Liquid Biopsies for Pancreatic Cancer: A Step Towards Early Detection
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Rapidly proliferating tumor cells undergo ROS mediated spontaneous DNA damage and aberrant chemical modifications like DNA methylation and histone acetylation/ deacetylation leading to the formation of a pool of modified bases. Owing to DNA repair mechanisms and enhanced cellular turnover, those altered bases are generally excised and expelled from the system. Elevated levels of such modified nucleosides in the urine are evolving as important biomarkers in different cancers including liver, breast, colorectal cancer, hepatocellular carcinoma and leukemia [37-39]. Sarcosine is produced by transfer of an N-methyl group on glycine during DNA methylation and its level in the urine is shown to increase during prostate cancer progression and metastasis [40]. This finding indicates that one of the potential metabolites that can be used as a cancer biomarker are modified nucleosides.
Infections
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
NRTIs function by inhibiting the synthesis of DNA by reverse transcriptase, the viral enzyme that copies viral RNA into DNA in the newly infected cell. Nucleoside analogues bear a structural resemblance to the natural building blocks of DNA: the purine nucleosides adenosine (A) and guanosine (G), and the pyrimidine nucleosides thymidine (T) and cytidine (C). Nucleoside analogues are triphosphorylated within the cell, and some undergo further modifications. Nucleotide analogues resemble monophosphorylated nucleo-sides, and therefore require only two additional phosphorylations to become active inhibitors of DNA synthesis. Reverse transcriptase fails to distinguish the phosphorylated NRTIs from their natural counterparts, and attempts to use the drugs in the synthesis of viral DNA. When an NRTI is incorporated into a strand of DNA being synthesised, the addition of further nucleotides is prevented, and a full length copy of the viral DNA is not produced.
Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
Since many antineoplastic agents are nucleoside analogs, phosphorylation is one of the most common mechanisms for activation of anticancer drugs. For example, phosphorylated metabolites of cytosine arabinoside (Figure 1) and 5-azacytidine represent the intracellular active forms of these drugs, which then exert their cytotoxic effects through a variety of mechanisms.23 The enzymes catalyzing the rate-limiting steps in the phosphorylation (activation) of these drugs are deoxycytidine kinase12 and uridine-cytidine kinase,14,24 respectively. A number of studies of cultured cell lines,14 clinical isolates,13 and experimental tumor models13 indicate that decreased activities of these enzymes within target cells can be responsible for resistance to both of these pyrimidine analogs.
Gastroprotective effects of water extract of domesticated Amauroderma rugosum against several gastric ulcer models in rats
Published in Pharmaceutical Biology, 2022
Yanzhen Mai, Siyuan Xu, Ru Shen, Bairu Feng, Hong He, Yifei Xu
Dried domesticated A. rugosum was purchased from Longmen Maling Ganoderma lucidum planting base (Huizhou, China) and identified by morphological, microscopic and gene sequencing (the internal transcribed spacer (ITS). Sequence analysis showed that the similarity between the sample (GenBank accession number: MK660145) and A. rugosum (GenBank accession number: MG021113.1) was 99%. The authenticated voucher specimen (voucher 20-07-02) was kept in Huizhou Health Sciences Polytechnic. Dried domesticated A. rugosum mycelia powder as above was extracted for 1 h in hot water (98 °C) in proportion (1:17, w/v) by heating reflux, thrice. The extracting solution was mixed, filtered, concentrated and lyophilized to obtain WEA. The powder of WEA was dissolved in appropriate distilled water to prepare the extract solution (1 mL equivalent to 1 g of A. rugosum mycelia powder) for test. The polysaccharide content was determined according to Chinese Pharmacopoeia (version 2020) based on the method of Ganoderma lucidum (Curtis: Fr.) P. Karst. (Ganodermataceae) polysaccharide quantification. The nucleosides were determined by high-performance liquid chromatography (HPLC). The total polysaccharides of WEA were analysed by anthrone-sulphuric acid colorimetry at 625 nm. The contents of four nucleosides, namely, including cytidine, uridine, guanosine and adenosine, were determined by HPLC.
Research progress on antiviral constituents in traditional Chinese medicines and their mechanisms of action
Published in Pharmaceutical Biology, 2022
Zhi Chen, Si-yong Ye
Viruses are a class of highly infectious intracellular parasitic microorganisms, which seriously endanger human and animal health. Western antiviral medicines, including nucleoside analogues, reverse transcriptase inhibitors, neuraminidase inhibitors, etc., exert their antiviral functions mainly by inhibiting viral processes such as adsorption, invasion, nucleic acid synthesis, and uncoating (Shahabadi and Moshtkoob 2020; Kaczmarek et al. 2021; Taieb et al. 2021). The problems with these antiviral agents, however, are the development of drug resistance due to viral mutations, the functional inability caused by viral incubation, the evident adverse reactions, as well as the complex therapeutic regimes (Amarelle et al. 2017). TCM has been used effectively to combat epidemics infection, and saved many lives. So far, hundreds of TCM prescriptions have been developed for the prevention and treatment of infectious diseases and it is now credited for the successful battle against COVID-19 in China (Zheng, Baak, et al. 2020; Lee et al. 2021). TCM with their unique perspectives, emphasize the interactions with viruses and organisms, which have comprehensive effects such as inhibiting viral replication, preventing virus-induced cytopathy, and regulating immunity (Chen, Zhong, et al. 2019; Shen et al. 2019; Huang et al. 2020). With the continuous emergence of large-scale screening technologies for antiviral agents, the development of highly effective antiviral TCM has become a current hot topic in drug R&D.
The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19)
Published in Expert Opinion on Drug Discovery, 2022
Pasquale Pagliano, Carmine Sellitto, Tiziana Ascione, Giuliana Scarpati, Veronica Folliero, Ornella Piazza, Gianluigi Franci, Amelia Filippelli, Valeria Conti
Many nucleoside analogues have been used in the treatment of viral diseases, some of these have historical value only, but other retain their antiviral efficacy years after their introduction. Antiviral activity of nucleoside analog is driven by the interaction with viral DNA/RNA polymerase or reverse transcriptase, which finally inhibits nucleic acid elongation or causes loss of viral information [19]. Active triphosphate nucleosides have poor chemical stability and cannot cross cellular barrier and penetrate the cell due to their negative charge. Drugs interacting with RdRp must be administered as nucleosides and converted into their triphosphate form, which is finally incorporated into the growing RNA chain. As conversion of a nucleoside to its monophosphate form can be a limiting passage, stable protected monophosphate nucleosides have been developed. RDV, Sofosbuvir, and Tenofovir, well-known drugs currently administered to patients with COVID-19, HCV, or HIV infection, are available as the prodrugs of their monophosphate (ProTide), which can be finally converted into the active compound once they reach the targeted cell [20,21].
Related Knowledge Centers
- Anomer
- De Novo Synthesis
- DNA
- Nucleobase
- Nucleotide
- Phosphate
- Purine
- Pyrimidine
- Rna
- Glycosylamine
- DNA
- Rna