Association between Adverse Maternal Clinical Outcomes and Imbalance of Cytokines and Angiogenic Factors in Preterm Preeclampsia / Associação entre desfechos maternos adversos e desbalanço de citocinas e fatores angiogênicos em pré-eclâmpsia pré-termo

Abstract Objective Preeclampsia (PE) is a pregnancy-specific syndrome characterized by abnormal levels of cytokines and angiogenic factors, playing a role in the disease development. The present study evaluated whether immunological markers are associated with the gestational age and with the disease severity in preeclamptic women. Methods Ninety-five women who developed PE were stratified for gestational age as preterm PE (< 37 weeks) and term PE (≥ 37 weeks of gestation) and compared for disease severity as well as plasma concentration of angiogenic factors and cytokines. The concentrations of placental growth factor (PlGF), vascular endothelial growth factor (VEGF), Fms-like soluble tyrosine kinase (sFlt-1) and soluble endoglin (sEng), as well as the cytokines, tumor necrosis factor-α (TNF-α) and interleukin 10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA). Results The comparison between preeclamptic groups showed a higher percentage of severe cases in preterm PE (82.1%) than in term PE (35.9%). Similarly, the concentrations of TNF-α, sFlt-1, and sEng, as well as TNF-α/IL-10 and sFlt-1/PlGF ratios were significantly higher in the preterm PE group. In contrast, concentrations of PlGF, VEGF, and IL-10 were significantly lower in women with preterm PE. Negative correlations between TNF-α and IL-10 (r = 0.5232) and between PlGF and sFlt1 (r = 0.4158) were detected in the preterm PE. Conclusion In pregnant women with preterm PE, there is an imbalance between immunological markers, with the predominance of anti-angiogenic factors and TNF-α, associated with adverse maternal clinical outcomes.

Resumo Objetivo A pré-eclâmpsia (PE) é uma síndrome específica da gravidez caracterizada por níveis anormais de citocinas e fatores angiogênicos, que desempenham um papel no desenvolvimento da doença. Este estudo avaliou se os marcadores imunológicos estão associados à idade gestacional e à gravidade da doença em mulheres com pré-eclâmpsia. Métodos Noventa e cinco mulheres que desenvolveram PE foram estratificadas pela idade gestacional em PE pré-termo (< 37 semanas) e PE a termo (≥ 37 semanas de gestação) e comparadas quanto à gravidade da doença, bem como à concentração plasmática de fatores angiogênicos e citocinas. As concentrações de fator de crescimento placentário (PlGF), fator de crescimento endotelial vascular (VEGF), tirosina quinase solúvel semelhante a Fms (sFlt-1) e endoglina solúvel (sEng), bem como as citocinas, fator de necrose tumoral alfa (TNF- α) e interleucina 10 (IL-10), foram determinados porensaio de imunoabsorção enzimática (ELISA, na sigla em inglês). Resultados A comparação entre os grupos com pré-eclâmpsia mostrou maior porcentagem de casos graves em PE pré-termo (82,1%) do que em PE a termo (35,9%). Da mesma forma, as concentrações de TNF-α, sFlt-1 e sEng, bem como as razões TNF-α/IL-10 e sFlt-1/PlGF foram significativamente maiores no grupo de PE pré-termo. Em contraste, as concentrações de PlGF, VEGF e IL-10 foram significativamente menores em mulheres com PE pré-termo. Correlações negativas entre TNF-α e IL-10 (r = 0.5232) e entre PlGF e sFlt1 (r = 0.4158) foram detectadas no grupo de PE pré-termo. Conclusão Em gestantes com PE pré-termo, ocorre um desequilíbrio entre os marcadores imunológicos, com predomínio de fatores antiangiogênicos e TNF-α, associados a desfechos clínicos maternos adversos.

Evaluation of angiogenic factors (PlGF and sFlt-1) in pre-eclampsia diagnosis / Avaliação dos fatores angiogênicos (PlGF e sFlt-1) no diagnóstico de pré-eclâmpsia

Abstract Objective: Recent observations support the hypothesis that an imbalance between angiogenic factors has a fundamental role in the pathogenesis of pre-eclampsia and is responsible for the clinical manifestations of the disease. The goal of the present study was to evaluate the sensitivity, specificity, and the best accuracy level of Soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in maternal serum and protein/creatinine ratio in urine sample to define the best cutoff point of these tests to discriminate between the patients with gestational hypertension and the patients with pre-eclampsia, to evaluate the possibility of using them as diagnostic methods. Methods: A prospective longitudinal study was performed, and blood samples were collected from 95 pregnant patients with hypertension to measure serum concentrations of biomarkers sFlt-1 and PlGF. Urine samples were collected for protein screening. Significance was set as p < 0.05. Results: The sFlt-1/PlGF ratio demonstrated a sensitivity of 57.5% and a specificity of 60% using 50.4 as a cutoff point. The test that showed the best accuracy in the diagnosis of pre-eclampsia was protein/creatinine ratio, with a sensitivity of 78.9% and a specificity of 70% using 0.4 as a cutoff point and showing an area under the receiver operating characteristic curve of 0.80 (p < 0.001). Conclusion: No studied laboratory test proved to be fairly accurate for the diagnosis of pre-eclampsia, except for the protein/creatinine ratio. The evidence is insufficient to recommend biomarkers sFlt-1 and PlGF to be used for the diagnosis of pre-eclampsia.

