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Exosomes derived from human umbilical cord mesenchymal stem cells alleviate acetaminophen-induced acute liver failure through activating ERK and IGF-1R/PI3K/AKT signaling pathway
- Source :
- Journal of Pharmacological Sciences, Vol 147, Iss 1, Pp 143-155 (2021)
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- This study aimed to investigate the therapeutic potential of human umbilical cord mesenchymal stem cells derived exosomes (hUCMSC-Exo) in acute liver failure (ALF) in mice as well as its underlying mechanism. We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over production of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways.
- Subjects :
- 0301 basic medicine
MAP Kinase Signaling System
Apoptosis
RM1-950
Exosomes
medicine.disease_cause
Receptor, IGF Type 1
Umbilical Cord
Proinflammatory cytokine
Superoxide dismutase
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
ERK1/2 and IGF-1R/PI3K/AKT signaling pathways
Animals
Humans
LY294002
Protein kinase B
Cells, Cultured
PI3K/AKT/mTOR pathway
Acetaminophen
Pharmacology
biology
digestive, oral, and skin physiology
Mesenchymal Stem Cells
Disease Models, Animal
Oxidative Stress
030104 developmental biology
chemistry
Hepatocytes
biology.protein
Cancer research
Molecular Medicine
Therapeutics. Pharmacology
Liver function
Human umbilical cord mesenchymal stem cells
Proto-Oncogene Proteins c-akt
Acute liver failure
Liver Failure
030217 neurology & neurosurgery
Oxidative stress
Signal Transduction
Subjects
Details
- ISSN :
- 13478613
- Volume :
- 147
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacological Sciences
- Accession number :
- edsair.doi.dedup.....1b1684abb0f71f55fa0b2e9093515d72