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Nutrients Mar 2022This study measured the total potentially available nucleoside (TPAN) content in breast milk from six different regions of China as a part of the Maternal Nutrition and...
This study measured the total potentially available nucleoside (TPAN) content in breast milk from six different regions of China as a part of the Maternal Nutrition and Infant Investigation (MUAI) study. A total of 631 breast milk samples were collected from healthy, lactating women with singleton, full-term pregnancies between 40 and 45 days postpartum in Changchun, Chengdu, Lanzhou, Shanghai, Tianjin, and Guangzhou. TPAN and free 5′-monophosphate nucleotide (5′-MNT) contents were determined by high-performance liquid chromatography. The TPAN content of the Chinese mature milk ranged from 11.61 mg/L to 111.09 mg/L, with a median level of 43.26 mg/L. Four types of nucleotides were identified, and the median levels of cytidine monophosphate (CMP), uridine monophosphate (UMP), guanosine monophosphate (GMP), and adenosine monophosphate (AMP) were 22.84 mg/L, 9.37 mg/L, 4.86 mg/L, and 4.80 mg/L, respectively. CMP was the predominant nucleotide, accounting for 52.9% of the TPAN content, while free 5′-MNT accounted for 18.38% of the TPAN content. The distribution pattern of the TPAN content and level of the individual nucleotides were significantly different among the selected regions (p < 0.05), but the result showed no significant differences in the TPAN level in breast milk (p > 0.05). In addition, no correlation was reported between the geographic distribution and TPAN levels. This result showed that TPAN better reflects the level of total potential nucleosides in Chinese breast milk rather than 5′-MNT in free form. CMP, UMP, GMP, and AMP are the only 4 types of nucleotides reported in all detections. In addition, results revealed a large variation of TPAN levels in Chinese breast milk across six regions, so that the median value may not be the optimal fortification level of TPAN for Chinese infant populations.
Topics: Adenosine Monophosphate; China; Cytidine Monophosphate; Female; Humans; Infant; Lactation; Milk, Human; Nucleosides; Nucleotides; Uridine Monophosphate
PubMed: 35406031
DOI: 10.3390/nu14071418 -
Expert Opinion on Drug Safety Aug 2015The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free... (Review)
Review
INTRODUCTION
The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy.
AREAS COVERED
The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available.
EXPERT OPINION
In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug-drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug-drug interactions.
Topics: Antiviral Agents; Benzimidazoles; Drug Approval; Drug Combinations; Drug Interactions; Fluorenes; Hepatitis C; Humans; Sofosbuvir; Uridine Monophosphate
PubMed: 26043900
DOI: 10.1517/14740338.2015.1053868 -
Expert Review of Clinical Pharmacology Sep 2014Hepatitis C (HCV) remains an important cause of chronic liver disease worldwide. Historically, treatment included pegylated-interferon and ribavirin with low efficacy... (Review)
Review
Hepatitis C (HCV) remains an important cause of chronic liver disease worldwide. Historically, treatment included pegylated-interferon and ribavirin with low efficacy and numerous side effects contributing to poor adherence and impairment of patients' well-being. The next step in developing better treatment regimens for HCV led to the development of the first-generation direct acting antivirals (DAAs). Although these DAAs improved efficacy, they also added substantial side effects. The next generation of DAAs include Simeprevir and Sofosbuvir (SOF) which not only further enhanced the efficacy of the regimens but also improve their safety profile. This review summarizes the current clinical experience with SOF. SOF, an HCV-specific uridine nucleotide analog which inhibits the NS5B polymerase, is now available in the USA, Canada and Europe. Clinical trials of SOF-containing regimens have shown that these regimens are safe, efficacious, and well-tolerated in all genotypes. Additionally, SOF is associated with improved patient reported outcomes.
Topics: Antiviral Agents; Genotype; Hepacivirus; Hepatitis C; Humans; Sofosbuvir; Uridine Monophosphate; Viral Nonstructural Proteins
PubMed: 24918162
DOI: 10.1586/17512433.2014.928196 -
Bioorganic & Medicinal Chemistry Letters Aug 2021The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the...
The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2YR agonist and P2YR partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2YR agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2YR potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2YR, respectively. However, 3-alkyl (31-33, 37, 38), β-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2YR activation. Thus, we have identified new α,β-methylene bridged N-extended CDP analogues as P2YR agonists that are highly selective over the P2YR.
