Current Medicinal Chemistry - Online First

Intellectual disability (ID) is characterized by impairments in cognitive functioning and adaptive behavior. Globally, it affects 1-3% of the general population, with an increased prevalence in consanguineous families. It is a clinically heterogeneous disorder that can manifest as a variable phenotype. Intellectual developmental disorder and retinitis pigmentosa (IDDRP) is a rare syndrome in which patients present with both ID and retinitis pigmentosa.

This study examined a consanguineous family to identify disease-associated pathogenic mutations and elucidate their potential functional impact in patients with IDDRP.

Clinical assessment of the patients revealed characteristics consistent with both intellectual disability (ID) and retinitis pigmentosa. Individuals affected by IDDRP were subjected to whole exome sequencing (WES), and the identified candidate pathogenic variants were validated by Sanger sequencing. Computational analyses were conducted to evaluate the impact of these mutations on the protein structure and function.

WES identified a protein-truncating variant, c.2605A>T (p.Lys869Ter), in the S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) gene. SCAPER has previously been reported to cause IDDRP. In silico analyses revealed structural and interactional alterations in the SCAPER protein. This variant is novel in the Pakistani population and has not been previously reported. This variant exhibits an autosomal recessive mode of inheritance and segregates among the investigated affected and unaffected family members.

The present study expands the spectrum of disease-causing variants in SCAPER and will contribute to a better understanding of the genetic etiology of IDDRP.

Renal cancer presents a significant global health challenge due to its rising incidence and mortality rates. Often undetected in early stages, it complicates diagnosis and treatment. Current therapies face resistance and limited effectiveness, especially in advanced stages. The diverse subtypes of renal cancer highlight the need for new biomarkers and risk assessment tools for targeted treatments.

This study aims to assess the prognostic significance of global DNA methylation (GM) levels in renal cancer, identify new biomarkers, and evaluate the therapeutic potential of the DNA methyltransferase inhibitor decitabine.

Data on RNA sequencing, gene mutations, DNA methylation, and clinical outcomes were collected from TCGA and GEO databases. We calculated global DNA methylation scores (GMS) and categorized patients into high, intermediate, and low GMS groups. Survival analysis and genomic analyses were conducted to explore the relationships between GMS, clinical outcomes, and tumor characteristics.

Higher GMS was identified as an independent prognostic factor associated with worse outcomes in renal cancer. Patients with elevated GMS showed increased mutations, copy number variations, and a more aggressive tumor phenotype. Treatment with decitabine was observed to reduce tumor hypermethylation and downregulate cell cycle pathway activity, indicating potential therapeutic benefits.

Global DNA methylation plays a significant role in renal cancer prognosis. GMS may serve as valuable biomarkers for prognosis and personalized treatment strategies. Decitabine shows potential efficacy for high GMS patients, particularly through its impact on cell cycle regulation, underscoring the importance of personalized approaches in cancer treatment.

Endothelial dysfunction (ED) results from impaired vascular endothelial cell function, disrupting key processes such as hemostasis, vascular tone regulation, vasculogenesis, angiogenesis, and inflammation. These processes are mediated by a complex signaling network involving hormones, cytokines, and chemokines. ED is recognized as a major contributor to the onset and progression of several micro- and macrovascular diseases, including diabetes. Our previous study demonstrated that the polyphenol Rosolic acid (RA) protects against endoplasmic reticulum (ER) stress-induced ED in vitro by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Additionally, RA enhanced the proliferation and survival of pancreatic β-cells in a co-culture model with endothelial cells under ER stress conditions.

In this study, we investigated RA's protective effects against diabetes-induced ED using high-fat diet (HFD)-fed and streptozotocin-induced type-2 diabetic rat models. We evaluated RA’s impact on vascular function and metabolic parameters in these models.

RA significantly mitigated diabetes-induced ED in the aortic tissues of HFD-fed diabetic Wistar rats. RA treatment improved glucose tolerance and reduced hyperlipidemia, showing efficacy comparable to the anti-diabetic drug Gliclazide. Moreover, RA elevated Nrf2 levels and its downstream target genes in aortic tissues while reducing ED markers such as Intercellular Adhesion Molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and endothelin-1.

These findings highlight RA as a promising therapeutic agent for diabetes and its associated vascular complications, with potential for broader clinical applications.

The precise function of DDX59 Antisense RNA 1 (DDX59-AS1) in lung adenocarcinoma (LUAD) has yet to be fully elucidated.

This study uses bioinformatics analysis and experimental validation to investigate the association between DDX59-AS1 and LUAD.

