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Molecules (Basel, Switzerland) Mar 2022Reactive oxygen species (ROS) are continuously produced in living cells due to metabolic and biochemical reactions and due to exposure to physical, chemical and... (Review)
Review
Reactive oxygen species (ROS) are continuously produced in living cells due to metabolic and biochemical reactions and due to exposure to physical, chemical and biological agents. Excessive ROS cause oxidative stress and lead to oxidative DNA damage. Within ROS-mediated DNA lesions, 8-oxoguanine (8-oxoG) and its nucleotide 8-oxo-2'-deoxyguanosine (8-oxodG)-the guanine and deoxyguanosine oxidation products, respectively, are regarded as the most significant biomarkers for oxidative DNA damage. The quantification of 8-oxoG and 8-oxodG in urine, blood, tissue and saliva is essential, being employed to determine the overall effects of oxidative stress and to assess the risk, diagnose, and evaluate the treatment of autoimmune, inflammatory, neurodegenerative and cardiovascular diseases, diabetes, cancer and other age-related diseases. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) is largely employed for 8-oxoG and 8-oxodG determination in biological samples due to its high selectivity and sensitivity, down to the femtomolar range. This review seeks to provide an exhaustive analysis of the most recent reports on the HPLC-ECD determination of 8-oxoG and 8-oxodG in cellular DNA and body fluids, which is relevant for health research.
Topics: 8-Hydroxy-2'-Deoxyguanosine
PubMed: 35268721
DOI: 10.3390/molecules27051620 -
Cell Proliferation Oct 2022Musculoskeletal disorder (MSD) are a class of inflammatory and degener-ative diseases, but the precise molecular mechanisms are still poorly understood. Noncoding RNA... (Review)
Review
BACKGROUND
Musculoskeletal disorder (MSD) are a class of inflammatory and degener-ative diseases, but the precise molecular mechanisms are still poorly understood. Noncoding RNA (ncRNA) N6-methyladenosine (m6A) modification plays an essential role in the pathophysiological process of MSD. This review summarized the interaction between m6A RNA methylation and ncRNAs in the molecular regulatory mechanism of MSD. It provides a new perspective for the pathophysiological mechanism and ncRNA m6A targeted therapy of MSD.
METHODS
A comprehensive search of databases was conducted with musculoskeletal disorders, noncoding RNA, N6-methyladenosine, intervertebral disc degeneration, osteoporosis, osteosarcoma, osteoarthritis, skeletal muscle, bone, and cartilage as the key-words. Then, summarized all the relevant articles.
RESULTS
Intervertebral disc degeneration (IDD), osteoporosis (OP), osteosarcoma (OS), and osteoarthritis (OA) are common MSDs that affect muscle, bone, cartilage, and joint, leading to limited movement, pain, and disability. However, the precise pathogenesis remains unclear, and no effective treatment and drug is available at present. Numerous studies confirmed that the mutual regulation between m6A and ncRNAs (i.e., microRNAs, long ncRNAs, and circular RNAs) was found in MSD, m6A modification can regulate ncRNAs, and ncRNAs can also target m6A regulators. ncRNA m6A modification plays an essential role in the pathophysiological process of MSDs by regulating the homeostasis of skeletal muscle, bone, and cartilage.
CONCLUSION
m6A interacts with ncRNAs to regulate multiple biological processes and plays important roles in IDD, OP, OS, and OA. These studies provide new insights into the pathophysiological mechanism of MSD and targeting m6A-modified ncRNAs may be a promising therapy approach.
Topics: Adenosine; Bone Neoplasms; Humans; Intervertebral Disc Degeneration; Methylation; MicroRNAs; Osteoarthritis; Osteoporosis; Osteosarcoma; RNA, Circular; RNA, Long Noncoding; RNA, Untranslated
PubMed: 35735243
DOI: 10.1111/cpr.13294 -
Biological & Pharmaceutical Bulletin 2023Cancer treatment with natural killer (NK) cell immunotherapy is promising. NK cells can recognize and kill cancer cells without sensitization, making them a potential...
Cancer treatment with natural killer (NK) cell immunotherapy is promising. NK cells can recognize and kill cancer cells without sensitization, making them a potential cancer treatment alternative. To improve clinical efficacy and safety, more research is needed. Enhancing NK cell function improves therapeutic efficacy. Due to its potent apoptosis induction, Cordycepin, a bioactive compound from Cordyceps spp., inhibits cancer cell growth. Cordycepin has immunoregulatory properties, making it a promising candidate for combination therapy with NK cell-based immunotherapy. Cordycepin may enhance NK cell function and have clinical applications, but more research is needed. In this study, cordycepin treatment of NK-92 MI cells increased THP-1 and U-251 cell cytotoxicity. Cordycepin also significantly increased the mRNA expression of cytokine-encoding genes, including tumour necrosis factor (TNF), interferon gamma (IFNG), and interleukin 2 (IL2). NK-92 MI cells notably secreted more IFNG and granzyme B. Cordycepin also decreased CD27 and increased CD11b, CD16, and NKG2D in NK-92 MI cells, which improved its anti-cancer ability. In conclusion, cordycepin could enhance NK cell cytotoxicity against cancerous cells for the first time, supporting its use as an alternative immunoactivity agent against cancer cells. Further studies are needed to investigate its efficacy and safety in clinical settings.
