Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that is strongly associated with aging. How aging contributes to fibroblast state remodeling and intercellular signaling dysregulation in IPF remains poorly defined. We integrated bulk transcriptomics, single-cell RNA sequencing, spatial transcriptomics, and DNA methylation data from human IPF lungs to characterize fibroblast heterogeneity, trajectory dynamics, intercellular communication, and epigenetic aging. SLIT2 downregulation and senescence-associated changes were then examined in a bleomycin (BLM)-induced mouse model of pulmonary fibrosis. The effects of SLIT2 on fibroblast senescence and paracrine pro-fibrotic activity were assessed in BLM-treated MRC-5 fibroblasts using recombinant SLIT2 supplementation and siRNA-mediated knockdown. In an independent DNA methylation cohort, epigenetic aging clocks and mediation analyses in both directions were used to examine statistical relationships among epigenetic age acceleration, SLIT2 expression, and IPF risk. These analyses identified five fibroblast subtypes, with TCF21⁺ fibroblasts predominating in normal lung and CTHRC1⁺ fibroblasts markedly enriched in IPF. Trajectory analyses inferred a potential fibroblast state trajectory from homeostatic TCF21⁺ toward pathological CTHRC1⁺ fibroblast states, along which a senescent TCF21⁺ subpopulation showed preferential trajectory bias toward the CTHRC1⁺ endpoint. SLIT2 was preferentially expressed in TCF21⁺ fibroblasts, which represented an important predicted sender population within the SLIT-ROBO communication network. In a BLM-induced mouse model, fibrotic remodeling was accompanied by increased senescent cell burden and SLIT2 downregulation, consistent with the observations in human IPF. In vitro, rhSLIT2 attenuated BLM-induced senescence and pro-fibrotic paracrine activation, whereas SLIT2 knockdown exacerbated both. SLIT2 manipulation also altered NF-κB signaling and SASP-associated responses, supporting a regulatory role for SLIT2 in senescence-associated inflammatory and pro-fibrotic remodeling. In an independent DNA methylation cohort, SLIT2 promoter hypermethylation co-occurred with multi-dimensional epigenetic aging acceleration and was inversely correlated with SLIT2 expression. Mediation analyses suggested potential reciprocal associations between epigenetic aging acceleration and SLIT2 silencing in relation to IPF risk. Overall, this study identifies an aging-associated fibroblast remodeling pattern in IPF, characterized by senescence-associated TCF21⁺ fibroblasts and an inferred relationship toward pathological CTHRC1⁺ fibroblast states. SLIT2 emerged as a regulator of TCF21⁺ fibroblast homeostasis, with its reduction associated with NF-κB/SASP activation and pro-fibrotic phenotypes. Epigenetic aging acceleration and SLIT2 dysregulation were associated with IPF risk, highlighting SLIT2 as a potential therapeutic target in aging-associated pulmonary fibrosis.

Objective To investigate the effects of isorhamnetin (ISO) on the viability and apoptosis of breast cancer cells and the underlying mechanisms.Methods The CCK-8 assay was used to evaluate the effect of ISO on the proliferative activity of MDA-MB-231 cells and to calculate the half-maximal inhibitory concentration (IC50). Plate colony formation assay and flow cytometry were performed to detect cell proliferation and apoptosis. Microarray sequencing and bioinformatics analysis were conducted to identify differentially expressed genes and related biological functions after ISO treatment. Intracellular reactive oxygen species (ROS) levels were measured using the DCFH-DA fluorescent probe, and the contents of malondialdehyde (MDA) and glutathione (GSH) were determined. The expression of proteins in the Keap1-Nrf2 signaling pathway was assessed by qRT-PCR and Western Blot. An Nrf2-knockdown MDA-MB-231 cell model was established using siRNA, and the above indicators were re-evaluated following ISO treatment.Results ISO inhibited the viability of MDA-MB-231 cells in a concentration-dependent manner (IC50 = 23.38 μmol/L), reduced cell proliferation, and induced apoptosis. Sequencing analysis revealed that the biological functions affected by ISO were closely associated with the Keap1-Nrf2 signaling pathway. ISO treatment significantly increased intracellular ROS and MDA levels and decreased GSH content in MDA-MB-231 cells. It downregulated Keap1 mRNA and protein expression while upregulating the mRNA and protein expression of Nrf2, HO-1, GCLM, and NQO1. Knockdown of Nrf2 combined with ISO treatment further enhanced ROS accumulation, inhibited cell proliferation, promoted apoptosis, and weakened the activation of the Keap1-Nrf2 signaling pathway by ISO.Conclusion ISO inhibits the malignant progression of breast cancer cells by inducing ROS accumulation, but simultaneously activates the Keap1-Nrf2 signaling pathway to attenuate its cytotoxicity. Targeted inhibition of Nrf2 effectively dismantles this defense mechanism, synergistically enhancing the antitumor effect of ISO by promoting ROS accumulation.

