Increase In Fibroblast Growth Factor-2 Research Articles

Biochemical markers of depression - an up-to-date review

IntroductionDepression or Major Depressive Disorder (MDD) is the most prevalent psychiatric disorder and a leading cause of disability worldwide. Currently affecting around 300 million people worldwide, depression is a major clinical, emotional, and socioeconomic strain for society. There is a growing interest in the biological underpinnings of depression, which are reflected by altered levels of biomarkers.ObjectivesThe aim of the study was to present an up-to-date review of potential MDD biomarkers.MethodsPubMed, Scopus, and Web of Science databases were searched.ResultsEnhanced inflammation has been reported in MDD, as reflected by increased concentrations of inflammatory markers – interleukin-6, C-reactive protein, tumor necrosis factor-α, and soluble interleukin-2 receptor. Dysregulation of the hypothalamus-pituitary-adrenals axis, along with increased cortisol levels, have also been reported in MDD. Oxidative and nitrosative stress also plays an important role in the pathophysiology of MDD. Notably, increased levels of lipid peroxidation markers are characteristic of MDD. Kynurenine metabolites, increased glutamate and decreased total cholesterol are also features of MDD. Finally, alterations in growth factors, with a significant decrease in brain-derived neurotrophic factor and an increase in fibroblast growth factor-2 and insulin-like growth factor-1 concentrations have also been found in MDD.ConclusionsA group of substances holds promise as reliable biomarkers for MDD. However, biomarker research in depression faces many difficulties, such as insufficient understanding of MDD etiopathogenesis, substantial heterogeneity of the disorder and low specificity of biomarkers. The construction of biomarker panels and their evaluation with use of new technologies may have the potential to overcome the above mentioned obstacles.DisclosureNo significant relationships.

Peripheral Markers of Depression.

Major Depressive Disorder (MDD) is a leading cause of disability worldwide, creating a high medical and socioeconomic burden. There is a growing interest in the biological underpinnings of depression, which are reflected by altered levels of biological markers. Among others, enhanced inflammation has been reported in MDD, as reflected by increased concentrations of inflammatory markers—C-reactive protein, interleukin-6, tumor necrosis factor-α and soluble interleukin-2 receptor. Oxidative and nitrosative stress also plays a role in the pathophysiology of MDD. Notably, increased levels of lipid peroxidation markers are characteristic of MDD. Dysregulation of the stress axis, along with increased cortisol levels, have also been reported in MDD. Alterations in growth factors, with a significant decrease in brain-derived neurotrophic factor and an increase in fibroblast growth factor-2 and insulin-like growth factor-1 concentrations have also been found in MDD. Finally, kynurenine metabolites, increased glutamate and decreased total cholesterol also hold promise as reliable biomarkers for MDD. Research in the field of MDD biomarkers is hindered by insufficient understanding of MDD etiopathogenesis, substantial heterogeneity of the disorder, common co-morbidities and low specificity of biomarkers. The construction of biomarker panels and their evaluation with use of new technologies may have the potential to overcome the above mentioned obstacles.

Neutralizing BDNF and FGF2 injection into denervated skeletal muscle improve recovery after nerve repair.

After facial nerve injury and surgical repair in rats, recovery of vibrissal whisking is associated with a high proportion of mono-innervated neuro-muscular junctions (NMJs). Our earlier work with Sprague Dawley (SD)/Royal College of Surgeons (RCS) rats, which are blind and spontaneously restore NMJ-monoinnervation and whisking, showed correlations between functional recovery and increase of fibroblast growth factor-2 (FGF2) and brain-derived neurotrophic factor (BDNF) in denervated vibrissal muscles. We used normally sighted rats (Wistar), in which NMJ-polyinnervation is highly correlated with poor whisking recovery, and injected the vibrissal muscle levator labii superioris (LLS) with combinations of BDNF, anti-BDNF, and FGF2 at different postoperative periods after facial nerve injury. Rats receiving anti-BDNF+FGF2 showed low NMJ-polyinnervation and best recovery of whisking amplitude. Restoration of target reinnervation after peripheral nerve injury requires a complex mixture of trophic factors with a specific time course of availability for each of them.

Candida albicans Morphology-Dependent Host FGF-2 Response as a Potential Therapeutic Target.

Angiogenesis mediated by proteins such as Fibroblast Growth Factor-2 (FGF-2) is a vital component of normal physiological processes and has also been implicated in contributing to the disease state associated with various microbial infections. Previous studies by our group and others have shown that Candida albicans, a common agent of candidiasis, induces FGF-2 secretion in vitro and angiogenesis in brains and kidneys during systemic infections. However, the underlying mechanism(s) via which the fungus increases FGF-2 production and the role(s) that FGF-2/angiogenesis plays in C. albicans disease remain unknown. Here we show, for the first time, that C. albicans hyphae (and not yeast cells) increase the FGF-2 response in human endothelial cells. Moreover, Candidalysin, a toxin secreted exclusively by C. albicans in the hyphal state, is required to induce this response. Our in vivo studies show that in the systemic C. albicans infection model, mice treated with FGF-2 exhibit significantly higher mortality rates when compared to untreated mice not given the angiogenic growth factor. Even treatment with fluconazole could not fully rescue infected animals that were administered FGF-2. Our data suggest that the increase of FGF-2 production/angiogenesis induced by Candidalysin contributes to the pathogenicity of C. albicans.

Comparison of trophic factors' expression between paralyzed and recovering muscles after facial nerve injury. A quantitative analysis in time course

After peripheral nerve injury, recovery of motor performance negatively correlates with the poly-innervation of neuromuscular junctions (NMJ) due to excessive sprouting of the terminal Schwann cells. Denervated muscles produce short-range diffusible sprouting stimuli, of which some are neurotrophic factors. Based on recent data that vibrissal whisking is restored perfectly during facial nerve regeneration in blind rats from the Sprague Dawley (SD)/RCS strain, we compared the expression of brain derived neurotrophic factor (BDNF), fibroblast growth factor-2 (FGF2), insulin growth factors 1 and 2 (IGF1, IGF2) and nerve growth factor (NGF) between SD/RCS and SD-rats with normal vision but poor recovery of whisking function after facial nerve injury. To establish which trophic factors might be responsible for proper NMJ-reinnervation, the transected facial nerve was surgically repaired (facial-facial anastomosis, FFA) for subsequent analysis of mRNA and proteins expressed in the levator labii superioris muscle. A complicated time course of expression included (1) a late rise in BDNF protein that followed earlier elevated gene expression, (2) an early increase in FGF2 and IGF2 protein after 2days with sustained gene expression, (3) reduced IGF1 protein at 28days coincident with decline of raised mRNA levels to baseline, and (4) reduced NGF protein between 2 and 14days with maintained gene expression found in blind rats but not the rats with normal vision. These findings suggest that recovery of motor function after peripheral nerve injury is due, at least in part, to a complex regulation of lesion-associated neurotrophic factors and cytokines in denervated muscles. The increase of FGF-2 protein and concomittant decrease of NGF (with no significant changes in BDNF or IGF levels) during the first week following FFA in SD/RCS blind rats possibly prevents the distal branching of regenerating axons resulting in reduced poly-innervation of motor endplates.

Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation.

