Energy restriction and exercise modulate angiopoietins and vascular endothelial growth factor expression in the cavernous tissue of high-fat diet-fed rats

The purpose of the current study was to evaluate the effect of a high-fat （HF） diet, energy restriction and exercise on the expression of vascular endothelial growth factor （VEGF）, angiopoietin （Ang） I and 2, and their receptors in rat corpus cavernosum （CC）. Male Wistar rats were fed adlibitum with an H F diet for 8 or 16 weeks. After 8 weeks of the H F diet, a group of rats was subjected to energy restriction with or without exercise for 8 weeks. Control animals had free access to standard diet for the same period. After euthanasia, blood was collected and the penises removed for immunofluorescence assays （VEGF, VEGF receptor （VEGFR） I and 2, Angl, Ang2 and Tie2） and semiquantification of VEGF, VEGFR 1, VEGFR2, Angl, Ang2, Tie2, endothelial nitric oxide synthase （eNOS） and Aktlphospho-Akt by Western blotting. HF diet-fed rats exhibited lower high-density lipoprotein cholesterol （HDL-c） levels, higher systolic blood pressure and an increased atherogenic index. A significant increase in Ang2 expression in the CC was verified and coupled to a decrease in VEGF and VEGFRs. The Akt pathway was activated by the HF diet. Energy restriction and exercise increased eNOS expression and restored most HF diet-induced modifications except for VEGFR2 expression. These results emphasize the role of diet on vascular function regulation, demonstrating that cavernous imbalance of VEGF/VEGFRs and Angs/Tie2 systems occurs before serum lipid changes and obesity onset, antedating structural atherosclerotic features.

A Potential Pathological Role of Angiopoietins Expression in Glomeruli during Progressive Glomerulisclerosis Related to Podocyte Injury

A potential pathological role of angiopoietins （Ang） in glomeruli following podocyte injury-induced progressive glomerulosclerosis was explored. Eighty male Wistar rats were randomly allocated into sham operation group （Sham, n= 25）, Uninephrectomy group （UPHT, n= 25） and Uninephrectomy＋Daunorubicin group （DRB, n= 30）. In DRB group, daunorubicin （5 mg/kg） was injected via tail vein on the 7th and 14th day after uninephrectomy. At week 1, 2, 4, 6 and 8 respectively following establishment of the animal model, 5 rats in Sham group and UPHT group, and 6 in DRB group were taken respectively for determining 24-h urinary protein excretion rate （24hUPER）, blood urea nitrogen （BUN） and serum creatinine （Scr）. The sections of kidneys were examined by an electric microscope, PAS staining, immunohistochemical staining and in situ hy-bridization histochemistry. The results showed that 24hUPER, BUN and Scr in DRB group were more than those in Sham group and UPHT group at the same time points, and there was a trend towards an increase on level of GSI in DRB group from week 2 to week 8. Electric microscopy revealed that podocyte injury presented in DRB group. The expression of Angl mRNA and protein in glomeruli of DRB group was decreased, while the expression of Ang2 protein in glomeruli of DRB group increased. Meanwhile, the expression of Angl mRNA had a negative correlation with the expression of Ang2 mRNA, and the expression of Angl protein had a positive correlation with the expression of Angl mRNA, and had a negative correlation with 24hUPER, BUN, Scr, glomerular sclerotic index （GSI）, the expression of Ang2 protein and CoIV protein. The expression of Ang2 protein had a positive correlation with the expression of Ang2 mRNA, and had a positive correlation with 24hUPER, BUN, Scr, GSI, the expression of CoIV protein. It was concluded that podocyte injury might lead to an alteration in the expression of Angl and Ang2 within glomeruli. Ang2 may get rid of inhibition from Angl for downregulation of the Angl expression, which facilitate upregulation of the Ang2 expression in glomeruli to promote progressive glomerulosclerosis in the rats.

