Vascular endothelial growth factor A, secreted in response to transforming growth factor-β1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells

Hypoxia and transforming growth factor-β1 （TGF-β1） increase vascular endothelial growth factor A （VEGFA） expression in a number of malignancies. This effect of hypoxia and TGF-β1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-β1 was shown to induce VEGFA165 secretion from both normal cell lines （HPV7 and RWPE1） and prostate cancer cell lines （DU 145 and PC3）. Conversely, hypoxia-stimulated VEGFA165 secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-β1 expression in PC3 prostate cancer cells, and the TGF-β1 type I receptor （ALK5） kinase inhibitor partially blocked hypoxia-mediated VEGFA16s secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor （VEGFR） 1 （Fit-l） and 2 （FIk-I/KDR）. Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA165 treatment induced phosphorylation of extracellular signal-regulated kinase 1/2 （ERKI/2） in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA165 was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-β1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-β1 and hypoxia on metastatic prostate cancers.

The Effect of Simvastatin on mRNA Expression of Transforming Growth Factor-β1,Bone Morphogenetic Protein-2 and Vascular Endothelial Growth Factor in Tooth Extraction Socket

Aim To determine the effect of local simvastatin application on the mRNA expression level of transforming growth factor-β1 （TGF-β1）, bone morphogenetic protein-2 （BMP-2） and vascular endothelial growth factor （VEGF） in the tooth sockets of rat. Methodology Forty-eight male Wistar rats were randomly divided into experimental and control groups （n=24）. Polylactic acid/polyglycolic acid copolymer carriers, with or without simvastatin, were implanted into extraction sockets of right mandibular incisors. The expression of TGF-β1, BMP-2 and VEGF mRNA was determined by in situ hybridization in the tooth extraction socket at five days, one week, two weeks and four weeks after implantation. Results The fusiform stroma cells in the tooth extraction socket began to express TGF-β1, BMP-2 and VEGF mRNA in both experimental and control groups from one week after tooth extraction until the end of experiment. The expression of TGF-131 and BMP-2 mRNA in the experimental group was significantly up-regulated after one, two and four weeks, and expression of VEGF mRNA was significantly increased after one and two weeks compared with that in the control group. Conclusion The findings indicate that local administration of simvastatin can influence alveolar bone remodeling by regulating the expression of a school of growth factors which are crucial to osteogenesis in the tooth extraction socket.

Elevated levels of interleukin-1β, interleukin-6, tumor necrosis factor-α and vascular endothelial growth factor in patients with knee articular cartilage injury

BACKGROUND Inflammatory cytokines play a vital role in the occurrence of osteoarticular injury and inflammation. Whether inflammation-associated factors interleukin-1β(IL- 1β), IL-6, tumor necrosis factor-α(TNF-α) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of keen articular cartilage injury remains poorly understood. AIM To measure the levels of inflammatory factors [IL-1β, IL-6, TNF-α and VEGF] in patients with knee articular cartilage injury. METHODS Fifty-five patients with knee articular cartilage injury were selected as patient groups, who were divided into three grades [mild (n = 20), moderate (n = 19) and severe (n = 16)] according to disease severity and X-ray examinations. Meanwhile, 30 healthy individuals who underwent physical examination were selected as the control group. The levels of IL-1β, IL-6, TNF-α and VEGF were measured by ELISA and immunohistochemical staining. RESULTS Compared with the control group, patient groups displayed significantly higher levels of IL-1β, IL-6, TNF-α and VEGF, and the extent of increase was directly proportional to the severity of injury (P < 0.05). In addition, the number of cells with positive staining of IL-1β, IL-6, TNF-α and VEGF in the synovial membrane were significantly increased, along with increased disease severity (P < 0.05). After treatment, the scores of visual analogue scale and the Western Ontario and McMaster University of Orthopaedic Index in patient groups were 2.26 ± 1.13 and 15.56 ± 7.12 points, respectively, which were significantly lower than those before treatment (6.98 ± 1.32 and 49.48 ± 8.96). Correlation analysis suggested that IL-1β and TNF-α were positively correlated with VEGF. CONCLUSION IL-1β, IL-6, TNF-α and VEGF levels are increased in patients with knee articular cartilage injury, and are associated with the disease severity, indicating they might play an important role in the occurrence and development of knee articular cartilage injury. Furthermore, therapeutically targeting them might be a novel approach for the treatment of keen articular cartilage injury.

Vascular endothelial growth factor-165b protects the blood-retinal barrier from damage after acute high intraocular pressure in rats

AIM:To elucidate the role of vascular endothelial growth factor-165b(VEGF-165b)in blood-retinal barrier(BRB)injury in the rat acute glaucoma model.METHODS:In this study,the rat acute high intraocular pressure(HIOP)model was established before and after intravitreous injection of anti-VEGF-165b antibody.The expression of VEGF-165b and zonula occludens-1(ZO-1)in rat retina was detected by double immunofluorescence staining and Western blotting,and the breakdown of BRB was detected by Evans blue(EB)dye.RESULTS:The intact retina of rats expressed VEGF-165b and ZO-1 protein,which were mainly located in the retinal ganglion cell layer and the inner nuclear layer and were both co-expressed with vascular endothelial cell markers CD31.After acute HIOP,the expression of VEGF-165b was up-regulated;the expression of ZO-1 was down-regulated at 12h and then recovered at 3d;EB leakage increased,peaking at 12h.After intravitreous injection of anti-VEGF-165b antibody,the expression of VEGF-165b protein was no significantly changed;and the down-regulation of the expression of ZO-1 was more obvious;EB leakage became more serious,peaking at 3d.EB analysis also showed that EB leakage in the peripheral retina was greater than that in the central retina.CONCLUSION:The endogenous VEGF-165b protein may protect the BRB from acute HIOP by regulating the expression of ZO-1.The differential destruction of BRB after acute HIOP may be related to the selective loss of retinal ganglion cells.

Phosphatase and tensin homology deleted in chromosome 10,hypoxia-inducible factor-1 alpha gene expression in colorectal adenoma and adenocarcinoma and their relation to vascular endothelial growth factor protein expression

To examine phosphatase and tensin homology deleted in chromosome 10 (PTEN),hypoxia-inducible factor-1 alpha (HIF-1 alpha) gene expressions and their relation to vascular endothelial growth factor(VEGF) protein expression in the patients with human colorectal adenomas and adenocarcinomas.Methods The expression of PTEN,HIF-1 alpha gene was detected by using in situ hybridization,and the VEGF expression levels by immunohistochemistry in colorectal adenomas and primary colorectal adenocarcinoma.Results Strong expression of HIF-1 alpha was detectable in the majority of colorectal dadenocarcinoma,particularly surrounding areas of necrosis in adenocarcinoma.PTEN,HIF-1 alpha mRNA and VEGF protein were positive in 51.6%,67.7% and 59.7% respectively in 62 cases of adenocarcinomas,and 77.8%,44.4% and 33.3% respectively in 18 cases of adenomas.The positive rate of VEGF was higher in the patients with colorectal adenocarcinomas than that in those with adenomas,whereas that of PTEN mRNA was contrary.HIF-1 mRNA expression was correlated significantly with lymph node metastasis,liver metastasis,Duke’s stage and recurrence.During colorectal tumor progression,the expression of HIF-1 alpha mRNA was positively correlated with the VEGF protein expression (χ2= 4.751 ,P<0.05),but negatively with the PTEN mRNA expression(χ2=21.84,P<0.01).Conclusion The absence or low expression of PTEN and the increased levels of HIF-1α and VEGF may paly an important role in carcinogenesis and progression of colorectal carcinoma.These results suggest that VEGF upregulated by HIF-1 alpha gene may be involved in angiogenesis of colorectal adenocarcinoma.4 refs,1 tab.

Integrin binding peptides facilitate growth and interconnected vascular-like network formation of rat primary cortical vascular endothelial cells in vitro

Neovascularization and angiogenesis in the brain are important physiological processes for normal brain development and repair/regeneration following insults. Integrins are cell surface adhesion receptors mediating important function of cells such as survival, growth and development during tissue organization, differentiation and organogenesis. In this study, we used an integrin-binding array platform to identify the important types of integrins and their binding peptides that facilitate adhesion, growth, development, and vascular-like network formation of rat primary brain microvascular endothelial cells. Brain microvascular endothelial cells were isolated from rat brain on post-natal day 7. Cells were cultured in a custom-designed integrin array system containing short synthetic peptides binding to 16 types of integrins commonly expressed on cells in vertebrates. After 7 days of culture, the brain microvascular endothelial cells were processed for immunostaining with markers for endothelial cells including von Willibrand factor and platelet endothelial cell adhesion molecule. 5-Bromo-2′-dexoyuridine was added to the culture at 48 hours prior to fixation to assess cell proliferation. Among 16 integrins tested, we found that α5β1, αvβ5 and αvβ8 greatly promoted proliferation of endothelial cells in culture. To investigate the effect of integrin-binding peptides in promoting neovascularization and angiogenesis, the binding peptides to the above three types of integrins were immobilized to our custom-designed hydrogel in three-dimensional(3 D) culture of brain microvascular endothelial cells with the addition of vascular endothelial growth factor. Following a 7-day 3 D culture, the culture was fixed and processed for double labeling of phalloidin with von Willibrand factor or platelet endothelial cell adhesion molecule and assessed under confocal microscopy. In the 3 D culture in hydrogels conjugated with the integrin-binding peptide, brain microvascular endothelial cells formed interconnected vascular-like network with clearly discernable lumens, which is reminiscent of brain microvascular network in vivo. With the novel integrin-binding array system, we identified the specific types of integrins on brain microvascular endothelial cells that mediate cell adhesion and growth followed by functionalizing a 3 D hydrogel culture system using the binding peptides that specifically bind to the identified integrins, leading to robust growth and lumenized microvascular-like network formation of brain microvascular endothelial cells in 3 D culture. This technology can be used for in vitro and in vivo vascularization of transplants or brain lesions to promote brain tissue regeneration following neurological insults.

血清IL-8、ESM-1、VAP-1在慢性阻塞性肺疾病临床诊断及病情评估中的应用

目的探讨慢性阻塞性肺疾病(COPD)患者血清白细胞介素-8(IL-8)、内皮特异性分子-1(ESM-1)、血管黏附蛋白-1(VAP-1)表达水平,分析其与病情程度相关性及其对COPD的诊断价值。方法选取2021年11月至2022年8月郑州大学第一附属医院收治的153例COPD患者为研究对象,其中COPD稳定期42例(设为SCOPD组)、COPD急性加重期111例(设为AECOPD组),同时选取同期于医院体检的健康志愿者51例为对照组。比较两组临床资料及血清IL-8、ESM-1、VAP-1水平。对比不同病情程度患者血清IL-8、ESM-1、VAP-1水平。分析血清各指标与肺功能、生化指标、病情程度相关性。评价血清各指标对SCOPD、AECOPD的诊断价值。结果AECOPD组、SCOPD组血清IL-8、ESM-1、VAP-1水平高于对照组,且AECOPD组高于SCOPD组(P<0.05);IL-8、ESM-1、VAP-1与生化指标、COPD评估测试表(CAT)、病情程度呈正相关,与肺功能呈负相关(P<0.05);血清各指标联合诊断SCOPD与AECOPD的曲线下面积(AUC)大于单独指标诊断(P<0.05)。结论血清IL-8、ESM-1、VAP-1与COPD病情严重程度相关,联合检测其水平对COPD具有一定诊断价值,可能作为疾病诊断、病情评估的重要指标。

Transforming growth factor-β1 and vascular endothelial growth factor levels in senile acute myeloid leukemia and correlation with prognosis

BACKGROUND Acute myeloid leukemia(AML)is a disease in which immature hematopoietic cells accumulate in the bone marrow and continuously expand,inhibiting hematopoiesis.The treatment and prognosis of this disease have always been unsatisfactory.AIM To investigate the correlation between vascular endothelial growth factor(VEGF)and transforming growth factor-β1(TGFβ1)expression and prognosis in older adults with AML.METHODS This study enrolled 80 patients with AML(AML group),including 36 with complete response(AML-CR),23 with partial response(AML-PR),and 21 with no response(AML-NR).The expression levels of VEGF and TGFβ1 were detected by reverse transcription polymerase chain reaction in bone marrow mononuclear cells isolated from 56 healthy controls.Kaplan-Meier analysis was performed to assess overall survival(OS)and progression-or disease-free survival(DFS).Prognostic risk factors were analyzed using a Cox proportional hazards model.RESULTS The AML group showed a VEGF level of 2.68±0.16.VEGF expression was lower in patients with AML-CR than those with AML-PR or AML-NR(P<0.05).TGFβ1 expression in the AML group was 0.33±0.05.Patients with AML-CR showed a higher TGFβ1 expression than those with AML-PR or AML-NR(P<0.05).VEGF and TGFβ1 expression in patients with AML was significantly correlated with the counts of leukocytes,platelets,hemoglobin,and peripheral blood immature cells(P<0.05);Kaplan-Meier survival analysis revealed that patients with high TGFβ1 expression had better OS and DFS than those with low TGFβ1 expression(P<0.05),whereas patients with low VEGF levels showed better OS and DFS than those with high VEGF levels(P<0.05).VEGF,TGFβ1,and platelet count were identified by the Cox proportional hazards model as independent risk factors for OS(P<0.05),while VEGF,TGFβ1,and white blood cell count were independent risk factors for DFS(P<0.05).CONCLUSION Decreased VEGF expression and increased TGFβ1 expression in patients with AML provide valuable references for determining and individualizing clinical treatment strategies.

Apelin and vascular endothelial growth factor are associated with mobilization of endothelial progenitor cells after acute myocardial infarction

This study was designed to determine the levels of early endothelial progenitor cells （EPCs）, apelin, vascu- lar endothelial growth factor （VEGF） and stromal cell-derived growth factor-1 （SDF-1） after acute myocardial infarction （AMI）, and to investigate the relationships between these cytokines and early EPCs. Early EPCs, de- fined as CD133＋, KDR＋, and CD34~ cells, were quantified by flow cytometry. The levels of early EPCs and those cytokines in AMI patients were significantly different from those with coronary artery disease or controls （P 〈 0.05）. Plasma apelin levels were inversely correlated with Gensini score and early EPCs （both P 〈 0.01）. Early EPCs, VEGF and SDF-1 showed different patterns of changes in AMI patients during the first 24 h. The trend in the change of early EPCs was proportionally correlated with that of VEGF （P 〈 0.05）. AMI patients exhibited in- creased early EPCs with remarkably decreased apelin levels and enhanced VEGF levels.

miR-92a、sICAM-1、VEGF在乳腺癌组织中的表达及其与超声血流参数的相关性研究

目的探讨微小核糖核酸-92a(miR-92a)、可溶性细胞间黏附分子-1(sICAM-1)、血管内皮生长因子(VEGF)在乳腺癌组织中的表达差异,并分析其与患者超声血流参数的相关性。方法选取乳腺癌患者102例作为乳腺癌组,同期收集乳腺良性肿瘤患者100例作为对照组。比较miR-92a、sICAM-1、VEGF在两组间的表达,分析其诊断价值。采用多普勒超声检测患者病变部位的血流参数,主要包括动脉血流峰值速度(PSV)、舒张末期血流速度(EDV)、脉动指数(PI)、阻力指数(RI),分析miR-92a、sICAM-1、VEGF与乳腺超声血流参数的相关性。结果乳腺癌组患者miR-92a、sICAM-1、VEGF水平明显高于对照组,差异具有统计学意义(P<0.05),三项联合检测诊断乳腺癌的曲线下面积(AUC)为0.897,灵敏度为89.3%,特异度为90.0%。Logistic回归分析显示miR-92a、sICAM-1、VEGF是乳腺癌发生的重要危险因素(P<0.05)。乳腺癌组患者的PSV、EDV明显高于对照组,PI、RI明显低于对照组,差异具有统计学意义(P<0.05)。Spearman相关性分析结果显示miR-92a、sICAM-1、VEGF水平与PSV、EDV呈正相关,与PI、RI呈负相关(P<0.05)。结论miR-92a、sICAM-1、VEGF在乳腺癌患者中明显升高,且与患者超声血流参数密切相关,是乳腺癌发生的重要危险因素,三项联合检测有助于乳腺癌的早期诊断及病情评估。

Puerarin decreases hypoxia inducible factor-1 alpha in the hippocampus of vascular dementia rats

In this study, a rat vascular dementia model was established by permanent bilateral common carotid arterial occlusion. Rats were intraperitoneally injected with puerarin 3 days before modeling, for 45 successive days. Results demonstrated that in treated animals hippocampal structures were clear, nerve cells arranged neatly, and cytoplasm was rich in Nissl bodies. The number of cells positive for hypoxia inducible factor-1 alpha, erythropoietin and endothelial nitric oxide synthase was reduced; and the learning and memory abilities of rats were significantly improved. Our experimental findings indicate that puerarin can significantly improve learning and memory in a vascular dementia model, and that the underlying mechanism may be associated with the regulation of the expression of hypoxia inducible factor-1 alpha.

血清sICAM-1、VEGF、sFas水平在急性白血病中的变化及临床价值

目的探讨血清可溶性细胞间黏附分子-1(sICAM-1)、血管内皮生长因子(VEGF)、可溶性跨膜蛋白(sFas)在急性白血病中的变化及临床意义。方法选取2020年5月至2022年5月安岳县人民医院收治的急性白血病患者89例为观察组,另选同时段该院的体检健康者65例为对照组。所有患者入院后给予化疗,对其实施1年电话、门诊随访。比较两组患者血清sICAM-1、VEGF、sFas水平差异,比较不同疗效、不同预后急性白血病患者血清sICAM-1、VEGF、sFas水平差异。绘制受试者工作特征(ROC)曲线,评估相关指标对急性白血病疗效、预后的预测价值。结果与对照组比较,观察组血清sICAM-1、VEGF、sFas水平升高(P<0.05)。与非完全缓解(CR)患者比较,CR患者血清VEGF水平升高(P<0.05)。与预后良好患者比较,预后不良患者血清sICAM-1、VEGF、sFas水平升高(P<0.05)。ROC曲线分析结果显示,VEGF评估急性白血病疗效的曲线下面积(AUC)为0.778,sICAM-1、VEGF、sFas单独与联合评估急性白血病预后的AUC分别为0.793、0.729、0.666、0.889。结论血清sICAM-1、VEGF、sFas在急性白血病患者中水平升高,sICAM-1、VEGF、sFas联合评估急性白血病疗效、预后均有一定临床参考价值。

Ubiquitin Reduces Expression of Intercellular Adhesion Molecules and Tumor Necrosis Factor-α in Lung Tissue of Experimental Acute Lung Injury

Background Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important cytokines in inflammatory response, which may induce rolling and adhesion of both leukocytes and lymphocytes, while modulating vascular permeability at the same time. These adhesion molecules usually serve as surrogate markers of activation and injury of vascular endothelial cells. Tumor necrosis factor-α (TNF-α) is a key factor to induce the expression and production of the above cell adhesion molecules. However, it remains to be elucidated whether exogenous ubiquitin exerts any effect on the cytokines in sepsis-induced ALI. Methods Sixty mice were devided randomly into five groups with twelve mice in each group, i.e. CLP group, SHAM group, UB1 group (10 mg/kg), UB2 group (5 mg/kg) and UB3 group(1 mg/kg). Mice of SHAM group underwent sham operation, and other four groups underwent CLP. Six hours after surgery, mice of three UB groups received ubiquitin by caudal vein injection while CLP and SHAM group received vehicle. Seven hours after surgery, blood and lungs of all mice were collected. ICAM-1, VCAM-1 and TNF-α level of 9% lung homogenate and serum TNF-α level were measured by ELISA. Results Pulmonary ICAM-1, VCAM-1 and TNF-α level of three UB groups were lower than CLP and SHAM group, and there were several comparisons with a statistically significant difference. Serum TNF-α level of three UB groups were slightly lower than CLP group, but far higher than SHAM group. Pulmonary ICAM-1 level, VCAM-1 level and serum TNF-α level of UB3 group were lower than UB1 and UB2 group, and there was a significant difference in VCAM-1 between UB3 and UB1 group. Pulmonary TNF-α level of UB3 group was slightly higher than UB1 and UB2 group.

Vascular endothelial growth factor up-regulates the expression of intracellular adhesion molecule-1 in retinal endothelial cells via reactive oxygen species, but not nitric oxide

Background The vascular endothelial growth factor （VEGF） is involved in the initiation of retinal vascular leakage and nonperfusion in diabetes. The intracellular adhesion molecule-1 （ICAM-1） is the key mediator of the effect of VEGFs on retinal leukostasis. Although the VEGF is expressed in an early-stage diabetic retina, whether it directly up-regulates ICAM-1 in retinal endothelial cells （ECs） is unknown. In this study, we provided a new mechanism to explain that VEGF does up-regulate the expression of ICAM-1 in retinal ECs. Methods Bovine retinal ECs （BRECs） were isolated and cultured. Immunohistochemical staining was performed to identify BRECs. The cultured cells were divided into corresponding groups. Then, VEGF （100 ng/ml） and other inhibitors were used to treat the cells. Cell lysate and the cultured supernatant were collected, and then, the protein level of ICAM-1 and phosphorylation of the endothelial nitric oxide synthase （eNOS） were detected using Western blotting. Griess reaction was used to detect nitric oxide （NO）. Results Western blotting showed that the VEGF up-regulated the expression of ICAM-1 protein and increased phosphorylation of the eNOS in retinal ECs. Neither the block of NO nor protein kinase C （PKC） altered the expression of ICAM-1 or the phosphorylation of eNOS. The result of the Western blotting also showed that inhibition of phosphatidylinositol 3-kinase （PI3K） or reactive oxygen species （ROS） significantly reduced the expression of ICAM-1. Inhibition of PI3K also reduced phosphorylation of eNOS. Griess reaction showed that VEGF significantly increased during NO production. When eNOS was blocked by L-NAME or PI3K was blocked by LY294002, the basal level of NO production and the increment of NO caused by VEGF could be significantly decreased. Conclusion ROS-NO coupling in the retinal endothelium may be a new mechanism that could help to explain why VEGF induces ICAM-1 expression and the resulting leukostasis in diabetic retinopathy.

Effects of anisodamine on the expressions of vascular endothelial growth factor and intercellular adhesion molecule 1 in experimental infusion phlebitis

Background Infusion phlebitis is the most common side effect of clinical intravenous drug therapy and several clinical studies have demonstrated that anisodamine can effectively prevent the occurrence of infusion phlebitis.This study was designed to investigate effects of anisodamine on the expressions of vascular endothelial growth factor （VEGF） and intercellular adhesion molecule 1 （ICAM-1） in a rabbit model of infusion phlebitis and to analyze the mechanisms of anisodamine effect on the prevention and treatment of experimental infusion phlebitis.Methods Twenty-four specific pathogen-free male Japanese white rabbits were randomly assigned to the control group,the model group,the magnesium sulfate group and the anisodamine group.The rabbit model of infusion phlebitis,induced by intravenous administration,was established and expressions of VEGF and ICAM-1 were determined and contrasted with the control group treated with normal saline.We evaluated expression by histopathology,immunohistochemistry,reverse transcription-polymerase chain reaction,and Western blotting assay.Results Pathohistological changes of the model group were observed,such as loss of venous endothelial cells,inflammatory cell infiltration,edema and thrombus.The magnesium sulfate group and the anisodamine group showed significant protective effects on vascular congestion,inflammatory cell infiltration,proliferation,swelling of endothelium and perivascular hemorrhage.The model group showed the highest expressions of VEGF and ICAM-1 of the four groups （P〈0.01）.On the contrary,anisodamine alleviated the inflammatory damage by significantly reducing the expressions of VEGF and ICAM-1 compared with the model group （P 〈0.01）.There was no significant difference in the expressions of VEGF and ICAM-1 between the magnesium sulfate group and the anisodamine group （P 〉0.05）.Conclusion Anisodamine alleviates inflammatory damage by significantly reducing the expressions of VEGF and ICAM-1,and shows significant protective effects

The role of adhesion molecules in gastri c ulcer healing

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Expression of Nerve Growth Factor and Hypoxia Inducible Factor-1α and Its Correlation with Angiogenesis in Non-Small Cell Lung Cancer

Summary： In order to investigate the expression of nerve growth factor （NGF） and hypoxia inducible factor-1α （HIF-1α） and its correlation with angiogenesis in non-small cell lung cancer （NSCLC）, paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor （VEGF） in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density （MVD） was determined by CD31 staining. The resuits showed that the expression levels ofNGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues （P〈0.05）. There was significant difference in the MVD between the NSCLC tissues （9.19±1.43） and para-cancerous lung tissues （2.23±1.19） （P〈0.05）. There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors （P〈0.05）. Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC.

Clinicopathological and Prognostic Significance of Hypoxia-inducible Factor-1 alpha in Lung Cancer: a Systematic Review with Meta-analysis

Hypoxia-inducible factor-1 alpha（HIF-1α） plays a vital role in the initiation, evaluation and prognosis in lung cancer. The prognostic value of HIF-1α reported in diverse study remains disputable. Accordingly, a meta-analysis was implemented to further understand the prognostic role of HIF-1α in lung cancer. The relationship between HIF-1α and the clinicopathological characteristics and prognosis of lung cancer were investigated by a meta-analysis. Pub Med and Embase were searched from their inception to January 2015 for observational studies. Fixed-effects or random-effects meta-analyses were used to calculate odds ratios and 95% confidence intervals of different comparisons. A total of 20 studies met the criteria. The results showed that HIF-1α expression in lung cancer tissues was significantly higher than that in normal lung tissues. Expression of HIF-1α in patients with squamous cell carcinoma was significantly higher than that of patients with adenocarcinomas. Similarly, non-small cell lung cancer（NSCLC） patients had higher HIF-1α expression than small cell lung cancer（SCLC） patients. Moreover, lymph node metastasized tissues had higher HIF-1α expression than non-lymph node metastasized tissues. A high level HIF-1α expression was well correlated with the expression of vascular endothelial growth factor and epidermal growth factor receptor in the NSCLC. Notably, NSCLC or SCLC patients with positive HIF-1α expression in tumor tissues had lower overall survival rate than patients with negative HIF-1α expression. It was suggested that HIF-1α expression may be a prognostic biomarker and a potential therapeutic target for lung cancer.

Downregulation of miR-491-5p promotes neovascularization after traumatic brain injury

Micro RNA-491-5 p(miR-491-5 p) plays an important role in regulating cell proliferation and migration;however,the effect of miR-491-5 p on neovascularization after traumatic brain injury remains poorly understood.In this study,a controlled cortical injury model in C57 BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro,respectively.In the in vivo model,quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5 p increased or decreased following the intracerebroventricular injection of an miR-491-5 p agomir or antagomir,respectively,and the expression of miR-491-5 p decreased slightly after traumatic brain injury.To detect the neuroprotective effects of miR-491-p,neurological severity scores,Morris water maze test,laser speckle techniques,and immunofluorescence staining were assessed,and the results revealed that miR-491-5 p downregulation alleviated neurological dysfunction,promoted the recovery of regional cerebral blood flow,increased the number of lectin-stained microvessels,and increased the survival of neurons after traumatic brain injury.During the in vitro experiments,the potential mechanism of miR-491-5 p on neovascularization was explored through quantitative real-time-polymerase chain reaction,which showed that miR-491-5 p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5 p mimic or inhibitor,respectively.Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5 p.Cell counting kit 8(CCK-8) assay,flow cytometry,and 2′,7′-dichlorofluorescein diacetate(DCFH-DA) assay results confirmed that the downregulation of miR-491-5 p increased brain microvascular endothelial cell viability,reduced cell apoptosis,and alleviated oxidative stress under oxygen-glucose deprivation conditions.Cell scratch assay,Transwell assay,tube formation assay,and western blot assay results demonstrated that miR-491-5 p downregulation promoted the migration,proliferation,and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway.These findings confirmed that miR-491-5 p downregulation promotes neovascularization,restores cerebral blood flow,and improves the recovery of neurological function after traumatic brain injury.The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress.All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University,China(approval No.2020-304) on June 22,2020.

电针预处理对脑缺血再灌注损伤大鼠神经功能及缺血半暗带区VEGF、CD31表达的影响

目的通过观察电针预处理对脑缺血再灌注损伤大鼠神经功能、脑梗死体积及半暗带区脑组织血管内皮生长因子(vascular endothelial growth factor,VEGF)、血小板-内皮细胞黏附分子(platelet endothelial cell adhesion molecule-1,CD31)表达的影响,判断电针预处理对半暗带区血管新生的影响,探索电针预处理改善脑缺血再灌注损伤的可能作用机制。方法将36只SD大鼠按照随机数字表法分为假手术组、模型组、电针预处理组,每组12只。电针预处理组予以电针百会、水沟、大椎,每天1次,共7次;假手术组、模型组仅捆绑,不予电针处理。实验第8天,参照Zea Longa方法对模型组、电针预处理组进行大脑动脉栓塞(medial cerebral artery occlusion,MCAO)造模后灌注,假手术组仅切开皮肤暴露颈动脉,不做手术。造模24 h后,对各组大鼠进行神经功能缺损评分(neurological severity scores,NSS)法评估神经功能,评分后取大鼠梗死侧脑半球行红四氮唑(2,3,5-Triphenyltetrazolium Chloride,TTC)染色检测脑梗死面积,取脑缺血半暗带区组织进行HE染色观察脑组织形态变化,免疫组织化学法测定VEGF、CD31表达。结果假手术组未见梗死以及任何神经功能损伤,细胞形态正常;模型组半暗带区细胞损伤显著增加,排列紊乱,呈肿胀状,毛细血管管腔塌陷;电针预处理组损伤程度减轻,排列轻度紊乱,细胞肿胀不明显。与假手术组比较,模型组大鼠神经功能缺损评分明显升高(P<0.01),脑梗死面积明显增加(P<0.01),缺血半暗带区VEGF、CD31表达明显增加(P<0.01);与模型组比较,电针预处理组大鼠神经功能缺损评分降低(P<0.05),脑梗死面积明显减少(P<0.01),缺血半暗带区VEGF、CD31表达明显增加(P<0.01)。结论电针预处理可能通过促进缺血半暗带区血管新生,从而改善脑缺血再灌注损伤大鼠神经功能损伤、降低脑梗死体积。