Cobalt-Catalyzed Cascade C-H Activation/Annulation Polymerizations toward Diversified and Multifunctional Sulfur-Containing Fused Heterocyclic Polymers.

Transition-metal-catalyzed C-H activation has greatly benefited the synthesis and development of functional polymer materials, and the construction of multifunctional fused (hetero)cyclic polymers via novel C-H activation-based polyannulations has emerged as a charming but challenging area in recent years. Herein, we report the first cobalt(III)-catalyzed cascade C-H activation/annulation polymerization (CAAP) approach that can efficiently transform readily available aryl thioamides and internal diynes into multifunctional sulfur-containing fused heterocyclic (SFH) polymers. Within merely 3 h, a series of SFH polymers bearing complex and multisubstituted S,N-doped polycyclic units are facilely and efficiently produced with high molecular weights (absolute Mn up to 220400) in excellent yields (up to 99%), which are hard to achieve by traditional methods. The intermediate-terminated SFH polymer can be used as a reactive macromonomer to controllably extend or modify polymer main chains. The structural diversity can be further enriched through facile S-oxidation and N-methylation reactions of the SFH polymers. Benefiting from the unique structures, the obtained polymers exhibit excellent solution processability, high thermal and morphological stability, efficient and readily tunable aggregate-state fluorescence, stimuli-responsive properties, and high and UV-modulatable refractive indices of up to 1.8464 at 632.8 nm. These properties allow the SFH polymers to be potentially applied in diverse fields, including metal ion detection, photodynamic killing of cancer cells, fluorescent photopatterning, and gradient-index optical materials.

NFIC mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to represses malignant phenotype of non-small cell lung cancer cells.

BACKGROUND: Multiple genetic and epigenetic regulatory mechanisms are crucial in the development and tumorigenesis process. Transcriptional regulation often involves intricate relationships and networks with post-transcriptional regulatory molecules, impacting the spatial and temporal expression of genes. However, the synergistic relationship between transcription factors and N6-methyladenosine (m6A) modification in regulating gene expression, as well as their influence on the mechanisms underlying the occurrence and progression of non-small cell lung cancer (NSCLC), requires further investigation. The present study aimed to investigate the synergistic relationship between transcription factors and m6A modification on NSCLC. METHODS: The transcription factor NFIC and its potential genes was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). The association of NFIC and its potential target genes were validated through ChIP-qPCR and dual-luciferase reporter assays. Additionally, the roles of NFIC and its potential genes in NSCLC were detected in vitro and in vivo through silencing and overexpression assays. RESULTS: Based on multi-omics data, the transcription factor NFIC was identified as a potential tumor suppressor of NSCLC. NFIC was significantly downregulated in both NSCLC tissues and cells, and when NFIC was overexpressed, the malignant phenotype and total m6A content of NSCLC cells was suppressed, while the PI3K/AKT pathway was inactivated. Additionally, we discovered that NFIC inhibits the expression of METTL3 by directly binding to its promoter region, and METTL3 regulates the expression of KAT2A, a histone acetyltransferase, by methylating the m6A site in the 3'UTR of KAT2A mRNA in NSCLC cells. Intriguingly, NFIC was also found to negatively regulate the expression of KAT2A by directly binding to its promoter region. CONCLUSIONS: Our findings demonstrated that NFIC suppresses the malignant phenotype of NSCLC cells by regulating gene expression at both the transcriptional and post-transcriptional levels. A deeper comprehension of the genetic and epigenetic regulatory mechanisms in tumorigenesis would be beneficial for the development of personalized treatment strategies.

YY1-induced lncRNA00511 promotes melanoma progression via the miR-150-5p/ADAM19 axis.