It was recently shown that the conditioned media (CM) of Human Umbilical Cord Perivascular Cells (HUCPVCs), a mesenchymal progenitor population residing within the Wharton Jelly of the umbilical cord, was able to modulate in vitro the survival and viability of different neuronal and glial cells populations. In the present work, we aimed to assess if the secretome of HUCPVCs is able to 1) induce the differentiation of human telencephalon neural precursor cells (htNPCs) in vitro, and 2) modulate neural/glial proliferation, differentiation and survival in the dentate gyrus (DG) of adult rat hippocampus. For this purpose, two separate experimental setups were performed: 1) htNPCs were incubated with HUCPVCs-CM for 5days after which neuronal differentiation was assessed and, 2) HUCPVCs, or their respective CM, were injected into the DG of young adult rats and their effects assessed 7days later. Results revealed that the secretome of HUCPVCs was able to increase neuronal cell differentiation in vitro; indeed, higher densities of immature (DCX(+) cells) and mature neurons (MAP-2(+) cells) were observed when htNPCs were incubated with the HUCPVCs-CM. Additionally, when HUCPVCs and their CM were injected in the DG, results revealed that both cells or CM were able to increase the endogenous proliferation (BrdU(+) cells) 7days after injection. It was also possible to observe an increased number of newborn neurons (DCX(+) cells), upon injection of HUCPVCs or their respective CM. Finally western blot analysis revealed that after CM or HUCPVCs transplantation, there was an increase of fibroblast growth factor-2 (FGF-2) and, to a lesser extent, of nerve growth factor (NGF) in the DG tissue. Concluding, our results have shown that the transplantation ofHUCPVCs or the administration oftheir secretome were able to potentiate neuronal survival and differentiation in vitro and in vivo.

Klotho suppresses renal tubulo-interstitial fibrosis by controlling basic fibroblast growth factor-2 signalling.

Increased basic fibroblast growth factor-2 (FGF2) and reduced Klotho have both been reported to be closely associated with renal fibrosis. However, the relationship between Klotho and FGF2 remains unclear. We demonstrate that FGF2 induced tubulo-epithelial plasticity in cultured HK-2 cells, accompanied by a reduction in Klotho expression, whereas recombinant Klotho protein could inhibit the action of FGF2. The FGF2 effects required extracellular signal-regulated protein kinase 1/2 activation, which was suppressed by Klotho. Moreover, Klotho also restrained FGF2-induced fibroblast proliferation and activation. The inhibitory effect of Klotho on the activity of FGF2 was likely due to its potent ability to compete with FGF2 binding to FGF receptor 1. Unilateral ureteral obstruction (UUO)-induced renal fibrosis was associated with an increase in FGF2 and a reduction in Klotho expression in wild-type mice, whereas FGF2(-/-) mice largely preserved Klotho expression and developed only mild renal fibrosis after obstructive injury. Furthermore, administration of Klotho protein in UUO mice significantly reduced renal fibrosis, concomitant with a marked suppression of FGF2 production and signalling. These studies demonstrate a feedback loop between Klotho depletion and FGF2 activation in renal fibrosis. Our results also suggest that Klotho treatment reduces renal fibrosis, at least in part, by inhibiting FGF2 signalling.

Abstract 3623: Monoclonal antibody against the 4th extracellular domain of N-cadherin affects FGF2 mediated pathways in prostate cancer

Abstract Introduction: Fibroblast growth factor 2 (FGF2) has been reported to synergize with N-cadherin, a cell surface marker of epithelial mesenchymal transition (EMT), to enhance migration and invasion in breast cancer and other cancers. Recent studies from our group suggested that N-cadherin promotes castration resistance and metastasis in prostate cancer. In addition, our studies showed that antibodies against N-cadherin ectodomains blocked prostate cancer invasion and castration resistant growth. To investigate the mechanism of action of N-cadherin antibodies in prostate cancer cells, we seek to determine the contribution of the different N-cadherin domains in promoting invasion and growth in prostate cancer cells, with particular focus on interaction with FGF2. Methods: Chimeric constructs, in which a N-cadherin domain was swapped with an E-cadherin domain, were generated and ectopically expressed in androgen dependent prostate cancer cell line LNCaP. The following combinations were made: 1/ NE: N-cadherin ectodomains linked to E-cadherin cytoplasmic domain (NE), 2/ EN: the reverse of NE, 3/ NEN: swapping N-cadherin ectodomain 4 for that of E-cadherin. Full length N-cadherin and empty vector sublines served as positive and negative controls. All cell lines were assayed for invasion and growth in androgen depleted media in combination with recombinant FGF2, FGF2 neutralizing antibody and N-cadherin antibodies. Results: Ectopic expression of N-cadherin in N-cadherin negative cells result in a 5-fold increase of FGF2 secreted in the media. In vitro studies have shown that the addition of recombinant FGF2 enhanced invasion by 56%± 0.04 in N-cadherin positive cells while treatment with FGF2 neutralizing antibody resulted in a 65%± 0.03 reduction in invasion. Chimeric cell lines which harbor extracellular domain 4 of N-cadherin, N and NE cell lines, showed >56%± 0.11 enhanced invasion to the addition of recombinant FGF2 while EN, NEN, and control cell lines did not. Monoclonal antibodies developed against regions in the extracellular domain of N-cadherin block the response to recombinant FGF2 with 2A9 (antibody raised against extracellular domain 4) being the least responsive. Conclusions: These studies suggest that the relationship between N-cadherin and FGF2 is involved in prostate cancer progression. Therapeutic targeting of N-cadherin with monoclonal antibodies, alone or in combination with other drugs targeting those potentially involved in downstream pathways may have significant clinical benefit. Future experiments include in vivo models where chimeric cell lines will be implanted in mice as xenografts, and will be monitored for tumor growth, local invasion, and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2011-3623

