RESUMO
Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the SLC6A3 gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the SLC6A3 (DAT1) 3'UTR VNTR (rs28363170) gene variant's SS (9R/9R) genotype and S (9R) allele frequency fluctuation and its influence on the modulation of pharmacotherapy in MDD. For this purpose, we searched different databases, and after applying the eligibility criteria, six articles were selected. Studies have shown an association between the SS (9R/9R) genotypic and S (9R) allelic presence with the risk of developing MDD, in addition to influencing the decrease in response to antidepressant therapy. However, despite the findings, disagreements were observed between other studies. For this reason, further studies with the SLC6A3 3'UTR VNTR (rs28363170) variant in different populations are necessary to understand this polymorphism's role in the onset of this disease.
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BACKGROUND/AIMS: Polymorphisms in the enhancer of the lactase gene (LCT) are strongly associated with lactase persistence, but not always predictive of the phenotype. We investigated a possible association between the regulatory rs140433552*CA>del variant of LCT and lactose intolerance (LI). METHODS: We genotyped 122 individuals for rs140433552 and rs4988235 (-13910*C>T). RESULTS: Associations of rs140433552*CA>del with LI depend on -13910*C>T. Homozygous individuals for the C-CA haplotype, as well as C-CA+/C individuals, seem more likely to manifest LI (OR 3.33 [95% CI 1.32-8.35], p = 0.011, and OR 3.93 [95% CI 1.61-9.61], p = 0.003, respectively), while homozygous individuals for the T-CA haplotype seem more likely to be lactose tolerant (OR 0.04 [95% CI 0.002-0.70], p = 8 × 10-4). CONCLUSIONS: rs140433552*CA>del is not independently associated with LI.
Assuntos
Mutação INDEL , Lactase/genética , Intolerância à Lactose/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Alelos , Brasil/epidemiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Haplótipos , Homozigoto , Humanos , Lactose , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
We analyzed the association of polymorphisms from the 3' untranslated region of the HLA-G gene in 70 neuromyelitis optica spectrum disorder (NMOSD) patients and 162 healthy controls. No associations were found between the polymorphisms in NMOSD when compared to healthy controls, serology of the anti-AQP4 NMOSD biomarker and Expanded Disability Status Scale (EDSS). In conclusion, the 3' untranslated region 14 bp Ins/Del and +3142C/G polymorphisms seem not to be associated with NMOSD susceptibility, autoantibody production, nor a neurological deficit in patients.
Assuntos
Aquaporina 4/genética , Autoanticorpos/genética , Pessoas com Deficiência , Antígenos HLA-G/genética , Neuromielite Óptica/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/sangue , Autoanticorpos/sangue , Brasil/epidemiologia , Feminino , Antígenos HLA-G/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Neuromielite Óptica/epidemiologia , Regiões não Traduzidas/genética , Adulto JovemRESUMO
Abstract In trypanosomatids, gene expression is mainly regulated at posttranscriptional level, through mechanisms based on the interaction between RNA Binding Proteins [RBPs] and motifs present in the untranslated regions [UTRs] of the mRNAs, which altogether form ribonucleoproteic complexes [RNP] that define the fate of the mRNA. The pre-mRNA derived from the LYT1 gene of Trypanosoma cruzi, is processed by alternative trans-splicing, resulting in different mRNAs which code for the isoforms mLYTl and kLYTl, proteins having differential expression, cellular location and function. The aim of this study was to characterize the 5' and 3' UTRs of the LYT1 mRNAs as the initial step towards the objective of identification of the RBPs responsible for their differential expression. The presence of the two types of 5' UTRs were confirmed in two T. cruzi isolates belonging to the DTU I, thus, corroborating the occurrence of alternative trans-splicing also in the LYT1 gene of this T. cruzi DTU. In addition, for the first time, was unscovered the existence of two types of LYT1 mRNAs transcripts, differing in length by 116 nts, that are generated by alternative polyadenylation. Furthermore, an in-silico analysis of the experimentally obtained UTRs, and ten additional LYT1 sequences retrieved from TritrypDB and GenBank databases, together with a thoroughly search of structural motifs, showed a remarkable conservation of relevant structural motifs previously associated with RNA metabolism in the different UTRs; these elements might be involved in the differential stage-specific expression of each LYT1 isoform.
Resumen En los trypanosomátidos, la expresión génica se regula principalmente en el nivel post-transcripcional mediante mecanismos basados en la interacción entre las proteínas de unión del ARN [RBP] y las figuras presentes en las regiones no traducidas [UTR] de las ARN, que en conjunto forman complejos ribonucleoproteicos [RNP] que definen el destino de la ARN. El pre-ARN derivado del gen LYT1 del Trypanosoma cruzi es procesado por trans-empalme alternativo, dando como resultado diferentes ARN que codifican las isoformas mLYTl y kLYTl, proteínas con expresión diferencial, localización celular y función. El objetivo de este estudio fue caracterizar los 5' y 3' UTR de las ARN LYT1 como el paso inicial hacia la identificación de los RPB responsables de la expresión diferencial. Se confirmó la presencia de los dos tipos de 5' UTR en dos aislantes del T. cruzi pertenecientes al DTU I; de esta forma también se comprobó la ocurrencia del trans-empalme alternativo en el gen LYT1 de este T. cruzi DTU. Además, por primera vez, se pudo demostrar la existencia de dos tipos de transcripciones de ARN LYT1, que difieren en longitud por 116 nts, y son generadas por poliadenilación alternativa. Adicionalmente, se realizó un análisis in-silico de la UTR obtenida experimentalmente, y otras diez secuencias LYT1 recuperadas de las bases de datos TritrypDB y GenBank, junto con una búsqueda exhaustiva de figuras estructuradas, mostrando una notable conservación de los figuras estructurales asociadas con el metabolismo del ARN en los diferentes UTR; estos elementos podrían estar implicados en la expresión diferenciada de la etapa específica de cada isoforma LYT1.
Resumo Nos tripanossomatídeos, a expressão génica é regulada principalmente a nível pós-transcricional mediante mecanismos baseados na interação entre as proteínas de união do RNA [RBPs] e as fugiras presentes nas regiões não-traduzidas [UTRs] do RNA. O pré-RNA derivado do gene LYT1 do Trypanosoma cruzí é processado por uma junção trans-alternativa, resultando em diferentes RNA que codificam as isoformas mLYTl e kLYTl, proteínas com expressão, localização celular e função diferenciadas. O objetivo de este estudo foi caracterizar as 5' e 3' UTRs dos RNAs LYT1 como sendo o passo inicial na identificação das RBPs responsáveis pela expressão diferenciada. A presença dos dois tipos de 5' UTRs foi confirmada em dois isolados de T. cruzí pertencentes ao DTU I; corroborando assim com a ocorrência da junção trans-alternativa no gene LYT1 de este T. crují DTU. Adicionalmente, se demonstrou pela primeira vez a existência de dois tipos de transcrições de RNA LYT1, que se diferenciam em comprimento por 116 nts, e são geradas por poliadenização alternativa. Além disso, realizou-se uma análise in-sílico da UTR obtida experimentalmente e outras dez sequencias LYT1 recuperadas das bases de dados TritrypDB e GenBank, junto com uma busca exaustiva de figuras estruturadas, mostrando uma notável conservação das figuras estruturais associadas com o metabolismo do RNA nas diferentes UTRs. Estes elementos poderiam estar envolvidos na expressão estágio-específica diferenciada de cada isoforma LYT1.
Assuntos
Humanos , Trypanosoma cruzi , Regulação da Expressão Gênica , Proteínas de Ligação a RNA , Regiões não TraduzidasRESUMO
Most signals involved in post-transcriptional regulatory networks are located in the untranslated regions (UTRs) of the mRNAs. Therefore, to deepen our understanding of gene expression regulation, delimitation of these regions with high accuracy is needed. The trypanosomatid lineage includes a variety of parasitic protozoans causing a significant worldwide burden on human health. Given their peculiar mechanisms of gene expression, these organisms depend on post-transcriptional regulation as the main level of gene expression control. In this context, the definition of the UTR regions becomes of key importance. We have developed UTR-mini-exon (UTRme), a graphical user interface (GUI) stand-alone application to identify and annotate 5' and 3' UTR regions in a highly accurate way. UTRme implements a multiple scoring system tailored to address the issue of false positive UTR assignment that frequently arise because of the characteristics of the intergenic regions. Even though it was developed for trypanosomatids, the tool can be used to predict 3' sites in any eukaryote and 5' UTRs in any organism where trans-splicing occurs (such as the model organism C. elegans). UTRme offers a way for non-bioinformaticians to precisely determine UTRs from transcriptomic data. The tool is freely available via the conda and github repositories.
