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.This work is funded by FEDER Funds through the Operational Competitiveness Programme - COMPETE and by National Funds through FCT - Fundacao para a Ciencia e a Tecnologia under the project FCOMP-01-0124-FEDER-011062 (PTDC/SAU-FCF/101177/2008). TLD is supported by "Programa Ciencia - financiado pelo POPH - QREN - Tipologia 4.2 - Promocao do Emprego Cientifico, comparticipado pelo Fundo Social Europeu e por fundos nacionais do MCTES''

Development of policies and practices of social responsibility in Portuguese companies: implications of the SA8000 standard

Series: Management and Industrial EngineeringThis study aims to explore the implications of the SA8000 standard in the implementation of Corporate Social Responsibility (CSR) policies and practices in Portuguese companies. Although this is not a recent issue, it is a subject that has motivated a growing interest on the part of the business and academic community. CSR should be seen as a new business management model, which includes universal human values as well as ethical decisions that ensure the satisfaction of the interests and needs of all stakeholders and the community in general. Regarding the empirical aspect of this research, a qualitative approach was followed through the application of a semi-structured interview to certified and not certified companies by SA8000 standard, in order to understand possible disparities with regard to the implementation of CSR policies and practices. Although the certification is the guarantee of the commitment of the companies with the CSR, the truth is that this is seen by the companies as a form of differentiation in the market. In general terms, it can be concluded that the policies and practices of CSR do not differ in relation to certification, which means that all companies have the possibility of making a difference by being socially responsible.Delfina Gomes acknowledges that this study was conducted at the Research Center in Political Science (UID/CPO/0758/2019), University of Minho/University of Évora, and was supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Education and Science through national funds

Surviving in hot and cold: psychrophiles and thermophiles from Deception Island volcano, Antarctica

Polar volcanoes harbor unique conditions of extreme temperature gradients capable of selecting different types of extremophiles. Deception Island is a marine stratovolcano located at Maritime Antarctica that is notable for its pronounced temperature gradients over very short distances, reaching values up to 100 °C in the fumaroles, and subzero temperatures next to the glaciers. Due to these characteristics, Deception can be considered an interesting analogue of extraterrestrial environments. Our main goal in this study was to isolate thermophilic and psychrophilic bacteria from sediments associated with fumaroles and glaciers from two geothermal sites in Deception Island, comprising temperatures between 0 and 98 °C, and to evaluate their survivability to desiccation and UV-C radiation. Our results revealed that culturable thermophiles and psychrophiles were recovered among the extreme temperature gradient in Deception volcano, which indicates that these extremophiles remain alive even when the conditions do not comprise their growth range. The viability of culturable psychrophiles in hyperthermophilic environments is still poorly understood and our work showed the importance of future studies about their survival strategies in high temperatures. Finally, the spore-forming thermophilic isolates which we found have displayed good survival to desiccation and UV-C irradiation, which suggests their potential to be further explored in astrobiological studies

Participatory planning and quality assessment: contributions of a nursing management technology

Objective: to analyze the outcomes of participatory planning and quality assessment of the nursing care provided in a hospital ward using a nursing management technology. Method: Convergent care research focuses on research and practice intervention, developed in a hospital in southern Brazil from April to August 2016. Participatory planning and quality evaluation was performed using the PRAXIS® technology. Results: In the participatory planning, a survey of needs/problems was carried out by 33 professionals followed by 5 workshops, where mission, guiding principles, 4 priority problems, expected results, objectives and plans of activities were defined. For quality evaluation, two indicators were used: satisfaction and notification of adverse events. The evaluation was carried out with 101 patients and /or relatives, predominating “great or good”. Adverse events, 28 records, predominating medication errors. Conclusion: Participatory planning and quality assessment are essential to improve nursing care management and the PRAXIS® technological innovation has been a useful resource.info:eu-repo/semantics/publishedVersio

Characterization of Apoptosis-Related Oxidoreductases from Neurospora crassa

The genome from Neurospora crassa presented three open reading frames homologous to the genes coding for human AIF and AMID proteins, which are flavoproteins with oxidoreductase activities implicated in caspase-independent apoptosis. To investigate the role of these proteins, namely within the mitochondrial respiratory chain, we studied their cellular localization and characterized the respective null mutant strains. Efficiency of the respiratory chain was analyzed by oxygen consumption studies and supramolecular organization of the OXPHOS system was assessed through BN-PAGE analysis in the respective null mutant strains. The results demonstrate that, unlike in mammalian systems, disruption of AIF in Neurospora does not affect either complex I assembly or function. Furthermore, the mitochondrial respiratory chain complexes of the mutant strains display a similar supramolecular organization to that observed in the wild type strain. Further characterization revealed that N. crassa AIF appears localized to both the mitochondria and the cytoplasm, whereas AMID was found exclusively in the cytoplasm. AMID2 was detected in both mitochondria and cytoplasm of the amid mutant strain, but was barely discernible in wild type extracts, suggesting overlapping functions for the two proteins

