Intricate interplay between cell metabolism and necroptosis regulation in metabolic dysfunction-associated steatotic liver disease: A narrative review.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), encompasses a progressive spectrum of liver conditions, ranging from steatosis to metabolic dysfunction-associated steatohepatitis, characterised by hepatocellular death and inflammation, potentially progressing to cirrhosis and/or liver cancer. In both experimental and human MASLD, necroptosis-a regulated immunogenic necrotic cell death pathway-is triggered, yet its exact role in disease pathogenesis remains unclear. Noteworthy, necroptosis-related signalling pathways are emerging as key players in metabolic reprogramming, including lipid and mitochondrial metabolism. Additionally, metabolic dysregulation is a well-established contributor to MASLD development and progression. This review explores the intricate interplay between cell metabolism and necroptosis regulation and its impact on MASLD pathogenesis. Understanding these cellular events may offer new insights into the complexity of MASLD pathophysiology, potentially uncovering therapeutic opportunities and unforeseen metabolic consequences of targeting necroptosis.

Percepção de enfermeiros sobre as 3S ­ Smart Safe Shoes: meias para prevenção de quedas / Nurses perception of the 3S - Smart Safe Shoes: socks to prevent falls / Percepción de enfermeros sobre los 3S - Smart Safe Shoes: calcetines para prevenir caídas

Objetivo: analisar a percepção dos enfermeiros sobre o uso das 3S - Smart Safe Shoes na sua fase de protótipo e os resultados da avaliação do seu uso por idosos internados. Método: estudo de carater exploratório, descritivo e misto, entre novembro de 2021 e março de 2022. Incluiu idosos internados com capacidade de deambulação e identificados com risco de queda; e enfermeiros especialistas. Os dados quantitativos foram analisados por estatística descritiva e os qualitativos a partir de análise temática. Resultados: participaram 28 idosos e sete enfermeiros, ambos concordaram que as 3S ­ Smart Safe Shoes são confortáveis. Os enfermeiros consideram que as meias se adaptaram perfeitamente às diferentes regiões anatômicas do pé e que apresentam propriedades antiderrapantes nos pisos testados; e na maioria das situações, permitem uma boa mobilidade dos dedos, em todos os movimentos tibiotársicos (86%). Todos os enfermeiros destacam a facilidade de calçar as meias e consideram que estas devem ser incluídas como um elemento em estratégia de prevenção de quedas. Conclusão: as 3S - Smart Safe Shoes reunem as características necessárias para garantir uma marcha segura em idosos internados e o seu uso deve ser considerado em outros contextos.

Objective: to analyse nurse's perception about 3S - Smart Safe Shoes use in their prototype phase and describe their evaluation about this use by hospitalized elderly patients. Method: exploratory, descriptive and mixed study, between November 2021 and March 2022. It included hospitalized elderly people who were able to walk and identified as being at risk of falling; and specialist nurses. Quantitative data were analyzed using descriptive statistics and qualitative data using thematic analysis. Results: 28 seniors and seven nurses participated, both agreed that the 3S ­ Smart Safe Shoes are comfortable. The nurses consider that the socks adapt perfectly to the different anatomical regions of the foot and that they have non-slip properties on the tested floors; and in most situations, they allow good mobility of the fingers, in all tibiotarsal movements (86%). All nurses highlight the ease of putting on stockings and consider that these should be included as an element in a fall prevention strategy. Conclusion: 3S - Smart Safe Shoes have the necessary characteristics to guarantee a safe gait in hospitalized elderly patients and their use should be considered in other contexts.

O percurso construtivo do enfermeiro gestor: uma teoria fundamentada nos dados / The constructive path of the manager nurse: a grounded theory

RESUMO Objetivo compreender como os enfermeiros vivenciam o planejamento da sucessão na gestão. Métodos estudo qualitativo assente na teoria fundamentada nos dados como referencial teórico e metodológico, com uma amostra de 20 enfermeiros. A coleta dos dados foi efetuada por entrevista e análise de conteúdo, e do processo de codificação emergiu o modelo conceitual. Resultados verificou-se que o planejamento da sucessão é um processo implementado informalmente no diagnóstico dos enfermeiros gestores, mas persistem algumas lacunas na sistematização do processo. Os concursos, o perfil de liderança e a experiência assumem destaque no diagnóstico, e a experiência casual em gestão é relevante na preparação dos enfermeiros gestores. Apesar da sua necessidade, subsistem entraves como a resistência dos gestores, a rotatividade dos conselhos de administração hospitalares e a pandemia da COVID-19. Conclusão os enfermeiros destacam muitos benefícios com o planejamento da sucessão, mas identificam obstáculos à sua implementação, o que contribui para a relutância na participação ativa dos enfermeiros gestores. Contribuições para a prática o modelo conceitual teórico pode contribuir para a mudança e a estruturação sistemática do percurso construtivo dos enfermeiros gestores e permite identificar as condições promotoras e limitantes no diagnóstico, formação e desenvolvimento destes profissionais.

ABSTRACT Objective to understand how nurses experience the succession planning of manager nurses. Methods qualitative study using grounded theory as a theoretical and methodological reference, with a sample of 20 nurses. Data collection took place through interviews, content analysis, and the conceptual model originated from the coding process. Results the process of succession planning is informally implemented in the diagnosis of head nurses, but there are some gaps in the systematization of the process. The selection processes, the leadership profile, and experience stand out in the diagnosis, and a casual experience in management is relevant for the preparation of head nurses. Although this is necessary, there are still obstacles, such as the resistance of managers, the turnover of hospital administration councils, and the COVID-19 pandemic. Conclusion nurses interviewed highlighted many benefits from the planning of succession, but find obstacles to its implementation, which contributes to the reluctance of head nurses to actively participate. Contributions to practice the theoretical-conceptual model can contribute to change and systematically structure the constructive path of manager nurses, allowing the identification of conditions that promote or limit the diagnosis, education, and development of these professionals.

Neurotoxic effects of MPTP on mouse cerebral cortex: Modulation of neuroinflammation as a neuroprotective strategy.

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the progressive loss of dopaminergic neurons in the Substantia nigra pars compacta (SNpc) and by the presence of intracellular inclusions, known as Lewy bodies. Despite SNpc being considered the primary affected region in PD, the neuropathological features are confined solely to the nigro-striatal axis. With disease progression other brain regions are also affected, namely the cerebral cortex, although the spreading of the neurologic damage to this region is still not completely unraveled. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that has been shown to have antioxidant properties and to exhibit a neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD. Moreover, TUDCA anti-inflammatory properties have been reported in glial cells, making it a prominent therapeutic agent in PD. Here, we used C57BL/6 mice injected with MPTP in a sub-acute paradigm aiming to investigate if the neurotoxic effects of MPTP could be extended to the cerebral cortex. In parallel, we evaluated the anti-oxidant, neuroprotective and anti-inflammatory effects of TUDCA. The anti-inflammatory mechanisms elicited by TUDCA were further dissected in microglia cells. Our results show that MPTP leads to a decrease of ATP and activated AMP-activated protein kinase levels in mice cortex, and to a transient increase in the expression of antioxidant downstream targets of nuclear factor erythroid 2 related factor 2 (Nrf-2), and parkin. Notably, MPTP increases pro-inflammatory markers, while down-regulating the expression of the anti-inflammatory protein Annexin-A1 (ANXA1). Importantly, we show that TUDCA treatment prevents the deleterious effects of MPTP, sustains increased levels of antioxidant enzymes and parkin, and most of all negatively modulates neuroinflammation and up-regulates ANXA1 expression. Additionally, results from cellular models using microglia corroborate TUDCA modulation of ANXA1 synthesis, linking inhibition of neuroinflammation and neuroprotection by TUDCA.

Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation.

Parkin is an E3 ubiquitin ligase involved in Parkinson's disease (PD). Necroptosis is a regulated form of cell death that depends on receptor interacting protein 1 (RIP1) and 3 (RIP3). Importantly, parkin has been implicated in ubiquitination events that can alter inflammation and necroptosis. Here, we investigated how parkin influences microglial function. Incubation of BV-2 microglial cells with zVAD.fmk (zVAD) induced high levels of cell death and viability loss, while N9 microglial cells and primary microglia required further stimuli. Importantly, necrostatin-1 (Nec-1), an inhibitor of RIP1 kinase activity, abrogated cell death, thus implicating RIP1-dependent necroptosis in cell death. Cell death was characterized by necrosome assembly, as determined by sequestration of RIP1/RIP3 in insoluble fractions and by MLKL phosphorylation, which were all abolished by Nec-1. Also, necroptosis-inducing conditions led to TNF-α secretion, which may in turn contribute to autocrine necroptosis activation. Interestingly, parkin knockdown protected BV-2 cells from zVAD-induced necroptosis, which may depend on the higher RIP1 ubiquitination levels detected in siRNA-PARK2 transfected cells. This effect was independent of inflammation, since pro-inflammatory stimulation of BV-2 and primary microglia with silenced parkin resulted in stronger pro-inflammatory gene expression, an opposite observation from zVAD-exposed BV-2 cells. LPS-mediated inflammation was exacerbated by NF-κB/JNK over-activation. Finally, no alterations in mitochondrial ROS production were detected in any condition, thereby excluding the role of parkin in mitophagy. In conclusion, here, we reveal that parkin may have unsuspected roles in microglia by modulating ubiquitination. Parkin loss exacerbates inflammation and promotes survival of activated microglia, thus contributing to chronic neuroinflammation.

Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by severe motor symptoms, and currently there is no treatment that retards disease progression or reverses damage prior to the time of clinical diagnosis. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD; however, its effect in PD motor symptoms has never been addressed. In the present work, an extensive behavior analysis was performed to better characterize the MPTP model of PD and to evaluate the effects of TUDCA in the prevention/improvement of mice phenotype. MPTP induced significant alterations in general motor performance paradigms, including increased latency in the motor swimming, adhesive removal and pole tests, as well as altered gait, foot dragging, and tremors. TUDCA administration, either before or after MPTP, significantly reduced the swimming latency, improved gait quality, and decreased foot dragging. Importantly, TUDCA was also effective in the prevention of typical parkinsonian symptoms such as spontaneous activity, ability to initiate movement and tremors. Accordingly, TUDCA prevented MPTP-induced decrease of dopaminergic fibers and ATP levels, mitochondrial dysfunction and neuroinflammation. Overall, MPTP-injected mice presented motor symptoms that are aggravated throughout time, resembling human parkinsonism, whereas PD motor symptoms were absent or mild in TUDCA-treated animals, and no aggravation was observed in any parameter. The thorough demonstration of improvement of PD symptoms together with the demonstration of the pathways triggered by TUDCA supports a subsequent clinical trial in humans and future validation of the application of this bile acid in PD.

Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder, mainly characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the cause of PD remains elusive, mitochondrial dysfunction and severe oxidative stress are strongly implicated in the cell death that characterizes the disease. Under oxidative stress, the master regulator of cellular redox status, nuclear factor erythroid 2 related factor 2 (Nrf2), is responsible for activating the transcription of several cytoprotective enzymes, namely glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1). Nrf2 is a promising target to limit reactive oxygen species (ROS)-mediated damage in PD. Here, we show that tauroursodeoxycholic acid (TUDCA) prevents both 1-methyl-4-phenylpyridinium (MPP+)- and α-synuclein-induced oxidative stress, through Nrf2 activation, in SH-SY5Y cells. Additionally, we used C57BL/6 male mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to elucidate the effect of TUDCA in this in vivo model of PD. In vivo, TUDCA treatment increases the expression of Nrf2, Nrf2 stabilizer DJ-1, and Nrf2 downstream target antioxidant enzymes HO-1 and GPx. Moreover, we found that TUDCA enhances GPx activity in the brain. Altogether, our results suggest that TUDCA is a promising agent to limit ROS-mediated damage, in different models of PD acting, at least in part, through modulation of the Nrf2 signaling pathway. Therefore, TUDCA should be considered a promising therapeutic agent to be implemented in PD.

Cell Death and microRNAs in Cholestatic Liver Diseases: Update on Potential Therapeutic Applications.

