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Frontiers in Immunology 2024Immunotherapy for hematological malignancies is a rapidly advancing field that has gained momentum in recent years, primarily encompassing chimeric antigen receptor... (Review)
Review
Immunotherapy for hematological malignancies is a rapidly advancing field that has gained momentum in recent years, primarily encompassing chimeric antigen receptor T-cell (CAR-T) therapies, immune checkpoint inhibitors, and other modalities. However, its clinical efficacy remains limited, and drug resistance poses a significant challenge. Therefore, novel immunotherapeutic targets and agents need to be identified. Recently, N6-methyladenosine (m6A), the most prevalent RNA epitope modification, has emerged as a pivotal factor in various malignancies. Reportedly, m6A mutations influence the immunological microenvironment of hematological malignancies, leading to immune evasion and compromising the anti-tumor immune response in hematological malignancies. In this review, we comprehensively summarize the roles of the currently identified m6A modifications in various hematological malignancies, with a particular focus on their impact on the immune microenvironment. Additionally, we provide an overview of the research progress made in developing m6A-targeted drugs for hematological tumor therapy, to offer novel clinical insights.
Topics: Humans; Tumor Microenvironment; Hematologic Neoplasms; Adenosine; Animals; Immunotherapy
PubMed: 38868768
DOI: 10.3389/fimmu.2024.1374390 -
The Journal of Physiological Sciences :... Jun 2024Hibernation and torpor are not passive responses caused by external temperature drops and fasting but are active brain functions that lower body temperature. A...
Hibernation and torpor are not passive responses caused by external temperature drops and fasting but are active brain functions that lower body temperature. A population of neurons in the preoptic area was recently identified as such active torpor-regulating neurons. We hypothesized that the other hypothermia-inducing maneuvers would also activate these neurons. To test our hypothesis, we first refined the previous observations, examined the brain regions explicitly activated during the falling phase of body temperature using c-Fos expression, and confirmed the preoptic area. Next, we observed long-lasting hypothermia by reactivating torpor-tagged Gq-expressing neurons using the activity tagging and DREADD systems. Finally, we found that about 40-60% of torpor-tagged neurons were activated by succeeding isoflurane anesthesia and by icv administration of an adenosine A1 agonist. Isoflurane-induced and central adenosine-induced hypothermia is, at least in part, an active process mediated by the torpor-regulating neurons in the preoptic area.
Topics: Animals; Preoptic Area; Isoflurane; Adenosine; Neurons; Male; Anesthetics, Inhalation; Body Temperature; Hypothermia; Torpor; Mice; Proto-Oncogene Proteins c-fos
PubMed: 38867187
DOI: 10.1186/s12576-024-00927-2 -
Nature Communications Jun 2024Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS...
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA mA content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after mA downregulation. Notably, cells expressing mutant FUS were characterized by higher mA levels suggesting a possible link between mA homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.
Topics: RNA-Binding Protein FUS; Amyotrophic Lateral Sclerosis; Humans; Motor Neurons; Induced Pluripotent Stem Cells; Cytoplasmic Granules; Fibroblasts; Adenosine; Methyltransferases; Mutation; Inclusion Bodies; Stress Granules; Transcriptome
PubMed: 38866783
DOI: 10.1038/s41467-024-49416-5 -
BMJ (Clinical Research Ed.) Jun 2024To assess the effect of different antiplatelet strategies on clinical outcomes after coronary artery bypass grafting. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess the effect of different antiplatelet strategies on clinical outcomes after coronary artery bypass grafting.
DESIGN
Five year follow-up of randomised Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Grafting (DACAB) trial.
SETTING
Six tertiary hospitals in China; enrolment between July 2014 and November 2015; completion of five year follow-up from August 2019 to June 2021.
PARTICIPANTS
500 patients aged 18-80 years (including 91 (18.2%) women) who had elective coronary artery bypass grafting surgery and completed the DACAB trial.
INTERVENTIONS
Patients were randomised 1:1:1 to ticagrelor 90 mg twice daily plus aspirin 100 mg once daily (dual antiplatelet therapy; n=168), ticagrelor monotherapy 90 mg twice daily (n=166), or aspirin monotherapy 100 mg once daily (n=166) for one year after surgery. After the first year, antiplatelet therapy was prescribed according to standard of care by treating physicians.
MAIN OUTCOME MEASURES
The primary outcome was major adverse cardiovascular events (a composite of all cause death, myocardial infarction, stroke, and coronary revascularisation), analysed using the intention-to-treat principle. Time-to-event analysis was used to compare the risk between treatment groups. Multiple post hoc sensitivity analyses examined the robustness of the findings.
RESULTS
Follow-up at five years for major adverse cardiovascular events was completed for 477 (95.4%) of 500 patients; 148 patients had major adverse cardiovascular events, including 39 in the dual antiplatelet therapy group, 54 in the ticagrelor monotherapy group, and 55 in the aspirin monotherapy group. Risk of major adverse cardiovascular events at five years was significantly lower with dual antiplatelet therapy versus aspirin monotherapy (22.6% 29.9%; hazard ratio 0.65, 95% confidence interval 0.43 to 0.99; P=0.04) and versus ticagrelor monotherapy (22.6% 32.9%; 0.66, 0.44 to 1.00; P=0.05). Results were consistent in all sensitivity analyses.
CONCLUSIONS
Treatment with ticagrelor dual antiplatelet therapy for one year after surgery reduced the risk of major adverse cardiovascular events at five years after coronary artery bypass grafting compared with aspirin monotherapy or ticagrelor monotherapy.
TRIAL REGISTRATION
NCT03987373ClinicalTrials.gov NCT03987373.
Topics: Humans; Coronary Artery Bypass; Platelet Aggregation Inhibitors; Female; Male; Middle Aged; Ticagrelor; Aspirin; Aged; Follow-Up Studies; Adult; Aged, 80 and over; Drug Therapy, Combination; Adolescent; Postoperative Complications; Treatment Outcome; Young Adult; China; Dual Anti-Platelet Therapy
PubMed: 38862179
DOI: 10.1136/bmj-2023-075707 -
Cell Death & Disease Jun 2024Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM...
Diabetic cardiomyopathy (DCM) is a prevalent myocardial microvascular complication of the myocardium with a complex pathogenesis. Investigating the pathogenesis of DCM can significantly contribute to enhancing its prevention and treatment strategies. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Our study revealed an upregulation of lysine acetyltransferase 2 A (Kat2a) expression in DCM, accompanied by a decrease in N6-methyladenosine (m6A) modified Kat2a mRNA levels. Functionally, inhibition of Kat2a effectively ameliorated high glucose-induced cardiomyocyte injury both in vitro and in vivo by suppressing ferroptosis. Mechanistically, Demethylase alkB homolog 5 (Alkbh5) was found to reduce m6A methylation levels on Kat2a mRNA, leading to its upregulation. YTH domain family 2 (Ythdf2) played a crucial role as an m6A reader protein mediating the degradation of Kat2a mRNA. Furthermore, Kat2a promoted ferroptosis by increasing Tfrc and Hmox1 expression via enhancing the enrichment of H3K27ac and H3K9ac on their promoter regions. In conclusion, our findings unveil a novel role for the Kat2a-ferroptosis axis in DCM pathogenesis, providing valuable insights for potential clinical interventions.
Topics: Diabetic Cardiomyopathies; Animals; Ferroptosis; Humans; Heme Oxygenase-1; Mice; Histone Acetyltransferases; Male; Mice, Inbred C57BL; Myocytes, Cardiac; Membrane Proteins; Adenosine
PubMed: 38858351
DOI: 10.1038/s41419-024-06771-x -
Biology Direct Jun 2024The molecular mechanisms of osteosarcoma (OS) are complex. In this study, we focused on the functions of melanoma cell adhesion molecule (MCAM), methyltransferase 3...
BACKGROUND
The molecular mechanisms of osteosarcoma (OS) are complex. In this study, we focused on the functions of melanoma cell adhesion molecule (MCAM), methyltransferase 3 (METTL3) and insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) in OS development.
METHODS
qRT-PCR assay and western blot assay were performed to determine mRNA and protein expression of MCAM, METTL3, IGF2BP1 and YY1. MTT assay and colony formation assay were conducted to assess cell proliferation. Cell apoptosis, invasion and migration were evaluated by flow cytometry analysis, transwell assay and wound-healing assay, respectively. Methylated RNA Immunoprecipitation (MeRIP), dual-luciferase reporter, Co-IP, RIP and ChIP assays were performed to analyze the relationships of MCAM, METTL3, IGF2BP1 and YY1. The functions of METTL3 and MCAM in tumor growth were explored through in vivo experiments.
RESULTS
MCAM was upregulated in OS, and MCAM overexpression promoted OS cell growth, invasion and migration and inhibited apoptosis. METTL3 and IGF2BP1 were demonstrated to mediate the m6A methylation of MCAM. Functionally, METTL3 or IGF2BP1 silencing inhibited OS cell progression, while MCAM overexpression ameliorated the effects. Transcription factor YY1 promoted the transcription level of METTL3 and regulated METTL3 expression in OS cells. Additionally, METTL3 deficiency suppressed tumor growth in vivo, while MCAM overexpression abated the effect.
CONCLUSION
YY1/METTL3/IGF2BP1/MCAM axis aggravated OS development, which might provide novel therapy targets for OS.
Topics: Osteosarcoma; Methyltransferases; Humans; RNA-Binding Proteins; Adenosine; Cell Line, Tumor; Animals; Mice; Cell Proliferation; Bone Neoplasms; Disease Progression; Mice, Nude; Apoptosis; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 38849910
DOI: 10.1186/s13062-024-00486-x -
Nature Communications Jun 2024N-methyladenosine (mA) plays critical roles in regulating mRNA metabolism. However, comprehensive mA methylomes in different plant tissues with single-base precision...
N-methyladenosine (mA) plays critical roles in regulating mRNA metabolism. However, comprehensive mA methylomes in different plant tissues with single-base precision have yet to be reported. Here, we present transcriptome-wide mA maps at single-base resolution in different tissues of rice and Arabidopsis using mA-SAC-seq. Our analysis uncovers a total of 205,691 mA sites distributed across 22,574 genes in rice, and 188,282 mA sites across 19,984 genes in Arabidopsis. The evolutionarily conserved mA sites in rice and Arabidopsis ortholog gene pairs are involved in controlling tissue development, photosynthesis and stress response. We observe an overall mRNA stabilization effect by 3' UTR mA sites in certain plant tissues. Like in mammals, a positive correlation between the mA level and the length of internal exons is also observed in plant mRNA, except for the last exon. Our data suggest an active mA deposition process occurring near the stop codon in plant mRNA. In addition, the MTA-installed plant mRNA mA sites correlate with both translation promotion and translation suppression, depicting a more complicated regulatory picture. Our results therefore provide in-depth resources for relating single-base resolution mA sites with functions in plants and uncover a suppression-activation model controlling mA biogenesis across species.
Topics: Oryza; Arabidopsis; Adenosine; Gene Expression Regulation, Plant; RNA, Messenger; Transcriptome; RNA, Plant; 3' Untranslated Regions; Gene Expression Profiling; RNA Stability; Exons; Codon, Terminator
PubMed: 38849358
DOI: 10.1038/s41467-024-48941-7 -
BMC Ophthalmology Jun 2024The purpose of this study was to investigate the photoprotection effect of peroxiredoxin 1 (PRDX1) protein in ultraviolet B (UVB) irradiation-induced damage of retinal...
BACKGROUND
The purpose of this study was to investigate the photoprotection effect of peroxiredoxin 1 (PRDX1) protein in ultraviolet B (UVB) irradiation-induced damage of retinal pigment epithelium (RPE) and its possible molecular mechanism.
METHODS
ARPE-19 cell viability and apoptosis were assessed by MTT assay and flow cytometry, respectively. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the PRDX1 expression. The corresponding kits were employed to measure the levels or activities of lactate dehydrogenase (LDH), 8-hydroxy-2-deoxyguanosine (8-OHdG), reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD). Western blotting was applied to examine PRDX1 expression and mitogen-activated protein kinase (MAPK) signaling pathway-related proteins.
RESULTS
After exposure to 20 mJ/cm intensity of UVB irradiation for 24 h, ARPE-19 cells viability was decreased, the leakage degree of LDH and 8-OHdG were increased, and cell apoptosis was elevated. The expression of PRDX1 was significantly down-regulated in UVB-induced ARPE-19 cells. The low expression of PRDX1 was involved in high irradiation intensity. Overexpression of PRDX1 increased cell activity, decreased cell apoptosis, and LDH as well as 8-OHdG leakage in UVB-induced ARPE-19 cells. In addition to alleviating UVB-induced cell damage, PRDX1 overexpression also inhibited UVB-induced oxidative stress (down-regulation of ROS and MDA levels, up-regulation of GSH-Px and SOD activities) and the activation of MAPK signaling pathway in ARPE-19 cells.
CONCLUSION
PRDX1 exerts a photoprotection effect on RPE by attenuating UVB-induced cell damage and inhibiting oxidative stress, which can be attributed to the inhibition of MAPK signaling pathway activation.
Topics: Humans; Oxidative Stress; Retinal Pigment Epithelium; Peroxiredoxins; Ultraviolet Rays; Cell Survival; Apoptosis; Reactive Oxygen Species; MAP Kinase Signaling System; Cell Line; Blotting, Western; Cells, Cultured; 8-Hydroxy-2'-Deoxyguanosine; Signal Transduction
PubMed: 38844903
DOI: 10.1186/s12886-024-03489-4 -
Nature Communications Jun 2024Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins...
Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate gene expression programs shaping neuronal morphology are poorly understood. To address this, we studied how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the human neuronal differentiation. We perform a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we show that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity.
Topics: Humans; RNA-Binding Proteins; Microtubules; Neurons; Cell Differentiation; RNA, Messenger; Methylation; Neurogenesis; Adenosine; Gene Expression Regulation, Developmental
PubMed: 38844464
DOI: 10.1038/s41467-024-49139-7 -
PLoS Pathogens Jun 2024Although lack of ADAR (adenosine deaminase acting on RNA) orthologs, genome-wide A-to-I editing occurs specifically during sexual reproduction in a number of filamentous... (Review)
Review
Although lack of ADAR (adenosine deaminase acting on RNA) orthologs, genome-wide A-to-I editing occurs specifically during sexual reproduction in a number of filamentous ascomycetes, including Fusarium graminearum and Neurospora crassa. Unlike ADAR-mediated editing in animals, fungal A-to-I editing has a strong preference for hairpin loops and U at -1 position, which leads to frequent editing of UAG and UAA stop codons. Majority of RNA editing events in fungi are in the coding region and cause amino acid changes. Some of these editing events have been experimentally characterized for providing heterozygote and adaptive advantages in F. graminearum. Recent studies showed that FgTad2 and FgTad3, 2 ADAT (adenosine deaminase acting on tRNA) enzymes that normally catalyze the editing of A34 in the anticodon of tRNA during vegetative growth mediate A-to-I mRNA editing during sexual reproduction. Stage specificity of RNA editing is conferred by stage-specific expression of short transcript isoforms of FgTAD2 and FgTAD3 as well as cofactors such as AME1 and FIP5 that facilitate the editing of mRNA in perithecia. Taken together, fungal A-to-I RNA editing during sexual reproduction is catalyzed by ADATs and it has the same sequence and structural preferences with editing of A34 in tRNA.
Topics: RNA Editing; Adenosine Deaminase; Fungal Proteins; Ascomycota; RNA, Fungal; Adenosine; Inosine; Fusarium; Neurospora crassa
PubMed: 38843141
DOI: 10.1371/journal.ppat.1012238