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1.
J Craniofac Surg ; 30(7): 2082-2084, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31574782

RESUMO

BACKGROUND: To evaluate whether genetic polymorphisms in FGF3, FGF10, and FGF13 are associated with temporomandibular disorders (TMD) in patients that presented dentofacial deformities requiring orthognathic surgery. MATERIAL AND METHODS: The sample comprised a total of 113 patients of both sexes. The diagnosis of TMD was performed before orthognathic surgery between Research Diagnostic Criteria for Temporomandibular Disorders (RDC-TMD). According to the TMD assessment, the patients were divided into 3 major groups: myofascial pain, articular disc displacements and other TMD conditions (arthralgia, arthritis, and arthrosis). Genomic DNA was collected from saliva samples and genetic polymorphisms in FGF3 (rs1893047 and rs7932320), FGF10 (rs900379) and FGF13 (rs5931572 and rs5974804) were analyzed by real-time polymerase chain reactions. The association between the TMD conditions and the genetic polymorphisms assessed were analyzed by Poisson Regression. The model was calculated on bivariate and adjusted by sex. The established alpha was 5%. Data were analyzed by using SPSS software (IBM, Armonk, NY). RESULTS: The genetic polymorphisms rs7932320 in FGF3 (P < 0.001) and rs900379 in FGF10 (P < 0.05) were associated with the presence of muscle disorder. The genetic polymorphisms rs1893047 in FGF3, rs900379 in FGF10, and rs5974804 and rs5931572 in FGF13, were associated with the presence of disk displacement (P < 0.05). The genetic polymorphisms rs1893047 and rs7932320 in FGF3, rs900379 in FGF10, and rs900379 in FGF10 were associated with other TMD conditions (P < 0.05). CONCLUSION: Genetic polymorphisms in FGF3, FGF10, and FGF13 genes were associated with temporomandibular disorders in a population with dentofacial deformities.


Assuntos
Fator 10 de Crescimento de Fibroblastos/genética , Fator 3 de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/genética , Polimorfismo Genético , Transtornos da Articulação Temporomandibular/genética , Adolescente , Adulto , Artralgia , Artrite , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cirurgia Ortognática , Procedimentos Cirúrgicos Ortognáticos , Osteoartrite/diagnóstico , Inquéritos e Questionários , Transtornos da Articulação Temporomandibular/diagnóstico , Transtornos da Articulação Temporomandibular/cirurgia , Adulto Jovem
2.
Pediatr Endocrinol Rev ; 17(1): 17-34, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31599133

RESUMO

Fibroblast growth factor 23 (FGF23), one of the endocrine fibroblast growth factors, is a principal regulator in the maintenance of serum phosphorus concentration. Binding to its cofactor αKlotho and a fibroblast growth factor receptor is essential for its activity. Its regulation and interaction with other factors in the bone-parathyroid-kidney axis is complex. FGF23 reduces serum phosphorus concentration through decreased reabsorption of phosphorus in the kidney and by decreasing 1,25 dihydroxyvitamin D (1,25(OH)2D) concentrations. Various FGF23-mediated disorders of renal phosphate wasting share similar clinical and biochemical features. The most common of these is X-linked hypophosphatemia (XLH). Additional disorders of FGF23 excess include autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia. Treatment is challenging, requiring careful monitoring and titration of dosages to optimize effectiveness and to balance side effects. Conventional therapy for XLH and other disorders of FGF23-mediated hypophosphatemia involves multiple daily doses of oral phosphate salts and active vitamin D analogs, such as calcitriol or alfacalcidol. Additional treatments may be used to help address side effects of conventional therapy such as thiazides to address hypercalciuria or nephrocalcinosis, and calcimimetics to manage hyperparathyroidism. The recent development and approval of an anti-FGF23 antibody, burosumab, for use in XLH provides a novel treatment option.


