Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 143
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Genes (Basel) ; 10(11)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652793

RESUMO

Orofacial clefts (OFCs) are the most frequent craniofacial birth defects. An orofacial cleft (OFC) occurs as a result of deviations in palatogenesis. Cell proliferation, differentiation, adhesion, migration and apoptosis are crucial in palatogenesis. We hypothesized that deregulation of these processes in oral keratinocytes contributes to OFC. We performed microarray expression analysis on palatal keratinocytes from OFC and non-OFC individuals. Principal component analysis showed a clear difference in gene expression with 24% and 17% for the first and second component, respectively. In OFC cells, 228 genes were differentially expressed (p < 0.001). Gene ontology analysis showed enrichment of genes involved in ß1 integrin-mediated adhesion and migration, as well as in P-cadherin expression. A scratch assay demonstrated reduced migration of OFC keratinocytes (343.6 ± 29.62 µm) vs. non-OFC keratinocytes (503.4 ± 41.81 µm, p < 0.05). Our results indicate that adhesion and migration are deregulated in OFC keratinocytes, which might contribute to OFC pathogenesis.

2.
Small ; 15(8): e1805492, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30690890

RESUMO

MG53 is transcriptionally activated by the IRS-1/PI3K/AKT signal pathway, which is closely related with oncogenesis of several tumors. Here, the role of MG53 in the tumorigenesis of tongue cancer is analyzed in vitro and in vivo. The stable MG53 overexpression/knockdown SCC9 and SCC25 cells are constructed through retrovirus infection. Then a PLGA cylinder is used to provide a 3D culture environment for cell growth. Cell counting results suggest that overexpression of MG53 inhibits the cell proliferation and colony formation of SCC9 and SCC25 cells. While knockdown of MG53 has the opposite effect. Furthermore, knockdown of MG53 significantly promotes the invasion of SCC9 and SCC25 cells. Western blotting data confirm that MG53 affects the expression of the AKT signaling pathway. In a xenograft assay, knockdown of MG53 promotes the growth of xenograft which is induced by SCC25 cells in nude mice. The findings demonstrate that MG53 affects the biological behavior of human tongue cancer SCC9 and SCC25 cells.

3.
Arch Oral Biol ; 97: 42-51, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30342306

RESUMO

OBJECTIVES: Gingival recession and alveolar bone loss are common manifestations of periodontitis. Periodontal regeneration is the ideal strategy for rehabilitating periodontal tissue defects and preventing tooth loss. The present study examined whether localized, topical application of gingival overgrowth-inducing drugs, phenytoin, nifedipine or cyclosporine, induces periodontal regeneration. METHODS: Polylactic-co-glycolic acid (PLGA) was used as the carrier for preparation of phenytoin, nifedipine or cyclosporine-loaded PLGA microspheres, using an oil-in-water emulsification technique. The drug-loaded microspheres were delivered to periodontal defects created on alveolar ridges mesial to the first maxillary molars of Sprague-Dawley rats. After eight weeks, the operation area in each rat, including the maxillary molars and periodontal tissues, was harvested and evaluated by micro-computed tomography, histochemical and immunohistochemical analyses. RESULTS: Physical parameters representative of periodontal regeneration, including the length of new alveolar bone (p < 0.01) and the area of new alveolar bone (p < 0.01) were significantly improved in the phenytoin group. Compared to other groups, the phenytoin group demonstrated increased expression of COL-1, VEGF-A, osteoblast and osteoclast markers (BMP-2, TGF-ß1, OCN and TRAP staining), as well as decreased expression of MMP-8. CONCLUSIONS: Results of the present study provided new evidence that localized, controlled release of phenytoin confers therapeutic benefits toward gingival recession and alveolar bone loss. Phenytoin appears to be a promising drug that promotes periodontal regeneration.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Retração Gengival/tratamento farmacológico , Microesferas , Nifedipino/administração & dosagem , Fenitoína/administração & dosagem , Poliésteres/administração & dosagem , Administração Tópica , Animais , Biomarcadores/análise , Ciclosporina/administração & dosagem , Imuno-Histoquímica , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Método Simples-Cego , Microtomografia por Raio-X
4.
Inflamm Res ; 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30008029

