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.
Angiopoietins ; Endothelial Cells/metabolism* ; Humans ; Lymphatic Diseases ; Lymphatic System/metabolism* ; Receptor, TIE-2/metabolism* ; Signal Transduction ; Vascular Endothelial Growth Factor A

Objective: To improve the clinical understanding of Castleman disease (CD) with different types of thoracic involvement, including their clinical features, radiological and pathological findings, diagnosis and current treatment strategies. Methods: Retrospective analysis of 30 patients diagnosed with CD with thoracic involvement and hospitalized between June 2009 and May 2019 in The First Affiliated Hospital of Guangzhou Medical University was performed. Patients were divided into three groups for subsequent analysis based on the clinical data: CD with bronchiolitis obliterans (BO) , unicentric Castleman disease (UCD) without BO, and multicentric Castleman disease (MCD) without BO. Results: Among the 30 patients, there were 5 (16.7%) patients diagnosed with BO, 18 (60.0%) patients had UCD without BO and 7 (23.3%) patients had MCD without BO. The average age of MCD without BO patients was significantly older than that of BO and UCD without BO patients[ (49.29±5.39) ys vs (27.20±3.76) ys and (37.17±2.87) ys; P=0.005 and 0.034, respectively) ]. Pulmonary symptoms were commonly seen in BO group (100%) and MCD without BO group (71.4%) . while no pulmonary symptoms were seen in UCD without BO group. Key abnormal laboratory findings were erythrocyte sedimentation rate (ESR) increase (40%in BO group and 57.1% in MCD without BO group) and hypoxia (60% in BO group and 28.6% in MCD without BO group) . Other abnormal laboratory findings seen in MCD without BO group included anemia and IgG increase (both 57.1%) . Notably, all patients in BO group had extremely severe mixed ventilation dysfunction in the lung function test. CT scan showed lung parenchyma involvement in BO group (100%) , in UCD without BO group (11.1%) featured by solitary pulmonary nodule and in MCD without BO group (57.1%) featured by diffuse lesions in bilateral lungs. The size of lymph nodes was significantly smaller in MCD without BO group comparing to that in BO group and UCD without BO group[short diameter (1.83±0.51) cm vs (4.73±1.63) cm and (3.62±0.26) cm; P=0.006 and 0.011, respectively]. All patients (100%) in the BO group had a pathological type of transparent vascular variant while the same pathological type accounts for 88.9% in UCD without BO patients. The predominantly pathological type (57.1%) was plasma cell variant in the MCD without BO group. Oral ulcers presented in all patients in BO group but were relieved after the mass resection and immunomodulatory therapy, but the pulmonary symptoms were still progressively aggravated. Thoracoscopic mass excision was the main treatment for UCD without BO patients while chemotherapy, immunomodulatory and targeted therapy were commonly used for MCD without BO treatment. Conclusion The age, clinical symptom, laboratory finding, lung function, imaging manifestation, pathology, treatment and prognosis were different among the three groups. This classification could improve clinical understanding of the disease.

Ischemic stroke is a major health crisis causing high mortality and morbidity. The key treatment relies on the rapid intervention to dissolve thrombus, to reduce bleeding side effect and re-canalize clotted blood vessels using clot lysis drugs. Tissue plasminogen activator (tPA) is the only FDA-approved drug for ischemic stroke, but it has many limitations in clinical use. In recent years, the development of thrombolytic drugs and treatment strategies based on tPA has been progressed rapidly. Here we review the recent progress in this field, including the contributions from us and others, to promote the future development of novel thrombolytic drugs.
Brain Ischemia/drug therapy* ; Fibrinolytic Agents/therapeutic use* ; Humans ; Research/trends* ; Stroke/drug therapy* ; Thrombolytic Therapy/trends* ; Tissue Plasminogen Activator/therapeutic use*

Primary liver cancer ( PLC) , the most com-mon malignant carcinoma in the world , greatly impairs the hu-man health .Various treatments for PLC have been practiced but the therapeutic effects are still unsatisfied .Nowadays, interven-tional therapy , chemotherapy , radiotherapy , molecular targeted therapy and radiofrequency ablation are playing a key role in hepatocellular carcinoma treatment .In near future , more ad-vancements on comprehensive therapy for PLC are being expec-ted.This review aimed to describe the recent scenario and cur-rent advancement on non-surgical treatment for hepatocellular carcinoma .

