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dc.contributor.authorTanaka, R.
dc.contributor.authorIshima, Y.
dc.contributor.authorMaeda, H.
dc.contributor.authorKodama, A.
dc.contributor.authorNagao, S.
dc.contributor.authorWatanabe, H.
dc.contributor.authorChuang, Victor
dc.contributor.authorOtagiri, M.
dc.contributor.authorMaruyama, T.
dc.identifier.citationTanaka, R. and Ishima, Y. and Maeda, H. and Kodama, A. and Nagao, S. and Watanabe, H. and Chuang, V. et al. 2014. Albumin fusion prolongs the antioxidant and anti-inflammatory activities of thioredoxin in mice with acetaminophen-induced hepatitis. Molecular Pharmaceutics. 11 (4): pp. 1228-1238.

Overdoses of acetaminophen (APAP) are a major cause of acute liver failure. N-acetylcysteine (NAC) is the standard therapy for the patients with such an overdose because oxidative stress plays an important role in the pathogenesis of APAP-induced hepatitis. However, NAC is not sufficiently efficacious. We previously developed a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx), designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an endogenous protein with anti-oxidative and anti-inflammatory properties. In this study, we investigated the therapeutic impact of HSA-Trx in mice with APAP-induced hepatitis. The systemic administration of HSA-Trx significantly improved the survival rate of mice treated with a lethal dose of APAP compared with saline. HSA-Trx strongly attenuated plasma transaminases in APAP-induced hepatitis mice compared with HSA or Trx, components of the fusion protein. HSA-Trx also markedly caused a diminution in the histopathological features of hepatic injuries and the number of apoptosis-positive hepatic cells. In addition, an evaluation of oxidative stress markers and plasma cytokine and chemokine levels clearly showed that HSA-Trx significantly improved the breakdown of hepatic redox conditions and inflammation caused by the APAP treatment. HSA-Trx also significantly decreased oxidative and nitrosative/nitrative stress induced by SIN-1 in vitro. Finally, HSA-Trx, but not the NAC treatment at 4 hours after APAP injection, significantly inhibited the elevation in plasma transaminases levels. In conclusion, the findings suggest that HSA-Trx has considerable potential for use as a novel therapeutic agent for APAP-induced hepatitis, due to its long-lasting anti-oxidative and anti-inflammatory effects.

dc.publisherAmerican Chemical Society
dc.subjectrecombinant protein
dc.subjectdrug delivery system
dc.subjectoxidative stress
dc.titleAlbumin fusion prolongs the antioxidant and anti-inflammatory activities of thioredoxin in mice with acetaminophen-induced hepatitis
dc.typeJournal Article
dcterms.source.titleMolecular Pharmaceutics
curtin.accessStatusFulltext not available

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