Regulation of programmed cell death by Brd4.
Ontology highlight
ABSTRACT:
SUBMITTER: Hu J
PROVIDER: S-EPMC9767942 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
Publications
Regulation of programmed cell death by Brd4.
Hu Jinfeng J Pan Dun D Li Guo G Chen Kunqi K Hu Xiangming X
Cell death & disease 20221220 12
Epigenetic factor Brd4 has emerged as a key regulator of cancer cell proliferation. Targeted inhibition of Brd4 suppresses growth and induces apoptosis of various cancer cells. In addition to apoptosis, Brd4 has also been shown to regulate several other forms of programmed cell death (PCD), including autophagy, necroptosis, pyroptosis, and ferroptosis, with different biological outcomes. PCD plays key roles in development and tissue homeostasis by eliminating unnecessary or detrimental cells. Dy ...[more]
Similar Datasets
Project description:The programmed cell death protein 1/programmed cell death ligand 1 axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases, while its role in multiple sclerosis is unclear. Here, we aimed to analyse expression patterns of programmed cell death protein 1 and programmed cell death ligand 1 on peripheral blood mononuclear cells and their soluble variants in multiple sclerosis patients and controls, to determine their correlation with clinical disability and disease activity. In a cross-sectional study, we performed in-depth flow cytometric immunophenotyping of peripheral blood mononuclear cells and analysed soluble programmed cell death protein 1 and programmed cell death ligand 1 serum levels in patients with relapsing-remitting multiple sclerosis and controls. In comparison to control subjects, relapsing-remitting multiple sclerosis patients displayed distinct cellular programmed cell death protein 1/programmed cell death ligand 1 expression patterns in immune cell subsets and increased soluble programmed cell death ligand 1 levels, which correlated with clinical measures of disability and MRI activity over time. This study extends our knowledge of how programmed cell death protein 1 and programmed cell death ligand 1 are expressed in the membranes of patients with relapsing-remitting multiple sclerosis and describes for the first time the elevation of soluble programmed cell death ligand 1 in the blood of multiple sclerosis patients. The distinct expression pattern of membrane-bound programmed cell death protein 1 and programmed cell death ligand 1 and the correlation between soluble programmed cell death ligand 1, membrane-bound programmed cell death ligand 1, disease and clinical factors may offer therapeutic potential in the setting of multiple sclerosis and might improve future diagnosis and clinical decision-making.
| S-EPMC10411318 | biostudies-literature
Project description:The regulation of tumor suppressor genes by microRNAs (miRNAs) is often demonstrated as a one-miRNA-to-one-target relationship. However, given the large number of miRNA sites within a 3' untranslated region (UTR), most targets likely undergo miRNA cooperation or combinatorial action. Programmed cell death 4 (PDCD4), an important tumor suppressor, prevents neoplastic events and is commonly downregulated in cancer. This study investigates the relationship between miRNA 21 (miR-21) and miR-499 in regulating PDCD4. This was explored using miRNA overexpression, mutational analysis of the PDCD4 3' UTR to assess regulation at each miRNA site, and 50% inhibitory concentration (IC50) calculations for combinatorial behavior. We demonstrate that the first miR-499 binding site within PDCD4 is inactive, but the two remaining sites are both required for PDCD4 suppression. Additionally, the binding of miR-21 to PDCD4 influenced miR-499 activity through an increase in its silencing potency and stabilization of its mature form. Furthermore, adjoining miRNA sites more than 35 nucleotides (nt) apart could potentially regulate thousands of 3' UTRs, similar to that observed between miR-21 and miR-499. The regulation of PDCD4 serves as a unique example of regulatory action by multiple miRNAs. This relationship was predicted to occur on thousands of targets and may represent a wider mode of miRNA regulation.
