Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.914
Filtrar
1.
Nat Commun ; 11(1): 5114, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037205

RESUMO

Tissue growth in the adult is an orchestrated process that often requires biological clocks to time stem cell and progenitor activity. Here, we employed the hair follicle, which cycles between growth and regression in a timely-restricted mode, to show that some components of the hair cycle clock reside within the mesenchymal niche of the hair follicle, the dermal papilla (DP), and both Fgf and Wnt signaling pathways interact within the DP to regulate the expression of these components that include Wnt agonists (Rspondins) and antagonists (Dkk2 and Notum). The levels of Wnt agonists and antagonists in the DP are progressively reduced and elevated during the growth phase, respectively. Consequently, Wnt signaling activity in the overlying epithelial progenitor cells decreases, resulting in the induction of the regression phase. Remarkably, DP properties allow Wnt activity in the DP to persist despite the Wnt-inhibiting milieu and consequently synchronize the induction and progression of the regression phase. This study provides insight into the importance of signaling crosstalk in coupling progenitors and their niche to regulate tissue growth.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Folículo Piloso/citologia , Folículo Piloso/crescimento & desenvolvimento , Via de Sinalização Wnt/fisiologia , Animais , Esterases/genética , Esterases/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos Knockout , Camundongos Mutantes , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Pele/citologia , Trombospondinas/genética , Trombospondinas/metabolismo
3.
Nat Commun ; 11(1): 4673, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938917

RESUMO

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.


Assuntos
Proteínas de Ligação a DNA/genética , Haploinsuficiência , Sistema de Sinalização das MAP Quinases/genética , Síndrome de Noonan/etiologia , Fatores de Transcrição/genética , Proteínas ras/metabolismo , Anormalidades Múltiplas/genética , Animais , Deleção Cromossômica , Cromossomos Humanos Par 6 , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histonas/metabolismo , Humanos , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexo Correpressor Histona Desacetilase e Sin3/genética , Complexo Correpressor Histona Desacetilase e Sin3/metabolismo , Fatores de Transcrição/metabolismo , Proteínas ras/genética
4.
Nat Commun ; 11(1): 4653, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938923

RESUMO

Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.


Assuntos
Açúcares da Dieta/efeitos adversos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Neoplasias Experimentais/fisiopatologia , Prolina/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Animais Geneticamente Modificados , Carcinogênese , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Hemolinfa/efeitos dos fármacos , Hemolinfa/metabolismo , Larva , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Neoplasias Experimentais/etiologia , Proteínas Nucleares/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transativadores/genética , Proteínas ras/genética
5.
Anticancer Res ; 40(9): 5059-5069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878794

RESUMO

BACKGROUND/AIM: Liver cancer is the fourth leading cause of cancer-related mortality globally, of which hepatocellular carcinoma (HCC) accounts for 85-90% of total primary liver cancer. A drug shortage for HCC therapy triggered us to screen the small-molecule database with a high-throughput cellular screening system. Herein, we examined whether cetyltrimethylammonium bromide (CTAB) inhibits cellular mobility and invasiveness of Mahlavu HCC cells. MATERIALS AND METHODS: The effects of CTAB on cell viability were assessed using WST-1 assay, cell-cycle distribution using flow cytometric analysis, migration/invasion using woundhealing and transwell assays, and associated protein levels using western blotting. RESULTS: Treatment of Mahlavu cells with CTAB transformed its mesenchymal spindle-like morphology. In addition, CTAB exerted inhibitory effects on the migration and invasion of Mahlavu cells dose-dependently. CTAB also reduced the protein levels of matrix metalloproteinase-2 (MMP2), MMP9, RAC family small GTPase 1, SNAIL family transcriptional repressor 1 (SNAI1), SNAI2, TWIST family basic helix-loop-helix transcription factor 1 (TWIST1), vimentin, N-cadherin, phospho-fibroblast growth factor (FGF) receptor, phospho-phosphoinositide 3-kinase, phospho-v-Akt murine thymoma viral oncogene and phospho-signal transducer and activator of transcription 3 but increased the protein levels of tissue inhibitor of metalloproteinases-1/2 and E-cadherin. Rescue experiments proved that CTAB induced mesenchymal-epithelial transition in Mahlavu cells and this was significantly dose-dependently mitigated by basic FGF. CONCLUSION: CTAB suppressed the migration and invasion of Mahlavu cells through inhibition of the FGF signaling pathway. CTAB seems to be a potential agent for preventing metastasis of hepatic cancer.


