Biology Direct最新文献

Background: Carotid atherosclerotic plaque is the primary cause of cardiovascular and cerebrovascular diseases. It is closely related to oxidative stress and immune inflammation. This bioinformatic study was conducted to identify key oxidative stress-related genes and key immune cell infiltration involved in the formation, progression, and stabilization of plaques and investigate the relationship between them.

Results: We show that the up-regulation of oxidative stress-related genes such as IDH1 and CD36 in resident-like macrophages and foam macrophages play a key role in the formation and progression of carotid atherosclerotic plaques.

Conclusions: We discuss the role of oxidative stress and immune inflammation in the formation, progression, and stabilization of plaques by combining predictive models with analysis of single-cell data. It introduced novel insights into the mechanisms underlying carotid atherosclerosis formation and plaque progression and may assist in identifying potential therapeutic targets for their treatment.

Background: Regeneration is the preferred approach to restore the structure and function after tissue damage. Rapid proliferation of cells over the site of damage is integral to the process of regeneration. However, even subtle mutations in proliferating cells may cause detrimental effects by eliciting abnormal differentiation. Interestingly deer antlers, arguably the fastest regenerating mammalian tissue, have not been reported, thus far, to grow malignant tumors. They provide a mammalian model to understand the possible mechanism by which rapid regeneration is achieved while avoiding the development of malignancies. Antler regeneration is based on the proliferation and differentiation of antler stem cells (AnSCs).

Results: We identified 39 hub genes which may function in regulating the balance between rapid proliferation and genomic stability in the AnSCs during antler regeneration. Among these 39 genes, the tumor suppressor gene, BRCA1, was found to be more sensitive to DNA damage in the AnSCs compared to that in the deer somatic cells, and BRCA1 deletion in the AnSCs via CRISPR/Cas9 resulted in significantly higher levels of DNA damage. Lack of BRCA1 promoted cell apoptosis and cell senescence and inhibited cell proliferation and cell self-renewal. RNA-seq results showed that in the absence of BRCA1, the p53 signaling pathway was significantly up-regulated. Associated with this change, the cell apoptosis and cell senescence-relevant-genes, CDKN1A, CDKN2A and Fas were over expressed, but the expression of cell-cycle-progression-related genes was inhibited. In addition, BRCA1 expression levels were found to be more sensitive to endoplasmic reticulum stress (ERS) in the AnSCs compared to the somatic cells. Deletion of BRCA1 gene aggravated ERS and ERS-induced cell apoptosis.

Conclusions: Our results revealed that BRCA1 is involved in sustaining rapid antler growth possibly via promotion of DNA damage repair that acts to maintain genome stability while protecting cells from p53/ERS-induced cell death. Understanding the mechanisms underlying the role played by BRCA1 in the process of antler regeneration is of great significance not only for regenerative medicine, but also for the understanding of cancer development.

Introduction: Diabetic nephropathy (DN) is a common diabetes-related complication with unclear underlying pathological mechanisms. Although recent studies have linked glycolysis to various pathological states, its role in DN remains largely underexplored.

Methods: In this study, the expression patterns of glycolysis-related genes (GRGs) were first analyzed using the GSE30122, GSE30528, and GSE96804  datasets, followed by an evaluation of the immune landscape in DN. An unsupervised consensus clustering of DN samples from the same dataset was conducted based on differentially expressed GRGs. The hub genes associated with DN and glycolysis-related clusters were identified via weighted gene co-expression network analysis (WGCNA) and machine learning algorithms. Finally, the expression patterns of these hub genes were validated using single-cell sequencing data and quantitative real-time polymerase chain reaction (qRT-PCR).

Results: Eleven GRGs showed abnormal expression in DN samples, leading to the identification of two distinct glycolysis clusters, each with its own immune profile and functional pathways. The analysis of the GSE142153 dataset showed that these clusters had specific immune characteristics. Furthermore, the Extreme Gradient Boosting (XGB) model was the most effective in diagnosing DN. The five most significant variables, including GATM, PCBD1, F11, HRSP12, and G6PC, were identified as hub genes for further investigation. Single-cell sequencing data showed that the hub genes were predominantly expressed in proximal tubular epithelial cells. In vitro experiments confirmed the expression pattern in NC.

Conclusion: Our study provides valuable insights into the molecular mechanisms underlying DN, highlighting the involvement of GRGs and immune cell infiltration.

