Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients

In recent years a role has been recognized for fibroblast growth factor (FGF)-2 in the pathogenesis of demyelination and the failure of remyelination in experimental models of multiple sclerosis (MS). FGF-2 levels were determined using a sensitive immunoassay in the cerebrospinal fluid (CSF) of 20 patients with clinically isolated syndrome (CIS), 40 patients with relapsing-remitting (R-R) MS, and 30 patients with secondary progressive (SP) MS, correlated with MRI measures. Control CSF samples were obtained from 20 subjects who underwent lumbar puncture for diagnostic purposes and for whom all instrumental and laboratory analyses excluded systemic and nervous system diseases. FGF-2 levels in the CSF of MS and CIS patients were significantly higher than controls (P<0.001 and P<0.05, respectively). The highest levels were detected in R-R MS patients during relapse and in SP MS patients with an increase of 1 point in EDSS scores in the last 6 months. A significant correlation was found in SP MS patients with lesional load (R=0.43, P<0.01) but not with parenchymal fractions as measures of brain atrophy. A slight increase in serum FGF-2 levels was also found in R-R MS patients during relapse with gadolinium enhancing lesions and in SP patients with disability progression. These findings support the implication of FGF-2 in the pathogenesis of MS and concur with recent reports of the involvement of FGF receptor signalling in the disruption of myelin production in differentiated oligodendrocytes and in the loss of adult oligodendrocytes and myelin in vivo due to FGF-2.     

Fibroblast growth factor-2 induces astroglial and microglial reactivity in vivo

A role for fibroblast growth factor‐2 (FGF‐2) has been proposed in mediating the glial response to injury in the central nervous system (CNS). We have tested this possibility in vivo, by injecting FGF‐2 into the cerebrospinal fluid (CSF) of the brain ventricles of young rats and analysing glial cells in the anterior medullary velum (AMV), which partly roofs the IVth ventricle. FGF‐2 was administered at two different doses, low FGF‐2 (500 ng mL^?1 CSF) and high FGF‐2 (10 µg mL^?1 CSF), and saline vehicle was injected in controls. Injections were performed twice daily for three days, commencing at postnatal day (P) 6, and AMV were analysed at P9, using immunohistochemistry and Western blotting. Glial cells were unaffected by treatment with saline or low FGF‐2, whereas high FGF‐2 induced reactive changes in glial cell types: (1) there was increased GFAP expression in astrocytes, demonstrated by Western blot and immunohistochemistry, and astrocytes appeared hypertrophic, with increased process thickness and number; (2) the number of ED1 labelled microglia/macrophages was doubled, from 47 ± 6 to 114 ± 17 cells per field (0.75 mm²; values are mean ± SEM), and microglia appeared activated, with a multipolar and granular appearance; (3) NG2 positive glial cells appeared more fibrous and there was increased density of processes, although there was no significant increase in their number; (4) oligodendrocyte somata were enlarged and there was a loss of myelin sheaths. The results show that at high CSF titres of FGF‐2 induce glial reactivity in vivo and support a role for FGF‐2 in the pathology of CNS injury and EAE.     

脑肿瘤患者胰岛素样生长因子-1水平的研究

目的探讨血清胰岛素样生长因子（IGF）-1水平与脑肿瘤的关系,垂体瘤、颅咽管瘤手术与血清IGF-1水平变化是否存在联系。方法检测193例脑肿瘤患者血清及61例术后相应患者血清IGF-1水平,用SPSS16．0统计软件进行分析。结果①恶性脑肿瘤组与良性脑肿瘤组间的差异有统计学意义（P〈0．05）,侵袭性垂体瘤组与非侵袭性垂体瘤组间差异有统计学意义（P〈0．05）;②颅咽管瘤手术前后血清IGF-1水平差异有统计学意义（P〈0．05）,侵袭性与非侵袭性垂体瘤手术前后血清IGF-1水平差异无统计学意义（P〉0．05）。结论①IGF-1在良性脑肿瘤和恶性脑肿瘤患者血清中表达的水平存在差异,可帮助临床对肿瘤的恶性程度作出早期的判断;②颅咽管瘤患者手术前后血清IGF-1水平存在差异,对患者的预后判断具有参考价值。     

The levels of vascular endothelial growth factor-A and placental growth factor-2 in embryopathy associated with experimental diabetic gestation

The objective of this study was to investigate the role of vascular endothelial growth factor-A (VEGF-A) and placental growth factor-2 (PlGF-2) in fetal malformations associated with maternal diabetes. Diabetes was induced in female rats. Diabetic and control female rats were made pregnant. On Day 15 of gestation, rats were sacrificed and embryos and their placentas and membranes were dissected out of the uterine horns. Following morphological examination, embryos and their placentas and membranes were homogenized and used for assayed of VEGF-A and PlGF-2 levels. Embryos of diabetic mothers, exhibited significantly (P < 0.05) shorter crown-to-rump lengths, smaller weights, and heavier placental weights. Experimentally induced maternal diabetes was accompanied by decreased VEGF-A in embryos and associated structures. The levels of PlGF-2 in non-malformed embryos of diabetic gestation and their placentas were significantly (P < 0.05) lower than the average of controls. These results might indicate defective vascularization with a consequent morphological or anatomical anomalies or more subtle biochemical or metabolic changes. In diabetic mothers, a statistically significant (P < 0.05) decrease was noted in the level of VEGF-A in plasma of diabetic rats with a small non-significant decrease in PlGF-2. Like many other diabetic complications, diabetes-induced embryopathies might have vascular origin and correcting the disturbances in these angiogenic factors might help decrease the incidence of malformation in diabetic gestation     

Fibroblast growth factor-21 is positively associated with atrial fibrosis in atrial fibrillation patients with rheumatic heart disease

Objective: Fibroblast growth factor-21 (FGF-21) has been discovered as a strong hormone, plays an important role in lipid metabolism, glucose metabolism, associated with several diseases such as obesity, metabolic syndrome, diabetes mellitus, and cardiovascular events; however, no evidence is available concerning the relationship of FGF-21 and atrial fibrosis in patients with atrial fibrillation (AF) and rheumatic heart disease (RHD). Methods: Twenty-four rheumatic heart disease patients were divided into two groups, 12 cases with AF and 12 cases with sinus rhythm (SR). Clinical characteristics and blood samples were collected before surgery; right atrial appendage samples were taken in the surgery of valve replacement. HE staining was performed to determine cross-sectional area of atrial myocytes; Masson stained sections and mRNA levels of cardiac fibrosis biomarkers were used to evaluate the degree of cardiac fibrosis; the level of FGF-21 was evaluated via enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and real-time polymerase chain reaction (PCR). Results: Compared with SR group, cross-sectional area of atrial myocytes and collagen volume fraction were significantly increased in the atrial tissue of AF group. The distribution of FGF-21 in the AF group was remarkably higher than SR group. In addition, plasma and mRNA levels of FGF-21 in atrial tissue of AF showed the same trend as the result of immunohistochemistry. Using linear correlation analysis, the expression level of FGF-21 was found to be positively related to the degree of atrial fibrosis. Conclusion: FGF-21 might involve in the development and maintenance of atrial fibrosis in atrial fibrillation with rheumatic heart disease, and FGF-21 could be used as a novel biomarker to evaluate myocardial fibrosis in the future.     

Demographic and clinical correlates of metabolic syndrome in Native African type-2 diabetic patients

OBJECTIVES: To describe the metabolic syndrome and its demographic and clinical correlates in native African type-2 diabetic patients. METHODS: Cross-sectional analysis of 254 type-2 diabetic indigenous Nigerians consecutively recruited in a teaching hospital. The main outcome measure was metabolic syndrome. Variables of interest included family history/duration of diabetes mellitus and hypertension, gender, socioeconomic class, occupation and place of domicile (urban or rural). Intergroup comparisons were made with Chi-squared tests or t-tests. RESULTS: Patients were aged 35-80 years (mean: 52.0 +/- 11.7 years) and made of 154 (60.6%) males and 100 (39.4%) females. Full-blown metabolic syndrome was noted in 52 patients (20.5%). Metabolic syndrome, as defined by the WHO, was noted in 150 patients (59.1%). About 72.4% of patients were dyslipidemic, 54.3% were hypertensive, 42.5% were obese, 44.9% were microalbuminuric and 32.3% were hyperuricemic. Ischemic heart disease (myocardial infarction) occurred in only 2.4% of patients. Concurrent hypertension and dyslipidemia; obesity and dyslipidemia; and hypertension and obesity occurred in 44.4%, 42.5% and 33.1% of type-2 diabetics, respectively. Compared to the diabetics without metabolic syndrome, those with the syndrome had a significantly higher proportion of patients with a family history of hypertension and diabetes (44% versus 25%; p = 0.003); among the upper/middle socioeconomic class: 52.0% versus 30.8% (p = 0.001); and among the urban dwelling: 68.0% versus 49.0% (p = 0.004). Metabolic syndrome was inversely proportional to the physical activity of an individual (chi2 = 21.69, df = 5, p = 0.001). Blood pressure was significantly higher among patients with metabolic syndrome than those without it (140.6 +/- 22.9/85.2 +/- 12.9 mmHg versus 126.9 +/- 15.4 mmHg; P < 0.01). CONCLUSIONS: The development of metabolic syndrome in African type-2 diabetic patients is influenced by demographic and clinical factors. Vigilant dietary habit and physical exercise may reduce the chance of metabolic syndrome in urban Nigerian type-2 diabetics.     