Assuntos
Antineoplásicos/farmacologia , Cetrimônio/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Commun ; 11(1): 3612, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681035

RESUMO

Bile acid synthesis plays a key role in regulating whole body cholesterol homeostasis. Transcriptional factor EB (TFEB) is a nutrient and stress-sensing transcriptional factor that promotes lysosomal biogenesis. Here we report a role of TFEB in regulating hepatic bile acid synthesis. We show that TFEB induces cholesterol 7α-hydroxylase (CYP7A1) in human hepatocytes and mouse livers and prevents hepatic cholesterol accumulation and hypercholesterolemia in Western diet-fed mice. Furthermore, we find that cholesterol-induced lysosomal stress feed-forward activates TFEB via promoting TFEB nuclear translocation, while bile acid-induced fibroblast growth factor 19 (FGF19), acting via mTOR/ERK signaling and TFEB phosphorylation, feedback inhibits TFEB nuclear translocation in hepatocytes. Consistently, blocking intestinal bile acid uptake by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic TFEB nuclear localization and improves cholesterol homeostasis in Western diet-fed mice. This study has identified a TFEB-mediated gut-liver signaling axis that regulates hepatic cholesterol and bile acid homeostasis.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/antagonistas & inibidores , Linhagem Celular , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Células Hep G2 , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/prevenção & controle , Íleo/efeitos dos fármacos , Íleo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores
7.
PLoS One ; 15(7): e0235082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634148

RESUMO

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.


Assuntos
Densidade Óssea , Transplante de Rim , Minerais/metabolismo , Doadores de Tecidos , Adulto , Estudos de Casos e Controles , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/metabolismo , Fosfatos/metabolismo , Estudos Prospectivos , Fatores de Tempo
8.
PLoS One ; 15(6): e0235362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584895

RESUMO

OBJECTIVE: Cardiovascular disease is a leading cause of death worldwide. Obesity-related metabolic disorders including dyslipidemia cause impaired collateralization under ischemic conditions, thereby resulting in exacerbated cardiovascular dysfunction. Pemafibrate is a novel selective PPARα modulator, which has been reported to improve atherogenic dyslipidemia, in particular, hypertriglyceridemia and low HDL-cholesterol. Here, we investigated whether pemafibrate modulates the revascularization process in a mouse model of hindlimb ischemia. METHODS AND RESULTS: Male wild-type (WT) mice were randomly assigned to two groups, normal diet or pemafibrate admixture diet from the ages of 6 weeks. After 4 weeks, mice were subjected to unilateral hindlimb surgery to remove the left femoral artery and vein. Pemafibrate treatment enhanced blood flow recovery and capillary formation in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of endothelial nitric oxide synthase (eNOS). Treatment of cultured endothelial cells with pemafibrate resulted in increased network formation and migratory activity, which were blocked by pretreatment with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Pemafibrate treatment also increased plasma levels of the PPARα-regulated gene, fibroblast growth factor (FGF) 21 in WT mice. Systemic administration of adenoviral vectors expressing FGF21 (Ad-FGF21) to WT mice enhanced blood flow recovery, capillary density and eNOS phosphorylation in ischemic limbs. Treatment of cultured endothelial cells with FGF21 protein led to increases in endothelial cell network formation and migration, which were canceled by pretreatment with L-NAME. Furthermore, administration of pemafibrate or Ad-FGF21 had no effects on blood flow in ischemic limbs in eNOS-deficient mice. CONCLUSION: These data suggest that pemafibrate can promote revascularization in response to ischemia, at least in part, through direct and FGF21-mediated modulation of endothelial cell function. Thus, pemafibrate could be a potentially beneficial drug for ischemic vascular disease.


