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Emerging Perspectives of RNA -methyladenosine (mA) Modification on Immunity and Autoimmune Diseases.Frontiers in Immunology 2021-methyladenosine (mA) modification, the addition of a methylation decoration at the position of N6 of adenosine, is one of the most prevalent modifications among the... (Review)
Review
-methyladenosine (mA) modification, the addition of a methylation decoration at the position of N6 of adenosine, is one of the most prevalent modifications among the over 100 known chemical modifications of RNA. Numerous studies have recently characterized that RNA mA modification functions as a critical post-transcriptional regulator of gene expression through modulating various aspects of RNA metabolism. In this review, we will illustrate the current perspectives on the biological process of mA methylation. Then we will further summarize the vital modulatory effects of mA modification on immunity, viral infection, and autoinflammatory disorders. Recent studies suggest that mA decoration plays an important role in immunity, viral infection, and autoimmune diseases, thereby providing promising biomarkers and therapeutic targets for viral infection and autoimmune disorders.
Topics: Adaptive Immunity; Adenine; Autoimmune Diseases; Dendritic Cells; Humans; Immunity, Innate; Methylation; RNA Processing, Post-Transcriptional; Virus Diseases
PubMed: 33746967
DOI: 10.3389/fimmu.2021.630358 -
Annals of Internal Medicine Jul 2020
Topics: Adenine; Alanine; HIV Infections; Humans; Pre-Exposure Prophylaxis; Tenofovir
PubMed: 32628873
DOI: 10.7326/L20-0301 -
British Journal of Haematology May 2020This phase 2 study evaluated the activity and safety of ibrutinib, a Bruton's tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular...
This phase 2 study evaluated the activity and safety of ibrutinib, a Bruton's tyrosine kinase inhibitor, plus rituximab in adults with previously untreated follicular lymphoma. Patients received once-daily ibrutinib 560 mg continuously plus once-weekly rituximab 375 mg/m for 4 weeks beginning Week 1 (Arm 1, n = 60) or Week 9 (following an 8-week ibrutinib lead-in) to explore biomarkers (Arm 2, n = 20). The primary endpoint was the best overall response rate (ORR). The median age was 58 years; most had an Eastern Cooperative Oncology Group Performance Status of 0 (74%) and Stage III/IV disease (84%). At a median study follow-up of 34 months in Arm 1 and 29 months in Arm 2, ORRs were 85% [95% confidence interval (CI) 73-93] and 75% (95% CI 51-91), respectively, with complete responses in 40% and 50%. The median duration of response was not reached in either arm; 30-month progression-free and overall survival rates were 67% and 97% (Arm 1) and 65% and 100% (Arm 2). The most common adverse events were fatigue, diarrhoea and nausea. Higher grade (Grade 3/4) haematological, haemorrhagic and cardiac events occurred infrequently. Ibrutinib plus rituximab was active and tolerable in first-line follicular lymphoma.
Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lymphoma, Follicular; Male; Middle Aged; Piperidines; Rituximab
PubMed: 32180219
DOI: 10.1111/bjh.16424 -
International Journal of Molecular... Jun 2020Translation initiation plays a critical role in the regulation of gene expression for development and disease conditions. During the processes of development and... (Review)
Review
Translation initiation plays a critical role in the regulation of gene expression for development and disease conditions. During the processes of development and disease, cells select specific mRNAs to be translated by controlling the use of diverse translation initiation mechanisms. Cells often switch translation initiation from a cap-dependent to a cap-independent mechanism during epithelial-to-mesenchymal transition (EMT), a process that plays an important role in both development and disease. EMT is involved in tumor metastasis because it leads to cancer cell migration and invasion, and is also associated with chemoresistance. In this review we will provide an overview of both the internal ribosome entry site (IRES)-dependent and N-methyladenosine (mA)-mediated translation initiation mechanisms and discuss how cap-independent translation enables cells from primary epithelial tumors to achieve a motile mesenchymal-like phenotype, which in turn drives tumor metastasis.
