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Free Radical Biology & Medicine Mar 2022Heme-containing peroxidases catalyze the oxidation of a variety of substrates by consuming hydrogen peroxide (HO), and play diversified roles in physiology and pathology... (Review)
Review
Heme-containing peroxidases catalyze the oxidation of a variety of substrates by consuming hydrogen peroxide (HO), and play diversified roles in physiology and pathology including innate immunity, the synthesis of thyroid hormone and the extracellular matrix, as well as the pathogenesis of several inflammatory diseases. Peroxidasin (PXDN), also known as Vascular Peroxidase-1 (VPO1), is a newly identified peroxidase and expresses in multiple cells and tissues including cardiovascular system and the lung. Recent studies imply its roles in the innate immunity, cardiovascular physiology and diseases, and extracellular matrix formation. Studies on the role of PXDN in human diseases are entering a new and exciting stage, and this review provides the insights into this emerging field of PXDN.
Topics: Animals; Deoxyribonucleosides; Extracellular Matrix Proteins; Humans; Hydrogen Peroxide; Mammals; Peroxidase; Peroxidases; Purine Nucleosides; Peroxidasin
PubMed: 35219848
DOI: 10.1016/j.freeradbiomed.2022.02.026 -
Journal of the American Chemical Society Sep 2021The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent...
The hypothesis that life on Earth may have started with a heterogeneous nucleic acid genetic system including both RNA and DNA has attracted broad interest. The recent finding that two RNA subunits (cytidine, C, and uridine, U) and two DNA subunits (deoxyadenosine, dA, and deoxyinosine, dI) can be coproduced in the same reaction network, compatible with a consistent geological scenario, supports this theory. However, a prebiotically plausible synthesis of the missing units (purine ribonucleosides and pyrimidine deoxyribonucleosides) in a unified reaction network remains elusive. Herein, we disclose a strictly stereoselective and furanosyl-selective synthesis of purine ribonucleosides (adenosine, A, and inosine, I) and purine deoxynucleosides (dA and dI), alongside one another, via a key photochemical reaction of thioanhydroadenosine with sulfite in alkaline solution (pH 8-10). Mechanistic studies suggest an unexpected recombination of sulfite and nucleoside alkyl radicals underpins the formation of the ribo C2'-O bond. The coproduction of A, I, dA, and dI from a common intermediate, and under conditions likely to have prevailed in at least some primordial locales, is suggestive of the potential coexistence of RNA and DNA building blocks at the dawn of life.
Topics: Adenosine; Deoxyribonucleosides; Evolution, Chemical; Hydrogen-Ion Concentration; Models, Chemical; Purine Nucleosides; Ribonucleosides; Sulfites; Ultraviolet Rays
PubMed: 34469129
DOI: 10.1021/jacs.1c07403 -
CMAJ : Canadian Medical Association... Dec 1990Zidovudine (AZT) is the first antiretroviral agent to be licensed for the treatment of human immunodeficiency virus (HIV) infection. Since the initial placebo-controlled... (Clinical Trial)
Clinical Trial Randomized Controlled Trial Review
Zidovudine (AZT) is the first antiretroviral agent to be licensed for the treatment of human immunodeficiency virus (HIV) infection. Since the initial placebo-controlled trial showing improved survival among patients with acquired immunodeficiency syndrome (AIDS) or symptomatic HIV infection (AIDS-related complex [ARC]) zidovudine has been evaluated in other stages of HIV infection. This review offers physicians who treat patients with HIV infection a comprehensive analysis of the current data on the clinical efficacy of zidovudine in various stages of HIV infection and on zidovudine's adverse effects. After a search of MEDLINE for pertinent articles published since 1985, controlled studies and studies of long-term zidovudine therapy, of zidovudine therapy for HIV-related conditions and of the incidence and management of adverse reactions were evaluated. In addition, abstracts from international meetings were reviewed. No significant difference in clinical outcome was found between high-dose and low-dose zidovudine therapy, but there were significantly fewer toxic effects in the low-dose group. In two other studies zidovudine was found to delay disease progression in patients with asymptomatic or mildly symptomatic HIV infection who had an absolute CD4 count of less than 0.5 x 10(9)/L; the low incidence of adverse reactions may have been due to either the early stage of the infection or the low dose used. The demonstration of zidovudine-resistant isolates after at least 6 months of therapy has yet to be correlated with clinical deterioration. When to begin zidovudine therapy among asymptomatic patients with a CD4 count of less than 0.5 x 10(9)/L remains unclear. Zidovudine can be used safely to delay progression to AIDS or ARC in certain patients with asymptomatic or mildly symptomatic HIV infection and can prolong survival in those with more severe infection. Further studies are necessary to identify indicators that could better define when to start treatment and how to alleviate toxic effects. Combination therapy with such agents as interferon alpha may become the preferred choice of therapy to prevent toxic effects and zidovudine resistance. Zidovudine prophylaxis has been used after HIV exposure. Although studies with animal models have had encouraging results infection has occurred despite immediate prophylaxis and thus further investigation is required.
