Inhibition of ANGPT2 activates autophagy during hypertrophic scar formation via PI3K/AKT/mTOR pathway

Abstract Background Hypertrophic scar (HS), a fibroproliferative disorder caused by aberrant wound healing following skin injuries such as burns, lacerations and surgery, is characterized by invasive proliferation of fibroblasts and excessive extracellular matrix (ECM) accumulation. The dysregulation of autophagy is the pathological basis of HS formation. Previously, angiopoietin-2 (ANGPT2) was found to be overexpressed in HS fibroblasts (HSFs) compared with normal skin fibroblasts. However, whether ANGPT2 participates in the process of HS formation and the potential molecular mechanisms are not clear. Objective This study is intended to figure out the role of ANGPT2 and ANGPT2-mediated autophagy during the development of HS. Methods RT-qPCR was used to detect ANGPT2 expression in HS tissues and HSFs. HSFs were transfected with sh-ANGPT2 to knock down ANGPT2 expression and then treated with MHT1485, the mTOR agonist. The effects of sh-ANGPT2 or MHT1485 on the proliferation, migration, autophagy and ECM accumulation of HSFs were evaluated by CCK-8 assay, Transwell assay and western blotting. The expression of PI3K/Akt/mTOR pathway-related molecules (p-PI3K, p-Akt and p-mTOR) was assessed by western blotting. Results ANGPT2 expression was markedly upregulated in HS tissues and HSFs. ANGPT2 knockdown decreased the expression of p-PI3K, p-Akt and p-mTOR. ANGPT2 knockdown activated autophagy and inhibited the proliferation, migration, and ECM accumulation of HSFs. Additionally, the treatment of MHT1485, the mTOR agonist, on ANGPT2-downregulated HSFs, partially reversed the influence of ANGPT2 knockdown on HSFs. Study limitations The study lacks the establishment of more stable in vivo animal models of HS for investigating the effects of ANGPT2 on HS formation in experimental animals. Conclusions ANGPT2 downregulation represses growth, migration, and ECM accumulation of HSFs via autophagy activation by suppressing the PI3K/Akt/mTOR pathway. Our study provides a novel potential therapeutic target for HS.

Reduced Angiopoietin Factor 2 Levels Are Correlated with Better Cardiac Function and Prognosis in Valvular Heart Disease

ABSTRACT Introduction: There are few circulating biomarkers for valvular heart disease. Angiopoietin (Ang) 1, Ang2, and vascular endothelial growth factor are important inflammation-associated cytokines. The aim of this study was to investigate the clinical significance and association of Ang1, Ang2, and vascular endothelial growth factor in valvular heart disease. Methods: This is a retrospective study; a total of 62 individuals (valvular heart disease patients [n=42] and healthy controls [n=20]) were included. Plasma levels of Ang1, Ang2, and vascular endothelial growth factor were detected by enzyme-linked immunosorbent assays. We retrospectively collected the baseline characteristics and short-term outcomes; logistic regression was performed to identify predictor for short-term mortality. Results: Ang2 was significantly decreased in the valvular heart disease group compared with the healthy control group (P=0.023), while no significant difference was observed in the Ang1 and vascular endothelial growth factor levels. The Ang2 level of New York Heart Association (NYHA) I/II patients — but not NYHA III/IV patients — was significantly decreased compared with that of healthy control individuals (NYHA I/II: P=0.017; NYHA III/IV: P=0.485). Univariable logistic regression analysis indicated that Ang2 was a significant independent predictor for short-term mortality (odds ratio 18.75, P=0.033, 95% confidence interval 8.08-102.33). Ang1 was negatively correlated with Ang2 (P=0.032, Pearson's correlation coefficient =-0.317) and was positively correlated with vascular endothelial growth factor (P=0.019, Pearson's correlation coefficient = 0.359). Conclusion: Ang2 might serve as a therapeutic and prognostic target for valvular heart disease.

Dynamic changes and clinical value of serum angiopoietin-2 and surfactant protein D in pediatric acute respiratory distress syndrome / 中国小儿急救医学

