PDGF-BB在人脑血管母细胞瘤中的表达及意义

目的研究血小板源生长因子B链的纯合二聚体(PDGF-BB)在人脑血管母细胞瘤和正常脑组织中的表达。方法应用链霉菌抗生物素蛋白-过氧化物酶法(S-P法),观察PDGF-BB在32例人脑血管母细胞瘤组织中的表达情况,并与10例正常脑组织作对照。结果 PDGF-BB在人脑血管母细胞瘤组织中的灰度值明显高于正常脑组织(P<0.01)。结论 PDGF-BB在脑血管母细胞瘤血管生成中起着重要作用,抗PDGF-BB治疗可能成为治疗脑血管母细胞瘤的新方法。     

Epidermal growth factor receptor in glioblastoma

We compiled the current state of knowledge about the epidermal growth factor receptor (EGFR) in glioblastoma. Glioblastoma is one of the most common primary brain tumours and has an unfavourable prognosis despite aggressive treatment. These factors stimulate new research trials and a recent area of interest of neuro-oncologists is EGFR. This molecule is frequently altered in glioblastoma and constitutes the potential target for therapy. We decided to review the literature on biological structure of that molecule, its biological activity and the role in GBL with potential targeting it in the future neuro-oncological practice.     

Structural and functional analysis of the promoter region of the nerve growth factor gene

Molecular clones containing the NGF gene promoter regions and exons I were isolated from mouse and rat genomic libraries with synthetic oligonucleotide hybridization probes that corresponded to the 5' end of mouse submandibular gland NGF mRNA. The nucleotide sequences of the 5' flanking regions and exons I were determined and compared. There was 95% similarity in exons I and the adjacent promoter regions between mouse and rat sequences. Further upstream, the similarity decreased to 76%. Both mouse and rat promoter regions were only 33% similar to the presumptive human NGF gene promoter region. Upstream from the capsite of submandibular gland NGF mRNA as determined by an S1-nuclease protection assay, two promoter-like TATA-boxes were found at positions -28 and -49, resp., and two CAAT-like boxes at -379 and -546, resp. Both promoter regions contained a cluster of conserved CpG dinucleotide sequences in a GC-rich island whereas less conserved upstream regions contained only one CpG sequence. The promoter regions were fused to the human growth hormone gene reporter function. Transient expression in L929 cells yielded appropriate fusion mRNAs and secretion of hGH, demonstrating that the cloned promoters are functional.     

Effects of fibroblast growth factors and platelet-derived growth factor on food intake in rats

In the present study, the relations between acidic and basic fibroblast growth factors (aFGF and bFGF, respectively), platelet-derived growth factor (PDGF), and food intake were studied. When aFGF-, bFGF-, and PDGF-like activity in cerebrospinal fluid (CSF) was examined by bioassay, the activity of those factors significantly increased in postfeeding CSF, compared to prefeeding CSF. Injections of aFGF, bFGF, aFGF (synthetic amino-terminal peptide of aFGF), and PDGF into the third cerebral ventricle decreased food intake, and injections of anti-aFGF, anti-bFGF, and anti-aFGF antibodies into the lateral hypothalamus (LHA) increased food intake. The activity of LHA glucose-sensitive neurons was inhibited by electrophoretic application of aFGF. These results suggest that aFGF, bFGF and PDGF have in vivo physiological roles in the central nervous system, distinct from those as mitogens.     

bFGF和PDGF-B蛋白在脑缺血再灌注大鼠模型中的表达和血管形成的研究

目的 探讨脑缺血再灌注大鼠不同时间碱性成纤维细胞生长因子(bFGF)和血小板源性生长因子-B(PDGF-B)的表达水平及其与血管形成的关系。方法 采用线栓法制备大鼠大脑中动脉局灶性脑缺血再灌注(MCAO/R)模型,分为假手术组和MCAO/R组,MCAO/R组缺血2 h后根据再灌注时间窗的不同分为0、6、24 h、3、7、14、21 d共7组,应用HE染色观察病理变化并测定脑梗死体积,用免疫组化法检测CD34蛋白的表达水平并计数微血管密度(MVD),用免疫组化法检测bFGF和PDGF-B蛋白的表达水平。结果 bFGF蛋白表达水平在MCAO/R 6 h后即开始升高,3 d到达高峰,7 d开始降低。PDGF-B蛋白表达水平在MCAO/R 24 h后明显升高,3 d到达高峰,7 d有所下降,持续到14 d左右。MVD表达在MCAO/R 3 d开始升高,7 d到达高峰。bFGF和PDGF-B蛋白表达水平与MVD变化呈正相关(P<0.01)。结论 局灶性脑缺血再灌注损伤可诱导bFGF、PDGF-B和新生血管表达增加,激活内源性脑保护机制。     

