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Modulation of miR-466d-3p on Wnt signaling pathway in response to DEPs-induced blood-brain barrier disruption.
Jiang, Yue; Zhang, Ya; Suo, Huimin; Lv, Yanming; Liu, Siqi; Gao, Zhijian; Chen, Yingying; Zhang, Mingming; Meng, Xiangning; Gao, Shuying.
Afiliación
  • Jiang Y; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Zhang Y; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Suo H; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Lv Y; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Liu S; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Gao Z; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Chen Y; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China.
  • Zhang M; School of Bioinformatics, Harbin Medical University, Harbin 150081, China.
  • Meng X; Department of Medical Genetics, Harbin Medical University, Harbin 150081, China.
  • Gao S; Department of Toxicology, School of Public Health, Harbin Medical University, Harbin 150081, China. Electronic address: gsy@ems.hrbmu.edu.cn.
Ecotoxicol Environ Saf ; 284: 116869, 2024 Oct 01.
Article en En | MEDLINE | ID: mdl-39178759
ABSTRACT

BACKGROUND:

Diesel exhaust particles (DEPs), a predominant component of ambient particulate matter (PM), are classified as ultrafine particles with the capacity to penetrate the cerebral blood-brain barrier (BBB). This penetration is implicated in the pathogenesis of central nervous system (CNS) disorders. The integrity of the BBB is inextricably linked to cerebrovascular homeostasis and the development of neurodegenerative disease, highlighting the importance of studying the effects and mechanisms of DEPs on BBB function damage. METHODS AND

RESULTS:

Utilizing mouse cerebral microvascular endothelial cells (bEnd.3 cells) as an in vitro model of the BBB, we explored the detrimental effects of DEPs exposure on BBB permeability and integrity, with particular focus on inflammation, cell apoptosis, and miRNA expression profiles. Our findings revealed that exposure to DEPs at varying concentrations for 48 h resulted in the inhibition of bEND.3 cell proliferation, induction of cell apoptosis, and an upregulation in the secretion of inflammatory cytokines/chemokines and adhesion molecules. The BBB integrity was further compromised, as evidenced by a decrease in trans-epithelial electrical resistance(TEER), a reduction in cytoskeletal F-actin, and diminished tight junction (TJ) protein expression. Microarray analysis revealed that 23 miRNAs were upregulated and 11 were downregulated in response to a 50 µg/mL DEPs treatment, with miR-466d-3p being notably differentially expressed. Wnt3 was identified as a target of miR-466d-3p, with the Wnt signaling pathway being significantly enriched. We validated that miR-466d-3p expression was downregulated, and the protein expression levels of Wnt/ß-catenin and Wnt/PCP signaling components were elevated. The modulation of the Wnt signaling pathway by miR-466d-3p was demonstrated by the transfection of miR-466d-3p mimic, which resulted in a downregulation of Wnt3 and ß-catenin protein expression, and the mRNA level of Daam1, as well as an enhancement of TJ proteins ZO-1 and Claudin-5 expression.

CONCLUSIONS:

Our study further confirmed that DEPs can induce the disruption of BBB integrity through inflammatory processes. We identified alterations in the expression profile of microRNAs (miRNAs) in endothelial cells, with miR-466d-3p emerging as a key regulator of tight junction (TJ) proteins, essential for maintaining BBB integrity. Additionally, our findings primarily demonstrated that the Wnt/ ß-catenin and Wnt/PCP signaling pathway can be activated by DEPs and are regulated by miR-466d-3p. Under the combined effects of Wnt/PCP and inflammation, there is an ultimate increase in BBB hyperpermeability.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / MicroARNs / Vía de Señalización Wnt Límite: Animals Idioma: En Revista: Ecotoxicol Environ Saf Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / MicroARNs / Vía de Señalización Wnt Límite: Animals Idioma: En Revista: Ecotoxicol Environ Saf Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Países Bajos