Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury
Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of het...
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doaj-95eb0ce414094870ac25f8ac0d0157df2020-11-25T03:02:47ZengSAGE PublishingDose-Response1559-32582017-01-011510.1177/155932581769028710.1177_1559325817690287Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver InjuryVivekkumar P. Dadhania0Bharat Bhushan1Udayan Apte2Harihara M. Mehendale3 Department of Toxicology, College of Health & Pharmaceutical Sciences, The University of Louisiana at Monroe (ULM), Monroe, LA, USA Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center (KUMC), Kansas City, KS, USA Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center (KUMC), Kansas City, KS, USA Department of Toxicology, College of Health & Pharmaceutical Sciences, The University of Louisiana at Monroe (ULM), Monroe, LA, USAPreplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection.https://doi.org/10.1177/1559325817690287 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vivekkumar P. Dadhania Bharat Bhushan Udayan Apte Harihara M. Mehendale |
spellingShingle |
Vivekkumar P. Dadhania Bharat Bhushan Udayan Apte Harihara M. Mehendale Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury Dose-Response |
author_facet |
Vivekkumar P. Dadhania Bharat Bhushan Udayan Apte Harihara M. Mehendale |
author_sort |
Vivekkumar P. Dadhania |
title |
Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury |
title_short |
Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury |
title_full |
Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury |
title_fullStr |
Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury |
title_full_unstemmed |
Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury |
title_sort |
wnt/β-catenin signaling drives thioacetamide-mediated heteroprotection against acetaminophen-induced lethal liver injury |
publisher |
SAGE Publishing |
series |
Dose-Response |
issn |
1559-3258 |
publishDate |
2017-01-01 |
description |
Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection. |
url |
https://doi.org/10.1177/1559325817690287 |
work_keys_str_mv |
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