RESUMO
Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates ß-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of ß-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.
Assuntos
5-Metilcitosina , 5-Metilcitosina/análogos & derivados , Proteínas de Ligação a DNA , Dioxigenases , Glioma , Proteínas Musculares , Humanos , 5-Metilcitosina/metabolismo , beta Catenina/metabolismo , Cromatina , Antígeno CD47/genética , RNA , Evasão da Resposta Imune , Glioma/patologia , RNA Mensageiro/metabolismo , Metiltransferases/metabolismo , RNA Nuclear Pequeno , Microambiente Tumoral , Fatores de Processamento de RNA/genética , Proteínas Repressoras/metabolismoRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unknown etiology. It is associated with various factors and causes great inconvenience to the patient's life. The gut-brain axis (GBA), which serves as a bidirectional information channel for exchanging information between the gut microbiota and the brain, is vital in studying many neurodegenerative diseases. Dietary flavonoids provide anti-inflammatory and antioxidant benefits, as well as regulating the structure and function of the gut microbiota. The occurrence and development of ASD are associated with dysbiosis of the gut microbiota. Modulation of gut microbiota can effectively improve the severity of ASD. This paper reviews the links between gut microbiota, flavonoids, and ASD, focusing on the mechanism of dietary flavonoids in regulating ASD through the GBA.
Assuntos
Transtorno do Espectro Autista , Eixo Encéfalo-Intestino , Flavonoides , Microbioma Gastrointestinal , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Transtorno do Espectro Autista/microbiologia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/dietoterapia , Flavonoides/farmacologia , Dieta , Disbiose , Encéfalo/metabolismo , Animais , Antioxidantes/farmacologiaRESUMO
Polygonatum sibiricum has anti-inflammatory effects and is one of the well-known functional foods. Polygonatum sibiricum polysaccharide (PSP), as a traditional medicinal and food homologous substance, can regulate the balance of intestinal flora and short chain fatty acid levels, reduce intestinal permeability and serum endotoxin levels, and inhibit the activation of astrocytes and microglia. It can significantly alleviate neurological diseases and improve cognitive impairment. Current evidence suggests that bidirectional communication between the central nervous system and the gastrointestinal tract may affect the human nervous system, cognition, and behavior through the gut-brain axis. This article provides a systematic review, detailing the biological activity of PSP, and explores the pathogenesis of gut microbiota signaling in cognitive impairment, providing a promising strategy for improving cognitive impairment.
RESUMO
Inorganic arsenic is a carcinogen repeatedly found in water and foods threatening global human health. Prior work applied the Gutzeit method and X-ray fluorescence spectroscopy to quantify inorganic arsenic based on a harmful chemical, i.e., mercury bromide, to capture the arsine gas. In this project, we explored silver nitrate as an alternative to mercury bromide for the capture and detection of inorganic arsenic. To compare the performance of mercury bromide and silver nitrate, two standard curves were established in the range from 0 to 33.3 µg/L after optimization of reaction conditions such as the quantity of reagents and reaction time. Our result shows silver nitrate-based standard curve had a lower limit of detection and limit of quantification at 1.02 µg/L and 3.40 µg/L, respectively, as compared to the one built upon mercury bromide that has limit of detection of 4.86 µg/L and limit of quantification of 16.2 µg/L. The relative higher sensitivity when using silver nitrate was contributed by the less interfering elements for X-ray fluorescence analysis and thus lower background signals. A commercial apple juice was studied for matrix inference, and the results show 85%-99% recoveries and 7.4%-24.5% relative standard deviation. In conclusion, we demonstrated silver nitrate is a better choice in terms of safety restrictions and detection capability at lower inorganic arsenic concentrations.