| S-EPMC6712940 | biostudies-literature
Project description:A huge diversification of phospholipids, forming the aqueous interfaces of all biomembranes, cannot be accommodated within a simple concept of their role as membrane building blocks. Indeed, a number of signaling functions of (phospho)lipid molecules has been discovered. Among these signaling lipids, a particular group of oxygenated polyunsaturated fatty acids (PUFA), so called lipid mediators, has been thoroughly investigated over several decades. This group includes oxygenated octadecanoids, eicosanoids, and docosanoids and includes several hundreds of individual species. Oxygenation of PUFA can occur when they are esterified into major classes of phospholipids. Initially, these events have been associated with non-specific oxidative injury of biomembranes. An alternative concept is that these post-synthetically oxidatively modified phospholipids and their adducts with proteins are a part of a redox epiphospholipidome that represents a rich and versatile language for intra- and inter-cellular communications. The redox epiphospholipidome may include hundreds of thousands of individual molecular species acting as meaningful biological signals. This review describes the signaling role of oxygenated phospholipids in programs of regulated cell death. Although phospholipid peroxidation has been associated with almost all known cell death programs, we chose to discuss enzymatic pathways activated during apoptosis and ferroptosis and leading to peroxidation of two phospholipid classes, cardiolipins (CLs) and phosphatidylethanolamines (PEs). This is based on the available LC-MS identification and quantitative information on the respective peroxidation products of CLs and PEs. We focused on molecular mechanisms through which two proteins, a mitochondrial hemoprotein cytochrome c (cyt c), and non-heme Fe lipoxygenase (LOX), change their catalytic properties to fulfill new functions of generating oxygenated CL and PE species. Given the high selectivity and specificity of CL and PE peroxidation we argue that enzymatic reactions catalyzed by cyt c/CL complexes and 15-lipoxygenase/phosphatidylethanolamine binding protein 1 (15LOX/PEBP1) complexes dominate, at least during the initiation stage of peroxidation, in apoptosis and ferroptosis. We contrast cell-autonomous nature of CLox signaling in apoptosis correlating with its anti-inflammatory functions vs. non-cell-autonomous ferroptotic signaling facilitating pro-inflammatory (necro-inflammatory) responses. Finally, we propose that small molecule mechanism-based regulators of enzymatic phospholipid peroxidation may lead to highly specific anti-apoptotic and anti-ferroptotic therapeutic modalities.
| S-EPMC7933662 | biostudies-literature
Project description:Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1(-/-) mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.
| S-EPMC3088162 | biostudies-literature
Project description:Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. During aging the cell turnover rate declines for several highly-mitotic tissues. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.
| S-EPMC4480161 | biostudies-literature
Project description:Simple Summary Hepatocellular carcinoma is a prevalent and aggressive liver tumor. Non-coding RNAs that do not participate in protein synthesis but regulate gene expression have been found to influence programmed cell death. Understanding the clinical significance of non-coding RNA regulation of programmed cell death in hepatocellular carcinoma, such as patient diagnosis and prognosis, drug resistance, and drug side effects, can provide valuable insights into the diagnosis and treatment of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) is a widely prevalent and malignantly progressive tumor. Most patients are typically diagnosed with HCC at an advanced stage, posing significant challenges in the execution of curative surgical interventions. Non-coding RNAs (ncRNAs) represent a distinct category of RNA molecules not directly involved in protein synthesis. However, they possess the remarkable ability to regulate gene expression, thereby exerting significant regulatory control over cellular processes. Notably, ncRNAs have been implicated in the modulation of programmed cell death (PCD), a crucial mechanism that various therapeutic agents target in the fight against HCC. This review summarizes the clinical significance of ncRNA regulation of PCD in HCC, including patient diagnosis, prognosis, drug resistance, and side effects. The aim of this study is to provide new insights and directions for the diagnosis and drug treatment strategies of HCC.
