Apoptosis最新文献

To demonstrate the efficacy of machine learning models in predicting mortality in melanoma cancer, we developed an interpretability model for better understanding the survival prediction of cancer. To this end, the optimal features were identified, ten different machine learning models were utilized to predict mortality across various datasets. Then we have utilized the important features identified by those machines learning methods to construct a new model named NKECLR to forecast mortality of patient with cancer. To explicitly clarify the model's decision-making process and uncover novel findings, an interpretable technique incorporating machine learning and SHapley Additive exPlanations (SHAP), as well as LIME, has been employed, and four genes EPGN, PHF11, RBM34, and ZFP36 were identified from those machine learning(ML). The experimental analysis conducted on training and validation datasets demonstrated that the proposed model has a good performance com- pared to existing methods with AUC value 81.8%, and 79.3%, respectively. Moreover, when combined our NKECLR with PD-L1, PD-1, and CTLA-4 the AUC value was 83%0. Finally, these findings have been applied to comprehend the response of drugs and immunotherapy. Our research introduced an innovative predictive NKECLR model utilizing natural killer(NK) cell marker genes for cohorts with melanoma cancer. The NKECLR model can effectively predict the survival of melanoma cancer cohorts and treatment results, revealing distinct immune cell infiltration in the high-risk group.

Cell pyroptosis is a form of programmed cell death, with Gasdermin-D (GSDMD) acting as its key executor. While activating pyroptosis represents a promising therapeutic strategy for cancer, the regulatory mechanisms governing GSDMD expression during cell death remain poorly understood. In this study, we identified METTL3 as a negative regulator of GSDMD-mediated pyroptosis, with high expression in breast cancer (BC) cells. YTHDF2 was found to recognize the m6A modification of GSDMD, thereby decreasing its stability. Finally, in vivo experiments further demonstrated the inhibitory effect of the METTL3 inhibitor STM2457 on tumors. Overall, these findings suggest that inhibition of METTL3 can enhance GSDMD-mediated pyroptosis and reveal a novel regulatory mechanism governing GSDMD expression, presenting a novel strategy for cancer treatment.

Myocardial infarction (MI) is an important risk factor for the development of atrial fibrillation (AF), and the gut microbial metabolite phenylacetylglutamine (PAGln) is strongly associated with the prognosis of MI patients. However, whether PAGln is involved in the regulation of AF after MI is currently unknown. Therefore, the present study aimed to explore the effect of PAGln on the susceptibility to AF after MI. MI model was constructed by surgically ligating the left anterior descending branch of the coronary artery. PAGln was administered by intraperitoneal injection for 7 consecutive days starting after surgery and then investigated by histopathologic, molecular biological, and electrophysiologic studies. Myocardial ischemia resulted in intestinal barrier dysfunction and significantly increased circulating levels of PAGln. Compared with the myocardial ischemia group, administration of PAGln significantly exacerbated atrial fibrosis and atrial electrical remodeling in mice after myocardial ischemia, as evidenced by shortening of the ERP (at varying pacing cycle lengths of 40, 60, 80, and 100), ion channel remodeling (Nav1.5, Cav1.2, and Kv1.5), and decreased expression of CX40, which led to an increase in the susceptibility to AF (54.5% vs. 90.9%, P < 0.05). In addition, administration of PAGln further exacerbated MI-induced intestinal barrier dysfunction compared with the MI group. Mechanistically, PAGln may affect atrial remodeling and AF susceptibility after MI by modulating ferroptosis and NLRP3 inflammasome. The present study preliminarily reveals that the gut microbial metabolite PAGln exacerbates post-MI AF remodeling and AF susceptibility, possibly through ferroptosis and activation of NLRP3 inflammasome.

Extracellular vesicles facilitate cell-to-cell communication, and some enveloped viruses utilize these vesicles as carriers to mediate viral transmission. SARS-CoV-2 envelope protein (2-E) forms a cation channel and overexpression of 2-E led to the generation of a distinct type of large extracellular vesicles (2-E-EVs). Although 2-E-EVs have been demonstrated to facilitate viral transmission in a receptor-independent way, the characteristics and biogenesis mechanism remain enigmatic. Via lipidomics and proteomic analysis, we found 2-E-EVs are distinct from endosome-derived exosomes. 2-E-EVs are notably enriched in Golgi apparatus components, aligning with the observed fragmentation in Golgi morphology. Through live cell imaging, we established a connection between 2-E-EVs formation, Golgi fragmentation, and channel activity, emphasizing the role of 2-E-EVs as ion channel-induced extracellular vesicles. Our work highlights 2-E-EVs as distinctive Golgi-derived vesicles, contributing to a deeper understanding of 2-E channel-mediated virus-host dynamics, with implications for therapeutic strategies and drug delivery.

