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1.
Rev. bras. cir. plást ; 34(3): 391-398, jul.-sep. 2019. ilus
Artigo em Inglês, Português | LILACS | ID: biblio-1047162

RESUMO

Introdução: Queloides surgem de resposta excessiva à lesão da derme, resultando em proliferação de fibroblastos, produção exagerada de colágeno e comprometimento da pele sadia adjacente. O diagnóstico é clínico e muitos métodos conservadores e cirúrgicos já foram utilizados para tratamento. Porém, dados da eficácia desses tratamentos são limitados e não há consenso na literatura quanto a melhor técnica a ser empregada, permanecendo uma lacuna que necessita ser preenchida, a fim de que seus usos sejam indicados com maior confiabilidade, em um modelo de medicina baseada em evidências. Métodos: Revisão não sistemática da literatura sobre "queloides" nas bases de dados PubMed, Scielo, MEDLINE, UptoDate e livros-texto das áreas de Dermatologia e Cirurgia Dermatológica. Revisão de Literatura: Foram enumeradas e abordadas as principais informações sobre técnicas cirúrgicas e adjuvantes empregadas para essas lesões, que são: excisão, injeções intralesionais, crioterapia, laserterapia, revestimento com gel de silicone, radioterapia e pressoterapia. Torna-se relevante o levantamento dessas informações, tendo em vista que, além de poder causar dor, prurido e restrição de movimento, o principal motivo da procura de assistência médica para queloide é devido ao aspecto cosmético/estético, e as taxas de reincidência e falha terapêutica ainda são altas, sendo necessário conscientizar o paciente sobre o procedimento e seus efeitos. Conclusão: São muitos os tratamentos disponíveis para o queloide, sejam cirúrgicos ou não, todavia não há consenso sobre uma abordagem universalmente aceita. São necessários mais estudos, com a finalidade de definir a melhor conduta e atingir melhores resultados, visto a qualidade mediana das evidências apresentadas nos estudos.


Introduction: Keloids are characterized by an abnormal response to dermal trauma, resulting in fibroblast proliferation, excessive collagen production, and impairment of adjacent healthy tissue. The diagnosis is clinical, and many conservative and surgical methods can be used as treatments. However, data on the efficacy of these treatments are limited, and there is no consensus regarding the best treatment option. This gap needs to be filled by developing comprehensive evidence-based therapies. Methods: A non-systematic literature review of keloid scars was carried out using PubMed, Scielo, MEDLINE, UptoDate, and dermatology and dermatological surgery textbooks. Literature review: The search retrieved relevant information on surgical and adjuvant therapies used for keloids, including excision, intralesional injections, cryotherapy, laser therapy, silicone gel sheeting, radiation therapy, and pressure therapy. These data are crucial because, in addition to complaints of pain, itching, and restriction of movement, the main reason for seeking treatment for keloids is for cosmetic and aesthetic improvement, and the rates of recurrence and treatment failure are high, emphasizing the importance of creating awareness regarding the available procedures and their effectiveness. Conclusion: Many surgical and adjuvant therapies for keloids are available. Nonetheless, there is no consensus on a universally accepted treatment. Therefore, additional high-quality studies are needed to identify the most effective therapeutic approaches to achieve better results.


Assuntos
Humanos , História do Século XXI , Recidiva , Cirurgia Plástica , Terapêutica , Fator 1 de Crescimento de Fibroblastos , Fibroblastos , Procedimentos Cirúrgicos Dermatológicos , Queloide , Cirurgia Plástica/efeitos adversos , Cirurgia Plástica/métodos , Terapêutica/métodos , Ferimentos e Lesões , Ferimentos e Lesões/cirurgia , Ferimentos e Lesões/terapia , Fator 1 de Crescimento de Fibroblastos/análise , Fator 1 de Crescimento de Fibroblastos/efeitos adversos , Cicatriz , Cicatriz/complicações , Procedimentos Cirúrgicos Dermatológicos/métodos , Queloide/cirurgia
2.
Gene ; 717: 144047, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31421190

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways play important roles in the formation of the blood vascular system and nervous system across animal phyla. We have earlier reported VEGF and FGF from Hydra vulgaris Ind-Pune, a cnidarian with a defined body axis, an organized nervous system and a remarkable ability of regeneration. We have now identified three more components of VEGF and FGF signaling pathways from hydra. These include FGF-1, FGF receptor 1 (FGFR-1) and VEGF receptor 2 (VEGFR-2) with a view to deciphering their possible roles in regeneration. METHODS: In silico analysis of proteins was performed using Clustal omega, Swiss model, MEGA 7.0, etc. Gene expression was studied by whole mount in situ hybridization. VEGF and FGF signaling was inhibited using specific pharmacological inhibitors and their effects on head regeneration were studied. RESULTS: Expression patterns of the genes indicate a possible interaction between FGF-1 and FGFR-1 and also VEGF and VEGFR-2. Upon treatment of decapitated hydra with pharmacological inhibitor of FGFR-1 or VEGFR-2 for 48 h, head regeneration was delayed in treated as compared to untreated, control regenerates. When we studied the expression of head specific genes HyBra1 and HyKs1 and tentacle specific gene HyAlx in control and treated regenerates using whole mount in situ hybridization, expression of all the three genes was found to be adversely affected in treated regenerates. CONCLUSIONS: The results suggest that VEGF and FGF signaling play important roles in regeneration of hypostome and tentacles in hydra.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Cabeça/fisiologia , Hydra/fisiologia , Regeneração/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Simulação por Computador , Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Hydra/efeitos dos fármacos , Indóis/farmacologia , Domínios Proteicos , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais , Homologia Estrutural de Proteína , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Cells ; 8(6)2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146385

RESUMO

Tight regulation of signaling from receptor tyrosine kinases is required for normal cellular functions and uncontrolled signaling can lead to cancer. Fibroblast growth factor receptor 2 (FGFR2) is a receptor tyrosine kinase that induces proliferation and migration. Deregulation of FGFR2 contributes to tumor progression and activating mutations in FGFR2 are found in several types of cancer. Here, we identified a negative feedback loop regulating FGFR2 signaling. FGFR2 stimulates the Ras/MAPK signaling pathway consisting of Ras-Raf-MEK1/2-ERK1/2. Inhibition of this pathway using a MEK1/2 inhibitor increased FGFR2 signaling. The putative ERK1/2 phosphorylation site at serine 780 (S780) in FGFR2 corresponds to serine 777 in FGFR1 which is directly phosphorylated by ERK1/2. Substitution of S780 in FGFR2 to an alanine also increased signaling. Truncated forms of FGFR2 lacking the C-terminal tail, including S780, have been identified in cancer and S780 has been found mutated to leucine in bladder cancer. Substituting S780 in FGFR2 with leucine increased FGFR2 signaling. Importantly, cells expressing these mutated versions of S780 migrated faster than cells expressing wild-type FGFR2. Thus, ERK1/2-mediated phosphorylation of S780 in FGFR2 constitutes a negative feedback loop and inactivation of this feedback loop in cancer cells causes hyperactivation of FGFR2 signaling, which may result in increased invasive properties.


Assuntos
Retroalimentação Fisiológica , Sistema de Sinalização das MAP Quinases , Mutação/genética , Neoplasias/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Sequência de Aminoácidos , Linhagem Celular Tumoral , Progressão da Doença , Fator de Crescimento Epidérmico/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Fator 1 de Crescimento de Fibroblastos/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Serina/genética , Transdução de Sinais
4.
World Neurosurg ; 129: e343-e351, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31132502

RESUMO

OBJECTIVE: Repair of spinal cord injury (SCI) using peripheral nerve graft (PNG) and acidic fibroblast growth factor (aFGF) has shown promising results in rats and a few human patients, but not in nonhuman primates. The aim of this study was to verify the effective use of PNG and aFGF for repairing incomplete SCI in nonhuman primates. METHODS: Six adult rhesus macaques received spinal cord hemisection at T8 level and were grouped into repair and control groups (n = 3 in each). Animals in the repair group underwent nerve repair with autologous PNG plus aFGF immediately after lesioning. The control group received exactly the same operation for lesioning but no treatment. Postoperative behavioral evaluations, electrophysiologic tests (including motor and somatosensory evoked potentials), and magnetic resonance imaging were performed and compared between the 2 groups as well as histologic examination of the spinal cord cephalic to, at, and caudal to the lesion site after sacrifice. RESULTS: Animals in the repair group had better motor function in the lower limbs at every observed time point and demonstrated more improvement on electrophysiologic examinations than the control group. The repair group had smaller areas of myelomalacia on magnetic resonance imaging around the lesion compared with the control group, suggesting diminished inflammatory responses with the repair strategy. CONCLUSIONS: PNG plus aFGF for SCI in nonhuman primates yielded improvements in clinical behavior, electrophysiologic tests, and magnetic resonance imaging. This study suggests that the repair strategy is feasible and effective for nonhuman primate SCI. Further investigations are warranted to corroborate its effectiveness for clinical application.


Assuntos
Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Regeneração Nervosa/fisiologia , Transferência de Nervo/métodos , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/terapia , Animais , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Macaca mulatta , Masculino , Modelos Animais , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/cirurgia
5.
Int J Mol Sci ; 20(8)2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013829

RESUMO

Mitogen-activated protein kinases (MAPK): Erk1 and Erk2 are key players in negative-feedback regulation of fibroblast growth factor (FGF) signaling. Upon activation, Erk1 and Erk2 directly phosphorylate FGF receptor 1 (FGFR1) at a specific serine residue in the C-terminal part of the receptor, substantially reducing the tyrosine phosphorylation in the receptor kinase domain and its signaling. Similarly, active Erks can also phosphorylate multiple threonine residues in the docking protein FGF receptor substrate 2 (FRS2), a major mediator of FGFR signaling. Here, we demonstrate that in NIH3T3 mouse fibroblasts and human osteosarcoma U2OS cells stably expressing FGFR1, in addition to Erk1 and Erk2, p38 kinase is able to phosphorylate FRS2. Simultaneous inhibition of Erk1/2 and p38 kinase led to a significant change in the phosphorylation pattern of FRS2 that in turn resulted in prolonged tyrosine phosphorylation of FGFR1 and FRS2 and in sustained signaling, as compared to the selective inhibition of Erks. Furthermore, excessive activation of p38 with anisomycin partially compensated the lack of Erks activity. These experiments reveal a novel crosstalk between p38 and Erk1/2 in downregulation of FGF-induced signaling.


Assuntos
Fator 1 de Crescimento de Fibroblastos/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Animais , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/farmacologia , Camundongos , Células NIH 3T3 , Fosforilação
6.
FEBS Open Bio ; 9(5): 914-924, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30968602

RESUMO

Overexpression of fibroblast growth factor receptor 1 (FGFR1) is a common aberration in lung and breast cancers and has necessitated the design of drugs targeting FGFR1-dependent downstream signaling and FGFR1 ligand binding. To date, the major group of drugs being developed for treatment of FGFR1-dependent cancers are small-molecule tyrosine kinase inhibitors; however, the limited specificity of these drugs has led to increasing attempts to design molecules targeting the extracellular domain of FGFR1. Here, we used the phage display technique to select cyclic peptides F8 (ACSLNHTVNC) and G10 (ACSAKTTSAC) as binders of the fibroblast growth factor 1 (FGF1)-FGFR1 interface. ELISA and in vitro cell assays were performed to reveal that cyclic peptide F8 is more effective in preventing the FGF1-FGFR1 interaction, and also decreases FGF1-induced proliferation of BA/F3 FGFR1c cells by over 40%. Such an effect was not observed for BA/F3 cells lacking FGFR1. Therefore, cyclic peptide F8 can act as a FGF1-FGFR1 interaction antagonist, and may be suitable for further development for potential use in therapies against FGFR1-expressing cancer cells.


Assuntos
Bacteriófagos/metabolismo , Fator 1 de Crescimento de Fibroblastos/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Peptídeos Cíclicos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Linhagem Celular , Técnicas de Visualização da Superfície Celular , Perfilação da Expressão Gênica , Camundongos , Células NIH 3T3 , Transdução de Sinais
7.
Gene Expr Patterns ; 32: 28-37, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30825522

RESUMO

Midkine (MDK) and Pleiotrophin (PTN) belong to a group of heparin-binding growth factors that has been shown to have pleiotropic functions in various biological processes during development and disease. Development of the vertebrate eye is a multistep process that involves coordinated interactions between neuronal and non-neuronal cells, but very little is known about the potential function of MDK and PTN in these processes. In this study, we demonstrate by section in situ hybridization, the spatiotemporal expression of MDK and PTN during ocular development in chick and mouse. We show that MDK and PTN are expressed in dynamic patterns that overlap in a few non-neuronal tissues in the anterior eye and in neuronal cell layers of the posterior eye. We show that the expression patterns of MDK and PTN are only conserved in a few tissues in chick and mouse but they overlap with the expression of some of their receptors LRP1, RPTPZ, ALK, NOTCH2, ITGß1, SDC1, and SDC3. The dynamic expression patterns of MDK, PTN and their receptors suggest that they function together during the multistep process of ocular development and they may play important roles in cell proliferation, adhesion, and migration of neuronal and non-neuronal cells.


Assuntos
Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Olho/embriologia , Midkina/metabolismo , Animais , Proteínas de Transporte/fisiologia , Proliferação de Células/fisiologia , Embrião de Galinha , Citocinas/fisiologia , Olho/metabolismo , Feminino , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Heparina/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL/embriologia , Midkina/fisiologia , Gravidez , Retina/embriologia , Fator A de Crescimento do Endotélio Vascular
8.
Horm Mol Biol Clin Investig ; 38(1)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30840586

RESUMO

Background Irisin and fibroblast growth factor 1 (FGF1) are intricately involved in metabolic syndrome (MetS) and prediabetes (preDM) pathophysiology. This study aimed to compare and correlate irisin and FGF1 plasma levels, adiposity, atherogenicity and hematological indices in 29 normoglycemic MetS and 30 newly diagnosed drug naive prediabetic (PreDM) MetS patients vs. 29 lean and normoglycemic controls. Materials and methods Irisin and FGF1 plasma levels were measured using colorimetric assays. Intergroup comparisons were conducted by analysis of variance (ANOVA). Spearman's rank correlation was also examined. Results The mean circulating irisin levels (ng/mL) were significantly higher in the normoglycemic (but not prediabetic) MetS group (p < 0.01), while the mean circulating FGF1 levels (pg/mL) were markedly lower in the prediabetic (but not normoglycemic) MetS group (p < 0.05). Of note unlike FGF1, irisin in the MetS (both normoglycemic and prediabetic;N=59) groups correlated significantly and positively with each of waist circumference (WC), hip circumference (HC), body mass index (BMI), body adiposity index (BAI) and high-density lipoprotein-cholesterol (HDL-C) but not the non-HDL-C. Distinctively MetS-irisin negatively associated with the non-HDL-C/HDL-C ratio, total cholesterol (TC)/HDL-C ratio and the low-density lipoprotein-cholesterol (LDL-C)/HDL-C ratio, but positively with the red cell distribution width (RDW). In the same pool of 59 MetS reruits; Neither biomarker had a relationship with the visceral adiposity index (VAI), the lipid accumulation product (LAP), the conicity index (CI), the waist-hip ratio (WHR), the waist-to-height ratio (WHtR), the blood ratios or the atherogenicity index of plasma (AIP). Conclusions As any potential molecular crosstalk of irisin and FGF1 in MetS or its related dysregularities cannot be ruled out; Conversely the utility of irisin and FGF1 as surrogate prognostic biomarkers and putative pharmacotherapeutic targets in the predtion/prevention/management of diabetes and MetS is strongly suggested.


Assuntos
Adiposidade , Fator 1 de Crescimento de Fibroblastos/sangue , Fibronectinas/sangue , Síndrome Metabólica/sangue , Estado Pré-Diabético/sangue , Biomarcadores/sangue , HDL-Colesterol/sangue , Feminino , Humanos , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Estado Pré-Diabético/etiologia , Triglicerídeos/sangue
10.
Diabetes ; 68(5): 1054-1061, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796029

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of diabetic hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). To identify the brain areas responsible for this effect, we first used immunohistochemistry to map the hypothalamic distribution of phosphorylated extracellular signal-related kinase 1/2 (pERK1/2), a marker of mitogen-activated protein kinase-ERK signal transduction downstream of FGF receptor activation. Twenty minutes after icv FGF1 injection in adult male Wistar rats, pERK1/2 staining was detected primarily in two hypothalamic areas: the arcuate nucleus-median eminence (ARC-ME) and the paraventricular nucleus (PVN). To determine whether an action of FGF1 localized to either the ARC-ME or the PVN is capable of mimicking the sustained antidiabetic effect elicited by icv FGF1, we microinjected either saline vehicle or a low dose of FGF1 (0.3 µg/side) bilaterally into either the ARC-ME area or PVN of Zucker Diabetic Fatty rats, a model of T2D, and monitored daily food intake, body weight, and blood glucose levels over a 3-week period. Whereas bilateral intra-arcuate microinjection of saline vehicle was without effect, remission of hyperglycemia lasting >3 weeks was observed following bilateral microinjection of FGF1 into the ARC-ME. This antidiabetic effect cannot be attributed to leakage of FGF1 into cerebrospinal fluid and subsequent action on other brain areas, since icv injection of the same total dose was without effect. Combined with our finding that bilateral microinjection of the same dose of FGF1 into the PVN was without effect on glycemia or other parameters, we conclude that the ARC-ME area (but not the PVN) is a target for sustained remission of diabetic hyperglycemia induced by FGF1.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Fator 1 de Crescimento de Fibroblastos/farmacologia , Eminência Mediana/efeitos dos fármacos , Eminência Mediana/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ratos , Ratos Wistar , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
11.
Med Sci Monit ; 25: 984-990, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716059

RESUMO

BACKGROUND The expression and mechanism of IL-1, IL-2, IL-8, BMP, FGF1, and IGF-1 in Sprague-Dawley (SD) rats with lumbar disc herniation were investigated. MATERIAL AND METHODS Immunohistochemical methods were applied to identify IL-1, IL-2, IL-8, BMP, FGF1, and IGF-1. PI3K, AKT protein, and mRNA expression were detected and analyzed by Western blot analysis. We selected 30 healthy SD rats and divided them into 2 groups to construct an animal model that was validated by immediate CT scanning. Cartilage tissues from the lumbar disc herniation (experimental) group and control group were obtained and compared. RESULTS The expression of BMP was not significantly different between the control group and the experimental group (P>0.05). FGF1: There was no significant difference in the expression of FGF1 (P>0.05) between the control group and the experimental group. Compared with the control group, the expression of IGF-1 in the experimental group was significantly higher (P<0.05); the expression of IL-1 in the experimental group was significantly higher (P<0.05); and the expression of IL-2 in the experimental group was also significantly higher (P<0.05). There was no significant difference in IL-8 between the experimental group and the control group (P>0.05). The expression levels of PI3K and AKT protein and mRNA were significantly higher than those in healthy controls (P<0.05). CONCLUSIONS After lumbar disc herniation occurred, the IGF-1 was first activated; the PI3K/AKT signaling pathway was later activated, which resulted in the expression of IL-1 and IL-2 inflammation-related factors being increased.


Assuntos
Deslocamento do Disco Intervertebral/metabolismo , Vértebras Lombares/metabolismo , Vértebras Lombares/fisiopatologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Disco Intervertebral , Deslocamento do Disco Intervertebral/fisiopatologia , Região Lombossacral , Masculino , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
12.
Biopolymers ; 110(7): e23252, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30667535

RESUMO

Heparin is a key player in cell signaling via its physical interactions with protein targets in the extracellular matrix. However, basic molecular level understanding of these highly biologically relevant intermolecular interactions is still incomplete. In this study, for the first time, microsecond-scale MD simulations are reported for a complex between fibroblast growth factor 1 and heparin. We rigorously analyze this molecular system in terms of the conformational space, structural, energetic, and dynamic characteristics. We reveal that the conformational selection mechanism of binding denotes a recognition specificity determinant. We conclude that the length of the simulation could be crucial for evaluation of some of the analyzed parameters. Our data provide novel significant insights into the interactions in the fibroblast growth factor 1 complex with heparin, in particular, and into the physical-chemical nature of protein-glycosaminoglycan systems in general, which have potential applicability for biomaterials development in the area of regenerative medicine.


Assuntos
Fator 1 de Crescimento de Fibroblastos/química , Heparina/química , Simulação de Dinâmica Molecular , Sítios de Ligação , Fator 1 de Crescimento de Fibroblastos/metabolismo , Heparina/metabolismo , Humanos , Cinética , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Termodinâmica
13.
Diabetes ; 68(3): 654-664, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30523024

RESUMO

We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic ß-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of ß-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of ß-cell function and stimulation of HGU through increased hepatic glucokinase activity.


Assuntos
Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucoquinase/genética , Glucoquinase/metabolismo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Resistência à Insulina , Masculino , Ratos , Ratos Zucker , Reação em Cadeia da Polimerase em Tempo Real
14.
Int Endod J ; 52(1): 54-67, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29975794

RESUMO

AIM: To compare the formation of fibrous capsules around Biodentine and MTA Angelus implants as well as the participation of fibroblast growth factor-1 (FGF-1) and mast cells in the tissue response to these endodontic materials. METHODOLOGY: Sixty polyethylene tubes filled with Biodentine or MTA, and empty tubes (control group) were implanted into the dorsal subcutaneous tissues of male rats. After 7, 15, 30 and 60 days, the specimens were embedded in paraffin and the number of fibroblasts and mast cells was quantified in the sections stained with Masson's trichrome or Alcian Blue, respectively. FGF-1 and Ki-67 were detected by immunohistochemistry, and the number of immunolabelled cells was computed. The collagen content was estimated in the picrosirius red-stained sections. The data were subjected to two-way ANOVA followed by Tukey's test (P ≤ 0.05). RESULTS: The capsules were associated with a significant increase (P < 0.0001) in the number of fibroblasts and mast cells, and in the collagen content over time. A significant decrease (P < 0.0001) in the immunoexpression of FGF-1 and Ki-67 was observed in all groups from the 7th-60th day. At 60 days, the number of fibroblasts (P = 0.0226) and the collagen content (P < 0.0001) were significantly greater in MTA than Biodentine specimens, while the greatest number of mast cells and FGF-1-immunolabelled cells was observed in Biodentine specimens (P < 0.0001). A significant difference in Ki-67 immunoexpression was not detected between specimens of Biodentine and MTA. CONCLUSIONS: The collagen-rich capsule formed slowly around Biodentine in comparison with MTA. FGF-1 and mast cells participated in capsule remodelling, stimulating fibroblast proliferation and subsequent collagen production, in response to subcutaneous implants.


