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Purinergic Signalling Feb 2024A variety of observational studies have demonstrated that coffee, likely acting through caffeine, improves health outcomes in patients with chronic liver disease. The... (Review)
Review
A variety of observational studies have demonstrated that coffee, likely acting through caffeine, improves health outcomes in patients with chronic liver disease. The primary pharmacologic role of caffeine is to act as an inhibitor of adenosine receptors. Because key liver cells express adenosine receptors linked to liver injury, regeneration, and fibrosis, it is plausible that the biological effects of coffee are explained by effects of caffeine on adenosinergic signaling in the liver. This review is designed to help the reader make sense of that hypothesis, highlighting key observations in the literature that support or dispute it.
Topics: Humans; Coffee; Caffeine; Liver Cirrhosis; Adenosine; Liver; Receptors, Purinergic P1
PubMed: 37755557
DOI: 10.1007/s11302-023-09968-5 -
Advanced Science (Weinheim,... Sep 2023Abnormal resumption of meiosis and decreased oocyte quality are hallmarks of maternal aging. Transcriptional silencing makes translational control an urgent task during...
Abnormal resumption of meiosis and decreased oocyte quality are hallmarks of maternal aging. Transcriptional silencing makes translational control an urgent task during meiosis resumption in maternal aging. However, insights into aging-related translational characteristics and underlying mechanisms are limited. Here, using multi-omics analysis of oocytes, it is found that translatomics during aging is related to changes in the proteome and reveals decreased translational efficiency with aging phenotypes in mouse oocytes. Translational efficiency decrease is associated with the N6-methyladenosine (m6A) modification of transcripts. It is further clarified that m6A reader YTHDF3 is significantly decreased in aged oocytes, inhibiting oocyte meiotic maturation. YTHDF3 intervention perturbs the translatome of oocytes and suppress the translational efficiency of aging-associated maternal factors, such as Hells, to affect the oocyte maturation. Moreover, the translational landscape is profiled in human oocyte aging, and the similar translational changes of epigenetic modifications regulators between human and mice oocyte aging are observed. In particular, due to the translational silence of YTHDF3 in human oocytes, translation activity is not associated with m6A modification, but alternative splicing factor SRSF6. Together, the findings profile the specific translational landscapes during oocyte aging in mice and humans, and uncover non-conservative regulators on translation control in meiosis resumption and maternal aging.
Topics: Humans; Mice; Animals; Aged; Multiomics; Oocytes; Meiosis; Adenosine; Serine-Arginine Splicing Factors; Phosphoproteins
PubMed: 37401155
DOI: 10.1002/advs.202301538 -
Clinical and Translational Medicine Jun 2024Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal... (Review)
Review
Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N-methyladenosine (mA) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-mA RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the mA modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-mA RNA modifications. In this review, we mainly focus on the roles and implications of non-mA RNA modifications, including N-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2'-O-methylation, N-methyladenosine and N-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-mA RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-mA RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-mA modifiers in blood cancer.
Topics: Humans; Hematologic Neoplasms; RNA Processing, Post-Transcriptional; RNA; Adenosine
PubMed: 38880983
DOI: 10.1002/ctm2.1666 -
Sleep Medicine Mar 2024Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other... (Review)
Review
Sleep is a natural and recurring state of life. Long-term insomnia can lead to physical and mental fatigue, inattention, memory loss, anxiety, depression and other symptoms, imposing immense public health and economic burden worldwide. The sleep and awakening regulation system is composed of many nerve nuclei and neurotransmitters in the brain, and it forms a neural network that interacts and restricts each other to regulate the occurrence and maintenance of sleep-wake. Adenosine (AD) is a neurotransmitter in the central nervous system and a driver of sleep. Meanwhile, the functions and mechanisms underlying sleep-promoting effects of adenosine and its receptors are still not entirely clear. However, in recent years, the increasing evidence indicated that adenosine can promote sleep through inhibiting arousal system and activating sleep-promoting system. At the same time, astrocyte-derived adenosine in modulating sleep homeostasis and sleep loss-induced related cognitive and memory deficits plays an important role. This review, therefore, summarizes the current research on the functions and possible mechanisms of adenosine and its receptors in the regulation of sleep and homeostatic control of sleep. Understanding these aspects will provide us better ideas on clinical problems such as insomnia, hypersomnia and other sleep disorders.