Topics: Acquired Immunodeficiency Syndrome; Child; Humans; Zidovudine
PubMed: 2224694
DOI: No ID Found -
IARC Monographs on the Evaluation of... 2000
Review
Topics: Acyclovir; Animals; Antiviral Agents; Carcinogens; Didanosine; Disease Models, Animal; Evidence-Based Medicine; Humans; Intestinal Absorption; Neoplasms; Risk Factors; Tissue Distribution; Zalcitabine; Zidovudine
PubMed: 11000975
DOI: No ID Found -
PLoS Pathogens Dec 2023Staphylococcus aureus is a dangerous pathogen that evolved refined immuno-evasive strategies to antagonize host immune responses. This involves the biogenesis of...
Staphylococcus aureus is a dangerous pathogen that evolved refined immuno-evasive strategies to antagonize host immune responses. This involves the biogenesis of death-effector deoxyribonucleosides, which kill infectious foci-penetrating macrophages. However, the exact mechanisms whereby staphylococcal death-effector deoxyribonucleosides and coupled imbalances of intracellular deoxyribonucleotide species provoke immune cell death remain elusive. Here, we report that S. aureus systematically promotes an overload of deoxyribonucleotides to trigger mitochondrial rupture in macrophages, a fatal event that induces assembly of the caspase-9-processing apoptosome and subsequent activation of the intrinsic pathway of apoptosis. Remarkably, genetic disruption of this cascade not only helps macrophages coping with death-effector deoxyribonucleoside-mediated cytotoxicity but also enhances their infiltration into abscesses thereby ameliorating pathogen control and infectious disease outcomes in laboratory animals. Combined with the discovery of protective alleles in human CASP9, these data highlight the role of mitochondria-centered apoptosis during S. aureus infection and suggest that gene polymorphisms may shape human susceptibility toward a predominant pathogen.
Topics: Animals; Humans; Staphylococcus aureus; Nucleotides; Phagocytes; Cell Death; Apoptosis; Mitochondria; Deoxyribonucleosides
PubMed: 38157331
DOI: 10.1371/journal.ppat.1011892 -
Molecules (Basel, Switzerland) Sep 2011Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into... (Review)
Review
Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.
Topics: Animals; Bromodeoxyuridine; Cell Proliferation; Cells, Cultured; Click Chemistry; DNA; Deoxyuridine; Fluorescent Dyes; Humans; Staining and Labeling; Stem Cell Niche; Thymidine
PubMed: 21921870
DOI: 10.3390/molecules16097980 -
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 -
Journal of the American Chemical Society Oct 2022A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of...
A new approach for synthesizing polycyclic heterofused 7-deazapurine heterocycles and the corresponding nucleosides was developed based on C-H functionalization of diverse (hetero)aromatics with dibenzothiophene--oxide followed by the Negishi cross-cooupling with bis(4,6-dichloropyrimidin-5-yl)zinc. This cross-coupling afforded a series of (het)aryl-pyrimidines that were converted to fused deazapurine heterocycles through azidation and thermal cyclization. The fused heterocycles were glycosylated to the corresponding 2'-deoxy- and ribonucleosides, and a series of derivatives were prepared by nucleophilic substitutions at position 4. Four series of new polycyclic thieno-fused 7-deazapurine nucleosides were synthesized using this strategy. Most of the deoxyribonucleosides showed good cytotoxic activity, especially for the CCRF-CEM cell line. Phenyl- and thienyl-substituted thieno-fused 7-deazapurine nucleosides were fluorescent, and the former one was converted to 2'-deoxyribonucleoside triphosphate for enzymatic synthesis of labeled oligonucleotides.
