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American Journal of Physiology.... Jan 2023This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in... (Review)
Review
This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in cancer immunometabolism. The immune system plays a paradoxical role in cancer treatment. Antitumor immunity depends on the T-cell priming against tumor antigens, whereas inflammatory mediators trigger the protumor signaling in the tumor microenvironment. Studies link the microbiome with metabolism and immunity-two main factors implicated in carcinogenesis. Gut microbiota has been shown to affect both antitumor immunity and protumor immune signaling. There is mounting evidence that the human microbiome can play a role in the immunotherapeutic effects, both response and resistance. Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conservative enzyme widely expressed in mammals. Cell signaling pathways use molecular inosine, a crucial secondary metabolite in purine metabolism and a molecular messenger. Recent research has identified inosine as a critical regulator of immune checkpoint inhibition (ICI) therapeutic response in various tumor types. Some bacterial species were found to produce inosine or its metabolite hypoxanthine and induce T-helper 1 differentiation and effector functions via the inosine-A2AR-cAMP-PKA pathway upon ICI therapy. Also, inosine acts as a substitute carbon source for T-cell metabolism in glucose-restricted environments, i.e., the tumor microenvironment, assisting T-cell proliferation and differentiation while enhancing sensitivity to ICI, reinforcing the notion that inosine metabolism might contribute to antitumor immunity. Also, inosine is a potent agonist of the adenosine receptor, A2AR, and A2AR signaling can affect T-cell responses and antitumor immunity, making the inosine-A2AR pathway blockage a candidate for cancer treatment. Further research is required to investigate inosine as a cancer immunometabolism therapy.
Topics: Animals; Humans; Gastrointestinal Microbiome; Neoplasms; T-Lymphocytes; Inosine; Carcinogenesis; Mammals; Tumor Microenvironment
PubMed: 36416582
DOI: 10.1152/ajpendo.00207.2022 -
Blood Sep 2022
Topics: Anemia, Sickle Cell; Child; Hemoglobinopathies; Humans; Ticagrelor
PubMed: 36173660
DOI: 10.1182/blood.2022017213 -
Oxidative Medicine and Cellular... 2022N-Methyladenosine (mA) is the most abundant epigenetic RNA modification in eukaryotes, regulating RNA metabolism (export, stability, translation, and decay) in cells... (Review)
Review
N-Methyladenosine (mA) is the most abundant epigenetic RNA modification in eukaryotes, regulating RNA metabolism (export, stability, translation, and decay) in cells through changes in the activity of writers, erasers, and readers and ultimately affecting human life or disease processes. Inflammation is a response to infection and injury in various diseases and has therefore attracted significant attention. Currently, extensive evidence indicates that mA plays an essential role in inflammation. In this review, we focus on the mechanisms of mA in inflammatory autoimmune diseases, metabolic disorder, cardio-cerebrovascular diseases, cancer, and pathogen-induced inflammation, as well as its possible role as targets for clinical diagnosis and treatment.
Topics: Humans; RNA; Neoplasms; Adenosine; Epigenesis, Genetic
PubMed: 36578520
DOI: 10.1155/2022/9744771 -
Accounts of Chemical Research Oct 2023The function of cellular RNA is modulated by a host of post-transcriptional chemical modifications installed by dedicated RNA-modifying enzymes. RNA modifications are...
The function of cellular RNA is modulated by a host of post-transcriptional chemical modifications installed by dedicated RNA-modifying enzymes. RNA modifications are widespread in biology, occurring in all kingdoms of life and in all classes of RNA molecules. They regulate RNA structure, folding, and protein-RNA interactions, and have important roles in fundamental gene expression processes involving mRNA, tRNA, rRNA, and other types of RNA species. Our understanding of RNA modifications has advanced considerably; however, there are still many outstanding questions regarding the distribution of modifications across all RNA transcripts and their biological function. One of the major challenges in the study of RNA modifications is the lack of sequencing methods for the transcriptome-wide mapping of different RNA-modification structures. Furthermore, we lack general strategies to characterize RNA-modifying enzymes and RNA-modification reader proteins. Therefore, there is a need for new approaches to enable integrated studies of RNA-modification chemistry and biology.In this Account, we describe our development and application of chemoproteomic strategies for the study of RNA-modification-associated proteins. We present two orthogonal methods based on nucleoside and oligonucleotide chemical probes: 1) RNA-mediated activity-based protein profiling (RNABPP), a metabolic labeling strategy based on reactive modified nucleoside probes to profile RNA-modifying enzymes in cells and 2) photo-cross-linkable diazirine-containing synthetic oligonucleotide probes for identifying RNA-modification reader proteins.We use RNABPP with C5-modified cytidine and uridine nucleosides to capture diverse RNA-pyrimidine-modifying enzymes including methyltransferases, dihydrouridine synthases, and RNA dioxygenase enzymes. Metabolic labeling facilitates the mechanism-based cross-linking of RNA-modifying enzymes with their native RNA substrates in cells. Covalent RNA-protein complexes are then isolated by denaturing oligo(dT) pulldown, and cross-linked proteins are identified by quantitative proteomics. Once suitable modified nucleosides have been identified as mechanism-based proteomic probes, they can be further deployed in transcriptome-wide sequencing experiments to profile the substrates of RNA-modifying enzymes at nucleotide resolution. Using 5-fluorouridine-mediated RNA-protein cross-linking and sequencing, we analyzed the substrates of human dihydrouridine synthase DUS3L. 5-Ethynylcytidine-mediated cross-linking enabled the investigation of ALKBH1 substrates. We also characterized the functions of these RNA-modifying enzymes in human cells by using genetic knockouts and protein translation reporters.We profiled RNA readers for -methyladenosine (mA) and -methyladenosine (mA) using a comparative proteomic workflow based on diazirine-containing modified oligonucleotide probes. Our approach enables quantitative proteome-wide analysis of the preference of RNA-binding proteins for modified nucleotides across a range of affinities. Interestingly, we found that YTH-domain proteins YTHDF1/2 can bind to both mA and mA to mediate transcript destabilization. Furthermore, mA also inhibits stress granule proteins from binding to RNA.Taken together, we demonstrate the application of chemical probing strategies, together with proteomic and transcriptomic workflows, to reveal new insights into the biological roles of RNA modifications and their associated proteins.
