Nucleosides, Nucleotides & Nucleic Acids最新文献

Spectral studies of nucleotides are typically conducted for their deprotonated forms; consequently, there is a paucity of knowledge regarding the fluorescent properties of protonated nucleotide forms. Therefore, this work aimed to analyze and compare their spectral properties under conditions close to biological systems. We studied the absorption, excitation and emission of protonated and deprotonated forms of monoribonucleotides and their components dissolved in water at room temperature. From the data obtained, we calculated values for the energies of the first excited singlet electronic levels of the de- and protonated forms of nucleotides and their constituents. The most significant difference between the energies of the first excited states of the protonated and deprotonated forms of nucleotides was observed for uridine monophosphate. We observed a change in the ratio of bands in the absorption, excitation and fluorescence spectra of protonated and deprotonated forms of nucleotides.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors, making it unresponsive to targeted hormonal and HER2-based therapies. Current treatment options, including chemotherapy and radiation, have limited efficacy and are associated with severe side effects, emphasizing the need for innovative therapeutic strategies. Aptamer-siRNA conjugates have emerged as a promising gene-silencing approach, leveraging the high specificity of nucleic acid aptamers to selectively deliver short interfering RNA (siRNA) to TNBC cells. Aptamers, single-stranded DNA or RNA molecules generated via SELEX, exhibit nanomolar-range binding affinities (Kd ∼0.5-2.5 nM) for TNBC biomarkers such as EGFR, EpCAM, nucleolin, and MUC1, enabling receptor-mediated internalization of siRNA. Preclinical studies have demonstrated that aptamer-siRNA conjugates enhance cellular uptake by 5-10-fold, improve gene silencing efficiency (80-95%), and extend siRNA stability in circulation (from <2 h to 6-9 h). In xenograft models, aptamer-siRNA therapies have shown tumor volume reductions of 60-85%, outperforming non-targeted siRNA and chemotherapy. However, challenges such as nuclease degradation, immune responses, endosomal escape, and large-scale production remain significant hurdles to clinical translation. Recent advances in chemical modifications, lipid-based carriers, and artificial intelligence-driven aptamer design are addressing these limitations, paving the way for personalized, precision RNAi-based therapeutics. This review explores the mechanisms, recent advancements, challenges, and future directions of aptamer-siRNA therapeutics, providing a comprehensive analysis of their potential to revolutionize TNBC treatment by offering targeted, effective, and less toxic gene-silencing approaches.

Colon cancer is one of the most common cancers in worldwide. Emerging evidence has demonstrated distinct patterns of immune infiltration between left colon cancer (LCC) and right colon cancer (RCC), classified according to primary tumor location. However, the underlying mechanism was still unknown. Here, we identified 111 more up-regulated genes (MURGs) including PD1 (PDCD1) and CTLA4 in RCC and 166 more down-regulated genes (MDRGs) in LCC, all participating in immune-related biological processes. Notably, CD83, CXCR4 and ISL1 emerged as reversely regulated immune-related genes (IRGs) showing opposite regulation patterns between the two cancer types. Through regulatory network analysis, we found that genetic mutations predominantly drive enhanced immune infiltration in RCC through IRG up-regulation, whereas DNA methylation-mediated IRG suppression accounts for diminished immune responses in LCC. Furthermore, prognostic models based on these IRGs with high-quality were constructed in LCC and RCC respectively. In conclusion, our results provide crucial insights into the divergent immunoregulatory mechanisms governing LCC and RCC, potentially facilitating the discovery of novel biomarkers for prognosis prediction and targeted therapy.

Background: MicroRNAs play an extensive role in human chronic kidney diseases (CKD), but the role of miR-922 remains unclear.

Purpose: This study was designed to investigate the potential mechanism by which miR-922 acts in CKD.

