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Plant sterols are known for their hypocholesterolemic action, and the molecular mechanisms behind this within the gut have been extensively discussed and demonstrated to the point that there is a degree of consensus. However, recent studies show that these molecules exert an additional umbrella of therapeutic effects in other tissues, which are related to immune function, lipid metabolism, and glucose metabolism. A strong hypothesis to explain these effects is the structural relationship between plant sterols and the ligands of a group of nuclear receptors. This review delves into the molecular aspects of therapeutic effects related with lipid and energy metabolism that have been observed and demonstrated for plant sterols, and turns the perspective to explore the involvement of nuclear receptors as part of these mechanisms.
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Contamination of aquatic environments has been steadily increasing due to human activities. The Pacific oyster Crassostrea gigas has been used as a key species in studies assessing the impacts of contaminants on human health and the aquatic biome. In this context, cytochrome P450 (CYPs) play a crucial role in xenobiotic metabolism. In vertebrates many of these CYPs are regulated by nuclear receptors (NRs) and little is known about the NRs role in C. gigas. Particularly, the CgNR5A represents a homologue of SF1 and LRH-1 found in vertebrates. Members of this group can regulate genes of CYPs involved in lipid/steroid metabolism, with their activity regulated by other NR, called as DAX-1, generating a NR complex on DNA response elements (REs). As C. gigas does not exhibit steroid biosynthesis pathways, CgNR5A may play other physiological roles. To clarify this issue, we conducted an in silico investigation of the interaction between CgNR5A and DNA to identify potential C. gigas CYP target genes. Using molecular docking and dynamics simulations of the CgNR5A on DNA molecules, we identified a monomeric interaction with extended REs. This RE was found in the promoter region of 30 CYP genes and also the NR CgDAX. When the upstream regulatory region was analyzed, CYP2C39, CYP3A11, CYP4C21, CYP7A1, CYP17A1, and CYP27C1 were mapped as the main genes regulated by CgNR5A. These identified CYPs belong to families known for their involvement in xenobiotic and lipid/steroid metabolism. Furthermore, we reconstructed a trimeric complex, previously proposed for vertebrates, with CgNR5A:CgDAX and subjected it to molecular dynamics simulations analysis. Heterotrimeric complex remained stable during the simulations, suggesting that CgDAX may modulate CgNR5A transcriptional activity. This study provides insights into the potential physiological processes involving these NRs in the regulation of CYPs associated with xenobiotic and steroid/lipid metabolism.
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Crassostrea , Sistema Enzimático do Citocromo P-450 , Receptores Citoplasmáticos e Nucleares , Crassostrea/genética , Animais , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Simulação de Acoplamento Molecular , Regulação da Expressão Gênica , Simulação de Dinâmica Molecular , Xenobióticos/metabolismoRESUMO
The increasing presence of anthropogenic contaminants in aquatic environments poses challenges for species inhabiting contaminated sites. Due to their structural binding characteristics to ligands that inhibit or activate gene transcription, these xenobiotic compounds frequently target the nuclear receptor superfamily. The present work aims to understand the potential interaction between the hormone 17-ß-estradiol, an environmental contaminant, and the nuclear receptors of Crassostrea gigas, the Pacific oyster. This filter-feeding, sessile oyster species is subject to environmental changes and exposure to contaminants. In the Pacific oyster, the estrogen-binding nuclear receptor is not able to bind this hormone as it does in vertebrates. However, another receptor may exhibit responsiveness to estrogen-like molecules and derivatives. We employed high-performance in silico methodologies, including three-dimensional modeling, molecular docking and atomistic molecular dynamics to identify likely binding candidates with the target moecule. Our approach revealed that among the C. gigas nuclear receptor superfamily, candidates with the most favorable interaction with the molecule of interest belonged to the NR1D, NR1H, NR1P, NR2E, NHR42, and NR0B groups. Interestingly, NR1H and NR0B were associated with planktonic/larval life cycle stages, while NR1P, NR2E, and NR0B were associated with sessile/adult life stages. The application of this computational methodological strategy demonstrated high performance in the virtual screening of candidates for binding with the target xenobiotic molecule and can be employed in other studies in the field of ecotoxicology in non-model organisms.