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BACKGROUND: The human leukocyte antigen G (HLA-G) is a molecule involved in immune system modulation, acting in the maintenance of a state of immune tolerance. Some polymorphisms in the HLA-G gene 3' untranslated region (3'UTR) were associated to distinct levels of HLA-G expression and to sepsis development. In the present study, haplotypes and polymorphisms of the HLA-G 3'UTR were analyzed in Brazilian septic patients. METHODS: The HLA-G 3'UTR was amplified by PCR, sequenced and eight polymorphisms were genotyped (the 14bp insertion/deletion, +3003T/C, +3010C/G, +3027A/C, +3035C/T, +3142G/C, +3187A/G and+3196C/G) in DNA samples from septic patients (with severe sepsis or septic shock) and controls. The haplotypes were inferred and association tests were performed through Chi square test and binary logistic regression. RESULTS: The+3027AC genotype was associated asa risk factor to sepsis development (OR 3.17, PBonferroni 0.048). Further, the presence of the UTR-7 haplotype (OR 2.97, PBonferroni 0.018), and of 14bp-Ins_+3142G_+3187A haplotype (OR 2.39, PBonferroni 0.045) were associated with sepsis, conferring susceptibility. CONCLUSION: Our data confirm an important role of HLA-G 3'UTR polymorphisms in the development of severe forms of sepsis (severe sepsis and septic shock). The genotyping of HLA-G genetic variants and haplotypes could be useful as a prediction tool of increased risk to severe sepsis.
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Regiões 3' não Traduzidas/genética , Genótipo , Antígenos HLA-G/genética , Sepse/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Progressão da Doença , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Tolerância Imunológica , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto JovemRESUMO
The HLA-E gene is characterized by low but wide expression on different tissues. HLA-E is considered a conserved gene, being one of the least polymorphic class I HLA genes. The HLA-E molecule interacts with Natural Killer cell receptors and T lymphocytes receptors, and might activate or inhibit immune responses depending on the peptide associated with HLA-E and with which receptors HLA-E interacts to. Variable sites within the HLA-E regulatory and coding segments may influence the gene function by modifying its expression pattern or encoded molecule, thus, influencing its interaction with receptors and the peptide. Here we propose an approach to evaluate the gene structure, haplotype pattern and the complete HLA-E variability, including regulatory (promoter and 3'UTR) and coding segments (with introns), by using massively parallel sequencing. We investigated the variability of 420 samples from a very admixed population such as Brazilians by using this approach. Considering a segment of about 7kb, 63 variable sites were detected, arranged into 75 extended haplotypes. We detected 37 different promoter sequences (but few frequent ones), 27 different coding sequences (15 representing new HLA-E alleles) and 12 haplotypes at the 3'UTR segment, two of them presenting a summed frequency of 90%. Despite the number of coding alleles, they encode mainly two different full-length molecules, known as E*01:01 and E*01:03, which corresponds to about 90% of all. In addition, differently from what has been previously observed for other non classical HLA genes, the relationship among the HLA-E promoter, coding and 3'UTR haplotypes is not straightforward because the same promoter and 3'UTR haplotypes were many times associated with different HLA-E coding haplotypes. This data reinforces the presence of only two main full-length HLA-E molecules encoded by the many HLA-E alleles detected in our population sample. In addition, this data does indicate that the distal HLA-E promoter is by far the most variable segment. Further analyses involving the binding of transcription factors and non-coding RNAs, as well as the HLA-E expression in different tissues, are necessary to evaluate whether these variable sites at regulatory segments (or even at the coding sequence) may influence the gene expression profile.
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Regiões 3' não Traduzidas , Alelos , Variação Genética , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Íntrons , Regiões Promotoras Genéticas , Brasil , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Masculino , Antígenos HLA-ERESUMO
Human leukocyte antigen-G (HLA-G) presents inhibitory functions in immune cells and is located in a chromosomal region associated with systemic lupus erythematosus (SLE) susceptibility. Polymorphisms in 3' untranslated region (3'UTR) of HLA-G gene may influence protein expression. To date, no study analyzing HLA-G polymorphism and expression in childhood-onset systemic lupus erythematosus (cSLE) has been conducted. Therefore, we investigated the influence of HLA-G 3'UTR polymorphisms in 50 cSLE patients and 144 healthy controls. For the expression analysis, the control group included 26 healthy individuals. No significant difference in allele, genotype, and haplotype frequencies was observed between patients and control group. However, both the 14 bp deletion allele (odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.17-6.52, P = .028) and the 14 bp deletion-deletion genotype (OR = 8.00, 95% CI = 1.57-40.65, P = .006) showed an association with lupus nephritis. After Bonferroni correction, none P-value remained statistically significant. Regarding HLA-G expression, no significant difference was observed between plasma levels of cSLE patients (56.02 U/mL, interquartile range [IQR] = 37.54-75.41) and control group (49.2 U/mL, IQR = 27.84-154.4, P = .952). However, when the patients were stratified according to clinical manifestations, patients with hematological manifestations showed a lower plasma concentration of soluble HLA-G (sHLA-G) (47.08 U/mL, IQR = 34.15-61.56) than patients with no hematological manifestations (65.26 U/mL, IQR = 47.69-102.60, P = .013). These results suggest that HLA-G polymorphism has small effect on cSLE susceptibility and that sHLA-G may be involved in the pathogenesis of the disease.
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Regiões 3' não Traduzidas , Sequência de Bases , Antígenos HLA-G/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Deleção de Sequência , Adolescente , Idade de Início , Alelos , Estudos de Casos e Controles , Criança , Feminino , Expressão Gênica , Frequência do Gene , Antígenos HLA-G/sangue , Antígenos HLA-G/imunologia , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Projetos PilotoRESUMO
AIM: The dengue virus is responsible for a high worldwide incidence of infections, aggravated by late diagnosis, and often confused with other tropical diseases. Results/methodology: Oligonucleotide aptamers binding to the 5'-UTR from dengue virus selected after eight rounds by systematic evolution of ligands by exponential enrichment technology were analyzed by dot-blot assay and in silico prediction of secondary structures, demonstrating the presence of stem-loops that may have the potential for interaction with the viral genome, which can lead to loss of their original conformation. CONCLUSION: This is the first description of RNA aptamers against functional RNA elements of the dengue virus genome with implications for disease control, which may have potential as tools in the future of antiviral therapies and for diagnostics.
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Regiões 5' não Traduzidas/efeitos dos fármacos , Antivirais/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Vírus da Dengue/efeitos dos fármacos , Oligonucleotídeos/farmacologia , Regiões 5' não Traduzidas/genética , Antivirais/química , Aptâmeros de Nucleotídeos/química , Sítios de Ligação/efeitos dos fármacos , Vírus da Dengue/genética , Ligantes , Testes de Sensibilidade Microbiana , Oligonucleotídeos/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND Dengue is considered one of the world’s most important mosquito-borne diseases. MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that play an important role in the regulation of gene expression in eukaryotes. Although miRNAs possess antiviral activity against many mammalian-infecting viruses, their involvement in Dengue virus (DENV) replication remains poorly understood. OBJECTIVE To determine the role of miR-484 and miR-744 in DENV infection and to examine whether DENV infection alters the expression of both miRNAs. METHODS We used bioinformatics tools to explore the relationship between DENV and cellular miRNAs. We then overexpressed miR-484 or miR-744 in Vero cells to examine their role in DENV replication using flow cytometry, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), and western blotting. FINDINGS We found several cellular miRNAs that target a conserved region within the 3′ untranslated region (3′ UTR) of the genome of the four DENV serotypes and found that overexpression of miR-484 or miR-744 inhibits infection by DENV-1 to DENV-4. Furthermore, we observed that DENV RNA might be involved in the downregulation of endogenous miR-484 and miR-744. CONCLUSION Our study identifies miR-484 and miR-744 as two possible restriction host factors against DENV infection. However, further studies are needed to directly verify whether miR-484 and miR-744 both have an anti-DENV effect in vivo.