Topics: Humans; Killer Cells, Natural; Interferon-gamma; Deoxyadenosines; Tumor Necrosis Factor-alpha
PubMed: 37661405
DOI: 10.1248/bpb.b23-00221 -
Molecules (Basel, Switzerland) Mar 2020The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from (UP) and a purine nucleoside...
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from (UP) and a purine nucleoside phosphorylase from (PNP), was re-designed under continuous-flow conditions. Glyoxyl-agarose and EziG1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of UP and PNP, the results obtained pave the way to the use of the UP/PNP-based bioreactor for the preparation of other purine nucleosides.
Topics: Aeromonas hydrophila; Antiviral Agents; Biocatalysis; Bioreactors; Biotransformation; Clostridium perfringens; Enzymes, Immobilized; Glyoxylates; Humans; Protein Engineering; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Sepharose; Substrate Specificity; Vidarabine
PubMed: 32182773
DOI: 10.3390/molecules25051223 -
Viruses Jun 2021There are over 100 different chemical RNA modifications, collectively known as the epitranscriptome. -methyladenosine (mA) is the most commonly found internal RNA... (Review)
Review
There are over 100 different chemical RNA modifications, collectively known as the epitranscriptome. -methyladenosine (mA) is the most commonly found internal RNA modification in cellular mRNAs where it plays important roles in the regulation of the mRNA structure, stability, translation and nuclear export. This modification is also found in viral RNA genomes and in viral mRNAs derived from both RNA and DNA viruses. A growing body of evidence indicates that mA modifications play important roles in regulating viral replication by interacting with the cellular mA machinery. In this review, we will exhaustively detail the current knowledge on mA modification, with an emphasis on its function in virus biology.
Topics: Adenosine; Animals; Epigenesis, Genetic; Gene Expression Regulation, Viral; Host-Pathogen Interactions; Humans; Methylation; RNA, Viral; Species Specificity; Transcription, Genetic; Virus Replication
PubMed: 34205979
DOI: 10.3390/v13061049 -
Advances in Virus Research 2022Methylation at the N-position of either adenosine (mA) or 2'-O-methyladenosine (mAm) represents two of the most abundant internal modifications of coding and non-coding... (Review)
Review
Methylation at the N-position of either adenosine (mA) or 2'-O-methyladenosine (mAm) represents two of the most abundant internal modifications of coding and non-coding RNAs, influencing their maturation, stability and function. Additionally, although less abundant and less well-studied, monomethylation at the N-position (mA) can have profound effects on RNA folding. It has been known for several decades that RNAs produced by both DNA and RNA viruses can be mA/mAm modified and the list continues to broaden through advances in detection technologies and identification of the relevant methyltransferases. Recent studies have uncovered varied mechanisms used by viruses to manipulate the mA pathway in particular, either to enhance virus replication or to antagonize host antiviral defenses. As such, RNA modifications represent an important frontier of exploration in the broader realm of virus-host interactions, and this new knowledge already suggests exciting opportunities for therapeutic intervention. In this review we summarize the principal mechanisms by which mA/mAm can promote or hinder viral replication, describe how the pathway is actively manipulated by biomedically important viruses, and highlight some remaining gaps in understanding how adenosine methylation of RNA controls viral replication and pathogenesis.
Topics: Adenosine; Animals; Methylation; RNA; Virus Replication; Viruses
PubMed: 35840182
DOI: 10.1016/bs.aivir.2022.01.002 -
Nature Communications Mar 2023By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of...
By lacking de novo purine biosynthesis enzymes, Plasmodium falciparum requires purine nucleoside uptake from host cells. The indispensable nucleoside transporter ENT1 of P. falciparum facilitates nucleoside uptake in the asexual blood stage. Specific inhibitors of PfENT1 prevent the proliferation of P. falciparum at submicromolar concentrations. However, the substrate recognition and inhibitory mechanism of PfENT1 are still elusive. Here, we report cryo-EM structures of PfENT1 in apo, inosine-bound, and inhibitor-bound states. Together with in vitro binding and uptake assays, we identify that inosine is the primary substrate of PfENT1 and that the inosine-binding site is located in the central cavity of PfENT1. The endofacial inhibitor GSK4 occupies the orthosteric site of PfENT1 and explores the allosteric site to block the conformational change of PfENT1. Furthermore, we propose a general "rocker switch" alternating access cycle for ENT transporters. Understanding the substrate recognition and inhibitory mechanisms of PfENT1 will greatly facilitate future efforts in the rational design of antimalarial drugs.