Advances in sequencing technologies are reshaping clinical diagnostics, prompting the development of new software tools to decipher big data. To this end, we developed functional genomic imaging (FGI), a visualization tool designed to assist clinicians in interpreting RNA-Seq results from patient samples. FGI uses weighted gene co-expression network analysis (WGCNA), followed by a modified Phenograph clustering algorithm to identify co-expression gene clusters. These gene modules were annotated and projected onto a t-SNE map for visualization. Annotation of FGI gene clusters revealed three categories: tissue-specific, functional, and positional. These clusters may be used to build tumor subtypes with pre-annotated functions. At the multi-cancer cohort level, tissue-specific clusters are enriched, whereas at the single cancer level, such as in lung cancer or ovarian cancer, positional clusters can be more prominent. Moreover, FGI analysis could also reveal molecular tumor subtypes not documented in clinical records and generated a more detailed co-expression gene cluster map. Based on different levels of FGI modeling, each individual tumor sample can be customized to display various types of information such as tissue origin, molecular subtypes, immune activation status, stromal signaling pathways, cell cycle activity, and potential amplicon regions which can aid in diagnosis and guide treatment decisions. Our results highlight the potential of FGI as a robust visualization tool for personalized medicine in molecular diagnosis.

Background: Bladder cancer (BC) is a malignant tumor. Methyltransferase-like 7B (MEETL7B) is a methyltransferase and its role in BC has not yet been revealed.

Method: Stable METTL7B knockdown or overexpression were achieved by lentiviral transduction in SW780 and TCCSUP cell lines. Xenografts tumors were established via subcutaneous injection of stable transfectants in BALB/c mice.

Results: A database search indicated that METTL7B was elevated in BC and it was validated in BC cell lines. METTL7B silencing suppressed cell proliferation and tumorigenesis in vitro and in vivo. Besides, METTL7B knockdown induced cell cycle arrest in G1 phase with a reduction in cyclin D1(CCND1), CDK4, and CDK6 levels and an elevation in CDKN2D levels in cells. Considering that ferroptosis is emerging as a therapeutic target for cancer, and the possible relationship between METTL7B and antioxidant enzymes. We, here, examined that ectopic METTL7B expression abolished ferroptosis markers in cells raised by Erastin treatment, including the production of lipid ROS, the increased cellular iron and MDA content, the decreased gene expression of ACSL3, FANCD2, and FADS2, as well as the mitochondrial injury observed by electron microscopy. Mechanically, ectopic METTL7B expression promoted m⁶A modification on ACSL3 mRNA. Gain of functional experiment exhibited that METTL7B inhibited Erastin-induced ferroptosis via ACSL3. Overexpressed PLAGL2 is identified as a possible independent predictor in BC and bioinformatics predicted the potential binding sites between PLAGL2 and METTL7B promoter region. Dual luciferase and chromatin immunoprecipitation analysis provided evidence that PLAGL2 directly binds to METTL7B promoter region.

Conclusions: METTL7B is involved in BC development and progression. METTL7B may mediate m⁶A modification on ACSL3 mRNA to negatively regulate ferroptosis in BC cells, which provides a potential therapeutic target for BC via ferroptosis.

Tumor microenvironment (TME) takes an essential part in the bladder cancer progression, which is associated with intercellular cross-talk between stroma cells and cancer. We aimed use bioinformatics tools to analyze tumor microenvironment remodeling in bladder cancer. CIBERSORT and ESTIMATE are bioinformatics tools based on deconvolution for calculating proportions of tumor-infiltrating immune cells and stromal components in TME. We utilized these two algorithms to analyze the immune components of 433 bladder cancer cases from The Cancer Genome Atlas database, aiming to compensate for the current lack of large-sample single-cell information. Then we used Cox regression to analyze the prognostic value of differentially expressed genes, and the protein-protein interaction network was constructed. Matrix Metalloproteinase-9 (MMP9) was identified as a predictive biomarker related to immune microenvironment. Using Gene Set Enrichment Analysis, the genes from the group with high MMP9 expression gathered in items related to immune diseases, and genes in the group with low MMP9 expression were negatively associated with valine, leucine and isoleucine degradation and glycosylphosphatidylinositol anchor biosynthesis. MMP9 expression and presence of macrophages M0 were positively correlated, while naïve B cells, activated dendritic cells, monocytes and plasma cells were negatively correlated. The results were confirmed by brightfield and multiplex fluorescence immunohistochemistry using stained bladder cancer and normal tissue.