RESUMO

AIM: The study aimed to investigate the effects of DNA repair proteins on cell apoptosis in human DPSCs during inflammation. METHODS: Lipopolysaccharide (LPS) was used to stimulate inflammation in dental pulp in vivo and in vitro. We identified the activation of DSB response and DNA repair proteins in inflamed pulp tissue and in LPS-treated human DPSCs. Then we transfected the cells with Ku70 (a key protein involved in NHEJ) siRNA and detected the expression changes of γ-H2A.X, DNA repair proteins and cell apoptosis. RESULTS: Immunohistochemical staining showed that at 4 and 6 days of pulpitis the expression of Ku70 and γ-H2A.X significantly increased. The levels of γ-H2A.X, Ku70, Xrcc4, and Rad51 increased considerably in the LPS-treated DPSCs. Furthermore, decreased expression of Ku70 could increase the number of γ-H2A.X foci, apoptotic cells and reduce cell viability in DPSCs. CONCLUSIONS: The results indicate that NHEJ pathway was the main mechanism involved in DNA damage response induced by repeated LPS stimulation in DPSCs. Meanwhile, the findings suggested that Ku70 serves importantly in the apoptosis of DPSCs in the inflammatory environment.

5.
Biochim Biophys Acta Mol Cell Res ; 1865(9): 1161-1172, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29857020

RESUMO

Alternative splicing of precursor messenger RNA has been increasingly associated with tumorigenesis. The serine/arginine-rich protein (SR) family plays key roles in the regulation of pre-mRNA alternative splicing. Increasing evidence has demonstrated that the SR protein family is involved in tumorigenesis. However, the functions and mechanisms of SR proteins in tumourigenesis remain largely unknown. In the present study, we discovered that serine/arginine-rich splicing factor 5 (SRSF5) is a novel oncogenic splicing factor that is overexpressed in oral squamous cell carcinoma (OSCC) tissues and cells, being crucial for OSCC cell proliferation and tumor formation. Overexpression of SRSF5 transformed immortal rodent fibroblasts to form tumors in nude mice, while downregulation of SRSF5 in oral squamous cell lines retarded cell growth, cell cycle progression, and tumor growth. The expression of SRSF5 is controlled by an autoregulation mechanism. Serine/arginine-rich splicing factor 3 (SRSF3) has been identified as an oncogene. We found that SRSF5 is a novel target of SRSF3. SRSF3 impairs the autoregulation of SRSF5 and promotes SRSF5 overexpression in cancer cells. Altogether, the present study demonstrated that SRSF5 is a novel oncogene that is upregulated by SRSF3 in OSCC cells.

6.
Cleft Palate Craniofac J ; : 1055665618775723, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29738288

RESUMO

OBJECTIVE: Distal-less 4 ( DLX4) was recently identified as the causative gene for a syndromic form of cleft lip with or without cleft palate, and further biological analyses have established the importance of Dlx4 gene in craniofacial development, which suggested DLX4 as a promising candidate to further investigate any possible association between DLX4 polymorphisms and risk to nonsyndromic orofacial clefts (NSOFCs). DESIGN: Single-nucleotide polymorphisms (SNPs) with minor allele frequency >5% in the Han Chinese population which locate in the 5' flanking region, 5'/3'-untranslated region, or coding region with nonsynonymous changes in DLX4 were selected. Four SNPs (rs58769681, rs1058562, rs1058564, and rs8066341) were thus included in the following genotyping using the TaqMan 5'-exonuclease allelic discrimination assay in a case-control cohort with 1522 individuals. RESULTS: None of SNPs were associated with NSOFCat the allele and genotype levels in general and stratified single-marker analysis, including genotypic distributions under different modes of inheritance. In linkage disequilibrium (LD) analysis, we found strong LD ( r2 > 0.8) between any 2 of the SNPs, respectively. Further haplotyping identified haplotypes C-C (formed by rs1058564 and rs1058562) and C-C-A (formed by rs1058564, rs1058562, and rs58769681) which reached the significance threshold ( P < .05); nevertheless, none of them survived the multiple comparison correction. CONCLUSIONS: Our findings indicated the hypothesis that DLX4 variants contributing to NSOFC risk should be interpreted with caution. Further replications in diverse ethnic origins and larger cohorts are still warranted.