Methods: The human proximal renal tubular cell line (HK-2) was treated by LPS to build a CKD cell model. The expressions of miR-922, TGFβR1, and p-Smad2/3 were detected by RT-qPCR or western blotting. The dual-luciferase reporter assay verified the interaction of miR-922 with TGFβR1. Cell viability and apoptosis were assessed using the CCK-8 assay and Annexin V-FITC/PI method. An ELISA kit was used for the measure of TNF-α/IL-1β levels.

Results: MiR-922 was scanty in HK-2 cells with LPS treatment. MiR-922 was an upstream regulator of TGFβR1. The up-regulation of miR-922 restrained TGFβR1 expression, thereby hindering the activation of Smad2/3. Overexpression of miR-922 and inhibition of Smad2/3 alleviated the LPS-induced apoptosis and inflammation, while TGFβR1 played a pro-apoptotic and pro-inflammatory role.

Conclusion: MiR-922 rescued HK-2 cell apoptosis and inflammation damage induced by LPS through negative regulation of TGF-β/Smad pathway, which may be a vital molecular mechanism of CKD.

Lung squamous cell carcinoma (LUSC), a prevalent non-small cell lung cancer subtype, demonstrates marked heterogeneity and unpredictable prognosis. This study established a prognostic model using STING pathway-related genes to stratify LUSC patients and guide immunotherapy. Through weighted gene co-expression network analysis of TCGA-LUSC data, we identified the MEbrown module containing 13 STING-associated key genes (including CD47 and CLDN5) to develop the STING Pathway Death-Related Signature (SPDRS). LASSO regression refined the model, which effectively stratified patients into distinct high- and low-risk groups with significant survival differences. High-risk patients exhibited enhanced immune infiltration, particularly T cells CD4 memory resting and M2 macrophages, along with elevated immune checkpoint expression and stromal scores. Functional analyses revealed enrichment in immune-related pathways and tumor microenvironment regulation. Drug sensitivity predictions identified potential therapeutic agents targeting SPDRS components. A nomogram integrating SPDRS with clinical factors demonstrated strong prognostic accuracy. This work provides a novel STING pathway-based stratification system that elucidates tumor microenvironment heterogeneity and informs personalized treatment strategies. The findings highlight SPDRS as both a prognostic biomarker and therapeutic response predictor, advancing precision immunotherapy in LUSC management.

Examination of structures of DNA duplexes (A-, B-, and Z-DNA) showed a positive correlation between the pseudorotational phase angle P and the torsion angle δ_H (H4'-C4'-C3'-H3'). Such a P - δ_H plot reflects the structural features of the three types of DNA duplexes. Since the δ_H torsion angle can be measured by nuclear magnetic resonance, the linear correlation between P and δ_H provides a useful method for predicting the sugar pucker of nucleosides and nucleic acids.

Cancer cells often evade immune detection and destruction by inducing immune suppression genes, which include CTLA-4, TGF-β, and PD-L1, that inhibit immune responses and promote tumour progression. Recent studies have highlighted the significance of non-coding RNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in regulating these immune suppression pathways. miRNAs, short RNA molecules that target mRNA of immune genes at the post-transcription level and influence gene expression. Similarly, lncRNAs, which act as molecular scaffolds, sponges, or regulators of gene expression, are involved in modulating immune responses by interacting with miRNAs or directly binding to immune-related genes. This review explores the complex interplay between miRNAs, lncRNAs, and immune suppression genes, detailing how these non-coding RNAs contribute to immune evasion in cancer. Furthermore, the therapeutic potential of targeting these regulatory networks is examined, highlighting current strategies and challenges in using miRNA and lncRNA modulators to enhance anti-tumour immunity. Understanding these intricate regulatory networks offers new insights into the mechanisms of immune suppression in cancer and opens avenues for developing novel therapeutic interventions to restore immune surveillance and improve the efficacy of cancer immunotherapies.

