Proresolving lipid mediators and liver disease.

Inflammation is a characteristic feature of virtually all acute and chronic liver diseases. It intersects different liver pathologies from the early stages of liver injury, when the inflammatory burden is mild-to-moderate, to very advanced stages of liver disease, when the inflammatory response is very intense and drives multiple organ dysfunction and failure(s). The current review describes the most relevant features of the inflammatory process in two different clinical entities across the liver disease spectrum, namely non-alcoholic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). Special emphasis is given within these two disease conditions to gather the most relevant data on the specialized pro-resolving mediators that orchestrate the resolution of inflammation, a tightly controlled process which dysregulation commonly associates with chronic inflammatory conditions

Uma análise sobre a influência da liderança organizacional na gestão da inovação utilizando o método Fuzzy-AHP

Purpose – The changes that occurred in the market, resulting from technological advancement, made companies pay attention to innovation in their processes, products or services, as a way to stand out. To enhance innovation in companies, focusing on leadership is an effective way. In this sense, the present study aimed to develop a model in order to list the priorities related to leadership and its interface with innovation, under the top management perspective of a telecommunications company.Design/methodology/approach – For the development of the model, the Fuzzy Analytic Hierarchy Process (Fuzzy-AHP) method was used to identify such factors and the best alternatives so that the investigated company can make consistent decisions. Thus, the criteria chosen by the Manager and Director were discovered, as well as the alternatives that they cherish, contributing to the development of innovation within the company.Findings – The results showed that the perception of the two interviewees was similar, however, it is emphasized that they should better choose how to apply innovation within the company.Originality/value – This study opens the way to highlight the importance of the theme of leadership and its interface with innovation for professionals in the management area, favoring decision making, in addition to contributing to the literature, deepening the debate on the theme of leadership and innovation, which is still incipient and needs development.Objetivo – As mudanças ocorridas no mercado, decorrentes do avanço tecnológico, fizeram com que as empresas se preocupassem com a inovação em seus processos, produtos ou serviços, como forma de se destacar. Para potencializar a inovação nas empresas, o foco na liderança é uma forma eficaz. Nesse sentido, o presente estudo teve como objetivo desenvolver um modelo para elencar as prioridades relacionadas à liderança e sua interface com a inovação, sob a perspectiva da alta gestão de uma empresa de telecomunicações.Design/metodologia/abordagem – Para o desenvolvimento do modelo, foi utilizado o método Fuzzy Analytic Hierarchy Process (Fuzzy-AHP) para identificar tais fatores e as melhores alternativas para que a empresa investigada possa tomar decisões consistentes. Assim, foram descobertos os critérios escolhidos pelo Gerente e Diretor, bem como as alternativas que eles prezam, contribuindo para o desenvolvimento da inovação dentro da empresa.Achados – Os resultados mostraram que a percepção dos dois entrevistados foi semelhante, porém, destaca-se que eles deveriam escolher melhor a forma de aplicar a inovação dentro da empresa.Originalidade/valor – Esse estudo abre caminho para evidenciar a importância da temática da liderança e sua interface com a inovação para os profissionais da área de gestão, favorecendo a tomada de decisão, além de contribuir com a literatura, aprofundando o debate sobre o tema liderança e inovação, que ainda é incipiente e necessita de desenvolvimento

Albumin Lipidomics Reveals Meaningful Compositional Changes in Advanced Cirrhosis and Its Potential to Promote Inflammation Resolution

