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Drefs, M.* ; Thomas, M.N.* ; Guba, M.* ; Angele, M.K.* ; Werner, J.* ; Conrad, M. ; Steib, C.J.* ; Holdt, L.M.* ; Andrassy, J.* ; Khandoga, A.* ; Rentsch, M.*

Modulation of glutathione hemostasis by inhibition of 12/15-lipoxygenase prevents ROS-mediated cell death after hepatic ischemia and reperfusion.

Oxid. Med. Cell. Longev. 2017:8325754 (2017)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15-Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI. METHODS: Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry. RESULTS: TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose-polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers. CONCLUSION: Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Rat-liver Transplantation; Ischemia/reperfusion Injury; Oxidative Stress; Warm Ischemia; Molecular-mechanisms; Dimethyl-sulfoxide; Scutellaria-baicalensis; Cold Ischemia; Ferroptosis; Apoptosis
ISSN (print) / ISBN 1942-0900
e-ISSN 1942-0900
Quellenangaben Band: 2017, Heft: , Seiten: , Artikelnummer: 8325754 Supplement: ,
Verlag Landes Bioscience
Verlagsort Austin, Tex.
Begutachtungsstatus Peer reviewed