Topics: Diphosphonates; Dose-Response Relationship, Drug; Humans; Molecular Structure; Pyrimidine Nucleotides; Receptors, Purinergic P2; Structure-Activity Relationship
PubMed: 34048882
DOI: 10.1016/j.bmcl.2021.128137 -
Angewandte Chemie (International Ed. in... Aug 2021Linear or branched 1,3-diketone-linked thymidine 5'-O-mono- and triphosphate were synthesized through CuAAC click reaction of diketone-alkynes with 5-azidomethyl-dUMP or...
Linear or branched 1,3-diketone-linked thymidine 5'-O-mono- and triphosphate were synthesized through CuAAC click reaction of diketone-alkynes with 5-azidomethyl-dUMP or -dUTP. The triphosphates were good substrates for KOD XL DNA polymerase in primer extension synthesis of modified DNA. The nucleotide bearing linear 3,5-dioxohexyl group (HDO) efficiently reacted with arginine-containing peptides to form stable pyrimidine-linked conjugates, whereas the branched 2-acetyl-3-oxo-butyl (PDO) group was not reactive. Reaction with Lys or a terminal amino group formed enamine adducts that were prone to hydrolysis. This reactive HDO modification in DNA was used for bioconjugations and cross-linking with Arg-containing peptides or proteins (e.g. histones).
Topics: Animals; Arginine; Cattle; Cross-Linking Reagents; DNA; Histones; Ketones; Peptides; Proteins; Serum Albumin, Bovine; Thymine Nucleotides; Tumor Suppressor Protein p53
PubMed: 34107150
DOI: 10.1002/anie.202105126 -
Carbohydrate Research Jun 2023The non-natural nucleosides with a quaternary stereogenic center at C2' are crucial to drug discovery. They have become a cornerstone for the treatment of cancer and... (Review)
Review
The non-natural nucleosides with a quaternary stereogenic center at C2' are crucial to drug discovery. They have become a cornerstone for the treatment of cancer and various viral infections as exemplified by gemcitabine and sofosbuvir. Major research effort has been expended to gain synthetic access to these nucleoside analogues with a significant steric bulk at C2' in the furanoside ring. The 2'-ketonucleosides and 2'-deoxy-2'-methylenenucleosides emerged as key intermediates in these synthetic strategies. For example, α-face addition of methyl lithium to the 2'-ketonucleosides followed by fluorination of resulting tertiary arabino alcohol with DAST provided 2'-fluoro-2'-C-methyluridine - a core nucleoside component of sofosbuvir. The α-face addition of HCN or HN to the 2'-deoxy-2'-methylene nucleosides gave access to the synthetically versatile 2'-cyano-2'-C-methyl and 2'-azido-2'-C-methyl nucleosides. Likewise, the addition of diazomethane to the 2'-exomethylene group gave access to the 2'-spirocyclopropyl analogue. This review primarily discusses synthetic strategies which employs natural nucleosides as substrates but selected approaches involving coupling of the preelaborated sugar precursors with nucleobases are also examined.
Topics: Nucleosides; Sofosbuvir; Sugars; Antiviral Agents
PubMed: 37087776
DOI: 10.1016/j.carres.2023.108814 -
Biotechnology Advances Oct 2023Glycosyltransferases catalyse the transfer of a glycosyl moiety from a donor to an acceptor. Members of this enzyme class are ubiquitous throughout all kingdoms of life... (Review)
Review
Glycosyltransferases catalyse the transfer of a glycosyl moiety from a donor to an acceptor. Members of this enzyme class are ubiquitous throughout all kingdoms of life and are involved in the biosynthesis of countless types of glycosides. Family 1 glycosyltransferases, also referred to as uridine diphosphate-dependent glycosyltransferases (UGTs), glycosylate small molecules such as secondary metabolites and xenobiotics. In plants, UGTs are recognised for their multiple functionalities ranging from roles in growth regulation and development, in protection against pathogens and abiotic stresses and in adaptation to changing environments. In this study, we review UGT-mediated glycosylation of phytohormones, endogenous secondary metabolites, and xenobiotics and contextualise the role this chemical modification plays in the response to biotic and abiotic stresses and plant fitness. Here, the potential advantages and drawbacks of altering the expression patterns of specific UGTs along with the heterologous expression of UGTs across plant species to improve stress tolerance in plants are discussed. We conclude that UGT-based genetic modification of plants could potentially enhance agricultural efficiency and take part in controlling the biological activity of xenobiotics in bioremediation strategies. However, more knowledge of the intricate interplay between UGTs in plants is needed to unlock the full potential of UGTs in crop resistance.
