Hepato-protective effect of thymoquinone against acetaminophen induced liver injury is associated with regulation of JNK and AMPK signaling pathway

Yong YANG,Ting BAI,Ji-xing NAN,Qing-gao ZHANG

(1.Medical College of Dalian University,Dalian 116622,China;2.Key Laboratory for Natural Resource of Changbai Mountain&Functional Molecules,Ministry of Education,College of Pharmacy,Yanbian University,Yanji 133002,China）

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Hepato-protective effect of thymoquinone against acetaminophen induced liver injury is associated with regulation of JNK and AMPK signaling pathway

Yong YANG1,Ting BAI1,Ji-xing NAN2,Qing-gao ZHANG1

(1.Medical College of Dalian University,Dalian 116622,China;2.Key Laboratory for Natural Resource of Changbai Mountain&Functional Molecules,Ministry of Education,College of Pharmacy,Yanbian University,Yanji 133002,China）

OBJECTIVETo investigate the hepato-protective mechanism of thymoquinone(TQ)on the development of acetaminophen(APAP)-induced liver injury.METHODSIn vivo,male kunming mice were injected with a single dose of 300 mg·kg-1APAP.Some mice were pretreated with TQ(5 or 20 mg·kg-1)and N-acetylcysteine(NAC,300 mg·kg-1)2 h before APAP injection.Mice were euthanized at 2 h,6 h,12 h after APAP treatment.In vitro,human Chang liver cells were incubated with 3.125,6.25 or 12.5 μmol·L-1TQ,10 μmol·L-1SP600125 and 500 μmol·L-1AICAR in the presence of APAP for 24 h.Cell viability were analyzed by MTT assay,protein expressions were assessed by Western blot.RESULTSTQ pretreatment significantly reduced serum aminotransferase and increased hepatic gluta⁃thione(GSH)and glutathione peroxidase(GSH-PX)activities,while significantly inhibited interleukin-1β(IL-1β)levels.TQ significantly inhibited c-Jun N-terminal kinase(JNK),extracellular signal regulated kinase(ERK)and P38 phosphorylation induced by APAP.Moreover,TQ inhibited phosphatidylinositol 3-kinase(PI3K)/mammalian target of rapamycin(mTOR)signaling activation and activated AMPK phosphorylation induced by APAP.In addition,TQ inhibited signal transducer and activator of transcription 3(STAT3)phosphorylation on APAP-induced liver injury.In vitro,APAP enhanced JNK phosphorylation and attenuated AMPK phosphorylation in Chang liver cells,and these effects were blocked by pretreatment with TQ,SP600125(JNK inhibitor)and AICAR(AMPK activator).CONCLUSIONOur findings suggest that TQ may actively prevent APAP-induced liver injury,and this effect may be mediated by JNK and AMPK signaling pathways.

thymoquinone;acetaminophen;liver injury;c-Jun N-terminal kinase;AMP-activated protein kinase

The project supported by National Natural Science Foundation of China(81660689 and 81700523)

Qing-gao ZHANG,Tel:(0411)87402916,E-mail：zhangqinggao@dlu.edu.cn