Assuntos
Benzoxazóis/farmacologia , Butiratos/farmacologia , Isquemia/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , PPAR alfa/química , PPAR alfa/metabolismo , Fosforilação/efeitos dos fármacos
9.
Nat Commun ; 11(1): 2894, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518324

RESUMO

Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.


Assuntos
Aminoácidos Essenciais/deficiência , Ração Animal , Proteinúria/metabolismo , Animais , Proteínas na Dieta/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônios Gastrointestinais/metabolismo , Hepatócitos/metabolismo , Homeostase , Fígado/metabolismo , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Fenótipo , Treonina/deficiência , Triptofano/deficiência
10.
Nat Commun ; 11(1): 2796, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493965

RESUMO

Cell fate decisions involved in vascular and hematopoietic embryonic development are still poorly understood. An ETS transcription factor Etv2 functions as an evolutionarily conserved master regulator of vasculogenesis. Here we report a single-cell transcriptomic analysis of hematovascular development in wild-type and etv2 mutant zebrafish embryos. Distinct transcriptional signatures of different types of hematopoietic and vascular progenitors are identified using an etv2ci32Gt gene trap line, in which the Gal4 transcriptional activator is integrated into the etv2 gene locus. We observe a cell population with a skeletal muscle signature in etv2-deficient embryos. We demonstrate that multiple etv2ci32Gt; UAS:GFP cells differentiate as skeletal muscle cells instead of contributing to vasculature in etv2-deficient embryos. Wnt and FGF signaling promote the differentiation of these putative multipotent etv2 progenitor cells into skeletal muscle cells. We conclude that etv2 actively represses muscle differentiation in vascular progenitors, thus restricting these cells to a vascular endothelial fate.


Assuntos
Vasos Sanguíneos/citologia , Perfilação da Expressão Gênica , Músculo Esquelético/citologia , Análise de Célula Única , Células-Tronco/metabolismo , Proteínas de Peixe-Zebra/deficiência , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Biomarcadores/metabolismo , Diferenciação Celular/genética , Movimento Celular , Embrião não Mamífero/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Resposta ao Choque Térmico , Modelos Biológicos , Mutação/genética , Somitos/metabolismo , Transcrição Genética , Via de Sinalização Wnt , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
11.
J Nutr ; 150(8): 2101-2111, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470979

RESUMO

BACKGROUND: Dietary polyphenols including anthocyanins target multiple organs. OBJECTIVE: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G). METHODS: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2). RESULTS: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and ß-klotho (>3-fold, P < 0.05). CONCLUSIONS: Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.


Assuntos
Antocianinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Fatores de Crescimento de Fibroblastos/metabolismo , Intolerância à Glucose , Glucosídeos/farmacologia , Ganho de Peso/efeitos dos fármacos , Animais , Gorduras na Dieta/efeitos adversos , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Incretinas/genética , Incretinas/metabolismo , Leptina/metabolismo , Fígado , Masculino , Camundongos , Distribuição Aleatória , Perda de Peso/efeitos dos fármacos
12.
J Nutr ; 150(8): 2070-2076, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470983