Topics: Glycosyltransferases; Uridine Diphosphate; Crop Protection; Xenobiotics; Glycosylation; Plants; Phylogeny
PubMed: 37268151
DOI: 10.1016/j.biotechadv.2023.108182 -
Trends in Biochemical Sciences Jun 2022cCMP and cUMP have been identified in numerous biological systems and proposed to serve as second messengers. However, this proposal remained controversial because of...
cCMP and cUMP have been identified in numerous biological systems and proposed to serve as second messengers. However, this proposal remained controversial because of the base-promiscuity of generators, effectors, phosphodiesterases, and bacterial toxins. With the identification of specific cytidylyl and uridylyl cyclases, cCMP and cUMP research enters a new era.
Topics: Cyclic CMP; Nucleotides, Cyclic; Second Messenger Systems; Uridine Monophosphate
PubMed: 35031198
DOI: 10.1016/j.tibs.2021.12.008 -
Disability and Rehabilitation.... Nov 2023Public playgrounds afford children and families important opportunities for outdoor play, social participation, and inclusion. Unfortunately, many children and families... (Review)
Review
PURPOSE
Public playgrounds afford children and families important opportunities for outdoor play, social participation, and inclusion. Unfortunately, many children and families experience barriers to accessing, using, and being included in public playgrounds. Consequently, Universal Design (UD) is promoted for providing conceptual guidance for designing for inclusion in public playgrounds. However, a lack of research evidence means researchers have engaged in the ongoing interpretation of the UD concept and related non-discriminatory planning and design concepts. Therefore, the aim of this study was to examine how UD, and related concepts, are used in peer-reviewed articles concerning public playgrounds.
MATERIALS AND METHODS
A scoping review was conducted in November 2019, which identified 15 peer-reviewed articles that met the inclusion criteria.
RESULTS
Analysis revealed that the terms UD, inclusive design, accessibility, and usability are all being used to describe non-discriminatory planning and design concepts arbitrarily and without regard for higher or lower order concepts. Two broad interpretations were evident: (a) UD is synonymous with accessibility for some, and (b) UD is a higher-order concept that goes beyond accessibility for others. Nevertheless, findings highlight the utility of UD in underpinning the design of public playgrounds in many developed countries; however, the concept requires further clarity and specificity as it pertains to playground design and more pertinently inclusion in outdoor play.
CONCLUSIONS
We argue for further conceptual refinement to consolidate the importance and future application of UD for Play (UDP) in the design of public playgrounds that promote outdoor play, social participation, and inclusion.IMPLICATIONS FOR REHABILITATIONMost peer-reviewed journal articles reviewed fail to define what is meant by the term Universal Design.Of those that do provide a definition, the outcome of inclusion in play, or the application of Universal Design to enable play in public playgrounds was unclear.Research to date has mostly focused on related concepts, including accessibility and usability, with less emphasis on Universal Design.Recommend a tailored perspective of Universal Design for Play (UDP).
Topics: Child; Humans; Universal Design; Architectural Accessibility; Parks, Recreational; Uridine Diphosphate
PubMed: 35138989
DOI: 10.1080/17483107.2021.2022788 -
Trends in Biochemical Sciences Jan 2015The cyclic purine nucleotides cAMP and cGMP are established second messengers. By contrast, the existence of the cyclic pyrimidine nucleotides cytidine 3',5'-cyclic...
The cyclic purine nucleotides cAMP and cGMP are established second messengers. By contrast, the existence of the cyclic pyrimidine nucleotides cytidine 3',5'-cyclic monophosphate (cCMP) and uridine 3',5'-cyclic monophosphate (cUMP) has been controversial for decades. The recent development of highly sensitive mass spectrometry (MS) methods allowed precise quantitation and unequivocal identification of cCMP and cUMP in cells. Importantly, cCMP and cUMP generators, effectors, cleaving enzymes, and transporters have now been identified. Here, I discuss evidence in support of cCMP and cUMP as bona fide second messengers, the emerging therapeutic implications of cCMP and cUMP signaling, and important unresolved questions for this field.
Topics: Adenylyl Cyclases; Bacterial Proteins; Bacterial Toxins; Cyclic CMP; Glucosyltransferases; Guanylate Cyclase; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Protein Kinases; Pseudomonas aeruginosa; Uridine Monophosphate
PubMed: 25435399
DOI: 10.1016/j.tibs.2014.10.008