title: Caffeic acid attenuated acetaminophen-induced hepatotoxicity by inhibiting ERK1/2-mediated early growth response-1 transcriptional activation.
abstract: Caffeic acid (CA) is a natural compound abundant in fruits, coffee and plants. This study aims to investigate the involved mechanism of the therapeutic detoxification of CA against acetaminophen (APAP)-induced hepatotoxicity. CA (10, 30 mg/kg) was orally given to mice at 1 h after mice were pre-administrated with APAP (300 mg/kg). The therapeutic detoxification of CA against APAP-induced hepatotoxicity was observed by detecting serum aminotransferases, liver malondialdehyde (MDA) amount and liver histological evaluation in vivo. CA reduced APAP-induced increase in the mRNA expression of early growth response 1 (Egr1) in hepatocytes, and inhibited APAP-induced Egr1 transcriptional activation in vitro and in vivo. CA reduced the increased expression of growth arrest and DNA-damage-inducible protein (Gadd45)α induced by APAP in hepatocytes. Moreover, Egr1 siRNA reduced Gadd45α expression and reversed APAP-induced cytotoxicity in hepatocytes. Further results showed that CA blocked APAP-induced activation of extracellular-regulated protein kinase (ERK1/2) signaling cascade in vivo and in vitro. In addition, the application of ERK1/2 inhibitors (PD98059 and U0126) abrogated the nuclear translocation of Egr1 induced by APAP in hepatocytes. In conclusion, this study demonstrated the therapeutic detoxification of CA against APAP-induced liver injury, and the inhibition of CA on ERK1/2-mediated Egr1 transcriptional activation was involved in this process.
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Pang
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shi
authors.affiliation: Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: shengych@yeah.net.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Center for Traditional Chinese Medicine and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: lichenyue1307@126.com.
authors.forename: Lili
authors.initials: L
authors.lastname: Ji
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D021381:Protein Transport / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics; D000097642:GADD45 Proteins
chemical_list: D000082:Acetaminophen; D002109:Caffeic Acids; D051766:Early Growth Response Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D000097642:GADD45 Proteins; C040048:caffeic acid
keywords: Acetaminophen; Caffeic acid; Detoxification; ERK1/2; Egr1; Hepatotoxicity