Contemporary cancer treatments encompass diverse strategies like surgery, chemotherapy, radiation, immunotherapy, and targeted therapies, aiming for effective cancer cell control with minimal impact on healthy tissues. Aptamers are short nucleotide sequences typically containing 25-80 bases and can attach to specific target molecules as effectively as monoclonal antibodies. While the FDA has yet to approve any aptamers for oncology applications, a few, such as Pegaptanib (Macugen), have been approved for ophthalmologic conditions like age-related macular degeneration. Pegaptanib and Izervay are the approved aptamers against age-related macular degeneration (AMD) that target vascular endothelial growth factor (VEGF) and block complement component protein C5, respectively. A new type of highly sensitive and specific biosensor has recently been created to detect leukaemia cancer cells. Aptamosomes, encapsulating drugs like doxorubicin, effectively reduce tumour size and are highly advantageous over targeted drug delivery. Many aptamers have been generated against ERα, Epithelial cell adhesion molecule, EGFR, B subunit of platelet-derived growth factor, Vimentin, Osteopontin, Type II membrane protein PSMA, MUC-1, AXL receptor tyrosine kinase, CD28 agonistic aptamer, as well as for the B7-CD28 interaction, etc. This review suggests the pros and cons of aptamer usage and its advantages over antibody treatment. It also outlines the roles of aptamers and connects their modes of action with specific cancer types. The content is highly detailed, providing a comprehensive understanding of aptamer therapy and its applications.

Axitinib is an oral medication classified as a second-generation tyrosine kinase inhibitor. It serves as a primary treatment for metastatic renal cell carcinoma (RCC) due to its strong affinity for DNA, which leads to the disruption of the double helix structure. This disruption ultimately halts the cell cycle and induces senescence and mitotic catastrophe in RCC cells. Consequently, investigating the mechanism by which Axitinib binds to DNA is essential for comprehending its pharmacodynamic properties and for the advancement of more effective DNA-binding therapeutics. The present study aimed to examine the interaction between Axitinib and DNA through various analytical techniques, including UV-Vis spectroscopy, thermal denaturation assays, electrochemical methods, and fluorescence emission spectroscopy. According to the electrochemical studies, the binding constant (K_b) for Axitinib was calculated to be (5.13 ± 0.28) × 10⁴, suggesting the potential for groove binding. This finding was further supported by in-silico analyses, where molecular docking and molecular dynamics simulations indicated that the drug selectively binds to the DNA minor groove through partial intercalation, forming new hydrogen bonds with its functional groups while separating the guanine and cytosine base pairs.

Understanding the interaction of therapeutic drugs with DNA is crucial for designing highly selective DNA-targeted medicines that could overcome the current therapeutic limitations. In this endeavour, the DNA binding behaviour of arbutin (ATN) was explored using multi-spectroscopic, electrochemical and computational studies. The UV-Vis spectral studies authenticated the complexation of ATN with CT-DNA and exposed ATN as a moderately strong DNA binder with a binding constant of 8.029 × 10³ M^-1. The findings of fluorescence spectral studies not only revealed the spontaneous ground state complex formation between ATN and CT-DNA, but also emphasised the role of hydrogen bonding and Van der Waals interactions in stabilising the ATN/CT-DNA complex. Since the competitive dye displacement assay strongly excluded the plausibility of classical intercalation and conventional groove binding mode of ATN, viscosity studies provided clues regarding the external binding mode of ATN. The appreciable enhancement resulted in the fluorescence emission of the ATN/CT-DNA complex upon increasing NaCl concentration, which certified ATN as an external binder. The CD spectral results exposed the ATN-induced moderate conformational alterations in CT-DNA. Remarkably, the voltammetric titration results labelled the glucopyranoside moiety of ATN as a DNA binding unit with a formation constant of 2.57 × 10⁴ M^-1 rather than the hydroquinone moiety of ATN. Molecular docking and metadynamics simulation outcomes served as pictorial evidence of experimental results. They revealed the predominant contribution of hydrogen bonding interactions in stabilising ATN/DNA complexation.