7.
Proc Natl Acad Sci U S A ; 115(9): 2192-2197, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29440419

RESUMO

Pituitary hormones have long been thought solely to regulate single targets. Challenging this paradigm, we discovered that both anterior and posterior pituitary hormones, including FSH, had other functions in physiology. We have shown that FSH regulates skeletal integrity, and, more recently, find that FSH inhibition reduces body fat and induces thermogenic adipose tissue. A polyclonal antibody raised against a short, receptor-binding epitope of FSHß was found not only to rescue bone loss postovariectomy, but also to display marked antiobesity and probeiging actions. Questioning whether a single agent could be used to treat two medical conditions of public health importance--osteoporosis and obesity--we developed two further monoclonal antibodies, Hf2 and Mf4, against computationally defined receptor-binding epitopes of FSHß. Hf2 has already been shown to reduce body weight and fat mass and cause beiging in mice on a high-fat diet. Here, we show that Hf2, which binds mouse Fsh in immunoprecipitation assays, also increases cortical thickness and trabecular bone volume, and microstructural parameters, in sham-operated and ovariectomized mice, noted on microcomputed tomography. This effect was largely recapitulated with Mf4, which inhibited bone resorption by osteoclasts and stimulated new bone formation by osteoblasts. These effects were exerted in the absence of alterations in serum estrogen in wild-type mice. We also reconfirm the existence of Fshrs in bone by documenting the specific binding of fluorescently labeled FSH, FSH-CH, in vivo. Our study provides the framework for the future development of an FSH-based therapeutic that could potentially target both bone and fat.


Assuntos
Anticorpos Monoclonais/farmacologia , Epitopos , Subunidade beta do Hormônio Folículoestimulante/imunologia , Animais , Especificidade de Anticorpos , Densidade Óssea , Reabsorção Óssea , Domínio Catalítico , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Ovariectomia , Ligação Proteica , Conformação Proteica
8.
Sci Rep ; 7(1): 10495, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874755

RESUMO

Viruses modulate the host immune system to evade host antiviral responses. The poxvirus proteins serine proteinase inhibitor 2 (SPI-2) and cytokine response modifier A (CrmA) are involved in multiple poxvirus evasion strategies. SPI-2 and CrmA target caspase-1 to prevent apoptosis and cytokine activation. Here, we identified SPI-2 and CrmA as negative regulators of virus-triggered induction of IFN-ß. Ectopic expression of SPI-2 or CrmA inhibited virus-triggered induction of IFN-ß and its downstream genes. Consistently, knockdown of SPI-2 by RNAi potentiated VACV-induced transcription of antiviral genes. Further studies revealed that SPI-2 and CrmA associated with TBK1 and IKKε to disrupt the MITA-TBK1/IKKε-IRF3 complex. These findings reveal a novel mechanism of SPI-2/CrmA-mediated poxvirus immune evasion.

9.
PeerJ ; 5: e3691, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28875069

RESUMO

BACKGROUND: The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED. METHODS: The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene's promoter was evaluated by pyrosequencing. RESULTS: This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene's promoter was not related to carriers' phenotype changes in this family. DISCUSSION: We reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.

