellular Reactive Oxygen Species (ROS) and cell cycle were analyzed by flow cytometry. Genome-wide transcriptome profiling was conducted using RNA- sequencing technology and bioinformatics analyses. OMT synergistically augmented the antitumor activity of 5-FU in A549 cells by inhibiting the functions of APE1. OMT differentially modulated the secretion of IL-8, IL-6, and IL-2 from A549 cells in the presence of 5-FU. The inhibition of IL-8 and IL-6 by OMT predominantly occurred via APE1, whereas the inhibition of IL-2 by OMT was APE1-independent. OMT inhibited ROS production independent of APE1 and induced G2/M arrest in APE1-deficient cells. A genome-wide transcriptome analysis identified novel gene targets (B3GNT3, CRABP2, RHOV, and PCSK9) regulated by OMT, which contribute to its antitumor activity. These findings uncover a multitarget mechanism underlying the synergistic antitumor effect of OMT and 5-FU, confirming APE1 as a key regulatory factor linking inflammatory cytokine secretion, ROS homeostasis, and cell cycle progression in lung cancer cells. The newly identified target genes further elaborate the molecular basis of OMT-mediated tumor suppression. This work provides a potential strategy to overcome 5-FU resistance and optimize combination therapy for lung cancer treatment. This study addresses the issue of 5-FU chemoresistance in lung cancer by validating OMT as a functional synergistic adjuvant. The findings clarify the molecular mechanisms by which OMT enhances 5-FU antitumor efficacy, offering a credible experimental basis for the potential development of optimized combination therapeutic regimens for lung cancer.
In the last 15 years, the tobacco industry has marketed electronic cigarettes (e-cigarettes) as a tool to help adults to quit cigarette smoking, while also promoting their use in children and adolescents. As expected, this led to a marked increase in e-cigarette use (also called vaping) among children and adolescents in the U.S. Although the prevalence of vaping decreased after the 2019 EVALI epidemic and stricter regulations fueled by concurrent adoption of cigarette and marijuana smoking in youths, approximately 10% of middle- and high-school students in the U.S. report vaping. A growing body of experimental and epidemiologic evidence has implicated e-cigarette use in the pathogenesis of respiratory diseases such as chronic obstructive pulmonary disease (COPD), lung cancer, interstitial lung disease, and asthma. In this narrative review, we first evaluate the types and composition of e-cigarettes and trends in e-cigarette usage and then assess findings from experimental and epidemiologic studies of e-cigarette exposure and asthma published to date. We end by discussing future directions for research in this field while emphasizing the need for prevention of and screening for e-cigarette use in youths and adults, particularly those affected with asthma.
Avian colibacillosis caused by avian pathogenic Escherichia coli (APEC) results in high mortality and substantial economic losses in poultry production. Phage therapy represents a promising alternative strategy for controlling bacterial infections. In this study, we isolated the high-titer lytic APEC phage YX22 from poultry farm sewage, and evaluated its therapeutic potential in an experimental APEC infection model. Phage YX22 showed a short latent period of 10 min, a burst size of 158 PFU/cell, and stability across pH 4-10 and 30-60°C for 1 h. Transmission electron microscopy and whole-genome analysis indicated that YX22 belonged to the family Ackermannviridae and the AG3-like virus group. An experimental infection model was established in chicks using APEC strain IMT5155 to compare the effects of nebulized and oral phage administration. YX22 treatment reduced clinical symptom scores, tissue bacterial loads, and lung lesions in infected chicks. The survival rate of chicks receiving nebulized YX22 was 80%, compared with 70% in the oral phage and gentamicin groups and 53.33% in the APEC-challenged control group. Phage recovery assays showed that nebulized YX22 was detected in the respiratory tract within 3 h and in all tested tissues within 10 h. At 10 h after administration, YX22 titers in the lungs and spleen were higher after nebulized administration than after oral administration. These findings suggest that nebulized YX22 has therapeutic potential against experimental avian colibacillosis caused by APEC strain IMT5155, but further studies under production conditions are required.