Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice.

Iron overload (IOL) is hypothesized to contribute to dysplastic erythropoiesis. Several conditions, including myelodysplastic syndrome, thalassemia and sickle cell anemia, are characterized by ineffective erythropoiesis and IOL. Iron is pro-oxidant and may participate in the pathophysiology of these conditions by increasing genomic instability and altering the microenvironment. There is, however, lack of in vivo evidence demonstrating a role of IOL and oxidative damage in dysplastic erythropoiesis. NRF2 transcription factor is the master regulator of antioxidant defenses, playing a crucial role in the cellular response to IOL in the liver. Here, we crossed Nrf2-/- with hemochromatosis (Hfe-/-) or hepcidin-null (Hamp1-/-) mice. Double-knockout mice developed features of ineffective erythropoiesis and myelodysplasia including macrocytic anemia, splenomegaly, and accumulation of immature dysplastic bone marrow (BM) cells. BM cells from Nrf2/Hamp1-/- mice showed increased in vitro clonogenic potential and, upon serial transplantation, recipients disclosed cytopenias, despite normal engraftment, suggesting defective differentiation. Unstimulated karyotype analysis showed increased chromosome instability and aneuploidy in Nrf2/Hamp1-/- BM cells. In HFE-related hemochromatosis patients, NRF2 promoter SNP rs35652124 genotype TT (predicted to decrease NRF2 expression) associated with increased MCV, consistent with erythroid dysplasia. Our results suggest that IOL induces ineffective erythropoiesis and dysplastic hematologic features through oxidative damage in Nrf2-deficient cells.

Gendered traditional agroecological knowledge in agri-food systems: a systematic review.

Traditional agroecological knowledge (i.e. TAeK) is gaining recognition for its potential contribution to climate change adaptation in food systems, ecosystems restoration and food insecurity. Despite the existing literature on Traditional Ecological Knowledge and its nexus with food security, how gender critically influences the distribution of such knowledge within agri-food systems has not yet been systematically analysed. In this regard, this systematic review attempts to answer four questions: 1) How does the literature on gender and TAeK in agri-food systems evolved temporally, geographically and in different agroecosystems? 2) How are gender and intersectionality mainly approached by such literature? 3) How do the articles address gendered dimensions in TAeK within the agri-food system activities? 4) What are the main drivers of change that influence TAeK and adaptive responses? The results show the gendered nature of TAeK in relation to food production, processing, and conservation activities, and how these activities are linked to tasks and activities, gender-specific knowledge, and spaces where gender discrimination is reproduced. The review also identifies elements that delimit and/or take part of the development of TAeK, such as gendered access to resources, gendered institutions, and the identification of the main drivers of change and impacts of TAeK erosion and biodiversity loss. These results are discussed in terms of power relations that interact with sociocultural norms and practices according to the specific geographical context and agroecosystem.

Infants of mothers with higher physiological stress show alterations in brain function.

Chronic stress has been increasingly linked with aberrations in children's behavioral, cognitive, and social development, yet the effect of chronic physiological stress on neural development during the first year of life is largely unknown. The present study aims to link a physiological index of chronic stress (maternal hair cortisol concentration) to maturational differences in infant functional brain development during the first year of life. Participants were 94 mother-infant dyads. To index chronic physiological stress, maternal hair samples were assayed for the previous three months' cortisol output. To examine the development of brain function during the first year of life, six-to-twelve-month-old infants (N = 94) completed a resting electroencephalography (EEG) recording. Infants of mothers with evidence of higher physiological stress showed increased relative low-frequency (theta) power and reduced relative high-frequency (alpha, high-gamma) power, compared to infants of mothers with evidence of low physiological stress. This pattern of findings is consistent with other studies suggesting that early life stress may lead to alterations in patterns of infant brain development. These findings are important given that maturational lags in brain development can be long-lasting and are associated with deficits in cognitive and emotional development. The present research also suggests that reducing maternal physiological stress may be a useful target for future interventions aiming to foster neurodevelopment during the first year of life.

Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.

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

BACKGROUND AND AIMS: In 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). METHODS: Wild-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. RESULTS: Despite 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. CONCLUSIONS: The 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.

Antioxidant defense of Nrf2 vs pro-inflammatory system of NF-κB during the amoebic liver infection in hamster.

Entamoeba histolytica is the causative agent of amoebic liver abscess (ALA), which course with an uncontrolled inflammation and nitro-oxidative stresses, although it is well known that amoeba has an effective defence mechanisms against this toxic environment, the underlying molecular factors responsible for progression of tissue damage remain largely unknown. The purpose of the present study was to determine during the acute stage of ALA in hamsters, the involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and nuclear factor-kappa B (NF-κB), which are activated in response to oxidative stress. From 12 h post-infection the ALA was visible, haematoxylin-eosin and Masson's trichrome stains were consistent with these observations, and alanine aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase serum activities were increased too. At 48 h after infection, liver glycogen content was significantly reduced. Western blot analyses showed that 4-Hydroxy-2-nonenal peaked at 12 h, while glycogen synthase kinase-3ß, cleaved caspase-3, pNF-κB, interleukin-1ß and tumour necrosis factor-α were overexpressed from 12 to 48 h post-infection. Otherwise, Nrf2 and superoxide dismutase-1, decreased at 48 h and catalase declined at 36 and 48 h. Furthermore, heme oxygenase-1 was increased at 12 and 24 h and decreased to normal levels at 36 and 48 h. These findings suggest for the first time that the host antioxidant system of Nrf2 is influenced during ALA.

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death.

BACKGROUND & AIMS: The liver, being the major site of iron storage, is particularly exposed to the toxic effects of iron. Transcription factor NRF2 is critical for protecting the liver against disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload. METHODS: Wild-type and Nrf2(-/-) mouse primary hepatocytes were incubated with ferric ammonium citrate. Wild-type and Nrf2(-/-) mice were fed standard rodent chow or iron-rich diet for 2weeks, with or without daily injection of the antioxidant mito-TEMPOL. RESULTS: In mouse hepatocytes, iron induced the nuclear translocation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2(-/-) hepatocytes were highly susceptible to iron-induced cell death. Wild-type and Nrf2(-/-) mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to severe necroinflammatory lesions. Hepatocytic cell death was associated with gross ultrastructural damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL. CONCLUSIONS: NRF2 protects the mouse liver against the toxicity of dietary iron overload by preventing hepatocytic cell death. We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antioxidant mito-TEMPOL in a mouse model of dietary iron-induced liver injury.