Parthenolide (PTN), a sesquiterpene lactone derived from the medicinal plant feverfew (Tanacetum parthenium), and its derivatives such as dimethylamino parthenolide (DMAPT) and dimethylaminomicheliolide fumarate (ACT001) exhibit distinguished anti-inflammatory, anticancer, antioxidant, and epigenetic activities, with accumulating evidence demonstrating their therapeutic potential in respiratory diseases. This review systematically summarizes the antitumor, anti-inflammatory, antioxidative, and antifibrotic effects of PTN and its derivatives in relevant animal models, elucidates the underlying pharmacological mechanisms involving STAT3, NF-κB, MAPK/ERK, and PI3K signaling pathways, and highlights recent advances in clinical applications and drug delivery strategies. A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus up to February 2026. Results demonstrate that PTN and its derivatives exert significant therapeutic effects in lung cancer, pulmonary fibrosis, asthma, pneumonia, and acute lung injury. We summarize the clinical translation progress of ACT001, including its safety and pharmacokinetic profiles, discuss emerging delivery systems such as micelles, and review the patent landscape of PTN derivatives. By integrating mechanistic insights with progress in clinical applications and drug delivery, this review provides a foundation for further mechanistic studies and supports the translational development of PTN-based therapies for respiratory disorders.

Accurate prediction of postoperative recurrence in lung adenocarcinoma (LUAD) is essential for guiding clinical decision-making and improving patient outcomes. Although various predictive models have been developed, most rely on complex genomic analyses and high-dimensional clinical data. The complexity of these approaches substantially limits their feasibility for routine clinical use. To address this clinical challenge, this study aims to predict postoperative recurrence using routinely available hematoxylin and eosin (H E)-stained images and characterize the associated biological features. A total of 329 patients who underwent curative resection at the First Affiliated Hospital of Wenzhou Medical University (FHWMU) were retrospectively enrolled and randomly assigned to training and internal validation cohorts in a 7:3 ratio. An independent external validation cohort comprising 70 patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was included. Three patch-level feature extractors (Inception_V3, ResNet18, and DenseNet121) were evaluated within a weakly supervised multiple-instance learning (MIL) framework incorporating automated region-of-interest (ROI) detection on segmented whole-slide images (WSIs). Model performance was assessed using the area under the receiver operating characteristic curve (AUC), Kaplan–Meier (KM) survival analysis, and multivariable Cox proportional hazards regression. Transcriptomic profiling and gene set enrichment analysis (GSEA) were conducted to investigate biological differences between risk groups. The model achieved AUCs of 0.923 in the training cohort, 0.891 in the internal validation cohort, and 0.847 in the external validation cohort. The model effectively stratified patients into high- and low-risk groups with significantly different recurrence-free survival (RFS) across all cohorts (all P < 0.001) and retained prognostic value within AJCC stages I–III. Transcriptomic analyses revealed consistent enrichment of cell cycle-related pathways and neutrophil extracellular trap (NET) formation in high-risk patients across both institutional and CPTAC cohorts, aligning with distinct biological profiles of the model-derived risk stratification. This weakly supervised deep learning framework enables accurate and externally validated prediction of postoperative recurrence in LUAD using routinely available histopathological images, and integration of histopathological features with molecular analyses enhances biological interpretability. This work provides a clinically accessible and cost-effective tool for postoperative risk assessment in LUAD patients.