Thioredoxin1 (TRX1) and telomerase are both attractive oncology targets that are tightly implicated in tumor initiation and development. Here, we reported that the 6-dithio-2-deoxyguanosine analog thiotert exhibits an effective cytotoxic effect on myelodysplastic syndromes (MDS) cell SKM-1 and lymphoma cell U-937. Further studies confirmed that thiotert effectively disrupts cellular redox homeostasis, as evidenced by elevated intracellular reactive oxygen species (ROS) levels, increased MnSOD, accelerated DNA impairment, and activated apoptosis signal. Mechanistically, our present study revealed that thiotert treatment effectively inhibited the function of the TRX1/TRXR1 system and telomerase reverse transcriptase (TERT), rendering oxidative damage and impairment of telomeres. Meanwhile, pharmacological administration of glutathione (GSH), N-acetylcysteine (NAC), and mitoquinone (MitoQ), or genetic overexpression of TRX1 or TERT in MDS and cells could dampen the toxicity caused by thiotert. Remarkably, the in vivo mouse model of MDS demonstrated that thiotert administration exhibited greater efficacy in tumor reduction compared to the conventional chemotherapy drug cytarabine. Collectively, these results provide experimental insights into the mechanism of thiotert-induced MDS and lymphoma cell death and unveil that thiotert may be an effective and promising new drug for future MDS and lymphoma treatment.

Pancreatic cancer is a lethal disease with an insidious onset, and little is known about its early molecular events. Here, we found that the sterol regulatory element-binding protein 1 (SREBP1) expression is gradually upregulated during the initiation of pancreatic cancer. Through in vitro 3D culture of pancreatic acinar cells and experiments in LSL-Kras^G12D/+;Pdx1-Cre (KC) mice, we found that pharmacological inhibition of SREBP1 suppressed pancreatic tumorigenesis. In vitro, either knockdown or pharmacological inhibition of SREBP1 suppressed tumor proliferation but SREBP1 overexpression promoted tumor proliferation. In LSL-Kras^G12D/+;Trp53^fl/+;Pdx1-Cre (KPC) mice, we confirmed the tumor-promoting role of SREBP1 in pancreatic cancer progression. Mechanistically, we revealed SOX9 as a downstream target of SREPB1. SREBP1 inhibition decreased SOX9 expression in both acinar cells and pancreatic cancer cells. Indeed, we identified SREBP1 binding sites in the SOX9 promoter region and reported that SOX9 is transcriptionally regulated by SREBP1. Taken together, our findings demonstrate that SREBP1/SOX9 inhibition suppresses pancreatic cancer initiation and growth, suggesting that SREBP1 could serve as a potential target for cancer screening and treatment.

Background: Despite the increasing body of evidence that mitochondrial activities implicate in chronic obstructive pulmonary disease (COPD), we are still far from a causal-logical and mechanistic understanding of the mitochondrial malfunctions in COPD pathogenesis.

Results: Differential expression genes (DEGs) from six publicly available bulk human lung tissue transcriptomic datasets of COPD patients were intersected with the known mitochondria-related genes from MitoCarta3.0 to obtain mitochondria-related DEGs associated with COPD (MitoDEGs). The 32 hub MitoDEGs identified from protein-protein interaction (PPI) networks demonstrated superior overall diagnostic efficacy to non-hub MitoDEGs. Random forest (RF) analysis, least absolute shrinkage and selection operator (LASSO) regression, and Mendelian Randomization (MR) analysis of hub MitoDEGs further nominated NDUFS2, CAT, and MRPL2 as causal MitoDEGs for COPD, whose predominate expressions in pulmonary macrophages were revealed by an independent single-cell transcriptomic dataset of COPD human lungs. Finally, NDUFS2 was evaluated as the top-ranked contributor to COPD in the nomogram model and its downregulation in pulmonary macrophages could result in pro-inflammatory secretion, enhanced intercellular communications, whereas depressed phagocytosis of macrophages as revealed by gene set variation analysis (GSVA) and cell-cell interaction (CCI) analysis of single-cell transcriptomic dataset of COPD human lungs, which was later confirmed in COPD mouse model and macrophage cell lines.

Conclusions: Our study established the causal linkage between mitochondrial malfunctions and COPD, providing a potential therapeutic avenue to alleviate pulmonary inflammation accounting for COPD by targeting mitochondria-related genes. NDUFS2, a canonical component of mitochondrial electron respiratory chain, was highlighted instrumental for the susceptibility of risk-exposed individuals to COPD.