Topics: Humans; Adenosine; Sleep Initiation and Maintenance Disorders; Wakefulness; Sleep; Brain; Neurotransmitter Agents
PubMed: 38373361
DOI: 10.1016/j.sleep.2024.02.012 -
Pharmacology & Therapeutics Sep 2023Pulmonary fibrosis is a debilitating and life-limiting lung condition in which the damage- response mechanisms of mixed-population cells within the lungs go awry. The... (Review)
Review
Pulmonary fibrosis is a debilitating and life-limiting lung condition in which the damage- response mechanisms of mixed-population cells within the lungs go awry. The tissue microenvironment is drastically remodelled by aberrantly activated fibroblasts which deposit ECM components into the surrounding lung tissue, detrimentally affecting lung function and capacity for gas exchange. Growing evidence suggests a role for adenosine signalling in the pathology of tissue fibrosis in a variety of organs, including the lung, but the molecular pathways through which this occurs remain largely unknown. This review explores the role of adenosine in fibrosis and evaluates the contribution of the different adenosine receptors to fibrogenesis. Therapeutic targeting of the adenosine receptors is also considered, along with clinical observations pointing towards a role for adenosine in fibrosis. In addition, the interaction between adenosine signalling and other profibrotic signalling pathways, such as TGFβ1 signalling, is discussed.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Lung; Fibrosis; Fibroblasts; Adenosine; Receptors, Purinergic P1
PubMed: 37482099
DOI: 10.1016/j.pharmthera.2023.108504 -
International Journal of Molecular... Jul 2023The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a... (Review)
Review
The search for new and effective treatment targets for cancer immunotherapy is an ongoing challenge. Alongside the more established inhibitory immune checkpoints, a novel potential target is CD73. As one of the key enzymes in the purinergic signalling pathway CD73 is responsible for the generation of immune suppressive adenosine. The expression of CD73 is higher in tumours than in the corresponding healthy tissues and associated with a poor prognosis. CD73, mainly by the production of adenosine, is critical in the suppression of an adequate anti-tumour immune response, but also in promoting cancer cell proliferation, tumour growth, angiogenesis, and metastasis. The upregulation of CD73 and generation of adenosine by tumour or tumour-associated immune cells is a common resistance mechanism to many cancer treatments such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Therefore, the inhibition of CD73 represents a new and promising approach to increase therapy efficacy. Several CD73 inhibitors have already been developed and successfully demonstrated anti-cancer activity in preclinical studies. Currently, clinical studies evaluate CD73 inhibitors in different therapy combinations and tumour entities. The initial results suggest that inhibiting CD73 could be an effective option to augment anti-cancer immunotherapeutic strategies. This review provides an overview of the rationale behind the CD73 inhibition in different treatment combinations and the role of CD73 as a prognostic marker.
Topics: Humans; 5'-Nucleotidase; Adenosine; Clinical Relevance; Immunosuppression Therapy; Immunotherapy; Neoplasms
PubMed: 37511518
DOI: 10.3390/ijms241411759 -
Epigenetics Dec 2023Epitranscriptomic modifications have recently emerged into the spotlight of researchers due to their vast regulatory effects on gene expression and thereby cellular... (Review)
Review
Epitranscriptomic modifications have recently emerged into the spotlight of researchers due to their vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N,2'-O-dimethyladenosine (mAm) is one of the most prevalent chemical marks on RNA and is dynamically regulated by writers (PCIF1, METTL4) and erasers (FTO). The presence or absence of mAm in RNA affects mRNA stability, regulates transcription, and modulates pre-mRNA splicing. Nevertheless, its functions in the heart are poorly known. This review summarizes the current knowledge and gaps about mAm modification and its regulators in cardiac biology. It also points out technical challenges and lists the currently available techniques to measure mAm. A better understanding of epitranscriptomic modifications is needed to improve our knowledge of the molecular regulations in the heart which may lead to novel cardioprotective strategies.
Topics: RNA, Messenger; Adenosine; DNA Methylation; RNA; Biology
PubMed: 37331009
DOI: 10.1080/15592294.2023.2218771 -
Molecular Cell Aug 2023N-methyladenosine (mA) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and mA demethylases such as FTO play important roles in regulating...