Topics: Humans; Nucleosides; Adenosine; Proteomics; Diazomethane; Oligonucleotide Probes; RNA; AlkB Homolog 1, Histone H2a Dioxygenase
PubMed: 37733063
DOI: 10.1021/acs.accounts.3c00450 -
Frontiers in Bioscience (Landmark... Nov 2022The N6-methyladenosine (m6A) is the most abundant internal modification in advanced eukaryotic mRNAs, and it plays an important role in mRNA metabolism and diverse... (Review)
Review
The N6-methyladenosine (m6A) is the most abundant internal modification in advanced eukaryotic mRNAs, and it plays an important role in mRNA metabolism and diverse biological processes. Moreover, m6A modification is dynamically reversible and may reshape gene expression patterns after demethylation induced by drug interventions, which may reverse the occurrence and progression of certain diseases. Although the role of changes in DNA methylation in ophthalmic diseases has been well described, the regulatory role of the m6A modification in ophthalmic diseases is still a new field of study. This paper aims to systematically summarize the latest research progress about m6a-modification-related ophthalmic diseases and potential therapeutic strategies. All English literature relevant to our research was searched in PubMed and CNKI databases, using appropriate keywords. Our study reviews the regulatory role of m6A in ophthalmic diseases. It covers almost all of the reported m6A-related ophthalmic diseases and proposes potential treatment strategies for each disease. This review will provide direction for further research on m6A in ophthalmic diseases and help in the treatment of ophthalmic diseases in the future.
Topics: Adenosine; DNA Methylation; Eukaryota; Eukaryotic Cells
PubMed: 36472104
DOI: 10.31083/j.fbl2711304 -
Journal of Hematology & Oncology May 2024As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and... (Review)
Review
As the most common form of epigenetic regulation by RNA, N methyladenosine (mA) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between mA and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target mA regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting mA regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of mA regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure-activity relationships of small molecules targeting mA regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting mA.
Topics: Animals; Humans; Adenosine; Antineoplastic Agents; Epigenesis, Genetic; Neoplasms; Small Molecule Libraries
PubMed: 38711100
DOI: 10.1186/s13045-024-01546-5 -
Haematologica Jan 2024
Topics: Humans; Adenosine
PubMed: 37470140
DOI: 10.3324/haematol.2023.283469 -
Cell Communication and Signaling : CCS Sep 2022N6-methyl-adenosine (mA) is the most prevalent modification on mRNAs and long noncoding RNAs (lnRNAs) in higher eukaryotes. Modulation of mA relies on mA writers,... (Review)
Review
N6-methyl-adenosine (mA) is the most prevalent modification on mRNAs and long noncoding RNAs (lnRNAs) in higher eukaryotes. Modulation of mA relies on mA writers, erasers and readers. mA modification contributes to diverse fundamental biological functions at the molecular, cellular, and physiological levels. The dysregulation of mA modification has been implicated in various human diseases. Thus, mA modification has now become a research hotspot for its potential therapeutic applications in the treatment of various cancers and diseases. The immune system is essential to provide defense against infections and cancers. This review summarizes the current knowledge about the roles of mA in regulating immune cell functions and immune responses. Video abstract.
Topics: Adenosine; Humans; Methylation; Methyltransferases; Neoplasms
PubMed: 36085064
DOI: 10.1186/s12964-022-00939-8 -
Journal of Hematology & Oncology Jul 2021N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects... (Review)
Review
N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.
Topics: Adenosine; Animals; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 34315512
DOI: 10.1186/s13045-021-01129-8 -
Redox Biology Nov 2021Purinergic signaling is a cell communication pathway mediated by extracellular nucleotides and nucleosides. Tri- and diphosphonucleotides are released in physiological... (Review)
Review
Purinergic signaling is a cell communication pathway mediated by extracellular nucleotides and nucleosides. Tri- and diphosphonucleotides are released in physiological and pathological circumstances activating purinergic type 2 receptors (P2 receptors): P2X ion channels and P2Y G protein-coupled receptors. The activation of these receptors triggers the production of reactive oxygen and nitrogen species and alters antioxidant defenses, modulating the redox biology of cells. The activation of P2 receptors is controlled by ecto-enzymes named ectonucleotidases, E-NTPDase1/CD39 and ecto-5'-nucleotidase/CD73) being the most relevant. The first enzyme hydrolyzes adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine monophosphate (AMP), and the second catalyzes the hydrolysis of AMP to adenosine. The activity of these enzymes is diminished by oxidative stress. Adenosine actives P1 G-coupled receptors that, in general, promote the maintenance of redox hemostasis by decreasing reactive oxygen species (ROS) production and increase antioxidant enzymes. Intracellular purine metabolism can also contribute to ROS generation via xanthine oxidase activity, which converts hypoxanthine into xanthine, and finally, uric acid. In this review, we describe the mechanisms of redox biology modulated by purinergic signaling and how this signaling may be affected by disturbances in the redox homeostasis of cells.
Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Biology; Oxidation-Reduction
PubMed: 34563872
DOI: 10.1016/j.redox.2021.102137