Protein arginine methyltransferases (PRMTs): Orchestrators of cancer pathogenesis, immunotherapy dynamics, and drug resistance.

Protein Arginine Methyltransferases (PRMTs) are a family of enzymes regulating protein arginine methylation, which is a post-translational modification crucial for various cellular processes. Recent studies have highlighted the mechanistic role of PRMTs in cancer pathogenesis, immunotherapy, and drug resistance. PRMTs are involved in diverse oncogenic processes, including cell proliferation, apoptosis, and metastasis. They exert their effects by methylation of histones, transcription factors, and other regulatory proteins, resulting in altered gene expression patterns. PRMT-mediated histone methylation can lead to aberrant chromatin remodeling and epigenetic changes that drive oncogenesis. Additionally, PRMTs can directly interact with key signaling pathways involved in cancer progression, such as the PI3K/Akt and MAPK pathways, thereby modulating cell survival and proliferation. In the context of cancer immunotherapy, PRMTs have emerged as critical regulators of immune responses. They modulate immune checkpoint molecules, including programmed cell death protein 1 (PD-1), through arginine methylation. Drug resistance is a significant challenge in cancer treatment, and PRMTs have been implicated in this phenomenon. PRMTs can contribute to drug resistance through multiple mechanisms, including the epigenetic regulation of drug efflux pumps, altered DNA damage repair, and modulation of cell survival pathways. In conclusion, PRMTs play critical roles in cancer pathogenesis, immunotherapy, and drug resistance. In this overview, we have endeavored to illuminate the mechanistic intricacies of PRMT-mediated processes. Shedding light on these aspects will offer valuable insights into the fundamental biology of cancer and establish PRMTs as promising therapeutic targets.

Highly sensitive electrochemical immunoassay integrated with polymeric nanocomposites and enhanced SiO2@Au core-shell nanobioprobes for SirT1 determination.

An ultra-highly sensitive electrochemical immunosensor for SirT1 (a key protein in age-related diseases) evaluation has been designed, employing polymeric nanocomposites as sensing platform and core-shell SiO2@Au to immobilize HRP-Ab2 as nanobioprobes. The approach includes chemical synthesis of PAMAM-Au-MWCNT nanocomposites (PNCs) with abundant PAMAM-Au nanoparticles immobilized on the MWCNT matrix, and biochemically synthesis of nanobioprobes with highly dispersed SiO2@Au tracing tags for successive efficient load functionalized enzyme-antibodies (HRP-Ab2). The PNCs nanocomposites could improve the efficiency of immune response via abundant capture antibodies (Ab1#1) on the electrode surface, and accelerate electron transfer through MWCNT and Au nanoparticles. Besides, the SiO2@Au was employed as tracing tags to label numerous HRP-Ab2 to further enhance signal readout during HRP-thionine-H2O2 system. Under optimal conditions, the signal intensity was linearly related to the concentration of SirT1 in the range of 20 pg mL-1 to 500 ng ml-1, and the limit of detection was 12.5 pg mL-1. It is noteworthy that the proposed immunoassay protocol has been successfully applied to evaluate SirT1 expression in cells by different treatment with high sensitivity and accuracy.

A ratiometric fluorescent probe for rapid and sensitive detection of biothiols in fetal bovine serum.

Herein, a ratiometric turn-on fluorescent probe for sensitive detection of biothiols was designed. The probe consisted of two parts: one was rhodamine B serving as a fluorescence reference, and the other was coumarin derivative as the responsive fluorophore with an acrylate group for biothiols recognition. The response was based on the mechanism of Michael addition and intramolecular cyclization reaction, and the probe showed ratiometric and sensitive response to biothiols. Especially, the detection limit of this probe for cysteine was found to be 0.13µΜ. More importantly, the probe showed the advantage of fast response, of which the fluorescence intensity can reach the maximum within 10min. The ratiometric fluorescent probe has been successfully applied for the determination of biothiols in fetal bovine serum samples and the result was in good agreement with that tested by Ellman method.

A Self-Assembled Ratiometric Polymeric Nanoprobe for Highly Selective Fluorescence Detection of Hydrogen Peroxide.