ObjectiveTo explore the effects of glycomacropeptide (GMP) in human milk and formula milk on proliferation ofbifidobacterium infantis and their dose-response relationship.Methods Casein was isolated from the milk of 30 healthy postpartum women from Guangzhou Women and Children's Medical Center in September 2014, and hydrolyzed by rennet to obtain GMP, which was then purified by ultrafiltration and ion exchange chromatography. Human milk GMP and cow milk GMP (0, 250, 500, 1 000, 1 500, 2 000 and 3 000 mg/L) were added tobifidobacterium infantis liquid medium, and cultured under anaerobic conditions. Concentration of bacteria was measured by turbidimetric microplate assay (detection of OD600 nmvalue of medium). Difference of proliferative activities ofbiifdobacterium infantis in human milk GMP and cow milk GMP was compared with independent samplest-test.ResultsPurified human milk GMP concentration was 1 712.20 mg/L, with a purity of 80.3%. Increasing the cow milk GMP initial concentration in the culture medium at 250-2 000 mg/L could increase the concentration and proliferation rate ofbiifdobacteria infantis. When cultured at 36 h with GMP of various concentrations, the proliferation ofbiifdobacteria infantis maintained at a logarithmic phase. Therefore, 36 h was chosen as the test time point to compare the proliferation ofbifidobacterium infantis. At 36 h, when GMP in the medium was 1 000, 1 500, 2 000 and 3 000 mg/L, concentrations ofbiifdobacteria infantis in human milk GMP were 2.255±0.036, 2.583±0.088, 2.877±0.080 and 3.219±0.081, respectively, which were significantly higher than those in cow milk GMP (2.115±0.053, 2.312±0.064, 2.542±0.090 and 2.894±0.076;t=4.867, 5.569, 6.192 and 6.516; allP<0.01).Conclusions Both human milk GMP and cow milk GMP can promote the proliferation ofbiifdobacterium infantisin vitro, and the proliferative activity in human milk is greater than in cow milk at the same concentration of GMP.

Objective To study the effect of bifidobacterium on intestinal tissue of necrotizing enterocolitis (NEC)in newborn rats and its regulation of Wnt/β-Catenin signal pathway.Methods Seventy -five newborn SD rats were randomly divided into 5 groups,and each group had 1 5 rats.Group A was artificial feeding control group;group B was NEC model group;group C was bifidobacterium treatment group;group D was artificial feeding +bifidobacterium control group;group E was rat breast feeding control group.The localization expression of Toll -like re-ceptor 4(TLR4)of ileocecal ileum tissue was detected by immunohistochemical detection,and also the equivalen-tileum tissues were detected for the contents of glycogen synthase kinase -3β(GSK3β)and β-Catenin expression by Wes-tern blot.Comparing the differences of these indicators between the groups,in addition,the data of TLR4,GSK3βandβ-Catenin were analyzed by Bivariate correlations.Results The levels of TLR4 in ileum tissue of 5 groups were 0.36 ±0.03,0.48 ±0.05,0.34 ±0.03,0.37 ±0.04,0.35 ±0.02.The levels of GSK3βin ileum tissue of 5 groups were 0.98 ±0.23,1 .48 ±0.42,0.99 ±0.20,0.56 ±0.1 7,0.60 ±0.1 5.The levels of β-Catenin in ileum tissue of 5 groups were 1 .48 ±0.22,0.64 ±0.55,1 .27 ±0.36,1 .72 ±0.51 ,1 .82 ±0.44.The levels of TLR4 and GSK3βin ileum tissue of group B were significantly increased compared with group E (P <0.05).The levels of β-Catenin sig-nificantly decreased compared with group E (P <0.05).The levels of TLR4 and GSK3βin ileum tissue of group C were significantly decreased compared with group B (P <0.05).The levels of β-Catenin significantly increased com-pared with group B (P <0.05).Negative correlation was observed between the levels of GSK3βand β-Catenin(r =-0.592,P <0.05),while positive correlation was observed between the levels of TLR4 and GSK3β(r =0.295,P <0.05),and negative correlation was observed between the levels of TLR4 and β-Catenin(r =-0.426,P <0.05). Conclusions Bifidobacterium has certain protective effect on the NEC newborn rat intestines,which can reduce the in-cidence of experimental NEC and the severity of intestinal injury.Its effect may be achieved by regulating the Wnt/β-Catenin signal pathway,which decreases the expression of the level of GSK3βand increases the level of repair fac-tor β-Catenin.

Objective To discuss the possible molecular mechanisms involved in the protective effects of Biifdobacterium on intestinal tissue of necrotizing enterocolitis (NEC) newborn rats. Methods Seventy-five newborn Sprague-Dawley rats (born within 2 h) were randomly divided into five groups, each group with 15 rats. Group A was the NEC model group, and the rats were fed lipopolysaccharide (LPS) and formula. Group B was the Biifdobacterium treatment group, and the rats were fed LPS and formula and Biifdobacterium micro-capsule. Group C was the artificial feeding control group, and the rats were fed formula. Group D was the Biifdobacterium control group, and the rats were fed formula and Biifdobacterium micro-capsule. Group E was the breastfeeding control group, and the rats were fed rat breast milk by mothers. LPS 30 mg/kg was administered by gavage once per day for 3 days. Bifidobacterium micro-capsules were given as 1×1010 colony forming units/ml by gavage with formula once per day. After fed for 72 h and fasted for 12 h, the five groups of rats were killed by decapitation. Morphological changes in the terminal ileum tissue were observed under a light microscope and intestinal injury was scored. The expression of Toll-like receptor (TLR) 2, TLR4, and nuclear transcription factor (NF)-κB p65 was detected by immunohistochemical methods. Kruskal-Wallis test, analysis of variance, corrected Chi-square test and Fisher's exact test were used for statistics. Results The morbidity of NEC in group A to E was 11/15, 4/15, 3/15, 2/15 and 0/15, respectively;the intestinal injury score in group A to E was 3.37±0.27, 1.53±0.44, 1.75±0.37, 0.92±0.39 and 0.30±0.18, respectively; the expression level of TLR2 in group A to E was 0.35±0.05, 0.30±0.03, 0.32±0.04, 0.30±0.02 and 0.29±0.03, respectively;the expression level of TLR4 in group A to E was 0.48±0.05, 0.34±0.03, 0.36±0.03, 0.37±0.04 and 0.35±0.02, respectively;the expression level of NF-κB p65 in group A to E was 0.43±0.03, 0.29±0.03, 0.35±0.02, 0.32±0.02 and 0.30±0.02, respectively. The differences in NEC morbidity, intestinal injury score, and the expression levels of TLR4, TLR2 and NF-κB p65 among the five groups were all statistically significant (χ2, H or F=23.863, 70.290, 8.803, 38.599 and 75.076, respectively, all P<0.05). The values in the NEC model group were all significantly higher than those in the other four groups (all P<0.05). The morbidity of NEC in the Biifdobacterium treatment group compared with the three control groups was not significantly different (all P > 0.05). The intestinal injury score in the Bifidobacterium treatment group was significantly higher than that in the Bifidobacterium control group and the breastfeeding control group (both P < 0.01), but was not significantly different to that in the artificial feeding control group (P > 0.05). The expression levels of TLR4 and NF-κB p65 in the Biifdobacterium treatment group were significantly lower than those in the artificial feeding control group and the Biifdobacterium control group (all P < 0.05), and were not significantly different to those in the breastfeeding control group (P>0.05). The expression level of TLR2 in the Biifdobacterium treatment group compared with the three control groups was not significantly different (all P > 0.05). Conclusions Biifdobacterium may inhibit pathogenic bacteria or regulate the negative feedback of TLR2 to reduce the expression of TLR2 and TLR4 in intestinal mucosa cells, inhibit the NF-κB pathway, attenuate the inflammatory reaction, and play a role in the prevention and control of NEC.

Objective To investigate the effects of lipopolysaccharides (LPS) in different concentrations on the proliferation and interleukin(IL)-6,IL-1 β and tumor necrosis factor-α(TNF-o) secretion of intestinal epithelial cells (IEC-6) of rats in vitro.Methods IEC-6 of rats were divided into normal group (0 mg/L,group A),0.1 mg/L group (group B),0.5 mg/L group (group C),1.0 mg/L group (group D),5.0 mg/L group (group E) and 10.0 mg/L group(group F).Different groups cells were exposed to LPS with different concentrations for 3 h,5 h and 7 h.Thiazolyl blue(MTT) was performed to investigate the proliferation of IEC-6.The concentrations of IL-6,IL-1 β and TNF-α in culture supernatant were detected by enzyme linked immunosorbent assay(ELISA).Results The proliferation rate of IEC-6 was gradually lower while the concentration of LPS increased.After co-culture with LPS 3h and 5 h,the proliferation rates of group B,group C,group D,group E and group F had no significant difference with those of group A (all P ＞ 0.05);after co-culture with LPS 7 h,the proliferation rates of group B,group C,and group D had no significant difference with those of group A (all P ＞ 0.05);the proliferation rates of group E and group F had significant difference with those of group A(t =4.216,P =0.014;t =14.991,P =0.000).The proliferation rates of group E and group F were lower after co-culture with LPS 5 h than 7 h,and there were significant differences (t =2.576,P =0.033;t =2.975,P =0.018);but there was no significant differences between group E and group A after co-culture with LPS 5 h (P ＞ 0.05).Group B,group C,group D,group E and group F all had a significant higher level of IL-6 than group A after co-culture with LPS 3 h,5 h and 7 h(all P ＜0.01).In addition,group E had the highest level of IL-6 at all time points.And the peak level of IL-6 rose after co-culture with LPS 5 h.The TNF-α level and IL-1 β level of group B,group C,group D,group E and group F all had no significant differences than that of group A after co-culture with LPS 3 h,5 h and 7 h (all P ＞ 0.05).Conclusions In a certain concentration,incubation time range,the proliferation rates of IEC-6 cells were gradually lower while the concentration of LPS increased.Co-cultured IEC-6 cells with LPS(0-10.0 mg/L) can stimulate them secrete to IL-6.The highest level of IL-6 was of group E after 5 h co-culture.LPS had no effects on TNF-α and IL-1 β level of IEC-6 cells cultural supernatant.So 5.0 mg/L concentration of LPS stimulating IEC-6 cells for 5 h can be chosen to build the IEC-6 inflammatory models.

Objective To detect the effects of bifidobacterium or bifidobacterium cultured supernatant on the mRNA expression of tumor necrosis factor receptor-associated factor 6 (TRAF6),glycogen synthase kinase-3β (GSK-3β) and the miRNA-146a in rat small intestinal epithelial cell(IEC-6) induced by lipopolysaccharide (LPS).Methods IEC-6 in logarithmic phase were randomly divided into LPS group,cultured supernatant group and inactivated bacteria group.All the 3 groups were exposed to 5 mg/L LPS for 5 hours,and then 1 mL sterile saline was added in LPS group and culturing continued for 24 hours ; 1 mL bifidobacterium cultured supernatant was added in cultured supernatant group and culturing continued for 24 hours;1 mL inactivated bifidobacterium 1 x 1010 CFU/L added in inactivated bacteria group and continued culturing for 24 hours.The mRNA expressions of TRAF6,GSK-3 β and miRNA-146a were detected by reverse transcription-polymerase chain reaction (RT-PCR).Results The level of TRAF6,GSK-3 β of culture supematant group (0.72 ± 0.05,0.46 ± 0.14) were all lower than LPS group (1.01 ± 0.14,1.02 ± 0.25),but the level of miRNA-146a(3.05 ± 0.40) was higher than that in LPS group(1.01 ± 0.12),and there were significant differences between them (t =5.278,6.316,13.218,P =0.000).The level of GSK-3 β of inactivated bacteria group(0.59 ±0.13) was significantly lower than that in LPS group(t =4.837,P =0.000).The levels of TRAF6 and miRNA-146a of inactivated bacteria group(1.05 ±0.11,0.78 ±0.22) had no significant differences with LPS group (t =0.732,1.463,P ＞ 0.05).The level of TRAF6 of cultured supernatant group was lower than that in inactivated bacteria group,and the level of miRNA-146a was higher than that in inactivated bacteria group,and there were significant differences between 2 groups (t =6.009,14.687,P =0.000).Conclusions Bifidobacterium cultured supernatant and inactivated bacteria both have certain protective effect on the IEC-6 induced by LPS.One of the protective mechanisms of bifidobacterium cultured supernatant may be achieved by elevating the expression of miRNA-146a,and decreasing the levels of inflammation related factor TRAF6 and damage related factor GSK-3β.The protective effects of inactivated bifidobacterium may be achieved by decreasing the level of damage related factor GSK-3β.

Objective To investigate the relationship between myeloid differentiation (MD-2) gene polymorphisms and necrotizing enterocolitis (NEC) in neonates.Methods A gene-sequencing method was used to re-sequence the exons and the promoter functional polymorphism region (rs11465996) of MD-2 gene of 42 NEC neonates admitted in neonatal intensive care unit of Women and Children's Medical Center,Guangzhou Medical University from June 1,2011 to May 31,2012.These functional polymorphism loci were compared with 83 non NEC cases.The Chi square test was used for statistical analysis.Results No polymorphism was detected in the exons of MD-2 gene in any of the 42 cases of NEC.The C-1625G polymorphism [rs11465996 (C＞G)] was identified in both the NEC and control groups,and there were two genotypes,C/C and C/G.The frequency ofC/G genotype in the NEC group (38.1％,16/42) did not differ significantly compared to that in the control group (30.1％,25/83) (x2=0.805,P=0.370).However,the frequency of C/G genotype in severe NEC cases (operation group) (55.0％,11/20) was significantly higher than that in the control group (x2=4.388,P=0.036).Among the NEC group,the frequency of C/G genotype in operation cases and term infants was higher than that of the non-operation cases and preterm infants,although the differences were not significant (x2=3.343,P=0.067; xx2=0.913,P=0.339).Conclusions The polymorphisms in the exons of MD-2 gene are not associated with the development of NEC.The rs 1 1465996 polymorphism (G allele) in the promoter region may be related to the severity of NEC.