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1.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(6): 642-646, 2020 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-33377340

RESUMO

OBJECTIVE: To study the comprehensive impact of scar and maxillary expansion combined with protraction on the development of maxilla with cleft lip and palate after repair operation. METHODS: In the original finite element model of the maxilla with cleft palate, a finite element model of the maxilla with cleft lip and palate was established by using Boolean operation in ANSYS. Scar force after cleft lip and palate repair and maxillary expansion force combined with protraction were added simultaneously to process the stress analysis. RESULTS: Maxillary deformation occurred in the three-dimensional direction. The comparison of displacements was as follows: X-axis>Z-axis>Y-axis. CONCLUSIONS: Maxillary growth is significantly inhibited in the three-dimensional direction under the comprehensive impact of scar and maxillary expansion combined with protraction after repair operation, especially transverse and sagittal growth.


Assuntos
Fenda Labial , Fissura Palatina , Cicatriz/patologia , Fenda Labial/cirurgia , Fissura Palatina/patologia , Fissura Palatina/cirurgia , Análise de Elementos Finitos , Humanos , Maxila/patologia , Maxila/cirurgia , Técnica de Expansão Palatina
2.
Birth Defects Res ; 112(19): 1699-1719, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33118705

RESUMO

BACKGROUND: There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it. METHODS: Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007-2020) and combined using random-effects meta-analysis when appropriate. Quality assessments were conducted using the Newcastle-Ottawa scale and Cochrane's risk of bias tool. RESULTS: Sixty-four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid-containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51-0.69), with considerable between-study heterogeneity. The prevalence of CL/P showed a small decline post-folic acid fortification in seven studies (OR 0.94, 95% CI 0.86-1.02). No association was found between OFC and genetic markers of folate status. The coronavirus-19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins. CONCLUSIONS: The risk of non-syndromic OFC was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution.


Assuntos
Fenda Labial/tratamento farmacológico , Fissura Palatina/tratamento farmacológico , Ácido Fólico/administração & dosagem , Anormalidades da Boca/tratamento farmacológico , Biomarcadores/metabolismo , Fenda Labial/metabolismo , Fenda Labial/patologia , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Suplementos Nutricionais , Feminino , Humanos , Anormalidades da Boca/metabolismo , Anormalidades da Boca/patologia , Gravidez
3.
Sci Rep ; 10(1): 15236, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943682

RESUMO

Palatal fistula is a challenging complication following cleft palate repair. We investigated the usefulness of collagen matrix in the prevention of postoperative fistula. We performed a retrospective cohort study of patients with cleft palate who underwent primary palatoplasty (Furlow's double opposing z-plasty) in Seoul National University Children's Hospital. Collagen Graft and Collagen Membrane (Genoss, Suwon, Republic of Korea) were selectively used in patients who failed complete two-layer closure. The effect of collagen matrix on fistula formation was evaluated according to palatal ratio (cleft width to total palatal width) and cleft width. A total of 244 patients (male, 92 and female, 152; median age, 18 months) were analyzed. The average cleft width was 7.0 mm, and the average palatal ratio was 0.21. The overall fistula rate was 3.6% (9/244). Palatal ratio (p = 0.014) and cleft width (p = 0.004) were independent factors impacting the incidence of postoperative fistula. Receiver operating characteristic curve analysis showed that the cutoff values in terms of screening for developing postoperative fistula were a palatal ratio of 0.285 and a cleft width of 9.25 mm. Among nonsyndromic patients with values above those cutoffs, the rates of fistula development were 0/5, 1/6 (16.7%), and 4/22 (18.2%) for those who received Collagen Graft, Collagen Membrane, and no collagen, respectively. Collagen matrix may serve as an effective tool for the prevention of palatal fistula when complete two-layer closure fails, especially in wide palatal clefts. The benefit was most evident in Collagen Graft with thick and porous structure.


