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Medical Science Monitor : International... Apr 2020According to the World Health Organization cardiovascular disease risk charts, the mortality rate of cardiovascular diseases in people is still high. The medical... (Review)
Review
According to the World Health Organization cardiovascular disease risk charts, the mortality rate of cardiovascular diseases in people is still high. The medical expenses caused by cardiovascular diseases are increasing daily, and the medical burden is becoming heavier; as such, it is imperative to prevent and cure cardiovascular diseases. A large number of scholars are analyzing the pathogenesis of cardiovascular diseases from various perspectives. Recent findings suggest that N6-methyladenosine (m6A) plays a multifaceted role in the cardiovascular system. m6A is a methylated modification product on RNA molecules and exists on various RNA molecules. It is one of the most common epigenetic modifications discovered to date. It regulates the expression of genes and subsequent responses. The amount of m6A is determined by methylases (writers) and demethylases (erasers). The third type of proteins, readers, selectively bind to m6A to regulate RNA stability and gene expression. In this paper, the relationship between m6A and related enzymes and cardiovascular structure and function was reviewed based on recent research results regarding the cardiovascular system.
Topics: Adenosine; Cardiovascular Diseases; Cardiovascular System; Epigenesis, Genetic; Gene Expression; Humans; Lipid Metabolism; Lipids; Methylation; Methyltransferases
PubMed: 32350237
DOI: 10.12659/MSM.921742 -
Journal of Molecular Biology Sep 2022RNA folding free energy change parameters are widely used to predict RNA secondary structure and to design RNA sequences. These parameters include terms for the folding...
RNA folding free energy change parameters are widely used to predict RNA secondary structure and to design RNA sequences. These parameters include terms for the folding free energies of helices and loops. Although the full set of parameters has only been traditionally available for the four common bases and backbone, it is well known that covalent modifications of nucleotides are widespread in natural RNAs. Covalent modifications are also widely used in engineered sequences. We recently derived a full set of nearest neighbor terms for RNA that includes N-methyladenosine (mA). In this work, we test the model using 98 optical melting experiments, matching duplexes with or without N-methylation of A. Most experiments place RRACH, the consensus site of N-methylation, in a variety of contexts, including helices, bulge loops, internal loops, dangling ends, and terminal mismatches. For matched sets of experiments that include either A or mA in the same context, we find that the parameters for mA are as accurate as those for A. Across all experiments, the root mean squared deviation between estimated and experimental free energy changes is 0.67 kcal/mol. We used the new experimental data to refine the set of nearest neighbor parameter terms for mA. These parameters enable prediction of RNA secondary structures including mA, which can be used to model how N-methylation of A affects RNA structure.
Topics: Adenosine; Entropy; RNA; RNA Folding
PubMed: 35588868
DOI: 10.1016/j.jmb.2022.167632 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Sep 2023Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to... (Review)
Review
Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.
Topics: Humans; Adenosine; T-Lymphocytes; Adaptive Immunity; Cytokines; Neoplasms; Tumor Microenvironment
PubMed: 37916308
DOI: 10.3724/zdxbyxb-2023-0263 -
Bioorganic & Medicinal Chemistry Letters Jan 20085'-Fluoro-5'-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentylidenedioxy)-4-fluoromethylcyclopentan-1-ol with...
5'-Fluoro-5'-deoxyaristeromycin (2) has been prepared via a Mitsunobu coupling of (1S,2S,3R,4S)-2,3-(cyclopentylidenedioxy)-4-fluoromethylcyclopentan-1-ol with N6-bis-boc protected adenine. This procedure is adaptable to preparing a number of 5'-fluoro-5'-deoxycarbocyclic nucleoside analogs with diversity in the heterocyclic base. Antiviral analysis found promising activity for 2 toward measles but no other viruses. No cytotoxicity was observed for 2.
Topics: Adenosine; Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Deoxyadenosines; HeLa Cells; Humans; Hydrocarbons, Fluorinated; Vero Cells
PubMed: 18023578
DOI: 10.1016/j.bmcl.2007.10.095 -
Alcohol Health and Research World 1997The interaction between the neuromodulator adenosine and adenosine receptors on the surface of neurons modifies the neurons' responses to neurotransmitters. The... (Review)
Review
The interaction between the neuromodulator adenosine and adenosine receptors on the surface of neurons modifies the neurons' responses to neurotransmitters. The activated adenosine receptors alter the levels of small signaling molecules (i.e., second messengers) in the cells. Depending on the receptors and cells involved, these changes can make it easier or more difficult for neurotransmitters to excite the cell. Adenosine's activity is regulated by proteins called nucleoside transporters, which carry adenosine into and out of the cell. Alcohol interferes with the function of the adenosine system. For example, both acute and chronic alcohol exposure affect the function of the adenosine-carrying nucleoside transporters, thereby indirectly altering the second-messenger levels in the cells. Through this mechanism, adenosine may mediate some of alcohol's effects, such as intoxication, motor incoordination, and sedation.
Topics: Adenosine; Alcohol Drinking; Animals; Ethanol; Humans; Neurotransmitter Agents
PubMed: 15704350
DOI: No ID Found -
Journal of the American College of... Jun 2014This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The... (Review)
Review
This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists.
