Current Medicinal Chemistry - Online First

Angiogenesis plays an important role in progression of tumors including breast cancer, which accounts for the vast majority of women's malignant tumors globally, to meet the excessive requirement of oxygen and nutrition for growth, metastasis, and invasion of the tumor. Therefore, targeting tumor angiogenesis has turned into a significant target for cancer therapy. Erbin has a significant effect on the initiation and progression of cancer, including breast cancer, but its role in inhibiting vascular endothelial cell proliferation and angiogenesis by breast cancer cells remains unclear.

In this study, human SKBR3 and MCF-7 breast cancer cells were used and transfected with the plasmid and siRNA for overexpression and silence of Erbin, respectively. Western blot, qRT-PCR, CLEIA, CCK-8 and Matrigel Tube Formation Assay were used for the proteins detection, mRNAs detection, detection of VEGF in the culture supernatants, detection of cell proliferation and detection of the angiogenic ability of HUVECs in vitro, respectively.

It was shown that the expression of both Erbin protein and mRNA in SKBR3 cells was lower compared to that in MCF-7 cells (p < 0.05). While the expression of VEGF protein was higher in SKBR3 cells than that in MCF-7 cells (p < 0.05). Furthermore, the VEGF protein and mRNA in the cells, VEGF protein in the culture supernatant, HUVEC proliferation in the conditioned medium at 16 h and 24 h, the total length of tube formation in the conditioned medium, and pSTAT3 protein in the cells, were downregulated by transfection of Erbin gene in SKBR3 cells and upregulated (excluding HUVEC proliferation at 16 h) by transfection of Erbin siRNA in MCF-7 cells compared with their NC cells (p < 0.05).

It can be concluded that Erbin, with inhibiting the STAT3 pathway, suppresses the proangiogenic effects of breast cancer cells, thereby suggesting its potential as a therapeutic target for breast cancer.

Collagen type IV alpha 1 chain (COL4A1), which has been proven to be a potential biomarker in Gastric Cancer (GC), but its role in tumors and the tumor microenvironment (TME) needs further explanation.

We analysed the relationship between COL4A1 and clinical characteristics based on The Cancer Genome Atlas (TCGA) database and verified by tissue microarrays as well as GC cell lines using immunohistochemistry, Q-PCR, Western blot, cell proliferation assays, colony formation assays, cell invasion and migration assays. The immune infiltration and drug sensitivity information between high and low COL4A1 expression were analysed by R package and pRRophetic package. Finally, we established a nomogram based on COL4A1 expression using the bootstrap method.

COL4A1 was overexpressed in gastric carcinoma compared with normal gastric tissue, indicating a poor prognosis of GC patients in the TCGA database which were also validated by GC tissue microarrays. GO, KEGG and hallmark enrichment analyses indicated that COL4A1 was mainly associated with the extracellular matrix than malignant proliferation. By siRNA transfection, we found that COL4A1 knockdown inhibited cell colony formation, invasion and migration but did not affect cell proliferation, similar to previous results. Immune infiltration and drug sensitivity analysis showed that COL4A1 was negatively correlated with antitumor immunity and positively correlated with multidrug resistance. By developing a nomogram model based on 8 risk factors, including COL4A1, patients with better clinical outcomes could be accurately distinguished.

COL4A1 is identified as a prognostic marker and potential therapeutic target in gastric cancer. Its overexpression correlates with poor prognosis, tumor invasion, and immunosuppression. A nomogram based on COL4A1 can predict patient outcomes. Future research should validate these findings and explore targeted therapies.

The rise of drug-resistant strains of Mycobacterium tuberculosis (Mtb) represents a substantial public health challenge. Current TB treatments involve the combination of several antibiotics and other agents. However, the development of drug resistance, reduced bioavailability, and elevated toxicity have rendered most of the drugs less effective.

To resolve this problem, the identification of novel anti-tuberculosis agents with novel mechanisms of action is the need of the hour. HsaA monooxygenase is an enzyme involved in cholesterol metabolism, particularly in certain strains of Mycobacterium bacteria. This research focuses on discovering new inhibitors for HsaA from a pool of 40 compounds using computational techniques like molecular docking and Molecular Dynamics (MD) simulations along with comparing it with GSK2556286.

Docking studies revealed that AK05 and AK13 showed good binding affinity as compared to GSK2556286. The docking scores of AK05, AK13, and GSK2556286 are -9.4, -9.0, and -8.9 kcal/mol, respectively. ADMET studies showed that these thiadiazole derivatives can be investigated as lead molecules for the development of novel antituberculosis drugs. MD simulation studies showed that both of the compounds AK05 and AK13 were stable at the binding site with RMSD below 0.25 nm.

All these findings demonstrated that AK05 and AK13 could be used as potent compounds for the development of HsaA monooxygenase inhibitors.

As the leading cause of cancer-related deaths globally, colorectal cancer (CRC) ranks third in prevalence. Gene Expression Omnibus (GEO) offers clinicians and bioinformaticians an accessible platform for genomic research across various cancer types, with a particular emphasis on CRC.

We aim to uncover key genes and pathways in the Chinese CRC population.

We identified differentially expressed genes (DEGs) in CRC utilizing four microarray datasets sourced from the GEO database, all specifically from the Chinese population. Functional enrichment analysis was conducted to uncover the molecular mechanisms at play in CRC. The PPI network and CytoHubba tools were employed to identify key genes linked to CRC, with further validation through databases such as Gene Expression Profiling Interactive Analysis (GEPIA), ONCOMINE, and the Human Protein Atlas (HPA).

Our analysis identified 188 DEGs with overlapping significance, comprising 97 up-regulated and 91 down-regulated genes. Gene Ontology (GO) analysis indicated that up-regulated DEGs were predominantly involved in the extracellular space. In contrast, the down-regulated ones were linked to bicarbonate transport and extracellular exosomes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted the involvement of up-regulated DEGs in cytokine-cytokine receptor interactions and the TNF signaling pathway. In contrast, the down-regulated genes were associated with nitrogen metabolism and bicarbonate reclamation in the proximal tubule. Notably, the transcriptional levels of CCL20, CDC20, CXCL1, CXCL2, CXCL5, NEK2, and PPBP were elevated in CRC tissues compared to normal tissues. In addition, CXCL12 showed a decreased expression. Additionally, the translational levels of CDC20 and PPBP were found to be higher in CRC tissues.

Eight genes (CCL20, CDC20, CXCL1, CXCL12, CXCL2, CXCL5, NEK2, and PPBP) were identified as potential diagnostic indicators for CRC. The identified pathways, such as cytokine-cytokine receptor interactions and TNF signaling, along with nitrogen metabolism and bicarbonate reclamation in the proximal tubule, are hypothesized to have a role in the genesis and progression of CRC. This study provides unique insights into the etiology and progression of CRC within the Chinese population.

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.

This study aimed to construct a diagnostic risk model for Bipolar Disorder (BD) using inflammation-related genes (IRGs) and to explore the role of immune cell infiltration in BD pathogenesis.

BD datasets (GSE23848, GSE124326, GSE39653, and GSE46449) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the edgeR package. The intersection of DEGs and IRGs was defined as differentially expressed IRGs. A LASSO regression model was used to identify optimal biomarkers, which were then utilized to construct a diagnostic risk model. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic accuracy of the biomarkers. Internal validation was performed with GSE124326, while external validation utilized GSE23848, GSE39653, and GSE46449. The xCell module in the IOBR package was employed to assess immune cell infiltration proportions. The relationship between IRGs, the diagnostic risk model, and immune cell dynamics was further analyzed.

A total of 2345 DEGs were identified in GSE124326. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that inflammatory pathways are critically involved in BD pathogenesis. A total of 69 BD-related IRGs were identified. Six key IRGs (IL33, DNASE1L3, IL2RA, CD70, CLEC5A, and SLPI) were identified through LASSO regression analysis and used to develop a diagnostic risk model. Internal and external validations confirmed the robust diagnostic performance of the risk model. Immuno-infiltration analysis showed significant differences in immune cell infiltration between BD patients and healthy controls. The diagnostic risk model and four potential biomarkers (DNASE1L3, IL2RA, CD70, and SLPI) showed strong correlations with various immune cell types.

A diagnostic risk model for BD was constructed based on IRGs, highlighting the critical role of immune cell infiltration in BD pathogenesis.

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.