N-methyladenosine (mA) of mRNAs modulated by the METTL3-METTL14-WTAP-RBM15 methyltransferase complex and mA demethylases such as FTO play important roles in regulating mRNA stability, splicing, and translation. Here, we demonstrate that FTO-IT1 long noncoding RNA (lncRNA) was upregulated and positively correlated with poor survival of patients with wild-type p53-expressing prostate cancer (PCa). mA RIP-seq analysis revealed that FTO-IT1 knockout increased mRNA mA methylation of a subset of p53 transcriptional target genes (e.g., FAS, TP53INP1, and SESN2) and induced PCa cell cycle arrest and apoptosis. We further showed that FTO-IT1 directly binds RBM15 and inhibits RBM15 binding, mA methylation, and stability of p53 target mRNAs. Therapeutic depletion of FTO-IT1 restored mRNA mA level and expression of p53 target genes and inhibited PCa growth in mice. Our study identifies FTO-IT1 lncRNA as a bona fide suppressor of the mA methyltransferase complex and p53 tumor suppression signaling and nominates FTO-IT1 as a potential therapeutic target of cancer.
Topics: Male; Mice; Animals; RNA, Long Noncoding; Tumor Suppressor Protein p53; Adenosine; RNA, Messenger; Neoplasms; Methyltransferases; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 37478845
DOI: 10.1016/j.molcel.2023.06.024 -
Genomics, Proteomics & Bioinformatics Aug 2023N-methyladenine (mA) is the most abundant RNA modification in mammalian messenger RNAs (mRNAs), which participates in and regulates many important biological activities,... (Review)
Review
N-methyladenine (mA) is the most abundant RNA modification in mammalian messenger RNAs (mRNAs), which participates in and regulates many important biological activities, such as tissue development and stem cell differentiation. Due to an improved understanding of mA, researchers have discovered that the biological function of mA can be linked to many stages of mRNA metabolism and that mA can regulate a variety of complex biological processes. In addition to its location on mammalian mRNAs, mA has been identified on viral transcripts. mA also plays important roles in the life cycle of many viruses and in viral replication in host cells. In this review, we briefly introduce the detection methods of mA, the mA-related proteins, and the functions of mA. We also summarize the effects of mA-related proteins on viral replication and infection. We hope that this review provides researchers with some insights for elucidating the complex mechanisms of the epitranscriptome related to viruses, and provides information for further study of the mechanisms of other modified nucleobases acting on processes such as viral replication. We also anticipate that this review can stimulate collaborative research from different fields, such as chemistry, biology, and medicine, and promote the development of antiviral drugs and vaccines.
Topics: Animals; Viruses; RNA, Messenger; Adenosine; Cell Differentiation; Mammals
PubMed: 35835441
DOI: 10.1016/j.gpb.2022.04.009 -
Biomedicine & Pharmacotherapy =... Sep 2023Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular... (Review)
Review
Adenosine is an endogenous nucleoside that regulates many physiological and pathological processes. It is derived from either the intracellular or extracellular dephosphorylation of adenosine triphosphate and interacts with cell-surface G-protein-coupled receptors. Adenosine plays a substantial role in protecting against cell damage in areas of increased tissue metabolism and preventing organ dysfunction in pathological states. Targeting adenosine metabolism and receptor signaling may be an effective therapeutic approach for human diseases, including cardiovascular and central nervous system disorders, rheumatoid arthritis, asthma, renal diseases, and cancer. Several lines of evidence have shown that many drugs exert their beneficial effects by modulating adenosine signaling pathways but this knowledge urgently needs to be summarized, and most importantly, actualized. The present review collects pharmaceuticals and pharmacological or diagnostic tools that target adenosine signaling in their primary or secondary mode of action. We overviewed FDA-approved drugs as well as those currently being studied in clinical trials. Among them are already used in clinic A2A adenosine receptor modulators like istradefylline or regadenoson, but also plenty of anti-platelet, anti-inflammatory, or immunosuppressive, and anti-cancer drugs. On the other hand, we investigated dozens of specific adenosine pathway regulators that are tested in clinical trials to treat human infectious and noninfectious diseases. In conclusion, targeting purinergic signaling represents a great therapeutic challenge. The actual knowledge of the involvement of adenosinergic signaling as part of the mechanism of action of old drugs has open a path not only for drug-repurposing but also for new therapeutic strategies.
Topics: Humans; Adenosine; Adenosine Triphosphate; Receptors, Purinergic P1; Cell Membrane; Signal Transduction
PubMed: 37506580
DOI: 10.1016/j.biopha.2023.115184