Topics: Adenine; Animals; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Models, Biological; Neoplasm Metastasis; Neoplasms; Peptide Chain Initiation, Translational; RNA Caps
PubMed: 32517298
DOI: 10.3390/ijms21114075 -
Journal of Bacteriology Nov 1979The methylations of adenine in the sequence -GATC- and of the second cytosine in the sequence - [Formula: see text] - were studied in Salmonella typhimurium and in...
The methylations of adenine in the sequence -GATC- and of the second cytosine in the sequence - [Formula: see text] - were studied in Salmonella typhimurium and in Salmonella typhi. The study was carried out by using endonucleases which restrict the plasmid pBR322 by cleavage at the sequences -GATC- (DpnI and MboI) and - [Formula: see text] - (EcoRII). The restriction patterns obtained for this plasmid isolated from transformed S. typhimurium and S. typhi were compared with those of pBR322 isolated from Escherichia coli K-12. In E. coli K-12, adenines at the sequence -GATC- and the second cytosines at - [Formula: see text] - are met hylated by enzymes coded for by the genes dam and dem, respectively. From comparison of the restriction patterns obtained, it is concluded that S. typhimurium and S. typhi contain genes responsible for deoxyribonucleic acid methylation equivalent to E. coli K-12 genes dam and dcm.
Topics: Adenine; Base Sequence; Cytosine; DNA Restriction Enzymes; DNA, Bacterial; Genes; Methylation; Methyltransferases; Salmonella; Salmonella typhi; Salmonella typhimurium
PubMed: 387741
DOI: 10.1128/jb.140.2.574-579.1979 -
Current HIV/AIDS Reports Dec 2011Thirty years into the global HIV epidemic, the need for effective prevention strategies remains critical. In July 2010, the CAPRISA-004 study demonstrated that topical... (Review)
Review
Thirty years into the global HIV epidemic, the need for effective prevention strategies remains critical. In July 2010, the CAPRISA-004 study demonstrated that topical administration of a gel containing the antiretroviral agent tenofovir decreased the risk of HIV acquisition among at-risk heterosexual women. Subsequently, the iPrEx study reported that prophylactic use of a daily oral tablet containing tenofovir and emtricitabine reduced the risk of HIV acquisition among high-risk men who have sex with men. These studies illustrate the promise of antiretroviral pre-exposure chemoprophylaxis (PrEP) as an innovative prevention approach. This review discusses the rationale for chemoprophylaxis, compares the advantages of topical and oral delivery, outlines recommended safety monitoring, offers principles to guide selection of antiretroviral agents, and highlights potential unintended consequences of PrEP use. If future studies confirm the safety and efficacy of tenofovir gel and oral PrEP, successful implementation of these strategies could significantly impact the HIV epidemic.
Topics: Adenine; Anti-HIV Agents; Female; Gels; HIV Infections; Humans; Male; Organophosphonates; Reverse Transcriptase Inhibitors; Tenofovir
PubMed: 22002729
DOI: 10.1007/s11904-011-0094-4 -
Current Topics in Medicinal Chemistry 2004Selective agonists for A(3) adenosine receptors (ARs) could potentially be therapeutic agents for a variety of disorders, including brain and heart ischemic conditions,... (Review)
Review
Selective agonists for A(3) adenosine receptors (ARs) could potentially be therapeutic agents for a variety of disorders, including brain and heart ischemic conditions, while partial agonists may have advantages over full agonists as a result of an increased selectivity of action. A number of structural determinants for A(3)AR activation have recently been identified, including the N(6)-benzyl group, methanocarba substitution of ribose, 2-chloro and 2-fluoro substituents, various 2'- and 3'-substitutions and 4'-thio substitution of oxygen. The 2-chloro substitution of CPA and R-PIA led to A(3) antagonism (CCPA) and partial agonism (Cl-R-PIA). 2-Chloroadenosine was a full agonist, while 2-fluoroadenosine was a partial agonist. Both 2'- and 3'- substitutions have a pronounced effect on its efficacy, although the effect of 2'-substitution was more dramatic. The 4-thio substitution of oxygen may also diminish efficacy, depending on other substitutions. Both N(6)-methyl and N(6)-benzyl groups may contribute to the A(3) affinity and selectivity; however, an N(6)-benzyl group but not an N(6)-methyl group diminishes A(3)AR efficacy. N(6)-benzyl substituted adenosine derivatives have similar potency for human and rat A(3)ARs while N(6)-methyl substitution was preferable for the human A(3)AR. The combination of 2-chloro and N(6)-benzyl substitutions appeared to reduce efficacy further than either modification alone. The A(2A)AR agonist DPMA was shown to be an antagonist for the human A(3)AR. Thus, the efficacy of adenosine derivatives at the A(3)AR appears to be more sensitive to small structural changes than at other subtypes. Potent and selective partial agonists for the A(3)AR could be identified by screening known adenosine derivatives and by modifying adenosine and the adenosine derivatives.
