Apelin——肿瘤血管异生的有效激活剂

Apelin是1998年发现的孤儿G蛋白偶联受体APJ(又称为血管紧张素Ⅱ受体样受体1)的内源性配体,其前体由77个氨基酸残基组成,剪切后生成具有生物活性的apelin。Apelin具有调节血压、心脏收缩力、免疫反应、饮水和摄食的作用。Sorli SC等先前已经证明apelin能够促进内皮细胞有丝分裂     

Apelin/APJ：血管功能调节因子和药物治疗新靶点

Apelin(APJendogenousligand)是血管紧张素Ⅱ1型受体相关蛋白(angiotensin receptor-like 1,APJ)的内源性配体.Apelin/APJ系统在机体内广泛分布,在众多血管系统表达水平较高,如心血管系统、肺血管系统等.研究发现,apelin可调节血管张力,促进血管平滑肌细胞增殖、视网膜血管新生以及单核细胞向内皮细胞黏附,促进肝门静脉和冠状动脉侧枝形成等.本文就apelin调节血管功能及其相关疾病(高血压、肺动脉高压、动脉粥样硬化、胶质瘤、肺癌、门静脉高压、糖尿病血管并发症等)进行综述,揭示了apelin与血管及其相关疾病的内在联系,表明apelin/APJ可作为血管疾病的治疗靶点.     

肥胖时过表达的新的脂肪因子apelin：是友是敌？

Apelin是孤儿G蛋白偶联受体一血管紧张素受体AT1相关的受体蛋白（putative receptor protein related to the angiotensin receptor AT1,AH）的天然配体。Apelin及其受体APJ在体内分布广泛。Boucher等报道在分离出的人及小鼠成熟脂肪细胞有apelin的合成和分泌,并认为apelin是一种新的脂肪因子。     

Apelin/APJ系统-能量代谢调控的重要靶点

脂肪组织不仅储存能量,更可通过分泌多种脂肪因子调节胰岛素的敏感性和能量代谢平衡。Apelin是由脂肪组织产生和分泌的一类新型脂肪因子,其受体为血管紧张素1型受体(APJ),为G蛋白偶联受体家族的成员之一。迄今为止,apelin是APJ的唯一天然内源性配体。研究证明,apelin与心血管功能、内分泌调节、食物摄入、细胞增殖、免疫调节、体液平衡和血管生成密切相关。且apelin可以通过内分泌、旁分泌、自分泌等方式作用于不同组织,从而参与肥胖及相关疾病的发生与发展。本文对近年来apelin在各类组织中的能量代谢调节作用及信号通路等方面的研究进行了归纳,并对apelin/APJ系统在治疗代谢紊乱疾病等的前景进行了展望。     

全反式维甲酸在平滑肌细胞中上调apelin基因表达的分子机制

本文旨在研究全反式维甲酸(all-trans retinoic acid,ATRA)在血管平滑肌细胞(vascular smooth muscle cell,VSMC)中对apelin基因表达的影响及分子机制。我们用RT-PCR、实时定量PCR和免疫印迹分析检测ATRA对VSMC中apelin基因表达的影响,然后在VSMC中用小干扰RNA转染下调内源性维甲酸受体α(retinoic acid receptorα,RARα)或用腺病毒载体过表达RARα后,检测ATRA对apelin基因表达的影响。结果显示ATRA能以时间和浓度依赖的方式诱导apelin基因的表达,同时RARα表达水平也显著升高,但RARβ和RARγ表达水平无显著变化。利用小干扰RNA下调内源性RARα或用RARα选择性抑制剂Ro 41-5253抑制RARα活性后,再用ATRA刺激VSMC,ATRA对apelin基因表达的诱导作用受到显著抑制,而过表达RARα,则可促进apelin的表达升高。以上结果表明,ATRA可以上调VSMC中apelin基因表达水平,其分子机制是通过其核受体RARα介导完成的。     

血管紧张素受体AT1相关受体蛋白新的配体——Elabela的生物学效应及与心血管疾病的关系

Elabela是一种新型血管紧张素受体1相关受体蛋白的配体,与另一个配体apelin一样,参与胚胎心脏和血管发育以及很多心血管疾病的病生理过程,包括先兆子痫、高血压、肺动脉高压、冠心病和心力衰竭等。Elabela可能通过调节液体稳态、舒张血管、增加心肌收缩力等机制发挥心血管保护作用,是一个潜在的新的心血管疾病治疗靶点。     