Background:Systemic lupus erythematosus (SLE) is characterized by aberrant immune activation and disrupted iron metabolism, yet the molecular mediators that govern both processes remain unclear. This study aims to identify pivotal genes that modulate immune responses and iron metabolism, and to delineate their contributions to SLE pathogenesis. Methods:Differentially expressed genes related to iron metabolism (IM-DEGs) were identified using datasets (GSE72326, GSE110169, GSE126307, and GSE50772) from the GEO database and the MSigDB. Functional enrichment analyses were performed on the iron metabolism related genes (IM-Genes). A weighted gene co-expression network analysis was constructed to identify hub genes, which were further refined as potential biomarkers using the least absolute shrinkage and selection operator method. The predictive value of these biomarkers was validated using receiver operating characteristic (ROC) curves and the nomogram. CIBERSORT was employed to evaluate immune cell infiltration in SLE. Additionally, the expression and function of RSAD2 were confirmed using RNA interference, quantitative real-time PCR, and Western blotting techniques. Results:Bioinformatics analyses identified 4 potential biomarkers: RSAD2, MT2A, LCN2, and LTF. RSAD2 exhibited the highest clinical validity (AUC = 0.927) and was closely associated with classic diagnostic indicators. Its diagnostic potential was confirmed through ROC curve and nomogram, highlighting its role in SLE pathogenesis. Elevated RSAD2 expression was observed in peripheral blood mononuclear cells of SLE patients, positively correlating with activated dendritic cells (DCs). Notably, Rsad2 knockdown markedly impaired the function of activated DCs, as evidenced by suppressed expression of inflammatory mediators and iron metabolism-related genes. Conclusion:Our findings suggest that RSAD2 is a potential diagnostic biomarker and therapeutic target for SLE, elucidating the intricate relationship between immune dysregulation and aberrant iron metabolism in activated DCs, which exacerbates SLE.

Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the Protein kinase A (PKA) /CREB signalling pathway. PDE4DIP coordinates with A-kinase anchoring proteins 9 (AKAP9) to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC. Mechanistic exploration of PDE4DIP in the progression of non-small cell lung cancer (NSCLC) demonstrates that PDE4DIP coordinates with AKAP9 to promotes NSCLC growth via regulating PKA/CREB signaling pathway.

BACKGROUND:We aimed to explore the value of a PET/CT-based radiomics signature in predicting occult lymph node metastasis (OLM) and outcomes in clinical N0 (cN0) lung adenocarcinoma (LUAD), to uncover the biologic meaning of OLM-associated radiomics phenotypes and to validate the reproducibility of the identified radiomics-correlated key genes. METHODS:A radiomics signature for OLM prediction was developed in a training cohort and validated across multiple validation and testing cohorts in this multicenter study. Prognostic implications of the radiomics score (Radscore) were assessed by measuring recurrence-free survival. Biologic processes and pathways were enriched and correlated with Radscore and each of the 8 radiomics phenotypes using paired PET/CT and RNA sequencing data. The reproducibility of identified radiomics-associated key genes was validated using a public database, clinical tissue samples, and in vitro experiments. RESULTS:Here we show OLM is detected in 127 (19.9%) of 637 patients. The proposed signature achieves AUCs of 0.82, 0.81, 0.78 and 0.79 in the training, internal validation, prospective testing and external testing cohort, respectively. In addition, Radscore is identified as an independent predictive factor in predicting the risk of recurrence of LUAD. Furthermore, Radscore and OLM-related radiomics features are mostly associated with immune response. Finally, four key genes (MIR600HG, FAM13A-AS1, AQP4 and GRIA1), especially the MIR600HG gene, play important roles in OLM and prognosis of early-stage LUAD. CONCLUSIONS:We demonstrate that radiogenomics performed on PET/CT images provides complementary clinical, prognostic and molecular information with great potential for the prediction of OLM and risk stratification in cN0 LUAD.

