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1.
J Clin Invest ; 131(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623323

RESUMO

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-ß signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-ß pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-ß signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Animais , Endotélio/metabolismo , Endotélio/patologia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Masculino , Mesoderma/metabolismo , Mesoderma/patologia , Camundongos , Camundongos Knockout , Receptores de Fatores de Crescimento de Fibroblastos/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Remodelação Vascular
2.
Expert Rev Clin Pharmacol ; 14(10): 1233-1252, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34591728

RESUMO

Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.


Assuntos
Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias/patologia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Nutrients ; 13(9)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34578793

RESUMO

Obesity is one of the most challenging diseases of the 21st century and is accompanied by behavioural disorders. Exercise, dietary adjustments, or time-restricted feeding are the only successful long-term treatments to date. Fibroblast growth factor 21 (FGF21) plays a key role in dietary regulation, but FGF21 resistance is prevalent in obesity. The aim of this study was to investigate in obese mice whether weight reduction leads to improved behaviour and whether these behavioural changes are associated with decreased plasma FGF21 levels. After establishing a model for diet-induced obesity, mice were subjected to three different interventions for weight reduction, namely dietary change, treadmill exercise, or time-restricted feeding. In this study, we demonstrated that only the combination of dietary change and treadmill exercise affected all parameters leading to a reduction in weight, fat, and FGF21, as well as less anxious behaviour, higher overall activity, and improved olfactory detection abilities. To investigate the interrelationship between FGF21 and behavioural parameters, feature selection algorithms were applied designating FGF21 and body weight as one of five highly weighted features. In conclusion, we concluded from the complementary methods that FGF21 can be considered as a potential biomarker for improved behaviour in obese mice after weight reduction.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Locomoção , Obesidade/sangue , Olfato , Perda de Peso , Animais , Biomarcadores/sangue , Dieta Hiperlipídica , Teste de Labirinto em Cruz Elevado , Jejum , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Teste de Campo Aberto , Condicionamento Físico Animal
5.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502405

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1ind-/-) was achieved by tamoxifen application, EAE was induced using the MOG35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1ind-/- mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1ind-/-mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1ß, IL-6, and CD200 was downregulated in Fgfr1ind-/- mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1ind-/- mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Oligodendroglia/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Fatores de Crescimento de Fibroblastos/metabolismo , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/farmacologia , Oligodendroglia/patologia , Fosforilação , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Substância Branca/metabolismo
6.
Int J Mol Sci ; 22(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34502419

RESUMO

Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in Col4a3-/- mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 (Fstl1) was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the Fstl1 receptors, Tlr4 and Dip2a, increased in both Col4a-/- mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope® (Advanced Cell Diagnostics, Newark CA, USA) localized Fstl1 to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed Fstl1 confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. FSTL1 expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline FSTL1 mRNA levels. FSTL1 is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Relacionadas à Folistatina/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fatores de Crescimento de Fibroblastos/genética , Proteínas Relacionadas à Folistatina/genética , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
7.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576070

RESUMO

Oral squamous cell carcinomas (OSCCs) are one of the most prevalent malignancies, with a low five-year survival rate, thus warranting more effective drugs or therapy to improve treatment outcomes. Melatonin has been demonstrated to exhibit oncostatic effects. In this study, we explored the anti-cancer effects of melatonin on OSCCs and the underlying mechanisms. A human tongue squamous cell carcinoma cell line (SCC-15) was treated with 2 mM melatonin, followed by transwell migration and invasion assays. Relative expression levels of Fibroblast Growth Factor 19 (FGF19) was identified by Cytokine Array and further verified by qPCR and Western blot. Overexpression and downregulation of FGF19 were obtained by adding exogenous hFGF19 and FGF19 shRNA lentivirus, respectively. Invasion and migration abilities of SCC-15 cells were suppressed by melatonin, in parallel with the decreased FGF19/FGFR4 expression level. Exogenous hFGF19 eliminated the inhibitory effects of melatonin on SCC-15 cells invasion and migration, while FGF19 knocking-down showed similar inhibitory activities with melatonin. This study proves that melatonin suppresses SCC-15 cells invasion and migration through blocking the FGF19/FGFR4 pathway, which enriches our knowledge on the anticancer effects of melatonin. Blocking the FGF19/FGFR4 pathway by melatonin could be a promising alternative for OSCCs prevention and management, which would facilitate further development of novel strategies to combat OSCCs.


Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular , Fatores de Crescimento de Fibroblastos/metabolismo , Melatonina/farmacologia , Neoplasias Bucais/patologia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas/genética , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Bucais/genética , Invasividade Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos
8.
Cells ; 10(9)2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34572066

RESUMO

Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or ß-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure-function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Homeostase , Doenças Metabólicas/fisiopatologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Humanos , Fosforilação , Transdução de Sinais
9.
Nat Commun ; 12(1): 4768, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362888

RESUMO

Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective improvements in obesity and Type 2 diabetes. We hypothesized a potential role for the gut hormone Fibroblast-Growth Factor 15/19 which is increased after VSG and pharmacologically can improve energy homeostasis and glucose handling. We generated intestinal-specific FGF15 knockout (FGF15INT-KO) mice which were maintained on high-fat diet. FGF15INT-KO mice lost more weight after VSG as a result of increased lean tissue loss. FGF15INT-KO mice also lost more bone density and bone marrow adipose tissue after VSG. The effect of VSG to improve glucose tolerance was also absent in FGF15INT-KO. VSG resulted in increased plasma bile acid levels but were considerably higher in VSG-FGF15INT-KO mice. These data point to an important role after VSG for intestinal FGF15 to protect the organism from deleterious effects of VSG potentially by limiting the increase in circulating bile acids.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Gastrectomia/efeitos adversos , Tecido Adiposo , Animais , Cirurgia Bariátrica , Ácidos e Sais Biliares/sangue , Glicemia , Densidade Óssea , Medula Óssea , Diabetes Mellitus Tipo 2 , Dieta Hiperlipídica , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/cirurgia , Perda de Peso
10.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360670

RESUMO

BACKGROUND AND AIMS: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4-/- mice with deficiency of the hepatobiliary phospholipid transporter. METHODS: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4-/- (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. RESULTS: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. CONCLUSIONS: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Insuficiência Hepática Crônica Agudizada/patologia , Ácidos e Sais Biliares/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/patologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Insuficiência Hepática Crônica Agudizada/metabolismo , Animais , Estudos de Casos e Controles , Colesterol 7-alfa-Hidroxilase/genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética
11.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360745

RESUMO

A review of the available literature was performed in order to summarize the existing evidence between osteoblast dysfunction and clinical features in non-hereditary sclerosing bone diseases. It has been known that proliferation and migration of osteoblasts are concerted by soluble factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), bone morphogenetic protein (BMP) but also by signal transduction cascades such as Wnt signaling pathway. Protein kinases play also a leading role in triggering the activation of osteoblasts in this group of diseases. Post-zygotic changes in mitogen-activated protein kinase (MAPK) have been shown to be associated with sporadic cases of Melorheostosis. Serum levels of FGF and PDGF have been shown to be increased in myelofibrosis, although studies focusing on Sphingosine-1-phosphate receptor was shown to be strongly expressed in Paget disease of the bone, which may partially explain the osteoblastic hyperactivity during this condition. Pathophysiological mechanisms of osteoblasts in osteoblastic metastases have been studied much more thoroughly than in rare sclerosing syndromes: striking cellular mechanisms such as osteomimicry or complex intercellular signaling alterations have been described. Further research is needed to describe pathological mechanisms by which rare sclerosing non hereditary diseases lead to osteoblast dysfunction.


Assuntos
Sistema de Sinalização das MAP Quinases , Melorreostose/metabolismo , Osteoblastos/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Melorreostose/patologia , Osteoblastos/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo
12.
Oxid Med Cell Longev ; 2021: 5481228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457114

RESUMO

Peripheral nerve injury (PNI), resulting in the impairment of myelin sheaths and axons, seriously affects the transmission of sensory or motor nerves. Growth factors (GFs) provide a biological microenvironment for supporting nerve regrowth and have become a promising alternative for repairing PNI. As one number of intracellular growth factor family, fibroblast growth factor 13 (FGF13) was regard as a microtubule-stabilizing protein for regulating cytoskeletal plasticity and neuronal polarization. However, the therapeutic efficiency and underlying mechanism of FGF13 for treating PNI remained unknown. Here, the application of lentivirus that overexpressed FGF13 was delivered directly to the lesion site of transverse sciatic nerve for promoting peripheral nerve regeneration. Through behavioral analysis and histological and ultrastructure examinations, we found that FGF13 not only facilitated motor and sense functional recovery but also enhanced axon elongation and remyelination. Furthermore, pretreatment with FGF13 also promoted Schwann cell (SC) viability and upregulated the expression cellular microtubule-associated proteins in vitro PNI model. These data indicated FGF13 therapeutic effect was closely related to maintain cellular microtubule stability. Thus, this work provides the evident that FGF13-medicated microtubule stability is necessary for promoting peripheral nerve repair following PNI, highlighting the potential therapeutic value of FGF13 on ameliorating injured nerve recovery.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Microtúbulos/química , Regeneração Nervosa , Neurônios/citologia , Traumatismos dos Nervos Periféricos/terapia , Recuperação de Função Fisiológica , Células de Schwann/citologia , Animais , Fatores de Crescimento de Fibroblastos/genética , Masculino , Neurônios/fisiologia , Traumatismos dos Nervos Periféricos/etiologia , Traumatismos dos Nervos Periféricos/patologia , Ratos , Ratos Sprague-Dawley , Células de Schwann/fisiologia
13.
Nutrients ; 13(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34444768

RESUMO

Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.


