Vitamin E: Regulatory Redox Interactions

Miyazawa, Taiki; Burdeos, Gregor Carpentero; Itaya, Mayuko; Nakagawa, Kiyotaka; Miyazawa, Teruo

doi:10.1002/iub.2008

Cited by 225 publications

(158 citation statements)

References 112 publications

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“…Administration of DFO to the donor liver is also questionable in the clinical setting. On the other hand, α‐Toc, a component of vitamin E, has been used as an anti‐oxidant for a long time and proven its safety in humans . Therefore, we speculate that α‐Toc administration could be useful in clinical application for I/R injury and organ transplantation including the liver and other organs, and further investigations are required to determine the timing and route of α‐Toc administration.…”

Section: Discussionmentioning

confidence: 99%

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Yamada

Karasawa

Wakiya

et al. 2020

American Journal of Transplantation

193

130

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Hepatic ischemia-reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron-dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or α-tocopherol. Fer-1 also inhibited hepatic I/R-induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury. K E Y W O R D Scell death, liver transplantation/hepatology, liver transplantation: living donor, translational research/science

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Section: Discussionmentioning

confidence: 99%

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Yamada

Karasawa

Wakiya

et al. 2020

American Journal of Transplantation

193

130

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“…In fact, abnormal protein S-glutathionylation is related to diverse cellular detrimental changes, including protein aggregation, protein degradation, apoptosis and mitochondrial dysfunction [215]. A thiol redox system consisting of the glutathione system (glutathione/glutathione reductase/glutaredoxin/glutathione peroxidase) and the thioredoxin system (thioredoxin/thioredoxin peroxidase (peroxiredoxins)/sulfiredoxin/thioredoxin reductase [216] are believed to be the major players in redox status regulation [99,[217][218][219]. Further, the thioredoxin system is an important thiol/disulphide redox controller ensuring the redox homeostasis [220].…”

Section: Nad(p)h Quinone Oxidoreductase-1 Nqo1mentioning

confidence: 99%

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

et al. 2019

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Poultry in commercial settings are exposed to a range of stressors. A growing body of information clearly indicates that excess ROS/RNS production and oxidative stress are major detrimental consequences of the most common commercial stressors in poultry production. During evolution, antioxidant defence systems were developed in poultry to survive in an oxygenated atmosphere. They include a complex network of internally synthesised (e.g., antioxidant enzymes, (glutathione) GSH, (coenzyme Q) CoQ) and externally supplied (vitamin E, carotenoids, etc.) antioxidants. In fact, all antioxidants in the body work cooperatively as a team to maintain optimal redox balance in the cell/body. This balance is a key element in providing the necessary conditions for cell signalling, a vital process for regulation of the expression of various genes, stress adaptation and homeostasis maintenance in the body. Since ROS/RNS are considered to be important signalling molecules, their concentration is strictly regulated by the antioxidant defence network in conjunction with various transcription factors and vitagenes. In fact, activation of vitagenes via such transcription factors as Nrf2 leads to an additional synthesis of an array of protective molecules which can deal with increased ROS/RNS production. Therefore, it is a challenging task to develop a system of optimal antioxidant supplementation to help growing/productive birds maintain effective antioxidant defences and redox balance in the body. On the one hand, antioxidants, such as vitamin E, or minerals (e.g., Se, Mn, Cu and Zn) are a compulsory part of the commercial pre-mixes for poultry, and, in most cases, are adequate to meet the physiological requirements in these elements. On the other hand, due to the aforementioned commercially relevant stressors, there is a need for additional support for the antioxidant system in poultry. This new direction in improving antioxidant defences for poultry in stress conditions is related to an opportunity to activate a range of vitagenes (via Nrf2-related mechanisms: superoxide dismutase, SOD; heme oxygenase-1, HO-1; GSH and thioredoxin, or other mechanisms: Heat shock protein (HSP)/heat shock factor (HSP), sirtuins, etc.) to maximise internal AO protection and redox balance maintenance. Therefore, the development of vitagene-regulating nutritional supplements is on the agenda of many commercial companies worldwide.

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“…To explore a potential clinical application, we finally tested the effect of α-Toc (vitamin E) on APAP-induced hepatotoxicity because it has been used as a common lipophilic antioxidant in clinical practice 32 and has been shown to exert a radical trapping effect similar to Fer-1 33 . As expected, supplementation with α-Toc clearly attenuated liver damage (evaluated in terms of serum ALT and AST levels, and the histopathology score) and lipid peroxidation (4-HNE, MDA, and total GSH), but had no effect on CYP2E1 mRNA expression ( Fig.…”

Section: α-Toc Prevents Apap-induced Hepatotoxicity and Lipid Peroxidmentioning

confidence: 99%

Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure

et al. 2020

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Acetaminophen (APAP) overdose is a common cause of drug-induced acute liver failure. Although hepatocyte cell death is considered to be the critical event in APAP-induced hepatotoxicity, the underlying mechanism remains unclear. Ferroptosis is a newly discovered type of cell death that is caused by a loss of cellular redox homeostasis. As glutathione (GSH) depletion triggers APAP-induced hepatotoxicity, we investigated the role of ferroptosis in a murine model of APAP-induced acute liver failure. APAP-induced hepatotoxicity (evaluated in terms of ALT, AST, and the histopathological score), lipid peroxidation (4-HNE and MDA), and upregulation of the ferroptosis maker PTGS2 mRNA were markedly prevented by the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1). Fer-1 treatment also completely prevented mortality induced by high-dose APAP. Similarly, APAP-induced hepatotoxicity and lipid peroxidation were prevented by the iron chelator deferoxamine. Using mass spectrometry, we found that lipid peroxides derived from n-6 fatty acids, mainly arachidonic acid, were elevated by APAP, and that auto-oxidation is the predominant mechanism of APAP-derived lipid oxidation. APAP-induced hepatotoxicity was also prevented by genetic inhibition of acyl-CoA synthetase long-chain family member 4 or α-tocopherol supplementation. We found that ferroptosis is responsible for APAP-induced hepatocyte cell death. Our findings provide new insights into the mechanism of APAP-induced hepatotoxicity and suggest that ferroptosis is a potential therapeutic target for APAP-induced acute liver failure.

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Vitamin E: Regulatory Redox Interactions

Cited by 225 publications

References 112 publications

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Iron overload as a risk factor for hepatic ischemia-reperfusion injury in liver transplantation: Potential role of ferroptosis

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

Ferroptosis driven by radical oxidation of n-6 polyunsaturated fatty acids mediates acetaminophen-induced acute liver failure

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