Current Medicinal Chemistry - Online First

Cholesterol plays a key role in maintaining tumor cell homeostasis. Reduced IGFBP6 expression is associated with an increased risk of breast cancer recurrence. Previous studies showed that IGFBP6 knockdown decreases cholesterol levels in the MDA-MB-231 cell line. This study aimed to investigate how IGFBP6 influences genes involved in cholesterol metabolism.

We used MDA-MB-231 breast cancer cells with IGFBP6 knockdown. Transcriptomic and proteomic analyses were performed, with selected gene expression validated by RT-PCR. Correlations between IGFBP6 and cholesterol-related genes were evaluated using public RNA-seq datasets.

IGFBP6 knockdown in MDA-MB-231 cells resulted in a threefold decrease in low-density lipoprotein receptor (LDLR) expression and a twofold reduction in LDLR adaptor protein (LDLRAP1) mRNA levels, both responsible for exogenous cholesterol uptake. Meanwhile, PCSK9 expression increased 11-fold (p-adj = 1.4E-93), further limiting uptake. Despite the upregulation of genes involved in endogenous cholesterol synthesis (HMGCS1, HMGCR, FDFT1, SQLE, DHCR24), total cholesterol content in knockdown cells decreased, leading to activation of the sterol-dependent transcription factor SREBF1 (OR = 6.44; p-adj = 0.036). Correlation analysis revealed a significant association between IGFBP6 expression and cholesterol synthesis genes in basal-like breast cancer.

The altered expression profile of multiple cholesterol metabolism-related genes with known prognostic value aligns with a transcriptional program typical of poor-outcome basal-like tumors. These findings support the role of IGFBP6 as a regulator of lipid metabolism and a potential biomarker for therapeutic stratification.

The results of this study indicate that the reduction in cholesterol levels observed in breast cancer cells following IGFBP6 knockdown is primarily due to decreased exogenous uptake. These findings highlight the role of IGFBP6 in regulating cholesterol metabolism and further explain its clinical significance in predicting breast cancer recurrence and progression.

Breast cancer has become the most commonly diagnosed cancer in women worldwide, with advanced cases often leading to bone metastases that significantly affect prognosis and quality of life. This meta-analysis and systematic review aims to evaluate and compare the diagnostic performance of [¹⁸F]FDG PET/CT and bone scintigraphy for detecting bone metastases in breast cancer patients.

A systematic search was conducted across PubMed, Embase, Web of Science, and Scopus for studies published up to February 2025. Relevant articles were identified using a combination of subject-specific and free-text keywords, including “breast cancer,” “positron emission tomography,” “bone scintigraphy,” and “bone metastasis.” Studies assessing the diagnostic utility of [¹⁸F]FDG PET/CT and bone scintigraphy in detecting bone metastases were included. A bivariate random-effects model was used to calculate pooled estimates of sensitivity, specificity, and diagnostic accuracy with 95% confidence intervals (CIs). Potential sources of heterogeneity were explored using meta-regression analysis. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied to evaluate the methodological quality of the included studies.

A total of 1407 publications were initially retrieved, and 13 studies involving 892 patients met the inclusion criteria. The pooled diagnostic performance for [¹⁸F]FDG PET/CT demonstrated a sensitivity of 0.91 (95% CI: 0.81-0.96) and a specificity of 0.98 (95% CI: 0.93-1.00), with an area under the curve (AUC) of 0.99 (95% CI: 0.97-0.99). In comparison, bone scintigraphy showed a sensitivity of 0.82 (95% CI: 0.72-0.89), specificity of 0.81 (95% CI: 0.73-0.87), and an AUC of 0.88 (95% CI: 0.85-0.91). Despite its higher diagnostic accuracy, PET/CT exhibited notable heterogeneity across studies, potentially influenced by differences in patient populations and imaging interpretation criteria.

Our meta-analysis demonstrated the superior diagnostic performance of [¹⁸F]FDG PET/CT over bone scintigraphy, likely attributable to its enhanced sensitivity for osteolytic lesions and integrated anatomical-functional imaging. Nevertheless, considerable inter-study heterogeneity and incomplete clinical data reporting limit the generalizability and robustness, warranting further standardized prospective investigations.

The findings suggest that [¹⁸F]FDG PET/CT offers superior diagnostic accuracy compared to bone scintigraphy for detecting bone metastases in breast cancer patients. However, its clinical application requires further validation through large-scale, prospective studies. Additionally, considerations such as cost-effectiveness and accessibility must be addressed before widespread clinical adoption.

Current osteoporosis medications often prove ineffective for various reasons. Alongside optimizing available agents, new genetic targets should be proposed for drug development. Mendelian randomization (MR) may resolve throughput and confounding issues in traditional observational studies for druggable targets.

We employed two-sample MR with protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) data as exposures and six bone mineral density (BMD) sites as outcomes. By meta-analyzing pQTL evidence, validating eQTL evidence, conducting MR sensitivity tests, and assessing druggability, key druggable targets for BMD were identified. Additionally, we performed functional analysis, drug repurposing annotation, transcriptome analysis, in-house PCR, ELISA, and micro-CT validation to further investigate the functionality and expression levels of these targets across different tissues and conditions.

Out of 5,928 pQTLs from deCODE and UKB-PPP datasets, 16 were identified as prioritized targets with significant meta pQTL evidence. Tyrosine-protein kinase Lyn (LYN, meta beta -0.09, 95% CI -0.13 to -0.05), Chondroadherin (CHAD, meta beta -0.39, 95% CI -0.18 to -0.20), Tumor necrosis factor receptor superfamily member 19 (TNFRSF19, meta beta -0.03, 95% CI -0.05 to -0.02), and Transforming growth factor beta induced (TGFBI, meta beta -0.04, 95% CI -0.06 to -0.03) were identified as key druggable targets for BMD. R-spondin-3 (RSPO3) and SPARC-related modular calcium-binding protein 2 (SMOC2) were also suggested with consistent MR associations with previous studies.

We identified four novel BMD-related targets (CHAD, LYN, TGFBI, TNFRSF19) through pQTL meta-analysis, and validated RSPO3/SMOC2's positive effects. By integrating multi-tissue transcriptomics and OVX experiments, we further revealed elevated expression of TNFRSF19/TGFBI negatively correlated with BMD, providing new therapeutic insights.

This large-scale Proteome-Wide MR study introduced novel targets for BMD and osteoporosis at transcriptional and translational levels, presenting new prospects for drug repurposing and development.

This study aims to elucidate the mechanisms contributing to the transition from acute to chronic inflammation, particularly in the context of atherosclerosis, by investigating the pro-inflammatory responses of cybrid cell lines derived from patients with coronary heart disease.

Acute inflammatory reactions are essential components of the innate immune response, typically resolving within hours or days. However, disruptions in this process can lead to chronic inflammation, which is linked to significant morbidity and mortality. Atherosclerosis, characterized by chronic vascular inflammation, poses a major health threat, underscoring the need for understanding its underlying mechanisms.

The primary objective is to analyze the pro-inflammatory cytokine responses of 14 cellular lines, including 13 cybrids and one maternal line (THP-1), to identify intolerant and tolerant responses to key cytokines associated with inflammation.

We utilized cybrid cell lines created by fusing THP-1 monocytic cells with platelets from patients diagnosed with atherosclerosis. Cytokine responses were assessed through quantitative analysis of IL-1β, IL-6, MPC-1, IL-8, and TNF-α secretion. Gene expression profiles were analyzed to correlate cytokine secretion with specific gene regulation patterns, focusing on epigenetic mechanisms influencing immune responses.

Distinct intolerant and tolerant responses were observed across the cellular lines for key cytokines. Specifically, TC-HSMAM1 and TCP-521 were intolerant to IL-1β, TC-HSMAM1, TC-LSM2, and TC-522 were intolerant to IL-6, six lines exhibited intolerance to MPC-1, and eight lines were intolerant to IL-8. No intolerant responses were noted for TNF-α. Gene expression analysis revealed that at least ten genes correlated with increased cytokine secretion in intolerant reactions, while 23 genes showed higher expression during these intolerant responses, indicating significant roles for DNA modification and chromatin remodeling. An important finding emerged from the study of agents affecting histone modification. Specifically, unlike other agents, sodium butyrate not only exhibited a stronger suppression of the inflammatory response in cells but also eliminated their intolerance to inflammatory stimulation. Therefore, in the near future, sodium butyrate could be regarded as a fundamentally new anti-inflammatory preventive and therapeutic agent, with its mechanism of action rooted in the prevention and suppression of chronic inflammation.

In chronic non-infectious diseases like atherosclerosis the intolerant response or trained immunity can worsen inflammation. This study shows that both genetic and epigenetic regulation contribute to this intolerant response. It was also found that sodium butyrate can prevent the intolerant response, suggesting it may become a new anti-inflammatory agent that suppresses chronic inflammation.

Our findings have suggested that the interplay between pro-inflammatory cytokine responses and epigenetic regulation mechanisms is critical in determining whether a cell exhibits a normal or intolerant immune response. Understanding these dynamics may provide insights into the chronic inflammatory processes associated with atherosclerosis and other related conditions.

Coronavirus disease (COVID-19) is a highly infective disease caused by SARS-CoV-2. The SARS-CoV-2 spike protein binds with the human ACE2 receptor to facilitate viral entry into the host cell; therefore, spike protein serves as a potential target for drug development.

Keeping in view the significance of SARS-CoV-2 spike protein for viral replications, in the current study, we identified the potent inhibitors against SARS-CoV-2 spike protein in order to combat the viral infection.