Objective:To study the relationship between the dynamic changes of angiopoietin-2 (Ang-2) and surfactant protein D (SP-D) in pediatric acute respiratory distress syndrome (pARDS) and the severity and prognosis of the disease.Methods:Using nested case-control study method, 80 children with pneumonia complicated with pARDS admitted to PICU at Fujian Maternal and Child Health Hospital from June 2018 to May 2021 were selected as pARDS group, and 19 healthy children with corresponding age were selected as control group.According to the oxygenation, the children in pARDS group were divided into three subgroups: mild group (23 cases), moderate group (32 cases) and severe group (25 cases). According to the prognosis at discharge, the children in pARDS group were divided into survival group (67 cases) and death group (13 cases). Ang-2 and SP-D were detected by enzyme-linked immunosorbent assay.The levels of Ang-2 and SP-D in children with pARDS of different severity on the first day were compared; The changes of Ang-2 and SP-D levels on the 1st, 3rd and 8th day of children in survival group and death group were compared, and the receiver operating characteristic (ROC) curve was plotted to compare the predictive value of Ang-2 and SP-D for pARDS prognosis.Results:(1) The levels of Ang-2 and SP-D on the first day in pARDS group were significantly higher than those in control group( P<0.001). (2) The levels of Ang-2 and SP-D on the first day in children with pARDS of different severity levels were significantly different ( P<0.001), and the levels of Ang-2 and SP-D increased gradually with the increase of disease severity.(3) The levels of Ang-2 and SP-D in death group were significantly higher than those in survival group on the 1st, 3rd and 8th day ( P<0.05). (4) Prognostic efficacy of Ang-2 and SP-D levels in pARDS group at different time points: when the areas under the ROC curve predicted by Ang-2 on the 1st, 3rd and 8th day for inpatient mortality in children with pARDS were 0.808, 0.981 and 0.989, respectively; the optimal cut-off values were 6 000 pg/mL, 6 971 pg/mL and 4 171 pg/mL, respectively; the sensitivity was 84.6%, 92.3% and 92.3%, respectively; and the specificity was 76.1%, 97.0% and 98.5%, respectively.The areas under the ROC curve predicted by SP-D on the 1st, 3rd and 8th day for inpatient mortality in children with pARDS were 0.689, 0.993 and 0.983, respectively; the optimal cut-off values were 13544 pg/mL, 16003 pg/mL and 12294 pg/mL, respectively; the sensitivity was 84.6%, 100.0% and 100.0%, respectively; and the specificity was 46.3%, 98.5% and 97.0%, respectively. Conclusion:Serum Ang-2 and SP-D levels in children with pARDS increase with the aggravation of the disease.The dynamic changes of Ang-2 and SP-D in children with pARDS with different prognosis are different during the course of disease, and monitoring serum Ang-2 and SP-D during the course of disease has a certain predictive value for clinical outcome.

Research progress of novel bispecific monoclonal antibody Faricimab in the treatment of diabetic macular edema and age-related macular degeneration / 国际眼科杂志(Guoji Yanke Zazhi)

Diabetic macular edema(DME)and age-related macular degeneration(ARMD)are the leading causes of visual impairment and blindness worldwide, and their common pathological features are increased vascular permeability and abnormal neovascularization, in which cytokines such as vascular endothelial growth factor(VEGF)and angiopoietin-2(Ang-2)play an important role. Intravitreal injection of anti-VEGF agents significantly changed the clinical management of DME and ARMD, but limitations such as the non-responsive cases, the treatment burden and risks caused by frequent injections need to be overcome. Faricimab, a novel bispecific monoclonal antibody that simultaneously targets VEGF-A and Ang-2, can effectively reduce vascular permeability, decrease the number of neovascularization and alleviate retinal edema. Registered clinical studies have shown that Faricimab is effective in improving vision and reducing retinal edema, which is non-inferior to Aflibercept and Ranibizumab, maintains a long dosing interval, and has a high safety profile. This article reviews the latest advances in the treatment of DME and ARMD with Faricimab.

Sulfasalazine prevents lung injury due to intra-abdominal sepsis in rats: possible role of Nrf2 and angiopoietin-2

This study aimed to investigate the effect of sulfasalazine in preventing and treating intra-abdominal sepsis-induced acute respiratory distress syndrome (ARDS) in a rat model. Forty male Wistar albino rats were used. The rats were randomly divided into four equal groups, and sepsis was induced in 30 rats by intraperitoneal administration of a fecal saline solution prepared from rat feces. Group 1: normal control (n=10) [non-surgical], Group 2: fecal intraperitoneal injection (FIP) (n=10) [untreated septic group], Group 3: FIP+saline (placebo) (n=10) [saline administered intraperitoneally], Group 4 (n=10): FIP+sulfasalazine [250 mg/kg per day administered intraperitoneally]. Computed tomography was performed and blood samples were collected for biochemical and blood gas analysis. The lungs were removed for histopathological studies. Statistically significant reductions in interleukin (IL)-6, IL1-β, tumor necrosis factor (TNF)-α, malondialdehyde (MDA), and angiopoietin-2 (ANG-2) levels were observed in the sulfasalazine group compared to the FIP+saline group (P<0.001). Nrf2 levels were significantly higher in the sulfasalazine-treated group than in the FIP and FIP+saline groups (P<0.01). Lung tissue scores were significantly reduced in the sulfasalazine group compared to the other sepsis groups. The Hounsfield unit (HU) value was significantly lower in the sulfasalazine group than in the FIP+saline group (P<0.001). PaO2 values were significantly higher in the sulfasalazine-treated group than in the FIP+saline-treated group (P<0.05). Sulfasalazine was shown to be effective in preventing and treating ARDS.

