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1.
Anticancer Res ; 40(10): 5621-5630, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988886

RESUMO

BACKGROUND: Targeted therapies in the treatment of head and neck squamous cell carcinoma (HNSCC) are subject to extensive research. Different mutations of genes belonging to the fibroblast growth factor (FGF) family have been detected in HNSCC. In this study, we examined the expression of FGF1 and FGF2 after treatment with small-molecule tyrosine kinase inhibitors (TKIs) and an inhibitor of mechanistic target of rapamycin (mTOR) in vitro using human papillomavirus (HPV)-positive and -negative SCC lines. MATERIALS AND METHODS: Cells of two human HPV-negative cell lines (UMSCC-11A/-14C) and one HPV-positive cell line (CERV196) were incubated with 20 µmol/l of erlotinib, gefitinib, nilotinib, dasatinib, or everolimus for 24-96 h. Cell proliferation was assessed by proliferation assay and the protein concentrations of FGF1 and FGF2 by sandwich enzyme-linked immunosorbent assay. For statistical analysis, the results were compared with those for untreated HPV-negative SCC cells. RESULTS: FGF1 and FGF2 were detected in all three tested cell lines. The tested TKIs significantly (p<0.05 reduced) FGF1 expression in the UMSCC-11A cell line within the first 24 h. At later time points, the tested TKIs and everolimus significantly (p<0.05) increased FGF1 and FGF2 expression in HPV-negative and -positive cancer cell lines. The effect was stronger in the HPV-positive cell line. CONCLUSION: Alterations in FGF signalling are considered to be relevant drivers of tumourigenesis in some HNSCCs. Our results show that the expression of FGF1 and -2 can be influenced effectively by small-molecule TKIs and everolimus. Based on our data, future research should include combinations of specific FGF inhibitors, mTOR inhibitors and other TKIs in the treatment of HNSCC and research on FGF-mediated drug escape mechanisms.


Assuntos
Everolimo/farmacologia , Fatores de Crescimento de Fibroblastos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Serina-Treonina Quinases TOR/genética , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Cloridrato de Erlotinib/farmacologia , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Gefitinibe/farmacologia , Papillomavirus Humano 16/efeitos dos fármacos , Papillomavirus Humano 16/patogenicidade , Humanos , Papillomaviridae/efeitos dos fármacos , Papillomaviridae/patogenicidade , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
2.
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
3.
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
4.
Proc Natl Acad Sci U S A ; 117(27): 15712-15723, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32561646

RESUMO

The mechanisms used by embryos to pattern tissues across their axes has fascinated developmental biologists since the founding of embryology. Here, using single-cell technology, we interrogate complex patterning defects and define a Hedgehog (Hh)-fibroblast growth factor (FGF) signaling axis required for anterior mesoderm lineage development during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations, culminating in defects to anterior embryonic structures, including the pharyngeal arches, heart, and anterior somites. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and FGF signaling for mesoderm migration. Mesoderm-specific Fgf4/Fgf8 double-mutants recapitulated anterior mesoderm defects and Hh-dependent GLI transcription factors modulated enhancers at FGF gene loci. Cellular migration defects during gastrulation induced by Hh pathway antagonism were mitigated by the addition of FGF4 protein. These findings implicate a multicomponent signaling hierarchy activated by Hh ligands from the embryonic node and executed by FGF signals in nascent mesoderm to control anterior mesoderm patterning.