In this study, a dual-emission fluorescence resonance energy transfer (FRET) polymeric nanoprobe by single-wavelength excitation was developed for sensitive and selective hydrogen peroxide (H2O2) detection. Polymeric nanoprobe was prepared by simple self-assembly of functional lipopolymers, which were 4-carboxy-3-fluorophenylboronic acid (FPBA)-modified DSPE-PEG (DSPE-PEG-FPBA) and 7-hydroxycoumarin (HC)-conjugated DSPE-PEG (DSPE-PEG-HC). Subsequent binding of alizarin red S (ARS) to FPBA endowed the nanoprobe with a new fluorescence emission peak at around 600 nm. Because of the perfect match of the fluorescence emission spectra of HC with the absorbance spectra of ARS-FPBA, FRET was achieved between them. The sensing strategy for H2O2 was based on H2O2-induced deboronation reaction and boronic acid-mediated ARS fluorescence. Interaction between phenylboronic acid and ARS was revisited herein and it was found that electron-donating or -withdrawing group on phenylboronic acid (PBA) has significant influence on the fluorescence property of ARS, which enabled sensitive and selective H2O2 sensing. The nanoprobe displayed two well-separated emission bands (150 nm), providing high specificity and sensitivity for ratiometric detection of H2O2. Further application was exploited for the determination of glucose and the results demonstrated that the proposed strategy showed ratiometric response capability for glucose detection. The current method does not involve complicated organic synthesis and opens a new avenue for the construction of multifunctional polymeric fluorescent nanoprobe.

Hydrophobic-carbon-dot-based dual-emission micelle for ratiometric fluorescence biosensing and imaging of Cu2+ in liver cells.

Copper is closely related to liver damage, therefore, it is essential to develop a simple and sensitive strategy to detect copper ions (Cu2+) in liver cells. A hydrophobic carbon dots (HCDs)-based dual-emission fluorescent probe for Cu2+ was prepared by encapsulating HCDs in micelles formed by self-assembly of amphiphilic polymer DSPE-PEG and tetrakis (4-carboxyphenyl) porphyrin (TCPP)-modified DSPE-PEG. The obtained probe showed characteristic fluorescence emissions of HCDs and TCPP with large emission shift of 170nm with single-wavelength excitation. In the presence of Cu2+, the fluorescence of TCPP was quenched and that of HCDs remained unchanged, displaying ratiometric fluorescence response to Cu2+. The developed probe exhibited high sensitivity (detection limit down to 36nM) and selectivity to Cu2+ over other substances, and the probe was used to image the changes of Cu2+ level in liver cells successfully.

Selective amyloid ß oligomer assay based on abasic site-containing molecular beacon and enzyme-free amplification.

Amyloid-beta (Aß) oligomers are highly toxic species in the process of Aß aggregation and are regarded as potent therapeutic targets and diagnostic markers for Alzheimer's disease (AD). Herein, a label-free molecular beacon (MB) system integrated with enzyme-free amplification strategy was developed for simple and highly selective assay of Aß oligomers. The MB system was constructed with abasic site (AP site)-containing stem-loop DNA and a fluorescent ligand 2-amino-5,6,7-trimethyl-1,8-naphyridine (ATMND), of which the fluorescence was quenched upon binding to the AP site in DNA stem. Enzyme-free amplification was realized by target-triggered continuous opening of two delicately designed MBs (MB1 and MB2). Target DNA hybridization with MB1 and then MB2 resulted in the release of two ATMND molecules in one binding event. Subsequent target recycling could greatly amplify the detection sensitivity due to the greatly enhanced turn-on emission of ATMND fluorescence. Combining with Aß oligomers aptamers, the strategy was applied to analyze Aß oligomers and the results showed that it could quantify Aß oligomers with high selectivity and monitor the Aß aggregation process. This novel method may be conducive to improve the diagnosis and pathogenic study of Alzheimer's disease.

Activation of Mg(2+)-dependent DNAzymes based on AP site-containing triplex for specific melamine recognition.

Based on melamine binding-triggered triplex formation and subsequent activation of Mg(2+)-dependent DNAzymes, a novel strategy for DNAzyme regulation was proposed and developed for melamine recognition.