阿片肽对胰岛素释放的影响

阿片肽作为一类重要的神经活性物质发挥着许多生物学效应,近来已有研究证明类阿片物质有影响胰岛素释放的作用.胰岛素是由胰岛β细胞分泌的一种重要激素,它可以调节机体的血糖稳定.因此这些结果将可能为糖尿病治疗开辟新天地,但其具体作用机制目前尚不清楚.本文根据国内外研究成果及最新研究进展,主要介绍了阿片肽及其受体的生理功能,阿片受体介导的信号转导以及阿片肽对胰岛素释放的调节机制.     

替米沙坦在糖尿病防治中的应用

替米沙坦是经典的抗血压病药物。近年来人们发现替米沙坦除可以抑制血管紧张素Ⅱ-1型受体外,还可以部分激活过氧化物酶体增殖物激活受体γ。得益于其双靶点的作用机制,替米沙坦可以通过改善糖脂代谢紊乱和缓解糖尿病带来的并发症而使糖尿病或糖尿病高危病人获益。本文就替米沙坦在糖尿病预防和治疗中的作用及相关的机制研究作一阐述。     

VEGF受体信号转导在冠心病治疗中的研究现状

血管内皮细胞生长因子(VEGF)受体信号转导途径参与细胞的迁移、增殖、生存,在血管新生和血管保护中具有重要的作用.VEGF受体信号转导途径可能是治疗冠状动脉粥样硬化的理想靶点.本文针对VEGF受体信号转导途径及其与冠心病治疗的研究现状予以综述.     

Eph-Ephrin双向信号转导途径在眼部血管新生中的作用

Eph/Ephrin家族是受体酪氨酸激酶家族中的最大亚族,在生理和病理性血管形成中起重要作用。眼部血管生成是糖尿病视网膜病、早产儿视网膜等眼部疾病致盲的重要因素,Eph和Ephrin基因在上述眼部疾病中有不同程度表达改变。Eph受体及其配体Ephrin之间的双向信号机制是Eph-Ephrin发挥功能的主要方式。本文就Eph-Ephrin双向信号机制在眼部血管新生中的作用进行综述。     

Chronobiological study of the dynamics of blood intake of exogenously administered glucose

Experiments on mice were made to study the release to blood of exogenously injected glucose. It was established that this process was of rhythmical nature. Two periods of intense glucose release to blood were recognized: the maxima were attained at 4 and 12 o'clock. At other times glucose release to blood was negligible. It is assumed that oscillations in question are determined by the biological rhythms of glucose absorption by cross-striated muscle cells. Electromagnetic field altered the biological rhythms of glucose absorption by the muscles and raised glucose absorption. Mice with unmarked insulin deficiency preserved the tendency toward rhythmical changes in glucose release to blood, although muscle absorption of glucose was lowered.     

Finite Element Model of Oxygen Transport for the Design of Geometrically Complex Microfluidic Devices Used in Biological Studies

Red blood cells play a crucial role in the local regulation of oxygen supply in the microcirculation through the oxygen dependent release of ATP. Since red blood cells serve as an oxygen sensor for the circulatory system, the dynamics of ATP release determine the effectiveness of red blood cells to relate the oxygen levels to the vessels. Previous work has focused on the feasibility of developing a microfluidic system to measure the dynamics of ATP release. The objective was to determine if a steep oxygen gradient could be developed in the channel to cause a rapid decrease in hemoglobin oxygen saturation in order to measure the corresponding levels of ATP released from the red blood cells. In the present study, oxygen transport simulations were used to optimize the geometric design parameters for a similar system which is easier to fabricate. The system is composed of a microfluidic device stacked on top of a large, gas impermeable flow channel with a hole to allow gas exchange. The microfluidic device is fabricated using soft lithography in polydimethyl-siloxane, an oxygen permeable material. Our objective is twofold: (1) optimize the parameters of our system and (2) develop a method to assess the oxygen distribution in complex 3D microfluidic device geometries. 3D simulations of oxygen transport were performed to simulate oxygen distribution throughout the device. The simulations demonstrate that microfluidic device geometry plays a critical role in molecule exchange, for instance, changing the orientation of the short wide microfluidic channel results in a 97.17% increase in oxygen exchange. Since microfluidic devices have become a more prominent tool in biological studies, understanding the transport of oxygen and other biological molecules in microfluidic devices is critical for maintaining a physiologically relevant environment. We have also demonstrated a method to assess oxygen levels in geometrically complex microfluidic devices.     

