Current Medicinal Chemistry - Online First

The coronavirus 3C-like protease (3CLpro) is essential for SARS-CoV-2 replication, making it a key target for antiviral drug development. Natural products represent a valuable source of bioactive compounds. This study aimed to identify novel 3CLpro inhibitors from natural compounds through a combination of virtual screening and experimental validation.

Recombinant 3CLpro was expressed, purified, and evaluated for enzymatic activity using Fluorescence Resonance Energy Transfer (FRET) assays under optimized conditions. Out of 583 virtually screened compounds, 30 were selected for experimental validation. Epitheaflagallin 3-O-gallate (ETFGg) was further analyzed for binding interactions using Molecular Dynamics (MD) simulations.

ETFGg exhibited strong binding affinity (−66.90 kcal/mol) and inhibitory activity (IC50 = 8.73 ± 2.30 μM) against 3CLpro. MD simulations revealed stable interactions with key residues (HIE163, THR190, GLN192) in the 3CLpro active site.

Our findings demonstrate that ETFGg is a potent and stable inhibitor of SARS-CoV-2 3CLpro, with a binding profile distinct from known inhibitors such as ebselen. The substrate inhibition kinetics observed suggest a novel allosteric mechanism, which may provide a new strategy for targeting 3CLpro. This study supports the value of natural product libraries combined with computational and FRET-based screening for discovering antiviral leads.

ETFGg was identified as a promising 3CLpro inhibitor with high binding stability, highlighting its potential as a lead compound for the development of anti-COVID-19 drugs.

Lung cancer is a leading cause of cancer-related morbidity and mortality. The development and evaluation of effective treatment strategies for lung cancer are of high clinical importance. Everolimus (Eve) has been shown to upregulate the expression of phosphatases and inhibit the migration and proliferation of A549 cancer cells. The present study focuses on the synthesis of biodegradable bovine serum albumin (BSA) nanoparticles for the loading and delivery of Eve.

In the desolvation process, Eve molecules were kept in the BSA system. The physicochemical properties of the Eve drug containing BSA nanoparticles (Eve@BSA) have been exactly characterized. The loading and release assays of Eve were also studied at different glutaraldehyde percentages, times, and solvents.

Field emission scanning electron microscopy (FE-SEM) analysis of BSA nanoparticles revealed a spherical morphology with an average size of 93.7 ± 3.7 nm. The results demonstrated that BSA nanoparticles are highly efficient carriers, achieving an Eve loading efficiency of approximately 54% at 4% glutaraldehyde. The release of Eve from the BSA nanoparticles was dependent on the solvent and duration of incubation. According to the MTT assay, Eve@BSA exhibited low cytotoxicity and high biocompatibility against L929 fibroblast cells. In contrast, the cytotoxicity of Eve@BSA against A549 cells (IC50 ≈ 47 μg/mL) was significantly higher than that of free Eve (IC50 ≈ 283 μg/mL) after 48 hours.

The synergistic effects of Eva@BSA nanoformulation due to functional groups-rich BSA seemed to improve in vitro antiproliferation efficacies compared with the single treatment of Eve.

The findings confirm the synergistic anticancer effect of Eve@BSA, indicating that this nanosystem may serve as a promising candidate for the treatment of lung cancer.

The development and progression of non-small cell lung cancer (NSCLC) are intricately linked to immune cell activation, but its related signature has not been reported.

This study combines in silico and in vitro approaches. TCGA-NSCLC and Gene Expression Omnibus (GEO) datasets were utilized to develop and validate a prognostic signature based on cell activation genes. The signature’s validity was assessed through the identification of genomic, transcriptomic, tumor microenvironment (TME), and single-cell infiltration characteristics. The function of the candidate gene RORA was verified using CCK8, apoptosis, colony formation, wound healing, and transwell assays. The detailed mechanism of RORA was investigated through ChIP-PCR, luciferase assays, Western blot, and ROS detection.

The prognostic signature was constructed from TCGA-NSCLC datasets and validated in six independent datasets (GSE30219, GSE33072, GSE37745, GSE41271, GSE42127, GSE50081). The signature was associated with LRP1B and RYR2 mutations, NSCLC-related pathways, drug response, and immune cell infiltration. The candidate gene RORA significantly inhibits the proliferation and migration abilities of NSCLC cell lines (A549 and NCI-H1299). Furthermore, the transcription factor RORA promotes ZNF490 expression, which subsequently inhibits NUDFs expression and oxidative phosphorylation (oxphos).

The signature highlighted its significance with genomic features that were frequently reported as prognostic indicators (LRP1B and RYR2 mutations, cancer-related infiltration and pathway infiltration), and putative treatment response (IC50 in the TCGA dataset). Its detailed mechanism of candidate gene RORA revealed its role in oxphos, highlighting the crosstalk between metabolism and immune activation.

