Background: A hypoxic microenvironment may induce angiogenesis and promote the development of hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether ursodeoxycholic acid (UDCA) may inhibit hypoxic HCC cell-induced angiogenesis and the possible mechanisms. Methods: Tube formation and matrigel plug angiogenesis assays were used to evaluate angiogenesis in vitro and in vivo, respectively. Real-time PCR, enzyme-linked immunosorbent assay, and Western blot were used to evaluate the mRNA and protein expressions of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and IL-8, respectively. Dual-luciferase reporter assay was applied to assess the reporter gene expression of hypoxia-response element (HRE). Results: UDCA antagonized hypoxic Huh 7 cell-induced tube formation of EA.hy 926 cells. In HCC cells, UDCA inhibited hypoxia-induced upregulation of VEGF and IL-8 both in mRNA and protein levels. UDCA also inhibited IL-8-induced angiogenesis in vitro and in vivo through suppressing IL-8-induced phosphorylation of ERK. The levels of HIF-1α mRNA and protein and HRE-driven luciferase activity in HCC cells were upregulated by hypoxia and were all inhibited by UDCA. The proteasome inhibitor MG132 antagonized the effect of UDCA on HIF-1α degradation. In hypoxic condition, the phosphorylation of ERK and AKT was obviously increased in HCC cells, which was suppressed by UDCA. Transfection of the HIF-1α overexpression plasmid reversed the effects of UDCA on hypoxic HCC cell-induced angiogenesis, HRE activity, and expressions of IL-8 and VEGF. Conclusions: Our results demonstrated that UDCA could inhibit hypoxic HCC cell-induced angiogenesis through suppressing HIF-1α/VEGF/IL-8-mediated intercellular signaling between HCC cells and endothelial cells. 

pdf/udca-inhibits-hypoxic-hepatocellular-carcinoma-cell-induced-54ln23o7fw.pdf

UDCA Inhibits Hypoxic Hepatocellular Carcinoma Cell–Induced Angiogenesis Through Suppressing HIF-1α/VEGF/IL-8 Intercellular Signaling

Background: Although liver biopsy remains the gold standard for the diagnosis and the monitoring of liver disease, non-invasive biomarkers have been recently suggested to predict liver disease severity, progression, and response to therapy. We investigated multiple tissue and circulating markers of angiogenesis in predicting the severity of biopsy-validated chronic liver diseases in patients with chronic hepatitis C virus (HCV) and in NAFLD/NASH patients. Methods: We studied samples from forty-six patients with HCV and/or NAFLD who underwent liver biopsy, liver ultrasonography, and liver stiffness measurement. Ishak and Brunt scores were calculated. Expression of selective genes and luminex analyses of 17 different circulating pro-angiogenic factors were performed. Results: The phenotype of NAFLD/NASH or HCV subjects was similar, except for insulin, which was expressed at higher levels in NAFLD/NASH patients. A Mann–Whitney test showed significant differences for the circulating levels of HB-EGF and for follistatin between HCV and NAFLD/NASH patients. In HCV patients, we found an inverse correlation between disease stage and BMP-9 and VEGF-A circulating levels, while in NASH/NAFLD direct correlations between stage and BMP-9 and VEGF-A circulating levels were noted. The K-means algorithm divided HCV and NASH/NAFLD patients in two clusters with significant differences between them. Logistic regression models showed a positive relationship with BMP-9 levels for NASH/NAFLD and with HB-EGF circulating concentrations for HCV. ROC analysis showed for BMP-9 > 1188 pg/mL a worse disease in NASH/NAFLD, whereas for HB-EGF < 61 pg/mL a higher severity of disease in HCV. Conclusion: Our data show that circulating biomarker profiles can identify the severity of chronic liver disease of NAFLD/NASH or HCV origin.

/pdf/predictive-power-of-tissue-and-circulating-biomarkers-for-1ezj2ip8.pdf

Predictive Power of Tissue and Circulating Biomarkers for the Severity of Biopsy-Validated Chronic Liver Diseases

Background: Age-related macular degeneration (AMD) is the leading cause of late-onset blindness in elderly. The occurrence and development of AMD is a multifactorial complex process where autophagy plays an important role. The first-line drugs for neovascular AMD (nAMD) are inhibitors of VEGF, with up to 30% of patients having an incomplete response to treatment. Genetic factors may influence the response to anti-VEGF therapy and explain treatment outcome variability. We aimed to estimate the role of polymorphic markers of the MTOR (rs1064261, rs1057079, rs11121704, rs2295080), SQSTM1 (rs10277), ULK1 (rs11246867, rs3088051), MAP1LC3A (rs73105013) and ATG5 (rs573775) genes in the development of nAMD and the efficacy of anti-VEGF therapy response. Methods: Genotyping by allele-specific PCR was performed in 317 controls and 315 nAMD patients in the Russian population. Of them, 196 treatment-naive nAMD patients underwent three monthly intravitreal injections (IVIs) of aflibercept. Genotypic frequencies were compared with OCT markers of therapy effectiveness and best-corrected visual acuity (BCVA) measures. The main outcomes were the BCVA gain and decrease in central retinal thickness (CRT). Results: MTOR-rs1057079-C, MTOR-rs11121704-C and MTOR-rs2295080-G alleles were associated with an increased risk of nAMD. The BCVA was increased in 117 (59.7%) patients by 10 [5–20] letters, did not changed in 59 (30.1%), and was decreased in 20 (10.2%) patients. ULK1-rs3088051 was associated with BCVA change. Among patients with the TT and CT genotypes for ULK1-rs3088051, an improvement in visual acuity was noted in 67.6% and 53.8% of cases, while in patients with the CC genotype, an increase in BCVA was recorded in 37.5% of cases (p = 0.01). The decrease in CRT was associated with SQSTM1-rs10277 (p = 0.001): it was significantly higher in TT (93 [58–122] mkm) and CT (66 [30–105] mkm) carriers compared to the CC genotype (47 [24–68] mkm). Other SNPs did not show significant associations with the outcome of anti-VEGF treatment. Conclusions: MTOR gene polymorphisms are moderately associated with the risk of nAMD. SQSTM1-rs10277 and ULK1-rs3088051 may influence short-term response to intravitreal anti-VEGF treatment. The results suggest that autophagy could be a target for future drugs to overcome resistance to anti-VEGF therapy.

Pharmacogenetic Association between Allelic Variants of the Autophagy-Related Genes and Anti-Vascular Endothelial Growth Factor Treatment Response in Neovascular Age-Related Macular Degeneration

Limiting the availability of key angiogenesis-promoting factors is a successful strategy to ablate tumor-supplying blood vessels or to reduce excessive vasculature in diabetic retinopathy. However, the efficacy of such anti-angiogenic therapies (AATs) varies with tumor type, and regrowth of vessels has been observed upon termination of treatment. Our ability to understand and develop AATs remains limited by a lack of robust in vitro systems for modeling the recovery of vascular networks. Here, we engineer complex three-dimensional micro-capillary networks by sequentially seeding human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) and human umbilical vein endothelial cells (HUVECs) on a previously established, synthetic plug-and-play hydrogel platform. In the tightly interconnected vascular networks that form this way, the two cell types share a basement membrane-like layer and can be maintained for several days of co-culture. Pre-formed networks degrade in the presence of bevacizumab. Upon treatment termination, vessel structures grow back in their original positions after replenishment with new endothelial cells, which also integrate into unperturbed established networks. Our data suggests that this plug-and-play platform enables the screening of drugs with blood-vessel inhibiting functions. We believe that this platform could be of particular interest in studying resistance or recovery mechanisms to AAT treatment. This article is protected by copyright. All rights reserved.

Recovery of Therapeutically Ablated Engineered Blood-Vessel Networks on A Plug-And-Play Platform.

Chronic cerebral hypoperfusion (CCH) can cause a series of pathophysiological processes, including neuronal autophagy and apoptosis. VEGF-A has been reported to affect angiogenesis and neurogenesis in many CNS diseases. However, its effects on neuronal autophagy and apoptosis, as well as the underlying mechanisms in CCH remain unclear.To address these issues, the CCH model was established by permanent bilateral common carotid artery occlusion (2VO). Rats were sacrificed at different stages of CCH. Hippocampal morphological and ultrastructural changes were detected using HE staining and electron microscopy. The immunoreactivities of microtubule-associated protein 1 light chain 3 (LC3) and phospho-cAMP response element binding protein (p-CREB) were examined by immunofluorescence staining. The neuronal apoptosis was detected via TUNEL staining. The levels of LC3-II, Beclin-1, Akt, p-Akt, CREB, p-CREB, Caspase-3, and Bad were accessed by Western blotting. Furthermore, mouse hippocampal HT22 neurons received the oxygen and glucose deprivation (OGD) treatment, VEGF-A treatment, and GSK690693 (an Akt inhibitor) treatment, respectively.LC3-II protein started to increase at 3 days of CCH, peaked at 4 weeks of CCH, then decreased. CCH increased the levels of LC3-II, Caspase-3, and Bad, and decreased the levels of p-Akt, CREB, and p-CREB, which were reversed by VEGF-A treatment. VEGF-A also improved CCH-induced neuronal ultrastructural injuries and apoptosis in the hippocampus in vitro. In HT22, the anti-apoptosis and pro-phosphorylation of VEGF-A were reversed by GSK690693.Present results provide a novel neuroprotective effect of VEGF-A in CCH that is related to the inhibition of neuronal autophagy and activation of the Akt/CREB signaling, suggesting a potential therapeutic strategy for ischemic brain damage. 