RATIONALE AND OBJECTIVES:This study aimed to develop and validate machine learning (ML) models utilizing positron emission tomography (PET)-habitat of the tumor and its peritumoral microenvironment to predict progression-free survival (PFS) in patients with clinical stage IA pure-solid non-small cell lung cancer (NSCLC). MATERIALS AND METHODS:234 Patients who underwent lung resection for NSCLC from two hospitals were reviewed. Radiomic features were extracted from both intratumoral, peritumoral and habitat regions on PET. Univariate and multivariate logistic regression analyses were employed to determine significant clinical variables. Subsequently, a radiomics nomogram was developed by combining the radiomics signature with these identified clinical variables. Kaplan-Meier (KM) analysis was performed to investigate the prognostic value of the nomogram. Shapley Additive Explanations (SHAP) were used to interpret the ML models. RESULTS:The combination model which contained peritumoral 5 mm and habitat regions radiomics features, clinical variables obtained a strong well-performance, achieving area under the curve (AUC) of 0.905 (95% confidence interval (CI) 0.854-0.957) in the train set and 0.875 (95% CI 0.789-0.962) in the internal validation set. The radiomics signature was significantly associated with PFS, the model significantly discerned high and low-risk patients, and exhibited a significant benefit in the clinical use showed low-risk score given have far longer RFS than those with high-risk score (log-rank P＜0.001). CONCLUSION:The habitat and peritumoral radiomics signatures serve as an independent biomarker for predicting PFS in patients with early-stage NSCLC, effectively stratified survival risk among patients with clinical stage IA pure-solid non-small cell lung cancer.

PURPOSE:The aim of this study was to investigate the anti-tumor effects and mechanisms of Raddeanin A in NSCLC in vitro and in vivo. METHODS:The effects of Raddeanin A on cell cycle progression, proliferation, migration and invasion of NSCLC were assessed by flow cytometry and cell biological assays in multiple NSCLC cell lines. To identify possible targets of Raddeanin A in NSCLC, we employed a multifaceted approach incorporating network pharmacology, molecular docking, and molecular dynamics simulation, along with additional techniques such as SPR (Surface Plasmon Resonance), Co-IP (Co-Immunoprecipitation), and immunofluorescence. In vivo effects were investigated using a nude mouse xenograft tumor model. RESULTS:Raddeanin A inhibits NSCLC cell survival, inhibits invasion and migration and causes cell cycle arrest in G1 phase. Raddeanin A impacts NSCLC cellular activity by inhibiting CDK6, leading to anti-tumor effects. Molecular analysis confirms that the tight binding between Raddeanin A and CDK6, facilitated by specific hydrogen bonds at binding sites including VAL-101, HIS-100, GLN-149, LYS-147, THR-182, VAL-180, and ALA-23, stabilizes within the 40-100 ns interval. In a nude mouse xenograft tumor model, Raddeanin A also demonstrated an inhibitory effect on NSCLC tumor growth. CONCLUSIONS:Raddeanin A blocks the cell cycle in G1 phase by inhibiting CDK6. Raddeanin A is expected to be a novel antitumor agent against NSCLC.

Achieving precise delivery of extracellular vesicles (EVs) to treat pulmonary arterial hypertension (PAH) remains challenging. Here, we propose a strategy using hypoxia-induced and glucuronic acid (GA)-modified mesenchymal stromal-cell-derived EVs (MSC-EVs) to enhance their functionalities and therapeutic targeting. The hypoxia-induced EVs (Hypo-EVs) exhibit enriched exosomal signatures and display heightened inhibition of the proliferation of pulmonary arterial smooth muscle cells (PASMCs) compared to normoxic EVs (Norm-EV). We then modify Hypo-EVs by incorporating GA into their outer membrane, targeting glucose transporter-1 overexpressed on PASMCs. Our studies show that GA-EVs significantly enhance the therapeutic efficacy, both in vitro and in vivo, through improved targeted delivery to diseased PASMCs for improving vascular remodeling. Additionally, we identify miR-5119 involved in the PAH-associated calcium signaling pathway as a key contributor to GA-EVs' superior effects. This work provides a promising strategy for PAH treatment and advances the clinical potential of MSC-EV-based therapies.

