Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure

Autor: Norihiko Takeda, Kenji Takemoto, Saori Ohmae, Satoru Seo, Shinji Uemoto, Masataka Asagiri, Hirokazu Tanaka, Naruto Noma, Shigehira Saji, Keigo Machida, Kazutaka Tanabe, Masatoshi Takeiri, Kojiro Taura, Etsuro Hatano, Keiko Iwaisako, Kan Toriguchi
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Necrosis
AST
aspartate aminotransferase
Pharmacology
DMSO
dimethyl sulfoxide
medicine.disease_cause
Fulminant hepatic failure
bFGF
basic fibroblast growth factor
NAPQI
N-acetyl-p-benzoquinone
CXCL1
chemokine (C-X-C motif) ligand 1
GSH
glutathione
lcsh:QH301-705.5
chemistry.chemical_classification
LDH
lactate dehydrogenase
digestive
oral
and skin physiology
CM-H2DCFDA
5-(and-6)-chloromethyl-2′
7′-dichlorodihydrofluorescein diacetate
acetyl ester
CYP2E1
cytochrome P450 2E1
WST-8
2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2
4-disulfophenyl)-2H-tetrazolium
Necroptosis
medicine.symptom
λPP
lambda protein phosphatase
medicine.drug
Programmed cell death
SNAP
S-nitroso-N-acetyl-dl-penicillamine
APAP
acetaminophen
General Biochemistry
Genetics and Molecular Biology
Article
PI
propidium iodide
RIPK1
ROS
reactive oxygen species
FBS
fetal bovine serum
ABTS
2
2′-azino-bis (3-ethylbenzothiazoline)-6-sulfonic acid
ALF
acute liver failure
PGAM5
phosphoglycerate mutase family member 5
ALT
alanine aminotransferase
medicine
RIPK
receptor-interacting protein kinase
Drp1
dynamin-related protein 1
ComputingMethodologies_COMPUTERGRAPHICS
Acetaminophen
Reactive oxygen species
NO
nitric oxide
RIPK-dependent necrosis
Nec-1
necrostatin-1
lcsh:Biology (General)
chemistry
Immunology
Hepatocytes
Oxidative stress
Acute liver failure
Zdroj: FEBS Open Bio
FEBS Open Bio, Vol 4, Iss C, Pp 777-787 (2014)
ISSN: 2211-5463
Popis: Graphical abstract
Highlights • RIPK-dependent necrosis is involved in acetaminophen (APAP)-induced hepatotoxicity. • Necrostatin-1 (Nec-1) protects mice against APAP-induced acute liver damage. • Nec-1 suppresses APAP-induced ROS generation in hepatocytes. • Nec-1 promotes resistance to oxidative stress in hepatocytes.
Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.
Databáze: OpenAIRE
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