The model is robust and effectively reflects NSCLC heterogeneity while predicting prognosis. RORA promotes the expression of ZNF490 to inhibit NUDFs and oxidative phosphorylation.

An excessive inflammatory response plays a central role in the pathogenesis of ulcerative colitis (UC), but the specific cytokines involved remain unclear. This study aimed to identify inflammatory factors associated with UC and explore the possible mechanisms of the identified targets.

Protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) for inflammatory cytokines were obtained from a genome-wide pQTL study and the eQTL consortium, respectively. Summary data for UC from the exploration and validation cohorts were derived from a genome-wide association study and the Finngen cohort. MR and colocalization analyses were conducted to identify causal associations between inflammatory cytokines and UC. Bioinformatics analyses were employed to explore the involved biological processes of candidate targets. Immunohistochemistry was used to validate the expression of these candidate targets in colon tissues.

Among all inflammatory cytokines, a significant causal association was identified between C-X-C motif chemokine ligand 5 (CXCL5) and UC. Using eQTL data, a significant genetic association was established between the mRNA expression of CXCL5 and its receptor, C-X-C motif chemokine receptor 2 (CXCR2), with UC. Colocalization analysis further supported these identified links. Differential expression analysis confirmed the dysregulation of the CXCL5/CXCR2 axis in UC patients. Enrichment and immune infiltration analysis indicated that the CXCL5/CXCR2 axis was involved in neutrophil chemotaxis and immune activation in UC. Moreover, CXCL5 expression was found to correlate with neutrophil extracellular trap (NET) formation in UC. Immunohistochemistry further confirmed the dysregulation of the CXCL5/CXCR2 axis in colon tissues of UC patients.

The CXCL5/CXCR2 axis has been implicated to play a significant role within a broader inflammatory network that includes Interleukin (IL)-17, NF-κB, and Tumor Necrosis Factor (TNF) signaling pathways. Additionally, this axis interacts with macrophages and T cells, further contributing to the complexity of inflammatory responses in UC.

There is a significant association between CXCL5/CXCR2 and UC under the MR assumption, which is potentially linked with colonic chemotaxis and activation of neutrophils. These findings highlight the potential of CXCL5/CXCR2 as a therapeutic target for UC. However, future functional studies are needed to validate these findings and explore the exact mechanisms by which CXCL5/CXCR2 influences immune cell crosstalk in UC.

Spirooxindoles have been reported to be effective anticancer drug candidates by displaying promising pre-clinical results. Therefore, to find out a lead spirocyclic oxindole template, a series of spirooxindole derivatives bearing pyrrolizidine (14a-e) and N-methyl pyrrolidine (15a-e) were synthesized using an efficient multicomponent, one-pot, and stereoselective [3+2] cycloaddition reaction and evaluated in vitro against HT29 and HCT116 human colon cancer cell lines.

The pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives were synthesised in excellent regio- and stereoselectivity using previously optimized reaction conditions. They were evaluated in vitro against cell lines HT29 and HCT116. In silico ADME profiling, molecular docking, and dynamics simulation studies were performed to ascertain the probable mode of action of the lead derivative.

The spirooxindoles were characterized using FTIR, ESI-MS, ¹H and ¹³C NMR, purity was determined by RP-HPLC, and stereochemistry was confirmed by X-ray crystallography. Compound 14a produced the best anti-colon cancer activity with IC50 values of 62.66 and 9.55 µM against HT29 and HCT116 human colon cancer cell lines, respectively. The in silico studies revealed that MDM2 protein inhibition is a probable mode of anti-colon cancer activity, supported by the data obtained in the molecular docking and molecular dynamics study.

The described [3+2] cycloaddition reaction proved to be a highly efficient and catalyst-free reaction. The in vitro cell viability assays and in silico studies revealed that more spirooxindoles can be designed with a varied degree of substitution to target colon cancer.

Sarcomas are heterogeneous mesenchymal tumors with poor responses to systemic therapies. Ubiquitination is a post-translational modification that regulates various physiological processes and cancer growth.

We analyzed the transcriptomic data of 256 sarcoma patients from The Cancer Genome Atlas (TCGA) to define the network and prognostic value of predefined ubiquitination-related genes and performed subgroup analyses. Additionally, the role of TRIM21 in sarcoma progression was explored using cellular experiments.