BACKGROUND:Pulmonary hypertension (PH) is a chronic lung disease characterized by the progressive pulmonary vascular remodeling with increased pulmonary arterial pressure and right ventricular failure. Pulmonary vascular remodeling involves the proliferation, migration, and resistance to apoptosis of pulmonary artery smooth cells (PASMCs). Parthenolide (PTN) is a bioactive compound derived from a traditional medical plant feverfew (Tanacetum parthenium), and it has been studied for treatment of pulmonary fibrosis, lung cancer, and other related ailments. However, the function of PTN in the treatment of PH has not been studied. PURPOSE:This study aimed to evaluate the anti-proliferation and pro-apoptosis effects of PTN on PH and investigate its potential mechanisms. METHODS:An in vivo hypoxia-induced pulmonary hypertension (HPH) model was established by maintaining male rats in a hypoxia chamber (10% O2) for 3 weeks, and PTN was intraperitoneally administered at the dose of 10 or 30 mg/kg. We assessed the impact of PTN on mean pulmonary arterial pressure (mPAP), pulmonary vascular remodeling, and right ventricular hypertrophy. In vitro, we evaluated hypoxia-induced cellular proliferation, migration, and apoptosis of rat PASMCs. Proteins related to the STAT3 signaling axis were analyzed by western blotting and immunofluorescence assays. Recovery experiments were performed using the STAT3 activator, colivelin TFA. RESULTS:PTN significantly alleviated the symptoms of HPH rats by attenuating pulmonary arterial remodeling. It also prevented the proliferation and migration of PASMCs. PTN also induced the apoptosis of PASMCs. PTN could directly interact with STAT3 and markedly inhibited STAT3 phosphorylation and nuclear translocation. In vitro, and in vivo experiments demonstrated that overexpression of STAT3 partially suppressed the effect of PTN. CONCLUSION:Our study indicated that PTN alleviated hypoxia-induced pulmonary hypertension in rats by suppressing STAT3 activity.

Noncoding RNAs have been shown to play important roles in hypoxic pulmonary hypertension (HPH). Our preliminary data showed that HPH is attenuated by fibroblast growth factor 21 (FGF21) administration. Therefore, we further investigated the whole transcriptome RNA expression patterns and interactions in a mice HPH model treated with FGF21. By whole-transcriptome sequencing, differentially expressed mRNA, miRNA, lncRNA, and circRNA were successfully identified in normoxia (Nx) vs. hypoxia (Hx) and Hx vs. hypoxia + FGF21 (Hx + F21). Through intersection and predictive analysis, differentially co-expressed mRNA, miRNA, lncRNA, and circRNA were selected, followed by functional enrichment analysis. MAPK signaling pathway and epigenetic modification were enriched and may play fundamental roles in the therapeutic effects of FGF21. A ceRNA regulatory network was constructed with miR-7a-5p, miR-449c-5p, miR-676-3p and miR-674-3p as the core. Then the quantitative real time-PCR validation results were consistent with the results of whole-transcriptome sequencing. This study may provide potential biomarkers, pathway and ceRNA regulatory network in HPH treated with FGF21.

We attempted to investigate the role of HOXB7 in tumor progression and evolution by means of an extensive computer screening analysis of various cancer types. We performed univariate Cox regression and Kaplan-Meier survival analyses to assess the impact of HOXB7 on overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in different types of cancer. Furthermore, we examined the relationship between HOXB7 and several clinical features: tumor microenvironment, immune regulatory genes, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). We performed gene set enrichment analysis to gain deeper insights into the potential molecular mechanisms of HOXB7, and validated our findings through functional assays in cells, including methyl thiazolyl tetrazolium cytotoxicity and Transwell invasion assays. HOXB7 expression was associated with different clinical characteristics in numerous malignancies. Higher HOXB7 expression was associated with worse OS, DSS, and PFI in some cancer types. In particular, HOXB7 expression was favorably associated with immune cell infiltration, immune regulatory genes, immunological checkpoints, TMB, and MSI in malignancies. Furthermore, we identified a strong link between copper death-associated gene expression and HOXB7 expression. According to the findings of this study, HOXB7 might serve as an appealing focus for tumor diagnosis and immunotherapy and a prospective indicator of prognosis.

