Somatotropes Maintain Their Immature Cells Through Insulin-like Growth Factor I (IGF-I)

A pituitary tumor is considered to be composed of a heterogeneous population of hormone-producing endocrine cells, folliculo-stellate (FS) cells, and potential hormone-inactive progenitor cells to maintain a microenvironment such as that in angiogenesis for tumor development cooperatively. However, the system that maintains such a heterogeneous cell population has not been clarified yet. In the present study, we examined the mechanism for maintaining a heterogeneous cell population using two rat cell lines, MtT/S and MtT/E cells, which are known growth hormone (GH)-producing cells, and their progenitor cells, respectively. We found that conditioned medium of MtT/S cells could stimulate the growth of MtT/E cells. In addition, GH and insulin-like growth factor I (IGF-I) stimulated the growth of MtT/E cells. The messenger RNAs (mRNAs) of receptors for IGF-I and GH were expressed in the MtT/E cells. Moreover, IGF-I receptor inhibitor AG1024 could abolish the growth stimulatory activity in the conditioned medium of MtT/S cells. Therefore, we concluded that somatotropes (MtT/S) maintain their progenitor cells (MtT/E) through the GH–IGF-I signaling and IGF-I directly, which might be involved in the maintenance of progenitors of GH-producing cells and might contribute to pituitary tumor development.     

胰岛素样生长因子Ⅱ在肝细胞癌的免疫组化研究

以兔抗胰岛素样生长因子Ⅱ(IGF-2)的抗体,ABC法,对50例肝癌石蜡切片染色,结果:(1)正常肝有极微弱阳性,表明可分泌少量IGF-2;(2)癌旁肝27例,全部阳性,“++”者19例(70%),表明有大量IGF-2产生和存在;(3)50例肝癌,48例(96%)阳性,IGF-2呈胞浆弥散型分布,其中26例(52%)呈较强阳性(++),8例核内也有IGF-2,表明癌细胞能自己合成IGF-2为其恶性增殖创造条件,且不因分化程度之降低而有所减少;(4)IGF-2呈较强阳性(++)之细胞(包括小多角形肝细胞)既见于癌周肝,又见于慢性肝炎,表明胰岛素样生长因子Ⅱ直接和增殖而非与癌变相关。     

Histopathological Study of Evening Primrose Oil Effects on Experimental Diabetic Neuropathy

Diabetic polyneuropathy is a serious complication of diabetes mellitus and the most frequent neuropathy worldwide. Aim: This study was designed to investigate the possible beneficial effects of evening primrose oil (EPO) on histopathological changes of sciatic nerves in streptozotocin-induced diabetic rats. Materials and methods: The rats were randomly allotted into three experimental groups: A (control), B (diabetic untreated), and C (diabetic treated with EPO); each group contained 10 animals. Groups B and C received streptozotocin (STZ) to induce diabetes. The rats in group C were given EPO for 2 weeks after 6 weeks of STZ injection. Blood and tissue samples were obtained for biochemical and histopathological investigation. Results: STZ-treated diabetic rats showed reduction of the size of islets of Langerhans, fatty degeneration in the pancreatic acini with dilation, irregularity, and increased thickness of blood vessels. Electron micrography of sciatic nerves of diabetic rats showed multiple vaculations and partial separation of myelinated nerve fibers with axonal atrophy, endoneural edema, and increased collagen fibers. Compared with diabetic rats, EPO induced partial recovery from diabetes-induced pancreatic and nerve damage. Conclusions: Histologic evaluation of the tissues in diabetic animals treated with EPO showed fewer morphologic alterations with significant decrease of myelin breakdown. Furthermore, the ultrastructural features of axons showed partial improvement. It is believed that further preclinical research into the utility of EPO may indicate its usefulness as a potential treatment on peripheral neuropathy in STZ-induced diabetic rats.     

Mini ReviewSignalling by the Type 1 Insulin-like Growth Factor Receptor: Interplay with the Epidermal Growth Factor Receptor

The type 1 insulin-like growth factor receptor (IGF-1R) plays an essential role in mammalian growth and development, and has emerged as a candidate therapeutic target in the treatment of cancer. While the pleiotropic cellular responses elicited following tyrosine phosphorylation of the IGF-1R is usually seen to involve the direct recruitment/activation of classical intracellular effector proteins, it is now clear that cross-talk between the IGF-1R and members of distinct receptor families also plays a significant role in effecting intracellular signalling. In recent years, a number of studies have highlighted the interaction(s) between the IGF-1R and the epidermal growth factor receptor (EGFR), another transmembrane tyrosine kinase that is an established cancer target. This review describes the components of the IGF signalling system and gives an overview of the emerging picture of the interrelationship that is now known to exist between the IGF and EGF receptors.     

IGF-IA~（99）Tc~m标记及其在正常裸鼠体内放射性分布

目的：建立99Tcm标记胰岛素样生长因子I类似物（IGF-IA）的方法,观察其在正常裸鼠体内的生物学分布。方法：SnCl2.2H2O浓度0.75g～4g/L,IGF-IA的用量（20～100）μg,Tween80的用量从（0～10）μl,淋洗液的体积从（20～200）μl,在0.25h～6h不同时间点测定标记率及其在体外的稳定性。将标记物经正常裸鼠尾静脉注射,于5min、30min、1h、2h、4h取血液及主要脏器测量其放射性计数率值。结果：99Tcm标记IGF-IA的最佳标记方法为：浓盐酸溶解SnCl2.2H2O后用葡萄糖酸钠溶液配成3g/L,吸取100μl后加入40μlIGF-IA（2g/L）;300μlNa3PO4和2μl0.1%Tween80混匀后加入50μl99TcmO4-新鲜淋洗液;在IGF-IA体系中加入淋洗液体系,混匀,室温下反应0.5h;加入500μlNaH2PO4将pH值调节到7左右,99Tcm-IGF-IA最高标记率为（94.43±0.75）%,室温下放置6h标记率为（85.57±2.81）%。99Tcm-IGF-IA在正常裸鼠体内主要分布于肾脏和肝脏。结论：预锡化法进行99Tcm标记IGF-IA方法简捷且具有较高标记率和良好稳定性。99Tcm-IGF-IA在正常裸鼠体内主要被肾脏和肝脏摄取,血液清除快。     

糖尿病神经病变与微循环的关系

为研究糖尿病神经病变与微循环的关系，对１１７例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）并发糖尿病周围神经病变（ＤＰＮ）患者甲襞微循环进行了观察，并与无ＤＰＮ组（３６例）进行比较。结果显示，ＤＰＮ患者有明显的微循环障碍，ＤＰＮ组微血管形态、流态和袢周状态均有显著异常。与无ＤＰＮ组比较，ＤＰＮ患者血液流速明显减慢（Ｐ＜０．０５），并有明显的血细胞聚集（Ｐ＜０．０５）、袢周渗出（Ｐ＜０．０１）与出血（Ｐ＜０．０５）。Ｌｏｇｉｓｔｉｃ逐步回归分析显示，微循环障碍是糖尿病神经病变发病的独立危险因素（ＯＲ：１．５７；９５％ＣＩ：１．１８２．０９）。     

糖尿病性神经病变的机理

糖尿病性神经病变是糖尿病的常见慢性并发症之一,可引起神经系统结构和功能的改变。糖尿病性神经病变的机理复杂而又不甚明了。近年来发现糖尿病性神经病变与血管、代谢、神经营养因子、自身免疫、炎症反应、氧自由基、损伤和遗传等因素相关。本文就近年来糖尿病性神经病变机理的研究及进展作一综述。     

C-肽对1型糖尿病神经病变的影响

一系列关于C-肽的体外实验、1型糖尿病动物模型、亚临床试验证实C-肽具有维持、改善外周神经和自主神经功能的作用。C-肽的作用机制与调节神经细胞微循环、激活Na+-K+-ATP酶、刺激神经营养因子的表达相关。综合目前的研究结果,可以认为C-肽是一种具有重要生理功能的生物活性肽,具有一定的临床药用价值。     

Insulin-Like Growth Factor I Promotes Nerve Regeneration: An Experimental Study on Rat Sciatic Nerve

Abstract

Growth without growth hormone (GH) is often observed in the setup of obesity; however, the missing link between adipocytes and linear growth was until now not identified. 3T3L1 cells were induced to differentiate into adipocytes and their conditioned medium (CM) (adipocytes CM, CMA) was added to metatarsals bone culture and compared to CM derived from undifferentiated cells. CMA significantly increased metatarsals bone elongation. Adipogenic differentiation increased the expression of growth and differentiation factor (GDF)-5, also found to be secreted into the CMA. GDF-5 significantly increased metatarsal length in culture; treatment of the CMA with anti-GDF-5 antibody significantly reduced the stimulatory effect on bone length. The presence of GDF-5 receptor (bone morphogenetic protein receptor; BMPR1) in metatarsal bone was confirmed by immunohistochemistry. Animal studies in rodents subjected to food restriction followed by re-feeding showed an increase in GDF-5 serum levels concomitant with nutritional induced catch up growth. These results show that adipocytes may stimulate bone growth and suggest an additional explanation to the growth without GH phenomenon.     