Topics: Acute Coronary Syndrome; Adenosine; Humans; Purinergic P2Y Receptor Antagonists; Ticagrelor; Treatment Outcome
PubMed: 24768873
DOI: 10.1016/j.jacc.2014.03.031 -
Molecular Cancer May 2020As a critical internal RNA modification in higher eukaryotes, N-methyladenosine (mA) has become the hotspot of epigenetics research in recent years. Extensive studies on... (Review)
Review
As a critical internal RNA modification in higher eukaryotes, N-methyladenosine (mA) has become the hotspot of epigenetics research in recent years. Extensive studies on messenger RNAs have revealed that mA affects RNA fate and cell functions in various bioprocesses, such as RNA splicing, export, translation, and stability, some of which seem to be directly or indirectly regulated by noncoding RNAs. Intriguingly, abundant noncoding RNAs such as microRNAs, long noncoding RNAs, circular RNAs, small nuclear RNAs, and ribosomal RNAs are also highly modified with mA and require mA modification for their biogenesis and functions. Here, we discuss the interaction between mA modification and noncoding RNAs by focusing on the functional relevance of mA in cancer progression, metastasis, drug resistance, and immune response. Furthermore, the investigation of mA regulatory proteins and its inhibitors provides new opportunities for early diagnosis and effective treatment of cancer, especially in combination with immunotherapy.
Topics: Adenosine; Animals; Biomarkers, Tumor; DNA Methylation; Disease Progression; Epigenesis, Genetic; Humans; Methyltransferases; Neoplasms; RNA, Untranslated
PubMed: 32443966
DOI: 10.1186/s12943-020-01207-4 -
Journal of Cellular and Molecular... 2003Adenosine is a powerful modulator of neuronal function in the mammalian central nervous system. During a variety of insults to the brain, adenosine is released in large... (Review)
Review
Adenosine is a powerful modulator of neuronal function in the mammalian central nervous system. During a variety of insults to the brain, adenosine is released in large quantities and exerts a neuroprotective influence largely via the A(1) receptor, which inhibits glutamate release and neuronal activity. Using novel enzyme-based adenosine sensors, which allow high spatial and temporal resolution recordings of adenosine release in real time, we have investigated the release of adenosine during hypoxia/ischemia in the in vitro hippocampus. Our data reveal that during the early stages of hypoxia adenosine is likely released per se and not as a precursor such as cAMP or an adenine nucleotide. In addition, repeated hypoxia results in reduced production of extracellular adenosine and this may underlie the increased vulnerability of the mammalian brain to repetitive or secondary hypoxia/ischemia.
Topics: Adenosine; Animals; Brain Ischemia; Extracellular Fluid; Humans; Hypoxia, Brain; Models, Neurological; Receptors, Purinergic P1; Synaptic Transmission
PubMed: 14754505
DOI: 10.1111/j.1582-4934.2003.tb00239.x -
Molecular Pharmaceutics Sep 2022Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in...
Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in models of epilepsy, acute respiratory distress syndrome, and traumatic brain injury, among others. The currently licensed products Adenocard and Adenoscan are formulated at 3 mg/mL of ADO for rapid bolus intravenous injection, but the systemic administration of the saline formulations for anti-inflammatory purposes is limited by the nucleoside's profound hemodynamic effects. Moreover, concentrations that can be attained in the airway or the brain through direct instillation or injection are limited by the volumes that can be accommodated in the anatomical space (<5 mL in humans) and the rapid elimination by enzymatic and transport mechanisms in the interstitium (half-life <5 s). As such, highly concentrated formulations of ADO are needed to attain pharmacologically relevant concentrations at sites of tissue injury. Herein, we report a previously uncharacterized crystalline form of ADO (rcADO) in which 6.7 mg/mL of the nucleoside is suspended in water. Importantly, the crystallinity is not diminished in a protein-rich environment, as evidenced by resuspending the crystals in albumin (15% w/v). To the best of our knowledge, this is the first report of crystalline ADO generated using a facile and organic solvent-free method aimed at localized drug delivery. The crystalline suspension may be suitable for developing ADO into injectable formulations for attaining high concentrations of the endogenous nucleoside in inflammatory locales.
Topics: Adenosine; Adenosine Kinase; Anti-Inflammatory Agents; Enzyme Inhibitors; Humans; Nucleosides
PubMed: 36001090
DOI: 10.1021/acs.molpharmaceut.2c00527 -
Plant Biotechnology Journal Jul 2019N6-methyladenosine (m6A) RNA methylation, one of the most pivotal internal modifications of RNA, is a conserved post-transcriptional mechanism to enrich and regulate... (Review)
Review
N6-methyladenosine (m6A) RNA methylation, one of the most pivotal internal modifications of RNA, is a conserved post-transcriptional mechanism to enrich and regulate genetic information in eukaryotes. The scope and function of this modification in plants has been an intense focus of study, especially in model plant systems. The characterization of plant m6A writers, erasers and readers, as well as the elucidation of their functions, is currently one of the most fascinating hotspots in plant biology research. The functional analysis of m6A in plants will be booming in the foreseeable future, which could contribute to crop genetic improvement through epitranscriptome manipulation. In this review, we systematically analysed and summarized recent advances in the understanding of the structure and composition of plant m6A regulatory machinery, and the biological functions of m6A in plant growth, development and stress response. Finally, our analysis showed that the evolutionary relationships between m6A modification components were highly conserved across the plant kingdom.
Topics: Adenosine; Evolution, Molecular; Methylation; Plants; RNA, Plant
PubMed: 31070865
DOI: 10.1111/pbi.13149