RESUMO
Acute myocardial infarction (AMI) is triggered by the blockage of coronary arteries, leading to restricted blood flow to the myocardium, which results in damage and cell death. While the traditional understanding of cell death primarily revolves around apoptosis, a new player in the game has emerged: ferroptosis. This novel form of cell death relies on iron and is propelled by reactive oxygen species (ROS). Lipid metabolism, an indispensable physiological process, plays a vital role in preserving cellular homeostasis. However, when this metabolic pathway is disrupted, the accumulation of excess waste increases, specifically lipid peroxides, which are strongly linked to the occurrence and progression of AMI. As a result, comprehending this complex interaction between ferroptosis and lipid metabolism could pave the way for new therapeutic approaches in tackling AMI.
RESUMO
BACKGROUND: Acute myocardial infarction (AMI) is indeed a significant cause of mortality and morbidity in individuals with coronary heart disease. Ferroptosis, an iron-dependent cell death, is characterized by the accumulation of intracellular lipid peroxides, which is implicated in cardiomyocyte injury. This study aims to identify biomarkers that are indicative of ferroptosis in the context of AMI, and to examine their potential roles in immune infiltration. METHODS: Firstly, the GSE59867 dataset was used to identify differentially expressed ferroptosis-related genes (DE-FRGs) in AMI. We then performed gene ontology (GO) and functional enrichment analysis on these DE-FRGs. Secondly, we analyzed the GSE76591 dataset and used bioinformatic methods to build ceRNA networks. Thirdly, we identified hub genes in protein-protein interaction (PPI) network. After obtaining the key DE-FRGs through the junction of hub genes with ceRNA and least absolute shrinkage and selection operator (LASSO). ImmucellAI was applied to estimate the immune cell infiltration in each sample and examine the relationship between key DE-FRGs and 24 immunocyte subsets. The diagnostic performance of these genes was further evaluated using the receiver operating characteristic (ROC) curve analysis. Ultimately, we identified an immune-related ceRNA regulatory axis linked to ferroptosis in AMI. RESULTS: Among 56 DE-FRGs identified in AMI, 41 of them were integrated into the construction of competitive endogenous RNA (ceRNA) networks. TLR4 and PIK3CA were identified as key DE-FRGs and PIK3CA was confirmed as a diagnostic biomarker for AMI. Moreover, CD4_native cells, nTreg cells, Th2 cells, Th17 cells, central-memory cells, effector-memory cells, and CD8_T cells had higher infiltrates in AMI samples compared to control samples. In contrast, exhausted cells, iTreg cells, and Tfh cells had lower infiltrates in AMI samples. Spearman analysis confirmed the correlation between 24 immune cells and PIK3CA/TLR4. Ultimately, we constructed an immune-related regulatory axis involving XIST and OIP5-AS1/miR-216a/PIK3CA. CONCLUSION: Our comprehensive analysis has identified PIK3CA as a robust and promising biomarker for this condition. Moreover, we have also identified an immune-related regulatory axis involving XIST and OIP5-AS1/miR-216a/PIK3CA, which may play a key role in regulating ferroptosis during AMI progression.
Assuntos
Ferroptose , MicroRNAs , Infarto do Miocárdio , Humanos , Ferroptose/genética , Receptor 4 Toll-Like/genética , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Classe I de Fosfatidilinositol 3-Quinases , BiomarcadoresRESUMO
Coronary artery disease (CAD), caused by coronary artery occlusion, is a common cardiovascular disease worldwide. Long non-coding RNAs (lncRNAs) are implicated in the regulation of endothelial cell injury, angiogenesis, plaque formation, and other pathological mechanisms in CAD by acting on different cell types. Some lncRNAs are significantly upregulated in CAD patients; however, other lncRNAs are significantly downregulated. Differential expression of lncRNAs in CAD patients enables them to be exploited as potential biomarkers to evaluate disease progression and diagnosis/prognosis in CAD patients. In this study, we reviewed the role of lncRNAs in the development of different clinical subtypes of CAD.