RESUMO

BACKGROUND: Dietary supplemental nicotinamide is used to treat hyperphosphatemia in humans. However, the mechanisms of its impact on body phosphorus homeostasis remain unclear. OBJECTIVE: This study was to determine effects and molecular mechanisms of 3 dietary nicotinamide concentrations on body phosphorus homeostasis in laying hens. METHODS: Hy-Line Brown layers (total = 21; 40 wk old; body weight: 1,876 ± 24 g) were individually housed (n = 7) and fed a corn-soybean meal-based diet supplemented with nicotinamide at 20 (N20), 140 (N140), and 1000 (N1000) mg/kg for 21 d. Serum phosphorus and fibroblast growth factor 23 (FGF23) concentrations, phosphorus and calcium excretion, and mRNA and/or protein of type II sodium-phosphate co-transporters (NPt2a, NPt2ab) and FGF23 and FGF23 receptors were measured in the intestines, calvaria, kidney, and liver. RESULTS: Hens in the N1000 group had a 16% lower serum phosphorus concentration and 22% greater phosphorus excretion than those in the N20 or N140 group (P ≤ 0.05). Compared with hens in the N20 group, hens in the N140 and N1000 groups, which did not differ, had 15-21% lower serum FGF23 concentrations, 19-22% greater calcium excretion, 43-56% lower ileum NPT2b protein production, and 1.5- to 1.6-fold greater kidney NPT2a protein production, respectively (all differences at P ≤ 0.05). CONCLUSIONS: Supplementing high concentrations of nicotinamide in diets for laying hens led to accelerated phosphorus and calcium excretions and decreased serum phosphorus and FGF23 concentrations, which were associated with downregulated intestinal NPt2b protein production. Our findings exclude kidney NPt2a protein production as a primary mechanism for the nicotinamide-induced body phosphorus loss.


Assuntos
Galinhas , Regulação da Expressão Gênica/efeitos dos fármacos , Niacinamida/farmacologia , Fósforo/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/metabolismo , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/genética , Glucuronidase/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Rim/efeitos dos fármacos , Rim/metabolismo , Niacinamida/administração & dosagem , Oviposição , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo II/genética
13.
PLoS One ; 15(5): e0233030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413083

RESUMO

During mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterized by the expression of the transcription factors NANOG and GATA6, respectively. Here, we investigate the spatio-temporal distribution of NANOG and GATA6 expressing cells in the ICM of the mouse blastocysts with quantitative three-dimensional single cell-based neighbourhood analyses. We define the cell neighbourhood by local features, which include the expression levels of both fate markers expressed in each cell and its neighbours, and the number of neighbouring cells. We further include the position of a cell relative to the centre of the ICM as a global positional feature. Our analyses reveal a local three-dimensional pattern that is already present in early blastocysts: 1) Cells expressing the highest NANOG levels are surrounded by approximately nine neighbours, while 2) cells expressing GATA6 cluster according to their GATA6 levels. This local pattern evolves into a global pattern in the ICM that starts to emerge in mid blastocysts. We show that FGF/MAPK signalling is involved in the three-dimensional distribution of the cells and, using a mutant background, we further show that the GATA6 neighbourhood is regulated by NANOG. Our quantitative study suggests that the three-dimensional cell neighbourhood plays a role in Epi and PrE precursor specification. Our results highlight the importance of analysing the three-dimensional cell neighbourhood while investigating cell fate decisions during early mouse embryonic development.


Assuntos
Blastocisto/citologia , Animais , Biomarcadores/metabolismo , Blastocisto/metabolismo , Massa Celular Interna do Blastocisto/citologia , Massa Celular Interna do Blastocisto/metabolismo , Diferenciação Celular/fisiologia , Linhagem da Célula , Microambiente Celular , Simulação por Computador , Desenvolvimento Embrionário , Endoderma/citologia , Endoderma/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Fator de Transcrição GATA6/metabolismo , Camadas Germinativas/citologia , Camadas Germinativas/metabolismo , Imageamento Tridimensional , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Knockout , Modelos Biológicos , Proteína Homeobox Nanog/deficiência , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Gravidez
14.
Proc Natl Acad Sci U S A ; 117(21): 11444-11449, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32381735