This study uses statistical analysis and database interrogation to investigate the potential association between DDX59-AS1 expression and various clinical characteristics, prognostic factors, regulatory networks, and immune infiltration in LUAD. The quantification of DDX59-AS1 expression in LUAD cell lines is conducted through the use of quantitative real-time polymerase chain reaction (qRT-PCR).

DDX59-AS1 showed significantly elevated levels of expression in patients with LUAD. High levels of DDX59-AS1 expression were found to be significantly associated with poorer overall survival (OS) in patients with LUAD (p = 0.024). Furthermore, an independent correlation was observed between high DDX59-AS1 expression (p = 0.037) and OS in LUAD patients. DDX59-AS1 was found to be involved in various pathways, including glutathione metabolism, proteasome function, and the cytosolic DNA sensing pathway, among others. A significant correlation was observed between the expression levels of DDX59-AS1 and immune cell infiltration in the context of LUAD. Notably, elevated expression of DDX59-AS1 was observed in LUAD cell lines compared to the non-cancerous Beas-2B cell line.

A significant correlation was observed between elevated DDX59-AS1 expression in patients with LUAD and adverse prognosis, alongside increased immune infiltration. These results indicate that DDX59-AS1 may function as a prognostic marker for LUAD and a potential predictor of immunotherapy response.

We aimed to develop Ferroptosis-Related Gene (FRG) signatures to predict overall survival (OS) along with disease-free survival (DFS) in individuals with colorectal cancer (CRC).

Prediction of CRC prognosis is challenging. Ferroptosis constitutes a newly reported kind of cell death, and its association with CRC prognosis remains unexplored.

This research endeavored to establish a prognostic risk signature for colorectal cancer by leveraging ferroptosis-related genes (FRGs), with the objective of refining prognostic precision in clinical settings.

The clinical data and mRNA expression profiles were obtained from The Cancer Genome Atlas (TCGA) colorectal cancer cohorts. The Lasso algorithm was employed to develop the overall survival (OS) and disease-free survival (DFS) prediction models. These models were subsequently validated using independent data from GSE38832.

Our research unveiled a significant difference in the expression levels of 85% of ferroptosis-related genes (FRGs) between CRC tissues and paracancer tissues. Out of these, 11 prognostic genes were pinpointed through univariate Cox analysis. By employing two models, patients were stratified into low- and high-risk groups based on predicted risk scores, which were subsequently validated as independent prognostic factors via multivariate Cox analysis. The robustness of these models was further confirmed through Receiver Operating Characteristic (ROC) curve analysis. Functional enrichment analysis indicated a predominance of cancer-associated pathways in the high-risk group, including WNT signaling, along with variations in immune status between the two risk categories. Leveraging the Connectivity Map (CMap) database, a total of sixteen potential therapeutic drugs were identified. Additionally, in vitro experiments corroborated that Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1) was underexpressed in CRC and exhibited tumor suppressive properties. More specifically, FDFT1 may augment ferroptosis in CRC by modulating the expression of the Iron-Sulfur Cluster Assembly Enzyme (ISCU).

Our study highlighted the significance of ferroptosis-related genes in the pathogenesis of CRC and underscored the potential of ferroptosis-related gene-based risk signatures as valuable tools for improving prognostic accuracy and tailoring therapeutic strategies. However, the validity of these predictive models required further validation through real-world studies to ensure their reliability and applicability.

G-quadruplexes (G4s) are non-classical high-level structures that are formed by DNA/RNA sequences and have been a promising target for developing antitumor drugs. However, it is still a challenge to find a ligand that binds to a particular G4 with selectivity. Telomeric multimeric G4s are more accessible for screening for specific ligands due to their higher-order structure compared with telomeric monomeric G4s.

In this study, the natural product berberine was found to exhibit a higher selectivity for telomeric multimeric G4 in comparison with other G4s. The mechanism of interaction between telomeric G4s and berberine was further investigated by fluorescence spectra measurements, job plot analysis, and UV titrations. We found that there are three binding sites for berberine on telomeric dimeric G-quadruplex Tel45, which are located at the 5' and 3' terminal G-quartet surfaces and the pocket between the two quadruplex units of Tel45. It was worth noting that the berberine preferred to interact within the interfacial cavity between two G4 units.

Moreover, via dynamic light scattering (DLS) and native polyacrylamide gel electrophoresis (Native-PAGE) assays, it was found that the particle size of the telomeric multimeric G4s conformation was significantly increased by the addition of berberine. In contrast, the particle sizes of Tel21 did not change significantly after the addition of berberine. An immunofluorescence assay indicated that berberine induced the formation of endogenous telomeric G4 structures along with the related telomeric DNA damage response.

This study provides a hypothetical basis for the development of natural products targeting telomeric G4 as antitumor drugs.