10.
Nature ; 546(7656): 107-112, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28538730

RESUMO

Menopause is associated with bone loss and enhanced visceral adiposity. A polyclonal antibody that targets the ß-subunit of the pituitary hormone follicle-stimulating hormone (Fsh) increases bone mass in mice. Here, we report that this antibody sharply reduces adipose tissue in wild-type mice, phenocopying genetic haploinsufficiency for the Fsh receptor gene Fshr. The antibody also causes profound beiging, increases cellular mitochondrial density, activates brown adipose tissue and enhances thermogenesis. These actions result from the specific binding of the antibody to the ß-subunit of Fsh to block its action. Our studies uncover opportunities for simultaneously treating obesity and osteoporosis.


Assuntos
Tecido Adiposo/metabolismo , Adiposidade , Subunidade beta do Hormônio Folículoestimulante/antagonistas & inibidores , Termogênese , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Bege/efeitos dos fármacos , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Subunidade beta do Hormônio Folículoestimulante/imunologia , Haploinsuficiência , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Obesidade/prevenção & controle , Osteoporose/tratamento farmacológico , Ovariectomia , Consumo de Oxigênio/efeitos dos fármacos , Receptores do FSH/antagonistas & inibidores , Receptores do FSH/genética , Receptores do FSH/metabolismo , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1/biossíntese
11.
Environ Toxicol Pharmacol ; 51: 45-50, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28282589

RESUMO

This study investigated the correlation between differentially expressed proteins in amniotic fluid (AF) and cleft palate induced by all-trans retinoic acid (atRA), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Seven proteins were differentially expressed at embryonic day (E) 16.5 in atRA and control groups as revealed by label-based mouse antibody array. Enzyme-linked immunosorbent assay was further used to detect the expression levels of these proteins in AF from E13.5 to E16.5 in atRA, TCDD, and control groups. The cleft palate groups showed lower concentrations of receptor for advanced glycation end products (RAGE) and epiregulin at E16.5. RAGE immunostaining obviously decreased in palatal tissue sections obtained from E14.5 to E16.5 in the cleft palate groups as revealed by immunohistochemistry. These findings indicate that reduced levels of RAGE and epiregulin in AF are correlated to chemically induced cleft palate in mice.


Assuntos
Líquido Amniótico/metabolismo , Fissura Palatina/metabolismo , Epirregulina/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Biomarcadores/metabolismo , Fissura Palatina/induzido quimicamente , Modelos Animais de Doenças , Feminino , Idade Gestacional , Camundongos Endogâmicos C57BL , Palato/efeitos dos fármacos , Palato/embriologia , Palato/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Gravidez , Receptor para Produtos Finais de Glicação Avançada/genética , Tretinoína/toxicidade
12.
Nat Commun ; 8: 14364, 2017 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-28232668

RESUMO

Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Fatores Etários , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Fenda Labial/etnologia , Fissura Palatina/etnologia , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
13.
Artigo em Inglês | MEDLINE | ID: mdl-28153567

RESUMO

OBJECTIVE: This study aims to analyze the expression of T-cell receptor γ chain alternate reading frame protein (TARP) in salivary adenoid cystic carcinoma (SACC) and its distant metastases and to investigate its influences on the development and progression of SACC. STUDY DESIGN: TARP expression was analyzed in 50 primary SACCs, 13 specimens of metastatic adenoid cystic carcinoma of salivary gland origin, and 20 noncancerous tissues around SACC via immunohistochemistry. Cell Counting Kit-8 tests, wound healing assay, and Transwell experiments were performed to evaluate the effects of lentivirus-mediated TARP overexpression on the proliferation, migration, and invasion of SACC cells. RESULTS: TARP expression was significantly increased in primary SACCs compared with adjacent noncancerous tissues, and this increase was further enhanced in metastases compared with primary SACCs. The expression level of TARP correlated significantly with tumor size, tumor-node-metastasis stage, perineural invasion, histologic type, and distant metastasis. Furthermore, TARP overexpression promoted the growth, migration, and invasion of SACC cells. CONCLUSIONS: TARP plays an important role in and may be used as a marker to indicate the development and progression of SACC.


