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Epilepsy Research Aug 2009Deficiencies in the brain's own adenosine-based seizure control system contribute to seizure generation. Consequently, reconstitution of adenosinergic neuromodulation... (Review)
Review
Deficiencies in the brain's own adenosine-based seizure control system contribute to seizure generation. Consequently, reconstitution of adenosinergic neuromodulation constitutes a rational approach for seizure control. This review will critically discuss focal adenosine augmentation strategies and their potential for antiepileptic and disease modifying therapy. Due to systemic side effects of adenosine focal adenosine augmentation--ideally targeted to an epileptic focus--becomes a therapeutic necessity. This has experimentally been achieved in kindled seizure models as well as in post-status epilepticus models of spontaneous recurrent seizures using three different therapeutic strategies that will be discussed here: (i) polymer-based brain implants that were loaded with adenosine; (ii) brain implants comprised of cells engineered to release adenosine and embedded in a cell-encapsulation device; (iii) direct transplantation of stem cells engineered to release adenosine. To meet the therapeutic goal of focal adenosine augmentation, genetic disruption of the adenosine metabolizing enzyme adenosine kinase (ADK) in rodent and human cells was used as a molecular strategy to induce adenosine release from cellular brain implants, which demonstrated antiepileptic and neuroprotective properties. New developments and therapeutic challenges in using AATs for epilepsy therapy will critically be evaluated.
Topics: Adenosine; Animals; Anticonvulsants; Cell- and Tissue-Based Therapy; Drug Delivery Systems; Epilepsy; Genetic Therapy; Humans; Mice; Stem Cell Transplantation
PubMed: 19428218
DOI: 10.1016/j.eplepsyres.2009.03.019 -
RNA Biology Mar 2017Cellular RNAs with diverse chemical modifications have been observed, and N-methyladenosine (mA) is one of the most abundant internal modifications found on mRNA and... (Review)
Review
Cellular RNAs with diverse chemical modifications have been observed, and N-methyladenosine (mA) is one of the most abundant internal modifications found on mRNA and non-coding RNAs, playing a vital role in diverse biologic processes. In humans, mA modification is catalyzed by the METTL3-METTL14 methyltransferase complex, which is regulated by WTAP and another factor. Three groups have recently and independently reported the structure of this complex with or without cofactors. Here, we focus on the detailed mechanism of the mA methyltransferase complex and the properties of each subunit. METTL3 is predominantly catalytic, with a function reminiscent of N-adenine DNA methyltransferase systems, whereas METTL14 appears to be a pseudomethyltransferase that stabilizes METTL3 and contributes to target RNA recognition. The structural and biochemical characterization of the METTL3-METTL14 complex is a major step toward understanding the function of mA modification and developing mA-related therapies.
Topics: Adenosine; Catalysis; Cell Cycle Proteins; Epigenesis, Genetic; Humans; Methylation; Methyltransferases; Nuclear Proteins; RNA; RNA Splicing Factors; Structure-Activity Relationship
PubMed: 28121234
DOI: 10.1080/15476286.2017.1282025 -
PLoS Pathogens Mar 2017
Review
Topics: Adenosine; Animals; Humans; RNA Processing, Post-Transcriptional; RNA, Viral; Virus Diseases
PubMed: 28278189
DOI: 10.1371/journal.ppat.1006188 -
Molecular Therapy : the Journal of the... May 2021The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched... (Review)
Review
The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. The TME can be described in terms of hypoxia, metabolic dysregulation, immune escape, and chronic inflammation. RNA methylation, an epigenetic modification, has recently been found to have a pivotal role in shaping the TME. The N-methylation of adenosine (mA) modification is the most common type of RNA methylation that occurs in the N-position of adenosine, which is the primary internal modification of eukaryotic mRNA. Compelling evidence has demonstrated that mA regulates transcriptional and protein expression through splicing, translation, degradation, and export, thereby mediating the biological processes of cancer cells and/or stromal cells and characterizing the TME. The TME also has a crucial role in the complicated regulatory network of mA modifications and, subsequently, influences tumor initiation, progression, and therapy responses. In this review, we describe the features of the TME and how the mA modification modulates and interacts with it. We also focus on various factors and pathways involved in mA methylation. Finally, we discuss potential therapeutic strategies and prognostic biomarkers with respect to the TME and mA modification.