Albumin infusions are therapeutically used to revert hypoalbuminemia and to replace the extensively oxidized albumin molecule circulating in patients with acutely decompensated (AD) cirrhosis. Because albumin has high affinity for lipids, here we characterized the albumin lipidome in patients with AD and explored the albumin effects on the release of fatty acid (FA)-derived lipid mediators by peripheral leukocytes. Lipids and lipid mediators were measured by liquid chromatography-tandem mass spectrometry in albumin-enriched and albumin-depleted plasma fractions separated by affinity chromatography and in leukocyte incubations from 18 patients with AD and 10 healthy subjects (HS). Lipid mediators were also measured in 41 patients with AD included in an albumin therapy trial. The plasma lipidome associated with AD cirrhosis was characterized by generalized suppression of all lipid classes except FAs. In contrast to HS, albumin from patients with AD had lower content of polyunsaturated FAs (PUFAs), especially of the omega-3-PUFA docosahexaenoic acid. Consistent with this, the PUFA-derived lipid mediator landscape of albumin from patients with AD was dominated by lower content of monohydroxy FA precursors of anti-inflammatory/pro-resolving lipid mediators (i.e., 15-hydroxyeicosatetraenoic acid [15-HETE]). In addition, albumin from patients with AD was depleted in prostaglandin (PG) E2 , suggesting that this proinflammatory PG primarily travels disassociated to albumin in these patients. Incubation of leukocytes with exogenous albumin reduced PG production while inducing 15-lipoxygenase expression and 15-HETE release. Similar effects were seen under lipopolysaccharide plus N-formylmethionyl-leucyl-phenylalanine-stimulated conditions. Finally, PG levels were lower in patients with AD receiving albumin therapy, whereas 15-HETE was increased after albumin treatment compared with baseline. Conclusion: Our findings indicate that the albumin lipid composition is severely disorganized in AD cirrhosis and that administration of exogenous albumin has the potential to redirect leukocyte biosynthesis from pro-inflammatory to pro-resolving lipid mediators

The specialized pro-resolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are hallmarks of nonalcoholic fatty liver disease (NAFLD), which is the hepatic manifestation of the metabolic syndrome associated with obesity. The specialized proresolving lipid mediator maresin 1 (MaR1) preserves tissue homeostasis by exerting cytoprotective actions, dampening inflammation, and expediting its timely resolution. Here, we explored whether MaR1 protects liver cells from lipotoxic and hypoxia-induced ER stress. Mice were rendered obese by high-fat diet feeding, and experiments were performed in primary hepatocytes, Kupffer cells, and precision-cut liver slices (PCLSs). Palmitate-induced lipotoxicity increased ER stress and altered autophagy in hepatocytes, effects that were prevented by MaR1. MaR1 protected hepatocytes against lipotoxicity-induced apoptosis by activating the UPR prosurvival mechanisms and preventing the excessive up-regulation of proapoptotic pathways. Protective MaR1 effects were also seen in hepatocytes challenged with hypoxia and TNF-α-induced cell death. High-throughput microRNA (miRNA) sequencing revealed that MaR1 actions were associated with specific miRNA signatures targeting both protein folding and apoptosis. MaR1 also prevented lipotoxic-triggered ER stress and hypoxia-induced inflammation in PCLSs and enhanced Kupffer cell phagocytic capacity. Together, these findings describe the ability of MaR1 to oppose ER stress in liver cells under conditions frequently encountered in NAFLD.-Rius, B., Duran-Güell, M., Flores-Costa, R., López-Vicario, C., Lopategi, A., Alcaraz-Quiles, J., Casulleras, M., Lozano, J. J., Titos, E., Clària, J. The specialized proresolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress

Investigação e modelagem da incivilidade no trabalho na percepção dos professores de instituições públicas e privadas

O presente estudo tem como objetivo desenvolver uma modelagem visando elencar as prioridades referentes à incivilidade no ambiente de trabalho sob a percepção dos professores de escolas públicas e privadas situadas em Santa Maria – RS. Participaram da pesquisa 166 professores da educação básica de escolas públicas e privadas de Santa Maria – RS. A partir dos critérios da escala elaborada por Cortina et al. (2011) e validada no Brasil por Tonin (2018), desenvolveu-se a modelagem das prioridades a partir do Analytic Hierarchy Process. Os resultados sinalizaram que as variáveis “Falou em voz alta, gritou ou insultou você” e “Fez comentários insultuosos ou desrespeitosos sobre você” foram prioridades similares citadas pelos professores, sendo ações consideradas importantes  para contexto investigado