Topics: Adenine; Adenosine; Adenosine A3 Receptor Agonists; Animals; Humans; Ligands; Receptor, Adenosine A3; Ribose; Structure-Activity Relationship; Xanthine
PubMed: 15078216
DOI: 10.2174/1568026043450989 -
Antiviral Chemistry & Chemotherapy Dec 2014Since its approval for clinical use in 2001, tenofovir (TFV) has become one of the most frequently prescribed nucleotide analogues used in combination with other... (Review)
Review
Since its approval for clinical use in 2001, tenofovir (TFV) has become one of the most frequently prescribed nucleotide analogues used in combination with other antiretroviral agents against HIV-1 infection. Although reverse transcriptase inhibitors (RTIs) including TFV have been shown to be highly potent with reasonable safety profiles in the clinic, drug resistance hinders the effectiveness of current therapies and even causes treatment failure. Therefore, understanding the resistance mechanisms of RT and exploring the potential antiviral synergy between the different RTIs in combination therapies against the resistance mechanisms would greatly improve the long-term efficacy of existing and future regimens. We have studied the pyrophosphorolytic removal of TFV, a major resistance mechanism that RT utilizes, from two different viral sequences and observed interesting outcomes associated with the sequence context. Furthermore, addition of efavirenz, a non-nucleoside RTI, inhibits this removal process confirming the synergistic antiviral effects. This article highlights our recently published work on the viral sequence context contributing to the study of anti-HIV drug resistance in conjunction with the benefits of combining various RTIs that may have been neglected previously.
Topics: Adenine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Resistance, Viral; Drug Synergism; HIV-1; Organophosphonates; Tenofovir
PubMed: 23744599
DOI: 10.3851/IMP2628 -
Chimia Dec 2018Three kinds of amphiphilic polypeptides, X-poly(sarcosine)--(-Leu-Aib) (X = adenine, thymine, glycolic acid), were synthesized and self-assembled in a tris buffer to...
Three kinds of amphiphilic polypeptides, X-poly(sarcosine)--(-Leu-Aib) (X = adenine, thymine, glycolic acid), were synthesized and self-assembled in a tris buffer to take on nanotube morphology. The nanotubes were joined together to extend the nanotube length with the addition of trifluoroethanol and heat treatment at 50 °C for 24 h. The length extension rate decreased in the order of adenine > glycolic acid > thymine depending on the -terminal chromophores. Adenine-adenine interactions between the nanotubes were found to be more prevalent upon joining the nanotubes than adenine-thymine interactions. Further, adenines on the nanotube surface could chelate with Cu(ii) to thermodynamically stabilize the nanotube membrane. AFM imaging in liquid environment revealed that the membrane elasticity of the adenine nanotube was as high as ca. 1 MPa, which is considered to be strengthened as a result of the adenine-adenine interactions.
Topics: Adenine; Copper; Molecular Structure; Nanotubes; Nucleotides; Peptides
PubMed: 30648948
DOI: 10.2533/chimia.2018.842 -
Cell May 2015DNA N6-methyladenine (6mA) protects against restriction enzymes in bacteria. However, isolated reports have suggested additional activities and its presence in other... (Review)
Review
DNA N6-methyladenine (6mA) protects against restriction enzymes in bacteria. However, isolated reports have suggested additional activities and its presence in other organisms, such as unicellular eukaryotes. New data now find that 6mA may have a gene regulatory function in green alga, worm, and fly, suggesting m6A as a potential "epigenetic" mark.
Topics: Adenine; Animals; Bacteria; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Sequence Analysis, DNA
PubMed: 25936836
DOI: 10.1016/j.cell.2015.04.021