RESUMO

Morphogenetic flows in developmental biology are characterized by the coordinated motion of thousands of cells that organize into tissues, naturally raising the question of how this collective organization arises. Using only the kinematics of tissue deformation, which naturally integrates local and global mechanisms along cell paths, we identify the dynamic morphoskeletons behind morphogenesis, i.e., the evolving centerpieces of multicellular trajectory patterns. These features are model- and parameter-free, frame-invariant, and robust to measurement errors and can be computed from unfiltered cell-velocity data. We reveal the spatial attractors and repellers of the embryo by quantifying its Lagrangian deformation, information that is inaccessible to simple trajectory inspection or Eulerian methods that are local and typically frame-dependent. Computing these dynamic morphoskeletons in wild-type and mutant chick and fly embryos, we find that they capture the early footprint of known morphogenetic features, reveal new ones, and quantitatively distinguish between different phenotypes.


Assuntos
Embrião de Galinha/citologia , Embrião de Galinha/crescimento & desenvolvimento , Drosophila melanogaster/embriologia , Modelos Biológicos , Animais , Animais Geneticamente Modificados , Fenômenos Biomecânicos , Embrião de Galinha/efeitos dos fármacos , Simulação por Computador , Proteínas de Drosophila/genética , Embrião não Mamífero/citologia , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/metabolismo , Gástrula/crescimento & desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Indazóis/farmacologia , Microscopia/métodos , Morfogênese , Mutação , Proteína 1 Relacionada a Twist/genética
15.
Lab Invest ; 100(9): 1158-1168, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32404932

RESUMO

Alcoholic fatty liver disease (AFLD) is one of the major causes of liver morbidity and mortality worldwide. We have previously shown that whole-body, but not hepatocyte-specific, deficiency of farnesoid X receptor (FXR) in mice worsens AFLD, suggesting that extrahepatic FXR deficiency is critical for AFLD development. Intestinal FXR is critical in suppressing hepatic bile acid (BA) synthesis by inducing fibroblast growth factor 15 (FGF15) in mice and FGF19 in humans. We hypothesized that intestinal FXR is critical for reducing AFLD development in mice. To test this hypothesis, we compared the AFLD severity in wild type (WT) and intestine-specific Fxr knockout (FXRInt-/-) mice following treatment with control or ethanol-containing diet. We found that FXRInt-/- mice were more susceptible to ethanol-induced liver steatosis and inflammation, compared with WT mice. Ethanol treatment altered the expression of hepatic genes involved in lipid and BA homeostasis, and ethanol detoxification. Gut FXR deficiency increased intestinal permeability, likely due to reduced mucosal integrity, as revealed by decreased secretion of Mucin 2 protein and lower levels of E-cadherin protein. In summary, intestinal FXR may protect AFLD development by maintaining gut integrity.


Assuntos
Etanol/farmacologia , Mucosa Intestinal/metabolismo , Hepatopatias Alcoólicas/genética , Receptores Citoplasmáticos e Nucleares/genética , Animais , Ácidos e Sais Biliares , Etanol/administração & dosagem , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Citoplasmáticos e Nucleares/deficiência
16.
Sheng Li Xue Bao ; 72(2): 175-180, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32328611

RESUMO

The present study was aimed to clarify the signaling molecular mechanism by which fibroblast growth factor 21 (FGF21) regulates leptin gene expression in adipocytes. Differentiated 3T3-F442A adipocytes were used as study object. The mRNA expression level of leptin was detected by fluorescence quantitative RT-PCR. The phosphorylation levels of proteins of signal transduction pathways were detected by Western blot. The results showed that FGF21 significantly down-regulated the mRNA expression level of leptin in adipocytes, and FGF21 receptor inhibitor BGJ-398 could completely block this effect. FGF21 up-regulated the phosphorylation levels of ERK1/2 and AMPK in adipocytes. Either ERK1/2 inhibitor SCH772984 or AMPK inhibitor Compound C could partially block the inhibitory effect of FGF21, and the combined application of these two inhibitors completely blocked the effect of FGF21. Neither PI3K inhibitor LY294002 nor Akt inhibitor AZD5363 affected the inhibitory effect of FGF21 on leptin gene expression. These results suggest that FGF21 may inhibit leptin gene expression by activating ERK1/2 and AMPK signaling pathways in adipocytes.


Assuntos
Adipócitos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Leptina/metabolismo , Células 3T3 , Adenilato Quinase , Animais , Regulação para Baixo , Sistema de Sinalização das MAP Quinases , Camundongos , Fosforilação , Transdução de Sinais
17.
Int J Sports Med ; 41(7): 427-442, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32252102

RESUMO

Exercise is commonly utilized for weight loss, yet research has focused less on specific modifications to adipose tissue metabolism. White adipose tissue (WAT) is the storage form of fat, whereas brown adipose tissue (BAT) is a thermogenic tissue whose uncoupling increases energy expenditure. The most established BAT activator is cold exposure, which also transforms WAT into "beige cells" that express uncoupling protein 1 (UCP1). Preliminary evidence in rodents suggests exercise elicits similar effects. The purpose of this review is to parallel and examine differences between exercise and cold exposure on BAT activation and beige induction. Like cold exposure, exercise stimulates the sympathetic nervous system and activates molecular pathways responsible for BAT/beige activation, including upregulation of BAT activation markers (UCP1, proliferator-activated receptor-gamma coactivator-1α) and stimulation of endocrine activators (fibroblast growth factor-21, irisin, and natriuretic peptides). Further, certain BAT activators are altered exclusively by exercise (interleukin-6, lactate). Markers of BAT activation increase from both cold exposure and exercise, whereas effects in WAT are compartment-specific. Stimulation of endocrine activators depends on numerous factors, including stimulus intensity and duration. Evidence of these analogous, albeit not mirrored, mechanisms is demonstrated by increases in adipose activity in rodents, while effects remain challenging to quantify in humans.


Assuntos
Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Exercício Físico/fisiologia , Termogênese , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Fator Natriurético Atrial/metabolismo , Biomarcadores/metabolismo , Metabolismo Energético , Fatores de Crescimento de Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Peptídeo Natriurético Encefálico/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteína Desacopladora 1/metabolismo
18.
Obesity (Silver Spring) ; 28(6): 1075-1085, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32348021

RESUMO

OBJECTIVE: Identifying novel approaches to combat obesity is important to improve health span. It was hypothesized that methionine restriction (MR) will induce weight loss in obese mice by reducing adipose tissue mass caused by increased energy expenditure and reprogramming of adipose tissue homeostasis. The roles of adiponectin (ADIPOQ) and fibroblast growth factor 21 (FGF21) during weight loss in MR mice were also tested. METHODS: Diet-induced obese (DIO) male C57BL/6J (wild type), Adipoq-deficient (Adipoq knockout [KO]), Fgf21-KO, and Adipoq-Fgf21 double-KO mice were used. Following a switch to high-fat control (DIO-CF, 60% fat/0.86% methionine) or MR (DIO-MR, 60% fat/0.12% methionine) diet, physiological parameters were measured, and inguinal and perigonadal adipose tissues were examined. RESULTS: Obese mice subjected to MR showed loss of body weight and adiposity, increased energy expenditure, and improved glucose tolerance that were independent of the actions of ADIPOQ and FGF21. MR induced reduction of circulating lipids, glucose, insulin, leptin, and insulin like growth factor 1 and increased ß-hydroxybutyrate, ADIPOQ, and FGF21 concentrations. In fat, MR upregulated protein levels of adipose triglyceride lipase, apoptosis-inducing factor, lysosomal-associated membrane proteins 1 and 2, autophagy-related protein 5, beclin-1, and light chain 3B I and II. CONCLUSIONS: MR reduction of adipose tissue mass in obese mice is associated with elevated lipolysis, apoptosis, and autophagy and occurs independently of the actions of ADIPOQ and FGF21.


