36,505 research outputs found

    Descoberta da integração de fenómenos redox e bioelétricos na regeneração de vertebrados

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    Tese de Doutoramento Biologia Molecular e Ambiental (Especialidade Biologia Celular e Saúde)Regeneração, ou a capacidade de recuperar a forma e função em caso de lesão em larga escala, é um processo complexo. Múltiplas vias bioquímicas e biofísicas têm vindo a ser reveladas como importantes para a regeneração epimórfica. Entre elas, as espécies reativas de oxigénio (ROS) e a densidade de corrente elétrica (JI) modulam a regeneração. No entanto, a relação entre os sinais bioquímicos e biofísicos durante a regeneração permanece evasiva. Aqui, investiga-se a interação entre os estados redox (parte bioquímica) e bioelétrico (parte biofísica) na regeneração caudal de girinos Xenopus laevis. Uma regulação de duas vias das atividades bioelétricas pelos ROS é revelada. O fluxo de eletrões conduzido pelas NADPH oxidases (propriedade eletrogénica) despolariza o potencial de membrana (Vm), enquanto os ROS (propriedade catalítica) aumentam o potencial transepitelial (TEP) e revertem a JI durante a regeneração. A depleção dos ROS por inibição da produção, eliminação ou bloqueio da sua difusão para o interior das células, mimetiza os TEP e JI anormais do período refratário (não regenerativo). Crucialmente, a aplicação breve de peróxido de hidrogénio (H2O2) recupera (do decréscimo de ROS) e induz (do período refratário) regeneração, aumento do TEP e reversão do JI. Assim, H2O2 é necessário à e suficiente para induzir a regeneração e para regular os TEP e JI. Ensaios de epistasia mostram que os canais de Na+ dependente de voltagem (NaV) atuam a jusante de H2O2. Um micro-ótrodo detalhado é usado para traçar o perfil espácio-temporal de fluxo de O2 durante a regeneração. O perfil revela um aumento no influxo de O2, após amputação, que se correlaciona com a regeneração. A inibição da produção de ROS, mas não a sua eliminação, diminui a magnitude do influxo. Assim, a produção de ROS é responsável pela maior parte da força motriz que impulsiona o O2. Tanto o O2 como os ROS contribuem para a pressão parcial de O2, afetando a hipóxia e consequente estabilização do fator induzível pela hipóxia (HIF). Notavelmente, o bloqueio de HIF-1α impede a regeneração, enquanto a sua estabilização induz a regeneração no período refratário. A proteína de choque térmico (HSP) 90 é um potencial e a reversão do JI é um de facto alvo a jusante de HIF-1α. Em conjunto, estes resultados revelam a orquestração de atividades redox e bioelétricas e integram-nas durante a regeneração de um vertebrado. Estas descobertas poderão ser importantes para induzir a regeneração epimórfica no corpo humano, provavelmente a derradeira meta da medicina regenerativa.Regeneration, or the ability to regain the form and function upon large-scale injury, is a complex process. Multiple biochemical and biophysical pathways and cues play a key role during epimorphic regeneration. Among them, reactive oxygen species (ROS) and electric current densities (JI) modulate regeneration. However, the biochemical and biophysical crosstalk during regeneration remains elusive. Here, it is investigated the interplay between redox (biochemical part) and bioelectric (biophysical part) states during tail regeneration in Xenopus laevis tadpoles. A two-way regulation of bioelectric activities by the required NADPH oxidase-mediated production of ROS is unveiled. NADPH oxidase-driven electron flow (electrogenic property) depolarizes the membrane potential (Vm), while produced ROS (catalytic property) increases the transepithelial potential (TEP) and reverses JI during regeneration. Importantly, depletion of ROS levels by the inhibition of production, scavenging or blocking their diffusion into cells, mimics the abnormal TEP and JI observed in the refractory (non-regenerative) period. Crucially, short-term application of hydrogen peroxide (H2O2) rescues (from depleted ROS) and induces (from the refractory period) regeneration, TEP increase and JI reversal. Therefore, H2O2 is necessary for and sufficient to induce regeneration and to regulate TEP and JI. Epistasis assays show that voltage-gated Na+ channels (NaV) act downstream of H2O2. The stringently detailed micro-optrode is used to map the spatiotemporal oxygen (O2) flux during regeneration. The profile reveals an increased and steady O2 influx (an O2 sink) immediately upon amputation that correlates with regeneration. Inhibition of ROS production, but not their scavenging, decreases the magnitude of O2 influx. Therefore, ROS production accounts for most of the motive force driving O2 flux. Both O2 and ROS contribute to the local partial pressure of O2, affecting hypoxia and consequent hypoxia-inducible factor (HIF) stabilization in the regeneration bud. Notably, blocking HIF-1α abrogates regeneration, while stabilizing its activity induces regeneration in the refractory period. Heat shock protein (HSP) 90 is a potential and JI reversal is a de facto downstream target of HIF-1α activity. Altogether, these results unveil the orchestration of redox and bioelectric activities and integrate them during a vertebrate model of regeneration. These discoveries might be important to induce epimorphic regeneration in the human body, probably the ultimate goal of regenerative medicine.Fundação para a Ciência e Tecnologia (FCT