Increasing evidence indicates that long noncoding RNAs (lncRNAs) are therapeutic targets and key regulators of tumors development and progression, including melanoma. Long intergenic non-protein-coding RNA 511 (LINC00511) has been demonstrated as an oncogenic molecule in breast, stomach, colorectal, and lung cancers. However, the precise role and functional mechanisms of LINC00511 in melanoma remain unknown. This study confirmed that LINC00511 was highly expressed in melanoma cells (A375 and SK-Mel-28 cells) and tissues, knockdown of LINC00511 could inhibit melanoma cell migration and invasion, as well as the growth of subcutaneous tumor xenografts in vivo. By using Chromatin immunoprecipitation (ChIP) assay, it was demonstrated that the transcription factor Yin Yang 1 (YY1) is capable of binding to the LINC00511 promoter and enhancing its expression in cis. Further mechanistic investigation showed that LINC00511 was mainly enriched in the cytoplasm of melanoma cells and interacted directly with microRNA-150-5p (miR-150-5p). Consistently, the knockdown of miR-150-5p could recover the effects of LINC00511 knockdown on melanoma cells. Furthermore, ADAM metallopeptidase domain expression 19 (ADAM19) was identified as a downstream target of miR-150-5p, and overexpression of ADAM19 could promote melanoma cell proliferation. Rescue assays indicated that LINC00511 acted as a competing endogenous RNA (ceRNA) to sponge miR-150-5p and increase the expression of ADAM19, thereby activating the PI3K/AKT pathway. In summary, we identified LINC00511 as an oncogenic lncRNA in melanoma and defined the LINC00511/miR-150-5p/ADAM19 axis, which might be considered a potential therapeutic target and novel molecular mechanism the treatment of patients with melanoma.

Diagnostic and prognostic potential of exosome non-coding RNAs in bladder cancer: a systematic review and meta-analysis.

Background: Bladder cancer stands as the predominant malignant tumor in the urological system, presenting a significant challenge to public health and garnering extensive attention. Recently, with the deepening research into tumor molecular mechanisms, non-coding RNAs (ncRNAs) have emerged as potential biomarkers offering guidance for the diagnosis and prognosis of bladder cancer. However, the definitive role of ncRNAs in bladder cancer remains unclear. Hence, this study aims to elucidate the relevance and significance of ncRNAs through a Meta-analysis. Methods: A systematic meta-analysis was executed, including studies evaluating the diagnostic performance of ncRNAs and their associations with overall survival (OS) and disease-free survival (DFS). Key metrics such as hazard ratios, sensitivity, specificity, and diagnostic odds ratios were extracted and pooled from these studies. Potential publication bias was assessed using Deeks' funnel plot, and the robustness of the results was ascertained through a sensitivity analysis. Results: Elevated ncRNA expression showed a positive correlation with improved OS, evidenced by a hazard ratio (HR) of 0.82 (95% CI: 0.66-0.96, P<0.001). Similarly, a significant association was observed between heightened ncRNA expression and DFS, with an HR of 0.86 (95% CI: 0.73-0.99, P<0.001). Diagnostic performance analysis across 17 articles yielded a pooled sensitivity of 0.76 and a specificity of 0.83. The diagnostic odds ratio was recorded at 2.71, with the area under the ROC curve (AUC) standing at 0.85. Conclusion: Exosome ncRNAs appear to possess potential significance in the diagnostic and prognostic discussions of bladder cancer. Their relationship with survival outcomes and diagnostic measures suggests a possible clinical utility. Comprehensive investigations are needed to fully determine their role in the ever-evolving landscape of bladder cancer management, especially within the framework of personalized medicine.

METTL3 exerts synergistic effects on m6A methylation and histone modification to regulate the function of VGF in lung adenocarcinoma.

BACKGROUND: Multiple genetic and epigenetic regulatory mechanisms play a vital role in tumorigenesis and development. Understanding the interplay between different epigenetic modifications and its contribution to transcriptional regulation in cancer is essential for precision medicine. Here, we aimed to investigate the interplay between N6-methyladenosine (m6A) modifications and histone modifications in lung adenocarcinoma (LUAD). RESULTS: Based on the data from public databases, including chromatin property data (ATAC-seq, DNase-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and gene expression data (RNA-seq), a m6A-related differentially expressed gene nerve growth factor inducible (VGF) was identified between LUAD tissues and normal lung tissues. VGF was significantly highly expressed in LUAD tissues and cells, and was associated with a worse prognosis for LUAD, silencing of VGF inhibited the malignant phenotype of LUAD cells by inactivating the PI3K/AKT/mTOR pathway. Through the weighted correlation network analysis (WGCNA) and integration of TCGA-LUAD RNA-seq and m6A methyltransferase METTL3-knockdown RNA-seq data, a significant positive correlation between METTL3 and VGF was observed. By using the MeRIP-qPCR and dual-luciferase reporter assays, we demonstrated that METTL3 knockdown decreased m6A modification level of VGF coding sequences in LUAD cells, the colorimetric m6A quantification assay also showed that METTL3 knockdown significantly decreased global m6A modification level in LUAD cells. Interestingly, we found that METTL3 knockdown also reduced VGF expression by increasing H3K36me3 modification at the VGF promoter. Further research revealed that METTL3 knockdown upregulated the expression of histone methylase SETD2, the major H3K36me3 methyltransferase, by methylating the m6A site in the 3'UTR of SETD2 mRNA in LUAD cells. CONCLUSIONS: Overall, our results reveal that the expression of VGF in LUAD cells is regulated spatio-temporally by METTL3 through both transcriptional (via histone modifications) and post-transcriptional (via m6A modifications) mechanisms. The synergistic effect of these multiple epigenetic mechanisms provides new opportunities for the diagnosis and precision treatment of tumors.