Assuntos
Fator 4 de Crescimento de Fibroblastos/genética , Fator 8 de Crescimento de Fibroblasto/genética , Gastrulação/genética , Proteína GLI1 em Dedos de Zinco/genética , Animais , Padronização Corporal/genética , Linhagem da Célula/genética , Embrião de Galinha , Fatores de Crescimento de Fibroblastos/genética , Gástrula/crescimento & desenvolvimento , Gástrula/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Hedgehog/genética , Mesoderma/crescimento & desenvolvimento , Mesoderma/metabolismo , Camundongos , Transdução de Sinais/genética , Análise de Célula Única , Transcriptoma/genética
5.
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
6.
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
7.
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
8.
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
9.
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
11.
Horm Metab Res ; 52(3): 194-201, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32215890

RESUMO

Derangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=-0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in ßTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/sangue , Talassemia beta/sangue , Adolescente , Adulto , Feminino , Ferritinas/sangue , Fatores de Crescimento de Fibroblastos/genética , Humanos , Ferro/sangue , Quelantes de Ferro/administração & dosagem , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Talassemia beta/tratamento farmacológico
12.
Lancet Oncol ; 21(5): 671-684, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203698

RESUMO

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.


Assuntos
Colangiocarcinoma/tratamento farmacológico , Morfolinas/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Proteínas de Fusão Oncogênica/genética , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Receptores de Fatores de Crescimento de Fibroblastos/genética
13.
Sci Rep ; 10(1): 5133, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198380

RESUMO

The therapeutic effects of C16, which is an inhibitor of RNA-dependent protein kinase (PKR), on growth of hepatocellular carcinoma (HCC) cells and tumor progression in vitro and in vivo were evaluated. Huh7 cells, a human HCC cell line, were used. The effects of C16 on cell viability were evaluated with the MTT assay, and real-time RT-PCR was performed. Huh7 cells were grafted into immunodeficient mice, and the in vivo effects of C16 on tumorigenesis were examined. C16 suppressed proliferation of HCC cells in a dose-dependent manner in vitro. Mouse models with xenograft transplantation showed that the inhibitor suppressed the growth of HCC cells in vivo. Moreover, C16 decreased angiogenesis in HCC tissue in the xenograft model. Consistent with these results in mice, transcript levels of vascular endothelial growth factor-A and factor-B, platelet-derived growth factor-A and factor-B, fibroblast growth factor-2, epidermal growth factor, and hepatocyte growth factor, which are angiogenesis-related growth factors, were significantly decreased by C16 in vitro. In conclusion, the PKR inhibitor C16 blocked tumor cell growth and angiogenesis via a decrease in mRNA levels of several growth factors. C16 may be useful in the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Indóis/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Tiazóis/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fator de Crescimento Epidérmico/genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Células Hep G2 , Fator de Crescimento de Hepatócito/genética , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Proto-Oncogênicas c-sis/genética , RNA Mensageiro/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator B de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Steroid Biochem Mol Biol ; 199: 105587, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004706

RESUMO

Chronic kidney disease (CKD) is associated with elevated circulating fibroblast growth factor 23 (FGF23), impaired renal biosynthesis of 1α,25-dihydroxyvitamin D (1α,25(OH)2D), low bone mass, and increased fracture risk. Our previous data with human mesenchymal stem cells (hMSCs) indicated that vitamin D metabolism in hMSCs is regulated as it is in the kidney and promotes osteoblastogenesis in an autocrine/paracrine manner. In this study, we tested the hypothesis that FGF23 inhibits vitamin D metabolism and action in hMSCs. hMSCs were isolated from discarded marrow during hip arthroplasty, including two subjects receiving hemodialysis and a series of 20 subjects (aged 49-83 years) with estimated glomerular filtration rate (eGFR) data. The direct in vitro effects of rhFGF23 on hMSCs were analyzed by RT-PCR, Western immunoblot, and biochemical assays. Ex vivo analyses showed positive correlations for both secreted and membrane-bound αKlotho gene expression in hMSCs with eGFR of the subjects from whom hMSCs were isolated. There was downregulated constitutive expression of αKlotho, but not FGFR1 in hMSCs obtained from two hemodialysis subjects. In vitro, rhFGF23 countered vitamin D-stimulated osteoblast differentiation of hMSCs by reducing the vitamin D receptor, CYP27B1/1α-hydroxylase, biosynthesis of 1α,25(OH)2D3, and signaling through BMP-7. These data demonstrate that dysregulated vitamin D metabolism in hMSCs may contribute to impaired osteoblastogenesis and altered bone and mineral metabolism in CKD subjects due to elevated FGF23. This supports the importance of intracellular vitamin D metabolism in autocrine/paracrine regulation of osteoblast differentiation in hMSCs.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Insuficiência Renal Crônica/genética , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Idoso , Idoso de 80 Anos ou mais , Proteína Morfogenética Óssea 7/genética , Diferenciação Celular/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Osteoblastos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Vitamina D/análogos & derivados , Vitamina D/biossíntese , Vitamina D/genética
15.
Arch Med Res ; 51(1): 76-81, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32109713

