Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice

Eismann, Thorsten; Huber, Nadine; Shin, Taehoon; Kuboki, Satoshi; Galloway, Elizabeth; Wyder, Michael; Edwards, Michael J.; Greis, Kenneth D.; Shertzer, Howard G.; Fisher, Aron B.; Lentsch, Alex B.

doi:10.1152/ajpgi.90583.2008

Cited by 127 publications

(118 citation statements)

References 47 publications

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“…2/2 mice linked to a different model of hepatic ischemia-reperfusion injury (38). Moreover, our results are in agreement with previous work, which demonstrated that transgenic diabetic mice with overexpression of PRDX4 had reduced NASH scores and a significant improvement of dyslipidemia (39).…”

Section: Discussionsupporting

confidence: 92%

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Pacifici

Arriga

Sorice³

et al. 2014

Diabetes

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Enhanced oxidative stress contributes to the pathogenesis of diabetes and its complications. Peroxiredoxin 6 (PRDX6) is a key regulator of cellular redox balance, with the peculiar ability to neutralize peroxides, peroxynitrite, and phospholipid hydroperoxides. In the current study, we aimed to define the role of PRDX6 in the pathophysiology of type 2 diabetes (T2D) using PRDX6 knockout (2/2) mice. Glucose and insulin responses were evaluated respectively by intraperitoneal glucose and insulin tolerance tests. Peripheral insulin sensitivity was analyzed by euglycemic-hyperinsulinemic clamp, and molecular tools were used to investigate insulin signaling. Moreover, inflammatory and lipid parameters were evaluated. We demonstrated that PRDX6 2/2 mice developed a phenotype similar to early-stage T2D caused by both reduced glucose-dependent insulin secretion and increased insulin resistance. Impaired insulin signaling was present in PRDX6 2/2 mice, leading to reduction of muscle glucose uptake. Morphological and ultrastructural changes were observed in islets of Langerhans and livers of mutant animals, as well as altered plasma lipid profiles and inflammatory parameters. In conclusion, we demonstrated that PRDX6 is a key mediator of overt hyperglycemia in T2D glucose metabolism, opening new perspectives for targeted therapeutic strategies in diabetes care.A large body of evidence supports a pivotal role for oxidative stress in the etiopathogenesis of insulin resistance (IR) and diabetes (1). Oxidative stress is characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense systems. Among all body tissues, pancreatic b-cells are very sensitive to oxidative stress because of their low expression of antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (2). Moreover, hyperglycemia by itself induces IR, increasing oxidative stress injuries, which lead to overt type 2 diabetes (T2D) (3). Interestingly, a relatively new family of antioxidant proteins, the peroxiredoxins (PRDXs), is more highly expressed in pancreatic b-cells (4). Among the six members of this non-seleno peroxidase family, PRDX6 is present in the cytoplasm and is unique because it has peroxidase and also phospholipase A 2 activity (5). Several findings demonstrate the importance of PRDX6 in maintaining redox homeostasis, as follows: lack of PRDX6, in fact, increases the susceptibility to oxidative stress in different tissues (6,7). Nevertheless, data on the relationship between PRDX6 and the pathogenesis of IR and T2D are not available (8). Therefore, we hypothesized that, in terms of physiological status, PRDX6 may play a role in the etiology of IR and diabetes conditions through tissue redox levels. In the current study, we tested our hypothesis in a model of PRDX6 knockout mice (PRDX6 2/2). RESEARCH DESIGN AND METHODS Animal ModelsC57BL/6J wild-type (WT) mice weighing 18-20 g were obtained from The Jackson Laboratory (Bar Harbor, ME), while PRDX6 2/2 mice of mixed background (C57BL6/129SvJ)...

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Section: Discussionsupporting

confidence: 92%

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Pacifici

Arriga

Sorice³

et al. 2014

Diabetes

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“…Prx, a diverse and ubiquitous family of antioxidant proteins, includes six mammalian isoforms: Prx1-6 (Rhee et al, 2005). There are already reports demonstrating that Prx3-knockout increased pyrazole-induced liver oxidative damage (Bae et al, 2012), and Prx6-knockout increased ischemia-reperfusion-induced liver injury (Eismann et al, 2009). In the present study, we found that CGA reversed the decreased mRNA expression of Prx1, 2, 3, 5, and 6 induced by AP.…”

Section: Discussionsupporting

confidence: 66%

Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

Pang

Sheng

Jiang

et al. 2015

J. Zhejiang Univ. Sci. B

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Chlorogenic acid (CGA), a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen (AP)-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cell viability induced by AP in L-02 cells in vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase (ALT/AST) in vivo. The effect of CGA on cytochrome P450 (CYP) enzymatic (CYP2E1, CYP1A2, and CYP3A4) activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased mRNA expression of peroxiredoxin (Prx) 1, 2, 3, 5, 6, epoxide hydrolase (Ephx) 2, and polymerase (RNA) II (DNA directed) polypeptide K (Polr2k), and nuclear factor erythroid-2-related factor 2 (Nrf2). In summary, CGA ameliorates the AP-induced liver injury probably by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties. In addition, cellular important antioxidant signals such as Prx1, 2, 3, 5, 6, Ephx2, Polr2k, and Nrf2 also contributed to the protection of CGA against AP-induced oxidative stress injury.

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“…Phospholipase A 2 is a target for regulation by Pin1, which as just discussed, has been reported to be downregulated and showed oxidative dysfunction in the AD brain (65,363). PRX VI has been found to be protective against mitochondrial dysfunction, a feature that pinpoints its effectiveness as an antioxidant (136). PRX VI also plays important roles in cell differentiation and apoptosis, and HNE modification may lead to tau hyperphosphorylation and NFT formation in addition to development of OS.…”

Section: Ead Carbonylated Proteinsmentioning

confidence: 93%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

157

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice

Cited by 127 publications

References 47 publications

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Peroxiredoxin 6, a Novel Player in the Pathogenesis of Diabetes

Chlorogenic acid prevents acetaminophen-induced liver injury: The involvement of CYP450 metabolic enzymes and some antioxidant signals

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

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