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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 -
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 -
Antiviral Research Feb 2022Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2...
Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid global emergence of SARS-CoV-2 highlights the importance and urgency for potential drugs to control the pandemic. The functional importance of RNA-dependent RNA polymerase (RdRp) in the viral life cycle, combined with structural conservation and absence of closely related homologs in humans, makes it an attractive target for designing antiviral drugs. Nucleos(t)ide analogs (NAs) are still the most promising broad-spectrum class of viral RdRp inhibitors. In this study, using our previously developed cell-based SARS-CoV-2 RdRp report system, we screened 134 compounds in the Selleckchemicals NAs library. Four candidate compounds, Fludarabine Phosphate, Fludarabine, 6-Thio-20-Deoxyguanosine (6-Thio-dG), and 5-Iodotubercidin, exhibit remarkable potency in inhibiting SARS-CoV-2 RdRp. Among these four compounds, 5-Iodotubercidin exhibited the strongest inhibition upon SARS-CoV-2 RdRp, and was resistant to viral exoribonuclease activity, thus presenting the best antiviral activity against coronavirus from a different genus. Further study showed that the RdRp inhibitory activity of 5-Iodotubercidin is closely related to its capacity to inhibit adenosine kinase (ADK).
Topics: Antiviral Agents; Cell Line; Deoxyguanosine; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Microbial Sensitivity Tests; Nucleic Acid Synthesis Inhibitors; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Thionucleosides; Tubercidin; Vidarabine; Vidarabine Phosphate; COVID-19 Drug Treatment
PubMed: 35101534
DOI: 10.1016/j.antiviral.2022.105254 -
Advances in Clinical and Experimental... 2017Under homeostatic conditions, an equilibrium state between amounts of free radicals formed and their scavenging is observed. Free radicals are destructive only when... (Review)
Review
Under homeostatic conditions, an equilibrium state between amounts of free radicals formed and their scavenging is observed. Free radicals are destructive only when present in excess. Pathological changes within cells and tissues can result from a persistent excess of free radicals. Living organisms are increasingly exposed to oxidative stress, resulting in oxidative DNA modifications. One such modification is 8-hydroxy-2'-deoxyguanosine (8-OHdG). It is considered a biomarker of oxidative stress and oxidative DNA damage. It has been found both in physiological fluids and in cells. This paper presents methods found in the literature for determining 8-OHdG expression in various kinds of biological material - blood, urine or liver homogenates. Methods for determining the biomarker expression have been grouped into direct and indirect methods, and the various levels of 8-hydroxy-2'-deoxyguanosine that can be determined by the different techniques are presented. The basic pros and cons of the various techniques are also discussed.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; DNA Damage; Deoxyguanosine; Free Radicals; Humans; Oxidative Stress
PubMed: 28397448
DOI: 10.17219/acem/43272 -
Natural Product Reports Jun 2024Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is... (Review)
Review
Covering: 2019 to 2023Nucleoside analogues represent one of the most important classes of small molecule pharmaceuticals and their therapeutic development is successfully established within oncology and for the treatment of viral infections. However, there are currently no nucleoside analogues in clinical use for the management of bacterial infections. Despite this, a significant number of clinically recognised nucleoside analogues are known to possess some antibiotic activity, thereby establishing a potential source for new therapeutic discovery in this area. Furthermore, given the rise in antibiotic resistance, the discovery of new clinical candidates remains an urgent global priority and natural product-derived nucleoside analogues may also present a rich source of discovery space for new modalities. This Highlight, covering work published from 2019 to 2023, presents a current perspective surrounding the synthesis of natural purine nucleoside antibiotics. By amalgamating recent efforts from synthetic chemistry with advances in biosynthetic understanding and the use of recombinant enzymes, prospects towards different structural classes of purines are detailed.
Topics: Anti-Bacterial Agents; Purine Nucleosides; Biological Products; Molecular Structure; Humans
PubMed: 38197414
DOI: 10.1039/d3np00051f -
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 -
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