靶向肿瘤新生血管唑来膦酸阳离子隐形脂质体抗肿瘤作用的研究

目的:研究APRPG（Ala-Pro-Arg-Pro-Gly）修饰的隐形唑来膦酸阳离子脂质体对荷前列腺癌PC-3裸鼠的抗肿瘤作用。方法: 构建荷前列腺癌PC-3裸鼠模型,比较研究唑来膦酸阳离子脂质体、APRPG修饰的隐形唑来膦酸阳离子脂质体对肿瘤体积增长的抑制作用,计算肿瘤抑制率,并通过免疫组化实验分析其对肿瘤相关因子血管内皮生长因子（VEGF）和分化抗原簇44（CD44）表达的影响。结果: 唑来膦酸阳离子脂质体、APRPG修饰的隐形唑来膦酸阳离子脂质体对荷前列腺癌PC-3裸鼠的肿瘤抑制率分别为31.81%、68.18%,后者的肿瘤抑制率明显高于前者（P<0.05）,免疫组化结果显示VEGF和CD44蛋白在模型对照组中表达呈强阳性,在唑来膦酸阳离子脂质体组中呈中度阳性表达,而在APRPG修饰的隐形唑来膦酸阳离子脂质体中表达较为微弱。结论:APRPG修饰的隐形唑来膦酸阳离子脂质体对前列腺癌PC-3裸鼠具有更强的肿瘤抑制率。     

Nanoparticle Accumulation in Angiogenic Tissues: Towards Predictable Pharmacokinetics

Nanoparticles are increasingly used in medical applications such as drug delivery, imaging, and biodiagnostics, particularly for cancer. The design of nanoparticles for tumor delivery has been largely empirical, owing to a lack of quantitative data on angiogenic tissue sequestration. Using fluorescence correlation spectroscopy, the deposition rate constants of nanoparticles into angiogenic blood vessel tissue are determined. It is shown that deposition is dependent on surface charge. Moreover, the size dependency strongly suggests that nanoparticles are taken up by a passive mechanism that depends largely on geometry. These findings imply that it is possible to tune nanoparticle pharmacokinetics simply by adjusting nanoparticle size.     

去甲苔藓葸噻吩抑制血管生成作用的体外实验研究

Objective:The aim of the study was to investigate the effect of Demethyl bryoanthrathiophene (DBT) on pro-liferations of human umbilical vein endothelial cells (HUVECs) and human lung adenocarcinoma cell line A549, and antian-giogenic effect of DBT on HUVECs in vitro. Methods: MTT assay was used to observe the effect of DBT on proliferations of HUVECs and A549 cells, fiat plate scarification assay and tube formation in vitro test were used to observe the impact of DBT on migration and vaso-formed ability of HUVECs. The effects of DBT on apoptosis and cell cycle of HUVECs were calculated by flow cytometry. Results: MTT assay showed that treatment with DBT resulted in strong inhibition to the growth of HUVECs and A549 cells. The inhibition effects of DBT on HUVECs and A549 cells were related to dosage and times of dependency.In different doses of DBT (0.16, 0.32 and 0.48 μmol/L) of fiat plate scarification for 24 h, inhibition rates of DBT to migration of HUVECs were 14.70%, 38.23% and 58.82%, respectively. In dose of DBT from 0.04, 0.20 to 0.40 μmol/L for 24 h in tube formation, there were significance differences (P < 0.01) in the decreasing number of angiogenesis and incomplete blood vessel compared with control groups. All results showed that DBT promoted the apoptosis rate of HUVECs, and the increase of concentration of DBT accompanied the acceleration of apoptosis rate. Conclusion: DBT could inhibit the proliferations of HUVECs and A549 cells, and effectively suppress angiogenesis in vitro.     

骨肉瘤CT灌注成像与血管生成的关系

Objective:The aim of the study was to explore the application of 64-slice spiral computed tomography perfusion imaging (CTPI) in evaluating angiogenesis in human osteosarcoma.Methods:Twenty-six patients (18 males and 8 females ranging from 9 to 56 years old,with an average of 19 years) with osteosarcoma underwent 64-slice spiral CTPI.We analyzed the correlations of CTPI parameters including blood flow (BF),blood volume (BV),time to peak (TTP),and permeability surface (PS) with the expression of markers of angiogenesis.Statistical analysis was performed with paired-samples t test,and Pearson correlation analysis was employed to investigate the correlations of CTPI parameters with microvessel density (MVD).Results:Mean BF,BV,TTP,and PS values of osteosarcoma group were (46.6 ± 25.1) mL/100 g/min,(61.8 ± 29.5) mL/100 g,(122.9 ± 26.2) seconds,and (44.5 ± 14.6) mL/100 g/min,respectively.Those in the normal muscle group were (5.2 ± 6.6) mL/100 g/min,(9.6 ± 7.3) mL/100 g,(115.5 ± 33.1) seconds and (17.0 ± 29.3) mL/100 g/min,respectively.Osteosarcoma group showed higher BF,BV and PS compared with the normal muscle group (P = 0.000,P = 0.000,and P = 0.000,respectively).However,no significant difference was found in TTP between osteosarcoma tissue and normal adjacent muscle tissue (P = 0.273).BF,BV,and PS were positively correlated with MVD (r = 0.83,P = 0.000;r = 0.87,P = 0.000;and r = 0.63,P = 0.001,respectively).No correlation was found between TTP and MVD (r = –0.02,P = 0.93).Conclusion:CTPI is useful for assessing tumor vascularity of osteosarcoma and CTPI parameters are positively correlated with MVD.     

