Apoptosis最新文献

Globally, esophageal cancer stands as a prominent contributor to cancer-related fatalities, distinguished by its poor prognosis. Mitophagy has a significant impact on the process of cancer progression. This study investigated the prognostic significance of mitophagy-related genes (MRGs) in esophageal carcinoma (ESCA) to elucidate molecular subtypes. By analyzing RNA-seq data from The Cancer Genome Atlas (TCGA), 6451 differentially expressed genes (DEGs) were identified. Cox regression analysis narrowed this list to 14 MRGs with potential prognostic implications. ESCA patients were classified into two distinct subtypes (C1 and C2) based on these genes. Furthermore, leveraging the differentially expressed genes between Cluster 1 and Cluster 2, ESCA patients were classified into two novel subtypes (CA and CB). Importantly, patients in C2 and CA subtypes exhibited inferior prognosis compared to those in C1 and CB (p < 0.05). Functional enrichments and immune microenvironments varied significantly among these subtypes, with C1 and CB demonstrating higher immune checkpoint expression levels. Employing machine learning algorithms like LASSO regression, Random Forest and XGBoost, alongside multivariate COX regression analysis, two core genes: HSPD1 and MAP1LC3B were identified. A prognostic model based on these genes was developed and validated in two external cohorts. Additionally, single-cell sequencing analysis provided novel insights into esophageal cancer microenvironment heterogeneity. Through Coremine database screening, Icaritin emerged as a potential therapeutic candidate to potentially improve esophageal cancer prognosis. Molecular docking results indicated favorable binding efficacies of Icaritin with HSPD1 and MAP1LC3B, contributing to the understanding of the underlying molecular mechanisms of esophageal cancer and offering therapeutic avenues.

Systemic sclerosis, also termed scleroderma, is a severe and debilitating autoimmune disease characterized by fibrosis, an aberrant immune response, and vascular dysfunction. Cell death is essential to the body's continued normal development as it removes old or damaged cells. This process is governed by several mechanisms, including programmed cell death through apoptosis, necrosis, and pyroptosis, as well as metabolic processes, such as ferroptosis and cuproptosis. This review describes the signaling pathways associated with each form of cell death, examining the linkages between these pathways, and discussing how the dysregulation of cell death processes is involved in the development of autoimmune disorders such as systemic sclerosis. Existing and promising therapeutic strategies aimed at restoring the balance of cell death in systemic sclerosis and other autoimmune disorders are also emphasized.

Microplastics (MPs) are widely distributed environmental pollutants around the world. Although studies have demonstrated that MPs have adverse effects on human health, the relationship between MPs and tumors remains unclear. The gut is the main site of microplastics absorption, and the function of MPs in the chemoresistance and progression of colorectal cancer (CRC) needs more investigation. Here, we show that MPs exist in human CRC tissues for the first time by using a laser direct infrared chemical imaging system. MPs can cause an increase in CRC incidence in animal models and promote resistance to oxaliplatin. It is illustrated that the uptake of MPs enhances levels of autophagy by activating the mTOR pathway. MPs can also promote the disorder of intestinal flora and intestinal inflammation, serving as an essential component in the onset and advancement of CRC. These results indicated that microplastic pollutants in colorectal cancer could mediate protective autophagy through the mTOR/ULK1 axis, which is one of the new reasons for chemo-resistance in CRC under the background of increasingly serious microplastics pollution. This study identified the adverse effects of MPs on colorectal cancer progression and chemotherapy prognosis, and attempted to block the intake of MPs to propose a novel approach for clinical precision treatment.

Research on cell death is getting diverse. Apoptosis and other forms of programmed cell death play a critical role in maintaining cellular homeostasis and defending an organism from infections, cancer, and degenerative diseases. Apoptosis, a well-known form of programmed cell death, involves non-inflammatory and orderly organized dismantling of a cell. Different pathways and mechanisms have emerged that challenge the traditional apoptosis-centric view, such as necroptosis, panoptosis, pyroptosis, paraptosis, ferroptosis and autophagic cell death. This editorial aims to highlight some of these emerging pathways, expanding our understanding of cellular death and its implications in health and disease. Over the years, Apoptosis has been at the forefront of publishing discoveries on these diverse and impactful processes.

Subarachnoid hemorrhage (SAH), representing 5-10% of all stroke cases, is a cerebrovascular event associated with a high mortality rate and a challenging prognosis. The role of IRG1-regulated itaconate in bridging metabolism, inflammation, oxidative stress, and immune response is pivotal; however, its implications in the early brain injury following SAH remain elusive. The SAH nerve inflammation model was constructed by Hemin solution and BV2 cells. In vitro and in vivo SAH models were established by intravascular puncture and Hemin solution treatment of HT22 cells. To explore the relationship between IRG1 and neuroinflammation by interfering the expression of Irg1 in BV2 cells. By adding itaconate and its derivatives to explore the relationship between mitophagy and ferroptosis. IRG1 knockdown increased the expression of inflammatory factors and induced the transformation of microglia to pro-inflammatory phenotype after SAH; Itaconate and itaconate derivative 4-OI can reduce oxidative stress and lipid peroxidation level in neuron after SAH, and reduce EBI after SAH; IRG1/ itaconate promotes mitophagy through PINK1/Parkin signaling pathway to inhibit neuronal ferroptosis. IRG1 can improve nerve inflammation after SAH, M2 of microglia induced polarization. IRG1/ Itaconate participates in mitophagy through PINK1/Parkin to alleviate neuronal ferroptosis after SAH and play a neuroprotective role.

Over the recent years, our understanding of the cell death machinery of mature erythrocytes has been greatly expanded. It resulted in the discovery of several regulated cell death (RCD) pathways in red blood cells. Apoptosis (eryptosis) and necroptosis of erythrocytes share certain features with their counterparts in nucleated cells, but they are also critically different in particular details. In this review article, we summarize the cell death subroutines in the erythroid precursors (apoptosis, necroptosis, and ferroptosis) in comparison to mature erythrocytes (eryptosis and erythronecroptosis) to highlight the consequences of organelle clearance and associated loss of multiple components of the cell death machinery upon erythrocyte maturation. Recent advances in understanding the role of erythrocyte RCDs in health and disease have expanded potential clinical applications of these lethal subroutines, emphasizing their contribution to the development of anemia, microthrombosis, and endothelial dysfunction, as well as their role as diagnostic biomarkers and markers of erythrocyte storage-induced lesions. Fas signaling and the functional caspase-8/caspase-3 system are not indispensable for eryptosis, but might be retained in mature erythrocytes to mediate the crosstalk between both erythrocyte-associated RCDs. The ability of erythrocytes to switch between eryptosis and necroptosis suggests that their cell death is not a simple unregulated mechanical disintegration, but a tightly controlled process. This allows investigation of eventual pharmacological interventions aimed at individual cell death subroutines of erythrocytes.

Background: Colorectal cancer (CRC) represents a significant global health burden, with chemotherapy resistance representing a significant challenge to effective treatment. SEC23A, a core component of the COPII vesicle trafficking system, is of critical importance with regard to protein transport and cellular homeostasis. Nevertheless, its function in CRC progression and chemoresistance remains uncertain. The present study investigates the correlation between SEC23A expression and sensitivity to 5-fluorouracil (5-FU), a widely used chemotherapeutic agent, with particular emphasis on ER stress-induced apoptosis.

Methods: A bioinformatic analysis was conducted to evaluate SEC23A expression in CRC and its association with patient prognosis. Chemotherapy sensitivity was predicted using GDSC data and validated experimentally using CRC cell lines with manipulated SEC23A expression. In order to explore the role of SEC23A in acquired drug resistance, patient-derived xenograft (PDX) models and 5-FU-resistant cell lines were employed. Apoptosis assays, cell cycle analysis, and ER stress modulation experiments were performed to elucidate the underlying mechanisms.

Results: SEC23A expression was significantly reduced in CRC samples compared to normal tissues. This reduction was linked to a poorer prognosis, including both overall and disease-specific survival. A correlation was observed between low SEC23A expression and increased resistance to 5-FU, as evidenced by both bioinformatic predictions and in vitro experiments. In PDX models, metastatic lesions exhibited decreased SEC23A expression following 5-FU treatment in comparison to primary tumors. Overexpression of SEC23A in 5-FU-resistant cell lines restored sensitivity to the drug and increased apoptosis. Bioinformatic and experimental analyses revealed a robust correlation between SEC23A and ER stress-related apoptotic pathways. Elevated expression of SEC23A was observed to facilitate the accumulation of misfolded proteins in response to 5-FU treatment, which in turn resulted in increased ER stress and apoptosis.