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Animais , Replicação Viral/fisiologia , Replicação Viral/genética , Chlorocebus aethiops , Regulação da Expressão Gênica/genética , Western Blotting , Reação em Cadeia da Polimerase , Biologia Computacional , Regiões não Traduzidas , Regiões não Traduzidas/fisiologia , Vírus da Dengue/fisiologia , Vírus da Dengue/genética , MicroRNAs/metabolismo , Citometria de FluxoRESUMO
The family Flaviviridae comprises a wide variety of viruses that are distributed worldwide, some of which are associated with high rates of morbidity and mortality. There are neither vaccines nor antivirals for most flavivirus infections, reinforcing the importance of research on different aspects of the viral life cycle. During infection, cytoplasmic accumulation of RNA fragments mainly originating from the 3' UTRs, which have been designated subgenomic flavivirus RNAs (sfRNAs), has been detected. It has been shown that eukaryotic exoribonucleases are involved in viral sfRNA production. Additionally, viral and human small RNAs (sRNAs) have also been found in flavivirus-infected cells, especially microRNAs (miRNAs). miRNAs were first described in eukaryotic cells and in a mature and functional state present as single-stranded 18-24 nt RNA fragments. Their main function is the repression of translation through base pairing with cellular mRNAs, besides other functions, such as mRNA degradation. Canonical miRNA biogenesis involves Drosha and Dicer, however miRNA can also be generated by alternative pathways. In the case of flaviviruses, alternative pathways have been suggested. Both sfRNAs and miRNAs are involved in viral infection and host cell response modulation, representing interesting targets of antiviral strategies. In this review, we focus on the generation and function of viral sfRNAs, sRNAs and miRNAs in West Nile, dengue, Japanese encephalitis, Murray Valley encephalitis and yellow fever infections, as well as their roles in viral replication, translation and cell immune response evasion. We also give an overview regarding other flaviviruses and the generation of cellular miRNAs during infection.
Assuntos
Infecções por Flavivirus/imunologia , Infecções por Flavivirus/virologia , Interações Hospedeiro-Patógeno , MicroRNAs/análise , RNA Viral/análise , Animais , Flaviviridae/genética , Flaviviridae/imunologia , Flaviviridae/fisiologia , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , RNA Viral/genética , Replicação ViralRESUMO
Human leukocyte antigen G (HLA-G) is an immunomodulatory molecule with important roles both physiologically as well as an escape mechanism of cancer cells. In this study, we evaluated the impact of eight polymorphisms at the 3' untranslated region (3'UTR) of the HLA-G gene in the development of prostate cancer (PCa) and benign prostatic hyperplasia (BPH). A total of 468 DNA samples of Brazilian men predominantly Euro-descendant with PCa (N = 187), BPH (N = 152) and healthy control individuals (N = 129) were evaluated. The HLA-G 3'UTR region was amplified by polymerase chain reaction (PCR), sequenced and genotyped to identify the 14 bp insertion/deletion (rs371194629), +3003T/C (rs1707), +3010C/G (rs1710), +3027A/C (rs17179101), +3035C/T (rs17179108), +3142G/C (rs1063320), +3187A/G (rs9380142) and +3196C/G (rs1610696) polymorphisms. Regression logistic and chi-square tests were performed to verify the influence of single nucleotide polymorphisms (SNPs) in PCa and/or BPH susceptibility, as well as in PCa progression (clinicopathological status). Our data showed the UTR-4 haplotype as a risk factor to PCa in comparison with control [odds ratio (OR) 2.35, 95% confidence interval (CI) 1.39-3.96, P adjusted = 0.003) and BPH groups (OR 1.82, 95% CI 1.15-2.86, P adjusted = 0.030). Further, the 'non-14bp Ins_ + 3142G_+3187A' haplotype (OR 1.56, 95% CI 1.10-2.20, P adjusted = 0.036), the +3003CT genotype (OR 4.44, 95% CI 1.33-4.50, P adjusted = 0.032) and the +3003C allele (OR 2.33, 95% CI 1.38-3.92, P adjusted = 0.016) also conferred susceptibility to PCa. Our data suggest an important influence of HLA-G 3'UTR polymorphisms in PCa susceptibility and support the use of the +3003 variant as a tag SNP for PCa risk.
