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We began analyzing https://link.springer.com/article/10.1007/s00204-018-2331-8, but it redirected us to https://link.springer.com/article/10.1007/s00204-018-2331-8. The analysis below is for the second page.

Title[redir]:
Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity | Archives of Toxicology
Description:
We previously reported that delayed treatment with Mito-tempo (MT), a mitochondria-targeted superoxide dismutase mimetic, protects against the early phase of acetaminophen (APAP) hepatotoxicity by inhibiting peroxynitrite formation. However, whether this protection is sustained to the late phase of toxicity is unknown. To investigate the late protection, C57Bl/6J mice were treated with 300 mg/kg APAP followed by 20 mg/kg MT 1.5 h or 3 h later. We found that both MT treatments protected against the late phase of APAP hepatotoxicity at 12 and 24 h. Surprisingly, MT-treated mice demonstrated a significant increase in apoptotic hepatocytes, while the necrotic phenotype was observed almost exclusively in mice treated with APAP alone. In addition, there was a significant increase in caspase-3 activity and cleavage in the livers of MT-treated mice. Immunostaining for active caspase-3 revealed that the positively stained hepatocytes were exclusively in centrilobular areas. Treatment with the pan-caspase inhibitor ZVD-fmk (10 mg/kg) 2 h post-APAP neutralized this caspase activation and provided additional protection against APAP hepatotoxicity. Treatment with N-acetylcysteine, the current standard of care for APAP poisoning, protected but did not induce this apoptotic phenotype. Mechanistically, MT treatment inhibited APAP-induced RIP3 kinase expression, and RIP3-deficient mice showed caspase activation and apoptotic morphology in hepatocytes analogous to MT treatment. These data suggest that while necrosis is the primary cause of cell death after APAP hepatotoxicity, treatment with the antioxidant MT may switch the mode of cell death to secondary apoptosis in some cells. Modulation of mitochondrial oxidative stress and RIP3 kinase expression play critical roles in this switch.

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pubmed, article, google, scholar, cas, jaeschke, acetaminophen, liver, hepatotoxicity, mice, apoptosis, acetaminopheninduced, central, toxicol, injury, cell, pharmacol, necrosis, mitochondrial, death, hepatology, ramachandran, caspase, farhood, zhang, sci, mcgill, bajt, appl, protection, acute, hepatocytes, hepatic, wang, apap, stress, glutathione, williams, mitotempo, protects, mechanisms, treatment, role, late, nacetylcysteine, rip, protein, antoine, biomarkers, lemasters,

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wen-xing ding & hartmut jaeschke nrf-2/ho-1-sod-2 signaling pathway pan-caspase inhibitor zvd-fmk month download article/chapter d-galactosamine-sensitized mice accounts drug-induced liver injury fas receptor-mediated apoptosis acetaminophen-induced liver injury hepatic ischemia/reperfusion injury acetaminophen-induced hepatic inflammation n-acetyl-m-aminophenol acetaminophen-induced oxidant stress acetaminophen-mediated liver injury acetaminophen-induced hepatocyte necrosis related subjects mito-tempo protects acetaminophen-induced cell death caspase-dependent fulminant hepatitis mitochondrial oxidative stress mito-tempo nac full article pdf acute liver injury emergency department visits rip1/rip3 necrosome forms acute liver failure mt-treated mice demonstrated antoine dj d-galactosamine gsh privacy choices/manage cookies nuclear dna fragmentation mitochondrial permeability transition acetaminophen-induced necrosis mitochondrial oxidant stress acetaminophen-induced hepatotoxicity acetaminophen induced hepatotoxicity article du acetaminophen-induced apoptosis mito-tempo hepatic mitochondrial respiration hepatic inflammatory response acetaminophen-induced inhibition peroxynitrite-induced mitochondrial article archives oxidative stress liver cell death woolbright bl neutrophil-mediated necrosis caspase-dependent apoptosis male cd-1 mice fas receptor

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Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H (2002) Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis?

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         description:We previously reported that delayed treatment with Mito-tempo (MT), a mitochondria-targeted superoxide dismutase mimetic, protects against the early phase of acetaminophen (APAP) hepatotoxicity by inhibiting peroxynitrite formation. However, whether this protection is sustained to the late phase of toxicity is unknown. To investigate the late protection, C57Bl/6J mice were treated with 300 mg/kg APAP followed by 20 mg/kg MT 1.5 h or 3 h later. We found that both MT treatments protected against the late phase of APAP hepatotoxicity at 12 and 24 h. Surprisingly, MT-treated mice demonstrated a significant increase in apoptotic hepatocytes, while the necrotic phenotype was observed almost exclusively in mice treated with APAP alone. In addition, there was a significant increase in caspase-3 activity and cleavage in the livers of MT-treated mice. Immunostaining for active caspase-3 revealed that the positively stained hepatocytes were exclusively in centrilobular areas. Treatment with the pan-caspase inhibitor ZVD-fmk (10 mg/kg) 2 h post-APAP neutralized this caspase activation and provided additional protection against APAP hepatotoxicity. Treatment with N-acetylcysteine, the current standard of care for APAP poisoning, protected but did not induce this apoptotic phenotype. Mechanistically, MT treatment inhibited APAP-induced RIP3 kinase expression, and RIP3-deficient mice showed caspase activation and apoptotic morphology in hepatocytes analogous to MT treatment. These data suggest that while necrosis is the primary cause of cell death after APAP hepatotoxicity, treatment with the antioxidant MT may switch the mode of cell death to secondary apoptosis in some cells. Modulation of mitochondrial oxidative stress and RIP3 kinase expression play critical roles in this switch.
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