BACKGROUND & AIMS: Genetic studies have recently revealed a role for transforming growth factor-beta-1 (TGF-beta 1) and its receptors (TGF-beta Rs I and II as well as endoglin) in embryonic vascular assembly and in the establishment and maintenance of vessel wall integrity. The purpose of this review is threefoldfirst, to reassess previous studies on TGF-beta and endothelium in the light of these recent findings; second, to describe some of the well-established as well as controversial issues concerning TGF-beta and its regulatory role in angiogenesis; and third, to explore the notion of "context' with respect to TGF-beta and endothelial cell function. Although the focus of this review will be on the endothelium, other vascular wall cells are also likely to be important in the pathogenesis of the vascular lesions revealed by genetic studies.

背景与目标： 遗传研究最近揭示了转化生长因子-beta-1 (TGF-beta 1) 及其受体 (TGF-beta Rs I和II以及endoglin) 在胚胎血管组装以及血管壁完整性的建立和维持中的作用。这篇综述的目的是三重首先，根据这些最新发现重新评估先前关于TGF-β 和内皮的研究; 第二，描述一些关于TGF-β 及其在血管生成中的调节作用的公认的和有争议的问题; 第三，探讨TGF-β 和内皮细胞功能的 “背景” 概念。尽管本综述的重点将放在内皮上，但其他血管壁细胞也可能在遗传学研究揭示的血管病变的发病机理中很重要。

BACKGROUND & AIMS: :Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis.

背景与目标： 血管生成是许多病理的关键步骤，包括肿瘤的生长和转移。在这里，我们显示倾斜肽具有抗血管生成活性。倾斜 (或倾斜定向) 肽是短肽，已知会破坏膜和脂质核的稳定性，其特征是螺旋时疏水残基沿轴的不对称分布。我们先前已经证明，人类催乳素/生长激素 (PRL/GH) 家族成员的16 kDa片段是有效的血管生成抑制剂。在这里，我们证明了所有这些片段都具有具有倾斜肽特征的14-aa序列。人催乳素和人生长激素的倾斜肽在体外和体内均诱导内皮细胞凋亡，抑制内皮细胞增殖并抑制毛细血管形成。当肽的疏水性梯度因突变而改变时，这些抗血管生成作用就会消失。我们进一步证明，猿猴免疫缺陷病毒gp32和阿尔茨海默氏 β-淀粉样肽的众所周知的倾斜肽也是血管生成抑制剂。总之，这些结果指出了倾斜肽在调节血管生成中的潜在新作用。

BACKGROUND & AIMS: :Peripheral artery disease (PAD) is a result of the atherosclerotic narrowing of blood vessels to the extremities, and the subsequent tissue ischemia can lead to the up-regulation of angiogenic growth factors and formation of new vessels as a recovery mechanism. Such formation of new vessels can be evaluated with various non-invasive molecular imaging techniques, where serial images from the same subjects can be obtained to allow the documentation of disease progression and therapeutic response. The most commonly used animal model for preclinical studies of PAD is the murine hindlimb ischemia model, and a number of radiotracers have been investigated for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of PAD. In this review article, we summarize the PET/SPECT tracers that have been tested in the murine hindlimb ischemia model as well as those used clinically to assess the extremity blood flow.

背景与目标： : 外周动脉疾病 (PAD) 是血管向四肢动脉粥样硬化狭窄的结果，随后的组织缺血可导致血管生成生长因子的上调和新血管的形成作为恢复机制。可以使用各种非侵入性分子成像技术评估新血管的这种形成，其中可以获得来自相同受试者的连续图像，以记录疾病进展和治疗反应。PAD临床前研究最常用的动物模型是鼠后肢缺血模型，并且已经研究了许多放射性示踪剂用于PAD的正电子发射断层扫描 (PET) 和单光子发射计算机断层扫描 (SPECT) 成像。在这篇综述文章中，我们总结了在鼠后肢缺血模型中测试的PET/SPECT示踪剂以及临床上用于评估肢体血流的示踪剂。

BACKGROUND & AIMS: :Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression.

背景与目标： : 胶质母细胞瘤是一种高度血管化的脑肿瘤，抗血管生成治疗可改善其无进展生存期。然而，当前的抗血管生成疗法会引起严重的不良反应，包括神经元细胞毒性，肿瘤侵袭性和对治疗的抵抗力。尽管已经提出物理微环境在肿瘤血管生成和进展中起关键作用，但细胞外基质的物理特性控制肿瘤血管生成和胶质母细胞瘤进展的机制尚不完全清楚。在本文中，我们显示了人胶质母细胞瘤细胞系U87MG，U251的物理压实 (细胞聚集并聚集在一起并引起细胞形状和大小相关变化的过程)，LN229诱导 ⅳ 型和 ⅵ 型胶原和胶原交联酶赖氨酰氧化酶的表达，并上调血管生成因子血管内皮生长因子的体外表达。在小鼠原位脑肿瘤模型中，赖氨酰氧化酶抑制剂 β-氨基丙腈破坏肿瘤中的胶原蛋白结构并抑制肿瘤血管生成和多形性胶质母细胞瘤的生长。同样，d-青霉胺通过消耗脑内铜来抑制赖氨酰氧化酶的酶活性，也对小鼠脑肿瘤生长表现出抗血管生成作用。这些发现表明，胶原结构控制的肿瘤微环境在肿瘤血管生成和脑肿瘤进展中很重要。

BACKGROUND & AIMS: :Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.

背景与目标： : 尽管许多多发性骨髓瘤 (MM) 患者最初对细胞毒性治疗有反应，但大多数最终复发。采用化疗与靶向生物制剂相结合的新型治疗策略可能会显着增强肿瘤细胞对治疗的反应。我们测试了针对MM的全人抗igf-ir抗体 (A12)，并在体外显示了对MM细胞中igf-i或血清诱导的igf-ir信号的特异性抑制。在各种皮下异种移植MM模型中，A12作为单一药物被证明对体内肿瘤生长具有适度至显着的抑制作用。还在播散性异种移植MM.1S NOD/SCID模型中评估了A12，作为单一疗法或与目前临床使用的其他药物 (硼替佐米，美法仑) 联合使用。通过荧光素酶生物成像确定的肿瘤负荷急剧降低，并且当联合治疗时，总生存期显着延长。免疫组织化学分析表明，与对照肿瘤相比，A12治疗的肿瘤血管形成明显减少。此外，大多数MM系组成型分泌了大量的VEGF，并且在igf-i治疗后这种情况得到了增强。体外A12抑制igf-ir抑制了组成型和igf-i诱导的VEGF分泌，表明与A12治疗相关的推定抗血管生成机制可能有助于其抗肿瘤作用。

BACKGROUND & AIMS: :Previous in vivo and in vitro studies have shown that Akt1 serves as a crucial regulator of vascular maturation, extracellular matrix composition, and angiogenesis in tumors. Hence, we hypothesized that Akt1 may be necessary for other angiogenesis-dependent processes, including wound healing. Using Akt1 (-/-) and Akt2 (-/-) mice, we demonstrate that deficiency of Akt1, but not Akt2, results in impaired assembly of collagen in skin wounds and around the blood vessels. Wounds in Akt1 (-/-) mice, but not in Akt2 (-/-) mice, were characterized by reduced vascular area as well as impaired vascular maturation as evidenced by reduced smooth muscle cell recruitment. Expression level of a major angiogenic growth factor, VEGF, was significantly lower in wound tissues of Akt1 (-/-) mice as compared to WT. However, despite the impaired collagen assembly and reduced angiogenesis in Akt1 (-/-) wounds, no significant difference in migration of fibroblasts into the wound area was observed between WT and Akt1 (-/-) mice. Importantly, the dynamics of wound closure were similar between WT, Akt1 (-/-), and Akt2 (-/-) mice. Thus, it appears that although the lack of Akt1 impairs VEGF expression, wound angiogenesis, and subsequent maturation of vasculature, it has no effect on the wound closure. These findings may have clinical applications for the improvement of treatment procedures with reported history of wound healing complications.