VEGFA、VEGFC及其受体和angiopoietin-1/angiopoietin-2及其受体在发育第3-12周人胚胎肝的表达

本研究观察VEGFA和VEGFC及其受体和angiopoietin 1 angiopoietin 2及其受体在发育第 3- 12周人胚胎肝的表达。在征得意外流产孕妇同意并签字后 ,收集其意外流产受精龄为第 3- 12周的人胚胎 ,4 %多聚甲醛固定 ,石蜡包埋切片 ,HE和免疫组织化学染色 ,光镜观察。结果表明 :在发育第 4周 ,肝由少量肝索组成 ,肝内未见造血细胞和血细胞。肝内大、圆、有核的原始血细胞于发育第 5周开始出现 ,并强表达VEGFA、flt 4和Tie 2 ,其数量在发育第 7周达高峰。第 11- 12周 ,阳性细胞数量减少。这类细胞仅于发育第 6周时短暂表达Flk 1。第 7- 12周 ,肝细胞表达VEGFC和flt 1,阳性反应产物积聚在细胞质中。发育第 5周到第 12周胚胎肝血管内 ,有angiopoietin 1和angiopoietin 2阳性反应的细胞存在 ,细胞形态同上述VEGFA、flt 4和Tie 2阳性细胞。angiopoietin 1和angiopoietin 2阳性反应较弱 ,Tie 2的免疫反应强。发育各期 ,肝细胞也弱表达angiopoietin 1和angiopoietin 2和Tie 2。发育各期血管内皮细胞为上述各种因子和受体阴性反应。结论 :发育第 7周之前和第 7周之后 ,VEGF家族及其受体在肝内造血灶的细胞表达模式不同。胎肝造血与肝细胞的发育可能相关。

VEGF和Angiopoietin家族在早期人胚肝发育过程中的作用

目的:观察血管内皮细胞生长因子A(VEGFA)、血管内皮细胞生长因子C(VEGFC)、Angiopo- ietin-1(Ang-1)、Angiopoietin-2(Ang-2)及其受体在发育第3-5 wk人胚胎肝的表达,以了解早期人胚发育过程中血管内皮细胞、造血干细胞与肝干细胞之间的相互关系．方法:实验用发育3,4,5 wk人胚胎标本各8例(共24例),石蜡切片,连续切片,进行 CD34、VEGFA、VEGFC、fms样酪氨酸激酶-1(FLT-1)、胚胎肝激酶1(Flk-1)、FLT-4、 Ang-1、Ang-2、Tie-2免疫组化染色,光镜下观察．结果:3 wk时靠近肝芽的间充质中的血管内皮细胞多,而肝芽内未见血管内皮细胞及造血细胞;4 wk时,肝索形成处可见较多正在形成的新生血管增多,肝索间开始出现少量的造血细胞;5 wk时肝索间出现原始的肝血窦结构,血窦内造血细胞的数量较4 wk明显增多. 发育的3-5 wk,部分肝干细胞及血细胞中出现 VEGFA阳性反应,多数肝细胞及内皮细胞中均有VEGFC免疫反应,而造血细胞中无．多数肝干细胞和少数血管内皮细胞呈flt-1和flk-1 阳性,造血细胞呈flt-1、flk-1免疫反应阴性, 而呈flt-4阳性．肝干细胞强表达Ang-2,而造血细胞表达其受体Tie-2,与此同时,内皮细胞表达Ang-1和Ang-2,而不表达其受体Tie-2．结论:来自肝干细胞的VEGFA信号可使内皮细胞分化、增殖并形成血管;来自内皮细胞的VEGFC、Angiopoietin信号对肝干细胞的生长和分化起作用;造血细胞分泌的VEGFA 可以通过旁分泌途径调节肝干细胞的发育;造血细胞的发育依赖于肝干细胞产生的 VEGFC和Ang-2．

The molecular mechanism underlying angiogenesis in hepatocellular carcinoma: the imbalance activation of signaling pathways