Correlation between serum angiopoietin-2 levels and the severity of community acquired pneumonia in elderly patients / 中华老年医学杂志

Objective:To investigate the expression of serum angiopoietin-2(Ang-2)in elderly community acquired pneumonia(CAP)patients and to evaluate the correlation between Ang-2 levels and the severity of CAP.Methods:As a case-control study, a total of 118 hospitalized elderly CAP patients were selected.According to the severity of CAP, patients were divided into the general pneumonia group( n=67)and the severe pneumonia group( n=51). At the same time, 40 elderly healthy people without pneumonia were selected as the control group.Serum Ang-2, interleukin-6(IL-6), procalcitonin(PCT)and C-reactive protein(CRP)levels were measured, and CURB-65 scores were obtained for patients with CAP. Results:Serum levels of Ang-2, IL-6, PCT and CRP in elderly CAP patients were significantly higher than those in the control group, and the differences were statistically significant( H=70.698, 25.752, 15.982, 30.588, all P<0.001). Spearman correlation analysis showed that Ang-2 levels were positively correlated with IL-6, PCT, CRP, and CURB-65 scores( r=0.715, 0.531, 0.558, 0.450, all P<0.001). Using Ang-2 as a predictor for severe pneumonia in community-dwelling elderly patients, the area under the ROC curve(AUC)was 0.866(95% CI: 0.809-0.924), the optimal cutoff point was 5.24 μg/L, and the corresponding sensitivity and specificity were 72.5% and 84.1%. Conclusions:Serum Ang-2 levels in elderly patients with CAP are significantly higher than those in healthy people, and are correlated with the severity of CAP.The detection of Ang-2 levels is helpful for early intervention management and improved prognosis of elderly CAP patients.

Mechanism of Xianlian Jiedu Prescription in Maintaining Cancer Relative Vascular Endothelial Cell Homeostasis and Inhibiting Tumor Neovascularization / 中国实验方剂学杂志

ObjectiveTo observe the effect of Xianlian Jiedu prescription （XLJDP） on the proliferation， apoptosis， and migration of cancer-relative endothelial （CRE） cells， and to decipher the mechanism of XLJDP in regulating angiopoietin2 （Ang2） to maintain CRE cell homeostasis and inhibit tumor neovascularization. MethodHuman umbilical vein endothelial cell line （HUVEC-c） was induced into CRE cells in the human colorectal cancer HCT-116 cell-conditioned medium. The CRE cells were assigned into the blank group， conditioned medium group， and XLJDP groups （1， 2， 3 g·L-1） and treated for 48 h. The proliferation of CRE cells was detected by methyl thiazolyl tetrazolium （MTT） colorimetry. The morphological changes of CRE cells were observed via an inverted microscope. The apoptosis rate was detected by flow cytometry. Wound healing test and Transwell migration assay were employed to detect the 2D/3D migration ability of CRE cells. The protein levels of vimentin， N-cadherin， matrix metalloproteinase-9 （MMP-9）， and Ang2 in CRE cells were measured by Western blot. ResultThe MTT results showed that the cell viability was higher in the conditioned medium group than in the blank group （P<0.05）. Compared with the conditioned medium group， XLJDP decreased the cell proliferation rate （P<0.01） and changed the cell morphology. The total apoptosis rates of all the XLJDP groups were higher than that of the conditioned medium group （P<0.01）. The 2D and 3D migration abilities of the conditioned medium group were higher than those of the blank group （P<0.05， P<0.01）. Compared with the conditioned medium group， XLJDP at all the concentrations weakened the 2D migration ability （P<0.01） and medium- and high-concentration XLJDP weakened the 3D migration ability （P<0.01）. The protein levels of N-cadherin， Vimentin， MMP-9， and Ang2 were up-regulated in the conditioned medium group compared with those in the blank group （P<0.05， P<0.01）. Compared with the conditioned medium group， XLJDP at all the concentrations down-regulated the protein level of Ang2 （P<0.05， P<0.01）， and medium- and high-concentration XLJDP down-regulated those of N-cadherin， vimentin， and MMP-9 protein （P<0.01）. ConclusionXLJDP may inhibit the proliferation， migration， differentiation， and apoptosis of CRE cells by down-regulating the expression of Ang2， inhibiting tumor neovascularization， and maintaining the cell homeostasis.