Resumo Objetivo: Pesquisas recentes sustentam a hipótese de que um desequilíbrio entre fatores angiogênicos desempenhe um papel fundamental na patogênese da pré-eclâmpsia e seja responsável pelas manifestações clínicas da doença. O objetivo do presente estudo foi avaliar a sensibilidade, a especificidade e o nível de melhor acurácia do Fator semelhante a tirosina quinase 1 (sFlt-1), Fator de crescimento placentário (PlGF), e relação sFlt-1/PlGF no soro materno e relação proteína/creatinina em amostra de urina e definir o melhor ponto de corte desses testes para distinguir pacientes com hipertensão gestacional daquelas com pré-eclâmpsia, a fim de avaliar a possibilidade de utilizá-los como métodos diagnósticos. Métodos: Foi realizado um estudo prospectivo longitudinal e foram coletadas amostras de sangue de 95 gestantes com hipertensão arterial para dosar as concentrações séricas dos biomarcadores sFlt-1 e PlGF. Amostras de urina foram coletadas para pesquisa de proteinúria. Foram consideradas significativas as diferenças com p < 0,05. Resultados: A relação sFlt-1/PlGF demonstrou sensibilidade de 57,5% e especificidade de 60% utilizando 50,4 como ponto de corte. O teste que apresentou a melhor acurácia no diagnóstico de pré-eclâmpsia foi a relação proteína/creatinina, com sensibilidade de 78,9% e especificidade de 70%, utilizando 0,4 como ponto de corte e demostrando uma área sob a curva receiver operating characteristic (ROC, na sigla em inglês) de 0,80 (p < 0,001). Conclusão: Nenhum método de rastreamento isolado se mostrou com boa acurácia para o diagnóstico de pré-eclâmpsia, exceto a relação proteína/creatinina. As evidências são insuficientes para recomendar os biomarcadores sFlt-1 e PlGF como diagnóstico de pré-eclâmpsia.

Correlación de los valores de sFlt-1, PlGF y su cociente en preeclampsia con criterios de severidad en una Unidad de Cuidados Intensivos / Correlation of the values of sFlt-1, PlGF and its precilampsy court with severity criteria in an Intensive Care Unit / Correlação dos valores de sFlt-1, PlGF e seu coeficiente em preeclampsia com critérios de gravidade em uma Unidade de Terapia Intensiva

Resumen: Introducción: La detección del desequilibrio entre los factores proangiogénicos/antiangiogénico (sFlt-1, PlGF, cociente sFlt-1/PlGF) en la sangre materna son herramientas de pronóstico y diagnóstico en preeclampsia. Objetivo: Determinar la correlación entre los valores sanguíneos de sFlt-1, PlGF, cociente sFlt-1/PlGF y las complicaciones en mujeres con preeclampsia severa. Material y métodos: Se estudiaron a mujeres que ingresaron a la UCI con diagnóstico de preeclampsia con criterios de severidad y se determinaron las variables clínicas y de laboratorio. Las concentraciones séricas de sFlt-1 y PlGF se realizaron con un equipo automático KRYPTOR compact Plus. Resultados: Encontramos que 33.3% fue preeclampsia temprana y 66.7% tardía. Los criterios de severidad fueron: 66.7% crisis hipertensiva y 33.3% encefalopatía hipertensiva. Existió una correlación negativa entre los valores de sFlt-1 y urea, creatinina, proteínas de orina en 24 horas, presión sistólica (TAS) y presión diastólica (TAD). La correlación fue pobre y no fue estadísticamente significativa. Existió una correlación positiva y estadísticamente significativa para ácido úrico. Existió una correlación negativa entre los valores de PlGF en TAS, TAD. No existió correlación entre los valores cociente sFlt-1/PlGF y las variables medidas como TAS, TAD. Conclusiones: Este estudio confirma que es posible identificar un desbalance angiogénico en mujeres con preeclampsia severa. Sin embargo, los marcadores angiogénicos no presentaron una correlación estadísticamente significativa con respecto a las variables clínicas y bioquímicas de preeclampsia en la Unidad de Cuidados Intensivos.

Abstract: Introduction: The detection of the imbalance between proangiogenic/antiangiogenic factors (sFlt-1, PlGF, sFlt-1/PlGF ratio), in maternal blood are prognostic and diagnostic tools in preeclampsia. Objective: To determine the correlation between blood values of (sFlt-1, PlGF, sFlt-1/PlGF ratio) and complications in women with severe preeclampsia. Material and methods: Women who were admitted to the ICU with a diagnosis of preeclampsia with severity criteria were studied, clinical and laboratory variables were determined. Serum concentrations of sFlt-1, PLGF were performed with a KRYPTOR compact Plus automatic equipment. Results: 33.3% were early preeclampsia and 66.7% late. The severity criteria occurred with 66.7% with hypertensive crisis and 33.3% with hypertensive encephalopathy. There was a negative correlation between the values of sFlt-1 and urea, creatinine, urine proteins in 24 hours, systolic pressure (ASD), diastolic pressure (ADT). The correlation was poor and not statistically significant. There was a positive and statistically significant correlation for uric acid. There was a negative correlation between PlGF values in TAS, TAD. There was no correlation between the sFlt-1/PlGF quotient values and the variables measured as TAS, TAD. Conclusions: This study confirms that it is possible to identify an angiogenic imbalance in women with severe preeclampsia. However, the angiogenic markers did not show a statistically significant correlation, with respect to the clinical and biochemical variables of preeclampsia in the Intensive Care Unit.

Resumo: Introdução: A detecção de desequilíbrio entre fatores pró-angiogênicos/antiangiogênicos (sFlt-1, PlGF, coeficiente sFlt-1/PlGF) no sangue materno são ferramentas de prognóstico e diagnóstico na pré-eclâmpsia. Objetivo: Determinar a correlação entre os valores sanguíneos de (sFlt-1, PlGF, coeficiente sFlt-1/PlGF) e complicações em mulheres com pré-eclâmpsia grave. Material e métodos: Foram estudadas mulheres admitidas na UTI com diagnóstico de pré-eclâmpsia com critérios de gravidade, determinou-se variáveis clínicas e laboratoriais. As concentrações séricas de sFlt-1, PLGF foram realizadas com um equipamento automático KRYPTOR compact Plus. Resultados: 33.3% eram pré-eclâmpsia precoce e 66.7% tardia. Os critérios de gravidade ocorreram com 66.7% com crise hipertensiva e 33.3% com encefalopatia hipertensiva. Houve correlação negativa entre os valores de sFlt-1 e uréia, creatinina, proteínas da urina em 24 horas, pressão sistólica (PAS) e pressão diastólica (PAD). A correlação foi ruim e estatisticamente não significante. Houve uma correlação positiva e estatisticamente significante para o ácido úrico. Encontrou-se uma correlação negativa entre os valores de PLGF no TAS, TAD. Não houve correlação entre os valores do quociente sFlt-1/PlGF e as variáveis medidas como PAS e PAD. Conclusões: Este estudo confirma que é possível identificar um desequilíbrio angiogênico em mulheres com pré-eclâmpsia grave. No entanto, os marcadores angiogênicos não apresentaram correlação estatisticamente significante com relação às variáveis clínicas e bioquímicas da pré-eclâmpsia na unidade de terapia intensiva.

Progress of anti-angiogenesis targeted therapy of advanced osteosarcoma / 肿瘤研究与临床

Osteosarcoma is a malignant tumor of mesenchymal origin and occurs mostly in young people, which is characterized with high malignancy, poor prognosis, easy recurrence and metastasis, as well as a great difficulty in treatment. Osteosarcoma is rich in blood supply, and its growth, invasion and metastasis highly depend on the tumor new angiogenesis. The process of angiogenesis is mainly initiated by various pro-angiogenic factors secreted by tumor cells, and the anti-angiogenic targeted therapy has been taken based on the targets spot and signal pathways of various angiogenic factors, which can effectively suppress the various biological behaviors of the osteosarcoma and improve the survival rate. However, a series of problems, such as drug resistance, side effects, different evaluation criteria, and difficulties in selecting effective treatment strategies also exist in the process of anti-angiogenesis therapy, and thus, further studies are needed. This paper mainly reviews the clinical trials of anti-angiogenic drugs, main barriers in usage, as well as the feasible treatment strategies in clinical practice.

Clinical assessment after human adipose stem cell transplantation into dogs

Adipose tissue-derived stem cell (ASCs) are an attractive source of stem cells with therapeutic applicability in various fields for regenerating damaged tissues because of their stemness characteristics. However, little has reported on evaluating adverse responses caused by human ASC therapy. Therefore, in the present study, a clinical assessment after human ASC transplantation into dogs was undertaken. A total of 12 healthy male dogs were selected and divided into four groups: saline infusion, saline bolus, ASC infusion, and ASC bolus groups. Physical assessment and blood analysis were performed following ASC transplantation, and the concentrations of angiogenic factors, and pro- and anti-inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). There were no adverse vital sign responses among the dogs. Blood analyses revealed no remarkable complete blood count or serum chemistry results. ELISA results for angiogenic and anti-inflammatory factors including matrix metalloproteinase 9 (MMP9), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and interleukin-10 (IL-10) were significantly higher in the two ASCs groups than in the controls. In conclusion, this study demonstrated that transplantation of human ASCs produced no adverse effects and could be used safely in dogs. In addition, human ASCs could be involved in modulating secretions of angiogenic factors including MMP9, VEGF, bFGF, and HGF and anti-inflammatory factor IL-10.

Effect of fluoxetine on the expression of angiogenic factors in hippocampus of depressive rats / 中华行为医学与脑科学杂志

Objective Effect of fluoxetine on the expression of angiogenic factors in hippocampus of depressive rats.Methods 32 male SD rats (3 month) of SPF level were randomly divided into fluoxetine group (n=8),fluoxetine ± LY294002 intervention group (n=8),model group (n=8) and control group (n =8).Control group without any treatment was free to eat and water for 5 weeks.The rats in the other groups were modeled by chronic,mild and unpredictable multiphase stress.The fluoxetine group was treated with fluoxetine for 2 weeks after modeling,and the intervention group was given LY294002 intervention,then the fluoxetine treatment for 2 weeks,the model group was free to eat and drink for 2 weeks.At the end of the 5th week,all the rats were decapitated and the hippocampus was removed on the ice bath.Western blot was performed to detect the expression of angiogenic factors.Results Compared with the model group (vascular endothelial growth factor(VEGF) (0.44 ± 0.08),fetal liver kinase 1 (FLK1) (0.37 ± 0.15),protein kinase B1 (AKT1) (0.40±0.10),p-AKT1 (0.53±0.07)),the expression of VEGF (0.98± 0.13),FLK1 (1.09± 0.21),AKT1 (1.05±0.05) and p-AKT1 (1.01±0.13)in hippocampus of fluoxetine group were significantly increased,and the differences were statistically significant (P＜ 0.01).And the expression of VEGT,FLK1,p-AKT1 in fluoxetine group increased compared with those of fluoxetine ± LY294002 intervention group (VEGF (0.55±0.08),FLK1 (0.55±0.14) and p-AKT1 (0.60±0.05)),and the difference were statistically significant (P＜0.01).Conclusion Fluoxetine can increase the expression of VEGF/FLK1 and p-AKT1 proteins in the hippocampus of depressed rats,which in turn may be involved in the regeneration of hippocampal blood vessels.This effect of fluoxetine may be related to the PI3K/AKT signaling pathway.

Research progress on molecular mechanisms of angiogenesis after acute myocardial infarction / 中国比较医学杂志

Angiogenesis is a process that new blood vessels generate on the basis of an original vascular plexus via sprouting or other forms during normal growth and development of an organism or under particular conditions such as wound repairing and ischemic hypoxia. In general, angiogenesis includes five stages: degradation of the vascular basement membrane, endothelial cell proliferation, vascular sprouting, lumen formation and vascular network turning stable and mature. Among ischemic heart diseases, acute myocardial infarction seriously threatens human health, its pathological characteristics include myocardial vascular stenosis and blockage,leading to myocardial infarction. Therefore,the promotion of angiogenesis has become one of the therapies for ischemic heart diseases. A variety of pro-angiogenic cytokines are involved in the process of angiogenesis, such as polypeptide growth factors and lipid mediators. In this paper we review the recent progress in research on the expression of pro-angiogenic factors in myocardium after ischemic myocardial infarction.

Effects of Trastuzumab Combined with Neoadjuvant Chemotherapy on Clinical Efficacy and Related Index-es of Breast Cancer Patients after Surgery / 中国药房

OBJECTIVE:To investigate the effects of trastuzumab combined with neoadjuvant chemotherapy on clinical effica-cy of breast cancer patients,serum angiogenic factors and apoptosis factors of breast tissue. METHODS:A total of 116 breast can-cer in patients were selected from our hospital during Jan. 2012-Dec. 2014 as research object,and then divided into control group and observation group according to random number table,with 58 cases in each group. Control group was given Carboplatin for in-jection 100 mg(added into 500 mL 5% Glucose injection after diluted into 10 mg/mL),ivgtt,200-400 mg/m2 on the first day of each chemotherapy cycle;Docetaxel injection ivgtt,75 mg/m2 on the first day of each chemotherapy cycle. On the basis of control group,observation group was additionally given Trastuzumab for injection,4 mg/kg in the first week,2 mg/kg in the 2nd-8th week,once a week,ivgtt. A treatment course lasted for 3 weeks,and both groups received 6 courses of treatment. Both groups re-ceived modified radical mastectomy 2 weeks after treatment. The levels of serum angiogenic factors and apoptosis factors of breast tissue were observed in 2 groups before and after treatment. Clinical efficacies and the occurrence of ADR were compared between 2 groups 1 year after treatment. RESULTS:Before treatment,there was no statistical significance in the levels of serum angiogenic factors and apoptosis factors of breast tissue between 2 groups (P>0.05). After treatment,the levels of serum angiogenic factors and apoptosis factors of breast tissue were decreased significantly in 2 groups,and the observation group was significantly lower than the control group,with statistical significance(P0.05). CONCLUSIONS:Trastuzumab combined with neoadjuvant chemotherapy is helpful to improve the therapeutic effect with breast cancer, prevent recnrence,and reduce the expression of serum angiogenic fac-tors and apoptosis factors of breast tissue with good safety.

Diferencia entre la concentración de factores angiogénicos en preeclampsia e hipertensión gestacional y su relación con el resultado materno y perinatal / Differences between concentrations of angiogenic factors in preeclampsia and gestational hypertension and their relationship with adverse maternal and perinatal outcome

Resumen OBJETIVO: determinar la relación entre las concentraciones séricas de factores angiogénicos con la severidad de la preeclampsia e hipertensión gestacional y con el resultado materno y perinatal adverso. MATERIALES Y MÉTODOS: estudio transversal y comparativo efectuado en pacientes atendidas entre los meses de septiembre de 2013 y agosto de 2015 en la Unidad Médica de Alta Especialidad. La población de estudio se dividió en cinco grupos: 1) hipertensión gestacional leve, 2) preeclampsia leve, 3) hipertensión gestacional severa, 4) preeclampsia severa y 5) preeclampsia severa complicada. Además, el total de pacientes se analizó según el resultado materno o perinatal adverso. Las concentraciones séricas de sFlt-1, PlGF y su relación sFlt1/PlGF se midieron con electroquimioluminiscencia. RESULTADOS: se estudiaron 196 mujeres con embarazo único ≥ 20 semanas de gestación, con hipertensión gestacional y preeclampsia. Las concentraciones de sFlt-1, PlGF y la relación sFlt1/PlGF fueron significativamente diferentes entre los cinco grupos de estudio (p < 0.001). La diferencia en la concentración de los factores angiogénicos fue más marcada conforme mayor fue la severidad de la enfermedad hipertensiva en el embarazo (p < 0.001). La relación sFlt-1/PIGF fue significativamente mayor en las pacientes con resultado materno o perinatal adverso en comparación con quienes no lo tuvieron (222.5 vs 112.8 y 158.3 vs 53.1, respectivamente) p < 0.001. CONCLUSIÓN: conforme mayor fue la severidad de la enfermedad hipertensiva en el embarazo se observó mayor alteración en la concentración de factores angiogénicos (p < 0.001). Así mismo, la relación sFlt-1/PIG fue mayor en pacientes con resultado materno y perinatal adverso (p < 0.001).

Abstract BACKGROUND: Preeclampsia is a major cause of maternal and fetal morbidity and mortality. The loss of the balance between pro-angiogenic and antiangiogenic factors precedes the clinical presentation of preeclampsia. This alteration is greater in early and severe forms of the disease and shows association to adverse perinatal outcome. OBJECTIVE: To determine the relationship between serum concentrations of angiogenic factors and the severity of preeclampsia and gestational hypertension with the maternal and perinatal outcome. MATERIALS AND METHODS: A cross-sectional comparative study from September 2013 to August 2015 was performed in the Hospital of Gynecology and Obstetrics No. 4 IMSS Luis Castelazo Ayala. A total of 196 patients were analyzed including singleton pregnancies ≥ 20 weeks' gestation diagnosed with preeclampsia and gestational hypertension. The patients were divided in five groups: mild gestational hypertension (n = 46), mild preeclampsia (n = 20), severe gestational hypertension (n = 19), severe preeclampsia (n = 89), and severe complicated preeclampsia (n = 22). Additionally the total patients were divided in two groups: with and without adverse maternal outcome and the second group with and without adverse perinatal outcome. The serum concentration of sFlt-1, PlGF and the respective sFlt1/PLGF ratio were determinate with electrochemiluminescence. The management and timing of the termination of pregnancy was performed based on established guidelines for clinical practice. RESULTS: The serum concentration of sFlt-1, PlGF and the respective sFlt1/PLGF ratio were significant different between the 5 groups analyzed (p < 0.001). Moreover, the difference of the concentrations of angiogenic factors are closely associated with the severity of hypertensive disease of pregnancy (p < 0.001). The sFlt1/PLGF ratio was higher in those with adverse maternal and fetal outcomes compared to those who did not had (222.5 vs 112.8 and 158.3 vs 53.1 respectively) p < 0.001. CONCLUSION: Major alteration was observed in the concentration of angiogenic factors as the greater the severity of hypertensive disease in pregnancy. Likewise, the sFlt-1/PlGF ratio was higher in those with adverse maternal and perinatal outcomes compared to those who did not have. Therefore this relationship has potential use as a biochemical marker of severity and risk stratification.

Effect of hypoxia on angiogenesis-related proteins in human dental pulp cells

Dental pulp is a highly vascularized tissue with high regenerative potential. Revascularization of severed vasculature in the tooth is required for pulp healing during avulsed tooth treatment. In this study, the relative expression of angiogenesis-related proteins was determined in human dental pulp cells using a human angiogenesis proteome profiler array. The proteome profiler array detected differentially expressed angiogenesis-related factors under conditions of hypoxia, which enhances the angiogenic potential of dental pulp cells. We confirmed that hypoxia regulates the mRNA expression of angiogenesis-related factors, including CXCL16 in dental pulp cells. Furthermore, conditioned media of hypoxic pulp cells induced tube-like structures of vascular endothelial cells, which were reduced by the neutralization of CXCL16 function. In conclusion, our data show that angiogenesis-related factors are differentially expressed by hypoxia in dental pulp cells and suggest that CXCL16 may involve in the revascularization of hypoxic dental pulp.

Changes of expression of angiogenic factor mRNA in the spinal cord of rat models of protruded intervertebral disc and the effects of electroacupuncture / 中国实验动物学报

Objective The purpose of this study was to determine the changes of expression of angiogenic factor mRNA in the spinal cord of rats with protruded intervertebral disc and the effects of electroacupuncture , and to analyze the role of electroacupuncture in the spinal microvascular angiogenesis .Method Eighteen healthy male Sprague-Dawley rats were divided randomly into 3 groups:the electroacupuncture group , model group and sham-operated group .The protruded intervertebral disc models were generated by the left lateral and ventral spinal cord compression at T 13 using a self-made silicon sheet.Only the rats in the first group were treated by electroacupuncture once a day for consecutive 7 days.Spinal cord tissue samples were taken from the compression site at 7 days after operation .The mRNA levels of Ang-1, Tie-1, Ang-2, Tie-2, VEGF, Flt-1, caspase-3 and Tsp-1 were determined by RT-PCR, and the pathological changes of the spinal cord was examined using HE staining .Results The rats in the electroacupuncture treated group showed significantly im-proved hind leg function , a relatively complete spinal cord structure , and a clear boundary between grey and white matters . The expression levels of Ang-1, Ang-2, Tie-1, Tie-2, capase-3 and Tsp-1 in the spinal cord tissues of the model group were significantly higher than those of sham-operated group ( P0.05).The expression levels of Ang-2, Tie-1, Tie-2, caspase-3 and Tsp-1 of the electroacupuncture group were significantly lower than those in the model group (P0.05).All the indexes be-tween electroacupuncture and sham-operated groups showed no significant difference ( P>0.05 ) .Conclusions Our re-sults demonstrate that mRNA expression of relevant angiogenic factors were abnormal after spinal cord compression , while electroacupuncture can down-regulate the expression of Ang-2, Tie-2,Tsp-1 and caspase-3, and modulate the promoting and inhibiting factors of angiogenesis to return towards normal , therefore , to create beneficial conditions for the repair of spinal cord injuries .

Angiogenic factors are associated with development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation / 华中科技大学学报（医学）（英德文版）

Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-β in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-β promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD.

Significancia del desbalance de los factores angiogénicos en preeclampsia

La participación de los factores antiangiogénicos, la forma soluble de la fms-semejante a la tirosina quinasa (Flt-1s) y la endoglina soluble (Engs), en el desarrollo de la preeclampsia (PE) se ha demostrado en múltiples estudios clínicos y experimentales. Estos estudios están complementados por estudios en animales, en los cuales la sobreexpresión de estos factores antiangiogénicos origina manifestaciones clínicas muy similares a la PE. El origen de esta enfermedad permanece desconocido. Sin embargo, factores genéticos, ambientales e inmunológicos parecen alterar el desarrollo normal de la placenta, lo cual conduce últimamente a la PE. Flt-1s y Engs inhiben la producción y las propiedades proangiogénicas del factor de crecimiento vascular endotelial (FCVE) y del factor de crecimiento placentario (FCP), necesarios para el desarrollo normal vascular de la placenta y las adaptaciones vasculares fisiológicas del embarazo. Cantidades exageradas de Flt-1s y Engs se producen en la placenta disfuncional y se liberan en la circulación materna. Altas concentraciones de Flt-1s y Engs se encuentran en la circulación materna semanas antes de que la enfermedad sea detectada clínicamente. Las capacidades de los factores angiogénicos para predecir PE en embarazos asintomáticos de riesgo bajo y alto son inconsistentes y no útiles para el uso clínico. Por otro lado, proporciones de los factores Flt-1s/FCP, FCP/Flt-1s, y FCP/Eng poseen valores predictivos más altos para diagnosticar PE y predecir sus complicaciones en mujeres con sintomatología de PE. En estas condiciones, el uso clínico de estos marcadores biológicos podría ser implementado en un futuro cercano. Las propiedades biológicas y farmacocinéticas de las estatinas las convierten en uno de los medicamentos con más potencial preventivo para la PE. Otros opciones terapéuticas que se están estudiando son medicamentos que directamente inhiban los factores antiangiogénicos circulantes. Estudios in vitro y estudios pilotos clínicos se están realizando actualmente examinando la seguridad materno-fetal, la transferencia placentaria y la efectividad de estas terapias.

The role of the antiangiogenic factors, the soluble form of the fms-like tyrosine kinase receptor 1 (sFlt1) and the soluble endoglin (sEng), in the development of preeclampsia (PE) has been demonstrated in multiple clinical and experimental studies. These studies are complemented by animal studies, in which overexpression of these antiangiogenic factors leads to clinical manifestations similar to PE. Although, the origin of this disease remains unknown, genetic, environmental, and immunological factors appear to affect the normal placental development, resulting ultimately in PE. sFlt-1 and sEng inhibit the proangiogenic properties of the vascular endothelial growth factor (VEGF) and the placental growth factor (PlGF), affecting the normal vascular development in the placenta and the physiological vascular adaptations that occur in pregnancy. Exaggerated amounts of sFlt-1 and sEng, produced in the dysfunctional placenta, are released into the maternal circulation and elevated circulating concentrations of these antiangiogenic factors are found several weeks prior to the clinical manifestations of the disease. Multiple studies have reported the capacity of circulating antiangiogenic factor concentrations to predict PE in asymptomatic low and high risk pregnancies. The reported predictive values of sFlt-1 and sEng are inconsistent across these studies and therefore their clinical use in this population is not recommended. On the other hand, maternal plasma concentrations of these factors appear to have a better performance in women with symptoms of PE. Among the possible combinations, the ratios of sFlt-1/PlGF, PlGF/sFlt-1, and PlGF/Engs seem to have the highest sensitivities and specificities to diagnose PE as well as the highest predictive values for PE-related adverse outcomes. These properties support their clinical use in this setting and it is likely those ancillary tests will be incorporated to the clinical practice in the near future. The participation of antiangiogenic factors in the pathogenesis of PE, also have stimulated investigation of new targeted therapies. The biological and pharmacokinetic properties of statins have converted them in one of the most promising preventive therapies for this disease. Others are investigating agents that directly inhibit the circulating antiangiogenic factors. In-vitro and pilot clinical studies are currently evaluating the effectiveness, maternal-fetal safety, and placental transference of these therapies.

Research Advances in Mechanism of Bioactive Tanshinones in Salviae Miltiorrhiae Regulating Angiogenesis / 浙江中医药大学学报

[Objective]To explore the mechanism of bioactive tanshinones in Salviae Miltiorrhiae regulating angiogenesis and lay the foundation for the prevention and treatment of cancer, atherosclerosis, ischemic heart disease and other angiogenesis-related diseases. [Method]Based on angiogenesis mechanisms, infer to recent 10 years of articles from home and abroad, analyze and summarize the angiogenesis regulatory mechanisms of various bioactive ingredients in Danshen on endothelial cells, in vitro tumour cells and in vivo xenograft tumor. [Result] Among various bioactive ingredients of Salvia, Salvianolic acid B, Tanshinone IIA, Cryptotanshinone, Dihydrotanshinone I can promote or inhibit angiogenesis. Furthermore, Salvianolic acid B and Tanshinone IIA are considered to be the most important bioactive ingredients in Danshen and exhibit a dual angiogenic regulating activity through regulating various approaches, such as pro-angiogenic factors, MMPs, HIF-1α, the PI3K/AKT/eNOS signal pathway and so on. [Conclusion]Various bioactive ingredients of Salvia can serve as a regulator of angiogenesis, and it may provide new ideas for the prevention of angiogenesis-related diseases.

Biomarkers for the management of pre-eclampsia in pregnant women.

Pre-eclampsia (PE) is a pregnancy related disorder characterized by hypertension and proteinuria noticeable after 20 wk of gestation. It is a leading cause of maternal and foetal mortality and morbidity worldwide. The aetiology of the disease is unknown, but recent studies have revealed that this disorder appears to originate in placenta and is characterized by widespread maternal endothelial dysfunction. Till date, delivery of placenta is the only cure for the disease. So, there is a need for the identification of highly specific and sensitive biochemical markers that would allow early identification of patients at risk and thus help in providing proper prenatal care. Several promising biomarkers have been proposed, alone or in combination, that may help in predicting women who are likely to develop PE. Maternal serum concentrations of these biomarkers either increase or decrease in PE during gestation. This review focuses on the various biomarkers available and their utility in predicting pre-eclampsia.

