Deoxynivalenol induces cell senescence in RAW264.7 macrophages via HIF-1 α-mediated activation of the p53/p21 pathway

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F24%3A10484171" target="_blank" >RIV/00179906:_____/24:10484171 - isvavai.cz</a>

Alternative codes found

RIV/62690094:18470/24:50021541

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=2v7b0J-IUF" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=2v7b0J-IUF</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.tox.2024.153868" target="_blank" >10.1016/j.tox.2024.153868</a>

Result language

angličtina

Original language name

Deoxynivalenol induces cell senescence in RAW264.7 macrophages via HIF-1 α-mediated activation of the p53/p21 pathway

Original language description

Deoxynivalenol (DON), a potent mycotoxin, exhibits strong immunotoxicity and poses a significant threat to human and animal health. Cell senescence has been implicated in the immunomodulatory effects of DON; however, the potential of DON to induce cell senescence remains inadequately explored. Emerging evidence suggests that hypoxia-inducible factor-1 alpha (HIF-1 alpha) serves as a crucial target of mycotoxins and is closely involved in cell senescence. To investigate this potential, we employed the RAW264.7 macrophage model and treated the cells with varying concentrations of DON (2-8 mu M) for 24 h. Transcriptome analysis revealed that 2365 genes were significantly upregulation while 2405 genes were significantly decreased after exposure to DON. KEGG pathway enrichment analysis demonstrated substantial enrichment in pathways associated with cellular senescence and hypoxia. Remarkably, we observed a rapid and sustained increase in HIF-1 alpha expression following DON treatment. DON induced cell senescence through the activation of the p53/p21WAF1/CIP1 (p21) and p16INK4A (p16) pathways, while also upregulating the expression of nuclear factor-kappa B, leading to the secretion of senescence-associated secretory phenotype (SASP) factors, including IL-6, IL-8, and CCL2. Crucially, HIF-1 alpha positively regulated the expression of p53, p21, and p16, as well as the secretion of SASP factors. Additionally, DON induced cell cycle arrest at the S phase, enhanced the activity of the senescence biomarker senescenceassociated beta-galactosidase, and disrupted cell morphology, characterized by mitochondrial damage. Our study elucidates that DON induces cell senescence in RAW264.7 macrophages by modulating the HIF-1 alpha/p53/p21 pathway. These findings provide valuable insights for the accurate prevention of DON-induced immunotoxicity and associated diseases.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Toxicology

ISSN

0300-483X

e-ISSN

1879-3185

Volume of the periodical

506

Issue of the periodical within the volume

AUG

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

10

Pages from-to

153868

UT code for WoS article

001259700900001

EID of the result in the Scopus database

2-s2.0-85196387633