Fibroblast growth factor-2 acutely influences the impulse activity of rat dorsal horn neurones

The neurotrophic and neuroprotective actions of fibroblast growth factor-2 (FGF-2) are well-established. The signal cascade mediating these effects includes steps that are likely to influence also the electrical properties of neurones. However, the possibility that FGF-2 may acutely affect the processing of neuronal impulse activity is largely unexplored. In the present study the impulse activity of single dorsal horn neurones was recorded in the rat during ionophoretical administration of FGF-2 close to the neurones. Before and during FGF-2 ionophoresis the receptive field of each cell was tested with defined mechanical stimuli. At a concentration of 10 nM in the ionophoresis pipette, FGF-2 reduced the responses of the cells to mechanical stimulation. There was no preferential action of FGF-2 on a particular functional type of dorsal horn neurone; both non-nociceptive and nociceptive cells exhibited a reduced mechanical responsiveness. The background (ongoing) activity was also depressed in most neurones. The results of the study show that in addition to neurotrophic and neuroprotective actions FGF-2 has an acute inhibitory influence on the impulse activity of spinal sensory neurones. This depression of neuronal activity could add to the neuroprotective action of FGF-2 by counteracting glutamate excitotoxicity following a central nervous trauma.     

Fibroblast growth factor-2 drives and maintains progressive corneal neovascularization following HSV-1 infection

Herpes simplex virus type 1 (HSV-1) infection of the cornea induces vascular endothelial growth factor A (VEGF-A)-dependent lymphangiogenesis that continues to develop well beyond the resolution of infection. Inflammatory leukocytes infiltrate the cornea and have been implicated to be essential for corneal neovascularization, an important clinically relevant manifestation of stromal keratitis. Here we report that cornea infiltrating leukocytes including neutrophils and T cells do not have a significant role in corneal neovascularization past virus clearance. Antibody-mediated depletion of these cells did not impact lymphatic or blood vessel genesis. Multiple pro-angiogenic factors including IL-6, angiopoietin-2, hepatocyte growth factor, fibroblast growth factor-2 (FGF-2), VEGF-A, and matrix metalloproteinase-9 were expressed within the cornea following virus clearance. A single bolus of dexamethasone at day 10 post infection (pi) resulted in suppression of blood vessel genesis and regression of lymphatic vessels at day 21 pi compared to control-treated mice. Whereas IL-6 neutralization had a modest impact on hemangiogenesis (days 14–21 pi) and lymphangiogenesis (day 21 pi) in a time-dependent fashion, neutralization of FGF-2 had a more pronounced effect on the suppression of neovascularization (blood and lymphatic vessels) in a time-dependent, leukocyte-independent manner. Furthermore, FGF-2 neutralization suppressed the expression of all pro-angiogenic factors measured and preserved visual acuity.     

Fibroblast growth factor-21 protects against fibrosis in hypertensive heart disease

