The <i>Sod2</i> mutant mouse as a model for oxidative stress: A functional proteomics perspective

Lee, Yie Hou; Lin, Qingsong; Boelsterli, Urs A.; Chung, Maxey C. M.

doi:10.1002/mas.20226

Cited by 9 publications

(6 citation statements)

References 142 publications

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“…The latter mice have a mild, subclinical oxidative stress phenotype and have previously shown utility in toxicological studies. 34 The Sod2 þ/À mice had no obvious phenotype, and SOD2 expression was approximately 60% of control. 27 In the absence of alcohol, SOD2 level was not influenced by the presence of HCV protein expression.…”

Section: Effects Of Alcohol On Hcv Transgenic Micementioning

confidence: 97%

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Tumurbaatar

Tikhanovich

et al. 2013

The American Journal of Pathology

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Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3 À/À mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2 þ/À ) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcoholeinduced liver injury. (Am J Pathol 2013 http://dx

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Section: Effects Of Alcohol On Hcv Transgenic Micementioning

confidence: 97%

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Tumurbaatar

Tikhanovich

et al. 2013

The American Journal of Pathology

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“…Glutamine is a precursor of GSH, and the overrepresentation of glutamine metabolism ( P adj = × 10 –05 ) and GSH metabolism ( P adj = 8.66 × 10 –05 ) provided further evidence of GSH perturbation. Taken together, our data suggest that there is attenuation of ROS due to an upregulated antioxidant defense, and also discrete molecular aberrations that are present that may sensitize the Sod2 +/– mouse to clinically silent drug toxicities …”

Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

“…Taken together, our data suggest that there is attenuation of ROS due to an upregulated antioxidant defense, and also discrete molecular aberrations that are present that may sensitize the Sod2 +/− mouse to clinically silent drug toxicities. 37 Troglitazone Administration Leads to Delayed Hepatic Sod2 +/− Mitoproteome Damage A hallmark of TILI is the delayed onset of liver injury, which could abruptly progress to life-threatening irreversible liver failure. 5 Troglitazone administration in Sod2 +/+ (wild type) mice did not result in hepatic injuries, 16 and because Sod2 +/− mice below the age of 20 weeks accumulate clinically silent oxidative stress, 28 we focused on studying troglitazone effects on the Sod2 +/− hepatic mitochondria.…”

Section: Sod2 Haplodeficiency Moderately Affects the Mitoproteomementioning

confidence: 99%

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Integrative Toxicoproteomics Implicates Impaired Mitochondrial Glutathione Import as an Off-Target Effect of Troglitazone

Lee

Goh

et al. 2013

J. Proteome Res.

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Troglitazone, a first-generation thiazolidinedione of antihyperglycaemic properties, was withdrawn from the market due to unacceptable idiosyncratic hepatotoxicity. Despite intensive research, the underlying mechanism of troglitazone-induced liver toxicity remains unknown. Here we report the use of the Sod2+/– mouse model of silent mitochondrial oxidative-stress-based and quantitative mass spectrometry-based proteomics to track the mitochondrial proteome changes induced by physiologically relevant troglitazone doses. By quantitative untargeted proteomics, we first globally profiled the Sod2+/– hepatic mitochondria proteome and found perturbations including GSH metabolism that enhanced the toxicity of the normally nontoxic troglitazone. Short- and long-term troglitazone administration in Sod2+/– mouse led to a mitochondrial proteome shift from an early compensatory response to an eventual phase of intolerable oxidative stress, due to decreased mitochondrial glutathione (mGSH) import protein, decreased dicarboxylate ion carrier (DIC), and the specific activation of ASK1-JNK and FOXO3a with prolonged troglitazone exposure. Furthermore, mapping of the detected proteins onto mouse specific protein-centered networks revealed lipid-associated proteins as contributors to overt mitochondrial and liver injury when under prolonged exposure to the lipid-normalizing troglitazone. By integrative toxicoproteomics, we demonstrated a powerful systems approach in identifying the collapse of specific fragile nodes and activation of crucial proteome reconfiguration regulators when targeted by an exogenous toxicant.

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“…Mass spectrometry‐based proteomics strategy is capable of identifying the differentially expressed proteins from a large validated protein database, that together. The combination of with genetic/transcriptomic/metabolomics and bioinformatics identification and integration of these multiple ‘omics can determine the functional significance of proteins and biochemical pathways responsible for as HCC pathogenesis, as well as other diseases (Cui et al, ; Codarin et al, ; Gstaiger & Aebersold, ; Corona et al, ; Lee et al, ).…”

Section: Proteomic Snapshot Of the Molecular Signature Of Hccmentioning

confidence: 99%

Advanced mass spectrometry‐based multi‐omics technologies for exploring the pathogenesis of hepatocellular carcinoma

Nie

Yan

Lee

et al. 2014

Mass Spectrometry Reviews

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Hepatocellular carcinoma (HCC) is one of the primary hepatic malignancies and is the third most common cause of cancer related death worldwide. Although a wealth of knowledge has been gained concerning the initiation and progression of HCC over the last half century, efforts to improve our understanding of its pathogenesis at a molecular level are still greatly needed, to enable clinicians to enhance the standards of the current diagnosis and treatment of HCC. In the post‐genome era, advanced mass spectrometry driven multi‐omics technologies (e.g., profiling of DNA damage adducts, RNA modification profiling, proteomics, and metabolomics) stand at the interface between chemistry and biology, and have yielded valuable outcomes from the study of a diversity of complicated diseases. Particularly, these technologies are being broadly used to dissect various biological aspects of HCC with the purpose of biomarker discovery, interrogating pathogenesis as well as for therapeutic discovery. This proof of knowledge‐based critical review aims at exploring the selected applications of those defined omics technologies in the HCC niche with an emphasis on translational applications driven by advanced mass spectrometry, toward the specific clinical use for HCC patients. This approach will enable the biomedical community, through both basic research and the clinical sciences, to enhance the applicability of mass spectrometry‐based omics technologies in dissecting the pathogenesis of HCC and could lead to novel therapeutic discoveries for HCC. © 2014 Wiley Periodicals, Inc. Mass Spec Rev 35:331–349, 2016.

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The Sod2 mutant mouse as a model for oxidative stress: A functional proteomics perspective

Cited by 9 publications

References 142 publications

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Hepatitis C and Alcohol Exacerbate Liver Injury by Suppression of FOXO3

Integrative Toxicoproteomics Implicates Impaired Mitochondrial Glutathione Import as an Off-Target Effect of Troglitazone

Advanced mass spectrometry‐based multi‐omics technologies for exploring the pathogenesis of hepatocellular carcinoma

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