Effect of comprehensive intervention on ANGPTL2 and vascular endothelial function in obese male adolescents / 中国学校卫生

Objective@#To investigate the effect of a comprehensive exercise intervention program combined with diet control on ANGPTL2 and vascular endothelial function in obese male adolescents, and to provide theoretual basis for exercise to reduce the risk of cardiovascular disease in obese male adolescents.@*Methods@#Forty two obese male adolescents and 10 healthy male adolescents were selected, a comprehensive intervention of 6 weeks of exercise combined with diet control was carried out on obese male adolescents, and changes in morphological function, glucose and lipid metabolism, inflammation level and vascular endothelial function were measured before and after the intervention.@*Results@#After 6 weeks of comprehensive intervention, the morphological and functional indicators of obese adolescents were significantly reduced:weight, BMI, waist circumference, waist to hip ratio, systolic blood pressure, diastolic blood pressure ( P <0.05); blood lipid levels significantly decreased, including TC, TG and LDL-C ( P <0.05); inflammation levels significantly decreased, including TNF α and ANGPTL2 ( P <0.05); Vascular endothelial function significantly improved:RHI, NO/ET-1, NO, AI( P <0.05). Before and after 6 weeks of comprehensive intervention, the ANGPTL2 of obese adolescents was significantly correlated with weight ( r =0.37), BMI ( r =0.45), RHI ( r =-0.46), NO/ET-1 ( r =-0.41), NO( r =-0.45), and AI ( r =0.33)( P <0.05).@*Conclusion@#The comprehensive intervention can effectively improve the morphological function, blood lipid level and vascular endothelial function of obese male adolescents, and reduce the circulating level of ANGPTL2. ANGPTL2 may be involved in the process of comprehensive intervention to improve the vascular endothelial function of obese adolescents.

Advances of Angiopoietin-Tie axis in vascular and lymphatic system-related diseases / 生物工程学报

Endothelial cells that form the inner layers of both blood and lymphatic vessels are important components of the vascular system and are involved in the pathogenesis of vascular and lymphatic diseases. Angiopoietin (Ang)-Tie axis in endothelial cells is the second endothelium-specific ligand-receptor signaling system necessary for embryonic cardiovascular and lymphatic development in addition to the vascular endothelial growth factor receptor pathway. The Ang-Tie axis also maintains vascular homeostasis by regulating postnatal angiogenesis, vessel remodeling, vascular permeability, and inflammation. Therefore, the dysfunction of this system leads to many vascular and lymphatic diseases. In light of the recent advances on the role of the Ang-Tie axis in vascular and lymphatic system-related diseases, this review summarizes the functions of the Ang-Tie axis in inflammation-induced vascular permeability, vascular remodeling, ocular angiogenesis, shear stress response, atherosclerosis, tumor angiogenesis, and metastasis. Moreover, this review summarizes the relevant therapeutic antibodies, recombinant proteins, and small molecular drugs associated with the Ang-Tie axis.

The role of HIF-VEGF-Ang-2 signal transduction-mediated synovial angiogenesis in rheumatoid arthritis / 药学学报

Rheumatoid arthritis (RA) is an autoimmune disease with angiogenesis, inflammatory factor infiltration and joint destruction as the main pathological features. Angiogenesis promotes the development of RA and plays an important role in its pathogenesis. The hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF)-angiopoietin-2 (Ang-2) signal transduction is a critical pathway to induce synovial angiogenesis. Targeting HIF-VEGF-Ang-2 signal transduction to inhibit synovial angiogenesis is a promising approach for RA treatment. This article reviews the role and mechanism of HIF-VEGF-Ang-2 signal transduction-mediated synovial angiogenesis in RA, in order to provide a new target and strategy for RA treatment.

Relationship between the expression and ratio of Ang-1 and Ang-2 in serum and prognosis in patients with cervical cancer / 中国医师杂志

Objective:To investigate the expression and ratio of serum angiopoietin-1/-2 (sAng-1/-2) in patients with cervical cancer and its relationship with clinicopathological features and prognosis.Methods:Eighty-seven patients with cervical cancer (FIGO Ⅰa1-Ⅳ) who were admitted to the First Affiliated Hospital of Shihezi University School of Medicine from September 2015 to December 2017 were selected as subjects. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of sAng-1 and sAng-2 in serum samples of 87 patients at admission. The correlation between the sAng-1 and sAng-2 levels was analyzed by statistical analysis.Results:The expression of sAng-1 in patients with Ⅰa1-Ⅱa2 was significantly higher than those in advanced stage of Ⅱb-Ⅳ ( P<0.05). The expression of sAng-2 in patients with Ⅱb-Ⅳ or adenocarcinoma was significantly higher than that of patients with Ⅰa1-Ⅱa2 or squamous cell carcinoma ( P<0.05). The ratio of sAng-2/sAng-1 in patients with lymph node metastasis or Ⅱb-Ⅳ stage was higher than that in patients without lymph node metastasis or Ⅰa1-Ⅱa2 ( P<0.05). In addition, the expression level of sAng-2 and sAng-2/sAng-1 ratio in cervical cancer patients were related to the 3-year overall survival (OS) and pregression-free survival (PFS) ( P<0.05). Conclusions:The expression of sAng-1 and sAng-2 in patients with cervical cancer may be related to tumor pathological type, disease progression or prognosis. The expression of sAng-2 or the ratio of sAng-2/sAng-1 may be tumor markers to evaluate the prognosis of patients with cervical cancer.