Topics: Adenosine; Biomarkers, Tumor; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Tumor Microenvironment
PubMed: 33839323
DOI: 10.1016/j.ymthe.2021.04.009 -
Journal of Neurochemistry Oct 2018Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the... (Meta-Analysis)
Meta-Analysis
Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies. We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and adenosine monophosphate in microdialysates. We performed a meta-regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area and anaesthesia versus freely behaving, on the adenosine concentration. Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline adenosine monophosphate concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p ≤ 0.001), but not of probe membrane surface, species, or brain area (p ≥ 0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, for example, post-surgical recovery time, could not be analysed because of a lack of reported data. This study shows that meta-regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve.
Topics: Adenosine; Adenosine Monophosphate; Animals; Brain Chemistry; Humans; Microdialysis
PubMed: 30025168
DOI: 10.1111/jnc.14552 -
International Journal of Molecular... Jun 2019Among a number of mRNA modifications, N6‑methyladenosine (m6A) modification is the most common type in eukaryotes and nuclear‑replicating viruses. m6A has a... (Review)
Review
Among a number of mRNA modifications, N6‑methyladenosine (m6A) modification is the most common type in eukaryotes and nuclear‑replicating viruses. m6A has a significant role in numerous cancer types, including leukemia, brain tumors, liver cancer, breast cancer and lung cancer. Although m6A methyltransferases are essential during RNA modifications, the biological functions of m6A and the underlying mechanisms remain to be fully elucidated, predominantly due to the limited detection methods for m6A. In the present review, the currently available m6A detection methods and the respective scope of their applications are presented to facilitate the further investigation of the roles of m6A in biological process.
Topics: Adenosine; Animals; Biosensing Techniques; Blotting, Northern; Chromatography, High Pressure Liquid; Electrochemical Techniques; Humans; Immunoblotting; Immunoprecipitation; Methylation; Neoplasms; RNA; Sequence Analysis, RNA
PubMed: 31017262
DOI: 10.3892/ijmm.2019.4169 -
International Journal of Molecular... May 2022Epitranscriptomic modifications can affect every aspect of RNA biology, including stability, transport, splicing, and translation, participate in global intracellular... (Review)
Review
Epitranscriptomic modifications can affect every aspect of RNA biology, including stability, transport, splicing, and translation, participate in global intracellular mRNA metabolism, and regulate gene expression and a variety of biological processes. N6-methyladenosine (m6A) as the most prevalent modification contributes to normal embryonic brain development and memory formation. However, changes in the level of m6A modification and the expression of its related proteins cause abnormal nervous system functions, including brain tissue development retardation, axon regeneration disorders, memory changes, and neural stem cell renewal and differentiation disorders. Recent studies have revealed that m6A modification and its related proteins play key roles in the development of various neuropsychiatric disorders, such as depression, Alzheimer's disease, and Parkinson's disease. In this review, we summarize the research progresses of the m6A modification regulation mechanism in the central nervous system and discuss the effects of gene expression regulation mediated by m6A modification on the biological functions of the neuropsychiatric disorders, thereby providing some insight into new research targets and treatment directions for human diseases.
