• 【山青石根提取物及其组成成分shisophloroglucin A在体外和体内高糖诱导的血管生成中减弱。】 复制标题 收藏 收藏
    DOI:10.3390/ijms20225542 复制DOI
    作者列表:Fernando KHN,Yang HW,Jiang Y,Jeon YJ,Ryu B
    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。
  • 【具有血管生成和Gibbs-Thomson关系的肿瘤生长的时延自由边界问题的定性分析。】 复制标题 收藏 收藏
    DOI:10.3934/mbe.2019372 复制DOI
    作者列表:Xu SH,Wu J
    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:
  • 【类黄酮,饮食衍生的细胞增殖和体外血管生成抑制剂。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Fotsis T,Pepper MS,Aktas E,Breit S,Rasku S,Adlercreutz H,Wähälä K,Montesano R,Schweigerer L
    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。
  • 【来自大戟的新的mirsinane型二萜。对VEGF诱导的血管生成具有抑制作用。】 复制标题 收藏 收藏
    DOI:10.1007/s11418-012-0686-3 复制DOI
    作者列表:Ghanadian SM,Ayatollahi AM,Afsharypuor S,Javanmard SH,Dana N
    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。
  • 【开发3D血管生成模型以研究肿瘤-内皮细胞相互作用和抗血管生成药物的作用。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-03010-6 复制DOI
    作者列表:Amann A,Zwierzina M,Koeck S,Gamerith G,Pechriggl E,Huber JM,Lorenz E,Kelm JM,Hilbe W,Zwierzina H,Kern J
    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。
  • 【通过调节细胞氧化还原状态控制肿瘤血管生成和转移。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbcan.2020.188352 复制DOI
    作者列表:Serrano JJ,Delgado B,Medina MÁ
    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。
  • 【纳米库黄素通过下调斑马鱼中的hif1a/vegf-a信号来抑制血管生成。】 复制标题 收藏 收藏
    DOI:10.2174/1567202617666200207130039 复制DOI
    作者列表:Cao Z,He S,Peng Y,Liao X,Lu H
    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:
  • 【在氧诱导的视网膜病变大鼠模型中,布美他尼抑制血管生成。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21030987 复制DOI
    作者列表:Guzel S,Cai CL,Ahmad T,Quan M,Valencia GB,Aranda JV,Beharry KD
    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。
  • 【血管生成素: 肿瘤血管生成中的一种平衡。】 复制标题 收藏 收藏
    DOI:10.1158/1541-7786.MCR-07-0072 复制DOI
    作者列表:Shim WS,Ho IA,Wong PE
    BACKGROUND & AIMS: :Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, alpha(5)beta(1) and alpha(v)beta(5) integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2-dependent and TIE-2-independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway.
    背景与目标: : 血管生成素 (ANG-1和ANG-2) 及其TIE-2受体酪氨酸激酶对肿瘤恶性肿瘤具有广泛的作用,包括血管生成,炎症和血管外渗。这些多方面的途径为开发新的抑制癌症治疗策略提供了宝贵的机会。然而,ANG-1和ANG-2在肿瘤血管生成中的调节作用仍存在争议。在塑造血管生成结果中,两个ANGs的互补但相互矛盾的作用之间存在复杂的相互作用。胚胎血管发育表明,ANG-1在参与内皮细胞和血管周围细胞之间的相互作用中至关重要。然而,最近通过ANG-1募集血管周围细胞与其对肿瘤生长的抗血管生成作用有关。很明显,TIE-2信号传导可能直接在肿瘤细胞上以旁分泌和自分泌的方式起作用,因为该受体已在肿瘤细胞中越来越多地发现。此外,α (5) β (1) 和 α (v) β (5) 整联蛋白最近被认为是ANG-1和ANG-2的功能受体。因此,这两种配体在影响整体肿瘤发展的细胞活性中可能具有广泛的功能。总的来说,这些TIE-2依赖性和TIE-2依赖性活性可能解释了肿瘤血管生成中ANG-1和ANG-2的矛盾发现。这些不确定性阻碍了针对这一重要血管生成途径的明确策略的开发。更好地了解血管生成的病理生理调节中ANG-1和ANG-2活性的分子基础,可能为靶向该途径的新疗法奠定基础。
  • 【SP1/tgf-β1/SMAD2途径参与成骨过程中的血管生成。】 复制标题 收藏 收藏
    DOI:10.3892/mmr.2020.10965 复制DOI
    作者列表:Ding A,Bian YY,Zhang ZH