VIVÊNCIAS MULTIPROFISSIONAIS FRENTE À PANDEMIA DE COVID-19: CONTRIBUIÇÕES DA ERGOLOGIA

A Ergologia é uma proposta multidisciplinar de análise do trabalho como atividade humana. É uma teoria que pode ser usada para a análise de cotidianos laborais com o objetivo de contribuir com a saúde dos trabalhadores. Este Boletim propõe-se a analisar o modo como os trabalhadores vivenciam o enfrentamento ao trabalho real imposto pela pandemia, trazendo uma reflexão a partir dos referenciais da ergologia. A pandemia da COVID-19 oferece uma nova e desafiadora rotina diária para os profissionais da saúde, que atuam diretamente ou indiretamente no atendimento à população. O Brasil, muito antes da chegada do SARS-CoV-2, já enfrentava impasses em seu sistema de saúde sobrecarregado. O Boletim apresenta relatos de experiências de profissionais da área da saúde, três enfermeiras e uma fisioterapeuta da linha de frente, no início dos primeiros movimentos de implementação das políticas de combate à COVID-19. São profissionais que atuam no Sistema Único de Saúde (SUS) - hospitais, unidade básica de saúde e vigilância em saúde de municípios do interior e da capital do Rio Grande do Sul. Pensar nos cenários enfrentados pelos trabalhadores da saúde compreende resgatar histórias singulares vividas, que efetivaram parceria em tempos de pandemia. Cotidianos de trabalho diferentes, porém, vivenciados em um mesmo cenário de perdas e de problemas em comum, com a incerteza em relação à segurança no trabalho e suas complexas repercussões. A pandemia evidencia a importância das pesquisas e dos pesquisadores e, mais do que nunca, a necessidade de que os trabalhadores sejam ouvidos e participem, colaborando, para juntos, tornar as atividades com menor risco possível e, consequentemente, manter a qualidade no cuidado à saúde e segurança das pessoas.Palavra-chave: Ergologia. Sistema Único de Saúde. COVID-19

Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit

Soluble guanylate cyclase (sGC) catalyzes the conversion of guanosine triphosphate into cyclic guanosine-3',5'-monophosphate, a key second messenger in cell signaling and tissue homeostasis. It was recently demonstrated that sGC stimulation is associated with a marked antiinflammatory effect in the liver of mice with experimental nonalcoholic steatohepatitis (NASH). Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver. Therapeutic administration of PRL exerted antiinflammatory and antifibrotic actions in mice with choline-deficient l-amino acid-defined high-fat diet-induced NASH. The PRL antiinflammatory effect was associated with lower F4/80- and CX3CR1-positive macrophage infiltration into the liver in parallel with lower Ly6CHigh- and higher Ly6CLow-expressing monocytes in peripheral circulation. The PRL antiinflammatory effect was also associated with suppression of hepatic levels of interleukin (IL)-1β, NLPR3 (NACHT, LRR, and PYD domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain), and active cleaved-caspase-1, which are components of the NLRP3 inflammasome. In Kupffer cells challenged with the classical inflammasome model of lipopolysaccharide plus adenosine triphosphate, PRL inhibited the priming (expression of Il1b and Nlrp3) and blocked the release of mature IL-1β. Mechanistically, PRL induced the protein kinase G (PKG)-mediated phosphorylation of the VASP (vasodilator-stimulated phosphoprotein) Ser239 residue which, in turn, reduced nuclear factor-κB (NF-κB) activity and Il1b and Nlrp3 gene transcription. PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit

Small fragments of hyaluronan are increased in individuals with obesity and contribute to low-grade inflammation through TLR-mediated activation of innate immune cells.