In the current study, we screened an in-house library of ~900 natural and synthesized compounds against the spike protein receptor binding domain (RBD) using a structure-based virtual approach, followed by an in-vitro inhibition bioassay.

Seven (C1-C7) potent compounds were identified with docking scores ≥ −6.66 Kcal/mol; their drug-likeness, pharmacokinetic, and pharmacodynamic characteristics were excellent with no toxic effect. Those molecules were subjected to a triplicate simulation for 200 ns, which further confirmed their stable binding with RBD. This tight packing of complexes was reflected by calculated binding free energy, which disclosed higher binding free energy of C4, C7 and C6 than C1-C3, while predicted entropic energy demonstrates higher values for C4, C7 and C1 than the rest of the compounds, indicating more thermodynamic stability in protein due to conformational changes in spike protein induced by binding of C4, C7 and C1. These computational analyses were later validated through in-vitro bioassay. Remarkably, C2-C7 displayed significant inhibitory potential with >76 to 89% inhibition and C3, C4, C6 and C7 demonstrated the highest inhibition of RBD.

The current findings suggest that compounds C3 and C6 effectively disrupt the function of RBD of SARS-CoV-2 spike protein and can serve as potential drug candidates for spike protein.

Centromere protein M (CENPM), a member of the CENP family, is correlated with several malignancies, but its role in colon adenocarcinoma (COAD) is unclear. This study aims to explore the expression, prognostic significance, and biological role of CENPM in COAD.

The association of CENPM with the occurrence and progression of COAD was thoroughly analyzed via several bioinformatics databases. Furthermore, the correlation between CENPM expression and clinicopathological features and prognostic value was validated via immunohistochemistry (IHC) of tissue microarrays (TMAs) from 80 patients.

CENPM mRNA expression was significantly elevated in COAD samples compared with healthy tissues. As COAD progressed, CENPM expression decreased, and patients with lower CENPM transcript levels had a worse prognosis. IHC results further confirmed the overexpression of CENPM in COAD patients, identifying this gene as an independent prognostic factor. Additionally, high CENPM expression was linked to methylation in COAD patients, and the primary function of CENPM and its neighboring genes was determined to be cell cycle regulation. Immunological analysis demonstrated that CENPM expression was positively correlated with activated CD8+ T cells, CD4+ T cells, and dendritic cells (DCs) but negatively correlated with regulatory T cells (Tregs). CENPM expression was positively correlated with that of the immune checkpoint genes LAG3, CD244, LGALS9, PDCD1 (PD1), and PVRL2 but negatively correlated with the expression of BTLA, CSF1R, KDR, IL10RB, PDCD1LG2, and TGFBR1.

These findings collectively highlight a multifaceted role of CENPM in COAD, linking its overexpression to improved patient outcomes through mechanisms involving cell cycle control and immunomodulation. Its significant correlation with key immune infiltrates and checkpoint markers implies potential utility as a novel predictor for immunotherapy responsiveness.

CENPM is an independent prognostic factor for COAD, with its overexpression associated with improved survival. It regulates the cell cycle and tumor microenvironment, making it a promising potential predictive biomarker for immune therapy response.

This study aims to elucidate the role of Phosphoribosyl Transferase Domain Containing 1 (PRTFDC1) in Lung Adenocarcinoma (LUAD) through bioinformatics analysis and experimental validation, exploring its potential as a biomarker for prognosis and treatment response.

We analyzed PRTFDC1 gene expression patterns in 539 LUAD and 59 normal lung tissue samples from The Cancer Genome Atlas (TCGA). Using bioinformatics tools, we examined the correlation between PRTFDC1 expression and clinical characteristics, immune infiltration, Tumor Mutation Burden (TMB), and drug responsiveness. Experimental validation was conducted in LUAD cell lines (A549 and HCC-78) through the overexpression of PRTFDC1, followed by cell proliferation and cell cycle assays.

PRTFDC1 expression was significantly elevated in LUAD compared to normal tissues, correlating with poorer Progression-Free Survival (PFS) and Disease-Specific Survival (DSS). PRTFDC1 was associated with immune cell infiltration, TMB, and mRNA stemness index (mRNAsi). Overexpression of PRTFDC1 in LUAD cell lines promoted cell proliferation and cell cycle progression, mediated by Threonine Tyrosine Kinase (TTK).

The findings suggest that PRTFDC1 may serve as an independent prognostic marker for LUAD, influencing tumor progression and immune response. The correlation with TTK indicates a potential mechanism for PRTFDC1's impact on cell proliferation. However, further research is needed to validate these findings in larger cohorts and explore the underlying molecular mechanisms.

PRTFDC1 is a promising biomarker for LUAD prognosis and treatment response, with potential implications for targeted therapies and personalized medicine.