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Receptores Citoplasmáticos e Nucleares , Xenobióticos , Animais , Simulação de Acoplamento Molecular , Estrogênios , EstradiolRESUMO
Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)-binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1-PABPC4 interface might be a new road to the treatment of metabolic diseases.
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Receptores Citoplasmáticos e Nucleares , Fatores de Transcrição , Animais , Camundongos , Proteínas Correpressoras/metabolismo , Correpressor 1 de Receptor Nuclear/genética , Correpressor 1 de Receptor Nuclear/metabolismo , Fosforilação Oxidativa , Receptores Citoplasmáticos e Nucleares/metabolismo , Estresse Fisiológico , Fatores de Transcrição/metabolismoRESUMO
Consuming foods of vegetable origin has been shown to exert multiple health-related effects, many of them attributed to their phenolic compounds. These molecules are known for being bioactive across multiple cells and organs, with documented changes in gene expression being commonly reported. Nuclear receptors are signal transducers capable of regulating gene expression in response to endogenous and/or exogenous ligands. Liver X receptor (LXR) and retinoid X receptor (RXR) are two important nuclear receptors that can be acted on by phenolic compounds, thereby modifying gene expression and potentially exerting numerous subsequent bioactivities. The present work summarizes recent evidence of the effects of the phenolic compounds that are exerted by targeting LXR and/or RXR. The data show that, when LXR is being targeted, changes in lipid metabolism are commonly observed, due to its ability to regulate genes relevant to this process. The effects vary widely when RXR is the target since it is involved in processes like cell proliferation, vitamin D metabolism, and multiple others by forming heterodimers with other transcription factors that regulate said processes. The evidence therefore shows that phenolic compounds can exert multiple bioactivities, with a mechanism of action based, at least in part, on their ability to modulate the cell at the molecular level by acting on nuclear receptors. The data point to a promising and novel area of study that links diet and health, although various unknowns justify further experimentation to reveal the precise way in which a given phenolic can interact with a nuclear receptor.
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Hippeastrum stapfianum (Kraenzl.) R.S.Oliveira & Dutilh (Amaryllidaceae) is an endemic plant species from the Brazilian savannah with biological and pharmacological potential. This study evaluated the effects of ethanol extract from H. stapfianum leaves on acetylcholinesterase enzyme activity and the action on nuclear receptors PPAR-α and PPAR-γ. A gene reporter assay was performed to assess the PPAR agonist or antagonist activity with a non-toxic dose of H. stapfianum ethanol extract. The antioxidant capacity was investigated using DPPH⢠scavenging and fosfomolybdenium reduction assays. The identification of H. stapfianum's chemical composition was performed by gas chromatography-mass spectrometry (GC-MS) and HPLC. The ethanol extract of H. stapfianum activated PPAR-α and PPAR-γ selectively, inhibited the acetylcholinesterase enzyme, and presented antioxidant activity in an in vitro assay. The major compounds identified were lycorine, 7-demethoxy-9-O-methylhostasine, and rutin. Therefore, H. stapfianum is a potential source of drugs for Alzheimer's disease due to its ability to activate PPAR receptors, acetylcholinesterase inhibition activity, and antioxidant attributes.