A super active cyclic hexapeptide analog of somatostatin

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50–100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1–3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.     

Exercise induces the release of heat shock protein 72 from the human brain in vivo

The present study tested the hypothesis that in response to physical stress the human brain has the capacity to release heat shock protein 72 (Hsp72) in vivo. Therefore, 6 humans (males) cycled for 180 minutes at 60% of their maximal oxygen uptake, and the cerebral Hsp72 response was determined on the basis of the internal jugular venous to arterial difference and global cerebral blood flow. At rest, there was a net balance of Hsp72 across the brain, but after 180 minutes of exercise, we were able to detect the release of Hsp72 from the brain (335 +/- 182 ng/min). However, large individual differences were observed as 3 of the 6 subjects had a marked increase in the release of Hsp72, whereas exercise had little effect on the cerebral Hsp72 balance in the remaining 3 subjects. Given that cerebral blood flow was unchanged during exercise compared with values obtained at rest, it is unlikely that the cerebral Hsp72 release relates to necrosis of specific cells within the brain. These data demonstrate that the human brain is able to release Hsp72 in vivo in response to a physical stressor such as exercise. Further study is required to determine the biological significance of these observations.     

Nonlinear magic: multiphoton microscopy in the biosciences

Multiphoton microscopy (MPM) has found a niche in the world of biological imaging as the best noninvasive means of fluorescence microscopy in tissue explants and living animals. Coupled with transgenic mouse models of disease and 'smart' genetically encoded fluorescent indicators, its use is now increasing exponentially. Properly applied, it is capable of measuring calcium transients 500 microm deep in a mouse brain, or quantifying blood flow by imaging shadows of blood cells as they race through capillaries. With the multitude of possibilities afforded by variations of nonlinear optics and localized photochemistry, it is possible to image collagen fibrils directly within tissue through nonlinear scattering, or release caged compounds in sub-femtoliter volumes.     

The state of commercial augmentative biological control: plenty of natural enemies,but a frustrating lack of uptake

Augmentative biological control concerns the periodical release of natural enemies. In commercial augmentative biological control, natural enemies are mass-reared in biofactories for release in large numbers to obtain an immediate control of pests. The history of commercial mass production of natural enemies spans a period of roughly 120 years. It has been a successful, environmentally and economically sound alternative for chemical pest control in crops like fruit orchards, maize, cotton, sugar cane, soybean, vineyards and greenhouses. Currently, augmentative biological control is in a critical phase, even though during the past decades it has moved from a cottage industry to professional production. Many efficient species of natural enemies have been discovered and 230 are commercially available today. The industry developed quality control guidelines, mass production, shipment and release methods as well as adequate guidance for farmers. However, augmentative biological control is applied on a frustratingly small acreage. Trends in research and application are reviewed, causes explaining the limited uptake are discussed and ways to increase application of augmentative biological control are explored.     

Fullerene nanomaterials inhibit the allergic response

Fullerenes are a class of novel carbon allotropes that may have practical applications in biotechnology and medicine. Human mast cells (MC) and peripheral blood basophils are critical cells involved in the initiation and propagation of several inflammatory conditions, mainly type I hypersensitivity. We report an unanticipated role of fullerenes as a negative regulator of allergic mediator release that suppresses Ag-driven type I hypersensitivity. Human MC and peripheral blood basophils exhibited a significant inhibition of IgE dependent mediator release when preincubated with C(60) fullerenes. Protein microarray demonstrated that inhibition of mediator release involves profound reductions in the activation of signaling molecules involved in mediator release and oxidative stress. Follow-up studies demonstrated that the tyrosine phosphorylation of Syk was dramatically inhibited in Ag-challenged cells first incubated with fullerenes. In addition, fullerene preincubation significantly inhibited IgE-induced elevation in cytoplasmic reactive oxygen species levels. Furthermore, fullerenes prevented the in vivo release of histamine and drop in core body temperature in vivo using a MC-dependent model of anaphylaxis. These findings identify a new biological function for fullerenes and may represent a novel way to control MC-dependent diseases including asthma, inflammatory arthritis, heart disease, and multiple sclerosis.     

