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International Journal of Molecular... Oct 2023Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor... (Review)
Review
Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities by inducing tumor cell proliferation, migration or invasion, tumor tissue angiogenesis, and chemoresistance. In addition, adenosine plays an important role in regulating anti-tumor immune responses and facilitating tumor immune escape. Adenosine receptors are broadly expressed by tumor-infiltrated immune cells, including suppressive tumor-associated macrophages and CD4 regulatory T cells, as well as effector CD4 T cells and CD8 cytotoxic T lymphocytes. Therefore, adenosine is indispensable in down-regulating anti-tumor immune responses in the tumor microenvironment and contributes to tumor progression. This review describes the current progress on the role of adenosine/adenosine receptor pathway in regulating the tumor-infiltrating immune cells that contribute to tumor immune evasion and aims to provide insights into adenosine-targeted tumor immunotherapy.
Topics: Humans; Adenosine; Tumor Microenvironment; Adenosine Triphosphate; Neoplasms; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; 5'-Nucleotidase
PubMed: 37834375
DOI: 10.3390/ijms241914928 -
Cancer Medicine Oct 2023CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab.... (Review)
Review
BACKGROUND
CD38 has been established as an important therapeutic target for multiple myeloma (MM), for which two CD38 antibodies are currently approved-daratumumab and isatuximab. CD38 is an ectoenzyme that degrades NAD and its precursors and is involved in the production of adenosine and other metabolites.
AIM
Among the various mechanisms by which CD38 antibodies can induce MM cell death is immunomodulation, including multiple pathways for CD38-mediated T-cell activation. Patients who respond to anti-CD38 targeting treatment experience more marked changes in T-cell expansion, activity, and clonality than nonresponders.
IMPLICATIONS
Resistance mechanisms that undermine the immunomodulatory effects of CD38-targeting therapies can be tumor intrinsic, such as the downregulation of CD38 surface expression and expression of complement inhibitor proteins, and immune microenvironment-related, such as changes to the natural killer (NK) cell numbers and function in the bone marrow niche. There are numerous strategies to overcome this resistance, which include identifying and targeting other therapeutic targets involved in, for example, adenosine production, the activation of NK cells or monocytes through immunomodulatory drugs and their combination with elotuzumab, or with bispecific T-cell engagers.
Topics: Humans; Multiple Myeloma; ADP-ribosyl Cyclase 1; Immunomodulation; Immunologic Factors; Adenosine; Tumor Microenvironment
PubMed: 37840445
DOI: 10.1002/cam4.6619 -
Autoimmunity Dec 2023Skin diseases are global health issues caused by multiple pathogenic factors, in which epigenetics plays an invaluable role. Post-transcriptional RNA modifications are... (Review)
Review
Skin diseases are global health issues caused by multiple pathogenic factors, in which epigenetics plays an invaluable role. Post-transcriptional RNA modifications are important epigenetic mechanism that regulate gene expression at the genome-wide level. N6-methyladenosine (m6A) is the most prevalent modification that occurs in the messenger RNAs (mRNA) of most eukaryotes, which is installed by methyltransferases called "writers", removed by demethylases called "erasers", and recognised by RNA-binding proteins called "readers". To date, m6A is emerging to play essential part in both physiological processes and pathological progression, including skin diseases. However, a systematic summary of m6A in skin disease has not yet been reported. This review starts by illustrating each m6A-related modifier specifically and their roles in RNA processing, and then focus on the existing research advances of m6A in immune homeostasis and skin diseases.
Topics: Humans; Adenosine; Methylation; Methyltransferases; RNA; RNA, Messenger; Skin Diseases
PubMed: 36708146
DOI: 10.1080/08916934.2023.2167983 -
Nature Dec 2023The group II intron ribonucleoprotein is an archetypal splicing system with numerous mechanistic parallels to the spliceosome, including excision of lariat introns....
The group II intron ribonucleoprotein is an archetypal splicing system with numerous mechanistic parallels to the spliceosome, including excision of lariat introns. Despite the importance of branching in RNA metabolism, structural understanding of this process has remained elusive. Here we present a comprehensive analysis of three single-particle cryogenic electron microscopy structures captured along the splicing pathway. They reveal the network of molecular interactions that specifies the branchpoint adenosine and positions key functional groups to catalyse lariat formation and coordinate exon ligation. The structures also reveal conformational rearrangements of the branch helix and the mechanism of splice site exchange that facilitate the transition from branching to ligation. These findings shed light on the evolution of splicing and highlight the conservation of structural components, catalytic mechanism and dynamical strategies retained through time in premessenger RNA splicing machines.
