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Drug Delivery Nov 2018Fibroblast growth factor-20 (FGF20) is a paracrine member of the FGF family that is preferentially expressed in the substantia nigra pars compacta (SNpc). Previous...
Fibroblast growth factor-20 (FGF20) is a paracrine member of the FGF family that is preferentially expressed in the substantia nigra pars compacta (SNpc). Previous studies have demonstrated that FGF20 enhances the survival of dopaminergic neurons suggesting the potential use of FGF20 to treat Parkinson's disease (PD). However, the reduced solubility of the bacterial recombinant human FGF20 (rhFGF20) and the absence of efficient strategies to transport rhFGF20 across the blood-brain barrier (BBB) have halted its clinical application. In the present study, we have examined the efficiency of fuzing a small ubiquitin-related modifier (SUMO) to rhFGF20 to enhance its soluble expression and further investigated the efficacy of FUS-guided, rhFGF20-liposome transport across the BBB. We also examined the bioavailability and behavioral improvement in a 6-hydroxydopamine-lesioned rat model of PD following 2 weeks' FUS-liposomal combinatorial treatment. Our results showed that, in contrast with rhFGF20 or LIP-FGF20, the FUS-LIP-rhFGF20 treatment could significantly improve the apomorphine-induced rotations by protecting against the loss of dopaminergic neurons in the SNpc. Our Results suggest that our combinatorial method would help overcome key challenges that hinder the currently available methods for the use of rhFGF20 in PD treatment.
Topics: Animals; Cell Line, Tumor; Corpus Striatum; Fibroblast Growth Factors; Humans; Liposomes; Male; Mice; NIH 3T3 Cells; Oxidopamine; PC12 Cells; Parkinson Disease; Proteolipids; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome; Ultrasonography
PubMed: 30043675
DOI: 10.1080/10717544.2018.1482972 -
The EMBO Journal Jan 2005beta-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize beta-catenin result in augmented gene...
beta-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize beta-catenin result in augmented gene transcription and play a major role in many human cancers. We employed microarrays to identify transcriptional targets of deregulated beta-catenin in a human epithelial cell line (293) engineered to produce mutant beta-catenin and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/beta-catenin pathway. Two genes strongly induced in both systems-FGF20 and DKK1-were studied in detail. Elevated levels of FGF20 RNA were also observed in adenomas from mice carrying the Apc(Min)allele. Both XFGF20 and Xdkk-1 are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. Furthermore, FGF20 and DKK1 appear to be direct targets for beta-catenin/TCF transcriptional regulation via LEF/TCF-binding sites. Finally, by using small inhibitory RNAs specific for FGF20, we show that continued expression of FGF20 is necessary for maintenance of the anchorage-independent growth state in RK3E cells transformed by beta-catenin, implying that FGF-20 may be a critical element in oncogenesis induced by the Wnt signaling pathway.
Topics: Adenocarcinoma; Adenoma; Animals; Cell Line; Cytoskeletal Proteins; Epithelial Cells; Female; Fibroblast Growth Factors; Gene Expression Profiling; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins; Intestinal Mucosa; Mice; Neoplasms; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Promoter Regions, Genetic; Proteins; RNA, Small Interfering; Signal Transduction; Trans-Activators; Transcription, Genetic; Wnt Proteins; Xenopus Proteins; Xenopus laevis; beta Catenin
PubMed: 15592430
DOI: 10.1038/sj.emboj.7600460 -
Medicine Jun 2017To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism... (Observational Study)
Observational Study
To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism (MP) in the general Chinese population systematically.Targeted sequencing of the FGF/FGFR genes was conducted in 176 MP individuals and 155 class I malocclusion controls. The associations of common and rare variants with MP as a categorical phenotype and also continuous malocclusion phenotypes generated by principal component (PC) analysis were analyzed.One common variant, rs372127537, located in the 3'-untranslated region of FGF7 gene, was significantly related to PC1 (P = 4.22 × 10), which explained 23.23% of the overall phenotypic variation observed and corresponded to vertical discrepancies ranging from short anterior face height to long anterior face height, after Bonferroni correction. Also, 15 other variants were associated with PC1-4, although not significant after multiple corrections (P < .05). We also identified 3 variants: rs13317 in FGFR1, rs149242678 in FGF20, and rs79176051 FGF12 associated with MP (P < .05). With respect to rare variant analysis, variants within the FGF12 gene showed significant association with MP (P = .001).Association between FGF/FGFR signaling pathway and MP has been identified. We found a previously unreported SNP in FGF7 significantly related to increased facial height. Also, rare variants within the FGF12 were associated with MP. Our results provide new clues for genetic mechanisms of MP and shed light on strategies for evaluating rare variants that underlie complex traits. Future studies with larger sample sizes and more comprehensive genome coverage, and also in other population are required to replicate these findings.
