Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats.
Administration, Oral
Animals
Apoptosis
/ drug effects
Ellagic Acid
/ administration & dosage
Gene Expression Regulation
/ drug effects
Humans
Male
Malondialdehyde
/ metabolism
Methotrexate
/ adverse effects
Mitochondria
/ drug effects
NF-E2-Related Factor 2
/ metabolism
NF-KappaB Inhibitor alpha
/ metabolism
NF-kappa B
/ metabolism
Rats
Rats, Wistar
Up-Regulation
Apoptosis
Ellagic acid
Inflammation
Mitochondrial dysfunction
Oxidative stress
Journal
Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences
ISSN: 2008-2231
Titre abrégé: Daru
Pays: Switzerland
ID NLM: 101125969
Informations de publication
Date de publication:
Dec 2019
Dec 2019
Historique:
received:
08
03
2019
accepted:
22
10
2019
pubmed:
19
11
2019
medline:
10
4
2020
entrez:
19
11
2019
Statut:
ppublish
Résumé
The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties. The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity. Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p). After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats. EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application. Graphical abstract Beneficial effect of Ellagic acid (EA) on Methotrexate (MTX)-induced liver injury: molecular mechanism.
Sections du résumé
BACKGROUND
BACKGROUND
The clinical application of methotrexate (MTX), an efficacious cytotoxic drug, is restricted due to its associated liver toxicity. Ellagic acid (EA), a natural polyphenol, possesses hepatoprotective, antioxidant and anti-inflammatory properties.
OBJECTIVES
OBJECTIVE
The present study seeks to address the hepatoprotective effects of Ellagic acid (EA) against MTX-mediated oxidative stress (OS) and widen our current knowledge of the underlying molecular mechanisms of MTX toxicity.
METHODS
METHODS
Wistar rats were orally given EA (5 mg/kg and 10 mg/kg) for 10 successive days and at the end of the third day they were administered a single dose of MTX (20 mg/kg i.p).
RESULTS
RESULTS
After performing biochemical analysis, liver enzymes and malondialdehyde were significantly higher in the MTX group, indicating hepatic oxidative damage. MTX-induced OS was further confirmed with observation of events such as reactive oxygen species (ROS) overproduction, mitochondrial outer membrane potential decrease, mitochondrial swelling, cytochrome c release and caspase-3/9 increase, resulting in apoptosis. Furthermore, overexpression of pro-inflammatory factors such as nuclear factor kappa B (NF-ĸB) and interleukin 6 (IL-6) indicated the MTX-induced inflammation in MTX-treated group. Interestingly, EA was able to significantly prevent OS, mitochondrial dysfunction, apoptosis and inflammation induced by MTX. Also, EA-treated rats demonstrated significant upregulation of both nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1), which were considerably downregulated in MTX-treated rats.
CONCLUSIONS
CONCLUSIONS
EA protects rats against MTX-induced apoptosis and mitochondrial dysfunction via up-Regulating Nrf2 and HO-1 expression and inhibiting the NF-κB signaling pathway. Therefore, EA may protect patients against MTX-induced hepatotoxicity and encourage its clinical application. Graphical abstract Beneficial effect of Ellagic acid (EA) on Methotrexate (MTX)-induced liver injury: molecular mechanism.
Identifiants
pubmed: 31736017
doi: 10.1007/s40199-019-00309-9
pii: 10.1007/s40199-019-00309-9
pmc: PMC6895372
doi:
Substances chimiques
NF-E2-Related Factor 2
0
NF-kappa B
0
Nfe2l2 protein, rat
0
NF-KappaB Inhibitor alpha
139874-52-5
Ellagic Acid
19YRN3ZS9P
Malondialdehyde
4Y8F71G49Q
Methotrexate
YL5FZ2Y5U1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
721-733Subventions
Organisme : Vice Chancellor for Research
ID : 96-03-169-36364
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