Assuntos
Antígenos HLA-G/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Thyroid hormones are critical for the normal development, growth, and functional maturation of several tissues, including the central nervous system. Iodine is an essential constituent of the thyroid hormones, the only iodine-containing molecules in vertebrates. Dietary iodide (I(-)) absorption in the gastrointestinal tract is the first step in I(-) metabolism, as the diet is the only source of I(-) for land-dwelling vertebrates. The Na(+)/I(-) symporter (NIS), an integral plasma membrane glycoprotein located in the brush border of enterocytes, constitutes a central component of the I(-) absorption system in the small intestine. In this chapter, we review the most recent research on structure/function relations in NIS and the protein's I(-) transport mechanism and stoichiometry, with a special focus on the tissue distribution and hormonal regulation of NIS, as well as the role of NIS in mediating I(-) homeostasis. We further discuss recent findings concerning the autoregulatory effect of I(-) on I(-) metabolism in enterocytes: high intracellular I(-) concentrations in enterocytes decrease NIS-mediated uptake of I(-) through a complex array of posttranscriptional mechanisms, e.g., downregulation of NIS expression at the plasma membrane, increased NIS protein degradation, and reduction of NIS mRNA stability leading to decreased NIS mRNA levels. Since the molecular identification of NIS, great progress has been made not only in understanding the role of NIS in I(-) homeostasis but also in developing protocols for NIS-mediated imaging and treatment of various diseases.
Assuntos
Dieta , Absorção Gastrointestinal/fisiologia , Homeostase/fisiologia , Iodetos/metabolismo , Simportadores/metabolismo , Regulação para Baixo , Enterócitos/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citologia , Iodetos/administração & dosagem , RNA Mensageiro/metabolismo , Simportadores/genética , Glândula Tireoide/metabolismo , Hormônios Tireóideos/metabolismoRESUMO
The HLA-G gene is a non-classical class I MHC, responsible for modulating immune responses by inhibiting Natural Killer and cytotoxic T cells, presenting a crucial role in maternal tolerance to the fetus. In non-pathological conditions, its expression is restricted to certain tissues such as cornea and placenta. The HLA-G 3' untranslated region (3'UTR) has been reported to play an important role in the control of mRNA and protein levels, and polymorphisms in this region may influence mRNA stability and microRNA binding. In this study, we propose an approach to detect and classify microRNAs regarding their ability to bind the target (in this case, HLA-G 3'UTR) and the specificity of such interactions. Then, a panel of microRNAs with potential to modulate HLA-G expression is proposed, in which some microRNAs, such as miR-139-3p, would bind to non-polymorphic sequences of the HLA-G 3'UTR in a stable and specific manner, while others, such as miR-608, binds to polymorphic sequences and therefore the binding might be influenced by the variant actually present. Additionally, both HLA-G 3'UTR polymorphisms and the microRNA microenvironment must be considered when studies correlating HLA-G expression profiles and polymorphisms are being conducted. These new data may provide a remarkable contribution to the understanding of the mechanisms underlying HLA-G post-transcriptional regulation, disclosing the impact of variable and non-variable regions on HLA-G biology and providing a unique microRNA repertoire for future functional studies and therapeutic use.
Assuntos
Regiões 3' não Traduzidas/fisiologia , Bases de Dados de Ácidos Nucleicos , Regulação da Expressão Gênica/fisiologia , Antígenos HLA-G/imunologia , MicroRNAs/imunologia , Antígenos HLA-G/genética , Humanos , Imunomodulação/fisiologia , MicroRNAs/genética , Polimorfismo Genético/imunologia , Estabilidade de RNA/fisiologiaRESUMO
Dengue is a major threat for public health in tropical and subtropical countries around the world. In the absence of a licensed vaccine and effective antiviral therapies, control measures have been based on education activities and vector elimination. Current efforts for developing a vaccine are both promising and troubling. At the advent of the introduction of a tetravalent dengue vaccine, molecular surveillance of the circulating genotypes in different geographical regions has gained considerable importance. A growing body of in vitro, preclinical, and clinical phase studies suggest that vaccine conferred protection in a geographical area could depends on the coincidence of the dengue virus genotypes included in the vaccine and those circulating. In this review we present the state-of-the-art in this field, highlighting the need of deeper knowledge on neutralizing immune response for making decisions about future vaccine approval and the potential need for different vaccine composition for regional administration.
