贝伐单抗抑制角膜新生血管形成的实验研究

目的观察贝伐单抗在抑制角膜新生血管形成中的作用,并探讨其机制。方法将64只新西兰大白兔分为实验组(32只)及对照组(32只),采用碱烧伤法进行角膜新生血管形成(CNV)造模,实验组给予角膜下注射贝伐单抗,对照组给予生理盐水角膜下注射,观察角膜水肿程度、CNV面积及长度,Western印迹法检测VEGF、IL-8及PIGF在角膜中的表达水平。结果角膜水肿程度:在造模24 h后,实验组与对照组比较差异无统计学意义(P>0.05);造模21 d后,实验组轻于对照组,差异有统计学意义(P<0.05)。造模3、7、14及21 d时,实验组CNV面积、平均长度均明显小于对照组(P<0.05或P<0.01)。Western blot显示,VEGF在角膜中蛋白水平表达,对照组高于实验组(t=11.516,P<0.01);对照组与实验组PIGF比较差异无统计学意义(t=1.29,P>0.05);IL-8在对照组中表达高于实验组(t=4.49,P<0.05)。结论贝伐单抗可通过降低角膜中VEGF及IL-8表达有效抑制角膜水肿及新生血管形成。     

微管抑制剂C9抑制新生血管生成的作用机制

目的:研究微管抑制剂C9对新生血管生成的抑制作用及其机制。方法:利用流式细胞术和TUNEL法,检测C9逆转血管内皮生长因子(vascular endothelial growth factor,VEGF)和碱性成纤维细胞生长因子(basic fibroblast growth factor,bFGF)抗无血清诱导的内皮细胞凋亡;Western Blot法检测C9对生长因子VEGF和bFGF刺激的下游与新生血管生成相关的两条通路Raf-Mek-Erk和PI3K-AKT中Raf,Mek,Erk,Akt磷酸化影响。结果:C9能够逆转VEGF和bFGF抗无血清诱导的内皮细胞凋亡,可以剂量依赖性地下调生长因子VEGF和bFGF下游与新生血管生成相关的两条通路Raf-Mek-Erk和PI3K-AKT中Raf,Mek,Erk,Akt磷酸化,但是对VEGF受体KDR及bFGF受体FGFR1的磷酸化没有影响。结论:C9主要通过直接抑制Raf-Mek-Erk信号通路而抑制生长因子的抗内皮细胞凋亡作用,并产生抑制新生血管生成作用。     

兰尼单抗的药理作用及临床评价

脉络膜新生血管(choroidal neovascularization,CNV)是引起多种眼底疾病、导致视力丧失的重要原因之一.CNV的发生机制尚不清楚,目前一般认为血管生成因子与抑制因子之间平衡的破坏具有关键作用,而血管内皮生长因子(vascular endothelial growth factor,VEGF)是其重要的激发因素.兰尼单抗(ranibizumab,商品名Lucentis)是一种重组的抗血管内皮生长因子(VEGF-A)中和抗体片断,可用于治疗年龄相关性黄斑变性(AMD).本品能减慢脉络膜新生血管的形成,降低病变血管的渗漏.临床研究证明其治疗渗出性AMD疗效显著,且耐受性良好.文中对兰尼单抗的药理作用及临床评价做一综述.     

汉防己甲素抑制鼠角膜新生血管VEGF、TGF-β的实验研究

目的 探讨汉防己甲素(tetrandrine,Tet)对大鼠角膜新生血管(corneal neovascularization,CNV)中血管内皮生长因子(vascular endothelial growth factor,VEGF)与转化生长因子-β(transforming growth factor,TGF-13)表达的影响.方法 碱烧伤法制作大鼠角膜新生血管模型,采用裂隙灯照相和免疫组化等方法,分别观察Tet组与其他对照组模型大鼠角膜新生血管每天的生长状况及榆测各组模型大鼠角膜中VEGF和TGF-β在各时期的表达情况.结果 Tet组模型大鼠角膜新生血管及VEGF和TGF-B的表达情况均较对照组有显著变化.结论 Tet能有效抑制碱烧伤诱发的大鼠角膜新生血管,同时降低新生血管中VEGF和TGF-B的表达.     