Assuntos
Fatores de Crescimento de Fibroblastos , Hipofosfatemia/terapia , Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Raquitismo Hipofosfatêmico Familiar/terapia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Hipofosfatemia/fisiopatologia , Osteomalacia/fisiopatologia , Osteomalacia/terapia , Fosfatos/metabolismo , Fosfatos/uso terapêutico
3.
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
4.
Cell Mol Life Sci ; 76(23): 4705-4724, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31350618

RESUMO

Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23-αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Nefropatias/patologia , Animais , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/química , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Nefropatias/metabolismo , Domínios Proteicos , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais
5.
Nat Cell Biol ; 21(6): 674-686, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160712

RESUMO

In vertebrates, multipotent progenitors located in the pharyngeal mesoderm form cardiomyocytes and branchiomeric head muscles, but the dynamic gene expression programmes and mechanisms underlying cardiopharyngeal multipotency and heart versus head muscle fate choices remain elusive. Here, we used single-cell genomics in the simple chordate model Ciona to reconstruct developmental trajectories forming first and second heart lineages and pharyngeal muscle precursors and characterize the molecular underpinnings of cardiopharyngeal fate choices. We show that FGF-MAPK signalling maintains multipotency and promotes the pharyngeal muscle fate, whereas signal termination permits the deployment of a pan-cardiac programme, shared by the first and second heart lineages, to define heart identity. In the second heart lineage, a Tbx1/10-Dach pathway actively suppresses the first heart lineage programme, conditioning later cell diversity in the beating heart. Finally, cross-species comparisons between Ciona and the mouse evoke the deep evolutionary origins of cardiopharyngeal networks in chordates.


Assuntos
Ciona intestinalis/genética , Coração/crescimento & desenvolvimento , Músculos Faríngeos/crescimento & desenvolvimento , Proteínas com Domínio T/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Ciona intestinalis/crescimento & desenvolvimento , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Genômica , Mesoderma/crescimento & desenvolvimento , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genética
6.
Chem Biol Interact ; 309: 108705, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31199929

RESUMO

MicroRNAs have emerged as critical mediators of cerebral ischaemia/reperfusion injury. Recent studies have demonstrated that microRNA-302b-3p (miR-302b-3p) plays an important role in regulating apoptosis and oxidative stress in various cells. However, whether miR-302b-3p is involved in regulating cerebral ischaemia/reperfusion injury-induced neuronal apoptosis and oxidative stress remains unknown. In the present study, we explored the potential function and molecular mechanism of miR-302b-3p in oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal injury, using an in vitro model of cerebral ischaemia/reperfusion injury. We found that miR-302b-3p expression was up-regulated by OGD/R treatment in neurons. The inhibition of miR-302b-3p improved cell viability, and reduced apoptosis and the production of reactive oxygen species, showing a protective effect against OGD/R-induced injury. Interestingly, miR-302b-3p was shown to target and modulate murine fibroblast growth factor 15 (FGF15). Moreover, our results showed that miR-302b-3p down-regulation contributed to the promotion of nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE)-mediated antioxidant signaling associated with the inactivation of glycogen synthase kinase-3ß. However, the knockdown of FGF15 significantly reversed the miR-302b-3p inhibition-mediated protective effect in OGD/R-treated neurons. Overall, these results demonstrated that miR-302b-3p inhibition confers a neuroprotective effect in OGD/R-treated neurons by up-regulating Nrf2/ARE antioxidant signaling via targeting FGF15, providing a novel target for neuroprotection in cerebral ischaemia/reperfusion injury.


Assuntos
Hipóxia Celular , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Elementos de Resposta Antioxidante/genética , Linhagem Celular , Sobrevivência Celular , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/genética , Glucose/deficiência , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neurônios/citologia , Neurônios/metabolismo , Neuroproteção , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Regulação para Cima
7.
Cell Mol Life Sci ; 76(20): 3939-3952, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31201464

RESUMO

Articular cartilage is formed at the end of epiphyses in the synovial joint cavity and permanently contributes to the smooth movement of synovial joints. Most skeletal elements develop from transient cartilage by a biological process known as endochondral ossification. Accumulating evidence indicates that articular and growth plate cartilage are derived from different cell sources and that different molecules and signaling pathways regulate these two kinds of cartilage. As the first sign of joint development, the interzone emerges at the presumptive joint site within a pre-cartilage tissue. After that, joint cavitation occurs in the center of the interzone, and the cells in the interzone and its surroundings gradually form articular cartilage and the synovial joint. During joint development, the interzone cells continuously migrate out to the epiphyseal cartilage and the surrounding cells influx into the joint region. These complicated phenomena are regulated by various molecules and signaling pathways, including GDF5, Wnt, IHH, PTHrP, BMP, TGF-ß, and FGF. Here, we summarize current literature and discuss the molecular mechanisms underlying joint formation and articular development.