Extracellular vesicles (EVs) serve as critical mediators of intercellular communication, encompassing exosomes, microvesicles, and apoptotic vesicles that play significant roles in diverse physiological and pathological contexts. Numerous studies have demonstrated that EVs derived from mesenchymal stem cells (MSC-EVs) play a pivotal role in facilitating tissue and organ repair, alleviating inflammation and apoptosis, enhancing the proliferation of endogenous stem cells within tissues and organs, and modulating immune function-these functions have been extensively utilized in clinical applications. The precise classification, isolation, and identification of MSC-EVs are essential for their clinical applications. This article provides a comprehensive overview of the biological properties of EVs, emphasizing both their advantages and limitations in isolation and identification methodologies. Additionally, we summarize the protein markers associated with MSC-EVs, emphasizing their significance in the treatment of various diseases. Finally, this article addresses the current challenges and dilemmas in developing clinical applications for MSC-EVs, aiming to offer valuable insights for future research.

Cholangiocarcinoma (CCA) is known for its high aggressiveness and dismal prognosis, whose effectiveness of systemic therapy remains limited. As a multi-target drug, lenvatinib has exhibited promising effects in many solid tumors. However, the therapeutic role of lenvatinib in CCA is rarely investigated. Here, the in vitro assays including EdU, colony formation, transwell, wound healing, and apoptosis analyses demonstrated that lenvatinib significantly inhibited the proliferation, migration, and invasion, while simultaneously inducing apoptosis of CCA cells. Mechanistically, lenvatinib downregulated the expression of FGF19 and inactivated the PI3K/AKT signaling pathway. Depletion of FGF19 enhanced the anti-tumor effects of lenvatinib, which was attributed to the inhibition of p-PI3K and p-AKT expression in CCA cells. In contrast, overexpression of FGF19 activated the PI3K/AKT signaling pathway, thereby impairing the inhibitory effects of lenvatinib against CCA. In addition, the AKT inhibitor, MK-2206, reinforced the lenvatinib-induced CCA inhibition. Notably, the in vivo experiment confirmed that the subcutaneous tumorigenicity of CCA cells in nude mice was weakened by lenvatinib. Lenvatinib markedly downregulated the expression of FGF19, p-AKT, Ki-67, vimentin, and VEGF in the xenograft tumor tissues. Collectively, these findings demonstrated that lenvatinib inhibits CCA progression by targeting the FGF19/PI3K/AKT signaling pathway. The present study provides novel experimental evidence for the potential clinical application of lenvatinib in CCA, which also highlights the promising role of targeting FGF19 in combined therapeutic approaches for CCA.

Tumors comprise a heterogeneous collection of tumor cells with distinct genetic and phenotypic characteristics that differentially promote malignant progression. Therefore, it is essential to depict the heterogeneous landscape of clones for understanding the cancer biology and overcoming the resistance of cancer therapy. To determine the dynamic clonal feature of OSCC, we constructed the evolutionary trajectory of tumor cells based on single-cell RNA sequencing data. A special transcriptional states of clones with distinct highly malignant features was identified, and FBXO2 was determined as the key switch gene causing the transition of tumor cells into this special state. FBXO2 exhibited a significantly high expression in OSCC than normal samples, especially in those with high clinical stages. The knockdown or overexpression of FBXO2 in OSCC cells correspondingly inhibited or promoted the abilities of proliferation, G1-S phase transition, migration, invasion, EMT, and resisting apoptosis. Moreover, FBXO2 was indicated to be involved in an intricate network to regulate multiple processes, modifying the interactions between tumor cells and other cells and thus defining different functional subtypes of tumor cells to affect tumor progression. These results provide new insights into clonal fate and pave the way for more effective therapy of OSCC.

Cell death is a normal physiological process within cells that involves multiple pathways, such as normal DNA damage, cell cycle arrest, and programmed cell death (PCD). Cell death has been a hot spot of research in tumor-related fields, especially programmed cell death, which is a key form of cell death and is classified into different types according to the mechanism of occurrence, such as apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and disulfidptosis. Given the important role of PCD in maintaining tissue homeostasis and inhibiting tumorigenesis and development, more and more basic and clinical studies are devoted to revealing its potential application in anti-tumor strategies. The purpose of this review is to systematically review the regulatory mechanisms of PCD and to summarize the latest research progress of anti-tumor treatment strategies based on PCD.

Dysregulated R-loop homeostasis leads to DNA replication stress and genomic instability, a major driver of cancer. However, the role of R-loops in melanoma development remains unclear. We established an R-loop scoring model based on a single-cell RNA sequencing dataset and evaluated the association between the R-loop score with the melanoma immune microenvironment and treatment response. We explored the role of CENPA-mediated changes in R-loop distribution during melanoma progression by DNA/RNA immunoprecipitation and sequencing and a series of functional experiments. We found that malignant cells with high R-loop scores may be involved in melanoma progression by modulating immune evasion, metabolic reprogramming, and cancer-related pathways. A cell communication analysis revealed that high-score R-loops play an important role in altering cell-cell interactions and limiting the CD8 + cytotoxic T cell response and T cell accumulation. CENPA silencing induced changes in R-loop distribution, upregulated Hippo signaling activity, and inhibited tumor cell proliferation and migration. Moreover, the R-loop score can predict the prognosis and immunotherapy effect of melanoma patients. Our work reveals the potential molecular mechanism by which abnormal R-loops promote melanoma progression, which may help develop anticancer therapies based on R-loops or R-loop regulators.

Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.