Background and aim: Extracellular matrix (ECM) components released during excessive fat mass expansion are considered potential endogenous danger/alarm signals contributing to innate immune system activation. The aim of the current study was to specifically measure plasma levels of low molecular weight (LMW) hyaluronan (HA) and to evaluate its role as pro-inflammatory damage-associated molecular pattern (DAMP) on leukocyte response in the context of human obesity. Subjects and methods: Participants were selected according to their body mass index (BMI, kg/m2) as non-obese (BMI 29.9, n = 33). Plasma samples were size-dependent fractionated using ion-exchange chromatography to specifically obtain LMW HA fractions that were subsequently quantified by ELISA. Cell incubation experiments with synthetic HA molecules were performed on freshly Ficoll-isolated neutrophils (PMN) and peripheral blood monocytes (PBMC). Leukocyte and adipose tissue gene expression was assessed by real-time PCR and NF-κB activation by western blot. Plasma cytokine levels were measured by fluorescent bead-based (Luminex) immunoassay. Results: We observed a statistically significant increase in the circulating levels of HA fragments of LMW in individuals with obesity which were consistent with significant up-regulated expression of the LMW HA synthesizing enzyme hyaluronan synthase-1 (HAS-1) in obese adipose tissue. Gene expression assessment of HA receptors revealed up-regulated levels for TLR2 in both obese PMN and PBMC. Synthetic HA molecules of different sizes were tested on leukocytes from healthy donors. LMW HA fragments (15-40 kDa) and not those from intermediate molecular sizes (75-350 kDa) induced a significant up-regulation of the expression of major pro-inflammatory cytokines such as IL-1β, MCP-1 and IL-8 in PBMC. Importantly, LMW HA was able to induce the phosphorylation of IKK α/β complex supporting its pro-inflammatory role through NF-κB activation. Conclusion: Circulating LMW HA molecules are elevated in obesity and may play an important role in triggering low-grade inflammation and the development of metabolic complications

Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure.

Background & aims: Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated with increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways with emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients with acutely decompensated (AD) cirrhosis, with and without ACLF. Methods: The study included samples from patients with AD cirrhosis (108 without and 128 with ACLF) and 41 healthy individuals. Leukocyte mitochondrial ultrastructure was visualized by transmission electron microscopy and cytosolic and mitochondrial metabolic fluxes were determined by assessing NADH/FADH2 production from various substrates. Plasma GDF15 and FGF21 were determined by Luminex and acylcarnitines by LC-MS/MS. Gene expression was analyzed by RNA-sequencing and PCR-based glucose metabolism profiler array. Results: Mitochondrial ultrastructure in patients with advanced cirrhosis was distinguished by cristae rarefication and swelling. The number of mitochondria per leukocyte was higher in patients, accompanied by a reduction in their size. Increased FGF21 and C6:0- and C8:0-carnitine predicted mortality whereas GDF15 strongly correlated with a gene set signature related to leukocyte activation. Metabolic flux analyses revealed increased energy production in mononuclear leukocytes from patients with preferential involvement of extra-mitochondrial pathways, supported by upregulated expression of genes encoding enzymes of the glycolytic and pentose phosphate pathways. In patients with ACLF, mitochondrial function analysis uncovered break-points in the TCA cycle at the isocitrate dehydrogenase and succinate dehydrogenase level, which were bridged by anaplerotic reactions involving glutaminolysis and nucleoside metabolism. Conclusions: Our findings provide evidence at the cellular, organelle and biochemical levels that severe mitochondrial dysfunction governs immunometabolism in leukocytes from patients with AD cirrhosis and ACLF. Lay summary: Patients at advanced stages of liver disease have dismal prognosis due to vital organ failures and the lack of treatment options. In this study, we report that the functioning of mitochondria, which are known as the cell powerhouse, is severely impaired in leukocytes of these patients, probably as a consequence of intense inflammation. Mitochondrial dysfunction is therefore a hallmark of advanced liver disease