    BACKGROUND & AIMS: :The relationship between osteoblasts and angiogenesis is vital for bone regeneration, especially mandibular and maxillary bones. Transforming growth factor β1 (TGF‑β1) and vascular endothelial growth factor (VEGF) are closely related to angiogenesis; however, the regulatory mechanism between them remains unknown. The present study aimed to reveal this mechanism to provide novel insight for development of potential therapeutic opportunities. Western blotting and reverse transcription‑quantitative PCR was used to assess the protein and mRNA expression levels in MC3T3‑E1 preosteoblast cells and HUVECs, ELISAs were used to detect the expression levels of secreted VEGF, MTT assays were used to assess the viability of the cells, migratory ability was assessed using Transwell assays, angiogenesis assays were used to analyze the formation of blood vessels, and TGF‑β1 regulation was confirmed using a dual‑luciferase reporter assay. The overexpression of specificity protein 1 (SP1) or TGF‑β1 increased VEGF expression levels and secretion, and promoted angiogenesis of co‑cultured HUVECs. SP1 also promoted SMAD2 phosphorylation. These effects of SP1 were all reversed by the TGF‑β1 inhibitor. The VEGF inhibitor bevacizumab also reduced the SP1/TGF‑β1/SMAD2 pathway‑induced angiogenesis of preosteoblasts. In conclusion, it was demonstrated that SP1 promoted TGF‑β1 expression, activated the SMAD2 pathway and induced VEGF secretion, which may enhance angiogenic processes in preosteoblasts.
    背景与目标: : 成骨细胞与血管生成之间的关系对于骨再生至关重要,尤其是下颌骨和上颌骨。转化生长因子 β1 (tgf-β1) 和血管内皮生长因子 (VEGF) 与血管生成密切相关,但它们之间的调控机制尚不清楚。本研究旨在揭示这一机制,为潜在治疗机会的开发提供新的见解。Western blotting和逆转录-定量PCR用于评估MC3T3 ‑ E1前成骨细胞和HUVECs中的蛋白质和mRNA表达水平,ELISAs用于检测分泌的VEGF的表达水平,MTT测定用于评估细胞的活力,使用tranwell测定评估迁移能力,血管生成测定法用于分析血管的形成,并使用双荧光素酶报告测定法确认tgf-β1调节。特异性蛋白1 (SP1) 或tgf-β1的过表达增加了VEGF的表达水平和分泌,并促进了共培养的HUVECs的血管生成。SP1也促进了SMAD2磷酸化。SP1的这些作用都被tgf-β1抑制剂逆转。VEGF抑制剂贝伐单抗还减少了SP1/tgf-β1/SMAD2途径诱导的前成骨细胞血管生成。总之,已证明SP1促进tgf-β1表达,激活SMAD2途径并诱导VEGF分泌,这可能会增强成骨细胞的血管生成过程。
  • 【ETS-1的转录沉默可有效抑制胰腺癌的血管生成。】 复制标题 收藏 收藏
    DOI:10.1038/cgt.2008.65 复制DOI
    作者列表:Lefter LP,Dima S,Sunamura M,Furukawa T,Sato Y,Abe M,Chivu M,Popescu I,Horii A
    BACKGROUND & AIMS: :In this study, we addressed the hypothesis that transcriptional suppression of erythroblastosis virus E26 oncogene homolog 1 (ETS-1) is an efficient therapeutic approach to pancreatic adenocarcinoma by investigating the effect of ETS-1 suppression in human pancreatic cancer cells. We accomplished this by using an adenoviral vector encoding only the DNA-binding domain of wild-type ETS-1 (ETS-1 dominant negative, ETS-1-DN). ETS-1-DN decreases ETS-1-binding by competing for its binding to DNA. Adenoviral-mediated transfer of ETS-1-DN (adenoviral ETS-1-DN construct, AdETS-1-DN) into pancreatic tumor cell lines did not affect their proliferation rate in vitro but did significantly inhibit their in vivo growth in nude mice. Furthermore, to test the efficacy of ETS-1-DN in vivo, we injected the AdETS-1-DN into established human pancreatic adenocarcinomas grown in nude mice. This treatment significantly reduced tumor size as compared to saline