The clinical value of combined detection of serum angiopoietin 2 and Clara cell protein 16 in the early diagnosis of acute respiratory distress syndrome / 中华急诊医学杂志

Objective@#To investigate the clinical value of combined detection of serum angiopoietin 2 (Ang-2) and Clara cell protein 16 (CC16) in the early diagnosis of acute respiratory distress syndrome (ARDS).@*Methods@#Two hundred critical patients, treated at the Department of Critical Care Medicine, Bao'an District People's Hospital, Shenzhen during March 2015 and September 2016,were included in the study. According to the Berlin standard, patients were divided into two groups (n=100 each group): the ARDS group and non-ARDS group.The serum levels of Ang-2 and CC16 were measured by enzyme-linked immunosorbent assay (ELISA) on the first and second day of admission for each patient, in addition to completing APACHEⅡ score, medical history, vital signs collection and other biochemical indicators detection. Finally, paired-samples t test was used to analyze the data. The multiple ROC curve was used to calculate the area under the curve of the reference index of the serum levels of Ang-2 and CC16 on the first and second day.@*Results@#On the first and second day, the serum levels of Ang-2 and CC16 were significantly higher in ARDS patients than those in non-ARDS patients, and there was a correlation between the serum levels of Ang-2 and CC16 in ARDS patients. The ROC curve showed that the combined detection of Ang-2 and CC16 on the first day achieved a highest sensitivity of 75.9% and detection of CC16 on the first day achieved a highest specificity of 70.2%.@*Conclusion@#Single-detection of serum levels of Ang-2 and CC16 could be used for early diagnosis of ARDS, and the combined detection of both has a higher sensitivity than single detection.

Prognostic value of the dynamic changes in extra vascular lung water index and angiopoietin-2 in severe multiple trauma patients with acute respiratory distress syndrome / 中华危重病急救医学

Objective To observe the dynamic changes in extra vascular lung water index (EVLWI) and angiopoietin-2 (Ang-2) in severe multiple trauma patients with acute respiratory distress syndrome (ARDS), analyze the risk factor for short-term mortality, and to evaluate their prognostic values for prognosis. Methods A total of 54 severe multiple trauma patients with ARDS admitted to emergency intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from June 2014 to December 2018 were enrolled. The acute physiology and chronic health evaluation Ⅱ (APACHEⅡ), injury severity score (ISS) and oxygenation index (PaO2/FiO2), EVLWI [pulse-induced contour cardiac output (PiCCO) monitor] and plasma Ang-2 level [enzyme-linked immunosorbent assay (ELISA)] at 0 (immediately), 24, 48 and 72 hours after ICU admission, and the differences in PaO2/FiO2, EVLWI and Ang-2 between 0 hour and 72 hours (ΔPaO2/FiO2, ΔEVLWI, ΔAng-2) were calculated. The 28-day survival of patients was recorded, and the patients were divided into survival group and non-survival group. The differences in above mentioned parameters between the two groups were compared. Multivariate Logistic regression was used to analyze the independent risk factors associated with the prognosis. Receiver operating characteristic (ROC) curve was drawn to evaluate the prognostic values of ΔEVLWI and ΔAng-2 on the prognosis, and the Kaplan-Meier survival curve was plotted. Results 115 patients were enrolled in the final analysis, 72 survived in 28 days, 43 died, and the mortality rate was 37.4%. The APACHEⅡ and ISS scores of the non-survival group were significantly higher than those of the survival group [APACHEⅡscore: 25.7±2.7 vs. 20.6±2.2, ISS score: 22.1±3.1 vs. 18.1±2.1, both P < 0.05]. EVLWI and Ang-2 showed a gradual downwards tendency with the prolongation of the length of ICU stay in the survival group, but no significant change was found in the non-survival group. Parallel contour test showed that both P < 0.05, indicating that the curves between the two groups had different tendencies and were not parallel. The levels of EVLWI, Ang-2 and PaO2/FiO2 showed no statistical differences from 0 hour to 24 hours between the two groups, but EVLWI and Ang-2 in the non-survival group were significantly higher than those in the survival group from 48 hours on [EVLWI (mL/kg): 15.5±4.2 vs. 10.8±3.2, Ang-2 (ng/L): 352.7±51.2 vs. 237.9±42.8, both P < 0.05], and PaO2/FiO2 was significantly decreased [mmHg (1 mmHg = 0.133 kPa): 126.1±43.7 vs. 211.2±33.8, P < 0.05]. The ΔEVLWI and ΔAng-2 in the non-survival group were significantly lower than those in the survival group [ΔEVLWI (mL/kg): -0.9±6.1 vs. 3.1±6.4, ΔAng-2 (ng/L): -45.3±32.1 vs. 79.8±58.2, both P < 0.05], but ΔPaO2/FiO2 showed no significant difference as compared with the survival group (mmHg: 23.2±24.2 vs. -22.1±22.8, P > 0.05). Multivariate Logistic regression analysis demonstrated that ΔEVLWI [odds ratio (OR) = 2.811, 95% confidence interval (95%CI) = 1.232-3.161, P = 0.001], ΔAng-2 (OR = 2.204, 95%CI = 1.012-3.179, P = 0.001) and APACHEⅡ (OR = 1.206, 95%CI = 1.102-1.683, P = 0.002) were independent risk factors for 28-day mortality of severe multiple trauma patients with ARDS. ROC curve analysis showed that the area under ROC curve (AUC) of ΔEVLWI for predicting 28-day prognosis of severe multiple trauma patients with ARDS was 0.832, which was higher thanΔAng-2 (AUC = 0.790) and APACHEⅡ (AUC = 0.735). When the cut-off value of ΔEVLWI was 2.3 mL/kg, the sensitivity was 79.1%, and the specificity was 81.9%. Kaplan-Meier survival curve showed that the patients with ΔEVLWI > 2.3 mL/kg had a significantly higher 28-day cumulative survival rate as compared with the patients with ΔEVLWI ≤ 2.3 mL/kg (log-rank test: χ2 = 23.385, P = 0.000). Conclusions ΔEVLWI and ΔAng-2 can be used as independent risk factors for 28-day mortality of severe multiple trauma patients with ARDS, and the predictive value of ΔEVLWI was better than Ang-2 and APACHEⅡ. Dynamic observation of EVLWI could improve the accuracy of death forecasting for severe multiple trauma patients with ARDS.