RESUMO

BACKGROUND AND AIMS: Osteoarthritis (OA) is the most common type of arthritis disease. Previous etiological studies indicated that both environmental and genetic factors play important roles in the occurrence and development of knee OA (KOA). In the present study, we aimed to investigate the association between the FGF18 gene and susceptibility to KOA in Han Chinese population. METHODS: A total of 2,556 unrelated Han Chinese individuals, including 866 KOA patients and 1,688 healthy controls, were recruited. Nine tag SNPs located within the gene region of FGF18 were selected for genotyping. Logistic models were fitted for single marker-based association analyses. Age, gender and BMI were included in each model as covariates. To investigate the functional consequences of significant SNP, we extracted expression quantitative trait loci (eQTL) data from the GTEx database. RESULTS: SNP rs3884606 was significantly associated with the risk of KOA (OR [95% CI] = 1.25 [1.11-1.41], p = 0.0002) after adjusting for age, gender and BMI. The G allele was significantly associated with an increased risk of KOA. No significant eQTL signals could be identified for SNP rs3884606 on FGF18. CONCLUSION: In this study, we identified a genetic polymorphism in FGF18 that was significantly associated with the risk of KOA based on samples with Chinese Han ancestry. Our findings replicated the recent GWAS report and supported an association between KOA and FGF18.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/epidemiologia , Locos de Características Quantitativas , Fatores de Risco
16.
J Clin Invest ; 130(3): 1106-1108, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32065594

RESUMO

The rapid rise in circulating fibroblast growth factor 23 (FGF23) associated with kidney injury results in calcitriol deficiency, altered calcium homeostasis, and secondary hyperparathyroidism, and may contribute to cardiovascular complications and death. However, the mechanisms of increased FGF23 in states of kidney injury remain unclear. In this issue of the JCI, Simic et al. screened plasma taken from the renal vein of patients undergoing cardiac catheterization and identified glycerol-3-phosphate (G-3-P) as the most significant correlate of simultaneous arterial FGF23 levels. When G-3-P was administered to mice, FGF23 production increased in bone. In a series of elegant mouse studies, the authors discovered a pathway linking increased G-3-P to increased FGF23 via increases in lysophosphatidic acid (LPA), which activates the LPA receptor 1 in FGF23-secreting cells in the bone and bone marrow. Although the authors present human data that broadly support the results from the mouse models, further research is needed to determine whether targeting the G-3-P/FGF23 pathway has the potential to modify FGF23-related complications in the clinic.


Assuntos
Fatores de Crescimento de Fibroblastos , Glicerol , Animais , Fatores de Crescimento de Fibroblastos/genética , Humanos , Rim , Camundongos , Fosfatos
17.
J Clin Invest ; 130(3): 1513-1526, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32065590

RESUMO

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.


