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International Journal of Molecular... Sep 2019Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.
Topics: Animals; Deoxycytidine; Drug Resistance, Neoplasm; Genome; Humans; Pancreatic Neoplasms; Treatment Outcome; Tumor Microenvironment; Gemcitabine
PubMed: 31514451
DOI: 10.3390/ijms20184504 -
Journal of Food and Drug Analysis Jan 2017Cordyceps sinensis has various biological and pharmacological functions, and it has been claimed as a tonic supplement for sexual and reproductive dysfunctions for a... (Review)
Review
Cordyceps sinensis has various biological and pharmacological functions, and it has been claimed as a tonic supplement for sexual and reproductive dysfunctions for a long time in oriental society. In this article, the in vitro and in vivo effects of C. sinensis and cordycepin on mouse Leydig cell steroidogenesis are briefly described, the stimulatory mechanisms are summarized, and the recent findings related to the alternative substances regulating male reproductive functions are also discussed.
Topics: Animals; Cordyceps; Deoxyadenosines; Male; Reproduction
PubMed: 28911537
DOI: 10.1016/j.jfda.2016.10.020 -
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 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Dec 2021Pentostatin is a nucleoside antibiotics with a strong inhibitory effect on adenosine deaminase, and is widely used in the clinical treatment of malignant tumors.... (Review)
Review
Pentostatin is a nucleoside antibiotics with a strong inhibitory effect on adenosine deaminase, and is widely used in the clinical treatment of malignant tumors. However, the high cost hampers its application. In the past 10 years, the biosynthesis of pentostatin were focused on strain breeding, optimization of medium composition and fermentation process. To date, there are no reviews summarizing the elucidated biosynthetic mechanism of pentostatin. This review starts by introducing the various chemical route for production of pentostatin, followed by summarizing the mechanisms of pentostatin biosynthesis in different microorganisms. Finally, challenges for biosynthesis of pentostatin were discussed, and strategies for regulating and improving the microbial synthesis of pentostatin were proposed.
Topics: Anti-Bacterial Agents; Pentostatin
PubMed: 34984865
DOI: 10.13345/j.cjb.210066 -
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 -
Angewandte Chemie (International Ed. in... Oct 2021Cellular DNA is composed of four canonical nucleosides (dA, dC, dG and T), which form two Watson-Crick base pairs. In addition, 5-methylcytosine (mdC) may be present....
Cellular DNA is composed of four canonical nucleosides (dA, dC, dG and T), which form two Watson-Crick base pairs. In addition, 5-methylcytosine (mdC) may be present. The methylation of dC to mdC is known to regulate transcriptional activity. Next to these five nucleosides, the genome, particularly of stem cells, contains three additional dC derivatives, which are formed by stepwise oxidation of the methyl group of mdC with the help of Tet enzymes. These are 5-hydroxymethyl-dC (hmdC), 5-formyl-dC (fdC), and 5-carboxy-dC (cadC). It is believed that fdC and cadC are converted back into dC, which establishes an epigenetic control cycle that starts with methylation of dC to mdC, followed by oxidation and removal of fdC and cadC. While fdC was shown to undergo intragenomic deformylation to give dC directly, a similar decarboxylation of cadC was postulated but not yet observed on the genomic level. By using metabolic labelling, we show here that cadC decarboxylates in several cell types, which confirms that both fdC and cadC are nucleosides that are directly converted back to dC within the genome by C-C bond cleavage.
Topics: Animals; CHO Cells; Cricetulus; DNA; Decarboxylation; Deoxycytidine; Deuterium; Genome; Mice; Nitrogen Isotopes
PubMed: 34432359
DOI: 10.1002/anie.202109995 -
Microbial Physiology 20215-Deoxyadenosine (5dAdo) is a by-product of many radical SAM enzyme reactions in all domains of life, and an inhibitor of the radical SAM enzymes themselves. Hence,... (Review)
Review
5-Deoxyadenosine (5dAdo) is a by-product of many radical SAM enzyme reactions in all domains of life, and an inhibitor of the radical SAM enzymes themselves. Hence, pathways to recycle or dispose of this toxic by-product must exist but remain largely unexplored. In this review, we discuss the current knowledge about canonical and atypical 5dAdo salvage pathways that have been characterized in the last years. We highlight studies that report on how, in certain organisms, the salvage of 5dAdo via specific pathways can confer a growth advantage by providing either intermediates for the synthesis of secondary metabolites or a carbon source for the synthesis of metabolites of the central carbon metabolism. Yet, an alternative recycling route exists in organisms that use 5dAdo as a substrate to synthesize and excrete 7-deoxysedoheptulose, an allelopathic inhibitor of one enzyme of the shikimate pathway, thereby competing for their own niche. Remarkably, most steps of 5dAdo salvage are the result of the activity of promiscuous enzymes. This strategy enables even organisms with a small genome to synthesize bioactive compounds which they can deploy under certain conditions to gain a competitive growth advantage. We conclude emphasizing that, unexpectedly, 5dAdo salvage pathways seem not to be ubiquitously present, raising questions about the fate of such a toxic by-product in those species. This observation also suggests that additional 5dAdo salvage pathways, possibly relying on the activity of promiscuous enzymes, may exist. The future challenge will be to bring to light these "cryptic" 5dAdo recycling pathways.