Assuntos
Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Condrogênese/genética , Regulação da Expressão Gênica , Cápsula Articular/metabolismo , Via de Sinalização Wnt , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Cartilagem Articular/citologia , Cartilagem Articular/crescimento & desenvolvimento , Diferenciação Celular , Linhagem da Célula/genética , Movimento Celular , Condrócitos/citologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fator 5 de Diferenciação de Crescimento/genética , Fator 5 de Diferenciação de Crescimento/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Cápsula Articular/citologia , Cápsula Articular/crescimento & desenvolvimento , Osteogênese/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
8.
Nat Commun ; 10(1): 2479, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171783

RESUMO

The tauopathy-like phenotype observed in the rTg4510 mouse line, in which human tauP301L expression specifically within the forebrain can be temporally controlled, has largely been attributed to high overexpression of mutant human tau in the forebrain region. Unexpectedly, we found that in a different mouse line with a targeted-insertion of the same transgene driven by the same tetracycline-TransActivator (tTA) allele, but with even higher overexpression of tauP301L than rTg4510, atrophy and tau histopathology are delayed, and a different behavioral profile is observed. This suggests that it is not overexpression of mutant human tau alone that contributes to the phenotype in rTg4510 mice. Furthermore we show that the tauopathy-like phenotype seen in rTg4510 requires a ~70-copy tau-transgene insertion in a 244 kb deletion in Fgf14, a ~7-copy tTA-transgene insertion in a 508 kb deletion that disrupts another five genes, in addition to high transgene overexpression. We propose that these additional effects need to be accounted for in any studies using rTg4510.


Assuntos
Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Camundongos , Prosencéfalo/metabolismo , Agregação Patológica de Proteínas/genética , Tauopatias/genética , Proteínas tau/genética , Animais , Atrofia , Camundongos Transgênicos , Fenótipo , Prosencéfalo/patologia , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Tauopatias/metabolismo , Tauopatias/patologia
9.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31142002

RESUMO

Mesenchymal stem cells (MSCs) are emerging as a potential therapeutic intervention for brain injury due to their neuroprotective effects and safe profile. However, the homing ability of MSCs to injury sites still needs to be improved. Fibroblast Growth Factor 21 (FGF21) was recently reported to enhance cells migration in different cells type. In this study, we investigated whether MSCs that overexpressing FGF21 (MSC-FGF21) could exhibit enhanced homing efficacy in brain injury. We used novel Molday IONEverGreen™ (MIEG) as cell labeling probe that enables a non-invasive, high-sensitive and real-time MRI tracking. Using a mouse model of traumatic brain injury (TBI), MIEG labeled MSCs were transplanted into the contralateral lateral ventricle followed by real-time MRI tracking. FGF21 retained MSC abilities of proliferation and morphology. MSC-FGF21 showed significantly greater migration in transwell assay compared to control MSC. MIEG labeling showed no effects on MSCs' viability, proliferation and differentiation. Magnetic resonance imaging (MRI) revealed that FGF21 significantly enhances the homing of MSC toward injury site. Histological analysis further confirmed the MRI findings. Taken together, these results show that FGF21 overexpression and MIEG labeling of MSC enhances their homing abilities and enables non-invasive real time tracking of the transplanted cells, provides a promising approach for MSC based therapy and tracking in TBI.


Assuntos
Lesões Encefálicas Traumáticas/terapia , Movimento Celular , Fatores de Crescimento de Fibroblastos/genética , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Animais , Células Cultivadas , Fatores de Crescimento de Fibroblastos/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
10.
Pediatr Dent ; 41(2): 132-135, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30992111

RESUMO

Purpose: The purpose of this study was to determine if dental ages are more advanced in overweight children and influenced by genetic variation. Methods: Panoramic radiographs from 577 children were obtained. For performing genetic studies, an additional 236 subjects had panoramic radiographs and whole saliva samples collected. Genotyping of IGF, FGF, and FGFR markers was done. Dental age was determined in 177 patients utilizing Demerjian's method and panoramic radiographs. Skeletal maturation was determined in 28 patients using Baccetti's cervical vertebral maturation method on lateral cephalograms. PLINK was used to test for over-representation of alleles. Results: FGF7, FGF10, and FGF13 were significantly associated with obesity (P = 0.02). When dental age was considered, overweight and obese children are more likely to have dental ages more advanced than their chronological ages (P = 0.05). An excess of heterozygotes of FGF18 rs4073716 was found in children with dental age more advanced than their chronological age (P=0.04). Conclusions: Overweight and obese children have dental ages more advanced than their chronological ages, and this occurrence may be influenced by genetic variation in FGF18.


Assuntos
Determinação da Idade pelos Dentes , Variação Genética , Obesidade Pediátrica , Radiografia Panorâmica , Dente/crescimento & desenvolvimento , Determinação da Idade pelo Esqueleto , Índice de Massa Corporal , Vértebras Cervicais/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Fatores de Crescimento de Fibroblastos/genética , Marcadores Genéticos , Humanos , Masculino , Pennsylvania , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor IGF Tipo 2/genética
11.
FEBS Open Bio ; 9(4): 769-780, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984550

RESUMO

Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor superfamily. Here, we identified FGF11 as a novel mediator of adipogenesis. During 3T3-L1 adipocyte differentiation, the expression of FGF11 decreased at the mitotic clonal expansion stage and increased at the terminal differentiation stage. FGF11 knockdown reduced the expression of peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipogenesis, resulting in the inhibition of adipocyte differentiation. Treatment with the PPARγ agonist rosiglitazone restored the inhibition of adipogenesis caused by FGF11 knockdown. We also report that the expression of the PPARγ regulators CCAAT/enhancer-binding protein α, sterol regulatory element-binding protein 1, KLF9, KLF2, GATA binding factor 2, and GATA binding factor 3 was influenced by FGF11. These results suggest that FGF11 indirectly controls the expression of PPARγ through modifying the expression of multiple PPARγ regulators, thereby mediating adipogenesis.


Assuntos
Adipogenia/genética , Fatores de Crescimento de Fibroblastos/genética , PPAR gama/genética , Células 3T3-L1 , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Camundongos , PPAR gama/metabolismo
12.
In Vitro Cell Dev Biol Anim ; 55(5): 355-367, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30993557

RESUMO

N-terminal acetylation (Nt-acetylation) refers to the acetylation of the free α-amino group at the N-terminus of a polypeptide. While the effects of Nt-acetylation are multifaceted, its most known function is in the acetylation-dependent N-end rule protein degradation pathway (Ac/N-end rule pathway), where Nt-acetylation is recognized as a degron by designated E3 ligases, eventually leading to target degradation by the ubiquitin-proteasome system. Naa10 is the catalytic subunit of the major Nt-acetylation enzyme NatA, which Nt-acetylates proteins whose second amino acid has a small side chain. In humans, NAA10 is the responsible mutated gene in Ogden syndrome and is thought to play important roles in development. However, it is unclear how the Ac/N-end rule pathway affects the differentiation ability of mouse embryonic stem cells (mESCs). We hypothesized that the balance of pluripotency factors may be maintained by the Ac/N-end rule pathway. Thus, we established Naa10 knockout mESCs to test this hypothesis. We found that Naa10 deficiency attenuated differentiation towards the epiblast lineage, deviating towards primitive endoderm. However, this was not caused by disturbing the balance of pluripotency factors, rather by augmenting FGF/MAPK signaling.


Assuntos
Linhagem da Célula/genética , Camadas Germinativas/crescimento & desenvolvimento , Células-Tronco Embrionárias Murinas/metabolismo , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal E/genética , Acetilação , Animais , Diferenciação Celular/genética , Endoderma/crescimento & desenvolvimento , Endoderma/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Técnicas de Inativação de Genes , Camadas Germinativas/metabolismo , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/metabolismo , Processamento de Proteína Pós-Traducional/genética , Proteólise , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética
13.
Mol Genet Genomic Med ; 7(5): e640, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30968605

RESUMO

BACKGROUND: One of the major problems in wound healing is scar formation; however, there are few ways to prevent or treat it. Different species of Achillea are used to treat wounds in folk medicine from the past but there are few studies on the effect of it on wound healing and inhibition of scar formation. The aim of this study was to investigate the effect of Achillea biebersteinii Afan hydroethanolic extract on the expression of TGFß1 and bFGF as effective growth factors of wound healing in mouse embryonic fibroblast cells. METHODS: Mouse embryonic fibroblast cells were exposed to different concentrations of Achillea extract at two different time (12 and 24 hr); the expression of TGFß1 and bFGF was performed by real-time-PCR and ELISA at the level of gene and protein. RESULTS: It was observed that the plant extract at 5 and 10 µg/ml downregulated the expression of TGFß1 and upregulated the expression of bFGF at the level of gene and protein. CONCLUSION: The results showed that the pattern of changes in the expression of TGFß1 and bFGF by Achillea biebersteinni Afan extract may inhibit scar formation.


Assuntos
Achillea/química , Cicatriz/metabolismo , Fibroblastos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Camundongos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
14.
Inflamm Res ; 68(5): 351-358, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30863887

RESUMO

OBJECTIVE AND DESIGN: Hypothalamic inflammation is closely associated with metabolic dysregulation. Fibroblast growth factor 21 (FGF21) is known to be an important metabolic regulator with anti-inflammatory properties. In this study, we investigated the effects of FGF21 deficiency on obesity-induced hypothalamic inflammation and thermogenic responses. MATERIALS AND METHODS: FGF21-deficient mice and/or wild-type (WT) mice were fed a high-fat diet (HFD) for 12 weeks. RESULTS: FGF21-deficient mice fed an HFD showed increased levels of inflammatory cytokines compared with WT obese control, and this was accompanied by upregulation of gliosis markers in the hypothalamus. Expression of heat-shock protein 72, a marker of neuronal damage, was increased in the FGF21-deficient obese mice, and the expression of hypothalamic neuronal markers involved in anti-thermogenic or thermogenic responses was altered. Moreover, the protein level of uncoupling protein 1 and other thermogenic genes were markedly reduced in the brown adipose tissue of the FGF21-deficient obese mice. CONCLUSIONS: These findings suggest that FGF21 deficiency aggravates obesity-induced hypothalamic inflammation and neuronal injury, leading to alterations in hypothalamic neural circuits accompanied by a reduction of the thermogenic response.


Assuntos
Encéfalo/patologia , Fatores de Crescimento de Fibroblastos/deficiência , Inflamação/etiologia , Obesidade/complicações , Termogênese/genética , Tecido Adiposo Marrom/metabolismo , Animais , Atrofia/etiologia , Atrofia/patologia , Encéfalo/metabolismo , Citocinas/genética , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/genética , Proteínas de Choque Térmico HSP72/genética , Inflamação/genética , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/patologia , Obesidade/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
15.
Cardiovasc Pathol ; 40: 47-54, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30852297

RESUMO

OBJECTIVE: We aimed to elucidate the local role of FGF23 after myocardial infarction in a mouse model induced by left anterior descending artery (LAD) ligation. APPROACH AND RESULTS: (C57BL/6 N) mice underwent MI via LAD ligation and were sacrificed at different time-points post MI. The expression and influence of FGF23 on fibroblast and macrophages was also analyzed using isolated murine cells. We identified enhanced cardiac FGF23 mRNA expression in a time-dependent manner with an early increase, already on the first day after MI. FGF23 protein expression was abundantly detected in the infarcted area during the inflammatory phase. While described to be primarily produced in bone or macrophages, we identified cardiac fibroblasts as the only source of local FGF23 production after MI. Inflammatory mediators, such as IL-1ß, IL-6 and TNF-α, were able to induce FGF23 expression in these cardiac fibroblasts. Interestingly, we were not able to detect FGF23 at later time points after MI in mature scar tissue or remote myocardium, most likely due to TGF-ß1, which we have shown to inhibit the expression of FGF23. We identified FGFR1c to be the most abundant receptor for FGF23 in infarcted myocardium and cardiac macrophages and fibroblasts. FGF23 increased migration of cardiac fibroblast, as well as expression of Collagen 1, Periostin, Fibronectin and MMP8. FGF23 also increased expression of TGF-ß1 in M2 polarized macrophages. CONCLUSION: In conclusion, cardiac fibroblasts in the infarcted myocardium produce and express FGF23 as well as its respective receptors in a time-dependent manner, thus potentially influencing resident cell migration. The transitory local expression of FGF23 after MI points towards a complex role of FGF23 in myocardial ischemia and warrants further exploration, considering its role in ventricular remodeling.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Animais , Movimento Celular , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibronectinas/metabolismo , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
16.
J Mol Histol ; 50(3): 217-227, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30895425

RESUMO

Sjögren's syndrome or radiotherapy for head and neck cancer leads to the irreversible hypofunction of salivary gland (SG). The stem/progenitor cell-based regenerative strategy has been proven to be the most promising approach to repair the function of SG. The molecular mechanisms that regulate SG morphogenesis, especially during lumen formation, provide valuable hints for establishment of such regenerative strategies. It has been demonstrated that numerous growth factors particularly belonging to SHH, BMP, and FGF signaling pathway are involved in the regulation of lumen formation and have shown protective effects on the SG from irradiation in mouse models. However, it remains elusive whether the expression pattern and function of these signaling molecules are conserved in humans. In this study, we examined the expression patterns of the molecules critical for SHH, BMP, and FGF signaling cascades from the canalicular stage to the terminal bud stage, the key stages for lumen formation, in human SG and compared them with the expression data observed in mice. Our results manifested that genes involved in SHH signaling pathway showed identical expression patterns, while genes involved in BMP as well as FGF pathway exhibited similar but distinct expression patterns in humans to those in the mouse. We concluded that the expression patterns of genes involved in SHH, BMP, and FGF pathways in the development of human SG exhibit high similarity to that in the development of mouse SG during lumen formation, suggesting that the molecular mechanism regulating the morphogenesis of SG during lumen formation may be conserved in mice and humans. Our results will have an implication in the future establishment of stem-cell based approaches for the repair of SG function.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Proteínas Hedgehog/genética , Morfogênese/genética , Glândulas Salivares/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Hibridização In Situ , Camundongos , Glândulas Salivares/crescimento & desenvolvimento , Transdução de Sinais/genética , Células-Tronco/metabolismo
17.
Gene ; 702: 123-132, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-30926307

RESUMO

Fibroblast growth factor (FGF) 5 regulates the development and periodicity of hair follicles, which can affect hair traits. Loss-of-function mutations associated with long-hair phenotypes have been described in several mammalian species. Sheep is an important economic animal, however, the evolution characterizations and biological mechanism of oFGF5 (Ovis aries FGF5) gene are still poorly understood. In this study, oFGF5 gene was obtained by resequencing the whole genome of three Dorper sheep and RACE of two Kazakh sheep FGF5. We proposed FGF5 was phylogenetically related to FGF4 family and oFGF5 clearly orthologed to goat FGF5. Six loci were found from the positive selection results of FGF5 and half of them located on signal peptide. The basically similar rates of function-altering substitutions in sheep and goat lineage and the rest of the mammalian lineage of 365 SNPs indicated that the FGF5 gene was quite conservative during evolution. Homology modeling of the oFGF5 suggested that it has a highly conserved FGF superfamily domain containing 10 ß-strands. Furthermore, the protein-protein docking analysis revealed that oFGF5 have the potential to form heterodimers with oFGFR1, the predicted interaction interface of FGF5-FGFR1 heterodimer was formed mainly by residues from FGF superfamily domain. Our observations suggested the evolutionary and structural biology features of oFGF5 might be relevant to its function about hair follicle development and modulating hair growth, and we confirmed our speculation by using the FGF5 gene editing sheep produced by CRISPR/Cas9 technology.


Assuntos
Fator 5 de Crescimento de Fibroblastos/química , Fator 5 de Crescimento de Fibroblastos/genética , Ovinos/genética , Animais , Sistemas CRISPR-Cas , Biologia Computacional , Evolução Molecular , Fator 4 de Crescimento de Fibroblastos/classificação , Fator 5 de Crescimento de Fibroblastos/classificação , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/genética , Humanos , Camundongos , Modelos Moleculares , Mutação , Filogenia , Conformação Proteica em Folha beta , Multimerização Proteica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Alinhamento de Sequência , Ovinos/anatomia & histologia , Lã/anatomia & histologia
18.
J Agric Food Chem ; 67(13): 3691-3701, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30864445

RESUMO

Bile acids, synthesized in the liver and metabolized by microbiota, have emerged as important signaling molecules regulating immune responses and cell proliferation. However, the crosstalk among nutrition, microbiota, and bile acids remains unclear. Our study indicated that undernutrition in weaning piglets led to intestinal atrophy, increased colonic production, and systemic accumulation of lithocholic acid (LCA), deoxycholic acid (DCA), or their conjugated forms, which might be associated with decreased Lactobacillus abundance. Moreover, undernutrition led to increased portal fibroblast growth factor 19 ( FGF19) level, upregulated hepatic heterodimer partner ( SHP), and downregulated cholesterol 7a-hydroxylase ( CYP7A1) expression. The detrimental effects of DCA and LCA on proliferation and barrier function were confirmed in porcine enterocytes, whereas their roles in weaning piglets warrant further research. In summary, undernutrition in weaning piglets led to increased secondary bile acids production, which might be related to altered gut microbiome and enhanced farnesoid X receptor (FXR) signaling while CYP7A1 expression was suppressed.


Assuntos
Ácidos e Sais Biliares/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Desnutrição/veterinária , Receptores Citoplasmáticos e Nucleares/metabolismo , Doenças dos Suínos/metabolismo , Animais , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Intestinos/microbiologia , Masculino , Desnutrição/genética , Desnutrição/metabolismo , Desnutrição/microbiologia , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais , Suínos/genética , Suínos/metabolismo , Doenças dos Suínos/genética , Doenças dos Suínos/microbiologia , Doenças dos Suínos/fisiopatologia , Desmame
19.
BMC Genomics ; 20(1): 199, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30866796

RESUMO

BACKGROUND: Peroxisome Proliferator-Activated receptor α (PPARα) and cAMP-Responsive Element Binding Protein 3-Like 3 (CREB3L3) are transcription factors involved in the regulation of lipid metabolism in the liver. The aim of the present study was to characterize the interrelationship between PPARα and CREB3L3 in regulating hepatic gene expression. Male wild-type, PPARα-/-, CREB3L3-/- and combined PPARα/CREB3L3-/- mice were subjected to a 16-h fast or 4 days of ketogenic diet. Whole genome expression analysis was performed on liver samples. RESULTS: Under conditions of overnight fasting, the effects of PPARα ablation and CREB3L3 ablation on plasma triglyceride, plasma ß-hydroxybutyrate, and hepatic gene expression were largely disparate, and showed only limited interdependence. Gene and pathway analysis underscored the importance of CREB3L3 in regulating (apo)lipoprotein metabolism, and of PPARα as master regulator of intracellular lipid metabolism. A small number of genes, including Fgf21 and Mfsd2a, were under dual control of PPARα and CREB3L3. By contrast, a strong interaction between PPARα and CREB3L3 ablation was observed during ketogenic diet feeding. Specifically, the pronounced effects of CREB3L3 ablation on liver damage and hepatic gene expression during ketogenic diet were almost completely abolished by the simultaneous ablation of PPARα. Loss of CREB3L3 influenced PPARα signalling in two major ways. Firstly, it reduced expression of PPARα and its target genes involved in fatty acid oxidation and ketogenesis. In stark contrast, the hepatoproliferative function of PPARα was markedly activated by loss of CREB3L3. CONCLUSIONS: These data indicate that CREB3L3 ablation uncouples the hepatoproliferative and lipid metabolic effects of PPARα. Overall, except for the shared regulation of a very limited number of genes, the roles of PPARα and CREB3L3 in hepatic lipid metabolism are clearly distinct and are highly dependent on dietary status.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Perfilação da Expressão Gênica/métodos , Fígado/crescimento & desenvolvimento , PPAR alfa/genética , Ácido 3-Hidroxibutírico/sangue , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dieta Cetogênica , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Metabolismo dos Lipídeos , Fígado/química , Masculino , Camundongos , PPAR alfa/metabolismo , Transdução de Sinais , Triglicerídeos/sangue , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma
20.
Nat Commun ; 10(1): 1368, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911006

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as important components of gene regulatory network in embryonic stem cells (ESCs). However, the function and molecular mechanism of lncRNAs are still largely unknown. Here we identifies Trincr1 (TRIM71 interacting long noncoding RNA 1) lncRNA that regulates the FGF/ERK signaling and self-renewal of ESCs. Trincr1 is exported by THOC complex to cytoplasm where it binds and represses TRIM71, leading to the downregulation of SHCBP1 protein. Knocking out Trincr1 leads to the upregulation of phosphorylated ERK and ERK pathway target genes and the decrease of ESC self-renewal, while knocking down Trim71 completely rescues the defects of Trincr1 knockout. Furthermore, ectopic expression of Trincr1 represses FGF/ERK signaling and the self-renewal of neural progenitor cells (NPCs). Together, this study highlights lncRNA as an important player in cell signaling network to coordinate cell fate specification.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Células-Tronco Embrionárias Murinas/metabolismo , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Embrião de Mamíferos , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Sistema de Sinalização das MAP Quinases , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fosforilação , Ligação Proteica , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
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