RESUMO
The globin superfamily of proteins is ancient and diverse. Regular assessments based on the increasing number of available genome sequences have elaborated on a complex evolutionary history. In this review, we present a summary of a decade of advances in characterising the globins of cyanobacteria and green algae. The focus is on haem-containing globins with an emphasis on recent experimental developments, which reinforce links to nitrogen metabolism and nitrosative stress response in addition to dioxygen management. Mention is made of globins that do not bind haem to provide an encompassing view of the superfamily and perspective on the field. It is reiterated that an effort toward phenotypical and in-vivo characterisation is needed to elucidate the many roles that these versatile proteins fulfil in oxygenic photosynthetic microbes. It is also proposed that globins from oxygenic organisms are promising proteins for applications in the biotechnology arena.
Assuntos
Clorófitas , Cianobactérias , Globinas , Cianobactérias/metabolismo , Cianobactérias/genética , Clorófitas/metabolismo , Clorófitas/genética , Globinas/genética , Globinas/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Heme/metabolismo , Nitrogênio/metabolismo , FotossínteseRESUMO
Globin adducts of various chemicals, persisting in organism over the whole lifetime of erythrocytes, have been used as biomarkers of cumulative exposures to parent compounds. After removal of aged erythrocytes from the bloodstream, cleavage products of these adducts are excreted with urine as alternative, non-invasively accessible biomarkers. In our biomonitoring studies on workers exposed to ethylene oxide, its adduct with globin, N-(2-hydroxyethyl)valine, and the related urinary cleavage product N-(2-hydroxyethyl)-L-valyl-L-leucine have been determined. To describe a toxicokinetic relationship between the above types of biomarkers, a general compartmental model for simulation of formation and removal of globin adducts has been constructed in the form of code in R statistical computing environment. The essential input variables include lifetime of erythrocytes, extent of adduct formation following a single defined exposure, and parameters of exposure scenario, while other possible variables are optional. It was shown that both biomarkers reflect the past exposures differently as the adduct level in globin is a mean value of adduct levels across all compartments (subpopulations of erythrocytes of the same age) while excretion of cleavage products reflects the adduct level in the oldest compartment. Application of the model to various scenarios of continuous exposure demonstrated its usefulness for human biomonitoring data interpretation.
Assuntos
Monitoramento Biológico , Biomarcadores , Eritrócitos , Exposição Ocupacional , Humanos , Biomarcadores/urina , Biomarcadores/sangue , Eritrócitos/metabolismo , Eritrócitos/efeitos dos fármacos , Modelos Biológicos , Óxido de Etileno/toxicidade , Óxido de Etileno/farmacocinética , Óxido de Etileno/urina , Toxicocinética , Globinas/metabolismo , Valina/análogos & derivados , Valina/farmacocinética , Valina/urina , Valina/sangue , Simulação por ComputadorRESUMO
Hell's Gate globin-I (HGb-I) is a thermally stable globin from the aerobic methanotroph Methylacidiphilium infernorum. Here we report that HGb-I interacts with lipids stoichiometrically to induce structural changes in the heme pocket, changing the heme iron distal ligation coordination from hexacoordinate to pentacoordinate. Such changes in heme geometry have only been previously reported for cytochrome c and cytoglobin, linked to apoptosis regulation and enhanced lipid peroxidation activity, respectively. However, unlike cytoglobin and cytochrome c, the heme iron of HGb-I is altered by lipids in ferrous as well as ferric oxidation states. The apparent affinity for lipids in this thermally stable globin is highly pH-dependent but essentially temperature-independent within the range of 20-60 °C. We propose a mechanism to explain these observations, in which lipid binding and stability of the distal endogenous ligand are juxtaposed as a function of temperature. Additionally, we propose that these coupled equilibria may constitute a mechanism through which this acidophilic thermophile senses the pH of its environment.
Assuntos
Temperatura , Concentração de Íons de Hidrogênio , Globinas/química , Globinas/metabolismo , Lipídeos/química , Heme/metabolismo , Heme/química , Conformação Proteica , Modelos Moleculares , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismoRESUMO
Androglobin (ADGB) is a highly conserved and recently identified member of the globin superfamily. Although previous studies revealed a link to ciliogenesis and an involvement in murine spermatogenesis, its physiological function remains mostly unknown. Apart from FOXJ1-dependent regulation, the transcriptional landscape of the ADGB gene remains unexplored. We, therefore, aimed to obtain further insights into regulatory mechanisms governing ADGB expression. To this end, changes in ADGB promoter activity were examined using luciferase reporter gene assays in the presence of a set of more than 475 different exogenous transcription factors. MYBL2 and PITX2 resulted in the most pronounced increase in ADGB promoter-dependent luciferase activity. Subsequent truncation strategies of the ADGB promoter fragment narrowed down the potential MYBL2 and PITX2 binding sites within the proximal ADGB promoter. Furthermore, MYBL2 binding sites on the ADGB promoter were further validated via a guide RNA-mediated interference strategy using reporter assays. Chromatin immunoprecipitation (ChIP)-qPCR experiments illustrated enrichment of the endogenous ADGB promoter region upon MYBL2 and PITX2 overexpression. Consistently, ectopic MYBL2 expression induced endogenous ADGB mRNA levels. Collectively, our data indicate that ADGB is strongly regulated at the transcriptional level and might have functions beyond ciliogenesis.
Assuntos
Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Fatores de Transcrição , Regiões Promotoras Genéticas/genética , Humanos , Sítios de Ligação , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Animais , Proteína Homeobox PITX2 , Globinas/genética , Globinas/metabolismo , Expressão Ectópica do Gene , Camundongos , Ligação ProteicaRESUMO
Globins, such as myoglobin (Mb) and neuroglobin (Ngb), are ideal protein scaffolds for the design of functional metalloenzymes. To date, numerous approaches have been developed for enzyme design. This review presents a summary of the progress made in the design of functional metalloenzymes based on Mb and Ngb, with a focus on the exploitation of covalent interactions, including coordination bonds and covalent modifications. These include the construction of a metal-binding site, the incorporation of a non-native metal cofactor, the formation of Cys/Tyr-heme covalent links, and the design of disulfide bonds, as well as other Cys-covalent modifications. As exemplified by recent studies from our group and others, the designed metalloenzymes have potential applications in biocatalysis and bioconversions. Furthermore, we discuss the current trends in the design of functional metalloenzymes and highlight the importance of covalent interactions in the design of functional metalloenzymes.
Assuntos
Globinas , Mioglobina , Proteínas do Tecido Nervoso , Neuroglobina , Neuroglobina/metabolismo , Neuroglobina/química , Mioglobina/química , Mioglobina/metabolismo , Globinas/química , Globinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/química , Humanos , Animais , Heme/química , Heme/metabolismo , Sítios de Ligação , Metaloproteínas/química , Metaloproteínas/metabolismo , Engenharia de Proteínas/métodosRESUMO
The heterogeneous composition of cellular transcriptomes poses a major challenge for detecting weakly expressed RNA classes, as they can be obscured by abundant RNAs. Although biochemical protocols can enrich or deplete specified RNAs, they are time-consuming, expensive and can compromise RNA integrity. Here we introduce RISER, a biochemical-free technology for the real-time enrichment or depletion of RNA classes. RISER performs selective rejection of molecules during direct RNA sequencing by identifying RNA classes directly from nanopore signals with deep learning and communicating with the sequencing hardware in real time. By targeting the dominant messenger and mitochondrial RNA classes for depletion, RISER reduces their respective read counts by more than 85%, resulting in an increase in sequencing depth of 47% on average for long non-coding RNAs. We also apply RISER for the depletion of globin mRNA in whole blood, achieving a decrease in globin reads by more than 90% as well as an increase in non-globin reads by 16% on average. Furthermore, using a GPU or a CPU, RISER is faster than GPU-accelerated basecalling and mapping. RISER's modular and retrainable software and intuitive command-line interface allow easy adaptation to other RNA classes. RISER is available at https://github.com/comprna/riser .
Assuntos
RNA Mensageiro , Análise de Sequência de RNA , Análise de Sequência de RNA/métodos , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Longo não Codificante/genética , RNA/genética , Software , Globinas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Aprendizado Profundo , Transcriptoma , RNA Mitocondrial/genética , RNA Mitocondrial/metabolismoRESUMO
Neuroglobin, a member of the globin superfamily, is abundant in the brain, retina, and cerebellum of mammals and localizes to mitochondria. The protein exhibits neuroprotective capacities by participating in electron transfer, oxygen supply, and protecting against oxidative stress. Our objective was to determine whether neuroglobin overexpression can be used to treat neurological disorders. We chose Harlequin mice, which harbor a retroviral insertion in the first intron of the apoptosis-inducing factor gene resulting in the depletion of the corresponding protein essential for mitochondrial biogenesis. Consequently, Harlequin mice display degeneration of the cerebellum and suffer from progressive blindness and ataxia. Cerebellar ataxia begins in Harlequin mice at the age of 4 months and is characterized by neuronal cell disappearance, bioenergetics failure, and motor and cognitive impairments, which aggravated with aging. Mice aged 2 months received adeno-associated viral vectors harboring the coding sequence of neuroglobin or apoptosis-inducing factor in both cerebellar hemispheres. Six months later, Harlequin mice exhibited substantial improvements in motor and cognitive skills; probably linked to the preservation of respiratory chain function, Purkinje cell numbers and connectivity. Thus, without sharing functional properties with apoptosis-inducing factor, neuroglobin was efficient in reducing ataxia in Harlequin mice.
Assuntos
Ataxia Cerebelar , Cerebelo , Globinas , Mitocôndrias , Proteínas do Tecido Nervoso , Neuroglobina , Animais , Camundongos , Fator de Indução de Apoptose/metabolismo , Fator de Indução de Apoptose/genética , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/genética , Ataxia Cerebelar/terapia , Cerebelo/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Expressão Gênica , Terapia Genética/métodos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Globinas/metabolismo , Globinas/genética , Homeostase , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Neuroglobina/metabolismo , Neurônios/metabolismoRESUMO
Ovarian fibrosis contributes to age-related ovarian dysfunction. In our previous study, we observed ovarian fibrosis in both obese and aging mice with intracellular lipid droplets in the fibrotic ovaries. Although the importance of mitochondria in ovarian fibrosis has been recognized in pharmacological studies, their role in lipid metabolism remains unclear. Globin peptide (GP), derived from hemoglobin, enhances lipid metabolism in obese mice. This study aimed to elucidate the importance of lipid metabolism in ovarian fibrosis by using GP. Treatment of ovarian stromal cells with GP increased mitochondrial oxygen consumption during ß-oxidation. Lipid accumulation was also observed in the ovaries of granulosa cell-specific Nrg1 knockout mice (gcNrg1KO), and the administration of GP to gcNrg1KO mice for two months reduced ovarian lipid accumulation and fibrosis in addition to restoring the estrous cycle. GP holds promise for mitigating lipid-related ovarian issues and provides a novel approach to safeguarding ovarian health by regulating fibrosis via lipid pathways.
Assuntos
Envelhecimento , Fertilidade , Fibrose , Globinas , Células da Granulosa , Metabolismo dos Lipídeos , Camundongos Knockout , Neuregulina-1 , Animais , Feminino , Camundongos , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Fertilidade/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Globinas/metabolismo , Globinas/genética , Neuregulina-1/metabolismo , Neuregulina-1/genética , Ovário/efeitos dos fármacos , Ovário/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Peptídeos/farmacologiaRESUMO
BACKGROUND/AIM: Cytoglobin (Cygb), a protein involved in cellular oxygen metabolism and protection, has garnered attention owing to its potential role in the initiation and progression of cancer, particularly colon cancer (CC). This study investigated the expression and significance of Cygb in CC. PATIENTS AND METHODS: This study included 145 patients who underwent R0 surgery for CC (clinical stage II/III) at our institution between January 2007 and December 2014. Immunohistochemical analysis was performed to evaluate the Cygb expression patterns in CC tissues. Additionally, the correlation between Cygb expression levels and the clinicopathological characteristics of patients with CC was investigated. RESULTS: Colon cancer tissues were categorized into high-expression (95 cases) and low-expression (50 cases) groups. Cygb was highly expressed in well-differentiated cases, whereas its expression decreased in poorly differentiated cases. No significant differences in other clinicopathological factors were observed between the two groups. Cygb expression had no significant effect on recurrence-free survival or overall survival. CONCLUSION: This study contributes to the growing understanding of Cygb expression and its significance in CC. The expression of Cygb in CC was found to be unrelated to the recurrence rate and prognosis, but showed a correlation with differentiation status.
Assuntos
Neoplasias do Colo , Globinas , Humanos , Citoglobina , Globinas/metabolismoRESUMO
Agrobacterium tumefaciens is a soil-borne pathogenic bacterium that causes crown gall disease in many plants. Chemotaxis offers A. tumefaciens the ability to find its host and establish infection. Being an aerobic bacterium, A. tumefaciens possesses one chemotaxis system with multiple potential chemoreceptors. Chemoreceptors play an important role in perceiving and responding to environmental signals. However, the studies of chemoreceptors in A. tumefaciens remain relatively restricted. Here, we characterized a cytoplasmic chemoreceptor of A. tumefaciens C58 that contains an N-terminal globin domain. The chemoreceptor was designated as Atu1027. The deletion of Atu1027 not only eliminated the aerotactic response of A. tumefaciens to atmospheric air but also resulted in a weakened chemotactic response to multiple carbon sources. Subsequent site-directed mutagenesis and phenotypic analysis showed that the conserved residue His100 in Atu1027 is essential for the globin domain's function in both chemotaxis and aerotaxis. Furthermore, deleting Atu1027 impaired the biofilm formation and pathogenicity of A. tumefaciens. Collectively, our findings demonstrated that Atu1027 functions as an aerotaxis receptor that affects agrobacterial chemotaxis and the invasion of A. tumefaciens into its host.
Assuntos
Agrobacterium tumefaciens , Quimiotaxia , Agrobacterium tumefaciens/genética , Quimiotaxia/genética , Tumores de Planta/microbiologia , Plantas , GlobinasRESUMO
Globin-coupled sensors constitute an important family of heme-based gas sensors, an emerging class of heme proteins. In this study, we have identified and characterized a globin-coupled sensor phosphodiesterase containing an HD-GYP domain (GCS-HD-GYP) from the human pathogen Vibrio fluvialis, which is an emerging foodborne pathogen of increasing public health concern. The amino acid sequence encoded by the AL536_01530 gene from V. fluvialis indicated the presence of an N-terminal globin domain and a C-terminal HD-GYP domain, with HD-GYP domains shown previously to display phosphodiesterase activity toward bis(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP), a bacterial second messenger that regulates numerous important physiological functions in bacteria, including in bacterial pathogens. Optical absorption spectral properties of GCS-HD-GYP were found to be similar to those of myoglobin and hemoglobin and of other bacterial globin-coupled sensors. The binding of O2 to the Fe(II) heme iron complex of GCS-HD-GYP promoted the catalysis of the hydrolysis of c-di-GMP to its linearized product, 5'-phosphoguanylyl-(3',5')-guanosine (pGpG), whereas CO and NO binding did not enhance the catalysis, indicating a strict discrimination of these gaseous ligands. These results shed new light on the molecular mechanism of gas-selective catalytic regulation by globin-coupled sensors, with these advances apt to lead to a better understanding of the family of globin-coupled sensors, a still growing family of heme-based gas sensors. In addition, given the importance of c-di-GMP in infection and virulence, our results suggested that GCS-HD-GYP could play an important role in the ability of V. fluvialis to sense O2 and NO in the context of host-pathogen interactions.
Assuntos
Globinas , Diester Fosfórico Hidrolases , Vibrio , Humanos , Diester Fosfórico Hidrolases/genética , Globinas/genética , Proteínas de Bactérias/química , Catálise , GMP Cíclico/metabolismo , Heme/químicaRESUMO
Bacteria utilize heme proteins, such as globin coupled sensors (GCSs), to sense and respond to oxygen levels. GCSs are predicted in almost 2000 bacterial species and consist of a globin domain linked by a central domain to a variety of output domains, including diguanylate cyclase domains that synthesize c-di-GMP, a major regulator of biofilm formation. To investigate the effects of middle domain length and heme edge residues on GCS diguanylate cyclase activity and cellular function, a putative diguanylate cyclase-containing GCS from Shewanella sp. ANA-3 (SA3GCS) was characterized. Binding of O2 to the heme resulted in activation of diguanylate cyclase activity, while NO and CO binding had minimal effects on catalysis, demonstrating that SA3GCS exhibits greater ligand selectivity for cyclase activation than many other diguanylate cyclase-containing GCSs. Small angle X-ray scattering analysis of dimeric SA3GCS identified movement of the cyclase domains away from each other, while maintaining the globin dimer interface, as a potential mechanism for regulating cyclase activity. Comparison of the Shewanella ANA-3 wild type and SA3GCS deletion (ΔSA3GCS) strains identified changes in biofilm formation, demonstrating that SA3GCS diguanylate cyclase activity modulates Shewanella phenotypes.
Assuntos
GMP Cíclico/análogos & derivados , Proteínas de Escherichia coli , Shewanella , Globinas/química , Oxigênio/metabolismo , Proteínas de Escherichia coli/química , Fósforo-Oxigênio Liases/química , Biofilmes , Heme/química , Proteínas de Bactérias/químicaRESUMO
Our globin census update allows us to refine our vision of globin origin, evolution, and structure to function relationship in the context of the currently accepted tree of life. The modern globin domain originates as a single domain, three-over-three α-helical folded structure before the diversification of the kingdoms of life (Bacteria, Archaea, Eukarya). Together with the diversification of prokaryotes, three monophyletic globin families (M, S, and T) emerged, most likely in Proteobacteria and Actinobacteria, displaying specific sequence and structural features, and spread by vertical and horizontal gene transfer, most probably already present in the last universal common ancestor (LUCA). Non-globin domains were added, and eventually lost again, creating multi-domain structures in key branches of M- (FHb and Adgb) and the vast majority of S globins, which with their coevolved multi-domain architectures, have predominantly "sensor" functions. Single domain T-family globins diverged into four major groups and most likely display functions related to reactive nitrogen and oxygen species (RNOS) chemistry, as well as oxygen storage/transport which drives the evolution of its major branches with their characteristic key distal residues (B10, E11, E7, and G8). M-family evolution also lead to distinctive major types (FHb and Fgb, Ngb, Adgb, GbX vertebrate Gbs), and shows the shift from high oxygen affinity controlled by TyrB10-Gln/AsnE11 likely related to RNOS chemistry in microorganisms, to a moderate oxygen affinity storage/transport function controlled by hydrophobic B10/E11-HisE7 in multicellular animals.
Assuntos
Evolução Molecular , Globinas , Filogenia , Globinas/genética , Globinas/química , Globinas/metabolismo , Humanos , Bactérias/genética , Bactérias/metabolismo , Animais , Archaea/genética , Archaea/metabolismo , Domínios Proteicos , Transferência Genética HorizontalRESUMO
Specific sequences within RNA encoded by human genes essential for survival possess the ability to activate the RNA-dependent stress kinase PKR, resulting in phosphorylation of its substrate, eukaryotic translation initiation factor-2α (eIF2α), either to curb their mRNA translation or to enhance mRNA splicing. Thus, interferon-γ (IFNG) mRNA activates PKR through a 5'-terminal 203-nucleotide pseudoknot structure, thereby strongly downregulating its own translation and preventing a harmful hyper-inflammatory response. Tumor necrosis factor-α (TNF) pre-mRNA encodes within the 3'-untranslated region (3'-UTR) a 104-nucleotide RNA pseudoknot that activates PKR to enhance its splicing by an order of magnitude while leaving mRNA translation intact, thereby promoting effective TNF protein expression. Adult and fetal globin genes encode pre-mRNA structures that strongly activate PKR, leading to eIF2α phosphorylation that greatly enhances spliceosome assembly and splicing, yet also structures that silence PKR activation upon splicing to allow for unabated globin mRNA translation essential for life. Regulatory circuits resulting in each case from PKR activation were reviewed previously. Here, we analyze mutations within these genes created to delineate the RNA structures that activate PKR and to deconvolute their folding. Given the critical role of intragenic RNA activators of PKR in gene regulation, such mutations reveal novel potential RNA targets for human disease.
Assuntos
Precursores de RNA , RNA , Humanos , RNA/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Biossíntese de Proteínas , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo , RNA Mensageiro/genética , Fosforilação , Fator de Necrose Tumoral alfa/metabolismo , Nucleotídeos/metabolismo , Globinas/genética , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismoRESUMO
ß-Thalassemia is a genetic form of anemia due to mutations in the ß-globin gene, that leads to ineffective and extramedullary erythropoiesis, abnormal red blood cells and secondary iron-overload. The severity of the disease ranges from mild to lethal anemia based on the residual levels of globins production. Despite being a monogenic disorder, the pathophysiology of ß-thalassemia is multifactorial, with different players contributing to the severity of anemia and secondary complications. As a result, the identification of effective therapeutic strategies is complex, and the treatment of patients is still suboptimal. For these reasons, several models have been developed in the last decades to provide experimental tools for the study of the disease, including erythroid cell lines, cultures of primary erythroid cells and transgenic animals. Years of research enabled the optimization of these models and led to decipher the mechanisms responsible for globins deregulation and ineffective erythropoiesis in thalassemia, to unravel the role of iron homeostasis in the disease and to identify and validate novel therapeutic targets and agents. Examples of successful outcomes of these analyses include iron restricting agents, currently tested in the clinics, several gene therapy vectors, one of which was recently approved for the treatment of most severe patients, and a promising gene editing strategy, that has been shown to be effective in a clinical trial. This review provides an overview of the available models, discusses pros and cons, and the key findings obtained from their study.
Assuntos
Talassemia beta , Animais , Humanos , Talassemia beta/genética , Talassemia beta/terapia , Eritropoese/genética , Ferro/metabolismo , Globinas/genética , Modelos Animais de DoençasRESUMO
Most hemoproteins display an all-α-helical fold, showing the classical three on three (3/3) globin structural arrangement characterized by seven or eight α-helical segments that form a sandwich around the heme. Over the last decade, a completely distinct class of heme-proteins called nitrobindins (Nbs), which display an all-ß-barrel fold, has been identified and characterized from both structural and functional perspectives. Nbs are ten-stranded anti-parallel all-ß-barrel heme-proteins found across the evolutionary ladder, from bacteria to Homo sapiens. Myoglobin (Mb), commonly regarded as the prototype of monomeric all-α-helical globins, is involved along with the oligomeric hemoglobin (Hb) in diatomic gas transport, storage, and sensing, as well as in the detoxification of reactive nitrogen and oxygen species. On the other hand, the function(s) of Nbs is still obscure, even though it has been postulated that they might participate to O2/NO signaling and metabolism. This function might be of the utmost importance in poorly oxygenated tissues, such as the eye's retina, where a delicate balance between oxygenation and blood flow (regulated by NO) is crucial. Dysfunction in this balance is associated with several pathological conditions, such as glaucoma and diabetic retinopathy. Here a detailed comparison of the structural, spectroscopic, and functional properties of Mb and Nbs is reported to shed light on the similarities and differences between all-α-helical and all-ß-barrel heme-proteins.
Assuntos
Globinas , Mioglobina , Humanos , Globinas/química , Heme/química , Hemoglobinas/química , Mioglobina/química , Análise EspectralRESUMO
The vertebrate respiratory protein cytoglobin (Cygb) is thought to exert multiple cellular functions. Here we studied the phenotypic effects of a Cygb knockout (KO) in mouse on the transcriptome level. RNA sequencing (RNA-Seq) was performed for the first time on sites of major endogenous Cygb expression, i.e. quiescent and activated hepatic stellate cells (HSCs) and two brain regions, hippocampus and hypothalamus. The data recapitulated the up-regulation of Cygb during HSC activation and its expression in the brain. Differential gene expression analyses suggested a role of Cygb in the response to inflammation in HSCs and its involvement in retinoid metabolism, retinoid X receptor (RXR) activation-induced xenobiotics metabolism, and RXR activation-induced lipid metabolism and signaling in activated cells. Unexpectedly, only minor effects of the Cygb KO were detected in the transcriptional profiles in hippocampus and hypothalamus, precluding any enrichment analyses. Furthermore, the transcriptome data pointed at a previously undescribed potential of the Cygb- knockout allele to produce cis-acting effects, necessitating future verification studies.
Assuntos
Globinas , Células Estreladas do Fígado , Animais , Camundongos , Citoglobina/genética , Citoglobina/metabolismo , Citoglobina/farmacologia , Perfilação da Expressão Gênica , Globinas/genética , Globinas/metabolismo , Células Estreladas do Fígado/metabolismo , Hipocampo/metabolismo , Camundongos Knockout , TranscriptomaRESUMO
Introducción: Los defectos genéticos en la molécula de hemoglobina se dividen en aquellos que tienen una tasa reducida de producción de una o más cadenas de globina, las talasemias; y en los que se producen cambios estructurales que conducen a inestabilidad o transporte anormal de oxígeno. Objetivo: Explicar los diferentes mecanismos por los cuales ocurren las talasemias y otras alteraciones en la síntesis de las cadenas de globina, así como las características moleculares, fisiopatogénicas y los cambios hematológicos. Métodos: Se realizó una revisión de la literatura, en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico de artículos publicados en los últimos 10 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: Las talasemias son un grupo heterogéneo de defectos genéticos en la síntesis de hemoglobina, que causa una disminución en la tasa de producción de una o más cadenas de la molécula. De acuerdo a la cadena de globina que presenta el defecto se dividen en α-β-, δβ- o γδβ-talasemias. Conclusiones: Las talasemias y las hemoglobinopatías son las enfermedades hemolíticas hereditarias más comunes en muchas partes del mundo, caracterizadas por complejas interacciones entre anemia, eritropoyesis ineficaz y alteraciones del metabolismo del hierro(AU)
Introduction: Genetic disorders in the hemoglobin molecule are divided into those that have a reduced rate of production of one or more globin chains, thalassemias; and those in which structural changes occur that lead to instability or abnormal oxygen transport. Objective: To explain the different mechanisms by which thalassemias and other alterations in the synthesis of globin chains occur, as well as molecular, physiopathogenic and hematological changes. Methods: A review of the literature in English and Spanish was carried out through the PubMed website and the Google Scholar search engine, searching for articles published in the last ten years. The revised bibliography was analyzed and summarized. Information analysis and synthesis: Thalassemias make up a heterogeneous group of genetic defects in the synthesis of hemoglobin, which causes a decrease in the rate of production of one or more chains of the molecule. According to the globin chain that presents the defect, they are divided into α-β-, δβ- or γδβ-thalassemias. Conclusions: Thalassemias and hemoglobinopathies are the most common hereditary hemolytic diseases in many parts of the world. They are characterized by complex interactions between anemia, ineffective erythropoiesis, and alterations in iron metabolism(AU)
Assuntos
Humanos , Masculino , Feminino , Globinas , Eritropoese , Hemoglobinopatias/genética , Doenças Genéticas Inatas/epidemiologiaRESUMO
OBJETIVO: Analisar os fatores pessoais associados à prevalência e duração dos benefícios auxílio-doença decorrentes de sinovite e tenossinovite (CID10 M65). MÉTODO: Estudo transversal referente aos benefícios auxílio-doença decorrentes de sinovite e tenossinovite concedidos pelo Instituto Nacional de Seguro Social aos empregados no Brasil em 2008. Dados sobre o ramo de atividade econômica (Classificação Nacional de Atividades Econômicas - CNAE divisão, classe), sexo, idade, espécie e duração dos benefícios foram coletados do Sistema Único de Benefícios. A população corresponde à média mensal dos vínculos empregatícios declarados ao Cadastro Nacional de Informações Sociais. RESULTADOS: Em 2008 foram concedidos 35.601 benefícios auxílio-doença decorrentes de sinovite e tenossinovite, com prevalência de 10,9/10.000 vínculos empregatícios. No conjunto dos benefícios auxílio-doença houve maior razão de prevalência (RP) acidentária (RP 1,2), sendo esta maior em mulheres (RP 3,3), e em trabalhadores com idade acima de 39 anos (RP 1,4). As CNAE 37-Esgoto (55,4) e 60-Atividade de rádio e TV (47,1) apresentaram as maiores prevalências, no entanto, 64-Atividade de serviços financeiros e 6422-Bancos múltiplos caracterizaram mais acidentes de trabalho (RP 3,2 e 3,8, respectivamente) e maior duração (70 e 73 dias, respectivamente). A maior duração de benefício ocorreu entre trabalhadores com idade superior a 39 anos. Tanto a CNAE-divisão 60-Atividade de rádio e TV, quanto a CNAE-classe 6010-Atividade de rádio apresentaram elevadas razões de feminilidade (RP 8,1 e 10,8, respectivamente). CONCLUSÃO: A incapacidade para o trabalho por sinovite e tenossinovite apresenta associação tanto da prevalência quanto da duração com o ramo de atividade, sexo, idade e espécie de benefício (previdenciário/acidentário). .
OBJECTIVE: To analyse the personal and occupational factors associated with the prevalence and duration of sickness benefit claims due to synovitis and tenosynovitis (CID10 M65). METHODS: Cross-sectional study regarding sickness benefit claims due to synovitis and tenosynovitis granted to employees by National Institute of Social Security in Brazil in 2008. Data on economic activity (Economic Activities National Classification - CNAE division, class), sex, age, type and duration of benefits were collected from the Unified Benefit System. The study's population consists of the average monthly employment contracts declared to the National Register of Social Information. RESULTS: In 2008, 35,601 employees were granted sickness benefits due to synovitis and tenosynovitis, with a prevalence of 10.9/10,000 employments. Sickness benefits showed higher prevalence rates (PR) for work-related claims (PR 1,2), mostly made by females (PR 3.3) and by workers older than 39 years (PR 1,4). The CNAE 37-Sewage (55.4) and 60-Broadcasting Activity (47.1) had the highest overall prevalence. However, the 64-Financial service activities, except insurance and pension funding and 6422-Multiple banks with commercial service had the highest rates of work-related claims (RP 3.2 and 3.8, respectively), and the longer duration (70 and 73 days, respectively). Workers older than 39 years had the highest durations of work disability claims. Both the CNAE-division 60-Broadcasting Activity, and the CNAE-class 6010-Radio showed a high activity ratio of females (PR 8.1 and 10.8, respectively). CONCLUSION: The work disability due to synovitis and tenosynovitis presents prevalence and duration associated with economic activity, sex, age and kind of benefit (non work-related and work-related claims). .
Assuntos
Humanos , Globinas/química , Peróxido de Hidrogênio/química , Proteínas do Tecido Nervoso/química , Nitritos/química , Sequência de Aminoácidos , Sítios de Ligação , Catálise , Cisteína/química , Cisteína/metabolismo , Dissulfetos/química , Dissulfetos/metabolismo , Globinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Cinética , Modelos Moleculares , Dados de Sequência Molecular , Mioglobina/química , Mioglobina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nitritos/metabolismo , Oxirredução , Conformação Proteica , Fenol/química , Fenóis/química , Fenilacetatos/química , Espectrometria de Massas em TandemRESUMO
OBJETIVOS: Verificar se a presença de agentes infecciosos no conteúdo vaginal ou cervical pode alterar os resultados dos testes da proteína-1 fosforilada ligada ao fator de crescimento insulina-símile (phIGFBP-1) e das medidas do comprimento do colo uterino (CC) pela ultrassonografia transvaginal. MÉTODOS: Um total de 107 gestantes com antecedente de prematuridade espontânea foram submetidas ao teste da phIGFBP-1 e à realização da ultrassonografia transvaginal para medida do comprimento do colo uterino, a cada três semanas, entre 24 e 34 semanas. As infecções genitais foram pesquisadas imediatamente antes da realização dos testes. As pacientes foram distribuídas em quatro grupos (GA, GB, GC e GD) e dentro de cada grupo foi avaliada a correlação entre infecção genital e alteração nos testes utilizando a análise das razões de chance (OR) e o coeficiente de correlação de Pearson. RESULTADOS: Em cada grupo, mais de 50% das pacientes apresentaram infecção genital (GA 10/17; GB 28/42; GC 15/24; GD 35/53), sendo a vaginose bacteriana a principal alteração de flora vaginal. O resultado positivo para phIGFBP-1 (GA 10/10; GB 18/28; GC 15/15; GD 19/35) e CC≤20 mm (GA 10/10; GB 20/28; GC 10/15; GD 20/35) foram os resultados encontrados com maior frequência nas pacientes com infecção genital em todos os grupos. Porém, aplicando o coeficiente de correlação de Pearson foi identificada correlação entre infecção genital e positividade para os marcadores. CONCLUSÃO: A presença de alteração da flora vaginal e de outras infecções genitais não alteram significativamente os resultados do teste da phIGFBP-1 e da medida do colo uterino quando comparados aos casos sem infecção. No entanto, é necessária ...
PURPOSE: To determine if the presence of infectious agents in vaginal or cervical content can alter the results of the insulin-like growth factor binding protein-1 (phIGFBP-1) test and the measurement of cervical length (CC) by transvaginal ultrasonography. METHODS: A total of 107 pregnant women with a history of spontaneous preterm birth were submitted to the phIGFBP-1 test and to measurement of CC by transvaginal ultrasonography every 3 weeks, between 24 and 34 weeks of gestation. Genital infections were determined immediately before testing. The patients were distributed into four groups (GA, GB, GC, and GD) and the correlation between genital infection and changes in the tests was determined within each group based on the odds ratio (OR) and the Pearson correlation coefficient. RESULTS: In each group, over 50% of the patients had genital infections (GA 10/17; GB 28/42; GC 15/24; GD 35/53), with bacterial vaginosis being the main alteration of the vaginal flora. Positive results for phIGFBP-1(GA 10/10; GB 18/28; GC 15/15; GD 19/35) and CC≤20 mm (GA 10/10; GB 20/28; GC 10/15; GD 20/35) were obtained more frequently in patients with genital infection in all groups. Nonetheless, when applying the Pearson correlation coefficient we detected a poor correlation between genital infection and positivity for markers. CONCLUSION: The presence of changes in the vaginal flora and of other genital infections does not significantly alter the results of phIGFBP-1 and the measurement of cervical length when compared to cases without infection. However, more studies with larger samples are necessary to confirm these results. .