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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 -
Cell Research Mar 2024Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a...
Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2-3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.
Topics: Humans; Child; Animals; Mice; Sleep Initiation and Maintenance Disorders; Sleep; Signal Transduction; Adenosine; Astrocytes
PubMed: 38332199
DOI: 10.1038/s41422-023-00920-1 -
Accounts of Chemical Research Sep 2023The term RNA editing refers to any structural change in an RNA molecule ( insertion, deletion, or base modification) that changes its coding properties and is not a...
The term RNA editing refers to any structural change in an RNA molecule ( insertion, deletion, or base modification) that changes its coding properties and is not a result of splicing. An important class of enzymes involved in RNA editing is the ADAR family (adenosine deaminases acting on RNA), which facilitate the deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). Inosines are decoded as guanosines (G) in most cellular processes; hence, A-to-I editing can be considered an A-to-G substitution. Among the RNA editing enzymes, ADARs are of particular interest because a large portion of RNA editing events are due to A-to-I editing by the two catalytically active human ADARs (ADAR1 and ADAR2). ADARs have diverse roles in RNA processing, gene expression regulation, and innate immunity; and mutations in the ADAR genes and dysregulated ADAR activity have been associated with cancer, autoimmune diseases, and neurological disorders. A-to-I editing is also currently being explored for correcting disease-causing mutations in the RNA, where therapeutic guide oligonucleotides complementary to the target transcript are used to form a dsRNA substrate and site-specifically direct ADAR editing. Knowledge of the mechanism of ADAR-catalyzed reaction and the origin of its substrate selectivity will allow understanding of ADAR’s role in disease biology and expedite the process of developing ADAR-targeted therapeutics. Chemically modified oligonucleotides provide a versatile platform for modulating the activity and interrogating the structure, function, and selectivity of nucleic acid binding or modifying proteins. In this account, we provide an overview of oligonucleotide modifications that have allowed us to gain deeper understanding of ADAR’s molecular mechanisms, which we utilize in the rational design and optimization of ADAR activity modulators. First, we describe the use of the nucleoside analog 8-azanebularine (8-azaN) to generate high-affinity ADAR-RNA complexes for biochemical and biophysical studies with ADARs, with particular emphasis on X-ray crystallography. We then discuss key observations derived from the crystal structures of ADAR bound to 8-azaN-modified RNA duplexes and describe how these findings provided insight into ADAR editing optimization by introducing nucleoside modifications at various positions in synthetic guide strands. We also present the informed design of 8-azaN-modified RNA duplexes that selectively bind and inhibit ADAR1 but not the closely-related ADAR2 enzyme. Finally, we conclude with some open questions on ADAR structure and substrate recognition and share our current endeavors in the development of ADAR guide oligonucleotides and inhibitors.
Topics: Humans; RNA; Adenosine Deaminase; Hydrolases; Adenosine; Autoimmune Diseases
PubMed: 37665999
DOI: 10.1021/acs.accounts.3c00390 -
Clinical Medicine (London, England) May 2024
Topics: Humans; Adenosine; Tachycardia, Ventricular; Electrocardiography; Anti-Arrhythmia Agents; Male
PubMed: 38710329
DOI: 10.1016/j.clinme.2024.100216 -
Nutrients Dec 2023, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the... (Review)
Review
, also known as "zombie fungus", is a non-poisonous mushroom that parasitizes insects for growth and development by manipulating the host system in a way that makes the victim behave like a "zombie". These species produce promising bioactive metabolites, like adenosine, β-glucans, cordycepin, and ergosterol. has been used in traditional medicine due to its immense health benefits, as it boosts stamina, appetite, immunity, longevity, libido, memory, and sleep. Neuronal loss is the typical feature of neurodegenerative diseases (NDs) (Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS)) and neurotrauma. Both these conditions share common pathophysiological features, like oxidative stress, neuroinflammation, and glutamatergic excitotoxicity. bioactives (adenosine, N-(2-hydroxyethyl)-adenosine, ergosta-7, 9 (11), 22-trien-3β-ol, active peptides, and polysaccharides) exert potential antioxidant, anti-inflammatory, and anti-apoptotic activities and display beneficial effects in the management and/or treatment of neurodegenerative disorders in vitro and in vivo. Although a considerable list of compounds is available from , only a few have been evaluated for their neuroprotective potential and still lack information for clinical trials. In this review, the neuroprotective mechanisms and safety profile of extracts/bioactives have been discussed, which might be helpful in the identification of novel potential therapeutic entities in the future.
Topics: Neuroprotective Agents; Cordyceps; Agaricales; Neuroprotection; Adenosine
PubMed: 38201932
DOI: 10.3390/nu16010102 -
Cellular & Molecular Biology Letters Dec 2023Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous... (Review)
Review
Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous cancer cell population. There is a significantly high mortality rate in GBM patients. Molecular biomarkers related to GBM malignancy may have prognostic values in predicting survival outcomes and therapeutic responses, especially in patients with high-grade gliomas. In particular, N6-methyladenine (m6A) mRNA modification is the most abundant form of post-transcriptional RNA modification in mammals and is involved in regulating mRNA translation and degradation. Cumulative findings indicate that m6A methylation plays a crucial part in neurogenesis and glioma pathogenesis. In this review, we summarize recent advances regarding the functional significance of m6A modification and its regulatory factors in glioma occurrence and progression. Significant advancement of m6A methylation-associated regulators as potential therapeutic targets is also discussed.