Glucose Modulates Basement Membrane Fibroblast Growth Factor-2 via Alterations in Endothelial Cell Permeability

The effects of glucose extremes on vascular physiology and endothelial cell function have been examined across a range of time scales. Not unexpectedly, chronic glucose exposure induces long term tissue effects. Yet short term exposure can also impose lasting consequences. The persistence of vascular pathology after euglycemic restoration further suggests a glucose exposure memory. Slow turnover reservoirs such as basement membrane are candidates for prolongation of acute events. We hypothesized that glucose-induced vascular dysfunction is related to altered vasoactive compound handling within the endothelial cell-basement membrane co-regulatory unit. Endothelial cell basement membrane-associated fibroblast growth factor-2 increased linearly with culture glucose within days of elevated glucose exposure. Surprisingly, basement membrane fibroblast growth factor-2 binding kinetics remained unchanged. The glucose-induced increase in basement membrane fibroblast growth factor-2 was instead related to enhanced endothelial cell fibroblast growth factor-2 release and permeability. Cellular fibroblast growth factor-2 release occurred concomitant with apoptosis but was not blocked by caspase inhibitors. These data suggest that release was associated with sub-lethal early apoptotic cell membrane damage, perhaps related to reactive oxygen species formation. High glucose basement membrane in turn enhanced endothelial cell proliferation in a fibroblast growth factor-2-dependent manner. We now show that glucose-induced alterations in endothelial cell function promote changes in basement membrane composition, and these changes further affect endothelial cell function. These data highlight the interrelationship of cell and basement membrane in pathological conditions such as hyperglycemia. These phenomena may explain long term effects on the endothelium of short term exposure to glucose extremes.

Egr‐1 transcription activation exists in placental endothelium when vascular disease is present

To seek evidence of early vascular injury in the placental villous microcirculation in placental insufficiency identified by a high-resistance umbilical Doppler study by examining for expression of fibroblast growth factor receptor-1 (FGFR-1), its transcription factor, early growth response factor-1 (Egr-1) and plasma fibroblast growth factor-2 (FGF-2). Case-control study. University teaching hospital. Placentas and umbilical vein blood were collected at delivery from 12 women with normal pregnancy delivered at term and 14 with placental vascular disease defined by an abnormal umbilical artery Doppler study. Microvascular endothelial cells were isolated from fresh human placentas using collagenase digestion and Dynabeads coated with monoclonal antibody against CD31. RNA was extracted from the isolated endothelial cells. The messenger RNA (mRNA) expression of FGFR-1 and Egr-1 production were assessed by reverse transcription polymerase chain reaction and factored relative to 18S ribosomal RNA. To confirm that FGF-2 was playing a significant role in this microvascular endothelial cell injury in the placenta, we also measured the soluble fraction of FGF-2 in fetal plasma from same groups of pregnancies using an enzyme-linked immunosorbent assay. Microvascular endothelial cells expression of Egr-1mRNA, FGFR-1 mRNA and presence of soluble FGF-2 in fetal plasma. The soluble level of FGF-2 in the fetal placental circulation from pregnancy with placental vascular disease was increased when compared with normal pregnancy (median 10.15 pg/ml and interquartile range 5.34-21.83 pg/ml versus 4.46 pg/ml and 3.69-5.66 pg/ml; P < 0.05). Microvascular endothelial cells from the placental villi with placental vascular disease showed upregulation of both FGFR-1 mRNA expression (median 0.72 and interquartile range 0.40-1.64 versus 0.34 and 0.19-0.71; P<0.05) and Egr-1 expression (median 0.79 and interquartile range 0.27-1.86 versus 0.23 and 0.17-0.67; P<0.05) in comparison with normal pregnancy. Endothelial cells from the placental villi are upregulated for expression of Egr-1 transcription factor gene in placental vascular disease. The FGFR-1 activation and increase in FGF-2 in the fetal circulation are known to be very early features of the response of endothelium to injury. Egr-1 is a promoter of many key pathophysiologically relevant target genes, which influence the development of subsequent vascular lesions. This change may occur before the pathological features recognised on microscopy.

