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Sample records for basic fibroblast growth

  1. Treatment of Skin Avulsion Injuries with Basic Fibroblast Growth Factor

    OpenAIRE

    Hajime Matsumine, MD, PhD

    2015-01-01

    Summary: This report describes favorable outcomes in 9 patients with skin avulsion injuries of the extremities who underwent full-thickness skin grafting and basic fibroblast growth factor (bFGF) application. Following removal of contaminated subcutaneous fat tissue on the inside of skin, the avulsed skin was processed into a full-thickness skin graft, with as much of the skin used as possible irrespective of damage. Several drainage holes (5–10 mm in diameter) were made on the graft for drai...

  2. Recombinant basic fibroblast growth factor accelerates wound healing.

    Science.gov (United States)

    McGee, G S; Davidson, J M; Buckley, A; Sommer, A; Woodward, S C; Aquino, A M; Barbour, R; Demetriou, A A

    1988-07-01

    Basic fibroblast growth factor (bFGF) stimulates extracellular matrix metabolism, growth, and movement of mesodermally derived cells. We have previously shown that collagen content in polyvinyl alcohol sponges increased after bFGF treatment. We hypothesized that bFGF-treated incisional wounds would heal more rapidly. After intraperitoneal pentobarbital anesthesia, male, 200- to 250-g, Sprague-Dawley rats (n = 27) each underwent two sets of paired, transverse, dorsal incisions closed with steel sutures. On Day 3 postwounding, 0.4 ml of bFGF (recombinant, 400 ng. Synergen) or normal saline was injected into one of each paired incisions. Animals were killed with ether on postwounding Days 5, 6, and 7 and their dorsal pelts were excised. Fresh or formalin-fixed wound strips were subjected to tensile strength measurements using a tensiometer. Breaking energy was calculated. Wound collagen content (hydroxyproline) was measured in wound-edge samples following hydrolysis using high-performance liquid chromatography. There was an overall significant increase in fresh wound tensile strength (13.7 +/- 1.06 vs 19.1 +/- 1.99 g/mm, P less than 0.01) and wound breaking energy (476 +/- 47 vs 747 +/- 76 mm2, P less than 0.001) in bFGF-treated incisions. There was an increase in wound collagen content which was not statistically significant and there was no difference in fixed incisional tensile strength. Histologic examination showed better organization and maturation in bFGF wounds. Recombinant bFGF accelerates normal rat wound healing. This may be due to earlier accumulation of collagen and fibroblasts and/or to greater collagen crosslinking in bFGF-treated wounds. PMID:3392988

  3. Treatment of Skin Avulsion Injuries with Basic Fibroblast Growth Factor

    Directory of Open Access Journals (Sweden)

    Hajime Matsumine, MD, PhD

    2015-04-01

    Full Text Available Summary: This report describes favorable outcomes in 9 patients with skin avulsion injuries of the extremities who underwent full-thickness skin grafting and basic fibroblast growth factor (bFGF application. Following removal of contaminated subcutaneous fat tissue on the inside of skin, the avulsed skin was processed into a full-thickness skin graft, with as much of the skin used as possible irrespective of damage. Several drainage holes (5–10 mm in diameter were made on the graft for drainage from the graft bed and to prevent seroma and hematoma formation. Genetically recombinant human bFGF was sprayed at a dose of 1 μg/cm2 onto the graft bed, which was then covered with the graft and sutured. Pressure immobilization with ointment gauzes and elastic bandages was administered for 1 week postoperatively, and the surface of the skin grafts that did not take was scraped away, preserving the revascularized dermal component on the debrided raw surface as much as possible. bFGF was sprayed again onto the debrided surface to promote epithelialization. Wound closure was achieved in all cases with conservative therapy. The surgical procedure was effective in preventing postoperative ulcer formation and scar contracture and resulted in wound healing with the formation of good-quality, flexible scars.

  4. Effects of Electromagnetic Field and Basic Fibroblast Growth Factor on Osteoblast's Growth

    Institute of Scientific and Technical Information of China (English)

    GUOYong; ZHANGXi-zheng; WANGHao; LIBin; LIRui-xin; WUJin-hui; ZHAOYun-shan; WUJi-min

    2004-01-01

    Osteoblasts of rat cultured in vitro were stimulated with pulsed 50 Hz electromagnetic field and basic fibroblast growth factor(bFGF). The MTT method, flow cytometry and histochemistry staining were used to detect cell proliferation, cell cycle and alkaline phosphatase. The results indicated : after stimulated by 1 mT electromagnetic field, the cells are more abundant,have more S phase percentages, 2 mT electromagnetic field have no evident effect on cells' growth;compared with electromagnetic field, the cells stimulated by bFGF are more abundant and have larger S phase ratios. Electromagnetic field and bFGF have no effect on cells, alkaline phosphatase. Therefore ,we concluded that electromagnetic field can enhance osteoblasts growth like some growth factor such as basic fibroblast growth factor, and the osteoblasts', characteristics was not changed.

  5. Degradable PLGA Scaffolds with Basic Fibroblast Growth Factor: Experimental Studies in Myocardial Revascularization

    OpenAIRE

    Wang, Ying(School of Physics, Shandong University, Jinan, 250100, PR China); Liu, Xiao-Cheng; Zhao, Jian; Kong, Xiang-Rong; Shi, Rong-Fang; Zhao, Xiao-Bin; Song, Cun-Xian; Liu, Tian-Jun; Lu, Feng

    2009-01-01

    Our goal was to investigate the efficacy of degradable poly(D,L-lactic-coglycolic acid) (PLGA) scaffolds loaded with basic fibroblast growth factor (bFGF) in inducing cardiac neovascularization, increasing perfusion, and improving cardiac function.

  6. Noggin versus basic fibroblast growth factor on the differentiation of human embryonic stem cells*

    Institute of Scientific and Technical Information of China (English)

    Yan Zhang; Junmei Zhou; Zhenfu Fang; Manxi Jiang; Xuejin Chen

    2013-01-01

    The difference between Noggin and basic fibroblast growth factor for the neural precursor differen-tiation from human embryonic stem cel s has not been studied. In this study, 100 µg/L Noggin or 20 µg/L basic fibroblast growth factor in serum-free neural induction medium was used to differen-tiate human embryonic stem cel s H14 into neural precursors using monolayer differentiation. Two weeks after induction, significantly higher numbers of neural rosettes formed in the Noggin-induced group than the basic fibroblast growth factor-induced group, as detected by phase contrast micro-scope. Immunofluorescence staining revealed expression levels of Nestin,β-III Tubulin and Sox-1 were higher in the induced cel s and reverse-transcription PCR showed induced cel s expressed Nestin, Sox-1 and Neurofilament mRNA. Protein and mRNA expression in the Noggin-induced group was increased compared with the basic fibroblast growth factor-induced group. Noggin has a greater effect than basic fibroblast growth factor on the induction of human embryonic stem cel differentiation into neural precursors by monolayer differentiation, as Noggin accelerates and in-creases the differentiation of neural precursors.

  7. Purification and Refolding of Overexpressed Human Basic Fibroblast Growth Factor in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Mona Alibolandi

    2011-01-01

    Full Text Available This work describes the integration of expanded bed adsorption (EBA and adsorptive protein refolding operations used to recover purified and biologically active human basic fibroblast growth factor from inclusion bodies expressed in E. coli. Insoluble overexpressed human basic fibroblast growth factor has been purified on CM Hyper Z matrix by expanded bed adsorption after isolation and solubilization in 8 M urea. The adsorption was made in expanded bed without clarification steps such as centrifugation. Column refolding was done by elimination of urea and elution with NaCl. The human basic fibroblast growth factor was obtained as a highly purified soluble monomer form with similar behavior in circular dichroism and fluorescence spectroscopy as native protein. A total of 92.52% of the available human basic fibroblast growth factor was recovered as biologically active and purified protein using the mentioned purification and refolding process. This resulted in the first procedure describing high-throughput purification and refolding of human basic fibroblast growth factor in one step and is likely to have the greatest benefit for proteins that tend to aggregate when refolded by dilution.

  8. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues.

    OpenAIRE

    J.A. Takahashi; Mori, H.; Fukumoto, M; Igarashi, K; Jaye, M; Oda, Y.; Kikuchi, H; Hatanaka, M

    1990-01-01

    The growth autonomy of human tumor cells is considered due to the endogenous production of growth factors. Transcriptional expression of candidates for autocrine stimulatory factors such as basic fibroblast growth factor (FGF), acidic FGF, and transforming growth factor type beta were determined in human brain tumors. Basic FGF was expressed abundantly in 17 of 18 gliomas, 20 of 22 meninglomas, and 0 of 5 metastatic brain tumors. The level of mRNA expression of acidic FGF in gliomas was signi...

  9. Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas.

    OpenAIRE

    Ohta, T.(Research Center for Nuclear Physics, Osaka University, Ibaraki, Osaka 567-0047, Japan); Yamamoto, M.; Numata, M; Iseki, S.; Tsukioka, Y.; Miyashita, T; Kayahara, M.; Nagakawa, T.; Miyazaki, I.; Nishikawa, K.; Yoshitake, Y

    1995-01-01

    We examined the expression of basic fibroblast growth factor (FGF) and FGF receptor by immunohistochemistry in 32 human pancreatic ductal adenocarcinomas. Mild to marked basic FGF immunoreactivity was noted in 19 (59.4%) of the 32 tumours examined, and 30 (93.3%) of the tumours exhibited a cytoplasmic staining pattern against FGF receptor. The tumours were divided into two groups according to the proportion of positively stained tumour cells: a low expression group (positive cells < 25%) and ...

  10. The role of calcineurin in the lung fibroblasts proliferation and collagen synthesis induced by basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    陈亚红; 赵鸣武; 符民桂; 姚婉贞; 唐朝枢

    2003-01-01

    Objective To investigate the role of calcineurin (CaN) in the lung fibroblast proliferation and collagen synthesis induced by basic fibroblast growth factor (bFGF).Methods We used Western blot and immunohistochemical methods for investigating the content and distribution of calcineurin in the lung tissue. Calcineurin activity in different tissues was measured using 32P-labelled substrate. In the primary culture of lung fibroblasts, 3H-thymidine (3H-TdR) and 3H-proline incorporation methods were used to study the effect of cyclosporin A(CsA), an inhibitor of calcineurin, on the lung fibroblast DNA and collagen synthesis stimulated by bFGF. Results We found that calcineurin was expressed in lung tissue and has phosphatase activity (7.1±2.0 pmol Pi/mg pr/min). CsA(10-8-10-6mol/L) inhibited lung fibroblast,3H-TdR incorporation induced by bFGF in a dose-dependent manner, with the inhibitory rates by20%, 46% and 66%(P<0.01). CsA(10-7-10-6mol/L) inhibited 3H-proline incorporation in lung fibroblasts stimulated by bFGF, with the inhibitory rates by 21% and 37%(P<0.01). In a culture medium, CsA (10-8-10-6mol/L) inhibited 3H-proline secretion induced by bFGF in a dose-dependent manner, with the inhibitory rates by 19%,29%(P<0.05) and 56% (P<0.01). CsA (10-7mol/L) could inhibit calcineurin activity by 44% in lung fibroblasts(P<0.01). Conclusions Calcineurin is expressed in lung tissue and has phosphatase activity. It is involved in the bFGF stimulated lung fibroblast DNA and collagen synthesis.

  11. Stability and biological activity evaluations of PEGylated human basic fibroblast growth factor

    OpenAIRE

    Hadadian, Shahin; Shamassebi, Dariush Norouzian; Mirzahoseini, Hasan; Shokrgozar, Mohamad Ali; Bouzari, Saeid; Sepahi, Mina

    2015-01-01

    Background: Human basic fibroblast growth factor (hBFGF) is a heparin-binding growth factor and stimulates the proliferation of a wide variety of cells and tissues causing survival properties and its stability and biological activity improvements have received much attention. Materials and Methods: In the present work, hBFGF produced by engineered Escherichia coli and purified by cation exchange and heparin affinity chromatography, was PEGylated under appropriate condition employing 10 kD pol...

  12. Basic fibroblast growth factor gene transfection in repair of internal carotid artery aneurysm wall

    Institute of Scientific and Technical Information of China (English)

    Lei Jiao; Ming Jiang; Jinghai Fang; Yinsheng Deng; Zejun Chen; Min Wu

    2012-01-01

    Surgery or interventional therapy has some risks in the treatment of cerebral aneurysm. We established an internal carotid artery aneurysm model by dripping elastase in the crotch of the right internal and external carotid arteries of New Zealand rabbits. Following model induction, lentivirus carrying basic fibroblast growth factor was injected through the ear vein. We found that the longer the action time of the lentivirus, the smaller the aneurysm volume. Moreover, platelet-derived growth factor expression in the aneurysm increased, but smooth muscle 22 alpha and hypertension-related gene 1 mRNA expression decreased. At 1, 2, 3, and 4 weeks following model establishment, following 1 week of injection of lentivirus carrying basic fibroblast growth factor, the later the intervention time, the more severe the blood vessel damage, and the bigger the aneurysm volume, the lower the smooth muscle 22 alpha and hypertension-related gene 1 mRNA expression. Simultaneously, platelet-derived growth factor expression decreased. These data suggest that recombinant lentivirus carrying basic fibroblast growth factor can repair damaged cells in the aneurysmal wall and inhibit aneurysm dynamic growth, and that the effect is dependent on therapeutic duration.

  13. Basic fibroblast growth factor improves learning and memory functions in chronic stress mice

    Institute of Scientific and Technical Information of China (English)

    Xian Qu; Chunying Li; Hongchang Liu; Chang Su

    2011-01-01

    Four weeks of uncertain stress was used to establish an animal model of chronic stress.Basic fibroblast growth factor was injected daily for 15 days following stress induction.Cell morphology in the hippocampal CA3 region of chronic stress mice revealed cell damage.Nitric oxide content and calcium concentration were significantly increased in the hippocampus,and learning and memory functions were significantly decreased.After basic fibroblast growth factor intervention,Ca2+ overload was decreased and neuronal damage was relieved in hippocampal neurons,which improved learning and memory functions in chronic stress mice.Latency was prolonged and the number of errors was decreased in a passive avoidance test.

  14. Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features

    OpenAIRE

    Skevaki Chrysanthi L; Psarras Stelios; Volonaki Eleni; Pratsinis Harris; Spyridaki Irini S; Gaga Mina; Georgiou Vassiliki; Vittorakis Stylianos; Telcian Aurica G; Maggina Paraskevi; Kletsas Dimitris; Gourgiotis Dimitrios; Johnston Sebastian L; Papadopoulos Nikolaos G

    2012-01-01

    Abstract Background Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling. Methods Levels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by D...

  15. Basic fibroblast growth factor attenuates the degeneration of injured spinal cord motor endplates**

    Institute of Scientific and Technical Information of China (English)

    Jianlong Wang; Jianfeng Sun; Yongxiang Tang; Gangwen Guo; Xiaozhe Zhou; Yanliang Chen; Minren Shen

    2013-01-01

    The distal end of the spinal cord and neuromuscular junction may develop secondary degeneration and damage fol owing spinal cord injury because of the loss of neural connections. In this study, a rat model of spinal cord injury, established using a modified Al en’s method, was injected with basic fibroblast growth factor solution via subarachnoid catheter. After injection, rats with spinal cord injury displayed higher scores on the Basso, Beattie and Bresnahan locomotor scale. Motor function was also wel recovered and hematoxylin-eosin staining showed that spinal glial scar hyperplasia was not apparent. Additional y, anterior tibial muscle fibers slowly, but progressively, atrophied. Immunohistochemical staining showed that the absorbance values of calcitonin gene related pep-tide and acetylcholinesterase in anterior tibial muscle and spinal cord were similar, and injection of basic fibroblast growth factor increased this absorbance. Results showed that after spinal cord injury, the distal motor neurons and motor endplate degenerated. Changes in calcitonin gene related pep-tide and acetylcholinesterase in the spinal cord anterior horn motor neurons and motor endplate then occurred that were consistent with this regeneration. Our findings indicate that basic fibroblast growth factor can protect the endplate through attenuating the decreased expression of calcitonin gene related peptide and acetylcholinesterase in anterior horn motor neurons of the injured spinal cord.

  16. Infant guinea pig retina model of glutamate toxicity and intervention of basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    Yunzhi Shi; Lihua Wei; Mingshan Song; Min Chen; Changqing Du; Baoliang Sun

    2011-01-01

    Impaired vision with oligemic ophthalmopathy is a result of excitotoxicity caused by excitatory amino acids, resulting in pathological changes, such as loss of retinal neurons and in particular retinal ganglionic cells. The present study utilized infant guinea pigs, aged 45-50 days, to establish injury models via intrapedtoneal injection of fixed sodium glutamate doses. Results from hematoxylin- eosin staining revealed significantly reduced retinal ganglionic cell numbers and retinal damage at 10 days after 7 consecutive days of 3 g/kg sodium glutamate treatment; these animals sewed as the injury model group. In addition, models of moderate injury (glutamate 3 g/kg daily, for 7 consecutive days) were intrapedtoneally pretreated with basic fibroblast growth factor (800 U/kg daily). Immunohistochemistry results confirmed reduced anti-apoptotic gene bcl-2 expression in the ganglion cell layer of glutamate-injured guinea pigs. Expression of the pro-apoptotic gene caspase-3 was increased in the ganglion cell layer and inner plexiform layer. Somatostatin expression was primadly distributed in the ganglion cell layer and inner nuclear layer. Expression of the presynaptic element synaptophysin was weak. However, following basic fibroblast growth factor injection, expressions of the above-described bioactive molecules were reversed, which suggested that basic fibroblast growth factor exerted protective effects on sodium glutamate-induced retinal injury in infant guinea pigs by regulating expression of synaptophysin, somatostatin, Bcl-2, and caspase-3.

  17. Effect of charge at an amino acid of basic fibroblast growth factor on its mitogenic activity

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The amino acid at the 119th position of human basic fibroblast growth factor(hbFGF),lysine(K119),is a critical component for its mitogenic activity.However,little is known about the effects of the characteristics of this residue including charge on the mitogenic activity of hbFGF.Herein,this basic residue was replaced with neutral glutamine residue and acidic glutamic acid residue to construct mutants hbFGF~(K119Q) and hbFGF~(K119E),respectively.The mutants were produced by BL21(DE3)/pET3c expression sys...

  18. Angiogenesis with intramyocardial administration of basic fibroblast growth factor in canine ischemic myocardium

    International Nuclear Information System (INIS)

    Objective: To evaluate the effect of intramyocardial administration of basic fibroblast growth factor on angiogenesis of infarcted myocardium in dogs. Methods: Twenty-four mongrel dogs were randomized into control group and therapeutic group. Acute myocardial infarction was made by ligation of the left anterior descending coronary artery distal to its first diagonal branch. As soon as coronary artery was occluded, 50 mg of basic fibroblast growth factor in 15 ml of saline was injected into the infarcted and border zone in therapeutic group, whereas 15 ml saline alone was used in the same way in control dogs. Every 3 dogs in each group was studied on the 1st day, the 3rd day, the 10th day, and the 17th day, respectively. Electron microscope was used to observe the growth of capillaries. Angiogenesis was evaluated by immunohistochemical studies with VIII factor. With sensitivity encoded technique, cine MR and MR perfusion imaging were performed on each dog within 3 hours after surgery and before euthanasia to evaluate cardiac function and the characteristics of myocardial perfusion. Results: In therapeutic group, LVEF improved markedly since the 10th day (on the 10th day: control group 24.09 ± 3.32, therapeutic group 45.71 ± 6.27; on the 17th day: control group 31.46 ± 4.60, therapeutic group 53.46 ± 5.24). Hypoenhancement on first pass and hyperenhancement on delayed phase appeared in infarcted myocardium. There were significant differences for the time of upslope, peak time of signal intensity, upslope curves ratio, and contrast enhancement ratio between infarcted and normal myocardium. The size of infarcted myocardium was markedly decreased on the 17th day [control group (9.04 ± 1.59)%, therapeutic group (4.07 ± 1.20)%]. The capillaries grew actively in therapeutic group and microvessel density was higher in therapeutic group than in control group except the first day (control group and therapeutic group respectively on the 3rd day: 92.3 ± 11.6, 147.3 ± 11

  19. Immunohistochemical localization of basic fibroblast growth factor in bovine ovarian follicles.

    Science.gov (United States)

    van Wezel, I L; Umapathysivam, K; Tilley, W D; Rodgers, R J

    1995-12-29

    Basic fibroblast growth factor (bFGF, FGF2) controls cell proliferation and differentiation in many organs and tissues. In the ovary, cells proliferate and differentiate during folliculogenesis and during formation of the corpus luteum. While previous studies have inferred a role for bFGF in these processes, the precise contribution of bFGF to follicular activation or recruitment has not been established. For this reason, bFGF was immunolocalized in bovine follicles, using anti-bFGF immunoglobulin specific for the 1-24-amino acid terminus of the 18-kDa peptide. Basic FGF was immunolocalized to the cytoplasm of oocytes from bovine primordial and primary follicles. Strong immunostaining was also observed in corpora lutea, the ovarian surface epithelium, and smooth muscle cells surrounding blood vessels, while substantial levels of immunostaining were also present in cells of the theca interna. In most of the healthy antral follicles examined, the three or so layers of granulosa cells which were closest to the basement membrane were also stained, with greatest levels of staining at the most basal region of each cell. Atretic antral follicles had significant and uniform levels of immunostaining throughout the theca interna and the membrana granulosa. Immunostaining as described above was reduced to background levels when the primary specific immunoglobulin was preabsorbed with a 350 molar excess of peptide comprising the NH2-terminal 24 amino acids of bFGF. Based upon our previous observations and those reported here, we propose that basic fibroblast growth factor is synthesized by immature oocytes, especially those from primordial and primary follicles, and that bFGF has a potential role in activating follicle growth via stimulation of granulosa cell proliferation and follicular basement membrane synthesis. PMID:8824888

  20. The Effect of Hypoxia on Expression of Basic Fibroblast Growth Factor in Pulmonary Vascular Pericytes

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To examine whether hypoxia exerts effect on the expression of basic fibroblast growth fac tor (bFGF) in pulmonary vascular pericytes (PC), cell culture, in situ hybridization with probe of digoxigenin-11-dUTP-labled cDNA, immunocytochemistry and image analysis were employed in this study. The rtsults showed that the expression amount of bFGF mRNA and protein in PC of hypoxia (H) group was 1.31 times (P<0.01) and 1.17 times (P<0. 01) that of normoxia (N) group re spectively. It suggests that hypoxia can directly enhance the expression of bFGF mRNA and protein in PC. Increased expression of bFGF may play an important role in the process of PC proliferation and differentiation of PC into smooth muscle-like cells.

  1. Effect of recombinant human basic fibroblast growth factor on angiogenesis during mandible fracture healing in rabbits

    Institute of Scientific and Technical Information of China (English)

    龚振宇; 周树夏; 顾晓明; 李涤尘; 孙明林

    2003-01-01

    Objective: To investigate the effect of recombinant human basic fibroblast growth factor (rhbFGF) on angiogenesis during mandible fracture healing in rabbit. Methods: Fifty adult white rabbits were used for animal model and randomly divided into a control group (25 rabbits) and an experimental group (25 rabbits). The membranous complex of rhbFGF and bovine type I collagen was prepared and implanted into the rabbit mandible fracture site under periosteum. The animals were sacrificed on 7, 14, 28, 56 and 84 days respectively after operation and the whole mandibles were harvested. The expression of factor VIII related antigen (F8-RA) in callus was examined with immunohistochemical staining. Results: The amounts of microvascular formation in calluses in the rhbFGF-treating group on days 7, 14, 28 and 56 were more than those of the control group (P<0.01).Conclusions: The results indicated that rhbFGF could stimulate microvascular formation during mandible fracture healing in rabbits.

  2. Ontogeny of expression of basic fibroblast growth factor and its receptors in human fetal skin

    Institute of Scientific and Technical Information of China (English)

    CHEN Wei; FU Xiao-bing; GE Shi-li; SUN Tong-zhu; SHENG Zhi-yong

    2005-01-01

    Objective : To investigate the expression characteristics of basic fibroblast growth factor (bFGF)and its receptors, flg ( FGFR1 ) and bek ( FGFR2), in fetal skin at different gestational ages underlying the relevance of these 3 proteins to skin development and the mechanisms underlying the phenotypic transition from scarless to scarforming healing.Methods: Eighteen specimens of fetal skin biopsies of human embryo were obtained from spontaneous abortions at different gestational ages of 13-32 weeks. Gene expression of bFGF, bek and flg was examined with reverse transcription-polymerase chain reaction (RT-PCR). The dynamic expression and distribution of these 3 proteins were detected with streptavidin peroxidase ( SP )immunohistochemical staining method.Results: In the early gestational fetal skin, genes of bFGF and flg were strongly expressed and more protein contents of these 2 proteins were found as compared with the genes at late gestation fetal skin (2.446 ± 0.116 and 2.066 ± 0. 152 versus 2.157 ± 0. 101 and 1.818 ± 0.086,respectively, P < 0.05). On the contrary, the levels of gene expression and protein content of bek were not differently expressed in the early gestational fetal skin versus the late ones. Protein particles of bFGF were mainly distributed in the epidermal cells and some fibroblasts. Bek was mainly located in the cell membrane and cytoplasm of epidermal cells while flg protein was principally located in the epidermal cells, endothelial cells and some fibroblasts.Conclusions: The endogenous bFGF and their receptors might be involved in the cutaneous development at fetal stage. The differently expressing levels of bFGF and flg during gestation may be related to scarless or scarforming repair during gestation.

  3. Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats

    Directory of Open Access Journals (Sweden)

    J.C. Zhang

    2014-10-01

    Full Text Available Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs expressing human basic fibroblast growth factor (hbFGF. After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC, MSCs expressing hbFGF (hbFGF-MSC, MSC controls, and phosphate-buffered saline (PBS controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001; however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008 and microvessel density (P<0.001. Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease.

  4. Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats

    International Nuclear Information System (INIS)

    Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs) expressing human basic fibroblast growth factor (hbFGF). After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC), MSCs expressing hbFGF (hbFGF-MSC), MSC controls, and phosphate-buffered saline (PBS) controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF) expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001); however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008) and microvessel density (P<0.001). Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease

  5. Bone marrow mesenchymal stem cells overexpressing human basic fibroblast growth factor increase vasculogenesis in ischemic rats

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    Zhang, J.C. [Department of Vascular Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China); Zheng, G.F. [Department of Vascular Surgery, The People' s Hospital of Ganzhou, Ganzhou (China); Wu, L.; Ou Yang, L.Y.; Li, W.X. [Department of Vascular Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou (China)

    2014-08-08

    Administration or expression of growth factors, as well as implantation of autologous bone marrow cells, promote in vivo angiogenesis. This study investigated the angiogenic potential of combining both approaches through the allogenic transplantation of bone marrow-derived mesenchymal stem cells (MSCs) expressing human basic fibroblast growth factor (hbFGF). After establishing a hind limb ischemia model in Sprague Dawley rats, the animals were randomly divided into four treatment groups: MSCs expressing green fluorescent protein (GFP-MSC), MSCs expressing hbFGF (hbFGF-MSC), MSC controls, and phosphate-buffered saline (PBS) controls. After 2 weeks, MSC survival and differentiation, hbFGF and vascular endothelial growth factor (VEGF) expression, and microvessel density of ischemic muscles were determined. Stable hbFGF expression was observed in the hbFGF-MSC group after 2 weeks. More hbFGF-MSCs than GFP-MSCs survived and differentiated into vascular endothelial cells (P<0.001); however, their differentiation rates were similar. Moreover, allogenic transplantation of hbFGF-MSCs increased VEGF expression (P=0.008) and microvessel density (P<0.001). Transplantation of hbFGF-expressing MSCs promoted angiogenesis in an in vivo hind limb ischemia model by increasing the survival of transplanted cells that subsequently differentiated into vascular endothelial cells. This study showed the therapeutic potential of combining cell-based therapy with gene therapy to treat ischemic disease.

  6. A heparin-mimicking polymer conjugate stabilizes basic fibroblast growth factor

    Science.gov (United States)

    Nguyen, Thi H.; Kim, Sung-Hye; Decker, Caitlin G.; Wong, Darice Y.; Loo, Joseph A.; Maynard, Heather D.

    2013-03-01

    Basic fibroblast growth factor (bFGF) is a protein that plays a crucial role in diverse cellular functions, from wound healing to bone regeneration. However, a major obstacle to the widespread application of bFGF is its inherent instability during storage and delivery. Here, we describe the stabilization of bFGF by covalent conjugation with a heparin-mimicking polymer, a copolymer consisting of styrene sulfonate units and methyl methacrylate units bearing poly(ethylene glycol) side chains. The bFGF conjugate of this polymer retained bioactivity after synthesis and was stable to a variety of environmentally and therapeutically relevant stressors—such as heat, mild and harsh acidic conditions, storage and proteolytic degradation—unlike native bFGF. Following the application of stress, the conjugate was also significantly more active than the control conjugate system in which the styrene sulfonate units were omitted from the polymer structure. This research has important implications for the clinical use of bFGF and for the stabilization of heparin-binding growth factors in general.

  7. In Situ Loading of Basic Fibroblast Growth Factor Within Porous Silica Nanoparticles for a Prolonged Release

    Directory of Open Access Journals (Sweden)

    Postovit Lynne-Marie

    2009-01-01

    Full Text Available Abstract Basic fibroblast growth factor (bFGF, a protein, plays a key role in wound healing and blood vessel regeneration. However, bFGF is easily degraded in biologic systems. Mesoporous silica nanoparticles (MSNs with well-tailored porous structure have been used for hosting guest molecules for drug delivery. Here, we report an in situ route to load bFGF in MSNs for a prolonged release. The average diameter (d of bFGF-loaded MSNs is 57 ± 8 nm produced by a water-in-oil microemulsion method. The in vitro releasing profile of bFGF from MSNs in phosphate buffer saline has been monitored for 20 days through a colorimetric enzyme linked immunosorbent assay. The loading efficiency of bFGF in MSNs is estimated at 72.5 ± 3%. In addition, the cytotoxicity test indicates that the MSNs are not toxic, even at a concentration of 50 μg/mL. It is expected that the in situ loading method makes the MSNs a new delivery system to deliver protein drugs, e.g. growth factors, to help blood vessel regeneration and potentiate greater angiogenesis.

  8. Basic fibroblast growth factor protects against excitotoxicity and chemical hypoxia in both neonatal and adult rats.

    Science.gov (United States)

    Kirschner, P B; Henshaw, R; Weise, J; Trubetskoy, V; Finklestein, S; Schulz, J B; Beal, M F

    1995-07-01

    Basic fibroblast growth factor (bFGF) is a polypeptide growth factor that promotes neuronal survival. We recently found that systemic administration of bFGF protects against both excitotoxicity and hypoxia-ischemia in neonatal animals. In the present study, we examined whether systemically administered bFGF could prevent neuronal death induced by intrastriatal injection of N-methyl-D-aspartate (NMDA) or chemical hypoxia induced by intrastriatal injection of malonate in adult rats and 1-methyl-4-phenylpyridinium (MPP+) in neonatal rats. Systemic administration of bFGF (100 micrograms/kg) for three doses both before and after intrastriatal injection of either NMDA or malonate in adult rats produced a significant neuroprotective effect. In neonatal rats, bFGF produced dose-dependent significant neuroprotective effects against MPP+ neurotoxicity, with a maximal protection of approximately 50% seen with either a single dose of bFGF of 300 micrograms/kg or three doses of 100 micrograms/kg. These results show that systemic administration of bFGF is effective in preventing neuronal injury under circumstances in which the blood-brain barrier may be compromised, raising the possibility that this strategy could be effective in stroke.

  9. Rhinovirus-induced basic fibroblast growth factor release mediates airway remodeling features

    Directory of Open Access Journals (Sweden)

    Skevaki Chrysanthi L

    2012-08-01

    Full Text Available Abstract Background Human rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling. Methods Levels of basic fibroblast growth factor (bFGF mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations. Results Rhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations. Conclusions Rhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma.

  10. Basic fibroblast growth factor predicts cardiovascular disease occurrence in participants from the Veterans Affairs Diabetes Trial

    Directory of Open Access Journals (Sweden)

    Mark B Zimering

    2013-11-01

    Full Text Available Aim: Cardiovascular disease is a leading cause of morbidity and mortality in adults with type 2 diabetes mellitus. The aim of the present study was to test whether plasma basic fibroblast growth factor (bFGF levels predict future cardiovascular disease (CVD occurrence in adults from the Veterans Affairs Diabetes Trial. Methods: Nearly four- hundred veterans, 40 years of age or older, having a mean baseline diabetes duration of 11.4 years were recruited from outpatient clinics at six geographically distributed sites in the Veterans Affairs Diabetes Trial (VADT. Within the VADT, they were randomly assigned to intensive or standard glycemic treatment, with follow-up as much as seven and one-half years. Cardiovascular disease occurrence was examined at baseline in the patient population and during randomized treatment. Plasma bFGF was determined with a sensitive, specific two-site enzyme-linked immunoassay at the baseline study visit in all 399 subjects. Results: One hundred-five first cardiovascular events occurred in these 399 subjects. The best fit model of risk factors associated with the time to first cardiovascular disease occurrence (in the study over a seven and one-half year period had as significant predictors: prior cardiovascular event, (hazard ratio [HR] 3.378; 95% confidence intervals [CI] 3.079- 3.807; P < .0001, baseline plasma bFGF (HR 1.008; 95% CI 1.002-1.014; P =.01, age, (HR 1.027; 95% CI 1.004-1.051; P =.019, baseline plasma triglycerides, (HR 1.001; 95% CI 1.000-1.002; P =.02 and diabetes duration-treatment interaction (P =.03. Intensive glucose-lowering was associated with significantly decreased hazard ratios for CVD occurrence (0.38-0.63 in patients with known diabetes duration of 0-10 years, and non-significantly increased hazard ratios for CVD occurrence (0.82-1.78 in patients with longer diabetes duration. Conclusion: High level ofplasma basic fibroblast growth factor is a predictive biomarker of future cardiovascular

  11. Comparison of human dermal fibroblasts (HDFs) growth rate in culture media supplemented with or without basic fibroblast growth factor (bFGF).

    Science.gov (United States)

    Abdian, Narges; Ghasemi-Dehkordi, Payam; Hashemzadeh-Chaleshtori, Morteza; Ganji-Arjenaki, Mahbobe; Doosti, Abbas; Amiri, Beheshteh

    2015-12-01

    Basic fibroblast growth factor (bFGF or FGF-2) is a member of the FGF family secreted by different kinds of cells like HDFs and it is an important nutritional factor for cell growth and differentiation. The HDFs release bFGF in culture media at very low. The present study aims to investigate the HDFs growth rate in culture media supplemented either with or without bFGF. In brief, HDFs were isolated from human foreskin sample and were cultured in vitro in media containing bFGF and lack of this factor. The cells growth rate was calculated by trypan blue. The karyotyping was performed using G-banding to investigate the chromosomal abnormality of HDFs in both groups. Total RNA of each groups were extracted and cDNA samples were synthesized then, real-time Q-PCR was used to measure the expression level of p27kip1 and cyclin D1 genes normalized to internal control gene (GAPDH). The karyotype analysis showed that HDFs cultured in media or without bFGF had normal karyotype (46 chromosomes, XY) and chromosomal abnormalities were not observed. The cell growth rates in both groups were normal with proliferated exponentially but the slope of growth curve in HDFs cultured in media containing bFGF was increased. Karyotyp test showed that bFGF does not affect on cytogenetic stability of cells. The survey of p27kip1 and cyclin D1 genes by real-time Q-PCR showed that the expression level of these genes were up-regulated when adding bFGF in culture media (p media with growth factor like bFGF could enhance the proliferation and differentiation capacity of cells and improve cells growth rate. Similarly, fibroblast growth factors did not induce any chromosomal abnormality in cells. Furthermore, in HDFs cultured in bFGF supplemented media, the p27kip1 and cyclin D1 genes were up-regulated and suggesting an important role for bFGF in cell-cycle regulation and progression and fibroblast division stimulation. It also suggests that the effects of bFGF on different cell types with

  12. Delivery of basic fibroblast growth factors from heparinized decellularized adipose tissue stimulates potent de novo adipogenesis.

    Science.gov (United States)

    Lu, Qiqi; Li, Mingming; Zou, Yu; Cao, Tong

    2014-01-28

    Scaffolds based on decellularized adipose tissue (DAT) are gaining popularity in adipose tissue engineering due to their high biocompatibility and adipogenic inductive property. However, previous studies involving DAT-derived scaffolds have not fully revealed their potentials for in vivo adipose tissue construction. With the aim of developing a more efficient adipose tissue engineering technique based on DAT, in this study, we investigated the in vivo adipogenic potential of a basic fibroblast growth factor (bFGF) delivery system based on heparinized DAT (Hep-DAT). To generate this system, heparins were cross-linked to mouse DATs by using 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide and N-Hydroxysuccinimide. The bFGF-binding Hep-DATs were first tested for controlled release ability in vitro and then transplanted subcutaneously. Highly vascularized adipose tissues were formed 6weeks after transplantation. Histology and gene expression analysis revealed that majority of the Hep-DAT scaffolds were infiltrated with host-derived adipose tissues that possessed similar adipogenic and inflammatory gene expression as endogenous adipose tissues. Additionally, strong de novo adipogenesis could also be induced when bFGF-binding Hep-DATs were thoroughly minced and injected subcutaneously. In conclusion, our study demonstrated that bFGF-binding Hep-DAT could be an efficient, biocompatible and injectable adipogenic system for in vivo adipose tissue engineering.

  13. Salivary Basic Fibroblast Growth Factorin Patients with Oral Squamous Cell Carcinoma or Oral Lichen Planus

    Science.gov (United States)

    Gorugantula, Lakshmi Mitreyi; Rees, Terry; Plemons, Jacqueline; Chen, Huey-Shys; Cheng, Yi-Shing Lisa

    2012-01-01

    Objective To gather preliminary data concerning the feasibility of using salivary basic fibroblast growth factor (bFGF) for detecting development of oral squamous cell carcinoma (OSCC) in oral lichen planus (OLP) patients, and in OSCC patients whose disease was in remission. Study Design Saliva samples were collected from five patient groups: newly diagnosed OSCC patients; OSCC patients in remission; OLP patients in disease-active state; OLP patients in disease-inactive state; and normal controls. Salivary bFGF levels were determined by ELISA, and data was analyzed using the Mann Whitney U test. Results Salivary bFGF levels were significantly elevated in newly diagnosed OSCC patients compared with OSCC remission patients, disease-active OLP patients, and normal controls. No significant difference was found between newly diagnosed OSCC patients and disease-inactive OLP patients. Conclusion Our results suggested that salivary bFGF might be a potential biomarker for detecting OSCC development in OSCC patients in remission, but not in OLP patients. PMID:22769407

  14. EXPRESSION AND SIGNIFICANCE OF BASIC FIBROBLAST GWOWTH FACTOR AND FIBROBLAST GROWTH FACTOR RECEPTOR-1 IN OVARIAN EPITHELIAL NEOPLASM

    Institute of Scientific and Technical Information of China (English)

    高尚风; 杨蓉; 高博; 刘惠喜

    2003-01-01

    fibroblast growth factor (bFGF), fibroblast growth factor receptor-1 (FGFR-1) and carcinogenesis and progression of ovarian epithelial neoplasm. Methods Ten cases of normal ovarian tissues and 75 cases of ovarian epithelial neoplasm tissues were detected by immunohistochemical methods: S-P for bFGF, FGFR-1,double immunohistochemistry Lab-SA for Ki-67 antigen and bFGF. Results The expression level of bFGF, FGFR-1in ovarian epithelium and ovarian epithelial neoplasm showed a step-wise increase in the following order:normal〈benign〈borderline〈malignant; The expression level and intensity of bFGF and FGFR-1 were increased with the decrease of differentiation degree and increase of clinical stage in ovarian carcinoma; There was no statistical difference between the expression of bFGF, FGFR-1 in serous cystadenocarcinoma and that of mucinous cystadenocarcinoma; The expression of bFGF was correlated with that of FGFR-1 in neoplastic tissues; There were positive expression rates of bFGF and Ki-67 antigen in ovarian epithelial neoplasm. Conclusion As an important proliferative factor, bFGF plays an important role in carcinogenisis and progression of ovarian epithelial neoplasm.

  15. Roles of cyclooxygenase-2 in microvascular endothelial cell proliferation induced by basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background The level of basic fibroblast growth factor (bFGF) increases rapidly after cerebral ischemia. However, the molecular mechanisms for the effects of bFGF on cerebral microvascular endothelial cells (cMVECs) have not yet been fully elucidated. In this study, a murine cMVEC line, bend.3, was employed to study the effects of bFGF on cyclooxygenase (COX) expression and its downstream effects in cMVECs. Methods After treatment with bFGF, RT-PCR and Western blotting analyses were carried out to evaluate the changes in COX-2 mRNA and protein expression, respectively. Ml-r assays were performed to measure cell proliferation. The prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA). Results COX-2 mRNA and protein expressions in bEnd.3 cells were induced by bFGF in time- and dose-dependent manners. The bFGF-induced COX-2 upregulation led to enhanced PGE2 production by bEnd.3 cells, and this effect was abolished by the selective COX-2 inhibitor NS-398. bFGF also increased VEGF production by bend.3 cells, and this effect was blocked by NS-398 and the EP1/2 (PGE2 receptors) antagonist AH6809. Furthermore, exogenous PGE2 increased VEGF production in bend.3 cells, and AH6809 blocked this effect. Conclusion bFGF increases VEGF production in an autocrine manner by increasing COX-2-generated PGE2 in cMVECs and subsequently stimulates MVEC proliferation and angiogenesis.

  16. XML Designing and Construction of Recombinant Plasmid Consisting of Basic Fibroblast Growth Factor and Immunodominant Fragments of Pseudomonas Exotoxin

    OpenAIRE

    Haghighatfard, H. (BSc; Yazdani, Y. (PhD

    2015-01-01

    Background and Objective: the inhibition of tumor-associated angiogenesis can significantly reduce the tumor proliferation. The basic fibroblast growth factor (bFGF), an important angiogenic factor, is considered as a potential therapeutic target for cancer therapy. The purpose of this study was evaluating, designing and construction of new recombinant DNA molecule in order to have efficient expression of a fusion protein consisting of the bFGF and immunodominant epitopes of Pseudomonas toxin...

  17. Effects of Basic Fibroblast Growth Factor and Insulin-like Growth Factor on Cultured Cartilage Cells from Skate Raja porasa

    Institute of Scientific and Technical Information of China (English)

    樊廷俊; 晋凌云; 汪小锋

    2003-01-01

    Effects of basic fibroblast growth factor (bFGF) and insulin-like growth factor II (IGF-II) on cartilage cells from proboscis of skate, Raja porasa Günther, were investigated in this study. The cartilage cells were cultured in 20% FBS-supplemented MEM medium at 24℃. Twelve hours after culture initiation, the cartilage cells were treated with bFGF and IGF-II at different concentration combinations. It was found that 20 ng/ml of bFGF or 80 ng/ml of IGF-II was enough to have obvious stimulating effect on the growth and division of skate cartilage cells. Test of bFGF and IGF-II together, revealed that 20 ng/ml of bFGF and 80 ng/ml of IGF-II together had the best stimulating effect on the growth and division of skate cartilage cells. The cartilage cells cultured could form a monolayer at day 7.

  18. Basic fibroblast growth factor protects auditory neurons and hair cells from noise exposure and glutamate neurotoxicity

    Institute of Scientific and Technical Information of China (English)

    翟所强; 王大君; 王嘉陵

    2003-01-01

    The purpose of the present study was to determine protectivie effects of basic fibroblast growth factor (bFGF) on cochlear neurons and hair cells in vitro and in vivo. In experiment I, cultured spiral ganglion neurons (SGNs) prepared from P3 mice were exposed to 20mM glutamate for 2 hours before the culture medium was replaced with fresh medium containing 0, 25, 50, and 100 ng/ml bFGF, respectively. Fourteen days later, all cultures were fixed with 4% paraformaldehyde, and stained with 1% toluidine blue. The number of surviving SGNs were counted and the length of SGNs neurites were measured. Exposure to 20 mM glutamate for 24 hours resulted in an inhibition on neurite outgrowth of SGNs and elevated cell death. Treatment of the cultures with bFGF led to promotion of neurite outgrowth and elevated number of surviving SGNs. Effects of bFGF were dose dependent with the highest potency at 100 ng/ml. In experiment Ⅱ, in vivo studies were carried out with guinea pigs in which bFGF or artificial perilymph was perfused into the cochlea to assess possible protective effects of bFGF on cochlear hair cells and compound action potentials(CAP). The CAPs were measured before, immediatly and 48 hours after exposure to noise. Significant differences in CAP were observed (p<0. 05 ) among the bFGF perfused group, control group(t =3. 896 ) and artificial perilymph perfused group (t =2. 520) at 48 hours after noise exposure, Cochleae were removed and hair cell Loss was analyzed in surface preparations prepared from all experimental animals. Acoustic trauma caused loss of 651 and 687 inner hair cells in the control and artificial perilymph perfused group, respectively. In sharp contrast, only 31 inner hair cells were lost in the bFGF perfused ears. Similarly, more outer hair cells died in the control and perilymph perfuesed group (41830 and 41968, respectively) than in the group treated with bFGF (34258). Our results demonstrate that bFGF protected SGNs against glutmate

  19. Expression of Basic Fibroblast Growth Factor in Rat Liver Fibrosis and Hepatic Stellate Cells

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The expression of basic fibroblast growth factor (bFGF) in rat liver fibrosis and hepatic stellate cells (HSCs) and the relationship between the expression of bFGF and rat liver fibrogenesis were studied. Sixty male SD rats (230-260 g) were divided into 4 groups randomly (the 0 week group, 1 week group, 4 week group and 8 week group). Liver fibrosis was induced by subcutaneous injection of carbon tetrachloride. The sections of rats' liver in each group were tested by VanGieson (V-G) staining and immunohistochemistry. The expression of bFGF mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). HSCs were isolated by the combined methods of collagenase Ⅳ perfusion and density gradient centrifugation. The expression of bFGF protein in cultured HSCs was detected by Western blot. Images of immunohistochemistry detec tion, agarose gel electrophoresis of RT-PCR and SDS-polyacrylamide gel electrophoresis of Western blot were analyzed semiquantitatively by image-analyzing system. The results were analyzed by statistics. The results showed that the fibers were gradually increased in the sections of rat liver with the prolongation of the model induction. At the end of the 8th weeks, liver fibrosis was formed.The expression of bFGF detected by immunohistochemistry showed a similar tendency of gradual increase. At the end of the 8th weeks, the bFGF expression could be observed in many regions in sections and the strongest expression was in interstitial cells including HSCs and some hepatocytes in regions around the portal area and central veins. Also there was moderate expression widely in extracellular matrix (ECM). In RT-PCR detection and Western blot detection of HSCs cultured in vitro, the similar tendency of gradual increase was evident either. It is suggested that bFGF is related with liver fibrosis of rats closely and may be a fibrogenesis factor of liver. bFGF possibly regulates liver fibrogenesis through regulating metabolism of extracellular

  20. Effect of early administration of exogenous basic fibroblast growth factor on acute edematous pancreatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Qiang Yan; Xing Yao; Li-Cheng Dai; Guo-Lei Zhang; Jin-Liang Ping; Jian-Fang He; Chun-Fan Han

    2006-01-01

    AIM: To observe the therapeutic effect of early administration of exogenous Basic fibroblast growth factor (bFGF) on acute edematous pancreatitis (AEP) in rats.METHODS: Thirty male Sprague-Dawley rats were ran-domly divided into three (n = 10): normal control group (group Ⅰ), AEP group (group Ⅱ) and AEP with bFGF treatment group (group Ⅲ). AEP was induced by subcutaneous injection of cerulein (5.5 μg/kg and 7.5 μg/kg) at 1 h interval into rats of groups Ⅱ and Ⅲ. Three hours after induction of AEP, 100 μg/kg bFGF was administrated intraperitoneally for 1h to group Ⅲ rats. For test of DNA synthesis in acinar cells, 5-bromo-2'-deoxyuridine (BrdU) labeling solution was intraperitoneally injected into the rats of groups Ⅱ and Ⅲ 24 h after bFGF treatment. The changes in serum amylase, lipase, pancreatic tissue wet/dry ratio were detected.RESULTS: In bFGF treatment group, there was a significant decrease in the volume of serum amylase, lipase and the pancreatic wet/dry weight ratio(1383.0±94.6 U/L, 194.0 ± 43.6 U/L, 4.32 ± 0.32) compared to AEP group (3464 ± 223.7 U/L, 456 ±68.7 U/L, 6.89 ± 0.47) (P < 0.01), and no significant difference was found between bFGF treatment and control group (1289 ± 94.0 U/L, 171 ± 23.4 U/L, 4.12 ± 0.26, P > 0.05). The inflammatory changes such as interstitial edema, polymorphonuclear neutrophils (PMNs) and vacuolization were significantly ameliorated compared to AEP group (P < 0.01). A small number of BrdU-labeled nuclei were observed in acinar cells of AEP rats (1.8 ± 0.3 nuclei/microscopic field, n = 10) while diffuse BrdU-labeled nuclei were found in bFGF-treated rats (18.9 ± 1.4 nuclei/microscopic field, n = 10) (P < 0.01). Immunohistochemical study showed increased DNA synthesis in pancreatic acinar cells.CONCLUSION: Early administration of exogenous bFGF has significant therapeutic effect on cerulein-induced acute edematous pancreatitis in rats. Its mechanism is related to the amelioration of

  1. Expression of vascular endothelial growth factor and basic fibroblast growth factor in acute rejection reaction following rat orthotopic liver transplantation.

    Science.gov (United States)

    Zhang, Changsong; Yang, Guangshun; Lu, Dewen; Ling, Yang; Chen, Guihua; Zhou, Tianbao

    2014-08-01

    The aim of the present study was to investigate the expression levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in acute rejection reaction (ARR) following orthotopic liver transplantation in a rat model. Serum VEGF and bFGF levels were detected using ELISA, and their expression levels in liver and spleen tissues were determined using immunohistochemistry. The mRNA expression levels of VEGF and bFGF were detected by conducting a quantitative polymerase chain reaction during the ARR following orthotopic liver transplantation. The expression levels of VEGF and bFGF in the serum 3 days following liver transplantation were significantly higher compared with those in the other groups (1 and 7 days following transplantation; Pliver tissue that were shown to be positive for the expression VEGF and bFGF using immunohistochemistry were significantly higher 3 days following transplantation than at the other time points (Pspleen detected 3 days following the transplantation surgery were also significantly higher compared with those at the other time points (Pchanged dynamically, by peaking and then declining, in ARR following orthotopic liver transplantation. These changes may have an important impact on angiogenesis and the inflammatory reaction, and the identification of these changes increases the current understanding of ARR following orthotopic liver transplantation.

  2. Quantitative analysis using ELISA of vascular endothelial growth factor and basic fibroblast growth factor in human colorectal cancer, liver metastasis of colorectal cancer and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Fran(c)ois Labrousse; Véronique Truffinet; Yves Denizot

    2006-01-01

    @@ TO THE EDITOR Angiogenesis consists of the sprouting of capillaries from pre-existing vessels[1]. It is well-known that tumor growth is angiogenesis-dependent. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)stimulated vascular endothelial cell proliferation and are involved in the neoplastic angiogenesis of several types of tumors including those of the intestinal tract[1-5].

  3. Secreted proteoglycans directly mediate human embryonic stem cell-basic fibroblast growth factor 2 interactions critical for proliferation.

    Science.gov (United States)

    Levenstein, Mark E; Berggren, W Travis; Lee, Ji Eun; Conard, Kevin R; Llanas, Rachel A; Wagner, Ryan J; Smith, Lloyd M; Thomson, James A

    2008-12-01

    Human embryonic stem (ES) cells can be maintained in an undifferentiated state if the culture medium is first conditioned on a layer of mouse embryonic fibroblast (MEF) feeder cells. Here we show that human ES cell proliferation is coordinated by MEF-secreted heparan sulfate proteoglycans (HSPG) in conditioned medium (CM). These HSPG and other heparinoids can stabilize basic fibroblast growth factor (FGF2) in unconditioned medium at levels comparable to those observed in CM. They also directly mediate binding of FGF2 to the human ES cell surface, and their removal from CM impairs proliferation. Finally, we have developed a purification scheme for MEF-secreted HSPG in CM. Using column chromatography, immunoblotting, and mass spectrometry-based proteomic analysis, we have identified multiple HSPG species in CM. The results demonstrate that HSPG are key signaling cofactors in CM-based human ES cell culture.

  4. Effect of basic fibroblast growth factor combined with laser on content of a variety of cytokines in acne scar wound

    Institute of Scientific and Technical Information of China (English)

    Zi-Xuan Dong

    2016-01-01

    Objective:To study the effect of basic fibroblast growth factor combined with laser on the content of a variety of cytokines in acne scar wound.Methods:A total of 64 patients with facial acne scars who received laser treatment in Dermatology Department of our hospital from June 2012 to October 2015 were studied and divided into two groups. Experimental group received collagen dressing combined with bFGF dressing change after surgery, and control group only received collagen dressing change after surgery. Wound healing as well as the content of type I collagen, type III collagen, TGF-β1, TAK and VEGF in the wound of two groups were compared.Results:Five days after surgery, the wound of experimental group had apparently scabbed and the scabby area was significantly greater than that of control group while the wound of control group showed visible granulation tissue proliferation and the scabby area was smaller; the levels of type I collagen, type III collagen, TGF-β1, TAK and VEGF in scab tissue of experimental group were significantly lower than those of control group.Conclusions:Basic fibroblast growth factor combined with laser can promote the healing of acne scar wound, decrease the type I collagen, type III collagen, TGF-β1 and VEGF content and prevent scar healing.

  5. Evaluation of polycaprolactone scaffold with basic fibroblast growth factor and fibroblasts in an athymic rat model for anterior cruciate ligament reconstruction.

    Science.gov (United States)

    Leong, Natalie Luanne; Kabir, Nima; Arshi, Armin; Nazemi, Azadeh; Wu, Ben; Petrigliano, Frank A; McAllister, David R

    2015-06-01

    Anterior cruciate ligament (ACL) rupture is a common ligamentous injury often necessitating surgery. Current surgical treatment options include ligament reconstruction with autograft or allograft, which have their inherent limitations. Thus, there is interest in a tissue-engineered substitute for use in ACL regeneration. However, there have been relatively few in vivo studies to date. In this study, an athymic rat model of ACL reconstruction was used to evaluate electrospun polycaprolactone (PCL) grafts, with and without the addition of basic fibroblast growth factor (bFGF) and human foreskin fibroblasts. We examined the regenerative potential of tissue-engineered ACL grafts using histology, immunohistochemistry, and mechanical testing up to 16 weeks postoperatively. Histology showed infiltration of the grafts with cells, and immunohistochemistry demonstrated aligned collagen deposition with minimal inflammatory reaction. Mechanical testing of the grafts demonstrated significantly higher mechanical properties than immediately postimplantation. Acellular grafts loaded with bFGF achieved 58.8% of the stiffness and 40.7% of the peak load of healthy native ACL. Grafts without bFGF achieved 31.3% of the stiffness and 28.2% of the peak load of healthy native ACL. In this in vivo rodent model study for ACL reconstruction, the histological and mechanical evaluation demonstrated excellent healing and regenerative potential of our electrospun PCL ligament graft.

  6. Evaluation of polycaprolactone scaffold with basic fibroblast growth factor and fibroblasts in an athymic rat model for anterior cruciate ligament reconstruction.

    Science.gov (United States)

    Leong, Natalie Luanne; Kabir, Nima; Arshi, Armin; Nazemi, Azadeh; Wu, Ben; Petrigliano, Frank A; McAllister, David R

    2015-06-01

    Anterior cruciate ligament (ACL) rupture is a common ligamentous injury often necessitating surgery. Current surgical treatment options include ligament reconstruction with autograft or allograft, which have their inherent limitations. Thus, there is interest in a tissue-engineered substitute for use in ACL regeneration. However, there have been relatively few in vivo studies to date. In this study, an athymic rat model of ACL reconstruction was used to evaluate electrospun polycaprolactone (PCL) grafts, with and without the addition of basic fibroblast growth factor (bFGF) and human foreskin fibroblasts. We examined the regenerative potential of tissue-engineered ACL grafts using histology, immunohistochemistry, and mechanical testing up to 16 weeks postoperatively. Histology showed infiltration of the grafts with cells, and immunohistochemistry demonstrated aligned collagen deposition with minimal inflammatory reaction. Mechanical testing of the grafts demonstrated significantly higher mechanical properties than immediately postimplantation. Acellular grafts loaded with bFGF achieved 58.8% of the stiffness and 40.7% of the peak load of healthy native ACL. Grafts without bFGF achieved 31.3% of the stiffness and 28.2% of the peak load of healthy native ACL. In this in vivo rodent model study for ACL reconstruction, the histological and mechanical evaluation demonstrated excellent healing and regenerative potential of our electrospun PCL ligament graft. PMID:25744933

  7. Effects of leukemia inhibitory factor and basic fibroblast growth factor on free radicals and endogenous stem cell proliferation in a mouse model of cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Weihui Huang; Yadan Li; Yufeng Lin; Xue Ye; Dawei Zang

    2012-01-01

    The present study established a mouse model of cerebral infarction by middle cerebral artery occlusion,and monitored the effect of 25 μg/kg leukemia inhibitory factor and (or) basic fibroblast growth factor administration 2 hours after model establishment.Results showed that following administration,the number of endogenous neural stem cells in the infarct area significantly increased,malondialdehyde content in brain tissue homogenates significantly decreased,nitric oxide content,glutathione peroxidase and superoxide dismutase activity significantly elevated,and mouse motor function significantly improved as confirmed by the rotarod and bar grab tests.In particular,the effect of leukemia inhibitory factor in combination with basic fibroblast growth factor was the most significant.Results indicate that leukemia inhibitory factor and basic fibroblast growth factor can improve the microenvironment after cerebral infarction by altering free radical levels,improving the quantity of endogenous neural stem cells,and promoting neurological function of mice with cerebral infarction.

  8. BASIC FIBROBLAST GROWTH FACTOR GENE TRANSFECTION TO ENHANCE THE REPAIR OF AVASCULAR NECROSIS OF THE FEMORAL HEAD

    Institute of Scientific and Technical Information of China (English)

    Cao Yang; Shu-hua Yang; Jing-yuan Du; Jin Li; Wei-hua Xu; Yu-fang Xiong

    2004-01-01

    Objective To explore a new method for the therapy ofavascular necrosis of the femoral head.Method The recombinant plasmid pCD-rbFGF was mixed with collagen and was implanted in the necrotic femoral head. Expression of basic fibroblast growth factor (bFGF) was examined by RT-PCR and immunohistochemical method. Repair of the femoral head was observed by histological and histomorphometric analysis.Result Expression of bFGF was detected in the femoral head transfected with bFGF gene, indicating significant increase of angiogenesis 2 weeks after gene transfection and increased new bone formation 8 weeks after gene transfection on histomorphometric analysis (P < 0.01).Conclusion Transfection ofbFGF gene enhances bone tissue angiogenesis. Repair in osteonecrosis would be accelerated accordingly.

  9. Improved wound healing in pressure-induced decubitus ulcer with controlled release of basic fibroblast growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Jiang Wei [Department of Respiratory Diseases, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Wang Hailun [Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Jin Faguang [Department of Respiratory Diseases, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)], E-mail: nidewenzhang@163.com; Yu Chunyan [Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Chu Dongling [Department of Respiratory Diseases, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China); Wang Lin [Department of Internal Medicine, 316 Hospital of PLA, Beijing 100093 (China); Lu Xian [93942 Unit Hospital of PLA, Xianyang 710012 (China)

    2008-07-14

    The purpose was to evaluate the efficacy of the wound dressing containing basic fibroblast growth factor (bFGF)-loaded microspheres on promoting healing in pressure-induced decubitus ulcer. In this study, the pressure-induced ulcer in swine was used as a model to demonstrate the hypothesis that controlled release of bFGF has the potential to provide optimal healing milieu for chronic wounds in the repair process. Average size of the microspheres was 14.36 {+-} 3.56 {mu}m and the network gelatin sponges were characterized with an average pore size of 80-160 {mu}m. Both the in vitro release efficiency and the protein bioactivity revealed that bFGF was released from the microspheres in a controlled manner and it was biologically active as assessed by its ability to induce the proliferation of fibroblasts. Pressure-induced ulcer was created at 500 g/cm{sup 2} pressure loaded on swine dorsal skin 12 h daily for 2 consecutive days. After removal of the pressure load, the gelatin sponge containing bFGF gelatin microspheres or bFGF in solution was implanted into the wound. Swine were sacrificed at 7, 14, and 21 days after implantation, and a full-thickness biopsy was taken and stained for histological analysis. It was observed that controlled release of bFGF provided an accelerated recovery in the wound areas. Histological investigations showed that the dressings were biocompatible and had capability of proliferating fibroblasts and inducing neovascularisation. The present study implied the clinical potential of gelatin sponge with bFGF microspheres to promote the healing in pressure-induced decubitus ulcer.

  10. The role of basic fibroblast growth factor in glioblastoma multiforme and glioblastoma stem cells and in their in vitro culture.

    Science.gov (United States)

    Haley, Elizabeth M; Kim, Yonghyun

    2014-04-28

    Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor, and current therapies are largely ineffective at treating the cancer. Developing a more complete understanding of the mechanisms controlling the tumor is important in order to explore new possible treatment options. It is speculated that the presence of glioblastoma stem or stem-like cells (GSCs), a rare type of pluripotent cancer cell that possesses the ability to self-renew and generate tumors, could be an important factor contributing to the resistance to treatment and deadliness of the cancer. A comprehensive knowledge of the mechanisms controlling the expression and properties of GSCs is currently lacking, and one promising area for further exploration is in the influence of basic fibroblast growth factor (FGF-2) on GSCs. Recent studies reveal that FGF-2 plays a significant part in regulating GBM, and the growth factor is commonly included as a supplement in media used to culture GSCs in vitro. However, the particular role that FGF-2 plays in GSCs has not been as extensively explored. Therefore, understanding how FGF-2 is involved in GSCs and in GBMs could be an important step towards a more complete comprehension of the managing the disease. In this review, we look at the structure, signaling pathways, and specific role of FGF-2 in GBM and GSCs. In addition, we explore the use of FGF-2 in cell culture and using its synthetic analogs as a potential alternative to the growth factor in culture medium.

  11. Effect of the combination of basic fibroblast growth factor and cysteine on corneal epithelial healing after photorefractive keratectomy in patients affected by myopia

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    Alessandro Meduri

    2014-01-01

    Full Text Available Background: This study sought to evaluate the effect of basic fibroblast growth factor eye drops and cysteine oral supplements on corneal healing in patients treated with photorefractive keratectomy (PRK. Materials and Methods: One hundred and twenty patients treated bilaterally with PRK for myopia were enrolled at one of two eye centers (Clinica Santa Lucia, Bologna, Italy and Department of Ophthalmology, University of Magna Graecia, Catanzaro, Italy and were treated at the former center. Sixty patients included in the study group (Group 1 were treated postoperatively with topical basic fibroblast growth factor plus oral L-cysteine supplements, whereas 60 subjects included in the control group (Group 2 received basic fibroblast growth factor eye drops. We recorded the rate of corneal re-epithelialization and patients were followed-up every 30 days for 6 months. Statistical analyses were performed on the collected data. Results: The eyes in Group 1 demonstrated complete re-epithelialization at Day 5, whereas the eyes in Group 2 achieved this status on Day 6. No side-effects were reported. Conclusions : Patients treated with basic fibroblast growth factor eye drops and L-cysteine oral supplements benefit from more rapid corneal re-epithelialization. In human eyes, this combination treatment appeared to be safe and effective in accelerating corneal surfacing after surgery. Financial Disclosure: No author has any financial or proprietary interest in any material or method used in this study. Trial Registration: Current Controlled Trials ISRCTN73824458.

  12. Improved myocardial perfusion and cardiac function by controlled-release basic fibroblast growth factor using fibrin glue in a canine infarct model*

    OpenAIRE

    Nie, Shao-Ping; Wang, Xiao; Qiao, Shi-bin; Zeng, Qiu-Tang; Jiang, Ju-quan; Liu, Xiao-Qing; Zhu, Xiang-ming; Cao, Guo-xiang; Ma, Chang-Sheng

    2010-01-01

    Objective: Angiogenic therapy is emerging as a potential strategy for the treatment of ischemic heart disease but is limited by a relatively short half-life of growth factors. Fibrin glue (FG) provides a reservoir for controlled-release of growth factors. The aim of this study was to evaluate the effects of basic fibroblast growth factor (bFGF) incorporating FG on angiogenesis and cardiac performance in a canine infarct model. Methods: Acute myocardial infarction was induced by ligation of th...

  13. Basic fibroblast growth factor is pro-adipogenic in rat skeletal muscle progenitor clone, 2G11 cells.

    Science.gov (United States)

    Nakano, Shin-ichi; Nakamura, Katsuyuki; Teramoto, Naomi; Yamanouchi, Keitaro; Nishihara, Masugi

    2016-01-01

    Intramuscular adipose tissue (IMAT) formation is a hallmark of marbling in cattle. IMAT is considered to originate from skeletal muscle progenitor cells with adipogenic potential. However, the mechanism involved in IMAT formation from these progenitor cells in vivo remains unclear. In the present study, among the growth factors tested, which were known to be expressed in skeletal muscle, we found only basic fibroblast growth factor (bFGF) has a pro-adipogenic effect on skeletal muscle derived adipogenic progenitor clone, 2G11 cells. Pre-exposure of 2G11 cells to bFGF did not affect initial gene expressions of CCAAT/enhancer-binding protein (C/EBP)β and C/EBPδ, while resulting in an enhancement of subsequent expressions of C/EBPα and proliferator-activated receptor gamma (PPARγ) during adipogenesis, indicating that bFGF is acting on the transcriptional regulation of C/EBPα and PPARγ. In addition, the effect of bFGF is mediated via two types of FGF receptor (FGFR) isoforms: FGFR1 and FGFR2 IIIc, and both receptors are prerequisite for bFGF to express its pro-adipogenic effect. These results suggest that bFGF plays an important role as a key trigger of IMAT formation in vivo. PMID:26154243

  14. Multipotential stem cells from the adult mouse brain proliferate and self-renew in response to basic fibroblast growth factor.

    Science.gov (United States)

    Gritti, A; Parati, E A; Cova, L; Frolichsthal, P; Galli, R; Wanke, E; Faravelli, L; Morassutti, D J; Roisen, F; Nickel, D D; Vescovi, A L

    1996-02-01

    It has been established that the adult mouse forebrain contains multipotential (neuronal/glial) progenitor cells that can be induced to proliferate in vitro when epidermal growth factor is provided. These cells are found within the subventricular zone of the lateral ventricles, together with other progenitor cell populations, whose requirements for proliferation remain undefined. Using basic fibroblast growth factor (bFGF), we have isolated multipotential progenitors from adult mouse striatum. These progenitors proliferate and can differentiate into cells displaying the antigenic properties of astrocytes, oligodendrocytes, and neurons. The neuron-like cells possess neuronal features, exhibit neuronal electrophysiological properties, and are immunoreactive for GABA, substance P, choline acetyl-transferase, and glutamate. Clonal analysis confirmed the multipotency of these bFGF-dependent cells. Most significantly, subcloning experiments demonstrated that they were capable of self-renewal, which led to a progressive increase in population size over serial passaging. These results demonstrate that bFGF is mitogenic for multipotential cells from adult mammalian forebrain that possess stem cell properties. PMID:8558238

  15. In vitro characteristics of poly(lactic-co-glycolic acid) microspheres incorporating gelatin particles loading basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    Shao-hong LI; Shao-xi CAI; Bing LIU; Kai-wang MA; Zhen-ping WANG; Xiao-kun LI

    2006-01-01

    Aim: To construct a sustained drug release system for basic fibroblast growth factor (bFGF). With this special system, bFGF can be used to repair an injured peripheral nerve, injured spinal cord, or as a carrier for other drugs that need to be released over a long time. Methods: Microsphere composite was prepared by encapsulating bFGF into gelatin particles with poly(lactic-co-glycolic acid) (PLGA) as its outer-coating. The encapsulation was conducted by a phase separation method. Results: The average diameter of the gelatin particle-PLGA microsphere composite was 5-18 μm, and bFGF-loading efficiency was up to 80.5%. The bFGF releasing experiment indicated that this new composite system could release bFGF continuously and protect bFGF from denaturation. Conclusion: A modified approach was successfully employed to develop a biodegradable system for sustained release of the drug of bFGF in vitro.

  16. THE EFFECT OF BASIC FIBROBLAST GROWTH FACTOR SLOW-RELEASE MICROCAPSULES ON ANGIOGENESIS IN INFARCTED RABBIT MYOCARDIUM

    Institute of Scientific and Technical Information of China (English)

    朱洪生; 连锋; 郑家豪

    2000-01-01

    Objectives. To observe the effect of basic fibroblast growth factor (bFGF) slow-release microcapsules on angiogen esis in infarcted myocardial regions. Methods. Myocardial infarction was induced in 24 New Zealand rabbits by ligating the root of left anterior de scending coronary artery. Group Ⅰ (n = 8) served as control, group Ⅱ (n = 8) as a blank microcapsule group, group Ⅲ (n = 8, each microcapsule contains lμg bFGF) as micrpcapsule group. In group Ⅱ and Ⅲ, 5 blank microcapsules or bFGF slow-release microcapsules were implanted into myocardium underneath the epicardium between the left ante fior descending coronary artery and left circumflex artery. Infarct size was evaluated by infarcted weight/left ventricle weight ratio and angiogenesis was evaluated by immunohistochemical examinations 5 weeks later. Results. As compared with group Ⅰ and Ⅱ, rabbits treated with bFGF slow-release microcapsules showed higher microvessel counts (group Ⅰ 37.75 + 4.50, group Ⅱ 38.37 ± 4.98, vs. group Ⅲ 135.50 ± 4.81, P < 0. 001 ) and less infarcted weight/left ventricle weight (group Ⅰ 16.8% ± 0.4%, group Ⅱ 16.7% ± 0.5%, vs. group Ⅲ 7.0% ± 0.2% ,P< 0.001). Conclusions. Subepicardial administration of bFGF slow-release microcapsule in the infarcted rabbit model results in effective angiogenesis and reduction in infarct size.

  17. XML Designing and Construction of Recombinant Plasmid Consisting of Basic Fibroblast Growth Factor and Immunodominant Fragments of Pseudomonas Exotoxin

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    Haghighatfard, H. (BSc

    2015-05-01

    Full Text Available Background and Objective: the inhibition of tumor-associated angiogenesis can significantly reduce the tumor proliferation. The basic fibroblast growth factor (bFGF, an important angiogenic factor, is considered as a potential therapeutic target for cancer therapy. The purpose of this study was evaluating, designing and construction of new recombinant DNA molecule in order to have efficient expression of a fusion protein consisting of the bFGF and immunodominant epitopes of Pseudomonas toxin. Material and Methods: Different types of peptide linker, codon adaptation index (CAI and adding signal peptide were considered in designing of immunogenic coding sequence. After software evaluation, the recombinant DNA molecule was ordered in the puc57 cloning vector. Then, coding sequence inserted into the multiple cloning site of pET28-a plasmid. Finally, PCR and enzymatic digestion tests were done for evaluation of recombinant expression vector. Results: Optimization of DNA sequence, codon adaptation index (CAI increased from 0.69 to 0.83 and GC content decreased from 61 to 54.77. The presence of 1214-bp PCR product and 1029-bp one obtaining from enzymatic digestion confirmed the correction of the cloning process. Conclusion: According to the previous studies, it is the first work for designing, optimizing and synthesis of recombinant DNA consisting of bFGF and immunodominant epitopes of Pseudomonas toxin

  18. The effect of basic fibroblast growth factor on regeneration in a surgical wound model of rat submandibular glands

    Institute of Scientific and Technical Information of China (English)

    Fumitaka Kobayashi; Kenichi Matsuzaka; Takashi Inoue

    2016-01-01

    This study developed an animal model of surgically wounded submandibular glands (SMGs) and investigated the effects of collagen gel with basic fibroblast growth factor (bFGF) on tissue regeneration of surgically wounded SMGs in vivo. The animal model was produced by creating a surgical wound using a 3-mm diameter biopsy punch in SMGs. The wound was filled with collagen gel with bFGF (bFGF group) or without bFGF (control group). In the animal model of surgically wounded SMGs, salivary glands without scar tissue around the wound area were observed with smaller areas of collagen gel. Small round and spindle-shape cells invaded the collagen gel in both groups after operation day (AOD) 5, and this invasion dramatically increased at AOD 7. Host tissue completely replaced the collagen gel at AOD 21. The invading immune cells in the group treated with collagen gel with bFGF were positive for vimentin, a-smooth muscle actin (aSMA), CD49f, c-kit and AQP5 at AOD 7. Similarly, the mRNA expression of vimentin, aSMA, CD49f, keratin19 and AQP5 was also increased. This study suggests that the use of collagen gels with bFGF improves salivary gland regeneration.

  19. In vivo radioprotective effects of basic fibroblast growth factor in C3H mice

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    Kim, Yeon Shil; Yoon, Sei Chul [Catholic University of Korea, Seoul (Korea, Republic of)

    2002-09-15

    In order to understand in vivo radiation damage modifying effect of bFGF on jejunal mucosa, bone marrow and the effect of bFGF on the growth of transplanted mouse sarcoma 180 tumor in mice. Mice were treated with 6 {mu} g of bFGF at 24 hours and 4 hours before exposing to 600 cGy, 800 cGy, and 1,000 cGy total body irradiation (TBI), and then exposed to 3,000 cGy local radiation therapy on the tumor bearing thigh. Survival and tumor growth curve were plotted in radiation alone group and combined group of bFGF and irradiation (RT). Histologic examination was performed in another experimental group. Experimental groups consisted of normal control, tumor control, RT (radiation therapy) alone, 6 {mu} g bFGF alone, combined group of 3 {mu} g bFGF and irradiation (RT), combined group of 6 {mu} g bFGF and irradiation (RT). Histologic examination was performed with H-E staining in marrow, jejunal mucosa, lung and sarcoma 180 bearing tumor. Radiation induced apoptosis was determined in each group with the DNA terminal transferase nick-end labeling method (ApopTag S7100-kit, Intergen Co.) The results were as follows 1) 6 {mu} g bFGF given before TBI significantly improved the survival of lethally irradiated mice. bFGF would protect against lethal bone marrow syndrome. 2) 6 {mu} g bFGF treated group showed a significant higher crypt depth and microvilli length than RT alone group ({rho} < 0.05). 3) The bone marrow of bFGF treated group showed less hypocellularity than radiation alone group on day 7 and 14 after TBI ({rho} < 0.05), and this protective effect was more evident in 6 {mu} g bFGF treated group than that of 3 {mu} g bFGF treated group. 4) bFGF protected against early radiation induced apoptosis in intestinal crypt cell but might have had no antiapoptotic effect in bone marrow stem cell and pulmonary endothelial cells. 5) There was no significant differences in tumor growth rate between tumor control and bFGF alone groups ({rho} > 0.05). 6) There were no significant

  20. Effect of basic fibroblast growth factor on the proliferation, migration and phenotypic modulation of airway smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    ZOU Hui; NIE Xiu-hong; ZHANG Yi; HU Mu; ZHANG Yu Alex

    2008-01-01

    Background Proliferation,cell migration and phenotypic modulation of airway smooth muscle cells(ASMCs)are important features of airway remodelling in asthma.The precise cellular and molecular mechanisms that regulate ASMCs proliferation,migration and phenotypic modulation in the lung remain unknown.Basic fibroblast growth factor(bFGF),a highly specific chemotactic and mitogenic factor for many cell types,appears to be involved in the development of airway remodelling.Our study assessed whether bFGF directly stimulates the proliferation,migration and phenotypic modulation of ASMCs.Methods Confluent and growth arrested human ASMCs were treated with human recombinant FGF.Proliferation was measured by BrdU incorporation and cell counting.Migration was examined using Boyden chamber apparatus.Expressions of smooth muscle(sm)-α-actin and sm-myosin heavy chain(MHC)isoform 1 were determined by RT-PCR and Western blot analysis.Results It was found that hrbFGF(10 ng/ml),when added to ASMCs,induced a significant increase in BrdU uptake and cell number by ASMCS as compared to controls and a significant increase in ASMCs migration with respect to controls.The mRNA and protein expressions of sm-α-actin and sm-MHC in ASMCs that were stimulated with hrbFGF decreased with respect to controls.Conclusion It appears that bFGF can directly stimulate proliferation and migration of ASMCs.however,the expressions of cells'contractive phenotype decreased.

  1. Effect of basic fibroblast growth factor (bFGF) on the treatment of exposure of the orbital implants

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To evaluate the efficacy and the indication of basic fibroblast growth factor (bFGF) in the treatment of exposure of orbital implants. Design: Retrospective and observational case series. Methods: We reviewed 41 patients (41 eyes) suffering exposure of orbital implants from Jan. 2000 to June 2006. The study group patients with mild exposure received combined treatment with bFGF and antibiotic drops, and while the control group patients with mild exposure were treated with antibiotic drops only. The study group patients with moderate and severe exposure received combined treatment with bFGF and antibiotic drops, and after 2 months they were subjected to amniotic membrane transplantation, while the control group patients with moderate and severe exposure underwent amniotic membrane transplantation after using antibiotic drops. Observation of the growth of conjunctival epithelium and comparison of the healing rate of the two groups. Results: The healing rates of the mild,moderate and severe exposure study group were 100% and 92.3%. The healing rates of the mild, moderate and severe exposure control group were 55.6% and 66.7% respectively. The difference of the healing rates of the mild exposure study group and the control group was significant (P=0.033). And the difference of the healing rates of the moderate and severe exposure study group and the control group was not significant (P=0.167). Conclusion: bFGF may promote obviously the healing of orbital implant exposure, particularly it can be the first choice for the treatment of mild degree exposure. For the moderate and severe cases, it can be administered before surgical repair to enhance neovascularization and will tend to increase the success rate of surgical repair.

  2. Using basic fibroblast growth factor nanoliposome combined with ultrasound-introduced technology to early intervene the diabetic cardiomyopathy.

    Science.gov (United States)

    Zhao, Ying-Zheng; Zhang, Ming; Tian, Xin-Qiao; Zheng, Lei; Lu, Cui-Tao

    2016-01-01

    Basic fibroblast growth factor (bFGF)-loaded liposome (bFGF-lip) combined with ultrasound-targeted microbubble destruction (UTMD) technique was investigated to prevent diabetic cardiomyopathy (DCM). Cardiac function and myocardial ultrastructure were assessed. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, immunohistochemistry staining, and Western blot assay were used to investigate the signal pathway underlying the expression of bFGF in DCM treatment. From Mason staining and TUNEL staining, bFGF-lip + UTMD group showed significant differences from the diabetes group and other groups treated with bFGF or bFGF-lip. The diabetes group showed similar results (myocardial capillary density, collagen volume fraction, and cardiac myocyte apoptosis index) to other bFGF treatment groups. Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis, and metabolic disturbances could be suppressed by the different extents of twice-weekly bFGF treatments for 12 consecutive weeks (free bFGF or bFGF-lip +/- UTMD), with the strongest improvements observed in the bFGF-lip + UTMD group. The group combining bFGF-lip with UTMD demonstrated the highest level of bFGF expression among all the groups. The bFGF activated the PI3K/AKT signal pathway, causing the reduction of myocardial cell apoptosis and increase of microvascular density. This strategy using bFGF-lip and UTMD is a potential strategy in early intervention of DCM in diabetes.

  3. Induction of Neuronal Differentiation of Rat Muscle-Derived Stem Cells in Vitro Using Basic Fibroblast Growth Factor and Ethosuximide

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    Jin Seon Kwon

    2013-03-01

    Full Text Available Several studies have demonstrated that basic fibroblast growth factor (bFGF can induce neural differentiation of mesenchymal stem cells. In this study, we investigated the neural differentiation of muscle-derived stem cells (MDSCs following treatment with bFGF and ethosuximide, a small molecule used as an anticonvulsant in humans. Stem cells isolated from rat skeletal muscle (rMDSCs were pre-induced by culturing with 25 ng/mL bFGF for 24 h and then were transferred to a medium supplemented with or without 4 mM ethosuximide. Neuronal differentiation was assessed by immunocytochemical and western blotting analyses of marker expression. Immunocytochemistry of rMDSCs treated with bFGF and ethosuximide identified abundant cells expressing neuronal markers (TuJ1, neuron-specific class III β-tubulin; NeuN, neuronal nuclear antigen; and NF-MH; neurofilament M and H. Olig2 (oligodendrocyte transcription factor 2-positive cells were also observed, indicating the presence of oligodendrocyte lineage cells. These findings were substantiated by western blotting analysis of marker proteins. In particular, the expression of NeuN and TuJ1 was significantly higher in rMDSCs treated with ethosuximide and bFGF than in cells stimulated with bFGF alone (NeuN, p < 0.05 and TuJ1, p < 0.001. Expression of the astrocyte marker GFAP (glial fibrillary acidic protein was not detected in this study. Collectively, the results showed that treatment with bFGF and ethosuximide induced effective transdifferentiation of rMDSCs into cells with a neural-like phenotype. Notably, rMDSCs treated with a combination of bFGF plus ethosuximide showed enhanced differentiation compared with cells treated with bFGF alone, implying that ethosuximide may stimulate neuronal differentiation.

  4. Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats.

    Science.gov (United States)

    Fisher, M; Meadows, M E; Do, T; Weise, J; Trubetskoy, V; Charette, M; Finklestein, S P

    1995-11-01

    Basic fibroblast growth factor (bFGF) is a polypeptide that supports the survival of brain cells (including neurons, glia, and endothelia) and protects neurons against a number of toxins and insults in vitro. This factor is also a potent dilator of cerebral pial arterioles in vivo. In previous studies, we found that intraventricularly administered bFGF reduced infarct volume in a model of focal cerebral ischemia in rats. In the current study, bFGF (45 micrograms/kg/h) in vehicle, or vehicle alone, was infused intravenously for 3 h, beginning at 30 min after permanent middle cerebral artery occlusion by intraluminal suture in mature Sprague-Dawley rats. After 24 h, neurological deficit (as assessed by a 0- to 5-point scale, with 5 = most severe) was 2.6 +/- 1.0 in vehicle-treated and 1.5 +/- 1.3 in bFGF-treated rats (mean +/- SD; N = 12 vs. 11; p = 0.009). Infarct volume was 297 +/- 65 mm3 in vehicle- and 143 +/- 135 mm3 in bFGF-treated animals (p = 0.002). During infusion, there was a modest decrease in mean arterial blood pressure but no changes in arterial blood gases or core or brain temperature in bFGF-treated rats. Autoradiography following intravenous administration of 111In-labeled bFGF showed that labeled bFGF crossed the damaged blood-brain barrier to enter the ischemic (but not the nonischemic) hemisphere. Whether the infarct-reducing effects of bFGF depend on intraparenchymal or intravascular mechanisms requires further study.

  5. Pharmacokinetics of recombinant human basic fibroblast growth factor in rabbits and mice serum and rabbits aqueous humor

    Institute of Scientific and Technical Information of China (English)

    Qi ZHANG; Guang-ji WANG; Jian-guo SUN

    2004-01-01

    AIM: To study the pharmacokinetics of recombinant human basic fibroblast growth factor (rhbFGF) in rabbits and mice after iv and postocular administration, and the changes of rhbFGF in rabbits aqueous humor after postocular administration. METHODS: After iv or postocular administration three doses of rhbFGF in rabbits and mice,rhbFGF concentration in serum and rabbit aqueous humor was determined by enzyme-linked immunosorbent .assay. RESULTS: Serum concentration-time data of rabbits after iv administration of rhbFGF 1, 2, and 4 μg/kg were fitted to bi-exponential equations with half-lives of 0.9, 0.9, and 0.6 min for T1/2α and 7, 8, and 4.7 min for T1/2β.Plasma concentration-time data of mice after iv administration of rhbFGF 2.5, 5 and 10 μg/kg were fitted to biexponential equations with half-lives of 0.4, 0.6, and 0.9 min for T1/2α and 6, 5, and 7 min for T1/2β. The AUCs were linearly correlated to doses in both cases (rrabbit=0.997, rmouse=0.999). The serum concentrations of rhbFGF were very low, near to the background after postocular administration of 2 or 5 μg/kg, in both rabbits and mice. The rhbFGF levels in rabbits aqueous humor were higher than control 8 h postdose (P<0.01). CONCLUSION: rhbFGF within the examined doses had a linear pharmacokinetics in rabbits and mice. High concentration of rhbFGF was found in rabbits aqueous humor after postocular administration.

  6. Effect of Basic Fibroblast Growth Factor on in Vitro Maturation of Oocytes of Mouse at the Stage of Germinal Vesicle

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    R Khanbabaee

    2014-10-01

    Full Text Available Introduction: In vitro maturation (IVM of oocytes, providing oocytes maturation out of normal conditions, is an appropriate infertility treatment system, though the clinical use of IVM is limited due to low rate of success. Accordingly, this study aimed to analyze the effect of fibroblast growth factor on in vitro maturation of immature oocytes. Methods: Immature oocytes of 20 female mice of NMRI strain aged 8-10 weeks were obtained 46-48 hours after intraperitoneal injection of 10 units of Pregnant Mare`s Serum Gonadotrophin (PMSG. The oocytes were treated within Modified Essential Medium (MEM-α supplemented with 0 ng/ml, 10 ng/ml, 20 ng/ml and 40 ng/ml doses of fibroblast growth factor respectively. After 24 hours, Oocyte maturation stage was scrutinized by an invert microscope and its growth rate was analyzed via SPSS software utilizing ANOVA test. Results: The resumption percentage of meiosis was reported as 23 in the first control group, while it was 25.7, 26.2, 27.3 % respectively for the second, third and fourth experimental groups; thus, no significant differences was observed among control groups and experimental groups. Yet in vitro maturation of the control group, a significant difference was observed compared to those of the second and third experimental groups (p<0.01. In fact, the rate of vitro metaphase matured oocytes were reported as 45, 60.8, 62.6 and 45.2 % respectively in the control group and the second, third, and fourth experimental groups. Conclusion: The obtained results of study illustrated that 10 ng/ml and 20 ng/ml concentrations of fibroblast growth factor have a major impact on resumption of meiosis, nucleus break down and extrusion of the first polar body, whereas the effect of 40 mg/ml concentration on improvement of oocyte maturation was trivial.

  7. Using basic fibroblast growth factor nanoliposome combined with ultrasound-introduced technology to early intervene the diabetic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Zhao YZ

    2016-02-01

    Full Text Available Ying-Zheng Zhao,1,2 Ming Zhang,1 Xin-Qiao Tian,3 Lei Zheng,4 Cui-Tao Lu1,2 1College of Pharmaceutical Sciences, Wenzhou Medical University, 2Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 3Department of Ultrasonic Diagnosis, Henan Provincial People’s Hospital, Zhengzhou City, Henan, 4Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Abstract: Basic fibroblast growth factor (bFGF-loaded liposome (bFGF-lip combined with ultrasound-targeted microbubble destruction (UTMD technique was investigated to prevent diabetic cardiomyopathy (DCM. Cardiac function and myocardial ultrastructure were assessed. Terminal deoxynucleotidyl transferase (TdT-mediated dUTP nick-end labeling (TUNEL staining, immunohistochemistry staining, and Western blot assay were used to investigate the signal pathway underlying the expression of bFGF in DCM treatment. From Mason staining and TUNEL staining, bFGF-lip + UTMD group showed significant differences from the diabetes group and other groups treated with bFGF or bFGF-lip. The diabetes group showed similar results (myocardial capillary density, collagen volume fraction, and cardiac myocyte apoptosis index to other bFGF treatment groups. Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis, and metabolic disturbances could be suppressed by the different extents of twice-weekly bFGF treatments for 12 consecutive weeks (free bFGF or bFGF-lip +/- UTMD, with the strongest improvements observed in the bFGF-lip + UTMD group. The group combining bFGF-lip with UTMD demonstrated the highest level of bFGF expression among all the groups. The bFGF activated the PI3K/AKT signal pathway, causing the reduction of myocardial cell

  8. Effects of basic fibroblast growth factor on superoxide dismutase activity and malondialdehyde content in the rat brain following intracerebral hemorrhage

    Institute of Scientific and Technical Information of China (English)

    Hongqiao Wei; Juen Huang; Junjie Huang; Bing Li; Qianming Li

    2008-01-01

    BACKGROUND: Studies have confirmed that basic fibroblast growth factor (bFGF) promotes neuronal survival and neurite outgrowth. OBJECTIVE: To compare and verify the effects of bFGF on superoxide dismutase activity and malondialdehyde content in rat brain tissues surrounding a hemorrhagic lesion, as well as the hippocampus at the hemorrhagic side. DESIGN, TIME AND SETTING: The randomized, controlled, neurobiological study was performed at the Science Experimental Center and Research Laboratory, Guangxi Medical University, China, from September to December 2006. MATERIALS: Ninety-two adult, healthy, Wistar rats of equal gender were used to establish intraeerebral hemorrhage by infusing type VII collagenase into the left internal capsule. Type Ⅶ collagenase (Sigma, USA), superoxide dismutase and malondialdehyde kits (Jiancheng, China), and bFGF (Institute of Bioengineering, Ji'nan University, China) were used for this study. METHODS: Ninety successfully lesioned rats were equally and randomly divided into three groups. Rats in the bFGF group were intramuscularly injected daily with bFGF (8μg/kg). Rats in the saline control group received an equal volume of saline. The rats in the model group did not receive other interventions. Superoxide dismutase activity was measured using the xanthine oxidase method. Malondialdehyde contents were detected using the thiobarbituric acid method. MAIN OUTCOME MEASURES: At 1, 3, and 7 days following intracerebral hemorrhage, superoxide dismutase and malondialdehyde were determined in the brain tissue surrounding the hematoma and in the hippocampus in the affected hemisphere. RESULTS: In brain tissue surrounding the hematoma, superoxide dismutase activity was significantly increased in the bFGF group at 3 and 7 days after intracerebral hemorrhage compared with the saline control group, whereas malondialdehyde content was significantly decreased (P 0.05). CONCLUSION: Increased superoxide dismutase activity and decreased

  9. One-stage, simultaneous skin grafting with artificial dermis and basic fibroblast growth factor successfully improves elasticity with maturation of scar formation.

    Science.gov (United States)

    Hamuy, Rodrigo; Kinoshita, Naoshi; Yoshimoto, Hiroshi; Hayashida, Kenji; Houbara, Seiji; Nakashima, Masahiro; Suzuki, Keiji; Mitsutake, Norisato; Mussazhanova, Zhanna; Kashiyama, Kazuya; Hirano, Akiyoshi; Akita, Sadanori

    2013-01-01

    The efficacy of one-stage artificial dermis and skin grafting was tested in a nude rat model. Reconstruction with artificial dermis is usually a two-stage procedure with 2- to 3-week intermission. If one-stage use of artificial dermis and split-thickness skin grafting are effective, the overall burden on patients and the medical cost will markedly decrease. The graft take rate, contraction rate, tissue elasticity, histology, morphometric analysis of the dermal thickness, fibroblast counting, immunohistochemistry of α-smooth muscle actin, matrix metalloproteinase-2, CD31, and F4/80, as well as gelatin zymography, real-time reverse transcriptase polymerase chain reaction for matrix metalloproteinase-2, and electron microscopy, were investigated from day 3 to 3 months postoperatively. The graft take rate was good overall in one-stage artificial dermis and skin grafting groups up to 3 weeks, and the contraction rate was greater in the two-staged artificial dermis and skin grafting group than in the skin grafting alone or one stage of artificial dermis and skin grafting groups. Split-thickness skin grafting with artificial dermis and basic fibroblast growth factor at a concentration of 1 μg/cm(2) showed significantly greater elasticity by Cutometer, and the dermal thickness was significantly thinner, fibroblast counting was significantly greater, and the α-smooth muscle actin expression level was more notable with a more mature blood supply in the dermis and more organized dermal fibrils by electron microscopy at 3 weeks. Thus, one-stage artificial dermis and split-thickness skin grafting with basic fibroblast growth factor show a high graft take rate and better tissue elasticity determined by Cutometer analysis, maturity of the dermis, and increased fibroblast number and blood supply compared to a standard two-stage reconstruction.

  10. The impact of hyperbaric oxygen therapy on serological values of vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF

    Directory of Open Access Journals (Sweden)

    Ziebura Thomas

    2010-12-01

    Full Text Available Abstract Background Hyperbaric oxygen (HBO therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF and vascular endothelial growth factor (VEGF; their in-vivo function is still not fully understood. Methods Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO. Results There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature. Conclusions A significant effect of HBO on serum

  11. Efficient delivery to human lung fibroblasts (WI-38) of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor and its inhibitory effect on collagen synthesis in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Togami, Kohei; Miyao, Aki; Miyakoshi, Kei; Kanehira, Yukimune; Tada, Hitoshi; Chono, Sumio

    2015-01-01

    In the present in vitro study, we assessed the delivery of pirfenidone incorporated into liposomes modified with truncated basic fibroblast growth factor (tbFGF) to lung fibroblasts and investigated the anti-fibrotic effect of the drug. The tbFGF peptide, KRTGQYKLC, was used to modify the surface of liposomes (tbFGF-liposomes). We used the thin-layer evaporation method, followed by sonication, to prepare tbFGF-liposomes containing pirfenidone. The cellular accumulation of tbFGF-liposomes was 1.7-fold greater than that of non-modified liposomes in WI-38 cells used as a model of lung fibroblasts. Confocal laser scanning microscopy showed that tbFGF-liposomes were widely localized in WI-38 cells. The inhibitory effects of pirfenidone incorporated into tbFGF-liposomes on transforming growth factor-β1 (TGF-β1)-induced collagen synthesis in WI-38 cells were evaluated by measuring the level of intracellular hydroxyproline, a major component of the protein collagen. Pirfenidone incorporated into tbFGF-liposomes at concentrations of 10, 30, and 100 µM significantly decreased the TGF-β1-induced hydroxyproline content in WI-38 cells. The anti-fibrotic effect of pirfenidone incorporated into tbFGF-liposomes was enhanced compared with that of pirfenidone solution. These results indicate that tbFGF-liposomes are a useful drug delivery system of anti-fibrotic drugs to lung fibroblasts for the treatment of idiopathic pulmonary fibrosis.

  12. EXPRESSION OF BASIC FIBROBLAST GROWTH FACTOR,TRANSFORMING GROWTH FACTOR β1 AND THEIR RECEPTORS IN OSTEOSARCOMA AND ITS RELATIONSHIP TO ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    WANG Dong; XIAO Hualiang; LI Zengpeng; CHEN Li

    1999-01-01

    Objective: To investigate the expression of angiogenic factors, basic fibroblast growth factor (bFGF)and transforming growth factor (TGF)-β1 in osteosarcoma, its association with neovascularization and prognosis. Methods: The expression of bFGF, TGFβ1 and their receptors, as well as intratumoral microvessel count (MVD) were studied in 80osteosarcomas by immunohistochemical staining and morphometry. The relationship between the angiogenic factors expression and prognosis was evaluated by a multivariate analysis using Cox proportion hazard model. Results: Among 80 cases of osteosarcoma, 46cases were positive for bFGF/bFGFr (57.5%), and 31cases for TGF-β1/TGF-β (RI)(38.8%) respectively. The MVD and bFGF, TGF-β1 were important indicators to predict the prognosis of patients with osteosarcoma by the Cox proportion hazard model analysis. Conclusion:The angiogenic factors bFGF and TGF-β1 are involved in the angiogenesis of osteosarcoma, and the angiogenesis influences the prognosis. Also they may be useful in the evaluation of the prognosis of patients with osteosarcoma.

  13. The angiogenic peptide vascular endothelial growth factor-basic fibroblast growth factor signaling is up-regulated in a rat pressure ulcer model.

    Science.gov (United States)

    Yang, Jing-Jin; Wang, Xue-Ling; Shi, Bo-Wen; Huang, Fang

    2013-08-01

    The purpose of this study is to investigate the mRNA and protein expression levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in pressure ulcers, and to elucidate the molecular mechanism by which VEGF and bFGF are involved in pressure ulcer formation. A rat model of ischemia-reperfusion pressure ulcer was established by magnetic disk circulating compression method. Real-time fluorescence quantitative PCR and Western blot assays were conducted to detect the mRNA and protein expression of VEGF and bFGF in the tissues of rat I-, II-, and III-degree pressure ulcers, the surrounding tissues, and normal skin. Our study confirmed that the mRNA and protein expression levels of VEGF and bFGF in the tissues of rat I-degree pressure ulcer were significantly higher than that in the II- and III-degree pressure ulcer tissues (P ulcers were higher than the rats with normal skin. The expression of VEGF and bFGF in the tissues of rat III-degree pressure ulcer was lower than that in the surrounding tissues and normal skin (P ulcers, the expression of VEGF and bFGF in pressure ulcers tissue are decreased. This leads to a reduction in angiogenesis and may be a crucial factor in the formation of pressure ulcers.

  14. Rapid mitogen-activated protein kinase by basic fibroblast growth factor in rat intestin after ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Xiao-Bing Fu; Yin-Hui Yang; Tong-Zhu Sun; Wei Chen; Jun-You Li; Zhi-Yong Sheng

    2003-01-01

    AIM: Previous studies showed that exogenous basic fibroblast growth factor (bFGF or FGF-2) could improve physiological dysfunction after intestinal ischemia/reperfusion (I/R) injury. However, the mechanisms of this protective effect of bFGF are still unclear. The present study was to detect the effect of bFGF on the activities of mitogen-activated protein kinase (MlAPK) signaling pathway in rat intestine after I/R injury, and to investigate the protective mechanisms of bFGF on intestinal ischemia injury. METttODS: Rat intestinal I/R injury was produced by clamping the superior mesenteric artery (SMA) for 45minutes and followed by repeffusion for 48 hours. Seventyeight Wistar rats were used and divided randomly into sham-operated group (A), normal saline control group (B),bFGF antibody pre-treated group (C), and bFGF treated group (D). Tn group A, SMA was separated without occlusion. In groups B, C and D, SMA was separated and occluded for 45 minutes, then, released for reperfusion for 48 hours. After the animals were sacrificed, blood and tissue samples were taken from the intestine 45 minutes after ischemia in group A and 2, 6, 24, and 48 hours after reperfusion in the other groups. Phosphorylated forms of p42/p44 MAPK, p38 MAPK and stress activated protein kinase/C-Jun N-terminal kinase (SAPK/JNK) were measured by immunohistochemistry. Plasma levels of D-lactate were examined and histological changes were observed under the light microscope. RESULTS: Intestinal I/R injury induced the expression of p42/p44 MAPK, p38 MAPK, and SAPK/JNK pathways and exogenous bFGF stimulated the early activation of p42/p44 MAPK and p38 MlAPK pathways. The expression of phosphorylated forms of p42/p44 MAPK was primarily localized in the nuclei of crypt cells and in the cytoplasm and nuclei of villus cells. The positive expression of p38MAPK was localized mainly in the nuclei of crypt cells, very few in villus cells. The activities of p42/p44 MAPK and p38MAPK peaked 6 hours after

  15. Prothrombin kringle-2 domain has a growth inhibitory activity against basic fibroblast growth factor-stimulated capillary endothelial cells.

    Science.gov (United States)

    Lee, T H; Rhim, T; Kim, S S

    1998-10-30

    Recently, O'Reilly et al. (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328; O'Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., and Folkman, J. (1997) Cell 88, 277-285) developed a simple in vitro angiogenesis assay system using bovine capillary endothelial cell proliferation and purified potent angiogenic inhibitors, including angiostatin and endostatin. Using a simple in vitro assay for angiogenesis, we purified a protein molecule that showed anti-endothelial cell proliferative activity from the serum of New Zealand White rabbits, which was stimulated by lipopolysaccharide. The purified protein showed only bovine capillary endothelial cell growth inhibition and not any cytotoxicity. This molecule was identified as a prothrombin kringle-2 domain (fragment-2) using Edman degradation and the amino acid sequence deduced from the cloned cDNA. Both the prothrombin kringle-2 domain released from prothrombin by factor Xa cleavage and the angiogenic inhibitor purified from rabbit sera exhibited anti-endothelial cell proliferative activity. The recombinant rabbit prothrombin kringle-2 domain showed potent inhibitory activity with half-maximal concentrations (ED50) of 2 microg/ml media. As in angiostatin, the recombinant rabbit prothrombin kringle-2 domain also inhibited angiogenesis in the chorioallantoic membrane of chick embryos. PMID:9786880

  16. In vitro stress effect on degradation and drug release behaviors of basic fibroblast growth factor – poly(lactic-co-glycolic-acid) microsphere

    OpenAIRE

    Xiong Y.; Yu ZP; Lang Y; Hu JY; Li H; Yan YG; Tu CQ; Yang TF; Song YM; Duan H; Pei FX

    2016-01-01

    Yan Xiong,1 Zeping Yu,1 Yun Lang,1 Juanyu Hu,1 Hong Li,2 Yonggang Yan,2 Chongqi Tu,1 Tianfu Yang,1 Yueming Song,1 Hong Duan,1 Fuxing Pei11Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Biomechanical Engineering, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaObjective: To study the degradation and basic fibroblast growth factor (bFGF) release activity of bFGF – poly...

  17. Edited by SONG Shuang-mingEffect of basic fibroblast growth factor and hyaluronic acid on proliferation of rabbit chondrocytes in vitro

    Institute of Scientific and Technical Information of China (English)

    沈雁; 李斯明; 唐毅; 钟灿灿; 梁佩红; 陈鸿辉

    2004-01-01

    Objective: To investigate the effect of basic fibroblast growth factor (bFGF) and hyaluronic acid (HA) on the proliferation of rabbit chondrocytes in vitro.Methods: Chondrocytes from the knee joints of New Zealand white rabbits were cultured. bFGF or HA or both were added into the culture medium respectively, and the proliferation of the chondrocytes was measured with MTT 3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyl-tetra-zolium bromide. (MTT, Sigma, M2128).Results: Basic fibroblast growth factor (10 ng/ml) with low concentration of fetal bovine serum in the culture medium promoted the proliferation of chondrocytes significantly, and this effect reached its maximum when concentration of bFGF reached 50 ng/ml. HA itself had no effect on the proliferation of chondrocytes. However, when bFGF was used in combination with HA, especially when the concentration of bFGF was 50-500 ng/ml and that of HA was 10-50 ng/ml, the effect on the proliferation of chondrocytes was much more than when bFGF or HA was used alone. Conclusions: bFGF can promote the proliferation of chondrocytes. HA, which has no effect on the proliferation of the cells, can maintain a normal growth of chondrocytes. When bFGF is used in combination with HA, more proliferation is obtained.

  18. Combination of basic fibroblast growth factor and epidermal growth factor enhances proliferation and neuronal/glial differential of postnatal human enteric neurosphere cells in vitro.

    Science.gov (United States)

    Pan, Wei-Kang; Yu, Hui; Wu, A-Li; Gao, Ya; Zheng, Bai-Jun; Li, Peng; Yang, Wei-Li; Huang, Qiang; Wang, Huai-Jie; Ge, Xin

    2016-08-01

    Human enteric neural stem cells (hENSCs) proliferate and differentiate into neurons and glial cells in response to a complex network of neurotrophic factors to form the enteric nervous system. The primary aim of this study was to determine the effect of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) on in-vitro expansion and differentiation of postnatal hENSCs-containing enteric neurosphere cells. Enteric neurosphere cells were isolated from rectal polyp specimens of 75 children (age, 1-13 years) and conditioned with bFGF, EGF, bFGF+EGF, or plain culture media. Proliferation of enteric neurosphere cells was examined using the methyl thiazolyl tetrazolium colorimetric assay over 7 days of culture. Fetal bovine serum (10%) was added to induce the differentiation of parental enteric neurosphere cells, and differentiated offspring cells were immunophenotyped against p75 neutrophin receptor (neural stem cells), peripherin (neuronal cells), and glial fibrillary acidic protein (glial cells). Combining bFGF and EGF significantly improved the proliferation of enteric neurosphere cells compared with bFGF or EGF alone (both P<0.01) throughout 7 days of culture. The addition of bFGF drove a significantly greater proportion of enteric neurosphere cells to differentiate into neuronal cells than that of EGF (P<0.01), whereas addition of EGF resulted in significantly more glial differentiation compared with addition of bFGF (P<0.01). Combining bFGF and EGF drove enteric neurosphere cells to differentiate into neuronal cells in a proportion similar to glial cells. Our results showed that the combination of bFGF and EGF significantly enhanced the proliferation and differentiation of postnatal hENSCs-containing enteric neurosphere cells in vitro. PMID:27306591

  19. Effect of basic fibroblast growth factor and transforming growth factor β1 on the healing of reconstructed dura by carbon dioxide laser soldering in minipigs

    Institute of Scientific and Technical Information of China (English)

    ZHONG Hong-liang; WANG Zhen-min; YANG Zhi-jun; ZHAO Fu; WANG Bo; WANG Zhong-cheng; LIU Pi-nan

    2012-01-01

    Background Carbon dioxide (CO2) laser soldering is an alternative technique for tissue bonding.Basic fibroblast growth factor (bFGF) and transforming growth factor β1 (TGFβ1) are two key factors for wound healing.This study was performed to demonstrate the efficacy of CO2 laser soldering for dural reconstruction and the effect of bFGF and TGFβ1 on healing.Methods In Part Ⅰ,10 minipigs were randomized into two equal groups.Dural defects were reconstructed by conventional fibrin glue bonding (group Ⅰa) or CO2 laser soldering (group Ⅰb).The reconstructed dura was subjected to burst pressure (BP) measurement and immunohistochemical staining after 1 week.In Part Ⅱ,36 minipigs were randomized into three equal groups.Dural reconstruction was achieved by CO2 laser soldering.Exogenous bFGF (group Ⅱb) or TGFβ1 (group Ⅱc) was administered while group Ⅱa served as a control group.The specimens were subjected to BP measurement after 1,2,3,and 4 weeks,respectively.Results In Part Ⅰ,the dura specimens displayed positive staining of only bFGF in group la and of both bFGF and TGFβ1 in group lb.Group Ⅰb showed higher BP than group la ((98.00-±21.41) mmHg vs.(70.80±15.09) mmHg,respectively; P <0.05).In Part Ⅱ,BP of group Ⅱc was significantly higher than that of group Ⅱla (P <0.01).The BP of group Ⅱa trended toward stabilization after 3 weeks of growth,while that of groups lⅡb and Ⅱc trended toward stabilization after 2 weeks of growth.Conclusions CO2 laser soldering is a reliable technique for dural reconstruction.The superior healing of dural reconstruction by CO2 laser soldering may be related to higher expression of bFGF and TGFβ1,and CO2 lasers may stimulate their secretion.Exogenous bFGF or TGFβ1 may improve healing by shortening the wound healing time,and exogenous TGFβ1 may improve the tensile strength.

  20. Expression of Basic Fibroblast Growth Factor Results in the Decrease of Myostatin mRNA in Murine C2C12 Myoblasts

    Institute of Scientific and Technical Information of China (English)

    Hua-Zhong LIU; Qing LI; Xing-Yuan YANG; Lin LIU; Lei LIU; Xiao-Rong AN; Yong-Fu CHEN

    2006-01-01

    During the development and regeneration of skeletal muscle, many growth factors, such as basic fibroblast growth factor (bFGF, FGF-2) and myostatin, have been shown to play regulating roles.bFGF contributes to promote proliferation and to inhibit differentiation of skeletal muscle, whereas myostatin plays a series of contrasting roles. In order to elucidate whether the expression of bFGF has any relationship with the expression of myostatin in skeletal muscle cells, we constructed a eukaryotic expression vector for the expression of exogenous bFGF in murine C2C12 myoblasts. Quantitative RT-PCR assays indicated that with the increase of the expression of exogenous bFGF gene, the expression of endogenous myostatin gene was suppressed at mRNA level and protein level.

  1. Angiogenic synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in an in vitro quantitative microcarrier-based three-dimensional fibrin angiogenesis system

    Institute of Scientific and Technical Information of China (English)

    Xi-Tai Sun; Yi-Tao Ding; Xiao-Gui Yan; Ling-Yun Wu; Qiang Li; Ni Cheng; Yu-Dong Qiu; Min-Yue Zhang

    2004-01-01

    AIM: To develop an in vitro three-dimensional (3-D)angiogenesis system to analyse the capillary sprouts induced in response to the concentration ranges of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and to quantify their synergistic activity.METHODS: Microcarriers (MCs) coated with human microvascular endothelial cells (HMVECs) were embedded in fibrin gel and cultured in 24-well plates with assay media. The growth factors bFGF, or VEGF, or both were added to the system. The wells (n = 8/group) were digitally photographed and the average length of capillary-like sprouts (ALS) from each microcarrier was quantitated.RESULTS: In aprotinin-stabilized fibrin matrix, human microvascular endothelial cells on the MCs invaded fibrin,forming sprouts and capillary networks with lumina. The angiogenic effects of bFGF or VEGF were dose-dependent in the range from 10 to 40 ng/mL. At d 1, 10 ng/mL of bFGF and VEGF induced angiogenesis with an ALS of 32.13±16.6 μm and 43.75±27.92 μm, respectively, which were significantly higher than that of the control (5.88±4.45 μm, P<0.01),and the differences became more significant as the time increased. In addition, the combination of 10 ng/mL of bFGF and VEGF each induced a more significant effect than the summed effects of bFGF (10 ng/mL) alone and VEGF (10 ng/mL) alone when analyzed using SPSS system for general linear model (GLM) (P= 0.011), and that also exceeded the effects by 20 ng/mL of either bFGF or VEGF.CONCLUSION: A microcarrier-based in vitro threedimensional angiogenesis model can be developed in fibrin.It offers a unique system for quantitative analysis of angiogenesis. Both bFGF and VEGF exert their angiogenic effects on HMVECs synergistically and in a dose-dependent manner.

  2. Sequential treatment with basic fibroblast growth factor and parathyroid hormone restores lost cancellous bone mass and strength in the proximal tibia of aged ovariectomized rats

    DEFF Research Database (Denmark)

    Wronski, T.J.; Ratkus, A.M.; Thomsen, Jesper Skovhus;

    2001-01-01

    This study was designed to determine whether sequential treatment with basic fibroblast growth factor (bFGF) and parathyroid hormone (PTH) can restore lost cancellous bone mass and strength at a severely osteopenic skeletal site in aged ovariectomized (OVX) rats. Female Sprague-Dawley rats were...... for quantitative bone histomorphometry and the left proximal tibia was subjected to biomechanical testing. Baseline and vehicle-treated OVX rats were severely osteopenic because their tibial cancellous bone volumes were less than 5% compared with mean values of 20.3% and 15.0% in baseline and vehicle......-treated control rats, respectively. Treatment of OVX rats for 2 weeks with bFGF alone did not significantly increase tibial cancellous bone volume but induced marked increases in osteoid volume, osteoblast surface, and osteoid surface. Sequential treatment of aged OVX rats with bFGF and PTH increased tibial...

  3. THE EFFECT OF BASIC FIBROBLAST GROWTH FACTOR SLOW-RELEASE MICROCAPSULES ON ANGIOGENESIS IN INFARCTED RABBIT MYOCARDIUM

    Institute of Scientific and Technical Information of China (English)

    朱洪生; 连锋; 郑家豪

    2000-01-01

    Objectives. To observe the effect of basic flbroblast growth factor (bFGF) slow-release mierocapsules on angiogen-esis in infarcted myocardial regions.Methods. Myocardial infarction was induced in 24 New Zealand rabbits by ligating the root of left anterior de-scending coronary artery. Group Ⅰ (n=8) served as control, group Ⅱ (n=8) as a blank mieroeapsule group, group Ⅲ (n= 8, each mierocapsule contains 1μg bFGF) as mierpcapsule group. In group Ⅱ and Ⅲ, 5 blank mierocapsules or bFGF slow-release mierocapsules were implanted into myocardium underneath the epieardium between the left ante-rior descending coronary artery and left circumflex artery. Infarct size was evaluated by infarcted weight/left ventricle weight ratio and angiogenesis was evaluated by immunohistochemieal examinations 5 weeks later.Results. As compared with group Ⅰ and Ⅱ , rabbits treated with bFGF slow-release mierocapsules showed higher microvessel counts (group Ⅰ37.75±4.50, group Ⅱ8.37 ±4.98,vs.group Ⅲ 135.50±4.81,P<0.001) and lessinfarcted weight/left ventricle weight ( group Ⅰ 16.8 % ± 0.4 %, group Ⅱ 16.7 % ± 0.5 %, vs. group Ⅲ 7.0 % ±0.2%,P< 0.001).Conclusions. Subepicardial administration of bFGF slow-release microcapsule in the infarcted rabbit model results in effective angiogenesis and reduction in infarct size.

  4. mRNA Expression of Basic Fibroblast Growth Factor from A Single Intratracheal Instillation of Papain-induced Emphysema in Rats

    Institute of Scientific and Technical Information of China (English)

    FU; Juan(

    2001-01-01

    [1]Snider G L Boston M A Kleinerman J et al.The definition of emphysema.Report of a national heart lung and blood institute.Division of lung disease workshop.Am Rev Respir Dis 1985 132:182[2]杜敏捷 王辰 曹大德等.慢性阻塞性肺疾病合并肺间质纤维化的病理学研究.中华结核和呼吸杂志 1999 22:30[3]单兆运 陈治安 马文富等.慢性阻塞性肺疾病的光镜、电镜及免疫病理研究.中华结核和呼吸杂志 1990 13:311[4]Kobrle V Hurych J Halusa R et al.Changes in pulmonary connective tissue after a single intratracheal instillation of papain in the rat.Am Rev Respir Dis 1982 125:239[5]Gospodarowicz D.Fibroblast growth factor chemical structure and biologic function.Clin Orthop Relat Res 1990 257:231[6]Sannes P L Khosla J Johnson S et al.Basic fibroblast growth factor in fibrosing alveolitis induced by oxygen stress.Chest 1996 109 (Suppl):44[7]Jay M Schlessinger J Graig A et al.FGFR tyrosine kinases molecular analysis and signal transduction.Biochem Biophy Acta 1992 1135:185[8]Edgar C Ronald H Phillip J et al.Remodeling of alveolar walls after elastase treatment of hamsters.Am J Respir Crit Care Med 1998 158:555

  5. Basic fibroblast growth factor increases the number of endogenous neural stem cells and inhibits the expression of amino methyl isoxazole propionic acid receptors in amyotrophic lateral sclerosis mice

    Institute of Scientific and Technical Information of China (English)

    Weihui Huang; Dawei Zang; Yi Lu; Ping Jiang

    2012-01-01

    This study aimed to investigate the number of amino methyl isoxazole propionic acid (AMPA) re-ceptors and production of endogenous neural stem cells in the SOD1G93AG1H transgenic mouse model of amyotrophic lateral sclerosis, at postnatal day 60 following administration of basic fibroblast growth factor (FGF-2). A radioligand binding assay and immunohistochemistry were used to estimate the number of AMPA receptors and endogenous neural stem cells respectively. Results showed that the number of AMPA receptors and endogenous neural stem cells in the brain stem and sensorimotor cortex were significantly increased, while motor function was significantly decreased at postnatal days 90 and 120. After administration of FGF-2 into mice, numbers of endogenous neural stem cells increased, while expression of AMPA receptors decreased, whilst motor functions were recovered. At postnatal day 120, the number of AMPA receptors was negatively correlated with the number of endogenous neural stem cells in model mice and FGF-2-treated mice. Our experimental findings indicate that FGF-2 can inhibit AMPA receptors and increase the number of endogenous neural stem cells, thus repairing neural injury in amyotrophic lateral sclerosis mice.

  6. Effects of recombinant human basic fibroblast growth factor on cell proliferation during mandibular fracture healing in rabbits

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the effects of recombinant human basicfibroblast growth factor (rhbFGF) on the cell proliferation during mandibular fracture healing in rabbits.Methods: The complex of rhbFGF and bovine type I collagen was implanted into the mandibular fracture site under periosteum of the animal. The whole mandible was harvested at 7, 14, 28, 56 and 84 days respectively after operation. The expression of proliferating cell nuclear antigen (PCNA) in callus was examined with immunohistochemical staining.Results: PCNA-positive cells in callus in the rhbFGF-treated group on days 7 and 14 were more than that in the control group (P<0.01).Conclusions: It indicates that rhbFGF can stimulate cell proliferation during mandibular fracture healing in rabbits.

  7. A mutein of human basic fibroblast growth factor TGP-580 accelerates colonic ulcer healing by stimulating angiogenesis in the ulcer bed in rats.

    Science.gov (United States)

    Satoh, H; Szabo, S

    2015-10-01

    Previously, we reported that TGP-580, a mutein of human basic fibroblast growth factor (bFGF), accelerated the healing of gastric and duodenal ulcers in rats. In the present study, we examined the effect of TGP-580 on the healing of colonic ulcers. In male Sprague Dawley rats, ulcers were induced in the colon 6 cm from the anus by enema of 50 μl of 3% N-ethylmaleimide, a sulfhydryl alkylator. The lesions were examined under a dissecting microscope (x10). The concentration of bFGF in the ulcerated colon was measured by enzyme immunoassay, and both the distribution of bFGF and the density of microvessels in the ulcer bed were examined by immunohistochemical staining. The content of bFGF in the ulcerated colon was markedly increased associated with ulcer healing, and ulcer healing was significantly delayed by intravenous administration of a monoclonal antibody for bFGF (MAb 3H3) once daily for 10 days. In the ulcer bed, many cells such as fibroblasts, vascular endothelial cells and macrophages were positively stained with bFGF antiserum. TGP-580, human bFGF or dexamethasone was given intracolonally twice daily for 10 days, starting the day after ulcer induction. TGP-580 (0.2 - 20 μg/ml, 200 μl/rat) dose-dependently accelerated ulcer healing, and its effect was more than 10 times stronger than that of human bFGF. Density (μm/0.01 mm(2)) of microvessels in the ulcer bed was significantly increased by treatment with TGP-580, and there was a good correlation between the density of microvessels and the decrease of ulcerated area (R(2) = 0.633). On the other hand dexamethasone (20 μg/ml) inhibited angiogenesis in the ulcer bed and delayed ulcer healing. These results suggest that angiogenesis in the ulcer bed plays an important role in ulcer healing, and that bFGF mutein TGP-580 accelerated colonic ulcer healing, at least in part, by stimulating angiogenesis, whereas glucocorticoids may delay the healing by inhibiting angiogenesis.

  8. Insulin-like growth factors act synergistically with basic fibroblast growth factor and nerve growth factor to promote chromaffin cell proliferation

    DEFF Research Database (Denmark)

    Frödin, M; Gammeltoft, S

    1994-01-01

    and immunocytochemical staining of cell nuclei. After 6 days in culture in the absence of growth factors, nuclear BrdUrd incorporation was detected in 30% of fetal chromaffin cells, 1.5% of neonatal cells, and 0.1% of adult cells. Addition of 10 nM IGF-I or IGF-II increased the fraction of BrdUrd-labeled nuclei to 50......% of fetal, 20% of neonatal, and 2% of adult chromaffin cells. The ED50 value of IGF-I- and IGF-II-stimulated BrdUrd labeling in neonatal chromaffin cells was 0.3 nM and 0.8 nM, respectively. In neonatal and adult chromaffin cells, addition of 1 nM bFGF or 2 nM NGF stimulated nuclear BrdUrd incorporation...... was further improved when bFGF or NGF was added together with IGF-II. In conclusion, we propose that IGF-I and IGF-II act in synergy with bFGF and NGF to stimulate proliferation and survival of chromaffin cells during neonatal growth and adult maintenance of the adrenal medulla. Our findings may have...

  9. Bone regeneration with active angiogenesis by basic fibroblast growth factor gene transfected mesenchymal stem cells seeded on porous β-TCP ceramic scaffolds

    International Nuclear Information System (INIS)

    Large segmental bone defect repair remains a clinical and scientific challenge with increasing interest focused on combining gene transfer with tissue engineering techniques. Basic fibroblast growth factor (bFGF) is one of the most prominent osteogenic growth factors that has the potential to accelerate bone healing by promoting the proliferation and differentiation of mesenchymal stem cells (MSCs) and the regeneration of capillary vasculature. However, the short biological half-lives of growth factors may impose severe restraints on their clinical usefulness. Gene-based delivery systems provide a better way of achieving a sustained high concentration of growth factors locally in the defect and delivering a more biologically active product than that achieved by exogenous application of recombinant proteins. The objective of this experimental study was to investigate whether the bFGF gene modified MSCs could enhance the repair of large segmental bone defects. The pcDNA3-bFGF gene transfected MSCs were seeded on biodegradable porous β tricalcium phosphate (β-TCP) ceramics and allografted into the 15 mm critical-sized segmental bone defects in the radius of 18 New Zealand White rabbits. The pcDNA3 vector gene transfected MSCs were taken as the control. The follow-up times were 2, 4, 6, 8, 10 and 12 weeks. Scanning electron microscopic, roentgenographic, histologic and immunohistological studies were used to assess angiogenesis and bone regeneration. In vitro, the proliferation and differentiation of bFGF gene transfected MSCs were more active than that of the control groups. In vivo, significantly more new bone formation accompanied by abundant active capillary regeneration was observed in pores of the ceramics loaded with bFGF gene transfected MSCs, compared with control groups. Transfer of gene encoding bFGF to MSCs increases their osteogenic properties by enhancing capillary regeneration, thus providing a rich blood supply for new bone formation. This new b

  10. Neuronal-like differentiation of single versus multiple treatments with human amnion-derived mesenchymal stem cells induced by basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    Hongliang Jiao; Fangxia Guan; Xiang Hu; Jianbin Li; Hong Shan; Wei Li; Jun Li; Ying Du; Bo Yang; Yunfan Zhou

    2009-01-01

    BACKGROUND: Cultures from multiple portions of umbilical cord blood mesenchymal stem cells have been shown to undergo more rapid proliferation and attachment than single portions. OBJECTIVE: To observe growth of basic fibroblast growth factor (bFGF)-induced cultures of human amnion-derived mesenchymal stem cells (AMSCs) and differentiation into neuronal-like cells. DESIGN, TIME AND SETTING: Comparative observation. The study was performed at the Laboratory of Microbiology and Immunology, Basic Medical School of Zhengzhou University from January to May 2008.METHODS: Amnia from full-term, uterine-incision delivery were donated by 12 healthy women. AMSCs were obtained by cell separation and culture techniques, and were passaged and induced by bFGF. From the third passage, a total of 1 mL AMSCs, at a density of 1.0 ×10 4/mL, was separately harvested from six samples, which served as group A. A total of 1 mL AMSCs, at a density of 1.0×10 4 /mL, was harvested separately from the remaining six samples, which served as group B. A total of 0.5 mL from the six samples of group A and 0.5 mL from the six samples of group B were combined to form group C. MAIN OUTCOME MEASURES: Differences in cell quantity among the three groups were compared by cell quantification and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT)analysis. Expression of a glial cell marker, neuron-specific enolase, and nestin was detected in the three groups by immunocytochemistry. RESULTS: Cell quantification and MTT analysis of live cells, as well as AMSC absorbance, were significantly greater in group C compared with groups A and B at 18 days of culture (P<0.05), and no significant difference was observed between groups A and B. Glial fibrillary acidic protein, neuron-specific enolase, and nestin were expressed in all groups following bFGF induction. CONCLUSION: Mixed AMSC cultures promoted proliferation, and bFGF-induced AMSCs differentiated into neuronal-like cells.

  11. Co-localization and regulation of basic fibroblast growth factor and arginine vasopressin in neuroendocrine cells of the rat and human brain

    Directory of Open Access Journals (Sweden)

    Gonzalez Ana M

    2010-08-01

    Full Text Available Abstract Background Adult rat hypothalamo-pituitary axis and choroid plexus are rich in basic fibroblast growth factor (FGF2 which likely has a role in fluid homeostasis. Towards this end, we characterized the distribution and modulation of FGF2 in the human and rat central nervous system. To ascertain a functional link between arginine vasopressin (AVP and FGF2, a rat model of chronic dehydration was used to test the hypothesis that FGF2 expression, like that of AVP, is altered by perturbed fluid balance. Methods Immunohistochemistry and confocal microscopy were used to examine the distribution of FGF2 and AVP neuropeptides in the normal human brain. In order to assess effects of chronic dehydration, Sprague-Dawley rats were water deprived for 3 days. AVP neuropeptide expression and changes in FGF2 distribution in the brain, neural lobe of the pituitary and kidney were assessed by immunohistochemistry, and western blotting (FGF2 isoforms. Results In human hypothalamus, FGF2 and AVP were co-localized in the cytoplasm of supraoptic and paraventricular magnocellular neurons and axonal processes. Immunoreactive FGF2 was associated with small granular structures distributed throughout neuronal cytoplasm. Neurohypophysial FGF2 immunostaining was found in axonal processes, pituicytes and Herring bodies. Following chronic dehydration in rats, there was substantially-enhanced FGF2 staining in basement membranes underlying blood vessels, pituicytes and other glia. This accompanied remodeling of extracellular matrix. Western blot data revealed that dehydration increased expression of the hypothalamic FGF2 isoforms of ca. 18, 23 and 24 kDa. In lateral ventricle choroid plexus of dehydrated rats, FGF2 expression was augmented in the epithelium (Ab773 as immunomarker but reduced interstitially (Ab106 immunostaining. Conclusions Dehydration altered FGF2 expression patterns in AVP-containing magnocellular neurons and neurohypophysis, as well as in choroid

  12. Neural Differentiation of Mouse Bone Marrow-Derived Mesenchymal Stem Cells Treated with Sex Steroid Hormones and Basic Fibroblast Growth Factor

    Directory of Open Access Journals (Sweden)

    Kazem Parivar

    2015-04-01

    Full Text Available Objective: There are several factors, like environmental agents, neurotrophic factors, serotonin and some hormones such as estrogen, affecting neurogenesis and neural differentiation. Regarding to importance of proliferation and regeneration in central nervous system, and a progressive increase in neurodegenerative diseases, cell therapy is an attractive approach in neuroscience. The aim of the present study was to investigate the effects of sex steroid hormones and basic fibroblast growth factor (bFGF on neuronal differentiation of mouse bone marrow-derived mesenchymal stem cells (BM-MSCs. Materials and Methods: This experimental study was established in Kharazmi University. BM was isolated from the bones of femur and tibia of 4-6-week old Naval Medical Research Institute (NMRI mice, and the cells were cultured. The cells were divided into following 4 groups based on the applied treatments: I. control (no treatment, II. steroid hormones (β-estradiol, progesterone and testosterone, III. bFGF and IV. combination of steroid hormones and bFGF. Immunocytochemistry and flow cytometery analyses were applied for beta III-tubulin (β-III tubulin and microtubule-associated proteins-2 (MAP-2 in 4 days of treatment for all groups. Results: The cells treated with combination of bFGF and steroid hormones represented more expressions of neural markers as compared to control and to other two groups treated with either bFGF or steroid hormones. Conclusion: This study showed that BM-MSCs can express specific neural markers after receiving bFGF pretreatment that was followed by sex steroid hormones treatment. More investigations are necessary to specify whether steroid hormones and bFGF can be considered for treatment of CNS diseases and disorders.

  13. Effect of basic fibroblast growth factor on the expression of glial fibrillary acidic protein after tractive spinal cord injury in rats

    Institute of Scientific and Technical Information of China (English)

    LIU Lei; L(U) Bo; TU Chong-qi; CHI Lei-ting; WANG Guang-lin; PEI Fu-xing

    2005-01-01

    Objective: To investigate the effects of basic fibroblast growth factor (bFGF) on the expression of glial fibrillary acidic protein (GFAP) after tractive spinal cord injury in rats and to explore the recovery of spinal cord function.Methods: The rats were subjected to tractive spinal cord injury at T13-L2. Cortical somatosensory-evoked potential (CSEP) was closely monitored and when P1-N1 wave amplitude decreased to 70% of that before operation, a small-bore catheter was inserted below the injured plane through subarachnoid cavity. In the treatment groups, 20 μl of bFGF solution (containing 20 μg of bFGF) was injected through the catheter right after the operation and 1,2, 3, 4, 8, 12 and 24 h postoperatively. In the control group, same volume of normal saline was injected and every four rats were killed at 1, 4, 7, 14 and 21 d after the operation. Combined behavior score (CBS) and electro-physiological examination were adopted to evaluate function recovery. Expression of GFAP was observed by immuno-histochemical staining and was analyzed quantitatively by computer image analysis.Results: There was statistically significant difference in GFAP-positive cells between bFGF treatment group and the control group (P<0.01). Similar tendency was indicated by the results of CBS and CSEP.Conclusions: bFGF can induce large expression of GFAP after tractive spinal cord injury in rats and promote spinal function recovery, which is highly important for spinal cord regeneration.

  14. Effect of Non-Anticoagulant N-Desulfated Heparin on Basic Fibroblast Growth Factor Expression, Angiogenesis, and Metastasis of Gastric Carcinoma In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Jin-Lian Chen

    2012-01-01

    Full Text Available Objective. The present study was performed to investigate the effect of N-desulfated heparin on basic fibroblast growth factor (bFGF expression, tumor angiogenesis and metastasis of gastric carcinoma. Methods. Human gastric cancer SGC-7901 tissues were orthotopically implanted into the stomach of NOD SCID mice. Twenty mice were randomly divided into two groups which received either intravenous injection of 0.9% NaCl solution (normal saline group or 10 mg/kg N-desulfated heparin (N-desulfated heparin group twice weekly for three weeks. In vitro, human gastric carcinoma SGC-7901 cells were treated with N-desulfated heparin in different concentration (0.1 mg/mL, 1 mg/mL, N-desulfated heparin group, and treated with medium (control group. Results. In vivo, the tumor metastasis rates were 9/10 in normal saline group and 2/10 in N-desulfated heparin group (P<0.05. The intratumoral microvessel density was higher in normal saline group than in N-desulfated heparin group (P<0.05. bFGF expression in gastric tissue was inhibited by N-desulfated heparin (P<0.05. There was no bleeding in N-desulfated heparin group. In vitro, N-desulfated heparin inhibited significantly bFGF protein and mRNA expression of gastric carcinoma cells (P<0.05. Conclusions. N-desulfated heparin can inhibit the metastasis of gastric cancer through inhibiting tumor bFGF expression and tumor angiogenesis with no obvious anticoagulant activity.

  15. bFGF对成纤维细胞增殖和胶原及纤维连接蛋白的影响%Effects of Basic Fibroblast Growth Factor on Proliferation as well as Collagen and Fibronectin Expression on Fibroblasts

    Institute of Scientific and Technical Information of China (English)

    武艳; 杨岚; 张羽飞; 袁晓环; 初彦辉

    2014-01-01

    目的:探讨碱性成纤维细胞因子( bFGF)调节皮肤创伤修复的作用机制。方法采用组织块贴壁法培养来源于正常皮肤和增生性瘢痕的成纤维细胞(FB),加入含有不同浓度bFGF(0,0.1,1,10,100,1000 ng·mL-1)的无血清培养液培养72 h,采用细胞计数法和锥虫蓝染色检测各组FB增殖和凋亡,酶联免疫吸附法( ELISA)和逆转录PCR ( RT-PCR)分别检测Ⅰ型、Ⅲ型胶原和纤维连接蛋白浓度及基因表达情况。结果 bFGF促进FB增殖,当浓度过高时则抑制FB增殖,促进其凋亡,并且增生性瘢痕FB增殖较来源于正常皮肤的FB缓慢;bFGF明显抑制增生性瘢痕FB Ⅰ型胶原产生,对来源于正常皮肤FB无影响;bFGF上调来源于正常皮肤FB的纤维连接蛋白基因表达,对增生性瘢痕FB中的表达无影响;bFGF对两种来源的FBⅢ型胶原的分泌和表达均无显著作用。结论 bFGF对来源正常皮肤和增生性瘢痕的FB具有不同的影响和作用机制,可能对创伤修复早期和瘢痕形成过程发挥作用。%Objective To explore the mechanism and effects of basic fibroblast growth factor( bFGF)on skin wound healing. Methods Fibroblasts( FB)were isolated from normal skin and hypertrophic scar and cultivated by direct adherence method. FB were then treated with different concentrations of bFGF(0,0. 1,1,10,100,1 000 ng·mL-1 )and cultivated with serum-free medium for 72 hours. The proliferation and apoptosis of FB in each group were detected by cell counting and trypan blue staining. Content and gene expression of typeⅠand type Ⅲ collagen and fibronectin were determined by ELISA and RT-PCR,respectively. Results bFGF promoted the proliferation of FB at low concentrations promoted apoptosis of FB at higher concentrations. The proliferation of FB from hypertrophic scar was slower than that from the normal skin. bFGF significantly inhibited type Ⅰ collagen production from

  16. Fibroblast Growth Factors Stimulate Hair Growth through β-Catenin and Shh Expression in C57BL/6 Mice

    OpenAIRE

    Wei-hong Lin; Li-Jun Xiang; Hong-Xue Shi; Jian Zhang; Li-ping Jiang; Ping-tao Cai; Zhen-Lang Lin; Bei-Bei Lin; Yan Huang; Hai-Lin Zhang; Xiao-Bing Fu; Ding-Jiong Guo; Xiao-Kun Li; Xiao-Jie Wang; Jian Xiao

    2015-01-01

    Growth factors are involved in the regulation of hair morphogenesis and cycle hair growth. The present study sought to investigate the hair growth promoting activities of three approved growth factor drugs, fibroblast growth factor 10 (FGF-10), acidic fibroblast growth factor (FGF-1), and basic fibroblast growth factor (FGF-2), and the mechanism of action. We observed that FGFs promoted hair growth by inducing the anagen phase in telogenic C57BL/6 mice. Specifically, the histomorphometric ana...

  17. Basic fibroblast growth factor induces matrix metalloproteinase-13 via ERK MAP kinase-altered phosphorylation and sumoylation of Elk-1 in human adult articular chondrocytes

    Directory of Open Access Journals (Sweden)

    Hee-Jeong Im

    2009-10-01

    Full Text Available Hee-Jeong Im,1–4 Andrew D Sharrocks,5 Xia Lin,6 Dongyao Yan,1 Jaesung Kim,1 Andre J van Wijnen,7 Robert A Hipskind81Departments of Biochemistry, 2Internal Medicine, 3Section of Rheumatology, Orthopedic Surgery, 4Rush University Medical Center, and Department of Bioengineering; University of Illinois at Chicago, IL USA; 5Faculty of Life Sciences, University of Manchester, Oxford Rd, Manchester, UK; 6Michael D DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA; 7Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA; 8Institute De Genetique Moleculaire de Montpellier, FranceAbstract: Degradation of the extracellular matrix (ECM by matrix metalloproteinases (MMPs and release of basic fibroblast growth factor (bFGF are principal aspects of the pathology of osteoarthritis (OA. ECM disruption leads to bFGF release, which activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK pathway and its downstream target the Ets-like transcription factor Elk-1. Previously we demonstrated that the bFGF-ERK-Elk-1 signaling axis is responsible for the potent induction of MMP-13 in human primary articular chondrocytes. Here we report that, in addition to phosphorylation of Elk-1, dynamic posttranslational modification of Elk-1 by small ubiquitin-related modifier (SUMO serves as an important mechanism through which MMP-13 gene expression is regulated. We show that bFGF activates Elk-1 mainly through the ERK pathway and that increased phosphorylation of Elk-1 is accompanied by decreased conjugation of SUMO to Elk-1. Reporter gene assays reveal that phosphorylation renders Elk-1 competent for induction of MMP-13 gene transcription, while sumoylation has the opposite effect. Furthermore, we demonstrate that the SUMO-conjugase Ubc9 acts as a key mediator for Elk-1 sumoylation. Taken together, our results suggest that sumoylation antagonizes the phosphorylation

  18. Effects of basic fibroblast growth factor transfection on canine gingival fibroblasts%碱性成纤维细胞生长因子基因转染对犬牙龈成纤维细胞的影响

    Institute of Scientific and Technical Information of China (English)

    陈欣戬; 闫福华; 钟泉; 赵欣; 江一平

    2009-01-01

    BACKGROUND: Studies have demonstrated that exogenous basic fibroblast growth factor (bFGF) has intensive effects to promote proliferation of gingival fibroblasts (GFs) cultured in vitro and the heeling of gingival wounds. OBJECTIVE: To investigate the effects of bFGF gene transfection on the biological performance of Beagle canine GFs. DESIGN, TIME AND SETTING: An observation and comparison in vitro experiment regarding cells was accomplished in Centre of Cell Biology and Development of Fujian Medical University and Department of Comparative Medicine in Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA from April to September of 2008. MATERIALS: Four beagle dogs, male, 12 months old, weighing 10-13 kg were used in this experiment, plRES2-EGFP-bFGF plasmid containing full-length human bFGF gene cDNA was constructed and conserved by our institution. METHODS: Free gingiva of the 2nd, 3rd and 4th premolars were excised from left upper jaw of Beagle dogs, dnsed with aseptic phosphate buffer four times, then cut into pieces and digested with 2.5 g/L pancreetin for 2 hours at 37 ℃. After the cantrifugation and supernatant removal, DMEM containing 10% fetal bovine serum was added to incubate on 6-well plate with coverlips in 5% CO2 incubator at 37 ℃. Logadthrnically growing cells were digested and passaged. GFs were transfected with pIRES2-EGFP-bFGF plasmid using liposome mediated method, while vacant plasmid transfection and un-transfection group served as controls.MAIN OUTCOME MEASURES: Proliferation and apoptosis feature of the GFs were evaluated by M'rE and AOEB, respectively. The activity of alkaline phosphatase was assayed by chemical coledmetry. RESULTS: All of three groups cells entered log phrase on three days after transfection. MTT results showed that the proliferation of GFs transfected with bFGF was greater than cells transfected with vacant vector and untransfected cells (P 的培养箱培养,取对数生长期细胞消化传代.利

  19. Stimulation of α7 nicotinic acetylcholine receptor regulates glutamate transporter GLAST via basic fibroblast growth factor production in cultured cortical microglia.

    Science.gov (United States)

    Morioka, Norimitsu; Harano, Sakura; Tokuhara, Masato; Idenoshita, Yuko; Zhang, Fang Fang; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

    2015-11-01

    The α7 nicotinic acetylcholine (nACh) receptor expressed in microglia has a crucial role in neuroprotection. Simulation of α7 nACh receptor leads to increased expression of glutamate/aspartate transporter (GLAST), which in turn decreases synaptic glutamate levels. However, the upregulation of GLAST in cultured rat cortical microglia appears long after (over 18 h) stimulation of the α7 nACh receptor with nicotine. Thus, the current study elucidated the pathway responsible for the induction of GLAST expression in cultured cortical microglia. Nicotine-induced GLAST mRNA expression was significantly inhibited by cycloheximide pretreatment, indicating that a protein intermediary, such as a growth factor, is required for GLAST expression. The expression of fibroblast growth factor-2 (FGF-2) mRNA in cortical microglia was significantly increased 6 and 12h after treatment with nicotine, and this increase was potently inhibited by pretreatment with methyllycaconitine, a selective α7 nACh receptor antagonist. The treatment with nicotine also significantly increased FGF-2 protein expression. Furthermore, treatment with recombinant FGF-2 increased GLAST mRNA, protein expression and (14)C-glutamate uptake, a functional measurement of GLAST activity. Conversely, pretreatment with PD173074, an inhibitor of FGF receptor (FGFR) tyrosine kinase, significantly prevented the nicotine-induced expression of GLAST mRNA, its protein and (14)C-glutamate uptake. Reverse transcription polymerase chain reaction confirmed FGFR1 mRNA expression was confined to cultured cortical microglia. Together, the current findings demonstrate that the neuroprotective effect of activation of microglial α7 nACh receptors could be due to the expression of FGF-2, which in turn increases GLAST expression, thereby clearing glutamate from synapse and decreasing glutamate neurotransmission.

  20. Neonatal Fibroblast Growth Factor Treatment Enhances Cocaine Sensitization

    OpenAIRE

    Clinton, Sarah M; Turner, Cortney A.; Flagel, Shelly B.; Simpson, Danielle N.; Watson, Stanley J.; Akil, Huda

    2012-01-01

    Growth factors are critical in neurodevelopment and neuroplasticity, and recent studies point to their involvement in addiction. We previously reported increased levels of basic fibroblast growth factor (FGF2) in high novelty/drug-seeking rats (bred High Responders, bHR) compared to low novelty/drug-seeking rats (bred Low Responders, bLRs). The present study asked whether an early life manipulation of the FGF system (a single FGF2 injection on postnatal day 2) can impact cocaine sensitization...

  1. Fibroblast growth factors in neurodevelopment and psychopathology

    NARCIS (Netherlands)

    Terwisscha van Scheltinga, Afke F; Bakker, Steven C; Kahn, René S; Kas, Martien J H

    2013-01-01

    In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting b

  2. Fibroblast growth factor 23--et fosfatregulerende hormon

    DEFF Research Database (Denmark)

    Beck-Nielsen, Signe Sparre; Pedersen, Susanne Møller; Kassem, Moustapha;

    2010-01-01

    Fibroblast growth factor 23 (FGF23) is a recently identified phosphatonin. Its main physiological functions are to maintain serum phosphate within its reference range and to counter regulate the effects of vitamin D. Diseases correlated to high serum values of FGF23 are hypophosphatemic rickets...

  3. Basic FGF and PDGF-BB synergistically stimulate hyaluronan and IL-6 production by orbital fibroblasts.

    Science.gov (United States)

    Virakul, Sita; Heutz, Judith W; Dalm, Virgil A S H; Peeters, Robin P; Paridaens, Dion; van den Bosch, Willem A; Hirankarn, Nattiya; van Hagen, P Martin; Dik, Willem A

    2016-09-15

    Orbital fibroblast activation is a central pathologic feature of Graves' Ophthalmopathy (GO). Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) have been proposed to contribute to GO, but their effects on orbital fibroblasts are largely unknown. We found that bFGF stimulated proliferation and hyaluronan production, but not IL-6 production by orbital fibroblasts, while VEGF hardly affected orbital fibroblast activity. Remarkably, co-stimulation of orbital fibroblasts with bFGF and PDGF-BB synergistically enhanced IL-6 and hyaluronan production and displayed an additive effect on proliferation compared to either bFGF or PDGF-BB stimulation. Nintedanib, a FGF- and PDGF-receptor targeting drug, more efficiently blocked bFGF + PDGF-BB-induced IL-6 and hyaluronan production than dasatinib that only targets PDGF-receptor. In conclusion, bFGF may contribute to orbital inflammation and tissue remodeling in GO, especially through synergistic interaction with PDGF-BB. Multi-target therapy directed at the bFGF and PDGF pathways may potentially be of interest for the treatment of GO. PMID:27267669

  4. Roles of extracellular signal-regulated kinase 1/2 on the suppression of myostatin gene expression induced by basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    Huazhoag Liu; Xiaorong An; Yongfu Chen; Jieping Zhong

    2008-01-01

    Basic fibmblast growth factor (bFGF, FG F-2 ) has an inhibitory effect on the expression of the myostatin gene in murine C2C12 myoblasts, as shown in our recent investigation. To further verify the regulatory effects of bFGF on the myostalin gene and to better understand its mechanism in skeletal muscle, and to promote clinical applications of bFGF to treat skeletal muscle diseases correlated to muscular dystrophy or AIDS and so on, recombinant human bFGF (rh-bFGF) was added into media and stimulated murine C2C12 myoblasts to investigate the dose-dependent effect ofbFGF on suppression of myostatin gene expression and the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in the regulatory mechanism. Simultaneously, complete coding sequence of ovine 18 kDa-bFGF gene was inserted into eukaryotic vector pCMV-neo (originated from pEGFP-N1 vector, from which the EGFP gene has been removed), the recombinant plasmid pCMV-neo-bFGF was harvested and injected into the mouse skeletal muscle of posterior limb. Expression levels of bFGF,myostatin, and ERKI/2 genes in murine C2C12 myoblasts and the skeletal muscle were analyzed by real-time reverse transcription-polymerase chain reaction and Western blotting analysis, respectively. The results showed that bFGFimpaired the expression ofmyostatin gene in a dose-dependent manner in C2C12 cells, with increasing concentration of rh-bFGF,myostatin mRNA declined gradually. In addition, results in skeletal muscle indicated that bFGF also suppressed the expression of the myostatin gene in vivo. Furthermore, we found ERKI/2 participated in the regulatory mechanism of bFGF on the expression of the myostatin gene.

  5. Analysis of relationship between basic fibroblast growth factor and liver fibrosis caused by hepatitis%碱性成纤维细胞生长因子与乙型肝炎致纤维化的相关性分析

    Institute of Scientific and Technical Information of China (English)

    陈文笔; 严家春; 马勇; 徐长江

    2002-01-01

    @@ Background: Now, many researcher are interested in expression of basic fibroblast growth factor(bFGF) in hepatic tissue. Nevertheless,hepatic tissue of experimental animals and liver cancer were employed.Studies about expression of bFGF and mRNA bFGF in hepatic tissues are now unavailable.

  6. Short-term administration of basic fibroblast growth factor enhances coronary collateral development without exacerbating atherosclerosis and balloon injury-induced vasoproliferation in atherosclerotic rabbits with acute myocardial infarction.

    Science.gov (United States)

    Zhang, Chunxiang; Yang, Jian; Feng, Jianzhang; Jennings, Lisa K

    2002-08-01

    We evaluated the effect of basic fibroblast growth factor (bFGF) on the extent of atherosclerosis and balloon injury-induced vasoproliferation in atherosclerotic animals with acute myocardial infarction (AMI). Fifty-six rabbits were fed a 1% cholesterol diet. Balloon injury of iliac arteries and experimental acute myocardial infarction were induced in the same animals. Rabbits were then randomized to a bFGF group (20 pg/day, intravenously) or a control group (intravenous saline solution). The beneficial effects of bFGF on cardiac function, infarct size, and collateral vessel development, and the possible effect on vasoproliferation of balloon-injured vessels, were measured after 1 and 2 weeks. The extent of atherosclerosis was measured after 1, 2, and 4 weeks. Our results showed that bFGF significantly reduced infarct size and increased collateral-vessel density (P atherosclerosis and the vasoproliferation in chronic atherosclerotic vessels induced by balloon injury and cholesterol diet were not significantly different between the two groups. Our results suggest that short-term treatment with bFGF enhances collateral development and produces maximum therapeutic benefits without exacerbating atherosclerosis and cell proliferation in stenotic vessels after AMI in atherosclerotic rabbits. PMID:12228768

  7. Assessment of Retrograde Coronary Venous Infusion of Mesenchymal Stem Cells Combined with Basic Fibroblast Growth Factor in Canine Myocardial Infarction Using Strain Values Derived from Speckle-Tracking Echocardiography.

    Science.gov (United States)

    Sun, Qi-Wei; Zhen, Lei; Wang, Qin; Sun, Yan; Yang, Jiao; Li, Yi-Jia; Li, Rong-Juan; Ma, Ning; Li, Zhi-An; Wang, Lu-Ya; Nie, Shao-Ping; Yang, Ya

    2016-01-01

    Speckle-tracking echocardiography was used to assess retrograde coronary venous infusion of mesenchymal stem cells (MSCs) combined with basic fibroblast growth factor (bFGF) in a canine model of acute myocardial infarction (AMI). AMI was induced by ligation of the left anterior descending coronary artery. Coronary venous retroperfusion was performed at 1 wk after AMI. Twenty-eight animals were randomized into four groups: saline, bFGF+saline, saline+MSCs and bFGF+MSCs. Echocardiography was performed before AMI, at 7 d post-AMI and 40 d after retroperfusion. Apoptotic cardiomyocytes in the border zone of the ischemic region were evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling. Vascular endothelial growth factor and factor VIII concentrations were measured by western blotting. The left ventricular end-systolic volume increased significantly, whereas the left ventricular ejection fraction and global and segmental strain values decreased significantly after AMI. After retroperfusion, the strain values of the infarct zone, but not conventional echocardiographic parameters, were significantly different between control and bFGF+MSC groups. Cardiomyocyte apoptosis decreased, whereas vascular endothelial growth factor and factor VIII concentrations were higher in the bFGF+MSC, bFGF and MSC groups. Cardiomyocyte apoptosis was well correlated with the strain values. Although retrograde coronary venous infusion of bFGF and MSCs promoted neo-vascularization of the infarcted myocardium and inhibited apoptosis, there was only a slight strain improvement without a substantial increase in global cardiac functions.

  8. Effects of hirudin on the expression of basic fibroblast growth factor and transforming growth factor-β1 in human gin-gival fibroblasts%水蛭素对牙龈成纤维细胞碱性成纤维细胞生长因子和转化生长因子-β1表达的影响

    Institute of Scientific and Technical Information of China (English)

    郑怡; 禤坤; 南澜; 莫水学

    2015-01-01

    Objective This study aimed to investigate the effects of hirudin on the expression of transforming growth factor (TGF-β1) and basic fibroblast growth factor (bFGF) in human gingival fibroblasts (HGFs) in vitro, as well to explore its func-tion in the mechanism of gingival remodeling. Methods After culturing was performed with classic tissue-explant method, HGFs were derived from normal gingival and gingival hyperplasia tissues followed by orthodontic treatments with different concentrations of hirudin. The mRNA and protein expression levels of TGF-β1 and bFGF were respectively detected by real time quantity polymerase chain reaction and immunocytochemistry. Results Compared with normal HGFs, TGF-β1 expres-sion promoted collagen synthesis of fibroblasts, whereas bFGF collagen synthesis was decreased in hyperplasia HGFs without hirudin (P<0.05). Hirudin significantly upregulated the expression levels of bFGF but downregulated TGF-β1 in hyperplasia HGFs (P<0.05). Conclusion Orthodontic force may influence the balance of collagen synthesis and degradation in HGFs. Hirudin may modulate the balance of HGF collagen metabolism, thereby promoting gingival remodeling.%目的:观察水蛭素对人牙龈成纤维细胞(HGFs)碱性成纤维细胞生长因子(bFGF)及转化生长因子-β1(TGF-β1)表达变化的规律,探讨水蛭素影响牙龈改建的可能作用机制。方法体外培养并鉴定HGFs,利用不同浓度的水蛭素分别作用于正常(对照组)和受长期机械外力作用后增生的HGFs(实验组),通过实时定量聚合酶链反应法和免疫细胞化学法检测TGF-β1及bFGF的表达。结果未加入水蛭素时,受长期机械外力作用后,实验组促进HGFs增殖胶原合成的TGF-β1表达升高,而抑制胶原合成的bFGF表达降低(P<0.05)。加入水蛭素干预增生的HGFs后,可正向调节bFGF表达,而负向调节TGF-β1的表达(P<0.05)。结论外力作用干扰了HGFs胶原合

  9. 碱性成纤维细胞生长因子加速慢性难愈合创面愈合%Healing of chronic cutaneous wounds by topical treatment with basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    付小兵; 沈祖尧; 郭振荣; 张明良; 盛志勇

    2002-01-01

    Objective To evaluate the safety and efficacy of topical application of recombinant bovine basic fibroblast growth factor (rbFGF) on the healing of chronic cutaneous wounds. Methods Twenty-eight patients with thirty-three chronic cutaneous wounds resulting from trauma, diabetes mellitus, pressure sore and radiation injuries were enrolled in this prospective, open-label crossover trial. Prior to treatment with rbFGF, all wounds failed to heal with conventional therapies within 4 weeks. All wounds were locally treated with rbFGF at a dose of 150?AU/cm2. Healing time and the quality of wounds were used to evaluate the efficacy of the treatment.Results Healing of all chronic wounds was expedited. During the study, eighteen wounds completely healed within 2 weeks, four healed within 3 weeks, and another eight completely healed within 4 weeks. Only three wounds failed to heal within 4 weeks, but healed at 30, 40 and 42 days after treatment with rbFGF. Thus, compared with conventional therapies, the effective rate of rbFGF treatment within 4 weeks was 90.9%. Histological assessment showed more abundant capillary sprouts or tubes and that fibroblasts were differentiated in wounds treated with rbFGF. No adverse side effects related to basic fibroblast growth factor were observed.Conclusions Our results indicate that rbFGF could be used to accelerate healing in chronic wounds. It is our belief that this may be a more effective method of chronic wound management.%目的 观察重组中碱性成纤维细胞生长因子(rbFGF)对慢性难愈合创面(溃疡)的促修复作用并探讨其促修复机制。方法 本组28例共33个慢性难愈合创面,其中创伤性溃疡12例(13个创面)、压迫性溃疡9例(13个创面),糖尿病溃疡4例,放射性溃疡3例。所有创面经清创后用rbFGF治疗(150?AU/cm2创面,每天1次)。结果 所有经rbFGF治疗的创面都产生了明显的愈合,其中2周内愈合为18例,2-3周内愈合为4

  10. Diagnostic and prognostic value of serum nitric oxide, tumor necrosis factor-alpha, basic fibroblast growth factor and copper as angiogenic markers in premenopausal breast cancer patients: a case-control study.

    Science.gov (United States)

    Hewala, T I; Abd El-Moneim, N A; Ebied, S Abd El-Moneim; Sheta, M I; Soliman, K; Abu-Elenean, A

    2010-01-01

    Many studies demonstrate that increased microvessel density (MVD) surrounding primary tumour is associated with decreased overall survival in patients with breast cancer. This study compares the diagnostic and prognostic values of the angiogenic serum factors nitric oxide (NO), tumour necrosis factor-alpha (TNFalpha), basic fibroblast growth factor (bFGF) and copper with those of serum CA15-3 as the standard tumour marker in breast cancer patients. Microvessel density was estimated in CD31-immunostained sections from breast cancer patients. Before surgery, NO, TNFalpha, bFGF, copper and CA 15-3 were measured in serum samples from 30 premenopausal breast cancer patients in comparison with 15 healthy controls. The diagnostic values of the assayed parameters were compared using receiver operating characteristic (ROC) curve analysis. Univariate survival analysis of patients was assessed using the Kaplan-Meier method. Breast cancer tissues showed higher MVD than did normal breast tissues adjacent to the tumour (P = 0.008). Before surgery, tumour MVD correlated significantly with serum NO, TNFalpha, bFGF and copper (r = 0.458, P = .011; r = 0.379, P = .039; r = 0.513, P = .004 and r = 0.613, P = 0.000, respectively). Serum NO, TNFalpha, bFGF, copper and CA 15-3 levels in patients were significantly elevated compared with controls (P = 0.011, P = 0.004, P = 0.039, P = 0.000 and P = 0.001, respectively). Kaplan-Meier analysis revealed that patients with elevated serum TNFalpha, CA 15-3 and copper (P = 0.035, P = 0.040, P = 0.0339, respectively) had an overall survival significantly shorter than those who had lower levels of these parameters. These data suggest that serum TNFalpha, CA 15-3 and copper are useful predictive markers for overall survival in premenopausal breast cancer patients.

  11. Respiratory activity and growth of human skin derma fibroblasts.

    Science.gov (United States)

    Papa, F; Scacco, S; Vergari, R; Bucaria, V; Dioguardi, D; Papa, S

    1998-09-01

    A study has been made on the speed of growth and respiratory activity of fibroblast cultures from control derma, cheloid (hypertrophic) scar and stabilized scar taken from human skin. The speed of growth and the efficiency of plaque formation of fibroblasts from cheloid scar were greater in comparison with those of fibroblasts from stabilized scar and were stimulated by the addition to the culture medium of the exudate from post-traumatic ulcer. Measurement of the contents of cytochromes showed a decrease in the content of cytochromes b562 and c + c1 in the fibroblast culture from both cheloid and stabilized scar as compared to the fibroblast culture from control derma. Cytochrome aa3 content did not show significant difference among the three types of fibroblast cultures. The respiratory activities supported by pyruvate plus malate, succinate or ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine did not show, however, significant difference among the three fibroblast cultures. These observations show that the speed of growth of skin fibroblasts does not depend on the overall respiratory capacity. The exudate stimulated the activity of cytochrome c oxidase in fibroblasts from control derma, and cheloid scar. This effect and the accompanying stimulation of fibroblast growth might be correlated with the balance of oxygen free radicals.

  12. Fibroblast growth factor 23 and bone mineralisation

    Institute of Scientific and Technical Information of China (English)

    Yu-Chen Guo; Quan Yuan

    2015-01-01

    Fibroblast growth factor 23 (FGF23) is a hormone that is mainly secreted by osteocytes and osteoblasts in bone. The critical role of FGF23 in mineral ion homeostasis was first identified in human genetic and acquired rachitic diseases and has been further characterised in animal models. Recent studies have revealed that the levels of FGF23 increase significantly at the very early stages of chronic kidney disease (CKD) and may play a critical role in mineral ion disorders and bone metabolism in these patients. Our recent publications have also shown that FGF23 and its cofactor, Klotho, may play an independent role in directly regulating bone mineralisation instead of producing a systematic effect. In this review, we will discuss the new role of FGF23 in bone mineralisation and the pathophysiology of CKD-related bone disorders.

  13. Effects of basic fibroblast growth factor on hippocampal and parietal cortical neuronal cAMP-response element-binding protein expression in a rat model of focal cerebral ischemia/reperfusion

    Institute of Scientific and Technical Information of China (English)

    Chunyu Qu; Xuesong Xing; Jin Zang

    2009-01-01

    BACKGROUND: cAMP-response element binding protein (CREB) is a key modulator of various signaling pathways. CREB activation initiates a series of intracellular signaling pathways that promote neuronal survival. OBJECTIVE: To investigate the regulatory effects of basic fibroblast growth factor (bFGF) on cerebral neuronal CREB expression following ischemia/reperfusion injury. DESIGN, TIME AND SETTING: An immunohistochemical detection experiment was performed at the Department of Anatomy, Shenyang Medical College, between October 2006 and April 2008.MATERIALS: A total of 60 healthy, adult, Wistar rats were randomly divided into three groups: sham-operated (n=12), ischemia/reperfusion (n=24), and bFGF-treated (n=24). Rabbit anti-rat CREB (1: 100) and biotin labeled goat anti-rabbit IgG were purchased from the Wuhan Boster Company, China. MetaMorph-evolution MPS. 0-BX51 microscopy imaging system was provided by China Medical University, China. METHODS: Rat models of cerebral ischemia/reperfusion injury were developed using the suture method for right middle cerebral artery occlusion. Two-hour ischemia was followed by reperfusion. Rats from the bFGF-treated and ischemia/reperfusion groups were intraperitoneally administered endogenous bFGF (500 IU/mL, 2 000 IU/kg) or an equal amount of physiological saline. Rats from the sham-operated group underwent a similar surgical procedure, without induction of ischemia/reperfusion injury and drug administration. MAIN OUTCOME MEASURES: After 48-hour reperfusion, hippocampal and parietal cortical neuronal CREB expression was detected by immunohistochemistry, and the absorbance of hippocampal CREB-positive products was determined using MetaMorph-evolutionMP5.0-BX51 microscopy imaging system. RESULTS: The sham-operated group exhibited noticeable CREB expression in hippocampal and parietal cortical neurons. In the ischemia/reperfusion group, the CREB expression was discrete and neurons were poorly arranged. The bFGF-treated group

  14. 碱性成纤维细胞生长因子转染兔关节软骨细胞的研究%Transfection of basic fibroblast growth factor in rabbits' articular chondrocytes

    Institute of Scientific and Technical Information of China (English)

    曾庆彩; 鲍丽娟; 龙源深; 杨炎馨; 董文其; 李明

    2004-01-01

    背景:软骨细胞体外培养困难和表型难以维持是软骨组织工程研究的一大难题.目的:探讨碱性成纤维细胞生长因子(basic Fibroblast Growth Factor,bFGF)基因转染兔关节软骨细胞后对培养的关节软骨细胞形态、分裂增殖及代谢等方面的影响.设计:完全随机对照实验研究.地点和方法:实验在解放军第一军医大学热带军队卫生学系完成,对象为兔软骨细胞(3周龄新西兰新生兔购于第一军医大学实验动物中心).干预:将bFGF基因克隆于真核表达载体pHβ0AP-1中,构建重组真核表达载体pHβ-bFGF,转染兔关节软骨细胞.G418筛选阳性克隆,检测阳性细胞bFGF基因的表达水平.测定培养软骨细胞的DNA含量、糖醛酸含量、软骨细胞增殖情况及进行细胞周期分析.主要观察指标:DNA含量、糖醛酸含量、软骨细胞增殖情况及细胞周期分析.结果:bFGF基因转染软骨细胞表型未见显著变化;bFGF基因转染组、载体对照组、空白对照组DNA含量分别为(77.37±6 21),(40.39±4.33),(33.77±4.25)μg/瓶(P<0.01),糖醛酸含量分别为(308.8±10.2),(77.9±8.7),(80.2±10.5)μg/瓶(P<0.01),软骨细胞G1期分别为59.3±2.1,69.5±4.0,73.1±3.9(P<0.05).结论:bFGF转染关节软骨细胞后,可显著促进细胞分裂增殖并缩短细胞周期,为软骨组织工程研究提供新的技术路线及理论基础.%BACKGROUND: The difficulties in the culture in vitro of chondrocytes and in the maintenance of phenotype are big problems in the research of cartilage engineering.OBJECTIVE: To discuss the impact of basic fibroblast growth factor(bFGF)gene on the morphology, division, proliferation and metabolism of chondrocytes in culture after the transfection in articular chondrocytes of rabbits.DESIGN: A complete randomized controlled study was conducted.SETTING and PARTICIPANTS: The study was completed in the Department of Military Tropical Medicine and Hygiene, First Military Medical

  15. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3

    International Nuclear Information System (INIS)

    The fibroblast growth factors are a family of polypeptide growth factors involved in a variety of activities including mitogenesis, angiogenesis, and wound healing. Fibroblast growth factor receptors (FGFRs) have previously been identified in chicken, mouse, and human and have been shown to contain an extracellular domain with either two or three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. The authors have isolated a human cDNA for another tyrosine kinase receptor that is highly homologous to the previously described FGFR. Expression of this receptor cDNA in COS cells directs the expression of a 125-kDa glycoprotein. They demonstrate that this cDNA encodes a biologically active receptor by showing that human acidic and basic fibroblast growth factors activate this receptor as measured by 45Ca2+ efflux assays. These data establish the existence of an additional member of the FGFR family that they have named FGFR-3

  16. Expressions of annexin-1 and basic fibroblast growth factor in prostatic carcinoma%膜联蛋白-1及碱性成纤维细胞生长因子在前列腺癌中的表达

    Institute of Scientific and Technical Information of China (English)

    赵宪龙; 黄琼; 刘景忠; 王建平; 常斌

    2012-01-01

    目的 探讨膜联蛋白-1及碱性成纤维细胞生长因子在前列腺癌组织的表达及意义.方法 61例前列腺癌组织、40例癌旁组织、40例正常前列腺组织,应用免疫组织化学法检测膜联蛋白-1及碱性成纤维细胞生长因子在3种组织中的表达.结果 正常前列腺癌组织、癌旁组织及前列腺组织中膜联蛋白-1阳性表达率分别为19.67%,22.50%及72.50%,碱性成纤维细胞生长因子阳性表达率分别为70.49%,42.50%及25.00%,差异有统计学意义(P<0.01);碱性成纤维细胞生长因子阳性表达在年龄、肿瘤大小、组织分化程度、肿瘤浸润深度、淋巴结转移、TNM分期及远期转移上差异有统计学意义(P<0.05).结论 联合检测膜联蛋白-1及碱性成纤维细胞生长因子有助于前列腺癌的早期诊断与治疗.%Objective To study the expressions of annexin 1 (ANX-1) and basic fibroblast growth factor (bFGF) in prostatic carcinoma. Methods The expressions of ANX-1 and bFGF were detected with immunohistochemical SABC method in 61 cases of prostatic carcinoma, 40 cases of adjacent tissues and 40 cases of normal prostate mucosa. Results The expression rate of ANX-1 was 19. 67% , 22. 5% and 72. 5% respectively, and of bFGF was 70.49% , 42. 50% and 25. 00% in prostatic carcinoma, adjacent tissues and normal prostate mucosa, which showed significant differences among these three groups (F<0.01). There was a significant difference in positive expression of bFGF in different ages, tumor sizes, histologic differentiation degrees, depths of tumor invasion, lymph node metastasis or not, TNM stages and long-term metastasis (P<0.05). Conclusion The combination detection of ANX-1 and bFGF helps the diagnosis and therapy of prostatic carcinoma in the early period.

  17. Effect of basic fibroblast growth factor and danshen on bcl-2 and p53 mRNA expression in the brain of rats exposed to repeated,high,positive acceleration(+Gz)

    Institute of Scientific and Technical Information of China (English)

    Hongjin Liu; Qing Cai

    2008-01-01

    BACKGROUND:Both animal experiments and clinical studies have shown that basic fibroblast growth factor(bFGF)and danshen(Salvia miltiorrhiza)can exhibit protective effects on ischemia-reperfusion cerebral injury.OBJECTIVE:To test whether bFGF and danshen can protect cerebral injury induced by exposure to repeated,high,positive acceleration(+Gz)in an animal model and to analyze the possible mechanisms.DESIGN,TIME AND SETTING:Randomized controlled animal study.The experiment was performed at the Research Center for Molecular Biology,Air-force General Hospital of Chinese PLA from April to August 2000.MATERIALS:A total of 20 clean grade,healthy,Sprague Dawley rats of both genders,weighing(200±15)g,were provided by our experimental animal center.Rats were randomly divided into 5 groups:the control group,+Gz exposure group,bFGF group,danshen group,and saline group,with 4 animals per group.bFGF(Beijing Bailuyuan Biotechnology Co.Ltd.)and danshen solution(Shanghai Zhongxi Pharmaceutical Co.Ltd.)were used.METHODS:All rats were fixed on a rotary arm of a centrifugal apparams(2 m in radius)with their heads oriented towards the center of the apparatus.Except for rats in the control group.the value of+Gz exposure was+14 Gz with an acceleration rate of 1.5 G/s.The peak force lasted for 45 seconds.+Gz exposure was performed three times with intervals of 30 minutes.Rats in the control group received the same+Gz procedure,but the G value was+1 Gz.Rats in bFGF group and danshen group were intraperitoneally injected with 100 μg/kg bFGF or 15 g/kg danshen solution,respectively,at 30 minutes prior to centrifugation and immediately after tentrifugation.Rats in saline group were injected with the same volume of saline.Six hours after exposure,rats were decapitated.One hemisphere was preserved in liquid nitrogen for RNA extraction and the other was processed for apoptosis detection.MAIN OUTCOME MEASURES:mRNA levels of bcl-2 and p53 were measured by semi-quantitative reverse

  18. Glial cell line-derived neurotrophic factor in combination with insulin-like growth factor 1 and basic fibroblast growth factor promote in vitro culture of goat spermatogonial stem cells.

    Science.gov (United States)

    Bahadorani, M; Hosseini, S M; Abedi, P; Abbasi, H; Nasr-Esfahani, M H

    2015-01-01

    Growth factors are increasingly considered as important regulators of spermatogonial stem cells (SSCs). This study investigated the effects of various growth factors (GDNF, IGF1, bFGF, EGF and GFRalpha-1) on purification and colonization of undifferentiated goat SSCs under in vitro and in vivo conditions. Irrespective of the culture condition used, the first signs of developing colonies were observed from day 4 of culture onwards. The number of colonies developed in GDNF + IGF1 + bFGF culture condition was significantly higher than the other groups (p GDNF + EGF + LIF culture condition was significantly higher than the other groups (p GDNF + IGF1 + bFGF treatment group was significantly higher than the other groups (p GDNF with IGF1 and bFGF promote in vitro culture of goat SSCs while precludes uncontrolled proliferation of somatic cells.

  19. 碱性成纤维细胞生长因子对大鼠神经损伤后肌肉的影响%Effect of basic fibroblast growth factor on muscle after nerve injury in rats

    Institute of Scientific and Technical Information of China (English)

    刘海美; 刘洁; 魏佑震; 孙丰刚

    2003-01-01

    目的研究碱性成纤维细胞生长因子( bFGF)对大鼠坐骨神经钳夹损伤后小腿三头肌的保护作用.方法 42只大鼠随机等分成 6组,钳夹对照: 4周组( C4) ,8周组( C8) ,12周组( C12) ;bFGF用药: 4周组( F4) ,8周组( F8) ,12周组( F12).手术暴露坐骨神经,外科止血钳钳夹坐骨神经.实验组夹伤后即刻于损伤处神经干内分别注射 bFGF,对照组注射等量生理盐水,术后在术侧腓肠肌注射药物, 1次 /d,直到实验结束.分别存活 4,8,12周时,进行足印分析及坐骨神经功能指数( sciatic nerve function index,SFI)测定实验;随后麻醉动物, 20 g/L多聚甲醛和 12.5 g/L戊二醛,经心灌注固定,切取小腿三头肌,称重,后取其中段,石蜡包埋、切片,光镜下测量小腿三头肌的横截面直径.结果大鼠坐骨神经钳夹损伤后各组之间小腿三头肌质量比结果不同, C4组 0.708± 0.015, F4组 0.763± 0.035, t=1.6,P< 0.01; C8组 0.903± 0.032, F8组 0.963± 0.013, t=5.0,P< 0.01; C12组 0.920± 0.073, F12组 0.980± 0.014, t=16.7,P< 0.01.肌纤维直径不同,正常侧( 15.2± 0.6)μ m, C4组( 10.8± 0.9)μ m, F4组( 12.2± 0.7) μ m, t=6.7,P < 0.01, C8组( 11.1± 0.1)μ m, F8组( 13.5± 0.9) μ m, t=10.2,P< 0.01, C12组 (13.1± 0.8) μ m, F12组 (14.2± 1.0) μ m, t=4.8,P < 0.01,组间差异具有显著性意义.结论大鼠坐骨神经钳夹损伤后 ,bFGF能减轻或延缓小腿三头肌的萎缩.%Aim To investigate the protecting effects of basic fibroblast growth factor (bFGF) on muscle atrophy after sciatic nerve clipping lesion in adult rats in vivo.Methods 42 rats were divided into 6 groups randomly: control 4 weeks group(C4),8 weeks group(C8),12 weeks group(C12),bFGF 4 weeks group(F4),8 weeks group(F8) and 12 weeks group(F12). The right sciatic nerve of rat was injured by forceps clip.After that the animals in experiment group received either recombinant human bFGF (800 U/kg ) while normal saline was injected in control group.Durgs were

  20. Autophagy is required for IL-2-mediated fibroblast growth

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Rui [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States); Tang, Daolin, E-mail: tangd2@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States); Lotze, Michael T., E-mail: lotzemt@upcm.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States); Zeh III, Herbert J., E-mail: zehh@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States)

    2013-02-15

    Autophagy is an evolutionarily conserved pathway responsible for delivery of cytoplasmic material into the lysosomal degradation pathway to enable vesicular exocytosis. Interleukin (IL)-2 is produced by T-cells and its activity is important for immunoregulation. Fibroblasts are an immune competent cell type, playing a critical role in wound healing, chronic inflammation, and tumor development. Although autophagy plays an important role in each of these processes, whether it regulates IL-2 activity in fibroblasts is unknown. Here, we show that autophagy is required for IL-2-induced cell growth in fibroblasts. IL-2 significantly induced autophagy in mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts. Autophagy inhibitors (e.g., 3-methylamphetamine and bafilomycin A1) or knockdown of ATG5 and beclin 1 blocked clinical grade IL-2-induced autophagy. Moreover, IL-2 induced HMGB1 cytoplasmic translocation in MEFs and promoted interaction between HMGB1 and beclin1, which is required for autophagy induction. Pharmacological and genetic inhibition of autophagy inhibited IL-2-induced cell proliferation and enhanced IL-2-induced apoptosis. These findings suggest that autophagy is an important pro-survival regulator for IL-2-induced cell growth in fibroblasts.

  1. Keratinocyte growth factor mRNA expression in periodontal ligament fibroblasts

    DEFF Research Database (Denmark)

    Dabelsteen, S; Wandall, H H; Grøn, B;

    1997-01-01

    Keratinocyte growth factor (KGF) is a fibroblast growth factor which mediates epithelial growth and differentiation. KGF is expressed in subepithelial fibroblasts, but generally not in fibroblasts of deep connective tissue, such as fascia and ligaments. Here we demonstrate that KGF mRNA is expres......Keratinocyte growth factor (KGF) is a fibroblast growth factor which mediates epithelial growth and differentiation. KGF is expressed in subepithelial fibroblasts, but generally not in fibroblasts of deep connective tissue, such as fascia and ligaments. Here we demonstrate that KGF m...

  2. Growth properties and growth factor responsiveness in skin fibroblasts from centenarians.

    Science.gov (United States)

    Tesco, G; Vergelli, M; Grassilli, E; Salomoni, P; Bellesia, E; Sikora, E; Radziszewska, E; Barbieri, D; Latorraca, S; Fagiolo, U; Santacaterina, S; Amaducci, L; Tiozzo, R; Franceschi, C; Sorbi, S

    1998-03-27

    Human fibroblast cultures, which have a finite replicative lifespan in vitro, are the most widely used model for the study of senescence at the cellular level. An inverse relationship between replicative capability and donor age has been reported in human fibroblast strains. We studied the growth capacity of fibroblast primary cultures derived from people whose lifespan was as closer as possible to the expected maximum human lifespan, i.e. people over one hundred. Our data suggest that outgrowth of fibroblasts from biopsies, growth kinetics at different population doubling levels, capability to respond to a classical mitogenic stimulus (such as 20% serum) and a variety of growth factors, were remarkably similar in fibroblasts from centenarians and young controls. On the whole, our data challenge the tenet of a simple and strict relationship between in vivo aging and in vitro proliferative capability of human fibroblasts, at least at the individual level. PMID:9535767

  3. Growth factor modulation of fibroblast proliferation, differentiation, and invasion: implications for tissue valve engineering.

    Science.gov (United States)

    Narine, Kishan; De Wever, Olivier; Van Valckenborgh, Dillis; Francois, Katrien; Bracke, Marc; DeSmet, Stefaan; Mareel, Marc; Van Nooten, Guido

    2006-10-01

    We have previously shown that transforming growth factor-beta1 (TGF-beta1) stimulates transdifferentiation of fibroblasts into smooth muscle alpha-actin (alpha-SMA) positive myofibroblasts. However, TGF-beta, as such, is unsuitable for effective population of a heart valve matrix, because it dose-dependently inhibits growth of fibroblasts. The aim of this study was to investigate combinations of other growth factors with TGF-beta to stimulate the proliferation of suitably differentiated cells and to enhance their invasion into aortic valve matrices. Human dermal mesenchymal cells (hDMC1.1) were treated with combinations of growth factors to stimulate these cells to trans-differentiate into myofibroblasts, to proliferate, and to invade. Growth factors were chosen after expression of their respective receptors was confirmed in hDMC1.1 using reverse transcriptase polymerase chain reaction. We combined TGF-beta with several growth factors such as insulin-like growth factor (IGF-1, IGF-2), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF-AA, PDGF-BB, and PDGFAB). Nuclear Ki67 staining, MTT assay, and cell counting revealed that only EGF and bFGF were capable of overcoming TGF-beta-induced growth inhibition. However, bFGF but not EGF inhibited TGF-beta-induced alpha-SMA expression, as evidenced by immuno-cytochemistry and Western blotting. A growth factor cocktail (TGF-beta, EGF, bFGF) has been established that maintains TGF-beta-induced trans-differentiation but overcomes TGF-beta-induced growth inhibition while stimulating fibroblast proliferation and invasion. PMID:17518640

  4. Fibroblast Growth Factor-2 Alters the Nature of Extinction

    Science.gov (United States)

    Graham, Bronwyn M.; Richardson, Rick

    2011-01-01

    These experiments examined the effects of the NMDA-receptor (NMDAr) antagonist MK801 on reacquisition and re-extinction of a conditioned fear that had been previously extinguished before injection of fibroblast growth factor-2 (FGF2) or vehicle. Recent findings have shown that relearning and re-extinction, unlike initial learning and extinction,…

  5. Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs

    OpenAIRE

    Song, SaeHeum; Wientjes, M. Guillaume; Gan, Yuebo; Au, Jessie L. -S.

    2000-01-01

    Based on the observation that removal of tumors from metastatic organs reversed their chemoresistance, we hypothesized that chemoresistance is induced by extracellular factors in tumor-bearing organs. By comparing chemosensitivity and proteins in different tumors (primary vs. metastases) and different culture systems (tumor fragment histocultures vs. monolayer cultures derived from the same tumor), we found elevated levels of acidic (aFGF) and basic (bFGF) fibroblast growth factors in the con...

  6. Effect of jog stress at fracture site on local basic fibroblast growth factor%骨折端微动应力对局部碱性成纤维细胞生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    乔林; 侯树勋; 张树明; 刘敏; 孙大铭

    2007-01-01

    BACKGROUND: Some researches demonstrate that jog stress at fracture part can promote formation of callus, but molecular biological mechanism of jog stress on fracture healing is still unclear.OBJECTIVE:To study the effect of jog stress at fracture site on basic fibroblast growth factor(bFGF)at broken parts.DESIGN:Randomized controlled animal study.SETTING:Department of Orthopaedics,General Hospital of the Second Artilleryman of Chinese PLA;Departments of Orthopaedics and Pharmacy,the First Affiliated Hospital of General Hospital of Chinese PLA.MATERIALS:The experiment was carried out in the Animal Laboratory,the First Affiliated Hospital of General Hospital of Chinese PLA and the 8th Laboratory,Academy of Military Medical Sciences of Chinese PLA from March 2003 to April 2004.A total of 72 healthy purebred New Zealand rabbits,of general grade,5-6 months old,weighing 2.5-3.0 kg,were provided by Animal Center of Academy of Military Medical Sciences of Chinese PLA.All rabbits were randomly divided into jog group and fixation group with 36 rabbits in each group.And then,every 6 rabbits in both groups were respectively observed at 6 time points,including 7,14,21,28,42 and 56 days.METHODS:All animals were anesthetized with ketamine and sumian xinji.Fixation needle was rotated into 3,3.5,5.5 and 6 cm below platform of tibia,respectively,and then external fixators were installed.Chuck which was located at 1.5 cm from internal cortical bone and 4.5 cm below platform of tibia crossly cut off tibia.Fracture space was 2.0 mm and 2.5 mm in the fixation group and jog group,respectively.Animals in the fixation group were fixed with unilateral external fixator to dissect replace fracture part.In addition,animals in the jog group cut off their bone,fixed,and moved 0.5 mm to axis along central staff of external fixator.Animals were able to freely walk and external fixator was slightly shaken based on body mass of animal.Furthermore,all animals were sacrificed at 7,14,21,28,42 and 56

  7. Neonatal fibroblast growth factor treatment enhances cocaine sensitization.

    Science.gov (United States)

    Clinton, Sarah M; Turner, Cortney A; Flagel, Shelly B; Simpson, Danielle N; Watson, Stanley J; Akil, Huda

    2012-11-01

    Growth factors are critical in neurodevelopment and neuroplasticity, and recent studies point to their involvement in addiction. We previously reported increased levels of basic fibroblast growth factor (FGF2) in high novelty/drug-seeking rats (bred high responders, bHR) compared to low novelty/drug-seeking rats(bred low responders, bLRs). The present study asked whether an early life manipulation of the FGF system(a single FGF2 injection on postnatal day 2) can impact cocaine sensitization and associated neurobiological markers in adult bHR/bLR animals. Neonatal FGF2- and vehicle-treated bHR/bLR rats were sensitized to cocaine(7 daily injections, 15 mg/kg/day, i.p.) in adulthood. Neonatal FGF2 markedly increased bLRs' typically low psychomotor sensitization to cocaine (day 7 locomotor response to cocaine), but had little effect on bHRs' cocaine sensitization. Gene expression studies examined dopaminergic molecules as well as FGF2 and the FGFR1 receptor in cocaine naïve animals, to investigate possible neurobiological alterations induced by neonatal FGF2 exposure that may influence behavioral response to cocaine. bLRs showed decreased tyrosine hydroxylase in the ventral tegmental area (VTA), decreased D1 and increased D2 receptor expression in the nucleus accumbens core, as well as decreased FGF2 in the VTA, substantia nigra, accumbens core, and caudate putamen compared to bHRs. Neonatal FGF2 selectively increased D1 receptor and FGF2 mRNA in the accumbens core of bLRs, which may contribute to their heightened cocaine sensitization. Our results suggest increased FGF2 in the mesodopaminergic circuit (as in baseline bHRs and neonatal FGF2-exposed bLRs vs. baseline bLRs) enhances an individual's susceptibility to cocaine sensitization and may increase vulnerability to drug seeking and addiction. PMID:22819969

  8. 骨形态发生蛋白、碱性成纤维细胞生长因子生物材料在关节软骨缺损修复中的生物性能%Biological properties of bone morphogenetic proteins and basic fibroblast growth factor in biological materials for repair of articular cartilage defect

    Institute of Scientific and Technical Information of China (English)

    董君博

    2016-01-01

    BACKGROUND:Articular cartilage regeneration can be regulatedbyautocrineorparacrinesecretionof various cytokines. OBJECTIVE:To analyze biological properties of bone morphogenetic proteins and basic fibroblast growth factor in biological materials for repair of articular cartilage defect. METHODS:Forty New Zealand white rabbits were used and equaly randomized intofourgroups: fibrin, basic fibroblast growth factor, bone morphogenetic protein, and combined treatment (basic fibroblast growth factor combined with bone morphogenetic protein) groups, respectively.Bioactivescaffolds with fibrin, basic fibroblast growth factor,bone morphogenetic protein, and basic fibroblast growth factor combined with bone morphogenetic protein were injected to repair the articular cartilage defect. Therapeutic effect andbiological properties of biological materials were compared. RESULTS AND CONCLUSION:(1) Inthefibrin group,tworabbits appearedto havelimps. Inthebasic fibroblast growth factor group hand functionwaslimited inonerabbit. Inthebone morphogenetic protein group, one had a limpandonewasin a limitation of activity. Inthecombined treatment group,rabbitsrecovered wel andshowedno differencesintheknee joint before and aftersurgery (P  目的:分析骨形态发生蛋白、碱性成纤维细胞生长因子生物材料在关节软骨缺损修复中的生物性能。  方法:选取40只新西兰家兔,随机分为4组,纤维蛋白组、碱性成纤维细胞生长因子组、骨形态发生蛋白组、复合组(骨形态发生蛋白+碱性成纤维细胞生长因子),每组10只。建立兔关节软骨缺损模型,止血彻底后将纤维蛋白、碱性成纤维细胞生长因子、骨形态发生蛋白以及骨形态发生蛋白、碱性成纤维细胞生长因子复合等材料组成的支架分别植入缺损部位。比较不同注射材料在家兔关节软骨缺损中的效果及复合材料的生物性能。  结果与结论:①关节软骨缺损修复情

  9. P物质抑制剂辣椒素和抗碱性成纤维细胞生长因子抗体联合应用对小鼠切口中胶原沉积的影响%Effects of inhibitory substance P, capsaicin and anti-basic fibroblast growth factor antibody on collagen deposition of excision scar formation in mice

    Institute of Scientific and Technical Information of China (English)

    肖丽玲; 刘宏伟; 张海伟; 杜彬; 郑佩娥

    2009-01-01

    目的 观察抗碱性成纤维细胞(bFGF)抗体和辣椒素对小鼠切口瘢痕组织中胶原沉积的影响,探讨它们对切口愈合期间瘢痕形成的作用.方法 建立小鼠背部切口愈合模型;应用不同种浓度(每只20、80 μg/0.1 ml)剂量的辣椒素组、抗bFGF抗体组(每只20、80μg/0.1 ml)、辣椒素(每只20μg/0.1 ml)+抗bFGF抗体(每只20 μg/0.1 ml)组作用于其切口瘢痕;于术后14 d切取切口瘢痕组织,采用Mason染色和计算机图像分析结合透射电镜来观察、分析切口瘢痕组织中胶原沉积情况.结果 低剂量的辣椒素(每只20 μg/0.1 ml)或抗bFGF抗体(每只20μg/0.1 ml)单独作用后14 d,切口瘢痕中胶原纤维分布的密度无明显变化;高剂量的辣椒素(每只80 μg/0.1 ml)或抗bFGF抗体(每只80 μg/0.1 ml)单独作用后14 d,切口瘢痕中胶原纤维分布的密度均明显减少;但低剂量的辣椒素(每只20 μg/0.1 ml)和抗bFGF抗体(每只20μg/0.1 ml)联合作用后14 d,切口瘢痕中胶原纤维分布的密度明显减少,显示了协同抑制作用.结论 辣椒素及抗bFGF抗体可抑制小鼠皮肤切口愈合过程中局部胶原的沉积,两者联合用药可协同抑制切口瘢痕的增生.%ObJective To observe the effects of inhibitory substance P (capsaicin) and anti-bas-ic fibroblast growth factor antibody on collagen deposition during excision scar formation and explore their effects on scar formation.Methods The excision injury model on the back of mice skin was developed,and the different final concentrations of capsaicin (20 and 80 μg/0.1 ml), anti-basic fibroblast growth fac-tor antibody (20 and 80 μg/0.1 ml),or capsaicin (20 μg/0.1 ml) in combination with anti-basic fibro-blast growth factor antibody (20 μg/0.1) were used in the excision injury.Results The high dose of capsaicin (80 μg/0.1 ml) or high anti-basic fibroblast growth factor antibody (80 μg/0.1 ml) markedly inhibited collagen deposition in the excision site, but low

  10. Fibroblast Growth Factor–23 and Cardiac Structure and Function

    OpenAIRE

    Agarwal, Isha; Ide, Noriko; Ix, Joachim H.; Kestenbaum, Bryan; Lanske, Beate; Schiller, Nelson B.; Mary A Whooley; Mukamal, Kenneth J.

    2014-01-01

    Background: Fibroblast growth factor–23 (FGF‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether FGF‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of FGF‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential b...

  11. Fibroblast Growth Factors: Biology, Function, and Application for Tissue Regeneration

    OpenAIRE

    Ye-Rang Yun; Jong Eun Won; Eunyi Jeon; Sujin Lee; Wonmo Kang; Hyejin Jo; Jun-Hyeog Jang; Ueon Sang Shin; Hae-Won Kim

    2010-01-01

    Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain opt...

  12. Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Szlachcic A

    2016-08-01

    Full Text Available Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Abstract: Fibroblast growth factor receptors (FGFRs are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V, was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE, and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. Keywords: fibroblast growth factor 1, FGF receptor, targeted cancer therapy, cytotoxic conjugates, FGFR-dependent cancer, MMAE, auristatin

  13. c-fos与c-jun癌蛋白在溃疡与增生性瘢痕创面联合表达的特征与意义%Expression of oncoproteins c-fos and c-jun in hypertrophic scars and chronic dermal ulcers and their regulation of basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    目的探讨c-fos与c-jun两种原癌基因产物在溃疡与增生性瘢痕创面表达的特征与规律以及与不同组织修复结局发生的关系。 方法 16例标本均取自于外科手术患者,其中增生性瘢痕8例,溃疡创面8例,另有正常对照皮肤5例取自增生性瘢痕患者作为对照。用免疫组化法(ABC法)检测c-fos与c-jun两种癌蛋白以及bFGF在三种组织切片的分布特征。 结果在正常皮肤c-fos与c-jun的阳性表达主要见于表皮基底细胞和少量皮下成纤维细胞,但在相应部位c-jun的表达较c-fos为弱。在增生性瘢痕,c-fos与c-jun均出现强阳性表达,主要见于成纤维细胞。在溃疡组织,c-fos与c-jun的联合表达多见于毛细血管内皮细胞、部分炎症细胞以及成纤维细胞胞浆。 结论增生性瘢痕与溃疡创面c-fos与c-jun表达量与部位同正常皮肤存在显著差异,提示这两种原癌基因产物在影响和调控组织修复中有重要作用。%Objective To explore the characteristics of oncoprotein expression of c-fos and c-jun in hypertrophic scars and chronic dermal ulcers and their regulation of basic fibroblast growth factor (bFGF). Methods Tissues of hypertrophic scars (n=8), chronic dermal ulcers (n=8) and normal skin (n=5) were taken from 21 patients with burns and chronic dermal ulcers in operation. The ABC immunohistochemical method was used to characterize the gene product expression of c-fos, c-jun and bFGF in the above tissues. Results In normal skin, both c-fos and c-jun protein expression and bFGF protein expression were observed. The signals of both oncoproteins were localized mainly in subcutaneous fibroblasts, but, positive expression of the bFGF protein was mainly in keratinocytes. In hypertrophic scars, positive expression of both oncoproteins could be found mainly in fibroblasts, but bFGF was mainly in fibroblasts and endothelial cells. In chronic dermal ulcers, endothelial cells, some

  14. Reduced growth factor requirement of keloid-derived fibroblasts may account for tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Russell, S.B.; Trupin, K.M.; Rodriguez-Eaton, S.; Russell, J.D.; Trupin, J.S.

    1988-01-01

    Keloids are benign dermal tumors that form during an abnormal wound-healing process is genetically susceptible individuals. Although growth of normal and keloid cells did not differ in medium containing 10% (vol/vol) fetal bovine serum, keloid culture grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) fetal bovine serum, keloid cultures grew to significantly higher densities than normal cells in medium containing 5% (vol/vol) plasma or 1% fetal bovine serum. Conditioned medium from keloid cultures did not stimulate growth of normal cells in plasma nor did it contain detectable platelet-derived growth factor or epidermal growth factor. Keloid fibroblasts responded differently than normal adult fibroblasts to transforming growth factor ..beta... Whereas transforming growth factor ..beta.. reduced growth stimulation by epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from normal adult skin or scars, it enhanced the activity of epidermal growth factor in cells from keloids. Normal and keloid fibroblasts also responded differently to hydrocortisone: growth was stimulated in normal adult cells and unaffected or inhibited in keloid cells. Fetal fibroblasts resembled keloid cells in their ability to grow in plasma and in their response to hydrocortisone. The ability of keloid fibroblasts to grow to higher cell densities in low-serum medium than cells from normal adult skin or from normal early or mature scars suggests that a reduced dependence on serum growth factors may account for their prolonged growth in vivo. Similarities between keloid and fetal cells suggest that keloids may result from the untimely expression of growth-control mechanism that is developmentally regulated.

  15. 重组牛碱性成纤维细胞生长因子联合康复新液治疗新生儿尿布皮炎的效果观察%Effect of recombinant bovine basic fibroblast growth factors combined with new rehabilitative liquid on neonatal diaper dermatitis

    Institute of Scientific and Technical Information of China (English)

    王卓; 胡楠

    2015-01-01

    Objective To investigate the effects of recombinant bovine basic fibroblast growth factors combined with new rehabilitative liquid on neonatal diaper dermatitis. Methods One hundred and twenty neotates with neonatal diaper dermatitis from August 2013 to July 2014 were randomly divided into the control group and experiment group, 60 cases in each group. The control group was treated with conventional care, while the observation group with recombinant bovine basic fibroblast growth factors combined with new rehabilitative liquid. The total effective rate and the treatment time were compared between the two groups. Result The total effective rate of the observation group was significantly higher than that of the control group (P<0.05) and the treatment time of the observation group was statistically significantly shorter than that of the control group (P<0.05). Conclusion Recombinant bovine basic fibroblast growth factors combined with new rehabilitative liquid is effective in the treatment of neonatal diaper dermatitis and it is worth promoting and using clinically.%目的:探讨重组牛碱性成纤维细胞生长因子联合康复新液治疗新生儿尿布皮炎的效果。方法选择2013年8月~2014年7月本院儿科住院的新生儿尿布皮炎患儿120例,采用随机数字表法分为对照组和观察组,每组各60例,对照组患儿采用常规护理,观察组患儿使用重组牛碱性成纤维细胞生长因子联合康复新液护理。比较两组患儿的治疗总有效率和愈合时间。结果观察组患儿治疗总有效率为95.00%,对照组患儿治疗总有效率为70.00%,两组比较,差异有统计学意义(P<0.05)。观察组患儿愈合时间(4.00±0.82)d,对照组患儿愈合时间(6.00±1.64)d,两组比较,差异有统计学意义(P<0.05)。结论重组牛碱性成纤维细胞生长因子联合康复新液治疗新生儿尿布皮炎疗效显著,减少愈合时间,值得在临床推广和应用。

  16. Effect of Nd:YAG laser on the expression of basic fibroblast growth factor in inflammatory dental pulp%激光对炎症牙髓中碱性成纤维细胞生长因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    毛小泉; 郁豆; 程亚楠; 王月燕; 刘德达

    2014-01-01

    背景:激光应用于口腔临床主要用于龋齿的早期诊断、龋坏组织的清除、活髓切断术牙髓止血、牙本质过敏治疗、感染的根管消毒、牙周炎治疗。目的:观察炎症牙髓使用激光处理后碱性成纤维细胞生长因子的变化。方法:5只成年健康beagle犬,每只随机选择6颗牙齿,分为3组,每组10颗,分别使用激光、生理盐水、庆大霉素处理,于术后第1,2,3天用纸尖收集牙髓分泌物检测碱性成纤维细胞生长因子的含量,并进行牙髓苏木精-伊红染色和免疫组织化学检查。结果与结论:生理盐水处理组、庆大霉素处理组及激光处理组第3天碱性成纤维细胞生长因子表达量均明显多于第1天和第2天,第1天和第2天比较差异无显著性意义,3种处理方法之间比较差异无显著性意义。牙髓苏木精-伊红染色和免疫组织学检查显示,髓腔血管状况良好,牙髓排列紧密良好。结果表明,激光治疗对炎症牙髓中碱性成纤维细胞生长因子的释放没有影响。提示激光在口腔临床上的应用是安全、方便、有效的,不会对炎症牙髓组织造成损伤。%BACKGROUND:The laser applied in the clinical oral medicine is mainly for early diagnosis of caries, removal of carious tissue, pulpotomy for pulp bleeding, dentin hypersensitivity treatment, disinfection of infected root canals, and periodontitis treatment. OBJECTIVE:To explore the changes of basic fibroblast growth factor in inflammatory pulp after laser treatment. METHODS:Five healthy adult beagle dogs were enroled, and six teeth were randomly selected from each dog. Then, these teeth were randomly divided into three groups, 10 teeth in a group, and they were treated with laser irradiation, saline and gentamicin irrigation respectively. At days 1, 2, 3 after operation, exudates from the pulp were colected for detection of basic fibroblast growth factor expression. Meanwhile

  17. Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

    OpenAIRE

    Santiago Vernia; Julie Cavanagh-Kyros; Tamera Barrett; Cathy Tournier; Roger J. Davis

    2016-01-01

    The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21-deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. ...

  18. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    International Nuclear Information System (INIS)

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease

  19. Cancer Associated Fibroblasts and Tumor Growth: Focus on Multiple Myeloma

    Energy Technology Data Exchange (ETDEWEB)

    De Veirman, Kim, E-mail: kdeveirm@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Rao, Luigia [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari Medical School, Bari I-70124 (Italy); De Bruyne, Elke; Menu, Eline; Van Valckenborgh, Els [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Van Riet, Ivan [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium); Stem Cell Laboratory, Division of Clinical Hematology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels 1090 (Belgium); Frassanito, Maria Antonia [Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari Medical School, Bari I-70124 (Italy); Di Marzo, Lucia; Vacca, Angelo [Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine, University of Bari Medical School, Bari I-70124 (Italy); Vanderkerken, Karin, E-mail: kdeveirm@vub.ac.be [Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels 1090 (Belgium)

    2014-06-27

    Cancer associated fibroblasts (CAFs) comprise a heterogeneous population that resides within the tumor microenvironment. They actively participate in tumor growth and metastasis by production of cytokines and chemokines, and the release of pro-inflammatory and pro-angiogenic factors, creating a more supportive microenvironment. The aim of the current review is to summarize the origin and characteristics of CAFs, and to describe the role of CAFs in tumor progression and metastasis. Furthermore, we focus on the presence of CAFs in hypoxic conditions in relation to multiple myeloma disease.

  20. Effect of hepatocyte growth factor and transforming growth factor-β1 on atrial fibroblasts fibrosis

    Institute of Scientific and Technical Information of China (English)

    张建成

    2012-01-01

    Objective To investigate the effect of hepatocyte growth factor (HGF) and transforming growth factor-β1 (TGFβ1) on the expression of α-smooth muscle actin(α-SMA) and collagen I in human atrial fibroblast in vitro, and to explore the possible molecular mechanism of atrial fibrosis in patients

  1. Plasma vascular endothelial but not fibroblast growth factor levels correlate with colorectal liver metastasis vascularity and volume

    OpenAIRE

    Davies, M M; Jonas, S. K.; Kaur, S.; Allen-Mersh, T G

    2000-01-01

    The extent to which plasma levels of angiogenic factors in healthy individuals and tumour volume-related variations in colorectal cancer affect the accuracy of circulating angiogenic factors as predictors of colorectal cancer vascularity is unknown. We used enzyme-linked immunosorbant assay to measure plasma vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) levels in colorectal liver metastasis (CLM) patients, and ‘no cancer’ controls. CLM volume was determin...

  2. Single-domain antibodies that compete with the natural ligand fibroblast growth factor block the internalization of the fibroblast growth factor receptor 1

    Energy Technology Data Exchange (ETDEWEB)

    Veggiani, Gianluca; Ossolengo, Giuseppe; Aliprandi, Marisa; Cavallaro, Ugo [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Marco, Ario de, E-mail: ario.demarco@ung.si [IFOM-IEO Campus, Via Adamello 16, 20139 Milano (Italy); Dept. Environmental Sciences, University of Nova Gorica (UNG), Vipavska 13, P.O. Box 301-SI-5000, Rozna Dolina, Nova Gorica (Slovenia)

    2011-05-20

    Highlights: {yields} Recombinant antibodies for FGFR1 were isolated from a llama naive library in VHH format. {yields} These antibodies compete with the natural ligand FGF-2 for the same epitope on FGFR1. {yields} The antibody competition inhibits the FGF-2-dependent internalization of FGFR1. -- Abstract: Single-domain antibodies in VHH format specific for fibroblast growth factor receptor 1 (FGFR1) were isolated from a phage-display llama naive library. In particular, phage elution in the presence of the natural receptor ligand fibroblast growth factor (FGF) allowed for the identification of recombinant antibodies that compete with FGF for the same region on the receptor surface. These antibodies posses a relatively low affinity for FGFR1 and were never identified when unspecific elution conditions favoring highly affine binders were applied to panning procedures. Two populations of competitive antibodies were identified that labeled specifically the receptor-expressing cells in immunofluorescence and recognize distinct epitopes. Antibodies from both populations effectively prevented FGF-dependent internalization and nuclear accumulation of the receptor in cultured cells. This achievement indicates that these antibodies have a capacity to modulate the receptor physiology and, therefore, constitute powerful reagents for basic research and a potential lead for therapeutic applications.

  3. Mutagenesis of the crystal contact of acidic fibroblast growth factor

    International Nuclear Information System (INIS)

    Several mutations at Glu81 located on the crystal contact of human acidic fibroblast growth factor were studied in an effort to improve crystal growth. Mutation to Ser and Thr resulted in crystallization of a rather bulky form of the wild type, whereas mutation to Val prohibited crystallization. These results suggest that crystal growth may be controlled by designing a new interface by protein engineering. An attempt has been made to improve a crystal contact of human acidic fibroblast growth factor (haFGF; 140 amino acids) to control the crystal growth, because haFGF crystallizes only as a thin-plate form, yielding crystals suitable for X-ray but not neutron diffraction. X-ray crystal analysis of haFGF showed that the Glu81 side chain, located at a crystal contact between haFGF molecules, is in close proximity with an identical residue related by crystallographic symmetry, suggesting that charge repulsion may disrupt suitable crystal-packing interactions. To investigate whether the Glu residue affects the crystal-packing interactions, haFGF mutants in which Glu81 was replaced by Ala, Val, Leu, Ser and Thr were constructed. Although crystals of the Ala and Leu mutants were grown as a thin-plate form by the same precipitant (formate) as the wild type, crystals of the Ser and Thr mutants were grown with increased thickness, yielding a larger overall crystal volume. X-ray structural analysis of the Ser mutant determined at 1.35 Å resolution revealed that the hydroxy groups of Ser are linked by hydrogen bonds mediated by the formate used as a precipitant. This approach to engineering crystal contacts may contribute to the development of large protein crystals for neutron crystallography

  4. 脂肪干细胞与碱性成纤维细胞生长因子在颗粒脂肪移植中应用的研究进展%Research Progress of Application of Adipose-derived Stem Cells and Basic Fibroblast Growth Factor in Pearl Fat Transplantation

    Institute of Scientific and Technical Information of China (English)

    孙哲

    2012-01-01

    The survival rate of autologous graft pearl fats are influenced by revascularization and the shortage of tissue cell differentiation,the study of adipose tissue derived stem cells( ASCs )and basic fibroblast growth factor( bFGF )in the application of autologous fat transplantation found that both factors can improve the survival rate of autologous graft pearl fats obviously. Here is to extensively collect and comprehensively analyse the relevant literature of the roles of ASCs and bFGF in pearl fat graft transplantation recently, to discuss the progress of ASCs and bFGF in the research of pearl fat grafts.%自体移植颗粒脂肪的成活率受到再血管化及组织细胞分化不足等问题的影响,对脂肪组织来源干细胞(ASCs)及碱性成纤维细胞生长因子(bFGF)在自体颗粒脂肪移植中应用的研究中发现,两者能明显提高自体颗粒脂肪移植后的成活率.现广泛查阅近年ASCs和bFGF在颗粒脂肪移植中作用的相关文献,并进行综合分析,探讨ASCs和bFGF在颗粒脂肪移植中的研究进展.

  5. Effect of atomizing inhalation of basic fibroblast growth factor on vascular endothelial growth factor in patients with vascular dementia%雾化吸入碱性成纤维细胞生长因子对血管性痴呆患者血管内皮生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    叶建新; 林航; 穆军山; 崔晓萍

    2015-01-01

    目的:研究雾化吸入碱性成纤维细胞生长因子( b-FGF )对血管性痴呆患者血清血管内皮生长因子( VEGF)的影响。方法:采用临床痴呆评定量表( CDR)筛选出轻度血管性痴呆( VD)患者60例,分成轻度VD治疗组34例,轻度VD对照组26例,另设正常对照组30例,VD对照组患者常规抗动脉硬化、抗血小板聚集及抗痴呆治疗, VD治疗组在其对照组常规治疗基础上给予bFGF 4800 AU/d加入生理盐水10 mL氧气雾化吸入,每次10 min,1次/d,连续14 d。比较2组VD患者治疗前、治疗后14、30 d血清VEGF的表达。结果:2组VD患者治疗前血清VEGF水平明显低于正常对照组,VD治疗组患者治疗后14、30 d血清VEGF水平逐渐升高,与VD对照组比较有统计学意义(P<0.01)。结论:bFGF通过鼻黏膜进入中枢神经系统,促进VD患者血清VEGF的表达。%Objective:To study the effect of atomizing inhalation of basic fibroblast growth factor (bFGF) on serum vas-cular endothelial growth factor (VEGF) in patients with vascular dementia (VD).Methods: Sixty patients with mild VD were selected by using the clinical dementia rating scale (CDR), and were divided into VD treatment group (34 cases) and VD control group (26 cases), another 30 cases as the normal control group .Patients in VD control group received conven-tional anti atherosclerosis , anti platelet aggregation and anti dementia treatment .On the basis of conventional treatment , pa-tients in VD treatment group were given bFGF 4800 AU/d in 10mL normal saline for oxygen inhalation , 10 minutes each time, once a day, continuous for 14 days.The expression of VEGF was compared between the two groups before treatment and after treated for 14 and 30 days.Results:The expression of VEGF was lower in two VD groups before treatment than that of normal control group .The expression of VEGF increased gradually in VD treatment groups after treated for 14 and 30

  6. Expressions of vascular endothelial growth factor and basic fibroblast growth factor in the late stage of pressure ulcer%血管内皮生长因子及碱性成纤维细胞生长因子在晚期压疮中的表达

    Institute of Scientific and Technical Information of China (English)

    代彦丽; 潘莹莹; 孙熠; 崔飞飞; 张龙; 肖健; 姜丽萍

    2012-01-01

    目的 寻找血管内皮生长因子(VEGF)、bFGF 在Ⅲ~Ⅳ期压疮创面中的分布规律及表达特征,探讨其其与溃疡形成之间的关系.方法 选择2010年6月-2012年3月温州医学院2家附属医院收治的41例患者,其中Ⅲ~Ⅳ期压疮患者21例共23个创面、急性外伤患者14例、正常皮肤供者6例.将上述患者手术中采集的样本分为4组:压疮中心组、压疮边缘组、急性创面组、正常皮肤组,样本数分别为23、23、14、6.HE染色观察创面的组织形态,Masson染色观察胶原纤维在创面中的分布,免疫组织化学染色观察VEGF、bFGF在创面中的表达.对数据进行独立样本t检验及配对样本t检验.结果 (1)2个压疮创面组见大量炎性细胞聚集,胶原纤维减少或消失;VEGF、bFGF阳性表达主要位于Fb和内皮细胞,在压疮中心组表达量分别为100±39、132 ±46,在压疮边缘组表达量分别为228 ±48、299±80. 2组之间比较,差异有统计学意义(t值分别为13.497、13.020,P值均小于0.01).(2)急性创面组Fb增多,可见少量胶原纤维;VEGF、bFGF阳性表达主要位于Fb,表达量分别为292±59、443±194,与2个压疮创面组比较,差异有统计学意义(t值为2.370~ 11.570,P<0.05或P<0.01).(3)正常皮肤组的组织结构合理,胶原纤维丰富;VEGF、bFGF表达较少,分别为45 ±18、54±22.与其他3组比较,差异具有统计学意义(t值为3.983~ 14.087,P值均小于 0.01).结论 Ⅲ~Ⅳ期压疮创面VEGF、bFGF表达显著低于急性外伤创面,胶原纤维合成减少或消失可能是其重要因索.%Objective To study the distribution and expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growthth factor (bFGF) in the Ⅲ-Ⅳ stage of pressre ulcer wound,and to explore their correlation with ulceration.Methods Forty-one patients hospitalized in the two Affiliated Hospital of Wenzhou Medical College from June 2010 to March 2012 were recruited

  7. Serum platelet-derived growth factor and fibroblast growth factor in patients with benign and malignant ovarian tumors

    DEFF Research Database (Denmark)

    Madsen, Christine Vestergaard; Steffensen, Karina Dahl; Olsen, Dorte Aalund;

    2012-01-01

    New biological markers with predictive or prognostic value are highly warranted in the treatment of ovarian cancer. The platelet-derived growth factor (PDGF) system and fibroblast growth factor (FGF) system are important components in tumor growth and angiogenesis....

  8. Human epidermal growth factor and the proliferation of human fibroblasts.

    Science.gov (United States)

    Carpenter, G; Cohen, S

    1976-06-01

    The effect of human epidermal growth factor (hEGF), a 5,400 molecular weight polypeptide isolated from human urine, on the growth of human foreskin fibroblasts (HF cells) was studied by measuring cell numbers and the incorporation of labeled thymidine. The addition of hEGF to HF cells growing in a medium containing 10% calf serum resulted in a 4-fold increase in the final density. The presence of hEGF also promoted the growth of HF cells in media containing either 1% calf serum or 10% gamma globulin-free serum. The addition of hEGF to quiescent confluent monolayers of HF cells, maintained in a medium with 1% calf serum for 48 hours, resulted in a 10- to 20-fold increase in the amount of 3H-thymidine incorporation after 20-24 hours. The stimulation of thymidine incorporation was maximal at an hEGF concentration of 2 ng/ml, was dependent on the presence of serum, and was enhanced by the addition of ascorbic acid. In confluent cultures of HF cells, subject to density dependent inhibition of growth, hEGF was able to stimulate DNA synthesis more effectively than fresh calf serum. Human EGF stimulated DNA synthesis in quiescent cultures, however, regardless of cell density. The addition of rabbit anti-hEGF inhibited all effects of this growth factor on HF cells.

  9. Fibroblast Growth Factor-23 in Bed Rest and Spaceflight

    Science.gov (United States)

    Bokhari, R.; Zwart, S. R; Fields, E.; Heer, M.; Sibonga, J.; Smith, S. M.

    2014-01-01

    Many nutritional factors influence bone, from the basics of calcium and vitamin D, to factors which influence bone through acid/base balance, including protein, sodium, and more. Fibroblast growth factor 23 (FGF23) is a recently identified factor, secreted from osteocytes, which is involved in classic (albeit complex) feedback loops controlling phosphorus homeostasis through both vitamin D and parathyroid hormone (PTH) (1, 2). As osteocytes are gravity sensing cells, it is important to determine if there are changes in FGF23 during spaceflight. In extreme cases, such as chronic kidney disease, FGF23 levels are highly elevated. FGF23 imbalances, secondary to dietary influences, may contribute to skeletal demineralization and kidney stone risk during spaceflight. Presented with an imbalanced dietary phosphorus to calcium ratio, increased secretion of FGF23 will inhibit renal phosphorus reabsorption, resulting in increased excretion and reduced circulating phosphorus. Increased intake and excretion of phosphorus is associated with increased kidney stone risk in both the terrestrial and microgravity environments. Highly processed foods and carbonated beverages are associated with higher phosphorus content. Ideally, the dietary calcium to phosphorus ratio should be at minimum 1:1. Nutritional requirements for spaceflight suggest that this ratio not be less than 0.67 (3), while the International Space Station (ISS) menu provides 1020 mg Ca and 1856 mg P, for a ratio of 0.55 (3). Subjects in NASA's bed rest studies, by design, have consumed intake ratios much closer to 1.0 (4). FGF23 also has an inhibitory influence on PTH secretion and 1(alpha)-hydroxylase, both of which are required for activating vitamin D with the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Decreased 1,25-dihydroxyvitamin D will result in decreased intestinal phosphorus absorption, and increased urinary phosphorus excretion (via decreased renal reabsorption). Should a decrease in 1

  10. Growth stimulation of 3T3 fibroblasts by Cystatin

    Energy Technology Data Exchange (ETDEWEB)

    Quan Sun (Michigan State Univ., East Lansing (United States) Beijing Medical Univ. (China))

    1989-01-01

    Treatment of cultures of mouse 3T3 fibroblasts with Cystatin C, a thiol-proteinase inhibitor isolated from chicken egg white, resulted in an enhanced rate of cell proliferation. This stimulation was demonstrated using two independent assay systems: (a) assessment of total cell number and (b) measurement of ({sup 3}H)thymidine incorporated into acid-precipitable DNA. In both assays, the dose-response curves of Cystatin stimulation showed a rising function that plateaued at a concentration of {approximately}120 {mu}g/ml. The addition of Cystatin to cultures of Kirsten murine sarcoma virus-transformed 3T3 cells also enhanced DNA synthesis in these target cells. Control experiments showed that the presence of Cystatin did not alter the level of binding of radioactively labeled epidermal growth factor and platelet derived growth factor to 3T3 cells. These results argue against the possibility that the observed growth stimulation by Cystatin was due to growth factor contamination of the Cystatin preparation.

  11. Development and testing of radio and enzyme immunoassays for acidic fibroblast growth factor (aFGF)

    International Nuclear Information System (INIS)

    Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor from bovine brain stimulate growth in a variety of tissues in several species. Despite the 55% amino acid sequence homology of the two forms of FGF, a specific immunoassay of aFGF has been developed using a polyclonal antibody raised in a rabbit. Two immunoassays were compared: a radioimmunoassay (RIA) using 125I aFGF and an enzyme immunoassay (EIA) using aFGF coupled to the tetrameric form of acetylcholinesterase (aFGF-AchE) as tracer. With EIA, the detection limit was 1.5 ng/ml, versus 2.2 ng/ml with RIA, while the dose at 50% was 5.9 ng/ml for EIA and 9.6 ng/ml for RIA. Using a modified EIA procedure where aFGF-AchE was added 2 h after the other reagents, the dose at 50% binding was 1.5 ng/ml. Examples of the performance of both immunoassays are presented for various brain extracts of different species including human. The aFGF content obtained by these methods correlates (CR = 0.987) with the values obtained by biological assay

  12. Actomyosin organisation for adhesion, spreading, growth and movement in chick fibroblasts

    DEFF Research Database (Denmark)

    Couchman, J R; Rees, D A

    1979-01-01

    Examination of the actomyosin structures and their relation to adhesion, movement and growth in the first fibroblasts migrating from chick heart explants shows striking differences with fibroblasts adapted to grow in culture. The latter have focal adhesions which seem to immobilize them for ancho......Examination of the actomyosin structures and their relation to adhesion, movement and growth in the first fibroblasts migrating from chick heart explants shows striking differences with fibroblasts adapted to grow in culture. The latter have focal adhesions which seem to immobilize them...

  13. Functional upregulation of system xc- by fibroblast growth factor-2.

    Science.gov (United States)

    Liu, Xiaoqian; Resch, Jon; Rush, Travis; Lobner, Doug

    2012-02-01

    The cystine/glutamate antiporter (system xc-) is a Na(+)-independent amino acid transport system. Disruption of this system may lead to multiple effects in the CNS including decreased cellular glutathione. Since multiple neurological diseases involve glutathione depletion, and disruption of growth factor signaling has also been implicated in these diseases, it is possible that some growth factors effects are mediated by regulation of system xc-. We tested the growth factors fibroblast growth factor-2 (FGF-2), insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG), neurotrophin-4 (NT-4), and brain derived neurotrophic factor (BDNF) on system xc- mediated 14C-cystine uptake in mixed neuronal and glial cortical cultures. Only FGF-2 significantly increased cystine uptake. The effect was observed in astrocyte-enriched cultures, but not in cultures of neurons or microglia. The increase was blocked by the system xc- inhibitor (s)-4-carboxyphenylglycine, required at least 12 h FGF-2 treatment, and was prevented by the protein synthesis inhibitor cycloheximide. Kinetic analysis indicated FGF-2 treatment increased the V(max) for cystine uptake while the K(m) remained the same. Quantitative PCR showed an increase in mRNA for xCT, the functional subunit of system xc-, beginning at 3 h of FGF-2 treatment, with a dramatic increase after 12 h. Blocking FGFR1 with PD 166866 blocked the FGF-2 effect. Treatment with a PI3-kinase inhibitor (LY-294002) or a MEK/ERK inhibitor (U0126) for 1 h prior to and during the FGF-2 treatment, each partially blocked the increased cystine uptake. The upregulation of system xc- by FGF-2 may be responsible for some of the known physiological actions of FGF-2. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  14. Fibroblast growth factor 10-fibroblast growth factor receptor 2b mediated signaling is not required for adult glandular stomach homeostasis.

    Directory of Open Access Journals (Sweden)

    Allison L Speer

    Full Text Available The signaling pathways that are essential for gastric organogenesis have been studied in some detail; however, those that regulate the maintenance of the gastric epithelium during adult homeostasis remain unclear. In this study, we investigated the role of Fibroblast growth factor 10 (FGF10 and its main receptor, Fibroblast growth factor receptor 2b (FGFR2b, in adult glandular stomach homeostasis. We first showed that mouse adult glandular stomach expressed Fgf10, its receptors, Fgfr1b and Fgfr2b, and most of the other FGFR2b ligands (Fgf1, Fgf7, Fgf22 except for Fgf3 and Fgf20. Fgf10 expression was mesenchymal whereas FGFR1 and FGFR2 expression were mostly epithelial. Studying double transgenic mice that allow inducible overexpression of Fgf10 in adult mice, we showed that Fgf10 overexpression in normal adult glandular stomach increased epithelial proliferation, drove mucous neck cell differentiation, and reduced parietal and chief cell differentiation. Although a similar phenotype can be associated with the development of metaplasia, we found that Fgf10 overexpression for a short duration does not cause metaplasia. Finally, investigating double transgenic mice that allow the expression of a soluble form of Fgfr2b, FGF10's main receptor, which acts as a dominant negative, we found no significant changes in gastric epithelial proliferation or differentiation in the mutants. Our work provides evidence, for the first time, that the FGF10-FGFR2b signaling pathway is not required for epithelial proliferation and differentiation during adult glandular stomach homeostasis.

  15. Embryonic stem cell test for the study of the developmentaltoxicity of basic fibroblast growth factor%应用胚胎干细胞试验模型对碱性成纤维细胞生长因子发育毒性的初步评价

    Institute of Scientific and Technical Information of China (English)

    许华; 邓淑琴; 何清; 苏本金; 江海香; 黄亚东

    2012-01-01

    目的 利用小鼠胚胎干细胞试验(EST)模型,初步评价bFGF的发育毒性.方法 体外培养小鼠胚胎干细胞(ESC),通过形态学观察、碱性磷酸酶染色和RT-PCR方法进行ESC未分化鉴定;MTT法检测不同浓度bFGF对ESC和3T3细胞的毒性,RT-PCR半定量分析法检测bFGF对未分化基因Sox-2表达的影响.结果 bFGF对ESC和3T3的半数抑制浓度和ESC的半数抑制分化浓度分别为IC50 ESC=15.2 mg·L-1,IC50 3T3=24.2 mg·L-1,ID50 ESC=1.7 mg·L-1.结论 bFGF发育毒性的判定为弱胚胎毒性.%Aim To research the developmental toxicity of basic Fibroblast Growth Factor ( bFGF ) by theembryonic stem cell test. Methods Mouse embryonic stem cells were cultured and their undifferentiationswere identified by the methods of morphology, alkaline phosphatase staining and RT-PCR. The cytotoxic effect of bFGF was detected by MTT assay. The effect of bF-GF on Sox-2 gene expression was determined by semi-quantitative RT-PCR. Result The IC50 of bFGF on3T3 was 24. 2 mg · L-1, while IC50 and ID50 on ESCwere 15. 2 mg · L -1 and 1. 7 mg · L -1 respectively. Conclusion The developmental toxicity of bFGF is e-valuated as weak embryotoxicity.

  16. Injectable fibroblast growth factor-2 coacervate for persistent angiogenesis.

    Science.gov (United States)

    Chu, Hunghao; Gao, Jin; Chen, Chien-Wen; Huard, Johnny; Wang, Yadong

    2011-08-16

    Enhancing the maturity of the newly formed blood vessels is critical for the success of therapeutic angiogenesis. The maturation of vasculature relies on active participation of mural cells to stabilize endothelium and a basal level of relevant growth factors. We set out to design and successfully achieved robust angiogenesis using an injectable polyvalent coacervate of a polycation, heparin, and fibroblast growth factor-2 (FGF2). FGF2 was loaded into the coacervate at nearly 100% efficiency. In vitro assays demonstrated that the matrix protected FGF2 from proteolytic degradations. FGF2 released from the coacervate was more effective in the differentiation of endothelial cells and chemotaxis of pericytes than free FGF2. One injection of 500 ng of FGF2 in the coacervate elicited comprehensive angiogenesis in vivo. The number of endothelial and mural cells increased significantly, and the local tissue contained more and larger blood vessels with increased circulation. Mural cells actively participated during the whole angiogenic process: Within 7 d of the injection, pericytes were recruited to close proximity of the endothelial cells. Mature vasculature stabilized by vascular smooth muscle cells persisted till at least 4 wk. On the other hand, bolus injection of an identical amount of free FGF2 induced weak angiogenic responses. These results demonstrate the potential of polyvalent coacervate as a new controlled delivery platform.

  17. Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

    Directory of Open Access Journals (Sweden)

    Santiago Vernia

    2016-03-01

    Full Text Available The cJun NH2-terminal kinase (JNK-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21 is a target of the hepatic JNK-signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome.

  18. Mutational identification of fibroblast growth factor receptor 1 and fibroblast growth factor receptor 2 genes in craniosynostosis in Indian population

    Directory of Open Access Journals (Sweden)

    Rajeev Kumar Pandey

    2013-01-01

    Full Text Available Objective: The Objective of this study was to identify the association of mutation of fibroblast growth factor receptor 1 (FGFR1, FGFR2 genes with syndromic as well as non-syndromic craniosynostosis in Indian population. Materials and Methods: Retrospective analysis of our records from January 2008 to December 2012 was done. A total of 41 cases satisfying the inclusion criteria and 51 controls were taken for the study. A total volume of 3 ml blood from the patient as well as parents was taken. Deoxyribonucleic acid extracted using phenol chloroform extraction method followed by polymerase chain reaction-restriction fragment length polymorphism method. Results: There were 33 (80.4% non-syndromic cases of craniosynostosis while 8 (19.5% were syndromic. Out of these 8 syndromic cases, 4 were Apert syndrome, 3 were Crouzon syndrome and 1 Pfeiffer syndrome. Phenotypically the most common non-syndromic craniosynostosis was scaphocephaly (19, 57.7% followed by plagiocephaly in (14, 42.3%. FGFR1 mutation (Pro252Arg was seen in 1 (2.4% case of non-syndromic craniosynostosis while no association was noted either with FGFR1 or with FGFR2 mutation in syndromic cases. None of the control group showed any mutation. Conclusion: Our study proposed that FGFR1, FGFR2 mutation, which confers predisposition to craniosynostosis does not exist in Indian population when compared to the western world.

  19. Pentadecapeptide BPC 157 Enhances the Growth Hormone Receptor Expression in Tendon Fibroblasts

    Directory of Open Access Journals (Sweden)

    Chung-Hsun Chang

    2014-11-01

    Full Text Available BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.

  20. Expression of fibroblast growth factor 23 by canine soft tissue sarcomas.

    Science.gov (United States)

    Hardcastle, M R; Dittmer, K E

    2016-09-01

    Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of humans. Some mesenchymal tumours (often resembling haemangiopericytomas) express molecules that normally regulate phosphorus metabolism; most frequently, fibroblast growth factor 23. Patients develop renal phosphate wasting and inappropriately low serum concentrations of 1, 25 (OH)2 vitamin D3 , leading to osteomalacia. Surgical removal of the tumour is curative. The authors examined expression of canine fibroblast growth factor 23 in 49 soft tissue sarcomas, and control tissues from normal adult dogs. RNA extracted from bone or formalin-fixed, paraffin-embedded tissues was analysed by end point and quantitative reverse transcriptase-polymerase chain reaction. Fibroblast growth factor 23 expression was detected in bone, lung, kidney, lymph node and thymus. Fifteen of 49 sarcomas (31%) expressed fibroblast growth factor 23, three of these had high relative expression and some features resembling phosphatonin-expressing mesenchymal tumours of humans. Further work is required to determine whether TIO may occur in dogs. PMID:24923416

  1. Study of early bone formation of basic fibroblast growth factor combined collagen slow-release carrier in mandibular defects of rabbit%复合碱性成纤维细胞生长因子胶原蛋白缓释载体促进早期兔下颌骨缺损修复的研究

    Institute of Scientific and Technical Information of China (English)

    许丽; 范伟伟; 黄志峰; 马锴; 李偲; 顾玲; 李洪远; 王彦亮

    2013-01-01

    目的:观察复合碱性成纤维细胞生长因子(bFGF)的胶原蛋白缓释载体在兔下颌骨缺损成骨修复中的作用,研究bFGF在骨缺损修复中的作用机制及缓释后的作用效果。方法将30只日本大耳白兔随机分成3组:bFGF胶原海绵组、胶原海绵组及对照组,每组各10只。随后外科手术建立兔双侧下颌骨洞穿性骨缺损,实验各组放入相应生物材料。术后2、6周分别处死两组兔,取标本进行大体观察、CT影像学观察和组织病理切片观察。结果实验组与对照组骨缺损愈合均为二期愈合(间接愈合)方式,术后不同时期组织病理切片观察,实验组形成成纤维细胞或类骨质、骨质的速度较对照组快,生成数量较对照组多,分布也较均匀;CT观察显示实验组骨创愈合速度较快。结论复合bFGF的胶原蛋白缓释载体在骨缺损的愈合方面有明显的促进作用。胶原蛋白海绵还能在缺损早期发挥促凝血功能,减少动物出血损伤,加速血肿形成和机化。%Objective To observe the application of basic fibroblast growth factor (bFGF) combined with collagen slow-release carrier in mandibular defects of rabbit, and to study the mechanism as well as the effect of bFGF in bone formation . Methods 30 Japanese white rabbits were randomly divided into three groups:the bFGF collagen sponge group, the collagen sponge group and the control group, 10 rabbits in each group.The bone defects were made in the rabbits’ bilateral mandibles, and the biological materials correspond with each group were inserted into defects. After 2 or 6 weeks of surgery, the postoperative animals were sacrificed,hile the mandible specimens were assessed by gross inspection, CT image and light microscopy. Results The second stage recoveries of operation incisions were obtained for both groups. Form the pathological section , the experiment groups repaired with bigger quantity, faster forming

  2. Growth modulation of fibroblasts by chitosan-polyvinyl pyrrolidone hydrogel: Implications for wound management?

    Indian Academy of Sciences (India)

    Makarand Risbud; Anandwardhan Hardikar; Ramesh Bhonde

    2000-03-01

    Wounds in adults and fetuses differ in their healing ability with respect to scar formation. In adults, wounds lacking the epidermis exhibit excess collagen production and scar formation. Fibroblasts synthesize and deposit a collagen rich extracellular matrix. The early migration and proliferation of fibroblasts in the wound area is implicated in wound scarring. We have synthesized a hydrogel from chitosan-polyvinyl pyrrolidone (PVP) and examined its effect on fibroblast growth modulation in vitro. The hydrogel was found to be hydrophilic as seen from its octane contact angle (141·2 ± 0·37°). The hydrogel was non-toxic and biocompatible with fibroblasts and epithelial cells as confirmed by the 3(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazolium bromide (MTT) assay. It showed dual properties by supporting growth of epithelial cells (SiHa) and selectively inhibiting fibroblast (NIH3T3) growth. Growth inhibition of fibroblasts resulted from their inability to attach on to the hydrogel. These findings are supported by image analysis, which revealed a significant difference ( < 0·05) between the number of fibroblasts attached to the hydrogel in tissue culture as compared to tissue culture treated polystyrene (TCPS) controls. However, no significant difference was observed ( > 0·05) in the number of epithelial (SiHa) cells attached on to the hydrogel as compared to the TCPS control. Although in vivo experiments are awaited, these findings point to the possible use of chitosan-PVP hydrogels in wound-management.

  3. 联合地塞米松治疗与肺炎链球菌脑膜炎室管膜下区碱性成纤维细胞生长因子表达的关系%The relationship between dexamethasone and the expression of basic fibroblast growth factor in subventricular zone of experimental streptococcus pneumoniae meningitis

    Institute of Scientific and Technical Information of China (English)

    赵秀英; 李玲; 廖锋; 向伟

    2013-01-01

    Objective To investigate the relationship between dexamethasone (DEX) and the expression of basic fibroblast growth factor (bFGF) in subventricular zone (SVZ) of experimental streptococcus pneumoniae meningitis. Methods Forty 3-week-old rats were used to develop the model of streptococcus pneumoniae meningitis, and were randomly divided into 4 groups of 10 rats each, antibiotic group, antibiotic plus DEX group, infection control group and normal control group. The expression level of bFGF in SVZ was detected by immunohistochemical staining. Results The expression level of bFGF in SVZ of rats in antibiotic group was similar to that of rats in infection control group (P>O.05). However, the expression level of bFGF in SVZ of rats in antibiotic plus DEX group was significantly higher than that of rats in antibiotic group and infection control group (P<0.01). Conclusions In the course of streptococcus pneumoniae meningitis, the combination therapy of antibiotics and DEX can up-regulate the expression level of bFGF in SVZ, which may promote neurogenesis and protect against brain injury in bacterial meningitis.%目的 探讨联合地塞米松(DEX)治疗与肺炎链球菌脑膜炎脑生发区域-室管膜下区(SVZ)碱性成纤维细胞生长因子(bFGF)表达的关系.方法 40只3周龄大鼠建立肺炎链球菌脑膜炎模型,分为抗生素组、抗生素联合DEX组、感染对照组、正常对照组,每组10只.免疫组化检测脑组织bFGF的表达.结果 抗生素组大鼠SVZ中的bFGF表达与感染对照组差异无统计学意义(P>0.05),而使用抗生素联合DEX组大鼠bFGF表达高于抗生素治疗组及感染对照组,差异均有统计学意义(P<0.01).结论 在肺炎链球菌脑膜炎病程中,联合DEX治疗可以上调bFGF在SVZ中的表达,可能有利于其促进神经生发,有利于抵御细菌性脑膜炎脑损伤.

  4. Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression.

    Science.gov (United States)

    Girer, Nathaniel G; Murray, Iain A; Omiecinski, Curtis J; Perdew, Gary H

    2016-07-15

    The Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in many physiological processes. Several studies indicate that AHR is also involved in energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator of the fasting and feeding responses. When administered to various genetic and diet-induced mouse models of obesity, FGF21 can attenuate obesity-associated morbidities. Here, we explore the role of AHR in hepatic Fgf21 expression through the use of a conditional, hepatocyte-targeted AHR knock-out mouse model (Cre(Alb)Ahr(Fx/Fx)). Compared with the congenic parental strain (Ahr(Fx/Fx)), non-fasted Cre(Alb)Ahr(Fx/Fx) mice exhibit a 4-fold increase in hepatic Fgf21 expression, as well as elevated expression of the FGF21-target gene Igfbp1 Furthermore, in vivo agonist activation of AHR reduces hepatic Fgf21 expression during a fast. The Fgf21 promoter contains several putative dioxin response elements (DREs). Using EMSA, we demonstrate that the AHR-ARNT heterodimer binds to a specific DRE that overlaps binding sequences for peroxisome proliferator-activated receptor α (PPARα), carbohydrate response element-binding protein (ChREBP), and cAMP response element-binding protein, hepatocyte specific (CREBH). In addition, we reveal that agonist-activated AHR impairs PPARα-, ChREBP-, and CREBH-mediated promoter activity in Hepa-1 cells. Accordingly, agonist treatment in Hepa-1 cells ablates potent ER stress-driven Fgf21 expression, and pre-treatment with AHR antagonist blocks this effect. Finally, we show that pre-treatment of primary human hepatocytes with AHR agonist diminishes PPARα-, glucose-, and ER stress-driven induction of FGF21 expression, indicating the effect is not mouse-specific. Together, our data show that AHR contributes to hepatic energy homeostasis, partly through the regulation of FGF21 expression and signaling. PMID:27226639

  5. Endoglin negatively regulates transforming growth factor beta1-induced profibrotic responses in intestinal fibroblasts.

    LENUS (Irish Health Repository)

    Burke, J P

    2012-02-01

    BACKGROUND: Fibroblasts isolated from strictures in Crohn\\'s disease (CD) exhibit reduced responsiveness to stimulation with transforming growth factor (TGF) beta1. TGF-beta1, acting through the smad pathway, is critical to fibroblast-mediated intestinal fibrosis. The membrane glycoprotein, endoglin, is a negative regulator of TGF-beta1. METHODS: Intestinal fibroblasts were cultured from seromuscular biopsies of patients undergoing intestinal resection for CD strictures or from control patients. Endoglin expression was assessed using confocal microscopy, flow cytometry and western blot. The effect of small interfering (si) RNA-mediated knockdown and plasmid-mediated overexpression of endoglin on fibroblast responsiveness to TGF-beta1 was assessed by examining smad phosphorylation, smad binding element (SBE) promoter activity, connective tissue growth factor (CTGF) expression and ability to contract collagen. RESULTS: Crohn\\'s stricture fibroblasts expressed increased constitutive cell-surface and whole-cell endoglin relative to control cells. Endoglin co-localized with filamentous actin. Fibroblasts treated with siRNA directed against endoglin exhibited enhanced TGF-beta1-mediated smad-3 phosphorylation, and collagen contraction. Cells transfected with an endoglin plasmid did not respond to TGF-beta1 by exhibiting SBE promoter activity or producing CTGF. CONCLUSION: Fibroblasts from strictures in CD express increased constitutive endoglin. Endoglin is a negative regulator of TGF-beta1 signalling in the intestinal fibroblast, modulating smad-3 phosphorylation, SBE promoter activity, CTGF production and collagen contraction.

  6. 成纤维细胞生长因子和胰岛素促小鼠软骨细胞增殖分化的效应%Effect of basic fibroblast growth factor and insulin on the proliferation and differentiation of mouse chondrocytes

    Institute of Scientific and Technical Information of China (English)

    史剑波; 江逊; 狄静芳; 许庚; 崔蕴霞

    2005-01-01

    背景:根据软骨为单一类型细胞组成的无血管组织,对氧和营养的供应要求较低,同种免疫性较低,体内功能较简单,易于在体外构建成可供移植的人工移植细胞系等特点,从建立用于组织工程的通用人类同种软骨细胞系着手,为人工组织和人工器官走向标准化和批量生产奠定基础.目的:探讨碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)和胰岛素在原代培养软骨细胞的增殖过程中的效应,为组织工程中细胞因子的应用与作用进行评估.设计:以细胞为研究对象,分组对照重复观察测量.单位:一所大学的组织移植与免疫实验室.材料:实验于2002-11/2003-05在暨南大学组织移植与免疫教育部重点实验室完成,研究对象为随机获取的培养的软骨细胞.方法:在低血清培养基培养条件下进行小鼠原代软骨细胞培养,采用WST1比色法和荧光染色法观察不同浓度bFGF和胰岛素对软骨细胞增殖的影响.主要观察指标:主要结局:①bFGF对小鼠原代软骨细胞增殖影响.②胰岛素对小鼠原代软骨细胞增殖的影响.次要结局:软骨细胞形态学观察.结果:原代软骨细胞在4 g/L胎牛血清培养基培养条件下,不同浓度的bFGF和胰岛素对软骨细胞的增殖有剂量相关性.形态学观察表明,bFGF和胰岛素不仅促进细胞增殖,而且可使细胞分泌基质增多.结论:胰岛素和bFGF均能促进软骨细胞的增殖.%BACKGROUND: Based on the characteristics of cartilage tissue, such as consisting of single type of cells, the cartilage cells or chondrocyte, absence of blood vessel, rather low consumption level of oxygen and nutrition, low level of allo-immunocompetence and simple function in vivo, it seems to be easy for cartilage cell lines to be established for tissue and cell transplantation. We want to set up a cell line with the purpose of current use in tissue engineering in vitro. It will provide the basis

  7. Effects of cigarette smoke exposure on expression of basic fibroblast growth factor and matrix metalloproteinase-12 in pulmonary vascular of rats%烟雾暴露对大鼠肺血管壁碱性成纤维细胞生长因子及基质金属蛋白酶12表达的影响

    Institute of Scientific and Technical Information of China (English)

    熊雪; 张爱珍; 邢爱萍; 李毅; 杜永成

    2015-01-01

    Objective To observe the expression of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-12 (MMP-12) in pulmonary vascular wall induced by cigarette smoke exposure in rats,and to explore their role in pulmonary vascular remodeling.Methods 40 male SD rats were randomly divided into control group,smoke exposure for one month group,smoke exposure for two months group,smoke exposure for three months group,with ten rats in each group.The ratio of pulmonary vascular wall thickness and vascular external diameter (WT%),and the ratio of pulmonary vascular wall area and total pulmonary vascular area (WA%) were measured by the image analysis system.The collagen fiber formation was observed by Van Gieson staining.The expressions of bFGF and MMP-12 in pulmonary vascular wall were detected by immunohistochemical staining,the protein expression was reflected by average grey value.Results ①As the extension of smoke exposure time,WT% and WA% were increased gradually,there was statistical significance among groups (P <0.05).②As the extension of smoke exposure time,bFGF and MMP-12 protein expressions increased,there was statistical significance among groups (P <0.05).③ bFGF was positivily correlated with WT% (r =-0.748,P <0.05) and WA% (r =-0.834,P <0.05),MMP-12 was positivily correlated with WT% (r =-0.565,P <0.05) and WA% (r =-0.504,P <0.05),bFGF was positively related with MMP-12 (r =0.738,P <0.05).Conclusions By upregulating the expressions of bFGF and MMP-12 protein in pulmonary vascular,cigarette smoke exposure induces the remodeling of pulmonary vascular.%目的 观察碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)及基质金属蛋白酶12(matrix metalloproteinase-12,MMP-12)在烟雾暴露大鼠肺血管壁上的表达情况,并探讨它们在肺血管重塑中的作用.方法 40只雄性SD大鼠按随机数字表法分为对照组(C组)、烟雾暴露1月组(S1m组)、烟雾暴露2月组(S2m

  8. The Role of Fibroblast Growth Factor-23 in Cardiorenal Syndrome

    Science.gov (United States)

    Kovesdy, Csaba P.; Quarles, L. Darryl

    2016-01-01

    Abnormalities in chronic kidney disease-related bone and mineral metabolism (CKD-MBD) have emerged as novel risk factors in excess cardiovascular mortality in patients with CKD and end-stage renal disease (ESRD). The pathophysiological links between CKD-MBD and adverse cardiovascular events in this patient population are unclear. Hyperphosphatemia through induction of vascular calcifications and decreased active vitamin D production leading to activation of the renin angiotensin system (RAS) along with defects in innate immunity are purported to be the proximate cause of CKD-MBD-associated mortality in CKD. Recently, this view has been challenged by the observation that fibroblast growth factor-23 (FGF23), a newly discovered hormone produced in the bone that regulates phosphate and vitamin D metabolism by the kidney, is a strong predictor of adverse cardiovascular outcomes in patients with CKD and ESRD. Whether these associations between elevated circulating FGF23 levels and cardiovascular outcomes are causative, and if so, the mechanisms mediating the effects of FGF23 on the cardiovascular system are not clear. The principal physiological functions of FGF23 are mediated by activation of FGF receptor/α-klotho coreceptor complexes in target tissues. Elevated FGF23 has been associated with left ventricular hypertrophy (LVH), and it has been suggested that FGF23 may induce myocardial hypertrophy through a direct effect on cardiac myocytes. A direct ‘off target’ effect of FGF23 on LVH is controversial, however, since α-klotho (which is believed to be indispensable for the physiologic actions of FGF23) is not expressed in the myocardium. Another possibility is that FGF23’s effect on the heart is mediated indirectly, via ‘on target’ regulation of hormonal pathways in the kidney, which include suppression of angiotensin-converting enzyme 2, Cyp27b1and α-klotho, which would be predicted to act on circulating factors known to regulate RAS, 1,25(OH)2 D

  9. Matrine inhibits proliferation of mouse skin fibroblasts induced by platelet-derived growth factor-BB

    Institute of Scientific and Technical Information of China (English)

    WU Yan-an; GAO Chun-fang; WANG Hao; HUANG Chao; KONG Xian-tao

    2001-01-01

    To study the effect of matrine on proliferation of mouse skin fibroblasts induced by platelet-derived growth factor-BB (PDGF-BB). Methods: Mouse skin fibroblasts were obtained from newborn ⅠCR mice and propagated in vitro. Proliferation of cell was analyzed by mitochondrial reduction of tetrazolium salt MTT and actual cell count. Results: Matrine (50 to 500 μg/ml) caused dose-dependent reduction of serum-stimulated cell growth. Growth inhibition was totally reversed after removal of the drug. Matrine also inhibited PDGF-BB induced cell growth dose-dependently. Conclusion: Matrine exhibits potent anti-proliferation effect on mouse skin fibroblast. This effect appears to be mediated by decrease of PDGF-induced growth. These results suggest that matrine might have preventive and therapeutic implication in skin fibrosis.

  10. Adhesion, growth, and matrix production by fibroblasts on laminin substrates

    DEFF Research Database (Denmark)

    Couchman, J R; Höök, M; Rees, D A;

    1983-01-01

    Human embryonic skin fibroblasts have been shown to attach and spread on laminin substrates in the absence of protein synthesis and presence of fibronectin-depleted serum and anti-fibronectin antibodies. Rates of attachment and the type of spreading are virtually identical on fibronectin...

  11. Growth Habit of the Basic Oxysulfate Magnesium Whisker

    Institute of Scientific and Technical Information of China (English)

    WU Jiansong; GAO Yimin

    2016-01-01

    The growth habit of the basic magnesium oxysulfate whisker was investigated based on the theoretical model of anion coordination polyhedron growth units. It is found that typical basic magnesium oxysulfate whisker growth is consistent with anion tetrahedral coordination incorporation rules. The growth units of basic magnesium oxysulfate whiskers are [Mg-(OH)4]2- and HSO4-. [Mg-(OH)4]2- is the favorable growth unit and whisker growth is in the direction of the [Mg-(OH)4]2- combination. A plurality of [Mg-(OH)4]2- s combine and become a larger dimensional growth unit in a one-dimensional direction. Then HSO4-and larger dimensional growth units connect as basic magnesium sulfate whiskers, according to the structural characteristics of the basic magnesium sulfate whisker, which can guide the synthesis of magnesium hydroxide whisker.

  12. Effects of basic fibroblast growth factor on cartilaginous tissue formation from epiphyseal plate chondrocytes cultured in centrifuge tube%碱性成纤维细胞生长因子对离心管内培养骺板细胞生成软骨组织的作用

    Institute of Scientific and Technical Information of China (English)

    李文超; 许瑞江; 黄靖香; 张丽; 聂少波

    2011-01-01

    BACKGROUND: There have been many reports regarding epiphyseal plate cells cultured in the centrifuge tube technique.OBJECTIVE: To observe the effects of basic fibroblast growth factor (bFGF) on cartilaginous tissue formation from epiphysealplate chondrocytes cultured in centrifuge tube.METHODS: Chondrocytes were isolated from 3-week-old New Zealand rabbits using the method of tissue-yarn. A total of 5×106chondrocytes obtained by centrifugation were cultured in a plasti c centrifuge tube (15 mL) with the DMEM culture fluid including10 μg/L bFGF for 4 weeks continuously. Cell morphology was investigated with light and inverted microscope, and the histologicalstructure of new cartilaginous tissue was observed by histological staining.RESULTS AND CONCLUSIONS: Cartilaginous tissue regenerated from growth plate chondrocytes cultured in centrifuge tubewith bFGF in the DMEM culture medium. The periphery of the cartilaginous tissue was resembled with the germinal layer of growthplate, consisting of several cellular layers. The chondrocytes in the centre of tissue grew well, and several were differentiating tothe mast chondrocytes. The cartilaginous tissue appeared strongly positive for safranine "O" and toluidine blue staining, whichshowed that the chondrocytes could synthesize the proteoglycans. Type II collagen immunohistochemistry appeared stronglymetachromatic. bFGF could promote the formation of cartilaginous tissue, rich in proteoglycans and type II collagen, fromepiphyseal plate cells cultured in centrifuge tune.%背景:采用离心管技术体外培养骺板细胞的报道已很多.目的:观察碱性成纤维细胞生长因子对离心管内培养的骺板细胞生成类骺板组织的影响.方法:获取3周龄新西兰白兔股骨远端的骺板组织,利用组织块纱巾培养法获得骺板细胞,加入含有10 μg/L碱性成纤维细胞生长因子的DMEM培养液,连续培养4周.结果与结论:离心管内聚集的骺板细胞在含有碱性成纤维细

  13. 生物可降解聚合物结合碱性成纤维细胞生长因子与内皮细胞的黏附%Adhesion of endothelial cells with biodegradable polymer and basic fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    武欣; 冯增国; 汪忠镐; 谷涌泉; 张建; 叶霖; 段红永; 吴英峰; 陈兵; 李建新; 张淑文

    2011-01-01

    BACKGROUND:The application of biodegradable materials is the important research component of small-caliber tissue engineered vessels in vitro. How to modify degradable materials so as to facilitate in vitro anticoagulant and promote endothelial cell adhesion, is one of the hotspots in the study of vascular tissue engineering.OBJECTIVE:To in vitro load basic fibroblast growth factor (bFGF) by using biodegradable polycaprolactone (PCL) graft heparin materials, and to observe the effects on endothelial cell adhesion.METHODS:Applying PCL biodegradable materials, the activated heparin esterified with PCL hydroxyl end and then anchored at both ends of the PCL. The vascular scaffold was prepared with electrospinning technique. Using the electrostatic adsorption between heparin and growth factors, the scaffold was loaded with bFGF. After low-density short-term static cultivation of endothelial cells, the bFGF-loaded biodegradable PCL on the adhesion of endothelial cells was investigated.RESULTS AND CONCLUSION:The bFGF-loaded biodegradable PCL graft heparin scaffold is successfully fabricated.Endothelial adhesion experiments demonstrated that the biodegradable scaffold was conducive to endothelial cell adhesion.Biodegradable PCL graft heparin material loading bFGF is beneficial to endothelial cell adhesion in vitro.%背景:可降解材料的应用是体外构建小口径组织工程血管的重要研究部分.如何对可降解材料进行改性,以利于材料本身体外抗凝与促进内皮细胞黏附,是目前血管组织工程研究的热点之一.目的:利用可降解聚己内酯接枝肝素材料体外负载碱性成纤维细胞生长因子,观察其对于内皮细胞黏附的影响.方法:应用聚己内酯可降解材料,将肝素活化后并与聚己内酯的端羟基发生酯化反应从而被锚定在聚己内酯两端.经过电纺丝技术,制备血管支架.同时利用肝素和生长因子间的静电吸附作用,使支架负载碱性成纤维细胞生长

  14. The effect of fibroblast growth factors and advanced glycation end-products on the intima-media complex thickness in patients with coronary heart disease and type 2 diabetes

    OpenAIRE

    Ekaterina Vladimirovna Ivannikova; Victor Yurievich Kalashnikov; Olga Mikhaylovna Smirnova; Alexander Borisovich Kuznetsov; Sergei Anatolievich Terekhin; Alexander Viktorovich Il'in

    2014-01-01

    ObjectiveTo determine the levels of fibroblast transforming growth factor (TGFβ1), basic fibroblast growth factor (β-FGF), markers of nonspecific inflammatory response (interleukin-6 (IL-6)), C-reactive protein (CRP), advanced glycation end-products (AGEs) and their receptors (RAGEs) and to study their effect on the intima-media complex (IMC) thickness in patients with coronary heart disease (CHD) and type 2 diabetes, depending on carbohydrate metabolism compensation.Materials and Methods37 p...

  15. 外用重组牛碱性成纤维细胞生长因子结合中药沐足治疗糖尿病足难愈创口临床研究%Clinical research of recombinant bovine basic fibroblast growth factor for external use combined with traditional Chinese medicine foot bath in treatment of diabetic foot with badly healing wound

    Institute of Scientific and Technical Information of China (English)

    徐继周

    2015-01-01

    目的:探讨外用重组牛碱性成纤维细胞生长因子结合中药沐足治疗糖尿病足难愈创口的临床疗效。方法选取2012年8月~2014年1月我院糖尿病足部溃疡患者60例,随机分为观察组和对照组,各30例。观察组给予中药沐足、l% Ag-SD霜联合重组牛碱性成纤维细胞生长因子局部外用,而对照组仅局部外用l% Ag-SD霜。观察及比较两组患者治疗后临床疗效、创面愈合时间、住院时间及不良反应情况。结果观察组患者总有效率明显高于对照组,创面愈合时间和住院时间明显短于对照组(P<0.05),且两组均未见不良反应。结论外用重组牛碱性成纤维细胞生长因子联合中药沐足治疗糖尿病足难愈创口患者疗效安全、有效,能促进创面愈合,缩短住院时间。%Objective To investigate the clinical efficacy of recombinant bovine basic fibroblast growth factor for external use combined with traditional Chinese medicine foot bath in treatment of diabetic foot with badly healing wound.Methods 60 patients of diabetic foot ulcer from August 2012 to January 2014 in our hospital were chosed and randomly divided into the observation group and control group,each group in 30 cases.The observation group was given traditional Chinese medicine foot bath,l% Ag-SD cream combined with recombinant bovine basic fibroblast growth factor for external use,while the control group was given only l% Ag-SD cream for external use.The clinical efficacy,wound healing time,hospitalization time and adverse reactions of patients in two groups after treatment were observed and compared.Results The total effective rate of patients in the observation group was significantly better than that in the control group,wound healing time and hospitalization time were significantly shorter than those in the control group (P<0.05),and no adverse reactions happened in the two groups.ConclusionRecombinant bovine basic fibroblast growth

  16. Enhanced effect of fibroblast growth factor-2-containing dalteparin/protamine nanoparticles on hair growth

    Directory of Open Access Journals (Sweden)

    Takabayashi Y

    2016-05-01

    Full Text Available Yuki Takabayashi,1 Masaki Nambu,1 Masayuki Ishihara,2 Masahiro Kuwabara,1 Koichi Fukuda,2 Shingo Nakamura,2 Hidemi Hattori,2Tomoharu Kiyosawa1 1Department of Plastic and Reconstructive Surgery, 2Division of Biomedical Engineering, Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan Purpose: Although treatments for alopecia are in high demand, not all treatments are safe and reliable. Dalteparin/protamine nanoparticles (D/P NPs can effectively carry growth factors (GFs such as fibroblast GF (FGF-2. The purpose of this study was to identify the effects of FGF-2-containing D/P NPs (FGF-2&D/P NPs on hair growth.Patients and methods: In this study, the participants were 12 volunteers with thin hair. One milliliter of FGF-2 (100 ng/mL and D/P NPs (56 μg/mL was applied and massaged on the skin of the scalp by the participants twice a day. They were evaluated for 6 months. Participants were photographed using a digital camera for general observation and a hair diagnosis system for measuring hair diameter.Results: The mean diameter of the hairs was significantly higher following the application of FGF-2&D/P NPs for 6 months. Objective improvements in thin hair were observed in two cases. Nine participants experienced greater bounce and hair resilience.Conclusion: The transdermal application of FGF-2&D/P NPs to the scalp can be used as a new treatment for alopecia. Keywords: hair growth, dalteparin/protamine nanoparticles, fibroblast growth factor, transdermal application

  17. Effects of basic fibroblast growth factor on adenosine triphosphatase activity and antioxidation of alcoholism rat models%碱性成纤维细胞生长因子对乙醇中毒大鼠ATP酶及抗氧化作用的影响

    Institute of Scientific and Technical Information of China (English)

    黄俊杰; 王彩冰; 何显教; 黄丽娟; 黄彦峰; 梁祚仁; 阳秀英; 黎昀; 赵善民

    2012-01-01

    BACKGROUND: Basic fibroblast growth factor(bFGF) has multiple biological activities, and has positive effect on the recovery oftissue trauma. But the effect of bFGF against alcoholism has not been reported.OBJECTIVE: To study the effect of bFGF on the activities of adenosine triphosphatase (ATPase) and superoxide dismutase(SOD) and malondialdehyde (MDA)in cerebral cortex and liver tissue of alcoholism rat model.METHODS: The alcoholism rat models were established by perfusing stomach with alcohol. Thirty Wistar rats were randomlydivided into three groups. Normal saline group and bFGF treatment group were injected with normal saline and bFGF,respectively, at 60 days after modeling; Alcoholism model group was treated with no intervention. Another 10 rats without alcoholserved as control group.RESULTS AND CONCLUSION: The activities of ATPase and SOD in the cerebral cortex and livertissue of alcoholism modelgroup were significantly decreased than those in the control group, but the content of M DA was significantly higher than that inthe control group (P<0.05). After bFGF intervention, the activities of ATPase and SOD in the cerebral cortex and livertissuewere significantly increased compared with the normal saline group and alcoholism model group, but the content of MDA wassignificantly decreased (P<0.05-0.01). bFGF can increase the activities of ATPase and the antioxidative ability of brain tissue inalcoholism model rats. The bFGF can protect the brain and liver of rats against alcoholism.%背景:碱性成纤维细胞生长因子具有多种生物活性,对组织创伤具有修复作用,但其对乙醇中毒的保护作用至今未见报道.目的:观察碱性成纤维细胞生长因子对乙醇中毒大鼠脑和肝组织中ATP 酶、超氧化物歧化酶活力和丙二醛水平的影响.方法:选择成年Wistar 雄性大鼠,采用白酒灌胃建立乙醇中毒模型,30 只造模成功的大鼠分为3 组,生理盐水组和碱性成纤维细胞生长

  18. CO2激光焊接SD鼠小肠对吻合口羟脯氨酸和碱性成纤维细胞生长因子含量的影响%Impact of CO2 Laser Welding on Contents of Hydroxyproline and Basic Fibroblast Growth Factor in Anastomotic Stoma of SD Rats

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    目的 观察激光焊接与传统肠管缝合的吻合口羟脯氨酸(hydroxyproline,Hyp)和碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)含量在愈合过程中的变化.方法 将60只SD大鼠分为实验组和对照组两组,每组30只.2个大组再根据术后观察时间不同分为3小组,分别为术后7d组、术后14 d组和术后28 d组,每组10只大鼠.实验组采用CO2激光焊接,用3针等距缝线以牵引固定肠管,激光焊接功率密度19.11 mW/cm2,光斑直径0.1cm,持续脉冲时间为0.2s.激光焊接后将3根缝线抽走,激光焊接点40~ 50个.对照组采用3-0丝线行单层间断缝合,缝合需9~10针.分别于术后7d、14 d和28 d,测定吻合口破裂压.另外取吻合口近远端各0.5cm的小肠组织分别测定Hyp和bFGF含量.结果 术后60只大鼠均存活.实验组破裂压不同时期均高于对照组,第14和28天均明显高于对照组(P<0.05).术后第7d实验组Hyp含量与对照组比较,差异无显著意义;术后第14和28天实验组Hyp的含量明显高于对照组(分别为P<0.05,P<0.001).实验组bFGF的含量不同时期均高于对照组,第7、14天均明显高于对照组(P<0.05).结论 CO2激光焊接肠管可促进吻合口处小肠组织内羟脯氨酸和碱性成纤维胞生长因子的分泌,从而加速吻合口的愈合.

  19. Effects of basic fibroblast growth factor on Id2 expression in rat hippocampus neural stem cells after focal cerebral ischemia reperfusion injury%bFGF在局灶性脑缺血后内源性神经干细胞增殖过程中对Id2的影响

    Institute of Scientific and Technical Information of China (English)

    吕威力; 邢雪松; 张玲; 张岷; 姜海波

    2011-01-01

    目的 检测DNA结合抑制物2(inhibitor of DNA binding 2,Id2)在大鼠脑缺血再灌注海马组织神经干细胞中的表达及bFGF的干预作用.探讨影响神经干细胞增殖分化的分子调控机制.方法 采用大脑中动脉栓塞(MCAO)制作大鼠脑缺血再灌注模型.用免疫组织化学法检测海马神经干细胞BrdU、Id2的表达及bFGF的干预作用.结果 随着脑缺血再灌注第3天缺血海马神经元BrdU阳性细胞明显增多,第7天达高峰,Id2反应产物脑缺血再灌注第3天较正常组增多,随缺血再灌注时间的延长逐渐增多,第7天表达最强,以后表达逐渐减少.注射bFGF后BrdU、Id2的表达明显增加.结论 bFGF促进神经干细胞的增殖及缺血脑组织Id2的表达,提示bFGF促进神经干细胞增殖作用可能由Id2信号介导.%Objective To investigate the effects of basic fibroblast growth factor (bFGF) on Id2 expression and hippocampal neurogenesis in a rat model of cerebral ischemia / reperfusion , explore the related molecular mechanism.Methods The model of transient focal ischemia was made by occlusion of the middle cerebral artery , the expression of BrdU and Id2 and in hippocampus was detected with immunohistochemical method analyzed by microimage system.Results Neural stem cells were activated after cerebral ischemia.After three days , BrdU positive cells in hippocampus were obviously increased.To the seventh day, BrdU positive cells were more than those at any time.The expression of Id2 had similar trend with the expression of BrdU.Following bFGF injection, the expression of hippocampal Id2 had apparently increased in each group.Conclusions bFGF promotes the expression of Id2 in the hippocampus tissue.These findings indicate that bFGF promotion of neural stem cell proliferation may be mediated by ld2 signaling pathway.

  20. Basic Fibroblast Growth Factor Combined with Heparin Therapy and Red Light Therapy in Enhancing Burn Wound Healing%碱性成纤维细胞生长因子联合肝素及红光疗法对促进烫伤创面愈合的作用

    Institute of Scientific and Technical Information of China (English)

    吴娟; 何青峰; 林莉

    2012-01-01

    目的:比较3种疗法治疗深Ⅱ度烫伤创面的临床效果.方法:135例181个深Ⅱ度烫伤创面患者分为3组,A组43例58个创面采用常规生理盐水冲洗创面,庆大霉素生理盐水纱布包扎;B组47例63个创面,在常规治疗基础上给予碱性成纤维细胞生长因子(bFGF)凝胶及肝素局部涂抹治疗;C组45例60个创面,在A、B治疗方法的基础上联合局部红光照射.治疗后观察3组患者创面愈合时间及愈合率,评定临床疗效.结果:经过平均21 d的治疗,创面愈合率C组>B组>A组(96.7%±4.8%,88.7%±5.1%,70.1%±11.3%,P<0.01).结论:bFGF外用联合肝素、红光疗法可显著提高深Ⅱ度烫伤创面的临床效果,增加愈合率,缩短治疗时间.%Objective: To explore the treatment effect of basic fibroblast growth factor (bFGF) combined with heparin therapy and red light therapy for deep Ⅱ degree burn wounds. Methods: From February 2008 to March 2011, 135 patients with deep Ⅱ degree burn wounds (181 wounds), according to gender, age, duration, burn area, drug use area, were randomly divided into three groups, which were given conventional treatment (group A), joint heparin treatment (group B), and joint heparin plus red light (group C), respectively. By using SPSS 16. 0 software, the clinical data were analyzed by Student t test, chi-square test and variance analysis. Results: All cases were followed up for 6 - 12 months (9 months on average). The wound healing time in groups A, B and C was (28. 1 + 6. 3), (20. 9 + 4. 5) and (16. 9±3. 9) days respectively (F=ll. 53,P<0. 01). The wound healing rate in groups A, B and C was 70. 1% + 11.3%, 88. 7% + 5. 1%, and 96. 7%+4. 8% respectively (F= 8.24, P<0. 01). The therapeutic effective rate in groups A,B and C was 74. 1%, 90. 4% and 100. 0% respectively (F=8. 95, P< 0. 01). Conclusion: The bFGF combined with heparin and red light therapy can enhance deep Ⅱ degree burn wound healing and shorten the treatment duration.

  1. Effects of thalidomide on proliferation of human renal cancer cell and expression of basic fibroblast growth factor%沙利度胺对人肾癌细胞增生及碱性成纤维细胞生长因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    姜文华; 刘鹏飞; 李小东

    2008-01-01

    目的 观察沙利度胺对人肾癌细胞株786-0增生及碱性成纤维细胞生长因子(bFGF)表达的影响.方法 将细胞分成沙利度胺6.25、25、100 μg/ml组及对照组;应用MIT方法测定细胞抑制率;半定量RT-PCR和流式细胞术分别从mRNA和蛋白水平观察沙利度胺对786-0细胞bFGF表达的作用.结果 沙利度胺在6.25~100 μg/ml范围内能明显抑制786-0细胞增生,作用48、72 h,IC50分别为46.42、19.56μg/ml.凋亡率从12.43%增加到30.30%.并伴随bFGF表达水平下降,以25μg/ml对bFGF抑制最显著.结论 沙利度胺能抑制肾癌细胞bFGF的表达,促进凋亡,抑制细胞增生.%Objective To elucidate the effects of thalidomide on proliferation of human renal cell line 786-0 and the expression of basic fibroblast growth factor (bFGF) in this cell line. Methods Cell was treated with different doses of thalidomide(6.25 μg/ml, 25 μg/ml, 100 μg/ml) respectively or normal saline as control; cell survival rate was analyzed by MTT assay. The mRNA level of bFGF was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). bFGF protein expression in 786-0 cells was detected by flow cytometry (FCM). Results Thalidomide, ranging from 6.25 μg/ml to 100 μg/ml, suppressed the proliferation of 786-0 cell line in vitro significantly. After application of thalidomide for 48 and 72 hours, the IC50 was 46.42 μg/ml and 19.56 μg/ml respectively. Apoptosis rate increased from 12.43 % to 30.30 %, accompanying with reducing expression of bFGF. Application of thalidomide (25 μg/ml) induced the most significant inhibition to the bFGF in the cell line. Conclusion Thalidomide down-regulates bFGF expression, inhibit the proliferation, and induce apoptosis in 786-0 cell line.

  2. Impact of negative pressure wound therapy on basic fibroblast growth factor in human diabetic foot wounds%创面负压治疗对糖尿病足创面肉芽组织碱性成纤维细胞生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    杨少玲; 孙蕾蕾; 胡丽叶; 李晓玲; 厚荣荣; 朱旅云

    2016-01-01

    Objective To assess the endogenous regulation of basic fibroblast growth factor(bFGF) in the foot wound healing response induced by negative pressure wound therapy (NPWT) in diabetic patients. Methods From January 2010 to December 2014, 40 patients with diabetic foot wounds fitting the inclusion criteria were enrolled in the clinical trial. The subjects were randomly assigned for NPWT or conventional (control group) treatment with a computer randomization algorithm, with 20 cases in each group. Granulated tissue biopsies were collected before(0 day) and 7 days after treatment in both groups. All biopsies were subdivided into two parts. One part was preserved in 4% paraformaldehyde for HE staining, Masson′s trichrome staining and immunocytochemical staining for bFGF expression. Another part was stored at-80 ℃ for Western blotting analysis of bFGF protein expression. Differences between two groups were analyzed by using two-sample t test. Results Compared with control group, the NPWT-treated wounds developed characteristics of granulated tissue, which presented with intense inflammatory cells, fibroblasts and neoformation of vessels. Masson′s trichrome staining showed that the collagen content in the NPWT group was significantly increased compared with that in the control group after treatment(13.4%±5.3%vs 1.1%± 2.6%,t=9.26,P<0.01,α=0.05). The immunohistochemical analysis revealed that the bFGF expression was significantly up-regulated in foot wounds of NPWT-treated groups when compared with that in the control group(0.21 ± 0.06 vs 0.01 ± 0.03,t=12.06,P<0.01,α=0.05). And the protein expression of bFGF in NPWT group with Western blotting analysis was significantly up-regulated when compared with that in the control group (2.30 ± 1.00 vs 0.12 ± 0.07,t=10.43,P<0.01, α=0.05). Conclusion NPWT enhances the bFGF expression in granulation tissue in diabetic foot wound and promotes the wound healing.%目的:探讨创面负压治疗对糖尿病足肉芽组

  3. Fabrication of chondroitin sulfate-chitosan composite artificial extracellular matrix for stabilization of fibroblast growth factor.

    Science.gov (United States)

    Mi, Fwu-Long; Shyu, Shin-Shing; Peng, Chih-Kang; Wu, Yu-Bey; Sung, Hsing-Wen; Wang, Pei-Shan; Huang, Chi-Chuan

    2006-01-01

    The development of a novel, three-dimensional, macroporous artificial extracellular matrix (AECM) based on chondroitin sulfate (ChS)-chitosan (Chito) combination is reported. The composite AECM composed of ChS-Chito conjugated network was prepared by a homogenizing interpolyelectrolyte complex/covalent conjugation technique through co-crosslinked with N,N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide (EDC) and N-hydroxysuccinimide (NHS). In contrast to EDC/NHS, two different reagents, calcium ion and glutaraldehyde, were used to react with ChS or Chito for the preparation of ChS-Chito composites containing crosslinked ChS or Chito network in the matrix. The stability and in vitro enzymatic degradability of the glutaraldehyde-, EDC/NHS-, and Ca2+ -crosslinked ChS-Chito composite AECMs were all investigated in this study. The results showed that crosslinking improved the stability of prepared ChS-Chito AECMs in physiological buffer solution (PBS) and provided superior protective effect against the enzymatic hydrolysis of ChS, compared with their non-crosslinked counterpart. Because ChS was a heparin-like glycosaminoglycan (GAG), the ChS-Chito composite AECMs appeared to promote binding efficiency for basic fibroblast growth factor (bFGF). The bFGF releasing from the ChS-Chito composite AECMs retained its biological activity as examined by the in vitro proliferation of human fibroblast, depending on the crosslinking mode for the preparation of these composite AECMs. Histological assay showed that the EDC/NHS-crosslinked ChS-Chito composite AECM, after incorporated with bFGF, was biodegradable and could result in a significantly enhanced vascularization effect and tissue penetration. These results suggest that the ChS-Chito composite AECMs fabricated in this study may be a promising approach for tissue-engineering application. PMID:16224775

  4. Basic fibroblast growth factor-transfected bone marrow mesenchymal stem cell transplantation for acute kidney injury%碱性成纤维细胞生长因子基因修饰骨髓间充质干细胞移植修复急性肾损伤

    Institute of Scientific and Technical Information of China (English)

    崔利德; 李铁民

    2016-01-01

    BACKGROUND:It has been confirmed that basic fibroblast growth factor (bFGF) can promote the growth, proliferation, differentiation and functional expression of most cels derived from neuroderm and mesoderm. OBJECTIVE:To investigate the effect of bFGF-transfected bone marrow mesenchymal stem cel transplantation in rats with acute kidney injury. METHODS: bFGF genes were transfected into bone marrow mesenchymal stem cels via an adenovirus vector, and then expression of bFGF in transfected cels was identified using RT-PCR technology. Rat models of acute kidney injury were prepared by clipping bilateral renal pedicles, and then randomized into three groups (n=20): rats were given injection of bone marrow mesenchymal stem cel suspensionsvia tail vein as negative transfected group, those given injection of bFGF-transfected bone marrow mesenchymal stem cel suspensionsvia tail vein as bFGF-transfected group, and the others given injection of DMEMvia tail vein as model group. Four weeks later, levels of serum creatinine and urea nitrogen were detected, expressions of connective tissue growth factor and growth factor in renal tissues were detected by Western blot assay, and morphology of renal tissues was observed using hematoxylin-eosin staining. RESULTS AND CONCLUSION:bFGF genes were successfuly transfected into bone marrow mesenchymal stem cels. Compared with the model group, the levels of serum creatinine and urea nitrogen were significantly reduced in bFGF-transfected and negative transfected groups, especialy in the bFGF-transfected group (P 0.05). Besides, renal tissues necrosis and inflammatory reactions were mitigated in the negative transfected group; renal tubules with normal outlines and no overt necrotic cels could be found in the bFGF-transfected group. These findings show that bFGF-transfected bone marrow mesenchymal stem cel transplantation plays a better role in acute kidney injury repair in rats.%背景:研究表明,碱性成纤维细胞生长因子对

  5. Expression of fibroblast growth factor-2 and fibroblast growth factor receptor-1 protein in the hippocampus in rats exhibiting chronic stress-induced depression

    Institute of Scientific and Technical Information of China (English)

    Gonglin Hou; Mingming Tang

    2011-01-01

    There is evidence that the expression of members of the fibroblast growth factor (FGF) protein family is altered in post-mortem brains of humans suffering from major depressive disorder. The present study examined whether the expression of fibroblast growth factor-2 (FGF2) and fibroblast growth factor receptor-1 (FGFR1) protein is altered following chronic stress in an animal model. Rats were exposed to 35 days of chronic unpredictable mild stress, and then tested using open-field and sucrose consumption tests. Compared with the control group, rats in the chronic stress group exhibited obvious depressive-like behaviors, including anhedonia, anxiety and decreased mobility. The results of western blot analysis and immunohistochemical analysis revealed a downregulation of the expression of FGF2 and FGFR1 in the hippocampus of rats, particularly in the CA1, CA3 and dentate gyrus. This decreased expression is in accord with the results of post-mortem studies in humans with major depressive disorder. These findings suggest that FGF2 and FGFR1 proteins participate in the pathophysiology of depressive-like behavior, and may play an important role in the mechanism of chronic stress-induced depression.

  6. Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.

    OpenAIRE

    Igarashi, A; Okochi, H; Bradham, D M; Grotendorst, G R

    1993-01-01

    Connective tissue growth factor (CTGF) is a cysteine-rich peptide that exhibits platelet-derived growth factor (PDGF)-like biological and immunological activities. CTGF is a member of a family of peptides that include serum-induced immediate early gene products, a v-src-induced peptide, and a putative avian transforming gene, nov. In the present study, we demonstrate that human foreskin fibroblasts produce high levels of CTGF mRNA and protein after activation with transforming growth factor b...

  7. Altered nerve growth factor in fibroblasts from patients with familial dysautonomia.

    OpenAIRE

    Schwartz, J P; Breakefield, X O

    1980-01-01

    Nerve growth factor was measured in cultured human skin fibroblasts from controls and from patients with familial dysautonomia and dystonia musculoram deformans. Cells from these sources grown over a range of cell densities contained similar levels of beta-nerve growth factor as measured by radioimmunoassay. Results of bioassay demonstrated that the nerve growth factor from dysautonomic cells was only approximately 10% as active per ng of immunoreactive protein as that from control and dyston...

  8. Cyclical cell stretching of skin-derived fibroblasts downregulates connective tissue growth factor (CTGF) production.

    Science.gov (United States)

    Kanazawa, Yuichiro; Nomura, Jun; Yoshimoto, Shinya; Suzuki, Toshikazu; Kita, Kazuko; Suzuki, Nobuo; Ichinose, Masaharu

    2009-01-01

    Delayed healing of skin wounds can be caused by wound instability, whereas appropriate massage or exercise prevents sclerosis and scar contracture. However, the mechanism by which wound healing is related to mechanical stress has not been fully elucidated. The present study aimed to identify whether mechanical stretching of fibroblasts reduces their production of extracellular matrix. We transferred skin fibroblasts into collagen-coated elastic silicone chambers, cultured them on a stretching apparatus, and used RT-PCR to examine the effects of mechanical stretching on the expression levels of 17 genes related to extracellular matrix production and growth factor secretion. We found that connective tissue growth factor (CTGF) was downregulated after 24 hr of cell stretching. Specifically, the CTGF mRNA and protein levels were 50% and 48% of the control levels, respectively. These findings suggest that cyclic stretching of fibroblasts contributes to anti-fibrotic processes by reducing CTGF production.

  9. Dupuytren's disease: comparative growth dynamics and morphology between cultured myofibroblasts (nodule) and fibroblasts (cord).

    Science.gov (United States)

    Vande Berg, J S; Gelberman, R H; Rudolph, R; Johnson, D; Sicurello, P

    1984-01-01

    The excised palmar fascia of 11 patients with Dupuytren's disease was separated clinically into nodules and cords. Myofibroblasts were seen by light and electron microscopy in each of the nodules, but the cords generally lacked myofibroblasts. Only one cord specimen had microscopic features that were intermediate between nodule and cord. Electron microscopy demonstrated that in vivo differences between myofibroblasts from nodules and fibroblasts from cords and control skin samples could be preserved in vitro. Growth studies showed slower growth of cultured myofibroblasts (mean +/- SD generation time 68.7 +/- 15 h) than cord-derived fibroblasts (mean +/- SD generation time 51.5 +/- 0.9 h). These data suggest that the life cycle of the myofibroblasts from Dupuytren's disease nodules differs from that of fibroblasts found in cordlike tissues. These myofibroblasts have biological characteristics nearly identical to those of myofibroblasts found in other contracting tissues, such as granulating wounds and breast cancer.

  10. Radioprotection of hematopoietic tissue by fibroblast growth factors in fractionated radiation experiments

    International Nuclear Information System (INIS)

    Acidic and basic fibroblast growth factors (FGF1/2) myeloprotect mice in single dose total body irradiation (TBI) experiments with a dose modification factor (DMF) of ∼1.15. CFU-C assay suggests that one of the mechanisms is augmentation of the shoulder of the radiation dose response curve, and thus protection could be greater with fractionation. Four equal fractions of TBI were delivered to C3H/He mice at times 0 h, 8 h, 24 h, and 32 h. FGF1/2 dose was 3 μg per IV injection given 24 and 4 hrs before the first radiation dose. FGF2 treated mice had a significant survival advantage over saline-treated mice with a DMF of 1.22±0.07 (p2, had no additional benefit on LD50/30 (dose of radiation lethal to 50% of animals measured at day 30) (DMF=1.23±0.06, p1 was not as effective with fractionation (DMF=1.04±0.03). Increased survival in FGF2 treated mice was due to the a more rapid recovery of bone marrow hematopoietic cells and peripheral WBC, RBC and platelets. FGF2 may prove a useful treatment response modifier in clinical fractionated irradiation. (orig.)

  11. 碱性成纤维细胞生长因子缓释微球促进神经干细胞生长的体外实验研究%Promotion role of basic fibroblast growth factor slow-release microsphere in neural stem cells proliferation in vitro

    Institute of Scientific and Technical Information of China (English)

    薛杉; 吴钢; 祝爱萍; 郭燕舞; 汪求精; 周振军; 姜晓丹; 柯以铨; 全大萍

    2013-01-01

    Objective To prepare a kind ofmicrosphere being able to load and slowly release basic fibroblast growth factor (bFGF).Methods The bFGF-sustained release microspheres were established and their in vitro release process was detected.The bFGF sustained release microspheres and neural stem cells were co-cultured as experimental group; neural stem cells added bFGF for several times were chosen as control group.AlamarBlue assay was employed to detect the cell survival; ELISA was used to observe the supematant bFGF content; morphological changes of the cells were observed regularly and nidogen fluorescence immunocytochemical staining was employed to detect the neural stem cell marker.Results AlamarBlue assay showed that the cell survival of the experimental group and control group had significant difference on the 3rd,5th d of culture (P<0.05).ELISA showed that supematant bFGF could only be detected in the experimental group,reaching 200 pg/mL.Cell morphology observation found formation of neural stem cell spheres in the experimental group on the 3rd d of culture,maintaining good transparency and cell activity on the 7th d of culture.Fluorescence immunocytochemistry staining revealed nidogen positive expression in the experimental group.Conclusion The bFGF sustained release microsphere material has no biological toxicity,enjoying good biological compatibility; the slow release ofbFGF can meet the need of neural stem cell growth and keep their cell characteristics of neural stem cells; the bFGF sustained release microspheres is safe and effective,and can be applied to clinical experimental study of central nervous system injury.%目的 制备一种能够负载足量碱性成纤维细胞生长因子(bFGF)并且能够以理想的速度缓慢释放的载体. 方法 构建负载bFGF的缓释微球,并检测其体外释放过程.将bFGF缓释微球与神经干细胞共培养,以常规多次添加bFGF的神经干细胞培养组作为对照,用AlamarBlue法检测培养细胞

  12. Correction of Hypertension by Normalization of Endothelial Levels of Fibroblast Growth Factor and Nitric Oxide Synthase in Spontaneously Hypertensive Rats

    Science.gov (United States)

    Cuevas, Pedro; Garcia-Calvo, Margarita; Carceller, Fernando; Reimers, Diana; Zazo, Mercedes; Cuevas, Begona; Munoz-Willery, Isabel; Martinez-Coso, Victoria; Lamas, Santiago; Gimenez-Gallego, Guillermo

    1996-10-01

    Acidic and basic fibroblast growth factors (FGFs) share a wide range of diverse biological activities. To date, low levels of FGF have not been correlated with a pathophysiologic state. We report that blood vessels of spontaneously hypertensive rats are shown to be associated with a marked decrement in endothelial basic FGF content. This decrement correlates both with hypertension and with a decrease in the endothelial content of nitric oxide synthase. restoration of FGF to physiological levels in the vascular wall, either by systemic administration or by in vivo gene transfer, significantly augmented the number of endothelial cells with positive immunostaining for nitric oxide synthase, corrected hypertension, and ameliorated endothelial-dependent responses to vasoconstrictors. These results suggest an important role for FGFs in blood pressure homeostasis and open new avenues for the understanding of the etiology and treatment of hypertension.

  13. Intraarticular Sprifermin (Recombinant Human Fibroblast Growth Factor 18) in Knee Osteoarthritis

    DEFF Research Database (Denmark)

    Lohmander, L. S.; Hellot, S.; Dreher, D.;

    2014-01-01

    Objective. To evaluate the efficacy and safety of intraarticular sprifermin (recombinant human fibroblast growth factor 18) in the treatment of symptomatic knee osteoarthritis (OA). Methods. The study was a randomized, double-blind, placebo-controlled, proof-of-concept trial. Intraarticular sprif...

  14. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia

    DEFF Research Database (Denmark)

    Imel, Erik A; Peacock, Munro; Pitukcheewanont, Pisit;

    2006-01-01

    Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors...

  15. Common primary fibroblastic growth factor receptor-related craniosynostosis syndromes: A pictorial review

    Directory of Open Access Journals (Sweden)

    Rohit K Singh

    2010-01-01

    Full Text Available Mutations in different types of fibroblastic growth factor receptors (FGFRs have been associated with a variety of phenotype abnormalities, the common ones being Apert, Crouzon and Pfeiffer syndromes. In this study, we present two representative cases having the Apert and Pfeiffer syndromes, respectively, and discuss their clinical presentation, sequel and surgical implications.

  16. Problem-Based Test: The Effect of Fibroblast Growth Factor on Gene Expression

    Science.gov (United States)

    Szeberenyi, Jozsef

    2011-01-01

    This paper shows the results of an experiment in which the effects of fibroblast growth factor (FGF), actinomycin D (Act D; an inhibitor of transcription), and cycloheximide (CHX; an inhibitor of translation) were studied on the expression of two genes: a gene called "Fnk" and the gene coding for glyceraldehyde-3-phosphate dehydrogenase (GAPDH).…

  17. Nectin-1 binds and signals through the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Bojesen, Kirsten Borup; Clausen, Ole; Rohde, Kristian;

    2012-01-01

    protein and induced neurite outgrowth in primary cultures of hippocampal and cerebellar granule neurons, an effect abolished by treatment with the fibroblast growth factor receptor (FGFR) inhibitor SU5402, or by transfection with a dominant-negative FGFR1 construct. We showed by surface plasmon resonance...

  18. Fibroblast growth factor 23 in hypophosphataemic HIV-positive adults on tenofovir

    NARCIS (Netherlands)

    Bech, A.; Bentum, P. van; Nabbe, K.; Gisolf, J.; Richter, C.; Boer, H. de

    2012-01-01

    OBJECTIVES: Hypophosphataemia is common in HIV-positive patients, in particular in those using tenofovir disoproxil fumarate (TDF). Its pathogenesis is not well understood. The importance of fibroblast growth factor 23 (FGF-23), the most potent phosphaturic hormone known today, has not been studied

  19. Neuritogenic and neuroprotective properties of peptide agonists of the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Li, Shizhong; Bock, Elisabeth Marianne; Berezin, Vladimir

    2010-01-01

    Fibroblast growth factor receptors (FGFRs) interact with their cognate ligands, FGFs, and with a number of cell adhesion molecules (CAMs), such as the neural cell adhesion molecule (NCAM), mediating a wide range of events during the development and maintenance of the nervous system. Determination...... developed functional peptide agonists of FGFR with possible therapeutic potential....

  20. The influence of different nanostructured scaffolds on fibroblast growth

    Directory of Open Access Journals (Sweden)

    I-Cheng Chung, Ching-Wen Li and Gou-Jen Wang

    2013-01-01

    Full Text Available Skin serves as a protective barrier, modulating body temperature and waste discharge. It is therefore desirable to be able to repair any damage that occurs to the skin as soon as possible. In this study, we demonstrate a relatively easy and cost-effective method for the fabrication of nanostructured scaffolds, to shorten the time taken for a wound to heal. Various scaffolds consisting of nanohemisphere arrays of poly(lactic-co-glycolic acid (PLGA, polylactide and chitosan were fabricated by casting using a nickel (Ni replica mold. The Ni replica mold is electroformed using the highly ordered nanohemisphere array of the barrier-layer surface of an anodic aluminum oxide membrane as the template. Mouse fibroblast cells (L929s were cultured on the nanostructured polymer scaffolds to investigate the effect of these different nanohemisphere arrays on cell proliferation. The concentration of collagen type I on each scaffold was then measured through enzyme-linked immunosorbent assay to find the most effective scaffold for shortening the wound-healing process. The experimental data indicate that the proliferation of L929 is superior when a nanostructured PLGA scaffold with a feature size of 118 nm is utilized.

  1. Effects of recombinant basic fibroblast growth factor on transplanted fat grafts in different delivery systems%不同缓释体系下基因重组型碱性成纤维细胞生长因子对脂肪移植终体积的影响

    Institute of Scientific and Technical Information of China (English)

    伍俊妍; 李国成; 蔡尤彪

    2009-01-01

    AIM To study the effects of recombinant basic fibroblast growth factor (bFGF) on transplanted fat grafts in different delivery systems and the possibility of adopting bioactive fat transplantation technique in clinical practice. METHODS Dextran beads and agar beads were soaked in 2 mg · L~(-1) bFGF solution and 0.9% sodium chloride solution, respectively. Four different fat graft compositions were created and subcutaneous injected into the SD rats back in different experimental groups: Group A, free fat alone; Group B, free fat with dextran beads previously soaked in 0.9% sodium chloride solution (10 : 1, V/V); Group C, free fat with dextran beads presoaked in 2 mg· L~(-1) bFGF sloution (10 : 1, V/V); Group D, free fat with agar beads presoaked in 0.9% sodium chloride solution (10 : 1, V/V) ; Group E, free fat with agar beads presoaked in 2 mg· L~(-1) bFGF (10 : 1, V/V) . The grafts were assessed by volume at 24 wk postoperatively and histology at different intervals. Revascularization of free fat grafts and bioactive free fat grafts were compared and evaluated with the techniques of microangiography, section observation, and gross observation. RESULTS The largest graft volume maintained the volume of (1.50 ± s 0.24) mL in group C, which was statistically different from group A, B, D and E (P < 0.05). Group A, B, D and E maintained (0.87 ± s 0.24), (0.86 ± 0.29), (0.8 ± 0.3), and (0.8 ± 0.3) mL, respectively, with no significance among the four groups (P > 0.05) . CONCLUSION Recombinant bFGF delivered by dextran beads may improve the graft volume retention to a certain extent whereas bFGF delivered by agar beads dose not show the same effect.%目的 研究基因重组型碱性成纤维细胞生长因子(bFGF)的不同缓释体系对脂肪移植终体积的影响.方法 分别以葡聚糖颗粒及琼脂粉浸泡2 mg·L~(-1)浓度的bFGF生理盐水溶液制成缓释颗粒,并以上述2种载体以同法浸泡0.9%生理盐水制

  2. Delivery of basic fibroblast growth factor gene to healing tendon by adeno-associated virus 2 vector and tissue reactions of adeno-associated virus vectors%腺相关病毒载体转导基因至愈合肌腱及载体组织反应的研究

    Institute of Scientific and Technical Information of China (English)

    朱蓓; 汤锦波; 曹怡; 陈传好

    2008-01-01

    目的 探讨腺相关病毒(AAV)载体转导碱性成纤维细胞牛长因子(bFGF)基因对肌腱愈合的影响,并观察腺病毒、AAV以及脂质体一质粒三种基因治疗载体应用于肌腱所产生的组织反应.方法 取13只成年白色来亨鸡的双侧巾趾趾深屈肌腱(26根),随机分为实验组和对照组,每组13根,实验组肌腱完全切断后注射AAV2-bFGF并以改良Kessler法修复,对照组不注射AAV2-bFGF,仪以改良Kessler法修复.第4周未行免疫组织化学染色,第8周术测定趾屈曲功.将6只成年新西兰白兔的趾深屈肌腱(36根)分成二组,每组12根,分别注射10μL的腺病毒、AAV2和脂质体.质粒载体,术后第3、7、14天分别取肌腱,进行石蜡切片、HE染色.结果 AAV2-bFGF可以在术后4周显著地提高肌腱bFGF的表达,而且不增加趾屈曲阻力(粘连形成).所测屈曲功第8周末实验组为(0.052±0.031)J,对照组为(0.049±0.035)J,两组问差异无统计学意义(t=0.31266,P=0.8984).脂质体-质粒载体组肌腱组织反廊重于腺病毒载体组,AAV2载体组肌腱组织反应最轻,在腱外膜处有组织反应,而腱内膜区域几乎无组织反应.结论 用AAV2载体转bFGF基因至肌腱能有效增加愈合肌腱的bFGF.在三种所研究的载体中,腺病毒和AAV2载体引起的组织反应比脂质体.质粒载体轻.AAV2引起的组织反应最轻.AAV2可能会成为肌腱的转基因良好载体.%Objective To explore the effect of basic fibroblast growth factor (bFGF) gene transferred by adeno-associated virus (AAV) 2 vectors on tendon healing and to observe tissue reactions of adenovirus, AAV and liposome-plasmid vectors in tendons, Methods Twenty-six flexor digitorum profundus (FDP) tendons from bilateral long toes of 13 chickens were randomly divided into equal 2 groups. Tendons in the experimental group were cut completely and treated with AAV2-bFGF before repair by the modified Kessler method. Tendons as controls were not treated with

  3. PROTEOMICS STUDY ON EFFECT OF BASIC FIBROBLAST GROWTH FACTOR LONG CIRCULATION LIPOSOME ON SPINAL CORD TRACTION INJURY IN RATS%bFGF长循环脂质体对大鼠脊髓牵张性损伤影响的蛋白质组学研究

    Institute of Scientific and Technical Information of China (English)

    王文岳; 杨天府; 刘雷; 裴福兴

    2014-01-01

    目的 从蛋白质组学方面探讨bFGF长循环脂质体对大鼠脊髓牵张性损伤神经保护作用的可能机制.方法 取20只SD大鼠随机分为脊髓牵张性损伤模型组(A组)和bFGF长循环脂质体治疗组(B组),每组10只.术后3周取材行脊髓组织蛋白的提取制备及定量;应用双向凝胶电泳对两组脊髓组织样品进行分离,建立差异表达图谱,通过凝胶成像分析和人工比对,分别确定差异蛋白点,采用超高效纳升液相色谱-电喷雾串联质谱(nano ultra-high performance liquid chromatography-electrospray tandem mass spectrometry,NanoUPLC-ESI-MS/MS)技术鉴定差异蛋白,检索数据库,对差异蛋白分类.结果 两组间找到完全相同的差异蛋白点,B组与A组相比,得到差异蛋白点10个,其中6个下调,4个上调.采用NanoUPLC-ESI-MS/MS技术鉴定了26个差异蛋白点,共鉴定出18种有意义的蛋白;其中与凋亡相关的蛋白4种,神经传导和信号转导相关的蛋白3种,参与代谢的蛋白7种,1种功能不明,未知蛋白3种.结论 bFGF长循环脂质体影响了大鼠牵张性脊髓损伤组织的蛋白质组表达,其对损伤脊髓的保护及修复作用可能是通过神经信号转导、调节细胞凋亡及细胞代谢等途径实现.%Objective To explore the possible active mechanism of the basic fibroblast growth factor (bFGF) long circulation liposome (LCL) (bFGF + LCL) on spinal cord traction injury in rats at the level ofproteomics.Methods Twenty Sprague Dawly rats were randomly divided into groups A and B,10 rats in each group.The models of spinal cord traction injury was established at T12-L3 spines.The rats were not treated in group A,and the rats were treated with bFGF + LCL (20 μg/kg) in group B.At 3 weeks after operation,the rats were sacrificed for harvesting T13-L2 spinal tissue specimens.The protein was extracted and quantified in the spinal tissue firstly.The proteins from spinal tissue were separated by two-dimensional gel

  4. 联合bFGF的负压创面治疗技术在难治性压力性溃疡治疗中的应用%Clinical observations of negative pressure wound therapy and basic fibroblast growth factor in the treatment of intractable pressure ulcer

    Institute of Scientific and Technical Information of China (English)

    张诚; 杨金存; 冯永强; 王海涛; 李霞; 陈宁杰

    2012-01-01

    Objective To observe the clinical efficacies and costs of negative pressure wound therapy (NPWT) and basic fibroblast growth factor (bFGF) in the treatment of stage Ⅲ or Ⅳ pressure ulcer (PU).Methods From July 2008 to December 2011,48 patients fulfilling the study inclusion or exclusion criteria at Weihai Municipal Hospital were divided randomly into experiment and control groups (n =24 each).On the basis of routine treatment and NPWT of each inpatient,the patients in the experiment group were treated with bFGF.The changes of healing rate of PU were measured at Days 7 and 14 post-treatment in each group.Meanwhile,the granulation duration,preoperative time and total preoperative cost were compared.Results The granulation duration,healing rate of Days 7 and 14,preoperative time and total preoperative cost in the experiment group was (10.8 ± 2.7) days,10.1% ± 2.9%,22.3% ± 3.1%,(18.2±2.6) days and (7946±245) yuan RMB versus (16.3±3.9) days,6.9% ±1.9%,13.4% ± 2.8%,(27.1 ± 3.3) days and (10 951 ± 285) yuan RMB in the control group respectively.The differences between two groups were statistically significant (all P < 0.01).Conclusion As a preoperative therapeutic modality of intractable PU,NPWT and bFGF offer better therapeutic efficacies and lower therapeutic costs as compared with NPWT alone.%目的 观察联合碱性成纤维细胞生长因子(bFGF)的负压创面治疗(NPWT)技术在难治性压力性溃疡创面治疗中的应用.方法 将2008年7月至2011年12月大连医科大学附属威海市立医院收治的48例符合入选标准的难治性压力性溃疡患者随机分成试验组和对照组,每组24例.除常规治疗外,试验组应用NPWT联合bFGF进行治疗,对照组应用NPWT进行治疗.治疗期间定期测量溃疡大小,比较两组创面肉芽形成时间及治疗后第7、14天的创面缩小率、术前创面处理时间、术前治疗费用.结果 试验组的肉芽形成时间、治疗后第7、14天的创

  5. 乙酰肝素酶、碱性成纤维细胞生长因子的表达与子宫内膜癌浸润、转移及预后的关系%Relationship between expressions of heparanase and basic fibroblast growth factor and invasion, metastasis and prognosis of endometrial carcinoma

    Institute of Scientific and Technical Information of China (English)

    毕冬华

    2012-01-01

    目的:探讨乙酰肝素酶、碱性成纤维细胞生长因子的表达与子宫内膜癌浸润、转移及预后的关系.方法:选择2008年3月~2010年10月期间,在该院切除并存档的子宫内膜癌患者子宫内膜石蜡包埋组织标本48例作为研究组,另选同期该院妇产科收治的其他疾病患者,手术切除或刮宫的子宫内膜标本34例作为比较组,及正常子宫内膜21例作为对照组,分别比较分析Hpa和bFGF的染色强度及表达阳性率.结果:与FIGO Ⅰ期相比,Ⅱ期和Ⅲ期患者Hpa和bFGF的阳性率明显提高;与G1分化相比,G2分化患者Hpa和bFGF的阳性率明显提高;与无肌层浸润相比,肌层浸润浅部和深部患者Hpa和bFGF的阳性率明显提高,差异均具有统计学意义(P<0.05);与对照组患者相比,比较组患者和研究组患者的Hpa和bFGF阳性率均明显提高,差异均具有统计学意义(P<0.05),且研究组的阳性率高于比较组.结论:乙酰肝素酶和碱性成纤维细胞生长因子的表达与子宫内膜癌浸润、转移、预后密切相关,并且有望成为子宫内膜癌联合诊断和病情评估以及疗效观察和预后预测的重要检测指标,同时也可能为子宫内膜癌的治疗提供一种更为有效的解决方案.%Objective; To explore the relationship between expressions of heparanase (Hpa) and basic fibroblast growth factor ( bF-GF) and invasion, metastasis and prognosis of endometrial cancer. Methods: Four - eight paraffin - embeded endometrial samples from the patients with endometrial cancer who received surgery and were recorded in the hospital from March 2008 to October 2010 were selected as study group, while 34 paraffin -embeded endometrial samples from the patients with other endometrial diseases who received surgery and u-terine curettage in the hospital during the same period were selected as comparison group, 21 normal paraffin - embeded endometrial samples were selected as control group; the staining

  6. Angiogenic effect of basic fibroblast growth factor on anterior cruciate ligament reconstruction with freeze-dried tendon implants at early stage: A histological observation%碱性成纤维细胞生长因子促进冻干肌腱移植重建前交叉韧带的早期血管生成:组织学表现

    Institute of Scientific and Technical Information of China (English)

    张春礼; 徐虎; 范宏斌; 郑佳鹏; 陈戎波

    2008-01-01

    背景:以往实验已证实碱性成纤维细胞生长因子在体内外均有促新生血管形成的作用.冻干法可以减低移植物的抗原性,经冻干处理后的移植物保存时间长并且运输方便,更容易商品化.冻干肌腱补充活性细胞生长因子有望加速新血管的牛成.目的:拟验证碱性成纤维细胞生长因子促进冻干肌腱移植重建前交叉韧带后早期血管的生成作用.设计、时间及地点:对照观察动物实验,于2006-06/20017-06在解放军第四军医大学西京医院骨科研究所完成.材料:选用健康成年家犬14只.方法:取2只犬,无菌手术取其双下肢伸趾长肌腱16条,冻干处理后供实验用.将其余12只犬左、右侧膝关节分别移植单纯冻干肌腱和复合100 u g/L碱性成纤维细胞生长因子后冻干肌腱重建前交叉韧带.主要观察指标:分别于移植后1, 2,3,4,5,6 周取材,每次取2只.进行苏木精-伊红染色,通过图像分析仪定性观察新生血管的生成情况.结果:复合碱性成纤维细胞生长因子冻干肌腱组移植后两三周出现新生血管,四五周达到高峰;单纯冻干肌腱组移植后四五周出现新生血管.复合碱性成纤维细胞生长因子冻干肌腱组新血管长入肌腱的时间先于对照组,深度深于对照组.结论:复合100 u g/L碱性成纤维细胞生长因子的冻干肌腱移植重建前交叉韧带后,在新血管形成的时间及长入肌腱的深度方面均优于单纯冻干肌腱.%BACKGROUND: Based on previous studies, the combination of basic fibroblast growth factor (bFGF) with graft may accelerate the procedure of vascular invasion of anterior cruciate ligament (ACL) graft. The antigenicity of graft could be inhibited by the destruction of major histolocompatibility complex (MHC) through the treatment of allogenous tendon by freeze. The freeze. dried tendon showed advantages including prolonged storage time. availability for transport and possibility of

  7. Nicotine stimulates nerve growth factor in lung fibroblasts through an NFκB-dependent mechanism.

    Directory of Open Access Journals (Sweden)

    Cherry Wongtrakool

    Full Text Available Airway hyperresponsiveness (AHR is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF secretion into the environment.Primary lung fibroblasts isolated from wild type and α7 nicotinic acetylcholine receptor (α7 nAChR deficient mice were treated with nicotine (50 µg/ml in vitro for 72 hours. NGF levels were measured in culture media and in bronchoalveolar lavage (BAL fluid from asthmatic, smoking and non-smoking subjects by ELISA. The role of the NFκB pathway in nicotine-induced NGF expression was investigated by measuring NFκB nuclear translocation, transcriptional activity, chromatin immunoprecipitation assays, and si-p65 NFκB knockdown. The ability of nicotine to stimulate a fibroblast-mediated, contractile ASM cell phenotype was confirmed by examining expression of contractile proteins in ASM cells cultured with fibroblast-conditioned media or BAL fluid.NGF levels were elevated in the bronchoalveolar lavage fluid of nicotine-exposed mice, current smokers, and asthmatic children. Nicotine increased NGF secretion in lung fibroblasts in vitro in a dose-dependent manner and stimulated NFκB nuclear translocation, p65 binding to the NGF promoter, and NFκB transcriptional activity. These responses were attenuated in α7 nAChR deficient fibroblasts and in wild type fibroblasts following NFκB inhibition. Nicotine-treated, fibroblast-conditioned media increased expression of contractile proteins in ASM cells.Nicotine stimulates NGF release by lung fibroblasts through α7 nAChR and NFκB dependent pathways. These novel findings

  8. Fibroblast Growth Factor Receptor Signaling in Oligodendrocytes Regulates Myelin Sheath Thickness

    OpenAIRE

    Furusho, M.; Dupree, J. L.; Nave, K-A; Bansal, R.

    2012-01-01

    Formation of the central nervous system (CNS) white matter is developmentally tightly regulated, but the molecules and mechanisms of myelination control in the postnatal CNS are poorly understood. Here, we show that myelin growth is controlled by Fibroblast Growth Factor (FGF) signaling, originally identified as a proliferative signal for oligodendrocyte precursor cells (OPC) in vitro. We created two lines of mice lacking both FGF-receptor 1 (Fgfr1) and Fgfr2 in oligodendrocyte lineage cells ...

  9. Influence of basic fibroblast growth factor on protein kinase B activity in Bel- 7402 cells%碱性成纤维细胞生长因子对人肝癌细胞蛋白激酶B活性的影响

    Institute of Scientific and Technical Information of China (English)

    孙波; 颜鑫; 李文超; 陈剑峰; 朱海峰

    2012-01-01

    目的 探讨碱性成纤维细胞生长因子(fibroblast growth factor,FGF)对人肝癌细胞(BEL - 7402)蛋白激酶B(protein kinase B,PKB)活性的影响.方法 以碱性FGF(b FGF)和wortmannin处理人肝癌细胞(BEL - 7402),Western blot检测细胞外信号调节蛋白激酶B的活性.结果 25 ng/ml bFGF刺激人肝癌细胞(BEL - 7402)10 min,细胞膜和胞质PKB酶活性达高峰.Wortmannin预处理后,人肝癌细胞(Bel - 7402)细胞膜和胞质PKB活性在各时间点均明显降低.结论 bFGF能通过磷脂酰肌醇3-激酶(phosphatidylinositol3 - kinase,PI3K)途径迅速激活人肝癌细胞(BEL -7402)的PKB活性.

  10. A comparison of the effect of epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor on rat periodontal ligament fibroblast-like cells' DNA synthesis and morphology

    DEFF Research Database (Denmark)

    Blom, S; Holmstrup, P; Dabelsteen, Erik

    1994-01-01

    An enhanced formation of bone, dentin, and collagen fibers in periodontal wounds after application of polypeptide growth factors has recently been reported. However, the complex environment in vivo makes it impossible to determine the specific effects of growth factors on various cells involved...... in the wound-healing process. We have therefore investigated the mitogenic and morphogenic effects of recombinant epidermal growth factor (rEGF), natural platelet-derived growth factor (nPDGF), and natural fibroblast growth factor (nFGF) on periodontal ligament fibroblast-like cells. A cell line...... was established from rat PDL tissue. The cell line was characterized according to morphology, growth pattern, cytoskeletal proteins, and growth kinetics. The mitogenic effect of growth factors was assessed by incorporation of [3H]thymidine in the cellular DNA for 4 hours. Differences between groups...

  11. Construction and identification of recombinant human basic fibroblast growth factor expression vector for lactic acid bacteria%乳酸菌重组人碱性成纤维生长因子表达载体的构建及鉴定

    Institute of Scientific and Technical Information of China (English)

    蒋永洪; 陈科全; 陈学清

    2016-01-01

    [Abstract] Objective To explore a new way for the oral treatment of inflammatory bowel disease by constructing the recombinant human basic fibroblast protein expression vector. Methods The Ptuf promoter, pePN terminator, USP45 and bFGF were spliced by fusion PCR technology. The full-length constructed cDNA fragment was cloned into pBlueScript vector, as well as the pTRKH2 vector after identification. Results DNA sequencing and double enzyme digestion results showed that the expression vector pTR-bFGF was successful-l y constructed. Conclusion The pTR-bFGF plasmid laid a foundation for expression of bFGF in lactobacillus and oral treatment of inflammatory bowel disease.%目的构建乳酸菌重组人碱性成纤维蛋白表达载体,为口服治疗炎症性肠病探索新途径。方法利用融合PCR技术,将Ptuf启动子及pePN终止子与USP45-bFGF融合,构建全长片段后克隆于pbluescript载体中,经验证后亚克隆于pTRKH2载体中。结果双酶切及DNA测序结果证实成功构建乳酸菌表达载体pTR-bFGF。结论乳酸菌表达载体pTR-bFGF为实现bFGF在乳酸菌表达及口服治疗炎症性肠病奠定了基础。

  12. Structure of rat acidic fibroblast growth factor at 1.4 Å resolution

    International Nuclear Information System (INIS)

    The structure of rat acidic fibroblast growth factor was determined and compared with those of human, bovine and newt origin. The rat and human structures were found to be very similar. Fibroblast growth factors (FGFs) constitute a family of 22 structurally related heparin-binding polypeptides that are involved in the regulation of cell growth, survival, differentiation and migration. Here, a 1.4 Å resolution X-ray structure of rat FGF1 is presented. Two molecules are present in the asymmetric unit of the crystal and they coordinate a total of five sulfate ions. The structures of human, bovine and newt FGF1 have been published previously. Human and rat FGF1 are found to have very similar structures

  13. Autocrine and paracrine actions of intestinal fibroblast-derived insulin-like growth factors.

    Science.gov (United States)

    Simmons, J G; Pucilowska, J B; Lund, P K

    1999-04-01

    Paracrine and autocrine actions of the insulin-like growth factors (IGFs) are inferred by local expression within the bowel. CCD-18Co cells, IEC-6 cells, and immunoneutralization were used to analyze whether IGFs have direct autocrine or paracrine effects on proliferation of cultured intestinal fibroblasts and epithelial cells. Growth factor expression was analyzed by ribonuclease protection assay and RT-PCR. Extracellular matrix (ECM) was analyzed for effects on cell proliferation. CCD-18Co cells express IGF-II mRNAs and low levels of IGF-I mRNA. Conditioned medium from CCD-18Co cells (CCD-CM) stimulated proliferation of IEC-6 and CCD-18Co cells. Neutralization of IGF immunoreactivity in CCD-CM reduced but did not abolish this effect. RT-PCR and immunoneutralization demonstrated that other growth factors contribute to mitogenic activity of CCD-CM. Preincubation of CCD-CM with ECM prepared from IEC-6 or CCD-18Co cells reduced its mitogenic activity. ECM from CCD-18Co cells enhanced growth factor-dependent proliferation of IEC-6 cells. IEC-6 cell ECM inhibited IGF-I action on CCD-18Co cells. We conclude that IGF-II is a potent autocrine mitogen for intestinal fibroblasts. IGF-II interacts with other fibroblast-derived growth factors and ECM to stimulate proliferation of intestinal epithelial cells in a paracrine manner. PMID:10198323

  14. Effects of growth factors on the proliferation of human keratinocytes and fibroblasts in vitro.

    Science.gov (United States)

    Kim, D S; Korting, H C; Schäfer-Korting, M

    1998-01-01

    Growth/differentiation factor-5 (GDF-5) is a new member of the transforming growth factor-beta (TGF-beta) superfamily of multifunctional peptide growth factors that appear to mediate many key events in cell growth and development. The effects of GDF-5 and other growth factors (epidermal growth factor, EGF; TGF-beta 1) on the proliferation of human keratinocytes and fibroblasts compared with desoximetasone and calcipotriol have been investigated. The proliferation rate was determined by a hemocytometer, MTT assay and the incorporation of [3H]-thymidine. Moreover, cell cycle analyses were performed and the influence on interleukin-1 alpha (IL-1 alpha) production in keratinocytes was measured by enzyme-linked immunosorbent assay (ELISA) because of its pronounced proinflammatory effect. In keratinocytes, GDF-5 stimulated cell proliferation to a minor extent. The drug already proved to be effective at very low concentrations (0.1 ng/ml). Growth stimulatory effects with EGF have been observed only in keratinocyte basal medium (KBM), but not in keratinocyte growth medium (KGM). TGF-beta 1 markedly inhibited the proliferation of keratinocytes at concentrations > 1 ng/ml. Calcipotriol and desoximetasone also showed a dose-dependent cell growth inhibition in epidermal cell cultures. IL-1 alpha synthesis was greatly suppressed by calcipotriol 10(-8)-10(-6) M. EGF at 10 ng/ml, in contrast, strongly stimulated IL-1 alpha production. Neither GDF-5 nor TGF-beta 1 had a significant effect on IL-1 alpha production in keratinocyte monolayer cultures. In fibroblasts, GDF-5 induced very weak antiproliferative effects. Calcipotriol and desoximetasone also inhibited cell growth in fibroblast cultures whereas proliferation and DNA synthesis were strongly stimulated by 1 ng/ml EGF. There was, however, a contradiction between TGF-beta 1 results on fibroblasts. Whereas TGF-beta 1 increased proliferation in cell number determination and in the thymidine incorporation assay, MTT assays showed

  15. Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Schievenbusch, Stephanie; Strack, Ingo; Scheffler, Melanie; Wennhold, Kerstin; Maurer, Julia [Institute for Pathology, University Hospital Cologne, Kerpener Str. 62, 50924 Koeln (Germany); Nischt, Roswitha [Department of Dermatology, University Hospital of Cologne (Germany); Dienes, Hans Peter [Institute for Pathology, University Hospital Cologne, Kerpener Str. 62, 50924 Koeln (Germany); Odenthal, Margarete, E-mail: m.odenthal@uni-koeln.de [Institute for Pathology, University Hospital Cologne, Kerpener Str. 62, 50924 Koeln (Germany)

    2009-07-17

    Hepatocyte growth factor (HGF) is a multifunctional growth factor affecting cell proliferation and differentiation. Due to its mitogenic potential, HGF plays an important role in tubular repair and regeneration after acute renal injury. However, recent reports have shown that HGF also acts as an anti-inflammatory and anti-fibrotic factor, affecting various cell types such as renal fibroblasts and triggering tubulointerstitial fibrosis of the kidney. The present study provides evidence that HGF stimulation of renal fibroblasts results in the activation of both the Erk1/2 and the Akt pathways. As previously shown, Erk1/2 phosphorylation results in Smad-linker phosphorylation, thereby antagonizing cellular signals induced by TGF{beta}. By siRNA mediated silencing of the Erk1/2-Smad linkage, however, we now demonstrate that Akt signaling acts as an auxiliary pathway responsible for the anti-fibrotic effects of HGF. In order to define the anti-fibrotic function of HGF we performed comprehensive expression profiling of HGF-stimulated renal fibroblasts by microarray hybridization. Functional cluster analyses and quantitative PCR assays indicate that the HGF-stimulated pathways transfer the anti-fibrotic effects in renal interstitial fibroblasts by reducing expression of extracellular matrix proteins, various chemokines, and members of the CCN family.

  16. 碱性成纤维细胞生长因子单克隆抗体通过P-糖蛋白逆转乳腺癌MCF-7/ADM细胞多药耐药性的分子机制%Molecular mechanism of reversal effect of monoclonal antibody to basic fibroblast growth factor-mediated expression of P-glycoprotein on multiple drug resistance in adriamycin-resistant human breast cancer cell line MCF-7/ADM

    Institute of Scientific and Technical Information of China (English)

    陈文慧; 徐萌; 杜超超; 赵建夫; 潘兰红; 李汉初; 向军俭; 邓宁

    2013-01-01

    Objective: To investigate the mechanism of reversal effect of bFGF mAb (monoclonal antibody to basic fibroblast growth factor)-mediated expression of P-gp (permeability glycoprotein) on MDR (multidrug resistance) in ADM (adriamycin)-resistant human breast cancer cell line MCF-7/ADM. Methods: The effects of bFGF mAb on the proliferation of MCF-7/ADM cells and the reversal of MDR were detected by CCK-8 (cell counting kit-8) method. The cell cycle distribution of MCF-7/ADM cells and the expression of P-gp and intracellular fluorescence intensity of Rho123 (rhodamine 123) in MCF-7/ADM cells after bFGF mAb intervention were analyzed by flow cytometry. The expressions of MDR 1 (multidrug resistance protein 1) and bFGF mRNAs in MCF-7/ADM cells were examined by real-time fluorescence quantitative PCR. Results: The growth inhibition rates of MCF-7 cells and MCF-7/ADM cells after treatment with 1 μj/mL bFGF mAb were (1 9.87+1.05)% and (27.34±2.79)% (P < 0.01). bFGF mAb intervention could reverse ADM-, GEM (gemcitabine)- and OXA (oxaliplatin)-resistance of MCF-7/ADM cells, and the corresponding reversal index were 4.46, 4.25 and 2.18, respectively. As compared with the MCF-7/ADM cells without bFGF mAb intervention, the cell cycle of MCF-7/ADM cells after bFGF mAb intervention was arrested at G0/G1 phase, the expression level of P-gp was down-regulated, the intracellular Rho123 fluorescence intensity was increased, and the expression levels of MDR 1 and bFGF mRNAs were both decreased (P < 0.01). Conclusion: bFGF mAb can inhibit the proliferation of MCF-7/ADM and reverse MDR. This mechanism may be related to down-regulation of the expression levels of MDR 1 and P-gp, inhibition of the function of P-gp, and increasement of intracellular concentration of chemotherapeutic drugs.%目的:探讨碱性成纤维细胞生长因子单克隆抗体(monoclonal antibody to basic fibroblast growth factor,bFGF mAb)通过P-糖蛋白(permeability glycoprotein,P-gp)对人乳腺癌多柔比

  17. 基因枪转人碱性成纤维细胞生长因子基因促进深Ⅱ度烧伤创面的愈合%Gene gun-delivered human basic fibroblast growth factor gene facilitates the healing of deep partial thickness burn wounds

    Institute of Scientific and Technical Information of China (English)

    常菲; 吴杭庆; 张毅; 张望; 杨长伟; 夏照帆; 路卫

    2009-01-01

    烧伤创面愈合进程.%BACKGROUND: A large amount of in vivo and in vitro experiments have confirmed that, basic fibroblast growth factor (bFGF) has been widely utilized in various tissues and cells, it can facilitate the wound healing.OBJECTIVE: To observe the efficacy and feasibility of gene gun-mediate delivery of human bFGF on the healing of deep partial thickness bum wounds.DESIGN, TIME AND SETTING: Randomized design,an observational trial was performed at the Military Central Laboratory of Changhai Hospital in the Second Military Medical University of Chinese PLA between December 2007 and October 2008.MATERIALS: SD rats of clean grade, weighing 200-250 g, irrespective of genders, ware involved in this study.METHODS: Natural human bFGF gene was recombined and optimized, then eukaryotic expression vector pCI-neo-bFGF was constructed taking pCI-neo as a vector, and transfeoted with human embryonic kidney cells 293 T cells. Dot blot and Western blot methods were utilized to determine the bFGF expression. Rat model of deep partial thickness burn wounds was processed into transgene process using gene gun technique, pCI-neo-bFGF-transfected ones served as experiment group while pCI-neo-transfected ones served as controls.MAIN OUTCOME MEASURES:Wound healing time was recorded and the efficacy was evaluated. The contents of hydroxyproline and collaganase Ⅰ in burn wound tissues were determined at 24 hours, 48 hours, 96 hours, 7 days, 10 days and 14 days following transgene process.RESULTS: the recombinant pCI-neo-bFGF was transfected with human embryonic kidney 293T cells. Dot blot and Western blot analysis have showed that, the constructed pCI-neo-bFGF expression vector could express human bFGF, and the expression of synthesized gene was remarkably higher than that of natural gene under fluorescence microscope; gene gun-mediated transgene experiment have showed that, the wound healing time was (13.00+1.31) days in the experiment group and (14.75±1.28) days in the control group, with significant

  18. Targeting of Interferon Gamma to Stromal Fibroblasts Using a PDGF Receptor Recognizing Carrier Reduces Tumour Growth in Vivo

    NARCIS (Netherlands)

    Prakash, J.; Bansal, R.; Tomar, T.; Ostman, A.; Poelstra, K.

    2011-01-01

    Background: Stromal fibroblasts are the key cell types in tumour stroma, that support angiogenesis, tumour cell proliferation and metastasis. Therefore, inhibition of stromal fibroblasts activity might inhibit tumour growth. Interferon gamma (IFNγ) is a potent cytokine and has been used for the trea

  19. Advanced Research of Fibroblast Growth Factor Receptor 
in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Dan PU

    2013-11-01

    Full Text Available Lung cancer is severely threatening human health. In recent years, the treatment for lung adenocarcinoma has made a great progress, targeted therapy has been widely applied in clinic, and benefits amount of patients. However, in squamous cell lung cancer, the incidence of epidermal growth factor receptor (EGFR gene mutant and ALK fusion gene are low,and targeted therapy like Tarceva and crizotinib, can hardly work. Since the fibroblast growth factors (fibroblast growth factor, FGF pathway is considered to be related to tumor cell proliferation, metastasis and angiogenesis, more and more researches proved the amplification of fibroblast growth factor receptor (FGFR in squamous cell lung cancer. Experiments in vivo and in vitro found that blocking FGF pathway could reduce the proliferation of tumor cells and inhibit metastasis. The FGF pathway might be a new target for treatment of squamous cell lung cancer. This article reviews the effect of FGFR in tumorigenesis,as well as the prospect as a therapeutic target in non-small cell lung cancer.

  20. Revascularizing effect of basic fibroblast growth factor and partially deproteinised bone on femoral head defects in rabbits%碱性成纤维细胞生长因子和部分脱蛋白骨对兔股骨头缺损再血管化的影响

    Institute of Scientific and Technical Information of China (English)

    龚跃昆; 彭吾训; 李晓辉; 李世和; 李彦林; 杨浩

    2005-01-01

    管数量/视野),P<0.01,P<0.05];4周和8周微血管计数复合骨组和脱蛋白骨组均显著高于空白对照组.②微血管面积图像分析:20μm厚的透明标本光镜下观察见:术后2,4,8周,复合骨组修复区血管丰富并吻合成网,部分脱蛋白骨组血管丰富吻合成网,空白组血管散在.结论:碱性成纤维细胞生长因子具有促进股骨头缺损的再血管化作用,其在治疗股骨头坏死方面具备一定的潜能和优势.%BACKGROUND:The treatment of avascular necrosis of femoral head remains a clinical challenge. However, recent study shows that basic fibroblast growth factor (Bfgf) is an effective angiogenic growth factor. We suppose that Bfgf has the potential in treating avascular necrosis of femoral head through revascularizing effect and steogenesis.OBJECTIVE: To develop a rabbit model that simulates the clinical situation with trapdoor bone rafting and evaluate the revascularizing effect in the repair of femoral head defect with Bfgf/partially deproteinised bone (PDPB).DESIGN: A completely randomized controlled trial.SETTING: Animal Experimental Center of Kunming Medical College.MATERIALS: The experiment was conducted in the Animal Experimental Center of Kunming Medical College between July 2002 and July 2003.Totally 27 adult male healthy New Zealand rabbits, weighing 2.2 to 2.8 kg,were recruited and randomly divided into Bfgf/composite PDPB group,single PDPB group, and blank control group with 9 rabbits in each group.INTERVENTIONS: ① Preparation of Bfgf/PDPB: containing Bfgf 10 ng/mm3. ② Establishment and repair of femoral head defect model:Totally 27 rabbits were chosen. Bone defect model was stablished by opening a trapdoor between femoral head and femoral neck. Bfgf/PDPB was implanted in composite group; single PDPB was implanted in PDPB group; no implants were given in blank control group. The rabbits were killed after injection through blood vessels with prepared Chinese ink 2, 4and 8 weeks after operation, and then

  1. Rational Design of a Fibroblast Growth Factor 21-Based Clinical Candidate, LY2405319

    OpenAIRE

    Alexei Kharitonenkov; Beals, John M.; Radmila Micanovic; Strifler, Beth A.; Radhakrishnan Rathnachalam; Wroblewski, Victor J; Shun Li; Anja Koester; Ford, Amy M.; Tamer Coskun; Dunbar, James D.; Christine C Cheng; Frye, Christopher C.; Bumol, Thomas F.; Moller, David E.

    2013-01-01

    Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21) has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stab...

  2. Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids

    OpenAIRE

    Zhang, Justine H.; Nolan, Jonathan D.; Kennie, Sarah L.; Johnston, Ian M.; Dew, Tracy; Dixon, Peter H.; Williamson, Catherine; Walters, Julian R.F.

    2013-01-01

    Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. Ileal and colonic mucosal biopsies were obtained at endoscopy and analyzed for FGF19 transcript expression. Primary explants were incubated with physiological concentrations of various BA for up to 6 h, and expression of FGF19 and other genes w...

  3. Large-scale production of bioactive recombinant human acidic fibroblast growth factor in transgenic silkworm cocoons

    OpenAIRE

    Wang, Feng; Wang, Riyuan; Wang, Yuancheng; ZHAO, PING; Xia, Qingyou

    2015-01-01

    With an increasing clinical demand for functional therapeutic proteins every year, there is an increasing requirement for the massive production of bioactive recombinant human acidic fibroblast growth factor (r-haFGF). In this present study, we delicately explore a strategy for the mass production of r-haFGF protein with biological activity in the transgenic silkworm cocoons. The sequence-optimized haFGF was inserted into an enhanced sericin-1 expression system to generate the original transg...

  4. Molecular Mechanisms of Fibroblast Growth Factor Signaling in Physiology and Pathology

    OpenAIRE

    Belov, Artur A.; Mohammadi, Moosa

    2013-01-01

    Fibroblast growth factors (FGFs) signal in a paracrine or endocrine fashion to mediate a myriad of biological activities, ranging from issuing developmental cues, maintaining tissue homeostasis, and regulating metabolic processes. FGFs carry out their diverse functions by binding and dimerizing FGF receptors (FGFRs) in a heparan sulfate (HS) cofactor- or Klotho coreceptor-assisted manner. The accumulated wealth of structural and biophysical data in the past decade has transformed our understa...

  5. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern.

    OpenAIRE

    Partanen, J. (Joni); Mäkelä, T P; Eerola, E.; Korhonen, J; Hirvonen, H; Claesson-Welsh, L; Alitalo, K

    1991-01-01

    We have previously identified two novel members of the fibroblast growth factor receptor (FGFR) gene family expressed in K562 erythroleukemia cells. Here we report cDNA cloning and analysis of one of these genes, named FGFR-4. The deduced amino acid sequence of FGFR-4 is 55% identical with both previously characterized FGFRs, flg and bek, and has the structural characteristics of a FGFR family member including three immunoglobulin-like domains in its extracellular part. Antibodies raised agai...

  6. Cardiac fibroblasts are predisposed to convert into myocyte phenotype: Specific effect of transforming growth factor. beta

    Energy Technology Data Exchange (ETDEWEB)

    Eghbali, M.; Tomek, R.; Woods, C.; Bhambi, B. (Univ. of Chicago, IL (United States))

    1991-02-01

    Cardiac fibroblasts are mainly responsible for the synthesis of major extracellular matrix proteins in the heart, including fibrillar collagen types I and III and fibronectin. In this report we show that these cells, when stimulated by transforming growth factor {beta}{sub 1} (TGF-{beta}{sub 1}), acquire certain myocyte-specific properties. Cultured cardiac fibroblasts from adult rabbit heart were treated with TGF-{beta}{sub 1}, (10-15 ng/ml) for different periods of time. Northern hybridization analysis of total RNA showed that cells treated with TGF-{beta}{sub 1} became stained with a monoclonal antibody to muscle-specific actin. After treatment of quiescent cells with TGF-{beta}{sub 1}, cell proliferation (as measured by ({sup 3}H)thymidine incorporation) was moderately increased. Cultured cardiac fibroblasts at the subconfluent stage, when exposed to TGF-{beta}{sub 1} in the presence of 10% fetal bovine serum, gave rise to a second generation of slowly growing cells that expressed muscle-specific actin filaments. The findings demonstrate that cardiac fibroblasts can be made to differentiate into cells that display many characteristics of cardiac myocytes. TGF-{beta}{sub 1} seems to be a specific inducer of such conversion.

  7. Enhanced expression of fibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    A.R. Kranenburg (Andor); W.I. de Boer (Pim); J.H.J.M. van Krieken (Han); W.J. Mooi (Wolter); J.E. Walters (Jane); P.R. Saxena (Pramod Ranjan); P.J. Sterk (Peter); H.S. Sharma (Hari)

    2002-01-01

    textabstractImportant characteristics of chronic obstructive pulmonary disease (COPD) include airway and vascular remodeling, the molecular mechanisms of which are poorly understood. We assessed the role of fibroblast growth factors (FGF) in pulmonary vascular remodeling by examini

  8. Effect of transforming growth factor-beta on activity of connective tissue growth factor gene promoter in mouse NIH/3T3 fibroblasts

    Institute of Scientific and Technical Information of China (English)

    Qing ZHAO; Nan CHEN; Wei-ming WANG; Jian LU; Bing-bing DAI

    2004-01-01

    AIM: To investigate the regulatory mechanism of transforming growth factor-beta on activity of connective tissue growth factor promoter in mouse NIH/3T3 fibroblasts. METHODS: The regulation fragment of the 5' flanking region of the human CTGF gene was linked to pGL3-Basic vector, a firefly luciferase reporter construct without promoter. The recombinant plasmid pCTGF-luc was transiently transfected to NIH/3T3 fibroblasts. The activity of CTGF promoter after treatment of TGF-β1 and MAPK pathway inhibitors were assayed with luciferase reporter gene assay system. RESULTS: TGF-β1-induced increase of CTGF promoter activity was concentration-dependent,with a plateau at 5 μg/L by 2.67-fold vs control (P<0.05). The TGF-β1 stimulation of CTGF promoter activity was time-dependent, too. After exposure to TGF-β1 (5 μg/L), the maximal level of luciferase activity was reached at 12 h and maintained to 24 h by 2.76- and 2.20-fold vs control, respectively (P<0.05). Blockade of mitogen-activated protein kinases (MAPK) pathway with PD98059 (10 μmnol/L), the MAP kinase kinase 1 inhibitor, and SB203580 (10μmol/L), the p38 MAP kinase inhibitor, decreased basal and TGF-β1-induced activation of CTGF promoter. However,inhibition of c-Jun-N-terminal kinase/stress-activated protein kinase by SP600125 (20 μmol/L) was without effect.CONCLUSION: TGF-β1 stimulated the transcriptional activity of CTGF gene promoter in NIH/3T3 fibroblasts in a dose- and time-dependent manner. MAPK pathway may play a role in the regulation of TGF-β1-induced CTGF expression.

  9. Structure of rat acidic fibroblast growth factor at 1.4 A resolution

    DEFF Research Database (Denmark)

    Kulahin, Nikolaj; Kiselyov, Vladislav; Kochoyan, Artur;

    2007-01-01

    Fibroblast growth factors (FGFs) constitute a family of 22 structurally related heparin-binding polypeptides that are involved in the regulation of cell growth, survival, differentiation and migration. Here, a 1.4 A resolution X-ray structure of rat FGF1 is presented. Two molecules are present in...... in the asymmetric unit of the crystal and they coordinate a total of five sulfate ions. The structures of human, bovine and newt FGF1 have been published previously. Human and rat FGF1 are found to have very similar structures....

  10. Cyclic mechanical deformation stimulates human lung fibroblast proliferation and autocrine growth factor activity.

    Science.gov (United States)

    Bishop, J E; Mitchell, J J; Absher, P M; Baldor, L; Geller, H A; Woodcock-Mitchell, J; Hamblin, M J; Vacek, P; Low, R B

    1993-08-01

    Cellular hypertrophy and hyperplasia and increased extracellular matrix deposition are features of tissue hypertrophy resulting from increased work load. It is known, for example, that mechanical forces play a critical role in lung development, cardiovascular remodeling following pressure overload, and skeletal muscle growth. The mechanisms involved in these processes, however, remain unclear. Here we examined the effect of mechanical deformation on fibroblast function in vitro. IMR-90 human fetal lung fibroblasts grown on collagen-coated silastic membranes were subjected to cyclical mechanical deformation (10% increase in culture surface area; 1 Hz) for up to 5 days. Cell number was increased by 39% after 2 days of deformation (1.43 +/- .01 x 10(5) cells/membrane compared with control, 1.03 +/- 0.02 x 10(5) cells; mean +/- SEM; P < 0.02) increasing to 163% above control by 4 days (2.16 +/- 0.16 x 10(5) cells compared with 0.82 +/- 0.03 x 10(5) cells; P < 0.001). The medium from mechanically deformed cells was mitogenic for IMR-90 cells, with maximal activity in the medium from cells mechanically deformed for 2 days (stimulating cell replication by 35% compared with media control; P < 0.002). These data suggest that mechanical deformation stimulates human lung fibroblast replication and that this effect is mediated by the release of autocrine growth factors.

  11. Experimental study on He- Ne laser irradiation to inhibit scar fibroblast growth in culture

    Institute of Scientific and Technical Information of China (English)

    舒彬; 吴宗耀; 郝林林; 曾登芬; 冯光锐; 林永辉

    2002-01-01

    To explore the inhibitory effect of He-Ne laser irradiation on fibroblast growth of hypertrophic scars in culture. Methods: He-Ne laser with wavelength of 632.8 nm,power density of 50 mW/cm2 and doses of 3 J/cm2,30 J/cm2, 90 J/cm2 and 180 J/cm2 was used to irradiate human scar fibroblasts in culture 1, 3 and 5 times respectively, and then the cell count and cell cycle analysis were done. Results: Repeated irradiation with He-Ne laser at dose of 180 J/cm2 three and five times led to an evident decrease in total cell number compared with that of the control group and there was a significant difference ( P <0.05). The cell cycle analysis showed after three and five times of irradiation with 180 J/cm2 He-Ne laser the cell number in S-phase decreased from 51% to 20% and 14% respectively, the cell number in G0/G1 phase increased from 28% to 55% and 60% respectively, and the cell percentage in Sub-G1 phase was 6.7% and 9.8% respectively. Conclusions: Repeated irradiation with 180 J/cm2 He-Ne laser can inhibit scar fibroblasts growth in culture.It may be that He-Ne laser irradiation causes cell stagnation in G0/G1 phase and apoptosis.

  12. Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts

    DEFF Research Database (Denmark)

    Micutkova, Lucia; Diener, Thomas; Li, Chen;

    2011-01-01

    Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26...... extracellular proteins with significantly different abundance in conditioned media from young and senescent fibroblasts. Among these was insulin-like growth factor binding protein-6 (IGFBP-6), which was chosen for further analysis. When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited...... and apoptotic cell death was increased. Furthermore, downregulation of IGFBP-6 led to premature entry into cellular senescence. Since IGFBP-6 overexpression increased cellular lifespan, the data suggest that IGFBP-6, in contrast to other IGF binding proteins, is a negative regulator of cellular...

  13. Growth inhibitory effects of endotoxins from Bacteroides gingivalis and intermedius on human gingival fibroblasts in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Layman, D.L.; Diedrich, D.L.

    1987-06-01

    Purified endotoxin or lipopolysaccharide from Bacteroides gingivalis and Bacteroides intermedius caused a similar dose-dependent inhibition of growth of cultured human gingival fibroblasts as determined by /sup 3/H-thymidine incorporation and direct cell count. Approximately 200 micrograms/ml endotoxin caused a 50% reduction in /sup 3/H-thymidine uptake of logarithmically growing cells. Inhibition of growth was similar in cultures of fibroblasts derived from either healthy or diseased human gingiva. When examining the change in cell number with time of exposure in culture, the rate of proliferation was significantly suppressed during the logarithmic phase of growth. However, the cells recovered so that the rate of proliferation, although reduced, was sufficient to produce a cell density similar to the control cells with prolonged culture. The endotoxins were characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The profiles of the Bacteroides endotoxins were different. B. gingivalis endotoxin showed a wide range of distinct bands indicating a heterogeneous distribution of molecular species. Endotoxin from B. intermedius exhibited a few discrete low molecular weight bands, but the majority of the lipopolysaccharides electrophoresed as a diffuse band of high molecular weight material. The apparent heterogeneity of the two Bacteroides endotoxins and the similarity in growth inhibitory capacity suggest that growth inhibitory effects of these substances cannot be attributed to any polysaccharide species of endotoxin.

  14. The chalcone butein from Rhus verniciflua Stokes inhibits clonogenic growth of human breast cancer cells co-cultured with fibroblasts

    Directory of Open Access Journals (Sweden)

    Tan Jenny

    2005-03-01

    Full Text Available Abstract Background Butein (3,4,2',4'-tetrahydroxychalone, a plant polyphenol, is a major biologically active component of the stems of Rhus verniciflua Stokes. It has long been used as a food additive in Korea and as an herbal medicine throughout Asia. Recently, butein has been shown to suppress the functions of fibroblasts. Because fibroblasts are believed to play an important role in promoting the growth of breast cancer cells, we investigated the ability of butein to inhibit the clonogenic growth of small numbers of breast cancer cells co-cultured with fibroblasts in vitro. Methods We first measured the clonogenic growth of small numbers of the UACC-812 human breast cancer cell line co-cultured on monolayers of serum-activated, human fibroblasts in the presence of butein (2 μg/mL or various other modulators of fibroblast function (troglitazone-1 μg/mL; GW9662-1 μM; meloxican-1 μM; and 3,4 dehydroproline-10 μg/mL. In a subsequent experiment, we measured the dose-response effect on the clonogenic growth of UACC-812 breast cancer cells by pre-incubating the fibroblasts with varying concentrations of butein (10 μg/ml-1.25 μg/mL. Finally, we measured the clonogenic growth of primary breast cancer cells obtained from 5 clinical specimens with normal fibroblasts and with fibroblasts that had been pre-treated with a fixed dose of butein (2.5 μg/mL. Results Of the five modulators of fibroblast function that we tested, butein was by far the most potent inhibitor of clonogenic growth of UACC-812 breast cancer cells co-cultured with fibroblasts. Pre-treatment of fibroblasts with concentrations of butein as low as 2.5 μg/mL nearly abolished subsequent clonogenic growth of UACC-812 breast cancer cells co-cultured with the fibroblasts. A similar dose of butein had no effect on the clonogenic growth of breast cancer cells cultured in the absence of fibroblasts. Significantly, clonogenic growth of the primary breast cancer cells was also

  15. Elevated transforming growth factor β and mitogen-activated protein kinase pathways mediate fibrotic traits of Dupuytren's disease fibroblasts

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    Krause Carola

    2011-06-01

    Full Text Available Abstract Background Dupuytren's disease is a fibroproliferative disorder of the palmar fascia. The treatment used to date has mostly been surgery, but there is a high recurrence rate. Transforming growth factor β (TGF-β has been implicated as a key stimulator of myofibroblast activity and fascial contraction in Dupuytren's disease. Results We studied Dupuytren's fibroblasts in tissues ex vivo and in cells cultured in vitro and found increased TGF-β expression compared to control fibroblasts. This correlated not only with elevated expression and activation of downstream Smad effectors but also with overactive extracellular signal-regulated kinase 1/2 (ERK1/2/mitogen-activated protein (MAP kinase signalling. Treatment with the TGF-β type I receptor kinase inhibitor SB-431542 and bone morphogenetic protein 6 (BMP6 led to inhibition of elevated Smad and ERK1/2/MAP kinase signalling as well as to inhibition of the increased contractility of Dupuytren's fibroblasts. BMP6 attenuated TGF-β expression in Dupuytren's fibroblasts, but not in control fibroblasts. Platelet-derived growth factor (PDGF expression was strongly promoted by TGF-β in Dupuytren's fibroblasts and was curbed by SB-431542 or BMP6 treatment. High basal expression of phosphorylated ERK1/2 MAP kinase and fibroproliferative markers was attenuated in Dupuytren's fibroblasts by a selective PDGF receptor kinase inhibitor. Cotreatment of Dupuytren's fibroblasts with SB-431542 and the mitogen-activated protein kinase kinase 1 inhibitor PD98059 was sufficient to abrogate proliferation and contraction of Dupuytren's fibroblasts. Conclusions Both TGF-β and ERK1/2 MAP kinase pathways cooperated in mediating the enhanced proliferation and high spontaneous contraction of Dupuytren's fibroblasts. Our data indicate that both signalling pathways are prime targets for the development of nonsurgical intervention strategies to treat Dupuytren's disease.

  16. Hydrogen sulfide suppresses transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts.

    Science.gov (United States)

    Zhang, YouEn; Wang, JiaNing; Li, Hua; Yuan, LiangJun; Wang, Lei; Wu, Bing; Ge, JunBo

    2015-11-01

    In heart disease, transforming growth factor-β1 (TGF-β1) converts fibroblasts into myofibroblasts, which synthesize and secrete fibrillar type I and III collagens. The purpose of the present study was to investigate how hydrogen sulfide (H2S) suppresses TGF-β1-induced differentiation of human cardiac fibroblasts to myofibroblasts. Human cardiac fibroblasts were serum-starved in fibroblast medium for 16 h before exposure to TGF-β1 (10 ng mL(-1)) for 24 h with or without sodium hydrosulfide (NaHS, 100 µmol L(-1), 30 min pretreatment) treatment. NaHS, an exogenous H2S donor, potently inhibited the proliferation and migration of TGF-β1-induced human cardiac fibroblasts and regulated their cell cycle progression. Furthermore, NaHS treatment led to suppression of fibroblast differentiation into myofibroblasts, and reduced the levels of collagen, TGF-β1, and activated Smad3 in TGF-β1-induced human cardiac fibroblasts in vitro. We therefore conclude that H2S suppresses TGF-β1-stimulated conversion of fibroblasts to myofibroblasts by inhibiting the TGF-β1/Smad3 signaling pathway, as well as by inhibiting the proliferation, migration, and cell cycle progression of human cardiac myofibroblasts. These effects of H2S may play significant roles in cardiac remodeling associated with heart failure.

  17. Fibroblast growth factor-1 attenuates TGF-β1-induced lung fibrosis.

    Science.gov (United States)

    Shimbori, Chiko; Bellaye, Pierre-Simon; Xia, Jiaji; Gauldie, Jack; Ask, Kjetil; Ramos, Carlos; Becerril, Carina; Pardo, Annie; Selman, Moises; Kolb, Martin

    2016-10-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibroblast and myofibroblast proliferation, and extensive deposition of extracellular matrix (ECM). Fibroblast growth factor-1 (FGF-1) belongs to the FGF family and has been shown to inhibit fibroblast collagen production and differentiation into myofibroblasts, and revert epithelial-mesenchymal transition by inhibiting TGF-β1 signalling pathways. However, the precise role of FGF-1 in pulmonary fibrosis has not yet been elucidated. In this study, we explore the mechanisms underlying the anti-fibrogenic effect of FGF-1 in pulmonary fibrosis in vitro and in vivo by prolonged transient overexpression of FGF-1 (AdFGF-1) and TGF-β1 (AdTGF-β1) using adenoviral vectors. In vivo, FGF-1 overexpression markedly attenuated TGF-β1-induced pulmonary fibrosis in rat lungs when given both concomitantly, or delayed, by enhancing proliferation and hyperplasia of alveolar epithelial cells (AECs). AdFGF-1 also attenuated the TGF-β1 signalling pathway and induced FGFR1 expression in AECs. In vitro, AdFGF-1 prevented the increase in α-SMA and the decrease in E-cadherin induced by AdTGF-β1 in normal human lung fibroblasts, primary human pulmonary AECs, and A549 cells. Concomitantly, AdTGF-β1-induced Smad2 phosphorylation was significantly reduced by AdFGF-1 in both cell types. AdFGF-1 also attenuated the increase in TGFβR1 protein and mRNA levels in fibroblasts. In AECs, AdFGF-1 decreased TGFβR1 protein by favouring TGFβR1 degradation through the caveolin-1/proteasome pathway. Furthermore, FGFR1 expression was increased in AECs, whereas it was decreased in fibroblasts. In serum of IPF patients, FGF-1 levels were increased compared to controls. Interestingly, FGF-1 expression was restricted to areas of AEC hyperplasia, but not α-SMA-positive areas in IPF lung tissue. Our results demonstrate that FGF-1 may have preventative and therapeutic effects on TGF-β1-driven pulmonary fibrosis via inhibiting

  18. Resinous perforation-repair materials inhibit the growth, attachment, and proliferation of human gingival fibroblasts.

    Science.gov (United States)

    Huang, Fu-Mei; Tai, Kuo-Wei; Chou, Ming-Yung; Chang, Yu-Chao

    2002-04-01

    The choice of repair material is one of the important factors in the prognosis of the endodontically treated tooth with a perforation defect. The cytotoxicity of perforation-repair materials must be investigated to ensure a safe biological response. The aim of this in vitro study was to evaluate the effect of resin-modified, glass-ionomer cement, compomer, and resin on human-gingival fibroblasts. Human gingival fibroblasts from crown lengthening surgery were cultured by using an explant technique with the consent of the patient. Cytotoxicity was judged by using an assay of tetrazolium bromide reduction. The results showed that resin-modified, glass-ionomer cement Fuji II LC, compomer Compoglass, and resin SpectrumTPH (TPH) were cytotoxic to primary human gingival fibroblast cultures by inhibiting cell growth and proliferation. TPH alone had an effect on cell attachment. It was found that TPH was the most cytotoxic repair material among those tested in all cultures. The toxicity decreased in the order of TPH>FLC>CG.

  19. Serum levels of fibroblast growth factor in patients with intracerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Cüneyt Ölmez

    2011-09-01

    Full Text Available Objectives: Intracerebral hemorrhage (ICH is one of the most mortal subtypes of stroke. Due to the angiogenic, neurotropic, and vessel-dilating properties of basic fibroblast growth factor (bFGF in the brain, role of bFGF has been investigated in a number of neurological disorders. So far, there is only study about serum bFGF levels in patients with ICH. The first aim of the present research is to investigate whether increased serum bFGF in patients with ICH. Also, second aim was to study the association between serum levels of bFGF and clinical status in patients with ICH.Materials and methods: We measured the serum levels of bFGF in 30 patients with ICH during acute period. Age and sex matched healthy subjects (n=30 were included in controls. Serum bFGF levels were measured using an enzyme-linked immunosorbent assay method.Results: The patients with intracerebral hemorrhage had higher serum levels of bFGF when compared with the healthy controls (12.89±3.23 ng/ml, 5.28±1.75 ng/ml; p=0.001. No statistically significant difference was determined between bFGF levels of the patients who died as compared to the patients who lived (13.49±4.13 ng/ml; 12.43±3.43 ng/ml, p>0.05. No statistically significant difference was found between bFGF levels of the patients with intraventricular hemorrhage as compared to the patients without intraventricular hemorrhage (13.54±3.92 ng/ml; 12.24±2.29 ng/ml, p>0.05. There was no correlation between serum bFGF, hematoma volume, Gloskow coma scale, and National Institutes of Health stroke scale (p>0.05.Conclusion: The increased bFGF level may be one of the mechanisms that lead to angiogenesis and neuroprotection after ICH in human. . J Clin Exp Invest 2011; 2 (3: 282-286.

  20. Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1.

    Directory of Open Access Journals (Sweden)

    Zhao-Jun Liu

    Full Text Available Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM. They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox embryonic fibroblasts (MEFs. Notch1-deficient (Notch1(-/- MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1 in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441, which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1. Functionally, "Notch-activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4 in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression.

  1. Effect of transforming growth factor beta on synthesis of glycosaminoglycans by human lung fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Dubaybo, B.A.; Thet, L.A. (Veterans Administration Medical Center, Allen Park, MI (USA))

    1990-09-01

    The processes of lung growth, injury, and repair are characterized by alterations in fibroblast synthesis and interstitial distribution of extracellular matrix components. Transforming growth factor beta (TGF-beta), which is postulated to play a role in modulating lung repair, alters the distribution of several matrix components such as collagen and fibronectin. We studied the effect of TGF-beta on the synthesis and distribution of the various glycosaminoglycans (GAGs) and whether these effects may explain its role in lung repair. Human diploid lung fibroblasts (IMR-90) were exposed to various concentrations of TGF-beta (0-5 nM) for variable periods of time (0-18 h). Newly synthesized GAGs were labeled with either (3H)glucosamine or (35S)sulfate. Individual GAGs were separated by size exclusion chromatography after serial enzymatic and chemical digestions and quantitated using scintillation counting. There was a dose-dependent increase in total GAG synthesis with maximal levels detected after 6 h of exposure. This increase was noted in all individual GAG types measured and was observed in both the cell associated GAGs (cell-matrix fraction) as well as the GAGs released into the medium (medium fraction). In the cell-matrix fraction, TGF-beta increased the proportion of heparan sulfate that was membrane bound as well as the proportion of dermatan sulfate in the intracellular compartment. In the medium fraction, TGF-beta increased the proportion of hyaluronic acid, chondroitin sulfate and dermatan sulfate released. We conclude that the role of TGF-beta in lung growth and repair may be related to increased synthesis of GAGs by human lung fibroblasts as well as alterations in the distribution of individual GAGs.

  2. Intravenous Phosphate Loading Increases Fibroblast Growth Factor 23 in Uremic Rats

    OpenAIRE

    Noriko Arai-Nunota; Masahide Mizobuchi; Hiroaki Ogata; Ai Yamazaki-Nakazawa; Chiaki Kumata; Fumiko Kondo; Nozomu Hosaka; Fumihiko Koiwa; Eriko Kinugasa; Takanori Shibata; Tadao Akizawa

    2014-01-01

    Oral phosphate loading and calcitriol stimulate Fibroblast growth factor 23 (FGF23) secretion, but the mechanisms underlying the stimulation of FGF23 remain to be studied. We compared the effect of intravenous phosphate loading with that of oral loading on FGF23 levels in normal and 5/6 nephrectomized uremic rats. Uremic rats (Nx) and sham-operated rats were fed a normal phosphate diet for 2 weeks and then divided into 3 groups: 1) with the same phosphate diet (NP), 2) with a high phosphate d...

  3. Fibroblast growth factor homologous factors in the heart: a potential locus for cardiac arrhythmias.

    Science.gov (United States)

    Wei, Eric Q; Barnett, Adam S; Pitt, Geoffrey S; Hennessey, Jessica A

    2011-10-01

    The four fibroblast growth factor homologous factors (FHFs; FGF11-FGF14) are intracellular proteins that bind and modulate voltage-gated sodium channels (VGSCs). Although FHFs have been well studied in neurons and implicated in neurologic disease, their role in cardiomyocytes was unclear until recently. This review discusses the expression profile and function of FHFs in mouse and rat ventricular cardiomyocytes. Recent data show that FGF13 is the predominant FHF in the murine heart, directly binds the cardiac VGSC α subunit, and is essential for normal cardiac conduction. FHF loss-of-function mutations may be unrecognized causes of cardiac arrhythmias, such as long QT and Brugada syndromes.

  4. Synthetic NCAM-derived Ligands of the Fibroblast Growth Factor Receptor

    DEFF Research Database (Denmark)

    Hansen, Stine; Li, Shizhong; Bock, Elisabeth;

    2008-01-01

    The neural cell adhesion molecule (NCAM) responds to cues in the external environment and transmits signals to the cell through extracellular and intracellular interactions with a number of other signal transduction molecules. One such NCAM interaction partner is the fibroblast growth factor...... receptor (FGFR). NCAM interacts with FGFR via two fibronectin type III (FN3) modules in the extracellular part of NCAM. These modules consist of beta-strands and connecting loop regions. Based on structural analysis of the NCAM FN3 modules, four peptide sequences, FGL, BCL, dekaCAM, and FRM, encompassing...

  5. Significant gender difference in serum levels of fibroblast growth factor 21 in Danish children and adolescents

    DEFF Research Database (Denmark)

    Bisgaard, Amalie; Sørensen, Kaspar; Johannsen, Trine Holm;

    2014-01-01

    INTRODUCTION: Fibroblast Growth Factor 21 (FGF21) is a novel metabolic factor with effect on glucose and lipid metabolism, and shown to be elevated in diseases related to metabolic syndrome. Due to the increasing frequency of metabolic syndrome in the pediatric population, and as FGF21 studies...... or adiponectin levels, respectively. Neither was any correlation found between baseline FGF21-levels and the dynamic changes in glucose and insulin levels during the OGTT. CONCLUSION: FGF21 is independent of adiposity in children, and the significant metabolic effect seems to be limited to pathological...

  6. Induction of an Osteocyte-like Phenotype by Fibroblast Growth Factor-2

    OpenAIRE

    Gupta, Rishi R; Yoo, David J; Hebert, Carla; Niger, Corinne; Stains, Joseph P.

    2010-01-01

    The purpose of this study was to characterize the molecular phenotype that occurs during the profound morphological shift of cultured osteogenic cells upon treatment with fibroblast growth factor-2 (FGF2). A time course of treatment with FGF2 was performed on an osteoblast cell line, primary bone marrow stromal cells and an osteocyte-like cell line. Morphologic changes were recorded, and gene profiling was carried out by real time PCR. By 8 hours of FGF2 treatment, there is a striking morphol...

  7. Agonists of fibroblast growth factor receptor induce neurite outgrowth and survival of cerebellar granule neurons

    DEFF Research Database (Denmark)

    Li, Shizhong; Christensen, Claus; Køhler, Lene B;

    2009-01-01

    Fibroblast growth factor receptor (FGFR) signaling is pivotal in the regulation of neurogenesis, neuronal differentiation and survival, and synaptic plasticity both during development and in adulthood. In order to develop low molecular weight agonists of FGFR, seven peptides, termed hexafins...... phosphorylation, indicating that hexafins act as partial agonists. Hexafin2, 3, 8, 10, and 17 (but not 1 or 9) induced neurite outgrowth from cerebellar granule neurons (CGNs), an effect that was abolished by two inhibitors of FGFR, SU5402 and inositol hexaphosphate (IP6) and a diacylglycerol lipase inhibitor...

  8. Induction of growth and proliferation of fibroblast cells in magnetic field

    Directory of Open Access Journals (Sweden)

    Naghmeh Ezatti

    2015-02-01

    Full Text Available Background: Tissue engineering is generally defined as developing and changing the laboratory growth of molecules and cells in tissues or organs to replace and repair the damaged part of body. This study was carried out to stimulate the growth of cultured fibroblast cells by a physical electromagnetic method. Methods: First, an air-core coil was prepared and the cell culture plate was placed comfortably into the mold, then the plate containing the culture medium and human fibroblast cell along with air-core coil were placed in an incubator and then connected to the power supply. Thus, the sample underwent electromagnetic field at different times, and cell proliferation was studied by MTTassay. Results: Microscopic images indicated that the cells undergoing electromagnetic field (0.35 amps had a significant growth compared to the cells in control group in a definit range of stimulation. Conclusion: In conclusion, electromagnetic stimulation in a definite range led to cell proliferation and could be used as a positive factor in tissue engineering.

  9. Fibroblasts from long-lived Snell dwarf mice are resistant to oxygen-induced in vitro growth arrest

    DEFF Research Database (Denmark)

    Maynard, Scott P; Miller, Richard A

    2006-01-01

    Snell dwarf mice live longer than controls, and show lower age-adjusted rates of lethal neoplastic diseases. Fibroblast cells from adult dwarf mice are resistant to the lethal effects of oxidative and nonoxidative stresses, including the carcinogen methyl methanesulfonate. We now report that dwarf...... in skin fibroblasts by the hormonal milieu of the Snell dwarf lead to resistance to multiple forms of injury, including the oxidative damage that contributes to growth arrest in vitro and neoplasia in intact mice....

  10. Blocking transforming growth factor- receptor signaling down-regulates transforming growth factor-β1 autoproduction in keloid fibroblasts

    Institute of Scientific and Technical Information of China (English)

    刘伟; 蔡泽浩; 王丹茹; 武小莉; 崔磊; 商庆新; 钱云良; 曹谊林

    2002-01-01

    Objective: To study transforming growth factor-β1(TGF-β1) autoproduction in keloid fibroblasts and theregulation effect of blocking TGF-β intracellular signalingon rhTGF-β1 autoproduction.Methods: Keloid fibroblasts cultured in vitro weretreated with either rhTGF-β1 (5 ng/ml ) or recombinantadenovirus containing a truncated type II TGF-β receptorgene (50 pfu/cell ). Their effects of regulating geneexpression of TGF-β1 and its receptor I and II wereobserved with Northern blot.Results: rhTGF-β1 up-regulated the gene expressionof TGF-β1 and receptor I, but not receptor II. Over-expression of the truncated receptor II down-regulated thegene expression of TGF-β1 and its receptor I, but notreceptor II.Conclusions: TGF-β1 autoproduction was observed inkeloid fibroblasts. Over-expression of the truncated TGF-βreceptor H decreased TGF-β1 autoproduction via blockingTGF-β receptor signaling.

  11. Diversity of Interstitial Lung Fibroblasts Is Regulated by Platelet-Derived Growth Factor Receptor α Kinase Activity.

    Science.gov (United States)

    Green, Jenna; Endale, Mehari; Auer, Herbert; Perl, Anne-Karina T

    2016-04-01

    Epithelial-mesenchymal cell interactions and factors that control normal lung development are key players in lung injury, repair, and fibrosis. A number of studies have investigated the roles and sources of epithelial progenitors during lung regeneration; such information, however, is limited in lung fibroblasts. Thus, understanding the origin, phenotype, and roles of fibroblast progenitors in lung development, repair, and regeneration helps address these limitations. Using a combination of platelet-derived growth factor receptor α-green fluorescent protein (PDGFRα-GFP) reporter mice, microarray, real-time polymerase chain reaction, flow cytometry, and immunofluorescence, we characterized two distinct interstitial resident fibroblasts, myo- and matrix fibroblasts, and identified a role for PDGFRα kinase activity in regulating their activation during lung regeneration. Transcriptional profiling of the two populations revealed a myo- and matrix fibroblast gene signature. Differences in proliferation, smooth muscle actin induction, and lipid content in the two subpopulations of PDGFRα-expressing fibroblasts during alveolar regeneration were observed. Although CD140α(+)CD29(+) cells behaved as myofibroblasts, CD140α(+)CD34(+) appeared as matrix and/or lipofibroblasts. Gain or loss of PDGFRα kinase activity using the inhibitor nilotinib and a dominant-active PDGFRα-D842V mutation revealed that PDGFRα was important for matrix fibroblast differentiation. We demonstrated that PDGFRα signaling promotes alveolar septation by regulating fibroblast activation and matrix fibroblast differentiation, whereas myofibroblast differentiation was largely PDGFRα independent. These studies provide evidence for the phenotypic and functional diversity as well as the extent of specificity of interstitial resident fibroblasts differentiation during regeneration after partial pneumonectomy. PMID:26414960

  12. 骨形态发生蛋白与碱性成纤维细胞生长因子联合修复软骨缺损的效果评价%Effects of recombinant human bone morphogenetic protein combined with basic fibroblast growth factor on the repair of articular cartilage defects

    Institute of Scientific and Technical Information of China (English)

    朱国华; 蔡建平; 郭翠玲; 廖家新; 刘勇; 罗洪涛; 许国华; 胡红涛

    2012-01-01

    背景:多种细胞生长因子在骨软骨代谢过程中的协同作用越来越受到重视,但目前复合细胞生长因子修复软骨缺损报道较少,且修复效果尚无定论.目的:探讨骨形态发生蛋白和碱性成纤维细胞生长因子联合应用修复关节软骨缺损的效果.方法:24 只日本大耳白兔建立骨软骨缺损模型后随机等分为4 组,对照组缺损处仅填塞明胶海绵,其他3 组在对照组基础上,缺损处分别注射骨形态发生蛋白和碱性成纤维细胞生长因子、骨形态发生蛋白、碱性成纤维细胞生长因子.结果与结论:大体观察显示联合应用2 种细胞因子后,软骨缺损面基本修复但稍不平整,单独使用其中1 种细胞因子缺损面未完全修复,对照组无明显修复.联合应用2 种细胞因子缺损部位软骨细胞数多于其他3 组(P < 0.05),且Ⅱ型胶原免疫组化染色深于其他组.提示联合应用骨形态发生蛋白和碱性成纤维细胞生长因子可以促进关节软骨损伤的修复,疗效优于单独应用骨形态发生蛋白或碱性成纤维细胞生长因子.%BACKGROUND: The synergy of various cell growth factors attracts more and more attention in the course of cartilage metabolism.However, there are few reports of repairing cartilage defects with combined cell growth factors, and the effect remains unknown atpresent.OBJECTIVE: To study the repairing effect of recombinant human bone morphogenetic protein (rhBMP) combined with basicfibroblast growth factor (bFGF) on articular cartilage defects.METHODS: After the model of articular cartilage defects was made, 24 Japan big-eared white rabbits were randomly divided intofour groupsforintervention: rhBMP combined with bFGF (group A), single rhBMP (group B), single bFGF (group C), the fourthgroup was without injection and just filled with gelatin sponge (group D).RESULTS AND CONCLUSION: In general observation, articular cartilage defects were basically repaired but slightly

  13. Gentisic Acid, a Compound Associated with Plant Defense and a Metabolite of Aspirin, Heads a New Class of in Vivo Fibroblast Growth Factor Inhibitors*

    OpenAIRE

    Fernández, Israel S.; Cuevas, Pedro; Angulo, Javier; López-Navajas, Pilar; Canales-Mayordomo, Ángeles; González-Corrochano, Rocío; Lozano, Rosa M.; Valverde, Serafín; Jiménez-Barbero, Jesús; Romero, Antonio; Giménez-Gallego, Guillermo

    2010-01-01

    Fibroblast growth factors are key proteins in many intercellular signaling networks. They normally remain attached to the extracellular matrix, which confers on them a considerable stability. The unrestrained accumulation of fibroblast growth factors in the extracellular milieu, either due to uncontrolled synthesis or enzymatic release, contributes to the pathology of many diseases. Consequently, the neutralization of improperly mobilized fibroblast growth factors is of clear therapeutic inte...

  14. Effects of the basic fibroblast growth factor and its anti-factor in the healing and collagen maturation of infected skin wound Efeitos do fator de crescimento de fibroblastos básico e do seu anti-fator na cicatrização e maturação do colágeno de feridas infectadas de pele

    Directory of Open Access Journals (Sweden)

    Antonio Medeiros Dantas Filho

    2007-01-01

    Full Text Available PURPOSE: The infection is one of the main factors that affect the physiological evolution of the surgical wounds. The aim of this work is to evaluate the effects of fibroblast growth factor (FGFâ and anti-FGFâ in the healing, synthesis and maturation of collagen when topically used on infected skin wounds of rats. METHODS: An experimental study was perfomed in 60 male Wistar rats. All animals were divided in two groups (A and B. Each group was divided in three subgroups A1, B1; A2, B2 and A3, B3. After anesthesia with pentobarbital, two open squared wounds (1cm², 4cm distant to each other, were done in the dorsal skin of all the rats. In group A (n=30 the wounds were contaminated with multibacterial standard solution, and in group B(n=30 the wounds were maintained sterile. These wounds were named F1 (for inflammation analysis and F2 (for collagen study. The open wounds of A1 and B1 rats were topically treated with saline solution, A2 and B2 were treated with FGFâ and subgroups A3 and B3 were treated with FGFâ and anti-FGFâ. The rats were observed until complete epitelization of F2 wounds for determination of healing time and the expression of types I and III collagen, using Picro Sirius Red staining. Inflammatory reaction in F1 wounds was studied using hematoxilineosin staining. The three variable was measured by the Image Pro-Plus Média Cybernetics software. The statistical analysis was performed by ANOVA and Tukey test, considering pOBJETIVO: Avaliar os efeitos do fator de crescimento de fibroblastos básico (FCFâ e do anti-FCFâ na cicatrização e maturação do colágeno em feridas infectadas na pele de ratos. MÉTODOS: Um estudo experimental foi realizado em 60 ratos Wistar, divididos em dois grupos (A e B. Cada grupo foi divididos em 03 subgrupos A1,B1; A2,B2 e A3,B3. Após anestesia com pentobarbital sódico intraperitoneal, foram feitas duas feridas abertas de 1cm² na pele no dorso distando 4cm uma da outra. Essas feridas foram

  15. Inhibition of growth of Toxoplasma gondii in cultured fibroblasts by human recombinant gamma interferon.

    Science.gov (United States)

    Pfefferkorn, E R; Guyre, P M

    1984-01-01

    The growth of Toxoplasma gondii in cultured human fibroblasts was inhibited by recombinant human gamma interferon at concentrations of 8 to 16 U/ml. The interferon was titrated by observing a total inhibition of parasite plaque formation 7 days after infection. Inhibition of the growth of T. gondii in the early days after infection was measured by marked reductions in the incorporation of radioactive uracil, a precursor that can only be used by the parasites. This assay showed that when cells were pretreated with gamma interferon for 1 day and then infected, inhibition of T. gondii growth could be readily detected 1 or 2 days after infection. When the pretreatment was omitted and parasites and gamma interferon were added at the same time, no inhibition of parasite growth could be detected 1 day later, although it was apparent after 2 days. Cultures from which the gamma interferon had been removed by washing after a 1-day treatment showed inhibition of T. gondii growth. Gamma interferon had no effect on the viability of extracellular parasites, but it did inhibit the synthesis of host cell RNA and protein by ca. 50% 3 days after treatment. This degree of inhibition is unlikely, of itself, to compromise the growth of T. gondii. Recombinant alpha and beta interferons had no effect on the growth of T. gondii. Images PMID:6425215

  16. Fibroblast growth factor-2 stimulates adipogenic differentiation of human adipose-derived stem cells

    International Nuclear Information System (INIS)

    Adipose-derived stem cells (ASCs) have demonstrated a capacity for differentiating into a variety of lineages, including bone, cartilage, or fat, depending on the inducing stimuli and specific growth and factors. It is acknowledged that fibroblast growth factor-2 (FGF-2) promotes chondrogenic and inhibits osteogenic differentiation of ASCs, but thorough investigations of its effects on adipogenic differentiation are lacking. In this study, we demonstrate at the cellular and molecular levels the effect of FGF-2 on adipogenic differentiation of ASCs, as induced by an adipogenic hormonal cocktail consisting of 3-isobutyl-1-methylxanthine (IBMX), dexamethasone, insulin, and indomethacin. FGF-2 significantly enhances the adipogenic differentiation of human ASCs. Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor γ2 (PPARγ2), a key transcription factor in adipogenesis, was upregulated. The results of FGF-2 supplementation suggest the potential applications of FGF-2 and ASCs in adipose tissue regeneration

  17. Functions and Mechanisms of Fibroblast Growth Factor (FGF Signalling in Drosophila melanogaster

    Directory of Open Access Journals (Sweden)

    Hans-Arno J. Müller

    2013-03-01

    Full Text Available Intercellular signalling via growth factors plays an important role in controlling cell differentiation and cell movements during the development of multicellular animals. Fibroblast Growth Factor (FGF signalling induces changes in cellular behaviour allowing cells in the embryo to move, to survive, to divide or to differentiate. Several examples argue that FGF signalling is used in multi-step morphogenetic processes to achieve and maintain a transitional state of the cells required for the control of cell fate. In the genetic model Drosophila melanogaster, FGF signalling via the receptor tyrosine kinases Heartless (Htl and Breathless (Btl is particularly well studied. These FGF receptors affect gene expression, cell shape and cell–cell interactions during mesoderm layer formation, caudal visceral muscle (CVM formation, tracheal morphogenesis and glia differentiation. Here, we will address the current knowledge of the biological functions of FGF signalling in the fly on the tissue, at a cellular and molecular level.

  18. Photodynamic therapy inhibit Fibroblast Growth Factor-10 induced keratinocyte differentiation and proliferation through ROS in Fibroblast Growth Factor Receptor-2b pathway.

    Science.gov (United States)

    Gozali, Maya Valeska; Yi, Fei; Zhang, Jia-An; Liu, Juan; Wu, Hong-Jin; Xu, Yang; Luo, Dan; Zhou, Bing-Rong

    2016-01-01

    5-aminolevulinic acid-photodynamic therapy (ALA-PDT) is known to be effective in several skin diseases such as acne, actinic keratoses, condyloma acuminata. However, some detailed mechanisms of ALA-PDT to treat these skin diseases still remain elusive. In this study, we aimed to investigate mechanism of ALA-PDT in in-vitro and in-vivo models. For in vitro, we use human keratinocyte cell line (HaCaT) cells. CCK-8 was used to detect cell proliferation activity, immunofluorescence and western blotting method to detect the content of keratin (K)1, K6, K16, protein kinase C (PKC), fibroblast growth factor receptor-2b (FGFR2b) protein, ELISA and RT-PCR to detect expression of interleukin (IL) 1α in the cell supernatant, and detect reactive oxygen species (ROS). For in vivo, we use 20 rabbits to induce hyperkeratosis acne model in their ear. Dermatoscope was used to see follicle hyperkeratosis and skin biopsy to analyze histology and immunohistochemical of PKC, FGFR2b, K1, K6 and K16. Results from this study suggest that ROS stimulated by ALA-PDT lead to inhibition of FGFR2b pathway in PKC downstream to cause reduction of IL1α expression, and eventually, keratinocytes differentiation and proliferation. Our data thus reveal a treatment mechanism of ALA-PDT underlying hyperkeratosis related dermatoses. PMID:27273653

  19. Effect of substance P on gene expression of transforming growth factor β-1 and its receptors in rat's fibroblasts

    Institute of Scientific and Technical Information of China (English)

    赖西南; 王正国; 朱金明; 王丽丽

    2003-01-01

    Objective: To investigate the effect of substance P (SP) on gene expression of transforming growth factor β-1 (TGFβ-1), transforming growth factor receptor-1 (TGFR-1) and transforming growth factor receptor-2 (TGFR-2) in fibroblasts cultured in vitro from rat's granulation tissues.Methods: The fibroblasts from the granulation tissues in the skeletal muscle of rat's hind limbs injured by formaldehyde were cultured in vitro. When different concentrations (10-9-10-5 mol/L) of SP were added into the culture medium, the changes of gene expression of TGFβ-1, TGFR-1 and TGFR-2 in the cultured fibroblasts were observed with reverse transcription polymerase chain reaction at different intervals (0, 3, 6, 12 and 24 hours after incubation).Results: The gene expression of TGFβ-1, TGFR-1 and TGFR-2 in the fibroblasts cultured from rat's granulation tissues was up-regulated by SP. The peak level of the mRNA expression was found at 10-8 mol/L SP and the up-regulation effect was not found at 10-5 mol/L and 10-6 mol/L. The peak levels of gene expression of TGFβ-1, TGFR-1 and TGFR-2 in the fibroblasts treated with SP were achieved at 6 and 12 hours, respectively.Conclusions: SP has up-regulation effect on the gene expression of TGFβ-1, TGFR-1 and TGFR-2 in fibroblasts from rat's granulation tissues in vitro, and the effect is related to different stimulating concentrations of SP. It may be concerned with proliferation and differentiation of fibroblasts and formation of scar tissues during wound healing.

  20. Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.

    Science.gov (United States)

    Brown, Wells S; Tan, Li; Smith, Andrew; Gray, Nathanael S; Wendt, Michael K

    2016-09-01

    Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR. PMID:27371729

  1. Selection and characterization of a human neutralizing antibody to human fibroblast growth factor-2

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Jun [Department of Immunology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Xiang, Jun-Jian, E-mail: txjj@jnu.edu.cn [Laboratory of Antibody Engineering, College of Life Sciences and Technologies, Jinan University, Guangzhou 510632 (China); Department of Immunology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Li, Dan [Department of Immunology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Deng, Ning; Wang, Hong; Gong, Yi-Ping [Laboratory of Antibody Engineering, College of Life Sciences and Technologies, Jinan University, Guangzhou 510632 (China)

    2010-04-09

    Compelling evidences suggest that fibroblast growth factor-2 (FGF-2) plays important roles in tumor growth, angiogenesis and metastasis. Molecules blocking the FGF-2 signaling have been proposed as anticancer agents. Through screening of a human scFv phage display library, we have isolated several human single-chain Fv fragments (scFvs) that bind to human FGF-2. After expression and purification in bacteria, one scFv, named 1A2, binds to FGF-2 with a high affinity and specificity, and completes with FGF-2 binding to its receptor. This 1A2 scFv was then cloned into the pIgG1 vector and expressed in 293T cells. The purified hIgG1-1A2 antibody showed a high binding affinity of 8 x 10{sup -9} M to rhFGF-2. In a set of vitro assays, it inhibited various biological activities of FGF-2 such as the proliferation, migration and tube formation of human umbilical vein endothelial cells. More importantly, hIgG1-1A2 antibody also efficiently blocked the growth while inducing apoptosis of glioma cells. For the first time, we generated a human anti-FGF-2 antibody with proven in vitro anti-tumor activity. It may therefore present a new therapeutic candidate for the treatment of cancers that are dependent on FGF-2 signaling for growth and survival.

  2. Study of the interaction of the Ig2 module of the fibroblast growth factor receptor, FGFR Ig2, with the fibroblast growth factor 1, FGF1, by means of NMR spectroscopy

    DEFF Research Database (Denmark)

    Kochoyan, Artur; Poulsen, Flemming M; Berezin, Vladimir;

    2008-01-01

    Fibroblast growth factor (FGF) receptor (FGFR) consists extracellularly of three immunoglobulin (Ig) modules (Ig1-3). Currently, there are two competing models (symmetric and asymmetric) of the FGF-FGFR-heparin complex based on crystal structures. Indirect evidence exists in support of both model...

  3. Fibroblast Growth Factor 23 (FGF23 and Disorders of Phosphate Metabolism

    Directory of Open Access Journals (Sweden)

    Tasuku Saito

    2009-01-01

    Full Text Available Derangements in serum phosphate level result in rickets/osteomalacia or ectopic calcification indicating that healthy people without these abnormalities maintain serum phosphate within certain ranges. These results indicate that there must be a regulatory mechanism of serum phosphate level. Fibroblast growth factor 23 (FGF23 was identified as the last member of FGF family. FGF23 is produced by bone and reduces serum phosphate level by suppressing phosphate reabsorption in proximal tubules and intestinal phosphate absorption through lowering 1,25-dihydroxyvitamin D level. It has been shown that excess and deficient actions of FGF23 result in hypophosphatemic rickets/osteomalacia and hyperphosphatemic tumoral calcinosis, respectively. These results indicate that FGF23 works as a hormone, and several disorders of phosphate metabolism can be viewed as endocrine diseases. It may become possible to treat patients with abnormal phosphate metabolism by pharmacologically modifying the activity of FGF23.

  4. Use of fibroblast growth factor 2 for expansion of chondrocytes and tissue engineering

    Science.gov (United States)

    Martin, Ivan (Inventor); Freed, Lisa E. (Inventor); Langer, Robert (Inventor); Vunjak-Novakovic, Gordana (Inventor)

    2003-01-01

    The present invention provides an improved method for expanding cells for use in tissue engineering. In particular the method provides specific biochemical factors to supplement cell culture medium during the expansion process in order to reproduce events occurring during embryonic development with the goal of regenerating tissue equivalents that resemble natural tissues both structurally and functionally. These specific biochemical factors improve proliferation of the cells and are capable of de-differentiation mature cells isolated from tissue so that the differentiation potential of the cells is preserved. The bioactive molecules also maintain the responsiveness of the cells to other bioactive molecules. Specifically, the invention provides methods for expanding chondrocytes in the presence of fibroblast growth factor 2 for use in regeneration of cartilage tissue.

  5. Solution structure of human acidic fibroblast growth factor and interaction with heparin-derived hexasaccharide

    International Nuclear Information System (INIS)

    Fibroblast growth factors (FGFs) bind to extracellular matrices, especially heparin-like carbohydrates of heparansulfate proteoglycans which stabilize FGFs to protect against inactivation by heat, acid, proteolysis and oxidation. Moreover, binding of FGFs to cell surface proteoglycans promotes to form oligomers, which is essential for receptor oligomerization and activation. In the present study, we determined the solution structure of acidic FGF using a series of triple resonance multi-dimensional NMR experiments and simulated annealing calculations. Furthermore, we prepared the sample complexed with a heparin-derived hexasaccharide which is a minimum unit for aFGF binding. From the chemical shift differences between free aFGF and aFGF-heparin complex, we concluded that the major heparin binding site was located on the regions 110-131 and 17-21. The binding sites are quite similar to those observed for bFGF-heparin hexasaccharide complex, showing that both FGFs recognize heparin- oligosaccharides in a similar manner

  6. pH-sensitive polymer-assisted refolding of urea-denatured fibroblast growth factor

    Institute of Scientific and Technical Information of China (English)

    Zhi Feng Huang; Shan Shan Wang; Chun Yan Ni; Shu Lin Yang; Xiao Kun Li; Susanna S.J.Leong

    2009-01-01

    A pH-responsive polymer Eudragit S-100 has been found to assist in correct folding of FGF-2(fibroblast growth factor-2)denatured with 8 mol/L urea and 10 mmol/L dithiothreitol at pH 7.2.The refolding of FGF-2 was performed by directly diluting denatured FGF-2 into a refolding buffer containing Eudragit S-100.The ability of Eudragit S-100 to enhance protein refolding level was investigated using MTT method,fluorescence emission spectroscopy and reversc phase HPLC.On the other hand,the result shows the ability of Eudragit S-100 to enhance the refolding level of protein is due to the interaction between Eudragit S-100 and positively charged FGF-2.

  7. Expression and clinical significance of fibroblast growth factor 1 in gastric adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Liu NQ

    2015-03-01

    Full Text Available Naiqing Liu,1,2,* Jingyu Zhang,2,* Shuxiang Sun,2 Liguang Yang,2 Zhongjin Zhou,2 Qinli Sun,2 Jun Niu11Department of General Surgery, Qilu Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 2Department of General Surgery, Yishui Central Hospital, Linyi, People’s Republic of China*These authors contributed equally to this workBackground: The clinical significance of fibroblast growth factor 1 (FGF1 has been revealed in several cancers, including ovarian cancer, breast cancer, and bladder cancer. However, the clinical significance of FGF1 in gastric adenocarcinoma has not been explored.Patients and methods: In our experiments, we systematically evaluated FGF1 expression in 178 cases of gastric adenocarcinoma with immunohistochemistry, and subsequently analyzed the correlation between FGF1 expression and clinicopathologic features. Moreover, FGF1 expression in tumor tissue and corresponding adjacent tissue was detected and compared by real-time polymerase chain reaction. The Kaplan–Meier method and the Cox-regression model were used with univariate and multivariate analysis, respectively, to evaluate the prognostic value of FGF1 in gastric adenocarcinoma.Results: Higher FGF1 expression rate is 56.7% (101/178 in gastric adenocarcinoma. FGF1 expression in gastric adenocarcinoma was significantly higher than adjacent tissue (P<0.0001. Expression of FGF1 is significantly associated with lymph node invasion (P<0.001, distant metastasis (P=0.013, and differentiation (P=0.015. Moreover, FGF1 overexpression was closely related to unfavorable overall survival rate (P=0.021, and can be identified to be an independent unfavorable prognostic factor (P=0.004.Conclusion: FGF1 is an independent prognostic factor, indicating that FGF1 could be a potential molecular drug target in gastric adenocarcinoma.Keywords: fibroblast growth factor 1, gastric adenocarcinoma, prognosis, biomarker, lymph node, gene fusion

  8. Enhanced expression of fibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease.

    NARCIS (Netherlands)

    Kranenburg, A.R.; Boer, W.I.; Krieken, J.H.J.M. van; Mooi, W.J.; Walters, J.E.; Saxena, P.R.; Sterk, P.J.; Sharma, H.S.

    2002-01-01

    Important characteristics of chronic obstructive pulmonary disease (COPD) include airway and vascular remodeling, the molecular mechanisms of which are poorly understood. We assessed the role of fibroblast growth factors (FGF) in pulmonary vascular remodeling by examining the expression pattern of F

  9. Neural stem cell regulation, fibroblast growth factors, and the developmental origins of neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Hanna E Stevens

    2010-09-01

    Full Text Available There is increasing appreciation for the neurodevelopmental underpinnings of many psychiatric disorders. Disorders that begin in childhood such as autism, language disorders or mental retardation as well as adult-onset mental disorders may have origins early in neurodevelopment. Neural stem cells (NSCs can be defined as self-renewing, multipotent cells that are present in both the embryonic and adult brain. Several recent research findings demonstrate that psychiatric illness may begin with abnormal specification, growth, expansion and differentiation of embryonic NSCs. For example, candidate susceptibility genes for schizophrenia, autism and major depression include the signaling molecule Disrupted In Schizophrenia-1 (DISC-1, the homeodomain gene engrailed-2 (EN-2, and several receptor tyrosine kinases (RTKs, including MET, brain-derived growth factor (BDNF and fibroblast growth factors (FGF, all of which have been shown to play important roles in NSCs or neuronal precursors. We will discuss here stem cell biology, signaling factors that affect these cells, and the potential contribution of these processes to the etiology of neuropsychiatric disorders. Hypotheses about how some of these factors relate to psychiatric disorders will be reviewed.

  10. Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies.

    OpenAIRE

    Conover, C A; Kiefer, M C; Zapf, J

    1993-01-01

    Insulin-like growth factor binding protein-4 (IGFBP-4) is a 24-26-kD protein expressed by a variety of cell types in vivo and in vitro. Treatment of normal adult human fibroblasts with 10 nM insulin-like growth factor II (IGF-II) for 24 h resulted in an 85% decrease in endogenous IGFBP-4, as assessed by Western ligand blot analysis of the conditioned medium. Incubation of human fibroblast-conditioned medium (HFCM) with IGF-II under cell-free conditions led to a similar loss of IGFBP-4. This p...

  11. The effect of pantothenic acid deficiency on keratinocyte proliferation and the synthesis of keratinocyte growth factor and collagen in fibroblasts.

    Science.gov (United States)

    Kobayashi, Daisaku; Kusama, Miho; Onda, Masaaki; Nakahata, Norimichi

    2011-01-01

    It has been reported that pantothenic acid (vitamin B5) and panthenol, an alcohol derivative of pantothenic acid, have beneficial moisturizing effects on the skin. However, few studies have investigated the mechanism of action of pantothenic acid on skin tissues. We tried to clarify the role of pantothenic acid on skin function by using keratinocytes and fibroblasts. The depletion of pantothenic acid from the culture medium suppressed keratinocyte proliferation and promoted differentiation. Moreover, pantothenic acid depletion decreased the synthesis of keratinocyte growth factor and procollagen 4a2 in fibroblasts. These results suggest that pantothenic acid is essential for maintaining keratinocyte proliferation and differentiation. PMID:21258175

  12. Characterization of the growth of murine fibroblasts that express human insulin receptors. II. Interaction of insulin with other growth factors

    Energy Technology Data Exchange (ETDEWEB)

    Randazzo, P.A.; Jarett, L. (Univ. of Pennsylvania, Philadelphia (USA))

    1990-09-01

    The effects of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin on DNA synthesis were studied in murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental NIH 3T3 cells. In NIH 3T3/HIR cells, individual growth factors in serum-free medium stimulated DNA synthesis with the following relative efficacies: insulin greater than or equal to 10% fetal calf serum greater than PDGF greater than IGF-1 much greater than EGF. In comparison, the relative efficacies of these factors in stimulating DNA synthesis by NIH 3T3 cells were 10% fetal calf serum greater than PDGF greater than EGF much greater than IGF-1 = insulin. In NIH 3T3/HIR cells, EGF was synergistic with 1-10 ng/ml insulin but not with 100 ng/ml insulin or more. Synergy of PDGF or IGF-1 with insulin was not detected. In the parental NIH 3T3 cells, insulin and IGF-1 were found to be synergistic with EGF (1 ng/ml), PDGF (100 ng/ml), and PDGF plus EGF. In NIH 3T3/HIR cells, the lack of interaction of insulin with other growth factors was also observed when the percentage of cells synthesizing DNA was examined. Despite insulin's inducing only 60% of NIH 3T3/HIR cells to incorporate thymidine, addition of PDGF, EGF, or PDGF plus EGF had no further effect. In contrast, combinations of growth factors resulted in 95% of the parental NIH 3T3 cells synthesizing DNA. The independence of insulin-stimulated DNA synthesis from other mitogens in the NIH 3T3/HIR cells is atypical for progression factor-stimulated DNA synthesis and is thought to be partly the result of insulin receptor expression in an inappropriate context or quantity.

  13. Characterization of the growth of murine fibroblasts that express human insulin receptors. II. Interaction of insulin with other growth factors

    International Nuclear Information System (INIS)

    The effects of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin on DNA synthesis were studied in murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental NIH 3T3 cells. In NIH 3T3/HIR cells, individual growth factors in serum-free medium stimulated DNA synthesis with the following relative efficacies: insulin greater than or equal to 10% fetal calf serum greater than PDGF greater than IGF-1 much greater than EGF. In comparison, the relative efficacies of these factors in stimulating DNA synthesis by NIH 3T3 cells were 10% fetal calf serum greater than PDGF greater than EGF much greater than IGF-1 = insulin. In NIH 3T3/HIR cells, EGF was synergistic with 1-10 ng/ml insulin but not with 100 ng/ml insulin or more. Synergy of PDGF or IGF-1 with insulin was not detected. In the parental NIH 3T3 cells, insulin and IGF-1 were found to be synergistic with EGF (1 ng/ml), PDGF (100 ng/ml), and PDGF plus EGF. In NIH 3T3/HIR cells, the lack of interaction of insulin with other growth factors was also observed when the percentage of cells synthesizing DNA was examined. Despite insulin's inducing only 60% of NIH 3T3/HIR cells to incorporate thymidine, addition of PDGF, EGF, or PDGF plus EGF had no further effect. In contrast, combinations of growth factors resulted in 95% of the parental NIH 3T3 cells synthesizing DNA. The independence of insulin-stimulated DNA synthesis from other mitogens in the NIH 3T3/HIR cells is atypical for progression factor-stimulated DNA synthesis and is thought to be partly the result of insulin receptor expression in an inappropriate context or quantity

  14. Intracellular modification of 125I-labeled epidermal growth factor by normal human foreskin fibroblasts

    International Nuclear Information System (INIS)

    Intracellular processing of 125I-labeled epidermal growth factor (EGF) in normal human foreskin fibroblasts was examined after incubation with saturating concentrations of [125I]EGF. This report describes the column chromatographic separation of multiple processed forms of EGF generated by human foreskin fibroblasts and their structural characterization. More than 95% of the cell-bound [125I]EGF was converted into multiple forms, which were separated into four distinct peaks of radioactivity using columns of Bio-Gel P-150 equilibrated with 0.2% sodium dodecyl sulfate. These were designated peaks 1-4. Cellular generation of these four peaks was dependent on culture conditions. Differences in absolute and relative amounts of peaks 1-4 were observed as a function of time of incubation at 37 C. In addition, chromatographic profiles of cell-associated 125I varied in relation to cell density. The radioactivity in peak 1 comigrated with 125I-labeled native EGF on nondenaturing polyacrylamide gels (pH 9.5), whereas peaks 2 and 3 exhibited more rapid electrophoretic mobilities. Electrophoretic mobilities of the radioactivity in peaks 2 and 3 were indistinguishable from those of chemically prepared derivatives of [125I]EGF which were lacking either one or six amino acid residues from the carboxyterminus, respectively. The EGF receptor bound the radioactive material in peak 2 with an affinity equal to or greater than that of EGF; however, the radioactivity in peak 3 was bound to a much lesser extent. The radiolabel in both peaks 2 and 3 was greater than 95% precipitable by antiserum to native EGF. The labeled material in peak 4 was composed of [125I]monoiodotyrosine, 125I-, and an unidentified peptide. None of the radiolabeled compounds in peak 4 interacted with the EGF receptor or with antiserum to native EGF

  15. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    Science.gov (United States)

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury.

  16. A novel fibroblast growth factor receptor family member promotes neuronal outgrowth and synaptic plasticity in aplysia.

    Science.gov (United States)

    Pollak, Daniela D; Minh, Bui Quang; Cicvaric, Ana; Monje, Francisco J

    2014-11-01

    Fibroblast Growth Factor (FGF) Receptors (FGFRs) regulate essential biological processes, including embryogenesis, angiogenesis, cellular growth and memory-related long-term synaptic plasticity. Whereas canonical FGFRs depend exclusively on extracellular Immunoglobulin (Ig)-like domains for ligand binding, other receptor types, including members of the tropomyosin-receptor-kinase (Trk) family, use either Ig-like or Leucine-Rich Repeat (LRR) motifs, or both. Little is known, however, about the evolutionary events leading to the differential incorporation of LRR domains into Ig-containing tyrosine kinase receptors. Moreover, although FGFRs have been identified in many vertebrate species, few reports describe their existence in invertebrates. Information about the biological relevance of invertebrate FGFRs and evolutionary divergences between them and their vertebrate counterparts is therefore limited. Here, we characterized ApLRRTK, a neuronal cell-surface protein recently identified in Aplysia. We unveiled ApLRRTK as the first member of the FGFRs family deprived of Ig-like domains that instead contains extracellular LRR domains. We describe that ApLRRTK exhibits properties typical of canonical vertebrate FGFRs, including promotion of FGF activity, enhancement of neuritic outgrowth and signaling via MAPK and the transcription factor CREB. ApLRRTK also enhanced the synaptic efficiency of neurons known to mediate in vivo memory-related defensive behaviors. These data reveal a novel molecular regulator of neuronal function in invertebrates, provide the first evolutionary linkage between LRR proteins and FGFRs and unveil an unprecedented mechanism of FGFR gene diversification in primeval central nervous systems.

  17. Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report.

    Science.gov (United States)

    Sato, Takeshi; Muroya, Koji; Asakura, Yumi; Yachie, Akihiro; Nishimura, Gen; Aida, Noriko; Machida, Jiro; Tanaka, Yukichi; Hasegawa, Tomonobu; Adachi, Masanori

    2015-10-01

    We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-β and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction.

  18. Large-scale production of bioactive recombinant human acidic fibroblast growth factor in transgenic silkworm cocoons

    Science.gov (United States)

    Wang, Feng; Wang, Riyuan; Wang, Yuancheng; Zhao, Ping; Xia, Qingyou

    2015-11-01

    With an increasing clinical demand for functional therapeutic proteins every year, there is an increasing requirement for the massive production of bioactive recombinant human acidic fibroblast growth factor (r-haFGF). In this present study, we delicately explore a strategy for the mass production of r-haFGF protein with biological activity in the transgenic silkworm cocoons. The sequence-optimized haFGF was inserted into an enhanced sericin-1 expression system to generate the original transgenic silkworm strain, which was then further crossed with a PIG jumpstarter strain to achieve the remobilization of the expression cassette to a “safe harbor” locus in the genome for the efficient expression of r-haFGF. In consequence, the expression of r-haFGF protein in the mutant line achieved a 5.6-fold increase compared to the original strain. The high content of r-haFGF facilitated its purification and large-scald yields. Furthermore, the r-haFGF protein bioactively promoted the growth, proliferation and migration of NIH/3T3 cells, suggesting the r-haFGF protein possessed native mitogenic activity and the potential for wound healing. These results show that the silk gland of silkworm could be an efficient bioreactor strategy for recombinant production of bioactive haFGF in silkworm cocoons.

  19. Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia

    Institute of Scientific and Technical Information of China (English)

    XIA Wei-bo; ZHOU Xue-ying; JIANG Yan; LI Mei; XING Xiao-ping; WANG Ou; HU Ying-ying; ZHANG Hua-bing; LIU Huai-cheng; MENG Xun-wu

    2010-01-01

    Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 (FGF-23) in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. Methods Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group (HP, 12 female and 7 male, mean age was 30 years), and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay.Results Mean FGF-23 concentrations were significantly higher in the HP group ((87.4±43.6) pg/ml) compared with the control group ((19.2±6.16) pg/ml; P <0.001). In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection (7.8 pg/ml). Subsequently, serum 1,25(OH)2 vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. Conclusions Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.

  20. Fibroblast growth factor receptor signaling in kidney and lower urinary tract development.

    Science.gov (United States)

    Walker, Kenneth A; Sims-Lucas, Sunder; Bates, Carlton M

    2016-06-01

    Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development. FGFR signaling has been shown to be critical for early metanephric mesenchymal patterning, Wolffian duct patterning including induction of the ureteric bud, ureteric bud branching morphogenesis, nephron progenitor survival and nephrogenesis, and bladder mesenchyme patterning. FGFRs pattern these tissues by interacting with many other growth factor signaling pathways. Moreover, the many genetic Fgfr and Fgf animal models have structural defects mimicking numerous congenital anomalies of the kidney and urinary tract seen in humans. Finally, many studies have shown how FGFR signaling is critical for kidney and lower urinary tract patterning in humans. PMID:26293980

  1. Involvement of Fibroblast Growth Factor Receptor Genes in Benign Prostate Hyperplasia in a Korean Population

    Directory of Open Access Journals (Sweden)

    Hae Jeong Park

    2013-01-01

    Full Text Available Fibroblast growth factors (FGFs and their receptors (FGFRs have been implicated in prostate growth and are overexpressed in benign prostatic hyperplasia (BPH. In this study, we investigated whether single nucleotide polymorphisms (SNPs of the FGFR genes (FGFR1 and FGFR2 were associated with BPH and its clinical phenotypes in a population of Korean men. We genotyped four SNPs in the exons of FGFR1 and FGFR2 (rs13317 in FGFR1; rs755793, rs1047100, and rs3135831 in FGFR2 using direct sequencing in 218 BPH patients and 213 control subjects. No SNPs of FGFR1 or FGFR2 genes were associated with BPH. However, analysis according to clinical phenotypes showed that rs1047100 of FGFR2 was associated with prostate volume in BPH in the dominant model (GA/AA versus GG, P = 0.010. In addition, a significant association was observed between rs13317 of FGFR1 and international prostate symptom score (IPSS in the additive (TC versus CC versus TT, P = 0.0022 and dominant models (TC/CC versus TT, P = 0.005. Allele frequency analysis also showed significant association between rs13317 and IPSS (P = 0.005. These results suggested that FGFR genes could be related to progression of BPH.

  2. X-ray structure and biophysical properties of rabbit fibroblast growth factor 1

    International Nuclear Information System (INIS)

    This report shows that the tertiary structure of rabbit FGF-1 is essentially identical to that of human FGF-1, with four surface mutations (140-amino-acid form). Biophysical data indicate that rabbit FGF-1 is less thermostable than human FGF-1 and has a slower association rate with the FGF-1 receptor. Mitogenic assays indicate that rabbit FGF-1 is tenfold less potent than human FGF-1; however, rabbit FGF-1 exhibits greater heparin stimulation such that its mitogenic activity in the presence of heparin is essentially indistinguishable from that of human FGF-1. The rabbit is an important and de facto animal model in the study of ischemic disease and angiogenic therapy. Additionally, fibroblast growth factor 1 (FGF-1) is emerging as one of the most important growth factors for novel pro-angiogenic and pro-arteriogenic therapy. However, despite its significance, the fundamental biophysical properties of rabbit FGF-1, including its X-ray structure, have never been reported. Here, the cloning, crystallization, X-ray structure and determination of the biophysical properties of rabbit FGF-1 are described. The X-ray structure shows that the amino-acid differences between human and rabbit FGF-1 are solvent-exposed and therefore potentially immunogenic, while the biophysical studies identify differences in thermostability and receptor-binding affinity that distinguish rabbit FGF-1 from human FGF-1

  3. Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate.

    Science.gov (United States)

    Shiang, Christine Y; Qi, Yuan; Wang, Bailiang; Lazar, Vladimir; Wang, Jing; Fraser Symmans, W; Hortobagyi, Gabriel N; Andre, Fabrice; Pusztai, Lajos

    2010-10-01

    Fibroblast growth factor receptor-1 (FGFR-1) is amplified in 10% of human breast cancers. The goal of this study was to test the correlation between FGFR-1 amplification and expression and sensitivity to brivanib, an FGFR-1 small molecule inhibitor, in breast cancer cell lines in vitro. Using CGH array and gene expression profiling, FGFR-1 DNA copy number, mRNA, and protein expression were measured in 21 cell lines and correlated with growth inhibition by brivanib. We examined FGFR-1 autophosphorylation and kinase activity, as well as phosphorylation of downstream signaling molecules in response to bFGF and brivanib exposure. CAMA, MDA-MB-361, and HCC38 cells had FGFR-1 amplification and protein overexpression. Brivanib GI(50) values were significantly lower in the gene amplified (15.17 μM, n = 3) compared to normal copy number (69.09 μM, n = 11) or FGFR-1 deleted (76.14 μM, n = 7) cells (P = 0.0107). Among nonamplified cells, there was no correlation between FGFR-1 mRNA or protein expression levels and brivanib sensitivity. Two of three FGFR-1 amplified cells were sensitive to bFGF-induced growth stimulation, which was blocked by brivanib. In cells with amplified FGFR-1, brivanib decreased receptor autophosphorylation, inhibited bFGF-induced tyrosine kinase activity, and reduced phosphorylation of ERK and AKT. Breast cancer cell lines with FGFR-1 gene amplification and protein overexpression are more sensitive to growth inhibition by brivanib than nonamplified cells. These findings suggest that FGFR-1 amplification or protein overexpression in breast cancers may be an indicator for brivanib treatment, where it may have direct anti-proliferative effects in addition to its' anti-angiogenic effects.

  4. Chicken stem cell factor enhances primordial germ cell proliferation cooperatively with fibroblast growth factor 2.

    Science.gov (United States)

    Miyahara, Daichi; Oishi, Isao; Makino, Ryuichi; Kurumisawa, Nozomi; Nakaya, Ryuma; Ono, Tamao; Kagami, Hiroshi; Tagami, Takahiro

    2016-04-22

    An in vitro culture system of chicken primordial germ cells (PGCs) has been recently developed, but the growth factor involved in the proliferation of PGCs is largely unknown. In the present study, we investigated the growth effects of chicken stem cell factor (chSCF) on the in vitro proliferation of chicken PGCs. We established two feeder cell lines (buffalo rat liver cells; BRL cells) that stably express the putative secreted form of chSCF (chSCF1-BRL) and membrane bound form of chSCF (chSCF2-BRL). Cultured PGC lines were incubated on chSCF1 or chSCF2-BRL feeder cells with fibroblast growth factor 2 (FGF2), and growth effects of each chSCF isoform were investigated. The in vitro proliferation rate of the PGCs cultured on chSCF2-BRL at 20 days of culture was more than threefold higher than those cultured on chSCF1-BRL cells and more than fivefold higher than those cultured on normal BRL cells. Thus, use of chSCF2-BRL feeder layer was effective for in vitro proliferation of chicken PGCs. However, the acceleration of PGC proliferation on chSCF2-BRL was not observed without FGF2, suggesting that chSCF2 would act as a proliferation co-factor of FGF2. We transferred the PGCs cultured on chSCF2-BRL cells to recipient embryos, generated germline chimeric chickens and assessed the germline competency of cultured PGCs by progeny test. Donor-derived progenies were obtained, and the frequency of germline transmission was 3.39%. The results of this study demonstrate that chSCF2 induces hyperproliferation of chicken PGCs retaining germline competency in vitro in cooperation with FGF2. PMID:26727404

  5. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

    International Nuclear Information System (INIS)

    Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R. Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC

  6. Fibroblast growth factor 8 increases breast cancer cell growth by promoting cell cycle progression and by protecting against cell death

    Energy Technology Data Exchange (ETDEWEB)

    Nilsson, Emeli M., E-mail: Emeli.Nilsson@med.lu.se [Department of Laboratory Medicine, Tumour Biology, Lund University, CRC, Building 91, Plan 10, Entrance 72, UMAS, 205 02 Malmoe (Sweden); Brokken, Leon J.S., E-mail: Leon.Brokken@med.lu.se [Department of Laboratory Medicine, Tumour Biology, Lund University, CRC, Building 91, Plan 10, Entrance 72, UMAS, 205 02 Malmoe (Sweden); Haerkoenen, Pirkko L., E-mail: Pirkko.Harkonen@med.lu.se [Department of Laboratory Medicine, Tumour Biology, Lund University, CRC, Building 91, Plan 10, Entrance 72, UMAS, 205 02 Malmoe (Sweden)

    2010-03-10

    Fibroblast growth factor 8 (FGF-8) is expressed in a large proportion of breast cancers, whereas its level in normal mammary gland epithelium is low. Previous studies have shown that FGF-8b stimulates breast cancer cell growth in vitro and in vivo. To explore the mechanisms by which FGF-8b promotes growth, we studied its effects on cell cycle regulatory proteins and signalling pathways in mouse S115 and human MCF-7 breast cancer cells. We also studied the effect of FGF-8b on cell survival. FGF-8b induced cell cycle progression and up-regulated particularly cyclin D1 mRNA and protein in S115 cells. Silencing cyclin D1 with siRNA inhibited most but not all FGF-8b-induced proliferation. Inhibition of the FGF-8b-activated ERK/MAPK pathway decreased FGF-8b-stimulated proliferation. Blocking the constitutively active PI3K/Akt and p38 MAPK pathways also lowered FGF-8b-induced cyclin D1 expression and proliferation. Corresponding results were obtained in MCF-7 cells. In S115 and MCF-7 mouse tumours, FGF-8b increased cyclin D1 and Ki67 levels. Moreover, FGF-8b opposed staurosporine-induced S115 cell death which effect was blocked by inhibiting the PI3K/Akt pathway but not the ERK/MAPK pathway. In conclusion, our results suggest that FGF-8b increases breast cancer cell growth both by stimulating cell cycle progression and by protecting against cell death.

  7. The effects of swimming on the expression of glial fibrillary acidic protein and basic fibroblast growth factor after cerebral ischemia and reperfusion%不同游泳训练强度对脑缺血再灌注大鼠胶质纤维酸性蛋白及碱性成纤维细胞生长因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    王佩佩; 吴艺玲; 王强

    2012-01-01

    Objective To explore the effects of different swimming training intensities on the expression of glial fibrillary acidic protein (GFAP) and basic fibroblast growth factor (bFGF) around a cerebral infarct. Methods The intraluminal thread method was applied to establish left middle cerebral artery occlusion (MCAO) for 2 h in 180 rats.They were then reperfused for 3,7 and 14 days.The rats were divided into four groups ( Ⅰ -Ⅳ) according to the intensity of the swimming training they were required to do,plus a control group and a sham operation group.The rats in training group Ⅰ swam 5 min,once daily; group Ⅱ trained for 5 min twice daily; group Ⅲ swam for 10 min once daily and group Ⅳ trained for 10 min twice daily.Neurological function was evaluated using Bederson's test,the cerebral infarction volume was calculated by tripeny tetrazolium chloride (TTC) staining.The expression of GFAP and bFGF around the infract were detected using immunohistochemistry. Results The average Bederson scores of the exercise training groups on the 7th and 14th days were significantly lower than that of the control group.The infarction volumes of each exercise training group were significantly lower than that of the control group,and cells positive for GFAP and bFGF in all training groups were significantly more numerous on the 3th,7th and 14th day after MCAO,especially in training group Ⅳ. Conclusion Intensive exercise can adjust the expression of GFAP and bFGF and promote the repair of brain damage after cerebral ischemia and reperfusion.%目的 探讨强化训练对脑缺血再灌注大鼠梗死周围区胶质纤维酸性蛋白(GFAP)和碱性成纤维细胞生长因子(bFGF)表达的影响.方法 成年健康年雄性Wistar大鼠286只,体重250 ~300 g,清洁级,线栓法制作大脑中动脉缺血2h后再灌注3、7和14d大鼠模型,将造模成功的180只大鼠纳入研究,按随机数字表法分为运动训练Ⅰ组、运动训练Ⅱ组、运动训练Ⅲ组、运

  8. Murine gamma interferon fails to inhibit Toxoplasma gondii growth in murine fibroblasts.

    Science.gov (United States)

    Schwartzman, J D; Gonias, S L; Pfefferkorn, E R

    1990-01-01

    Although treatment of human macrophages or fibroblasts with human gamma interferon results in the inhibition of intracellular Toxoplasma gondii, murine gamma interferon stimulated only murine macrophages, not murine fibroblasts, to inhibit T. gondii. This species difference may be important in understanding the control of acute and chronic toxoplasmosis. PMID:2106497

  9. Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase

    Directory of Open Access Journals (Sweden)

    Kenneth W. Jackson

    2015-01-01

    Full Text Available Tumor microenvironments (TMEs are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP and prolyl oligopeptidase (POP, are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth >90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.

  10. The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers

    Directory of Open Access Journals (Sweden)

    Mohamed M. NasrAllah

    2013-11-01

    Full Text Available Background: Fibroblast growth factor-23 (FGF-23 has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD, although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated. Methods: We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP, endogenous soluble receptor of advanced glycation end products (esRAGE, advanced oxidation protein products (AOPP, parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI was determined using non-contrast CT scans of the abdominal aorta. Results: FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906 and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p 2 = 0.65, p Conclusion: FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers.

  11. The ORF 113 of Heliocoverpa armigera Single Nucleopolyhedrovirus Encodes a Functional Fibroblast Growth Factor

    Institute of Scientific and Technical Information of China (English)

    Xiang LI; Chang-yong LIANG; Jian-hua SONG; Xin-wen CHEN

    2008-01-01

    Fibroblast growth factor (FGF) is a key regulator of developmental processes. A FGF homolog (vFGF) is found in all lepidopteran baculoviruses. Autographa californica nucleopolyhedrovirus (AcMNPV) and Bombyx mori NPV (BmNPV) vFGFs are chemotactic factors. Here we analyzed the vfgf of Helicoverpa armigera NPV (HearNPV), a group Ⅱ NPV. The HearNPV vfgftranscripts were detected from 18 to 96 h post-infection (hpi) of Hz-AMI cells with HearNPV and encoded a 36 kDa protein, which was secreted into the culture medium. HearNPV vFGF had strong affinity to heparin, a property important for FGF signaling via an FGF receptor. Unlike its AcMNPV homolog, HearNPV vFGF specially chemoattracted Hz-AM 1, but not other insect cells such as Sf9 and Se-UCR and not the mammalian cells 293 and HepG2. HearNPV vFGF is also associated with the envelope of BV but is absent in occlusion-derived virus, which coordinated to the chemotatic activity analysis.

  12. Fluid flow releases fibroblast growth factor-2 from human aortic smooth muscle cells

    Science.gov (United States)

    Rhoads, D. N.; Eskin, S. G.; McIntire, L. V.

    2000-01-01

    This study tested the hypothesis that fluid shear stress regulates the release of fibroblast growth factor (FGF)-2 from human aortic smooth muscle cells. FGF-2 is a potent mitogen that is involved in the response to vascular injury and is expressed in a wide variety of cell types. FGF-2 is found in the cytoplasm of cells and outside cells, where it associates with extracellular proteoglycans. To test the hypothesis that shear stress regulates FGF-2 release, cells were exposed to flow, and FGF-2 amounts were measured from the conditioned medium, pericellular fraction (extracted by heparin treatment), and cell lysate. Results from the present study show that after 15 minutes of shear stress at 25 dyne/cm(2) in a parallel-plate flow system, a small but significant fraction (17%) of the total FGF-2 was released from human aortic smooth muscle cells. FGF-2 levels in the circulating medium increased 10-fold over medium from static controls (Pheparin treatment). Furthermore, a significant decrease in FGF-2 was detected in the cell lysate, indicating that FGF-2 was released from inside the cell. Cell permeability studies with fluorescent dextran were performed to examine whether transient membrane disruption caused FGF-2 release. Flow cytometry detected a 50% increase in mean fluorescence of cells exposed to 25 dyne/cm(2) versus control cells. This indicates that the observed FGF-2 release from human aortic smooth muscle cells is likely due to transient membrane disruption on initiation of flow.

  13. Fibroblast growth factor receptor 4 polymorphism is associated with liver cirrhosis in hepatocarcinoma.

    Directory of Open Access Journals (Sweden)

    Ming-Jen Sheu

    Full Text Available Fibroblast growth factor receptor 4 (FGFR4 polymorphisms are positively correlated with tumor progression in numerous malignant tumors. However, the association between FGFR4 genetic variants and the risk of hepatocellular carcinoma (HCC has not yet been determined. In this study, we investigated the potential associations of FGFR4 single nucleotide polymorphisms (SNPs with HCC susceptibility and its clinicopathological characteristics.Four SNPs in FGFR4 (rs1966265, rs351855, rs2011077, and rs7708357 were analyzed among 884 participants, including 595 controls and 289 patients with HCC. The samples were further analyzed to clarify the associations between these gene polymorphisms and the risk of HCC, and the impact of these SNPs on the susceptibility and clinicopathological characteristics of HCC. After adjusting for other covariants, HCC patients who carrying at least one A genotype (GA and AA at rs351855 were observed to have a higher risk of liver cirrhosis compared with those carrying the wild-type genotype (GG (OR: 2.113, 95% CI: 1.188-3.831. Moreover, the patients with at least one A genotype were particularly showed a high level of alpha-fetoprotein (AFP.Our findings suggest that genetic polymorphism in FGFR4 rs351855 may be associated with the risk of HCC coupled with liver cirrhosis and may markedly increase the AFP level in Taiwanese patients with HCC. In addition, this is the first study that evaluated the risk factors associated with FGFR4 polymorphism variants in Taiwanese patients with HCC.

  14. Association between fibroblast growth factor 7 and the risk of chronic obstructive pulmonary disease

    Institute of Scientific and Technical Information of China (English)

    Si-cheng XU; Jiang-ying KUANG; Jin LIU; Chun-lan MA; Yu-lin FENG; Zhi-guang SU

    2012-01-01

    Aim:Fibroblast growth factor 7 (FGF7) is involved in a number of physiological and pathological processes,including lung disease.However,relatively little is known about the effect of FGF7 gene polymorphisms on chronic obstructive pulmonary disease (COPD) susceptibility.This study aimed to investigate the association between FGF7 polymorphisms with COPD susceptibility in a Chinese Han population.Methods:We conducted a case-control study of 279 COPD patients and 367 age- and gender-distribution-matched control subjects.The tagging SNPs rs10519225 and rs7170426 in FGF7 were genotyped by SNaPshot.The associations of each SNP genotype and haplotype constructed by these loci with COPD were analyzed.Results:A multivariate analysis showed that rs10519225 was significantly associated with an increased risk of COPD (P=-0.011,OR=1.535,FDR q=0.022),whereas no association was found for rs7170426.Linkage disequilibrium (LD) analysis showed that these loci were in weak LD,with an r2 of 0.033 and a D' of 0.232 (95% CI:0.150-0.520).The haplotype constructed by allele G at rs10519225 and allele A at rs7170426 was associated with a decreased susceptibility to COPD (P=0.012,OR=0.751,FDR q=0.048).Conclusion:These findings suggest that FGF7 may be one susceptibility factor for COPD.

  15. Fibroblast growth factor (Fgf) signaling pathway regulates liver homeostasis in zebrafish.

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    Tsai, Su-Mei; Liu, Da-Wei; Wang, Wen-Pin

    2013-04-01

    In mammals, fibroblast growth factor (FGF) signaling controls liver specification and regulates the metabolism of lipids, cholesterol, and bile acids. FGF signaling also promotes hepatocyte proliferation, and helps detoxify hepatotoxin during liver regeneration after partial hepatectomy. However, the function of Fgf in zebrafish liver is not yet well understood, specifically for postnatal homeostasis. The current study analyzed the expression of fgf receptors (fgfrs) in the liver of zebrafish. We then investigated the function of Fgf signaling in the zebrafish liver by expressing a dominant-negative Fgf receptor in hepatocytes (lfabp:dnfgfr1-egfp, lf:dnfr). Histological analysis showed that our genetic intervention resulted in a small liver size with defected medial expansion of developing livers in transgenic (Tg) larvae. Morphologically, the liver lobe of lf:dnfr adult fish was shorter than that of control. Ballooning degeneration of hepatocytes was observed in fish as young as 3 months. Further examination revealed the development of hepatic steatosis and cholestasis. In adult Tg fish, we unexpectedly observed increased liver-to-body-weight ratios, with higher percentages of proliferating hepatocytes. Considering all these findings, we concluded that as in mammals, in adult zebrafish the metabolism of lipid and bile acids in the liver are regulated by Fgf signaling. Disruption of the Fgf signal-mediated metabolism might indirectly affect hepatocyte proliferation. PMID:22820869

  16. Nucleolin regulates phosphorylation and nuclear export of fibroblast growth factor 1 (FGF1.

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    Torunn Sletten

    Full Text Available Extracellular fibroblast growth factor 1 (FGF1 acts through cell surface tyrosine kinase receptors, but FGF1 can also act directly in the cell nucleus, as a result of nuclear import of endogenously produced, non-secreted FGF1 or by transport of extracellular FGF1 via endosomes and cytosol into the nucleus. In the nucleus, FGF1 can be phosphorylated by protein kinase C δ (PKCδ, and this event induces nuclear export of FGF1. To identify intracellular targets of FGF1 we performed affinity pull-down assays and identified nucleolin, a nuclear multifunctional protein, as an interaction partner of FGF1. We confirmed a direct nucleolin-FGF1 interaction by surface plasmon resonance and identified residues of FGF1 involved in the binding to be located within the heparin binding site. To assess the biological role of the nucleolin-FGF1 interaction, we studied the intracellular trafficking of FGF1. In nucleolin depleted cells, exogenous FGF1 was endocytosed and translocated to the cytosol and nucleus, but FGF1 was not phosphorylated by PKCδ or exported from the nucleus. Using FGF1 mutants with reduced binding to nucleolin and a FGF1-phosphomimetic mutant, we showed that the nucleolin-FGF1 interaction is critical for the intranuclear phosphorylation of FGF1 by PKCδ and thereby the regulation of nuclear export of FGF1.

  17. Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology.

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    Belov, Artur A; Mohammadi, Moosa

    2013-06-01

    Fibroblast growth factors (FGFs) signal in a paracrine or endocrine fashion to mediate a myriad of biological activities, ranging from issuing developmental cues, maintaining tissue homeostasis, and regulating metabolic processes. FGFs carry out their diverse functions by binding and dimerizing FGF receptors (FGFRs) in a heparan sulfate (HS) cofactor- or Klotho coreceptor-assisted manner. The accumulated wealth of structural and biophysical data in the past decade has transformed our understanding of the mechanism of FGF signaling in human health and development, and has provided novel concepts in receptor tyrosine kinase (RTK) signaling. Among these contributions are the elucidation of HS-assisted receptor dimerization, delineation of the molecular determinants of ligand-receptor specificity, tyrosine kinase regulation, receptor cis-autoinhibition, and tyrosine trans-autophosphorylation. These structural studies have also revealed how disease-associated mutations highjack the physiological mechanisms of FGFR regulation to contribute to human diseases. In this paper, we will discuss the structurally and biophysically derived mechanisms of FGF signaling, and how the insights gained may guide the development of therapies for treatment of a diverse array of human diseases. PMID:23732477

  18. Fibroblast Growth Factor 21 Protects against Atherosclerosis via Fine-Tuning the Multiorgan Crosstalk

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    Leigang Jin

    2016-02-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.

  19. Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual Screening

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    Ravindranathan, K.; Mandiyan, V; Ekkati, A; Bae, J; Schlessinger, J; Jorgensen, W

    2010-01-01

    Fibroblast growth factors (FGFs) play important roles in embryonic development, angiogenesis, wound healing, and cell proliferation and differentiation. In search of inhibitors of FGFR1 kinase, 2.2 million compounds were docked into the ATP binding site of the protein. A co-crystal structure, which shows two alternative conformations for the nucleotide binding loop, is reported. Docking was performed on both conformations and, ultimately, 23 diverse compounds were purchased and assayed. Following hit validation, two compounds 10 and 16, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, respectively, were discovered that inhibit FGFR1 kinase with IC{sub 50} values of 23 and 50 {micro}M. Initial optimization of 16 led to the more unsaturated 40, which has significantly enhanced potency, 1.9 {micro}M. The core structures represent new structural motifs for FGFR1 kinase inhibitors. The study also illustrates complexities associated with the choice of protein structures for docking, possible use of multiple kinase structures to seek selectivity, and hit identification.

  20. Dietary moderately oxidized oil induces expression of fibroblast growth factor 21 in the liver of pigs

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    Varady Juliane

    2012-03-01

    Full Text Available Abstract Background Fibroblast growth factor 21 (FGF21, whose expression is induced by peroxisome proliferator-activated receptor α (PPARα, has been recently identified as a novel metabolic regulator which plays a crucial role in glucose homeostasis, lipid metabolism, insulin sensitivity and obesity. Previous studies have shown that administration of oxidized fats leads to an activation of PPARα in the liver. Therefore, the present study investigated the hypothesis that feeding of oxidized fats causes an induction of FGF21 in the liver. Methods Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h. Results In pigs fed the oxidized fat mRNA abundance and protein concentrations of FGF21 in liver were significantly increased (P P P Conclusion The present study shows for the first time that administration of an oxidized fat induces the expression of FGF21 in the liver, probably mediated by activation of PPARα. Induction of FGF21 could be involved in several effects observed in animals administered an oxidized fat.

  1. Novel Bioluminescent Binding Assays for Ligand–Receptor Interaction Studies of the Fibroblast Growth Factor Family

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    Song, Ge; Shao, Xiao-Xia; Wu, Qing-Ping; Xu, Zeng-Guang; Liu, Ya-Li; Guo, Zhan-Yun

    2016-01-01

    We recently developed novel bioluminescent binding assays for several protein/peptide hormones to study their interactions with receptors using the so far brightest NanoLuc reporter. To validate the novel bioluminescent binding assay using a variety of protein/peptide hormones, in the present work we applied it to the fibroblast growth factor (FGF) family using the prototype member FGF2 as an example. A fully active recombinant FGF2 retaining a unique exposed cysteine (Cys) residue was chemically conjugated with an engineered NanoLuc carrying a unique exposed Cys residue at the C-terminus via formation of an intermolecular disulfide linkage. The NanoLuc-conjugated FGF2 (FGF2-Luc) retained high binding affinity to the overexpressed FGFR1 and the endogenous FGF receptor with the calculated dissociation constants of 161 ± 21 pM (n = 3) and 25 ± 4 pM (n = 3), respectively. In competition binding assays using FGF2-Luc as a tracer, receptor-binding potencies of wild-type or mutant FGF2s were accurately quantified. Thus, FGF2-Luc represents a novel non-radioactive tracer for the quantitative measurement of ligand–receptor interactions in the FGF family. These data suggest that the novel bioluminescent binding assay can be applied to a variety of protein/peptide hormones for ligand–receptor interaction studies. PMID:27414797

  2. Fluid flow releases fibroblast growth factor-2 from human aortic smooth muscle cells

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    Rhoads, D. N.; Eskin, S. G.; McIntire, L. V.

    2000-01-01

    This study tested the hypothesis that fluid shear stress regulates the release of fibroblast growth factor (FGF)-2 from human aortic smooth muscle cells. FGF-2 is a potent mitogen that is involved in the response to vascular injury and is expressed in a wide variety of cell types. FGF-2 is found in the cytoplasm of cells and outside cells, where it associates with extracellular proteoglycans. To test the hypothesis that shear stress regulates FGF-2 release, cells were exposed to flow, and FGF-2 amounts were measured from the conditioned medium, pericellular fraction (extracted by heparin treatment), and cell lysate. Results from the present study show that after 15 minutes of shear stress at 25 dyne/cm(2) in a parallel-plate flow system, a small but significant fraction (17%) of the total FGF-2 was released from human aortic smooth muscle cells. FGF-2 levels in the circulating medium increased 10-fold over medium from static controls (Pmuscle cells is likely due to transient membrane disruption on initiation of flow.

  3. Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells

    Institute of Scientific and Technical Information of China (English)

    L(U) Yun; ZHANG Ying-chuan; LIU Jing-hua; ZHANG Li-ke; DU Jie; ZENG Xiang-jun; HAO Gang; HUANG Ji; ZHAO Dong-hui; WANG Guo-zhong

    2010-01-01

    Background Fibroblast growth factor 21 (FGF21) is a new member of FGF super family that is an important endogenous regulator for systemic glucose and lipid metabolism. This study aimed to explore whether FGF21 reduces atherosclerotic injury and prevents endothelial dysfunction as an independent protection factor.Methods The present study was designed to investigate the changes of FGF21 levels induced by oxidized-low density lipoprotein (ox-LDL), and the changes of apoptosis affected by regulating FGF21 expression. The FGF21 mRNA levels of cultured cardiac microvascular endothelial cells (CMECs) were determined by real time-PCR and the protein concentration in culture media was detected by enzyme-linked immunosorbent assay. We analyzed the different expression levels of untreated controls and CMFCs incubated with ox-LDL, and the changes of CMECs apoptosis initiated by the enhancement or suppression of FGF21 levels.Results The secretion levels of FGF21 mRNA and protein were significantly upregulated in CMECs incubated with ox-LDL. Furthermore, FGF21 levels increased by 200 μmol/L bezafibrate could reduce CMECs apoptosis, and inhibit FGF21 expression by shRNA induced apoptosis (P <0.05).Conclusions FGF21 may be a signal of injured target tissue, and may play physiological roles in improving the endothelial function at an early stage of atherosclerosis and in stopping the development of coronary heart disease.

  4. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia

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    Alshammari, T K; Alshammari, M A; Nenov, M N; Hoxha, E; Cambiaghi, M; Marcinno, A; James, T F; Singh, P; Labate, D; Li, J; Meltzer, H Y; Sacchetti, B; Tempia, F; Laezza, F

    2016-01-01

    Cognitive processing is highly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons in the brain. These cells regulate excitability and synaptic plasticity of principal neurons balancing the excitatory/inhibitory tone of cortical networks. Reduced function of parvalbumin (PV) interneurons and disruption of GABAergic synapses in the cortical circuitry result in desynchronized network activity associated with cognitive impairment across many psychiatric disorders, including schizophrenia. However, the mechanisms underlying these complex phenotypes are still poorly understood. Here we show that in animal models, genetic deletion of fibroblast growth factor 14 (Fgf14), a regulator of neuronal excitability and synaptic transmission, leads to loss of PV interneurons in the CA1 hippocampal region, a critical area for cognitive function. Strikingly, this cellular phenotype associates with decreased expression of glutamic acid decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) and also coincides with disrupted CA1 inhibitory circuitry, reduced in vivo gamma frequency oscillations and impaired working memory. Bioinformatics analysis of schizophrenia transcriptomics revealed functional co-clustering of FGF14 and genes enriched within the GABAergic pathway along with correlatively decreased expression of FGF14, PVALB, GAD67 and VGAT in the disease context. These results indicate that Fgf14−/− mice recapitulate salient molecular, cellular, functional and behavioral features associated with human cognitive impairment, and FGF14 loss of function might be associated with the biology of complex brain disorders such as schizophrenia. PMID:27163207

  5. Effect of Fibroblast Growth Factor 2 on Equine Synovial Fluid Chondroprogenitor Expansion and Chondrogenesis

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    Marta Bianchessi

    2016-01-01

    Full Text Available Mesenchymal stem cells have been identified in the synovial fluid of several species. This study was conducted to characterize chondroprogenitor (CP cells in equine synovial fluid (SF and to determine the effect of fibroblast growth factor 2 (FGF-2 on SF-CP monolayer proliferation and subsequent chondrogenesis. We hypothesized that FGF-2 would stimulate SF-CP proliferation and postexpansion chondrogenesis. SF aspirates were collected from adult equine joints. Colony-forming unit (CFU assays were performed during primary cultures. At first passage, SF-cells were seeded at low density, with or without FGF-2. Following monolayer expansion and serial immunophenotyping, cells were transferred to chondrogenic pellet cultures. Pellets were analyzed for chondrogenic mRNA expression and cartilage matrix secretion. There was a mean of 59.2 CFU/mL of SF. FGF-2 increased the number of population doublings during two monolayer passages and halved the population doubling times. FGF-2 did not alter the immunophenotype of SF-CPs during monolayer expansion, nor did FGF-2 compromise chondrogenesis. Hypertrophic phenotypic markers were not expressed in control or FGF-2 groups. FGF-2 did prevent the development of a “fibroblastic” cell layer around pellet periphery. FGF-2 significantly accelerates in vitro SF-CP expansion, the major hurdle to clinical application of this cell population, without detrimentally affecting subsequent chondrogenic capacity.

  6. Fluid flow releases fibroblast growth factor-2 from human aortic smooth muscle cells

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    Rhoads, D. N.; Eskin, S. G.; McIntire, L. V.

    2000-01-01

    This study tested the hypothesis that fluid shear stress regulates the release of fibroblast growth factor (FGF)-2 from human aortic smooth muscle cells. FGF-2 is a potent mitogen that is involved in the response to vascular injury and is expressed in a wide variety of cell types. FGF-2 is found in the cytoplasm of cells and outside cells, where it associates with extracellular proteoglycans. To test the hypothesis that shear stress regulates FGF-2 release, cells were exposed to flow, and FGF-2 amounts were measured from the conditioned medium, pericellular fraction (extracted by heparin treatment), and cell lysate. Results from the present study show that after 15 minutes of shear stress at 25 dyne/cm(2) in a parallel-plate flow system, a small but significant fraction (17%) of the total FGF-2 was released from human aortic smooth muscle cells. FGF-2 levels in the circulating medium increased 10-fold over medium from static controls (PFlow cytometry detected a 50% increase in mean fluorescence of cells exposed to 25 dyne/cm(2) versus control cells. This indicates that the observed FGF-2 release from human aortic smooth muscle cells is likely due to transient membrane disruption on initiation of flow.

  7. Sprouty2 controls proliferation of palate mesenchymal cells via fibroblast growth factor signaling

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    Matsumura, Kaori [Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Taketomi, Takaharu, E-mail: taketomi@dent.kyushu-u.ac.jp [Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Yoshizaki, Keigo [Section of Orthodontics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Arai, Shinsaku [Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Sanui, Terukazu [Section of Periodontology, Division of Oral Rehabilitation, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Yoshiga, Daigo [Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Yoshimura, Akihiko [Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan); Japan Science and Technology Agency (JST), CREST, Chiyoda-ku, Tokyo 102-0075 (Japan); Nakamura, Seiji [Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2011-01-28

    Research highlights: {yields} Sprouty2-deficient mice exhibit cleft palate as a result of failure of palatal shelf elevation. {yields} We examined palate cell proliferation in Sprouty2-deficient mice. {yields} Palate mesenchymal cell proliferation was increased in Sprouty2 KO mice. {yields} Sprouty2 plays roles in murine palatogenesis by regulating cell proliferation. -- Abstract: Cleft palate is one of the most common craniofacial deformities. The fibroblast growth factor (FGF) plays a central role in reciprocal interactions between adjacent tissues during palatal development, and the FGF signaling pathway has been shown to be inhibited by members of the Sprouty protein family. In this study, we report the incidence of cleft palate, possibly caused by failure of palatal shelf elevation, in Sprouty2-deficient (KO) mice. Sprouty2-deficient palates fused completely in palatal organ culture. However, palate mesenchymal cell proliferation estimated by Ki-67 staining was increased in Sprouty2 KO mice compared with WT mice. Sprouty2-null palates expressed higher levels of FGF target genes, such as Msx1, Etv5, and Ptx1 than WT controls. Furthermore, proliferation and the extracellular signal-regulated kinase (Erk) activation in response to FGF was enhanced in palate mesenchymal cells transfected with Sprouty2 small interfering RNA. These results suggest that Sprouty2 regulates palate mesenchymal cell proliferation via FGF signaling and is involved in palatal shelf elevation.

  8. Fibroblast growth factor receptor-2 expression in thyroid tumor progression: potential diagnostic application.

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    Redler, Adriano; Di Rocco, Giorgio; Giannotti, Domenico; Frezzotti, Francesca; Bernieri, Maria Giulia; Ceccarelli, Simona; D'Amici, Sirio; Vescarelli, Enrica; Mitterhofer, Anna Paola; Angeloni, Antonio; Marchese, Cinzia

    2013-01-01

    Fibroblast growth factor receptor-2 (FGFR-2) plays an important role in tumorigenesis. In thyroid cancer it has been observed a FGFR-2 down-modulation, but the role of this receptor has not been yet clarified. Therefore, we decided to examine the expression of both FGFR-2 isoform, FGFR-2-IIIb and FGFR-2-IIIc, in different histological thyroid variants such as hyperplasia, follicular adenoma and papillary carcinoma. Immunohistochemistry and quantitative Real-Time PCR analyses were performed on samples of hyperplasia, follicular adenoma and papillary carcinoma, compared with normal thyroid tissue. Thyroid hyperplasia did not show statistically significant reduction in FGFR-2 protein and mRNA levels. Interestingly, in both follicular adenoma and papillary carcinoma samples we observed a strongly reduced expression of both FGFR-2 isoforms. We speculate that FGFR-2 down-modulation might be an early event in thyroid carcinogenesis. Furthermore, we suggest the potential use of FGFR-2 as an early marker for thyroid cancer diagnosis. PMID:23977259

  9. Fibroblast growth factor receptor-2 expression in thyroid tumor progression: potential diagnostic application.

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    Adriano Redler

    Full Text Available Fibroblast growth factor receptor-2 (FGFR-2 plays an important role in tumorigenesis. In thyroid cancer it has been observed a FGFR-2 down-modulation, but the role of this receptor has not been yet clarified. Therefore, we decided to examine the expression of both FGFR-2 isoform, FGFR-2-IIIb and FGFR-2-IIIc, in different histological thyroid variants such as hyperplasia, follicular adenoma and papillary carcinoma. Immunohistochemistry and quantitative Real-Time PCR analyses were performed on samples of hyperplasia, follicular adenoma and papillary carcinoma, compared with normal thyroid tissue. Thyroid hyperplasia did not show statistically significant reduction in FGFR-2 protein and mRNA levels. Interestingly, in both follicular adenoma and papillary carcinoma samples we observed a strongly reduced expression of both FGFR-2 isoforms. We speculate that FGFR-2 down-modulation might be an early event in thyroid carcinogenesis. Furthermore, we suggest the potential use of FGFR-2 as an early marker for thyroid cancer diagnosis.

  10. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism.

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    Hu, Ming Chang; Shiizaki, Kazuhiro; Kuro-o, Makoto; Moe, Orson W

    2013-01-01

    The metabolically active and perpetually remodeling calcium phosphate-based endoskeleton in terrestrial vertebrates sets the demands on whole-organism calcium and phosphate homeostasis that involves multiple organs in terms of mineral flux and endocrine cross talk. The fibroblast growth factor (FGF)-Klotho endocrine networks epitomize the complexity of systems biology, and specifically, the FGF23-αKlotho axis highlights the concept of the skeleton holding the master switch of homeostasis rather than a passive target organ as hitherto conceived. Other than serving as a coreceptor for FGF23, αKlotho circulates as an endocrine substance with a multitude of effects. This review covers recent data on the physiological regulation and function of the complex FGF23-αKlotho network. Chronic kidney disease is a common pathophysiological state in which FGF23-αKlotho, a multiorgan endocrine network, is deranged in a self-amplifying vortex resulting in organ dysfunction of the utmost severity that contributes to its morbidity and mortality. PMID:23398153

  11. Fibroblast growth factor signaling potentiates VE-cadherin stability at adherens junctions by regulating SHP2.

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    Kunihiko Hatanaka

    Full Text Available BACKGROUND: The fibroblast growth factor (FGF system plays a critical role in the maintenance of vascular integrity via enhancing the stability of VE-cadherin at adherens junctions. However, the precise molecular mechanism is not well understood. In the present study, we aimed to investigate the detailed mechanism of FGF regulation of VE-cadherin function that leads to endothelial junction stabilization. METHODS AND FINDINGS: In vitro studies demonstrated that the loss of FGF signaling disrupts the VE-cadherin-catenin complex at adherens junctions by increasing tyrosine phosphorylation levels of VE-cadherin. Among protein tyrosine phosphatases (PTPs known to be involved in the maintenance of the VE-cadherin complex, suppression of FGF signaling reduces SHP2 expression levels and SHP2/VE-cadherin interaction due to accelerated SHP2 protein degradation. Increased endothelial permeability caused by FGF signaling inhibition was rescued by SHP2 overexpression, indicating the critical role of SHP2 in the maintenance of endothelial junction integrity. CONCLUSIONS: These results identify FGF-dependent maintenance of SHP2 as an important new mechanism controlling the extent of VE-cadherin tyrosine phosphorylation, thereby regulating its presence in adherens junctions and endothelial permeability.

  12. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease.

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    Galitzer, H; Ben-Dov, I Z; Silver, Justin; Naveh-Many, Tally

    2010-02-01

    Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription-PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho-FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.

  13. Fibroblast Growth Factor 21 Suppresses Adipogenesis in Pig Intramuscular Fat Cells

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    Yongliang Wang

    2015-12-01

    Full Text Available Fibroblast growth factor 21 (FGF21 plays an important role in the treatment of disease associated with muscle insulin resistance which is characterized by various factors, such as intramuscular triglyceride (IMT content. Studies have also shown that FGF21 inhibits triglyceride synthesis in vivo. However, the precise mechanism whereby FGF21 regulates triglyceride metabolism in intramuscular fat (IMF, which may influence the muscle insulin sensitivity, is not clearly understood. In order to understand the role of FGF21 in IMF deposition, we performed FGF21 overexpression in IMF cells by stable transfection. Our results showed that FGF21 inhibited the key adipogenesis gene mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG, CCAAT/enhancer-binding protein (CEBP family by reducing lysine-specific demethylase 1 (LSD1 expression which led to significant decline in lipid accumulation, and the result was confirmed by Western blot. Moreover, triggered by FGF21, parts of the adipokines—fatty acid-binding protein 4 (FABP4, glucose transporter 4 (GLUT4, adiponectin (ADIPOQ, and perilipin (PLIN1—were also down-regulated. Furthermore, FGF21 gene expression was suppressed by transcription factor CEBP beta (CEBPB which contributed strongly to triglyceride synthesis. Taken together, our study is the first to experimentally demonstrate FGF21 emerging as an efficient blockade of adipogenesis in IMF, thus also providing a new understanding of the mechanism whereby FGF21 improves insulin sensitivity.

  14. IDENTIFICATION OF NOVEL FIBROBLAST GROWTH FACTOR RECEPTOR 3 GENE MUTATIONS IN ACTINIC CHEILITIS

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    Chou, Annie; Dekker, Nusi; Jordan, Richard C.K.

    2009-01-01

    Objective Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for several craniosynostosis and chondrodysplasia syndromes as well as some human cancers including bladder and cervical carcinoma. Despite a high frequency in some benign skin disorders, FGFR3 mutations have not been reported in cutaneous malignancies. Actinic cheilitis (AC) is a sun-induced premalignancy affecting the lower lip that frequently progresses to squamous cell carcinoma (SCC). The objective of this study was to determine if FGFR3 gene mutations are present in AC and SCC of the lip. Study Design DNA was extracted and purified from micro-dissected, formalin-fixed, paraffin-embedded tissue sections of 20 cases of AC and SCC arising in AC. Exons 7, 15, and 17 were PCR amplified and direct sequenced. Results Four novel somatic mutations in the FGFR3 gene were identified: exon 7 mutation 742C→T (amino acid change R248C), exon 15 mutations 1850A→G (D617G) and 1888G→A (V630M), and exon 17 mutation 2056G→A (E686K). Grade of dysplasia did not correlate with presence of mutations. Conclusion The frequency of FGFR3 receptor mutations suggests a functional role for the FGFR3 receptor in the development of epithelial disorders and perhaps a change may contribute to the pathogenesis of some AC and SCC. PMID:19327639

  15. Fibroblast Growth Factor-2 Enhanced The Recruitment of Progenitor Cells and Myelin Repair in Experimental Demyelination of Rat Hippocampal Formations

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    Mahdieh Azin

    2015-10-01

    Full Text Available Objective: Hippocampal insults have been observed in multiple sclerosis (MS patients. Fibroblast growth factor-2 (FGF2 induces neurogenesis in the hippocampus and enhances the proliferation, migration and differentiation of oligodendrocyte progenitor cells (OPCs. In the current study, we have investigated the effect of FGF2 on the processes of gliotoxin induced demyelination and subsequent remyelination in the hippocampus. Materials and Methods: In this experimental study adult male Sprague-Dawley rats received either saline or lysolecithin (LPC injections to the right hippocampi. Animals received intraperitoneal (i.p. injections of FGF2 (5 ng/g on days 0, 5, 12 and 26 post-LPC. Expressions of myelin basic protein (Mbp as a marker of myelination, Olig2 as a marker of OPC proliferation, Nestin as a marker of neural progenitor cells, and glial fibrillary acidic protein (Gfap as a marker of reactive astrocytes were investigated in the right hippocampi by reverse transcriptase-polymerase chain reaction (RT-PCR. Results: There was reduced Mbp expression at seven days after LPC injection, increased expressions of Olig2 and Nestin, and the level of Gfap did not change. FGF2 treatment reversed the expression level of Mbp to the control, significantly enhanced the levels of Olig2 and Nestin, but did not change the level of Gfap. At day-28 post- LPC, the expression level of Mbp was higher than the control in LPC-treated animals that received FGF2. The levels of Olig2, Nestin and Gfap were at the control level in the non-treated LPC group but significantly higher in the FGF2-t reated LPC group. Conclusion: FGF2 enhanced hippocampal myelination and potentiated the recruitment of OPCs and neural stem cells (NSCs to the lesion area. Long-term application of FGF2 might also enhance astrogliosis in the lesion site.

  16. ATP differentially upregulates fibroblast growth factor 2 and transforming growth factor α in neonatal and adult mice: effect on neuroproliferation.

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    Jia, C; Cussen, A R; Hegg, C C

    2011-03-17

    Multiple neurotrophic factors play a role in proliferation, differentiation and survival in the olfactory epithelium (OE); however, the signaling cascade has not been fully elucidated. We tested the hypotheses that ATP induces the synthesis and secretion of two neurotrophic factors, fibroblast growth factor 2 (FGF2) and transforming growth factor alpha (TGFα), and that these neurotrophic factors have a role in inducing proliferation. Protein levels of FGF2 and TGFα were increased 20 h post-intranasal instillation of ATP compared to vehicle control in adult Swiss Webster mice. Pre-intranasal treatment with purinergic receptor antagonist pyridoxal-phosphate-6-azophenyl-20,40-disulfonic acid (PPADS) significantly blocked this ATP-induced increase, indicating that upregulation of FGF2 and TGFα expression is mediated by purinergic receptor activation. However, in neonatal mouse, intranasal instillation of ATP significantly increased the protein levels of FGF2, but not TGFα. Likewise, ATP evoked the secretion of FGF2, but not TGFα, from neonatal mouse olfactory epithelial slices and PPADS significantly blocked ATP-evoked FGF2 release. To determine the role of FGF2 and TGFα in inducing proliferation, 5-bromo-2-deoxyuridine (BrdU) incorporation was examined in adult olfactory epithelium. Intranasal treatment with FGF receptor inhibitor PD173074 or epidermal growth factor receptor inhibitor AG1478 following ATP instillation significantly blocked ATP-induced BrdU incorporation. Collectively, these data demonstrate that ATP induces proliferation in adult mouse olfactory epithelium by promoting FGF2 and TGFα synthesis and activation of their receptors. These data suggest that different mechanisms regulate neurogenesis in neonatal and adult OE, and FGF2 and TGFα may have different roles throughout development. PMID:21187124

  17. Extracellular Matrix Modulates Morphology, Growth, Oxidative Stress Response and Functionality of Human Skin Fibroblasts during Aging In Vitro

    DEFF Research Database (Denmark)

    Jørgensen, Peter; Rattan, Suresh

    2014-01-01

    The Hayflick system of cellular aging and replicative senescence in vitro has been used widely in both basic and applied research in biogerontology. The state of replicative senescence is generally considered to be irreversible, but is modifiable by genetic and environmental manipulations. Some...... recent observations indicate that replicative lifespan, senescence and functionality of cells in vitro can be significantly affected by the quality of the extra cellular matrix (ECM). Following up on those reports, here we show that using the ECM prepared from early passage young cells, partial...... rejuvenation of serially passaged human facial skin fibroblasts was possible in pre-senescent middle-aged cells, but not in fully senescent late passage cells. ECM from young cells improved the appearance, viability, stress tolerance and wound healing ability of skin fibroblasts. Furthermore, young ECM...

  18. Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

    OpenAIRE

    Korf-Klingebiel, Mortimer; Kempf, Tibor; Schlüter, Klaus-Dieter; Willenbockel, Christian; Brod, Torben; Heineke, Jörg; Volker J Schmidt; Jantzen, Franziska; Ralf P Brandes; Sugden, Peter H.; Drexler, Helmut; Molkentin, Jeffery D.; Wollert, Kai C.

    2011-01-01

    BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardiu...

  19. MUC4 potentiates invasion and metastasis of pancreatic cancer cells through stabilization of fibroblast growth factor receptor 1

    OpenAIRE

    Rachagani, Satyanarayana; Muzafar A Macha; Moorthy P Ponnusamy; Haridas, Dhanya; Kaur, Sukhwinder; Jain, Maneesh; Batra, Surinder K.

    2012-01-01

    MUC4 is a type-1 transmembrane mucin differentially expressed in multiple cancers and has previously been shown to potentiate progression and metastasis of pancreatic cancer. In this study, we investigated the molecular mechanisms associated with the MUC4-induced invasion and metastasis in pancreatic cancer. Stable silencing of MUC4 in multiple pancreatic cancer cells resulted in the downregulation of N-cadherin and its interacting partner fibroblast growth factor receptor 1 (FGFR1) through d...

  20. Associations of Fibroblast Growth Factor 23 and Fetuin-A With Coronary Plaque Burden and Plaque Composition in Young Adults

    OpenAIRE

    Kanbay, Mehmet; Akın, F.; Ömer, C.; Ayça, B.; İbrahim, A.; Diker, V.; Covic, A.

    2015-01-01

    Objective The total burden of subclinical coronary artery disease (CAD) is significant among young adults. Serum fibroblast growth factor 23 (FGF-23) and fetuin-A are established predictors of morbidity and mortality because of cardiovascular disease. The objective of the study was to evaluate the relationship between subclinical CAD and serum FGF-23 and fetuin-A concentrations among a population of young adults. Methods A total of 241 subjects younger than 45 years who had undergone coron...

  1. Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI

    OpenAIRE

    Yu, Xin; Nieman, Brian J.; Sudarov, Anamaria; Szulc, Kamila U.; Abdollahian, Davood J.; Bhatia, Nitin; Lalwani, Anil K.; Joyner, Alexandra L.; Turnbull, Daniel H.

    2011-01-01

    With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17−/−) have anatomical abnormalities in the inferior colliculus (IC)–the auditory midbrain–and minor foliation defects in the cerebellum. In addition,...

  2. Lipoteichoic acid and interleukin 1 stimulate synergistically production of hepatocyte growth factor (scatter factor) in human gingival fibroblasts in culture.

    OpenAIRE

    Sugiyama, A; Arakaki, R; Ohnishi, T.; Arakaki, N.; Daikuhara, Y.; Takada, H

    1996-01-01

    Lipoteichoic acids (LTA) from various gram-positive bacteria, including oral streptococci such as Streptococcus sanguis, enhanced the production of hepatocyte growth factor (HGF) (scatter factor) by human gingival fibroblasts in culture, whereas lipopolysaccharides (LPS) from various gram-negative bacteria did not. In contrast, LPS induced interleukin 1 activity in human gingival epithelial cells in culture, while LTA had little effect. LTA and recombinant human interleukin 1 alpha enhanced s...

  3. Cooperative Heparin-Mediated Oligomerization of Fibroblast Growth Factor-1 (FGF1) Precedes Recruitment of FGFR2 to Ternary Complexes

    OpenAIRE

    Brown, Alan; Robinson, Christopher J.; Gallagher, John T.; Blundell, Tom L.

    2013-01-01

    Fibroblast growth factors (FGFs) utilize cell surface heparan sulfate as a coreceptor in the assembly of signaling complexes with FGF-receptors on the plasma membrane. Here we undertake a complete thermodynamic characterization of the assembly of the FGF signaling complex using isothermal titration calorimetry. Heparin fragments of defined length are used as chemical analogs of the sulfated domains of heparan sulfate and examined for their ability to oligomerize FGF1. Binding is modeled using...

  4. Downstream-of-FGFR Is a Fibroblast Growth Factor-Specific Scaffolding Protein and Recruits Corkscrew upon Receptor Activation

    OpenAIRE

    Petit, Valérie; Nussbaumer, Ute; Dossenbach, Caroline; Affolter, Markus

    2004-01-01

    Fibroblast growth factor (FGF) receptor (FGFR) signaling controls the migration of glial, mesodermal, and tracheal cells in Drosophila melanogaster. Little is known about the molecular events linking receptor activation to cytoskeletal rearrangements during cell migration. We have performed a functional characterization of Downstream-of-FGFR (Dof), a putative adapter protein that acts specifically in FGFR signal transduction in Drosophila. By combining reverse genetic, cell culture, and bioch...

  5. Phenotypic expression of the fibroblast growth factor receptor 3 (FGFR3) mutation P250R in a large craniosynostosis family.

    OpenAIRE

    Golla, A; Lichmer, P; von Gernet, S; Winterpacht, A; Fairley, J.; Murken, J.; Schuffenhauer, S.

    1997-01-01

    The craniosynostosis syndromes are a heterogeneous group of sporadic, autosomal dominant disorders with significant clinical overlap. Recently, we described a large family with autosomal dominant craniosynostosis suggestive of Saethre-Chotzen syndrome, in which linkage to the Saethre-Chotzen syndrome loci on 7p had been excluded. We now report the presence of a mutation in the fibroblast growth factor receptor 3 (FGFR3) in this family. The mutation, P250R, had been previously reported in 10 p...

  6. Carbon nanoparticles downregulate expression of basic fibroblast growth factor in the heart during embryogenesis

    DEFF Research Database (Denmark)

    Wierzbicki, Mateusz; Sawosz, Ewa; Grodzik, Marta;

    2013-01-01

    Carbon nanoparticles, with their high biocompatibility and low toxicity, have recently been considered for biomedical applications, including antiangiogenic therapy. Critical to normal development and tumor formation, angiogenesis is the process of forming capillary blood vessels from preexisting...

  7. Clinical Efficacy of Mupirocin Ointment,Recombinant Bovine Basic Fibroblast Growth Factor and Active Silver Ion So-lution for Transplantation of Free Skin Graft on Infectious Wounds%莫匹罗星和重组牛碱性成纤维细胞生长因子联合活性银离子治疗感染创面游离植皮的临床疗效研究

    Institute of Scientific and Technical Information of China (English)

    汪洋; 张小红; 冉辉; 谭加; 陶宏军

    2014-01-01

    目的:探讨莫匹罗星、重组牛碱性成纤维细胞生长因子( rb-bFGF)联合活性银离子治疗感染性创面游离植皮的疗效,为以后的治疗提供依据。方法选取2010年6月—2013年6月重庆三峡中心医院收治的行断层皮片封闭感染性创面手术的患者168例,采用随机数字表法分为观察组84例和对照组84例。观察组术中将莫匹罗星和rb-bFGF制成的混合液涂抹于受区,皮片移植后外用浸湿活性银离子的无菌绷带予以固定;对照组术中用油纱覆盖游离皮片。观察术后第4、8、12天创面情况,评估皮片存活率、创面愈合率、创面愈合时间及细菌清除率。皮片存活率、创面愈合率及细菌清除率比较采用χ2检验,创面愈合时间比较采用t检验。结果术后第4天观察组皮片存活率为(97.9±1.2)%,高于对照组的(85.8±5.7)%(t=20.62,P=0.002)。术后第8天观察组创面愈合率为7.1%(6/84),对照组为1.2%(1/84),差异无统计学意义(χ2=3.71,P =0.054);术后第12天观察组创面愈合率为98.8%(83/84),高于对照组的72.6%(61/84)(χ2=23.39,P <0.001)。观察组创面平均愈合时间为(11.4±1.4)d,短于对照组的(13.3±3.0)d(t =-5.92,P =0.007)。术后第4天观察组细菌清除率为72.6%(61/84),高于对照组的46.4%(39/84)(χ2=11.89,P=0.001);术后第8天观察组细菌清除率为90.5%(76/84),高于对照组的77.4%(65/84)(χ2=5.31,P=0.020);术后第12天观察组细菌清除率为100.0%(84/84),高于对照组的94.0%(79/84)(χ2=5.12,P=0.023)。结论莫匹罗星、rb-bFGF联合活性银离子能提高感染性创面游离植皮的成活率、加速创面愈合、增强局部抗感染能力。%Objective To study the efficacy of mupirocin ointment,recombinant bovine basic fibroblast growth factor ( rb-bFGF)combined with active silver ions solution on free skin

  8. 重组牛碱性成纤维细胞生长因子滴眼液与小牛血去蛋白提取物眼凝胶治疗角膜上皮缺损的疗效比较%Recombinant bovine basic fibroblast growth factor-containing eye drops versus deprotienized calf blood extract-based eye gel in the treatment of corneal epithelial defect contrast

    Institute of Scientific and Technical Information of China (English)

    邢滨

    2015-01-01

    Objective To compare the efficacy of deproteinized calf blood extract-base eye gel and recombinant bovine basic fibroblast growth factor ( bFGF )-containing eye drops in the treatment of corneal epithelial defect .Methods Sixty-two patients ( 62 eyes ) with corneal epithelial defect presenting to the Department, Zhengzhou First People′s Hospital between March , 2012 and March, 2014 were randomly allocated to one of the two treatment groups:deproteinized calf blood extract-based eye gel ( n =31 ) andrecombinant bovine bFGF-containing eye drops (n=31).After treatment for two weeks (one cycle),the effect size and adverse reactions were assessed .Results The deproteinized calf blood extract-based eye gel was significantly effective in 12 ( 38.71%) cases, moderately effective in 17 ( 54.84%) cases, and ineffective in 2 (6.45%) cases.The bFGF-containing eye drops were significantly effective in 8 (25.81%) cases,moderately effective in 16 ( 51.61%) cases and ineffective in 7 ( 22.58%) cases.The total effectiveness rate was 93.55%for the eye gel and 77.42%for the eye drops (Hc=6.5 237,P0.05).Conclusion Deprotienized calf blood extract-based therapy appears more effective and safe than bFGF-containing eye drops in treating corneal epithelial defect .%目的:探讨应用小牛血去蛋白提取物眼凝胶与重组牛碱性成纤维细胞生长因子滴眼液治疗角膜上皮缺损的临床效果。方法收集2012年3月至2014年3月郑州市第一人民医院眼科收治的62例(62只眼)角膜上皮缺损患者的临床资料。采用数字表法随机将患者分为A组和B组,每组各31例(31只眼)。 A组患者采用小牛血去蛋白提取物眼凝胶进行治疗,B组患者采用重组牛碱性成纤维细胞生长因子滴眼液进行治疗。两组患者的临床疗效按照显效、有效和无效分为3个等级,以例数和百分比的形式表示,并采用Kruskal-Wallis H秩和检验的方法进行比较。治疗前及治疗后3 d两

  9. Engineering an improved crystal contact across a solvent-mediated interface of human fibroblast growth factor 1

    International Nuclear Information System (INIS)

    A solvent-mediated crystal contact in fibroblast growth factor-1 was subjected to mutagenesis to improve crystal growth. The results indicate that improved growth was achieved upon elimination of the solvent-mediated interface and introduction of direct crystal contacts. Large-volume protein crystals are a prerequisite for neutron diffraction studies and their production represents a bottleneck in obtaining neutron structures. Many protein crystals that permit the collection of high-resolution X-ray diffraction data are inappropriate for neutron diffraction owing to a plate-type morphology that limits the crystal volume. Human fibroblast growth factor 1 crystallizes in a plate morphology that yields atomic resolution X-ray diffraction data but has insufficient volume for neutron diffraction. The thin physical dimension has been identified as corresponding to the b cell edge and the X-ray structure identified a solvent-mediated crystal contact adjacent to position Glu81 that was hypothesized to limit efficient crystal growth in this dimension. In this report, a series of mutations at this crystal contact designed to both reduce side-chain entropy and replace the solvent-mediated interface with direct side-chain contacts are reported. The results suggest that improved crystal growth is achieved upon the introduction of direct crystal contacts, while little improvement is observed with side-chain entropy-reducing mutations alone

  10. Controlling the Fibroblastic Differentiation of Mesenchymal Stem Cells Via the Combination of Fibrous Scaffolds and Connective Tissue Growth Factor

    Science.gov (United States)

    Tong, Zhixiang; Sant, Shilpa

    2011-01-01

    Controlled differentiation of multi-potent mesenchymal stem cells (MSCs) into vocal fold-specific, fibroblast-like cells in vitro is an attractive strategy for vocal fold repair and regeneration. The goal of the current study was to define experimental parameters that can be used to control the initial fibroblastic differentiation of MSCs in vitro. To this end, connective tissue growth factor (CTGF) and micro-structured, fibrous scaffolds based on poly(glycerol sebacate) (PGS) and poly(ɛ-caprolactone) (PCL) were used to create a three-dimensional, connective tissue-like microenvironment. MSCs readily attached to and elongated along the microfibers, adopting a spindle-shaped morphology during the initial 3 days of preculture in an MSC maintenance medium. The cell-laden scaffolds were subsequently cultivated in a conditioned medium containing CTGF and ascorbic acids for up to 21 days. Cell morphology, proliferation, and differentiation were analyzed collectively by quantitative PCR analyses, and biochemical and immunocytochemical assays. F-actin staining showed that MSCs maintained their fibroblastic morphology during the 3 weeks of culture. The addition of CTGF to the constructs resulted in an enhanced cell proliferation, elevated expression of fibroblast-specific protein-1, and decreased expression of mesenchymal surface epitopes without markedly triggering chondrogenesis, osteogenesis, adipogenesis, or apoptosis. At the mRNA level, CTGF supplement resulted in a decreased expression of collagen I and tissue inhibitor of metalloproteinase 1, but an increased expression of decorin and hyaluronic acid synthesase 3. At the protein level, collagen I, collagen III, sulfated glycosaminoglycan, and elastin productivity was higher in the conditioned PGS-PCL culture than in the normal culture. These findings collectively demonstrate that the fibrous mesh, when combined with defined biochemical cues, is capable of fostering MSC fibroblastic differentiation in vitro. PMID

  11. Fibroblast growth factor 23 contributes to diminished bone mineral density in childhood inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    El-Hodhod Mostafa

    2012-05-01

    Full Text Available Abstract Background Diminished bone mineral density (BMD is of significant concern in pediatric inflammatory bowel disease (IBD. Exact etiology is debatable. The recognition of fibroblast growth factor 23 (FGF23, a phosphaturic hormone related to tumor necrosis factor alpha (TNF-α makes it plausible to hypothesize its possible relation to this pathology. Methods In this follow up case control study, BMD as well as serum levels of FGF23, calcium, phosphorus, alkaline phosphatase, creatinine, parathyroid hormone, 25 hydroxy vitamin D3 and 1, 25 dihydroxy vitamin D3 were measured in 47 children with IBD during flare and reassessed in the next remission. Results Low BMD was frequent during IBD flare (87.2% with significant improvement after remission (44.7%. During disease flare, only 21.3% of patients had vitamin D deficiency, which was severe in 12.8%. During remission, all patients had normal vitamin D except for two patients with Crohn’s disease (CD who remained vitamin D deficient. Mean value of serum FGF23 was significantly higher among patients with IBD during flare compared to controls. It showed significant improvement during remission but not to the control values. 1, 25 dihydroxy vitamin D3, FGF23, serum calcium and urinary phosphorus were significant determinants of BMD in IBD patients. Conclusions We can conclude that diminished BMD in childhood IBD is a common multifactorial problem. Elevated FGF23 would be a novel addition to the list of factors affecting bone mineral density in this context. Further molecular studies are warranted to display the exact interplay of these factors.

  12. Molecular basis for the Kallmann syndrome-linked fibroblast growth factor receptor mutation

    Energy Technology Data Exchange (ETDEWEB)

    Thurman, Ryan D.; Kathir, Karuppanan Muthusamy; Rajalingam, Dakshinamurthy [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States); Kumar, Thallapuranam K. Suresh, E-mail: sthalla@uark.edu [Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701 (United States)

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer The structural basis of the Kallmann syndrome is elucidated. Black-Right-Pointing-Pointer Kallmann syndrome mutation (A168S) induces a subtle conformational change(s). Black-Right-Pointing-Pointer Structural interactions mediated by beta-sheet G are most perturbed. Black-Right-Pointing-Pointer Ligand (FGF)-receptor interaction(s) is completely abolished by Kallmann mutation. Black-Right-Pointing-Pointer Kallmann mutation directly affects the FGF signaling process. -- Abstract: Kallmann syndrome (KS) is a developmental disease that expresses in patients as hypogonadotropic hypogonadism and anosmia. KS is commonly associated with mutations in the extracellular D2 domain of the fibroblast growth factor receptor (FGFR). In this study, for the first time, the molecular basis for the FGFR associated KS mutation (A168S) is elucidated using a variety of biophysical experiments, including multidimensional NMR spectroscopy. Secondary and tertiary structural analysis using far UV circular dichroism, fluorescence and limited trypsin digestion assays suggest that the KS mutation induces subtle tertiary structure change in the D2 domain of FGFR. Results of isothermal titration calorimetry experiments show the KS mutation causes a 10-fold decrease in heparin binding affinity and also a complete loss in ligand (FGF-1) binding. {sup 1}H-{sup 15}N chemical perturbation data suggest that complete loss in the ligand (FGF) binding affinity is triggered by a subtle conformational change that disrupts crucial structural interactions in both the heparin and the FGF binding sites in the D2 domain of FGFR. The novel findings reported in this study are expected to provide valuable clues toward a complete understanding of the other genetic diseases linked to mutations in the FGFR.

  13. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yun-Fei [Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University (China); Yang, Xiao-Qing [Department of Pathology, Shandong University (China); Lu, Xiao-Fei [Department of Gastrointestinal Surgery, Jinan Central Hospital (China); Guo, Sen; Liu, Yi; Iqbal, Mohammad; Ning, Shang-Lei; Yang, Hui [Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University (China); Suo, Ning [Department of Anatomy, Shandong University (China); Chen, Yu-Xin, E-mail: yxu8@bidmc.harvard.edu [Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University (China)

    2014-03-28

    Highlights: • FGFR4 is significantly related with N stage in IHCC, with T stage and TNM stage in PHCC. • FGFR4 is an independent prognostic factor in IHCC and PHCC. • FGFR4 promotes proliferation, invasion and EMT in cholangiocarinoma cell lines. • Inhibitor AP24354 can decrease proliferation, invasion and induce apoptosis of CCA. - Abstract: Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P = 0.002) and PHCC (P = 0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P = 0.045) and PHCC (P = 0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial–mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.

  14. Scheduled transplantation of bone marrow cells preincubated with acidic fibroblast growth factor (aFGF)

    International Nuclear Information System (INIS)

    Objective: To develop a new method of bone marrow scheduled transplantation (BMST) by making use of the effects of acidic fibroblast growth factor (aFGF) on improving hematopoiesis. Methods: The scheduled transplantation of bone marrow cells preincubated with aFGF (aFGF-BMST) was carried out to study the effects of aFGF on hematopoietic reconstitution and reducing acute graft versus host disease (GVHD) in acute radiation disease model of Kunming mice. Results: The survival rate of the group of aFGF-BMST mice with 4 x 106 BMXs was 40%, which was higher than the survival of the group of BMT with 1 x 107 BMCs alone (30%), but was lower than the survival of the group of BMST with 4 x 106 BMCs. On the other hand, the recovery rates in numbers of leucocytes, nucleated cells and CFU-E, CFU-GM, CFU-S were faster than those in the group of BMT with 1 x 107 BMCs alone and in the group of BMST with 4 x 106 BMCs. In addition, the severity of GVHD in the group of aFGF-BMST mice with 4 x 106 BMCs was lower than that in the group of BMT with 1 x 107 BMCs alone but was higher than that in the group of BMST with 4 x 106 BMCs. Conclusion: Although aFGF can activate heterogeneous T cells to cause GVHD, there is prospect of making full use of the effects of aFGF on improving hematopoiesis and reducing the side effects of aFGF leading to GVHD through scheduled transplantation of bone marrow cells preincubated with aFGF

  15. Fibroblast growth factor 7 inhibits cholesterol 7{alpha}-hydroxylase gene expression in hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Zhichao [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Yu, Xuemei [Department of Endocrinology, Fengxian Central Hospital, Shanghai (China); Wu, Weibin; Jia, Dongwei; Chen, Yinle; Ji, Lingling; Liu, Xijun; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Li, Yintao [Institute of Endocrinology and Diabetology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai (China); Yang, Lili [Department of Endocrinology, Fengxian Central Hospital, Shanghai (China); Ruan, Yuanyuan; Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Ren, Shifang, E-mail: renshifang@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Songwen, E-mail: songwenzhang@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer FGF7 strongly and rapidly down-regulates the expression of CYP7A1 in hepatocytes. Black-Right-Pointing-Pointer FGF7 suppresses the expression of CYP7A1 via FGFR2 and downstream JNK activation. Black-Right-Pointing-Pointer Blocking FGF7 abrogates HSC-induced inhibition of CYP7A1 expression in hepatocytes. -- Abstract: Cholesterol 7{alpha}-hydroxylase (CYP7A1) is the initial and rate-limiting enzyme for bile acid synthesis. Transcription of the CYP7A1 gene is regulated by bile acids, nuclear receptors and cytokines. Fibroblast growth factor 7 (FGF7) secreted from activated hepatic stellate cells (HSC) during chronic liver fibrosis regulates hepatocyte survival and liver regeneration. In the carbon tetrachloride (CCl{sub 4})-induced fibrotic mouse liver, we demonstrated that the expression of CYP7A1 was largely decreased while the expression of FGF7 was significantly increased. We further demonstrated that FGF7 inhibited CYP7A1 gene expression in hepatocytes. Knockdown study by short interfering RNA, kinase inhibition and phosphorylation assays revealed that the suppression of CYP7A1 expression by FGF7 was mediated by FGFR2 and its downstream JNK signaling cascade. The FGF7 neutralizing antibody restored CYP7A1 expression in Hep3B cells treated with conditioned medium from HSC. In summary, the data suggest that FGF7 is a novel regulator of CYP7A1 expression in hepatocytes and may prevent hepatocytes from accumulating toxic bile acids during liver injury and fibrosis.

  16. Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Stephen L Roesch

    Full Text Available Fibroblast growth factors 19 and 21 (FGF19 and FGF21 have been implicated, independently, in type 2 diabetes (T2D but it is not known if their circulating levels correlate with each other or whether the associated hepatic signaling mechanisms that play a role in glucose metabolism are dysregulated in diabetes. We used a cross-sectional, case/control, experimental design involving Class III obese patients undergoing Roux-en-Y bariatric surgery (RYGB, and measured FGF19 and FGF21 serum levels and hepatic gene expression (mRNA in perioperative liver wedge biopsies. We found that T2D patients had lower FGF19 and higher FGF21 serum levels. The latter was corroborated transcriptionally, whereby, FGF21, as well as CYP7A1, β-Klotho, FGFR4, HNF4α, and glycogen synthase, but not of SHP or FXR mRNA levels in liver biopsies were higher in T2D patients that did not remit diabetes after RYGB surgery, compared to T2D patients that remitted diabetes after RYGB surgery or did not have diabetes. In a Phenome-wide association analysis using 205 clinical variables, higher FGF21 serum levels were associated with higher glucose levels and various cardiometabolic disease phenotypes. When serum levels of FGF19 were 500 mg/mL, 91% of patients had diabetes. These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.

  17. Rational design of a fibroblast growth factor 21-based clinical candidate, LY2405319.

    Directory of Open Access Journals (Sweden)

    Alexei Kharitonenkov

    Full Text Available Fibroblast growth factor 21 is a novel hormonal regulator with the potential to treat a broad variety of metabolic abnormalities, such as type 2 diabetes, obesity, hepatic steatosis, and cardiovascular disease. Human recombinant wild type FGF21 (FGF21 has been shown to ameliorate metabolic disorders in rodents and non-human primates. However, development of FGF21 as a drug is challenging and requires re-engineering of its amino acid sequence to improve protein expression and formulation stability. Here we report the design and characterization of a novel FGF21 variant, LY2405319. To enable the development of a potential drug product with a once-daily dosing profile, in a preserved, multi-use formulation, an additional disulfide bond was introduced in FGF21 through Leu118Cys and Ala134Cys mutations. FGF21 was further optimized by deleting the four N-terminal amino acids, His-Pro-Ile-Pro (HPIP, which was subject to proteolytic cleavage. In addition, to eliminate an O-linked glycosylation site in yeast a Ser167Ala mutation was introduced, thus allowing large-scale, homogenous protein production in Pichia pastoris. Altogether re-engineering of FGF21 led to significant improvements in its biopharmaceutical properties. The impact of these changes was assessed in a panel of in vitro and in vivo assays, which confirmed that biological properties of LY2405319 were essentially identical to FGF21. Specifically, subcutaneous administration of LY2405319 in ob/ob and diet-induced obese (DIO mice over 7-14 days resulted in a 25-50% lowering of plasma glucose coupled with a 10-30% reduction in body weight. Thus, LY2405319 exhibited all the biopharmaceutical and biological properties required for initiation of a clinical program designed to test the hypothesis that administration of exogenous FGF21 would result in effects on disease-related metabolic parameters in humans.

  18. Iron and obesity status-associated insulin resistance influence circulating fibroblast-growth factor-23 concentrations.

    Directory of Open Access Journals (Sweden)

    José Manuel Fernández-Real

    Full Text Available Fibroblast growth factor 23 (FGF-23 is known to be produced by the bone and linked to metabolic risk. We aimed to explore circulating FGF-23 in association with fatness and insulin sensitivity, atherosclerosis and bone mineral density (BMD. Circulating intact FGF-23 (iFGF-23 and C-terminal (CtFGF-23 concentrations (ELISA were measured in 133 middle aged men from the general population in association with insulin sensitivity (Cohort 1; and in association with fat mass and bone mineral density (DEXA and atherosclerosis (intima media thickness, IMT in 78 subjects (52 women with a wide range of adiposity (Cohort 2. Circulating iFGF-23 was also measured before and after weight loss. In all subjects as a whole, serum intact and C-terminal concentrations were linearly and positively associated with BMI. In cohort 1, both serum iFGF-23 and CtFGF-23 concentrations increased with insulin resistance. Serum creatinine contributed to iFGF-23 variance, while serum ferritin and insulin sensitivity (but not BMI, age or serum creatinine contributed to 17% of CtFGF-23 variance. In cohort 2, CtFGF-23 levels were higher in women vs. men, and increased with BMI, fat mass, fasting and post-load serum glucose, insulin, HOMA-IR and PTH, being negatively associated with circulating vitamin D and ferritin levels. The associations of CtFGF-23 with bone density in the radius, lumbar spine and carotid IMT were no longer significant after controlling for BMI. Weight loss led to decreased iFGF-23 concentrations. In summary, the associations of circulating FGF-23 concentration with parameters of glucose metabolism, bone density and atherosclerosis are dependent on iron and obesity status-associated insulin resistance.

  19. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma

    International Nuclear Information System (INIS)

    Highlights: • FGFR4 is significantly related with N stage in IHCC, with T stage and TNM stage in PHCC. • FGFR4 is an independent prognostic factor in IHCC and PHCC. • FGFR4 promotes proliferation, invasion and EMT in cholangiocarinoma cell lines. • Inhibitor AP24354 can decrease proliferation, invasion and induce apoptosis of CCA. - Abstract: Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P = 0.002) and PHCC (P = 0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P = 0.045) and PHCC (P = 0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial–mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target

  20. The synthetic inhibitor of Fibroblast Growth Factor Receptor PD166866 controls negatively the growth of tumor cells in culture

    Directory of Open Access Journals (Sweden)

    Castelli Mauro

    2009-12-01

    Full Text Available Abstract Background Many experimental data evidence that over-expression of various growth factors cause disorders in cell proliferation. The role of the Fibroblast Growth Factors (FGF in growth control is indisputable: in particular, FGF1 and its tyrosine kinase receptor (FGFR1 act through a very complex network of mechanisms and pathways. In this work we have evaluated the antiproliferative activity effect of PD166866, a synthetic molecule inhibiting the tyrosin kinase action of FGFR1. Methods Cells were routinely grown in Dulbecco Modified Eagle's medium supplemented with newborn serum and a penicillin-streptomycin mixture. Cell viability was evaluated by Mosmann assay and by trypan blue staining. DNA damage was assessed by in situ fluorescent staining with Terminal Deoxynucleotidyl Transferase dUTP nick end labeling (TUNEL assay. Assessment of oxidative stress at membrane level was measured by quantitative analysis of the intra-cellular formation of malonyl-dialdheyde (MDA deriving from the decomposition of poly-unsaturated fatty acids. The expression of Poly-ADP-Ribose-Polymerase (PARP, consequent to DNA fragmentation, was evidenced by immuno-histochemistry utilizing an antibody directed against an N-terminal fragment of the enzyme. Results The bioactivity of the drug was investigated on Hela cells. Cytoxicity was assessed by the Mosmann assay and by vital staining with trypan blue. The target of the molecule is most likely the cell membrane as shown by the significant increase of the intracellular concentration of malonyl-dihaldheyde. The increase of this compound, as a consequence of the treatment with PD166866, is suggestive of membrane lipoperoxidation. The TUNEL assay gave a qualitative, though clear, indication of DNA damage. Furthermore we demonstrate intracellular accumulation of poly-ADP-ribose polymerase I. This enzyme is a sensor of nicks on the DNA strands and this supports the idea that treatment with the drug induces cell

  1. Loss of Dlg-1 in the mouse lens impairs fibroblast growth factor receptor signaling.

    Directory of Open Access Journals (Sweden)

    SungKyoung Lee

    Full Text Available Coordination of cell proliferation, differentiation and survival is essential for normal development and maintenance of tissues in the adult organism. Growth factor receptor tyrosine kinase signaling pathways and planar cell polarity pathways are two regulators of many developmental processes. We have previously shown through analysis of mice conditionally null in the lens for the planar cell polarity gene (PCP, Dlg-1, that Dlg-1 is required for fiber differentiation. Herein, we asked if Dlg-1 is a regulator of the Fibroblast growth factor receptor (Fgfr signaling pathway, which is known to be required for fiber cell differentiation. Western blot analysis of whole fiber cell extracts from control and Dlg-1 deficient lenses showed that levels of the Fgfr signaling intermediates pErk, pAkt, and pFrs2α, the Fgfr target, Erm, and the fiber cell specific protein, Mip26, were reduced in the Dlg-1 deficient fiber cells. The levels of Fgfr2 were decreased in Dlg-1 deficient lenses compared to controls. Conversely, levels of Fgfr1 in Dlg-1 deficient lenses were increased compared to controls. The changes in Fgfr levels were found to be specifically in the triton insoluble, cytoskeletal associated fraction of Dlg-1 deficient lenses. Immunofluorescent staining of lenses from E13.5 embryos showed that expression levels of pErk were reduced in the transition zone, a region of the lens that exhibits PCP, in the Dlg-1 deficient lenses as compared to controls. In control lenses, immunofluorescent staining for Fgfr2 was observed in the epithelium, transition zone and fibers. By E13.5, the intensity of staining for Fgfr2 was reduced in these regions of the Dlg-1 deficient lenses. Thus, loss of Dlg-1 in the lens impairs Fgfr signaling and leads to altered levels of Fgfrs, suggesting that Dlg-1 is a modulator of Fgfr signaling pathway at the level of the receptors and that Dlg-1 regulates fiber cell differentiation through its role in PCP.

  2. Increased fibroblast telomerase expression precedes myofibroblast α-smooth muscle actin expression in idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Daniel Reis Waisberg

    2012-09-01

    Full Text Available OBJECTIVE: This study sought to identify the relationship between fibroblast telomerase expression, myofibroblasts, and telomerase-mediated regulatory signals in idiopathic pulmonary fibrosis. METHODS: Thirty-four surgical lung biopsies, which had been obtained from patients with idiopathic pulmonary fibrosis and histologically classified as usual interstitial pneumonia, were examined. Immunohistochemistry was used to evaluate fibroblast telomerase expression, myofibroblast α-smooth muscle actin expression and the tissue expression of inter leu kin-4, transforming growth factor-β, and basic fibroblast growth factor. The point-counting technique was used to quantify the expression of these markers in unaffected, collapsed, mural fibrosis, and honeycombing areas. The results were correlated to patient survival. RESULTS: Fibroblast telomerase expression and basic fibroblast growth factor tissue expression were higher in collapsed areas, whereas myofibroblast expression and interleukine-4 tissue expression were higher in areas of mural fibrosis. Transforming growth factor-β expression was higher in collapsed, mural fibrosis and honeycombing areas in comparison to unaffected areas. Positive correlations were found between basic fibroblast growth factor tissue expression and fibroblast telomerase expression and between interleukin-4 tissue expression and myofibroblast α-smooth muscle actin expression. Negative correlations were observed between interleukin-4 expression and basic fibroblast growth factor tissue expression in areas of mural fibrosis. Myofibroblast α-smooth muscle actin expression and interleukin-4 tissue expression in areas of mural fibrosis were negatively associated with patient survival. CONCLUSION: Fibroblast telomerase expression is higher in areas of early remodeling in lung tissues demonstrating typical interstitial pneumonia, whereas myofibroblast α-smooth muscle actin expression predominates in areas of late remodeling

  3. Prevention of experimental autoimmune encephalomyelitis in DA rats by grafting primary skin fibroblasts engineered to express transforming growth factor-beta1.

    Science.gov (United States)

    Zargarova, T; Kulakova, O; Prassolov, V; Zharmukhamedova, T; Tsyganova, V; Turobov, V; Ivanov, D; Parfenov, M; Sudomoina, M; Chernajovsky, Y; Favorova, O

    2004-08-01

    To determine whether primary fibroblasts producing latent transforming growth factor beta1 (TGF-beta1) are capable of down-regulating experimental autoimmune encephalomyelitis (EAE), a retroviral vector TGF-beta1-pBabe-neo (-5'UTR) was used for efficient gene transfer into primary skin fibroblasts of DA rats. After heat activation, conditioned medium from the transduced fibroblasts was found to inhibit significantly in vitro proliferation of lymphocytes from lymph nodes of DA rats with EAE. Intraperitoneal administration of TGF-beta1-transduced fibroblasts into DA rats during the priming phase of EAE resulted in a significant reduction in mortality and in the mean clinical and EAE scores versus the control immunized animals treated with non-transduced fibroblasts.

  4. Prevention of experimental autoimmune encephalomyelitis in DA rats by grafting primary skin fibroblasts engineered to express transforming growth factor-β1

    Science.gov (United States)

    Zargarova, T; Kulakova, O; Prassolov, V; Zharmukhamedova, T; Tsyganova, V; Turobov, V; Ivanov, D; Parfenov, M; Sudomoina, M; Chernajovsky, Y; Favorova, O

    2004-01-01

    To determine whether primary fibroblasts producing latent transforming growth factor β1 (TGF-β1) are capable of down-regulating experimental autoimmune encephalomyelitis (EAE), a retroviral vector TGF-β1-pBabe-neo (−5′UTR) was used for efficient gene transfer into primary skin fibroblasts of DA rats. After heat activation, conditioned medium from the transduced fibroblasts was found to inhibit significantly in vitro proliferation of lymphocytes from lymph nodes of DA rats with EAE. Intraperitoneal administration of TGF-β1-transduced fibroblasts into DA rats during the priming phase of EAE resulted in a significant reduction in mortality and in the mean clinical and EAE scores versus the control immunized animals treated with non-transduced fibroblasts. PMID:15270848

  5. Platelet-derived growth factor mediates interleukin-13-induced collagen I production in mouse airway fibroblasts

    Indian Academy of Sciences (India)

    Jiamei Lu; Yanting Zhu; Wei Feng; Yilin Pan; Shaojun Li; Dong Han; Lu Liu; Xinming Xie; Guizuo Wang; Manxiang Li

    2014-09-01

    Interleukin-13 (IL-13) is associated with the production of collagen in airway remodelling of asthma. Yet, the molecular mechanisms underlying IL-13 induction of collagen remain unclear; the aim of this study is to address this issue. IL-13 dose- and time-dependently-induced collagen I production in primary cultured airway fibroblasts; this was accompanied with the STAT6 phosphorylation, and pre-treatment of cells with JAK inhibitor suppressed IL-13-induced collagen I production. Further study indicated that IL-13 stimulated JAK/STAT6-dependent PDGF production and subsequent ERK1/2 MAPK activation in airway fibroblasts, and the presence of either PDGF receptor blocker or MEK inhibitor partially suppressed IL-13-induced collagen I production. Taken together, our study suggests that activation of JAK/STAT6 signal pathway and subsequent PDGF generation and resultant ERK1/2 MAPK activation mediated IL-13-induced collagen I production in airway fibroblasts.

  6. Future topics in basic nucleation and growth research

    International Nuclear Information System (INIS)

    An adequate knowledge of nucleation and growth processes leads to the design and manufacture of thin film deposits of desired properties. Research in randon heterogeneous nucleation, epitaxial nucleation and growth, angstrom-particle chemistry, and surface replication with atomistic resolution is discussed

  7. Trophic effect of human pericardial fluid on adult cardiac myocytes. Differential role of fibroblast growth factor-2 and factors related to ventricular hypertrophy.

    Science.gov (United States)

    Corda, S; Mebazaa, A; Gandolfini, M P; Fitting, C; Marotte, F; Peynet, J; Charlemagne, D; Cavaillon, J M; Payen, D; Rappaport, L; Samuel, J L

    1997-11-01

    Pericardial fluid (PF) may contain myocardial growth factors that exert paracrine actions on cardiac myocytes. The aims of this study were (1) to investigate the effects of human PF and serum, collected from patients undergoing cardiac surgery, on the growth of cultured adult rat cardiac myocytes and (2) to relate the growth activity of both fluids to the adaptive changes in overloaded human hearts. Both PF and serum increased the rate of protein synthesis, measured by [14C]phenylalanine incorporation in adult rat cardiomyocytes (PF, +71.9 +/- 8.2% [n = 17]; serum, +14.9 +/- 6.5% [n = 13]; both P < .01 versus control medium). The effects of both PF and serum on cardiomyocyte growth correlated positively with the respective left ventricular (LV) mass. However, the magnitude of change with PF was 3-fold greater than with serum (P < .01). These trophic effects of PF were mimicked by exogenous basic fibroblast growth factor (FGF2) and inhibited by anti-FGF2 antibodies and transforming growth factor-beta (TGF-beta), suggesting a relationship to FGF2. In addition, FGF2 concentration in PF was 20 times greater than in serum. On the other hand, the LV mass-dependent trophic effect, present in both fluids, was independent of FGF2 concentration or other factors, such as angiotensin II, atrial natriuretic factor, and TGF-beta. These data suggest that FGF2 in human PF is a major determining factor in normal myocyte growth, whereas unidentified LV mass-dependent factor(s), present in both PF and serum, participates in the development of ventricular hypertrophy. PMID:9351441

  8. Quantification of effects of irradiation of low power laser about fibroblast 3T3 in culture: Growth parameters

    International Nuclear Information System (INIS)

    This work focuses on the practical determination protocol of parameters two basic cell culture growth (latency time and period of exponential duplication or doubling time), for the monitoring of samples subjected to LLLT. (Author)

  9. The effects of maternal iron deficiency on infant fibroblast growth factor-23 and mineral metabolism.

    Science.gov (United States)

    Braithwaite, V S; Prentice, A; Darboe, M K; Prentice, A M; Moore, S E

    2016-02-01

    Fibroblast growth factor-23 (FGF23), a phosphate(Phos)-regulating hormone, is abnormally elevated in hypophosphataemic syndromes and an elevated FGF23 is a predictor of mortality in kidney disease. Recent findings suggest iron deficiency as a potential mediator of FGF23 expression and murine studies have shown in utero effects of maternal iron deficiency on offspring FGF23 and phosphate metabolism. Our aim was to investigate the impact of maternal iron status on infant FGF23 and mineral metabolites over the first 2years of life. Infants born to mothers with normal (NIn=25,) and low (LIn=25) iron status during pregnancy, from a mother-infant trial (ISRCTN49285450) in rural Gambia, West Africa, had blood and plasma samples analysed at 12, 24, 52, 78 and 104weeks (wk) of age. Circulating intact-FGF23 (I-FGF23), Phos, total alkaline phosphatase (TALP) and haemoglobin (Hb) decreased and estimated glomerular filtration rate increased over time [all P≤0.0001)]. C-terminal-FGF23 (C-FGF23) and TALP were significantly higher in LI compared with NI, from 52wk for C-FGF23 [Beta coefficient (SE) 18.1 (0.04) %, P=0.04] and from 24wk for TALP [44.7 (29.6) U/L, P=0.04]. Infant Hb was the strongest negative predictor of C-FGF23 concentration [-21% (4%) RU/mL, P≤0.0001], Phos was the strongest positive predictor of I-FGF23 [32.0(3.9) pg/mL, P≤0.0001] and I-FGF23 did not predict C-FGF23 over time [-0.5% (0.5%), P=0.3]. In conclusion, this study suggests that poor maternal iron status is associated with a higher infant C-FGF23 and TALP but similar I-FGF23 concentrations in infants and young children. These findings further highlight the likely public health importance of preventing iron deficiency during pregnancy. Whether or not children who are born to iron deficient mothers have persistently high concentrations of these metabolites and are more likely to be at risk of impaired bone development and pre-disposed to rickets requires further research.

  10. Fibroblast Growth Factor 21 (FGF-21 in Peritoneal Dialysis Patients: Natural History and Metabolic Implications.

    Directory of Open Access Journals (Sweden)

    Elena González

    Full Text Available Human fibroblast growth factor 21 (FGF-21 is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD patients suffer potential interference with FGF-21 status with as yet unknown repercussions.The aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time.We studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy.Plasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685 at baseline; 582 pg/ml (60.5-949 at first year and 647 pg/ml (120.5-1116.6 at third year (p<0.01. We found a positive correlation between time on dialysis and FGF-21 levels (p<0.001, and also, those patients with residual renal function (RRF had significantly lower levels of FGF-21 than those without RRF (ρ -0.484, p<0.05. Lastly, there was also a significant association between FGF-21 levels and peritoneal protein losses (PPL, independent of the time on dialysis (ρ 0.410, p<0.05.Our study shows that FGF-21 plasma levels in incident PD patients significantly increase during the first 3 years. This increment is dependent on or is associated with RRF and PPL (higher levels in patients with lower RRF and higher PPL. FGF-21 might be an important endocrine agent in PD patients and could act as hormonal signaling to maintain glucose homeostasis and prevent potential insulin resistance. These preliminary results suggest that FGF-21 might play a protective role as against the development of insulin resistance over

  11. Plasma intact fibroblast growth factor 23 levels in women with anorexia nervosa

    Directory of Open Access Journals (Sweden)

    Otani Makoto

    2008-04-01

    Full Text Available Abstract Background Fibroblast growth factor (FGF23 is a novel phosphaturic factor associated with inorganic phosphate homeostasis. Previous human studies have shown that serum FGF23 levels increase in response to a high phosphate diet. For anorexia nervosa (AN patients, inorganic phosphate homeostasis is important in the clinical course, such as in refeeding syndrome. The purpose of this study was to determine plasma levels of intact FGF23 (iFGF23 in restricting-type AN (AN-R patients, binge-eating/purging-type AN (AN-BP patients, and healthy controls. Methods The subjects consisted of 6 female AN-R patients, 6 female AN-BP patients, and 11 healthy female controls; both inpatients and outpatients were included. Plasma iFGF23, 1,25-dihydroxyvitamin D (1,25-(OH2D, and 25-hydroxyvitamin D (25-OHD levels were measured. Data are presented as the median and the range. A two-tailed Mann-Whitney U-test with Bonferroni correction was used to assess differences among the three groups, and a value of p Results There were no differences between AN-R patients and controls in the iFGF23 and 1,25-(OH2D levels. In AN-BP patients, the iFGF23 level (41.3 pg/ml; range, 6.1–155.5 pg/ml was significantly higher than in controls (3.8 pg/ml; range, not detected-21.3 pg/ml; p = 0.001, and the 1,25-(OH2D was significantly lower in AN-BP patients (7.0 pg/ml; range, 4.2–33.7 pg/ml than in controls (39.7 pg/ml; range, 6.3–58.5 pg/ml; p = 0.015. No differences in plasma 25-OHD levels were observed among the groups. Conclusion This preliminary study is the first to show that plasma iFGF23 levels are increased in AN-BP patients, and that these elevated plasma FGF23 levels might be related to the decrease in plasma 1,25-(OH2D levels.

  12. Acid fibroblast growth factor reduces rat intestinal mucosal damage caused by ischemia-reperfusion insult

    Institute of Scientific and Technical Information of China (English)

    Wei Chen; Xiao-Bing Fu; Shi-Li Ge; Tong-Zhu Sun; Wen-Juan Li; Zhi-Yong Sheng

    2005-01-01

    AIM: To detect the effects of acid fibroblast growth factor (aFGF) on apoptosis and proliferation of intestinal epithelial cells in differentiation or proliferation status to explore the protective mechanisms of aFGF.METHODS: Wistar rats were randomly divided into sham-operated control group (C, n = 6), intestinal ischemia group (I,n = 6), aFGF treatment group (A,n =48) and intestinal ischemia-reperfusion group (R, n = 48). Apoptosis of intestinal mucosal cells was determined with terminal deoxynucleotidyl transferasemediated dUTP-biotin nick-end labeling (TUNEL)technique. Proliferating cell nuclear. antigen (PCNA)protein expression and distribution were detected with immunohistochemical method. Plasma levels of D-lactate were determined with modified Brandts method.RESULTS: In A group, administration of exogenous aFGF could improve intestinal histological structure and decrease plasma D-lactate levels at 2-12 h after the reperfusion compared with R group. The apoptotic rates and PCNA protein expressions were not increased until 2 h after reperfusion and were maximal at 12 h. After reperfusion for 2-12 h, the apoptotic rates were gradually augmented along the length of jejunal crypt-villus units.Administration of aFGF could significantly reduce the apoptotic response at 2-12 h after reperfusion (P<0.05).Apoptosis rates in villus and crypt epithelial cells in A group at 12 h after reperfusion were (62.5±5.5)% and (73.2±18.6)% of those in R group, respectively.Treatment of aFGF could apparently induce protein expression of PCNA in intestinal mucosal cells of A group compared with R group during 2-12 h after reperfusion (P<0.05). There were approximately 1.3- and 1.5-times increments of PCNA expression levels in villus and crypt cells in A group at 12 h after reperfusion compared with R group, respectively.CONCLUSION: Intestinal I/R insult could lead to histological structure change and apoptotic rate increment. The protective effects of aFGF against ischemia

  13. Nerve Growth Factor Secretion From Pulp Fibroblasts is Modulated by Complement C5a Receptor and Implied in Neurite Outgrowth.

    Science.gov (United States)

    Chmilewsky, Fanny; Ayaz, Warda; Appiah, James; About, Imad; Chung, Seung-Hyuk

    2016-01-01

    Given the importance of sensory innervation in tooth vitality, the identification of signals that control nerve regeneration and the cellular events they induce is essential. Previous studies demonstrated that the complement system, a major component of innate immunity and inflammation, is activated at the injured site of human carious teeth and plays an important role in dental-pulp regeneration via interaction of the active Complement C5a fragment with pulp progenitor cells. In this study, we further determined the role of the active fragment complement C5a receptor (C5aR) in dental nerve regeneration in regards to local secretion of nerve growth factor (NGF) upon carious injury. Using ELISA and AXIS co-culture systems, we demonstrate that C5aR is critically implicated in the modulation of NGF secretion by LTA-stimulated pulp fibroblasts. The NGF secretion by LTA-stimulated pulp fibroblasts, which is negatively regulated by C5aR activation, has a role in the control of the neurite outgrowth length in our axon regeneration analysis. Our data provide a scientific step forward that can guide development of future therapeutic tools for innovative and incipient interventions targeting the dentin-pulp regeneration process by linking the neurite outgrowth to human pulp fibroblast through complement system activation. PMID:27539194

  14. MicroRNA-26a modulates transforming growth factor beta-1-induced proliferation in human fetal lung fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoou [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Liu, Lian [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Shen, Yongchun; Wang, Tao; Chen, Lei; Xu, Dan [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Wen, Fuqiang, E-mail: wenfuqiang.scu@gmail.com [Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China); Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan (China)

    2014-11-28

    Highlights: • Endogenous miR-26a inhibits TGF-beta 1 induced proliferation of lung fibroblasts. • miR-26a induces G1 arrest through directly targeting 3′-UTR of CCND2. • TGF indispensable receptor, TGF-beta R I, is regulated by miR-26a. • miR-26a acts through inhibiting TGF-beta 2 feedback loop to reduce TGF-beta 1. • Collagen type I and connective tissue growth factor are suppressed by miR-26a. - Abstract: MicroRNA-26a is a newly discovered microRNA that has a strong anti-tumorigenic capacity and is capable of suppressing cell proliferation and activating tumor-specific apoptosis. However, whether miR-26a can inhibit the over-growth of lung fibroblasts remains unclear. The relationship between miR-26a and lung fibrosis was explored in the current study. We first investigated the effect of miR-26a on the proliferative activity of human lung fibroblasts with or without TGF-beta1 treatment. We found that the inhibition of endogenous miR-26a promoted proliferation and restoration of mature miR-26a inhibited the proliferation of human lung fibroblasts. We also examined that miR-26a can block the G1/S phase transition via directly targeting 3′-UTR of CCND2, degrading mRNA and decreasing protein expression of Cyclin D2. Furthermore, we showed that miR-26a mediated a TGF-beta 2-TGF-beta 1 feedback loop and inhibited TGF-beta R I activation. In addition, the overexpression of miR-26a also significantly suppressed the TGF-beta 1-interacting-CTGF–collagen fibrotic pathway. In summary, our studies indicated an essential role of miR-26a in the anti-fibrotic mechanism in TGF-beta1-induced proliferation in human lung fibroblasts, by directly targeting Cyclin D2, regulating TGF-beta R I as well as TGF-beta 2, and suggested the therapeutic potential of miR-26a in ameliorating lung fibrosis.

  15. Neuroligin-1 induces neurite outgrowth through interaction with neurexin-1ß and activation of fibroblast growth factor receptor-1

    DEFF Research Database (Denmark)

    Gjørlund, Michelle D; Nielsen, Janne; Pankratova, Stanislava;

    2012-01-01

    have been linked to cognitive diseases such as autism. The roles of both NRXN1 and NLGN1 during synaptogenesis have been studied extensively, but little is known about the role of these molecules in neuritogenesis, which eventually results in neuronal circuitry formation. The present study investigated...... the neuritogenic effect of NLGN1 in cultures of hippocampal neurons. Our results show that NLGN1, both in soluble and membrane-bound forms, induces neurite outgrowth that depends on the interaction with NRXN1ß and on activation of fibroblast growth factor receptor-1. In addition, we demonstrate that a synthetic...

  16. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α-hydroxylase gene expression

    OpenAIRE

    Song, Kwang-Hoon; Li, Tiangang; Owsley, Erika; Strom, Stephen; Chiang, John Y. L.

    2009-01-01

    Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7α-hydroxylase gene transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and a farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 mRNA levels in primary h...

  17. TRANSFORMING GROWTH FACTOR-β AND FIBROBLAST GROWTH FACTOR INDUCE LENS EPITHELIAL EXPLANT METAPLASIA: IMPLICATIONS FOR THE FORMATION OF SUBCAPSULAR OPACIFICATION

    Institute of Scientific and Technical Information of China (English)

    刘颉; 叶俊杰

    1998-01-01

    Objective. This study was to investigate the effects of transforming growth factor-β(TGFβ) and fibroblast growth factor (FGF) in the subcapsular opaeification formation of the lens. Methods. Lens epithelial explants from 10-day-old rats were cultured with TGFβ1 or TGFβ2 in the presence of FGF for 5 days, then were examined by light and electron microscopy, and by immunolocalization of α-smooth muscle(α-sm) actin and type Ⅰ collagen. Resets. In TGFβ/FGF-treated explants,extensive proliferation oeeured, with formation of spindle and star-shaped cells. These cells showed ultrastructure and biochemical features of fibroblast or myofibroblast.Prominent Golgi apparatus and rough endoplaie reticulum were observed in scene cells, Intracellular microfilaments with cytoplasmic dense bodies and membrane associated dense bodies, features of smooth muscle cells, were also observed. Some cells showed reactivity to α-sin actin antibody. TGFβ/FGF-treated explants were strongly stained with type I collagen antibody. Conclusion. In the presence of FGF, TGFβ1 and TGFβ2 induced lens epithelial cell(LEC)proliferation and transformation into fibroblast or myofibroblast like ceils, with producing of abundant collagen matrix in the explants. The changes are similar to the metaplasia that oeeurrs in subeapsular opacification of the lens. The findings suggest that TGFβ and FGF plays a role in the pathogenesis of subcapsular opacification of the lens.

  18. Molecular mechanisms of the synergy between cysteinyl-leukotrienes and receptor tyrosine kinase growth factors on human bronchial fibroblast proliferation

    Directory of Open Access Journals (Sweden)

    Hajime Yoshisue

    2006-12-01

    Full Text Available We have reported that cysteinyl-leukotrienes (cys-LTs synergise not only with epidermal growth factor (EGF but also with platelet-derived growth factor (PDGF and fibroblast growth factor (FGF to induce mitogenesis in human bronchial fibroblasts. We now describe the molecular mechanisms underlying this synergism. Mitogenesis was assessed by incorporation of [3H]thymidine into DNA and changes in protein phosphorylation by Western blotting. Surprisingly, no CysLT receptor antagonists (MK-571, montelukast, BAY u9773 prevented the synergistic mitogenesis. LTD4 did not cause phosphorylation of EGFR nor did it augment EGF-induced phosphorylation of EGFR, and the synergy between LTD4 and EGF was not blocked by the metalloproteinase inhibitor GM6001 or by an HB-EGF neutralising antibody. The EGFR-selective kinase inhibitor, AG1478, suppressed the synergy by LTD4 and EGF, but had no effect on the synergy with PDGF and FGF. While inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase and protein kinase C (PKC prevented the synergy, these drugs also inhibited mitogenesis elicited by EGF alone. In contrast, pertussis toxin (PTX efficiently inhibited the potentiating effect of LTD4 on EGF-induced mitogenesis, as well as that provoked by PDGF or FGF, but had no effect on mitogenesis elicited by the growth factors alone. Whereas LTD4 alone did not augment phosphorylation of extracellular signal-regulated kinase (Erk-1/2 and Akt, it increased phosphorylation of PKC in a Gi-dependent manner. Addition of LTD4 prolonged the duration of EGF-induced phosphorylation of Erk-1/2 and Akt, both of which were sensitive to PTX. The effect of cys-LTs involves a PTX-sensitive and PKC-mediated intracellular pathway leading to sustained growth factor-dependent phosphorylation of Erk-1/2 and Akt.

  19. Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix

    Energy Technology Data Exchange (ETDEWEB)

    Kalinina, J.; Byron, S; Makarenkova, H; Olsen, S; Eliseenkova, A; Larochelle, W; Dhanabal, M; Blais, S; Mohammadi, M; et. al.

    2009-01-01

    Uncontrolled fibroblast growth factor (FGF) signaling can lead to human diseases, necessitating multiple layers of self-regulatory control mechanisms to keep its activity in check. Herein, we demonstrate that FGF9 and FGF20 ligands undergo a reversible homodimerization, occluding their key receptor binding sites. To test the role of dimerization in ligand autoinhibition, we introduced structure-based mutations into the dimer interfaces of FGF9 and FGF20. The mutations weakened the ability of the ligands to dimerize, effectively increasing the concentrations of monomeric ligands capable of binding and activating their cognate FGF receptor in vitro and in living cells. Interestingly, the monomeric ligands exhibit reduced heparin binding, resulting in their increased radii of heparan sulfate-dependent diffusion and biologic action, as evidenced by the wider dilation area of ex vivo lung cultures in response to implanted mutant FGF9-loaded beads. Hence, our data demonstrate that homodimerization autoregulates FGF9 and FGF20's receptor binding and concentration gradients in the extracellular matrix. Our study is the first to implicate ligand dimerization as an autoregulatory mechanism for growth factor bioactivity and sets the stage for engineering modified FGF9 subfamily ligands, with desired activity for use in both basic and translational research.

  20. Transforming growth factor-β1 phage model peptides isolated from a phage display 7-mer peptide library can inhibit the activity of keloid fibroblasts

    Institute of Scientific and Technical Information of China (English)

    ZONG Xian-lei; JIANG Du-yin; WANG Ji-chang; LIU Jun-li; LIU Zhen-zhong; CAI Jing-long

    2011-01-01

    Background Transforming growth factor-β1 (TGF-β1) is known to have a role in keloid formation through the activation of fibroblasts and the acceleration of collagen deposition. The objective of this current study was to isolate TGF-β1 phage model peptides from a phage display 7-mer peptide library to evaluate their therapeutic effect on inhibiting the activity of keloid fibroblasts.Methods A phage display 7-mer peptide library was screened using monoclonal anti-human TGF-β1 as the target to obtain specific phages containing ectogenous model peptides similar to TGF-β1. Enzyme-linked immunosorbent assay (ELISA) was performed to select monoclonal phages with good binding activity, which underwent DNA sequencing. MTT assay and apoptosis assessment were used to evaluate the biological effects of the phage model peptides on keloid fibroblasts. Immunofluorescence assay was employed to show the binding affinity of the model peptides on phages causing keloid fibroblasts. Quantitative real-time PCR analysis was carried out to detect the expressions of nuclear factor κB (NF-κB) mRNA, connective tissue growth factor (CTGF) mRNA and TGF-β receptor Ⅱ (TβRII) mRNA in keloid fibroblasts.Results Specific phages with good results of ELISA were beneficiated. Four phage model peptides were obtained. The data of MTT showed that TGF-β1 and one phage model peptide (No. 4) could promote keloid fibroblasts proliferation,however, three phage model peptides (No. 1-3) could inhibit keloid fibroblasts proliferation. The results of apoptosis assessment showed that the three phage model peptides could slightly induce the apoptosis in keloid fibroblasts. The data of immunofluorescence assay revealed that the model peptides on phages rather than phages could bind to keloid fibroblasts. The findings of quantitative real-time PCR analysis suggested that the expressions of NF-κB mRNA and CTGF mRNA in the three phage model peptide groups decreased, while the expression of TβRII m

  1. Epigallocatechin-3-gallate regulates cell growth, cell cycle and phosphorylated nuclear factor-KB in human dermal fibroblasts

    Institute of Scientific and Technical Information of China (English)

    Dong-Wook HAN; Mi Hee LEE; Hak Hee KIM; Suong-Hyu HYON; Jong-Chul PARK

    2011-01-01

    Aim: To investigate the effects of (-)epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, on cell growth, cell cycle and phosphorylated nuclear factor-kB (pNF-KB) expression in neonatal human dermal fibroblasts (nHDFs).Methods: The proliferation and cell-cycle of nHDFs were determined using WST-8 cell growth assay and flow cytometry, respectively. The apoptosis was examined using DNA ladder and Annexin V-FITC assays. The expression levels of pNF-kB and cell cycle-related genes and proteins in nHDFs were measured using cDNA microarray analyses and Western blot. The cellular uptake of EGCG was examined using fluorescence (FITC)-Iabeled EGCG (FITC-EGCG) in combination with confocal microscopy.Results: The effect of EGCG on the growth of nHDFs depended on the concentration tested. At a low concentration (200 μmol/L), EGCG resulted in a slight decrease in the proportion of ceils in the S and G/M phases of cell cycle with a concomitant increase in the proportion of cells in G/G phase. At the higher doses (400 and 800 pmol/L), apoptosis was induced. The regulation of EGCG on the expression of pNF-kB was also concentration-dependent, whereas it did not affect the unphosphorylated NF-kB expression, cDNA microarray analysis showed that cell cycle-related genes were down-regulated by EGCG (200 μmol/L). The expression of cyclins A/B and cyclin-dependent kinase 1 was reversibly regulated by EGCG (200 μmol/L). FITC-EGCG was found to be internalized into the cyto-plasm and translocated into the nucleus of nHDFs.Conclusion: EGCG, through uptake into cytoplasm, reversibly regulated the cell growth and expression of cell cycle-related proteins and genes in normal fibroblasts.

  2. Resistance to ultraviolet-induced apoptosis in DNA repair deficient growth arrested human fibroblasts is not related to recovery from RNA transcription blockage

    International Nuclear Information System (INIS)

    The impact of ultraviolet (UV-C) photoproducts on apoptosis induction was investigated in growth arrested (confluent) and proliferating human primary fibroblasts. Confluent fibroblasts were more resistant to UV-C-induced apoptosis than proliferating cells, and this was observed for normal human cells and for cells from patients with Cockayne and trichothiodystrophy syndromes, deficient in transcription coupled repair. This resistance was sustained for at least seven days and was not due to DNA repair efficiency, as the removal of CPDs in the genome was similar under both growth conditions. There was no correlation between reduced apoptosis and RNA synthesis recovery. Following UV-C treatment, proliferating and confluent fibroblasts showed a similar level of RNA synthesis inhibition and recovery from transcription blockage. These results support the hypothesis that the decrease of DNA replication, in growth arrested cells, protects cell from UV-C-induced apoptosis, even in the presence of DNA lesions

  3. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion.

    Science.gov (United States)

    Gorin, Caroline; Rochefort, Gael Y; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Muller, Laurent; Chaussain, Catherine; Germain, Stéphane

    2016-03-01

    Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF.

  4. Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice.

    OpenAIRE

    Selden, R F; Wagner, T E; Blethen, S; Yun, J S; Rowe, M E; Goodman, H M

    1988-01-01

    The nucleotide sequence of the human growth hormone variant gene, one of the five members of the growth hormone gene family, predicts that it encodes a growth hormone-like protein. As a first step in determining whether this gene is functional in humans, we have expressed a mouse metallothionein I/human growth hormone variant fusion gene in mouse L cells and in transgenic mice. The growth hormone variant protein expressed in transiently transfected L cells is distinct from growth hormone itse...

  5. Transforming growth factor β1 induces the expression of collagen type I by DNA methylation in cardiac fibroblasts.

    Directory of Open Access Journals (Sweden)

    Xiaodong Pan

    Full Text Available Transforming growth factor-beta (TGF-β, a key mediator of cardiac fibroblast activation, has a major influence on collagen type I production. However, the epigenetic mechanisms by which TGF-β induces collagen type I alpha 1 (COL1A1 expression are not fully understood. This study was designed to examine whether or not DNA methylation is involved in TGF-β-induced COL1A1 expression in cardiac fibroblasts. Cells isolated from neonatal Sprague-Dawley rats were cultured and stimulated with TGF-β1. The mRNA levels of COL1A1 and DNA methyltransferases (DNMTs were determined via quantitative polymerase chain reaction and the protein levels of collagen type I were determined via Western blot as well as enzyme-linked immunosorbent assay. The quantitative methylation of the COL1A1 promoter region was analyzed using the MassARRAY platform of Sequenom. Results showed that TGF-β1 upregulated the mRNA expression of COL1A1 and induced the synthesis of cell-associated and secreted collagen type I in cardiac fibroblasts. DNMT1 and DNMT3a expressions were significantly downregulated and the global DNMT activity was inhibited when treated with 10 ng/mL of TGF-β1 for 48 h. TGF-β1 treatment resulted in a significant reduction of the DNA methylation percentage across multiple CpG sites in the rat COL1A1 promoter. Thus, TGF-β1 can induce collagen type I expression through the inhibition of DNMT1 and DNMT3a expressions as well as global DNMT activity, thereby resulting in DNA demethylation of the COL1A1 promoter. These findings suggested that the DNMT-mediated DNA methylation is an important mechanism in regulating the TGF-β1-induced COL1A1 gene expression.

  6. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan.

    Science.gov (United States)

    Pfefferkorn, E R

    1984-01-01

    Treatment of human fibroblasts with human recombinant gamma interferon blocked the growth of Toxoplasma gondii, an obligate intracellular protozoan parasite. Growth of the parasite was measured by a plaque assay 7 days after infection or by the incorporation of [3H]uracil 1 or 2 days after infection. The antitoxoplasma activity induced in the host cells by gamma interferon was strongly dependent upon the tryptophan concentration of the medium. Progressively higher minimal inhibitory concentrations of gamma interferon were observed as the tryptophan concentration in the culture medium was increased. Treatment with gamma interferon did not make the cells impermeable to tryptophan. The kinetics of [3H]tryptophan uptake into the acid-soluble pools of control and gamma interferon-treated cultures were identical during the first 48 sec. Thereafter uptake of [3H]tryptophan into the acid-soluble pool of control fibroblasts reached the expected plateau after 96 sec. In contrast, uptake of [3H]tryptophan continued for at least 12 min in the gamma interferon-treated cultures. At that time, the acid-soluble pool of the gamma interferon-treated cultures contained 8 times the radioactivity of the control cultures. This continued accumulation was the result of rapid intracellular degradation of [3H]tryptophan into kynurenine and N-formylkynurenine that leaked slowly from the cells. These two metabolites were also recovered from the medium of cultures treated for 1 or 2 days with gamma interferon. Human recombinant alpha and beta interferons, which have no antitoxoplasma activity, did not induce any detectable degradation of tryptophan. Several hypotheses are presented to explain how the intracellular degradation of tryptophan induced by gamma interferon could restrict the growth of an obligate intracellular parasite. Images PMID:6422465

  7. Analysis of Activated Platelet-Derived Growth Factor β Receptor and Ras-MAP Kinase Pathway in Equine Sarcoid Fibroblasts

    Directory of Open Access Journals (Sweden)

    Gennaro Altamura

    2013-01-01

    Full Text Available Equine sarcoids are skin tumours of fibroblastic origin affecting equids worldwide. Bovine papillomavirus type-1 (BPV-1 and, less commonly, type-2 are recognized as etiological factors of sarcoids. The transforming activity of BPV is related to the functions of its major oncoprotein E5 which binds to the platelet-derived growth factor β receptor (PDGFβR causing its phosphorylation and activation. In this study, we demonstrate, by coimmunoprecipitation and immunoblotting, that in equine sarcoid derived cell lines PDGFβR is phosphorylated and binds downstream molecules related to Ras-mitogen-activated protein kinase-ERK pathway thus resulting in Ras activation. Imatinib mesylate is a tyrosine kinase receptors inhibitor which selectively inhibits the activation of PDGFβR in the treatment of several human and animal cancers. Here we show that imatinib inhibits receptor phosphorylation, and cell viability assays demonstrate that this drug decreases sarcoid fibroblasts viability in a dose-dependent manner. This study contributes to a better understanding of the molecular mechanisms involved in the pathology of sarcoids and paves the way to a new therapeutic approach for the treatment of this common equine skin neoplasm.

  8. Cross-talk between the calcium-sensing receptor and the epidermal growth factor receptor in Rat-1 fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Tomlins, Scott A.; Bollinger, Nikki; Creim, Jeffrey A.; Rodland, Karin D.

    2005-08-15

    The calcium-sensing receptor (CaR) is a G-protein coupled receptor that is activated by extracellular calcium (Ca2+o). Rat-1 fibroblasts have been shown to proliferate and increase ERK activity in response to elevation of [Ca2+]o, and these responses are dependent on functional CaR expression. In this report, we examined the role of cross-talk between the CaR and the epidermal growth factor receptor (EGFR) in mediating these responses in Rat-1 cells. This report shows that AG1478, a specific inhibitor of the EGFR kinase, significantly inhibits the increase in proliferation induced by elevated Ca2+o. Further, we show that AG1478 acts downstream or separately from G-protein subunit activation of phospholipase C. AG1478 significantly inhibits Ca2+o-stimulated ERK phosphorylation and in vitro kinase activity. A similar inhibition of ERK phosphorylation was observed in response to the inhibitor AG494. In addition, treatment with inhibitors of metalloproteases involved in shedding of membrane anchored EGF family ligands substantially inhibited the increase in ERK activation in response to elevated Ca2+o. This is consistent with the known expression of TGFa by Rat-1 cells. These results indicate that EGFR transactivation is an important component of the CaR mediated response to increased Ca2+o in Rat-1 fibroblasts, and most likely involves CaR-mediated induction of regulated proteolysis and ligand shedding.

  9. Transforming Growth Factor-β1 Induces Transdifferentiation of Fibroblasts into Myofibroblasts in Hypoxic Pulmonary Vascular Remodeling

    Institute of Scientific and Technical Information of China (English)

    Yong-Liang JIANG; Ai-Guo DAI; Qi-Fang LI; Rui-Cheng HU

    2006-01-01

    The muscularization of non-muscular pulmonary arterioles is animportant pathological feature of hypoxic pulmonary vascular remodeling. However, the origin of the cells involved in this process is still not well understood. The present study was undertaken to test the hypothesis that transforming growth factor-β 1 (TGF-β 1) can induce transdifferentiation of fibroblasts into myofibroblasts, which might play a key role in the muscularization of non-muscular pulmonary arterioles. It was found that mean pulmonary arterial pressure increased significantly after 7 d of hypoxia. Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d of hypoxia. The distribution of nonmuscular, partially muscular, and muscular vessels was significantly different after 7 d of hypoxia. Immunocytochemistry results demonstrated that the expression of α-smooth muscle actin was increased in intra-acinar pulmonary arteries with increasing hypoxic time. TGF-β1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, but showed no obvious changes after 3 or 7 d of hypoxia. In pulmonary tunica adventitia and tunica media, TGF-β1 protein staining was poorly positive in control rats, but was markedly enhanced after 3 d of hypoxia, reaching its peak after 7 d of hypoxia. The myofibroblast phenotype was confirmed by electron microscopy, which revealed microfilaments and a well-developed rough endoplasmic reticulum. Taken together, our results suggested that TGF-β1 induces transdifferentiation of fibroblasts into myofibroblasts, which is important in hypoxic pulmonary vascular remodeling.

  10. Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice

    International Nuclear Information System (INIS)

    The nucleotide sequence of the human growth hormone variant gene, one of the five members of the growth hormone gene family, predicts that it encodes a growth hormone-like protein. As a first step in determining whether this gene is functional in humans, the authors have expressed a mouse methallothionein I/human growth hormone variant fusion gene in mouse L cells and in transgenic mice. The growth hormone variant protein expressed in transiently transfected L cells is distinct from growth hormone itself with respect to reactivity with anti-growth hormone monoclonal antibodies, behavior during column chromatography, and isoelectric point. Transgenic mice expressing the growth hormone variant protein are 1.4- to 1.9-fold larger than nontransgenic controls, suggesting that the protein has growth-promoting properties

  11. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.

    Directory of Open Access Journals (Sweden)

    Debbie Liao

    Full Text Available BACKGROUND: Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+ T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.

  12. The effect of a heparin-based coacervate of fibroblast growth factor-2 on scarring in the infarcted myocardium.

    Science.gov (United States)

    Chu, Hunghao; Chen, Chien-Wen; Huard, Johnny; Wang, Yadong

    2013-02-01

    Effective delivery of exogenous angiogenic growth factors can provide a new therapy for ischemic diseases. However, clinical translation of growth factor therapies faces multiples challenges; the most significant one is the short half-life of the naked protein. We use heparin and a nontoxic polycation to form an injectable coacervate that protects growth factors and preserves their bioactivities. Here we report the effectiveness of fibroblast growth factor-2 (FGF2) coacervate in reducing scar burden in a mouse myocardial infarction model. The coacervate provides spatial and temporal control of the release of heparin-binding proteins. Coacervate treated animals show lower level of inflammation, fibrosis and cardiomyocyte death in the infarcted myocardium. Histological evaluation indicates that FGF2 coacervate significantly increases the number of endothelial and mural cells and results in stable capillaries and arterioles to at least 6 weeks post injection. Echocardiographic assessment shows that FGF2 coacervate promotes cardiac contractibility and inhibits ventricular dilation, suggesting that the improvement at the tissue level leads to better cardiac functions. On the contrary, identical dosage of free FGF2 shows no statistical difference from saline or vehicle control in histological or functional assessment. Overall, injection of FGF2 coacervate ameliorated the ischemic injury caused by myocardial infarction. The promising data in rodent warrant further examination of the potential of clinical translation of this technology.

  13. Expression of a synthetic gene encoding human insulin-like growth factor I in cultured mouse fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Bayne, M.L.; Cascieri, M.A.; Kelder, B.; Applebaum, J.; Chicchi, G.; Shapiro, J.A.; Pasleau, F.; Kopchick, J.J.

    1987-05-01

    A synthetic gene encoding human insulin-like growth factor I (hIGF-I) was assembled and inserted into an expression vector containing the cytomegalovirus immediate early (CMV-IE) transcriptional regulatory region and portions of the bovine growth hormone gene. The recombinant plasmid encodes a 97 amino acid fusion protein containing the first 27 amino acids of the bovine growth hormone precursor and the 70 amino acids of hIGF-I. This plasmid, when transiently introduced into cultured mouse fibroblasts, directs synthesis of the fusion protein, subsequent proteolytic removal of the bovine growth hormone signal peptide, and secretion of hIGF-I into the culture medium. Conditioned medium from transfected cells inhibits binding of /sup 125/I-labeled IGF-I to type I IGF receptors on human placental membranes and to acid-stable human serum carrier proteins. The recombinant hIGF-I produced is biologically active, as monitored by the stimulation of DNA synthesis in vascular smooth muscle cells.

  14. Expression of a synthetic gene encoding human insulin-like growth factor I in cultured mouse fibroblasts

    International Nuclear Information System (INIS)

    A synthetic gene encoding human insulin-like growth factor I (hIGF-I) was assembled and inserted into an expression vector containing the cytomegalovirus immediate early (CMV-IE) transcriptional regulatory region and portions of the bovine growth hormone gene. The recombinant plasmid encodes a 97 amino acid fusion protein containing the first 27 amino acids of the bovine growth hormone precursor and the 70 amino acids of hIGF-I. This plasmid, when transiently introduced into cultured mouse fibroblasts, directs synthesis of the fusion protein, subsequent proteolytic removal of the bovine growth hormone signal peptide, and secretion of hIGF-I into the culture medium. Conditioned medium from transfected cells inhibits binding of 125I-labeled IGF-I to type I IGF receptors on human placental membranes and to acid-stable human serum carrier proteins. The recombinant hIGF-I produced is biologically active, as monitored by the stimulation of DNA synthesis in vascular smooth muscle cells

  15. Acemannan stimulates gingival fibroblast proliferation; expressions of keratinocyte growth factor-1, vascular endothelial growth factor, and type I collagen; and wound healing.

    Science.gov (United States)

    Jettanacheawchankit, Suwimon; Sasithanasate, Siriruk; Sangvanich, Polkit; Banlunara, Wijit; Thunyakitpisal, Pasutha

    2009-04-01

    Aloe vera has long been used as a traditional medicine for inducing wound healing. Gingival fibroblasts (GFs) play an important role in oral wound healing. In this study, we investigated the effects of acemannan, a polysaccharide extracted from Aloe vera gel, on GF proliferation; keratinocyte growth factor-1 (KGF-1), vascular endothelial growth factor (VEGF), and type I collagen production; and oral wound healing in rats. [(3)H]-Thymidine incorporation assay and ELISA were used. Punch biopsy wounds were created at the hard palate of male Sprague Dawley rats. All treatments (normal saline; 0.1% triamcinolone acetonide; plain 1% Carbopol; and Carbopol containing 0.5%, 1%, and 2% acemannan (w/w)) were applied daily. Wounded areas and histological features were observed at day 7 after treatment. From our studies, acemannan at concentrations of 2, 4, 8, and 16 mg/ml significantly induced cell proliferation (P<0.05). Acemannan concentrations between 2 - 16 mg/ml significantly stimulated KGF-1, VEGF, and type I collagen expressions (P<0.05). Wound healing of animals receiving Carbopol containing 0.5% acemannan (w/w) was significantly better than that of the other groups (P<0.05). These findings suggest that acemannan plays a significant role in the oral wound healing process via the induction of fibroblast proliferation and stimulation of KGF-1, VEGF, and type I collagen expressions.

  16. Characterization of the growth of murine fibroblasts that express human insulin receptors. I. The effect of insulin in the absence of other growth factors

    Energy Technology Data Exchange (ETDEWEB)

    Randazzo, P.A.; Morey, V.A.; Polishook, A.K.; Jarett, L. (Univ. of Pennsylvania, Philadelphia (USA))

    1990-09-01

    The effect of insulin on the growth of murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental cells (NIH/3T3) was characterized. Insulin in the absence of other mitogens increased the rate of incorporation of thymidine into NIH 3T3/HIR cells with a half-maximal response occurring at an insulin concentration of 35 ng/ml and a maximal response that was equivalent to that elicited by 10% fetal calf serum. The thymidine incorporation rate was increased by 12 h, was maximal at approximately 16 h, and returned to basal rates at 24 h after the addition of insulin. Insulin induced a maximum of 65% of cells to incorporate thymidine. The increased DNA synthesis was accompanied by net growth. Addition of insulin to the NIH 3T3/HIR cells resulted in increased DNA content with a half-maximal response occurring at approximately 30 ng/ml insulin and a maximal response equivalent to that elicited by serum. An increase in cell number detected after the addition of insulin to the NIH 3T3/HIR suggests that the cells had progressed through mitosis. Insulin did not increase the rate of thymidine incorporation, DNA content, or number of the parental NIH 3T3 cells. These data show that insulin, in the absence of a second mitogen, is able to induce NIH 3T3/HIR fibroblasts to traverse the cell cycle.

  17. Characterization of the growth of murine fibroblasts that express human insulin receptors. I. The effect of insulin in the absence of other growth factors

    International Nuclear Information System (INIS)

    The effect of insulin on the growth of murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental cells (NIH/3T3) was characterized. Insulin in the absence of other mitogens increased the rate of incorporation of thymidine into NIH 3T3/HIR cells with a half-maximal response occurring at an insulin concentration of 35 ng/ml and a maximal response that was equivalent to that elicited by 10% fetal calf serum. The thymidine incorporation rate was increased by 12 h, was maximal at approximately 16 h, and returned to basal rates at 24 h after the addition of insulin. Insulin induced a maximum of 65% of cells to incorporate thymidine. The increased DNA synthesis was accompanied by net growth. Addition of insulin to the NIH 3T3/HIR cells resulted in increased DNA content with a half-maximal response occurring at approximately 30 ng/ml insulin and a maximal response equivalent to that elicited by serum. An increase in cell number detected after the addition of insulin to the NIH 3T3/HIR suggests that the cells had progressed through mitosis. Insulin did not increase the rate of thymidine incorporation, DNA content, or number of the parental NIH 3T3 cells. These data show that insulin, in the absence of a second mitogen, is able to induce NIH 3T3/HIR fibroblasts to traverse the cell cycle

  18. Fibroblast growth factor 2 and DNA repair involvement in the keratinocyte stem cells response to ionizing radiation

    International Nuclear Information System (INIS)

    Keratinocyte stem cells (KSCs) from the human inter follicular epidermis are regarded as the major target to radiation during radiotherapy. We found herein that KSCs are more resistant to ionizing radiation than their direct progeny, and presented more rapid DNA damage repair kinetics than the progenitors. Furthermore, we provided evidence describing the effect of fibroblast growth factor 2 (FGF2) signaling on the ability of KSCs and progenitors to repair damaged DNA. Despite our knowledge of the fact, that FGF is an anti-apoptotic factor in multiple cell types, the direct link between DNA repair and FGF2 signaling has rarely been shown. Existence of such link is an important issue with implications not only to stem cell field but also to cancer therapy. (author)

  19. Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system

    Directory of Open Access Journals (Sweden)

    Ribeiro-Resende Victor

    2012-07-01

    Full Text Available Abstract Background Among the essential biological roles of bone marrow-derived cells, secretion of many soluble factors is included and these small molecules can act upon specific receptors present in many tissues including the nervous system. Some of the released molecules can induce proliferation of Schwann cells (SC, satellite cells and lumbar spinal cord astrocytes during early steps of regeneration in a rat model of sciatic nerve transection. These are the major glial cell types that support neuronal survival and axonal growth following peripheral nerve injury. Fibroblast growth factor-2 (FGF-2 is the main mitogenic factor for SCs and is released in large amounts by bone marrow-derived cells, as well as by growing axons and endoneurial fibroblasts during development and regeneration of the peripheral nervous system (PNS. Results Here we show that bone marrow-derived cell treatment induce an increase in the expression of FGF-2 in the sciatic nerve, dorsal root ganglia and the dorsolateral (DL region of the lumbar spinal cord (LSC in a model of sciatic nerve transection and connection into a hollow tube. SCs in culture in the presence of bone marrow derived conditioned media (CM resulted in increased proliferation and migration. This effect was reduced when FGF-2 was neutralized by pretreating BMMC or CM with a specific antibody. The increased expression of FGF-2 was validated by RT-PCR and immunocytochemistry in co-cultures of bone marrow derived cells with sciatic nerve explants and regenerating nerve tissue respectivelly. Conclusion We conclude that FGF-2 secreted by BMMC strongly increases early glial proliferation, which can potentially improve PNS regeneration.

  20. The fibroblast growth factor-2 (F.G.F.-2) expression predicts the tumoral response and the local of non at small cells bronchi cancers after chemoradiotherapy

    International Nuclear Information System (INIS)

    The tumoral expression of the fibroblast growth factor-2 is correlated with a bad response to chemotherapy and a strong rate of local recurrence. F.G.F.-2 would define a radioresistant phenotype of non at small cells bronchi carcinoma. (N.C.)

  1. Improvements in glucose metabolism early after gastric bypass surgery are not explained by increases in total bile acids and fibroblast growth factor 19 concentrations

    DEFF Research Database (Denmark)

    Jørgensen, Nils B; Dirksen, Carsten; Bojsen-Møller, Kirstine N;

    2015-01-01

    Context: Bile acids and fibroblast growth factor 19 (FGF19) have been suggested as key mediators of the improvements in glucose metabolism after Roux-en-Y gastric bypass (RYGB). Objective: To describe fasting and postprandial state total bile acid (TBA) and FGF19 concentrations before and after...

  2. AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells.

    Science.gov (United States)

    Yao, Ting-Jing; Zhu, Jin-Hai; Peng, De-Feng; Cui, Zhen; Zhang, Chao; Lu, Pei-hua

    2015-07-01

    Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings. PMID:25691251

  3. Growth and Replication of Infectious Bursal Disease Virus in the DF-1 Cell Line and Chicken Embryo Fibroblasts

    Directory of Open Access Journals (Sweden)

    Kaliyaperumal Rekha

    2014-01-01

    Full Text Available Infectious bursal disease virus (IBDV causes a highly contagious disease in young chicks and leads to significant economic losses in the poultry industry. To determine a suitable cell line for IBDV infection, replication, and growth kinetics of the virus, DF-1 cells and chicken embryo fibroblasts (CEF were used. The population doubling per day (Pd/D was found to be higher in DF-1 as compared to CEF cells. A suitable time of infection (TOI was established for increased production of virus and greater infectivity titers. The DF-1 and CEF cells were found to be susceptible to infection by producing marked cytopathic effects (CPEs, and the growth curves of IBDV in DF-1 and CEF cells were evaluated by infectivity assay using tissue culture infectious dose (TCID50. The cytopathic effects of the virus in DF-1 and CEF cells were found to be similar, but higher viral titers were detected in the DF-1 cells as compared to CEF. Thus the DF-1 cell line had a higher growth potential and infectivity, which will be of advantage in vaccine production.

  4. Growth and motility of human skin fibroblasts on multilayer strong polyelectrolyte films.

    Science.gov (United States)

    Wytrwal, Magdalena; Koczurkiewicz, Paulina; Zrubek, Karol; Niemiec, Wiktor; Michalik, Marta; Kozik, Bartłomiej; Szneler, Edward; Bernasik, Andrzej; Madeja, Zbigniew; Nowakowska, Maria; Kepczynski, Mariusz

    2016-01-01

    Polyelectrolyte multilayers (PEMs) have found application in modifying material surfaces to make them adhesive or non-adhesive for animal cells. However, PEMs made of strong polyelectrolytes are not fully recognized in the literature. This study focuses on the interplay between the properties of PEM assembled from strong polyelectrolytes and cell adhesion and motility. Strong polycations (with quaternary ammonium groups) and a polyanion (with sulfonate groups) were obtained by modification of poly(allylamine hydrochloride) (PAH). Two types of multilayer films were assembled from these PAH derivatives and used to investigate the behavior of human skin fibroblasts (HSFs). The effect of surface charge, hydrophobicity, and film thickness on adhesion of HSFs in a serum-containing medium was studied with immunofluorescence microscopy. The results showed that adhesion of HSFs was strongly depended on the chemical functions of the terminal layer, whereas the wettability was not important. The surface of PEM can be strongly cytophobic (the quaternary ammonium terminal groups) or strongly cytophilic (the sulfonate terminal groups). Finally, the motile activity of HSFs seeded on glass coated with a varying number of polymer layers was investigated. It was demonstrated using an in vitro model that coating the substrate with only two polymer layers can considerably increase the average speed of HSFs movement and stimulate cell migration into the wound. PMID:26407058

  5. The effect of fibroblast growth factors and advanced glycation end-products on the intima-media complex thickness in patients with coronary heart disease and type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Ekaterina Vladimirovna Ivannikova

    2014-05-01

    Full Text Available ObjectiveTo determine the levels of fibroblast transforming growth factor (TGFβ1, basic fibroblast growth factor (β-FGF, markers of nonspecific inflammatory response (interleukin-6 (IL-6, C-reactive protein (CRP, advanced glycation end-products (AGEs and their receptors (RAGEs and to study their effect on the intima-media complex (IMC thickness in patients with coronary heart disease (CHD and type 2 diabetes, depending on carbohydrate metabolism compensation.Materials and Methods37 patients with CHD underwent a general clinical examination, analysis of the carbohydrate and lipid metabolism parameters and the renal function, and also were evaluated with instrumental methods of analysis (echocardiography, coronary angiography and duplex scanning of the brachiocephalic arteries. To determine the level of the analyzed parameters, blood samples were taken from the aorta during coronary angiography and concomitantly from the cubital vein in all patients.ResultsThe presence of diabetes mellitus (DM in patients with CHD was found to be associated with a more severe atherosclerotic disease of the coronary and brachiocephalic vessels. A direct correlation between the degree of stenosis and the level of fibroblast growth factors, inflammatory factors, and advanced glycation end-products was found. A direct correlation between AGE and TGFβ1 and the lipid metabolism parameters was established. A statistically significant elevation of the studied parameters in the arterial and venous blood of patients with DM was revealed.ConclusionThese findings confirm the relationship between connective tissue disorders and lipid metabolism in the pathogenesis of atherosclerosis. A negative effect of hyperglycaemia on atherosclerotic changes of the vascular wall was demonstrated.

  6. Action Mechanism of Fibroblast Growth Factor-2 (FGF-2 in the Promotion of Periodontal Regeneration in Beagle Dogs.

    Directory of Open Access Journals (Sweden)

    Toshie Nagayasu-Tanaka

    Full Text Available Fibroblast growth factor-2 (FGF-2 enhances the formation of new alveolar bone, cementum, and periodontal ligament (PDL in periodontal defect models. However, the mechanism through which FGF-2 acts in periodontal regeneration in vivo has not been fully clarified yet. To reveal the action mechanism, the formation of regenerated tissue and gene expression at the early phase were analyzed in a beagle dog 3-wall periodontal defect model. FGF-2 (0.3% or the vehicle (hydroxypropyl cellulose only were topically applied to the defect in FGF-2 and control groups, respectively. Then, the amount of regenerated tissues and the number of proliferating cells at 3, 7, 14, and 28 days and the number of blood vessels at 7 days were quantitated histologically. Additionally, the expression of osteogenic genes in the regenerated tissue was evaluated by real-time PCR at 7 and 14 days. Compared with the control, cell proliferation around the existing bone and PDL, connective tissue formation on the root surface, and new bone formation in the defect at 7 days were significantly promoted by FGF-2. Additionally, the number of blood vessels at 7 days was increased by FGF-2 treatment. At 28 days, new cementum and PDL were extended by FGF-2. Moreover, FGF-2 increased the expression of bone morphogenetic protein 2 (BMP-2 and osteoblast differentiation markers (osterix, alkaline phosphatase, and osteocalcin in the regenerated tissue. We revealed the facilitatory mechanisms of FGF-2 in periodontal regeneration in vivo. First, the proliferation of fibroblastic cells derived from bone marrow and PDL was accelerated and enhanced by FGF-2. Second, angiogenesis was enhanced by FGF-2 treatment. Finally, osteoblastic differentiation and bone formation, at least in part due to BMP-2 production, were rapidly induced by FGF-2. Therefore, these multifaceted effects of FGF-2 promote new tissue formation at the early regeneration phase, leading to enhanced formation of new bone, cementum

  7. Fibroblast growth factor rescues brain endothelial cells lacking presenilin 1 from apoptotic cell death following serum starvation.

    Science.gov (United States)

    Gama Sosa, Miguel A; De Gasperi, Rita; Hof, Patrick R; Elder, Gregory A

    2016-01-01

    Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1-/- embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1-/- cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1-/- cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1. Fibroblast growth factor (FGF1 and FGF2), but not vascular endothelial growth factor (VEGF) rescued Psen1-/- cells from serum starvation induced apoptosis. Inhibition of FGF signaling induced apoptosis in wt cells under serum withdrawal, while blocking γ-secretase activity had no effect. In the absence of serum, FGF2 immunoreactivity was distributed diffusely in cytoplasmic and nuclear vesicles of wt and Psen1-/- cells, as levels of FGF2 in nuclear and cytosolic fractions were not significantly different. Thus, sensitivity of Psen1-/- cells to serum starvation is not due to lack of FGF synthesis but likely to effects of Psen1 on FGF release onto the cell surface and impaired activation of the PI3K/AKT survival pathway. PMID:27443835

  8. Transmural endothelialization of vascular prostheses is regulated in vitro by Fibroblast Growth Factor 2 and heparan-like molecule.

    Science.gov (United States)

    Desgranges, P; Barritault, D; Caruelle, J P; Tardieu, M

    1997-10-01

    Endothelialization of vascular prostheses may result from transmural migration of endothelial cells. Angiogenesis is controlled by growth factors like Fibroblast Growth Factor 2 (FGF2) and regulators like heparan-like molecules. To that end, we used heparan-like molecules named RGTA for ReGeneraTing Agent. The RGTA11 used was a chemically derived dextran obtained by successive substitutions with carboxymethyl, benzylamide, and benzylamide sulfonate groups on glucose residues. This agent was further selected for its ability to bind, stabilize and protect FGF2. We defined firstly the angiogenic capability of FGF2 in combination with RGTA11 on bovine aortic endothelial cells (BAEC) cultured on collagen I gels. Secondly, the role of FGF2 and RGTA11 in transmural endothelialization was assessed in a three-dimensional in vitro model using a polyethylene terephtalate prosthesis included in collagen gel. BAEC seeded on the external face can migrate to the luminal face of the prosthesis. Microscopic and histological evaluations were performed at 4 and 7 days. Results showed that the addition of RGTA11 alone did not promote angiogenesis while FGF2 alone did. However, RGTA11 combined with FGF2 produced a significant acceleration in angiogenesis compared to FGF2 alone. This combination magnifies and enhances the angiogenic processes leading to endothelialization of luminal face through transmural cellular migration. Our data demonstrates that in vitro transmural endothelialization of porous vascular prostheses by BAEC cultured on collagen I gels is upregulated by RGTA11 combined with FGF2. PMID:9422495

  9. Cytokines modulate the sensitivity of human fibroblasts to stimulation with insulin-like growth factor-I (IGF-I) by altering endogenous IGF-binding protein production.

    Science.gov (United States)

    Yateman, M E; Claffey, D C; Cwyfan Hughes, S C; Frost, V J; Wass, J A; Holly, J M

    1993-04-01

    Human dermal fibroblasts produce a number of insulin-like growth factor-binding proteins (IGFBPs) including the main circulating form, IGFBP-3. It has been suggested that the regulation of IGFBP secretion may play a major role in modulating insulin-like growth factor (IGF) bioactivity. We have quantified the effects of two cytokines, transforming growth factor-beta 1 (TGF-beta 1) and tumour necrosis factor-alpha (TNF-alpha) which have opposing actions on fibroblast IGFBP-3 production, and examined their subsequent role in IGF-I mitogenesis. TGF-beta 1 caused a dose-dependent increase in IGFBP-3 in serum-free fibroblast-conditioned media. TGF-beta 1 (1 microgram/l) resulted in immunoreactive IGFBP-3 levels reaching 286.5 +/- 22.4% of control after 20 h, the increase being confirmed by Western ligand blot. TNF-alpha caused a dose-dependent decrease in fibroblast IGFBP-3 secretion, 1 microgram TNF-alpha/l reducing IGFBP-3 levels to 32.1 +/- 11.% of control. This effect was not due to cytotoxicity and was not cell-density-dependent. Fibroblast proliferation was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric cytochemical bioassay. The addition of IGF-I resulted in dose-dependent growth stimulation after 48 h, the effective range being 20-100 micrograms/l. The IGF-I analogue Long-R3-IGF-I which has little affinity for the IGFBPs was approximately 20-fold more potent in this assay, and was unaffected by exogenous IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7684061

  10. Beneficial use of fibroblast growth factor 2 and RGTA, a new family of heparan mimics, for endothelialization of PET prostheses.

    Science.gov (United States)

    Desgranges, P; Caruelle, J P; Carpentier, G; Barritault, D; Tardieu, M

    2001-01-01

    We have studied the endothelialization of polyethylene terephtalate (PET) prostheses coated with collagen by adult human saphenous endothelial cells (EC) under various in vitro conditions. Collagenous PET was impregnated either by Fibroblast Growth Factor 2 (FGF2), heparin, a synthetic heparan sulfate mimic named RGTA 11 (for ReGeneraTing Agent), or combinations of these products. RGTA 11 belongs to a new family of drugs, which have been previously described as stabilizer and protector of heparin binding growth factors (HBGF), and to act in vivo as to stimulate wounded tissue repair. As endothelialization of prosthesis can be obtained in vivo after EC seeding and/or by transanastomotic, as well as by transprosthetic EC migrations, we have designed in vitro models to study the growth of EC seeded on PET, the EC colonization of an acellular area on PET, and the migration of EC from a collagen gel through the prosthesis. The combinations of either RGTA11 or heparin with FGF2 enhanced after a week by 5-fold the growth of seeded EC compared to RGTA or heparin alone and by 3-fold compared to FGF2 alone (p < 0.05). More than 80% of the colonization of an acellular area was achieved within 6 days when FGF2 was combined with RGTA11 or heparin. In contrast, colonization was only of 20% promoted in presence of FGF2 alone and not promoted in the presence of RGTA or heparin alone (p < 0.05). In addition, transprosthetic migration of EC and endothelialization of the luminal side were observed only when gel contained RGTA11 or heparin in combination with FGF2. The present work did strongly indicate that RGTA11 could be used in vivo as to improve endothelialization and should be the focus of continued investigation. PMID:11152991

  11. Without continuous basic research technology will stagnate and economy will be in no growth. Why?

    DEFF Research Database (Denmark)

    Pedersen, Jørgen Lindgaard

    2008-01-01

    The paper presents some ideas about new knowledge and the effects from knowledge on development of new technology. Paul M. Romer established in the 1980s the so-called New Growth Economy. The basic idea is here that knowledge is included explicitly in the production function. With knowledge...

  12. Improved growth rates and purity of basic ammonothermal GaN

    Science.gov (United States)

    Pimputkar, S.; Kawabata, S.; Speck, J. S.; Nakamura, S.

    2014-10-01

    Improvements to the experimental setup for the basic ammonothermal growth of GaN and the introduction of a silver capsule into the autoclave have yielded an ultrahigh purity (UHP) growth environment with reproducible external wall temperature profiles to within the error of the thermocouples (type K with special limits of error (SLE), ±2.5 °C). 40 basic ammonothermal growth runs were performed on hydride vapor phase epitaxy (HVPE) GaN seed crystals with different crystal orientations to optimize the growth system. Due to the UHP growth environment, transition metal impurities in the GaN crystals were reduced to less than 1×1017 cm-3 and oxygen impurity concentrations were comparable to those of the polycrystalline HVPE GaN source material (1×1019 cm-3). Total growth rates improved to 344±30 μm/day for c-plane growth and 46±2 μm/day for m-plane growth. The crystal quality, as measured by the full width at half maximum (FWHM) of the ω-rocking curve using X-ray diffraction (ω-XRC), was comparable to that of the seed crystal, except for Ga-face growth on c-plane oriented seeds due to poor nucleation and cracking in thick growth layers due to strain originating from the HVPE seed crystals. The difference in total system pressure profiles during growth runs using autoclaves with and without a silver capsule was analyzed and the pressure drop due to outward diffusion of hydrogen during growth was modeled.

  13. Fibroblast growth factors 1 and 2 in cerebrospinal fluid are associated with HIV disease, methamphetamine use, and neurocognitive functioning

    Directory of Open Access Journals (Sweden)

    Bharti AR

    2016-04-01

    Full Text Available Ajay R Bharti,1 Steven Paul Woods,2 Ronald J Ellis,3 Mariana Cherner,2 Debra Rosario,3 Michael Potter,3 Robert K Heaton,2 Ian P Everall,4 Eliezer Masliah,5 Igor Grant,2 Scott L Letendre1 On behalf of the Translational Methamphetamine AIDS Research Center Group 1Department of Medicine, 2Department of Psychiatry, 3Department of Neurosciences, University of California San Diego, San Diego, CA, USA; 4Department of Psychiatry, University of Melbourne, Victoria, Australia; 5Department of Pathology, University of Californa San Diego, San Diego, CA, USA Background: Human immunodeficiency virus (HIV and methamphetamine use commonly affect neurocognitive (NC functioning. We evaluated the relationships between NC functioning and two fibroblast growth factors (FGFs in volunteers who differed in HIV serostatus and methamphetamine dependence (MAD. Methods: A total of 100 volunteers were categorized into four groups based on HIV serostatus and MAD in the prior year. FGF-1 and FGF-2 were measured in cerebrospinal fluid by enzyme-linked immunosorbent assays along with two reference biomarkers (monocyte chemotactic protein [MCP]-1 and neopterin. Comprehensive NC testing was summarized by global and domain impairment ratings. Results: Sixty-three volunteers were HIV+ and 59 had a history of MAD. FGF-1, FGF-2, and both reference biomarkers differed by HIV and MAD status. For example, FGF-1 levels were lower in subjects who had either HIV or MAD than in HIV– and MAD– controls (P=0.003. Multivariable regression identified that global NC impairment was associated with an interaction between FGF-1 and FGF-2 (model R2=0.09, P=0.01: higher FGF-2 levels were only associated with neurocognitive impairment among subjects who had lower FGF-1 levels. Including other covariates in the model (including antidepressant use strengthened the model (model R2=0.18, P=0.004 but did not weaken the association with FGF-1 and FGF-2. Lower FGF-1 levels were associated with impairment

  14. Fibroblast growth factors as regulators of stem cell self-renewal and aging

    NARCIS (Netherlands)

    Yeoh, Joyce S. G.; de Haan, Gerald

    2007-01-01

    Organ and tissue dysfunction which is readily observable during aging results from a loss of cellular homeostasis and reduced stem cell self-renewal. Over the past 10 years, studies have been aimed at delineating growth factors that will sustain and promote the self-renewal potential of stem cells a

  15. Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b over-expressing PC-3 prostate tumour xenografts

    Directory of Open Access Journals (Sweden)

    Kinnunen Ilpo

    2010-10-01

    Full Text Available Abstract Background Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF-expressing xenografts, representing another fast growing and angiogenic tumour model. Methods Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC, flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG and hypoxia ([18F]EF5, and intratumoral polarographic measurements of pO2. Results Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1 and hypoxia inducible factor (HIF 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. Conclusion FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts.

  16. Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts

    International Nuclear Information System (INIS)

    Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([18F]FDG) and hypoxia ([18F]EF5), and intratumoral polarographic measurements of pO2. Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO2 measurements, [18F]EF5 and [18F]FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts

  17. Novel Lobophorins Inhibit Oral Cancer Cell Growth and Induce Atf4- and Chop-Dependent Cell Death in Murine Fibroblasts.

    Science.gov (United States)

    Cruz, Patricia G; Fribley, Andrew M; Miller, Justin R; Larsen, Martha J; Schultz, Pamela J; Jacob, Renju T; Tamayo-Castillo, Giselle; Kaufman, Randal J; Sherman, David H

    2015-08-13

    As part of the International Cooperative Biodiversity Groups (ICBG) Program, we were interested in identifying biologically active unfolded protein response (UPR) inducing compounds from marine microorganisms isolated from Costa Rican biota. With this aim in mind we have now generated more than 33,000 unique prefractionated natural product extracts from marine and terrestrial organisms that have been submitted to the Center of Chemical Genomics (CCG) at the University of Michigan for high throughput screening (HTS). An effective complementary cell-based assay to identify novel modulators of UPR signaling was used for screening extracts. Active fractions were iteratively subjected to reverse-phase HPLC chromatographic analysis, and together with lobophorin A, B, E, and F (1-4), three new lobophorin congeners, designated as CR1 (5), CR2 (6), and CR3 (7) were isolated. Herein, we report that secondary assays revealed that the new lobophorins induced UPR-associated gene expression, inhibited oral squamous cell carcinoma cell growth, and led to UPR-dependent cell death in murine embryonic fibroblast (MEF) cells. PMID:26288688

  18. The Regulation and Function of Fibroblast Growth Factor 8 and Its Function during Gonadotropin-Releasing Hormone Neuron Development.

    Science.gov (United States)

    Chung, Wilson C J; Linscott, Megan L; Rodriguez, Karla M; Stewart, Courtney E

    2016-01-01

    Over the last few years, numerous studies solidified the hypothesis that fibroblast growth factor (FGF) signaling regulates neuroendocrine progenitor cell proliferation, fate specification, and cell survival and, therefore, is critical for the regulation and maintenance of homeostasis of the body. One important example that underscores the involvement of FGF signaling during neuroendocrine cell development is gonadotropin-releasing hormone (GnRH) neuron ontogenesis. Indeed, transgenic mice with reduced olfactory placode (OP) Fgf8 expression do not have GnRH neurons. This observation indicates the requirement of FGF8 signaling for the emergence of the GnRH neuronal system in the embryonic OP, the putative birth place of GnRH neurons. Mammalian reproductive success depends on the presence of GnRH neurons to stimulate gonadotropin secretion from the anterior pituitary, which activates gonadal steroidogenesis and gametogenesis. Together, these observations are critical for understanding the function of GnRH neurons and their control of the hypothalamus-pituitary-gonadal (HPG) axis to maintain fertility. Taken together, these studies illustrate that GnRH neuron emergence and hence HPG function is vulnerable to genomic and molecular signals that abnormally modify Fgf8 expression in the developing mouse OP. In this short review, we focus on research that is aimed at unraveling how androgen, all-trans retinoic acid, and how epigenetic factors modify control mouse OP Fgf8 transcription in the context of GnRH neuronal development and mammalian reproductive success. PMID:27656162

  19. EFFECTS OF TRANSFORMING GROWTH FACTOR β AND RECOMBINANT HUMAN BONE MORPHOGENETIC PROTEIN 2 ON HUMAN PERIODONTAL LIGAMENT FIBROBLASTS

    Institute of Scientific and Technical Information of China (English)

    司晓辉; 刘正

    2001-01-01

    Objective To evaluate the effects of transforming growth factor β(TGF-β) and recombinant human bone morphogenetic protein 2 (rhBMP2) on human periodontal ligament fibroblasts ( HPDLFs ). Methods HPDLFs were done primary culture to detect the distinct concentrations of TGF-β and rhBMP2 on its proliferation, alkaline phosphatase (ALP) activity, osteocalcin ( OC) synthesis and formation of the mineralized nodules, respectively. Results TGF-β(5~100ng /ml) significantly stimulated the proliferation of HPDLFs. The ALP activity of HPDLFs was evaluated evidently by 5ng /ml TGF-β. TGF-β(0.5~100ng /ml) had no effects on OC synthesis and formation of the mineralized nodules of HPDLFs. rhBMP2 (0.25~2mg/ ml) had no rernarkable effect on the proliferation of HPDLFs. The ALP activity, OC synthesis and formation of the mineralized nodules of HPDLFs were significantly stimulated by 0.5~2mg/ml rhBMP2. Conclusion The effects of TGF-β and rhBMP2 on HPDLFs are dose-dependent. TGF-β can stimulate HPDLFs to express the early marker of osteoblastic phenotype , and it lacks the ability to promote maturation of the osteogenic phenotype. rhBMP2 can not only stimulate the expression but also promote the maturation of osteoblastic phenotype of HPDLFs.

  20. A Functional Role of Fibroblast Growth Factor Receptor 1 (FGFR1 in the Suppression of Influenza A Virus Replication.

    Directory of Open Access Journals (Sweden)

    Xin Liu

    Full Text Available Influenza A virus causes annual epidemics and occasional pandemics in humans. Here, we investigated four members of the fibroblast growth factor receptor (FGFR family; FGFR1 to 4, and examined their expression patterns in human lung epithelial cells A549 with influenza A virus infection. We identified a functional role of FGFR1 in influenza A/Puerto Rico/8/1934 (PR8 and A/Anhui/01/2005 (H5N1 virus replication. Our results showed that FGFR1 silencing by siRNA interference promoted influenza A/PR8 and H5N1 virus replication in A549 cells, while lentivirus-mediated exogenous FGFR1 expression significantly suppressed influenza A virus replication; however, FGFR4 did not have the same effects. Moreover, FGFR1 phosphorylation levels were downregulated in A549 cells by influenza A virus infection, while the repression of FGFR1 kinase using PD173074, a potent and selective FGFR1 inhibitor, could enhance virus replication. Furthermore, we found that FGFR1 inhibits influenza virus internalization, but not binding, during viral entry. These results suggested that FGFR1 specifically antagonizes influenza A virus replication, probably by blocking viral entry.

  1. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

    Energy Technology Data Exchange (ETDEWEB)

    Bonaventure, J.; Rousseau, F.; Legeai-Mallet, L.; LeMerrer, M.; Munnich, A.; Maroteaux, P. [INSERM, Paris (France)

    1996-05-03

    The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases; in our series, seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder. 31 refs., 4 figs., 2 tabs.

  2. Changes in circulating levels of fibroblast growth factor 23 induced by short-term dietary magnesium deficiency in rats.

    Science.gov (United States)

    Matsuzaki, Hiroshi; Katsumata, Shinichi; Maeda, Yoshiaki; Kajita, Yasutaka

    2016-06-01

    Fibroblast growth factor 23 (FGF23) is a potent regulator of phosphorus (P) and vitamin D metabolism. Long-term dietary magnesium (Mg) deficiency increases circulating levels of FGF23, whereas the effects of short-term dietary Mg deficiency are unclear. Thus, the present study investigated whether short-term dietary Mg deficiency affects circulating levels of FGF23. We also assessed changes in renal mRNA expression of vitamin D metabolizing enzymes and type II sodium-phosphate (Na/Pi) cotransporters, since these are regulated by FGF23. Rats were fed a control diet (control group) or an Mg-deficient diet (Mg-deficient group) for 2, 4 or 7 days. Serum Mg levels were significantly lower in the Mg-deficient group than in the control group at all time points. Serum FGF23 levels were significantly higher in the Mg-deficient group than in the control group at day 7. The 25-hydroxyvitamin D-24-hydroxylase (24(OH)ase) mRNA levels were significantly higher in the Mg-deficient group than in the control group at day 7 . No significant differences in types IIa and IIc Na/Pi cotransporter mRNA levels were observed between the control and Mg-deficient groups. These results suggest that dietary Mg deficiency causes a rapid increase in circulating levels of FGF23 and renal 24(OH)ase mRNA levels. PMID:27624533

  3. Prognostic significance of fibroblast growth factor receptor 4 polymorphisms on biochemical recurrence after radical prostatectomy in a Chinese population.

    Science.gov (United States)

    Chen, Luyao; Lei, Zhengwei; Ma, Xin; Huang, Qingbo; Zhang, Xu; Zhang, Yong; Hao, Peng; Yang, Minggang; Zhao, Xuetao; Chen, Jun; Liu, Gongxue; Zheng, Tao

    2016-01-01

    Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor with ligand-induced tyrosine kinase activity and is involved in various biological and pathological processes. Several polymorphisms of FGFR4 are associated with the incidence and mortality of numerous cancers, including prostate cancer. In this study, we investigated whether the polymorphisms of FGFR4 influence the biochemical recurrence of prostate cancer in Chinese men after radical prostatectomy. Three common polymorphisms (rs1966265, rs2011077, and rs351855) of FGFR4 were genotyped from 346 patients with prostate cancer by using the Sequenom MassARRAY system. Kaplan-Meier curves and Cox proportional hazard models were used for survival analysis. Results showed biochemical recurrence (BCR) free survival was significantly affected by the genotypes of rs351855 but not influenced by rs1966265 and rs2011077. After adjusting for other variables in multivariable analysis, patients with rs351855 AA/AG genotypes showed significantly worse BCR-free survival than those with the GG genotype (HR = 1.873; 95% CI, 1.209-2.901; P = 0.005). Hence, FGFR4 rs351855 could be a novel independent prognostic factor of BCR after radical prostatectomy in the Chinese population. This functional polymorphism may also provide a basis for surveillance programs. Additional large-scale studies must be performed to validate the significance of this polymorphism in prostate cancer. PMID:27640814

  4. The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

    Science.gov (United States)

    Jung, Yoon Seok; Lee, Ji-Min; Kim, Don-Kyu; Lee, Yong-Soo; Kim, Ki-Sun; Kim, Yong-Hoon; Kim, Jina; Lee, Myung-Shik; Lee, In-Kyu; Kim, Seong Heon; Cho, Sung Jin; Jeong, Won-Il; Lee, Chul-Ho; Harris, Robert A.; Choi, Hueng-Sik

    2016-01-01

    Background Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown. Results Activation of the hepatic CB1 receptor by arachidonyl-2’-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) γ increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRγ decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRγ, but not ERRα and ERRβ, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRγ-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRγ to the FGF21 gene promoter. Finally, GSK5182, an ERRγ inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion. Conclusion Based on our data, we conclude that ERRγ plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion. PMID:27455076

  5. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Muenke, M.; Gripp, K.W.; McDonald-McGinn, D.M. [Univ. of Pennsylvania, Philadelphia, PA (United States)] [and others

    1997-03-01

    The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis. 54 refs., 4 figs., 2 tabs.

  6. Cooperative heparin-mediated oligomerization of fibroblast growth factor-1 (FGF1) precedes recruitment of FGFR2 to ternary complexes.

    Science.gov (United States)

    Brown, Alan; Robinson, Christopher J; Gallagher, John T; Blundell, Tom L

    2013-04-16

    Fibroblast growth factors (FGFs) utilize cell surface heparan sulfate as a coreceptor in the assembly of signaling complexes with FGF-receptors on the plasma membrane. Here we undertake a complete thermodynamic characterization of the assembly of the FGF signaling complex using isothermal titration calorimetry. Heparin fragments of defined length are used as chemical analogs of the sulfated domains of heparan sulfate and examined for their ability to oligomerize FGF1. Binding is modeled using the McGhee-von Hippel formalism for the cooperative binding of ligands to a monodimensional lattice. Oligomerization of FGFs on heparin is shown to be mediated by positive cooperativity (α = 6). Heparin octasaccharide is the shortest length capable of dimerizing FGF1 and on longer heparin chains FGF1 binds with a minimal footprint of 4.2 saccharide units. The thermodynamics and stoichiometry of the ternary complex suggest that in solution FGF1 binds to heparin in a trans-dimeric manner before FGFR recruitment. PMID:23601319

  7. Fibroblast Growth Factor-9 Activates c-Kit Progenitor Cells and Enhances Angiogenesis in the Infarcted Diabetic Heart

    Directory of Open Access Journals (Sweden)

    Dinender Singla

    2016-01-01

    Full Text Available We hypothesized that fibroblast growth factor-9 (FGF-9 would enhance angiogenesis via activating c-kit positive stem cells in the infarcted nondiabetic and diabetic heart. In brief, animals were divided into three groups: Sham, MI, and MI+FGF-9. Two weeks following MI or sham surgery, our data suggest that treatment with FGF-9 significantly diminished vascular apoptosis compared to the MI group in both C57BL/6 and db/db mice (p<0.05. Additionally, the number of c-kit+ve/SM α-actin+ve cells and c-kit+ve/CD31+ve cells were greatly enhanced in the MI+FGF-9 groups relative to the MI suggesting FGF-9 enhances c-Kit cell activation and their differentiation into vascular smooth muscle cells and endothelial cells, respectively (p<0.05. Histology shows that the total number of vessels were quantified for all groups and our data suggest that the FGF-9 treated groups had significantly more vessels than their MI counterparts (p<0.05. Finally, echocardiographic data suggests a significant improvement in left ventricular output, as indicated by fractional shortening and ejection fraction in both nondiabetic and diabetic animals treated with FGF-9 (p<0.05. Overall, our data suggests FGF-9 has the potential to attenuate vascular cell apoptosis, activate c-Kit progenitor cells, and enhance angiogenesis and neovascularization in C57BL/6 and db/db mice leading to improved cardiac function.

  8. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment.

    Science.gov (United States)

    Endo, Itsuro; Fukumoto, Seiji; Ozono, Keiichi; Namba, Noriyuki; Inoue, Daisuke; Okazaki, Ryo; Yamauchi, Mika; Sugimoto, Toshitsugu; Minagawa, Masanori; Michigami, Toshimi; Nagai, Masaki; Matsumoto, Toshio

    2015-01-01

    A nationwide epidemiologic survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases was conducted in 2010 to clarify the prevalence and the clinical presentations of the disorders. A questionnaire inquiring the experience of patients with these diseases was sent to randomly selected hospitals throughout Japan. The estimated annual incidence of the diseases was 117 cases (95% CI 75 - 160), 55 males (95% CI 30 - 81) and 62 females (95% CI 40 - 84). Tumor-induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH) were the most prevalent causes of acquired and genetic FGF23-related hypophosphatemic diseases, respectively. The estimated incidence of XLH was about 1 in 20,000. We have also collected clinical data of the patients by a secondary survey. These patients showed FGF23 levels of above 30 pg/mL by intact assay in the presence of hypophosphatemia. While complete resection of responsible tumors improved biochemical abnormalities in patients with TIO, treatment with phosphate and/or active vitamin D3 did not normalize serum phosphate and tubular maximum transport of phosphate in patients with XLH. Our results suggest that there is no racial difference in the incidence of XLH. While FGF23 measurement is useful for the diagnosis of FGF23-related hypophosphatemic diseases, the better management is necessary especially for patients with genetic hypophosphatemic rickets caused by excessive actions of FGF23. PMID:26135520

  9. C-Terminal to Intact Fibroblast Growth Factor 23 Ratio in Relation to Estimated Glomerular Filtration Rate in Elderly Population

    Directory of Open Access Journals (Sweden)

    Maria Bożentowicz-Wikarek

    2016-08-01

    Full Text Available Background/Aims: An analytical equivalence between intact fibroblasts growth factor(iFGF23 and C-terminal(cFGF23 assays is logically expected, however, numerous studies demonstrate lack of a strong association between them. Previously, we have demonstrated the increase in cFGF23 slightly precedes the increase of iFGF23 with the impairment of kidney excretory function; without actually analyzing the ratio between both assays, which are postulated to be affected by declining kidney function. Therefore, the aim of this study was to analyze the ratio between C and iFGF23 in relation to the estimated glomerular filtration rate (eGFR in an elderly population. Methods: We analysed the variability of c/iFGF23 ratio in the population of 3264 elderly PolSenior study participants (≥ 65years in the relation to eGFR calculated according full Modification of Diet in Renal Disease, serum levels of C-reactive protein (hs-CRP, and iron. Results: The log10(c/i FGF23 ratio increased in the subsequent CKD stages. Serum iron and CRP levels reduced the log10 and increased it with age in multivariate regression analysis. Conclusions: Our results suggest impairment in the cleavage of the C-terminal FGF23 fragments with the deterioration of kidney excretory function and age in the elderly population. Inflammation and low serum iron level seems to diminish degradation capacity of FGF23 fragments.

  10. Research on Growth Behavior of Embryos for Bovine and Murine on Primary Murine Embryos Fibroblast Cell Feeder Layer

    Institute of Scientific and Technical Information of China (English)

    AN Li-long; XIAO Mei; FENG Xiu-Liang; DOU Zhong-ying; QIU Huai; YANG Qi; LEI An-min; YANG Chun-rong; GAO Zhi-min

    2002-01-01

    The difference in growth behavior between bovine embryos and murine embryos was studied on PMEF(primary murine embryos fibroblast)feeder layer. The results showed as follows: With embryos having attached, bovine embryonic trophoblast formed a transparent membranous structure covering on inner cell mass (ICM), however, murine embryonic trophoblast formed disc structure. Bovine embryos formed four kinds of ICM colonies with different morphology including the mass-like, the net-like, the stream-like and the mixture-like colonies. Compared with Murine ICM, the bovine ICM grew more fast. So, the bovine ICM was passaged at first after a culture of approximately 5 - 6 days in vitro, but murine ICM was passaged at first after an attachment of 3 - 4 days on PMEF feeder layer. The mixture colonies of bovine ICM differentiated very early, while the others differentiated very late. Most ICM-like mass of Bovine grew in a defined spot, but bovine ICMs like stream and ICMs like net proliferated fast and dispersed quickly. We found that the single blastomeres derived from late bovine morula and late murine morula formed sub-blastophere; moreover, the bovine ICM cell would differentiate rapidly if the trophoblast was removed.

  11. Novel Method of Cell-Free In Vitro Synthesis of the Human Fibroblast Growth Factor 1 Gene

    Directory of Open Access Journals (Sweden)

    Peijun Zuo

    2010-01-01

    Full Text Available Recombinant DNA projects generally involve cell-based gene cloning. However, because template DNA is not always readily available, in vitro chemical synthesis of complete genes from DNA oligonucleotides is becoming the preferred method for cloning. This article describes a new, rapid procedure based on Taq polymerase for the precise assembly of DNA oligonucleotides to yield the complete human fibroblast growth factor 1 (FGF1 gene, which is 468 bp long and has a G+C content of 51.5%. The new method involved two steps: (1 the design of the DNA oligonucleotides to be assembled and (2 the assembly of multiple oligonucleotides by PCR to generate the whole FGF1 gene. The procedure lasted a total of only 2 days, compared with 2 weeks for the conventional procedure. This method of gene synthesis is expected to facilitate various kinds of complex genetic engineering projects that require rapid gene amplification, such as cell-free whole-DNA library construction, as well as the construction of new genes or genes that contain any mutation, restriction site, or DNA tag.

  12. Circulating Fibroblast Growth Factor 21 is Associated with Diastolic Dysfunction in Heart Failure Patients with Preserved Ejection Fraction.

    Science.gov (United States)

    Chou, Ruey-Hsing; Huang, Po-Hsun; Hsu, Chien-Yi; Chang, Chun-Chin; Leu, Hsin-Bang; Huang, Chin-Chou; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Fibroblast growth factor 21 (FGF21), a polypeptide ligand promoted glucose homeostasis and lipids metabolism, was recently reported to attenuate cardiac hypertrophy. The aim of this study was to investigate the impact of FGF21 in diastolic heart failure. Subjects admitted for coronary angiogram were screened for heart failure, and those with left ventricular (LV) ejection fraction functional abnormalities that exist during LV relaxation and filling by echocardiographic criteria. Plasma levels of FGF21 and N-terminal Pro-Brain Natriuretic Peptide (NT-pro-BNP) were determined. All patients were followed up for 1 year, or till the occurrence of heart failure readmission or death. Totally 95 patients with diastolic dysfunction and 143 controls were enrolled. Circulating FGF21 level was correlated with echocardiographic parameters of diastolic function and LV end-diastolic pressure (LVEDP). In multivariate logistic analysis, FGF21 was significantly associated with diastolic dysfunction, either identified by echocardiographic criteria (odds ratio: 2.97, p = 0.012) or confirmed with LVEDP level (odds ratio: 3.73, p = 0.030). Both plasma FGF21 (log rank p < 0.0001) and NT-pro-BNP levels (log rank p = 0.0057) showed good predictive power to the 1-year adverse cardiac events. This finding suggested FGF21 could be involved in the pathophysiology of diastolic heart failure. PMID:27650781

  13. Postnatal visual deprivation in rats regulates several retinal genes and proteins, including differentiation-associated fibroblast growth factor-2.

    Science.gov (United States)

    Prokosch-Willing, Verena; Meyer zu Hoerste, Melissa; Mertsch, Sonja; Stupp, Tobias; Thanos, Solon

    2015-01-01

    Little is known about the retinal cellular basis of amblyopia, which is a developmental disease characterized by impaired visual acuity. This study examined the retinal transcripts associated with experimentally induced unilateral amblyopia in rats. Surgical tarsorrhaphy of the eyelids on one side was performed in pups prior to eye opening at postnatal day 14, thereby preventing any visual experience. This condition was maintained for over 2 months, after which electroretinograms (ERGs) were recorded, the retinal ganglion cell (RGC) arrangement and number were determined using neuroanatomical tracing, the retinal transcripts were studied using microarray analysis, regulated mRNAs were confirmed with quantitative reverse-transcriptase PCR, and proteins were stained using Western blotting and immunohistochemistry. An attenuated ERG was found in eyes that were deprived of visual experience. Retrograde neuroanatomical staining disclosed a larger number of RGCs within the retina on the visually deprived side compared to the non-deprived, control side, and a multilayered distribution of RGCs. At the retinomic level, several transcripts associated with retinal differentiation, such as fibroblast growth factor 2 (FGF-2), were either up- or downregulated. Most of the transcripts could be verified at the mRNA level. To unravel the role of a differentiation-associated protein, we tested FGF-2 in dissociated postnatal retinal cell cultures and found that FGF-2 is a potent factor triggering ganglion cell differentiation. The data suggest that visual experience shapes the postnatal retinal differentiation, whereas visual deprivation induces changes at the functional, cellular and molecular levels within the retina.

  14. Fibroblast Growth Factor-23 Helps Explain the Biphasic Cardiovascular Effects of Vitamin D in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Peng Hu, Qiang Xuan, Bo Hu, Ling Lu, Jing Wang, Yuan Han Qin

    2012-01-01

    Full Text Available Hypovitaminosis D is highly prevalent in chronic kidney disease (CKD. Recently, vitamin D has sparked widespread interest because of its potential favorable benefits on cardiovascular disease (CVD. Evidence from clinical studies and animal models supports the existence of biphasic cardiovascular effects of vitamin D, in which lower doses suppress CVD and higher doses stimulate CVD. However, the mechanism for the different effects remains unclear. Fibroblast growth factor-23 (FGF-23 is a recently identified member of the FGF family, and thought to be actively involved in renal phosphate and vitamin D homeostasis. More specifically, Vitamin D stimulates FGF-23 secretion and is inhibited by increased FGF-23. Given this background, we hypothesize that FGF-23 may provide a unique tool to explain the biphasic cardiovascular effects of vitamin D in CKD. The data presented in this review support the hypothesis that FGF-23 may be linked with the high cardiovascular risk in CKD through accelerating the onset of vascular calcification, secondary hyperparathyroidism, left ventricular hypertrophy and endothelial dysfunction. Therefore, modulation of FGF-23 may become a potential therapeutic target to lowing cardiovascular risk in CKD. Several clinical interventions, including decreased phosphate intake, phosphate binders, cinacalcet plus concurrent low-dose vitamin D, C-terminal tail of FGF-23 and renal transplantation, have been employed to manipulate FGF-23.

  15. The Regulation and Function of Fibroblast Growth Factor 8 and Its Function during Gonadotropin-Releasing Hormone Neuron Development

    Science.gov (United States)

    Chung, Wilson C. J.; Linscott, Megan L.; Rodriguez, Karla M.; Stewart, Courtney E.

    2016-01-01

    Over the last few years, numerous studies solidified the hypothesis that fibroblast growth factor (FGF) signaling regulates neuroendocrine progenitor cell proliferation, fate specification, and cell survival and, therefore, is critical for the regulation and maintenance of homeostasis of the body. One important example that underscores the involvement of FGF signaling during neuroendocrine cell development is gonadotropin-releasing hormone (GnRH) neuron ontogenesis. Indeed, transgenic mice with reduced olfactory placode (OP) Fgf8 expression do not have GnRH neurons. This observation indicates the requirement of FGF8 signaling for the emergence of the GnRH neuronal system in the embryonic OP, the putative birth place of GnRH neurons. Mammalian reproductive success depends on the presence of GnRH neurons to stimulate gonadotropin secretion from the anterior pituitary, which activates gonadal steroidogenesis and gametogenesis. Together, these observations are critical for understanding the function of GnRH neurons and their control of the hypothalamus–pituitary–gonadal (HPG) axis to maintain fertility. Taken together, these studies illustrate that GnRH neuron emergence and hence HPG function is vulnerable to genomic and molecular signals that abnormally modify Fgf8 expression in the developing mouse OP. In this short review, we focus on research that is aimed at unraveling how androgen, all-trans retinoic acid, and how epigenetic factors modify control mouse OP Fgf8 transcription in the context of GnRH neuronal development and mammalian reproductive success. PMID:27656162

  16. Increased acidic fibroblast growth factor concentrations in the serum and cerebrospinal fluid of patients with Alzheimer's disease.

    Science.gov (United States)

    Mashayekhi, Farhad; Hadavi, Mahvash; Vaziri, Hamid Reza; Naji, Mohammad

    2010-03-01

    Acidic fibroblast growth factor (aFGF), also called FGF-1, which influences the proliferation and differentiation of various cell types in vitro, was originally isolated from neural tissue. It is released from the ependymal cells of the cerebral third ventricle into the cerebrospinal fluid (CSF). FGF-1 promotes the survival of neurons. Reactive astrocytes express FGF-1 in the brain of patients with Alzheimer's disease (AD). By comparing the CSF proteome of patients with AD and normal controls it might be possible to identify proteins that have a role in AD. Because CSF is in contact with the extracellular space of the brain, modifications in the brain biochemistry could be reflected in the CSF. The aim of this study was to determine concentrations of serum and CSF FGF-1 in patients with AD. This study consisted of 64 CSF samples, from patients with AD (n=32) and those without (normal controls) (n=32). The level of CSF and serum FGF-1 in patients with AD was higher than in patients without AD. We conclude that FGF-1 is a constant component of human serum and CSF and that FGF-1 may be involved in the pathophysiology of AD. PMID:20079650

  17. Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members

    Energy Technology Data Exchange (ETDEWEB)

    Goetz,R.; Beenken, A.; Ibrahimi, O.; Kalinina, J.; Olsen, S.; Eliseenkova, A.; Xu, C.; Neubert, T.; Zhang, F.; et al.

    2007-01-01

    Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/{beta}Klotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between {beta} strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the {beta}1-{beta}2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/{beta}Klotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors.

  18. High molecular weight fibroblast growth factor-2 in the human heart is a potential target for prevention of cardiac remodeling.

    Directory of Open Access Journals (Sweden)

    Jon-Jon Santiago

    Full Text Available Fibroblast growth factor 2 (FGF-2 is a multifunctional protein synthesized as high (Hi- and low (Lo- molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD and 68% (±25 SD of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2 reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes

  19. Targeting of Proteoglycan Synthesis Pathway: A New Strategy to Counteract Excessive Matrix Proteoglycan Deposition and Transforming Growth Factor-β1-Induced Fibrotic Phenotype in Lung Fibroblasts.

    Science.gov (United States)

    Shaukat, Irfan; Barré, Lydia; Venkatesan, Narayanan; Li, Dong; Jaquinet, Jean-Claude; Fournel-Gigleux, Sylvie; Ouzzine, Mohamed

    2016-01-01

    Stimulation of proteoglycan (PG) synthesis and deposition plays an important role in the pathophysiology of fibrosis and is an early and dominant feature of pulmonary fibrosis. Transforming growth factor-β1 (TGF-β1) is a major cytokine associated with fibrosis that induces excessive synthesis of matrix proteins, particularly PGs. Owing to the importance of PGs in matrix assembly and in mediating cytokine and growth factor signaling, a strategy based on the inhibition of PG synthesis may prevent excessive matrix PG deposition and attenuates profibrotic effects of TGF-β1 in lung fibroblasts. Here, we showed that 4-MU4-deoxy-β-D-xylopyranoside, a competitive inhibitor of β4-galactosyltransferase7, inhibited PG synthesis and secretion in a dose-dependent manner by decreasing the level of both chondroitin/dermatan- and heparin-sulfate PG in primary lung fibroblasts. Importantly, 4-MU4-deoxy-xyloside was able to counteract TGF-β1-induced synthesis of PGs, activation of fibroblast proliferation and fibroblast-myofibroblast differentiation. Mechanistically, 4-MU4-deoxy-xyloside treatment inhibited TGF-β1-induced activation of canonical Smads2/3 signaling pathway in lung primary fibroblasts. The knockdown of β4-galactosyltransferase7 mimicked 4-MU4-deoxy-xyloside effects, indicating selective inhibition of β4-galactosyltransferase7 by this compound. Collectively, this study reveals the anti-fibrotic activity of 4-MU4-deoxy-xyloside and indicates that inhibition of PG synthesis represents a novel strategy for the treatment of lung fibrosis.

  20. Expression of fibroblast growth factor-21 in muscle is associated with lipodystrophy, insulin resistance and lipid disturbances in patients with HIV

    DEFF Research Database (Denmark)

    Lindegaard, Birgitte; Hvid, Thine; Grøndahl, Thomas;

    2013-01-01

    Fibroblast growth factor (FGF)-21 is a novel regulator of glucose and lipid metabolism. Recently, increased FGF-21 mRNA expression in muscle was found in patients with type 2 diabetes, but the role for FGF-21 in muscle is not well understood. Patients with HIV-infection and lipodystrophy are char......Fibroblast growth factor (FGF)-21 is a novel regulator of glucose and lipid metabolism. Recently, increased FGF-21 mRNA expression in muscle was found in patients with type 2 diabetes, but the role for FGF-21 in muscle is not well understood. Patients with HIV-infection and lipodystrophy...... are characterised by various degree of lipid-driven insulin resistance. We hypothesized that muscle FGF-21 mRNA would be altered in HIV patients with lipodystrophy....

  1. Angiopoietin-1 prevents severe bleeding complications induced by heparin-like drugs and fibroblast growth factor-2 in mice

    Science.gov (United States)

    Jerebtsova, Marina; Das, Jharna R.; Tang, Pingtao; Wong, Edward

    2015-01-01

    Critically ill children can develop bleeding complications when treated with heparin-like drugs. These events are usually attributed to the anticoagulant activity of these drugs. However, previous studies showed that fibroblast growth factor-2 (FGF-2), a heparin-binding growth factor released in the circulation of these patients, could precipitate intestinal hemorrhages in mice treated with the heparin-like drug pentosan polysulfate (PPS). Yet very little is known about how FGF-2 induces bleeding complications in combination with heparin-like drugs. Here, we examined the mechanisms by which circulating FGF-2 induces intestinal hemorrhages in mice treated with PPS. We used a well-characterized mouse model of intestinal hemorrhages induced by FGF-2 plus PPS. Adult FVB/N mice were infected with adenovirus carrying Lac-Z or a secreted form of recombinant human FGF-2, and injected with PPS, at doses that do not induce bleeding complications per se. Mice treated with FGF-2 in combination with PPS developed an intestinal inflammatory reaction that increased the permeability and disrupted the integrity of submucosal intestinal vessels. These changes, together with the anticoagulant activity of PPS, induced lethal hemorrhages. Moreover, a genetically modified form of the endothelial ligand angiopoietin-1 (Ang-1*), which has powerful antipermeability and anti-inflammatory activity, prevented the lethal bleeding complications without correcting the anticoagulant status of these mice. These findings define new mechanisms through which FGF-2 and Ang-1* modulate the outcome of intestinal bleeding complications induced by PPS in mice and may have wider clinical implications for critically ill children treated with heparin-like drugs. PMID:26276817

  2. A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice.

    Science.gov (United States)

    Jerebtsova, Marina; Wong, Edward; Przygodzki, Ronald; Tang, Pingtao; Ray, Patricio E

    2007-02-01

    Pentosan polysulfate (PPS) is a heparin-like polysaccharide that can affect the binding interactions of fibroblast growth factor (FGF-2) with its high-affinity receptors. Patients with angiogenic tumors frequently show high levels of FGF-2 in the circulation. Since FGF-2 is a heparin-binding angiogenic growth factor, PPS has been used successfully to block its activity in patients with angiogenic tumors. However, because of its heparin-like activity, the major toxic effect of PPS is the development of bleeding disorders. The role that circulating FGF-2 plays in the pathogenesis of bleeding disorders in patients treated with PPS is currently unknown. Here we hypothesized that FGF-2 might play a physiological role in the pathogenesis of intestinal bleeding induced by PPS. This hypothesis is supported by previous studies showing that PPS is accumulated in the intestine and that circulating FGF-2 specifically binds to and modulates the angiogenic activity of intestinal submucosal endothelial cells. We used recombinant adenoviral vectors carrying a secreted form of FGF-2 and LacZ control vectors to determine whether high levels of circulating FGF-2 facilitate the development of intestinal bleeding disorders in FVB/N and C57BL/6J mice treated with PPS. We found that PPS, acting together with FGF-2, induced structural changes in intestinal vessels leading to the development of lethal intestinal hemorrhages. These findings might have wider clinical implications for the systemic use of PPS and other heparinoids in the treatment of patients with angiogenic diseases associated with high levels of circulating FGF-2.

  3. Poldip2 knockout results in perinatal lethality, reduced cellular growth and increased autophagy of mouse embryonic fibroblasts.

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    David I Brown

    Full Text Available Polymerase-δ interacting protein 2 (Poldip2 is an understudied protein, originally described as a binding partner of polymerase delta and proliferating cell nuclear antigen (PCNA. Numerous roles for Poldip2 have been proposed, including mitochondrial elongation, DNA replication/repair and ROS production via Nox4. In this study, we have identified a novel role for Poldip2 in regulating the cell cycle. We used a Poldip2 gene-trap mouse and found that homozygous animals die around the time of birth. Poldip2-/- embryos are significantly smaller than wild type or heterozygous embryos. We found that Poldip2-/- mouse embryonic fibroblasts (MEFs exhibit reduced growth as measured by population doubling and growth curves. This effect is not due to apoptosis or senescence; however, Poldip2-/- MEFs have higher levels of the autophagy marker LC3b. Measurement of DNA content by flow cytometry revealed an increase in the percentage of Poldip2-/- cells in the G1 and G2/M phases of the cell cycle, accompanied by a decrease in the percentage of S-phase cells. Increases in p53 S20 and Sirt1 were observed in passage 2 Poldip2-/- MEFs. In passage 4/5 MEFs, Cdk1 and CyclinA2 are downregulated in Poldip2-/- cells, and these changes are reversed by transfection with SV40 large T-antigen, suggesting that Poldip2 may target the E2F pathway. In contrast, p21CIP1 is increased in passage 4/5 Poldip2-/- MEFs and its expression is unaffected by SV40 transfection. Overall, these results reveal that Poldip2 is an essential protein in development, and underline its importance in cell viability and proliferation. Because it affects the cell cycle, Poldip2 is a potential novel target for treating proliferative conditions such as cancer, atherosclerosis and restenosis.

  4. Studying the Anti-aging Effect of Human Growth Hormone on Human Fibroblast Cells via Telomerase Activity

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    Nader Chaparzadeh

    2010-01-01

    Full Text Available Objective: In recent years, studies have focused on the telomerase for cancer treatmentby repressing telomerase in cancerous cells or prevent cell aging by activating it in theaged cells. Thus, in these studies natural and synthetic agents have been used to repressor activate telomerase. In this research, we investigated the effects of human growth hormone(hGH on aging via evaluation of telomerase activity.Materials and Methods: Primary human foreskin fibroblast cells were isolated, culturedand treated with different concentrations of hGH. BrdU and MTT cell proliferation assaysand cells number counting. Cell aging was assayed by the senescence sensitivegalactosidase staining method. Telomerase activity was measured with a telomerasePCR ELISA kit.Data were analyzed with SPSS software (one-way ANOVA and univariateANOVA.Results: Our results indicated that cells treated with a lower concentration (0.1, 1 ng/mlof hGH had more green color cells (aged cells. Furthermore, cell proliferation increasedwith increasing hGH concentrations (10 to 100 ng/ml which was significant in comparisonwith untreated control cells. TRAP assay results indicated that telomerase activityincreased with increasing hGH concentration, but there was no significant difference. Additionally,more rapid cell growth and telomerase activity was noted in the absence of H2O2when compared with the presence of H2O2, which was significantly different.Conclusion: Although increasing cell proliferation along with increasing hGH concentrationwas confirmed by all cell proliferation assays, only the cell counting test was statisticallysignificant. Thus, it is inconclusive that hGH (up to 100 ng/ml has an anti-agingeffect. Also, because there was no significant difference in the telomerase activity results(in spite of increasing progress along with increasing hGH concentration we can not certainlyconclude that hGH (up to 100 ng/ml impacts telomerase activity.

  5. Connective tissue growth factor differentially binds to members of the cystine knot superfamily and potentiates platelet-derived growth factor-B signaling in rabbit corneal fibroblast cells

    Institute of Scientific and Technical Information of China (English)

    Liya; Pi; Pei-Yu; Chung; Sriniwas; Sriram; Masmudur; M; Rahman; Wen-Yuan; Song; Edward; W; Scott; Bryon; E; Petersen; Gregory; S; Schultz

    2015-01-01

    AIM:To study the binding of connective tissue growth factor(CTGF) to cystine knot-containing ligands and how this impacts platelet-derived growth factor(PDGF)-B signaling. METHODS:The binding strengths of CTGF to cystine knot-containing growth factors including vascular en-dothelial growth factor(VEGF)-A,PDGF-B,bone morphogenetic protein(BMP)-4,and transforming growth factor(TGF)-β1 were compared using the LexA-based yeast two-hybrid system. EYG48 reporter strain that carried a wild-type LEU2 gene under the control of Lex A operators and a lac Z reporter plasmid(p80plac Z) containing eight high affinity Lex A binding sites were used in the yeast two-hybrid analysis. Interactions between CTGF and the tested growth factors were evaluated based on growth of transformed yeast cells on selective media and colorimetric detection in a liquid β-galactosidase activity assay. Dissociation constants of CTGF to VEGF-A isoform 165 or PDGF-BB homo-dimer were measured in surface plasma resonance(SPR) analysis. CTGF regulation in PDGF-B presentation to the PDGF receptor β(PDGFRβ) was also quantitatively assessed by the SPR analysis. Combinational effects of CTGF protein and PDGF-BB on activation of PDGFRβ and downstream signaling molecules ERK1/2 and AKT were assessed in rabbit corneal fibroblast cells by Western analysis. RESULTS:In the LexA-based yeast two-hybrid system,cystine knot motifs of tested growth factors were fused to the activation domain of the transcriptional factor GAL4 while CTGF was fused to the DNA binding domain of the bacterial repressor protein Lex A. Yeast cotransformants containing corresponding fusion proteins for CTGF and all four tested cystine knot motifs survived on selective medium containing galactose and raffinose but lacking histidine,tryptophan,and uracil. In liquid β-galactosidase assays,CTGF expressing cells that were co-transformed with the cystine knot of VEGF-A had the highest activity,at 29.88 ± 0.91 fold above controls(P < 0

  6. Modulation of Gingival Fibroblast Minocycline Accumulation by Biological Mediators

    OpenAIRE

    Walters, J.D.; Nakkula, R.J.; Maney, P.

    2005-01-01

    Gingival fibroblasts actively accumulate tetracyclines, thereby enhancing their redistribution from blood to gingiva. Since growth factors and pro-inflammatory cytokines regulate many fibroblast activities, they could potentially enhance fibroblast minocycline accumulation. To test this hypothesis, we treated gingival fibroblast monolayers for 1 or 6 hours with platelet-derived growth factor-BB (PDGF), fibroblast growth factor-2 (FGF), transforming growth factor-β1 (TGF), or tumor necrosis fa...

  7. Resistance to the Beneficial Metabolic Effects and Hepatic Antioxidant Defense Actions of Fibroblast Growth Factor 21 Treatment in Growth Hormone-Overexpressing Transgenic Mice

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    Ravneet K. Boparai

    2015-01-01

    Full Text Available Fibroblast growth factor 21 (FGF21 modulates a diverse range of biological functions, including glucose and lipid metabolism, adaptive starvation response, and energy homeostasis, but with limited mechanistic insight. FGF21 treatment has been shown to inhibit hepatic growth hormone (GH intracellular signaling. To evaluate GH axis involvement in FGF21 actions, transgenic mice overexpressing bovine GH were used. Expectedly, in response to FGF21 treatment control littermates showed metabolic improvements whereas GH transgenic mice resisted most of the beneficial effects of FGF21, except an attenuation of the innate hyperinsulinemia. Since FGF21 is believed to exert its effects mostly at the transcriptional level, we analyzed and observed significant upregulation in expression of various genes involved in carbohydrate and lipid metabolism, energy homeostasis, and antioxidant defense in FGF21-treated controls, but not in GH transgenics. The resistance of GH transgenic mice to FGF21-induced changes underlines the necessity of normal GH signaling for the beneficial effects of FGF21.

  8. Significant type I and type III collagen production from human periodontal ligament fibroblasts in 3D peptide scaffolds without extra growth factors.

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    Yoshiyuki Kumada

    Full Text Available We here report the development of two peptide scaffolds designed for periodontal ligament fibroblasts. The scaffolds consist of one of the pure self-assembling peptide scaffolds RADA16 through direct coupling to short biologically active motifs. The motifs are 2-unit RGD binding sequence PRG (PRGDSGYRGDS and laminin cell adhesion motif PDS (PDSGR. RGD and laminin have been previously shown to promote specific biological activities including periodontal ligament fibroblasts adhesion, proliferation and protein production. Compared to the pure RADA16 peptide scaffold, we here show that these designer peptide scaffolds significantly promote human periodontal ligament fibroblasts to proliferate and migrate into the scaffolds (for approximately 300 microm/two weeks. Moreover these peptide scaffolds significantly stimulated periodontal ligament fibroblasts to produce extracellular matrix proteins without using extra additional growth factors. Immunofluorescent images clearly demonstrated that the peptide scaffolds were almost completely covered with type I and type III collagens which were main protein components of periodontal ligament. Our results suggest that these designer self-assembling peptide nanofiber scaffolds may be useful for promoting wound healing and especially periodontal ligament tissue regeneration.

  9. Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts: a possible defense against transforming growth factor-β mediated fibrosis

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    Watson Chris J

    2012-07-01

    Full Text Available Abstract Background Mechanical overload of the heart is associated with excessive deposition of extracellular matrix proteins and the development of cardiac fibrosis. This can result in reduced ventricular compliance, diastolic dysfunction, and heart failure. Extracellular matrix synthesis is regulated primarily by cardiac fibroblasts, more specifically, the active myofibroblast. The influence of mechanical stretch on human cardiac fibroblasts’ response to pro-fibrotic stimuli, such as transforming growth factor beta (TGFβ, is unknown as is the impact of stretch on B-type natriuretic peptide (BNP and natriuretic peptide receptor A (NPRA expression. BNP, acting via NPRA, has been shown to play a role in modulation of cardiac fibrosis. Methods and results The effect of cyclical mechanical stretch on TGFβ induction of myofibroblast differentiation in primary human cardiac fibroblasts and whether differences in response to stretch were associated with changes in the natriuretic peptide system were investigated. Cyclical mechanical stretch attenuated the effectiveness of TGFβ in inducing myofibroblast differentiation. This finding was associated with a novel observation that mechanical stretch can increase BNP and NPRA expression in human cardiac fibroblasts, which could have important implications in modulating myocardial fibrosis. Exogenous BNP treatment further reduced the potency of TGFβ on mechanically stretched fibroblasts. Conclusion We postulate that stretch induced up-regulation of the natriuretic peptide system may contribute to the observed reduction in myofibroblast differentiation.

  10. Nuclear localization of vascular endothelial growth factor-D and regulation of c-Myc-dependent transcripts in human lung fibroblasts.

    Science.gov (United States)

    El-Chemaly, Souheil; Pacheco-Rodriguez, Gustavo; Malide, Daniela; Meza-Carmen, Victor; Kato, Jiro; Cui, Ye; Padilla, Philip I; Samidurai, Arun; Gochuico, Bernadette R; Moss, Joel

    2014-07-01

    Lymphangiogenesis and angiogenesis are processes that are, in part, regulated by vascular endothelial growth factor (VEGF)-D. The formation of lymphatic structures has been implicated in multiple lung diseases, including pulmonary fibrosis. VEGF-D is a secreted protein produced by fibroblasts and macrophages, which induces lymphangiogenesis by signaling via VEGF receptor-3, and angiogenesis through VEGF receptor-2. VEGF-D contains a central VEGF homology domain, which is the biologically active domain, with flanking N- and C-terminal propeptides. Full-length VEGF-D (∼ 50 kD) is proteolytically processed in the extracellular space, to generate VEGF homology domain that contains the VEGF-D receptor-binding sites. Here, we report that, independent of its cell surface receptors, full-length VEGF-D accumulated in nuclei of fibroblasts, and that this process appears to increase with cell density. In nuclei, full-length VEGF-D associated with RNA polymerase II and c-Myc. In cells depleted of VEGF-D, the transcriptionally regulated genes appear to be modulated by c-Myc. These findings have potential clinical implications, as VEGF-D was found in fibroblast nuclei in idiopathic pulmonary fibrosis, a disease characterized by fibroblast proliferation. These findings are consistent with actions of full-length VEGF-D in cellular homeostasis in health and disease, independent of its receptors.

  11. Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts: a possible defense against transforming growth factor-ß mediated fibrosis

    LENUS (Irish Health Repository)

    Watson, Chris J

    2012-07-07

    AbstractBackgroundMechanical overload of the heart is associated with excessive deposition of extracellular matrix proteins and the development of cardiac fibrosis. This can result in reduced ventricular compliance, diastolic dysfunction, and heart failure. Extracellular matrix synthesis is regulated primarily by cardiac fibroblasts, more specifically, the active myofibroblast. The influence of mechanical stretch on human cardiac fibroblasts’ response to pro-fibrotic stimuli, such as transforming growth factor beta (TGFβ), is unknown as is the impact of stretch on B-type natriuretic peptide (BNP) and natriuretic peptide receptor A (NPRA) expression. BNP, acting via NPRA, has been shown to play a role in modulation of cardiac fibrosis.Methods and resultsThe effect of cyclical mechanical stretch on TGFβ induction of myofibroblast differentiation in primary human cardiac fibroblasts and whether differences in response to stretch were associated with changes in the natriuretic peptide system were investigated. Cyclical mechanical stretch attenuated the effectiveness of TGFβ in inducing myofibroblast differentiation. This finding was associated with a novel observation that mechanical stretch can increase BNP and NPRA expression in human cardiac fibroblasts, which could have important implications in modulating myocardial fibrosis. Exogenous BNP treatment further reduced the potency of TGFβ on mechanically stretched fibroblasts.ConclusionWe postulate that stretch induced up-regulation of the natriuretic peptide system may contribute to the observed reduction in myofibroblast differentiation.

  12. Identification of fibroblast growth factor receptor 3 (FGFR3 as a protein receptor for botulinum neurotoxin serotype A (BoNT/A.

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    Birgitte P S Jacky

    Full Text Available Botulinum neurotoxin serotype A (BoNT/A causes transient muscle paralysis by entering motor nerve terminals (MNTs where it cleaves the SNARE protein Synaptosomal-associated protein 25 (SNAP25206 to yield SNAP25197. Cleavage of SNAP25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. The specific uptake of BoNT/A into pre-synaptic nerve terminals is a tightly controlled multistep process, involving a combination of high and low affinity receptors. Interestingly, the C-terminal binding domain region of BoNT/A, HC/A, is homologous to fibroblast growth factors (FGFs, making it a possible ligand for Fibroblast Growth Factor Receptors (FGFRs. Here we present data supporting the identification of Fibroblast Growth Factor Receptor 3 (FGFR3 as a high affinity receptor for BoNT/A in neuronal cells. HC/A binds with high affinity to the two extra-cellular loops of FGFR3 and acts similar to an agonist ligand for FGFR3, resulting in phosphorylation of the receptor. Native ligands for FGFR3; FGF1, FGF2, and FGF9 compete for binding to FGFR3 and block BoNT/A cellular uptake. These findings show that FGFR3 plays a pivotal role in the specific uptake of BoNT/A across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions.

  13. Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1).

    Science.gov (United States)

    Terranova, Christopher; Narla, Sridhar T; Lee, Yu-Wei; Bard, Jonathan; Parikh, Abhirath; Stachowiak, Ewa K; Tzanakakis, Emmanuel S; Buck, Michael J; Birkaya, Barbara; Stachowiak, Michal K

    2015-01-01

    Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development. PMID:25923916

  14. Global Developmental Gene Programing Involves a Nuclear Form of Fibroblast Growth Factor Receptor-1 (FGFR1.

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    Christopher Terranova

    Full Text Available Genetic studies have placed the Fgfr1 gene at the top of major ontogenic pathways that enable gastrulation, tissue development and organogenesis. Using genome-wide sequencing and loss and gain of function experiments the present investigation reveals a mechanism that underlies global and direct gene regulation by the nuclear form of FGFR1, ensuring that pluripotent Embryonic Stem Cells differentiate into Neuronal Cells in response to Retinoic Acid. Nuclear FGFR1, both alone and with its partner nuclear receptors RXR and Nur77, targets thousands of active genes and controls the expression of pluripotency, homeobox, neuronal and mesodermal genes. Nuclear FGFR1 targets genes in developmental pathways represented by Wnt/β-catenin, CREB, BMP, the cell cycle and cancer-related TP53 pathway, neuroectodermal and mesodermal programing networks, axonal growth and synaptic plasticity pathways. Nuclear FGFR1 targets the consensus sequences of transcription factors known to engage CREB-binding protein, a common coregulator of transcription and established binding partner of nuclear FGFR1. This investigation reveals the role of nuclear FGFR1 as a global genomic programmer of cell, neural and muscle development.

  15. Fibroblast growth factor-2 induced by enriched environment enhances angiogenesis and motor function in chronic hypoxic-ischemic brain injury.

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    Jung Hwa Seo

    Full Text Available This study aimed to investigate the effects of enriched environment (EE on promoting angiogenesis and neurobehavioral function in an animal model of chronic hypoxic-ischemic (HI brain injury. HI brain damage was induced in seven day-old CD-1® mice by unilateral carotid artery ligation and exposure to hypoxia (8% O2 for 90 min. At six weeks of age, the mice were randomly assigned to either EE or standard cages (SC for two months. Rotarod, forelimb-use asymmetry, and grip strength tests were performed to evaluate neurobehavioral function. In order to identify angiogenic growth factors regulated by EE, an array-based multiplex ELISA assay was used to measure the expression in frontal cortex, striatum, and cerebellum. Among the growth factors, the expression of fibroblast growth factor-2 (FGF-2 was confirmed using western blotting. Platelet endothelial cell adhesion molecule-1 (PECAM-1 and α-smooth muscle actin (α-SMA were also evaluated using immunohistochemistry. As a result, mice exposed to EE showed significant improvements in rotarod and ladder walking performances compared to SC controls. The level of FGF-2 was significantly higher in the frontal cortex of EE mice at 8 weeks after treatment in multiplex ELISA and western blot. On the other hand, FGF-2 in the striatum significantly increased at 2 weeks after exposure to EE earlier than in the frontal cortex. Expression of activin A was similarly upregulated as FGF-2 expression pattern. Particularly, all animals treated with FGF-2 neutralizing antibody abolished the beneficial effect of EE on motor performance relative to mice not given anti-FGF-2. Immunohistochemistry showed that densities of α-SMA(+ and PECAM-1(+ cells in frontal cortex, striatum, and hippocampus were significantly increased following EE, suggesting the histological findings exhibit a similar pattern to the upregulation of FGF-2 in the brain. In conclusion, EE enhances endogenous angiogenesis and neurobehavioral functions

  16. Astragaloside IV suppresses transforming growth factor-β1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Che, Xiajing; Wang, Qin; Xie, Yuanyuan; Xu, Weijia; Shao, Xinghua; Mou, Shan, E-mail: shan_mou@126.com; Ni, Zhaohui, E-mail: doctor_nzh@126.com

    2015-09-04

    Renal fibrosis, a progressive process characterized by the accumulation of extracellular matrix (ECM) leading to organ dysfunction, is a characteristic of chronic kidney diseases. Among fibrogenic factors known to regulate the renal fibrotic process, transforming growth factor-β (TGF-β) plays a central role. In the present study, we examined the effect of Astragaloside IV (AS-IV), a component of the traditional Chinese medicinal plant Astragalus membranaceus, on the processes associated with renal fibrosis in cultured mouse renal fibroblasts treated with TGF-β1. RT-PCR, western blotting, immunofluorescence staining and collagen assays showed that AS-IV suppressed TGF-β1 induced fibroblast proliferation, transdifferentiation, and ECM production in a dose-dependent manner. Examination of the underlying mechanisms showed that the effect of AS-IV on the inhibition of fibroblast differentiation and ECM formation were mediated by its modulation of the activity of the MAPK and NF-κB signaling pathways. Taken together, our results indicate that AS-IV alleviates renal interstitial fibrosis via a mechanism involving the MAPK and NF-κB signaling pathways and demonstrate the therapeutic potential of AS-IV for the treatment of chronic kidney diseases. - Highlights: • AS-IV suppressed TGF-β1 induced renal fibroblast proliferation. • AS-IV suppressed TGF-β1 induced renal fibroblast transdifferentiation. • AS-IV suppressed TGF-β1 induced ECM production. • AS-IV alleviates renal fibrosis via the MAPK and NF-κB signaling pathways.

  17. Astragaloside IV suppresses transforming growth factor-β1 induced fibrosis of cultured mouse renal fibroblasts via inhibition of the MAPK and NF-κB signaling pathways

    International Nuclear Information System (INIS)

    Renal fibrosis, a progressive process characterized by the accumulation of extracellular matrix (ECM) leading to organ dysfunction, is a characteristic of chronic kidney diseases. Among fibrogenic factors known to regulate the renal fibrotic process, transforming growth factor-β (TGF-β) plays a central role. In the present study, we examined the effect of Astragaloside IV (AS-IV), a component of the traditional Chinese medicinal plant Astragalus membranaceus, on the processes associated with renal fibrosis in cultured mouse renal fibroblasts treated with TGF-β1. RT-PCR, western blotting, immunofluorescence staining and collagen assays showed that AS-IV suppressed TGF-β1 induced fibroblast proliferation, transdifferentiation, and ECM production in a dose-dependent manner. Examination of the underlying mechanisms showed that the effect of AS-IV on the inhibition of fibroblast differentiation and ECM formation were mediated by its modulation of the activity of the MAPK and NF-κB signaling pathways. Taken together, our results indicate that AS-IV alleviates renal interstitial fibrosis via a mechanism involving the MAPK and NF-κB signaling pathways and demonstrate the therapeutic potential of AS-IV for the treatment of chronic kidney diseases. - Highlights: • AS-IV suppressed TGF-β1 induced renal fibroblast proliferation. • AS-IV suppressed TGF-β1 induced renal fibroblast transdifferentiation. • AS-IV suppressed TGF-β1 induced ECM production. • AS-IV alleviates renal fibrosis via the MAPK and NF-κB signaling pathways

  18. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR).

    Science.gov (United States)

    Cheng, Xingguo; Vispute, Saurabh G; Liu, Jie; Cheng, Christine; Kharitonenkov, Alexei; Klaassen, Curtis D

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200μg/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.

  19. The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

    Science.gov (United States)

    Zhang, Qian; Doucet, Michele; Tomlinson, Ryan E; Han, Xiaobin; Quarles, L Darryl; Collins, Michael T; Clemens, Thomas L

    2016-01-01

    Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 (FGF23) by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-1α (HIF-1α) in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-1α mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-1α and FGF23 were co-localized in spindle-shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-1α protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-1α expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-1α inhibitors decreased HIF-1α and FGF23 protein accumulation and inhibited HIF-1α-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-1α consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-1α inhibitor. These results show for the first time that HIF-1α is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-1α activity in TIO contributes to the aberrant FGF23 production in these patients. PMID:27468359

  20. Effects of Plasma Rich in Growth Factors and Platelet-Rich Fibrin on Proliferation and Viability of Human Gingival Fibroblasts

    Directory of Open Access Journals (Sweden)

    Surena Vahabi

    2016-01-01

    Full Text Available Objectives: Platelet preparations are commonly used to enhance bone and soft tissue regeneration. Considering the existing controversies on the efficacy of platelet products for tissue regeneration, more in vitro studies are required. The aim of the present study was to compare the in vitro effects of plasma rich in growth factors (PRGF and platelet-rich fibrin (PRF on proliferation and viability of human gingival fibroblasts (HGFs.Materials and Methods: Anitua's PRGF and Choukran's PRF were prepared according to the standard protocols. After culture periods of 24, 48 and 72 hours, proliferation of HGFs was evaluated by the methyl thiazol tetrazolium assay. Statistical analysis was performed using one-way ANOVA followed by Tukey-Kramer’s multiple comparisons and P-values<0.05 were considered statistically significant.Results: PRGF treatment induced statistically significant (P<0.001 proliferation of HGF cells compared to the negative control (100% viability at 24, 48 and 72 hours in values of 123%±2.25%, 102%±2.8% and 101%±3.92%, respectively. The PRF membrane treatment of HGF cells had a statistically significant effect on cell proliferation (21%±1.73%, P<0.001 at 24 hours compared to the negative control. However, at 48 and 72 hours after treatment, PRF had a negative effect on HGF cell proliferation and caused 38% and 60% decrease in viability and proliferation compared to the negative control, respectively. The HGF cell proliferation was significantly higher in PRGF than in PRF group (P< 0.001.Conclusion: This study demonstrated that PRGF had a strong stimulatory effect on HGF cell viability and proliferation compared to PRF.

  1. A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21 modified with polyethylene glycol.

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    Zhifeng Huang

    Full Text Available As one of fibroblast growth factor (FGF family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21 was modified with polyethylene glycol (PEGylation in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site-selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients.

  2. Fibroblast growth factor 10 protects neuron against oxygen–glucose deprivation injury through inducing heme oxygenase-1

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yong-Hua; Yang, Li-Ye; Chen, Wei; Li, Ying-Ke, E-mail: liyingke6f@126.com; Yuan, Hong-Bin, E-mail: yuanhongbin6f@126.com

    2015-01-02

    Highlights: • FGF10 attenuates OGD induced injury in cortical neuron. • FGF10 reduces OGD triggered ROS level in cortical neuron. • FGF10 induces HO-1 expression upon OGD stimuli in cortical neuron. • Knockdown of HO-1 impairs the neuroprotection of FGF10 in OGD model. - Abstract: Fibroblast growth factors (FGFs) are a family of structurally related heparin-binding proteins with diverse biological functions. FGFs participate in mitogenesis, angiogenesis, cell proliferation, development, differentiation and cell migration. Here, we investigated the potential effect of FGF10, a member of FGFs, on neuron survival in oxygen–glucose deprivation (OGD) model. In primary cultured mouse cortical neurons upon OGD, FGF10 treatment (100 and 1000 ng/ml) attenuated the decrease of cell viability and rescued the LDH release. Tuj-1 immunocytochemistry assay showed that FGF10 promoted neuronal survival. Apoptosis assay with Annexin V + PI by flow cytometry demonstrated that FGF10 treatment reduced apoptotic cell proportion. Moreover, immunoblotting showed that FGF10 alleviated the cleaved caspase-3 upregulation caused by OGD. FGF10 treatment also depressed the OGD-induced increase of caspase-3, -8 and -9 activities. At last, we found FGF10 triggered heme oxygenase-1 (HO-1) protein expression rather than hypoxia-inducible factor-1 (HIF-1), AMP-activated protein kinase (AMPK) signaling and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Knockdown of HO-1 by siRNA partly abolished the neuroprotection of FGF10 in OGD model. In summary, our observations provide the first evidence for the neuroprotective function of FGF10 against ischemic neuronal injury and suggest that FGF10 may be a promising agent for treatment of ischemic stroke.

  3. Fibroblast growth factor 10 alters the balance between goblet and Paneth cells in the adult mouse small intestine.

    Science.gov (United States)

    Al Alam, Denise; Danopoulos, Soula; Schall, Kathy; Sala, Frederic G; Almohazey, Dana; Fernandez, G Esteban; Georgia, Senta; Frey, Mark R; Ford, Henri R; Grikscheit, Tracy; Bellusci, Saverio

    2015-04-15

    Intestinal epithelial cell renewal relies on the right balance of epithelial cell migration, proliferation, differentiation, and apoptosis. Intestinal epithelial cells consist of absorptive and secretory lineage. The latter is comprised of goblet, Paneth, and enteroendocrine cells. Fibroblast growth factor 10 (FGF10) plays a central role in epithelial cell proliferation, survival, and differentiation in several organs. The expression pattern of FGF10 and its receptors in both human and mouse intestine and their role in small intestine have yet to be investigated. First, we analyzed the expression of FGF10, FGFR1, and FGFR2, in the human ileum and throughout the adult mouse small intestine. We found that FGF10, FGFR1b, and FGFR2b are expressed in the human ileum as well as in the mouse small intestine. We then used transgenic mouse models to overexpress Fgf10 and a soluble form of Fgfr2b, to study the impact of gain or loss of Fgf signaling in the adult small intestine. We demonstrated that overexpression of Fgf10 in vivo and in vitro induces goblet cell differentiation while decreasing Paneth cells. Moreover, FGF10 decreases stem cell markers such as Lgr5, Lrig1, Hopx, Ascl2, and Sox9. FGF10 inhibited Hes1 expression in vitro, suggesting that FGF10 induces goblet cell differentiation likely through the inhibition of Notch signaling. Interestingly, Fgf10 overexpression for 3 days in vivo and in vitro increased the number of Mmp7/Muc2 double-positive cells, suggesting that goblet cells replace Paneth cells. Further studies are needed to determine the mechanism by which Fgf10 alters cell differentiation in the small intestine.

  4. Engineering a Cysteine-Free Form of Human Fibroblast Growth Factor-1 for “Second Generation” Therapeutic Application

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Xue; Kumru, Ozan S.; Blaber, Sachiko I.; Middaugh, C. Russell; Li, Ling; Ornitz, David M.; Sutherland, Mason A.; Tenorio, Connie A.; Blaber, Michael (FSU); (WU-MED); (Kansas)

    2016-07-06

    Human fibroblast growth factor-1 (FGF-1) has broad therapeutic potential in regenerative medicine but has undesirable biophysical properties of low thermostability and 3 buried cysteine (Cys) residues (at positions 16, 83, and 117) that interact to promote irreversible protein unfolding under oxidizing conditions. Mutational substitution of such Cys residues eliminates reactive buried thiols but cannot be accomplished simultaneously at all 3 positions without also introducing further substantial instability. The mutational introduction of a novel Cys residue (Ala66Cys) that forms a stabilizing disulfide bond (i.e., cystine) with one of the extant Cys residues (Cys83) effectively eliminates one Cys while increasing overall stability. This increase in stability offsets the associated instability of remaining Cys substitution mutations and permits production of a Cys-free form of FGF-1 (Cys16Ser/Ala66Cys/Cys117Ala) with only minor overall instability. The addition of a further stabilizing mutation (Pro134Ala) creates a Cys-free FGF-1 mutant with essentially wild-type biophysical properties. The elimination of buried free thiols in FGF-1 can substantially increase the protein half-life in cell culture. Here, we show that the effective cell survival/mitogenic functional activity of a fully Cys-free form is also substantially increased and is equivalent to wild-type FGF-1 formulated in the presence of heparin sulfate as a stabilizing agent. The results identify this Cys-free FGF-1 mutant as an advantageous “second generation” form of FGF-1 for therapeutic application.

  5. Fibroblast growth factor-20 increases the yield of midbrain dopaminergic neurons derived from human embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Ana Sofia Correia

    2007-12-01

    Full Text Available In the central nervous system, fibroblast growth factor (FGF-20 has been reported to act preferentially on midbrain dopaminergic neurons. It also promotes the dopaminergic differentiation of stem cells. We have analyzed the effects of FGF-20 on human embryonic stem cells (hESCs differentiation into dopaminergic neurons. We induced neuronal differentiation of hESCs by co-culturing those with PA6 mouse stromal cells for 3 weeks. When we supplemented the culture medium with FGF-20, the number of tyrosine hydroxylase (TH- expressing neurons increased fivefold, from 3% to 15% of the hESC-derived cells. The cultured cells also expressed other midbrain dopaminergic markers (PITX3, En1, Msx1, and Aldh1, suggesting that some had differentiated into midbrain dopaminergic neurons. We observed no effect of FGF-20 on the size of the soma area or neurite length of the TH-immunopositive neurons. Regardless of whether FGF-20 had been added or not, 17% of the hESC-derived cells expressed the pan-neuronal marker b-III-Tubulin. The proportion of proliferating cells positive for Ki-67 was also not affected by FGF-20 (7% of the hESC-derived cells. By contrast, after 3 weeks in culture FGF-20 significantly reduced the proportion of cells undergoing cell death, as revealed by immunoreactivity for cleaved caspase-8, Bcl-2 associated X protein (BAX and cleaved caspase-3 (2.5% to 1.2% of cleaved caspase-3-positive cells out of the hESC-derived cells. Taken together, our results indicate that FGF-20 specifically increases the yield of dopaminergic neurons from hESCs grown on PA6 feeder cells and at least part of this effect is due to a reduction in cell death.

  6. Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR)

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Xingguo, E-mail: chengx@stjohns.edu [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Vispute, Saurabh G. [Department of Pharmaceutical Sciences, St. John' s University, 8000 Utopia Parkway, Queens, NY 11439 (United States); Liu, Jie [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Cheng, Christine; Kharitonenkov, Alexei [Lilly Research Laboratories, Division of Eli Lilly and Co., Indianapolis, IN 46285 (United States); Klaassen, Curtis D., E-mail: curtisklaassenphd@gmail.com [Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States)

    2014-07-01

    The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. - Highlights: • TCDD induced Fgf21 expression at both mRNA and protein levels. • Fgf21 induction by TCDD is AhR-dependent. • DEHP attenuated TCDD-induced Fgf21 expression.

  7. Interleukin-1-induced acute bone resorption facilitates the secretion of fibroblast growth factor 23 into the circulation.

    Science.gov (United States)

    Yamazaki, Miwa; Kawai, Masanobu; Miyagawa, Kazuaki; Ohata, Yasuhisa; Tachikawa, Kanako; Kinoshita, Saori; Nishino, Jin; Ozono, Keiichi; Michigami, Toshimi

    2015-05-01

    Fibroblast growth factor 23 (FGF23), a central regulator of phosphate and vitamin D metabolism, is mainly produced by osteocytes in bone and exerts its effects on distant organs. Despite its endocrine function, the mechanism controlling serum FGF23 levels is not fully understood. Here we tested the hypothesis that osteoclastic bone resorption may play a role in regulating circulating levels of FGF23, using a mouse model where injections of interleukin (IL)-1β into the subcutaneous tissue over the calvaria induced rapid bone resorption. A significant amount of FGF23 was detected in the extracts from mouse bones, which supports the idea that FGF23 stays in bone for a while after its production. IL-1β-induced bone resorption was associated with elevated serum FGF23 levels, an effect abolished by pre-treatment with pamidronate. Fgf23 expression was not increased in either the calvariae or tibiae of IL-1β-injected mice, which suggests that IL-1β facilitated the entry of FGF23 protein into circulation by accelerating bone resorption rather than increasing its gene expression. The direct effect of IL-1β on bone was confirmed when it increased FGF23 levels in the conditioned media of mouse calvariae in organ culture. Repeated treatment of the cultured calvariae with IL-1β led to a refractory phase, where FGF23 was not mobilized by IL-1β anymore. Consistent with the in vivo results, treatment with IL-1β failed to increase Fgf23 mRNA in isolated primary osteocytes and osteoblasts. These results suggest that FGF23 produced by osteocytes remains in bone, and that rapid bone resorption facilitates its entry into the bloodstream. PMID:24996526

  8. Effects of tanshinone IIA on the transforming growth factor β1/Smad signaling pathway in rat cardiac fibroblasts

    Directory of Open Access Journals (Sweden)

    Cheng-Ye Zhan

    2014-01-01

    Full Text Available Objectives: This study explores the mechanism of tanshinone IIA (TSN-mediated inhibition of myocardial fibrosis by investigating the effect of TSN on transforming growth factor β1 (TGFβ1 signal transduction in rat cardiac fibroblasts (CFs. Materials and Methods: CFs were isolated from neonatal Sprague-Dawley rats by trypsin digestion and differential adhesion and stimulated with 5 ng/mL TGFβ1 and TSN (10−6 , 10−5 , or 10−4 mol/L. The expression of fibronectin (FN mRNA in the CFs was determined using reverse transcriptase-polymerase chain reaction and the protein expression of FN and Smads in CFs was detected using Western blot. The intracellular expression and localization of Smads in the CFs were analyzed using immunocytochemistry. Results: TGFβ1 induced the expression of FN and Smads in a time-dependent manner. At the end of the culture treatment, the mRNA expression of FN and the expression of phosphorylated Smad2/3 (p-Smad2/3 increased significantly (P < 0.01. TSN pretreatment (10−5 and 10−4 mol/L reduced the expression of FN and p-Smad2/3 (P < 0.01 following TGFβ1 stimulation and led to a significant decrease in the nuclear staining intensity and a positive rate of p-Smad2/3 (P < 0.05 and P < 0.01, respectively. Conclusion: The inhibitory effect of TSN on myocardial fibrosis may be associated with its inhibition of TGFβ1-induced Smad2/3 phosphorylation and p-Smad2/3 nuclear translocation, which blocks the TGFβ1/Smad signaling pathway in CFs.

  9. A Fibroblast Growth Factor 21-Pregnane X Receptor Pathway Downregulates Hepatic CYP3A4 in Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Woolsey, Sarah J; Beaton, Melanie D; Mansell, Sara E; Leon-Ponte, Matilde; Yu, Janice; Pin, Christopher L; Adams, Paul C; Kim, Richard B; Tirona, Rommel G

    2016-10-01

    Nonalcoholic fatty liver disease (NAFLD) alters drug response. We previously reported that NAFLD is associated with reduced in vivo CYP3A drug-metabolism activity and hepatic CYP3A4 expression in humans as well as mouse and human hepatoma models of the disease. Here, we investigated the role of the lipid- and glucose-modulating hormone fibroblast growth factor 21 (FGF21) in the molecular mechanism regulating CYP3A4 expression in NAFLD. In human subjects, mouse and cellular NAFLD models with lower CYP3A4 expression, circulating FGF21, or hepatic FGF21 mRNA levels were elevated. Administration of recombinant FGF21 or transient hepatic overexpression of FGF21 resulted in reduced liver CYP3A4 luciferase reporter activity in mice and decreased CYP3A4 mRNA expression and activity in cultured Huh7 hepatoma cells. Blocking canonical FGF21 signaling by pharmacological inhibition of MEK1 kinase in Huh7 cells caused de-repression of CYP3A4 mRNA expression with FGF21 treatment. Mice with high-fat diet-induced simple hepatic steatosis and lipid-loaded Huh7 cells had reduced nuclear localization of the pregnane X receptor (PXR), a key transcriptional regulator of CYP3A4 Furthermore, decreased nuclear PXR was observed in mouse liver and Huh7 cells after FGF21 treatment or FGF21 overexpression. Decreased PXR binding to the CYP3A4 proximal promoter was found in FGF21-treated Huh7 cells. An FGF21-PXR signaling pathway may be involved in decreased hepatic CYP3A4 metabolic activity in NAFLD.

  10. Maternal behavior in transgenic mice with reduced fibroblast growth factor receptor function in gonadotropin-releasing hormone neurons

    Directory of Open Access Journals (Sweden)

    Brooks Leah R

    2012-09-01

    Full Text Available Abstract Background Fibroblast growth factors (FGFs and their receptors (FGFRs are necessary for the proper development of gonadotropin-releasing hormone (GnRH neurons, which are key activators of the hypothalamo-pituitary-gonadal axis. Transgenic mice that have the targeted expression of a dominant negative FGFR (dnFGFR in GnRH neurons (dnFGFR mice have a 30% decrease of GnRH neurons. Additionally, only 30–40% of the pups born to the transgenic dams survive to weaning age. These data raised the possibility that FGFR defects in GnRH neurons could adversely affect maternal behavior via novel mechanisms. Methods We first determined if defective maternal behavior in dnFGFR mothers may contribute to poor pup survival by measuring pup retrieval and a battery of maternal behaviors in primiparous control (n = 10–12 and dnFGFR (n = 13–14 mothers. Other endocrine correlates of maternal behaviors, including plasma estradiol levels and hypothalamic pro-oxyphysin and GnRH transcript levels were also determined using enzyme-linked immunoassay and quantitative reverse transcription polymerase chain reaction, respectively. Results Maternal behaviors (% time crouching with pups, time off pups but not feeding, time feeding, and total number of nesting bouts were not significantly different in dnFGFR mice. However, dnFGFR dams were more likely to leave their pups scattered and took significantly longer to retrieve each pup compared to control dams. Further, dnFGFR mothers had significantly lower GnRH transcripts and circulating E2, but normal pro-oxyphysin transcript levels. Conclusions Overall, this study suggests a complex scenario in which a GnRH system compromised by reduced FGF signaling leads to not only suboptimal reproductive physiology, but also suboptimal maternal behavior.

  11. Construction of recombinant adenovirus co-expression vector carrying the human transforming growth factor-β1 and vascular endothelial growth factor genes and its effect on anterior cruciate ligament fibroblasts

    Institute of Scientific and Technical Information of China (English)

    WEI Xue-lei; LIN Lin; HOU Yu; FU Xin; ZHANG Ji-ying; MAO Ze-bin; YU Chang-long

    2008-01-01

    Background Remodeling of the anterior cruciate ligament (ACL) graft usually takes longer than expected. Gene therapy offers a radical different approach to remodeling of the graft. In this study, the internal ribosome entry site (IRES) sequence was used to construct a new recombinant adenovirus which permits co-expression of transforming growth factor-β1 (TGFβ1) and vascular endothelial growth factor 165 (VEGF165) genes (named Ad-VEGF165-1RES-TGFβ1). We investigated the effects of the new adenovirus on the migration of and matrix synthesis by ACL fibroblasts.Methods Adenoviral vector containing TGFβ1 and VEGF165 genes was constructed. ACL fibroblasts were obtained from New Zealand white rabbits. After ACL fibroblasts were exposed to Ad-VEGF165-1RES-TGFβ1, the expression of VEGF165 and TGFβ1 proteins were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis. Bioassay of VEGF165 and TGFβ1 proteins were assessed by Western blotting analysis. Proliferation and migration of ACL fibroblasts were assessed by in vitro wound closure assay. Gene expression of collagen type I, collagen type Ⅲ, and fibronectin mRNA among matrix markers were assessed by real-time PCR.Results The results showed the successful construction of a recombinant co-expression adenovirus vector containing TGFβI and VEGF165 genes. Co-expression of TGFβ1 and VEGF165 can induce relatively rapid and continuous proliferation of ACL fibroblasts and high gene expression of collagen type Ⅰ, collagen typeⅢ, and fibronectin mRNA among matrix markers.Conclusion Co-expression of TGFβ1 and VEGF165 genes has more powerful and efficient effects on the migration of and matrix synthesis by ACL fibroblasts.

  12. Clinical implications of the growth-suppressive effects of chlorhexidine at low and high concentrations on human gingival fibroblasts and changes in morphology.

    Science.gov (United States)

    Wyganowska-Swiatkowska, Marzena; Kotwicka, Malgorzata; Urbaniak, Paulina; Nowak, Agnieszka; Skrzypczak-Jankun, Ewa; Jankun, Jerzy

    2016-06-01

    Chlorhexidine (CHX) is considered the gold standard in the antiseptic treatment of the oral cavity, due to its high antibactericidal capability. With the use of CHX mouth-rinse formulations, the bacteriostatic effects are maintained by the adsorption and prolonged release of CHX from oral surfaces. It was believed that antiplaque formation ability and the lack of systemic toxicity of CHX render it an excellent antiseptic in post-surgical dental treatment. However, recent studies have demonstrated that CHX exerts cytotoxic effects on human periodontal tissues, such as gingival fibroblasts and other cells. It also reduces gingival fibroblast adhesion to fibronectin and prevents fibroblast attachment to root surfaces, thus interfering with periodontal regeneration. In this study, using human gingival fibroblasts (HGFs), we investigated effects of CHX on the growth, morphology and proliferation of HGFs. We found that a low concentration (0.002%) of CHX does not interfere with the proliferation and morphology of HGFs. However, a higher concentration (≥0.04%) of CHX inhibits cell proliferation and to a certain extent, affects cell morphology in a time-dependent manner. A decrease in the percentage of cells in the G0/G1 phase and the accumulation of cells in the S phase following treatment with CHX also occurred in a dose-dependent manner. We thus concluded that CHX only at the concentration of 0.002% does not interfere with HGF growth, that is so critical to wound healing. Thus, the application of CHX in the post-surgical antiseptic treatment of the oral cavity should be limited. PMID:27082817

  13. Effect of Control-released Basic Fibroblast Growth Factor Incorporated in β-Tricalcium Phosphate for Murine Cranial Model

    Directory of Open Access Journals (Sweden)

    Azusa Shimizu, MD

    2014-03-01

    Conclusions: These findings suggest that control-released bFGF incorporated in β-TCP can accelerate bone regeneration in the murine cranial defect model and may be promising for the clinical treatment of cranial defects.

  14. The Effect of Control-released Basic Fibroblast Growth Factor in Wound Healing: Histological Analyses and Clinical Application

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    Shigeru Matsumoto, MD

    2013-09-01

    Conclusions: These findings suggest that control-released bFGF using gelatin sheet is effective for promoting wound healing. Such therapeutic strategy was considered to offer several clinical advantages including rapid healing and reduction of the dressing change with less patient discomfort.

  15. Growth factors and feeder cells promote differentiation of human embryonic stem cell into dopaminergic neurons: a novel role of fibroblast growth factor-20

    Directory of Open Access Journals (Sweden)

    Ana Sofia Correia

    2008-07-01

    Full Text Available Human embryonic stem cells (hESCs are a potential source of dopaminergic neurons for treatment of Parkinson’s disease (PD. Dopaminergic neurons can be derived from hESCs and display a characteristic midbrain phenotype. Once transplanted, they can induce partial behavioral recovery in animal models of PD. The potential research field faces several challenges that need to be overcome before clinical application of hESCs in a transplantation therapy in PD can be considered. These include low survival of the hESC-derived, grafted dopaminergic neurons after transplantation; unclear functional integration of the grafted neurons in the host brain; and, the risk of teratoma/tumor formation from the transplanted cells. This review is focused on our recent efforts to improve the survival of hESC-dervied dopaminergic neurons. We have examined the effect of fibroblast growth factor (FGF-20 in the differentiation of hESCs into dopaminergic neurons. We supplemented cultures of hESCs with FGF-20 during differentiation on PA6 mouse stromal cells for three weeks. When we added FGF-20 the yield of neurons expressing tyrosine hydroxylase increased. We demonstrated that at least part of the effect is contributed by enhanced cell differentiation towards the dopaminergic phenotype as well as reduced cell death. We compare our results with those obtained in other published protocols using different sets of growth factors. Our data indicate that FGF-20 has potent effects to generate large number of dopaminergic neurons derived from hESCs, which may be useful for cell therapy in PD.

  16. Without continuous basic research technology will stagnate and economy will be in no growth. Why?

    OpenAIRE

    Pedersen, Jørgen Lindgaard

    2008-01-01

    The paper presents some ideas about new knowledge and the effects from knowledge on development of new technology. Paul M. Romer established in the 1980s the so-called New Growth Economy. The basic idea is here that knowledge is included explicitly in the production function. With knowledge as a public good its unit costs will be declining and it can substitute other inputs with not-declining unit costs. A problem with that idea is the neglect of the cost connected with production of a new id...

  17. Plasma intact fibroblast growth factor 23 levels in women with bulimia nervosa: A cross-sectional pilot study

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    Yoshiuchi Kazuhiro

    2011-06-01

    Full Text Available Abstract Fibroblast growth factor (FGF 23, a circulating 26-kDa peptide produced by osteogenic cells, is a novel phosphaturic factor. In our previous study, binge-eating/purging type anorexia nervosa (AN-BP patients had elevated plasma intact FGF23 (iFGF23 levels, while restricting type (AN-R patients had plasma iFGF23 levels similar to healthy controls. Although bulimia nervosa (BN patients as well as some patients with AN-BP regularly engage in binge eating, there have been no studies regarding plasma iFGF23 levels in BN patients. Therefore, this study was performed to determine plasma iFGF23 concentrations in BN patients and healthy controls. The study population consisted of 13 female BN patients and 11 healthy female controls. Blood samples were collected from all subjects after overnight fasting. Plasma iFGF23 was measured using an ELISA kit in a cross-sectional manner. The two-tailed Mann-Whitney U-test was used to assess differences between BN patients and healthy controls. In addition, BN patients were divided into two groups based on questionnaire-reported binge eating frequency immediately prior to participation in this study: high frequency of binge eating (once a week or more; HF group; n = 8 and low frequency of binge eating (less than once a week; LF group; n = 5. Two-tailed Mann-Whitney U-test with Bonferroni's correction was performed after the Kruskal-Wallis test to assess differences between HF group, LF group, and healthy controls. Median (quartiles plasma iFGF23 levels were greater in BN patients (35.5 [14.8-65.0] pg/ml than in controls (3.8 [not detected-5.3] pg/ml; p = 0.002. In addition, median (quartiles plasma iFGF23 levels were greater in the HF group (62.3 [44.4-73.4] pg/ml than in controls (p

  18. Structural Stability of Human Fibroblast Growth Factor-1 Is Essential for Protective Effects Against Radiation-Induced Intestinal Damage

    Energy Technology Data Exchange (ETDEWEB)

    Nakayama, Fumiaki, E-mail: f_naka@nirs.go.jp [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Umeda, Sachiko [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Yasuda, Takeshi [Department of Radiation Emergency Medicine, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba (Japan); Asada, Masahiro; Motomura, Kaori; Suzuki, Masashi [Signaling Molecules Research Laboratory, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki (Japan); Zakrzewska, Malgorzata [Faculty of Biotechnology, University of Wroclaw (Poland); Imamura, Toru [Signaling Molecules Research Laboratory, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki (Japan); Imai, Takashi [Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan)

    2013-02-01

    Purpose: Human fibroblast growth factor-1 (FGF1) has radioprotective effects on the intestine, although its structural instability limits its potential for practical use. Several stable FGF1 mutants were created increasing stability in the order, wild-type FGF1, single mutants (Q40P, S47I, and H93G), Q40P/S47I, and Q40P/S47I/H93G. This study evaluated the contribution of the structural stability of FGF1 to its radioprotective effect. Methods and Materials: Each FGF1 mutant was administered intraperitoneally to BALB/c mice in the absence of heparin 24 h before or after total body irradiation (TBI) with {gamma}-rays at 8-12 Gy. Several radioprotective effects were examined in the jejunum. Results: Q40P/S47I/H93G could activate all subtypes of FGF receptors in vitro much more strongly than the wild-type without endogenous or exogenous heparin. Preirradiation treatment with Q40P/S47I/H93G significantly increased crypt survival more than wild-type FGF1 after TBI at 10 or 12 Gy, and postirradiation treatment with Q40P/S47I/H93G was effective in promoting crypt survival after TBI at 10, 11, or 12 Gy. In addition, crypt cell proliferation, crypt depth, and epithelial differentiation were significantly promoted by postirradiation treatmen