Assuntos
Dieta com Restrição de Proteínas , Metionina/metabolismo , Tecido Adiposo/metabolismo , Aminoácidos Essenciais , Aminoácidos Sulfúricos , Animais , Peso Corporal , Caseínas , Ingestão de Alimentos , Ingestão de Energia , Metabolismo Energético/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Humanos , Fígado/metabolismo , Masculino , Metionina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Soja , Transcriptoma
14.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360000

RESUMO

Growth factors belonging to the FGF family play important roles in tissue and organ repair after trauma. In this review, I discuss the regulation by FGFs of the aspects of cellular behavior important for reparative processes. In particular, I focus on the FGF-dependent regulation of cell proliferation, cell stemness, de-differentiation, inflammation, angiogenesis, cell senescence, cell death, and the production of proteases. In addition, I review the available literature on the enhancement of FGF expression and secretion in damaged tissues resulting in the increased FGF supply required for tissue repair.


Assuntos
Diferenciação Celular/genética , Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Regeneração/genética , Células-Tronco/metabolismo , Animais , Morte Celular/genética , Desdiferenciação Celular/genética , Proliferação de Células/genética , Senescência Celular/genética , Células Eucarióticas/citologia , Células Eucarióticas/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação , Família Multigênica , Neovascularização Fisiológica/genética , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Células-Tronco/citologia
15.
Cells ; 10(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34440915

RESUMO

Fibroblast growth factors (FGFs) comprise a large family of growth factors, regulating diverse biological processes including cell proliferation, migration, and differentiation. Each FGF binds to a set of FGF receptors to initiate certain intracellular signaling molecules. Accumulated evidence suggests that in early development and adult state of vertebrates, FGFs also play exclusive and context dependent roles. Although FGFs have been the focus of research for therapeutic approaches in cancer, cardiovascular disease, and metabolic syndrome, in this review, we mainly focused on their role in germ layer specification and axis patterning during early vertebrate embryogenesis. We discussed the functional roles of FGFs and their interacting partners as part of the gene regulatory network for germ layer specification, dorsal-ventral (DV), and anterior-posterior (AP) patterning. Finally, we briefly reviewed the regulatory molecules and pharmacological agents discovered that may allow modulation of FGF signaling in research.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Camadas Germinativas/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Vertebrados/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Camadas Germinativas/embriologia , Humanos , Modelos Biológicos , Ligação Proteica , Receptores de Fatores de Crescimento de Fibroblastos/genética , Vertebrados/embriologia , Vertebrados/genética
16.
Am J Physiol Cell Physiol ; 321(3): C559-C568, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34319830

RESUMO

In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how myokines affect the maturation, maintenance, and regeneration of tendons as a function of age is completely unstudied. Here we discuss the role of four myokines-fibroblast growth factors (FGF), myostatin, the secreted protein acidic and rich in cysteine (SPARC) miR-29-in tendon development and hypothesize a role for these factors in the progressive changes in tendon structure and function as a result of muscle wasting (disuse, aging, and disease). Because of the close relationship between mechanical loading and muscle and tendon regulation, disentangling muscle-tendon cross talk from simple mechanical loading is experimentally quite difficult. Therefore, we propose an experimental framework that hopefully will be useful in demonstrating muscle-tendon cross talk in vivo. Though understudied, the promise of a better understanding of muscle-tendon cross talk is the development of new interventions that will improve tendon development, regeneration, and function throughout the lifespan.


