Frontiers in Molecular Biosciences最新文献

Background: Prostate cancer (PCa), the most prevalent malignant neoplasm in males, involves complex biological mechanisms and risk factors, many of which remain unidentified. By employing a novel two-sample Mendelian randomization (MR) approach, this study aims to elucidate the causal relationships between the circulating metabolome and PCa risk, utilizing comprehensive data on genetically determined plasma metabolites and metabolite ratios.

Methods: For the MR analysis, we utilized data from the GWAS Catalog database to analyze 1,091 plasma metabolites and 309 ratios in relation to PCa outcomes within two independent GWAS datasets. The inverse variance weighted (IVW) method was the primary approach for determining the existence of the causal relationship, supplemented by additional MR methods for heterogeneity, pleiotropy, and cross-validation. The false discovery rate (FDR) and Bonferroni correction were applied to identify the most significant causative associations. Additionally, reverse MR and Steiger filtering were conducted to ascertain whether PCa influenced the observed metabolite levels. Furthermore, metabolic pathway analysis was conducted with MetaboAnalyst 6.0 software.

Results: In the MR analysis, our findings reveal three overlapped metabolite ratios (arginine to glutamate, phosphate to uridine, and glycerol to mannitol/sorbitol) inversely associated with PCa risk. Following FDR correction (FDR < 0.05), cysteinylglycine disulfide was identified as a potential reducer of PCa risk, whereas Uridine and N-acetyl-L-glutamine (NAG) were pinpointed as potential risk factors. Notably, NAG (OR 1.044; 95% CI 1.025-1.063) emerged as a metabolite with significant causal influence, as confirmed by stringent Bonferroni correction (P < 0.05/1400). Steiger's directionality test (P < 0.001) and reverse MR confirmed the proposed causal direction. Furthermore, metabolic pathway analysis revealed a significant association between the "Glutathione Metabolism" pathway and PCa development.

Conclusion: This study provides novel insights into the potential causal effects of plasma metabolites and metabolite ratios on PCa. The identified metabolites and ratios could serve as candidate biomarkers, contributing to the elucidation of PCa's biological mechanisms.

Introduction: Reverse transcription quantitative real-time polymerase chain reaction Q7 (RT‒qPCR) is a commonly used tool for gene expression quantification. Because the qPCR method depends on several variables that can influence the analysis process, stably expressed genes should be selected for relative gene expression studies. To date, there is insufficient information on the selection of appropriate reference genes for antimicrobial photodynamic inactivation (aPDI) and antimicrobial blue light (aBL) treatment. Therefore, the purpose of the present study was to determine the most stable reference gene under treatment with aBL under sublethal conditions and to evaluate differences in the expression of the selected gene after aBL treatment in comparison to the nontreated control.

Methods: Selection of stable reference genes was performed using 4 programs: BestKeeper, geNorm, NormFinder and RefFinder under 409 and 415 nm aBL treatment.

Results: The results revealed that the gene encoding the integration host factor β subunit (ihfB) in Escherichia coli was the most stably expressed gene after both 409 and 415 nm aBL treatment. Three programs, RefFinder, geNorm, and NormFinder, indicated that this gene had the most stable expression in comparison to the other reference gene candidates. The next best candidates were cysG, uidA, and gyrA. NormFinder revealed ihfB as the single gene and cysG - gyrA as the combination of reference genes with the best stability.

Discussion: Universal reference genes are characterized by stable expression that remains consistent across various stress conditions. Consequently, it is essential to evaluate reference genes for each specific stress factor under investigation. In the case of aBL at different wavelengths, we identified genes that maintain stable expression following irradiation.

Introduction: Extensive efforts have been made to explore members of the IL-10 family as potential therapeutic strategies for various diseases; however, their biological role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains underexplored.

Methods: Gene expression datasets GSE136825, GSE179265, and GSE196169 were retrieved from the Gene Expression Omnibus (GEO) for analysis. Candidate genes were identified by intersecting differentially expressed genes (DEGs) between the CRSwNP and control groups (DEGsall) with those between the high- and low-score groups within the CRSwNP cohort (DEGsNP). Biomarker selection was performed using the Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and the Boruta algorithm. Further refinement of biomarkers was carried out using receiver operating characteristic (ROC) analysis, with genes demonstrating an area under the curve (AUC) greater than 0.7 being considered significant. Genes exhibiting consistent expression trends and significant differences across both GSE136825 and GSE179265 were selected as potential biomarkers. Cell-type annotation was performed on GSE196169, and the expression profiles of the biomarkers across various cell types were analyzed. A competing endogenous RNA (ceRNA) network and a biomarker-drug interaction network were also established. Additionally, the mRNALocater database was utilized to determine the cellular localization of the identified biomarkers.

Results: The intersection of 1817 DEGsall and 24 DEGsNP yielded 15 candidate genes. Further filtering through LASSO, SVM-RFE, and Boruta led to the identification of seven candidate biomarkers: PRB3, KRT16, MUC6, SPAG4, FGFBP1, NR4A1, and GSTA2. Six of these genes demonstrated strong diagnostic performance in GSE179265, while four biomarkers, showing both significant differences and consistent expression trends, were validated in both GSE179265 and GSE136825. Single-cell sequencing analysis of GSE196169 revealed seven distinct cell types, including endothelial cells, with the biomarkers predominantly expressed in epithelial cells. The ceRNA network comprised nine nodes and eleven edges, with only FGFBP1 exhibiting a complete lncRNA-miRNA-mRNA interaction.

Discussion: This study identifies several novel biomarkers and their associated drugs for CRSwNP therapy, as well as potential therapeutic targets, such as spiperone and arnenous acid, identified through molecular docking. Ultimately, this work underscores the identification of four IL-10 family-related biomarkers, providing a theoretical foundation for future clinical research in CRSwNP.