Chemotherapy is regarded as a widely used and effective treatment strategy for lung cancer, although most conventional chemotherapeutics cause severe toxic side-effects due to their indiscriminate attacks on both cancerous and normal cells. Although nucleic acid nanomaterials are emerging as a promising drug delivery strategy, their clinical applications are limited by rapid degradation by nucleases and difficulties in targeting cancer cells. In this study, we have developed a Rhein-loaded aptamer-based DNA nanotube (DNT-S6@Rhein) for the targeted and efficient therapy of non-small cell lung cancer. Through the palindrome segments, two specified oligonucleotides were hybridized and folded into the well-defined nanotubes (DNT-S6), with the S6 aptamer distributed outside. The obtained nanotubes exhibited excellent serum stability and targeting ability towards A549 cells due to the firm structure and decoration of the S6 aptamer. Rhein, as an antitumor drug and DNA intercalator, can be effectively inserted into the DNT-S6. The drug-loaded nanotubes rapidly disassembled in intracellular environment and then the released Rhein was found to activate cellular apoptotic process and significantly suppress proliferation, migration and invasion of A549 cells. Moreover, DNT-S6@Rhein could efficiently accumulate in tumor regions, offering compelling therapeutic efficacy and biocompatibility under both in vitro and in vivo settings. These findings of this study provide a promising strategy for mitigating the inevitable systemic side-effects of chemotherapy and expand the potential application of DNA nanostructure on targeted drug delivery.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Background XueFuZhuYu (XFZY), a typical Chinese herbal formula, has remarkable clinical effects for treating Pulmonary Hypertension (PH) with unclear mechanisms. Our research involved the utilization of network pharmacology to explore the traditional Chinese herbal monomers and their related targets within XFZY for PH treatment. Furthermore, molecular docking verification was performed. Methods The XFZY's primary active compounds, along with their corresponding targets, were both obtained from the TCMSP, ChEMBL, and UniProt databases. The target proteins relevant to PH were sifted through OMIM, GeneCards and TTD databases. The common "XFZY-PH" targets were evaluated with Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses with the assistance of R software. The Protein-Protein Interaction (PPI) network and compound-target-pathway network were constructed and a systematic analysis of network parameters was performed by the powerful software Cytoscape. Molecular docking was employed for assessing and verifying the interactions between the core targets and the top Chinese herbal monomer. Results The screening included 297 targets of active compounds in XFZY and 8400 PH-related targets. DO analysis of the above common 268 targets indicated that the treatment of the diseases by XFZY is mediated by genes related to Chronic Obstructive Pulmonary Disease (COPD), Obstructive Lung Disease (OLD), ischemia, and myocardial infarction. The findings from molecular docking indicated that the binding energies of 57 ligand-receptor pairs in PH and 20 ligand-receptor pairs in COPD-PH were lower than -7kJ center dot mol-1. Conclusions This study indicates that XFZY is a promising option within traditional Chinese medicine compound preparation for combating PH, particularly in cases associated with COPD. Our demonstration of the specific molecular mechanism of XFZY anti-PH and its effective active ingredients provides a theoretical basis for better clinical application of the compound.

Extracellular vesicles (EVs) are increasingly acknowledged as important mediators of intercellular communication, closely related to the occurrence and development of a variety of diseases. Numerous studies have demonstrated that EVs play a multifaceted role in the infection process of viral diseases, elucidating their ability to both facilitate viral spread and inhibit infection progression. These versatile entities not only enhance infection rates and widen the scope of viral infection through the transmission of entire viruses or viral genomes, but also trigger antiviral responses and prompt cytokine secretion near the infection site, thereby fortifying the host's defense mechanisms and safeguarding neighboring cells against infection. This complicated crosstalk between EVs and viral infections prompts a deeper exploration into their roles in potential clinical applications. In this review, we aim to encapsulate the recent advances in understanding the intricate interplay between viruses and EVs, shedding light on the mechanisms underlying this vesicle-to-virion crosstalk. Furthermore, we underscore the significance of harnessing this knowledge for diagnostic and therapeutic functions in combating viral diseases.