We identified two ubiquitination-related clusters, and patients in the two clusters were characterized by different survival outcomes, enriched pathways, and characteristics of the tumor microenvironment. A ubiquitination-related signature involving LRRC41, RNF125, TRIM21, and UBE3D was identified to predict prognoses. The signature was associated with patient prognoses in the public sarcoma cohorts and our independent cohort. Immunohistochemistry analyses revealed that the risk score and CD8 could distinguish patients with different survival outcomes in our cohort. Mechanistically, different risk groups were also characterized by distinct enriched pathways and characteristics of the tumor microenvironment. Cellular experiments revealed that TRIM21 overexpression could suppress tumor progression in sarcomas.

This study provided a novel classification for sarcoma patients based on expressions of ubiquitination-related genes. The classification and the prognostic model may facilitate the understanding of sarcoma pathogenesis, the prediction of prognosis and immunotherapy response for sarcoma patients. Meanwhile, it was confirmed that TRIM21 suppressed sarcoma progression and identified it as a potential target for therapeutic interventions.

The classification and signature stratify sarcoma patients for prognosis and immunotherapy response, with TRIM21 representing a promising therapeutic target.

Ovarian cancer (OC), characterized by high mortality and lacking early diagnostic markers, poses a significant health threat. This study investigated the expression of metabolic reprogramming and circadian rhythm-related genes (MRCRRGs) in OC and their association with clinical features.

OC datasets and MRCRRG lists were sourced from TCGA, GEO, and GeneCards. Comprehensive bioinformatics analyses included calculating Metabolic Reprogramming and Circadian Rhythm Scores (MRCR.Score), identifying MRCR score-related genes (MRCRSRGs), building a Cox regression model, performing clustering for subtype identification, analyzing immune cell infiltration and immune checkpoint gene expression, conducting differential expression analysis, and performing Gene Set Enrichment Analysis (GSEA).

We identified 138 MRCRRGs. MRCR. Score differed significantly between OC and controls. Thirty-four MRCRSRGs were identified, and a Cox model based on four genes was developed. Clustering revealed two distinct OC subtypes with significant overall survival differences. Immune infiltration analysis showed significant expression differences in 26 immune cell types, and immune checkpoint genes differed between subtypes. Differential expression identified 89 genes (88 upregulated, 1 downregulated). A six-gene predictive model demonstrated moderate accuracy. GSEA revealed significant enrichment of key pathways, notably Fcgr3a-mediated IL-10 synthesis.

Findings demonstrate strong links between MRCRRGs, OC subtypes, patient survival, and the tumor immune microenvironment. Enrichment of pathways like Fcgr3a-mediated IL10 synthesis suggests novel OC mechanisms. Reliant on bioinformatics, the study provides insights into OC heterogeneity.

This study establishes a foundation for understanding MRCRRG molecular mechanisms in OC. The identified subtypes, prognostic model, immune landscape alterations, and enriched pathways offer valuable insights for future experimental validation and potential diagnostic/therapeutic strategies.

Malignant melanoma is a highly aggressive skin malignancy characterised by metastatic properties and resistance to conventional therapies. This indicates a necessity to explore novel, efficacious treatment modalities. Atranorin, a secondary metabolite derived from lichen, has demonstrated a diverse range of bioactivities. However, the antineoplastic mechanisms of atranorin in melanoma remain underexplored.

Human melanoma cancer cell lines (A-375, G-361, and MDA-MB-435) and normal human melanocytes were treated with various concentrations of atranorin. Cell viability and proliferation were evaluated by MTT assay, apoptosis was assessed using Annexin V-FITC/PI flow cytometry, and cell cycle distribution was determined by PI staining and flow cytometry. Gene expression of apoptosis-related markers was quantified by qRT-PCR, and protein levels were analyzed by Western blot. Cell migration was evaluated by the wound healing assay.

Atranorin demonstrated selective toxicity in human melanoma cancer cells, exhibiting minimal effect on normal human melanocytes. In a study on human malignant melanoma A-375 cells, it was found that atranorin, at an IC50 concentration of 12 μM, significantly increased the number of apoptotic cells by approximately 11-fold. Furthermore, the results of the study indicated that atranorin induced G1 phase arrest and inhibited migratory capacity by around 60%. Molecular profiling revealed the upregulation of the intrinsic (APAF1, BAX, and CASP9) and extrinsic (FAS, FADD and CASP10) apoptotic pathways, and the downregulation of the anti-apoptotic genes BCL2, MCL1, and BIRC5. In line with these observations, protein analyses revealed increased levels of cleaved caspase-3, caspase-9, and PARP, thereby providing evidence for the activation of apoptotic cascades.

In this study, the therapeutic effect of atranorin was comprehensively evaluated for the first time on A-375 melanoma cells, and it was highlighted as a natural compound with strong anti-cancer potential.