Assuntos
Adiponectina/metabolismo , Adiposidade/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Metionina/metabolismo , Camundongos Obesos/genética , Perda de Peso/fisiologia , Animais , Masculino , Camundongos
19.
PLoS One ; 15(4): e0231905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32315372

RESUMO

Myocardial fibrosis is often associated with cardiac hypertrophy; indeed, fibrosis is one of the most critical factors affecting prognosis. We aimed to identify the molecules involved in promoting fibrosis under hypertrophic stimuli. We previously established a rat model of cardiac hypertrophy by pulmonary artery banding, in which approximately half of the animals developed fibrosis in the right ventricle. Here, we first comprehensively analyzed mRNA expression in the right ventricle with or without fibrosis in pulmonary artery banding model rats by DNA microarray analysis (GSE141650 at NCBI GEO). The expression levels of 19 genes were up-regulated more than 1.5-fold in fibrotic hearts compared with non-fibrotic hearts. Among them, fibrosis growth factor (FGF) 23 showed one of the biggest increases in expression. Real-time PCR analysis also revealed that, among the FGF receptor (FGFR) family, FGFR1 was highly expressed in fibrotic hearts. We then found that FGF23 was expressed predominantly in cardiomyocytes, while FGFR1 was predominantly expressed in fibroblasts in the rat ventricle. Next, we added FGF23 and transforming growth factor (TGF)-ß1 (10-50 ng/mL of each) to isolated fibroblasts from normal adult rat ventricles and cultured them for three days. While FGF23 itself did not directly affect the expression levels of any fibrosis-related mRNAs, FGF23 enhanced the effect of TGF-ß1 on increasing the expression levels of α-smooth muscle actin (α-SMA) mRNA. This increase in xx-SMA mRNA levels due to the combination of TGF-ß1 and FGF23 was attenuated by the inhibition of FGFR1 or the knockdown of FGFR1 in fibroblasts. Thus, FGF23 synergistically promoted the activation of fibroblasts with TGF-ß1, transforming fibroblasts into myofibroblasts via FGFR1. Thus, we identified FGF23 as a paracrine factor secreted from cardiomyocytes to promote cardiac fibrosis under conditions in which TGF-ß1 is activated. FGF23 could be a possible target to prevent fibrosis following myocardial hypertrophy.


Assuntos
Fatores de Crescimento de Fibroblastos/farmacologia , Cardiopatias/patologia , Fator de Crescimento Transformador beta1/farmacologia , Regulação para Cima/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibrose , Cardiopatias/metabolismo , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo
20.
PLoS Genet ; 16(4): e1008731, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32302304

RESUMO

The number of adult myofibers in Drosophila is determined by the number of founder myoblasts selected from a myoblast pool, a process governed by fibroblast growth factor (FGF) signaling. Here, we show that loss of cabeza (caz) function results in a reduced number of adult founder myoblasts, leading to a reduced number and misorientation of adult dorsal abdominal muscles. Genetic experiments revealed that loss of caz function in both adult myoblasts and neurons contributes to caz mutant muscle phenotypes. Selective overexpression of the FGF receptor Htl or the FGF receptor-specific signaling molecule Stumps in adult myoblasts partially rescued caz mutant muscle phenotypes, and Stumps levels were reduced in caz mutant founder myoblasts, indicating FGF pathway deregulation. In both adult myoblasts and neurons, caz mutant muscle phenotypes were mediated by increased expression levels of Xrp1, a DNA-binding protein involved in gene expression regulation. Xrp1-induced phenotypes were dependent on the DNA-binding capacity of its AT-hook motif, and increased Xrp1 levels in founder myoblasts reduced Stumps expression. Thus, control of Xrp1 expression by Caz is required for regulation of Stumps expression in founder myoblasts, resulting in correct founder myoblast selection.


Assuntos
Proteínas de Drosophila/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Mioblastos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fator de Transcrição TFIID/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila , Proteínas de Drosophila/genética , Desenvolvimento Muscular , Mioblastos/citologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas de Ligação a RNA/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fator de Transcrição TFIID/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA