Risk ractors for the occurrence of preeclampsia and the predictive value of serum VEGFR-1 and PLGF for preeclampsia / 中国医师杂志

Objective:To explore the risk factors for the occurrence of preeclampsia (PE) and the predictive value of serum vascular endothelial growth factor receptor-1 (VEGFR-1) and placental growth factor (PLGF) for PE.Methods:A retrospective study was conducted to select 148 pregnant women who underwent prenatal examinations at the First People′s Hospital of Chenzhou from January 2020 to January 2022 and were ultimately diagnosed with PE as the PE group, and 148 healthy pregnant women who underwent prenatal examinations during the same period as the PE group were selected as the control group. The levels of VEGFR-1, PLGF, and VEGFR-1/PLGF were compared between two groups of pregnant women. Logistic regression analysis was performed on the risk factors for PE, and the correlation between VEGFR-1, PLGF, VEGFR-1/PLGF and risk factors was analyzed. The receiver operating characteristic (ROC) curve was used to analyze the predictive value of VEGFR-1, PLGF, and VEGFR-1/PLGF for PE and obtain cutoff values. The survival curve of pregnant women with PE was plotted based on the cutoff values.Results:The levels of VEGFR-1 and VEGFR-1/PLGF in the PE group were higher than those in the control group (all P<0.05), while the levels of PLGF were lower than those in the control group ( P<0.05). Logistic regression analysis showed that age, body mass index (BMI), pregnancy induced hypertension, pregnancy induced diabetes, family history of hypertension, preeclampsia, VEGFR-1 and VEGFR-1/PLGF were risk factors for PE (all P<0.05), and PLGF was a protective factor for PE ( P<0.05). VEGFR-1, VEGFR-1/PLGF were positively correlated with age, BMI, pregnancy induced hypertension, pregnancy induced diabetes, hypertension family history, and PE (all P<0.001), while PLGF was negatively correlated with age, BMI, pregnancy induced hypertension, pregnancy induced diabetes, hypertension family history, and preeclampsia (all P<0.001). VEGFR-1, PLGF, and VEGFR-1/PLGF had higher predictive value for PE (AUC=0.773, 0.791, 0.825), with cutoff values of 9190.83 ng/L, 508.17 ng/L, and 21.64, respectively. According to the cutoff value, 296 pregnant women were divided into three groups: low, medium, and high risk. The survival analysis results showed that the probabilities of PE occurrence in the three groups were 1.36%, 18.97%, and 66.67%, respectively. Conclusions:VEGFR-1 and PLGF have high predictive value for PE, and clinical monitoring of VEGFR-1/PLGF levels combined with other examination methods can improve the accuracy of PE diagnosis and prediction, and improve pregnancy outcomes.

Experimental study of vascular endothelial growth factor receptor 2 and integrin α vβ 3 dual-targeted microbubble to assess tumor angiogenesis of renal cell carcinoma in vivo / 中华超声影像学杂志

Objective:To evaluate the ability of vascular endothelial growth factor receptor 2(VEGFR2)/integrin α vβ 3 dual-targeted microubble (MBD) to target angiogenesis of renal cell carcinoma (RCC) in vivo. Methods:Non-targeted microbubble (MBN) USphere LA was employed as a template to prepare single- and dual-targeted microbubbles which could bind VEGFR2 and/or integrin α vβ 3 (MBV and MBI) by the biotin-avidin bridging method. A total of 40 RCC nude mice models were established by subcutaneously injecting 786-O cells.Twenty of the models were all injected with MBN, MBV, MBI and MBD in a random order, and the other 20 models were registered for antibody blocking assays. The results of ultrasound images were used for quantitative analyses, and the following quantitative parameters were obtained: intensity increment (a 1), peak halving speed (a 2), curve rising slope (a 3), perfusion time (t 0), time to peak (TTP), peak intensity (PI), mean transit time (MTT) and area under the curve (AUC) for the first three minutes, peak intensity at 10 s before (P 1) and after (P 2) ultrasound destruction, and the differences of tissue enhancement (dTE) between P 1 and P 2 (dTE=P 1-P 2). All the quantitative parameters of four contrast agents and the antibody blocking assays were compared.Besides, the immunohistochemical assays were performed to evaluate the expression of CD31, VEGFR2 and integrin α vβ 3 in tumor tissues. Results:The differences of parameters of a 1, a 3, t 0, TTP, PI and P 2 among four different microbubbles had no statistical significances (all P>0.05), and all parameters between the two single-targeted contrast agents were not statistically different (all P>0.05). The parameters of AUC, MTT, P 1 and dTE all showed a trend that dual-targeted bubbles > single-targeted bubbles > non-targeted bubbles (all P<0.05). On the contrary, the trend of dual-targeted bubbles < single-targeted bubbles < non-targeted bubbles (all P<0.05) was observed for a 2. In the antibody blocking experiment, a 2 was faster after the antibody injection ( P<0.001), while AUC, MTT, P 1 and dTE were all lower than those before the antibody injection ( P<0.001), and the other parameters were not statistically different before and after the antibody injection (all P>0.05). Immunohistochemical analyses confirmed the high expression of CD31, VEGFR2 and integrin β 3 in tumor tissues. Conclusions:The VEGFR2 and integrin α vβ 3 dual-targeted microbubble has a good potential to target the angiogenesis of human RCC in vivo.

Effect of Guiqi Baizhu Prescription Combined with Oxaliplatin on Expression of EGFR and VEGFR2 and Angiogenesis in Gastric Cancer-bearing Mice / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Guiqi Baizhu prescription （GQBZ） combined with oxaliplatin on the expression of epidermal growth factor receptor （EGFR） and vascular endothelial growth factor receptor-2 （VEGFR2） and angiogenesis in gastric cancer-bearing mice. MethodThe tumor-bearing model of gastric cancer was induced in Kunming mice. The mice were randomly divided into blank group， model group， oxaliplatin group （10 mg·kg-1）， and high- （17.68 g·kg-1）， medium- （8.84 g·kg-1）， and low-dose （4.42 g·kg-1） combination groups （GQBZ combined with oxaliplatin）. After the last administration， the transplanted tumor was collected and the tumor inhibition rate was calculated. Hematoxylin-eosin （HE） staining was used to observe the morphological changes of tumor tissues. Enzyme-linked immunosorbent assay （ELISA） was used to detect the serum content of epidermal growth factor （EGF）， interleukin-8 （IL-8）， and vascular endothelial growth factor （VEGF）. Western blot and immunohistochemistry （IHC） were used to detect the expression of EGFR， phosphorylated EGFR （p-EGFR）， VEGFR2， phosphorylated VEGFR2 （p-VEGFR2）， and platelet-endothelial cell adhesion molecule （CD31）. Real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of EGFR and VEGFR2. ResultThe tumor weight in the drug intervention groups was significantly lower than that in the model group （P<0.01）. Compared with the oxaliplatin group， the high- and medium-dose combination groups showed reduced tumor weight （P<0.05， P<0.01）. The tumor cells in the model groups were high in cell density and regular in shape， and no clear tissue necrosis was seen. The tumor cell density in the drug intervention groups was reduced， and clear tissue necrosis and large-scale inflammatory cells were visible. Compared with the blank group， the model group and the drug intervention groups showed increased serum levels of EGF， VEGF， and IL-8 （P<0.05， P<0.01）. Compared with the model group， the drug intervention groups showed decreased serum levels of EGF， VEGF， and IL-8 （P<0.01）， reduced protein expression of EGFR， p-EGFR， VEGFR2， p-VEGFR2， and CD31， and declining mRNA expression of EGFR and VEGFR （P<0.01）. Compared with the oxaliplatin group， the high- and medium-dose combination groups showed decreased serum levels of EGF， VEGF， and IL-8 （P<0.05， P<0.01）， reduced protein expression of EGFR， p-EGFR， VEGFR2， p-VEGFR2， and CD31， and dwindled mRNA expression of EGFR and VEGFR2 （P<0.05， P<0.01）. The low-dose combination group showed decreased serum levels of EGF， VEGF， and IL-8， reduced protein expression of EGFR， p-EGFR， VEGFR2， p-VEGFR2， and CD31， and dwindled mRNA expression of EGFR and VEGFR2， but the difference was not statistically significant. ConclusionGQBZ combined with oxaliplatin can inhibit the growth and angiogenesis of tumor tissues in gastric cancer-bearing mice by affecting the expression of EGFR and VEGFR2.

Research Progress of Targeted Ultrasound Contrast Agent BR55 / 中国医学科学院学报

BR55 is an ultrasound contrast agent targeting vascular endothelial growth factor receptor 2,which can be used to detect tumor neovascularization and improve the diagnostic accuracy.Overseas researchers have used BR55 for human ultrasound molecular imaging,which showed good safety and tolerance.We reviewed the research progress on BR55 applied in the evaluation of tumor neovascularization from the composition,characteristics,animal experiments,and clinical studies of BR55.

Effects of psychotherapy combined with early comprehensive rehabilitation therapy on cerebral infarction / 中国基层医药

Objective:To investigate the clinical efficacy of psychotherapy combined with early comprehensive rehabilitation therapy in the treatment of acute cerebral infarction and the possible mechanism of action.Methods:Eighty-four patients with acute cerebral infarction who received treatment in Yuhang Fifth People's Hospital, China between June 2018 and February 2020 were included in this study. They were randomly divided into an observation group ( n = 44) and a control group ( n = 40). The control group was treated with conventional therapy. The observation group was subjected to early comprehensive rehabilitation therapy combined with psychotherapy based on conventional therapy. All patients were treated for 1 month. Clinical efficacy, the percentage of highly glycosylated type I transmembrane glycoprotein-positive cells and vascular endothelial growth factor receptor-2-positive cells (CD 34+KDR +) in monocytes, and serum level of stromal cell-derived factor-1α were compared between the observation and control groups. Results:After treatment, the scores of Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD) and National Institutes of Health Stroke Scale (NIHSS) were (16.4 ± 3.8) points, (17.9 ± 5.2) points, (3.56 ± 0.46) points, respectively, which were significantly lower than those in the control group [(23.4 ± 5.6) points, (23.7 ± 6.4) points, (5.39 ± 0.87) points, t = 7.896, 7.258, 6.935, all P < 0.05]. Barthel Index, Fugl-Meyer score, and Functional Independence Score in the observation group were (79.7 ± 20.8) points, (54.6 ± 17.2) points, (96.8 ± 8.5) points, respectively, which were significantly higher than those in the control group [(60.4 ± 17.6) points, (39.6 ± 14.8) points, (83.1 ± 9.7) points, t = 8.123, 7.251, 8.009, all P < 0.05]. After treatment, the percentage of CD34 +KDR + in monocytes and serum level of stromal cell-derived factor-1α in the observation group were (1.58 ± 0.19)% and (1.84 ± 0.11) μg/L, respectively, which were significantly higher than those in the control group [(0.73 ± 0.20)% and (1.34 ± 0.09) μg/L, t = 7.125, 6.983, both P < 0.05). Conclusion:Based on conventional treatment, psychotherapy combined with early rehabilitation treatment can improve the clinical efficacy in the treatment of acute cerebral infarction possibly through increasing the percentage of CD 34+KDR + in monocytes and the serum level of stromal cell-derived factor-1α.

Serum exosomal miR-335-5p serves as a diagnostic biomarker of triple-negative breast cancer / 中华内分泌外科杂志

Objective:To investigate the expression and diagnostic value of microRNA-335-5p (miR-335-5p) and Human Vascular endothelial growth factor receptor 1 (VEGFR-1, FLT1) in serum exosomal bodies of patients with triple negative breast cancer (TNBC) .Methods:Gene Expression Omnibus database (GEO) analysis was performed and differentially expressed miRNA in breast cancer tissues was screened. From Jan. 2016 to Nov. 2017, the peripheral blood samples of 56 TNBC patients in People’s Hospital Affiliated to Ningbo University were collected, and the exosomes were isolated and identified. FLT1 was selected as the target gene of miR-335-5p by using bioinformatics analysis. Expression levels of miR-335-5p and FLT1 in serum exosome were detected by qRT-PCR. The relationship between miR-335-5p and clinicopathological parameters of TNBC patients was analyzed. The diagnostic value of miR-335-5p was evaluated by receiver operating characteristic (ROC) , and the survival prognosis of miR-335-5p and FLT1 was analyzed by Kaplan Meier survival curve.Results:The expression of miR-335-5p in the serum exosome of TNBC patients was lower than that of the control group, while the expression of FLT1 in the serum exosome was higher than that of the control group ( P<0.05) . The expression of miR-335-5p was related to tissue grade ( χ2=22.02, P<0.000 1) , degree of differentiation ( χ2=20.67, P<0.000 1) and lymph node metastasis ( χ2=4.667, P=0.030 8) in patients with TNBC ( P<0.05) . The area under ROC diagnosed by miR-335-5p was 0.809 8 (95% CI: 0.726 3-0.893 2, P<0.000 1) . Kaplan-Meier survival analysis showed that the overall survival time of patients with low expression of miR-335-5p was significantly shorter than that of patients with high expression of miR-335-5p ( P=0.004 5) . The high expression of its target gene FLT1 was associated with low survival rate ( P=0.048 0) . Conclusion:Serum exosomal miR-335-5p can be used as an important index to predict the prognosis of TNBF and is expected to play a role in diagnosis and treatment of TNBC.

An increase in proliferation of rat bone mesenchymal stem cells and secretion of vascular endothelial growth factor under negative pressure in vitro / 中国组织工程研究

BACKGROUND: How to enhance the proliferative activity of bone marrow mesenchymal stem cells and make their proper effects after transplantation is an urgent problem to be solved. OBJECTIVE: To investigate the effects of different negative pressures on the proliferation of rat bone mesenchymal stem cells and vascular endothelial growth factor secretion level. METHODS: Passage 3 bone marrow mesenchymal stem cells were cultured under normal conditions (control group) or under intermittent negative pressures (-6.65, -13.3, -26.6 kPa), once for 2 hours, with an interval of 12 hours. At 12, 24, 36, 48, and 60 hours of culture, cell proliferation was detected using cell counting kit-8, and mRNA expression of vascular endothelial growth factor receptor was detected by RT-PCR. Based on the above results, we selected the optimal negative pressure condition and time (-26.6 kPa, 24 hours). Bone marrow mesenchymal stem cells were treated normally, under -26.6 kPa or treated with Axitinib under -26.6 kPa. We detected the cell proliferation by cell counting kit-8, EDU cell positive rate by EDU kit, and cell colony forming unit by crystal violet staining thereafter. RESULTS AND CONCLUSION: Compared with the control group, the negative pressure groups had significantly increased cell proliferation, significantly increased vascular endothelial growth factor levels, and significantly up-regulated mRNA expression of vascular endothelial growth factor receptor (all P < 0.05). After being treated with Axitinib, the absorbance value of cell proliferation, the number of clone forming units and the rate of EDU positive cells in the negative pressure groups were markedly decreased. To conclude, in vitro negative pressure culture may promote the proliferation of mesenchymal stem cells through upregulation of vascular endothelial growth factor expression.

Evaluation of efficacy and safety of apatinib treatment in advanced gastric cancer

Aim: We aimed to evaluate the efficacy and safety of apatinib treatment and its impact on the quality of life (QOL) of patients with advanced gastric cancer (GC) who experienced failure with at least two chemotherapeutic regimens. Materials and Methods: All patients received apatinib at a daily dose of 500 mg for 4 weeks per cycle until it was stopped due to disease progression, intolerable toxicity. Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse events 4.0 were used to assess tumor responses and toxicities, respectively. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-STO22 were used to assess the impact on patient's QOL. Results: Twenty-five patients were enrolled, but only 24 were evaluated for therapeutic effects. After apatinib treatment, none of the patients achieved complete response (CR), one achieved partial response (PR), and eight had stable disease (SD), resulting in a disease control rate of 37.5% (CR + PR + SD). Responses to questions regarding abdominal pain, nausea/vomiting, insomnia, constipation, and diarrhea in QLQ-C30 and abdominal pain and reflux in QLQ-STO22 were changed over the course of treatment (P < 0.05). The QOL score was elevated after three treatment cycles, but it was not considered statistically significant (P > 0.05). Conclusion: Results indicated that apatinib was effective in heavily pretreated patients with advanced GC who experienced failure with two or more line chemotherapies. The toxicities were tolerable or could be clinically controlled. Apatinib treatment alleviated some of the clinical symptoms but did not improve QOL significantly.

Effect of Modified Si Junzitang on Angiogenesis of H22 Tumor-bearing Mice / 中国实验方剂学杂志

Objective:To investigate the effect of modified Si Junzitang on angiogenesis in transplanted tumor of H22 tumor-bearing mice. Method:The effect of modified Si Junzitang on tumor inhibition and growth of peripheral blood vessels in tumor-bearing mice was observed by tumorigenesis experiment in mice. Hematoxylin-eosin (HE) staining and immunohistochemistry (IHC) were used to detect the distribution of blood vessels and the expression of vascular endothelial markers (CD31) in tumor-bearing mice. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the mRNA expression levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2) and tumor necrosis factor-α (TNF-α) in tumor tissue. Result:The inhibition rates of modified Sijunzi Tang in low-dose group (ig, 11.83 mg·kg-1·d-1), middle-dose group (ig, 23.66 mg·kg-1·d-1) and high-dose group (ig, 47.32 mg·kg-1·d-1) were 29.97%, 59.80%and 82.34%, respectively. Compared with the model group, the average tumor weight was lower in middle and high-dose groups, with statistically significant differences (PPPα in middle and high-dose modified Si Junzitang groups were lower than those in the model group (PConclusion:Modified Si Junzitang can inhibit the tumor growth of H22 tumor-bearing mice and the angiogenesis of transplanted tumors, which may be related to the reduction of TNF-α, VEGF and VEGFR2 expression levels.

Effect of Modified Erchentang on VEGF,VEGFR2,IL-4,ET-1 in Chronic Obstructive Pulmonary Disease Rats / 中国实验方剂学杂志

Objective: To observe the effects of Erchen on vascular endothelial growth factor (VEGF) and its receptor R2 (VEGFR2), interleukin (IL)-4 and endothelin-1 (ET-1) in rats with chronic obstructive pulmonary disease (COPD). Method: The 50 SD rats were randomly divided into 5 groups, 10 rats in each group, which were normal group, model group, Erchentang low, medium and high dose group (10, 20, 40 g · kg-1 · d-1). COPD rat model was established by smoking combined with lipopolysaccharide (LPS) intratracheal drip. After successful modeling, the treatment group was given intragastric administration, and the normal group and the model group were given intragastric distilled water of equal volume. The pathological changes of pulmonary vessels in rats were observed by light microscopy, and the thickness of pulmonary vascular wall was measured. The concentration of IL-4 in rat serum, bronchoalveolar lavage fluid (BALF) and lung homogenate was measured by enzyme-linked immunosorbent assay (ELISA). Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) was used to detect the expression of ET-1 and immunohistochemistry was used to detect the expression of VEGF,VEGFR2 and ET-1 in lung tissue. Result: Compared with normal group, the concentration of IL-4 in serum, BALF and lung homogenate of model group rats decreased significantly (PPPPPPConclusion: Modified Erchentang can alleviate the process of pulmonary inflammation and pulmonary vascular remodeling in COPD rats, and slow down the progress of COPD and its complications by increasing the content of IL-4, inhibiting the expression of VEGF, VEGFR2, ET-1.

Different effects of pravastatin on sFlt-1, PlGF and VEGF in different preeclampsia-like mouse models / 中华妇产科杂志

Objective@#To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)-like mouse models.@*Methods@#C57BL/6J mice were randomly subcutaneously injected with N-nitro-L-arginine methyl ester (L-NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE-like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L-NAME+Pra, LPS+Pra, Con+Pra) and saline (L-NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt-1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real-time fluorescence quantitative PCR (RT-PCR).@*Results@#(1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50±4.31) levels were significantly increased in L-NAME+Pra group compared with L-NAME+NS group (all P<0.05). Serum VEGF (202.30±4.90, 144.50±6.71) and PlGF (121.50±3.86, 95.41±4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt-1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt-1 level in L-NAME+Pra group was significantly lower than that in L-NAME+NS group (2.60±0.06, 583.70±9.83; all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66±0.14) in the liver of mice in the L-NAME+Pra group were significantly higher than those in the L-NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L-NAME+Pra group were not significantly different from those of L-NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT-PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L-NAME+Pra group were not significantly different from those in L-NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05).@*Conclusions@#Pra has different regulatory effects on vascular endothelial function in different PE-like models. It reveals that different pathogenesis and pathways exist in different PE-like changes.

Different effects of pravastatin on sFlt?1, PlGF and VEGF in different preeclampsia?like mouse models / 中华妇产科杂志

Objective To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)?like mouse models. Methods C57BL/6J mice were randomly subcutaneously injected with N?nitro?L?arginine methyl ester (L?NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE?like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L?NAME+Pra, LPS+Pra, Con+Pra) and saline (L?NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt?1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real?time fluorescence quantitative PCR (RT-PCR). Results (1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50± 4.31) levels were significantly increased in L?NAME+Pra group compared with L?NAME+NS group (all P<0.05). Serum VEGF (202.30 ± 4.90, 144.50 ± 6.71) and PlGF (121.50 ± 3.86, 95.41 ± 4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt?1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt?1 level in L?NAME+Pra group was significantly lower than that in L?NAME+NS group (2.60±0.06, 583.70±9.83;all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66 ± 0.14) in the liver of mice in the L?NAME+Pra group were significantly higher than those in the L?NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L?NAME+Pra group were not significantly different from those of L?NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT?PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L?NAME+Pra group were not significantly different from those in L?NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05). Conclusions Pra has different regulatory effects on vascular endothelial function in different PE?like models. It reveals that different pathogenesis and pathways exist in different PE?like changes.

Effect of inhibitor of differentiation 1 deficiency on ocular neovascularization / 上海交通大学学报（医学版）

Objective · To study the effect of inhibitor of differentiation 1 (ID1) on ocular neovascularization. Methods · The oxygen-induced retinal neovascularization (OIR), laser-induced choroidal neovascularization (CNV) and over-expression of vascular endothelial growth factor (VEGF) (Rho-VEGF) transgenic mice were established. The localization and mRNA level of ID1 in retina of OIR mice and Rho-VEGF transgenic mice were determined by immunofluorescence staining and quantitative real-time PCR. Mice deficient in ID1 (ID1-/-) were used to induce retinal neovascularization in accordance with the above three models, and to compare the changes of ID1 on the number of retinal, subretinal and choroidal neovascularization areas. In order to explore the role ID1 in neovascularization, the numbers and areas of retinal, subretinal and choroidal neovascularization in the mice models with or without ID1 deficiency were compared. Its effect on the related factors, i.e. hypoxia-inducible factor-1α (HIF-1α), VEGF and vascular endothelial growth factor receptor 1/2 (VEGFR1/2) were also observed. Results · Mice deficient in ID1 showed a significant reduction in the area of neovascularization in these three models (P＜0.05). Mice lacking ID1 showed reduced levels of HIF-1α, VEGF and VEGFR 1. Conclusion · ID1 promotes the expression of HIF-1α, VEGF and VEGFR1 in the retina and choroidal neovascularization during hypoxia and oxidative injury.

Clinical application of Apatinib in the treatment of malignancies / 国际肿瘤学杂志

Apatinib is a kind of antiangiogenesis drug of small molecular tyrosine kinase inhibitor, which can strongly against tumor angiogenesis by inhibiting vascular endothelial growth factor receptor 2 with highly selectivity. Apatinib can block cell cycle and reverse drug resistance. Clinical studies have shown that Apatinib is effective for many malignant tumors,including non-small cell lung cancer,breast cancer and gastric cancer,which has encouraging objective response rate and survival benefit. Apatinib also has good safety and tolerance.

Effect of inhibitor of differentiation 1 deficiency on ocular neovascularization / 上海交通大学学报（医学版）

Objective • To study the effect of inhibitor of differentiation 1 (ID1) on ocular neovascularization. Methods • The oxygen-induced retinal neovascularization (OIR), laser-induced choroidal neovascularization (CNV) and over-expression of vascular endothelial growth factor (VEGF) (Rho-VEGF) transgenic mice were established. The localization and mRNA level of ID1 in retina of OIR mice and Rho-VEGF transgenic mice were determined by immunofluorescence staining and quantitative real-time PCR. Mice deficient in ID1 (ID1-/-) were used to induce retinal neovascularization in accordance with the above three models, and to compare the changes of ID1 on the number of retinal, subretinal and choroidal neovascularization areas. In order to explore the role ID1 in neovascularization, the numbers and areas of retinal, subretinal and choroidal neovascularization in the mice models with or without ID1 deficiency were compared. Its effect on the related factors, i.e. hypoxia-inducible factor-1α (HIF-1α), VEGF and vascular endothelial growth factor receptor 1/2 (VEGFR1/2) were also observed. Results • Mice deficient in ID1 showed a significant reduction in the area of neovascularization in these three models(P<0.05). Mice lacking ID1 showed reduced levels of HIF-1α, VEGF and VEGFR 1. Conclusion • ID1 promotes the expression of HIF-1α, VEGF and VEGFR1 in the retina and choroidal neovascularization during hypoxia and oxidative injury.

Progresses of VEGFR2 targeted ultrasound contrast imaging in diagnosis of breast cancer / 中国医学影像技术

Tumor angiogenesis plays an important role in growth and metastasis of breast cancer. Vascular endothelial growth factor receptor 2 (VEGFR2) is over-expressed on tumor neo-angiogenesis endothelial cells. Ultrasound molecular imaging (USMI) is a new technology to identify the specific expression of vascular endothelial cells by targeted ultrasound contrast agent (tUCAs). A large number of experimental and preliminary clinical studies have demonstrated that USMI with VEGFR2 tUCAs could be used to diagnose breast cancer. The progresses of VEGFR2 targeted ultrasound contrast imaging in the diagnosis of breast cancer were reviewed in this article.

Increased expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor-3 after pilocarpine-induced status epilepticus in mice

Vascular endothelial growth factor (VEGF)-C and its receptor, vascular endothelial growth factor receptor (VEGFR)-3, are responsible for lymphangiogenesis in both embryos and adults. In epilepsy, the expression of VEGF-C and VEGFR-3 was significantly upregulated in the human brains affected with temporal lobe epilepsy. Moreover, pharmacologic inhibition of VEGF receptors after acute seizures could suppress the generation of spontaneous recurrent seizures, suggesting a critical role of VEGF-related signaling in epilepsy. Therefore, in the present study, the spatiotemporal expression of VEGF-C and VEGFR-3 against pilocarpine-induced status epilepticus (SE) was investigated in C57BL/6N mice using immunohistochemistry. At 1 day after SE, hippocampal astrocytes and microglia were activated. Pyramidal neuronal death was observed at 4 days after SE. In the subpyramidal zone, VEGF-C expression gradually increased and peaked at 7 days after SE, while VEGFR-3 was significantly upregulated at 4 days after SE and began to decrease at 7 days after SE. Most VEGF-C/VEGFR-3-expressing cells were pyramidal neurons, but VEGF-C was also observed in some astrocytes in sham-manipulated animals. However, at 4 days and 7 days after SE, both VEGFR-3 and VEGF-C immunoreactivities were observed mainly in astrocytes and in some microglia of the stratum radiatum and lacunosum-moleculare of the hippocampus, respectively. These data indicate that VEGF-C and VEGFR-3 can be upregulated in hippocampal astrocytes and microglia after pilocarpine-induced SE, providing basic information about VEGF-C and VEGFR-3 expression patterns following acute seizures.

Biochemical scenario behind initiation of diabetic retinopathy in type 2 diabetes mellitus

Purpose: Despite the disease having similar glycemic status and duration microangiopathy in some patients develop within few years whereas it doesn't appear as a health complication in some diabetics for a considerable period. This study is undertaken to assess the hyperglycemia-induced biochemical background behind the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (DM). Methods: Following proper diagnosis, 100 patients of type 2 DM of 10–12 years duration having no DR, and 42 patients of type 2 DM of the same duration and glycemic status as the second group, with mild retinopathy were recruited in the study. Lactic acid, glutamate, malondialdehyde (MDA), nitrate, advanced glycation end-products (AGEs), peripheral blood mononuclear cell reactive oxygen species (ROS), vascular endothelial growth factor (VEGF), and its receptor 2 (VEGFR2) in these two groups were produced in an assay following standard methodology. Results: Biochemical markers of anaerobic glycolysis, lipid peroxidation, AGEs, glutamate concentration, oxidative stress, and expression of VEGF and its VEGFR2 with significantly elevated markings were found in them who developed earliest stage of DR rather than them who had not. Conclusion: Hyperglycemia-induced anomalous glucose metabolism, lipid peroxidation, advanced glycation, glutamate toxicity, and oxidative stress create a background where apoptosis of retinal capillary endothelial cells invite increased expression of VEGF and VEGFR2, these being the crucial factors behind the development of diabetic microangiopathy.

Mechanisms of vascular endothelial growth factor receptor 2 expression regulation by erythropoietin in a premature rat model of periventricular white matter damage / 中华围产医学杂志

Objective@#To explore the mechanisms of vascular endothelial growth factor receptor 2 (VEGFR2) expression regulated by recombinant human erythropoietin (rh-EPO) in a premature rat model of periventricular white matter damage. @*Methods@#Sprague-Dawley rats aged three days were randomly divided into five groups: sham group without hypoxia-ischemia (HI), HI group (HI with saline administration), HI+erythropoietin (EPO) group, HI+erythropoietin receptor (EPOR) antagonist group and HI+EPO+EPOR antagonist group. Rat pups were either subjected to permanent ligation of the right common carotid artery and 6% O2+94% N2 for two hours (HI) or sham operated and exposed to normal air (sham). After the operation, rats in the HI+EPOR antagonist and HI+EPO+EPOR antagonist groups received a single intraventricular injection of EPOR antagonist (5 μl). Four hours after the operation, rats in the HI+EPO and HI+EPO+EPOR antagonist groups received a single intraperitoneal injection of rh-EPO (5 U/g). Western-blot was performed to detect EPOR, phosphorylated EPOR (p-EPOR), extracellular regulated protein kinases (ERK) and phosphorylated ERK (p-ERK) at 60 and 90 minutes after the models were established successfully, and also used to analyze the expression of VECFR2 on day 2 and 4. Analysis of variance and SNK test were used as statistical methods. @*Results@#At 60 and 90 minutes after model establishment, the expression of EPOR protein in rat brain tissues was increased in HI (1.717±0.206 and 1.416±0.242), HI+EPO (2.557±0.222 and 2.111±0.159) and HI+EPO+EPOR antagonist (1.547±0.170 and 1.452±0.250) groups as compared with that in sham group (1.095±0.182 and 0.751±0.136), that in HI+EPO group was higher than that in HI and HI+EPO+EPOR antagonist groups, and that in HI+EPOR antagonist group (1.088±0.160 and 1.020±0.174) was lower than that in HI group. All differences were statistically significant (F=30.154 and 20.265, both P<0.05). The expressions of p-EPOR, p-ERK and VEGFR2 in the five groups were consistent with the expression of EPOR, and the differences were also statistically significant (all P<0.05). In addition, the expression of VEGFR2 in HI+EPO+EPOR antagonist group was lower than that in HI group on day 4 (1.053±0.118 vs 1.439±0.074, F=54.248, P<0.05). No statistically significant difference in ERK expression was found among all groups at 60 or 90 minutes after modeling (F=1.117 and 0.734, both P>0.05). @*Conclusions@#ERK signaling pathways will be affected by EPO binding to EPOR. As a result, VEGFR2 expression was increased leading to enhanced angiogenesis in a premature rat model of periventricular white matter damage.

The mechanism and biological function of chemokine receptor CXCR4 and its ligand CXCL12 in hepatocellular carcinoma / 天津医药

Objective To investigate the mechanism and function of chemokine receptor CXCR4 and its ligand CXCL12 (CXCL12 / CXCR4) in primary hepatocellular carcinoma (PHC). Methods Western blot assay, immunohistochemistry and Real-time PCR were used to detect the protein and mRNA expressions of CXCL12/CXCR4 in 60 PHC and corresponding paracancerous tissue samples. Four kinds of hepatoma cells (Huh7, MHCC97h, HepG2 and Hep3B) and normal hepatocytes (7702) were routinely cultured, and then real-time PCR was performed to detect the mRNA expressions of CXCL12/CXCR4 in these cells to screen suitable experimental cells. CXCR4 interference plasmid (sh-CXCR4) and corresponding empty vector (sh-control) were transfected into MHCC97h to construct stable transfected cell lines. The ability of invasion, migration, and proliferation of the 2 groups of cells were detected by Tanswell invasion experiment, cell scratch test and MTT test. The stably expressed sh-control and sh-CXCR4 MHCC97h cells were taken into the subcutaneous of six nude mice, and the growth of the tumor was observed. Western blot assay was used to detect the expressions of vascular endothelial growth factor-C (VEGF-C) in sh-control and sh-CXCR4 MHCC97h cell lines and corresponding xenografts in nude mice, as the same in MHCC97h, which was transfected with CXCR overexpressed plasmid. Results (1) The results of Western blot assay, immunohistochemistry and Real-time PCR showed that the expressions of CXCL12/CXCR4 protein and mRNA were significantly higher in liver cancer tissues than those of paracancerous tissues. (2) The expression levels of CXCL12/CXCR4 mRNA were higher in Huh7, MHCC97h, HepG2 and Hep3B cells than those of 7702 cells. MHCC97h was selected as the experimental cells. The ability of invasion, migration and proliferation of MHCC97h cells transfected with sh-CXCR4 were significantly lower than those of sh-control group. Meanwhile, the growth rate of nude mice transplanted with sh-CXCR4 MHCC97h cells was also significantly lower than that of sh-control group. (3) Both in vitro and in vivo experiments showed that the expression of VEGF-C was lower in sh-CXCR4 group than that in sh-control group, and the expression of VEGF-C was obviously up-regulated after overexpression of CXCR4. Conclusion High expressions of CXCL12/CXCR4 are found in primary cancer tissues and hepatoma cells. CXCL12/CXCR4 may inhibit the proliferation and invasion of hepatoma cells by regulating the expression of VEGF-C protein.