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The signaling complex around voltage-gated sodium (Nav) channels includes accessory proteins and kinases crucial for regulating neuronal firing. Previous studies showed that one such kinase, WEE1-critical to the cell cycle-selectively modulates Nav1.2 channel activity through the accessory protein fibroblast growth factor 14 (FGF14). Here, we tested whether WEE1 exhibits crosstalk with the AKT/GSK3 kinase pathway for coordinated regulation of FGF14/Nav1.2 channel complex assembly and function. Using the in-cell split luciferase complementation assay (LCA), we found that the WEE1 inhibitor II and GSK3 inhibitor XIII reduce the FGF14/Nav1.2 complex formation, while the AKT inhibitor triciribine increases it. However, combining WEE1 inhibitor II with either one of the other two inhibitors abolished its effect on the FGF14/Nav1.2 complex formation. Whole-cell voltage-clamp recordings of sodium currents (INa) in HEK293 cells co-expressing Nav1.2 channels and FGF14-GFP showed that WEE1 inhibitor II significantly suppresses peak INa density, both alone and in the presence of triciribine or GSK3 inhibitor XIII, despite the latter inhibitor's opposite effects on INa. Additionally, WEE1 inhibitor II slowed the tau of fast inactivation and caused depolarizing shifts in the voltage dependence of activation and inactivation. These phenotypes either prevailed or were additive when combined with triciribine but were outcompeted when both WEE1 inhibitor II and GSK3 inhibitor XIII were present. Concerted regulation by WEE1 inhibitor II, triciribine, and GSK3 inhibitor XIII was also observed in long-term inactivation and use dependency of Nav1.2 currents. Overall, these findings suggest a complex role for WEE1 kinase-in concert with the AKT/GSK3 pathway-in regulating the Nav1.2 channelosome.
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Proteínas de Ciclo Celular , Quinase 3 da Glicogênio Sintase , Canal de Sódio Disparado por Voltagem NAV1.2 , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas c-akt , Humanos , Células HEK293 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ciclo Celular/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Proteínas Tirosina Quinases/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Fibroblast growth factors (FGFs) are a group of structurally homologous yet functionally pleiotropic proteins. Canonical and intracellular FGFs have primarily autocrine or paracrine effects. However, the FGF19 subfamily, composed of FGF15/19, FGF21, and FGF23, act as endocrine hormones that regulate bile acid, metabolic, and phosphorus homeostasis, respectively. Current research in human and rodent models demonstrates the potential of these endocrine FGFs to target various diseases, including disorders of inherited hypophosphatemia, chronic liver disease, obesity, and insulin resistance. Many diseases targeted for therapeutic use in humans have pathophysiological overlaps in domestic animals. Despite the potential clinical and economic impact, little is known about endocrine FGFs and their signaling pathways in major domestic animal species compared with humans and laboratory animals. This review aims to describe the physiology of these endocrine FGFs, discuss their current therapeutic use, and summarize the contemporary literature regarding endocrine FGFs in domestic animals, focusing on potential future directions.
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Background: Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that regulates nutrient and metabolic homeostasis. Inflammatory state is one of the stimulators of FGF21 secretion. The aim of the study was to assess correlations between serum FGF21 level and inflammatory markers as well as nutritional status indicators in patients with inflammatory bowel disease (IBD). Methods: Fasting serum FGF21 level was measured using ELISA test in 105 IBD patients and 17 healthy controls. There were 31 subjects with active ulcerative colitis (UC), 16 with inactive UC, 36 with active Crohn's disease (CD), and 22 with inactive CD. Clinical and endoscopic activity of IBD was evaluated based on validated scales and indices. Fecal calprotectin, serum CRP, and selected parameters of nutritional status were tested in all patients. Results: Serum FGF21 level was characterized by fluctuations depending on the IBD activity. FGF21 level was significantly higher in both active UC and CD compared to inactive phases of the diseases and to the controls. A correlation between FGF21 and fecal calprotectin levels was also found in UC and CD. Additionally, in CD, FGF21 level positively correlated with CRP level. In both UC and CD, a negative correlation was noted between FGF21 level and nutritional status parameters including cholesterol, protein, albumin levels, and BMI. Conclusion: The intensity of intestinal inflammation is related to FGF21 level, which correlates negatively with nutritional status indicators in IBD. The disturbances in FGF21 secretion may contribute to the multifactorial pathogenesis of malnutrition and weight loss in IBD patients.
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Fibrilação Atrial , Átrios do Coração , Miócitos Cardíacos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibrilação Atrial/metabolismo , Fibrilação Atrial/etiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Miócitos Cardíacos/metabolismo , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/etiologiaRESUMO
Fibroblast growth factors (FGFs) have a key role in various critical steps of tumor growth and progression through effects on angiogenesis, inflammation and the growth and invasion of malignant cells. Nevertheless, the role of the FGF family in human glioblastoma (GBM) has been rarely studied. The objective of the present study was to assess the RNA expression of all FGF family members in tissues obtained from patients with GBM and to analyze the association between FGF expression and the survival of these patients. For this, the RNA expression of FGF family members in the malignant and proximal tissues of 12 patients with GBM was determined by analyzing high-throughput RNA transcriptome sequencing data uploaded to the National Center for Biotechnology Information database. The relationship between FGF genes and the survival of patients with GBM and glioma was also respectively studied by analyzing data from The Cancer Genome Atlas database using the Gene Expression Profiling Interactive Analysis tool. The results showed that the expression of FGF1, FGF17, FGF20 and FGF22 in GBM tissues was lower than that in adjacent tissues, with a difference of >2 times. Analysis of the overall survival of patients with GBM indicated there were no significant relationships between the expression of FGF1, FGF17, FGF20, FGF22 and overall survival. Analysis of the overall survival of patients with glioma showed that glioma patients with low FGF1 expression achieved a longer survival time than patients with high FGF1 expression; however, high expression of FGF17 and FGF22 indicated a longer survival time. In summary, the results of the present study demonstrated the panoramic expression of FGF family members in patients with GBM, and indicated that FGF1, FGF17 and FGF22 did not affect the survival of patients with GBM, but had a notable influence on the survival of patients with glioma.
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Introduction: The role of Adipose-derived mesenchymal stem cells (AD-MSCs) in skin wound healing remains to be fully characterized. This study aims to evaluate the regenerative potential of autologous AD-MSCs in a non-healing porcine wound model, in addition to elucidate key miRNA-mediated epigenetic regulations that underlie the regenerative potential of AD-MSCs in wounds. Methods: The regenerative potential of autologous AD-MSCs was evaluated in porcine model using histopathology and spatial frequency domain imaging. Then, the correlations between miRNAs and proteins of AD-MSCs were evaluated using an integration analysis in primary human AD-MSCs in comparison to primary human keratinocytes. Transfection study of AD-MSCs was conducted to validate the bioinformatics data. Results: Autologous porcine AD-MSCs improved wound epithelialization and skin properties in comparison to control wounds. We identified 26 proteins upregulated in human AD-MSCs, including growth and angiogenic factors, chemokines and inflammatory cytokines. Pathway enrichment analysis highlighted cell signalling-associated pathways and immunomodulatory pathways. miRNA-target modelling revealed regulations related to genes encoding for 16 upregulated proteins. miR-155-5p was predicted to regulate Fibroblast growth factor 2 and 7, C-C motif chemokine ligand 2 and Vascular cell adhesion molecule 1. Transfecting human AD-MSCs cell line with anti-miR-155 showed transient gene silencing of the four proteins at 24 h post-transfection. Discussion: This study proposes a positive miR-155-mediated gene regulation of key factors involved in wound healing. The study represents a promising approach for miRNA-based and cell-free regenerative treatment for difficult-to-heal wounds. The therapeutic potential of miR-155 and its identified targets should be further explored in-vivo.
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Diabetes affects about 422 million people worldwide, causing 1.5 million deaths each year. However, the incidence of diabetes is increasing, including several types of diabetes. Type 1 diabetes (5%-10% of diabetic cases) and type 2 diabetes (90%-95% of diabetic cases) are the main types of diabetes in the clinic. Accumulating evidence shows that the fibroblast growth factor (FGF) family plays important roles in many metabolic disorders, including type 1 and type 2 diabetes. FGF consists of 23 family members (FGF-1-23) in humans. Here, we review current findings of FGFs in the treatment of diabetes and management of diabetic complications. Some FGFs (e.g., FGF-15, FGF-19, and FGF-21) have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes, and their therapeutic roles in diabetes are currently under investigation in clinical trials. Overall, the roles of FGFs in diabetes and diabetic complications are involved in numerous processes. First, FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production. Second, modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components, promote diabetic wound healing process and bone repair, and inhibit cancer cell proliferation and migration. Finally, FGFs can regulate the activation of glucose-excited neurons and the expression of thermogenic genes.
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Heparan sulfate (HS) is a glycosaminoglycan, polysaccharides that are considered to have arisen in the last common unicellular ancestor of multicellular animals. In this light, the large interactome of HS and its myriad functions in relation to the regulation of cell communication are not surprising. The binding of proteins to HS determines their localisation and diffusion, essential for embryonic development and homeostasis. Following the biosynthesis of the initial heparosan polymer, the subsequent modifications comprise an established canonical pathway and a minor pathway. The more frequent former starts with N-deacetylation and N-sulfation of GlcNAc residues, the latter with C-5 epimerisation of a GlcA residue adjacent to a GlcNAc. The binding of proteins to HS is driven by ionic interactions. The multivalent effect arising from the many individual ionic bonds between a single protein and a polysaccharide chain results in a far stronger interaction than would be expected from an ion-exchange process. In many instances, upon binding, both parties undergo substantial conformational change, the resulting hydrogen and van der Waal bonds contributing significant free energy to the binding reaction. Nevertheless, ionic bonds dominate the protein-polysaccharide interaction kinetically. Together with the multivalent effect, this provides an explanation for the observed trapping of HS-binding proteins in extracellular matrix. Importantly, individual ionic bonds have been observed to be dynamic; breaking and reforming, while the protein remains bound to the polysaccharide. These considerations lead to a model for 1D diffusion of proteins in extracellular matrix on HS, involving mechanisms such as sliding, chain switching and rolling.
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BACKGROUND: Growth factor preparations have demonstrated effectiveness in reversing age-related changes in facial skin. TNS® Advanced+ Serum (TNS A+ Serum; SkinMedica®, Allergan Aesthetics, an AbbVie Company) and TNS Advanced+ Pro-Infusion Serum for DiamondGlow® (DG-TNS A+; Allergan Aesthetics) combine growth factor technology with active botanical ingredients to target signs of skin aging. AIMS: This prospective clinical study evaluated the effectiveness and tolerability of biweekly facial hydradermabrasion (DiamondGlow [DG]; Allergan Aesthetics) plus DG-TNS A+ combined with at-home topical TNS A+ Serum. METHODS: Females aged 25-65 years with mild to severe facial photodamage received 6 biweekly DG plus DG-TNS A+ in-office treatments with at-home twice-daily TNS A+ Serum for 12 weeks. Investigator-assessed clinical grading of multiple skin attributes, subject self-assessments, instrumentation measurements, and clinical grading of irritation parameters (0-3, none to severe) were conducted at Visit 1, Day 3, and biweekly from Weeks 2-12. RESULTS: Twenty-nine women (Fitzpatrick skin types II-VI; 52% White, 41% African American) were enrolled. Immediate significant improvements after 1 DG plus DG-TNS A+ treatment were observed for fine lines/wrinkles, skin smoothness (visual and tactile), radiance, and hydration (all p ≤ 0.004). From Weeks 6-12, all investigator-assessed parameters showed significant improvements versus baseline (all p ≤ 0.002 at Week 12). Mean tolerability scores were <1 across parameters. All subjects (100%) were satisfied with results at Weeks 2-12. CONCLUSIONS: The combination of biweekly hydradermabrasion plus DG-TNS A+ with at-home TNS A+ Serum treatments was well tolerated and produced immediate, progressive improvement in multiple signs of photoaging in facial skin.
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Cosméticos , Envelhecimento da Pele , Feminino , Humanos , Administração Cutânea , Estudos Prospectivos , Resultado do Tratamento , Pele , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
Purpose: To investigate the effect of ellagic acid (EA) in gingival tissues injury in rats. Methods: Twenty rats were categorized into two groups. In burn group, an excisional wound area was created by removing a 4-mm diameter flap from the left molar region in the mucoperiosteal region of the gingiva. In burn + ellagic acid group, 1.2 mg/mL EA was administered as irrigation for one week. Animals was sacrificed under anesthesia at the end of experiment. Malondialdehyde (MDA), myeloperoxidase (MPO) and glutathione (GSH) level were measured. Hematoxylin and eosin, fibroblast growth factor (FGF) and epidermal growth factor (EGF) immunostainings were applied to tissues. Results: MDA, MPO, inflammation and leukocyte infiltration were high in burn group. Degeneration epithelium, edema and inflammatory cell infiltration in connective tissue areas, and dilatation and congestion in blood vessels were observed in burn group. In burn + EA group, the gingival epithelium improved, collagen fiber production increased and organized dermis were observed. After burn injury, FGF and EGF activity was increased in EA treated groups. Conclusions: We suggest that EA have the potential for better healing outcomes in oral wounds. EA seems to have promising therapeutic efficacy to enhance oral wound healing.
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Animais , Ratos , Ácido Elágico , Fator de Crescimento Epidérmico , Fibroblastos , Gengiva/lesões , Animais de LaboratórioRESUMO
Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. Understanding the pathogenesis and appropriate diagnosis of GDM enables the implementation of early interventions during pregnancy that reduce the risk of maternal and fetal complications. At the same time, it provides opportunities to prevent diabetes, metabolic syndrome, and cardiovascular diseases in women with GDM and their offspring in the future. Fibroblast growth factors (FGFs) represent a heterogeneous family of signaling proteins which play a vital role in cell proliferation and differentiation, repair of damaged tissues, wound healing, angiogenesis, and mitogenesis and also affect the regulation of carbohydrate, lipid, and hormone metabolism. Abnormalities in the signaling function of FGFs may lead to numerous pathological conditions, including metabolic diseases. The FGF19 subfamily, also known as atypical FGFs, which includes FGF19, FGF21, and FGF23, is essential in regulating metabolic homeostasis and acts as a hormone while entering the systemic circulation. Many studies have pointed to the involvement of the FGF19 subfamily in the pathogenesis of metabolic diseases, including GDM, although the results are inconclusive. FGF19 and FGF21 are thought to be associated with insulin resistance, an essential element in the pathogenesis of GDM. FGF21 may influence placental metabolism and thus contribute to fetal growth and metabolism regulation. The observed relationship between FGF21 and increased birth weight could suggest a potential role for FGF21 in predicting future metabolic abnormalities in children born to women with GDM. In this group of patients, different mechanisms may contribute to an increased risk of cardiovascular diseases in women in later life, and FGF23 appears to be their promising early predictor. This study aims to present a comprehensive review of the FGF19 subfamily, emphasizing its role in GDM and predicting its long-term metabolic consequences for mothers and their offspring.
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Doenças Cardiovasculares , Diabetes Gestacional , Síndrome Metabólica , Criança , Feminino , Gravidez , Humanos , Diabetes Gestacional/metabolismo , Doenças Cardiovasculares/metabolismo , Placenta/metabolismo , Síndrome Metabólica/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônios/metabolismoRESUMO
OBJECTIVE: To investigate the effect of Bo's abdominal acupuncture (BOAA) on fibroblast growth factor 21 (FGF21) and its related adipokines in type 2 diabetes mellitus (T2DM) rats. METHODS: This study established obese T2DM rat model by high-fat diet (HFD) with a dose of streptozotocin (STZ, 30 mg/kg). Obese T2DM rats were randomly subdivided into four groups (n = 10): negative, BOAA, conventional acupuncture (COA group) and metformin group (Met group) groups. The biochemical parameters, mRNAs, and proteins were analyzed using enzyme-lined immunoassays kits, quantitative polymerase chain reaction and Western blot. RESULTS: Treatment with BOAA attenuated the histopathological changes in visceral fat and restored the alterations in the levels of body weight, fasting blood glucose (FBG), homeostasis model assessment for insulin resistance (HOMA-IR). BOAA treatment significantly decreased the levels of triglyceride, total cholesterol, low density lipoprotein cholesterol, leptin, and increased the serum levels of high-density lipoprotein cholesterol, fibroblast growth factor 21 (FGF21), adiponectin (ADP), peroxisome proliferator-activated receptor γ (PPAR-γ), C-peptide (C-P) in obese T2DM rats. Furthermore, BOAA treatment significantly increased the mRNA expressions of FGF21, ADP, leptin, PPAR-γ, PPAR-α and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Besides, BOAA treatment upregulated the protein expressions of fibroblast growth factor receptors3 (FGFR3), PPAR-α, extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), AMPK, p-AMPK, Liver kinase B1 (LKB1), phosphorylated LKB1 (p-LKB1), acetyl-CoA carboxylase (ACC) and phosphorylated ACC (p-ACC), while downregulated the protein expressions of FGF21 and PPAR-γ in visceral fat. CONCLUSIONS: BOAA treatment reduced FBG and body weight, and improved insulin sensitivity through regulating FGF21 signaling pathway and its related adipokine in obese T2DM rats.
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Terapia por Acupuntura , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Ratos , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/metabolismo , Leptina , Adipocinas , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/terapia , Receptores Ativados por Proliferador de Peroxissomo , Obesidade/complicações , Obesidade/terapia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , ColesterolRESUMO
Arterial stiffness has been linked to impaired cognitive function and dementia but the reason for the association is uncertain. This review proposes that collagen type IV is a critical factor linking arterial stiffness and dementia. Several genome wide association studies have related arterial stiffness to Collagen type IVα. Proteomic studies of arteries, demonstrated higher levels of collagen IVα1 in persons with high arterial stiffness. Collagen type IV defects are associated genetic causes of dementia as well as dementia of a variety of other causes. There are plausible causal roles for collagen type IV in dementia. Disorders of Collagen type IV can produce (I) fibro-hyalinosis and elastosis of small arterioles leading to cerebral ischemia and infarction; (II) dysfunction of the blood brain barrier leading to cerebral hemorrhage; (III) carotid artery stiffness with increase pulse pressure induces cerebral blood vessel damage leading to cerebral atrophy. The mechanisms by which Collagen type IV can lead to vascular stiffness include its degradation by matrix metalloprotease type 2 that (a) stimulates vascular smooth muscle cells to produce more extracellular matrix or (b) liberates peptides that damage the subendothelial space. Factors, such as TGF-ß1, and LDL cholesterol especially oxidized LDL can increase collagen type IV and produce vascular stiffness and dementia. Fibroblast growth factor 23, and abnormal NO signaling have been linked to collagen type IV or increased vascular stiffness and an increased risk of dementia. Recognition of the central role of collagen type IV in arterial stiffness and dementia will inspire new research focused on determining whether its modification can benefit arterial and brain health.
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Increasing evidence suggests that the brain plays a key role in glucose homeostasis, making it a potential target for the treatment of type 2 diabetes (T2D). Sun et al. recently reported that intracerebroventricular (ICV) administration of a single dose of fibroblast growth factor 4 (FGF4) can induce sustained T2D remission in mouse models in the absence of any risk of hypoglycemia.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Hipoglicemia , Animais , Camundongos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 4 de Crescimento de Fibroblastos , Hiperglicemia/tratamento farmacológico , Obesidade/tratamento farmacológicoRESUMO
Rationale: UV light deeply penetrates the dermis, leading to inflammation and cell death with prolonged exposure. This is a major contributor to skin photoaging. In the pharmaceutical field, fibroblast growth factors (FGFs) have gained popularity for enhancing skin quality as they facilitate tissue remodeling and re-epithelization. Nonetheless, their effectiveness is significantly hindered by limited absorption. Methods: We have successfully created a dissolving microneedle (MN) patch that contains hyaluronic acid (HA) loaded with FGF-2 and FGF-21. This patch aims to improve the therapeutic efficiency of these growth factors while providing a simple administration method. We determined the performance of this patch in an animal model of skin photoaging. Results: The FGF-2/FGF-21-loaded MN (FGF-2/FGF-21 MN) patch demonstrated a consistent structure and suitable mechanical properties, allowing for easy insertion and penetration into mouse skin. Within 10 minutes of application, the patch released approximately 38.50 ± 13.38% of the loaded drug. Notably, the FGF-2/FGF-21 MNs exhibited significant improvements in UV-induced acute skin inflammation and reduced mouse skin wrinkles within a span of two weeks. Furthermore, the positive effects continued to enhance over a four-week treatment period. Conclusion: The proposed HA-based peelable MN patch provides an efficient approach for transdermal drug delivery, providing a promising method for improved therapeutic outcomes.
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Envelhecimento da Pele , Camundongos , Animais , Fator 2 de Crescimento de Fibroblastos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Fatores de Crescimento de Fibroblastos , InflamaçãoRESUMO
Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival, migration, differentiation and metabolism. Recently, these molecules have emerged as the key components in forming the intricate connections within the nervous system. FGF and FGF receptor (FGFR) signaling pathways play important roles in axon guidance as axons navigate toward their synaptic targets. This review offers a current account of axonal navigation functions performed by FGFs, which operate as chemoattractants and/or chemorepellents in different circumstances. Meanwhile, detailed mechanisms behind the axon guidance process are elaborated, which are related to intracellular signaling integration and cytoskeleton dynamics.
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Fatores de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Orientação de Axônios , Transdução de Sinais/fisiologia , Axônios/metabolismoRESUMO
Growth factors are a class of proteins that play a role in the proliferation (the increase in the number of cells resulting from cell division) and differentiation (when a cell undergoes changes in gene expression becoming a more specific type of cell) of cells. They can have both positive (accelerating the normal healing process) and negative effects (causing cancer) on disease progression and have potential applications in gene therapy and wound healing. However, their short half-life, low stability, and susceptibility to degradation by enzymes at body temperature make them easily degradable in vivo. To improve their effectiveness and stability, growth factors require carriers for delivery that protect them from heat, pH changes, and proteolysis. These carriers should also be able to deliver the growth factors to their intended destination. This review focuses on the current scientific literature concerning the physicochemical properties (such as biocompatibility, high affinity for binding growth factors, improved bioactivity and stability of the growth factors, protection from heat, pH changes or appropriate electric charge for growth factor attachment via electrostatic interactions) of macroions, growth factors, and macroion-growth factor assemblies, as well as their potential uses in medicine (e.g., diabetic wound healing, tissue regeneration, and cancer therapy). Specific attention is given to three types of growth factors: vascular endothelial growth factors, human fibroblast growth factors, and neurotrophins, as well as selected biocompatible synthetic macroions (obtained through standard polymerization techniques) and polysaccharides (natural macroions composed of repeating monomeric units of monosaccharides). Understanding the mechanisms by which growth factors bind to potential carriers could lead to more effective delivery methods for these proteins, which are of significant interest in the diagnosis and treatment of neurodegenerative and civilization diseases, as well as in the healing of chronic wounds.
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Peptídeos e Proteínas de Sinalização Intercelular , Cicatrização , HumanosRESUMO
Fibroblast growth factors (FGFs) encode a large family of growth factor proteins that activate several intracellular signaling pathways to control diverse physiological functions. The human genome encodes 22 FGFs that share a high sequence and structural homology with those of other vertebrates. FGFs orchestrate diverse biological functions by regulating cellular differentiation, proliferation, and migration. Dysregulated FGF signaling may contribute to several pathological conditions, including cancer. Notably, FGFs exhibit wide functional diversity among different vertebrates spatiotemporally. A comparative study of FGF receptor ligands and their diverse roles in vertebrates ranging from embryonic development to pathological conditions may expand our understanding of FGF. Moreover, targeting diverse FGF signals requires knowledge regarding their structural and functional heterogeneity among vertebrates. This study summarizes the current understanding of human FGF signals and correlates them with those in mouse and Xenopus models, thereby facilitating the identification of therapeutic targets for various human disorders.
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Fatores de Crescimento de Fibroblastos , Neoplasias , Humanos , Animais , Camundongos , Xenopus laevis/metabolismo , Ligantes , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Desenvolvimento Embrionário/genética , Neoplasias/genéticaRESUMO
Nonalcoholic fatty liver disease (NAFLD), a chronic condition associated with metabolic dysfunction and obesity, has reached epidemic proportions worldwide. Although early NAFLD can be treated with lifestyle changes, the treatment of advanced liver pathology, such as nonalcoholic steatohepatitis (NASH), remains a challenge. There are currently no FDA-approved drugs for NAFLD. Fibroblast growth factors (FGFs) play essential roles in lipid and carbohydrate metabolism and have recently emerged as promising therapeutic agents for metabolic diseases. Among them, endocrine members (FGF19 and FGF21) and classical members (FGF1 and FGF4) are key regulators of energy metabolism. FGF-based therapies have shown therapeutic benefits in patients with NAFLD, and substantial progress has recently been made in clinical trials. These FGF analogs are effective in alleviating steatosis, liver inflammation, and fibrosis. In this review, we describe the biology of four metabolism-related FGFs (FGF19, FGF21, FGF1, and FGF4) and their basic action mechanisms, and then summarize recent advances in the biopharmaceutical development of FGF-based therapies for patients with NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fígado/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Obesidade/metabolismoRESUMO
BACKGROUND: With millions of victims worldwide, multiple sclerosis is the second most common cause of disability among young adults. Although formidable advancements have been made in understanding the disease, the neurodegeneration associated with multiple sclerosis is only partially counteracted by current treatments, and effective therapy for progressive multiple sclerosis remains an unmet need. Therefore, new approaches are required to delay demyelination and the resulting disability and to restore neural function by promoting remyelination and neuronal repair. AIMS: The article reviews the latest literature in this field. MATERIALS AND METHODS: The fibroblast growth factor (FGF) signaling pathway is a promising target in progressive multiple sclerosis. DISCUSSION: FGF signal transduction contributes to establishing the oligodendrocyte lineage, neural stem cell proliferation and differentiation, and myelination of the central nervous system. Furthermore, FGF signaling is implicated in the control of neuroinflammation. In recent years, interventions targeting FGF, and its receptor (FGFR) have been shown to ameliorate autoimmune encephalomyelitis symptoms in multiple sclerosis animal models moderately. CONCLUSION: Here, we summarize the recent findings and investigate the role of FGF/FGFR signaling in the onset and progression, discuss the potential therapeutic advances, and offer fresh insights into managing multiple sclerosis.