Assuntos
Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/patologia , Proteínas Nucleares/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/patologia , Adulto , Idoso , Western Blotting , Movimento Celular , Proliferação de Células , Eletroforese em Gel de Ágar , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Reação em Cadeia da Polimerase em Tempo Real
14.
Arch Oral Biol ; 75: 114-119, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27825676

RESUMO

OBJECTIVE: While hypoxia and inflammation are intimately linked, the effects of inflammatory hypoxia on the pathogenesis of periapical lesions remain largely unknown. The aim of this study was to examine hypoxia during the progression of experimentally induced rat periapical lesions, and to derive correlations between hypoxia-induced Semaphorin 7A (Sema7a) expression, severity of inflammation, and osteoclastogenesis in the lesions. DESIGN: Periapical lesions were developed after mandibular first molar pulp exposure in forty Sprague-Dawley rats. The animals were randomly divided into four groups and sacrificed at 0, 7, 14, and 28days after pulpal exposure. The bilateral mandibles containing the first molar were obtained and routinely prepared for histological, immunohistochemical, enzyme histochemical analyses and quantitative polymerase chain reaction detecting Sema7a mRNA expression. Data were analysed by one-way analysis of variance and the Pearson's correlation and linear tendency test. RESULTS: Periapical tissues become hypoxic during the development of experimentally induced periapical lesions, with steadily increasing numbers of HIF-1α-positive cells that positively correlate with the expression of Sema7a mRNA in the lesions. Furthermore, significant positive correlates were derived for the expression of Sema7a and the degree of inflammatory infiltration and osteoclast number, respectively. CONCLUSIONS: Hypoxia-induced Sema7a participates in the pathogenesis of periapical lesions, providing a novel therapeutic target for the treatment of this inflammatory disease in the future.


Assuntos
Antígenos CD/metabolismo , Hipóxia/complicações , Inflamação , Osteogênese , Doenças Periapicais/complicações , Doenças Periapicais/metabolismo , Semaforinas/metabolismo , Animais , Cavidade Pulpar/enzimologia , Cavidade Pulpar/lesões , Cavidade Pulpar/patologia , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imuno-Histoquímica , Masculino , Mandíbula , Dente Molar/lesões , Osteoclastos/metabolismo , Osteoclastos/patologia , Doenças Periapicais/enzimologia , Doenças Periapicais/patologia , Tecido Periapical/metabolismo , Tecido Periapical/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Am J Transl Res ; 8(9): 3861-3871, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27725865

RESUMO

This study aimed to investigate whether follicle-stimulating hormone (FSH)-induced alveolar bone resorption was mediated by a cyclooxygenase 2 (COX-2) enzyme related mechanism. Experimental periodontitis was induced in bilateral ovariectomized (OVX) rats, some of which were injected with triptorelin, an FSH inhibitor. After mandibles were collected, we performed micro-computed tomography to evaluate alveolar bone loss and immunohistochemical staining to assess COX-2 expression. As well, human periodontal ligament cells (PDLCs) were treated with FSH (30 ng/ml), and the COX-2 mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qPCR) and Western blotting, respectively; prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay (ELISA). The results indicated that FSH significantly increased alveolar bone resorption and the expression of COX-2 in the bilateral OVX + Ligatured rats compared with the other treatment groups. FSH also increased the mRNA and protein expression of COX-2 and PGE2 (P < 0.01) in human PDLCs. Further, the analysis of signaling pathways revealed the activation of COX-2-mediated pathways including Erk, p38, and Akt. These data suggest that FSH aggravates alveolar bone loss via a COX-2-upregulation mechanism and that the Erk, p38, and Akt pathways are involved in this pathological process.

