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1.
Eur J Hum Genet ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963334

RESUMO

Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10-9, replication P = 5.75 × 10-5) at the genome-wide significance level (ɑ = 5.0 × 10-8), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.

2.
Bone ; : 115652, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32971307

RESUMO

Recent studies have demonstrated the important role played by gut microbiota in regulating bone development, but the evidence of such causal relationship is still sparse in human population. The aim of this study is to assess the causal relationship from gut microbiota to bone development and to identify specific causal bacteria taxa via a Mendelian randomization (MR) approach. A genome-wide association study (GWAS) summary statistic based two-sample MR analysis was performed. Summary statistics of microbiome GWAS (MGWAS) in 1126 twin pairs of the TwinsUK study was used as discovery sample, and the MGWAS in 984 Dutch participants from the LifeLines-DEEP cohort was used as replication sample. Estimated heel bone mineral density (eBMD) GWAS in 426,824 participants from the UK biobank (UKB) cohort was used as outcome. Bacteria were grouped into taxa features at both order and family levels. In the discovery sample, a total of 25 bacteria features including 9 orders and 16 families were analyzed. Fourteen features (5 orders + 9 families) were nominally significant, including 5 orders (Bacteroidales, Clostridiales, Lactobacillales, Pasteurellales and Verrucomicrobiales) and 9 families (Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Mogibacteriaceae, Pasteurellaceae, Porphyromonadaceae, Streptococcaceae, Verrucomicrobiaceae and Veillonellaceae). One order Clostridiales and its child taxon, family Lachnospiraceae, were successfully replicated in the replication sample (Clostridiales Pdiscovery = 3.32 × 10-3Preplication = 7.29 × 10-3; Lachnospiraceae Pdiscovery = 0.03 Preplication = 7.29 × 10-3). Our findings provided evidence of causal relationship from microbiota to bone development, as well as identified specific bacteria taxa that regulated bone mass variation, thus providing new insights into the microbiota mediated bone development mechanism.

3.
Neurosci Bull ; 33(1): 1-16, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27995568

RESUMO

Abnormal expression and dysfunction of methyl-CpG binding protein 2 (MeCP2) cause Rett syndrome (RTT). The diverse phosphorylation modifications modulate MeCP2 function in neural cells. Using western blot and immunohistochemistry, we examined the expression patterns of MeCP2 and three phospho-MeCP2s (pMeCP2s) in the developing rat brain. The expression of MeCP2 and phospho-S80 (pS80) MeCP2 increased while pS421 MeCP2 and pS292 MeCP2 decreased with brain maturation. In contrast to the nuclear localization of MeCP2 and pS80 MeCP2, pS421 MeCP2 and pS292 MeCP2 were mainly expressed in the cytoplasmic compartment. Apart from their distribution in neurons, they were also detected at a low level in astrocytes. Postnatally-initiated MeCP2 deficiency affected cerebellar neural cell development, as determined by the abnormal expression of GFAP, DCX, Tuj1, MAP-2, and calbindin-D28k. Together, these results demonstrate that MeCP2 and diverse pMeCP2s have distinct features of spatio-temporal expression in the rat brain, and that the precise levels of MeCP2 in the postnatal period are vital to cerebellar neural cell development.


Assuntos
Encéfalo , Cerebelo/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/imunologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Monoéster Fosfórico Hidrolases/farmacologia , Fosforilação , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução Genética , Tubulina (Proteína)/metabolismo
4.
Brain Res ; 1599: 32-43, 2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25511996

RESUMO

PURPOSE: Astrocytes can be reactivated after cerebral ischemia by expressing nestin and other characteristic markers of neural stem cells (NSCs). However, the epigenetic features of reactive astrocytes are not well known. Methyl-CpG-binding protein 2 (MeCP2) is a vital transcriptional modulator in brain development. Although the expression and function of some phosphorylated MeCP2 isoforms have been clarified, phospho-serine 292 (pS292) MeCP2 has not yet drawn much attention. In this study, we used western blot analysis and immunohistochemical and immunofluorescent staining to reveal the expressive features of pS292 MeCP2 and MeCP2 in the adult rat striatum following transient middle cerebral artery occlusion (MCAO). RESULTS: We first discovered that the ischemia-induced expression of cytoplasmic pS292 MeCP2 is primarily accumulated in nestin-positive reactive astrocytes in the stroke-injured striatum. Moreover, the enhancement of astrocytic pS292 MeCP2 was correlated with the augmentation of VEGF in astrocytes, as determined by the substantial co-localization of pS292 MeCP2 and VEGF after stroke. Finally, the exogenous overproduction of VEGF further promoted the expression of pS292 MeCP2 in reactive astrocytes, and this effect was accompanied by a marked increase in reactive astrocytes. On the contrary, MeCP2 was predominantly expressed in the neuronal nucleus, and the level of this protein was not significantly altered after ischemic injury and VEGF overproduction. CONCLUSION: Our data provide the first demonstration that overexpression of VEGF enhances the accumulation of pS292 MeCP2 in reactive astrocytes in the ischemic-injured rat striatum, implicating a pS292 MeCP2-related epigenetic role of exogenous VEGF in reactive astrocytes following cerebral ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Corpo Estriado/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Isquemia Encefálica/patologia , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Corpo Estriado/patologia , Citoplasma/metabolismo , Citoplasma/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Masculino , Fosforilação , Distribuição Aleatória , Ratos Sprague-Dawley
5.
Neurochem Int ; 2012 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-22819795

RESUMO

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

6.
Zhonghua Nan Ke Xue ; 13(12): 1068-71, 2007 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-18284051

RESUMO

OBJECTIVE: To study the relationship between substance P (SP) and/or calcitonin gene-related peptide (CGRP) immunoreactive neurons in dorsal root ganglia (DRG) and the transmission of nociception in the penile frenulum of rats. METHODS: The fluoro-gold (FG) retrograde tracing method was used to trace the origin of nerve terminals in the penile frenulum of rats. And SP and/or CGRP immunofluorescence labeling was employed to detect the distribution of SP and/or CGRP immunoreactive neurons in DRG. RESULTS: FG retrograde tracing showed that the FG retrolabeled neurons were localized in L6-DRG and S1-DRG. SP and/or CGRP immunofluorescence labeling indicated that a large number of DRG neurons were SP- and CGRP-immunoreactive, different in size, bright red and bright green respectively in color, and arranged in rows or spots among nerve bundles. All the FG/SP and FG/CGRP double-labeled neurons were medium or small-sized. One third of the FG-labeled neurons were SP-immunoreactive, and a half of them CGRP-immunoreactive in L6-DRG and S1-DRG respectively. The FG/SP/CGRP-labeled neurons accounted for one fifth of the FG retro labeled neurons. CONCLUSION: SP- and CGRP-immunoreactive neurons in L6-DRG and SI-DRG of rats may be involved in the transmission of nociception in rat penile frenulum.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/análise , Neurônios/química , Pênis/inervação , Substância P/análise , Animais , Gânglios Espinais/química , Gânglios Espinais/citologia , Masculino , Microscopia de Fluorescência , Neurônios/fisiologia , Neurônios Aferentes/química , Neurônios Aferentes/fisiologia , Ratos , Ratos Sprague-Dawley
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