This study is the first to demonstrate the potent anti-melanoma effect of atranorin. This demonstrates the natural compounds' effects on cell proliferation, cell cycle progression, and the suppression of metastasis. These findings emphasize the potential of atranorin as a novel natural compound for use in adjunctive or targeted melanoma therapy, and highlight the need for further preclinical and clinical evaluation.

Chitosan nanoparticles (CNPs) are broadly explored for drug delivery due to their biocompatibility, biodegradability, and non-toxicity. This study encapsulated Brugmansia suaveolens leaf ethanol extract (BSLEE) into CNPs to enhance antioxidant and antibacterial activity.

The optimization of synthesis, such as chitosan concentration of (1:1) to cross-link BSLEE, maintaining an optimal acidic pH (~4.5-5.5), and applying mild stirring at 50 rpm resulted in an encapsulation efficiency ranging from 26.33 to 48.58%, indicating the successful encapsulation of BSLEE within the CNPs. Characterization by UV-Vis, FTIR, SEM, XRD, EDX, and zeta potential confirmed successful formulation, with semi-crystalline, porous nanoparticles.

DPPH, FRAP, and total phenolics assay indicate BSLEE CNPs exhibited stronger antioxidant activity in the range of 30.42 ±0.77% to 55.85± 0.69% of DPPH inhibition, 34.73±2.71 to 121.44±1.83 µg/ml FSE, and 58±2.27 to 149.5±2.48 µg GAE/ml, respectively, when compared to crude BSLEE. The antibacterial effectiveness of BSLEE CNPs against S. aureus and E. coli was more significant when compared to the BSLEE and chitosan alone, attributed to enhanced membrane permeability and disruption of the bacterial cell membrane.

Antibacterial studies showed significant inhibition against S. aureus and E. coli, linked to improved membrane disruption. The BSLEE CNPs demonstrated promising biocompatibility and potential for application in antimicrobial and antioxidant therapies, warranting further clinical validation and in vitro findings of BSLEE-conjugated chitosan nanoparticles.

The BSLEE CNPs showed promising pharmacological properties like antibacterial efficacy against E. coli and S. aureus, indicating their potential as an alternative approach to combat bacterial infections.

This study investigates the prognostic value of Epidermal Growth Factor (EGF) family genes in Cervical Cancer (CC) and experimentally validates the role of AREG in the progression of CC.

Transcriptome and clinical data of CC were obtained from the TCGA database. We constructed a prognostic model using LASSO Cox regression analysis based on candidate EGF family genes. Multiple bioinformatics approaches were employed to analyze functional pathways and immune characteristics. The biological function of Amphiregulin (AREG) was validated through in vitro experiments, including colony formation, CCK8 proliferation assay, wound healing assay, transwell assay, macrophage polarization analysis using the co-culture system, and in vivo subcutaneous tumor formation in nude mice. Combination therapy with anti-AREG and anti-PD-L1 antibodies was evaluated in a murine C57BL/6 model.

We identified 116 EGF family-related genes associated with CC progression and established a prognostic model. High-risk and low-risk groups showed distinct functional enrichment patterns and immune characteristics. AREG emerged as a key prognostic factor, with significantly elevated expression in CC cells. Knockdown of AREG suppressed CC cell proliferation, migration, and invasion, potentially through modulating Epithelial-Mesenchymal Transition (EMT). AREG promoted M2 macrophage polarization, fostering an immunosuppressive tumor microenvironment. Anti-AREG antibody treatment demonstrated antitumor effects in vitro and in vivo, synergizing with anti-PD-L1 therapy to significantly inhibit tumor growth and reverse EMT.

Our findings establish the first EGF family-based prognostic model for CC and reveal AREG's dual role in promoting EMT and reshaping the immune microenvironment. The observed synergy between AREG inhibition and PD-L1 blockade provides mechanistic insights for overcoming immunotherapy resistance. Limitations include retrospective data analysis and a lack of multi-omics validation.

Our study establishes a robust EGF family gene-based prognostic model for CC patients and identifies AREG as a promising therapeutic target. These findings provide new insights for CC prognosis assessment and treatment strategies.

The global incidence of colon cancer is rising, highlighting the need for complementary therapeutic approaches using natural products such as citral. A self-nano-emulsifying drug delivery system incorporated with citral (CIT-SNEDDS) was formulated, and prior studies have demonstrated its potent antiproliferative effects on colon cancer cell lines.

The apoptosis-inducing ability of CIT-SNEDDS treatment on SW620 cells was evaluated using Acridine Orange/Propidium Iodide (AO/PI) assay, Annexin V-FITC assay, and cell cycle analysis by flow cytometry. Scratch assay and migration, and invasion assays were performed to assess its anti-metastatic effects.

