Current Medicinal Chemistry - Online First

Sepsis remains a leading cause of global morbidity and mortality.

To identify candidate biomarkers that may be mechanistically related to the pathogenesis of sepsis.

The Gene Expression Omnibus database was leveraged to identify differentially expressed genes (DEGs) between the healthy control and septicemia groups. Genes causally related to sepsis were probed through the integration of GWAS and expression quantitative trait loci (eQTL) data in a two-sample Mendelian randomization (MR) analysis. A set of key sepsis-related genes was then selected based on the overlap between these putative causal genes and the DEGs. These genes were then subjected to enrichment analyses, testing set validation, and analyses of their expression dynamics in clinical samples.

An examination of the overlap between 228 sepsis-related DEGs identified in the training dataset and 275 candidate causal genes linked to sepsis derived from the MR analysis led to the selection of four overlapping (SLC22A15, IL5RA, HDC, and SLC46A2) that may play a key role in sepsis. Enrichment analyses indicated that these genes were involved in the regulation of histidine metabolism and immune/inflammatory responses. In immune cell infiltration analyses, these genes were positively correlated with inflammatory response activation and the suppression of adaptive immunity. Consistent findings were obtained through qPCR verification in clinical samples.

These results offer potential insight into the mechanisms that govern septicemia and thus suggest a promising series of candidates that may be amenable to targeting to prevent or treat sepsis more effectively.

Neuroblastoma (NB) is a prevalent pediatric solid malignancy associated with significant morbidity and mortality, largely driven by epigenetic alterations. This review aims to identify novel biomarkers related to long non-coding RNAs (lncRNAs) and DNA methylation in NB to enhance prognostic capabilities.

We conducted a detailed analysis of the interplay between lncRNAs and DNA methylation in NB, focusing on regulatory variations and their implications for disease progression. Key lncRNAs, including GTL2/MEG3, DALI, NBAT-1, and DLX6-AS1, were examined for their regulation by DNA methylation through cis- and trans-methylation mechanisms.

There are clinical and biological implications of lncRNAs in NB and related cancers. Notably, GTL2 and its alias MEG3 are implicated in tumorigenesis through epigenetic modifications, such as hypermethylation, leading to the loss of gene expression and aggressive tumor behavior. Similarly, the interactions of DALI with adjacent genes illustrate the crucial role lncRNAs play in neuronal differentiation and tumor progression, suggesting their potential to impact prognosis through regulatory effects. Furthermore, NBAT-1 emerges as a promising tumor suppressor with strong correlations to NB prognosis, where its methylation-induced silencing is associated with negative outcomes. DLX6-AS1 is also linked to increased NB risk, with expression patterns correlating to disease stage and survival rates; however, more extensive survival data are required to establish its prognostic value.

This review highlights the potential of lncRNAs as prognostic indicators in NB, emphasizing the need for further research to elucidate their roles and validate them as biomarkers for improved patient outcomes.

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.

Prevention of the formation of β-haematin is the target of several existing antimalarials drugs, most notably chloroquine. This target is therefore attractive for the development of new molecules with antimalarial potential.

In this study, we have used a combination of ab-initio molecular dynamics and density functional tight-binding to examine the possible interaction mechanisms between five amodiaquine analogues and four conformations of haematin. Reactivity and stability of these complexes were investigated using bond length (Fe-N and Fe-O), energies (HOMO-LUMO) and molecular dynamics.

Results revealed a good interaction between haem and the compounds, stable geometries of complexes.

The findings from this study are valuable because they can aid the design and understanding of new therapeutic molecules that could be used to treat drug-resistant malaria, a global threat of today.

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.

ZNF280A, a pivotal member of the zinc finger protein family, is significantly involved in vital cellular functions including cell proliferation, programmed cell death, cellular invasion, metastasis, and resistance to therapeutic drugs across various malignancies. However, its comprehensive role in pan-cancer has not been thoroughly investigated.

This research aims to elucidate the oncogenic and immunological functions of ZNF280A across different types of cancer. We conducted an extensive analysis of ZNF280A expression levels, prognostic significance, functional pathways, methylation status, and interactions with immune cells, while also examining immune infiltration patterns and responses to immunotherapy using diverse databases.

Our findings reveal that ZNF280A expression is significantly upregulated in numerous cancers, correlating with adverse patient prognosis. This association appears to be linked to its involvement in key cancer-related pathways, including the Ras signaling pathway, and its correlation with ZNF280A methylation levels, microsatellite instability (MSI), tumor mutational burden (TMB), and the dynamics of immune cells. Notably, ZNF280A seems to undermine anti-tumor immunity and the effectiveness of immunotherapeutic approaches by promoting the infiltration of immune cells and compromising the functionality of cytotoxic T lymphocytes.

These findings suggest that ZNF280A holds promise as a valuable indicator for forecasting patient outcomes and assessing the effectiveness of immunotherapy, thereby opening avenues for further exploration into targeted therapeutic approaches.