Behavioral control of the stressor modulates stress-induced changes in neurogenesis and fibroblast growth factor-2

The controllability of stressors modulates many of the consequences of stressor exposure. Here, we used immunohistochemistry to examine neural progenitor cell proliferation and survival and basic fibroblast growth factor-2 in the hippocampus of male rats after controllable or uncontrollable tailshock. A series of identical tailshocks were delivered to yoked pairs of rats. One rat could terminate shocks to both rats of the pair. Reductions in neural progenitor cells were observed at 1-2 days and at 28 days in rats exposed to uncontrollable shock. Controllable shock produced an increase in fibroblast growth factor-2 in the dentate gyrus and CA1 2 h after stress and in the dentate gyrus 24 h after stress. Thus, stressor controllability modulates stress-induced decreases in neurogenesis and increases in fibroblast growth factor-2.

The effects of repeated minimal electroconvulsive shock exposure on levels of mRNA encoding fibroblast growth factor-2 and nerve growth factor in limbic regions

Chronic, but not acute, exposure to minimal electroconvulsive shock (ECS) has been shown to decrease vulnerability to neuronal cell death, without itself causing neuronal damage. One potential mechanism for the neuroprotective effect of ECS is the increase in fibroblast growth factor-2 (FGF-2) which occurs after chronic, but not acute, ECS exposure. This raises the possibility that repeated seizures over a period of several days may alter the transcriptional regulation of FGF-2. To test this hypothesis, the present study compared the effect of acute (1 day) vs. chronic (7 days) ECS treatment on levels of mRNA for FGF-2 in rhinal and frontal cortices, hippocampus, and olfactory bulbs. In addition, mRNA for another prominent neurotrophic factor, nerve growth factor (NGF), was assayed concurrently. At 8 h after acute ECS, mRNA levels increased by 60% for FGF-2 and 136% for NGF in rhinal cortex, 32% for FGF-2 and 36% for NGF in frontal cortex, and by 13% for NGF in hippocampus. After 7 days of ECS treatment the respective increases were 72% and 80%, 53% and 38%, and 28%. No increases were observed in olfactory bulbs after either treatment regimen. The peak increases in FGF-2 mRNA were consistently greater after chronic treatment, but the differences from those seen acutely reached significance in frontal cortex only. However, the duration over which mRNA for FGF-2 was elevated did not differ between the acute and chronic ECS groups. NGF mRNA induction was neither enhanced nor prolonged as a result of chronic ECS as compared to acute ECS treatment. These results suggest that chronic ECS treatment may lead to an enhanced rate of transcription of message for FGF-2 but not for NGF, in selected brain regions. At the same time, the results indicate that chronic ECS treatment induces FGF-2 and NGF mRNA expression in a tissue-specific manner and that this induction is maintained over the 7-day treatment period. The sustained increases in mRNAs for these trophic factors may contribute to the neuroprotective actions of chronic ECS treatment.