Topics: Asian People; Cephalometry; China; Female; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genotyping Techniques; Humans; Male; Principal Component Analysis; Prognathism; Receptor, Fibroblast Growth Factor, Type 1; Young Adult
PubMed: 28640125
DOI: 10.1097/MD.0000000000007240 -
Molecular Brain Sep 2018Genetic studies of major depressive disorder and its associated endophenotypes are useful for the identification of candidate genes. In recent years, variations in...
Genetic studies of major depressive disorder and its associated endophenotypes are useful for the identification of candidate genes. In recent years, variations in non-coding RNA genes, such as miRNAs, have been explored as novel candidates for psychiatric disorders and related endophenotypes. The aim of the present study was to evaluate the possible association between a functional polymorphism (rs12720208) in the FGF20 gene, which regulates its modulation by miR-433, and depressive symptoms in young adults. A sample of 270 participants from Colombia were evaluated with the Hospital Anxiety and Depression Scale - Depression Subscale (HADS-D) and genotyped for the rs12720208 polymorphism using a TaqMan assay. A lineal regression analysis was used. A statistically significant association of the functional polymorphism in the FGF20 gene (rs12720208) with depressive symptoms was found. It was observed that individuals with the G/A genotype had higher scores for the HADS-D subscale. Our results are the first description in the scientific literature about a significant association between a functional polymorphism in the FGF20 gene, which regulates its modulation by miR-433, and depressive symptoms.
Topics: Binding Sites; Depression; Female; Fibroblast Growth Factors; Humans; Male; MicroRNAs; Polymorphism, Single Nucleotide; Young Adult
PubMed: 30241547
DOI: 10.1186/s13041-018-0397-0 -
Cancer Science Oct 2009To comprehensively screen for genetic events underlying colorectal cancer, we performed suppression subtraction hybridization analysis on an advanced colon cancer....
To comprehensively screen for genetic events underlying colorectal cancer, we performed suppression subtraction hybridization analysis on an advanced colon cancer. Because Dickkopf-4, a member of the Dickkopf family acting as a Wnt-signaling modulator, was identified as one of the upregulated genes in this specimen, we investigated expression profiles of all the Dickkopf family members in 55 colorectal tumors (21 cancers and 34 adenomas). We also investigated mechanisms regulating the expression of Dickkopf-4 in these cancers in vitro and in vivo. Compared with normal adjacent mucosae, Dickkopf-4 (median 27.4, P < 0.01) and -2 (median 51.4, P < 0.01) were strongly expressed in colorectal cancers. The level of Dickkopf-4 was positively correlated with fibroblast growth factor-20 (r(s) = 0.61, P = 0.00017), a representative beta-catenin transcriptional target gene, and with the degree of nuclear accumulation of beta-catenin in colorectal tumors. Dickkopf-4 was induced by activated beta-catenin in vitro. Reciprocally, recombinant Dickkopf-4 significantly inhibited T-cell factor/lymphocyte enhancer factor reporter activity stimulated by recombinant Wnt3a in human embryonic kidney 293 cells. We conclude that Dickkopf-4 and -2 are significantly upregulated in most colorectal tumors, and that Dickkopf-4 upregulation reflects activation of the Wnt/canonical pathway.
Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Blotting, Western; Colorectal Neoplasms; Female; Fibroblast Growth Factors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; RNA, Messenger; ROC Curve; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Up-Regulation; Wnt Proteins; beta Catenin
PubMed: 19659606
DOI: 10.1111/j.1349-7006.2009.01272.x -
Journal of Colloid and Interface Science Jan 2016Dental bleaching with H2O2 is a common daily practice in dentistry to correct discoloration of anterior teeth. The aim of this study has been to determine whether this...
HYPOTHESIS
Dental bleaching with H2O2 is a common daily practice in dentistry to correct discoloration of anterior teeth. The aim of this study has been to determine whether this treatment of human teeth affects growth, differentiation and activity of osteoclast-like cells, as well as the putative modulatory action of osteostatin and fibroblast growth factor 2 (FGF-2).
EXPERIMENTS
Previously to the in vitro assays, structural, physical-chemical and morphological features of teeth after bleaching were studied. Osteoclast-like cells were cultured on human dentin disks, pre-treated or not with 38% H2O2 bleaching gel, in the presence or absence of osteostatin (100 nM) or FGF-2 (1 ng/ml). Cell proliferation and viability, intracellular content of reactive oxygen species (ROS), pro-inflammatory cytokine (IL-6 and TNFα) secretion and resorption activity were evaluated.
FINDINGS
Bleaching treatment failed to affect either the structural or the chemical features of both enamel and dentin, except for slight morphological changes, increased porosity in the most superficial parts (enamel), and a moderate increase in the wettability degree. In this scenario, bleaching produced an increased osteoclast-like cell proliferation but decreased cell viability and cytokine secretion, while it augmented resorption activity on dentin. The presence of either osteostatin or FGF-2 reduced the osteoclast-like cell proliferation induced by bleaching. FGF-2 enhanced ROS content, whereas osteostatin decreased ROS but increased TNFα secretion. The bleaching effect on resorption activity was increased by osteostatin, but this effect was less evident with FGF-2.
CONCLUSIONS
These findings further confirm the deleterious effects of tooth bleaching by affecting osteoclast growth and function as well as different modulatory actions of osteostatin and FGF-2.
Topics: Adolescent; Adsorption; Adult; Animals; Cell Survival; Cells, Cultured; Dentin; Fibroblast Growth Factors; Flow Cytometry; Humans; Hydrogen Peroxide; Macrophages; Mice; Osteoclasts; Parathyroid Hormone-Related Protein; Particle Size; Peptide Fragments; Reactive Oxygen Species; Surface Properties; Tooth Bleaching; Wettability; Young Adult
PubMed: 26407056
DOI: 10.1016/j.jcis.2015.09.035 -
Journal of Cellular Biochemistry Apr 2013Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular...
Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-β1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair.
Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Cartilage, Articular; Cattle; Cell Differentiation; Cell Proliferation; Cells, Cultured; Chondrocytes; Collagen; Fibroblast Growth Factors; Gene Expression Regulation; Genetic Vectors; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Proteoglycans; Time Factors; Transfection; Transforming Growth Factor beta1; Transgenes
PubMed: 23097312
DOI: 10.1002/jcb.24430 -
Human Mutation Nov 2010MicroRNAs are short, approximately 22 nucleotide noncoding RNAs binding to partially complementary sites in the 3'UTR of target mRNAs. This process generally results in...
MicroRNAs are short, approximately 22 nucleotide noncoding RNAs binding to partially complementary sites in the 3'UTR of target mRNAs. This process generally results in repression of multiple targets by a particular microRNA. There is substantial interest in methods designed to predict the microRNA targets and effect of single nucleotide polymorphisms (SNPs) on microRNA binding, given the impact of microRNA on posttranscriptional regulation and its potential relation to complex diseases. We developed a web-based application, MicroSNiPer, which predicts the impact of a SNP on putative microRNA targets. This application interrogates the 3'-untranslated region and predicts if a SNP within the target site will disrupt/eliminate or enhance/create a microRNA binding site. MicroSNiPer computes these sites and examines the effects of SNPs in real time. MicroSNiPer is a user-friendly Web-based tool. Its advantages include ease of use, flexibility, and straightforward graphical representation of the results. It is freely accessible at http://cbdb.nimh.nih.gov/microsniper.
Topics: 3' Untranslated Regions; Algorithms; Animals; Base Sequence; Binding Sites; Computational Biology; Databases, Nucleic Acid; Fibroblast Growth Factors; Humans; Internet; Mice; MicroRNAs; Molecular Sequence Data; Polymorphism, Single Nucleotide; Software; User-Computer Interface
PubMed: 20809528
DOI: 10.1002/humu.21349 -
Genetics and Molecular Research : GMR Oct 2015Genome-wide association studies have reported numerous susceptibility loci for Parkinson's disease (PD). However, there have been few replication studies examining these...
Genome-wide association studies have reported numerous susceptibility loci for Parkinson's disease (PD). However, there have been few replication studies examining these loci in northern Chinese populations. To evaluate the relationships among 3 polymorphic markers located in the fibroblast growth factor 20 and transmembrane protein 175 genes and the genetic susceptibility to PD in northern Chinese subjects, 2 single nucleotide polymorphisms, and 1 insertion/deletion marker (rs591323 in FGF20; rs6599388 and rs142821586 in transmembrane protein 175 near the G-associated kinase/diacylglycerol kinase theta region) were investigated in 313 PD patients and 318 matched controls. Mismatched multiplex polymerase chain reaction-restriction fragment length polymorphism analysis as well as sequence-specific primer polymerase chain reaction and restriction fragment length polymorphism assays were performed. The genotypic frequency of rs591323 differed significantly between the patient and control groups; however, neither rs6599388 nor rs142821586 was associated with PD. We corrected the Hardy-Weinberg disequilibrium for rs6599388, which was previously reported to be common in 4 Asian descent populations into equilibrium status by simultaneously genotyping rs6599388 and rs142821586. In summary, we found that rs591323 was associated with PD but rs6599388 and rs142821586 were not associated with PD in a northern Chinese population.
Topics: Aged; Alleles; Asian People; Case-Control Studies; China; Female; Fibroblast Growth Factors; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; INDEL Mutation; Male; Middle Aged; Odds Ratio; Parkinson Disease; Polymorphism, Single Nucleotide; Potassium Channels
PubMed: 26535683
DOI: 10.4238/2015.October.28.30 -
The Journal of Neuroscience : the... Sep 2006The specific expression of fibroblast growth factor 20 (FGF-20) in the adult substantia nigra and the association between FGF-20 mutations and Parkinson's disease... (Comparative Study)
Comparative Study
The specific expression of fibroblast growth factor 20 (FGF-20) in the adult substantia nigra and the association between FGF-20 mutations and Parkinson's disease provoked exploration of the function of this growth factor. We show by gain- and loss-of-function in vitro experiments that FGF-20 promotes survival and stimulates dopamine (DA) release in a calbindin-negative subset of cells that are preferentially lost in Parkinson's disease. FGF-20 selectively activates tyrosine hydroxylase in calbindin-negative neurons. In the adult substantia nigra, calbindin-negative neurons specifically express high levels of FGFR1 (FGF receptor 1). These data show that FGF signals to elevate DA levels and protect the specific midbrain neuron type at most risk in Parkinson's patients.
Topics: Animals; Cell Survival; Cells, Cultured; Dopamine; Fibroblast Growth Factors; Humans; Mesencephalon; Parkinson Disease; Rats; Risk; Substantia Nigra
PubMed: 16988046
DOI: 10.1523/JNEUROSCI.2745-06.2006