16.
Mol Med Rep ; 14(4): 2997-3006, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27510616

RESUMO

Periapical bone loss is one of the prominent pathological and clinical features of periapical periodontitis. Previous studies have demonstrated that follicle­stimulating hormone (FSH) could directly affect skeletal remodelling by stimulating the formation and the function of osteoclasts in vitro and in vivo. However, the effect of FSH on periapical bone loss remained to be fully elucidated. In the current study, a rat model was established in order to verify the effect of FSH in experimental periapical lesions. It was identified that FSH aggravated the bone loss of periapical lesions. In addition, RANKL­, TRAP­, TNF­α­ and IL­1ß­positive cells were increased significantly in FSH­treated groups, which indicated that the function of FSH in bone loss may be mediated through the increasing activity of osteoclasts and the increased secretion of inflammatory cytokines. The results of the current study suggested that FSH, independent of oestrogen, may aggravate periapical bone loss by FSH receptors, which may serve an important role in the immune and inflammatory response of the host to root canal and periradicular infection during menopause.


Assuntos
Hormônio Foliculoestimulante/sangue , Osteoclastos/patologia , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/patologia , Periodontite Periapical/complicações , Periodontite Periapical/patologia , Animais , Feminino , Humanos , Interleucina-1beta/análise , Osteoporose Pós-Menopausa/sangue , Osteoprotegerina/análise , Ovariectomia , Periodontite Periapical/sangue , Tecido Periapical/patologia , Ligante RANK/análise , Ratos , Ratos Sprague-Dawley , Receptores do FSH/análise , Fator de Necrose Tumoral alfa/análise
17.
Eur J Hum Genet ; 24(12): 1663-1670, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27381090

RESUMO

The Msx1 transcription factor is involved in multiple epithelial-mesenchymal interactions during vertebrate embryogenesis. It has pleiotropic effects in several tissues. In humans, MSX1 variants have been related to tooth agenesis, orofacial clefting, and nail dysplasia. We correlate all MSX1 disease causing variants to phenotypic features to shed light on this hitherto unclear association. MSX1 truncations cause more severe phenotypes than in-frame variants. Mutations in the homeodomain always cause tooth agenesis with or without other phenotypes while mutations outside the homeodomain are mostly associated with non-syndromic orofacial clefts. Downstream effects can be further explored by the edgetic perturbation model. This information provides new insights for genetic diagnosis and for further functional analysis of MSX1 variants.


Assuntos
Anodontia/genética , Fator de Transcrição MSX1/genética , Anormalidades da Boca/genética , Mutação , Animais , Anodontia/diagnóstico , Estudos de Associação Genética , Humanos , Fator de Transcrição MSX1/metabolismo , Anormalidades da Boca/diagnóstico , Unhas Malformadas/diagnóstico , Unhas Malformadas/genética , Síndrome
18.
PLoS One ; 11(7): e0159940, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27459192

RESUMO

BACKGROUND: Grainyhead-like-3 (GRHL3) was recently identified as the second gene that, when mutated, can leads to Van der Woude syndrome, which is characterized by orofacial clefts (OFC) and lower lip pits. In addition, a missense variant (rs41268753) in GRHL3 confers risk for non-syndromic cleft palate cases of European ancestry. Together with interferon regulatory factor 6 (IRF6), GRHL3 may be associated with the risk of NSOFC which awaits for being verified across different ethnic populations. OBJECTIVE: The aim of this study was to investigate the possible relationship between common functional variants in GRHL3 and susceptibility to NSOFC, especially cleft palate cases, in a Han Chinese population, one of the ethnic groups with the highest birth prevalence of orofacial clefting. METHODS: Because the allele frequency for rs41268753 minor alleles was zero in our Chinese population, we selected functional single nucleotide polymorphisms (SNPs) spanning GRHL3 with minor allele frequencies (MAFs) > 5% in the Han Chinese population. Two SNPs which meet the above criteria were then genotyped in a case-control cohort comprising 1145 individuals using the TaqMan 5'-exonuclease allelic discrimination assay. RESULTS: SNPs rs2486668 and rs545809 were used in this study. Overall genotype and allele distributions of both SNPs in general and stratified genotyping analyses revealed no statistically significant differences between cases and controls. Further logistic regression analyses using different genetic models failed to reveal any evidence that these markers influence risk to NSOFC. CONCLUSIONS: The variant rs41268753 in GRHL3 increases the risk for cleft palate in European population, but our findings failed to detect the link between two GRHL3 SNPs (rs2486668 and rs545809) and risk to NSOFC in the Han Chinese cohort. Although the present study did not provide any evidence that common functional variants in GRHL3 may contribute to NSOFC etiology in this Chinese population, further studies with a larger sample size, additional SNPs, and a more diverse ethnic cohort are still warranted.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Estudos de Casos e Controles , China , Humanos
19.
Sci Rep ; 6: 26925, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27254469

RESUMO

Osteoporosis is a prominent disorder affecting over 200 million people worldwide. Recently, semaphorins have been implicated in the cell-cell communication between osteoclasts and osteoblasts and have been associated with the progression of osteoporosis. Previously, we demonstrated that knockdown of semaphorin4d (Sema4d) using siRNA delivered with a bone-targeting system prevented bone loss in an osteoporotic animal model. Here, we used this bone-specific technology containing siRNA-Sema4d and fabricated a PLLA scaffold capable of enhancing bone repair following fracture. We investigated the ability of the implant to release siRNA-Sema4d into the surrounding tissues over time and to influence new bone formation in a 3 mm femur osteoporotic defect model in ovariectomized rats. Delivery of the bone-targeting system released from PLLA scaffolds began 2 hours post-implantation, peaked at 1 day, and was sustained over a 21 day period. µCT analysis demonstrated a significantly higher bone volume/total volume bone mineral density and number of osteoblasts in the rats that were transplanted with scaffolds loaded with siRNA-Sema4d. These results confirm the specific role of Sema4d in bone remodeling and demonstrate that significant increases in the speed and quality of new bone formation occur when siRNA-Sema4d is delivered via a PLLA scaffold.


Assuntos
Antígenos CD/genética , Osteoporose/terapia , RNA Interferente Pequeno/genética , Semaforinas/genética , Animais , Antígenos CD/metabolismo , Substitutos Ósseos , Feminino , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Fêmur/patologia , Expressão Gênica , Técnicas de Silenciamento de Genes , Osteoclastos/metabolismo , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Ratos Wistar , Semaforinas/metabolismo , Tecidos Suporte
20.
Eur J Oral Sci ; 124(3): 228-33, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27090353

RESUMO

Tooth agenesis is a congenital anomaly frequently seen in humans. Several genes have been associated with non-syndromic tooth agenesis, including msh homeobox 1 (MSX1), paired box 9 (PAX9), axis inhibition protein 2 (AXIN2), ectodysplasin A (EDA), and wingless-type MMTV integration site family member 10A (WNT10A). In this study, we investigated a Chinese family with non-syndromic tooth agenesis. A novel missense mutation (c.C1978T) in AXIN2 was identified in affected members. The mutation results in a His660Tyr substitution located between the Axin beta-catenin binding domain and the DIX domain of the axis inhibition protein 2 (AXIN2). We analysed this novel AXIN2 mutant, together with two reported AXIN2 mutants [c.1966C>T (p.Arg656Stop) and c.1994delG (p.Leu688Stop)] that cause colorectal cancer with and without oligodontia, to study the effect of the mutant p.His660Tyr on the Wnt/ß-catenin signaling pathway and to compare the molecular pathogenesis of different AXIN2 mutants in tooth agenesis and carcinogenesis. Further in vitro experiments indicated that the mutant p.His660Tyr caused inhibition of the Wnt/ß-catenin pathway, and the mutants p.Arg656Stop and p.Leu688Stop resulted in over-activation of the Wnt/ß-catenin pathway. In line with previous AXIN2 mutation studies, we suggest that AXIN2 mutations with different levels of severity may have distinct effects on the Wnt pathway and the phenotype of disease. Our study provides functional evidence supporting the notion that both inhibition and over-activation of the Wnt pathway may lead to tooth agenesis.


Assuntos
Anodontia/genética , Proteína Axina/genética , Mutação de Sentido Incorreto , Humanos , Mutação , Fenótipo , beta Catenina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA