Aging-induced Suppression of Cirbp Compromises DHODH-Mediated Ferroptosis Defense and Attenuates Hypothermic Cardioprotection during Heart Transplantation
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE227005 | GEO | 2026/03/05
REPOSITORIES: GEO
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Project description:The purpose of this study was to explore the potential mechanism of attenuated hypothermic cardioprotection in the aging donor heart during transplantation and investigate its translational values.
2026-03-05 | GSE227004 | GEO
Project description:The purpose of this study was to explore the potential mechanism of attenuated hypothermic cardioprotection in the aging donor heart during transplantation and investigate its translational values. We performed chromatin occupancy of Sp1 profiling analysis using data obtained from chromatin immunoprecipitation-sequencing (ChIP-seq) of LV myocardium from the wild-type rat
2026-03-05 | GSE227003 | GEO
Project description:Aging-induced Suppression of Cirbp Compromises DHODH-Mediated Ferroptosis Defense and Attenuates Hypothermic Cardioprotection during Heart Transplantation
| PRJNA942887 | ENA
Project description:Aging-induced Suppression of Cirbp Compromises DHODH-Mediated Ferroptosis Defense and Attenuates Hypothermic Cardioprotection during Heart Transplantation [ChIP-seq]
| PRJNA942906 | ENA
Project description:Background/objectiveWe aimed to elucidate the roles of ferroptosis-associated differentially expressed genes (DEGs) in glioblastoma and provide a comprehensive resource for researchers in the field of glioblastoma cell ferroptosis.MethodsWe used RNA sequencing to identify the DEGs associated with erastin-induced ferroptosis in glioblastoma cells. We further unraveled the biological functions and clinical implications of cold-inducible RNA-binding protein (CIRBP) in the context of glioblastoma by using a multifaceted approach, encompassing gene expression profiling, survival analysis, and functional assays to elucidate its role in glioblastoma cell mortality and its potential influence on patient prognosis.ResultsWe identified and validated the gene encoding CIRBP, the expression of which is altered during glioblastoma ferroptosis. Our findings highlight the relationship between CIRBP expression and ferroptosis in glioblastoma cells. We demonstrated that CIRBP modulates key aspects of cell death, thereby altering the sensitivity of glioblastoma cells to erastin-induced ferroptosis. A prognostic model, constructed based on CIRBP expression levels, revealed an association between lower CIRBP levels and poorer prognosis in glioma patients; this finding was corroborated by our comprehensive in vitro and in vivo assays that highlighted the impact of modulating CIRBP expression on glioblastoma cell viability and ferroptotic response.ConclusionOur research unravels the complex molecular dynamics of ferroptosis in glioblastoma and underscores CIRBP as a potential biomarker and therapeutic target. This improved understanding of the role of CIRBP in ferroptosis paves the way for more precise and efficacious treatments for glioblastoma, potentially improving patient outcomes.
| S-EPMC11761263 | biostudies-literature
Project description:Plants manage the high cost of immunity activation by suppressing the expression of defense genes during normal growth and rapidly switching them on upon pathogen invasion. TGAs are key transcription factors controlling the expression of defense genes. However, how TGAs function, especially in monocot plants like rice with continuously high levels of endogenous salicylic acid (SA) remains elusive. In this study, we characterized the role of OsTGA5 as a negative regulator of rice resistance against blast fungus by transcriptionally repressing the expression of various defense-related genes. Moreover, OsTGA5 repressed PTI responses and the accumulation of endogenous SA. Importantly, we showed that the nucleus-localized casein kinase II (CK2) complex interacts with and phosphorylates OsTGA5 on Ser-32, which reduces the affinity of OsTGA5 for the JIOsPR10 promoter, thereby alleviating the repression of JIOsPR10 transcription and increasing rice resistance. Furthermore, the in vivo phosphorylation of OsTGA5 Ser-32 was enhanced by blast fungus infection. The CK2 α subunit, depending on its kinase activity, positively regulated rice defense against blast fungus. Taken together, our results provide a mechanism for the role of OsTGA5 in negatively regulating the transcription of defense-related genes in rice and the repressive switch imposed by nuclear CK2-mediated phosphorylation during blast fungus invasion.