RESUMO
Innate immune cells express danger-associated molecular pattern (DAMP) receptors, T-cell costimulation/coinhibition receptors, and major histocompatibility complex II (MHC-II). We have recently proposed that endothelial cells can serve as innate immune cells, but the molecular mechanisms involved still await discovery. Here, we investigated whether human aortic endothelial cells (HAECs) could be transdifferentiated into innate immune cells by exposing them to hyperlipidemia-up-regulated DAMP molecules, i.e. lysophospholipids. Performing RNA-seq analysis of lysophospholipid-treated HAECs, we found that lysophosphatidylcholine (LPC) and lysophosphatidylinositol (LPI) regulate largely distinct gene programs as revealed by principal component analysis. Metabolically, LPC up-regulated genes that are involved in cholesterol biosynthesis, presumably through sterol regulatory element-binding protein 2 (SREBP2). By contrast, LPI up-regulated gene transcripts critical for the metabolism of glucose, lipids, and amino acids. Of note, we found that LPC and LPI both induce adhesion molecules, cytokines, and chemokines, which are all classic markers of endothelial cell activation, in HAECs. Moreover, LPC and LPI shared the ability to transdifferentiate HAECs into innate immune cells, including induction of potent DAMP receptors, such as CD36 molecule, T-cell costimulation/coinhibition receptors, and MHC-II proteins. The induction of these innate-immunity signatures by lysophospholipids correlated with their ability to induce up-regulation of cytosolic calcium and mitochondrial reactive oxygen species. In conclusion, lysophospholipids such as LPC and LPI induce innate immune cell transdifferentiation in HAECs. The concept of prolonged endothelial activation, discovered here, is relevant for designing new strategies for managing cardiovascular diseases.
Assuntos
Aorta/imunologia , Transdiferenciação Celular/imunologia , Endotélio Vascular/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Lisofosfolipídeos/farmacologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Cálcio/metabolismo , Células Cultivadas , Citosol/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismoRESUMO
There is increasing clinical evidence to suggest a suppressive effect on hematopoiesis in myelodysplastic syndrome patients with iron overload. However, how iron overload influences hematopoiesis in myelodysplastic syndrome (MDS) remains unknown. Here, the RUNX1S291fs-transduced bone marrow mononuclear cells were yielded and transplanted into lethally irradiated recipient mice together with radioprotective bone marrow cells to generate MDS mice. Eight weeks post transplantation, the recipient mice received an intraperitoneal injection of 0.2 mL iron dextran at a concentration of 25 mg/mL once every other day for a total of 8 times to establish an iron overload model. In the present study, we show that iron overload impairs the frequency and colony-forming capacity of normal hematopoietic stem and progenitor cells, especially in erythroid, in MDS mice, which is due, at least in part, to growth differentiation factor 11-induced reactive oxygen species, shortening survival of MDS mice. Given that we are the first to construct an iron overload model in MDS mice, we hope this model will be helpful for further exploring the influence and mechanism of iron overload on MDS.
Assuntos
Células-Tronco Hematopoéticas/metabolismo , Sobrecarga de Ferro/metabolismo , Síndromes Mielodisplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/patologia , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/patologia , Camundongos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologiaRESUMO
Mitochondrial proton leak is the principal mechanism that incompletely couples substrate oxygen to ATP generation. This chapter briefly addresses the recent progress made in understanding the role of proton leak in the pathogenesis of cardiovascular diseases. Majority of the proton conductance is mediated by uncoupling proteins (UCPs) located in the mitochondrial inner membrane. It is evident that the proton leak and reactive oxygen species (ROS) generated from electron transport chain (ETC) in mitochondria are linked to each other. Increased ROS production has been shown to induce proton conductance, and in return, increased proton conductance suppresses ROS production, suggesting the existence of a positive feedback loop that protects the biological systems from detrimental effects of augmented oxidative stress. There is mounting evidence attributing to proton leak and uncoupling proteins a crucial role in the pathogenesis of cardiovascular disease. We can surmise the role of "uncoupling" in cardiovascular disorders as follows; First, the magnitude of the proton leak and the mechanism involved in mediating the proton leak determine whether there is a protective effect against ischemia-reperfusion (IR) injury. Second, uncoupling by UCP2 preserves vascular function in diet-induced obese mice as well as in diabetes. Third, etiology determines whether the proton conductance is altered or not during hypertension. And fourth, proton leak regulates ATP synthesis-uncoupled mitochondrial ROS generation, which determines pathological activation of endothelial cells for recruitment of inflammatory cells. Continue effort in improving our understanding in the role of proton leak in the pathogenesis of cardiovascular and metabolic diseases would lead to identification of novel therapeutic targets for treatment.
Assuntos
Doenças Cardiovasculares/metabolismo , Metabolismo Energético , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Trifosfato de Adenosina/metabolismo , Animais , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Transporte de Elétrons , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/patologia , Estresse Oxidativo , Prótons , Espécies Reativas de Oxigênio/metabolismoRESUMO
The purpose of this study was to investigate the potential cardioprotection roles of Rapamycin in anoxia/reoxygenation (A/R) injury of cardiomyocytes through inducing autophagy, and the involvement of PI3k/Akt pathway. We employed simulated A/R of neonatal rat ventricular myocytes (NRVM) as an in vitro model of ischemial/reperfusion (I/R) injury to the heart. NRVM were pretreated with four different concentrations of Rapamycin (20, 50, 100, 150 µmol/L), and pretreated with 10 mmol/L 3-methyladenine (3MA) for inhibiting autophagy during A/R. Then, Western blot analysis was used to examine variation in the expression of LC3-II, LC3-I, Bim, caspase-3, p-PI3KI, PI3KI, p-Akt and Akt. In our model, Rapamycin had a preferential action on autophagy, increasing the expression of LC3-II/LC3-I, whereas decreasing the expression of Bim and caspase-3. Moreover, our results also demonstrated that Rapamycin inhibited the activation of p-PI3KI and enhanced the activation of p-Akt. It is concluded that Rapamycin has a cardioprotection effect by inducing autophagy in a concentration-dependent manner against apopotosis through PI3K/Akt signaling pathway during A/R in NRVM.
Assuntos
Autofagia/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Sirolimo/farmacologia , Animais , Sequência de Bases , Células Cultivadas , Primers do DNA , Ratos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Non-exosomal non-coding RNAs (non-exo-ncRNAs) and exosomal ncRNAs (exo-ncRNAs) have been associated with the pathological development of myocardial infarction (MI). Accordingly, this analytical review provides an overview of current MI studies on the role of plasma non-exo/exo-ncRNAs. We summarize the features and crucial roles of ncRNAs and reveal their novel biological correlations via bioinformatics analysis. The following contributions are made: (1) we comprehensively describe the expression profile, competing endogenous RNA (ceRNA) network, and "pre-necrotic" biomarkers of non-exo/exo-ncRNAs for MI; (2) functional enrichment analysis indicates that the target genes of ncRNAs are enriched in the regulation of apoptotic signaling pathway and cellular response to chemical stress, etc.; (3) we propose an updated and comprehensive view on the mechanisms, pathophysiology, and biomarker roles of non-exo/exo-ncRNAs in MI, thereby providing a theoretical basis for the clinical management of MI.
Assuntos
MicroRNAs , Infarto do Miocárdio , Humanos , RNA não Traduzido/genética , RNA , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Biomarcadores , Biologia Computacional , MicroRNAs/genéticaRESUMO
Background: Alternative splicing (AS) is a biological process that allows genes to be translated into diverse proteins. However, aberrant AS can predispose cells to aberrations in biological mechanisms. RNA binding proteins (RBPs), closely affiliated with AS, have gained increased attention in recent years. Among these RBPs, RBM25 has been reported to participate in the cardiac pathological mechanism through regulating AS; however, the involvement of RBM25 as a splicing factor in heart failure remains unclarified. Methods: RBM25 was overexpressed in H9c2 cells to explore the target genes bound and regulated by RBM25 during heart failure. RNA sequencing (RNA-seq) was used to scrutinize the comprehensive transcriptional level before identifying AS events influenced by RBM25. Further, improved RNA immunoprecipitation sequencing (iRIP-seq) was employed to pinpoint RBM25-binding sites, and RT-qPCR was used to validate specific genes modulated by RBM25. Results: RBM25 was found to upregulate the expression of genes pertinent to the inflammatory response and viral processes, as well as to mediate the AS of genes associated with cellular apoptosis and inflammation. Overlap analysis between RNA-seq and iRIP-seq suggested that RBM25 bound to and manipulated the AS of genes associated with inflammation in H9c2 cells. Moreover, qRT-PCR confirmed Slc38a9, Csf1, and Coro6 as the binding and AS regulatory targets of RBM25. Conclusion: Our research implies that RBM25 plays a contributory role in cardiac inflammatory responses via its ability to bind to and regulate the AS of related genes. This study offers preliminary evidence of the influence of RBM25 on inflammation in H9c2 cells.
Assuntos
Processamento Alternativo , Insuficiência Cardíaca , Proteínas com Motivo de Reconhecimento de RNA , Fatores de Processamento de RNA , Processamento Alternativo/genética , Insuficiência Cardíaca/genética , Inflamação/genética , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Animais , Ratos , Fatores de Processamento de RNA/genética , Proteínas com Motivo de Reconhecimento de RNA/genéticaRESUMO
Aim & methods: Non-exosomal and exosomal ncRNAs have been reported to be involved in the regulation of coronary artery disease (CAD). Therefore, to explore the biological effects of non-exosomal/exosomal ncRNAs in CAD, the authors searched for studies published in the last 3 years on these ncRNAs in CAD and summarized their functions and mechanisms. Results: The authors summarized 120 non-exosomal ncRNAs capable of regulating CAD progression. In clinical studies, 47 non-exosomal and nine exosomal ncRNAs were able to serve as biomarkers for the diagnosis of CAD. Conclusion: Non-exosomal/exosomal ncRNAs are not only able to serve as biomarkers for CAD diagnosis but can also regulate CAD progression through ceRNA mechanisms and are a potential target for early clinical intervention in CAD.
ncRNAs are increasingly found to play regulatory roles in coronary artery disease (CAD), and transcriptome studies offer greater advantages for controlling CAD at its source. Therefore, the authors conducted an accurate search and summary of studies on CAD and ncRNAs published in the past 3 years to analyze the main pathological mechanisms in CAD progression, aiming to provide a research basis for clinical treatment of CAD.
Assuntos
Doença da Artéria Coronariana , Humanos , Doença da Artéria Coronariana/genética , RNA não Traduzido/genética , BiomarcadoresRESUMO
(1) Background: Targeting a sample of Chinese employees in this study, the correlation of work stress with changes in quality of life (QoL) was explored subsequent to acute coronary syndrome (ACS). (2) Methods: Patients suffering from the first ACS episode, with regular paid work before ACS, were eligible for this one-year longitudinal study. Effort-reward imbalance (ERI), together with job strain (JS) models, were employed to evaluate work stress before discharge, and QoL prior to discharge (baseline), as well as at 1, 6, and 12 months following discharge, were measured using the 8-Items Short Form (SF-8), in addition to the Seattle Angina Questionnaire (SAQ). Moreover, generalized estimating equations were used to determine the relationship of work stress to longitudinal QoL variations. (3) Results: After adjusting for covariates, high work stress at the baseline measured by JS was associated with the slow recovery of both mental health (p < 0.01) and physical health (p < 0.05) in SF-8, while ERI-measured work stress was related to slower improvement in SF-8 physical health (p < 0.001), SAQ-angina stability (AS) (p < 0.05), SF-8 mental health (p < 0.001), and SAQ-angina frequency (AF) (p < 0.05). After mutual adjustment for JS and ERI, high work stress as assessed by JS displayed no correlation with any QoL alteration (all p > 0.05), whereas ERI-determined work stress at a high level still presented a relationship to slow improvement in SF-8 physical health, SAQ-AS, SF-8 mental health, and SAQ-AF (all p < 0.05). (4) Conclusion: Work stress was associated with slow recovery of QoL in patients with ACS across one year. For ACS patients, ERI was a stronger predictor of QoL variations than JS.
Assuntos
Síndrome Coronariana Aguda , Estresse Ocupacional , Humanos , Qualidade de Vida , Síndrome Coronariana Aguda/epidemiologia , Estudos Longitudinais , Estresse Ocupacional/epidemiologia , Saúde Mental , Estresse Psicológico/epidemiologia , Estresse Psicológico/psicologia , Inquéritos e Questionários , RecompensaRESUMO
Septic cardiomyopathy (SCM) is a cardiac dysfunction caused by severe sepsis, which greatly increases the risk of heart failure and death, and its molecular mechanism is unclear. The immune response has been reported to be an important process in septic cardiomyopathy and is present in the cardiac tissue of patients with sepsis, suggesting that the immune response may be an underlying mechanism of myocardial injury in SCM. Therefore, we explored the role of immune-related genes (IRGs) in SCM and aimed to identify pivotal immune-related targets with the aim of identifying key immune-related targets in SCM and potential therapeutic mechanisms involved in the pathological process of SCM. To explore the regulatory mechanisms of immune responses in SCM, we identified differentially expressed genes (DEGs) shared in the SCM datasets GSE179554 and GSE40180 by bioinformatics analysis and then obtained hub genes from the DEGs. Then, we obtained the immune-related hub genes (IRHGs) by intersecting the hub genes with IRGs and performed quantitative reverse transcription polymerase chain reaction to confirm the abnormal expression of IRHGs. Finally, we further constructed an immune-related lncRNA-miRNA-IRHG ceRNA regulatory network. In this study, we identified an IRHG that may be involved in the pathogenesis of SCM, which helps us to further elucidate the role of immune response in SCM and gain insights into the molecular mechanisms and potential therapeutic targets of SCM.
Assuntos
Cardiomiopatias , Sepse , Biomarcadores , Cardiomiopatias/genética , Biologia Computacional , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , HumanosRESUMO
In order to seek a more outstanding diagnosis and treatment of diabetic retinopathy (DR), we predicted the miRNA biomarkers of DR and explored the pathological mechanism of DR through bioinformatics analysis. Method: Based on public omics data and databases, we investigated ncRNA (non-coding RNA) functions based on the ceRNA hypothesis. Result: Among differentially expressed miRNAs (DE-miRNAs), hsa-miR-1179, -4797-3p and -665 may be diagnosis biomarkers of DR. Functional enrichment analysis revealed differentially expressed mRNAs (DE-mRNAs) enriched in mitochondrial transport, cellular respiration and energy derivation. 18 tissue/organ-specific expressed genes, 10 hub genes and gene cluster modules were identified. The ceRNA networks lncRNA FBXL19-AS1/miR-378f/MRPL39 and lncRNA UBL7-AS1/miR-378f/MRPL39 might be potential RNA regulatory pathways in DR. Conclusion: Differentially expressed hsa-miR-1179, -4797-3p and -665 can be used as powerful markers for DR diagnosis, and the ceRNA network: lncRNA FBXL19-AS1/UBL7-AS1-miR-378f-MRPL39 may represent an important regulatory role in DR progression.
RESUMO
BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) caused by the reperfusion therapy of myocardial ischemic diseases is a kind of major disease that threatens human health and lives severely. There are lacking of effective therapeutic measures for MIRI. MicroRNAs (miRNAs) are abundant in mammalian species and play a critical role in the initiation, promotion, and progression of MIRI. However, the biological role and molecular mechanism of miRNAs in MIRI are not entirely clear. METHODS: We used bioinformatics analysis to uncover the significantly different miRNA by analyzing transcriptome sequencing data from myocardial tissue in the mouse MIRI model. Multiple miRNA-related databases, including miRdb, PicTar, and TargetScan were used to forecast the downstream target genes of the differentially expressed miRNA. Then, the experimental models, including male C57BL/6J mice and HL-1 cell line, were used for subsequent experiments including quantitative real-time polymerase chain reaction analysis, western blot analysis, hematoxylin and eosin staining, flow cytometry, luciferase assay, gene interference, and overexpression. RESULTS: MiR-582-5p was found to be differentially upregulated from the transcriptome sequencing data. The elevated levels of miR-582-5p were verified in MIRI mice and hypoxia/reperfusion (H/R)-induced HL-1 cells. Functional experiments revealed that miR-582-5p promoted apoptosis of H/R-induced HL-1 cells via downregulating cAMP-response element-binding protein 1 (Creb1). The inhibiting action of miR-582-5p inhibitor on H/R-induced apoptosis was partially reversed after Creb1 interference. CONCLUSIONS: Collectively, the research findings reported that upregulation of miR-582-5p promoted H/R-induced cardiomyocyte apoptosis by inhibiting Creb1. The potential diagnostic and therapeutic strategies targeting miR-582-5p and Creb1 could be beneficial for the MIRI treatment.
Assuntos
MicroRNAs , Traumatismo por Reperfusão Miocárdica , Masculino , Camundongos , Humanos , Animais , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Apoptose/genética , MicroRNAs/genética , Hipóxia/genética , Hipóxia/metabolismo , Modelos Animais de Doenças , Reperfusão , Mamíferos/genética , Mamíferos/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/farmacologiaRESUMO
Abstract: Septic cardiomyopathy (SCM) is a serious complication caused by sepsis that will further exacerbate the patient's prognosis. However, immune-related genes (IRGs) and their molecular mechanism during septic cardiomyopathy are largely unknown. Therefore, our study aims to explore the immune-related hub genes (IRHGs) and immune-related miRNA-mRNA pairs with potential biological regulation in SCM by means of bioinformatics analysis and experimental validation. Method: Firstly, screen differentially expressed mRNAs (DE-mRNAs) from the dataset GSE79962, and construct a PPI network of DE-mRNAs. Secondly, the hub genes of SCM were identified from the PPI network and the hub genes were overlapped with immune cell marker genes (ICMGs) to further obtain IRHGs in SCM. In addition, receiver operating characteristic (ROC) curve analysis was also performed in this process to determine the disease diagnostic capability of IRHGs. Finally, the crucial miRNA-IRHG regulatory network of IRHGs was predicted and constructed by bioinformatic methods. Real-time quantitative reverse transcription-PCR (qRT-PCR) and dataset GSE72380 were used to validate the expression of the key miRNA-IRHG axis. Result: The results of immune infiltration showed that neutrophils, Th17 cells, Tfh cells, and central memory cells in SCM had more infiltration than the control group; A total of 2 IRHGs were obtained by crossing the hub gene with the ICMGs, and the IRHGs were validated by dataset and qRT-PCR. Ultimately, we obtained the IRHG in SCM: THBS1. The ROC curve results of THBS1 showed that the area under the curve (AUC) was 0.909. Finally, the miR-222-3p/THBS1 axis regulatory network was constructed. Conclusion: In summary, we propose that THBS1 may be a key IRHG, and can serve as a biomarker for the diagnosis of SCM; in addition, the immune-related regulatory network miR-222-3p/THBS1 may be involved in the regulation of the pathogenesis of SCM and may serve as a promising candidate for SCM therapy.
RESUMO
Ibrutinib exerts promising anticancer effects in chronic lymphocytic leukaemia (CLL). However, acquired resistance occurs during treatment, necessitating the exploration of underlying mechanisms. Although three-dimensional genome organization has been identified as a major player in the development and progression of cancer, including drug resistance, little is known regarding its role in CLL. Therefore, we investigated the molecular mechanisms underlying ibrutinib resistance through multi-omics analysis, including high-throughput chromosome conformation capture (Hi-C) technology. We demonstrated that the therapeutic response to ibrutinib is associated with the expression of p21-activated kinase 1 (PAK1). PAK1, which was up-regulated in CLL and associated with patients' survival, was involved in cell proliferation, glycolysis and oxidative phosphorylation. Furthermore, the PAK1 inhibitor IPA-3 exerted an anti-tumour effect and its combination with ibrutinib exhibited a synergistic effect in ibrutinib-sensitive and -resistant cells. These findings suggest the oncogenic role of PAK1 in CLL progression and drug resistance, highlighting PAK1 as a potential diagnostic marker and therapeutic target in CLL including ibrutinib-resistant CLL.
Assuntos
Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Cromossomos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Quinases Ativadas por p21/genéticaRESUMO
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Histone deacetylase inhibitors (HDACis) have been widely applied in multiple tumours, but the expected efficacy was not observed in DLBCL. Therefore, this study is aimed to explore superior HDACis and optimise a relative combinational therapeutic strategy. METHODS: The antitumour effects of the drug were evaluated by Cell Counting Kit-8 (CCK-8) assay and apoptosis analysis. Single-cell RNA sequencing (scRNA-Seq) was used to analyse the intratumoural heterogeneity of DLBCL cells. Whole-exome sequencing and RNA sequencing were performed to analyse the genetic and transcriptional features. Western blotting, qRT-PCR, protein array, immunohistochemistry, and chromatin immunoprecipitation assays were applied to explore the involved pathways. The antitumour effects of the compounds were assessed using subcutaneous xenograft tumour models. RESULTS: LAQ824 was screened and confirmed to kill DLBCL cells effectively. Using scRNA-Seq, we characterised the heterogeneity of DLBCL cells under different drug pressures, and c-Fos was identified as a critical factor in the survival of residual tumour cells. Moreover, we demonstrated that combinatorial treatment with LAQ824 and a c-Fos inhibitor more potently inhibited tumour cells both in vitro and in vivo. CONCLUSION: Altogether, we found an HDACi, LAQ824, with high efficacy in DLBCL and provided a promising HDACi-based combination therapy strategy.
Assuntos
Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Apoptose , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/tratamento farmacológicoRESUMO
OBJECTIVE: Circular RNAs (circRNAs) play a critical role in the modulation of tumor metabolism. However, the expression patterns and metabolic function of circRNAs in chronic lymphocytic leukemia (CLL) remain largely unknown. This study aimed to elucidate the role of circRNAs in the lipid metabolism of CLL. METHODS: The expression and metabolic patterns of circRNAs in a cohort of 53 patients with CLL were investigated using whole transcriptome sequencing. Cell viability, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, lipid analysis, Nile red staining as well as triglyceride (TG) assay were used to evaluate the biological function of circRIC8B in CLL. The regulatory mechanisms of circRIC8B/miR-199b-5p/lipoprotein lipase (LPL) axis were explored by luciferase assay, RNA immunoprecipitation (RIP), qRT-PCR, and fluorescence in situ hybridization (FISH). CCK-8 and flow cytometry were used to verify the inhibition role of cholesterol absorption inhibitor, ezetimibe, in CLL cells. RESULTS: Increased circRIC8B expression was positively correlated with advanced progression and poor prognosis. Knockdown of circRIC8B significantly suppressed the proliferation and lipid accumulation of CLL cells. In contrast, the upregulation of circRIC8B exerted opposite effects. Mechanistically, circRIC8B acted as a sponge of miR-199b-5p and prevented it from decreasing the level of LPL mRNA, and this promotes lipid metabolism alteration and facilitates the progression of CLL. What's more, ezetimibe suppressed the expression of LPL mRNA and inhibited the growth of CLL cells. CONCLUSIONS: In this study, the expressional and metabolic patterns of circRNAs in CLL was illustrated for the 1st time. Our findings revealed that circRIC8B regulates the lipid metabolism abnormalities in and development of CLL through the miR-199b-5p/LPL axis. CircRIC8B may serve as a promising prognostic marker and therapeutic target, which enhances the sensitivity to ezetimibe in CLL.
RESUMO
The morbidity and mortality of myocardial ischemia-reperfusion injury (MIRI) have increased in modern society. Noncoding RNAs (ncRNAs), including lncRNAs, circRNAs, piRNAs and miRNAs, have been reported in a variety of studies to be involved in pathological initiation and developments of MIRI. Hence this review focuses on the current research regarding these ncRNAs in MIRI. We comprehensively introduce the important features of lncRNAs, circRNAs, piRNA and miRNAs and then summarize the published studies of ncRNAs in MIRI. A clarification of lncRNA-miRNA-mRNA, lncRNA-transcription factor-mRNA and circRNA-miRNA-mRNA axes in MIRI follows, to further elucidate the crucial roles of ncRNAs in MIRI. Bioinformatics analysis has revealed the biological correlation of mRNAs with MIRI. We provide a comprehensive perspective for the roles of these ncRNAs and their related networks in MIRI, providing a theoretical basis for preclinical and clinical studies on ncRNA-based gene therapy for MIRI treatment.