Topics: Humans; Plasmodium falciparum; Nucleoside Transport Proteins; Nucleobase, Nucleoside, Nucleotide, and Nucleic Acid Transport Proteins; Malaria, Falciparum; Purine Nucleosides; Inosine
PubMed: 36977719
DOI: 10.1038/s41467-023-37411-1 -
Immunity, Inflammation and Disease Apr 2023Adenosine receptors are P1 class of purinergic receptors that belong to G protein-coupled receptors. There are 4 subtypes of adenosine receptors, namely A1, A2A, A2B,... (Review)
Review
Adenosine receptors are P1 class of purinergic receptors that belong to G protein-coupled receptors. There are 4 subtypes of adenosine receptors, namely A1, A2A, A2B, and A3. A2AR has a high affinity for the ligand adenosine. Under pathological conditions or external stimuli, ATP is sequentially hydrolyzed to adenosine by CD39 and CD73. The combination of adenosine and A2AR can increase the concentration of cAMP and activate a series of downstream signaling pathways, and further playing the role of immunosuppression and promotion of tumor invasion. A2AR is expressed to some extent on various immune cells, where it is abnormally expressed on immune cells in cancers and autoimmune diseases. A2AR expression also correlates with disease progression. Inhibitors and agonists of A2AR may be potential new strategies for treatment of cancers and autoimmune diseases. We herein briefly reviewed the expression and distribution of A2AR, adenosine/A2AR signaling pathway, expression, and potential as a therapeutic target.
Topics: Humans; Receptor, Adenosine A2A; Adenosine; Autoimmune Diseases; Signal Transduction; Neoplasms
PubMed: 37102661
DOI: 10.1002/iid3.826 -
Nucleic Acids Research May 2021Deazapurine nucleosides such as 3-deazaadenosine (c3A) are crucial for atomic mutagenesis studies of functional RNAs. They were the key for our current mechanistic...
Deazapurine nucleosides such as 3-deazaadenosine (c3A) are crucial for atomic mutagenesis studies of functional RNAs. They were the key for our current mechanistic understanding of ribosomal peptide bond formation and of phosphodiester cleavage in recently discovered small ribozymes, such as twister and pistol RNAs. Here, we present a comprehensive study on the impact of c3A and the thus far underinvestigated 3-deazaguanosine (c3G) on RNA properties. We found that these nucleosides can decrease thermodynamic stability of base pairing to a significant extent. The effects are much more pronounced for 3-deazapurine nucleosides compared to their constitutional isomers of 7-deazapurine nucleosides (c7G, c7A). We furthermore investigated base pair opening dynamics by solution NMR spectroscopy and revealed significantly enhanced imino proton exchange rates. Additionally, we solved the X-ray structure of a c3A-modified RNA and visualized the hydration pattern of the minor groove. Importantly, the characteristic water molecule that is hydrogen-bonded to the purine N3 atom and always observed in a natural double helix is lacking in the 3-deazapurine-modified counterpart. Both, the findings by NMR and X-ray crystallographic methods hence provide a rationale for the reduced pairing strength. Taken together, our comparative study is a first major step towards a comprehensive understanding of this important class of nucleoside modifications.
Topics: Base Pairing; Crystallography, X-Ray; Mutagenesis; Purines; RNA; RNA Stability; Thermodynamics; Tubercidin
PubMed: 33856457
DOI: 10.1093/nar/gkab256 -
Molecular Cancer Jun 2020N-methyladenosine (mA), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular RNA... (Review)
Review
N-methyladenosine (mA), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular RNA (circRNA) is a class of covalently closed RNA molecules characterized by universality, diversity, stability and conservatism of evolution. Accumulating evidence shows that both mA modification and circRNAs participate in the pathogenesis of multiple diseases, such as cancers, neurological diseases, autoimmune diseases, and infertility. Recently, mA modification has been identified for its enrichment and vital biological functions in regulating circRNAs. In this review, we summarize the role of mA modification in the regulation and function of circRNAs. Moreover, we discuss the potential applications and possible future directions in the field.
Topics: Adenosine; Animals; DNA Methylation; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Methyltransferases; Neoplasms; RNA, Circular
PubMed: 32522202
DOI: 10.1186/s12943-020-01224-3