Topics: Adenosine; Axons; Humans; Nerve Regeneration; RNA
PubMed: 35682599
DOI: 10.3390/ijms23115922 -
American Journal of Physiology. Cell... Nov 2022Adenosine deaminases acting on RNAs convert adenosines (A) to inosines (I) in structured or double-stranded RNAs. In mammals, this process is widespread. In the human... (Review)
Review
Adenosine deaminases acting on RNAs convert adenosines (A) to inosines (I) in structured or double-stranded RNAs. In mammals, this process is widespread. In the human transcriptome, more than a million different sites have been identified that undergo an ADAR-mediated A-to-I exchange Inosines have an altered base pairing potential due to the missing amino group when compared to the original adenosine. Consequently, inosines prefer to base pair with cytosines but can also base pair with uracil or adenine. This altered base pairing potential not only affects protein decoding at the ribosome but also influences the folding of RNAs and the proteins that can associate with it. Consequently, an A to I exchange can also affect RNA processing and turnover (Nishikura K. 79: 321-349, 2010; Brümmer A, Yang Y, Chan TW, Xiao X. 8: 1255, 2017). All of these events will interfere with gene expression and therefore, can also affect cellular and organismic physiology. As double-stranded RNAs are a hallmark of viral pathogens RNA-editing not only affects RNA-processing, coding, and gene expression but also controls the antiviral response to double-stranded RNAs. Most interestingly, recent advances in our understanding of ADAR enzymes reveal multiple layers of regulation by which ADARs can control antiviral programs. In this review, we focus on the recoding of mRNAs where the altered translation products lead to physiological changes. We also address recent advances in our understanding of the multiple layers of antiviral responses and innate immune modulations mediated by ADAR1.
Topics: Animals; Humans; RNA Editing; RNA-Binding Proteins; Inosine; RNA, Double-Stranded; Adenosine; RNA, Viral; Mammals; Antiviral Agents
PubMed: 36036447
DOI: 10.1152/ajpcell.00191.2022 -
Molecular Cell Jan 2018N-methyladenosine (mA) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two...
N-methyladenosine (mA) and adenosine-to-inosine (A-to-I) editing are two of the most abundant RNA modifications, both at adenosines. Yet, the interaction of these two types of adenosine modifications is largely unknown. Here we show a global A-to-I difference between mA-positive and mA-negative RNA populations. Both the presence and extent of A-to-I sites in mA-negative RNA transcripts suggest a negative correlation between mA and A-to-I. Suppression of mA-catalyzing enzymes results in global A-to-I RNA editing changes. Further depletion of mA modification increases the association of mA-depleted transcripts with adenosine deaminase acting on RNA (ADAR) enzymes, resulting in upregulated A-to-I editing on the same mA-depleted transcripts. Collectively, the effect of mA on A-to-I suggests a previously underappreciated interplay between two distinct and abundant RNA modifications, highlighting a complex epitranscriptomic landscape.
Topics: Adenosine; Adenosine Deaminase; Cell Line, Tumor; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Inosine; Methyltransferases; RNA; RNA Editing; RNA-Binding Proteins
PubMed: 29304330
DOI: 10.1016/j.molcel.2017.12.006 -
Annual Review of Medicine Jan 2021Cancer immunotherapy has revolutionized the way that we think about treating cancer. Although checkpoint blockade therapy, including anti-PD-1/PD-L1 and anti-CTLA-4, has... (Review)
Review
Cancer immunotherapy has revolutionized the way that we think about treating cancer. Although checkpoint blockade therapy, including anti-PD-1/PD-L1 and anti-CTLA-4, has shown remarkable success, the responses are limited to only a subset of patients. This discrepancy highlights the many overlapping avenues for immune evasion or suppression that can be employed by a tumor. One such mechanism of immunosuppression is adenosinergic signaling within the tumor microenvironment. We provide an overview of the current status of clinical trials targeting the adenosine pathway, including CD73, CD39, and adenosine receptors. Additionally, we highlight several avenues that may be explored to further potentiate responses in the clinic by combining adenosine-targeting agents to target multiple arms of the pathway or by using conventional immunotherapy agents.
Topics: Adenosine; Humans; Immunotherapy; Neoplasms
PubMed: 32903139
DOI: 10.1146/annurev-med-060619-023155