背景与目标： : 先前的体内和体外研究表明，Akt1是肿瘤中血管成熟，细胞外基质组成和血管生成的关键调节剂。因此，我们假设Akt1可能是其他血管生成依赖性过程 (包括伤口愈合) 所必需的。使用Akt1 (-/-) 和Akt2 (-/-) 小鼠，我们证明Akt1的缺乏而不是Akt2的缺乏会导致皮肤伤口和血管周围胶原蛋白的组装受损。Akt1 (-/-) 小鼠的伤口，但Akt2 (-/-) 小鼠的伤口的特征是血管面积减少以及血管成熟受损，平滑肌细胞募集减少证明了这一点。与WT相比，Akt1 (-/-) 小鼠伤口组织中主要血管生成生长因子VEGF的表达水平显着降低。然而，尽管在Akt1 (-/-) 伤口中胶原蛋白组装受损且血管生成减少，但在WT和Akt1 (-/-) 小鼠之间未观察到成纤维细胞向伤口区域迁移的显着差异。重要的是，WT，Akt1 (-/-) 和Akt2 (-/-) 小鼠之间的伤口闭合动力学相似。因此，尽管缺乏Akt1会损害VEGF的表达，伤口血管生成以及随后的脉管系统成熟，但它对伤口闭合没有影响。这些发现可能具有临床应用，可用于改善伤口愈合并发症史的治疗程序。

BACKGROUND & AIMS: :Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by "on-off switch signals" between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia) and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies). Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

背景与目标： : 血管生成在人类生理中起着至关重要的作用，从生殖和胎儿生长到伤口愈合和组织修复。通过血管生成因子，细胞外基质成分和内皮细胞之间的 “开关信号”，以时空方式严格调节复杂的多步过程。不受控制的血管生成可能导致多种血管生成性疾病，包括血管功能不全 (心肌或严重肢体缺血) 和血管过度生长 (血管瘤，血管化肿瘤和视网膜病变)。因此，通过成功理解和随后操纵血管生成，可以设想许多治疗机会。在这里，我们回顾了血管生成的临床意义，并讨论了为癌症和其他血管生成疾病提供潜在治疗的促血管生成剂和抗血管生成剂。

BACKGROUND & AIMS: :Diabetes is associated with vascular complications, such as impaired wound healing and accelerated vascular growth. The different clinical manifestations, such as retinopathy and nephropathy, reveal the severity of enhanced vascular growth known as angiogenesis. This study was performed to evaluate the effects of an extract of Ishige okamurae (IO) and its constituent, Ishophloroglucin A (IPA) on high glucose-induced angiogenesis. A transgenic zebrafish (flk:EGFP) embryo model was used to evaluate vessel growth. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), gap closure, transwell, and Matrigel® assays were used to analyze the proliferation, migration, and capillary formation of EA.hy926 cells. Moreover, protein expression were determined using western blotting. IO extract and IPA suppressed vessel formation in the transgenic zebrafish (flk:EGFP) embryo. IPA attenuated cell proliferation, cell migration, and capillary-like structure formation in high glucose-treated human vascular endothelial cells. Further, IPA down regulated the expression of high glucose-induced vascular endothelial growth factor receptor 2 (VEGFR-2) and downstream signaling molecule cascade. Overall, the IO extract and IPA exhibited anti-angiogenic effects against high glucose-induced angiogenesis, suggesting their potential for use as therapeutic agents in diabetes-related angiogenesis.

背景与目标： : 糖尿病与血管并发症有关，如伤口愈合受损和血管生长加速。不同的临床表现，如视网膜病变和肾病，揭示了血管生长增强的严重程度，即血管生成。进行这项研究是为了评估石原 (IO) 提取物及其成分Ishophloroglucin A (IPA) 对高糖诱导的血管生成的影响。使用转基因斑马鱼 (flk:EGFP) 胚胎模型评估血管生长。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物 (MTT)，间隙闭合，tranwell和Matrigel®测定用于分析EA.hy926细胞的增殖，迁移和毛细血管形成。此外，使用蛋白质印迹法测定蛋白质表达。IO提取物和IPA抑制了转基因斑马鱼 (flk:EGFP) 胚胎中的血管形成。IPA减弱了高糖处理的人血管内皮细胞的细胞增殖，细胞迁移和毛细血管样结构的形成。此外，IPA下调高糖诱导的血管内皮生长因子受体2 (VEGFR-2) 和下游信号分子级联的表达。总体而言，IO提取物和IPA对高糖诱导的血管生成表现出抗血管生成作用，表明它们有潜力用作糖尿病相关血管生成的治疗剂。

BACKGROUND & AIMS: :In this paper we consider a time-delayed mathematical model describing tumor growth with angiogenesis and Gibbs-Thomson relation. In the model there are two unknown functions: One is $\sigma(r,t)$ which is the nutrient concentration at time $t$ and radius $r$, and the other one is $R(t)$ which is the outer tumor radius at time $t$. Since $R(t)$ is unknown and varies with time, this problem has a free boundary. Assume $\alpha(t)$ is the rate at which the tumor attracts blood vessels and the Gibbs-Thomson relation is considered for the concentration of nutrient at outer boundary of the tumor, so that on the outer boundary, the condition $$\dfrac{\partial \sigma}{\partial r}+\alpha(t)\left(\sigma-N(t)\right)=0,~~r=R(t)$$ holds, where $N(t)=\bar{\sigma}\left(1-\dfrac{\gamma}{R(t)}\right)H(R(t))$ is derived from Gibbs-Thomson relation. $H(\cdot)$ is smooth on $(0,\infty)$ satisfying $H(x)=0$ if $x\leq \gamma$, $H(x)=1$ if $x\geq 2\gamma$ and $0\leq H'(x)\leq 2/\gamma$ for all $x\geq 0$. In the case where $\alpha$ is a constant, the existence of steady-state solutions is discussed and the stability of the steady-state solutions is proved. In another case where $\alpha$ depends on time, we show that $R(t)$ will be also bounded if $\alpha(t)$ is bounded and some sufficient conditions for the disappearance of tumors are given.

背景与目标：

BACKGROUND & AIMS: :Consumption of a plant-based diet can prevent the development and progression of chronic diseases associated with extensive neovascularization, including solid malignant tumors. In previous studies, we have shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. In the present study, we report that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihydroxyflavone, fisetin, apigenin, and luteolin inhibited the proliferation of normal and tumor cells, as well as in vitro angiogenesis, at half-maximal concentrations in the low micromolar range. We have previously demonstrated that genistein concentrations in the urine of subjects consuming a plant-based diet is 30-fold higher than in subjects consuming a traditional Western diet. The wider distribution and the more abundant presence of flavonoids in the plant kingdom, together with the present results, suggest that flavonoids may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumors.

背景与目标： : 食用以植物为基础的饮食可以防止与广泛的新血管形成 (包括实体恶性肿瘤) 相关的慢性疾病的发展和进展。在先前的研究中，我们已经表明植物来源的异黄酮染料木素是细胞增殖和体外血管生成的有效抑制剂。在本研究中，我们报告某些结构相关的类黄酮比染料木黄酮更有效。实际上，3-羟基黄酮，3 '，4'-二羟基黄酮，2 '，3'-二羟基黄酮，fisetin，芹菜素和木犀草素抑制了正常细胞和肿瘤细胞的增殖，以及体外血管生成在低微摩尔范围内的最大浓度。我们以前已经证明，食用植物性饮食的受试者尿液中的染料木黄酮浓度比食用传统西方饮食的受试者高30倍。类黄酮在植物界的更广泛分布和更丰富的存在，以及目前的结果，表明类黄酮可能有助于植物性饮食对慢性疾病 (包括实体瘤) 的预防作用。

BACKGROUND & AIMS: :Euphorbia microsciadia (Euphorbiaceae) is a perennial plant growing in Iran. Two new cyclomyrsinol esters, 3-O-propionyl-5, 10, 14-O-triacetyl-8-O-(2'-methyl-butanoyl)-cyclomyrsinol (1) and 3, 5, 10, 14, 15-O-pentaacetyl-8-O-isobutanoyl-cyclomyrsinol (2) were isolated from the methanolic extract of its dried aerial parts. The structures were elucidated based on (13)C- and (1)H-NMR as well as 2D-NMR, IR and different MS spectra. Anti-angiogenic activity was also evaluated on vascular endothelium growth factor (VEGF)-induced angiogenesis in cultured human umbilical vein endothelial cells in vitro by assessing capillary-like tube network formation.

背景与目标： : 大戟科 (Euphorbiaceae) 是一种多年生植物，生长在伊朗。从其干燥的地上部分的甲醇提取物中分离出两种新的环氨酚酯，3-o-丙酰基-5,10，14-O-triacetyl-8-O-(2 '-甲基-丁酰基)-环氨酚 (1) 和3,5，10,14，15-O-pentaacetyl-8-O-isobutanoyl-cyclomyrsinol (2)。基于 (13)C-和 (1) h-nmr以及2D-NMR，IR和不同的MS光谱阐明了结构。还通过评估毛细血管样管网络的形成，评估了体外培养的人脐静脉内皮细胞中血管内皮生长因子 (VEGF) 诱导的血管生成的抗血管生成活性。

BACKGROUND & AIMS: :The tumour microenvironment and tumour angiogenesis play a critical role in the development and therapy of many cancers, but in vitro models reflecting these circumstances are rare. In this study, we describe the development of a novel tri-culture model, using non-small cell lung cancer (NSCLC) cell lines (A549 and Colo699) in combination with a fibroblast cell line (SV 80) and two different endothelial cell lines in a hanging drop technology. Endothelial cells aggregated either in small colonies in Colo699 containing microtissues or in tube like structures mainly in the stromal compartment of microtissues containing A549. An up-regulation of hypoxia and vimentin, ASMA and a downregulation of E-cadherin were observed in co- and tri-cultures compared to monocultures. Furthermore, a morphological alteration of A549 tumour cells resembling "signet ring cells" was observed in tri-cultures. The secretion of proangiogenic growth factors like vascular endothelial growth factor (VEGF) was measured in supernatants. Inhibition of these proangiogenic factors by using antiangiogenic drugs (bevacizumab and nindetanib) led to a significant decrease in migration of endothelial cells into microtissues. We demonstrate that our method is a promising tool for the generation of multicellular tumour microtissues and reflects in vivo conditions closer than 2D cell culture.

背景与目标： : 肿瘤微环境和肿瘤血管生成在许多癌症的发展和治疗中起着至关重要的作用，但是反映这些情况的体外模型很少。在这项研究中，我们描述了一种新的三培养模型的开发，使用非小细胞肺癌 (NSCLC) 细胞系 (A549和Colo699) 与成纤维细胞系 (SV 80) 和两种不同的内皮细胞系在悬挂式滴技术中。内皮细胞聚集在包含微组织的Colo699中的小菌落中，或主要在包含a549的微组织的基质区室中的管状结构中。与单培养相比，在共培养和三培养中观察到缺氧和波形蛋白，ASMA的上调以及E-cadherin的下调。此外，在三培养物中观察到类似于 “印戒细胞” 的A549肿瘤细胞的形态变化。在上清液中测量了促血管生成生长因子 (如血管内皮生长因子 (VEGF)) 的分泌。通过使用抗血管生成药物 (贝伐单抗和nindetanib) 抑制这些促血管生成因子导致内皮细胞向微组织的迁移显着减少。我们证明了我们的方法是产生多细胞肿瘤微组织的有前途的工具，并且反映了比2D细胞培养更接近的体内条件。

BACKGROUND & AIMS: :Redox reactions pervade all biology. The control of cellular redox state is essential for bioenergetics and for the proper functioning of many biological functions. This review traces a timeline of findings regarding the connections between redox and cancer. There is ample evidence of the involvement of cellular redox state on the different hallmarks of cancer. Evidence of the control of tumor angiogenesis and metastasis through modulation of cell redox state is reviewed and highlighted.

背景与目标： : 氧化还原反应遍布所有生物学。细胞氧化还原状态的控制对于生物能学和许多生物功能的正常运行至关重要。这篇综述追溯了有关氧化还原与癌症之间联系的发现时间表。有充分的证据表明细胞氧化还原状态参与了癌症的不同特征。回顾并强调了通过调节细胞氧化还原状态控制肿瘤血管生成和转移的证据。

BACKGROUND & AIMS: BACKGROUND:Curcumin has anti-inflammatory, antioxidant and anticancer properties. Despite the considerable evidence showing that curcumin is an efficacious and safe compound for multiple medicinal benefits, there are some demerits with respect to the therapeutic effectiveness of curcumin, namely, poor stability and solubility, and its role in angiogenesis in vivo is still not yet clear. More recently, the biodegradable polymer nanoparticles have been developed. This offers promise for the therapeutic effectiveness of curcumin by increasing its bioavailability, solubility and retention time. METHODS:Here, we compared the medicinal effectiveness of curcumin and nanocurcumin (NC), and found that nanocurcumin can inhibit angiogenesis more effectively than curcumin in zebrafish. Tests of proliferation and apoptosis showed no difference between nanocurcumin-treated and wildtype embryos. RESULTS:qPCR and in situ hybridization experiments indicated that the VEGF signaling pathway genes, vegfa, VEGF-C and flt4 were all down-regulated after nanocurcumin treatment, and vegfa over-expression rescued the vascular defective phenotype. Moreover, hif1a expression also decreased and hif1a over-expression also rescued the vascular defective phenotype but the Notch signaling pathway had no difference after nanocurcumin treatment. CONCLUSION:These results indicate that nano curcumin inhibits angiogenesis in zebrafish by downregulating hif1a/vegfa signaling pathway. Hence, our work reveals the key role of nanocurcumin in angiogenesis in vivo.

背景与目标：

BACKGROUND & AIMS: :Aquaporins (AQPs) are involved in hypoxia-induced angiogenesis and retinal damage. Bumetanide is a diuretic agent, Na+/K+/Cl- cotransporter (NKCC1), and AQP 1-4 inhibitor. We tested the hypothesis that early postnatal treatment with bumetanide suppresses biomarkers of angiogenesis and decreases severe retinopathy oxygen-induced retinopathy (OIR). Neonatal rats were exposed at birth (P0) to either (1) room air (RA); (2) hyperoxia (50% O2); or (3) intermittent hypoxia (IH) consisting of 50% O2 with brief, clustered episodes of 12% O2 from P0 to postnatal day 14 (P14), during which they were treated intraperitoneally (IP) with bumetanide (0.1 mg/kg/day) or an equivalent volume of saline, on P0-P2. Pups were examined at P14 or allowed to recover in RA from P14-P21. Retinal angiogenesis, morphometry, pathology, AQPs, and angiogenesis biomarkers were determined at P14 and P21. Bumetanide reduced vascular abnormalities associated with severe OIR. This was associated with reductions in AQP-4 and VEGF. Bumetanide suppressed sVEGFR-1 in the serum and vitreous fluid, but levels were increased in the ocular tissues during recovery. Similar responses were noted for IGF-I. In this model, early systemic bumetanide administration reduces severe OIR, the benefits of which appear to be mediated via suppression of AQP-4 and VEGF. Further studies are needed to determine whether bumetanide at the right doses may be considered a potential pharmacologic agent to treat retinal neovascularization.

背景与目标： : 水通道蛋白 (AQPs) 参与缺氧诱导的血管生成和视网膜损伤。布美他尼是一种利尿剂，Na/K/Cl-共转运蛋白 (NKCC1) 和AQP 1-4抑制剂。我们检验了以下假设: 布美他尼的早期产后治疗可抑制血管生成的生物标志物并减少严重的视网膜病变氧诱导的视网膜病变 (OIR)。新生大鼠在出生时 (P0) 暴露于 (1) 室内空气 (RA); (2) 高氧 (50% O2); 或 (3) 由50% O2组成的间歇性缺氧 (IH)，从P0到出生后第14天 (P14) 短暂的12% O2聚集发作，在此期间，他们P0-P2用布美他尼 (0.1 mg/kg/天) 或等效体积的盐水腹膜内 (IP) 治疗。在P14检查幼崽或使其从P14-P21中恢复RA。在P14和p21测定视网膜血管生成，形态计量学，病理学，AQPs和血管生成生物标志物。布美他尼减少了与严重OIR相关的血管异常。这与AQP-4和VEGF的减少有关。布美他尼抑制了血清和玻璃体液中的sVEGFR-1，但在恢复过程中眼组织中的水平增加。Igf-i也有类似的反应。在该模型中，早期全身性布美他尼给药减少了严重的OIR，其益处似乎是通过抑制AQP-4和VEGF介导的。需要进一步的研究来确定正确剂量的布美他尼是否可以被认为是治疗视网膜新生血管的潜在药物。