injection, without any detectable side effects. Microvessel density in mouse xenografts displayed significantly lower values in tumors in which ETS-1 was downregulated. In addition, expression of the ETS-1-DN in the pancreatic cancer cells resulted in downregulation of urokinase-type plasminogen activator (u-PA) and metalloproteinase-1 (MMP-1) expression. Taken together, these data suggest that transcriptional inactivation of ETS-1 is able to significantly affect angiogenesis and growth of pancreatic cancer. This effect may be due in part to downregulation of MMP-1 and u-PA expression. Our results suggest that ETS-1-DN is a promising candidate for antiangiogenic gene therapy in pancreatic cancer.
    背景与目标: : 在这项研究中,我们通过研究ETS-1抑制在人胰腺癌细胞中的作用,解决了促红细胞生成素病毒26癌基因同源物1 (ETS-1) 的转录抑制是胰腺癌的有效治疗方法的假说。我们通过使用仅编码野生型ETS-1 (ETS-1显性阴性,ETS-1-DN) 的DNA结合域的腺病毒载体来实现这一点。ETS-1-DN通过竞争其与DNA的结合来降低ETS-1-binding。腺病毒介导的ETS-1-DN (腺病毒ETS-1-DN构建体,AdETS-1-DN) 转移到胰腺肿瘤细胞系中不会影响其体外增殖速率,但会显着抑制其在裸鼠体内的生长。此外,为了在体内测试ETS-1-DN的功效,我们将AdETS-1-DN注射到在裸鼠中生长的已建立的人胰腺腺癌中。与注射盐水相比,这种治疗方法可显着减少肿瘤大小,没有任何可检测的副作用。小鼠异种移植物中的微血管密度在ETS-1被下调的肿瘤中显示出明显较低的值。此外,胰腺癌细胞中ETS-1-DN的表达导致尿激酶型纤溶酶原激活剂 (u-PA) 和metalloproteinase-1 (MMP-1) 表达的下调。综合起来,这些数据表明ETS-1的转录失活能够显著影响胰腺癌的血管生成和生长。这种作用可能部分归因于MMP-1和u-PA表达的下调。我们的结果表明,ETS-1-DN是胰腺癌抗血管生成基因治疗的有希望的候选者。
  • 【分泌卷曲相关蛋白2,一种通过血管生成诱导心肌缺血保护的新机制。】 复制标题 收藏 收藏
    DOI:10.1007/s00395-020-0808-0 复制DOI
    作者列表:Vatner DE,Oydanich M,Zhang J,Babici D,Vatner SF
    BACKGROUND & AIMS: :Our hypothesis is that Secreted Frizzled-Related Protein 2 (sFPR2) is an important mechanism mediating ischemic cardioprotection, since it is the most upregulated gene in the third window of ischemic preconditioning. One week after permanent coronary artery occlusion (CAO), sFRP2 TG mice exhibited a 49% higher LV ejection fraction and a 36% reduction in infarct size, p < 0.05, and reduced fibrosis in both adjacent and remote zones, along with an increase in collagen type III and a decrease in the collagen type I/III ratio compared with WTL. The ischemic cardioprotection was associated with increased angiogenesis and arteriogenesis, reflected by increased capillary and arteriolar proliferation in the ischemic zone, thereby preserving blood flow after CAO. The angiogenesis and arteriogenesis were mediated by cross talk between myocytes and endothelial cells. The mechanism for cardioprotection and angiogenesis/arteriogenesis did not involve a traditional vascular growth hormone, e.g., VEGF or FGF, but rather cTGF, and ATF6 through the stress signaling pathway. The ATF6 inhibitor, AEBSF, blocked the upregulation of cTGF and both the angiogenesis and arteriogenesis, resulting in abolition of the reduced infarct size and protection of cardiac function in the sFRP2 TG mouse following permanent CAO. sFRP2 is a novel mechanism to induce angiogenesis/arteriogenesis, mediated through the endoplasmatic reticulum (ER) stress signaling pathway, ATF6 and cTGF, which protects the heart from myocardial ischemia.
    背景与目标: : 我们的假设是,分泌的卷曲相关蛋白2 (sFPR2) 是介导缺血性心脏保护的重要机制,因为它是缺血预处理第三窗口中上调最多的基因。永久性冠状动脉闭塞 (CAO) 一周后,sFRP2 TG小鼠表现出49% 较高的左室射血分数,梗死面积36% 减少,p  <  0.05,邻近和偏远地区的纤维化减少,与WTL相比,随着III型胶原的增加和I/III型胶原比例的降低。缺血心脏保护与血管生成和动脉生成增加有关,这反映在缺血区域的毛细血管和小动脉增殖增加,从而保留了CAO后的血流。血管生成和动脉生成是由心肌细胞和内皮细胞之间的串扰介导的。心脏保护和血管生成/动脉生成的机制不涉及传统的血管生长激素,例如VEGF或FGF,而是cTGF和ATF6通过应激信号通路。ATF6抑制剂AEBSF阻止了cTGF的上调以及血管生成和动脉生成,从而消除了永久性CAO后sFRP2 TG小鼠的梗死面积减少并保护了心脏功能。sFRP2是一种通过内质网 (ER) 应激信号通路ATF6和cTGF介导的诱导血管生成/动脉生成的新机制,可保护心脏免受心肌缺血的侵害。
  • 【CircPDE4B通过靶向miR-181c促进HIF-1α 降解来抑制视网膜病理性血管生成。】 复制标题 收藏 收藏
    DOI:10.1002/iub.2307 复制DOI
    作者列表:Deng Y,Li S,Li S,Yu C,Huang D,Chen H,Yin X
    BACKGROUND & AIMS: :Retinopathy of prematurity is a major cause of childhood blindness worldwide. Hence, exploring the proper treatment methods is a must in tacking this disease. qRT-PCR and western blot were used to detect the expression of genes and proteins, respectively. The proliferation of human retinal vascular endothelial cells (HRECs) was ensured by MTT assay. The luciferase activity was measured through luciferase assay. The inverted phase-contrast light microscope was used to observe the formation of a vascular tube. In the present study, our data demonstrated that circPDE4B was downregulated, while hypoxia-inducible factor-1α (HIF-1α) and VEGFA were upregulated in the retinopathy of prematurity model in vitro and in vivo. CircPDE4B increasing remarkably inhibited the expression of HIF-1α and VEGFA in hypoxia-induced HRECs and subsequent repressed cell proliferation and pathological angiogenesis. We further found that miR-181c suppressed the expression of von Hippel-Lindau (VHL), while circPDE4B could promote VHL expression via binding to miR-181c. Finally, our results revealed that circPDE4B inhibited the expression of VEGFA and pathological angiogenesis via facilitating VHL-mediated ubiquitin degradation of HIF-1α. In conclusion, circPDE4B suppressed the expression of VEGFA and pathological angiogenesis via promoting VHL-mediated ubiquitin degradation of HIF-1α through binding to miR-181c. Our study indicated that circPDE4B might be an effective therapeutic target of retinopathy of prematurity.
    背景与目标: : 早产儿视网膜病变是全球儿童失明的主要原因。因此,探索正确的治疗方法是治疗这种疾病的必要条件。分别使用qRT-PCR和western blot检测基因和蛋白质的表达。通过MTT法确保人视网膜血管内皮细胞 (HRECs) 的增殖。荧光素酶活性通过荧光素酶法测定。使用倒置相差光学显微镜观察血管管的形成。在本研究中,我们的数据表明,在体外和体内的早产儿视网膜病变模型中,circPDE4B被下调,而缺氧诱导因子-1α (HIF-1α) 和VEGFA被上调。CircPDE4B的增加显着抑制了缺氧诱导的hrec中HIF-1α 和VEGFA的表达,随后抑制了细胞增殖和病理性血管生成。我们进一步发现miR-181c抑制了von Hippel-Lindau (VHL) 的表达,而circPDE4B可以通过与miR-181c结合来促进VHL的表达。最后,我们的结果表明,circPDE4B通过促进VHL介导的HIF-1α 的泛素降解来抑制VEGFA的表达和病理性血管生成。总之,circPDE4B通过与miR-181c结合促进VHL介导的HIF-1α 的泛素降解来抑制VEGFA的表达和病理性血管生成。我们的研究表明,circPDE4B可能是早产儿视网膜病的有效治疗靶标。
  • 【淋巴细胞诱导的血管生成因子是由L3T4 + 鼠T淋巴细胞产生的,其产生随着年龄的增长而下降。】 复制标题 收藏 收藏
    DOI:10.1007/BF00199844 复制DOI
    作者列表:Hadar EJ,Ershler WB,Kreisle RA,Ho SP,Volk MJ,Klopp RG
    BACKGROUND & AIMS: :Lymphocyte-induced angiogenesis factor (LIA) is a product of T lymphocytes which has been shown to stimulate new vessel formation. Because immune senescence most profoundly affects T lymphocyte functions, we suspected that LIA production would decline with age. An assay for angiogenesis stimulated by allogeneic reaction was performed by injecting spleen cells from young or old donor mice into the skin of irradiated allogeneic recipient mice. The spleen cells from young mice induced a significantly greater number of vessels than did cells from older mice. In additional experiments, spleen cells from young and old animals were treated with a monoclonal antibody GK 1.5) directed at the L3T4 antigen on murine T helper lymphocytes. Such treatment significantly reduced the new vessel formation induced by young lymphocytes but had no effect on that induced by lymphocytes from old animals. Studies employing indirect immunofluorescence demonstrated that the proportion of L3T4+ cells in the mononuclear fraction of splenocytes was nearly identical in both young and old mice. From these investigations we can conclude that (1) L3T4+ lymphocytes are responsible for LIA production, and (2) production, like that of other T lymphokines, declines with age.
    背景与目标: : 淋巴细胞诱导的血管生成因子 (LIA) 是T淋巴细胞的产物,已被证明可以刺激新的血管形成。由于免疫衰老最深刻地影响T淋巴细胞的功能,因此我们怀疑LIA的产生会随着年龄的增长而下降。通过将年轻或老年供体小鼠的脾细胞注射到受照射的同种异体受体小鼠的皮肤中来进行同种异体反应刺激的血管生成测定。与年长小鼠的细胞相比,年轻小鼠的脾细胞诱导的血管数量明显更多。在另外的实验中,来自年轻和老年动物的脾细胞用针对鼠T辅助淋巴细胞上的L3T4抗原的单克隆抗体GK 1.5) 处理。这种治疗显着减少了年轻淋巴细胞诱导的新血管形成,但对老年动物淋巴细胞诱导的新血管形成没有影响。使用间接免疫荧光的研究表明,在年轻和老年小鼠中,L3T4细胞在脾细胞单核部分中的比例几乎相同。从这些研究中,我们可以得出结论 :( 1) L3T4淋巴细胞负责LIA的产生,并且 (2) 与其他T淋巴因子一样,随着年龄的增长而下降。
  • 【异前列腺素通过激活血栓烷A(2) 受体抑制血管内皮生长因子诱导的内皮细胞迁移,管形成和体外心脏血管发芽以及体内血管生成: ox之间的潜在联系】 复制标题 收藏 收藏
    DOI:10.1161/CIRCRESAHA.108.184036 复制DOI
    作者列表:Benndorf RA,Schwedhelm E,Gnann A,Taheri R,Kom G,Didié M,Steenpass A,Ergün S,Böger RH
    BACKGROUND & AIMS: :Isoprostanes are endogenously formed end products of lipid peroxidation. Furthermore, they are markers of oxidative stress and independent risk markers of coronary heart disease. In patients experiencing coronary heart disease, impaired angiogenesis may exacerbate insufficient blood supply of ischemic myocardium. We therefore hypothesized that isoprostanes may exert detrimental cardiovascular effects by inhibiting angiogenesis. We studied the effect of isoprostanes on vascular endothelial growth factor (VEGF)-induced migration and tube formation of human endothelial cells (ECs), and cardiac angiogenesis in vitro as well as on VEGF-induced angiogenesis in the chorioallantoic membrane assay in vivo. The isoprostanes 8-iso-PGF(2alpha), 8-iso-PGE(2), and 8-iso-PGA(2) inhibited VEGF-induced migration, tube formation of ECs, and cardiac angiogenesis in vitro, as well as VEGF-induced angiogenesis in vivo via activation of the thromboxane A(2) receptor (TBXA2R): the specific TBXA2R antagonists SQ-29548, BM 567, and ICI 192,605 but not the thromboxane A(2) synthase inhibitor ozagrel blocked the effect of isoprostanes. The isoprostane 8-iso-PGA(2) degraded into 2 biologically active derivatives in vitro, which also inhibited EC tube formation via the TBXA2R. Moreover, short hairpin RNA-mediated knockdown of the TBXA2R antagonized isoprostane-induced effects. In addition, Rho kinase inhibitor Y-27632 reversed the inhibitory effect of isoprostanes and the thromboxane A(2) mimetic U-46619 on EC migration and tube formation. Finally, the various isoprostanes exerted a synergistic inhibitory effect on EC tube formation. We demonstrate for the first time that isoprostanes inhibit angiogenesis via activation of the TBXA2R. By this mechanism, isoprostanes may contribute directly to exacerbation of coronary heart disease and to capillary rarefaction in disease states of increased oxidative stress.
    背景与目标: : 异前列腺素是脂质过氧化的内源性终产物。此外,它们是氧化应激的标志物和冠心病的独立危险标志物。在经历冠心病的患者中,血管生成受损可能会加剧缺血性心肌的血液供应不足。因此,我们假设异前列腺素可能通过抑制血管生成而产生有害的心血管作用。我们研究了异前列腺素对血管内皮生长因子 (VEGF) 诱导的人内皮细胞 (ECs) 的迁移和管形成以及体外心脏血管生成的影响,以及在体内绒毛膜尿囊膜测定中对VEGF诱导的血管生成的影响。异前列腺素8-iso-PGF (2α),8-iso-PGE(2) 和8-iso-PGA(2) 在体外抑制VEGF诱导的迁移,ECs的管形成和心脏血管生成,以及通过激活血栓烷A(2) 受体 (TBXA2R) 在体内诱导的血管生成: 特异性TBXA2R拮抗剂SQ-29548、BM 567和ICI 192,605而非血栓烷A(2) 合酶抑制剂奥扎格雷阻断异前列腺素的作用。异前列腺素8-iso-PGA(2) 在体外降解为2种生物活性衍生物,这也通过TBXA2R抑制了EC管的形成。此外,短发夹RNA介导的TBXA2R敲除可拮抗异前列腺素诱导的作用。此外,Rho激酶抑制剂Y-27632逆转异前列腺素和血栓烷A(2) 模拟U-46619对EC迁移和管形成的抑制作用。最后,各种异前列腺素对EC管的形成具有协同抑制作用。我们首次证明异前列腺素通过激活TBXA2R抑制血管生成。通过这种机制,异前列腺素可能直接导致冠心病的加重和氧化应激增加的疾病状态下的毛细血管稀疏。

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