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1.
Cell ; 164(1-2): 81-90, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26748718

RESUMO

MicroRNA maturation is initiated by RNase III DROSHA that cleaves the stem loop of primary microRNA. DROSHA functions together with its cofactor DGCR8 in a heterotrimeric complex known as Microprocessor. Here, we report the X-ray structure of DROSHA in complex with the C-terminal helix of DGCR8. We find that DROSHA contains two DGCR8-binding sites, one on each RNase III domain (RIIID), which mediate the assembly of Microprocessor. The overall structure of DROSHA is surprisingly similar to that of Dicer despite no sequence homology apart from the C-terminal part, suggesting that DROSHA may have evolved from a Dicer homolog. DROSHA exhibits unique features, including non-canonical zinc-finger motifs, a long insertion in the first RIIID, and the kinked link between Connector helix and RIIID, which explains the 11-bp-measuring "ruler" activity of DROSHA. Our study implicates the evolutionary origin of DROSHA and elucidates the molecular basis of Microprocessor assembly and primary microRNA processing.


Assuntos
MicroRNAs/metabolismo , Processamento Pós-Transcricional do RNA , Ribonuclease III/química , Sequência de Aminoácidos , Cristalografia por Raios X , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/metabolismo , Evolução Molecular , Humanos , MicroRNAs/química , Modelos Químicos , Modelos Moleculares , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Dobramento de Proteína , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/genética , Ribonuclease III/metabolismo , Alinhamento de Sequência , Homologia Estrutural de Proteína
2.
Cell ; 161(6): 1374-87, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-26027739

RESUMO

MicroRNA (miRNA) maturation is initiated by Microprocessor composed of RNase III DROSHA and its cofactor DGCR8, whose fidelity is critical for generation of functional miRNAs. To understand how Microprocessor recognizes pri-miRNAs, we here reconstitute human Microprocessor with purified recombinant proteins. We find that Microprocessor is an ∼364 kDa heterotrimeric complex of one DROSHA and two DGCR8 molecules. Together with a 23-amino acid peptide from DGCR8, DROSHA constitutes a minimal functional core. DROSHA serves as a "ruler" by measuring 11 bp from the basal ssRNA-dsRNA junction. DGCR8 interacts with the stem and apical elements through its dsRNA-binding domains and RNA-binding heme domain, respectively, allowing efficient and accurate processing. DROSHA and DGCR8, respectively, recognize the basal UG and apical UGU motifs, which ensure proper orientation of the complex. These findings clarify controversies over the action mechanism of DROSHA and allow us to build a general model for pri-miRNA processing.


Assuntos
MicroRNAs/metabolismo , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/química , Ribonuclease III/química , Sequência de Bases , Dimerização , Humanos , MicroRNAs/genética , Dados de Sequência Molecular , Motivos de Nucleotídeos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ribonuclease III/genética , Ribonuclease III/metabolismo
3.
Cell ; 159(6): 1365-76, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25480299

RESUMO

Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. In cells depleted of TUT4/7, the vast majority of mRNAs lose the oligo-U-tails, and their half-lives are extended. Suppression of mRNA decay factors leads to the accumulation of oligo-uridylated mRNAs. In line with this, microRNA induces uridylation of its targets, and TUT4/7 are required for enhanced decay of microRNA targets. Our study explains the mechanism underlying selective uridylation of deadenylated mRNAs and demonstrates a fundamental role of oligo-U-tail as a molecular mark for global mRNA decay.


Assuntos
Proteínas de Ligação a DNA/metabolismo , RNA Nucleotidiltransferases/metabolismo , Estabilidade de RNA , Células HeLa , Humanos , MicroRNAs/metabolismo , Poli A/metabolismo , Proteínas de Ligação a Poli(A)/metabolismo , RNA Mensageiro/metabolismo , Uridina Monofosfato/metabolismo
4.
Cell ; 151(3): 521-32, 2012 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-23063654