FGF21 is an endocrine factor that contributes to multiple pathophysiological processes, mainly via its action as a metabolic regulator and cardioprotective agent. Recent studies have shown increased circulating FGF21 levels in hypertensive patients and in mouse models of hypertension. However, the relevance of FGF21 in hypertensive heart disease has not been addressed. Hypertension was induced by treating 4-month old WT and Fgf21^−/− mice with angiotensin II (AngII) for 1 week, resulting in a similar increase in blood pressure in both genotypes. Plasma FGF21 levels and expression in heart and liver were significantly increased in hypertensive WT mice relative to controls, an effect that was associated with increased expression levels of β-klotho specifically in the heart. Fgf21^−/− mice developed a greater degree of hypertensive heart disease than WT mice, notably characterized by extensive cardiac dysfunction and fibrosis. In vitro and in vivo studies further showed that FGF21 exerted a marked protective effect against cardiac fibrosis. Finally, left ventricle biopsies from human hypertensive heart donors, especially those developing cardiomyopathy, showed a significant increase in FGF21expression compared with normotensive controls, a finding that was associated with significantly enhanced cardiac hypertrophy and fibrosis. We conclude that during hypertension, both systemic and cardiac-produced FGF21 are induced and act on the heart, protecting it from hypertensive heart disease. Thus, FGF21 acts as key factor in the fibrogenesis associated with hypertensive heart disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms.

Intact endothelium acts as a sensor and transducer of signals and also provides a nonthrombogenic surface at the blood-vascular wall interface. Hence, mechanisms that maintain the integrity of the endothelium are of interest in physiological and pathological states. In this study we show that apoptosis induced by growth factor and serum deprivation of endothelial cells occurs at all phases of the cell cycle and can be blocked by fibroblast growth factor-2 (FGF-2) independently of its mitogenic activity. As the Bcl-2 family of proteins plays a prominent role in regulating cell survival, we attempted to identify Bcl-2 homologues expressed in endothelial cells. Here we demonstrate that, in addition to the previously identified A1, four other members of the Bcl-2 family, Bcl-2, Mcl-1, Bcl-X(L), and Bax, are expressed in endothelial cells. Of these family members, only Bcl-2 is induced by FGF-2. Overexpression of Bcl-2, using a retroviral vector, protects endothelial cells from serum and growth factor deprivation. There is no difference in FGF-2-induced proliferation between Bcl-2-overexpressing cells and those transduced with the empty retroviral vector. At early time points Bcl-2 is not up-regulated, but FGF-2 still has a protective effect. However, FGF-2 protects only adherent endothelial cells but not those that are cultured in suspension. The early effect of FGF-2 is dependent on tyrosine phosphorylation but not on activation of the MAP kinase pathway. Thus, FGF-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms.     

2型糖尿病患者血清IGF-1、TNF-α与视网膜病变的关系

目的:探讨胰岛素样生长因子-1(IGF-1)与肿瘤坏死因子-α(TNF-α)在2型糖尿病(DM)视网膜病变(DR)发病中的作用。方法:应用酶联免疫吸附方法(ELISA)对127例2型糖尿病患者及36例健康人血清中的IGF-1和TNF-α进行测定。结果:(1)DM组血清IGF-1的含量低于对照组(P<0.01),而TNF-α的含量高于对照组(P<0.01)。(2)BDR组的IGF-1、TNF-α的含量高于NDR组(P<0.05)。(3)PDR组的IGF-1、TNF-α的含量高于NDR组(P<0.01)。(4)DR的严重程度与IGF-1、TNF-α水平呈正相关(P<0.01)。结论;TNF-α的过度表达及IGF-1的降低在DM的发病机制中起重要作用,而糖尿病合并视网膜病变时,血中IGF-1和TNF-α水平升高,IGF-1和TNF-α可能参与了DR的发生和发展。     

多囊卵巢综合征患者的生长分化因子9基因的突变分析

目的通过对多囊卵巢综合征（PCOS）妇女的生长分化因子9（GDF-9）基因的突变分析，探索GDF-9基因与PCOS的发病机制的关系。方法对120例PCOS患者釉80例正常对照的GDF-9基因进行聚合酶链反应（PCR）特异扩增，应用单链构象多态性（SSCP）分析和DNA测序方法检测基因突变。结果PCOS患者的GDF-9的所有外显予均未发现错义突变。结论GDF-9因子的DNA变异可能与PCOS的发病没有相关关系。研究PCOS患者的GDF-9的mRNA与蛋白表达水平与其发病的关系可能是今后的研究方向。     

Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair through the Akt1 pathway

BackgroundFibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair. Fibroblast growth factor-2 acts through betaglycan which is known to bind both transforming growth factor-β and fibroblast growth factor-2 at different locations on the molecule. When fibroblast growth factor-2 binds to betaglycan, transforming growth factor-β binding to betaglycan is reduced, allowing for more transforming growth factor-β to be available to activate pSmad2/3 which then promotes repair. This study investigates another pathway through which fibroblast growth factor-2 regulates valve interstitial cell repair.MethodsWe used an in vitro model of cell culture disruption. Confluent valve interstitial cell monolayers were disrupted, creating an experimental wound in the confluent monolayer, and incubated in treatments of exogenous fibroblast growth factor-2, anti-fibroblast growth factor receptor antibody, active Akt1, and Akt inhibitor. Valve interstitial cell monolayers were immunohistochemically stained and quantified for nuclear pSmad2/3 at the wound edge. The extent of closure was measured up to 96 h after disruption.ResultsAnti-fibroblast growth factor receptor antibody significantly increased both nuclear pSmad2/3 staining at the wound edge and wound closure compared to nontreated control. This increase was less than that seen when valve interstitial cells were treated with fibroblast growth factor-2 and combined treatments of fibroblast growth factor-2 and anti-fibroblast growth factor receptor antibody did not further increase nuclear pSmad2/3 staining compared to fibroblast growth factor-2 alone. This suggested that the regulation of wound closure by fibroblast growth factor-2 also involved pathways other than transforming growth factor-β/Smad signaling. Treatment with Akt1 significantly increased wound closure, while Akt inhibitor reduced closure as compared to nontreated valve interstitial cells. Fibroblast growth factor-2 and fibroblast growth factor-2 neutralizing antibody up-regulated and down-regulated phosphorylated Akt1 expression in valve interstitial cells, respectively.ConclusionFibroblast growth factor-2 promotes valve interstitial cell repair in two ways: the fibroblast growth factor-2/fibroblast growth factor-2 receptor interaction through the activation of Akt1 independent of the transforming growth factor-β/Smad2/3 signaling pathway and the previously described transforming growth factor-β/Smad signaling.     

Improved metabolic control after supplemented fasting in overweight type II diabetic patients

Twenty obese type II diabetes patients were treated in a metabolic ward during 4 weeks with a very low calorie regimen (200 kcal/day). They were given dietary advice and reexamined 3 months after discharge. Mean body weight decreased by 10 kg during fasting, blood glucose was normalized, urinary glucose disappeared and the K-value at i.v. glucose tolerance test increased. Fasting serum insulin concentrations decreased by 54%. Serum triglycerides (TG) decreased by 65%, serum cholesterol (Chol) by 28% and high density lipoprotein (HDL) Chol by 14%. Three months later, only serum TG remained significantly decreased (-47%) while HDL Chol was significantly higher than on admission (+11%). Fasting blood glucose remained significantly lower (-25%) with a low urinary glucose excretion. Supplemented fasting appears to be a safe and useful tool in the treatment of obese type II diabetics. It causes, at least during a limited follow-up period, a significant improvement in glucose control and lipoprotein metabolism in spite of a concomitant reduction of the antidiabetic medication.     

Fibroblast growth factor-2-apatite composite layers on titanium screw to reduce pin tract infection rate

Fibroblast growth factor-2 (FGF-2)-apatite composite layers were formed on anodically oxidized titanium screws to improve bone-screw interface strength and to reduce pin tract infection rate through enhanced skin tissue healing in external fixation. A calcium-containing solution supplemented with FGF-2, a phosphate-containing solution, and a sodium bicarbonate solution were mixed at a Ca/P molar ratio of 2.0 to prepare a calcium phosphate solution supersaturated with respect to calcium phosphates. Screws were individually immersed in 10 mL of the calcium phosphate solution at 37 degrees C for 2 days. Low-crystalline apatite layers incorporating FGF-2 were formed on the screw surface at FGF-2 concentrations in the supersaturated calcium phosphate solution equal to or lower than 10 mug/mL. The amounts of FGF-2 immobilized on the screws ranged from 2.3- to 2.4-mug per screw. The immobilized FGF-2 retained biological activity, as demonstrated by NIH3T3 cell proliferation. Titanium screws with the composite layer were percutaneously implanted into the bilateral proximal tibial metaphyses in rabbits for 4 weeks. The titanium screws with the composite layer formed at the optimum FGF-2 concentration showed a significantly higher bone-screw interface strength and a lower pin tract infection rate than those without the composite layer: the extraction torque and infection rates were respectively 0.230 +/- 0.073 Nm and 43.8% for the screws with the composite layer, and 0.170 +/- 0.056 Nm and 93.8% for those without the composite layer. Therefore, titanium screws with the FGF-2-apatite composite layer are useful for improving bone-screw interface strength and infection resistance in external skeletal fixation.