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Vacinas contra Dengue/imunologia , Vacinas contra Dengue/isolamento & purificação , Vírus da Dengue/classificação , Vírus da Dengue/genética , Dengue/prevenção & controle , Dengue/virologia , Vírus da Dengue/isolamento & purificação , Aprovação de Drogas , Monitoramento Epidemiológico , Genótipo , Humanos , Epidemiologia MolecularRESUMO
In this study, we sought to investigate the genetic influence of two HLA-G 3'-untranslated region (3'-UTR) polymorphisms - 14 bp (rs66554220) and +3142C>G (rs1063320) and their compounding haplotypes in susceptibility to rheumatoid arthritis (RA) in a two-region Brazilian study comprising of 539 patients and 489 controls. All subjects were polymerase chain reaction (PCR) genotyped for the referred polymorphisms and logistic regression models controlling for sex, city and age were performed. Homozygozity for the +3142G allele was associated with an increased risk of RA [odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.075-1.959, P(Bonf) = 0.030], whereas no association was observed for the 14 bp polymorphism. Haplotype comparisons between patients and controls showed a decreased frequency of the delC haplotype in patients (OR = 0.70, 95% CI = 0.521-0.946, P(Bonf) = 0.040), which remained significant in the rheumatoid factor (RF)-positive group (OR = 0.66, 95% CI = 0.482-0.900, P(Bonf) = 0.018), but not in the RF-negative group. These results corroborate the hypothesis of an involvement of HLA-G in the susceptibility of RA. The +3142G allele is associated with haplotype lineages that share high identity and are regarded as low producers. The presence of the G allele in homozygosis could be responsible for a low HLA-G expression profile that could favor the triggering of RA.
Assuntos
Regiões 3' não Traduzidas , Alelos , Artrite Reumatoide/genética , Frequência do Gene , Antígenos HLA-G/genética , Polimorfismo Genético , Adulto , Idoso , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Uterine leiomyoma is a major reproductive health disease among women and in particular Black women. The present study sought to determine whether a single nucleotide polymorphism (SNP) of CYP17 (rs743572) was associated with the risk of developing uterine leiomyoma (UL) in affected women in Barbados; a majority Black population. It also sought to determine if BMI, waist circumference and oestradiol levels were associated with UL in this group. A total of 96 random persons were assessed in a case-control study using a PCR-RFLP assay, and measurements of body mass index, waist circumference, and oestradiol levels were also assessed. Our results showed no genetic association with the risk of UL and this gene. The genetic distribution of CYP 17α- alleles resembled a normal Hardy-Weinberg distribution, and a relatively low risk of 0.25 at a confidence interval at 95%, of UL disease development. However, a significant association was found between oestradiol levels and fibroids, as well as oestradiol levels and BMI, at P < 0.05 among cases. Therefore our study indicates that significant associations between physiochemical factors comprising BMI, waist circumference, and oestrogen levels are disease indicators in this population. In conclusion, our findings suggest that obesity and its associated risk factors are important in a majority Black Caribbean population, although the sample size needs to be increased.
RESUMO
BACKGROUND: Hepatitis A virus (HAV) has shown intermediate endemicity in Argentina, but notification of clinical cases has decreased since the introduction of the vaccine in 2005. OBJECTIVES: In order to get insight into the local circulation of this virus after four years of the official introduction of the vaccine, the aims of this study were to provide information on HAV immune status of the adult population of Córdoba city and to conduct environmental surveillance of HAV in sewage and river samples in the same region. STUDY DESIGN: The prevalence of anti-HAV was determined by EIA in 416 samples of people (without prior vaccination) from Córdoba city (2009-2010). Spline regression models were estimated under generalized additive models. Environmental surveillance was conducted in river and sewage samples collected in the same period. Viral detection was performed by RT-Nested PCR of the 5'UTR. RESULTS: In Córdoba, the global prevalence of anti-HAV was 73.5%. It increased with age (p<0.0001) and it was associated with the low-income population (OR: 1.14; 95% CI 1.05-1.25). This prevalence decreased in younger age groups, especially in the high-income population. Environmental monitoring revealed the presence of HAV (IA) in 20.8% and 16.1% of wastewater and river samples, respectively. CONCLUSIONS: As a consequence of a decrease in HAV circulation due to improvements in immunization, socio-economic and hygienic conditions, young adults are becoming increasingly susceptible to HAV infections. Environmental monitoring demonstrated that HAV circulates in the local population; therefore, health care systems should consider the implementation of preventive measures for susceptible adults in order to reduce the risk of HAV infection.
Assuntos
Monitoramento Ambiental , Anticorpos Anti-Hepatite A/sangue , Vírus da Hepatite A Humana/imunologia , Vírus da Hepatite A Humana/isolamento & purificação , Hepatite A/epidemiologia , Adolescente , Adulto , Idoso , Argentina/epidemiologia , Feminino , Vírus da Hepatite A Humana/classificação , Vírus da Hepatite A Humana/genética , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Viral/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rios/virologia , Análise de Sequência de DNA , Estudos Soroepidemiológicos , Esgotos/virologia , Adulto JovemRESUMO
Myostatin (MSTN) is a protein of the Transforming Growth Factor-ß (TGF-ß) superfamily and plays a crucial role in muscular development for higher vertebrates. However, its biological function in marine invertebrates remains undiscovered. This study characterizes the full-length sequence of the Mytilus chilensis myostatin gene (Mc-MSTN). Furthermore, tissue transcription patterns and putative single nucleotide polymorphisms (SNPs) were also identified. The Mc-MSTN cDNA sequence showed 3528 base pairs (bp), consisting of 161 bp of 5' UTR, 2,110 bp of 3' UTR, and an open reading frame of 1,257 bp encoding for 418 amino acids and with an RXXR proteolytic site and nine cysteine-conserved residues. Gene transcription analysis revealed that the Mc-MSTN has ubiquitous expression among several tissues, with higher expression in the gonads and mantle than in the digestive gland, gills, and hemolymph. Furthermore, high levels of polymorphisms were detected (28 SNPs in 3'-UTR and 9 SNPs in the coding region). Two SNPs were non-synonymous and involved amino acid changes between Glu/Asp and Thr/Ile. Until now, the MSTN gene has been mainly related to muscle growth in marine bivalves. However, the present study suggests a putative biological function not entirely associated to muscle tissue and contributes molecular evidence to the current debate about the function of the MSTN gene in marine invertebrates.
Assuntos
Expressão Gênica , Miostatina/genética , Mytilus/genética , Animais , Antígenos/genética , Antígenos/metabolismo , Sequência de Bases , Clonagem Molecular , Perfilação da Expressão Gênica , Dados de Sequência Molecular , Miostatina/metabolismo , Polimorfismo de Nucleotídeo Único , Distribuição TecidualRESUMO
The pregnane X receptor (PXR) (nuclear receptor NR1I2) is a ligand activated transcription factor, mediating responses to diverse xenobiotic and endogenous chemicals. The properties of PXR in fish are not fully understood. Here we report on cloning and characterization of full-length PXR of zebrafish, Danio rerio, and pxr expression in vivo. Initial efforts gave a cDNA encoding a 430 amino acid protein identified as zebrafish pxr by phylogenetic and synteny analysis. The sequence of the cloned Pxr DNA binding domain (DBD) was highly conserved, with 74% identity to human PXR-DBD, while the ligand-binding domain (LBD) of the cloned sequence was only 44% identical to human PXR-LBD. Sequence variation among clones in the initial effort prompted sequencing of multiple clones from a single fish. There were two prominent variants, one sequence with S183, Y218 and H383 and the other with I183, C218 and N383, which we designate as alleles pxr*1 (nr1i2*1) and pxr*2 (nr1i2*2), respectively. In COS-7 cells co-transfected with a PXR-responsive reporter gene, the full-length Pxr*1 (the more common variant) was activated by known PXR agonists clotrimazole and pregnenolone 16α-carbonitrile but to a lesser extent than the full-length human PXR. Activation of full-length Pxr*1 was only 10% of that with the Pxr*1 LBD. Quantitative real time PCR analysis showed prominent expression of pxr in liver and eye, as well as brain and intestine of adult zebrafish. The pxr was expressed in heart and kidney at levels similar to that in intestine. The expression of pxr in liver was weakly induced by ligands for mammalian PXR or constitutive androstane receptor (NR1I3). The results establish a foundation for PXR studies in this vertebrate model. PXR allelic variation and the differences between the full-length PXR and the LBD in reporter assays have implications for assessing the action of PXR ligands in zebrafish.