Cytosporone B is an agonist for nuclear orphan receptor Nur77

Nuclear orphan receptor Nur77 has important roles in many biological processes. However, a physiological ligand for Nur77 has not been identified. Here, we report that the octaketide cytosporone B (Csn-B) is a naturally occurring agonist for Nur77. Csn-B specifically binds to the ligand-binding domain of Nur77 and stimulates Nur77-dependent transactivational activity towards target genes including Nr4a1 (Nur77) itself, which contains multiple consensus response elements allowing positive autoregulation in a Csn-B-dependent manner. Csn-B also elevates blood glucose levels in fasting C57 mice, an effect that is accompanied by induction of multiple genes involved in gluconeogenesis. These biological effects were not observed in Nur77-null (Nr4a1-/-) mice, which indicates that Csn-B regulates gluconeogenesis through Nur77. Moreover, Csn-B induced apoptosis and retarded xenograft tumor growth by inducing Nur77 expression, translocating Nur77 to mitochondria to cause cytochrome c release. Thus, Csn-B may represent a promising therapeutic drug for cancers and hypoglycemia, and it may also be useful as a reagent to increase understanding of Nur77 biological function.     

Transport of the highly charged myo-inositol hexakisphosphate molecule across the red blood cell membrane: a phase transfer and biological study

To address the problem of delivering highly charged small molecules, such as phytic acid (InsP(6) or IHP), across biological membranes, we investigated an approach based on a non-covalent interaction between transport molecule(s) and IHP. Thus, we synthesized a collection of compounds containing IHP ionically bound to lipophilic (but non-lipidic) ammonium or poly-ammonium cations. First, we assessed the ability of these water-soluble salts to cross a biological membrane by measuring the partition coefficients between human serum and 1-octanol. In view of the ability of IHP to act as potent effector for oxygen release, the O(2)-hemoglobin dissociation curves were then measured for the most efficient salts on whole blood. From both the biological and the physical properties of IHP-ammonium salts we determined that cycloalkylamines (or poly-amines) were the best transport molecules, especially cycloheptyl- and cyclooctylamine. Indeed, the octanol/serum partition coefficient of IHP undecacyclooctylammonium salt, is superior to 1, which is very favorable for potential uptake into the red blood cell membrane. A qualitative correlation was found between the partitioning experiments and the biological evaluations performed on whole blood.     

Direct observation of trapping and release of nitric oxide by glutathione and cysteine with electron paramagnetic resonance spectroscopy

While the biosynthesis of nitric oxide (NO) is well established, one of the key issues that remains to be solved is whether NO participates in the biological responses right after generation through biosynthesis or there is a "secret passage" via which NO itself is trapped, transported, and released to exert its functions. It has been shown that NO reacts with thiol-containing biomolecules (RSH), like cysteine (Cys), glutathione (GSH), etc., to form S-nitrosothiols (RSNOs), which then release nitrogen compounds, including NO. The direct observation of trapping of NO and its release by RSNO has not been well documented, as most of the detection techniques measure the content of NO as well as nitrite and nitrate. Here we use spin-trapping electron paramagnetic resonance (EPR) technique to measure NO content directly in the reaction time course of samples of GSH and Cys ( approximately mM) mixed with NO ( approximately microM) in the presence of metal ion chelator, which pertains to physiological conditions. We demonstrate that NO is readily trapped by these thiols in less than 10 min and approximately 70-90% is released afterward. These data imply that approximately 10-30% of the reaction product of NO does not exist in the free radical form. The NO release versus time curves are slightly pH dependent in the presence of metal ion chelator. Because GSH and Cys exist in high molar concentrations in blood and in mammalian cells, the trapping and release passage of NO by these thiols may provide a mechanism for temporal and spatial sequestration of NO to overcome its concentration gradient-dependent diffusion, so as to exert its multiple biological effects by reacting with various targets through regeneration.