Insulin-like Growth Factor Binding Protein 2: Gene Expression Microarrays and the Hypothesis-generation Paradigm

A major goal of modern medicine is to identify key genes and their products that are altered in the diseased state and to elucidate the molecular mechanisms underlying disease development, progression, and resistance to therapy. This is a daunting task given the exceptionally high complexity of the human genome. The paradigm for research has historically been hypothesis-driven despite the fact that the hypotheses under scrutiny often rest on tenuous subjective grounds or are derived from and dependent on chance observation. The imminent deciphering of the complete human genome, coupled with recent advances in high-throughput bioanalytical technology, has made possible a new paradigm in which data-based hypothesis-generation is the initial step in the investigative process, followed by hypothesis-testing. Genomics technologies are the primary source of the new hypothesis-generating capabilities that are now empowering biomedical researchers. The synergistic interaction between contemporary genomics technologies and the hypothesis-generation paradigm is well-illustrated by the discovery and subsequent ongoing study of the role of insulin-like growth factor binding protein 2 (IGFBP2) in human glioma biology. Using gene expression microarray technology, the IGFBP2 gene was recently found to be highly and differentially overexpressed in the most advanced grade of human glioma, glioblastoma. Based on this discovery, subsequent functional studies were initiated that suggest that IGFBP2 overexpression may contribute to the invasive nature of glioblastoma, and that IGFBP2 may exert its function via a newly identified novel binding protein. The IGFBP2 story is but one example of the power and potential of the new molecular methodologies that are transforming modern diagnostic and investigative neuropathology.     

糖尿病周围神经病变的诊疗

糖尿病周围神经病变（DPN）是糖尿病最为常见、最严重的并发症之一,由于发病机制复杂,高血糖状态、氧化应激反应、脂代谢异常、微血管病变、自身免疫因素、神经营养障碍等均参与到了DPN的发生与发展中。目前,DPN诊断与治疗均缺乏统一的标准,本文对近年来DPN的诊断与治疗进行综述。     

窒息新生儿脐血胰岛素样生长因子1和免疫球蛋白水平变化

目的:观察窒息新生儿脐血中胰岛素样生长因子1(IGF-1)及其结合蛋白-3(IGFBP-3)和免疫球蛋白IgG、IgM、IgA以及补体C3、C4水平的变化。方法:选择临产急性胎儿窘迫孕妇,娩出新生儿正常者30例为窘迫组,娩出新生儿窒息者30例为窒息组,同期剖宫产正常新生儿30例为对照组。采集各组新生儿脐动脉血,用ELISA检测血清IGF-1和IGFBP-3水平;用免疫比浊法检测免疫球蛋白IgG、IgM和IgA及补体C3、C4含量。结果:窘迫组和窒息组新生儿脐血IGF-1、IGFBP-3、IgG、IgA水平均显著对照组(P0.05);窒息组新生儿脐血IGF-1、IGFBP-3、IgG、IgM、IgA、C3水平更低于窘迫组(P0.05)。结论:窒息新生儿IGF-1、IGFBP-3减少,体液免疫功能低下。     

糖尿病周围神经病变临床诊断的研究进展

糖尿病周围神经病变（DPN）是糖尿病最常见的慢性并发症之一,患者可出现肢体的麻木、疼痛及感觉异常,其中以远端对称性多发性周围神经病变（DSPN）最为多见。目前DPN的筛查方式多样,其中五项筛查、单丝和音叉检查是临床常用的初筛方式,各类量表可为DPN作等级评估,神经传导速度（NCV）是目前公认的诊断金标准。此外,高频超声、角膜共聚焦显微镜、磁共振神经成像等新兴检查方法优势逐步显露。由于DPN是炎症、氧化应激、免疫损伤等多种因素共同作用的结果,因此医师们也在积极探索相关血清学指标,以求为DPN的早期诊断提供更多临床依据。     

糖尿病痛性神经病变危险因素的研究

糖尿病痛性神经病变（PDN）是一种临床常见以疼痛为主要特征的周围神经病变,患者可出现剧烈的肢体疼痛、伴睡眠障碍及抑郁,同时易发生足部溃疡,甚至导致截肢,严重影响患者的生活质量。目前PDN发病机制尚未明确,探究PDN的危险因素对于疾病早期预防具有重要意义。本文通过对PDN的危险因素研究现状进行综述,旨在为临床防治PDN及探索发病机制提供依据。     

肝病患者血清胰岛素样生长因子I含量及与肝功能的关系

目的研究肝病患者血清中胰岛素样生长因子I(IGF-I)的变化及其与肝功能的关系. 方法各型肝炎患者113例,对照组30例,用放射免疫法检测血清IGF-I含量,同时检测有关肝功能指标. 结果急性肝炎、慢性肝炎轻度、慢性肝炎中度患者血清IGF-I含量分别为637.6±178.3 ng/ml、458.6±276.4 ng/ml、601.7±276.8ng/ml,明显高于对照组316.1±109.1 ng/ml (p<0.001).慢性肝炎重度、肝硬化患者血清IGF-I含量为224.5±168.2 ng/ml 和120.5±94.4 ng/ml明显低于对照组(p<0.05).IGF-I含量与部分肝功能指标相关(p<0.05). 结论检测IGF-I对估计慢性肝病预后有一定的价值.     

Recombinant Hepatocyte Growth Factor Accelerates Cutaneous Wound Healing in a Diabetic Mouse Model

We examined effects of recombinant hepatocyte growth factor (HGF) on cutaneous wound healing, using a full-thickness cutaneous excision model in diabetic mice. Topical administration of HGF, as well as basic fibroblast growth factor (bFGF), promoted the rate of wound closure and re-epithelialization. Both HGF and bFGF enhanced expansion of the granulation tissue and stimulated neovascularization on day 7 postwounding, wherein the increase in microvessel density in HGF-treated wounds was higher than that in bFGF-treated wounds. Matrix metalloproteinases (MMP-2 and MMP-9) activities involved in cell migration, angiogenesis, and extracellular matrix (ECM) remodeling, were enhanced by HGF-treatment on day 7. On day 28 postwounding (later stages of wound healing), granulation tissue in bFGF-treated wounds remained to a greater extent than that seen in saline- and HGF-treated wounds. Likewise, bFGF- but not HGF-treatment stimulated DNA synthesis of fibroblasts in granulation tissue, suggesting that HGF stimulates wound healing with lesser degree of susceptibility to cutaneous scarring. We propose that supplement of HGF may be a potential therapeutic approach for treatment of cutaneous ulcer.     

糖尿病肾病患者血清血管内皮生长因子和色素上皮衍生因子水平变化

目的:探讨2型糖尿病肾病(DN)患者血清血管内皮生长因子(VEGF)和色素上皮衍生因子(PEDF)水平变化及其在DN发生发展中的意义。方法:将175例研究对象分为正常对照组(NC组,n=35)、单纯糖尿病组(T2DM组,n=35)、DNⅢ期组(Ⅲ组,n=40)、DNⅣ期组(Ⅳ组,n=35)、DNⅤ期组(Ⅴ组,n=30)。采用酶联免疫法检测各组血清VEGF及PEDF水平并分析二者相关性,同时测定全血糖化血红蛋白(HbA1c)、血浆纤维蛋白原(Fib)、血肌酐(Cr)及24h尿微量白蛋白排泄率(UAER),并行UAER危险因素的多元回归分析。结果:五组血清PEDF、VEGF水平差异有统计学意义(P0.01),各病例组水平均高于NC组,且Ⅴ组Ⅳ组Ⅲ组,差异均有统计学意义(P0.01),T2DM组与Ⅲ组比较差异无统计学意义(P0.05)。研究对象血清VEGF与PEDF水平呈直线相关(r=0.847,P0.01)。血清VEGF、HbA1c是UAER的独立危险因素(R2=0.430)。结论:VEGF和PEDF可能参与了DN的发生发展。     

PPAR-γ激动剂对2型糖尿病大鼠肾脏血管内皮生长因子表达的影响

目的探讨PPAR-γ激动剂罗格列酮对糖尿病大鼠肾脏VEGF表达的影响。方法采用长期高脂饮食加小剂量链脲菌素（STZ）一次性腹腔注射，建立2型糖尿病大鼠模型，光镜及电镜行肾脏形态学检查；RT—PCR测定VEGF mRNA表达，VEGF免疫组化染色观察VEGF蛋白水平变化。结果2型糖尿病大鼠肾脏VEGFmRNA及其蛋白质表达明显高于正常对照组（均P〈0．01），同时大鼠肾脏出现糖尿病肾病的病理变化；PPAR-γ激动剂罗格列酮干预后，肾组织VEGF mRNA及其蛋白质表达较2型糖尿病组降低（均P〈0．01）,同时肾脏病理变化也得到明显改善。结论PPAR-γ激动剂罗格列酮可能通过抑制肾脏VEGF表达，延缓糖尿病肾病的发生。