VEGF-A ameliorates ischemia hippocampal neural injury via regulating autophagy and Akt/CREB signaling in a rat model of chronic cerebral hypoperfusion.

Different effects of anti-VEGF drugs (Ranibizumab, Aflibercept, Conbercept) on autophagy and its effect on neovascularization in RF/6A cells

Visfatin is a type of adipocytokine that is highly expressed in the serum and vitreous of patients with diabetic retinopathy. The purpose of the present study was to investigate the effect and mechanism of visfatin on angiogenesis in RF/6A monkey chorioretinal retinal endothelial cells under high glucose (HG) conditions in vitro. RF/6A cells were randomly divided into four groups: Control group, under high glucose (HG) group (25 mM D-glucose), visfatin group 1 (10 nM visfatin + 25 mM D-glucose), visfatin group 2 (20 nM visfatin + 25 mM D-glucose) and visfatin group 3 (30 nM visfatin + 25 mM D-glucose). After 24 and 48 h, a Cell Counting Kit-8, wound-healing assay and Matrigel tube formation assay were used to detect cell proliferation, migration and cell tube formation, respectively. Subsequently, the expression levels of VEGF and VEGF receptor 2 (VEGFR-2) in cells of visfatin group 3 were observed by western blot and reverse transcription-quantitative PCR analyses. At 24 and 48 h, the cell proliferation and migration distance in the HG group were reduced compared with those in the control group (P<0.05). Compared with those in the HG group, the cell proliferation and migration distance in all visfatin groups were significantly increased (P<0.05), with the highest significance in visfatin group 3. Visfatin significantly promoted tube-like structure formation by RF/6A cells, particularly at the concentration of 30 nM. The protein and mRNA expression levels of VEGF and VEGFR-2 were significantly increased in the HG group as compared with those in the control group (P<0.05). Furthermore, compared with those in the HG group, VEGF and VEGFR-2 protein and mRNA expression levels were significantly increased in visfatin group 3 (P<0.05). Overall, visfatin promoted the proliferation, migration and tube formation of RF/6A cells under HG conditions, suggesting that visfatin has a potent effect on retinal neovascularization and its mechanism may be associated with the promotion of VEGF and VEGFR-2 expression under HG conditions.

/pdf/visfatin-promotes-angiogenesis-of-rf-6a-cells-through-3t7cqwotij.pdf

Visfatin promotes angiogenesis of RF/6A cells through upregulation of VEGF/VEGFR-2 under high-glucose conditions.

PLVAP protein expression correlated with microbial composition, clinicopathological features, and prognosis of patients with stomach adenocarcinoma

AIM
To investigate the effect of leptin on the angiogenesis of RF/6A cells (monkey retinal choroidal endothelial cells) in vitro and test the cellular signaling in the mechanism.


METHODS
RF/6A cells were cultured in vitro and randomly divided into four groups: normal control, with leptin at 50, 100, 200 ng/mL for cell counting kit-8 (CCK8). RF/6A cell proliferation and migration were examined by Transwell assays, while RF/6A cell tube formation by Matrigel assay. JAK2, p-JAK2, STAT3, and p-STAT3 protein expression was measured by Western blotting. Cells were then divided into the following treatment groups: control, 100 ng/mL leptin and AG-490 (100 ng/mL leptin+10 µmol/L AG-490) for examinations of RF/6A cellular behaviour again. Analysis of differences was carried out using one-way ANOVA and least significant difference (LSD).


RESULTS
RF/6A cell proliferation, migration and cell tube formation were promoted significantly by leptin in a dose-dependent manner (P<0.05). Western blotting showed that leptin up-regulated p-JAK2 and p-STAT3 expression levels. Treatment with the JAK/STAT pathway inhibitor, AG-490, decreased leptin-induced p-JAK2 and p-STAT3 expression, and inhibited cell proliferation, migration and cell tube formation induced by leptin (P<0.05).


CONCLUSION
Leptin can promote RF/6A cell angiogenesis in vitro via activation of the JAK2/STAT3 signaling pathway.

Leptin activates the JAK/STAT pathway to promote angiogenesis in RF/6A cells in vitro.

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Different effects of anti-VEGF drugs (Ranibizumab, Aflibercept, Conbercept) on autophagy and its effect on neovascularization in RF/6A cells

Visfatin promotes angiogenesis of RF/6A cells through upregulation of VEGF/VEGFR-2 under high-glucose conditions.

PLVAP protein expression correlated with microbial composition, clinicopathological features, and prognosis of patients with stomach adenocarcinoma

Leptin activates the JAK/STAT pathway to promote angiogenesis in RF/6A cells in vitro.