OBJECTIVE: To explore the effect of two dominating signaling pathways, VEGF/KDR and angiopoietins/Tie2, on the formation of new blood vessel in hepatocellular carcinoma (HCC) growth and metastasis. METHODS: RT-PCR and Western blot were employed to evaluate the VEGF/KDR and angiopoietins/Tie2 expression in samples from 23 patients with HCC. Meanwhile, microvessel density (MVD) was determined as a marker of angiogenesis by counting CD34 positive cells with the method of immunohistochemistry. RESULTS: The two pathways were activated in all HCC samples. The expressions of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) were significantly higher (P<0.05) in hepatocellular carcinoma tissues and the margin of the tumor than those in control groups, and so did CD34 positive cells. Although significant difference in the expression of kinase insert domain containing receptor (KDR) and Ang1/Tie2 was not observed in all groups, their distinct high levels were seen in hepatoma and its margin compared with normal and cirrhotic liver. VEGF and Ang2 expressions were seen up-regulated in HCC with vascular invasion and satellite lesion. CONCLUSIONS: The two signaling pathways, VEGF/KDR and angiopoietins/Tie2 are activated in the process of angiogenesis in HCC and modulate the formation of new blood vessels. The imparity of the two signaling pathways' activation is to benefit HCC metastasis. In the two pathways, VEGF and Ang2 may play an important role in the process of angiogenesis, and are necessary indicators for the prognosis and metastasis of HCC. This study provides another clue for the exploration of anti-angiogenic agents.

人血管生成素1真核表达载体的构建及在兔骨髓间充质干细胞的表达

目的 探索构建人血管生成素1( human angiopoietin 1,h Ang- 1)真核表达载体,转染体外培养兔骨髓间充质干细胞( marrow mesenchymal stem cells,MSCs)修复骨缺损的可能性。 方法 基因重组和限制性内切酶酶切构建真核表达载体pc DNA3- h Ang- 1,经脂质体DOTAP介导质粒转染兔MSCs,G4 18筛选阳性克隆,RT- PCR及免疫印迹杂交检测h Ang- 1m RNA及蛋白表达。 结果 重组真核表达载体pc DNA3- h Ang- 1经限制性内切酶Xho- I和Bam H- I酶切后,电泳显示1.4 kb h Ang- 1目的片段和5 .4 kb pc DNA3载体片段,转染兔MSCs后,RT- PCR检测出目的基因m RNA,免疫印迹杂交检出h Ang- 1的蛋白表达。 结论 构建的真核表达载体pc DNA3- h Ang- 1能在转染的兔MSCs中表达。

Angiopoietin/Tie2系统在大鼠高动力型肺动脉高压形成中的作用(英文)

目的研究angiopoietin家族成员在高动力型肺动脉高压形成中的作用。方法通过左颈总动脉和左颈外静脉分流手术建立大鼠高动力型肺动脉高压模型。术后第1、2、4、8和12周检测肺组织内Ang-1、Ang-2、Ang-3、Tie2和激活型caspase-3的变化。结果高动力引起肺动脉高压,出现肺动脉内皮细胞增生肥大。在肺动脉高压形成的过程中,肺组织内Ang-1和Tie2的表达显著增高,而Ang-3的表达明显降低。肺微小动脉内皮细胞Tie2的磷酸化水平逐渐升高但激活型caspase-3却降低。Ang-2的表达未见明显变化。结论内皮细胞凋亡减少可能是高动力型肺动脉高压形成的一个重要的病理机制。Ang-1/Tie2可能通过抑制内皮细胞凋亡来促进高动力型肺动脉高压的形成。Ang-3的表达量下降可能也促进了这一过程。在高动力型肺动脉高压的形成过程中Ang-2可能不发挥作用。

胆管细胞性肝癌的血管新生及临床病理意义(英文)

目的目前关于胆管细胞性肝癌(CCC)的血管新生研究较少,本研究的目的在于描述CCC的血管新生的特点,其与血管新生调控因子之间的关系以及临床- 病理意义。方法调查33例手术切除的CCC标本。肿瘤微血管密度(MVD )使用抗CD34 抗体进行标记,并进行了VEGF Ang-1 Ang-2 and TSP-1的免疫组化染色。结果本组C CC的MVD为(87.2±52.6),范围为10-229。VEGF Ang-1 Ang-2和TSP-1的阳性率分别为75.6% ,36% ,57.6%和45.5% 。VEGF和Ang-2的阳性表达与高MVD相关,TSP-1则负相关(P值分别为0.004,0.015和0.005)。阳性TSP-1 与肝内转移正相关(46.7% vs.5.6% ,P=0.012)。除此之外,并没有发现VEGF Ang-1 Ang-2和TSP-1的阳性表达与肿瘤大小,包膜形成,包膜浸润,门脉侵犯,肝内转移,细胞分化之间的相关性。MVD的高低以及VEGF,Ang-1,Ang-2和TSP-1的阳性表达与根治性切除的23例的术后生存率之间没有发现相关性。结论CCC瘤内的血管新生活跃,其瘤内血管新生与病理类型有一定的关系。VEGF和Ang2的阳性表达与CCC血管新生正相关,TSP-1则与其负相关。TSP-1的阳性表达还与肝内转移正相关,除此此外,并没有发现MVD和VEGF,ANG1,orANG2的表达与肿瘤的恶性程度或者预后相关。

Effects of natural mineral-rich water consumption on the expression of sirtuin 1 and angiogenic factors in the erectile tissue of rats with fructose-induced metabolic syndrome

Consuming a high-fructose diet induces metabolic syndrome （MS）-Iike features, including endothelial dysfunction. Erectile dysfunction is an early manifestation of endothelial dysfunction and systemic vascular disease. Because mineral deficiency intensifies the deleterious effects of fructose consumption and mineral ingestion is protective against MS, we aimed to characterize the effects of 8weeks of natural mineral-rich water consumption on the structural organization and expression of vascular growth factors and receptors on the corpus cavernosum （CC） in 10% fructose-fed Sprague-Dawley rats （FRUCT）. Differences were not observed in the organization of the CC either on the expression of vascular endothelial growth factor （VEGF） or the components of the angiopoietins/Tie2 system. However, opposing expression patterns were observed for VEGF receptors （an increase and a decrease for VEGFR1 and VEGFR2, respectively） in FRUCT animals, with these patterns being strengthened by mineral-rich water ingestion. Mineral-rich water ingestion （FRUCTMIN） increased the proportion of smooth muscle cells compared with FRUCT rats and induced an upregulatory tendency of sirtuin I expression compared with the control and FRUCT groups. Western blot results were consistent with the dual immunofluorescence evaluation. Plasma oxidized low-density lipoprotein and plasma testosterone levels were similar among the experimental groups, although a tendency for an increase in the former was observed in the FRUCTMIN group. The mineral-rich water-treated rats presented changes similar to those observed in rats treated with MS-protective polyphenol-rich beverages or subjected to energy restriction, which led us to hypothesize that the effects of mineral-rich water consumption may be more vast than those directly observed in this study.

血管生成素(Angiopoietin)的作用机制和功能

0 引言 Angiopoietin 是一族分泌型的细胞因子,目前尚未见公认的译文,根据词根构成我们暂称为血管生成素。该细胞因子家族在血管重塑、胚胎血管发育、癌症等研究热点中所起的重要作用,使其成为热点中的焦点。 Ang 家族的4位成员 Ang-1、Ang-2、Ang-3和Ang-4 所起的作用各自不同,而其受体 Tie-1、Tie-2的功能也有差异。Ang-1 通过激活其受体酪氨酸激酶Tie-2发挥:①抑制内皮细胞凋亡。

Shared changes in angiogenic factors across gastrointestinal vascular conditions:A pilot study

BACKGROUND Neovascularisation is common to a variety of gastrointestinal(GI)disorders with differing aetiologies and presentations;usually affecting adults above 60 years.Shared angiogenic factors modulated by disease specific elements could be a common denominator and represent novel diagnostic and therapeutic targets.As yet,assessment of angiogenic factors across several GI vascular disorders associated with recurrent bleeding and anaemia has not been reported.AIM To assess serum levels of angiogenic factors in several intestinal vascular disorders.METHODS A case control study was performed in Tallaght University Hospital in patients with endoscopically proven small bowel angiodysplasia(SBA),portal hypertensive gastropathy(PHG),gastric antral vascular ectasia(GAVE)and nonbleeding,non-anaemic controls.Using enzyme-linked immunosorbent assay,concentrations of Angiopoietin 1(Ang-1),Ang-2 and vascular endothelial growth factor(VEGF)were measured from 2 serum tubes of blood following informed consent.The relative expression of Ang-1 and Ang-2 and Ang-1/2 ratio was calculated and compared between groups.Statistical analysis was applied using a t-test,and a P value of<0.05 was considered significant.RESULTS To date 44 samples were tested:10 SBA,11 PHG,8 GAVE and 15 controls.Mean age 60(range 20-85)years and 20(45%)were males.Controls were significantly younger(49 years vs 66 years,P=0.0005).There was no difference in VEGF levels between the groups(P=0.6).SBA,PHG and GAVE Ang-1 levels were similar and were significantly lower than controls,(P=0.0002,95%CI:241 to 701).Ang-2 levels were statistically higher in PHG and GAVE groups compared to controls(P= 0.01, 95%CI: 77.8 to 668) and as a result, also had a lower Ang-1/2 ratioscompared to controls. While SBA Ang-2 levels were higher than controls, this didnot reach statistical significance. Neither age nor haemoglobin level, which wassimilar between disease groups, could explain the difference. In addition, themedian Ang-1/Ang-2 ratio for all patients was found to be significantly lowercompared to controls, 8 vs 28 respectively, P = 0.001, 95%CI: -27.55 to -7.12.CONCLUSIONOur novel pilot study suggests common alterations in Ang-1 and Ang-2 levelsacross several GI vascular disorders. Differences in Ang-1/Ang-2 ratios amongvascular disorders compared to controls suggest disease-specific modulation.

血管生成素与动脉粥样硬化关系的研究进展

血管内皮细胞在炎症反应中发挥着重要的作用，它可调节血管的通透性，影响炎症细胞的局部浸润。炎症反应在动脉粥样硬化的进程中发挥着重要的作用，内皮细胞的完整性具有抑制动脉粥样硬化形成的作用［1］。多项研究表明，血管生成素（Angiopoietin ，Ang）-酪氨酸激酶受体（Tie）系统在调节血管内皮细胞炎性反应中起重要作用，影响动脉粥样硬化的形成与发展。本文根据国内外的研究进展，通过对Ang-Tie受体系统在血管性疾病的调节作用及机理，尤其是Ang-1及Ang-2对动脉粥样硬化进展的影响，进行简要综述和归纳，以进一步了解A ng在动脉粥样硬化中的作用。

血管形成因子与肾脏

血管形成因子(ANGPT)是近年来被发现的一组生长因子,主要包括ANGPT-1,2,3,4等,其通过Tie受体作用于血管内皮细胞,参与血管的生成、成熟和修复,调节毛细血管的通透性。在肾组织ANGPF作为血管内皮细胞生长因子的潜在调节因子,在维持肾小球毛细血管结构和调节肾小球通透性等诸方面发挥着重要作用。ANGPT表达异常在多种肾脏疾病发病机制中具有重要意义,因此,ANGPT有可能成为治疗与肾小球通透性增加或肾小球毛细血管损害相关疾病的一种新的治疗靶分子。

食管癌高发区食管癌组织中VEGF,Angiopoietin及其受体的表达及意义

目的血管生成在肿瘤生长和转移中起重要作用。VEGF和Angiopoietin是目前已知特异性作用血管内皮细胞的促血管生成因子。本研究采用RNA酶保护性分析和免疫组织化学的方法对30例食管癌高发区食管癌的癌组织和癌旁组织VEGF,An-giopoietin及其受体的mRNA和蛋白表达水平进行检测。食管癌组织中VEGF及其受体Flt-1,淋巴内皮特异性受体Flt-4,Angiopoietin受体Tie-2以及血管内皮标志物CD31和CD105mRNA较其癌旁组织显著升高(P<0.05),Angiopoietin-1无显著变化。VEGF和An-giopoietin-1分别与其受体Flt-1和Tie-2mRNA上调具有显著的正相关(r分别为0.54和0.71,P<0.05),与CD31和CD105mRNA也具有显著的正相关(P<0.05)。免疫组织化学显示VEGF和Angiopoietin-2在食管癌组织中过度表达,提示食管癌组织中存在血管内皮和淋巴内皮的活跃增殖。联合抑制VEGF,Angiopoietin和淋巴内皮生长因子或其受体可能抑制肿瘤新生血管和淋巴管的形成,从而降低淋巴及血行转移的潜能。

Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?

Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma(HCC) since 2007 and numerous studieshave investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.

Effects of laser photocoagulation on serum angiopoietin-1, angiopoietin-2, angiopoietin-1/angiopoietin-2 ratio, and soluble angiopoietin receptor Tie-2 levels in type 2 diabetic patients with proliferative diabetic retinopathy

·AIM: To determine the effects of laser photocoagulation on serum levels of angiopoietin-1(Ang-1),angiopoietin-2(Ang-2), soluble angiopoietin receptor Tie-2(Tie-2), Ang-1/Ang-2 ratio and vascular endothelial growth factor(VEGF) in patients with type 2diabetes mellitus(T2DM) and proliferative diabetic retinopathy(PDR). We also explored the role of the Ang/Tie system in PDR.·METHODS:Totally 160patientswithT2 DM, including50 patients with non-diabetic retinopathy(NDR), 58 patients with non-proliferative diabetic retinopathy(NPDR), and52 patients with PDR were enrolled in this study. Serum Ang-1, Ang-2, Tie-2 receptor and VEGF levels were measured using enzyme-linked immunosorbent assays for all patients and were repeated in 26 patients who underwent laser photocoagulation two months after the procedure.·RESULTS:ThemedianlevelsofAng-2andVEGFinserum were significantly higher in the NPDR group(4.23 ng/mL and 303.2 pg/mL, respectively) compared to the NDR group(2.67 ng/mL and 159.8 pg/mL, respectively, P 【0.01), with the highest level in the PDR group(6.26 ng/mL and531.2 pg/mL, respectively, P 【0.01). The median level of Ang-1 was significantly higher in the NPDR group(10.77ng/mL) compared to the NDR group(9.31 ng/mL) and the PDR groups(9.54 ng/mL)(P 【0.05), while no difference was observed between the PDR and NDR groups. Ang-1/Ang-2 ratio of PDR group was lowest in three groups(1.49 vs 2.69 and 2.90, both P 【0.01). The median level of Tie-2was not significantly different among three groups(P 】0.05).Ang-2 was positively correlated with VEGF and Tie-2 in the PDR and NPDR groups(both P 【0.05). Among the 26 patients who underwent laser photocoagulation, serum Ang-2 and VEGF levels significantly decreased(both P 【0.05), whereas serum Ang-1 level and Ang-1/Ang-2ratio were weakly increased(P 】0.05). The median levels of Ang-2 and VEGF in serum were highest in PDR group,however, Ang-1/Ang-2 ratio of PDR group was lowest in three groups.·CONCLUSION: Laser photocoagulation can reduce serum Ang-2 and VEGF levels. The Ang/Tie system and VEGF play an important role in the development and progression of T2 DM patients with PDR.

Total and not bevacizumab-bound vascular endothelial growth factor as potential predictive factors to bevacizumab-based chemotherapy in colorectal cancer

AIM: To identify suitable biomarkers of response to bevacizumab(BV)- it remains an open question. The measurement of serum vascular endothelial growth factor(VEGF) has been proposed as a predictive factor for this drug, even if literature data are contradictory. METHODS: We prospectively evaluated the role of BV, total and not BV-bound VEGF and angiopoietin-2(Ang-2) serum levels as potential predictive factors of response for BV in combination with an oxaliplatinbased chemotherapy. BV, Ang-2, total and not BVbound VEGF levels were measured at baseline, before 2^(nd) and 5^(th) cycle of oxaliplatin-based chemotherapy in 20 consecutive metastatic colorectal cancer patients. RESULTS: Results were correlated to response to treatment. Variability in BV levels have been found, with decreased level in less responding patients. In particular, the concentration of BV increased of 3.96 ± 0.69 folds in serum of responsive patients after 3 more cycles of therapy compared to those with stable or progressive disease with a 0.72 ± 0.25 and 2.10 ± 0.13 fold increase, respectively. The determination of free and total VEGF demonstrated that the ratio between the two values, evaluated immediately before the 2^(nd) and the 5^(th) cycle of therapy, decreased from 26.65% ± 1.33% to 15.50% ± 3.47% in responsive patients and from 53.41% ± 4.75 to 34.95% ± 2.88% in those with stable disease. Conversely, in those with progression of disease, the ratio showed the opposite behavior coming up from 25.99% ± 5.23% to 51.71% ± 5.28%. The Ang-2 levels did not show any relationship. CONCLUSION: Our data show that the ratio of not BV-bound VEGF to total VEGF serum and BV plasma concentrations for predicting the response to BV plus oxaliplatin-based chemotherapy could be a promising biomarker of response to BV.

ANGPTL2 expression in gastric cancer tissues and cells and its biological behavior

AIM To explore expression of angiopoietin-like protein 2(ANGpT L2) and its effect on biological behavior such as proliferation and invasiveness in gastric cancer. METHODS Western blotting was used to detect expression of ANGp TL2 in 60 human normal gastric tissues, 60 human gastric cancer tissues and gastric cell lines including GES-1, N87, SGC7901, BGC823 and pA MC82. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) and Transwell assay were used to detect the proliferation and invasive ability of gastric cancer cells. RESULTS Compared to normal tissues, ANGp TL2 protein levels were significantly upregulated in gastric tissues, and this level was closely correlated with gastric tumor grade, clinical stage and lymph node metastasis. Compared to GES-1 cells, ANGpT L2 mR NA and protein levels were significantly increased in gastric cancer cells including N87, SGC7901, BGC823 and p AMC82. The expression of ANGpT L2 in highly malignant gastric cancer cell lines BGC823 and pA MC82 was significantly higher than in low malignancy gastric cancer cell lines N87 and SGC7901. MTT and Transwell experiments indicated that the proliferation rate and invasive ability of stable overexpressed gastric cancer cells was faster than in cells transfected with Lv-NC and blank controlcells, and the invasive ability of stable overexpressed gastric cancer cells was higher than that of cells transfected with Lv-NC and blank control cells.CONCLUSION ANGp TL2 contributed to proliferation and invasion of gastric cancer cells. In clinical treatment, ANGpT L2 may become a new target for treatment of gastric cancer.

血管生成素样蛋白-4在动脉粥样硬化过程中的双重作用

血管生成素样蛋白（angiopoietin-like protein,ANGPTL）是分泌性糖蛋白,与血管生成素（angiopoietin）结构同源;其参与血管生成调控,以及糖脂代谢调控。血管生成素样蛋白-4（ANGPTL-4）,因具有抑制血管生成效应、以及对脂蛋白酯酶（lipoprotein lipase,LPL）的抑制效应,而成为近年来医学界的研究热点。最近,耶鲁大学Carlos F.Hernando团队揭示：ANGPTL-4密切参与动脉粥样硬化形成过程;尤为让人惊奇的是,该分子在动脉粥样硬化形成过程中,发挥＂双重作用＂。

Anti-angiogenesis and anti-inflammatory effects of Moringa oleifera leaf extract in the early stages of streptozotocin-induced diabetic nephropathy in rats

Objective:To investigate the effect of Moringa oleifera leaf extract on angiogenesis and inflammatory process in a rat model of streptozotocin-induced diabetic nephropathy.Methods:Four weeks after a single injection of 50 mg/kg streptozotocin,rats were treated with 100 or 200 mg/kg/day Moringa oleifera leaf extract,1 mg/kg/day dapagliflozin,or a combination of Moringa oleifera leaf extract and dapagliflozin for further eight weeks.Renal function,kidney histology,and gene expression were evaluated at the end of the experiment.Results:Renal function of diabetic rats was significantly impaired as evidenced by increased blood urea nitrogen,albuminuria,24-h proteinuria,and high creatinine clearance which indicated glomerular hyperfiltration.In addition,diabetic rats showed an increase in gene expressions of vascular endothelial growth factor-A(VEGF-A),angiopoietin-2(Ang2),the Ang2/Ang1 ratio,tumor necrosis factor-α,interleukin-1βand monocyte chemoattractant protein-1.Immunohistochemical staining demonstrated a significant increase in the density of glycoprotein CD34.Moringa oleifera leaf extract markedly improved all renal dysfunction markers and modulated the upregulated expression of angiogenic factors and inflammatory genes.Conclusions:Moringa oleifera leaf extract could suppress abnormal angiogenesis and inflammatory processes possibly by downregulating gene expression of angiogenesis factors and proinflammatory cytokines.