The cytotoxicity assay results showed that SNEDDS with citral (CIT-SNEDDS) significantly reduced cell viability in a dose-dependent manner compared to free citral and SNEDDS without citral. Acridine orange/propidium iodide staining and Annexin V assay results confirmed apoptosis in CIT-SNEDDS-treated cells. Cell cycle analysis indicated that CIT-SNEDDS induced arrest at the S and G2/M phases, which may contribute to apoptosis initiation. The scratch and trans-well assays demonstrated a reduction in SW620 cell migration and invasion capabilities following CIT-SNEDDS treatment, suggesting a potent anti-metastatic effect.

The ability of CIT-SNEDDS to induce apoptosis, disrupt the cell cycle, and inhibit cellular migration in cancer cells aligns with the goals of targeted cancer therapies, which aim to selectively eradicate cancer cells while minimizing effects on healthy tissue.

These findings highlight the therapeutic potential of CIT-SNEDDS for enhancing the efficacy of citral as an anti-tumor and antimetastatic agent for colorectal cancer, warranting further in vivo and preclinical studies to optimize its application.

Teixobactin (TX) is a new class of antibiotics with a unique structure and strong efficacy against gram-positive bacteria. It is a “head-to-side-chain” cyclodepsipeptide with considerable potential as a lead molecule for creating novel antibiotics to combat multidrug-resistant pathogens.

In this study, we systematically design, synthesize, and evaluate modified Teixobactin analogs (TX1-TX5) for antimicrobial activity. This study presents a novel peptide derived from linearized Teixobactin, with amino acid substitutions at aa1 (N-Me-D-Phe-OH), aa5 (H-L-allo-Ile-OH), and the exclusion of L-allo-Enduracididine at aa10, synthesized using solid-phase peptide synthesis. We employed various software tools, including Molinspiration and SwissADME, to estimate the pharmacokinetic features of the synthesized TX analogs. Molecular docking studies were performed using AutoDock Vina, and PyMOL and Biovia Discovery Studio visualizer were utilized to visualize the protein-ligand interactions. The molecular structures of TX and TX analogs were modeled using the Sinapsis software.

Antimicrobial susceptibility tests against Staphylococcus aureus, Bacillus subtilis, E. coli, Pseudomonas sp., Aspergillus niger, and Fusarium sp. identified novel TX analogs exhibiting strong bactericidal and fungicidal activity at 80 μg/mL. Bacterial cell wall lysis assays confirmed significant cell wall breakdown upon TX analog treatment. Glucose assay results indicate reduced glucose uptake in bacterial cells treated with TX analogs. Docking studies revealed that the synthesized TX analogs exhibited good binding affinity, ranging from -5.0 to -12.5 kcal/mol, compared with bacterial and fungal proteins, as well as the Delafloxacin and Ketoconazole standards. Density Functional Theory (DFT) computations were employed to investigate chemical reactivity descriptors.

In-vitro studies indicated that TX1 and TX3 showed excellent bactericidal activity by forming inhibition zone diameters (mm) from 6.49 ±0.31 to 11.50 ±0.59 at 70 and 80 μg/mL concentrations against Staphylococcus aureus, Bacillus subtilis, E. coli, and Pseudomonas sp., compared to the standards Streptomycin (+ve) and DMSO (-ve). The TX2, TX3, and TX5 exhibit excellent fungicidal activity with inhibition zone diameters (mm) from 7.23 ±0.25 to 10.23 ±0.30 at 70 and 80 μg/mL concentrations against Aspergillus niger and Fusarium sp., compared to the standards ketoconazole (+ve) and DMSO (-ve). The bacterial cells treated with TX1 displayed more dead cells than the control in all bacterial strains, indicating excellent cell lysis.

Mass, ¹H NMR, and HPLC analysis characterized the synthesized fine TX analogs (TX1-TX5). The DFT and docking studies' electronic characteristic calculations predicted that halogenated (TX1, TX2, and TX4) and methoxy (TX3) substituted analogs have higher stability and electrophilicity, making them suitable agents for antimicrobial activity.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition associated with high mortality and morbidity. However, targeted therapies that effectively improve patient outcomes remain limited. Exosomes play pivotal roles in intercellular communication and epigenetic regulation.

This study aimed to identify exosome-related differentially expressed genes (EXORDEGs) in whole blood associated with ARDS and to explore their potential mechanistic roles in the disease.

Two gene expression datasets (GSE32707 and GSE66890) were retrieved from the Gene Expression Omnibus for comprehensive bioinformatics analysis. Analytical approaches included Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, protein-protein interaction network construction using the STRING database, and immune infiltration profiling via single-sample gene set enrichment analysis in relation to hub genes.

We identified 21 EXORDEGs, primarily enriched in biological processes such as endothelial cell development and apoptosis. Four hub genes—PI3, EEF1A1, ANAPC1, and PSMD2—were robustly associated with ARDS, with PSMD2 showing the most pronounced differential expression. Immune infiltration analysis revealed significant disparities in nine immune cell populations between ARDS and control samples.

The results of this comprehensive bioinformatics analysis identified four EXORDEGs—PI3, EEF1A1, ANAPC1, and PSMD2—with important roles in acute respiratory distress syndrome.

This study first systematically identified EXORDEGs in ARDS, discovering four hub genes and their associations with immune cells. The hub genes may be implicated in endothelial injury, inflammation, and immune dysregulation. These findings provide novel insights into ARDS pathogenesis and highlight potential therapeutic targets for further investigation. Given the disease heterogeneity, our findings primarily reflect common molecular characteristics, while the specific features of different etiological subtypes require further investigation.

Lung cancer remains a major global health burden with high mortality rates and limited therapeutic options. Natural flavonoids, particularly those derived from Cassia species, have shown immunomodulatory and anticancer potential. This study investigates the therapeutic promise of selected Cassia-derived flavonoids targeting key lung cancer-associated proteins: Prostaglandin-endoperoxide synthase 2 (PTGS2), Mast/stem cell growth factor receptor (KIT), and Xanthine dehydrogenase (XDH).

Eight flavonoids were selected based on literature and database-reported bioactivity. Target prediction was performed using SwissTargetPrediction and STITCH, followed by pathway enrichment via STRING and KEGG databases. Molecular docking was conducted using AutoDock Vina against PTGS2 (PDB: 5IKQ), KIT (1N5X), and XDH (4U0I). Top-ranked complexes underwent 100 ns molecular dynamics (MD) simulations with GROMACS to assess binding stability, RMSD, and conformational behavior. Drug-likeness, ADME, and toxicity profiles were evaluated using SwissADME and ProTox-II. Standard drugs (Trametinib, Nivolumab, Erlotinib) were used for comparison.

Epicatechin and Hispidulin showed the strongest binding affinities with PTGS2 (−9.04 kcal/mol) and XDH (−8.22 kcal/mol), respectively, with stable RMSD profiles. Chrysoeriol demonstrated the highest binding to KIT (−8.68 kcal/mol), outperforming Nivolumab (−6.03 kcal/mol). All selected flavonoids displayed acceptable pharmacokinetic profiles and low predicted toxicity. MD simulations confirmed the dynamic stability of key complexes.

Cassia-derived flavonoids represent promising multi-target candidates for lung cancer therapy, particularly through modulation of PTGS2, KIT, and XDH. Their favorable interaction profiles and safety predictions warrant further experimental and in vivo validation.

Non-Small Cell Lung Cancer (NSCLC) treatment is often challenged by drug resistance. The antihypertensive drug telmisartan has shown anti-tumor potential, but its underlying mechanism remains unclear. Ferroptosis, a newly identified form of cell death, may serve as a promising therapeutic target. The objective is to investigate whether telmisartan inhibits NSCLC by inducing ferroptosis and to elucidate its underlying mechanism.

in vitro cell assays and in vivo mouse models were used, along with molecular biology techniques, to evaluate the effects of telmisartan on NSCLC and its mechanism of action.

Telmisartan significantly suppressed NSCLC cell proliferation and tumor growth. Mechanistic studies revealed that telmisartan induced ferroptosis by inhibiting the nuclear translocation of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) and downregulating Glutathione Peroxidase 4 (GPX4) expression. The anti-tumor effect of telmisartan was reversed by ferroptosis inhibitors.

Telmisartan can inhibit the proliferation of NSCLC cells in vitro and in vivo and induce cell ferroptosis. Telmisartan can also inhibit the nuclear translocation of NRF2, thereby affecting the expression of GPX4.

Telmisartan inhibited NSCLC by inducing ferroptosis via the NRF2/GPX4 axis, offering a new therapeutic strategy and potential clinical application for NSCLC treatment.

Neutrophils play a key role in host immune defense. At present, neutrophils in chronic bone infections exhibit significant heterogeneity but functional alterations that remain poorly understood.

A rat model of chronic bone infection induced by Methicillin-Resistant Staphylococcus Aureus (MRSA) was established. Bone marrow cells were analyzed using scRNA-seq with Gene Ontology (GO) and pathway enrichment analysis. Differentially Expressed Genes (DEGs) were identified to assess neutrophil dysfunction, validated by immunofluorescence staining and ROS quantification.

MRSA-induced chronic bone infection was confirmed by Gram and H&E staining, which showed bacterial colonization and inflammation. Neutrophils from infected rats showed downregulated immune-related genes (e.g., Clec7a, Ccr5) and upregulated immunosuppressive factors (e.g., Nfkbia, IL10ra). Enrichment analysis showed that immune responses and neutrophil functions were inhibited. Immunofluorescence showed neutrophil polarization towards N2 phenotype and reduced Reactive Oxygen Species (ROS) production in the infection group.

This study established a rat model of MRSA-induced chronic bone infection and identified 7 neutrophil subsets via scRNA-seq analysis, with the NeuP2ry10 subset showing the most significant changes. Neutrophils displayed decreased chemotaxis, phagocytosis, and ROS production, along with elevated anti-inflammatory gene expression, suggesting functional suppression and a shift toward an immunosuppressive state.

Chronic bone infection drives neutrophil polarization toward an N2 anti-inflammatory phenotype, reducing antimicrobial capacity and promoting infection persistence. Targeting neutrophil function may offer new therapeutic strategies for chronic bone infection.

The objective of the present study was to explore the bi-directional causal relationship between IPF and diabetes (type 1 diabetes and type 2 diabetes)/diabetic nephropathy/glycemic traits [fasting glucose and glycated hemoglobin (HbA1c)]/fasting blood insulin through MR analysis.

A bi-directional two-sample Mendelian randomization (MR) study design was adopted to evaluate the causal relationship between IPF and diabetes (type 1 diabetes and type 2 diabetes), diabetic complications (diabetic nephropathy) and glycemic traits [fasting blood glucose, glycated hemoglobin (HbA1c), fasting insulin] in a European population. Genome-wide association study summary data was obtained. The inverse variance weighted (IVW) method with a fixed-effects model was used to estimate the primary causal effects. The causal effects are represented by reporting odds ratios (OR) and their corresponding 95% confidence intervals (CI). The robustness of results was assessed using the MR-Egger and Weighted Median methods.

In the forward MR analysis, the IVW method revealed a significant causal effect of IPF on type 2 diabetes (OR=1.031, 95% CI: 1.011-1.052). Similar estimates were obtained through the Weighted Median method. However, no significant causal effects were observed on type 1 diabetes, diabetic nephropathy, fasting blood glucose, HbA1c, and fasting insulin, respectively (p>0.05). We performed the reverse MR analysis using similar methods to the forward MR approach. MR analysis only showed a significant causal association of fasting insulin with IPF risk, with an OR of 3.576 (95% CI: 1.958-6.531).

Genetically determined IPF was linked to an elevated risk of type 2 diabetes. The inverse MR analysis indicated that there was no causal impact of genetically predicted type 2 diabetes on the IPF risk.

Genetically predicted fasting blood insulin was found to be positively associated with IPF risk.

Osteoporosis (OP) and aortic stenosis (AS) are highly prevalent age-related disorders that frequently coexist. Epidemiological studies suggest a pathological link between OP and AS beyond age, yet the molecular mechanisms underlying this bone-vascular axis remain poorly defined. This study aimed to identify shared genes and pathways contributing to the comorbidity of OP and AS.

Publicly available AS and OP transcriptomic datasets were retrieved from the GEO database. Weighted gene co-expression network analysis (WGCNA) and differential gene expression (DEG) analysis were conducted to identify disease-associated genes. Candidate hub genes were screened through protein-protein interaction (PPI) network analysis using twelve network topology algorithms. High-confidence genes were obtained by intersecting candidates with AS-related genes from the Comparative Toxicogenomics Database (CTD). Independent cohorts were used to validate candidate genes, and least absolute shrinkage and selection operator (LASSO) regression was performed to assess their diagnostic potential.

WGCNA revealed 665 shared genes enriched in immune and inflammatory processes, cell adhesion, and glycosaminoglycan biosynthesis. PPI network analysis identified 32 candidate hub genes, and integration with CTD yielded 15 high-confidence genes. Validation across independent datasets confirmed dysregulated expression of CD4, GZMB, and SDC1 in both AS and OP samples. ROC analysis demonstrated high diagnostic accuracy of these genes, with a combined AUC of 0.94.

These findings highlight immune and inflammatory pathways as convergent mechanisms driving both AS and OP. The hub genes CD4, GZMB, and SDC1 participate in immune regulation and extracellular matrix remodeling, suggesting their involvement in the shared pathogenesis of skeletal and cardiovascular degeneration.

Integrative bioinformatics identified CD4, GZMB, and SDC1 as key genes linking OP and AS, providing potential biomarkers and therapeutic targets for managing these age-related comorbidities.

This study aimed to explore potential causal relationships between mitochondria-related genes and irritable bowel syndrome (IBS) using integrative multi-omics analysis.

Genome-wide association study data for IBS (1,480 cases and 454,868 controls) were integrated with mitochondrial gene data from DNA methylation quantitative trait loci, blood expression quantitative trait loci, and protein quantitative trait loci. Molecular trait associations with IBS were assessed through summary-based Mendelian randomization and co-localization analyses. Steiger filtering analysis was applied to identify causal directions, and candidate genes were independently replicated by two-sample MR in the FinnGen R11 cohort.

Three primary genes supported by multi-omics evidence—CASP3, GATM, and PDK1—were identified. Increased CASP3 methylation, expression, and protein were positively associated with IBS risk, indicating pro-apoptotic and pro-inflammatory mechanisms, whereas elevated GATM expression and protein were negatively associated, consistent with a protective role via creatine-mediated energy homeostasis.

Additionally, 19 genes were classified as secondary evidence genes and 5 as tertiary evidence genes. Among these, genes such as ACAD10 and MSRA were validated using FinnGen data.

This study represents the first application of multi-omics techniques to elucidate the relationship between mitochondrial genes and IBS. The findings indicate multiple candidate pathogenic genes and highlight the role of mitochondrial dysfunction in IBS pathogenesis. These findings offer new opportunities for the discovery of IBS biomarkers and the development of therapeutic strategies.

Curcuma longa, commonly known as turmeric, contains curcumin, which is its main compound and has been reported to possess a wide variety of pharmacological activities, such as anti-carcinogenic, anti-malarial, antioxidant, antibacterial, anti-mutagenic, anti-inflammatory, and immunomodulatory effects. Even though it has many strong biological properties, curcumin lacks solubility, which affects its clinical efficacy. DK1 is a curcumin analogue that has been found to possess selective cytotoxicity on breast cancer cells compared to normal breast cells; however, its effectiveness in colon cancer has yet to be validated. This study was performed to investigate the effects of DK1 on colon cancer using an in vivo model in terms of its anti-apoptotic, immunoregulatory, and antioxidant potential. The pathways affected by the DK1 treatment were also evaluated.

In this study, male BALB/c mice induced with colon cancer were utilized, and the resulting tumours and spleen were subjected to TUNEL, immunophenotyping, and several antioxidant assays, such as nitric oxide, malondialdehyde, and superoxide dismutase, as well as gene and protein expression analyses.

K1 treatment led to tumor shrinkage, an increase in apoptotic tumor cells, and elevated populations of helper and cytotoxic T cells by 5% and 3%, respectively. Besides that, the NO and MDA levels were also significantly reduced. This study also observed dysregulations in several oncogenes in the VEGF pathway, such as CMYC, iNOS, and IL-1β genes, which are involved in angiogenesis and inflammation.

The effects of DK1 treatment included antitumor and anti-inflammatory properties against the inoculated CT26 tumour. DK1 showed potential in regulating the inflammation via the VEGF pathway by the significant downregulation of TNF-α and IL-1β pro-inflammatory genes, as well as PTX3, OPN, and serpin-E1 pro-angiogenic proteins.

The results suggested that DK1 may potentially function as an immunoregulator and anti-cancer agent for colon cancer therapy.

Ischemic stroke (IS) is a major cause of death and disability worldwide. The transcriptional mechanism of neutrophil extracellular trap-related genes (NRGs) and their diagnostic potential remain unknown. This study aims to explore the mechanism of NRGs in IS through machine learning and single-cell RNA sequencing (scRNA-seq).

We conducted differential analysis and functional enrichment analysis on the GEO dataset. Machine learning algorithms were used to identify NRGs related to IS. ScRNA-seq analysis was employed to verify the expression of NRGs in different cell types, and cellchat was used to explore the interactions between cell types in the IS. The expression of Eno1 was also verified in the mouse model of middle cerebral artery occlusion (MCAO).

We identified 26 differentially expressed NRGs (DE-NRGs). The diagnostic models constructed from five DE-NRGs (ENO1, HMGB1, ILK, ORAI1, SUCNR1) demonstrated high predictive ability. Single-cell analysis revealed that NRGs were highly expressed in the IS group. The experiment verified the significant upregulation of Eno1.

This study employed machine learning and scRNA-seq to identify the DE-NRGs-related diagnostic model, providing a certain theoretical basis for IS risk stratification. More experiments are needed to verify the role of DE-NRGs in IS in the future.

This study identified DE-NRGs with diagnostic capabilities in IS and verified their high expression through scRNA and experimental methods. DE-NRGs may be potential therapeutic targets for IS.