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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/62690094:18470/24:50021541

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

Toxicology

ISSN

0300-483X

e-ISSN

1879-3185

Svazek periodika

506

Číslo periodika v rámci svazku

AUG

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

10

Strana od-do

153868

Kód UT WoS článku

001259700900001

EID výsledku v databázi Scopus

2-s2.0-85196387633