Assuntos
Envelhecimento/genética , Exossomos/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Tendões/metabolismo , Envelhecimento/metabolismo , Animais , Fenômenos Biomecânicos , Exossomos/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Células Musculares/metabolismo , Células Musculares/patologia , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miostatina/genética , Miostatina/metabolismo , Osteonectina/genética , Osteonectina/metabolismo , Transdução de Sinais , Tendões/patologia
17.
Am J Physiol Endocrinol Metab ; 321(2): E292-E304, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229476

RESUMO

We have generated the transgenic mouse line LTCFDN in which dominant negative TCF7L2 (TCF7L2DN) is specifically expressed in the liver during adulthood. Male but not female LTCFDN mice showed elevated hepatic and plasma triglyceride (TG) levels, indicating the existence of estrogen-ß-cat/TCF signaling cascade that regulates hepatic lipid homeostasis. We show here that hepatic fibroblast growth factor 21 (FGF21) expression was reduced in male but not in female LTCFDN mice. The reduction was not associated with altered hepatic expression of peroxisome proliferator-activated receptor α (PPARα). In mouse primary hepatocytes (MPH), Wnt-3a treatment increased FGF21 expression in the presence of PPARα inhibitor. Results from our luciferase-reporter assay and chromatin immunoprecipitation suggest that evolutionarily conserved TCF binding motifs (TCFBs) on Fgf21 promoter mediate Wnt-3a-induced Fgf21 transactivation. Female mice showed reduced hepatic FGF21 production and circulating FGF21 level following ovariectomy (OVX), associated with reduced hepatic TCF expression and ß-catenin S675 phosphorylation. Finally, in MPH, estradiol (E2) treatment enhanced FGF21 expression, as well as binding of TCF7L2 and ribonucleic acid (RNA) polymerase II to the Fgf21 promoter; and the enhancement can be attenuated by the G-protein-coupled estrogen receptor 1 (GPER) antagonist G15. Our observations hence indicate that hepatic FGF21 is among the effectors of the newly recognized E2-ß-cat/TCF signaling cascade.NEW & NOTEWORTHY FGF21 is mainly produced in the liver. Therapeutic effect of FGF21 analogues has been demonstrated in clinical trials on reducing hyperlipidemia. We show here that Fgf21 transcription is positively regulated by Wnt pathway effector ß-cat/TCF. Importantly, hepatic ß-cat/TCF activity can be regulated by the female hormone estradiol, involving GPER. The investigation enriched our understanding on hepatic FGF21 hormone production, and expanded our view on metabolic functions of the Wnt pathway in the liver.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Via de Sinalização Wnt , Animais , Células Cultivadas , Estrogênios/metabolismo , Feminino , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/metabolismo
18.
Cells ; 10(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200439

RESUMO

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.


Assuntos
Carcinogênese/metabolismo , Carcinoma Hepatocelular , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Hepáticas , Regeneração Hepática , Transplante de Fígado , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/prevenção & controle , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Roedores
19.
Sci Rep ; 11(1): 15090, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301962

RESUMO

The klotho gene encodes a transmembrane protein αKlotho that interacts with a fibroblast growth factor (FGF) receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. This bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, αKlotho knockout mice show an accelerated aging and a shortened life span. Similarly, C. elegans lacking the αklotho homologue showed a short life span. However, the physiological basis of aging-related function of αklotho remain unclear. The αklotho-deficient vertebrate animals other than mice have been awaited as an alternative model of premature aging. We here employed zebrafish in our study and revealed that αklotho mutant zebrafish appeared to be normal at 3 months postfertilization (mpf) but eventually underwent premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed the motor ability of zebrafish in a forced swimming assay and found that αklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that αklotho-deficient zebrafish exhibited a short life span and reduced spontaneous movements. Taken together, these results suggest that αKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.


Assuntos
Glucuronidase/metabolismo , Longevidade/fisiologia , Peixe-Zebra/metabolismo , Envelhecimento/metabolismo , Animais , Osso e Ossos/metabolismo , Caenorhabditis elegans/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Rim/metabolismo , Camundongos , Camundongos Knockout
20.
Clin Sci (Lond) ; 135(14): 1669-1687, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34283205

RESUMO

Diabetes is associated with a strongly elevated risk of cardiovascular disease, which is even more pronounced in patients with diabetic nephropathy. Currently available guideline-based efforts to correct traditional risk factors are only partly able to attenuate this risk, underlining the urge to identify novel treatment targets. Emerging data point towards a role for disturbances in phosphate metabolism in diabetes. In this review, we discuss the role of phosphate and the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) in diabetes. We address deregulations of phosphate metabolism in patients with diabetes, including diabetic ketoacidosis. Moreover, we discuss potential adverse consequences of these deregulations, including the role of deregulated phosphate and glucose as drivers of vascular calcification propensity. Finally, we highlight potential treatment options to correct abnormalities in phosphate and FGF23. While further studies are needed to more precisely assess their clinical impact, deregulations in phosphate and FGF23 are promising potential target in diabetes and diabetic nephropathy.


Assuntos
Diabetes Mellitus/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Miócitos de Músculo Liso/metabolismo , Fosfatos/metabolismo , Humanos , Insuficiência Renal Crônica/metabolismo , Calcificação Vascular/metabolismo
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