Assuntos
Fissura Palatina/cirurgia , Colágeno/administração & dosagem , Fístula/prevenção & controle , Palato , Complicações Pós-Operatórias/prevenção & controle , Criança , Pré-Escolar , Fissura Palatina/patologia , Estudos de Coortes , Feminino , Fístula/etiologia , Fístula/patologia , Humanos , Lactente , Masculino , Palato/patologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Procedimentos Cirúrgicos Reconstrutivos/métodos , República da Coreia , Estudos Retrospectivos
4.
Development ; 147(21)2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32994166

RESUMO

The Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Morfogênese , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/metabolismo , Animais , Osso e Ossos/anormalidades , Osso e Ossos/patologia , Cartilagem/patologia , Núcleo Celular/metabolismo , Proliferação de Células , Condrócitos/metabolismo , Condrócitos/patologia , Fissura Palatina/patologia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Lâmina de Crescimento/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfogênese/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo
5.
Sci Rep ; 10(1): 14940, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913205

RESUMO

Cleft palate (CP) is one of the most common craniofacial birth defects, impacting about 1 in 800 births in the USA. Tgf-ß3 plays a critical role in regulating murine palate development, and Tgf-ß3 null mutants develop cleft palate with 100% penetrance. In this study, we compared global palatal transcriptomes of wild type (WT) and Tgf-ß3 -/- homozygous (HM) mouse embryos at the crucial palatogenesis stages of E14.5, and E16.5, using RNA-seq data. We found 1,809 and 2,127 differentially expressed genes at E16.5 vs. E14.5 in the WT and HM groups, respectively (adjusted p < 0.05; |fold change|> 2.0). We focused on the genes that were uniquely up/downregulated in WT or HM at E16.5 vs. E14.5 to identify genes associated with CP. Systems biology analysis relating to cell behaviors and function of WT and HM specific genes identified functional non-Smad pathways and preference of apoptosis to epithelial-mesenchymal transition. We identified 24 HM specific and 11 WT specific genes that are CP-related and/or involved in Tgf-ß3 signaling. We validated the expression of 29 of the 35 genes using qRT-PCR and the trend of mRNA expression is similar to that of RNA-seq data . Our results enrich our understanding of genes associated with CP that are directly or indirectly regulated via TGF-ß.


Assuntos
Fissura Palatina/patologia , Embrião de Mamíferos/patologia , Regulação da Expressão Gênica , Mutação , Transcriptoma , Fator de Crescimento Transformador beta3/fisiologia , Animais , Fissura Palatina/genética , Transição Epitelial-Mesenquimal , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA-Seq , Transdução de Sinais
6.
Toxicol Lett ; 333: 90-96, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768652

RESUMO

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) effectively induces cleft palate at increased doses, but its mechanism of involvement is unclear, and arguments have examined palatal shelf contact and/or fusion failure. The role of different types of cells constituting palatal skulls remains elusive regarding TCDD dosage. No reports have simultaneously compared the biological behaviors of TCDD- induced mesenchymal and epithelial cells in vitro. This study employed primary epithelial and mesenchymal cells as models in vitro to explore proliferation, migration, apoptosis and epithelial-to-mesenchymal transition with two different doses of TCDD (10 nmol/L, 100 nmol/L), contrasted with a control group without TCDD. Interestingly, we found the EMT process of primary palatal epithelial cells occurred automatically in vitro without helping bilateral palatal contact. The results showed that, with the low dose of TCDD, transformation of epithelial cells to mesenchymal cells was inhibited, and mesenchymal cell proliferation and migration were promoted. At high doses, mesenchymal cells decreased, preventing palate development, uprising and contact, while the EMT of epithelial cells decreased. Regardless of dose of TCDD, no impact on migration and apoptosis of epithelial cells was noted, but there was increased apoptosis of mesenchymal cell in a dose-dependent manner.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Células Epiteliais/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Palato/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fissura Palatina/induzido quimicamente , Fissura Palatina/embriologia , Fissura Palatina/patologia , Relação Dose-Resposta a Droga , Células Epiteliais/patologia , Feminino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Palato/embriologia , Palato/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia
7.
Niger J Clin Pract ; 23(5): 596-602, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32367864

RESUMO

Aim: The aim of this retrospective study is to evaluate and compare the 3-dimensional (3D) crown sizes of the left and right sides of upper and lower dental arches in patients with unilateral cleft lip and palate (UCLP). Materials and Methods: Dental casts of 94 patients all in permanent dentition were included in this study. Dental casts were divided into three groups as 36 casts with unilateral left cleft lip and palate (ULCLP), 18 casts with unilateral right cleft lip and palate (URCLP), and 40 casts without cleft (control). Mesiodistal (MD), buccolingual (BL), and gingiva incisal (GI) values of each tooth were measured by scanning the dental models with a high-precision optical 3D scanner. Paired t-test and independent t-test were used for statistical analysis. Results: U1 MD, U6 MD (P = 0.001) and BL (P = 0.01), L3 GI (P = 0.05) were greater in UCLP patients on the non-cleft side while U1 GI, L1 BL, L5 MD (P = 0.001), L4 MD, and BL (P = 0.01) values were found to be greater on the cleft side. Comparison of the cleft-sides and the control group showed that MD, BL, and GI dimensions of teeth on the cleft sides were generally found to be smaller, excluding the UR7 GI values for URCLP group (P = 0.05). Conclusion: In the measurements of teeth size, reliable and repeatable results were acquired through 3D software. Tooth size asymmetries can occur non-syndromic UCLP patients in both jaws. MD, BL, and GI dimensions of teeth are mostly found to be smaller in patients with CLP.


Assuntos
Fenda Labial , Imageamento Tridimensional/métodos , Odontometria/métodos , Coroa do Dente/diagnóstico por imagem , Estudos de Casos e Controles , Criança , Fissura Palatina/patologia , Oclusão Dentária , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Maxila , Estudos Retrospectivos , Coroa do Dente/patologia
9.
Development ; 147(21)2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32253237

RESUMO

Cleft lip is one of the most common human birth defects. However, there remain a limited number of mouse models of cleft lip that can be leveraged to characterize the genes and mechanisms that cause this disorder. Crosstalk between epithelial and mesenchymal cells underlies formation of the face and palate, but the basic molecular events mediating this crosstalk remain poorly understood. We previously demonstrated that mice lacking the epithelial-specific splicing factor Esrp1 have fully penetrant bilateral cleft lip and palate. In this study, we further investigated the mechanisms leading to cleft lip as well as cleft palate in both existing and new Esrp1 mutant mouse models. These studies included a detailed transcriptomic analysis of changes in ectoderm and mesenchyme in Esrp1-/- embryos during face formation. We identified altered expression of genes previously implicated in cleft lip and/or palate, including components of multiple signaling pathways. These findings provide the foundation for detailed investigations using Esrp1 mutant disease models to examine gene regulatory networks and pathways that are essential for normal face and palate development - the disruption of which leads to orofacial clefting in human patients.


Assuntos
Fenda Labial/patologia , Fissura Palatina/patologia , Epitélio/patologia , Mesoderma/patologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Processamento Alternativo/genética , Animais , Proliferação de Células , Fenda Labial/embriologia , Fenda Labial/genética , Fissura Palatina/embriologia , Fissura Palatina/genética , Ectoderma/embriologia , Ectoderma/metabolismo , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Epitélio/embriologia , Face , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Mesoderma/embriologia , Camundongos Knockout , Organogênese/genética , Palato/embriologia , Palato/patologia
10.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 55(4): 249-252, 2020 Apr 09.
Artigo em Chinês | MEDLINE | ID: mdl-32268624

RESUMO

Objective: To evaluate the changes of nasalance when cleft palate patients examined using nasometer and nasopharyngeal fiberscopy simultaneously. Methods: A total of 33 cleft palate patients from August 2004 to August 2010 were examined by nasopharyngeal fiber endoscopy and nasometer simultaneously. The nasalance of 33 voice samples was compared under two situations only nasometer and nasometer with nasopharyngeal fiberscopy. Results: The statistics showed that the nasalance value of 33 voice samples of 33 participants under different situations were no significant difference through paired t-test (P>0.05). Conclusions: Nasopharyn fiber endoscopy had no influence to the results of the nasalance value under simultaneous condition. The nasometer and nasopharyn fiber endoscopy can be applied to evaluate the velopharyngeal function of cleft palate patients simultaneously.


Assuntos
Fissura Palatina , Endoscopia/métodos , Tecnologia de Fibra Óptica , Insuficiência Velofaríngea , Fissura Palatina/diagnóstico , Fissura Palatina/patologia , Endoscopia/instrumentação , Humanos , Nariz/patologia
11.
Toxicology ; 438: 152444, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32283119

RESUMO

As a common birth defect, Cleft palate can be caused by the disturbance during the developmental process of the palatal shelves. The 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) is a well-known environmental teratogenic agent for cleft palate and Aryl hydrocarbon receptor (AhR) pathway can be activated by dioxins. Oct4 as a pluripotent stem cell transcription factor is also involved in the process of embryonic development. The AHR and retinoid receptors have cross-talk at CYP1A1 (cytochrome P450, family 1, subfamily A, polypeptide 1) promoter. There are also bidirectional talk between AhR and Oct4. In this study, we used C57/BL6 N mice and TCDD (64 µg/Kg body weight) to establish a model of fetal cleft palate to observe the effects of dioxin on fetal mesenchymal proliferation and apoptosis, and explore the role of Oct4 in inducing cleft palate. The results showed that dioxin inhibited mesenchymal proliferation and promoted apoptosis. In addition, dioxin inhibited Oct4 expression, and preliminary data suggest that hypermethylation of the Oct4 promoter may be a putative mechanism, suggesting that TCDD might induce cleft palate by inhibiting the proliferation of palatal mesenchymal cells mediated by Oct4.


Assuntos
Proliferação de Células , Fissura Palatina/metabolismo , Mesoderma/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Palato/metabolismo , Dibenzodioxinas Policloradas , Animais , Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fissura Palatina/induzido quimicamente , Fissura Palatina/patologia , Metilação de DNA , Modelos Animais de Doenças , Feminino , Masculino , Mesoderma/anormalidades , Camundongos Endogâmicos C57BL , Fator 3 de Transcrição de Octâmero/genética , Palato/anormalidades , Gravidez , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais
12.
Hum Genet ; 139(10): 1261-1272, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32318854

RESUMO

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based sequencing probes were designed and used for sequencing 380 NSCLP probands (from multiplex and simplex families of non-Hispanic white (NHW) and Hispanic ethnicities) using Illumina MiSeq. The frequencies of identified variants were compared to ethnically matched European (CEU) and Los Angeles Mexican (MXL) control genomes and used for association analyses. Variants in mm427/MSX1 and hs1582/SPRY1 showed genome-wide significant association with NSCLP (p ≤ 6.4 × 10-11). In silico analysis showed that these enhancer variants may disrupt important transcription factor binding sites. Haplotypes involving these enhancers and also mm435/ABCA4 were significantly associated with NSCLP, especially in NHW (p ≤ 6.3 × 10-7). Importantly, groupwise burden analysis showed several enhancer combinations significantly over-represented in NSCLP individuals, revealing novel NSCLP pathways and supporting a polygenic inheritance model. Our findings support the role of craniofacial enhancer sequence variation in the etiology of NSCLP.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Variação Genética , Herança Multifatorial , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Doenças Assintomáticas , Fenda Labial/etnologia , Fenda Labial/patologia , Fissura Palatina/etnologia , Fissura Palatina/patologia , Embrião de Mamíferos , Grupo com Ancestrais do Continente Europeu , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Hispano-Americanos , Humanos , Fator de Transcrição MSX1/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Linhagem , Fosfoproteínas/genética , Estados Unidos
13.
Clin Dysmorphol ; 29(1): 24-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30946036

RESUMO

Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cistos , Família , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Lábio/anormalidades , Linhagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/genética , Fissura Palatina/patologia , Cistos/genética , Cistos/patologia , República Democrática do Congo , Feminino , Humanos , Lábio/patologia , Masculino
14.
Genes (Basel) ; 10(10)2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652620

RESUMO

Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palate is associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuous cleft. Although this phenotype may represent 5% of clefts of the lip and/or palate (CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing (WES) and apply a candidate gene approach to non-syndromic discontinuous CLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1 genes, which represents almost one third of this cohort. Whole exome sequencing of clinically well-defined subgroups of CLP, such as discontinuous cleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuous cleft lip and palate seems to have a strong genetic basis.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Mutação , Criança , Fenda Labial/patologia , Fissura Palatina/patologia , Proteína 1 Homóloga a Discs-Large/genética , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Sequenciamento Completo do Exoma/métodos
15.
Genes (Basel) ; 10(11)2019 10 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.


Assuntos
Adesão Celular , Fenda Labial/genética , Fissura Palatina/genética , Queratinócitos/metabolismo , Transcriptoma , Caderinas/genética , Caderinas/metabolismo , Movimento Celular , Células Cultivadas , Fenda Labial/patologia , Fissura Palatina/patologia , Feminino , Humanos , Lactente , Queratinócitos/fisiologia , Masculino
16.
EBioMedicine ; 49: 305-317, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31662288

RESUMO

BACKGROUND: Endocrine-cerebro-osteodysplasia (ECO) syndrome is a genetic disorder associated with congenital defects of the endocrine, cerebral, and skeletal systems in humans. ECO syndrome is caused by mutations of the intestinal cell kinase (ICK) gene, which encodes a mitogen-activated protein (MAP) kinase-related kinase that plays a critical role in controlling the length of primary cilia. Lack of ICK function disrupts transduction of sonic hedgehog (SHH) signaling, which is important for development and homeostasis in humans and mice. Craniofacial structure abnormalities, such as cleft palate, are one of the most common defects observed in ECO syndrome patients, but the role of ICK in palatal development has not been studied. METHODS: Using Ick-mutant mice, we investigated the mechanisms by which ICK function loss causes cleft palate and examined pharmacological rescue of the congenital defects. FINDINGS: SHH signaling was compromised with abnormally elongated primary cilia in the developing palate of Ick-mutant mice. Cell proliferation was significantly decreased, resulting in failure of palatal outgrowth, although palatal adhesion and fusion occurred normally. We thus attempted to rescue the congenital palatal defects of Ick mutants by pharmacological activation of SHH signaling. Treatment of Ick-mutant mice with an agonist for Smoothened (SAG) rescued several congenital defects, including cleft palate. INTERPRETATIONS: The recovery of congenital defects by pharmacological intervention in the mouse models for ECO syndrome highlights prenatal SHH signaling modulation as a potential therapeutic measure to overcome congenital defects of ciliopathies.


Assuntos
Doenças do Sistema Nervoso Central/congênito , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Endócrino/congênito , Doenças do Sistema Endócrino/metabolismo , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Receptor Smoothened/agonistas , Animais , Proliferação de Células , Doenças do Sistema Nervoso Central/genética , Cílios/metabolismo , Fissura Palatina/patologia , Modelos Animais de Doenças , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/patologia , Doenças do Sistema Endócrino/genética , Regulação da Expressão Gênica no Desenvolvimento , Camundongos Knockout , Modelos Biológicos , Mutação/genética , Palato/anormalidades , Palato/embriologia , Palato/ultraestrutura , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/metabolismo
17.
J Appl Oral Sci ; 27: e20180649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596367

RESUMO

OBJECTIVE: Cleft palate (CP) is a congenital birth defect caused by the failure of palatal fusion. Little is known about the potential role of DNA methylation in the pathogenesis of CP. This study aimed to explore the potential role of DNA methylation in the mechanism of CP. METHODOLOGY: We established an all-trans retinoic acid (ATRA)-induced CP model in C57BL/6J mice and used methylation-dependent restriction enzymes (MethylRAD, FspEI) combined with high-throughput sequencing (HiSeq X Ten) to compare genome-wide DNA methylation profiles of embryonic mouse palatal tissues, between embryos from ATRA-treated vs. untreated mice, at embryonic gestation day 14.5 (E14.5) (n=3 per group). To confirm differentially methylated levels of susceptible genes, real-time quantitative PCR (qPCR) was used to correlate expression of differentially methylated genes related to CP. RESULTS: We identified 196 differentially methylated genes, including 17,298 differentially methylated CCGG sites between ATRA-treated vs. untreated embryonic mouse palatal tissues (P<0.05, log2FC>1). The CP-related genes Fgf16 (P=0.008, log2FC=1.13) and Tbx22 (P=0.011, log2FC=1.64,) were hypermethylated. Analysis of Fgf16 and Tbx22, using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), identified 3 GO terms and 1 KEGG pathway functionally related to palatal fusion. The qPCR showed that changes in expression level negatively correlated with methylation levels. CONCLUSIONS: Taken together, these results suggest that hypermethylation of Fgf16 and Tbx22 is associated with decreased gene expression, which might be responsible for developmental failure of palatal fusion, eventually resulting in the formation of CP.


Assuntos
Fissura Palatina/genética , Metilação de DNA , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica , Proteínas com Domínio T/genética , Animais , Fissura Palatina/embriologia , Fissura Palatina/patologia , Feminino , Fatores de Crescimento de Fibroblastos/análise , Masculino , Camundongos Endogâmicos C57BL , Domínios e Motivos de Interação entre Proteínas , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Análise de Sequência de DNA , Proteínas com Domínio T/análise
18.
Mol Med Rep ; 20(4): 3326-3336, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432193

RESUMO

The aim of the present study was to determine the association between maternal metabolism and development of the fetal palate, and to suggest a potential non­invasive prenatal diagnostic method for fetal cleft palate (CP). Dexamethasone (DXM) was used to create a CP mouse model. A 9.4­Tesla (T) magnetic resonance spectroscopy (MRS) imager was used to measure an array of metabolites in the maternal serum, placental tissue, amniotic fluid and fetal palates. Multivariate statistical analysis was performed using SIMCA­P 14.1 software. Following DXM treatment, variations were detected in multiple metabolites in the female mice and their fetuses based on 9.4T MRS. It was indicated that in the experimental group during CP formation, leucine, valine, creatine, acetate and citrate levels in the palatal tissue were lower, whereas lactate, alanine, proline/inositol and glutamate­containing metabolite levels were higher, compared with the levels in the control group. In placental tissue and amniotic fluid, succinate and choline levels were lower in the experimental group. The relative concentrations of cholesterol and lipids in palatal tissues from mice treated with DXM were higher compared with the concentrations in tissues from mice in the control group, with the exception of (CH2)n lipids. In the placental tissue, the alteration in cholesterol level exhibited the opposite trend. Lipid levels for the different lipid forms varied and most of them were unsaturated lipids.


Assuntos
Fissura Palatina , Dexametasona/efeitos adversos , Embrião de Mamíferos , Desenvolvimento Embrionário/efeitos dos fármacos , Animais , Fissura Palatina/induzido quimicamente , Fissura Palatina/embriologia , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Dexametasona/farmacologia , Modelos Animais de Doenças , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Espectroscopia de Ressonância Magnética , Camundongos
19.
Am J Orthod Dentofacial Orthop ; 156(2): 257-265, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31375236

RESUMO

INTRODUCTION: Children with unilateral cleft lip and palate (UCLP) exhibit snoring and mouth breathing. They are also reported to show obstructive sleep apnea syndrome. However, their upper airway ventilation condition is not clearly understood. Therefore, this study was performed to evaluate upper airway ventilation condition in children with UCLP with the use of computational fluid dynamics. METHODS: Twenty-one children (12 boys, 9 girls; mean age 9.1 years) with UCLP and 25 children (13 boys, 12 girls; mean age 9.2 years) without UCLP who required orthodontic treatment underwent cone-beam computed tomography (CBCT). Nasal resistance and upper airway ventilation condition were evaluated with the use of computational fluid dynamics from CBCT data. The groups were compared with the use of Mann-Whitney U tests and Student t tests. RESULTS: Nasal resistance of the UCLP group (0.97 Pa/cm3/s) was significantly higher than that of the control group (0.26 Pa/cm3/s; P < 0.001). Maximal pressure of the upper airway (335.02 Pa) was significantly higher in the UCLP group than in the control group (67.57 Pa; P < 0.001). Pharyngeal airway (from choanae to base of epiglottis) pressure in the UCLP group (140.46 Pa) was significantly higher than in the control group (15.92 Pa; P < 0.02). CONCLUSIONS: Upper airway obstruction in children with UCLP resulted from both nasal and pharyngeal airway effects.


Assuntos
Fenda Labial/patologia , Fissura Palatina/patologia , Tomografia Computadorizada de Feixe Cônico/métodos , Hidrodinâmica , Laringe/anatomia & histologia , Nariz/anatomia & histologia , Tonsila Faríngea/anatomia & histologia , Pontos de Referência Anatômicos , Criança , Fenda Labial/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Epiglote/anatomia & histologia , Epiglote/diagnóstico por imagem , Feminino , Humanos , Osso Hioide/anatomia & histologia , Imageamento Tridimensional/métodos , Laringe/diagnóstico por imagem , Má Oclusão de Angle Classe I , Nasofaringe/anatomia & histologia , Nasofaringe/diagnóstico por imagem , Nariz/diagnóstico por imagem , Respiração , Apneia Obstrutiva do Sono
20.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340433

RESUMO

Lysyl oxidase like 3 (LOXL3) is a copper-dependent amine oxidase responsible for the crosslinking of collagen and elastin in the extracellular matrix. LOXL3 belongs to a family including other members: LOX, LOXL1, LOXL2, and LOXL4. Autosomal recessive mutations are rare and described in patients with Stickler syndrome, early-onset myopia and non-syndromic cleft palate. Along with an essential function in embryonic development, multiple biological functions have been attributed to LOXL3 in various pathologies related to amino oxidase activity. Additionally, various novel roles have been described for LOXL3, such as the oxidation of fibronectin in myotendinous junction formation, and of deacetylation and deacetylimination activities of STAT3 to control of inflammatory response. In tumors, three distinct roles were described: (1) LOXL3 interacts with SNAIL and contributes to proliferation and metastasis by inducing epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma cells; (2) LOXL3 is localized predominantly in the nucleus associated with invasion and poor gastric cancer prognosis; (3) LOXL3 interacts with proteins involved in DNA stability and mitosis completion, contributing to melanoma progression and sustained proliferation. Here we review the structure, function and activity of LOXL3 in normal and pathological conditions and discuss the potential of LOXL3 as a therapeutic target in various diseases.


Assuntos
Aminoácido Oxirredutases/genética , Artrite/genética , Fissura Palatina/genética , Doenças do Tecido Conjuntivo/genética , Matriz Extracelular/genética , Perda Auditiva Neurossensorial/genética , Miopia/genética , Neoplasias/genética , Descolamento Retiniano/genética , Aminoácido Oxirredutases/química , Aminoácido Oxirredutases/metabolismo , Artrite/enzimologia , Artrite/patologia , Fissura Palatina/enzimologia , Fissura Palatina/patologia , Colágeno/química , Colágeno/genética , Colágeno/metabolismo , Doenças do Tecido Conjuntivo/enzimologia , Doenças do Tecido Conjuntivo/patologia , Elastina/química , Elastina/genética , Elastina/metabolismo , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/química , Matriz Extracelular/enzimologia , Regulação da Expressão Gênica , Perda Auditiva Neurossensorial/enzimologia , Perda Auditiva Neurossensorial/patologia , Humanos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Miopia/enzimologia , Miopia/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Especificidade de Órgãos , Descolamento Retiniano/enzimologia , Descolamento Retiniano/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo
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