Apoptosis最新文献

The prognosis for patients with metastatic colorectal cancer (mCRC) remains poor primarily owing to immune escape caused by immunosuppressive tumor microenvironment (TME). M2 tumor-associated macrophages (TAMs) have been considered as a pivotal role in sustaining the immunosuppressive character in TME. Our previous studies have found that highly mCRC cells could promote M2 TAMs polarization, leading to the exhaustion of T cell antitumor immunity. Studies have reported that Bufalin (BU) could reverse the immunosuppressive TME via regulating TAMs polarization, but the mechanisms underlying remain elusive. In this study, we demonstrated that KLF4 secreted by highly mCRC cells not only promoted the polarization to M2 TAMs but also up-regulated the PD-L1 expression in TAMs, leading to suppressing cytotoxic T lymphocyte (CTL) function to facilitate tumor immune escape. Mechanistically, BU targeted the SRC-3 protein to reduce KLF4 release in highly mCRC cells to regulate the polarization of M2 TAMs and down-regulate PD-L1 expression in TAMs, resulting in reprogramming of the TME and enhancing the anti-tumor immunity. These results have also been validated in both subcutaneous tumor models and orthotopic tumor models. Overall, this research further elucidates the anti-tumor mechanism of BU for inhibiting immune escape in mCRC and facilitate exploitation of a new potential macrophage-based mCRC immunotherapeutic modality.

Ochratoxin A (OTA), a toxic secondary metabolite recognized for its harmful effects on the kidneys, and it is commonly present in various foods and animal feeds. Although there have been few reports on the involvement of metabolic enzymes in OTA-induced nephrotoxicity and metabolic reprogramming in OTA-induced digestive tract toxicity, it remains unclear whether OTA's primary nephrotoxic effects are mediated through metabolic reprogramming. In this study, we examined the effects of OTA and/or 2-deoxy-D-glucose (2-DG) on cell viability, levels of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and lactic acid (LA), as well as protein levels in human proximal tubule epithelial (HK-2) cells. The results indicate that OTA leads to a reduction in GSH levels and the protein levels of Lon protease 1 (Lonp1), tumor necrosis factor receptor-associated protein 1 (TRAP1), mitochondrial pyruvate carrier 1 (MPC1), glutathione peroxidase 4 (GPX4), B-cell lymphoma-2 (Bcl-2), and Bcl-2-like protein 1 (Bcl-xl), while increasing ROS, MDA, and LA levels, as well as the protein levels of glucose transporter type 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase 2 (PKM2), ATP-dependent 6-phosphofructokinase, platelet type (PFKP), long-chain fatty acid-CoA ligase 4 (ACSL4), Bcl-2-associated X protein (Bax), and cyclophilin D (CYPD) (P < 0.05). In conclusion, OTA induces mitochondrial pathway apoptosis and ferroptosis by disturbing mitochondrial homeostasis via the inhibition of Lonp1 and TRAP1, thereby reducing GSH levels, increasing ROS, MDA, and LA levels, and promoting glycolysis in vitro. This is the first report on OTA-induced mitochondrial pathway apoptosis and ferroptosis facilitated by mitochondrial homeostasis imbalance-mediated glycolysis in HK-2 cells.

The N6-Methyladenosine (m6A) modification is prevalent across various RNA species, including messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), and has garnered significant interest due to its potential implications in cardiovascular disease. Despite extensive research, the precise relationship between m6A and myocardial infarction (MI) remains inadequately understood. The human YTH domain family 2 (YTHDF2) protein has emerged as a critical factor in this context, selectively recognizing m6A-modified RNAs and modulating their degradation. Our investigation revealed that the knockdown of YTHDF2 markedly enhanced ferroptosis in vitro, whereas the overexpression of YTHDF2 exhibited a significant protective effect. Mechanistically, it was elucidated that YTHDF2 suppresses the expression of nuclear receptor coactivator 4 (NCOA4) via m6A methylation. Furthermore, the inhibition of cardiomyocyte ferroptosis by YTHDF2 is contingent upon its regulation of NCOA4. Additionally, the enzyme methyltransferase-like 3 (METTL3) was identified as a pivotal factor in the m6A-mediated degradation of NCOA4 mRNA. Taken together, our results highlight the significant role of YTHDF2-mediated NCOA4 m6A methylation in the regulation of myocardial infarction and myocardial ferroptosis, suggesting that YTHDF2 may be a promising target for therapeutic interventions in myocardial infarction.

X-linked inhibitor of apoptosis protein (XIAP) is the most potent endogenous member of the inhibitor of apoptosis protein family. XIAP exerts its anti-apoptotic effects by inhibiting both the death receptor pathway and mitochondrial pathway of apoptosis through various mechanisms such as directly binding to caspases, activating the nuclear factor kappa B (NF-κB) pathway, and other signaling pathways. These processes are closely related to tumor development and progression, making XIAP a therapeutic target for various types of cancer. This article will first review the structural characteristics and biological functions of XIAP, followed by its effects on tumors and an overview of XIAP-targeted inhibitors.

To clarify the biological functions and prognostic significance of migrasome-related integrin subunit alpha 5 (ITGA5) in hepatocellular carcinoma (HCC). We used The Cancer Genome Atlas datasets and RNA-seq data from nine sets of paired HCC and adjacent normal tissues to identify key migrasome-related genes through a comprehensive analysis and weighted correlation network analysis. We then confirmed their roles in HCC through analyses of gene mutations, methylation, and immune cell infiltration, as well as molecular docking, molecular dynamics, and cell experiments. A comprehensive analysis of migrasome-related genes showed that ITGA5 was a critical gene related to HCC, and it is highly expressed in HCC tissues, which is related to poor prognosis. Further enrichment analysis revealed that ITGA5 is involved in many pathways related to tumor occurrence and metastasis, such as the PI3K-AKT pathway. In addition, ITGA5 was found to be expressed in multiple types of immune cells and was closely associated with immune infiltration. Drug sensitivity, molecular docking, and molecular dynamics analyses indicated that ITGA5 may enhance the sensitivity of HCC to drug TGX221. Finally, cell phenotype experiments confirmed that ITGA5 knockdown suppressed the proliferation, migration, and invasion of HCC cells, and while overexpression exacerbated malignant phenotypes. Our analyses showed that ITGA5 is a key migrasome-related gene involved in the proliferation and metastasis of HCC that has promise as a therapeutic target and candidate prognostic indicator.

Necroptosis is a programmed form of cell death that has gained significant attention in the field of cardiovascular research due to its involvement in myocardial infarction (MI) and myocardial ischaemia-reperfusion (I/R) injury. Unlike apoptosis, necroptosis elicits a pro-inflammatory response, contributing to myocardial injury, fibrosis, and adverse remodelling. This review aims to provide an overview of the molecular mechanisms underlying necroptosis, with a particular focus on its role in myocardial I/R injury. Key regulatory proteins such as Receptor-interacting protein kinase 3 (RIPK3) and Mixed lineage kinase domain-like protein (MLKL) are central to the necroptotic process, mediating cell death and inflammation. The review discusses the potential of targeting necroptosis as a therapeutic strategy for managing cardiovascular diseases, particularly post-MI. The RIPK3-CaMKII-mitochondrial permeability transition pore (mPTP) pathway is identified as a critical signalling axis in necroptosis and its inhibition may offer protective benefits in myocardial injury. The review also considers the role of natural and chemical inhibitors and other genes in necroptosis regulation. Overall, targeting necroptosis represents a promising avenue for therapeutic intervention to mitigate cardiac injury, promote recovery, and improve long-term patient outcomes in cardiovascular diseases.

The precise pathogenic mechanisms underlying sepsis-induced acute kidney injury (AKI) remain elusive. Emerging evidence suggests a link between tubular ferroptosis and the pathogenesis of AKI, though the regulatory pathways are not fully understood. Stimulator of interferon genes (STING), previously recognized as a pivotal mediator of innate immunity via DNA-sensing pathways, is increasingly associated with lipid peroxidation, a hallmark of ferroptosis, and 4-octyl itaconate (4-OI) has been shown to inhibit STING activation, exerting anti-inflammatory effects. This study investigates the protective mechanisms of 4-OI in sepsis-AKI. Following cecal ligation and puncture (CLP), inflammation, oxidative stress, and ferroptosis levels in kidney tissue increased. Both 4-OI and ferrostatin-1 (Fer-1) mitigated renal ferroptosis, exerting anti-inflammatory and antioxidant stress effects, and improved renal function. Consistently, in vitro experiments demonstrated that 4-OI reduced ferroptosis in human renal proximal tubule (HK-2) cells induced by lipopolysaccharide (LPS). Mechanistically, 4-OI suppressed LPS-induced activation of the STING pathway and reduced levels of inflammatory cytokines in a manner independent of NF-E2-related factor 2 (Nrf2). Additionally, 4-OI inhibited STING transcription through the activation of Nrf2. These dual actions effectively suppressed LPS-induced STING pathway activation, thereby inhibiting STING-mediated autophagic degradation of glutathione peroxidase 4 (GPX4), reducing reactive oxygen species (ROS) accumulation, and alleviating ferroptosis. In summary, 4-OI is a promising therapeutic candidate, functioning both as a STING inhibitor and a ferroptosis inhibitor, with potential applications in the treatment of sepsis.

Neuronal damage in brain ischemia is characterized by a disassembly of the proteasome and a decrease in its proteolytic activity. However, to what extent these alterations are coupled to neuronal death is controversial since proteasome inhibitors were shown to provide protection in different models of stroke in rodents. This question was addressed in the present work using cultured rat cerebrocortical neurons subjected to transient oxygen- and glucose-deprivation (OGD) as a model for in vitro ischemia. Under the latter conditions there was a time-dependent loss in the proteasome activity, determined by cleavage of the Suc-LLVY-AMC fluorogenic substrate, and the disassembly of the proteasome, as assessed by native-polyacrylamide gel electrophoresis followed by western blot against Psma2 and Rpt6, which are components of the catalytic core and regulatory particle, respectively. Immunocytochemistry experiments against the two proteins also showed differential effects on their dendritic distribution. OGD also downregulated the protein levels of Rpt3 and Rpt10, two components of the regulatory particle, by a mechanism dependent on the activity of NMDA receptors and mediated by calpains. Activation of the proteasome activity, using an inhibitor of USP14, a deubiquitinase enzyme, inhibited OGD-induced cell death, and decreased calpain activity as determined by analysis of spectrin cleavage. Similar results were obtained in the presence of two oleic amide derivatives (B12 and D3) which directly activate the 20S proteasome core particle. Together, these results show that proteasome activation prevents neuronal death in cortical neurons subjected to in vitro ischemia, indicating that inhibition of the proteasome is a mediator of neuronal death in brain ischemia.

Colorectal cancer (CRC) is among the most prevalent and deadly gastrointestinal malignancies, with advanced-stage tumors often exhibiting resistance to both chemotherapy and targeted therapies, underscoring the urgent need for novel therapeutic targets to improve clinical outcomes. Sorting nexin 1 (SNX1), previously implicated in receptor trafficking between early and late endosomes/lysosomes in cancer studies, has an unclear role in CRC tumorigenesis and progression. Our study revealed that SNX1 expression was downregulated in CRC, and its low levels correlated with advanced tumor stages and unfavorable clinical outcomes. Functionally, SNX1 significantly inhibited tumor cell growth both in vitro and in vivo. Further experiments showed that SNX1 induced ferroptosis in CRC cells by modulating the PPARs-ACSL1/4 pathway downstream of EGFR signaling. Moreover, glucose deprivation suppressed the Hippo pathway, promoted YAP nuclear translocation, and activated the transcription factor Yin Yang 1 (YY1), leading to SNX1 downregulation. This subsequently activated EGFR signaling and ultimately suppressed ferroptosis in CRC cells. Notably, the combination of SNX1 overexpression and 5-fluorouracil (5-FU) treatment exhibited a synergistic anti-tumor effect in a cell-derived xenograft (CDX) model. These findings underscore the critical role of SNX1 in regulating ferroptosis and tumor progression in CRC and highlight its potential as a therapeutic target to enhance chemotherapy effectiveness in CRC.