Serum nerve growth factor concentration and its role in the preclinical stage of dementia

OBJECTIVE: Nerve growth factor is important for the development and function of the cholinergic basal forebrain. The authors examined the hypothesis that the concentration of nerve growth factor is lower than normal in the preclinical phase of neurodegenerative dementia, especially Alzheimer's disease. METHOD: The serum nerve growth factor concentration of subjects from the Berlin Aging Study and the Berlin Memory Clinic who later developed Alzheimer's disease were compared with those of subjects who were free of dementia and subjects who were already suffering from Alzheimer's disease. RESULTS: There were 17 subjects in each group, matched for age and sex. The three groups differed in log-10-transformed mean nerve growth factor concentrations: 1.62 (SD=0.59) for the healthy comparison subjects, 0.92 (SD=0.30) for the subjects with preclinical dementia, and 1.44 (SD=0.61) for the subjects with Alzheimer's disease. CONCLUSIONS: These results support the hypothesis of disturbed nerve growth factor regulation in the serum of patients with preclinical Alzheimer's disease. Mechanisms by which these disturbances appear are unclear, but they may reflect the situation in the preclinical Alzheimer's disease brain.     

Developmental distribution of platelet-derived growth factor in the mouse central nervous system.

Immunoblotting and immunohistochemical techniques have been used to characterize the developmental changes in the distribution and relative quantity of platelet-derived growth factor (PDGF), an important mitogen and growth regulator for glial (and possibly neuronal) cells. PDGF exists as a dimer of two chains, A and B, and antibodies which are relatively specific for one chain or the other can be used to localize PDGF isoforms during development. We have also studied the distribution of PDGF receptor beta subunit (PDGF-R beta)-like immunoreactivity using an antibody probe. All 3 isoforms of PDGF are found in neural structures during development, beginning at about the midpoint of embryogenesis. Immunoblotting studies confirm the presence of PDGF isoforms in brain during embryonic and postnatal development, with the distribution and relative abundance of each isoform appearing to be independently regulated. Similarly, immunoblotting studies have verified the relative abundance and specificity of PDGF receptor beta subunit. The immunohistochemical findings confirm and extend these biochemical observations. Each PDGF chain (A and B) has a discrete localization during nervous system development, and the immunohistochemical distribution of PDGF-R beta is distinct from each of the PDGF isoforms. PDGF A-chain (localized with an antibody to PDGF(AA) dimers) appears to be found in growth cones of developing neurons in mid-embryonic brain development. By 11.5 days post-conception (embryonic day 11.5, E11.5) to E12, PDGF isoforms are found in apparent neurons in the basal plate (future ventral horn) of spinal cord. PDGF-R beta-like immunoreactivity is localized to the boundary cap region of the developing spinal cord at the same age. Similarly, at E13.5, all 3 PDGF isoforms are found, to varying extents, within cells of the dorsal root ganglia and trigeminal ganglia. At the same developmental stage, PDGF receptor protein is most prevalent in the nerves accompanying these structures. By E15, both PDGF isoform and PDGF receptor beta subunit immunoreactivity have declined to near-background levels in the sensory ganglia, while in the spinal cord and developing forebrain, levels of all PDGF-related proteins remain high.     

血小板衍化生长因子在细胞增殖和组织修复中的作用及机制*★

背景：细胞增殖和组织修复是一个复杂的过程，这期间有大量生长因子参与，并且这些因子在发挥本身功效时，同时还相互影响和制约，从而更好地促进细胞增殖和组织修复。 目的：总结血小板衍化生长因子在细胞增殖和组织修复愈合过程中发挥的作用及其机制。 方法：检索PubMed数据库、EMbase数据库1960-01/2010-10期间相关文章，检索词为“platelet-derived growth factor，cell proliferation，tissue repair”。同时检索中国生物医学文献数据库、中文科技期刊全文数据库、中文学术期刊全文数据库2000-01/2010-10期间相关文章，检索词为“血小板衍化生长因子”。 结果与结论：血小板衍化生长因子是一种重要的促细胞分裂剂，可刺激各种类型细胞的分裂增殖。血小板衍化生长因子及其受体存在于机体的多种组织细胞，当机体受到一定的刺激时，血小板衍化生长因子与其受体结合，发挥作用，因此许多研究发现，在外科手术后和损伤修复过程中常伴随有局部血小板衍化生长因子基因表达量的升高和受体的上调，被称为损伤修复因子。但是它的具体作用机制尚不太明确，对细胞组织的增殖修复的认识还处于起始、发展阶段，还有许多的问题需要去探索研究。     