Assuntos
Lesão Renal Aguda/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Glicerofosfatos/metabolismo , Rim/metabolismo , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Linhagem Celular , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Rim/patologia , Masculino , Metabolômica , Camundongos , Camundongos Knockout , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo
18.
Sci Rep ; 10(1): 2735, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066763

RESUMO

Resistance to cancer therapy is a challenge because of innate tumor heterogeneity and constant tumor evolution. Since the pathway of resistance cannot be predicted, combination therapies may address this progression. We discovered that in addition to IGF1 and IGF2, IGFBP-3 binds bFGF, HGF, neuregulin, and PDGF AB with nanomolar affinity. Because growth factors drive resistance, simultaneous inhibition of multiple growth factor pathways may improve the efficacy of precision therapy. Growth factor sequestration by IGFBP-3-Fc enhances the activity of EGFR inhibitors by decreasing cell survival and inhibiting bFGF, HGF, and IGF1 growth factor rescue and also potentiates the activity of other cancer drugs. Inhibition of tumor growth in vivo with adjuvant IGFBP-3-Fc with erlotinib versus erlotinib after treatment cessation supports that the combination reduces cell survival. Inhibition of multiple growth factor pathways may postpone resistance and extend progression-free survival in many cancer indications.


Assuntos
Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Carga Tumoral/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Células HEK293 , Células HT29 , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/antagonistas & inibidores , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neuregulina-1/genética , Neuregulina-1/metabolismo , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Benef Microbes ; 11(1): 67-78, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32066255

RESUMO

Fibroblast growth factor 21 (FGF21), a metabolism regulator, has an important effect on metabolic diseases, such as obesity and diabetes. It is also expressed in mice, and the murine source has high homology with human FGF21. Recently, it has been extensively studied and has become a potential drug target for the treatment of metabolic diseases. As it is a protein-based hormone, FGF21 cannot be easily and quickly absorbed into the blood through oral administration. Moreover, it has a 0-2 h half-life in vivo, as shown in a previous study, thus its efficacy lasts for a short period of time when used to treat metabolic diseases, limiting its clinical applications. To avoid these limitations, we used Lactococcus lactis, a food-grade bacterium, as the host to express FGF21. It could be used successfully for the expression and long-term effect of FGF21 in vivo. Instead of antibiotic resistance genes, the LacF gene was used as a selection marker in the NZ3900/PNZ8149 expression system, which is safe and could reduce the antibiotic resistance crisis. In this study, we a constructed human FGF21 expressing L. lactis strain and administered it to Db/Db mice by gavage. Compared with the control group, the body weight of mice in the experimental group was significantly reduced, and the overall homeostasis was improved in mice treated with human FGF21. Moreover, the activity of brown adipose tissue was enhanced. These results revealed that oral administration of FGF21 through heterologous expression in L. lactis appears to be an effective approach for its clinical application.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/farmacologia , Lactococcus lactis/genética , Microrganismos Geneticamente Modificados , Probióticos/farmacologia , Tecido Adiposo Marrom/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , Humanos , Camundongos , Modelos Animais , Obesidade
20.
DNA Cell Biol ; 39(4): 661-670, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32101022

RESUMO

Fibroblast growth factor 21 (FGF21) is a hormone-like member of the FGF family that is associated with cell death in atherosclerosis. However, its underlying mechanisms remain unclear. In this study, the effect of FGF21 on endothelial cell pyroptosis and its potential mechanisms were investigated. Results showed that FGF21 inhibits oxidized low-density lipoprotein (ox-LDL)-induced pyroptosis and related molecular expression in human umbilical vein endothelial cells (HUVECs). Mitochondrial function was damaged by ox-LDL and restored by FGF21. A mechanism proved that ubiquinol cytochrome c reductase core protein I (UQCRC1) was downregulated by ox-LDL and upregulated by FGF21. Further, the silencing of UQCRC1 aggravated HUVEC pyroptosis and impaired mitochondrial function and reactive oxygen species (ROS) production. Moreover, Tet methylcytosine dioxygenase (TET2) was involved in the regulation of UQCRC1 expression and pyroptosis. In summary, FGF21 inhibited ox-LDL-induced HUVEC pyroptosis through the TET2-UQCRC1-ROS pathway.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Lipoproteínas LDL/metabolismo , Piroptose/fisiologia , Aterosclerose/patologia , Sobrevivência Celular , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/genética , Fatores de Crescimento de Fibroblastos/genética , Humanos , Potencial da Membrana Mitocondrial/fisiologia , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
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