RESUMO

RNase III Drosha initiates microRNA (miRNA) maturation by cleaving a primary miRNA transcript and releasing a pre-miRNA with a 2 nt 3' overhang. Dicer recognizes the 2 nt 3' overhang structure to selectively process pre-miRNAs. Here, we find that, unlike prototypic pre-miRNAs (group I), group II pre-miRNAs acquire a shorter (1 nt) 3' overhang from Drosha processing and therefore require a 3'-end mono-uridylation for Dicer processing. The majority of let-7 and miR-105 belong to group II. We identify TUT7/ZCCHC6, TUT4/ZCCHC11, and TUT2/PAPD4/GLD2 as the terminal uridylyl transferases responsible for pre-miRNA mono-uridylation. The TUTs act specifically on dsRNAs with a 1 nt 3' overhang, thereby creating a 2 nt 3' overhang. Depletion of TUTs reduces let-7 levels and disrupts let-7 function. Although the let-7 suppressor, Lin28, induces inhibitory oligo-uridylation in embryonic stem cells, mono-uridylation occurs in somatic cells lacking Lin28 to promote let-7 biogenesis. Our study reveals functional duality of uridylation and introduces TUT7/4/2 as components of the miRNA biogenesis pathway.


Assuntos
Proteínas de Ligação a DNA/metabolismo , MicroRNAs/metabolismo , Polinucleotídeo Adenililtransferase/metabolismo , RNA Nucleotidiltransferases/metabolismo , Processamento Pós-Transcricional do RNA , Uridina Monofosfato/metabolismo , Sequência de Bases , Células HeLa , Humanos , Dados de Sequência Molecular , Proteínas de Ligação a RNA/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA
5.
Cell ; 151(4): 765-777, 2012 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-23102813

RESUMO

LIN28 plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, LIN28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. In this study, we obtain a genome-wide view of the molecular function of LIN28A in mouse embryonic stem cells by carrying out RNA crosslinking-immunoprecipitation-sequencing (CLIP-seq) and ribosome footprinting. We find that, in addition to let-7 precursors, LIN28A binds to a large number of spliced mRNAs. LIN28A recognizes AAGNNG, AAGNG, and less frequently UGUG, which are located in the terminal loop of a small hairpin. LIN28A is localized to the periendoplasmic reticulum (ER) area and inhibits translation of mRNAs that are destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Our study suggests a selective regulatory mechanism for ER-associated translation and reveals an unexpected role of LIN28A as a global suppressor of genes in the secretory pathway.


Assuntos
Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Células-Tronco Embrionárias/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Imunoprecipitação/métodos , Camundongos , MicroRNAs/metabolismo , Ribossomos/metabolismo , Via Secretória , Análise de Sequência de RNA
6.
Mol Cell ; 73(3): 505-518.e5, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30554947

RESUMO

Microprocessor, composed of DROSHA and its cofactor DGCR8, initiates microRNA (miRNA) biogenesis by processing the primary transcripts of miRNA (pri-miRNAs). Here we investigate the mechanism by which Microprocessor selects the cleavage site with single-nucleotide precision, which is crucial for the specificity and functionality of miRNAs. By testing ∼40,000 pri-miRNA variants, we find that for some pri-miRNAs the cleavage site is dictated mainly by the mGHG motif embedded in the lower stem region of pri-miRNA. Structural modeling and deep-sequencing-based complementation experiments show that the double-stranded RNA-binding domain (dsRBD) of DROSHA recognizes mGHG to place the catalytic center in the appropriate position. The mGHG motif as well as the mGHG-recognizing residues in DROSHA dsRBD are conserved across eumetazoans, suggesting that this mechanism emerged in an early ancestor of the animal lineage. Our findings provide a basis for the understanding of miRNA biogenesis and rational design of accurate small-RNA-based gene silencing.


Assuntos
MicroRNAs/metabolismo , Motivos de Nucleotídeos , Processamento Pós-Transcricional do RNA , Ribonuclease III/metabolismo , Células HCT116 , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/química , MicroRNAs/genética , Modelos Moleculares , Conformação de Ácido Nucleico , Domínios e Motivos de Interação entre Proteínas , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/genética , Relação Estrutura-Atividade , Especificidade por Substrato
7.
Cell ; 136(1): 75-84, 2009 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-19135890

RESUMO

The Drosha-DGCR8 complex, also known as Microprocessor, is essential for microRNA (miRNA) maturation. Drosha functions as the catalytic subunit, while DGCR8 (also known as Pasha) recognizes the RNA substrate. Although the action mechanism of this complex has been intensively studied, it remains unclear how Drosha and DGCR8 are regulated and if these proteins have any additional role(s) apart from miRNA processing. Here, we report that Drosha and DGCR8 regulate each other posttranscriptionally. The Drosha-DGCR8 complex cleaves the hairpin structures embedded in the DGCR8 mRNA and thereby destabilizes the mRNA. We further find that DGCR8 stabilizes the Drosha protein via protein-protein interaction. This crossregulation between Drosha and DGCR8 may contribute to the homeostatic control of miRNA biogenesis. Furthermore, microarray analyses suggest that a number of mRNAs may be downregulated in a Microprocessor-dependent, miRNA-independent manner. Our study reveals a previously unsuspected function of Microprocessor in mRNA stability control.


Assuntos
Regulação da Expressão Gênica , Proteínas/genética , Estabilidade de RNA , Ribonuclease III/genética , Animais , Sequência de Bases , Linhagem Celular , Humanos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Proteínas/metabolismo , Interferência de RNA , Proteínas de Ligação a RNA , Ribonuclease III/metabolismo
8.
Nucleic Acids Res ; 49(5): e28, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33332543

RESUMO

RNA-protein interaction is central to post-transcriptional gene regulation. Identification of RNA-binding proteins relies mainly on UV-induced crosslinking (UVX) followed by the enrichment of RNA-protein conjugates and LC-MS/MS analysis. However, UVX has limited applicability in tissues of multicellular organisms due to its low penetration depth. Here, we introduce formaldehyde crosslinking (FAX) as an alternative chemical crosslinking for RNA interactome capture (RIC). Mild FAX captures RNA-protein interaction with high specificity and efficiency in cell culture. Unlike UVX-RIC, FAX-RIC robustly detects proteins that bind to structured RNAs or uracil-poor RNAs (e.g. AGO1, STAU1, UPF1, NCBP2, EIF4E, YTHDF proteins and PABP), broadening the coverage. Applied to Xenopus laevis oocytes and embryos, FAX-RIC provided comprehensive and unbiased RNA interactome, revealing dynamic remodeling of RNA-protein complexes. Notably, translation machinery changes during oocyte-to-embryo transition, for instance, from canonical eIF4E to noncanonical eIF4E3. Furthermore, using Mus musculus liver, we demonstrate that FAX-RIC is applicable to mammalian tissue samples. Taken together, we report that FAX can extend the RNA interactome profiling into multicellular organisms.


Assuntos
Proteômica/métodos , Ribonucleoproteínas/análise , Animais , Reagentes de Ligações Cruzadas , Embrião não Mamífero/metabolismo , Formaldeído , Células HeLa , Humanos , Fígado/metabolismo , Masculino , Camundongos , Oócitos/metabolismo , Peptídeos , Ribonucleoproteínas/metabolismo , Raios Ultravioleta , Xenopus laevis
9.
Nucleic Acids Res ; 48(19): 11097-11112, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33035348

RESUMO

The microprocessor complex cleaves the primary transcript of microRNA (pri-miRNA) to initiate miRNA maturation. Microprocessor is known to consist of RNase III DROSHA and dsRNA-binding DGCR8. Here, we identify Enhancer of Rudimentary Homolog (ERH) as a new component of Microprocessor. Through a crystal structure and biochemical experiments, we reveal that ERH uses its hydrophobic groove to bind to a conserved region in the N-terminus of DGCR8, in a 2:2 stoichiometry. Knock-down of ERH or deletion of the DGCR8 N-terminus results in a reduced processing of suboptimal pri-miRNAs in polycistronic miRNA clusters. ERH increases the processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144. Thus, the ERH dimer may mediate 'cluster assistance' in which Microprocessor is loaded onto a poor substrate with help from a high-affinity substrate in the same cluster. Our study reveals a role of ERH in the miRNA biogenesis pathway.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Células HCT116 , Células HEK293 , Humanos , Células K562 , MicroRNAs/metabolismo , Ligação Proteica , Conformação Proteica
10.
Osteoarthritis Cartilage ; 27(12): 1755-1760, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31400498

RESUMO

PURPOSE: Knee osteoarthritis (KOA) is characterized by pain and decreased gait function. This study assessed key features that can be used as mechanical biomarkers for KOA severity and progression. The identified features were validated statistically and were further examined by developing a classification model based on a machine-learning algorithm. METHODS: The study included 227 volunteers with various grades of KOA. The severity of KOA was graded using the Kellgren-Lawrence (KL) system. A total of 165 features were extracted from the gait data. The key features were selected using neighborhood component analysis. The selected features were validated using the t-test. Then, the features were examined by building a classification model using a random forest algorithm. RESULTS: Twenty features were identified that could discriminate the grade of KOA, including nine features extracted from the knee joint, seven from the hip, two from the ankle and two from the spatiotemporal gait parameters. The t-test showed that some features differed significantly between health and sever group, while some were significantly different among the severe group, and others were significantly different for all KL grades. The areas under the receiver operating characteristic curves for classification were 0.974, 0.992, 0.845, 0.894, and 0.905 for KL grades 0 through 4, respectively. CONCLUSION: Key gait features reflecting the grade of KOA were identified. The results of the statistical analysis and machine-learning algorithm show that the features can discriminate the severity of disease according to the KL grade.


Assuntos
Análise da Marcha , Aprendizado de Máquina , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/fisiopatologia , Adulto , Idoso , Feminino , Marcha/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Índice de Gravidade de Doença
11.
Eur J Neurol ; 26(6): 911-918, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30637882

RESUMO

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are a predictor of stroke among elderly individuals. This study aimed to evaluate the association between WMH severity and the risk of recurrent vascular events among Asian patients with ischaemic stroke with small-vessel disease (SVD) including micro/macrobleeds and lacunes. METHODS: Data from participants (n = 1454) in the PICASSO (PreventIon of CArdiovascular Events in iSchemic Stroke Patients with High Risk of Cerebral HemOrrhage) trial were reviewed. The severity of WMH in baseline brain magnetic resonance imaging scans was assessed using the Fazekas scale. The association between WMH severity and stroke (ischaemic or hemorrhagic) and major vascular events (MVEs) (a composite of stroke/myocardial infarction/vascular death) was assessed. RESULTS: Study patients had a significant burden of SVD: Fazekas score 0 (n = 2), 1 (n = 426), 2 (n = 650) and 3 (n = 376) [median Fazekas score 2 (mean follow-up, 1.9 ± 1.3 years)]. The stroke incidence rate per 100 personyears was 2.6 in the Fazekas 0-1 group, 3.6 in the Fazekas 2 group and 7.0 in the Fazekas 3 group, and the rates for MVEs were 3.3, 4.3 and 7.6, respectively. Compared with the Fazekas 0-1 group, the Fazekas 3 group was associated with a higher risk of stroke [adjusted hazard ratio (HR), 2.15; 95% confidence interval (CI), 1.19-3.88; P = 0.011], ischaemic stroke (adjusted HR, 2.11; 95% CI, 1.07-4.15; P = 0.031), hemorrhagic stroke (adjusted HR, 3.72; 95% CI, 1.09-12.70; P = 0.036) and MVEs (adjusted HR, 2.09; 95% CI, 1.20-3.66; P = 0.010). CONCLUSION: Advanced WMH in Asian patients with ischaemic stroke with SVD burden was associated with an increased risk of recurrent vascular events. It may exert an effect as a prognostic indicator in high risk of recurrent vascular events.


Assuntos
Isquemia Encefálica/etiologia , Hemorragia Cerebral/etiologia , Doenças de Pequenos Vasos Cerebrais/complicações , Acidente Vascular Cerebral/etiologia , Substância Branca/diagnóstico por imagem , Idoso , Isquemia Encefálica/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Acidente Vascular Cerebral/diagnóstico por imagem
12.
J Viral Hepat ; 25(11): 1321-1330, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29772084

RESUMO

Entecavir 0.5 mg (ETV) is widely used among treatment-naïve chronic hepatitis B (CHB) patients. However, 10%-30% of patients show partial virologic response (PVR) to the drug. If the hepatitis B virus (HBV) continues to replicate, the underlying liver disease may progress. Herein, we compared the efficacy of switching to tenofovir disoproxil fumarate (TDF) with that of continuing ETV in CHB patients with PVR to ETV. This was an open-label randomized controlled trial including CHB patients who had been receiving 0.5 mg of ETV for >12 months, but who still had detectable HBV DNA levels of >60 IU/mL without known resistance to ETV. Sixty patients were enrolled and 45 qualified for the study: Twenty-two patients were randomly assigned into the TDF group and 23 into the ETV group. After 12 months of treatment, the virologic response rate (HBV DNA <20 IU/mL) was significantly higher in the TDF group than in the ETV group, as measured using per-protocol analysis (55% vs 20%; P = .022) and intention-to-treat analysis (50% vs 17.4%; P = .020). The reduction in HBV DNA was greater (-1.13 vs -0.67 log10 IU/mL; P = .024), and the mean HBV DNA level was lower (1.54 vs 2.01 log10 IU/mL; P = .011) in the TDF group than in the ETV group. In conclusion, to achieve optimal response in CHB patients with PVR to ETV, switching to TDF would be a better strategy than continuing ETV. Appropriate modification of therapy would further improve the outcome of chronic HBV infection.


Assuntos
Substituição de Medicamentos , Guanina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Adulto , Antivirais/farmacologia , Antivirais/uso terapêutico , DNA Viral/sangue , Feminino , Guanina/farmacologia , Guanina/uso terapêutico , Anticorpos Anti-Hepatite B/sangue , Antígenos da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
13.
J Cosmet Laser Ther ; 20(1): 52-57, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29199877

RESUMO

BACKGROUND: Hyaluronidase injection is a commonly performed treatment for overcorrection or misplacement of hyaluronic acid (HA) filler. Many patients often wants the HA filler reinjection after the use of hyaluronidase, though the optimal timing of reinjection of HA filler still remains unknown. OBJECTIVES: To provide the optimal time interval between hyaluronidase injections and HA filler reinjections. METHODS: 6 Sprague-Dawley rats were injected with single monophasic HA filler. 1 week after injection, the injected sites were treated with hyaluronidase. Then, HA fillers were reinjected sequentially with differing time intervals from 30 minutes to 14 days. 1 hour after the reinjection of the last HA filler, all injection sites were excised for histologic evaluation. RESULTS: 3 hours after reinjection of HA filler, the appearance of filler material became evident again, retaining its shape and volume. 6 hours after reinjection, the filler materials restored almost its original volume and there were no significant differences from the positive control. CONCLUSIONS: Our data suggest that the hyaluronidase loses its effect in dermis and subcutaneous tissue within 3-6 hours after the injection and successful engraftment of reinjected HA filler can be accomplished 6 hours after the injection.


Assuntos
Preenchedores Dérmicos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Hialuronoglucosaminidase/farmacocinética , Pele/patologia , Animais , Biópsia , Hialuronoglucosaminidase/administração & dosagem , Injeções Subcutâneas , Masculino , Ratos Sprague-Dawley , Retratamento , Fatores de Tempo
14.
Proc Natl Acad Sci U S A ; 112(26): E3384-91, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26080438

RESUMO

Genetic screening based on loss-of-function phenotypes is a powerful discovery tool in biology. Although the recent development of clustered regularly interspaced short palindromic repeats (CRISPR)-based screening approaches in mammalian cell culture has enormous potential, RNA interference (RNAi)-based screening remains the method of choice in several biological contexts. We previously demonstrated that ultracomplex pooled short-hairpin RNA (shRNA) libraries can largely overcome the problem of RNAi off-target effects in genome-wide screens. Here, we systematically optimize several aspects of our shRNA library, including the promoter and microRNA context for shRNA expression, selection of guide strands, and features relevant for postscreen sample preparation for deep sequencing. We present next-generation high-complexity libraries targeting human and mouse protein-coding genes, which we grouped into 12 sublibraries based on biological function. A pilot screen suggests that our next-generation RNAi library performs comparably to current CRISPR interference (CRISPRi)-based approaches and can yield complementary results with high sensitivity and high specificity.


Assuntos
Genoma , Interferência de RNA , Animais , Inteligência Artificial , Humanos , Camundongos , RNA Interferente Pequeno/genética
15.
Osteoporos Int ; 28(4): 1445-1452, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28074252

RESUMO

The present cross-sectional study performed using data from the Korea National Health and Nutrition Examination Survey in 9526 women older than 18 years of age demonstrates that high sodium intake is associated with lower bone mineral density and sodium intake ≥2000 mg/day is a risk factor for osteoporosis in postmenopausal women. INTRODUCTION: Several studies have reported that large amount of dietary sodium intake is highly associated with elevated urinary calcium. However, the direct effect of excessive dietary sodium intake on bone mass, as a risk factor for osteoporosis, is still a controversial issue. The aim of the present study was to assess the relationship between high intake of sodium and lower bone mass and risk of osteoporosis in adult women. METHODS: This cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2011. Participants (n = 9526 women older than 18 years) were divided into a premenopausal (n = 4793) and postmenopausal (n = 4733) group. Both groups were subdivided into five groups according to quintiles of energy-adjusted sodium intake. Multiple regression analysis was performed to assess relationships between sodium intake and lower bone mass. RESULTS: Multivariate linear regression analysis showed that high sodium intake was negatively associated with bone mineral content (BMC) and bone mineral density (BMD) in postmenopausal women. After adjusting confounding factors, high sodium intake was negatively associated with BMC and BMD of the lumbar spine in postmenopausal women. Postmenopausal women, whose sodium intake was ≥2000 mg/day (odds ratio 1.284, 95% CI 1.029-1.603, P = 0.027), were at risk of developing osteoporosis after adjustment of confounding variables. CONCLUSIONS: The present study suggested that high sodium intake could be a potential risk factor for low bone mass after adjusting for confounding factors in postmenopausal women.