Developmental effects of basic fibroblast growth factor and platelet-derived growth factor on glial cells in a three-dimensional cell culture system

In order to study peptide growth factor action in a three-dimensional cellular environment, aggregating cell cultures prepared from 15-day fetal rat telecephalon were grown in a chemically defined medium and treated during an early developmental stage with either bovine fibroblast growth factor (bFGF) or platelet-derived growth factor (PDGF homodimers AA and BB). A single dose (5–50 ng/ml) of either growth factor given to the cultures on day 3 greatly enhanced the developmental increase of the two glia-specific enzyme activities, 2′,3′-cyclic nucleotide 3′-phosphohydrolase (CNP) and glutamine synthetase (GS), whereas it had relatively little effect on total protein and DNA content. Distinct patterns of dose-dependency were found for CNP and GS stimulation. At low concentrations of bFGF (0.5–5 ng/ml) and at all PDGF concentrations applied, the oligodendroglial marker enzyme CNP was the most affected. A relatively small but significant mitogenic effect was observed after treatment with PDGF, particularly at higher concentrations or after repetitive stimulation. The PDGF homodimers AA and BB were similar in their biological effects and potency. The present results show that under histotypic conditions both growth factors, bFGF and PDGF, promote the maturation rather than the proliferation of immature oligodendrocytes and astrocytes.     

The role of corticotropin-releasing factor in the pathogenesis of major depression

It is well established that corticotropin-releasing factor (CRF), a peptide comprised of 41 amino acids, is the major physiological regulator of the pituitary-adrenal axis by virtue of its role as the hypothalamic hypophysiotropic hormone that modulates the secretion of adrenocorticotropin (ACTH) from the anterior pituitary gland. In addition to its neuroendocrine role, CRF appears to function as a neurotransmitter or neuromodulator in extrahypothalamic brain areas. The peptide and its receptors are distributed throughout the central nervous system (CNS), and CRF is released by depolarizing concentrations of potassium in a calcium-dependent manner. After direct CNS administration, CRF produces a number of behavioral and physiological effects that are reminiscent of both an organism's response to stress and to the symptoms of patients with major depression. These include: diminished food consumption, decreased sexual behavior, disturbed sleep, alterations in locomotor activity and sympathetic nervous system activation. Alterations in regional brain CRF concentration in rats were observed after acute and chronic stress, i.e. decreased hypothalamic and increased locus coeruleus CRF concentrations. To test the hypothesis that CRF is hypersecreted in patients with major depression, the concentration of CRF in cerebrospinal fluid (CSF) in drug-free depressed patients and age- and sex-matched controles was measured in two studies. The depressed patients exhibited a clear group-related increase in CSF CRF concentrations. To further test this hypothesis that CRF is chronically hypersecreted in depressed patients, the number and affinity of CRF receptors in frontal cortex was measured in a group of suicides and age-matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidermal growth factor receptor extracellular domain mutations in primary glioblastoma

Aims: Novel missense mutations of the epidermal growth factor receptor (EGFR) extracellular domain have been recently described in a large series of glioblastomas. Methods: The exons 2, 3, 7, 8 and 15 coding for the EGFR extracellular domain were sequenced in a series of 161 consecutive primary glioblastomas and correlated with clinical features of patients in order to determine whether these alterations are linked to specific clinical characteristics of the disease. Results: Missense mutations were observed in 18 cases (11.2%), and 4 novel mutations were detected, including G178C, A271C, C818A and C1860G. Mutations of the EGFR extracellular domain were not associated with overall survival or with age at onset of the disease. In contrast, the EGFR extracellular domain mutations were significantly associated with patients' gender. Indeed, 15 mutations were observed in men vs. 3 in women ( P  < 0.05). EGFR extracellular domain mutations were also strongly associated with EGFR amplification ( P  < 0.0001). Conclusions: To our knowledge, EGFR extracellular domain mutations are the first genomic abnormalities associated with gender in primary glioblastomas, although a link between mutations of the EGFR tyrosine kinase domain and gender has been previously made in lung cancer.     

单侧输尿管梗阻模型大鼠肾间质纤维化过程中血小板衍生生长因子D的表达

背景：血小板衍生生长因子在肾间质中通过诱导肾小管间质细胞增生、表型转化、炎性细胞浸润等导致肾小管间质纤维化。 目的：观察血小板衍生生长因子D在单侧输尿管梗阻模型大鼠肾脏组织中的表达水平及随时间的演变情况。 方法：将成年健康雄性SD大鼠60只随机分为模型组及假手术组,将模型组大鼠左侧输尿管结扎剪断建立单侧输尿管梗阻模型,假手术组大鼠不结扎剪断仅游离左侧输尿管。术后3,7,14,21,28 d,通过免疫组化检测血小板衍生生长因子D在肾脏组织中的表达分布情况,实时荧光定量RT-PCR方法检测血小板衍生生长因子D mRNA的表达水平及变化。 结果与结论：假手术组血小板衍生生长因子D仅少量表达于肾小球系膜细胞及血管平滑肌细胞,而在模型组,血小板衍生生长因子D同时表达于肾间质纤维化区域,随纤维化程度加重,表达增多。同时模型组血小板衍生生长因子D mRNA表达量较假手术组显著增多(P < 0.05),且表达随时间延长逐渐增多。提示血小板衍生生长因子D在单侧输尿管梗阻模型肾间质纤维化过程中发挥着促纤维化的重要意义。     

Expression of platelet-derived growth factor ligand and receptor in cerebral arteriovenous and cavernous malformations

The aim of this study was to investigate the expression of platelet-derived growth factor (PDGF) ligands A and B and receptors α and β in cerebral arteriovenous and cavernous malformations. Fifteen arteriovenous malformation (AVM) and 15 cerebral cavernous malformation (CCM) tissue samples were immunostained for PDGF ligands A and B, PDGF receptors (PDGFR) α and β, and vascular endothelial growth factor. Tissues were compared in terms of expression levels within various vascular layers, and the results were confirmed using western blotting. AVM had higher levels of PDGF-A expression than CCM (p = 0.004, 0.009, 0.001, and 0.027, for endothelium, media, adventitia, and perilesional tissue, respectively) and western blotting showed that there was higher expression of PDGFR-α in AVM tissues. In contrast, CCM endothelium, media, and adventitia had higher PDGF-B expression compared with AVM (p = 0.007, 0.001, and 0.039, respectively). PDGFR-β expression was also significantly higher in the endothelium of CCM tissue (p = 0.007). Overexpression of PDGF ligands and receptors in AVM and CCM may mean that therapeutic strategies targeting the PDGF pathway could be useful in the treatment of these two malformations.     

血清血小板源性生长因子在脑出血患者中的临床意义

目的探讨血清血小板源性生长因子在脑出血患者中的临床意义。方法选取在我院收治的脑出血患者88例为治疗组,另选取同期健康体检的40例健康者为对照组,对比分析2组血清PDGF及与NIHSS评分的相关性。结果治疗组脑出血后第2天、第8天血清PDGF含量、血小板PDGF的表达水平均明显高于对照组,差异有统计学意义(t=20.156、12.896、13.024、13.138,P0.05);治疗组脑出血后第8天血清PDGF含量、血小板PDGF的表达水平均明显低于第2天,第12天明显低于第2天及第8天,差异均有统计学意义(P0.05);血清PDGF含量与NIHSS评分呈正相关(r=0.780,P0.001)。结论脑出血患者血清PDGF含量及血小板PDGF表达水平明显增高,可作为脑出血的早期诊断指标,且由血清PDGF水平的高低可判断患者神经功能受损程度。     

Basic fibroblast growth factor and platelet-derived growth factor prevent the death of spinal. motor neurons after sciatic nerve transection in the neonatal rats

In vivo, motor neurons are destined to die after axotomy. Several neuronal growth factors, such as ciliary neurotrophic factor, brain-derived neurotrophic factor, and leukemia inhfbitory factor rescue neuronal death ofaxotomized motor neurons. Here, we report that systemically administered basic fibroblast growth factor and platelet-derived growth factor prevented spinal motor neuron death in neonatal rats following sciatic nerve resection. These data indicate that basic fibroblast growth .factor and platelet derived growth factor playa role for motor neuron survival in vivo. [Neural Res 1997; 19: 555-557]