Current Medicinal Chemistry - Online First

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.

Ischemic Stroke (IS) represents the most prevalent subtype of cerebrovascular disease, characterized by complex pathophysiological mechanisms that remain inadequately characterized, particularly concerning mitochondrial dysfunctions. These mitochondrial impairments are increasingly recognized as contributory factors in IS pathogenesis, emphasizing the need for further investigation into the underlying molecular mechanisms involved.

In this study, we integrated transcriptomic datasets from the Gene Expression Omnibus (GEO) with the comprehensive MitoCarta3.0 mitochondrial proteome inventory to elucidate the role of dysregulated Mitochondrial-Related Genes (MRGs) in IS. We employed an advanced bioinformatics and machine learning pipeline, incorporating differential expression profiling alongside network-based prioritization using CytoHubba. Rigorous feature selection was conducted through LASSO regression, Support Vector Machine (SVM), and Random Forest (RF) algorithms to derive a robust core MRG signature. Our methodology included training and validation cohorts to construct diagnostic models, which were critically evaluated via Receiver Operating Characteristic (ROC) curves, nomograms, and calibration analyses.

Our analysis identified a seven-gene signature comprising DNAJA3, ACSL1, HSDL2, ECHDC2, ECHDC3, ALDH2, and PDK4, which demonstrated significant correlation with activated CD8⁺ T-cell and natural killer cell infiltration. Furthermore, integrative network analyses revealed intricate regulatory interactions among MRGs, microRNAs, and transcription factors. Notably, drug-target predictions indicated Bezafibrate as a promising therapeutic agent for modulating mitochondrial homeostasis in the context of IS.

These findings offer a novel framework for ischemic stroke diagnosis and therapy, yet their computational derivation underscores the need for thorough experimental validation of MRGs and drug candidates, along with the integration of diverse clinical data to confirm their real-world applicability.

Our findings underscore mitochondrial dysfunction not only as a critical factor in IS pathogenesis but also as a viable therapeutic target. The identified MRG signature presents potential for clinical application in diagnostic and pharmacological strategies aimed at ameliorating ischemic injury. This study highlights the translational significance of systems biology approaches within cerebrovascular medicine, warranting further mechanistic exploration of mitochondrial-immune interactions in stroke pathology.