Changes in serum concentrations of angiogenic factors in patients with type 2 diabetes mellitus / 中华内分泌代谢杂志

Forty-two patients with type 2 diabetes (DM group),23 type 2 diabetic patients with unstable angina pectoris (DM + UAP group),and 36 healthy subjects (control group) were enrolled in this study.Serum samples were collected for determining serum concentrations of vascular endothelial growth factor (VEGF),Angiopoietin (Ang)-1,Ang-2,angiogenin,angiostatin,basic fibroblast growth factor,and platelet-derived growth factor-BB using protein array technology.The results showed that there were no significant differences in serum concentrations of all 7 angiogenic factors between control group and DM group.Whereas,serum concentrations of V EGF and Ang-2 were significantly increased in DM + UAP group compared with control group [(3 532.10 ± 1 813.72vs 2 444.50 ± 1 152.21) pg/ml,(286.90-± 217.01 vs 171.92 ± 106.63) pg/ml,both P＜0.01].Pearson's correlation analysis revealed that serum concentrations of all 7 angiogenic factors were not related to HbA1C,fasting and 2 h postprandial plasma glucose,triglycerides,high density lipoprotein cholesterol,as well as low density lipoprotein cholesterol.

Changes in serum concentrations of angiogenic factors in patients with unstable angina pectoris / 中华急诊医学杂志

Objective To detect the changes in serum concentrations of angiogenic factors in patients with unstable angina pectoris.Methods A total of 57 patients with unstable angina pectoris were eligible for study and divided into diabetes group (n =23) and non-diabetes group (n =34).Exclusion criteria included complicated diseases,symptomatic peripheral vascular diseases,renal or liver diseases,cerebral embolism and evidence of ongoing infection.Another 36 age-matched healthy subjects from medical examination center were enrolled as control group.Serum samples were collected,and serum concentrations of vascular endothelial growth factor (VEGF),angiopoietin-1,angiopoietin-2,angiogenin,angiostatin,basic fibroblast growth factor (bFGF) and platelet-derived growth factor-BB (PDGF-BB) were measured by using cytokine array technology.The data were analyzed by independent-samples t test with the SPSS 13.0statistic software package.Results Compared with the control group,the serum concentrations of VEGF and angiopoietin-2 were significantly increased in patients with unstable angina pectoris (both P ＜ 0.01).Whereas,no significant differences in serum concentrations of angiogenin,angiopoietin-1,angiostatin,bFGF,and PDGF-BB were detected between control group and patient groups.There were no significant differences in serum concentrations of above all 7 biomarkers between diabetes group and non-diabetes group.Conclusions Serum concentrations of VEGF and angiopoietin-2 were increased in patients with unstable angina pectoris,and diabetes didn' t affect the increases in serum concentrations of VEGF and angiopoietin2 caused by unstable angina pectoris.

Pathogenesis and promising non-invasive markers for preeclampsia

Preeclampsia is one of the leading causes of maternal mortality/morbidity and preterm delivery in the world, affecting 3% to 5% of pregnant women. The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormalities in the development of placental vessels early in pregnancy may result in placental hypoperfusion, hypoxia, or ischemia. Hypoperfusion, hypoxia, and ischemia are critical components in the pathogenesis of preeclampsia because the hypoperfused placenta transfers many factors into maternal vessels that alter maternal endothelial cell function and lead to the systemic symptoms of preeclampsia. There are several hypotheses to explain the pathogenesis of preeclampsia, including altered angiogenic balance, circulating angiogenic factors (such as marinobufagenin, a bufadienolide trigger), and activation of the renin-angiotensin system. Epigenetically-modified cell-free nucleic acids that circulate in plasma and serum might be novel markers with promising non-invasive clinical applications in the diagnosis of preeclampsia.

Application of Angiogenic Factors to Cerebral Ischemia (review) / 中国康复理论与实践

@#Angiogenic factors possess the function of angiogenesis.The relationship between the angiogenic factors and the treatment of ischemic diseases is attracting increasing attention.The present article reviewed the progresses of angiogenic factors in the treatment of cerebral ischemia.

Electrical Stimulation and Cardiovascular Disease : A Novel Therapeutic Approach / The Japanese Journal of Rehabilitation Medicine

Electrical stimulation (ES) is an established method for providing muscle activity. Moreover, there are some reports that ES induces angiogenesis. It was thought that the angiogenesis from ES is induced by physical phenomenon such as calculated shear stress, capillary wall tension, and stretch. However, there is a report that the electrical field itself might play a role in angiogenesis by stimulating the vascular endothelial growth factor (VEGF) receptor signaling pathway. Therefore, there is a possibility that ES might be used as a new therapy for ischemic diseases such as arteriosclerosis obliterans (ASO). The limited physical performance of chronic heart failure (CHF) patients may not only be entirely due to impairment of cardiac and lung function but may also result from peripheral hemodynamic variables and abnormalities in skeletal muscle metabolism and structure, such as a decrease in capillary density, mitochondrial content etc. There are some studies showing the positive effect of low frequency electrical stimulation on muscle strength and blood flow in patients who have advanced CHF and can not achieve conventional exercise training. Thus, ES could be recommended for the treatment of patients with severe CHF. Furthermore, cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker would reduce the risk of death and hospitalization among patients with advanced CHF. Further studies are required to precisely define the underlying mechanism and determine the most effective mode of application.