Assuntos
Osteoporose Pós-Menopausa/etiologia , Sódio na Dieta/administração & dosagem , Adulto , Idoso , Densidade Óssea/fisiologia , Estudos Transversais , Feminino , Fêmur/fisiologia , Humanos , Vértebras Lombares/fisiologia , Pessoa de Meia-Idade , Inquéritos Nutricionais , Osteoporose Pós-Menopausa/epidemiologia , Osteoporose Pós-Menopausa/fisiopatologia , Pré-Menopausa/fisiologia , República da Coreia/epidemiologia , Fatores de Risco , Adulto Jovem
16.
Mol Psychiatry ; 21(2): 252-60, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25330740

RESUMO

Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.


Assuntos
Fluoxetina/farmacologia , Receptores de Glucocorticoides/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos de Segunda Geração/farmacologia , Corticosterona/farmacologia , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Fosforilação , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico
17.
BJOG ; 124(2): 314-320, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27342222

RESUMO

OBJECTIVE: The aim of the study was to investigate whether opportunistic salpingectomy has any deleterious effects on ovarian reserve and increases surgical risk in patients undergoing laparoscopic hysterectomy. DESIGN: A multicentre, randomised controlled trial. SETTING: Three university hospitals in Korea. POPULATION: Sixty-eight patients undergoing laparoscopic hysterectomy for the treatment of symptomatic benign uterine diseases. METHODS: Patients were randomised to undergo either opportunistic salpingectomy (n = 34) or no salpingectomy (n = 34) during laparoscopic hysterectomy. MAIN OUTCOME MEASUREMENTS: The primary and secondary outcome measures were the change of ovarian reserve, determined by the rate of decline in anti-Müllerian hormone (AMH) level from before surgery to 3 months post-surgery and surgical outcomes, respectively. RESULTS: Baseline demographic and clinical characteristics were similar between the two groups. There was also no difference in operative outcomes such as operative time, operative bleeding, or complications between the two groups. In both groups, postoperative AMH levels were significantly lower than preoperative AMH levels (both, P < 0.01). The decline rate in AMH was 12.5% (interquartile range 0.8-60.9%) in the opportunistic salpingectomy group and 10.8% (interquartile range 6.9-27.4%) in the no salpingectomy group, with no significant difference between both groups (P = 0.898). CONCLUSIONS: Opportunistic salpingectomy at the time of laparoscopic hysterectomy did not have any negative effects on ovarian reserve or increased surgical risk. TWEETABLE ABSTRACT: Opportunistic salpingectomy did not have any negative effects on ovarian reserve or increased surgical risk.


Assuntos
Hormônio Antimülleriano/sangue , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Salpingectomia/efeitos adversos , Doenças Uterinas/cirurgia , Adulto , Feminino , Humanos , Histerectomia/métodos , Laparoscopia/métodos , Pessoa de Meia-Idade , Reserva Ovariana/fisiologia , Período Pós-Operatório , Período Pré-Operatório , Estudos Prospectivos , República da Coreia , Salpingectomia/métodos , Resultado do Tratamento , Doenças Uterinas/sangue , Doenças Uterinas/fisiopatologia
18.
Acta Neurol Scand ; 135(4): 419-425, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27265610

RESUMO

BACKGROUND AND PURPOSE: Pain is common in post-stroke patients and has been shown to be associated with depression, fatigue, and decreased quality of life (QOL). However, studies examining different types of post-stroke pain are scarce. We investigated differences in the related factors and their QOL impacts between musculoskeletal pain (MSP) and central post-stroke pain (CPSP). METHODS: We assessed 364 consecutive stroke patients who were admitted to Asan Medical Center and contacted 12 months after stroke onset. We categorized pain and paresthesia as MSP, CPSP, combined pain, or other pain. Post-stroke depression (Beck Depression Inventory), fatigue (Fatigue Severity Scale), sleep disturbance (Verran Snyder-Halpern scale), social support (ENRICHED Social Support Instrument), and QOL (Medical Outcome Study 36-Item Short Form) were assessed. RESULTS: Of the 364 patients analyzed, 135 (37.1%) had pain, 78 (21.4%) had MSP, 22 (6.0%) had CPSP, 16 (4.4%) had combined pain, and 19 (5.2%) had other pain. In multivariate analyses, CPSP was related to modified Rankin scale (P=.004), sensory dysfunction (P<.001), thalamus lesion (P=.001), medulla lesion (P=.007), and fatigue (P=.026). MSP was related to motor dysfunction (P<.001) and fatigue (P=.003). QOL varied among groups with different types of pain (P<.001) and was the poorest in patients with combined pain. CONCLUSIONS: Pain is common 12 months post-stroke. The factors associated with CPSP and MSP differ, but are both closely associated with fatigue rather than depression. QOL is the poorest in patients with combined pain. Management of pain and fatigue may be important for improving the QOL in stroke patients.


Assuntos
Dor Musculoesquelética/etiologia , Qualidade de Vida , Acidente Vascular Cerebral/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Skin Res Technol ; 23(2): 186-193, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27514310

RESUMO

BACKGROUND: Rosacea is a common chronic inflammatory disorder affecting facial skin. Currently, no accurate and objective method is available for assessing the severity of rosacea. Most studies use the National Rosacea Society Standard (NRSS) grading method, which lacks objectivity and yields varying results. METHODS: Eighteen patients with rosacea were included. Clinical severity was assessed on the basis of the NRSS grade, Investigators' Global Assessment, Patients' Global Assessment, and Dermatology Quality of Life Index. A skin color analysis system was used to measure the facial area showing erythema, and biophysical parameters of facial skin (transepidermal water loss and skin surface hydration) were examined. To find statistical significant in classification severity of the rosacea, statistical analysis was performed with all parameters. RESULTS: A significant correlation (P < 0.05) was found between the NRSS grade, facial area showing erythema, and biophysical parameters. The latter two factors differed significantly among patients with rosacea of different levels of severity (mild, moderate, severe; P < 0.05). CONCLUSION: Color imaging systems can be useful and reliable for evaluating the severity of rosacea, in addition to biophysical parameter assessment. The combination of these two analytical methods enabled objective and quantitative evaluation of the severity of rosacea.


Assuntos
Colorimetria/métodos , Dermoscopia/métodos , Rosácea/diagnóstico , Rosácea/fisiopatologia , Índice de Gravidade de Doença , Pigmentação da Pele , Perda Insensível de Água , Diagnóstico por Computador/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Genet Mol Res ; 16(2)2017 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-28549200

RESUMO

Cell death-inducing DFF45-like effector (CIDE) B is a member of the CIDE family of apoptosis-inducing factors. In the present study, we detected a single nucleotide polymorphism (SNP), c.414G>A, which corresponds to the synonymous SNP 414Arg, in CIDE-B in the Berkshire pigs. We also analyzed the relationships between the CIDE-B SNP and various meat quality traits. The SNP was significantly associated with post-mortem pH24h, water-holding capacity (WHC), fat content, protein content, drip loss, post-mortem temperature at 12 h (T12) and 24 h (T24) in a co-dominant model (P < 0.05). A significant association was detected between the SNP and post-mortem pH24h, fat content, protein content, drip loss, shear force, and T24 in gilts; and color parameter b*, WHC, and T24 in barrows (P < 0.05). The SNP was significantly correlated with the fat content, and CIDE-B mRNA expression was significantly upregulated during the early stage of adipogenesis, suggesting that CIDE-B may contribute towards initiation of adipogenesis (P < 0.05). Furthermore, CIDE-B mRNA was strongly expressed in the liver, kidney, large intestine, and small intestine, and weakly expressed in the stomach, lung, spleen, and white adipose tissue. These results indicate that the CIDE-B SNP is closely associated with meat quality traits and may be a useful DNA marker for improving pork quality.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Carne/normas , Característica Quantitativa Herdável , Suínos/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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