Assuntos
Bismuto/farmacologia , Compostos de Cálcio/farmacologia , Fator 1 de Crescimento de Fibroblastos/metabolismo , Antígeno Ki-67/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Óxidos/farmacologia , Silicatos/farmacologia , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Imuno-Histoquímica , Implantes Experimentais , Masculino , Mastócitos/imunologia , Mastócitos/patologia , Teste de Materiais , Ratos , Materiais Restauradores do Canal Radicular/farmacologia , Tela Subcutânea/imunologia
17.
BMC Vet Res ; 14(1): 351, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445954

RESUMO

BACKGROUND: In the field of diabetes research, many studies on cell therapy have been conducted using mesenchymal stem cells. This research was intended to shed light on the influence of canine adipose-tissue-derived mesenchymal stem cell conditioned medium (cAT-MSC CM) on in vitro insulin resistance models that were induced in differentiated 3T3-L1 adipocytes and the possible mechanisms involved in the phenomenon. RESULTS: Gene expression levels of insulin receptor substrate-1 (IRS-1) and glucose transporter type 4 (GLUT4) were used as indicators of insulin resistance. Relative protein expression levels of IRS-1 and GLUT4 were augmented in the cAT-MSC CM treatment group compared to insulin resistance models, indicating beneficial effects of cAT-MSC to DM, probably by actions of secreting factors. With reference to previous studies on fibroblast growth factor-1 (FGF1), we proposed FGF1 as a key contributing factor to the mechanism of action. We added anti-FGF1 neutralizing antibody to the CM-treated insulin resistance models. As a result, significantly diminished protein levels of IRS-1 and GLUT4 were observed, supporting our assumption. Similar results were observed in glucose uptake assay. CONCLUSIONS: Accordingly, this study advocated the potential of FGF-1 from cAT-MSC CM as an alternative insulin sensitizer and discovered a signalling factor associated with the paracrine effects of cAT-MSC.


Assuntos
Tecido Adiposo/metabolismo , Fator 1 de Crescimento de Fibroblastos/metabolismo , Resistência à Insulina , Comunicação Parácrina , Adipócitos/metabolismo , Tecido Adiposo/citologia , Animais , Cães , Transportador de Glucose Tipo 4/metabolismo , Técnicas In Vitro , Proteínas Substratos do Receptor de Insulina/metabolismo , Células-Tronco Mesenquimais
18.
J Orthop Surg Res ; 13(1): 301, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30482233

RESUMO

BACKGROUND: The objective of the present study was to investigate the effectiveness of acidic fibroblast growth factor delivered in collagen (aFGF/collagen) for promoting tendon-bone interface healing after anterior cruciate ligament (ACL) reconstruction in rabbits. METHODS: ACL reconstructions were performed in the right hind limbs of New Zealand rabbits. Each left long digital extensor tendon was harvested as an autograft, and collagen incorporating different concentrations of aFGF or same amount of collagen alone was applied at the tendon-bone interface after ACL reconstruction. The control group underwent ACL reconstruction only. There were high and low aFGF/collagen groups, collagen alone group, and control group (n = 21 rabbits per group). Histological and biomechanical analyses were performed at 4, 8, and 12 weeks postoperatively to evaluate the effect of aFGF/collagen on tendon-bone interface healing. RESULTS: Results of biomechanical tests showed that at both 8 and 12 weeks postoperatively, the elastic modulus and stiffness in both the high and low aFGF/collagen treatment groups were significantly higher than those in the control group and collagen alone group, with that in the high aFGF/collagen concentration group being the highest. Histological analysis showed that at 8 weeks, tightly organized Sharpey-like fibers were observed in both aFGF/collagen groups with new bone growth into the tendon in the high concentration group. At 12 weeks postoperatively, a fibrocartilage transition zone was observed in the bone tunnels in both aFGF/collagen groups, especially in the high aFGF/collagen group. CONCLUSION: Application of the aFGF/collagen composite could enhance early healing at the tendon-bone interface after ACL reconstruction, especially with the use of a high aFGF/collagen concentration.


Assuntos
Reconstrução do Ligamento Cruzado Anterior/métodos , Colágeno/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Tendões/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Reconstrução do Ligamento Cruzado Anterior/tendências , Colágeno/metabolismo , Feminino , Fator 1 de Crescimento de Fibroblastos/metabolismo , Masculino , Coelhos , Distribuição Aleatória , Tendões/metabolismo , Tendões/patologia , Cicatrização/fisiologia
19.
Biochem Biophys Res Commun ; 505(2): 505-510, 2018 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-30268497

RESUMO

Age-related cataract, the most common cause of blindness worldwide, has been found closely associated with ß-crystallin B2 (ßB2 or CRYBB2). MicroRNAs (miRNAs) are the primary epigenetic regulators important for various biological processes. However, the role of miRNAs in the progression of lens cataract remains to be elucidated. In this study, we found a novel signal cascade miR-326-fibroblast growth factor 1 (FGF1)-ßB2 modulating the progression of lens cataract. In brief, miR-326 exacerbated but its antagomirs attenuated H2O2-induced apoptosis of HLEC-B3 human lens epithelial cells. Dual-luciferase reporter assay and Western blot showed that miR-326 inhibited FGF1 expression by directly targeting its mRNA 3'-UTR. Consistent with this result, miR-326 antagomir enhanced FGF1 protein level. In addition to FGF1, miR-326 antagomir also enhanced ßB2 expression and this enhancement was abolished by transfection of HLEC-B3 cells with FGF1 shRNA. These data demonstrated that miR-326 antagomir increased ßB2 expression via upregulating FGF1, which was further confirmed by the studies in a rat model of selenite-induced cataract. This work suggests that miR-326 antagomir might be a promising candidate to prevent progression of age-related cataract.


Assuntos
Antagomirs/metabolismo , Catarata/metabolismo , Fator 1 de Crescimento de Fibroblastos/metabolismo , MicroRNAs/antagonistas & inibidores , Cadeia B de beta-Cristalina/metabolismo , Regiões 3' não Traduzidas , Fatores Etários , Animais , Apoptose , Catarata/genética , Catarata/patologia , Catarata/terapia , Linhagem Celular , Progressão da Doença , Células Epiteliais/citologia , Fator 1 de Crescimento de Fibroblastos/genética , Humanos , Cristalino/citologia , Ratos Sprague-Dawley , Regulação para Cima
20.
J Cell Mol Med ; 22(12): 6294-6303, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30320493

RESUMO

Diabetic nephropathy (DN) is one of general and common complication of diabetes, which severely affects the physical and mental health of diabetic patients. Fibroblast growth factor 1 (FGF1), an effective control agent of blood glucose, plays an effective treatment role on diabetes-induced renal injury. But the specific molecule mechanism underlying it is still unclear. Since induction of cellular stress is the main and common mechanism of diabetes-induced complication, we hypothesized that reduction of cellular stress is also the molecular mechanism of FGF1 treatment for DN. Here, we have further confirmed that FGF1 significantly ameliorated the diabetes-induced renal interstitial fibrosis and glomerular damage. The expression levels of collagen and α-smooth muscle actin (α-SMA) also dramatically induced in kidney from db/db mice, but these effects were blocked by FGF1 administration. Our mechanistic investigation had further revealed that diabetes significantly induced oxidative stress, nitrosative stress, and endoplasmic reticulum (ER) stress with upregulation of malondialdehyde (MDA), nitrotyrosine level, ER stress makers and downregulation of antioxidant capacity (AOC). FGF1 treatment significantly attenuated the effect of diabetes on cellular stress. We conclude that FGF1-associated glucose decreases and subsequent reduction of cellular stress is the another potential molecule mechanism underlying FGF1 treatment for DN.


Assuntos
Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Fator 1 de Crescimento de Fibroblastos/genética , Fibrose/genética , Animais , Antioxidantes/metabolismo , Glicemia/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Estresse do Retículo Endoplasmático/genética , Fibrose/metabolismo , Fibrose/patologia , Regulação da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/genética
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