Topics: Adenosine; Biocatalysis; Cryoelectron Microscopy; Exons; Introns; Nucleic Acid Conformation; RNA Precursors; RNA Splice Sites; RNA Splicing
PubMed: 37993708
DOI: 10.1038/s41586-023-06746-6 -
Biomedicine & Pharmacotherapy =... Apr 2024Hepatocellular carcinoma (HCC) is one of the deadliest cancers of human, the tumor-related death of which ranks third among the common malignances. N-methyladenosine... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the deadliest cancers of human, the tumor-related death of which ranks third among the common malignances. N-methyladenosine (mA) methylation, the most abundant internal modification of RNA in mammals, participates in the metabolism of mRNA and interrelates with ncRNAs. In this paper, we overviewed the complex function of mA regulators in HCC, including regulating the tumorigenesis, progression, prognosis, stemness, metabolic reprogramming, autophagy, ferroptosis, drug resistance and tumor immune microenvironment (TIME). Furthermore, we elucidated the interplay between mA modification and non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Finally, we summarized the potential of mA regulators as diagnostic biomarkers. What's more, we reviewed the inhibitors targeting mA enzymes as promising therapeutic targets of HCC. We aimed to help understand the function of mA methylation in HCC systematically and comprehensively so that more effective strategies for HCC treatment will be developed.
Topics: Humans; Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Adenosine; MicroRNAs; Mammals; Tumor Microenvironment
PubMed: 38452654
DOI: 10.1016/j.biopha.2024.116365 -
Redox Biology Nov 2023Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective...
Adenosine kinase (ADK) plays the major role in cardiac adenosine metabolism, so that inhibition of ADK increases myocardial adenosine levels. While the cardioprotective actions of extracellular adenosine against ischemia/reperfusion (I/R) are well-established, the role of cellular adenosine in protection against I/R remains unknown. Here we investigated the role of cellular adenosine in epigenetic regulation on cardiomyocyte gene expression, glucose metabolism and tolerance to I/R. Evans blue/TTC staining and echocardiography were used to assess the extent of I/R injury in mice. Glucose metabolism was evaluated by positron emission tomography and computed tomography (PET/CT). Methylated DNA immunoprecipitation (MeDIP) and bisulfite sequencing PCR (BSP) were used to evaluate DNA methylation. Lentiviral/adenovirus transduction was used to overexpress DNMT1, and the OSI-906 was administered to inhibit IGF-1. Cardiomyocyte-specific ADK/IGF-1-knockout mice were used for mechanistic experiments.Cardiomyocyte-specific ADK knockout enhanced glucose metabolism and ameliorated myocardial I/R injury in vivo. Mechanistically, ADK deletion caused cellular adenosine accumulation, decreased DNA methyltransferase 1 (DNMT1) expression and caused hypomethylation of multiple metabolic genes, including insulin growth factor 1 (IGF-1). DNMT1 overexpression abrogated these beneficial effects by enhancing apoptosis and decreasing IGF-1 expression. Inhibition of IGF-1 signaling with OSI-906 or genetic knocking down of IGF-1 also abrogated the cardioprotective effects of ADK knockout, revealing the therapeutic potential of increasing IGF-1 expression in attenuating myocardial I/R injury. In conclusion, the present study demonstrated that cardiomyocyte ADK deletion ameliorates myocardial I/R injury via epigenetic upregulation of IGF-1 expression via the cardiomyocyte adenosine/DNMT1/IGF-1 axis.
Topics: Mice; Animals; Myocytes, Cardiac; Epigenesis, Genetic; Adenosine; Insulin-Like Growth Factor I; Positron Emission Tomography Computed Tomography; Ischemia; Myocardial Reperfusion Injury; Mice, Knockout; Apoptosis; Reperfusion; DNA; Glucose
PubMed: 37725888
DOI: 10.1016/j.redox.2023.102884 -
International Journal of Molecular... Aug 2023Pain represents an international burden and a major socio-economic public health problem. New findings, detailed in this review, suggest that adenosine plays a... (Review)
Review
Pain represents an international burden and a major socio-economic public health problem. New findings, detailed in this review, suggest that adenosine plays a significant role in neuropathic and inflammatory pain, by acting on its metabotropic adenosine receptors (AAR, AAR, AAR, AAR). Adenosine receptor ligands have a practical translational potential based on the favorable efficacy and safety profiles that emerged from clinical research on various agonists and antagonists for different pathologies. The present review collects the latest studies on selected adenosine receptor ligands in different pain models. Here, we also covered the many hypothesized pathways and the role of newly synthesized allosteric adenosine receptor modulators. This review aims to present a summary of recent research on adenosine receptors as prospective therapeutic targets for a range of pain-related disorders.
Topics: Humans; Ligands; Analgesics; Pain; Adenosine; Receptors, Purinergic P1
PubMed: 37685963
DOI: 10.3390/ijms241713160 -
Frontiers in Immunology 2023Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms... (Review)
Review
Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Cladribine; Central Nervous System Diseases
PubMed: 38162670
DOI: 10.3389/fimmu.2023.1290666 -
Theranostics 2024The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can...
The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. The senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation . RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8 T cell-mediated antitumor immunity. TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.
Topics: Humans; Tumor Microenvironment; Cisplatin; Macrophages; Cellular Senescence; Lung Neoplasms; Adenosine
PubMed: 38323313
DOI: 10.7150/thno.91119 -
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