Topics: Animals; Humans; Glioma; Central Nervous System; Brain Neoplasms; Adenosine; Methylation; Mammals
PubMed: 38072944
DOI: 10.1186/s11658-023-00514-0 -
Journal of the American Heart... Jun 2024Ticagrelor is a platelet P2Y receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic... (Review)
Review
Ticagrelor is a platelet P2Y receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic stroke or high-risk transient ischemic attack. Clinical trials have evaluated the efficacy and safety of ticagrelor on ischemic and bleeding outcomes for different indications and with varying treatment approaches. As a result, there is a large body of clinical evidence demonstrating different degrees of net clinical benefit compared with other platelet inhibitor drugs based on indication, patient characteristics, clinical presentation, treatment duration, and other factors. We provide a review of the major trials of ticagrelor in the context of other randomized trials of clopidogrel and prasugrel to organize the volume of available information, elevate corroborating and conflicting data, and identify potential gaps as areas for further exploration of optimal antiplatelet treatment.
Topics: Humans; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Randomized Controlled Trials as Topic; Treatment Outcome; Coronary Artery Disease; Hemorrhage
PubMed: 38804216
DOI: 10.1161/JAHA.123.031606 -
Accounts of Chemical Research Nov 2023The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are...
The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are essential for many biological functions including nervous system function, hematopoiesis, and innate immunity. Initially it was assumed that the wide-ranging biological roles of ADARs are due to inosine in mRNA being read as guanosine by the translational machinery, allowing incomplete RNA editing in a target codon to generate two different proteins from the same primary transcript. In humans, there are approximately seventy-six positions that undergo site-specific editing in tissues at greater than 20% efficiency that result in recoding. Many of these transcripts are expressed in the central nervous system (CNS) and edited by ADAR2. Exploiting mouse genetic models revealed that transgenic mice lacking the gene encoding Adar2 die within 3 weeks of birth. Therefore, the role of ADAR2 in generating protein diversity in the nervous system is clear, but why is ADAR RNA editing activity essential in other biological processes, particularly editing mainly involving ADAR1? ADAR1 edits human transcripts having embedded Alu element inverted repeats (AluIRs), but the link from this activity to innate immunity activation was elusive. Mice lacking the gene encoding Adar1 are embryonically lethal, and a major breakthrough was the discovery that the role of Adar1 in innate immunity is due to its ability to edit such repetitive element inverted repeats which have the ability to form dsRNA in transcripts. The presence of inosine prevents activation of the dsRNA sensor melanoma differentiation-associated protein 5 (Mda5). Thus, inosine helps the cell discriminate self from non-self RNA, acting like a barcode on mRNA. As innate immunity is key to many different biological processes, the basis for this widespread biological role of the ADAR1 enzyme became evident.Our group has been studying ADARs from the outset of research on these enzymes. In this Account, we give a historical perspective, moving from the initial purification of ADAR1 and ADAR2 and cloning of their encoding genes up to the current research focus in the field and what questions still remain to be addressed. We discuss the characterizations of the proteins, their localizations, posttranslational modifications, and dimerization, and how all of these affect their biological activities. Another aspect we explore is the use of mouse and genetic models to study ADAR functions and how these were crucial in determining the biological functions of the ADAR proteins. Finally, we describe the severe consequences of rare mutations found in the human genes encoding ADAR1 and ADAR2.
Topics: Animals; Mice; Humans; Adenosine Deaminase; RNA, Double-Stranded; Immunity, Innate; RNA, Messenger; Inosine
PubMed: 37906879
DOI: 10.1021/acs.accounts.3c00433 -
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... Oct 2023This review focuses on DNA damage caused by a variety of oxidizing, alkylating, and nitrating species, and it may play an important role in the pathophysiology of... (Review)
Review
This review focuses on DNA damage caused by a variety of oxidizing, alkylating, and nitrating species, and it may play an important role in the pathophysiology of inflammation, cancer, and degenerative diseases. Infection and chronic inflammation have been recognized as important factors in carcinogenesis. Under inflammatory conditions, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from inflammatory and epithelial cells, and result in the formation of oxidative and nitrative DNA lesions, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine. Cellular DNA is continuously exposed to a very high level of genotoxic stress caused by physical, chemical, and biological agents, with an estimated 10,000 modifications occurring every hour in the genetic material of each of our cells. This review highlights recent developments in the chemical biology and toxicology of 2'-deoxyribose oxidation products in DNA.
Topics: Humans; Neoplasms; Inflammation; DNA Damage; Oxidation-Reduction; Oxidative Stress; DNA; Deoxyguanosine
PubMed: 37894920
DOI: 10.3390/ijms242015240