RESUMO
BACKGROUND: Ulcerative colitis (UC) is defined by persistent inflammatory processes within the gastrointestinal tract of uncertain etiology. Current therapeutic approaches are limited in their ability to address oxidative stress, inflammation, barrier function restoration, and modulation of gut microbiota in a coordinated manner to maintain intestinal homeostasis. RESULTS: This study involves the construction of a metal-phenolic nanozyme (Cur-Fe) through a ferric ion-mediated oxidative coupling of curcumin. Cur-Fe nanozyme exhibits superoxide dismutase (SOD)-like and â¢OH scavenging activities, demonstrating significant anti-inflammatory and anti-oxidant properties for maintaining intracellular redox balance in vitro. Drawing inspiration from Escherichia coli Nissle 1917 (EcN), a biomimetic Cur-Fe nanozyme (CF@EM) is subsequently developed by integrating Cur-Fe into the EcN membrane (EM) to improve the in vivo targeting ability and therapeutic effectiveness of the Cur-Fe nanozyme. When orally administered, CF@EM demonstrates a strong ability to colonize the inflamed colon and restore intestinal redox balance and barrier function in DSS-induced colitis models. Importantly, CF@EM influences the gut microbiome towards a beneficial state by enhancing bacterial diversity and shifting the compositional structure toward an anti-inflammatory phenotype. Furthermore, analysis of intestinal microbial metabolites supports the notion that the therapeutic efficacy of CF@EM is closely associated with bile acid metabolism. CONCLUSION: Inspired by gut microbes, we have successfully synthesized a biomimetic Cur-Fe nanozyme with the ability to inhibit inflammation and restore intestinal homeostasis. Collectively, without appreciable systemic toxicity, this work provides an unprecedented opportunity for targeted oral nanomedicine in the treatment of ulcerative colitis.
Assuntos
Colite Ulcerativa , Microbioma Gastrointestinal , Homeostase , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Animais , Homeostase/efeitos dos fármacos , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Curcumina/farmacologia , Curcumina/química , Camundongos Endogâmicos C57BL , Escherichia coli/efeitos dos fármacos , Administração Oral , Biomimética/métodos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Modelos Animais de Doenças , Antioxidantes/farmacologia , Antioxidantes/químicaRESUMO
OBJECTIVE: MicroRNAs (miRNAs) have been recognized as possible biomarkers for Alzheimer's disease (AD). MiR-142-5p has been reported to be abnormally expressed in brain tissues. However, the role of miR-142-5p in AD pathogenesis keeps unclear. This study aimed to investigate the effect of miR-142-5p on the learning and memory of AD rats via regulation of protein tyrosine phosphatase nonreceptor type 1 (PTPN1)-mediated protein kinase B (Akt) pathway. METHODS: The AD model was established by injection of Aß1-42 oligomer once into the lateral ventricle of rats, and the spatial learning and memory ability of rats was measured. AD rats were injected with miR-142-5p or PTPN1 vectors to explore their functions in inflammation, Aß, p-tau protein, apoptosis in brain tissues, and the effects on Akt pathway. The targeting relationship between miR-142-5p and PTPN1 was detected. RESULTS: Overexpressed miR-142-5p, down-regulated PTPN1 and inactivated Akt pathway were exhibited in AD. MiR-142-5p targeted PTPN1 to mediate Akt pathway. Reduced miR-142-5p and elevated PTPN1 improved the behavior of AD rats. MiR-142-5p targeted PTPN1 to effectively inhibit Aß formation and abnormal phosphorylation of p-tau protein, suppress the inflammation in the brain tissues of AD rat, and improve the survival rate of brain tissue cells. MiR-142-5p regulated PTPN1 to activate the Akt pathway, further inhibiting the apoptosis of brain neurons in AD rats. CONCLUSION: Down-regulating miR-142-5p targets PTPN1 to activate Akt pathway, thus improving the learning and memory of AD rats and playing an anti-AD role.
Assuntos
Doença de Alzheimer , MicroRNAs , Ratos , Animais , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Hipocampo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose , Inflamação/metabolismoRESUMO
As a noninvasive treatment approach for cancer and other diseases, sonodynamic therapy (SDT) has attracted extensive attention due to the deep penetration of ultrasound, good focusing, and selective irradiation sites. However, intrinsic limitations of traditional sonosensitizers hinder the widespread application of SDT. With the development of nanotechnology, nanoparticles as sonosensitizers or as a vehicle to deliver sonosensitizers have been designed and used to target tissues or tumor cells with high specificity and accuracy. Autophagy is a common metabolic alteration in both normal cells and tumor cells. When autophagy happens, a double-membrane autophagosome with sequestrated intracellular components is delivered and fused with lysosomes for degradation. Recycling these cell materials can promote survival under a variety of stress conditions. Numerous studies have revealed that both apoptosis and autophagy occur after SDT. This review summarizes recent progress in autophagy activation by SDT through multiple mechanisms in tumor therapies, drug resistance, and lipid catabolism. A promising tumor therapy, which combines SDT with autophagy inhibition using a nanoparticle delivering system, is presented and investigated.