Conclusions: SEC23A plays a crucial role in modulating the sensitivity of CRC cells to 5-FU by regulating ER stress-induced apoptosis. Its downregulation contributes to chemoresistance, indicating that SEC23A may serve as a prognostic marker and therapeutic target in CRC. Strategies aimed at upregulating SEC23A or enhancing ER stress may provide new avenues for overcoming chemoresistance and improving treatment outcomes for CRC patients.

The T Cell Receptor (TCR) significantly contributes to tumor immunity, whereas the intricate interplay with the Hepatocellular Carcinoma (HCC) microenvironment and clinical significance remains largely unexplored. Here, we aimed to examine the function of TCR signaling in tumor immunity and its clinical significance in HCC. Our objective was to employ TCR signaling genes and a machine learning-based integrative methodology to construct a prognostic prediction system termed the TCR score. Herein, we revealed that the TCR score serves as an independent risk factor for overall survival in HCC patients, demonstrating stable and robust performance. The accuracy of the TCR score significantly exceeds that of traditional clinical variables and published signatures. Additionally, the immune infiltration was abundant in patients with low TCR scores. Single-cell cohort analysis further demonstrates that patients with low TCR scores possess an immune-active tumor microenvironment (TME), with T/NK cells enhancing interactions with myeloid cells through signaling networks such as MIF, MK, and SPP1. In response to these changes in the TME, patients with high TCR scores exhibit poorer outcomes and shorter survival in immunotherapy cohorts. In vitro experiments demonstrated that the key TCR signaling biomarker SOS1 knockdown significantly suppresses the HCC cells' capability to proliferate, invade, and migrate while enhancing tumor cell apoptosis. The TCR score could function as a robust and potential tool to predict immune activity and improve clinical outcomes for HCC patients.

Growing research indicates that long noncoding RNAs (lncRNAs) are pivotal in the development and advancement of hepatocellular carcinoma (HCC). Our research pinpointed LINC01547 as a notable lncRNA that was significantly downregulated in Hep3B cells treated with bufotalin, whereas it exhibited elevated expression levels in HCC tumor tissues. Further study found that silencing LINC01547 markedly suppressed proliferation, induced apoptosis, and inhibited migration and invasion in Hep3B and HepG2 cells. LINC01547 knockdown reduced ADAR1 expression, which led to apoptosis and suppressed metastasis via inhibition of the FAK signaling pathway. Additionally, silencing LINC01547 upregulated miR-146b-5p, which in turn decreased RAC1 levels, further promoting apoptosis and inhibiting metastasis in HCC cells. In vivo, a Hep3B tumor-bearing mouse model confirmed the antitumor effects of LINC01547 silencing. Our findings demonstrate that LINC01547 regulates HCC cell apoptosis and metastasis through the ADAR1/FAK and miR-146b-5p/RAC1 pathways, suggesting that LINC01547 may serve as a biomarker and potential therapeutic target for HCC.

Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. Immunotherapy, a promising therapeutic approach, often faces challenges due to the immunosuppressive tumor microenvironment. This study explores the innovative use of CRISPR-Cas9 technology in conjunction with FCPCV nanoparticles to target and edit the C-C Motif Chemokine Ligand 5 (CCL5) gene, aiming to improve the efficacy of breast cancer immunotherapy. Single-cell RNA sequencing (scRNA-seq) and TCGA-BRCA data identified CCL5 as a key immune-related gene in breast cancer. Using CRISPR-Cas9, sgRNA targeting CCL5 was designed and delivered to breast cancer cells and humanized mouse models via FCPCV nanoparticles. In vitro experiments demonstrated that FCPCV nanoparticles effectively silenced CCL5, enhanced CD8⁺ T cell activity, and increased the production of cytokines such as IFN-γ, TNF-α, and GZMB. In vivo studies revealed significant tumor suppression, improved immune microenvironment, and increased CD8⁺/CD4⁺ ratios in treated mice, without notable toxic side effects. These findings highlight the potential of CRISPR-Cas9 nanoparticle-mediated gene editing as a novel strategy for enhancing breast cancer immunotherapy, providing a new direction for personalized and effective cancer treatment.