BackgroundIn recent years, the hypervirulent and carbapenem-resistant Klebsiella pneumoniae has been increasingly reported worldwide. The objective of this study was to compare the antibiotic resistance and virulence profiles of carbapenem-resistant hypervirulent K.pneumoniae (CR-hvKP) and hypervirulent carbapenem-resistant K.pneumoniae (hv-CRKP) and identify the prevailing strain in clinical settings.MethodsIn this study, hv-CRKP or CR-hvKP were identified based on the results of whole-genome analysis (WGS), multilocus sequence typing (MLST) and the antimicrobial susceptibility testing. We then compared antibiotic resistance and virulence profiles between CR-hvKP and hv-CRKP through the antimicrobial susceptibility testing and a series of virulence experiments including biofilm formation ability detection method, the resistance test against human serum, siderophore production test, neutrophil phagocytosis assay and Galleria mellonella infection model. Additionally, pathway enrichment analysis was conducted to assess the effect of SNPs on the phenotype.ResultsIn this study, we categorized 17.4% of hypervirulent and carbapenem-resistant K. pneumoniae strains as CR-hvKP and 82.6% as hv-CRKP. Among them, 84.2% (16/19) of CR-hvKP strains harboring carbapenemase genes exhibited lower imipenem and meropenem MIC values compared to hv-CRKP strains. The virulence potential of hv-CRKP and CR-hvKP was confirmed by using virulence experiments in vitro and in vivo, showing that virulence of the CR-hvKP strains was comparable to that of hv-CRKP strains. Notably, the 90 hv-CRKP strains were classified into 3 different ST types and 8 capsule types, each showing varying degrees of resistance and virulence. We observed that subclonal replacement was within the predominant hv-CRKP clone, with the ST11-KL64 strain, characterized by high-level resistance and virulence emerging as the currently prevailing subclone, replacing ST11-KL47. KEGG enrichment analysis showed that pathways associated with the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, glutathione metabolism, two-component regulatory system, and folate metabolism were significantly enriched among the group expressing different levels of capsular polysaccharides.ConclusionsThe hv-CRKP strains exhibited a greater survival advantage in the hospital environment than CR-hvKP strains. Notably, the ST11-KL64 hv-CRKP strain which displayed a high level of resistance and hypervirulence, warrants the most clinical vigilance.Clinical trial numberNot applicable.

Ethnopharmacological relevance: Pulmonary fibrosis (PF) is a persistent and refractory illness accompanied by inflammation and fibrosis. Gracillin, a natural steroidal saponin, is one of the components of Dioscorea quinqueloba which has been used in herbal medicines for treating some inflammatory diseases. Therefore, it may be a potential drug candidate for PF management.Aim of the study: This study aims to elucidate and verify the anti-pulmonary fibrosis effect of gracillin.Methods: We established an in vivo model of PF by treatment of mice with bleomycin (BLM) and an in vitro model by treatment of NIH-3T3 cells with TGF-& beta;1. Pathological changes to the structure of lung tissue, pulmonary function, inflammatory exudation of bronchoalveolar lavage fluid (BALF) and deposition of collagen were detected in vivo, and extracellular matrix (ECM) deposition and migration were evaluated in vitro. The significance of gracillin on STAT3 phosphorylation and nuclear translocation were evaluated by western blotting, immunohistochemistry and immunofluorescence assays. The STAT3 transcriptional activity was quantified with a dual-luciferase reporter assay. Recovery experiments were performed by plasmid-directed overexpression of STAT3.Results: We found that gracillin could improve pulmonary function, reduce lung inflammation and mitigate collagen deposition to ameliorate BLM-induced PF in mice. Gracillin also suppressed TGF-& beta;1-induced increases in ECM deposition biomarkers, including COL1A1, fibronectin, & alpha;-SMA, N-cad and vimentin, and repressed migration in NIH-3T3 cells. Additionally, gracillin suppressed the phosphorylation, nuclear translocation and transcriptional action of STAT3. Furthermore, the decreased ECM deposition and migration upon gracillin treatment were abrogated upon overexpression of STAT3 in NIH-3T3 cells.Conclusions: Gracillin protects against PF by inhibiting the STAT3 axis, providing a safe and efficacious approach to treating PF.