    Plasma lipidome and risk of atrial fibrillation: results from the PREDIMED trial

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    The potential role of the lipidome in atrial fibrillation (AF) development is still widely unknown. We aimed to assess the association between lipidome profiles of the Prevenci\uf3n con Dieta Mediterr\ue1nea (PREDIMED) trial participants and incidence of AF. We conducted a nested case–control study (512 incident centrally adjudicated AF cases and 735 controls matched by age, sex, and center). Baseline plasma lipids were profiled using a Nexera X2 U-HPLC system coupled to an Exactive Plus orbitrap mass spectrometer. We estimated the association between 216 individual lipids and AF using multivariable conditional logistic regression and adjusted the p values for multiple testing. We also examined the joint association of lipid clusters with AF incidence. Hitherto, we estimated the lipidomics network, used machine learning to select important network-clusters and AF-predictive lipid patterns, and summarized the joint association of these lipid patterns weighted scores. Finally, we addressed the possible interaction by the randomized dietary intervention. Forty-one individual lipids were associated with AF at the nominal level (p < 0.05), but no longer after adjustment for multiple-testing. However, the network-based score identified with a robust data-driven lipid network showed a multivariable-adjusted ORper+1SD of 1.32 (95% confidence interval: 1.16–1.51; p < 0.001). The score included PC plasmalogens and PE plasmalogens, palmitoyl-EA, cholesterol, CE 16:0, PC 36:4;O, and TG 53:3. No interaction with the dietary intervention was found. A multilipid score, primarily made up of plasmalogens, was associated with an increased risk of AF. Future studies are needed to get further insights into the lipidome role on AF. Current Controlled Trials number, ISRCTN35739639

    Salinity stress endurance of the plants with the aid of bacterial genes

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    The application of plant growth-promoting bacteria (PGPB) is vital for sustainable agriculture with continuous world population growth and an increase in soil salinity. Salinity is one of the severe abiotic stresses which lessens the productivity of agricultural lands. Plant growth-promoting bacteria are key players in solving this problem and can mitigate salinity stress. The highest of reported halotolerant Plant growth-promoting bacteria belonged to Firmicutes (approximately 50%), Proteobacteria (40%), and Actinobacteria (10%), respectively. The most dominant genera of halotolerant plant growth-promoting bacteria are Bacillus and Pseudomonas. Currently, the identification of new plant growth-promoting bacteria with special beneficial properties is increasingly needed. Moreover, for the effective use of plant growth-promoting bacteria in agriculture, the unknown molecular aspects of their function and interaction with plants must be defined. Omics and meta-omics studies can unreveal these unknown genes and pathways. However, more accurate omics studies need a detailed understanding of so far known molecular mechanisms of plant stress protection by plant growth-promoting bacteria. In this review, the molecular basis of salinity stress mitigation by plant growth-promoting bacteria is presented, the identified genes in the genomes of 20 halotolerant plant growth-promoting bacteria are assessed, and the prevalence of their involved genes is highlighted. The genes related to the synthesis of indole acetic acid (IAA) (70%), siderophores (60%), osmoprotectants (80%), chaperons (40%), 1-aminocyclopropane-1-carboxylate (ACC) deaminase (50%), and antioxidants (50%), phosphate solubilization (60%), and ion homeostasis (80%) were the most common detected genes in the genomes of evaluated halotolerant plant growth-promoting and salinity stress-alleviating bacteria. The most prevalent genes can be applied as candidates for designing molecular markers for screening of new halotolerant plant growth-promoting bacteria

    Ferroptosis in hematological malignant tumors

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    Ferroptosis is a kind of iron-dependent programmed cell death discovered in recent years. Its main feature is the accumulation of lipid reactive oxygen species in cells, eventually leading to oxidative stress and cell death. It plays a pivotal role in normal physical conditions and the occurrence and development of various diseases. Studies have shown that tumor cells of the blood system, such as leukemia cells and lymphoma cells, are sensitive to the response to ferroptosis. Regulators that modulate the Ferroptosis pathway can accelerate or inhibit tumor disease progression. This article reviews the mechanism of ferroptosis and its research status in hematological malignancies. Understanding the mechanisms of ferroptosis could provide practical guidance for treating and preventing these dreaded diseases

    Mitochondria: It is all about energy

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    Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases

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    Oxidative stress response is a fundamental biological process mediated by conserved mechanisms. The identities and functions of some key regulators remain unknown. Here, we report a novel role of C. elegans casein kinase 1 gamma CSNK-1 (also known as CK1γ or CSNK1G) in regulating oxidative stress response and ROS levels. csnk-1 interacted with the bli-3/tsp-15/doxa-1 NADPH dual oxidase genes via genetic nonallelic noncomplementation to affect C. elegans survival in oxidative stress. The genetic interaction was supported by specific biochemical interactions between DOXA-1 and CSNK-1 and potentially between their human orthologs DUOXA2 and CSNK1G2. Consistently, CSNK-1 was required for normal ROS levels in C. elegans. CSNK1G2 and DUOXA2 each can promote ROS levels in human cells, effects that were suppressed by a small molecule casein kinase 1 inhibitor. We also detected genetic interactions between csnk-1 and skn-1 Nrf2 in oxidative stress response. Together, we propose that CSNK-1 CSNK1G defines a novel conserved regulatory mechanism for ROS homeostasis.</div
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