Cholestasis is the main pathogenic event in a wide range of genetic or acquired disorders of bile acid synthesis or bile flow, resulting in intrahepatic and systemic accumulation of bile acids. In turn, augmented levels of bile acids lead to hepatocellular injury and progressive liver damage, eventually culminating in fibrosis and end-stage liver disease. In the injured cholestatic liver, apoptosis has long been recognized as a direct consequence of bile acid-mediated injury. It is now apparent that inflammation and necrosis play an equal or even more prevalent role. Ursodeoxycholic acid is the mainstream treatment for several cholestatic syndromes, but has limited efficacy in certain circumstances. With the notion that miRNAs play key roles in basic biological processes and that their deregulation is common in human liver disease, prospective use of miRNAs as either therapeutic targets or disease biomarkers is now being increasingly documented. Deciphering the exact contribution of each player is crucial for directing efforts toward finding much needed novel therapeutic strategies for cholestasis.

Tauroursodeoxycholic Acid Protects Against Mitochondrial Dysfunction and Cell Death via Mitophagy in Human Neuroblastoma Cells.

Mitochondrial dysfunction has been deeply implicated in the pathogenesis of several neurodegenerative diseases. Thus, to keep a healthy mitochondrial population, a balanced mitochondrial turnover must be achieved. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in various neurodegenerative disease models; however, the mechanisms involved are still incompletely characterized. In this study, we investigated the neuroprotective role of TUDCA against mitochondrial damage triggered by the mitochondrial uncoupler carbonyl cyanide m-chlorophelyhydrazone (CCCP). Herein, we show that TUDCA significantly prevents CCCP-induced cell death, ROS generation, and mitochondrial damage. Our results indicate that the neuroprotective role of TUDCA in this cell model is mediated by parkin and depends on mitophagy. The demonstration that pharmacological up-regulation of mitophagy by TUDCA prevents neurodegeneration provides new insights for the use of TUDCA as a modulator of mitochondrial activity and turnover, with implications in neurodegenerative diseases.

Live-cell imaging of p53 interactions using a novel Venus-based bimolecular fluorescence complementation system.

p53 plays an important role in regulating a wide variety of cellular processes, such as cell cycle arrest and/or apoptosis. Dysfunction of p53 is frequently associated with several pathologies, such as cancer and neurodegenerative diseases. In recent years substantial progress has been made in developing novel p53-activating molecules. Importantly, modulation of p53 interaction with its main inhibitor, Mdm2, has been highlighted as a promising therapeutic target. In this regard, bimolecular fluorescence complementation (BiFC) analysis, by providing direct visualization of protein interactions in living cells, offers a straightforward method to identify potential modulators of protein interactions. In this study, we developed a simple and robust Venus-based BiFC system to screen for modulators of p53-p53 and p53-Mdm2 interactions in live mammalian cells. We used nutlin-3, a well-known disruptor of p53-Mdm2 interaction, to validate the specificity of the assay. The reduction of BiFC signal mediated by nutlin-3 was correlated with an increase in Puma transactivation, PARP cleavage, and cell death. Finally, this novel BiFC approach was exploited to identify potential modulators of p53-Mdm2 complex formation among a commercially available chemical library of 33 protein phosphatase inhibitors. Our results constitute "proof-of-concept" that this model has strong potential as an alternative to traditional target-based drug discovery strategies. Identification of new modulators of p53-p53 and p53-Mdm2 interactions will be useful to achieve synergistic drug efficacy with currently used anti-tumor therapies.

Colostomia: relato de experiência vivenciada por clientes colostomizados após hospitalizaçäo / Colostomy: the humans necessities related by a group of ostomies patients after hospitalization

A pesquisa do tipo descritiva, consiste de entrevistas a um grupo de colostomizados da Associaçäo Mineira dos Ostomizados (AMOS), que fica em Belo Horizonte, Minas Gerais. O instrumento usado foi um formulário que permitiu identificar as necessidades humanas básicas relatadas por indivíduos colostomizados após hospitalizaçäo, os elementos da equipe de Enfermagem que prestaram assistência aos pacientes, o atendimento de suas necessidades no período de hospitalizaçäo e o tipo de informaçäo recebida por esses indivíduos durante a hospitalizaçäo e/ou após a alta.