| S-EPMC9421590 | biostudies-literature
Project description:ObjectivesThe pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression.Methods and resultsCardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues.ConclusionsThe PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.
| S-EPMC11619700 | biostudies-literature
Project description:Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.
| S-EPMC8895686 | biostudies-literature
Project description:Exposure to the mold Aspergillus fumigatus may result in allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, or invasive aspergillosis (IA), depending on the host's immune status. Neutrophil deficiency is the predominant risk factor for the development of IA, the most life-threatening condition associated with A. fumigatus exposure. Here we demonstrate that in addition to neutrophils, eosinophils are an important contributor to the clearance of A. fumigatus from the lung. Acute A. fumigatus challenge in normal mice induced the recruitment of CD11b+ Siglec F+ Ly-6G(lo) Ly-6C(neg) CCR3+ eosinophils to the lungs, which was accompanied by an increase in lung Epx (eosinophil peroxidase) mRNA levels. Mice deficient in the transcription factor dblGATA1, which exhibit a selective deficiency in eosinophils, demonstrated impaired A. fumigatus clearance and evidence of germinating organisms in the lung. Higher burden correlated with lower mRNA expression of Epx (eosinophil peroxidase) and Prg2 (major basic protein) as well as lower interleukin 1β (IL-1β), IL-6, IL-17A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and CXCL1 levels. However, examination of lung inflammatory cell populations failed to demonstrate defects in monocyte/macrophage, dendritic cell, or neutrophil recruitment in dblGATA1-deficient mice, suggesting that the absence of eosinophils in dlbGATA1-deficient mice was the sole cause of impaired lung clearance. We show that eosinophils generated from bone marrow have potent killing activity against A. fumigtaus in vitro, which does not require cell contact and can be recapitulated by eosinophil whole-cell lysates. Collectively, our data support a role for eosinophils in the lung response after A. fumigatus exposure.
| S-EPMC3958002 | biostudies-literature
Project description:ObjectivesDonation after circulatory death provides excellent patient outcomes in heart transplantation; however, warm ischaemic graft damage remains a concern. We have reported that a brief period of hypothermic oxygenated perfusion prior to normothermic reperfusion improves graft recovery in a rat model. Here, we investigated the cardioprotective benefits and mechanisms of this approach compared to the current clinical standard in a large animal model.MethodsCirculatory death was induced in anaesthetized male Schweizer Edelschwein pigs (55 kg). Hearts underwent 20 min of warm, in-situ ischaemia, followed by a cold coronary flush and explantation. After 15 min backtable preparation, hearts underwent either 15 min cold static storage (control) or 30 min hypothermic oxygenated perfusion. All hearts were perfused ex vivo under normothermic conditions; 3 h in an unloaded mode, followed by 1 h with left ventricular loading to assess cardiac recovery.ResultsCompared to control conditions (n = 5), hypothermic oxygenated perfusion (n = 5) increased recovery of left ventricular function (cardiac output and maximum relaxation rate, P < 0.001 for both) and decreased cell death marker release (heart-type fatty acid binding protein, P = 0.009 and myoglobin, P < 0.001). In parallel, hypothermic oxygenated perfusion reduced the release of succinate and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine.ConclusionsA brief period of hypothermic oxygenated perfusion, applied as a reperfusion therapy between graft procurement and normothermic machine perfusion, provides cardioprotection in a porcine model of donation after circulatory death. Hypothermic oxygenated perfusion is a promising, easily applicable, cardioprotective reperfusion strategy; this study provides key evidence to support clinical translation.
| S-EPMC11919451 | biostudies-literature