Catalyst-free synthesis of diverse fluorescent polyoxadiazoles for the facile formation and morphology visualization of microporous films and cell imaging.

The development of facile polymerizations toward functional heterocyclic polymers is of great significance for chemistry and materials science. As an important class of heterocyclic polymers, polyoxadiazoles (PODs) have found applications in various fields. However, the synthetic difficulties of PODs greatly restrict their structural diversity and property investigation. Herein, we report a series of catalyst-free multicomponent polymerizations (MCPs) that can facilely synthesize functional PODs with well-defined and diversified topological structures from commercially available or readily accessible aldehydes, carboxylic acids, secondary amines, and (N-isocyanimino)triphenylphosphorane at room temperature. Unlike conventional Ugi polycondensations, the present Ugi-type MCPs can in situ generate oxadiazole moieties in polymer backbones. The obtained PODs possess good solubility, high thermal and morphological stability, and excellent film-forming ability. The introduction of aggregation-induced emission (AIE) moieties together with the inherent structural features of PODs endow these polymers with multiple functionalities. The AIE-active linear PODs can form fluorescent microporous films with stable and ordered structures based on the simple breath figure patterning method, and the self-assembly morphologies can be directly visualized by fluorescence microscopy in a high-contrast and sensitive manner. Moreover, both the linear and hyperbranched AIE-active PODs possess excellent biocompatibility, good lysosome specificity, and excellent photobleaching resistance, which enable them to serve as promising lysosome-specific fluorescent probes in biological imaging.

Autonomous Visualization of Damage in Polymers by Metal-Free Polymerizations of Microencapsulated Activated Alkynes.

The development of autonomous materials with desired performance and built-in visualizable sensing units is of great academic and industrial significance. Although a wide range of damage indication methods have been reported, the "turn-on" sensing mechanism by damaging events based on microcapsule systems, especially those relying on chemical reactions to elicit a chromogenic response, are still very limited. Herein, a facile and metal-free polymerization route with an interesting reaction-induced coloration effect is demonstrated. Under the catalysis of 1,4-diazabicyclo[2.2.2]octane (DABCO), the polymerizations of difunctional or trifunctional activated alkynes proceed very quickly at 0 °C in air. A series of polymers composed of stereoregular enyne structure (major unit) and divinyl ether structure (minor unit) are obtained. Both the catalyst and monomers are colorless while the polymerized products are deep-colored. This process can be applied for the damage visualization of polymers using the microencapsulation technique. Microcapsules containing the reactive alkyne monomer are prepared and mixed in a DABCO-dispersed polymer film. Both the external and internal damage regions of this composite film can be readily visualized once the reaction is initiated from the ruptured microcapsules. Moreover, the newly formed polymer automatically seals the cracks with an additional protection function.

Microwave-assisted fabrication of copper-functionalized carbon quantum dots for sensitive detection of histidine.

Fluorescent carbon quantum dots are emerging as a new class of fluorescent probes due to their unique optical properties. Herein, we presented a simple, one-pot and effective preparation strategy for copper-functionalized carbon quantum dots (Cu-CDs). The Cu-CDs demonstrated excitation-independent emissions, high fluorescent quantum yield (~ 24.4%) and excellent fluorescent stability. The fluorescence of Cu-CDs could be quenched efficiently in the presence of histidine (His) due to the coordination occurring between surface Cu and imidazole side chains of His. Thus, the Cu-CDs could be used as an efficient fluorescent probe for His detection. Under optimal conditions, the fluorescent signals of Cu-CDs decreased linearly with the concentrations of His over a range of 0.1-15 µM. The detection limit was 30 nM. The proposed method provided obvious advantages of rapid response, convenience, simplicity, high selectivity and sensitivity. Moreover, good results also have been obtained for His detection in real biological fluid samples.