Nucleosides, Nucleotides & Nucleic Acids最新文献

Hydrolytic and oxidative damage to pyrimidine nucleobases in DNA represents a significant source of mutations in the human genome. To better understand how these lesions are incorporated and repaired in human cells, it is desirable to have ready access to isotopically enriched nucleosides for use in isotope tracing and mass spectrometry-based quantification experiments. Here we report on improved syntheses of deoxyuridine, deoxycytidine, 5-hydroxydeoxyuridine, and 5-hydroxydeoxycytidine nucleosides labeled with ¹³C and ¹⁵N. Deoxyuridine was synthesized from uracil in a direct glycosylation reaction with excellent stereoselectivity without the need to reduce a ribonucleoside intermediate. Deoxyuridine was further converted to deoxycytidine using mild O4 activation conditions with high efficiency. Finally, we document the synthetic details of preparative oxidation of deoxyuridine and deoxycytidine to their 5-hydroxy counterparts. Overall, our protocols avoid hazardous reagents and tedious conditions found in previous methods.

Breast cancer is a heterogeneous disease that is ranked as one of the most common cancers worldwide. Currently, although there are existing molecules such as progesterone receptor and estrogen receptor for breast cancer treatment, discovering more effective drug targets is still in urgent need. In this study, we have obtained six sequencing datasets of breast cancer from GEO database and identified a set of differentially expressed molecules, including 67 miRNAs and 133 genes. Function enrichment analysis by miRPathDB database indicated that targets of 11 miRNAs could be enriched in breast cancer pathway with a p-value ≤ .05. A special miRNA-gene interaction network was constructed for analysis of the progression of breast cancer. We then ranked the importance of each molecule (i.e. miRNA and gene) by their node centrality indexes in the network and selected the top 10% of molecules. The statistical analysis of these molecules showed three miRNAs (hsa-miR-1275, hsa-miR-2392, hsa-miR-3141) have significant effects on the prognosis and survival of patients. By searching for potential drugs in Drugbank database, we have identified four candidates (phenethyl isothiocyanate, amuvatinib, theophylline, trifluridine) for targeting these genes. In conclusion, we believe that these drugs and their analogs could be used in the targeted therapy of breast cancer in the future.

PIWI-Interacting RNAs are small non-coding RNAs derived from single-stranded RNAs which plays a crucial role in epigenetic regulation through transposon silencing and mRNA degradation via deamination. This study aimed to inhibit piR-651 and piR-823 in MDA-MB-231 triple-negative breast cancer cells and to explore their potential effects on healthy HUVEC cells. Non-target, anti-piR-651, and anti-piR-823 sequences were transfected in bothHUVEC and MDA-MB-231 cells using Lipofectamine. Proliferation and motility were assessed at 24, 48, and 72 h post-transfection in both cell lines. Based on the motility findings, MDA-MB-231 cells were underwent an invasion assay using crystal violet staining. The expressions of Ki-67, HIF-1α, MMP-2, and MMP-9 genes were measured at 48 h, when both cell lines exhibited the most significant effects of inhibition. The optimal time for proliferation of anti-piR-651 and anti-piR-823 transfected MDA-MB-231 cells was determined to be at 48 h, as indicated by decreased motility and invasion assay results (p < 0.001). NeverthelessHowever, there was no significant difference in the motility and proliferation of HUVECss transfected with anti-piR-651 and anti-piR-823 compared to the control group (p > 0.05). Asides from MMP-2 in anti-piR-823 transfected HUVECs and HIF-1α in anti-piR-823 transfected MDA-MB-231 cells, gene expressions of Ki-67, HIF-1α, MMP-2, and MMP-9 were reduced in both cell lines (p < 0.001). Inhibition of piR-651 and piR-823 decreased the survival and metastasis of cancer cells, without causing vital structural changes in healthy cells. Future research in cancer gene therapy or genetic modification may benefit from investigating piR-651 and piR-823 as possible inhibitors of breast cancer invasion and metastasis.

The comprehensive advancement in DNA modification and coupling is driving DNA nanotechnology to new heights, paving the way for groundbreaking innovations in healthcare, materials science, and beyond. The ability to engineer DNA with tailored properties and functionalities underscores its immense potential in creating novel materials and devices. Utilizing a spectrum of techniques-such as amino handles, thiol groups, alkynes, azides, Diels-Alder reactions, hydrazides, and aminooxy functions-enables diverse coupling strategies, including Palladium-Catalyzed Couplings, to construct intricate DNA nanostructures. Further coupling modifications encompass hydrophobic alterations, redox-active moieties, chemical crosslinking agents, and Biotinylation. These modifications significantly broaden DNA's functional repertoire, offering precise control over interactions, structures, and features. By leveraging these advanced techniques, alongside next-generation sequencing (NGS)-based DNA modifications, researchers can design and implement DNA nanostructures with specific capabilities and applications, showcasing DNA's versatility as a programmable biomaterial. Through meticulous design and strategic implementation, DNA nanotechnology achieves unprecedented levels of precision and functionality, ushering in a new era of technological advancements and applications. These advanced DNA modification techniques hold great potential for transformative applications in nanotechnology, paving the way for innovations in drug delivery, diagnostics, and bioengineering.