The clinical value of combined detection of serum angiopoietin 2 and Clara cell protein 16 in the early diagnosis of acute respiratory distress syndrome / 中华急诊医学杂志

Objective To investigate the clinical value of combined detection of serum angiopoietin 2 (Ang-2) and Clara cell protein 16 (CC16) in the early diagnosis of acute respiratory distress syndrome (ARDS).Methods Two hundred critical patients, treated at the Department of Critical Care Medicine, Bao'an District People's Hospital, Shenzhen during March 2015 and September 2016,were included in the study. According to the Berlin standard, patients were divided into two groups (n=100 each group): the ARDS group and non-ARDS group.The serum levels of Ang-2 and CC16 were measured by enzyme-linked immunosorbent assay (ELISA) on the first and second day of admission for each patient, in addition to completing APACHEⅡ score, medical history, vital signs collection and other biochemical indicators detection. Finally, paired-samplest test was used to analyze the data. The multiple ROC curve was used to calculate the area under the curve of the reference index of the serum levels of Ang-2 and CC16 on the first and second day.Results On the first and second day, the serum levels of Ang-2 and CC16 were significantly higher in ARDS patients than those in non-ARDS patients, and there was a correlation between the serum levels of Ang-2 and CC16 in ARDS patients. The ROC curve showed that the combined detection of Ang-2 and CC16 on the first day achieved a highest sensitivity of 75.9％ and detection of CC16 on the first day achieved a highest specificity of 70.2％. Conclusion Single-detection of serum levels of Ang-2 and CC16 could be used for early diagnosis of ARDS, and the combined detection of both has a higher sensitivity than single detection.

Relationship between angiopoietin-2, vascular endothelial growth factor, carbohydrate antigen 199 and carcinoembryonic antigen in the diagnosis and postoperative recurrence and metastasis in colon cancer / 实用医学杂志

Objective To investigate the diagnosis of colon cancer patients and the prediction of postoperative recurrence and metastasis in patients with colon cancer by serum angiopoietin-2 (Ang-2) , vascular endothelial growth factor (VEGF) , carbohydrate antigen 199 and carcinoembryonic antigen CEA. Methods 100 patients with colon cancer, 100 patients with benign colonic lesions and 100 healthy subjects were examined. The levels of Ang-2, VEGF, CA19-9 and CEA in serum were detected, and the diagnosis and postoperative recurrence and metastasis of colon cancer were investigated. Results The levels of serum Ang-2, VEGF, CA19-9 and CEA in colon cancer group were higher than those in benign lesions and healthy controls (P < 0.05). The levels of Ang-2, VEGF, CA19-9 and CEA were detected. The sensitivity and specificity of each index were significantly higher in the diagnosis of colon cancer. The preoperative recurrence and metastasis rates of patients with positive Ang-2, VEGF, CA19-9 and CEA were higher than those of the negative patients respectively. Survival analysis showed a statistically significant difference in the time of distant metastasis between different expression states (P < 0.05). Conclusion The detection of serum levels of Ang-2, VEGF, CA19-9 and CEA has clinical significance for the diagnosis of colon cancer. Combined detection can improve the diagnostic efficiency; the levels of Ang-2, VEGF, CA19-9 and CEA in serum before surgery colon cancer is associated with recurrence and metastasis, and combined testing can help to assess tumor metastasis.

