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Science Immunology Jul 2023The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the... (Review)
Review
The extracellular nucleoside adenosine reduces tissue inflammation and is generated by irreversible dephosphorylation of adenosine monophosphate (AMP) mediated by the ectonucleotidase CD73. The pro-inflammatory nucleotides adenosine triphosphate, nicotinamide adenine dinucleotide, and cyclic guanosine -monophosphate-AMP (cGAMP), which are produced in the tumor microenvironment (TME) during therapy-induced immunogenic cell death and activation of innate immune signaling, can be converted into AMP by ectonucleotidases CD39, CD38, and CD203a/ENPP1. Thus, ectonucleotidases shape the TME by converting immune-activating signals into an immunosuppressive one. Ectonucleotidases also hinder the ability of therapies including radiation therapy, which enhance the release of pro-inflammatory nucleotides in the extracellular milieu, to induce immune-mediated tumor rejection. Here, we review the immunosuppressive effects of adenosine and the role of different ectonucleotidases in modulating antitumor immune responses. We discuss emerging opportunities to target adenosine generation and/or its ability to signal via adenosine receptors expressed by immune and cancer cells in the context of combination immunotherapy and radiotherapy.
Topics: Humans; Neoplasms; Adenosine; Adenosine Triphosphate; Adenosine Monophosphate; DNA Damage; Tumor Microenvironment
PubMed: 37418547
DOI: 10.1126/sciimmunol.abq3015 -
Clinical and Translational Medicine Sep 2023Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis....
Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis-induced acute lung injury (SI-ALI). We demonstrate that NETs induce SI-ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI-ALI is accompanied by upregulation of ferroptosis depending on METTL3-induced m6A modification of hypoxia-inducible factor-1α (HIF-1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI-ALI caused by NETs in a caecum ligation and puncture (CLP)-induced SI-ALI model using METTL3 condition knockout (CKO) mice and wild-type mice. Our results indicate the crucial role of NETs in the progression of SI-ALI via NET-activated METTL3 m6A-IGF2BP2-dependent m6A modification of HIF-1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.
Topics: Animals; Mice; Ferroptosis; Sepsis; Acute Lung Injury; Up-Regulation; Adenosine
PubMed: 37715457
DOI: 10.1002/ctm2.1389 -
Molecular Cancer Aug 2023Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose... (Review)
Review
Glycolytic reprogramming is one of the most important features of cancer and plays an integral role in the progression of cancer. In cancer cells, changes in glucose metabolism meet the needs of self-proliferation, angiogenesis and lymphangiogenesis, metastasis, and also affect the immune escape, prognosis evaluation and therapeutic effect of cancer. The n6-methyladenosine (m6A) modification of RNA is widespread in eukaryotic cells. Dynamic and reversible m6A modifications are widely involved in the regulation of cancer stem cell renewal and differentiation, tumor therapy resistance, tumor microenvironment, tumor immune escape, and tumor metabolism. Lately, more and more evidences show that m6A modification can affect the glycolysis process of tumors in a variety of ways to regulate the biological behavior of tumors. In this review, we discussed the role of glycolysis in tumor genesis and development, and elaborated in detail the profound impact of m6A modification on different tumor by regulating glycolysis. We believe that m6A modified glycolysis has great significance and potential for tumor treatment.
Topics: Humans; Neoplasms; Epigenesis, Genetic; Glycolysis; Epigenomics; Adenosine; Tumor Microenvironment
PubMed: 37582735
DOI: 10.1186/s12943-023-01841-8 -
Journal of Hematology & Oncology Aug 2023RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA... (Review)
Review
RNA modification has recently become a significant process of gene regulation, and the methyltransferase-like (METTL) family of proteins plays a critical role in RNA modification, methylating various types of RNAs, including mRNA, tRNA, microRNA, rRNA, and mitochondrial RNAs. METTL proteins consist of a unique seven-beta-strand domain, which binds to the methyl donor SAM to catalyze methyl transfer. The most typical family member METTL3/METTL14 forms a methyltransferase complex involved in N6-methyladenosine (m6A) modification of RNA, regulating tumor proliferation, metastasis and invasion, immunotherapy resistance, and metabolic reprogramming of tumor cells. METTL1, METTL4, METTL5, and METTL16 have also been recently identified to have some regulatory ability in tumorigenesis, and the rest of the METTL family members rely on their methyltransferase activity for methylation of different nucleotides, proteins, and small molecules, which regulate translation and affect processes such as cell differentiation and development. Herein, we summarize the literature on METTLs in the last three years to elucidate their roles in human cancers and provide a theoretical basis for their future use as potential therapeutic targets.
Topics: Humans; Methyltransferases; Adenosine; Methylation; MicroRNAs; Biology; Neoplasms
PubMed: 37533128
DOI: 10.1186/s13045-023-01477-7 -
Signal Transduction and Targeted Therapy Oct 2023Cardiovascular disease (CVD) is the leading cause of death in the world, with a high incidence and a youth-oriented tendency. RNA modification is ubiquitous and... (Review)
Review
Cardiovascular disease (CVD) is the leading cause of death in the world, with a high incidence and a youth-oriented tendency. RNA modification is ubiquitous and indispensable in cell, maintaining cell homeostasis and function by dynamically regulating gene expression. Accumulating evidence has revealed the role of aberrant gene expression in CVD caused by dysregulated RNA modification. In this review, we focus on nine common RNA modifications: N-methyladenosine (mA), N-methyladenosine (mA), 5-methylcytosine (mC), N-methylguanosine (mG), N-acetylcytosine (acC), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) RNA editing, and modifications of U34 on tRNA wobble. We summarize the key regulators of RNA modification and their effects on gene expression, such as RNA splicing, maturation, transport, stability, and translation. Then, based on the classification of CVD, the mechanisms by which the disease occurs and progresses through RNA modifications are discussed. Potential therapeutic strategies, such as gene therapy, are reviewed based on these mechanisms. Herein, some of the CVD (such as stroke and peripheral vascular disease) are not included due to the limited availability of literature. Finally, the prospective applications and challenges of RNA modification in CVD are discussed for the purpose of facilitating clinical translation. Moreover, we look forward to more studies exploring the mechanisms and roles of RNA modification in CVD in the future, as there are substantial uncultivated areas to be explored.
Topics: Humans; Adolescent; Cardiovascular Diseases; Adenosine; RNA; RNA Processing, Post-Transcriptional; RNA, Transfer
PubMed: 37884527
DOI: 10.1038/s41392-023-01638-7 -
Frontiers in Immunology 2023Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and... (Review)
Review
Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and autoimmune diseases have high incidence rates, still threaten human health, and represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis of various diseases. As the most widely discussed m6A methyltransferase, the pathogenic role of METTL3 in inflammatory diseases has become a research hotspot, but there has been no comprehensive review of the topic. Here, we summarize the expression changes, modified target genes, and pathogenesis related to METTL3 in cardiovascular, metabolic, degenerative, immune, and infectious diseases, as well as tumors. In addition to epithelial cells, endothelial cells, and fibroblasts, METTL3 also regulates the function of inflammation-related immune cells, including macrophages, neutrophils, dendritic cells, Th17 cells, and NK cells. Regarding therapeutic applications, METTL3 serves as a target for the treatment of inflammatory diseases with natural plant drug components, such as emodin, cinnamaldehyde, total flavonoids of , and resveratrol. This review focuses on recent advances in the initiation, development, and therapeutic application of METTL3 in inflammatory diseases. Knowledge of the specific regulatory mechanisms involving METTL3 can help to deepen understanding of inflammatory diseases and lay the foundation for the development of precisely targeted drugs to address inflammatory processes.
Topics: Humans; Endothelial Cells; Methyltransferases; Adenosine; Atherosclerosis; Autoimmune Diseases; Cardiovascular Diseases
PubMed: 37671161
DOI: 10.3389/fimmu.2023.1221609 -
Neurobiology of Disease Sep 2023Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal... (Review)
Review
Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal and disease conditions. During neurodegenerative illnesses, high concentrations of ATP are released from the damaged neuronal and non-neuronal cells of the brain; then, this ATP is enzymatically degraded to adenosine. Thus, the primary injury in neurodegenerative diseases appears to be caused by various protein aggregates on which a superimposed damage mediated by especially P2X7 and A2AR activation develops; this can be efficiently prevented by small molecular antagonists in animal models of the above diseases, or are mitigated in the respective knockout mice. Dementia is a leading symptom in Alzheimer's disease (AD), and accompanies Parkinson's disease (PD) and Huntington's disease (HD), especially in the advanced states of these illnesses. Animal experimentation suggests that P2X7 and A2ARs are also involved in a number of psychiatric diseases, such as major depressive disorder (MDD), obsessive compulsive behavior, and attention deficit hyperactivity disorder. In conclusion, small molecular antagonists of purinergic receptors are expected to supply us in the future with pharmaceuticals which are able to combat in a range of neurological/psychiatric diseases the accompanying cognitive deterioration.
Topics: Animals; Mice; Depressive Disorder, Major; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Nervous System Diseases; Cognition
PubMed: 37453562
DOI: 10.1016/j.nbd.2023.106229 -
Nature Nov 2023Microsatellite repeat expansions within genes contribute to a number of neurological diseases. The accumulation of toxic proteins and RNA molecules with repetitive...
Microsatellite repeat expansions within genes contribute to a number of neurological diseases. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N-methyladenosine (mA) by TRMT61A, and that mA can be demethylated by ALKBH3. We also observed that the mA/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with mA in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, mA in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of mA in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion.
Topics: Animals; Humans; Adenosine; Caenorhabditis elegans; DNA-Binding Proteins; Drosophila melanogaster; Neurodegenerative Diseases; RNA; Trinucleotide Repeat Expansion; Cytoplasm; Disease Models, Animal
PubMed: 37938769
DOI: 10.1038/s41586-023-06701-5 -
Nature Biotechnology Jul 2023N-methyladenosine (mA), the most abundant internal messenger RNA modification in higher eukaryotes, serves myriad roles in regulating cellular processes. Functional...
N-methyladenosine (mA), the most abundant internal messenger RNA modification in higher eukaryotes, serves myriad roles in regulating cellular processes. Functional dissection of mA is, however, hampered in part by the lack of high-resolution and quantitative detection methods. Here we present evolved TadA-assisted N-methyladenosine sequencing (eTAM-seq), an enzyme-assisted sequencing technology that detects and quantifies mA by global adenosine deamination. With eTAM-seq, we analyze the transcriptome-wide distribution of mA in HeLa and mouse embryonic stem cells. The enzymatic deamination route employed by eTAM-seq preserves RNA integrity, facilitating mA detection from limited input samples. In addition to transcriptome-wide mA profiling, we demonstrate site-specific, deep-sequencing-free mA quantification with as few as ten cells, an input demand orders of magnitude lower than existing quantitative profiling methods. We envision that eTAM-seq will enable researchers to not only survey the mA landscape at unprecedented resolution, but also detect mA at user-specified loci with a simple workflow.
Topics: Animals; Mice; Transcriptome; Methylation; Deamination; Adenosine
PubMed: 36593412
DOI: 10.1038/s41587-022-01587-6 -
Biomedicine & Pharmacotherapy =... Jul 2023Gastric cancer (GC) is a fatal illness, and its mortality rate is very high all over the world. At present, it is a serious health problem for any country. It is a... (Review)
Review
Gastric cancer (GC) is a fatal illness, and its mortality rate is very high all over the world. At present, it is a serious health problem for any country. It is a multifactorial disease due to the rising drug resistance and the increasing global cancer burden, the treatment of GC still faces many obstacles and problems. In recent years, research on GC is being carried out continuously, and we hope to address the new targets of GC treatment through this review. At the same time, we also hope to discover new ways to fight GC and create more gospel for clinical patients. First, we discuss the descriptive tumor microenvironment (TME), N6-methyladenosine (m6A), pyroptosis, autophagy, ferroptosis, and cuproptosis. Finally, we expounded on the new or potential targets of GC treatment.
Topics: Humans; Stomach Neoplasms; Ferroptosis; Pyroptosis; Tumor Microenvironment; Adenosine; Autophagy
PubMed: 37196545
DOI: 10.1016/j.biopha.2023.114883