| S-EPMC10452865 | biostudies-literature
Project description:Current research proves that immune dysregulation is a common feature of coronavirus disease 2019 (COVID-19), and immune exhaustion is associated with increased disease mortality. Immune checkpoint molecules, including the programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) axis, may serve as markers of disease severity. Accordingly, in this study, we evaluated the expression of PD-1/PD-L1 in patients with COVID-19. Blood immunophenotypes of hospitalized patients with moderate (n = 17, requiring oxygen support) and severe (n = 35, requiring mechanical ventilation in the intensive care setting) COVID-19 were compared and associated with clinical, laboratory, and survival data. The associations between severity and lymphocyte profiles were analysed at baseline and after 7 and 14 days of in-hospital treatment. Forty patients without COVID-19 infection were used as controls. For PD-1-positive T and B lymphocyte subsets, notable increases were observed between controls and patients with moderate or severe COVID-19 for CD4+PD-1+ T cells, CD8+PD-1+ T and CD19+PD-1+ B cells. Similar trends were observed for PD-L1-positive lymphocytes, namely, CD4+PD-L1+ T cells, CD8+PD-L1+ T cells and CD19+PD-L1+ B cells. Importantly, all markers associated with PD-1 and PD-L1 were stable over time for the analysed time points in the moderate and severe COVID-19 groups. Increased abundances of PD-1+ and PD-L1+ lymphocytes were associated with disease severity and mortality and were stable over time in patients with moderate to severe COVID-19. These immune exhaustion parameters may be attractive biomarkers of COVID-19 severity.
| S-EPMC9222173 | biostudies-literature
Project description:Hyperammonemia is common in liver cirrhosis and causally associated with hepatic encephalopathy development. Little is known about its hepatotoxic effects, which we aimed to characterize in this study. In a mouse model of chronic hyperammonemia without preexisting liver disease, we observed development of liver fibrogenesis and necroptotic cell death. Hyperammonemia also induced dysregulation of its main metabolic pathway, the urea cycle, as reflected by down-regulation of urea cycle enzyme protein expression and accumulation of its metabolites. Inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and its upstream inducer Toll-like receptor 4 (TLR4) protected against liver injury and further hyperammonemia. In clinically relevant rodent models of hyperammonemia (genetic ornithine transcarbamylase deficiency and bile duct ligation-induced cirrhosis), TLR4 inhibition reduced circulating ammonia. In conclusion, hyperammonemia induces liver fibrogenesis and RIPK1-mediated cell death, which is associated with urea cycle dysfunction. Inhibition of RIPK1 and TLR4 protects against hyperammonemia-induced liver injury and are potential therapeutic targets for hyperammonemia and chronic liver disease progression.
| S-EPMC11887801 | biostudies-literature
Project description:BackgroundIntracerebral hemorrhage (ICH) accounts for up to 15% of all strokes and is characterized by high rates of mortality and morbidity. The post-ICH brain injury can be distinguished in 1) primary, which are caused by disruption and mechanical deformation of brain tissue due to hematoma growth and 2) secondary, which are induced by microglia activation, mitochondrial dysfunction, neurotransmitter and inflammatory mediator release. Although these events typically lead to necrosis, the occurrence of programmed cell death has also been reported after ICH.MethodsWe reviewed recent publications describing advance in pre- and clinic ICH research.ResultsAt present, treatment of ICH patients is based on oral anticoagulant reversal, management of blood pressure and other medical complications. Several pre-clinical studies showed promising results and demonstrated that anti-oxidative and anti-inflammatory treatments reduced neuronal cell death, however, to date, all of these attempts have failed in randomized controlled clinical trials. Yet, the time frame of administration may be crucial in translation from animal to clinical studies. Furthermore, the latest pre-clinical research points toward the existence of other, apoptosisunrelated forms kinds of programmed cell death.ConclusionOur review summarizes current knowledge of pathways leading to programmed cell death after ICH in addition to data from clinical trials. Some of the pre-clinical results have not yet demonstrated clinical confirmation, however they significantly contribute to our understanding of post-ICH pathology and can contribute to development of new therapeutic approaches, decreasing mortality and improving ICH patients' quality of life.
| S-EPMC6251052 | biostudies-literature
Project description:The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional consequences of several key cell death pathways. Currently, the most intensively investigated programmed cell death (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, which has been discovered to play crucial roles in modulating the immunosuppressive tumor microenvironment (TME) and determining clinical outcomes of the cancer therapeutic approaches. PCD can play dual roles, either pro-tumor or anti-tumor, partly depending on the intracellular contents released during the process. PCD also regulates the enrichment of effector or regulatory immune cells, thus participating in fine-tuning the anti-tumor immunity in the TME. In this review, we focused primarily on apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, discussed the released molecular messengers participating in regulating their intricate crosstalk with the immune response in the TME, and explored the immunological consequence of PCD and its implications in future cancer therapy developments.
| S-EPMC9005769 | biostudies-literature