Topics: Nucleosides; Cell Line, Tumor; Ribonucleosides; Pyrimidines; Oxides; Zinc; Oligonucleotides; Deoxyribonucleosides; Purine Nucleosides
PubMed: 36245092
DOI: 10.1021/jacs.2c07517 -
Journal of Medical Microbiology Jan 2022is a bacterium belonging to the class . It causes acute and chronic infections of the urogenital tract. The main features of this bacterium are an absence of cell wall...
is a bacterium belonging to the class . It causes acute and chronic infections of the urogenital tract. The main features of this bacterium are an absence of cell wall and a reduced genome size (517-622 protein-encoding genes). Previously, we have isolated morphologically unknown colonies called micro-colonies (MCs) from the serum of patients with inflammatory urogenital tract infection. MCs are functionally different from the typical colonies (TCs) in terms of metabolism and cell division. To determine the physiological differences between MCs and TCs of and elucidate the pathways of formation and growth of MCs by a comparative proteomic analysis of these two morphological forms. LC-MS proteomic analysis of TCs and MCs using an Ultimate 3000 RSLC nanoHPLC system connected to a QExactive Plus mass spectrometer. The study of the proteomic profiles of colonies allowed us to reconstruct their energy metabolism pathways. In addition to the already known pentose phosphate and arginine deamination pathways, can utilise ribose phosphate and deoxyribose phosphate formed by nucleoside catabolism as energy sources. Comparative proteomic HPLC-MS analysis revealed that the proteomic profiles of TCs and MCs were different. We assume that MC cells preferably utilised deoxyribonucleosides, particularly thymidine, as an energy source rather than arginine or ribonucleosides. Utilisation of deoxyribonucleosides is less efficient as compared with that of ribonucleosides and arginine in terms of energy production. Thymidine phosphorylase DeoA is one of the key enzymes of deoxyribonucleosides utilisation. We obtained a DeoA overexpressing mutant that exhibited a phenotype similar to that of MCs, which confirmed our hypothesis. In addition to the two known pathways for energy production (arginine deamination and the pentose phosphate pathway) can use deoxyribonucleosides and ribonucleosides. MC cells demonstrate a reorganisation of energy metabolism: unlike TC cells, they preferably utilise deoxyribonucleosides, particularly thymidine, as an energy source rather than arginine or ribonucleosides. Thus MC cells enter a state of energy starvation, which helps them to survive under stress, and in particular, to be resistant to antibiotics.
Topics: Arginine; Humans; Mycoplasma Infections; Mycoplasma hominis; Phenotype; Phosphates; Proteome; Ribonucleosides; Thymidine
PubMed: 35037614
DOI: 10.1099/jmm.0.001468 -
Biochemistry. Biokhimiia Dec 20178-Oxo-7,8-dihydroguanine (8-oxo-G) is a key biomarker of oxidative damage to DNA in cells, and its genotoxicity is well-studied. In recent years, it has been confirmed... (Review)
Review
8-Oxo-7,8-dihydroguanine (8-oxo-G) is a key biomarker of oxidative damage to DNA in cells, and its genotoxicity is well-studied. In recent years, it has been confirmed experimentally that free 8-oxo-G and molecules containing it are not merely inert products of DNA repair or degradation, but they are actively involved in intracellular signaling. In this review, data are systematized indicating that free 8-oxo-G and oxidized (containing 8-oxo-G) extracellular DNA function in the body as mediators of stress signaling and initiate inflammatory and immune responses to maintain homeostasis under the action of external pathogens, whereas exogenous 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) exhibits pronounced antiinflammatory and antioxidant properties. This review describes known action mechanisms of oxidized guanine and 8-oxo-G-containing molecules. Prospects for their use as a therapeutic target are considered, as well as a pharmaceutical agent for treatment of a wide range of diseases whose pathogenesis is significantly contributed to by inflammation and oxidative stress.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; DNA Damage; DNA Repair; Deoxyguanosine; Guanine; Humans; Inflammation; Oxidative Stress
PubMed: 29523066
DOI: 10.1134/S0006297917130089