Role of 4-Hydroxynonenal-Protein Adducts in Human Diseases

Barrera, Giuseppina; Pizzimenti, Stefania; Ciamporcero, Eric; Daga, Martina; Ullio, Chiara; Arcaro, Alessia; Cetrangolo, Giovanni Paolo; Ferretti, Carlo; Dianzani, Chiara; Lepore, Alessio; Gentile, Fabrizio

doi:10.1089/ars.2014.6166

Cited by 105 publications

(99 citation statements)

References 223 publications

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“…9E). Likewise, the expression of p62/SQSTM1 protein, which is known to be increased in chronic liver diseases in response to oxidative stress and to the accumulation of toxic protein aggregates [25], was significantly greater in Hfe / Nrf2 -/- livers (Fig. 9F).…”

Section: Resultsmentioning

confidence: 92%

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

et al. 2017

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Background and AimsIn hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe-/- mice (an established model of human HFE-hemochromatosis).MethodsWild-type, Nrf2-/-, Hfe-/- and double knockout (Hfe/Nrf2-/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12–18 (middle-aged) or 24 months (old) for evaluation of liver pathology.ResultsDespite the parenchymal iron accumulation, Hfe-/- mice presented no liver injury. The combination of iron overload (Hfe-/-) and defective antioxidant defences (Nrf2-/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner.ConclusionsThe genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe-/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.

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Section: Resultsmentioning

confidence: 92%

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

et al. 2017

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“…This is because ROS-generated reactive lipids such as 4HNE form adducts with other cellular macromolecules including proteins or nuclear and mitochondrial DNA. For cancer the generation of 4HNE-protein and 4HNE-DNA adducts have been shown to contribute to pathogenesis and progression (Barrera et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions

et al. 2016

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SUMMARY The development of pancreatic cancer requires the acquisition of oncogenic Kras mutations and up-regulation of growth factor signaling, but the relationship between these is not well established. We here show that mutant Kras alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase Protein Kinase D1 and the transcription factors NF-κB1 and NF-κB2, which up-regulate expression of the epidermal growth factor, its ligands and their sheddase ADAM17. In vivo, intercepting Kras-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic Kras interacts with growth factor signaling to induce the formation of pancreatic cancer.

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“…disease, obesity, type II diabetes, neurodegenerative disease, atherosclerosis, asthma, chronic obstructive pulmonary disease, and cancer (15)(16)(17)(18)(19)(20)(21)(22)(23). Notwithstanding, a wide variety of other reactive lipid aldehyde species are formed at appreciable levels in mammalian cells, though the specific effect of these lipids on cellular metabolism is less defined.…”

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confidence: 99%