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Breast cancer is one of the leading causes of cancer death in women worldwide due to its variable aggressiveness and high propensity to develop distant metastases. The staging can be performed clinically or pathologically, generating the stage stratification by the TNM (T - tumor size; N- lymph node metastasis; M - distant organ metastasis) system. However, cancers with virtually identical TNM characteristics can present highly contrasting behaviors due to the divergence of molecular profiles. This review focuses on the histopathological nuances and molecular understanding of breast cancer through the profiling of gene and protein expression, culminating in improvements promoted by the integration of this information into the traditional staging system. As a culminating point, it will highlight predictive statistical tools for genomic risks and decision algorithms as a possible solution to integrate the various systems because they have the potential to reduce the indications for such tests, serving as a funnel in association with staging and previous classification.
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Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Linfática , Estadiamento de NeoplasiasRESUMO
Cytochrome P450s (P450s) are heme-containing proteins involved in several cellular functions, including biosynthesis of steroidal hormones, detoxification of xenobiotic compounds, among others. Damage response protein 1 (Dap1) has been described as a positive regulator of P450s through protein-protein interactions in organisms such as Schizosaccharomyces pombe. Three P450s in the carotenogenic yeast Xanthophyllomyces dendrorhous have thus far been characterized: Cyp51 and Cyp61, which are involved in ergosterol biosynthesis, and CrtS (astaxanthin synthase), which is involved in biosynthesis of the carotenoid astaxanthin. In this work, we describe the X. dendrorhous DAP1 gene, deletion of which affected yeast pigmentation by decreasing the astaxanthin fraction and increasing the ß-carotene (a substrate of CrtS) fraction, which is consistent with the known role of CrtS. We found that the proportion of ergosterol was also decreased in the Δdap1 mutant. However, even though the fractions of the end products of these two pathways (the synthesis of carotenoids and sterols) were decreased in the Δdap1 mutant, the transcript levels of genes from the P450 systems involved were higher than those in the wild-type strain. We demonstrate that Dap1 coimmunoprecipitates with these three P450s, suggesting that Dap1 interacts with these three proteins. We propose that Dap1 regulates the synthesis of astaxanthin and ergosterol in X. dendrorhous, probably by regulating the P450s involved in both biosynthetic pathways at the protein level. This work suggests a new role for Dap1 in the regulation of carotenoid biosynthesis in X. dendrorhous.
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Carotenoides , Fitosteróis , Basidiomycota , Carotenoides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ergosterol , EsteróisRESUMO
Along evolution, living organisms developed a precise timekeeping system, circadian clocks, to adapt life to the 24-h light/dark cycle and temporally regulate physiology and behavior. The transcriptional molecular circadian clock and metabolic/redox oscillator conforming these clocks are present in organs, tissues, and even in individual cells, where they exert circadian control over cellular metabolism. Disruption of the molecular clock may cause metabolic disorders and higher cancer risk. The synthesis and degradation of glycerophospholipids (GPLs) is one of the most highly regulated metabolisms across the 24-h cycle in terms of total lipid content and enzyme expression and activity in the nervous system and individual cells. Lipids play a plethora of roles (membrane biogenesis, energy sourcing, signaling, and the regulation of protein-chromatin interaction, among others), making control of their metabolism a vital checkpoint in the cellular organization of physiology. An increasing body of evidence clearly demonstrates an orchestrated and sequential series of events occurring in GPL metabolism across the 24-h day in diverse retinal cell layers, immortalized fibroblasts, and glioma cells. Moreover, the clock gene Per1 and other circadian-related genes are tightly involved in the regulation of GPL synthesis in quiescent cells. However, under proliferation, the metabolic oscillator continues to control GPL metabolism of brain cancer cells even after molecular circadian clock disruption, reflecting the crucial role of the temporal metabolism organization in cell preservation. The aim of this review is to examine the control exerted by circadian clocks over GPL metabolism, their synthesizing enzyme expression and activities in normal and tumorous cells of the nervous system and in immortalized fibroblasts.
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Ritmo Circadiano/fisiologia , Fibroblastos/metabolismo , Glicerofosfolipídeos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Neurônios/metabolismo , Animais , Relógios Circadianos/fisiologia , HumanosRESUMO
Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1ß were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-ß and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.