Topics: Deoxyadenosines
PubMed: 34126623
DOI: 10.1159/000516105 -
Cells Jun 2022Tagging proliferating cells with thymidine analogs is an indispensable research tool; however, the issue of the potential in vivo cytotoxicity of these compounds remains...
Tagging proliferating cells with thymidine analogs is an indispensable research tool; however, the issue of the potential in vivo cytotoxicity of these compounds remains unresolved. Here, we address these concerns by examining the effects of BrdU and EdU on adult hippocampal neurogenesis and EdU on the perinatal somatic development of mice. We show that, in a wide range of doses, EdU and BrdU label similar numbers of cells in the dentate gyrus shortly after administration. Furthermore, whereas the administration of EdU does not affect the division and survival of neural progenitor within 48 h after injection, it does affect cell survival, as evaluated 6 weeks later. We also show that a single injection of various doses of EdU on the first postnatal day does not lead to noticeable changes in a panel of morphometric criteria within the first week; however, higher doses of EdU adversely affect the subsequent somatic maturation and brain growth of the mouse pups. Our results indicate the potential caveats in labeling the replicating DNA using thymidine analogs and suggest guidelines for applying this approach.
Topics: Animals; Bromodeoxyuridine; Cell Count; Cell Proliferation; Mice; Neurogenesis; Thymidine
PubMed: 35741018
DOI: 10.3390/cells11121888 -
Biochemical and Biophysical Research... Oct 2023Hematological malignancies(HMs) are highly heterogeneous diseases with globally rising incidence. Despite major improvements in the management of HMs, conventional... (Review)
Review
Hematological malignancies(HMs) are highly heterogeneous diseases with globally rising incidence. Despite major improvements in the management of HMs, conventional therapies have limited efficacy, and relapses with high mortality rates are still frequent. Cordycepin, a nucleoside analog extracted from Cordyceps species, represents a wide range of therapeutic effects, including anti-inflammatory, anti-tumor, and anti-metastatic activities. Cordycepin induces apoptosis in different subtypes of HMs by triggering adenosine receptors, death receptors, and several vital signaling pathways such as MAPK, ERK, PI3K, AKT, and GSK-3β/β-catenin. This review article summarizes the impact of utilizing cordycepin on HMs, and highlights its potential as a promising avenue for future cancer research based on evidence from in vitro and in vivo studies, as well as clinical trials.
Topics: Humans; Glycogen Synthase Kinase 3 beta; Hematologic Neoplasms; Deoxyadenosines; Apoptosis
PubMed: 37634411
DOI: 10.1016/j.bbrc.2023.08.014 -
Nucleosides, Nucleotides & Nucleic Acids Mar 2017Reported is an efficient synthesis of adenyl and uridyl 5'-tetrachlorophthalimido-5'-deoxyribonucleosides, and guanylyl 5'-azido-5'-deoxyribonucleosides, which are...
Reported is an efficient synthesis of adenyl and uridyl 5'-tetrachlorophthalimido-5'-deoxyribonucleosides, and guanylyl 5'-azido-5'-deoxyribonucleosides, which are useful in solid-phase synthesis of phosphoramidate and ribonucleic guanidine oligonucleotides. Replacement of 5'-hydroxyl with tetrachlorophthalimido group was performed via Mitsunobu reaction for adenosine and uridine. An alternative method was applied for guanosine which replaced the 5'-hydroxyl with an azido group. The resulting compounds were converted to 5'-amino-5'-deoxyribonucleosides for oligonucleotide synthesis. Synthetic intermediates were tested as antimicrobials against six bacterial strains. All analogs containing the 2',3'-O-isopropylidine protecting group demonstrated antibacterial activity against Neisseria meningitidis, and among those analogs with 5'-tetrachlorophthalimido and 5'-azido demonstrated increased antibacterial effect.
Topics: Adenosine; Anti-Bacterial Agents; Azides; Chemistry Techniques, Synthetic; Deoxyribonucleosides; Drug Evaluation, Preclinical; Microbial Sensitivity Tests; Neisseria meningitidis; Phthalimides; Uridine
PubMed: 28045593
DOI: 10.1080/15257770.2016.1250906