三棱、莪术对大鼠皮下移植人工海绵新生血管的影响研究

目的:研究三棱、莪术抑制海绵内新生肉芽组织血管新生的作用及其可能机制。方法:复制大鼠皮下海绵移植模型,连续灌胃给药2周,观察三棱、莪术对海绵内新生肉芽组织生长及其新生血管的影响;通过免疫组化法进行内皮细胞特异性Ⅷ因子、血管内皮细胞生长因子(VEGF)染色;逆转录-聚合酶链反应法检测VEGFmRNA的表达。结果:三棱、莪术高剂量组大鼠海绵内新生肉芽组织侵入生长、血管数量、VEGF蛋白及VEGFmRNA的表达量均较模型组显著减少(P<0.01或P<0.05)。结论:三棱、莪术可抑制海绵内新生肉芽组织的血管新生,其机制可能与抑制新生血管表达VEGF有关。     

内皮抑素与角膜新生血管

正常角膜组织透明,无血管,周围血管终止于角膜缘,形成血管网,营养成分由此扩散入角膜。无血管是角膜的主要特征,也是维持角膜透明的重要条件。在病理状态下,新生毛细血管由角膜缘处侵入角膜内,称为角膜新生血管（corneal neovascularization,CNV）。内皮抑素（endostatin）是一种新型内源性新生血管生成抑制因子,可特异性抑制新生血管内皮细胞的增殖,封闭新生血管的形成,在肿瘤实验过程中表现出极强的抑瘤活性。实验表明,内皮抑素对多种起源的新生血管内皮细胞增殖有抑制作用,而不影响静止的血管内皮细胞,内皮抑素具有明显抑制角膜新生血管生长的作用,而无毒副作用,为临床防治CNV提供了一种新的途径。     

VEGF165_b的抗血管生成作用在肾癌发生、发展中的研究进展

肾癌是一种高度血管化的恶性实性肿瘤,其生长和转移依赖于新生血管的形成,而血管形成主要是由促血管生成因子和抑制因子调控失衡、促血管生成因子增多所致。血管内皮生长因子(VEGF)亚型VEGF165是机体内含量最多,生物活性最强的促血管生成因子,且在肾癌组织中高表达,与肿瘤的生长、转移密切相关。最新研究发现一种新的VEGF异构体VEGF165b具有抑制VEGF165介导的血管生成作用,有可能成为肾癌治疗过程中新的作用靶点,具有重要的临床应用价值。本文对VEGF165b的结构、作用机制进行综述。     

木犀草素抗肿瘤血管生成作用机制的研究进展

血管生成是恶性肿瘤的标志之一,涉及血管内皮细胞的增殖、迁移和细胞外基质分解等多种途径。血管内皮生长因子（VEGF）靶向抗肿瘤血管生成是临床肿瘤治疗的有效方法。木犀草素为黄酮类化合物,具有抗肿瘤活性,可通过抑制VEGF及相关信号通路、抑制磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路、抑制血管新生分子、抑制孕激素活性、靶向刺激Wnt信号通路、阻断生长停滞特异性蛋白6（Gas6）/受体酪氨酸激酶（Axl）信号通路而发挥抗肿瘤的血管生成作用。归纳了木犀草素抗肿瘤血管生成的作用机制,以期为木犀草素的临床应用提供参考。     

血管内皮细胞生长因子与抗肿瘤转移治疗的研究

血管内皮细胞生长因子(VEGF)是最重要的刺激血管新生的细胞因子。VEGF的生物学效应是通过其特异性的膜受体即VEGF受体介导实现的。本文就VEGF及其受体的基因和蛋白结构、生物学作用、信号转导通路及在抗肿瘤血管新生治疗方面的研究进展作一综述。     

平阳霉素对大鼠子宫肌瘤血管生成的抑制及VEGF表达的影响

目的:评价平阳霉素对大鼠子宫肌瘤血管新生的抑制作用,并研究其影响血管新生的详细分子机制。方法:通过大鼠子宫肌瘤模型,注射平阳霉素,比较用药组和对照组微血管密度的差异,免疫组化研究对血管内皮生长因子(VEGF)表达的影响。结果:注射平阳霉素之后,微血管密度显著降低(P<0.01),VEGF表达明显抑制(P<0.05)。平阳霉素可以通过降低VEGF表达,抑制血管新生,杀伤肿瘤细胞。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.