Inhalation Therapy in Patients Receiving Mechanical Ventilation: An Update

Incremental gains in understanding the influence of various factors on aerosol delivery in concert with technological advancements over the past 2 decades have fueled an ever burgeoning literature on aerosol therapy during mechanical ventilation. In-line use of pressurized metered-dose inhalers (pMDIs) and nebulizers is influenced by a host of factors, some of which are unique to ventilator-supported patients. This article reviews the impact of various factors on aerosol delivery with pMDIs and nebulizers, and elucidates the correlation between in-vitro estimates and in-vivo measurement of aerosol deposition in the lung. Aerosolized bronchodilator therapy with pMDIs and nebulizers is commonly employed in intensive care units (ICUs), and bronchodilators are among the most frequently used therapies in mechanically ventilated patients. The use of inhaled bronchodilators is not restricted to mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) and asthma, as they are routinely employed in other ventilator-dependent patients without confirmed airflow obstruction. The efficacy and safety of bronchodilator therapy has generated a great deal of interest in employing other inhaled therapies, such as surfactant, antibiotics, prostacyclins, diuretics, anticoagulants and mucoactive agents, among others, in attempts to improve outcomes in critically ill ICU patients receiving mechanical ventilation

Uncoupling human and climate drivers of late Holocene vegetation change in southern Brazil

In the highlands of southern Brazil an anthropogenitcally driven expansion of forest occurred at the expense of grasslands between 1410 and 900cal BP, coincident with a period of demographic and cultural change in the region. Previous studies have debated the relative contributions of increasing wetter and warmer climate conditions and human landscape modifcations to forest expansion, but generally lacked high resoltiuon proxies to measure these efects, or have relied on single proxies to reconstruct both climate and vegetation. Here, we develop and test a model of natural ecosystem distribution against vegetation histories, paleoclimate proxies, and the archaeological record to distinguish human from temperature and precipitation impacts on the distribution and expansion of Araucaria forests during the late Holocene. Carbon isotopes from soil profles confrm that in spite of climatic fuctuations, vegetation was stable and forests were spatially limited to south-facing slopes in the absence of human inputs. In contrast, forest management strategies for the past 1400 years expanded this economically important forest beyond its natural geographic boundaries in areas of dense pre-Columbian occupation, suggesting that landscape modifcations were linked to demographic changes, the efects of which are still visible today

Defining an Essence of Structure Determining Residue Contacts in Proteins

The network of native non-covalent residue contacts determines the three-dimensional structure of a protein. However, not all contacts are of equal structural significance, and little knowledge exists about a minimal, yet sufficient, subset required to define the global features of a protein. Characterisation of this “structural essence” has remained elusive so far: no algorithmic strategy has been devised to-date that could outperform a random selection in terms of 3D reconstruction accuracy (measured as the Ca RMSD). It is not only of theoretical interest (i.e., for design of advanced statistical potentials) to identify the number and nature of essential native contacts—such a subset of spatial constraints is very useful in a number of novel experimental methods (like EPR) which rely heavily on constraint-based protein modelling. To derive accurate three-dimensional models from distance constraints, we implemented a reconstruction pipeline using distance geometry. We selected a test-set of 12 protein structures from the four major SCOP fold classes and performed our reconstruction analysis. As a reference set, series of random subsets (ranging from 10% to 90% of native contacts) are generated for each protein, and the reconstruction accuracy is computed for each subset. We have developed a rational strategy, termed “cone-peeling” that combines sequence features and network descriptors to select minimal subsets that outperform the reference sets. We present, for the first time, a rational strategy to derive a structural essence of residue contacts and provide an estimate of the size of this minimal subset. Our algorithm computes sparse subsets capable of determining the tertiary structure at approximately 4.8 Å Ca RMSD with as little as 8% of the native contacts (Ca-Ca and Cb-Cb). At the same time, a randomly chosen subset of native contacts needs about twice as many contacts to reach the same level of accuracy. This “structural essence” opens new avenues in the fields of structure prediction, empirical potentials and docking