Rapid cellular genesis and apoptosis: Effects of exercise in the adult rat.

Long-term aerobic exercise improves cognition in both human and nonhuman animals and induces plastic changes in the central nervous system (CNS), including neurogenesis and angiogenesis. However, the early and immediate effects of exercise on the CNS have not been adequately explored. There is some evidence to suggest that exercise is initially challenging to the nervous system and that the plastic changes commonly associated with chronic exercise may result as adaptations to this challenge. The current experiment assessed levels of apoptosis, angiogenesis, and neurogenesis during the first week of an exercise regimen in the adult rat. The results indicate that exercise rapidly induces these processes in the hippocampus and cerebellum. The temporal pattern of these events suggests that voluntary exercise in the adult rat rapidly and transiently induces apoptosis, followed by angiogenesis. Neurogenesis is an immediate and independent consequence of exercise in the hippocampus that may require the additional metabolic support supplied by angiogenesis. This is the first report of CNS neuronal apoptosis as a consequence of exercise in the adult rat and suggests that this process is a potential mediator of rapid exercise-induced plasticity. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

抗血管生成药物的研究进展与临床应用

血管生成(angiogenesis)在恶性肿瘤和视网膜病变等疾病过程中发挥着重要作用。随着血管新生的调节机制逐渐被揭示,抗血管生成药物的研发也取得新的突破,目前成功获批上市的抗血管生成靶向药物已达十余种,主要包括小分子多靶点血管靶向药物、大分子单靶点血管靶向药物、内源性泛靶点血管靶向药物3类。本文对抗血管生成策略的理论基础、近年相关药物的研发进展,及其在临床治疗中的应用进行综述。     

Verifiable Hypotheses for Thymosin β4-Dependent and -Independent Angiogenic Induction of Trichinella spiralis-Triggered Nurse Cell Formation

Trichinella spiralis has been reported to induce angiogenesis for nutrient supply and waste disposal by the induction of the angiogenic molecule vascular endothelial cell growth factor (VEGF) during nurse cell formation. However, the action mechanism to induce VEGF in nurse cells by T. spiralis is not known. Hypoxia in nurse cells was suggested as a possible mechanism; however, the presence of hypoxic conditions in infected muscle or nurse cells and whether hypoxia indeed induces the expression of VEGF and subsequent angiogenesis in the infected muscle are both a matter of debate. Our recent studies have shown that thymosin β4, a potent VEGF inducing protein, is expressed in the very early stages of T. spiralis muscle infection suggesting the induction of VEGF in early stage nurse cells. Nevertheless, we now show that hypoxic conditions were not detected in any nurse cell stage but were detected only in the accumulated inflammatory cells. These studies propose that induction of angiogenesis by VEGF in T. spiralis-infected nurse cells was mediated by thymosin β4 and is unrelated to hypoxic conditions.     

Impact of DICER1 and DROSHA on the Angiogenic Capacity of Human Endothelial Cells

RNAi-mediated knockdown of DICER1 and DROSHA, enzymes critically involved in miRNA biogenesis, has been postulated to affect the homeostasis and the angiogenic capacity of human endothelial cells. To re-evaluate this issue, we reduced the expression of DICER1 or DROSHA by RNAi-mediated knockdown and subsequently investigated the effect of these interventions on the angiogenic capacity of human umbilical vein endothelial cells (HUVEC) in vitro (proliferation, migration, tube formation, endothelial cell spheroid sprouting) and in a HUVEC xenograft assay in immune incompetent NSG^TM mice in vivo. In contrast to previous reports, neither knockdown of DICER1 nor knockdown of DROSHA profoundly affected migration or tube formation of HUVEC or the angiogenic capacity of HUVEC in vivo. Furthermore, knockdown of DICER1 and the combined knockdown of DICER1 and DROSHA tended to increase VEGF-induced BrdU incorporation and induced angiogenic sprouting from HUVEC spheroids. Consistent with these observations, global proteomic analyses showed that knockdown of DICER1 or DROSHA only moderately altered HUVEC protein expression profiles but additively reduced, for example, expression of the angiogenesis inhibitor thrombospondin-1. In conclusion, global reduction of miRNA biogenesis by knockdown of DICER1 or DROSHA does not inhibit the angiogenic capacity of HUVEC. Further studies are therefore needed to elucidate the influence of these enzymes in the context of human endothelial cell-related angiogenesis.