Research Advances of Ang-2 in Non-small Cell Lung Cancer / 中国肺癌杂志

Non-small cell lung cancer (NSCLC) is one of the malignant tumors with highest mortality in the world, it is still a difficult problem in clinical field. Its occurrence and development are closely associated with tumor angiogenesis. Angiopoietin-2 (Ang-2) is an important angiogenesis factor that has involved in many researches and it has been confirmed that the expression of Ang-2 is significantly up-regulated in tissues and blood of NSCLC. Meanwhile, Ang-2 is related to malignant biological behavior of cancer cells, making it a potential biological marker for the diagnosis and prognosis of NSCLC. At present, researches on Ang-2 how to promote the progression of NSCLC around the world are focused on Ang-2 regulating the proliferation, invasion, and metastasis of NSCLC. This paper summarized and estimated the studies and literature reports of regulatory mechanisms of Ang-2 in NSCLC, hopefully it could help looking for targeted drug treatment of Ang-2 in the future.
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Chronic Cerebral Hypoperfusion Induces Alterations of Matrix Metalloproteinase-9 and Angiopoietin-2 Levels in the Rat Hippocampus

Angiogenic factors contribute to cerebral angiogenesis following cerebral hypoperfusion, and understanding these temporal changes is essential to developing effective treatments. The present study examined temporal alterations in angiogenesis-related matrix metalloproteinase-9 (MMP-9) and angiopoietin-2 (ANG-2) expression in the hippocampus following bilateral common carotid artery occlusion (BCCAo). Male Wistar rats (12 weeks of age) were randomly assigned to sham-operated control or experimental groups, and expression levels of MMP-9 and ANG-2 were assessed after BCCAo (1 week, 4 weeks, and 8 weeks), using western blotting. Protein expression increased 1 week after BCCAo and returned to control levels at 4 and 8 weeks. In addition, immunofluorescence staining demonstrated that the MMP-9- and ANG-2-positive signals were primarily observed in the NeuN-positive neurons with very little labeling in non-neuronal cells and no labeling in endothelial cells. In addition, these cellular locations of MMP-9- and ANG-2-positive signals were not altered over time following BCCAo. Other angiogenic factors such as vascular endothelial growth factor and hypoxia-inducible factor did not differ from controls at 1 week; however, expression of both factors increased at 4 and 8 weeks in the BCCAo group compared to the control group. Our findings increase understanding of alterations in angiogenic factors during the progression of cerebral angiogenesis and are relevant to developing effective temporally based therapeutic strategies for chronic cerebral hypoperfusion-associated neurological disorders such as vascular dementia.

Curative effect of stereotactic radiotherapy combined with TACE for patients with hepatic metastases of colorectal cancer and influence on the expressions of omentin-1 and Ang-2 / 国际肿瘤学杂志

Objective To explore the curative effect of stereotactic radiotherapy combined with transcatheter arterial chemoembolization (TACE) for patients with hepatic metastases of colorectal cancer and influence on the expressions of omentin-1 and angiopoietin-2 (Ang-2).Methods A total of 90 patients with hepatic metastases of colorectal cancer from December 2013 to December 2015 in our hospital were selected as the research objects.Patients were divided into observation group and control group according to random number table method with 45 cases respectively.Patients in control group were treated with TACE,and patients in observation group were treated with stereotactic radiotherapy combined with TACE.After treatment,the clinical efficacy,expression levels of plasma omentin-1 and Ang-2,score of quality of life and adverse reaction were compared in the two groups.Results The objective response rate in observation group (82.2％) was significantly higher than that in control group (60.0％),and the difference was statistically significant (x2 =5.409,P =0.020).After treatment,the omentin-1 and Ang-2 expression levels in observation group were lower than those in control group [(43.7 ± 18.1) ng/ml vs.(52.1 ± 17.9) ng/ml,t =2.214,P =0.029;(2.0 ±0.2) g/L vs.(2.3 ± 0.3) g/L,t =6.028,P ＜ 0.001].The score of quality of life in observation group was significantly higher than that in control group [(87.6 ± 11.2) vs.(68.7 ± 10.3)],and the difference was statistically significant (t =8.332,P ＜ 0.001).There were no differences on the adverse reaction rates such as abnormal liver function (35.6％ vs.42.2％,x2 =0.421,P =0.517),nausea and vomiting (44.4％ vs.37.8％,x2 =0.413,P=0.520),skin injury (6.7％ vs.0,x2 =3.101,P=0.078) and fever (35.6％ vs.31.1％,x2 =0.202,P =0.655) between the two groups.Conclusion The implementation of stereotactic radiotherapy combined with TACE in the treatment of hepatic metastases of colorectal cancer is a safety and effective method.It can significantly reduce the expression levels of plasma omentin-1 and Ang-2,inhibit of tumor angiogenesis,and improve the quality of life of patients.

The relationship between vimentin protein expression in endothelial cells and contrast-enhanced ultrasound characters in VETC (+ ) hepatocellular carcinoma / 中华肿瘤杂志

Objective@#To detect the possible molecular mechanisms of the formation of vessels that encapsulated tumor clusters (VETC) and identify the relationship between vimentin protein expression in endothelial cells and contrast-enhanced ultrasound characters in VETC (+ ) hepatocellular carcinoma (HCC).@*Methods@#A total of 64 paraffin embedded HCC tissue samples were collected, all of which the tumor diameters were between 2 cm and 5 cm measured by the preoperative ultrasound. Immunohistochemistry staining for CD34 was used to detect the formation of VETC and the expressions of angiopoietin-2 (Ang-2) and vimentin were also determined. Human umbilical vein endothelial cells (HUVECs) were treated with 150 ng/ml recombinant human Ang-2 protein (rhAng-2) at various times and the protein expression of vimentin was detected by western blot assay. The contrast-enhanced ultrasound characters were also analyzed in both VETC (+ ) and VETC (-) HCC.@*Results@#Tumor clusters encapsulated by vessels to form cobweb-like networks, which were identified as VETC phenotype, were observed in 27 HCC tissues (42.18%). In VETC (+ ) HCC tissues, Ang-2 was overexpressed in tumor cells and endothelial cells while vimentin was only upregulated in endothelial cells. With the treatment of 150 ng/ml rhAng-2 protein, the expression of vimentin in HUVECs was 0.878±0.102 and 0.918±0.092 at 12 h and 36 h, significantly upregulated when compared to the 0.322±0.061 at 6 h (P<0.01). In contrast-enhanced ultrasound, a crack and tendon-like filling character was observed in VETC (+ ) HCC during the arterial-phase, while the large scale and diffuse-like filling character was observed in VETC (-) HCC. The filling time of unit diameter in VETC (+ ) HCC was (3.95±0.22)s, significantly longer than (2.28±0.27)s of VETC (-) HCC (P<0.01).@*Conclusions@#The overexpressions of Ang-2 and vimentin are positively correlated with the formation of VETC and considered as potential therapeutic targets of VETC (+ ) HCC. The crack and tendon-like filling characters in arterial-phase of contrast-enhanced ultrasound indicates the VETC (+ ) HCC.

Local injection of angiopoietin 2 promotes angiogenesis in tissue engineered bone and repair of bone defect with autophagy induction in vivo / 中国修复重建外科杂志

Objective: To investigate the mechanism of early vascularization of the tissue engineered bone in the treatment of rabbit radial bone defect by local injection of angiopoietin 2 (Ang-2). Methods: A single 1.5 cm long radius defect model (left and right sides randomised) was constructed from 48 New Zealand white rabbits. After implantation of hydroxyapatite/collagen scaffolds in bone defects, the rabbits were randomly divided into 2 groups: control group (group A) and Ang-2 group (group B) were injected with 1 mL normal saline and 1 mL saline-soluble 400 ng/mL Ang-2 daily at the bone defect within 2 weeks after operation, respectively. Western blot was used to detect the expressions of autophagy related protein [microtubule associated protein 1 light chain 3 (LC3), Beclin-1], angiogenesis related protein [vascular endothelial growth factor (VEGF)], and autophagy degradable substrate protein (SQSTMl/p62) in callus. X-ray films examination and Lane-Sandhu X-ray scoring were performed to evaluate the bone defect repair at 4, 8, and 12 weeks after operation. The rabbits were sacrificed at 12 weeks after operation for gross observation, and the angiogenesis of bone defect was observed by HE staining. Results: Western blot assay showed that the relative expression of LC3-II/LC3-I, Beclin-1, and VEGF in group B was significantly higher than that in group A, and the relative expression of SQSTMl/p62 was significantly lower than that in group A ( P<0.05). Radiographic and gross observation of specimens showed that only a small number of callus were formed in group A, the bone defect was not repaired; more callus were formed and complete repair of bone defect was observed in group B. The Lane-Sandhu scores in group B were significantly higher than those in group A at 4, 8, and 12 weeks after operation ( P<0.05). HE staining showed that the Harvard tubes in group B were well arranged and the number of new vessels was significantly higher than that in group A ( t=-11.879, P=0.000). Conclusion: Local injection of appropriate concentration of Ang-2 may promote early vascularization and bone defect repair of rabbit tissue engineered bone by enhancing autophagy.