High HMGB1 levels contribute to the development and metastasis of tumors such as colorectal cancer (CRC). The current investigation sought to evaluate the association of a functional InDel polymorphism (rs34000982) on the HMGB1 gene with CRC susceptibility and tumor stage and the clinical relevance of HMGB1 gene expression. A total of 600 CRC patients and 600 healthy control individuals were genotyped by a polymerase chain reaction-polyacrylamide gel electrophoresis assay. The findings demonstrated that the rs34000982 Ins allele or Ins/Ins genotype was associated not only with reduced susceptibility to CRC, especially stage III-IV CRC (Ins vs. Del: OR = 0.65, 95%CI = 0.51-0.82, p < 0.001; Ins/Ins vs. Del/Del: OR = 0.29, 95%CI = 0.14- 0.60, p < 0.001), but also with tumor stage. CRC patients carrying the Ins allele or Ins/Ins genotype had a significantly lower risk of stage III-IV tumors (Ins vs. Del: OR = 0.69, 95%CI = 0.53- 0.91; Ins/Ins vs. Del/Del: OR = 0.41, 95%CI = 0.18-0.94). Functional research revealed that the rs34000982 Ins allele enabled hsa-miR-944 to interact with the 3' untranslated region of HMGB1. In addition, HMGB1 gene expression levels were associated not only with multiple immune cell infiltration, but also with multiple anti-CRC drug sensitivities. The current findings suggest that the HMGB1 rs34000982 polymorphism may serve as a marker of CRC susceptibility and progression in the Chinese population, and HMGB1 levels may serve as an anti-CRC drug sensitivity marker.

Determination of the different short oligonucleotide features in the full genome of fatal and mild coronavirus strains can show the researchers how these viruses evolved and became virulent strains. To this aim, at first, in the full genome of all coronavirus strains included in this study, the observed and expected frequency of dinucleotide to hexanucleotide was obtained using Markov method. Then odds ratio (observed/expected abundances) of short oligonucleotide was computed and considered as the raw data (features). Finally, ten distinct weighting algorithms approaches (Information Gain, Information Gain Ratio, Rule, Deviation, Chi Squared, Gini Index, Uncertainty, Relief, Support Vector Machine (SVM), and PCA) was employed on the features to identify oligonucleotide distribution differences across the full genome of SARS-related viruses compared to common cold coronaviruses. Totally among 5440 features (16 dinucleotides, 64 trinucleotides, 256 tetra nucleotides, 1024 penta-nucleotides, and 4096 Hexa-nucleotides), CC, CCA, CCAC, ACCAC, and CACCAC motifs were selected by 80 -90% of all weighting algorithms models to distinguish virulent strains from mild coronaviruses. These remarkable oligonucleotides might point toward the existence of some particular RNA elements that might be involved in viral virulence and thus can be targeted for viral treatment in the future.

The potential of neurotransmitters and neural hormones as possible G-quadruplex DNA binders was analyzed using fluorescence spectroscopy, surface-enhanced Raman spectroscopy (SERS), DNA melting analysis, and molecular docking. G-quadruplex sequences, (GGC)₃ and G₄C₂, with roles in Fragile X syndrome and amyotrophic lateral sclerosis (ALS), respectively, were selected, and their interactions with melatonin, serotonin, and gamma-aminobutyric acid (GABA), were studied. Both melatonin and serotonin demonstrated strong interactions with the DNA sequences with hydrogen bonding being the primary mode of interaction, with some non-intercalative interactions involving the π systems. GABA demonstrated much weaker interactions and may not be a suitable candidate as a probe for low concentrations of G-quadruplex DNA.

A novel acid-cleavable triazene linker was synthesized and then reacted with modified 2'-deoxyuridine triphosphate (dUTP), followed by Cy3 NHS ester, the final product serves as an excellent reversible terminator for DNA sequencing by synthesis (DNA SBS). The synthesized dye-labeled terminator incorporated into DNA strand faithfully in a DNA-elongation, and the fluorophore incorporated into DNA strands was cleaved completely under weak acidic conditions within short time. Further the first cleaved product can be incorporated with 100% efficiency for the second time. These preliminary evaluations show that the triazene reversible terminator has a great potential value in DNA sequencing.

Vascular calcification is a common complication of chronic kidney disease (CKD). The molecular mechanisms underlying this condition and the efficacy of potential treatments remain unclear. Bioinformatic methods were employed to analyze gene ontology (GO) annotations and pathway enrichments. Subsequently, an analysis of potential therapeutic agents for vascular calcification in CKD was performed. A total of 76 common genes, 181 enriched GO annotations-comprising 153 biological processes, 10 cellular components, and 18 molecular functions-41 KEGG pathways, 13 REACTOME pathways, and 3 BIOCARTA pathways were identified. Five key genes (PSMC5, TNFSF11, TNFRSF11A, TNFRSF12A, and ICAM1) were isolated. Most notably, the top five potential therapeutic drugs-ENAVATUZUMAB, DENOSUMAB, ALICAFORSEN, BI-505, and ENLIMOMAB PEGOL-were identified for vascular calcification in CKD. However, further molecular biological experiments are required to confirm these findings.

The substances that cause abnormal DNA structures are known as DNA damage-inducing factors, and their resulting DNA damage has been extensively studied and proven to be closely related to cancer, neurodegenerative diseases, and aging. Prolonged exposure to DNA damage-inducing factors can lead to a variety of difficult-to-treat diseases, yet these factors have not been well summarized. It is crucial to use a combination of environmental science and life science to gain a deep understanding of the environmental sources and biological consequences of DNA damage-inducing factors for mechanistic research and prevention of diseases such as cancer. This article selected 14 representative carcinogenic exogenous DNA damage-inducing factors and summarized them through a literature search, including both exogenous and endogenous DNA damage factors, and explored the types of DNA damage caused by the relevant damage factors.