Long non-coding RNAs (lncRNAs) are crucial regulatory molecules that participate in numerous cellular development processes, and they have gathered much interest recently. HOXA10 antisense RNA (HOXA10-AS, also known as HOXA-AS4) is a novel lncRNA that was identified to be dysregulated in some prevalent malignancies. In this review, the clinical significance of HOXA10-AS for the prognosis of various cancers is analyzed. In addition, the major advances in our understanding of the cellular biological functions and mechanisms of HOXA10-AS in different human cancers are summarized. These cancers include esophageal carcinoma (ESCA), gastric cancer (GC), glioma, laryngeal squamous cell carcinoma (LSCC), acute myeloid leukemia (AML), lung adenocarcinoma (LUAD), nasopharyngeal carcinoma (NPC), oral squamous cell carcinoma (OSCC), and pancreatic cancer. We also note that the aberrant expression of HOXA10-AS promotes malignant progression through various underlying mechanisms. In conclusion, HOXA10-AS is expected to serve as an ideal clinical biomarker and an effective cancer therapy target.

Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD).

Methods and results: We consulted the high-resolution RyR2 structure in both open and closed configuration to identify mutations G357S/R407I and A77T, which lie within the NTD intra- and inter-subunit interface with the Core Solenoid (CSol), respectively. Their structural and functional roles were compared to R169L, a mutation that lies within the NTD-NTD inter-subunit interface. Using chemical cross-linking and co-immunoprecipitation assays, we show that R169L disrupts NTD tetramerization, while it does not alter the NTD-CSol interaction. Single cell Ca²⁺ imaging revealed that R169L increases the number of spontaneous Ca²⁺ transients and the proportion of oscillating cells, while reducing the Ca²⁺ store content. G357S and R407I do not affect NTD tetramerization, but they also do not alter the NTD-CSol interaction. Functionally, RyR2^G357S-expressing cells have Ca²⁺ handling properties similar to RyR2^WT. A77T enhances the NTD-CSol interaction, while it does not affect NTD tetramerization. Like R169L, A77T also increases the number of spontaneous Ca²⁺ transients and the proportion of oscillating cells, and it reduces the Ca²⁺ store content. However, unlike R169L that displays Ca²⁺ transients of normal amplitude and shorter duration, Ca²⁺ transients for A77T are of smaller amplitude and normal duration.

Conclusion: The NTD-CSol inter-subunit interface variant, A77T, produces a hyperactive channel by altering a different structure-function parameter to other CPVT mutations within the RyR2 NTD. Reduced NTD-NTD inter-subunit interaction and reinforced NTD inter-subunit interaction with CSol are distinct molecular mechanisms for gain-of-function RyR2 arrhythmogenic mutations.

Dietary intake of Vaccinium berries has demonstrated significant potential in preventing many risk factors associated with metabolic syndromes in the human population. In recent years, a multitude of research has shown the role of antioxidants derived from Vaccinium berries on chronic diseases such as cardiovascular disorders, diabetes, obesity, and cancer. Several studies have also investigated the effect of Vaccinium berry consumption on their ability to modulate the risk factors associated with oxidative stress, vascular function, inflammation, and lipid metabolism. Regarding cancer, studies showed that the consumption of berries reduces inflammation, inhibits angiogenesis, protects against DNA damage within the cell, and controls apoptosis and proliferation rates in malignant tumours. However, which components are responsible for the health benefits is still unclear. Reports show that whole berry consumption usually confers positive effects on human health, and the health-promoting potentials are likely due to the presence of polyphenols with antioxidant activities. Among these polyphenols, various Vaccinium berry species have been reported to contain anthocyanins and flavonoids. These two polyphenolic compounds are known to have higher antioxidant activity and are beneficial for human health. There are now several studies and human clinical trials documenting the beneficial effects of Vaccinium berries, and these findings suggest that they may be promising for preventing and treating neurodegenerative diseases. This review focuses primarily on dietary Vaccinium berries consumption effects on human health and their potential role as therapeutic agents.

[This corrects the article DOI: 10.3389/fmolb.2021.776900.].

Introduction: Many breast cancer therapeutics target the PI3K/AKT/mTOR oncogenic pathway. Development of resistance to the therapeutics targeting this pathway is a frequent occurrence. Therapeutics targeting p70S6K1, a downstream member of this pathway, have recently gained importance due to its critical role in all types of breast cancer and its status as a prognostic marker. We have developed a new class of p70S6K1 inhibitors that show growth inhibition of MCF7 breast cancer cells.

Methods: A series of 6-amido-4-aminoisoindolyn-1,3-dione compounds was developed against p70S6K1 using docking, computational modeling tools, and synthesis of the designed compounds. The p70S6K1 inhibition potency of the compounds was investigated in an initial high-throughput screening followed by IC₅₀ determination for the most active ones. The best compounds were subjected to proliferation assays on MCF7 breast cancer cells. The targeting of p70S6K1 by the compounds was confirmed by studying the phosphorylation status of downstream protein rpS6.

Results: In this study, we have identified a new class of compounds as p70S6K1 inhibitors that function as growth inhibitors of MCF7 breast cancer cells. The structural features imparting p70S6K1 inhibition potency to the compounds have been mapped. Our studies indicate that substitutions on the phenacetyl group residing in the cleft A of the protein do not contribute to the inhibition potency. Three compounds (5b, 5d, and 5f) have been identified to have sub-micromolar inhibition potency for p70S6K1. These compounds also exhibited growth inhibition of MCF7 cells by 40%-60% in the presence of estradiol.