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Background: Ischemic stroke is a serious cerebrovascular disease with high morbidity and disability. Zinc accumulation has been shown to play a vital role in neuronal death and blood–brain barrier damage following ischemia in acute stage. However, almost nothing is known about whether zinc is involved in neurological recovery in ischemic prolonged period. This study investigates whether zinc promotes neurological recovery through astrocytes‐induced angiogenesis during ischemic repair phase. Methods: Sprague–Dawley rats were subjected to 2 h ischemia/14, 21, and 28 days reperfusion by middle cerebral artery occlusion, then administered ZnCl2 (10 mg/kg) via intraperitoneally daily from 7 days to tissue collection to observe brain tissue morphology, neurological function recovery by cortical width index, Adhesive removal test, and Forelimb placing test. Angiogenesis, astrocyte activation, and HIF‐1α/VEGF pathway were assessed via Western blot, immunofluorescence, and BrdU method in vivo and in vitro. Results: The results showed that zinc significantly alleviated brain atrophy and improved neurological function recovery during the cerebral ischemia repair stage. Zinc significantly increased the protein levels of HIF‐1α, VEGF‐A, and VEGF‐R2 in astrocytes, and promoted angiogenesis during cerebral ischemia repair. In vitro and in vivo studies confirmed that zinc promoted angiogenesis via the astrocyte‐mediated HIF‐1α/VEGF signaling pathway. Conclusions: Zinc significantly improves neurological function recovery during the cerebral ischemia repair stage, providing new evidence supporting zinc as a potential therapeutic target for ischemic stroke by promoting astrocyte induced angiogenesis. [ABSTRACT FROM AUTHOR]

Aim: Patients with advanced gastric cancer have a relatively poor prognosis with few therapeutic alternatives beyond first-line therapy. The purpose of this manuscript is to highlight the potential for prolonged responses in patients with HER-2-positive disease. Patients, materials & methods: We analyzed the data of patients diagnosed with HER-2-positive-advanced gastric cancer who progressed on trastuzumab-based combination therapy and subsequently received second-line therapy consisting of ramucirumab in combination with paclitaxel.Results: Most patients had a stable disease after ramucirumab-based therapy (50%, 5/10), median duration to disease control was 8 months.Conclusion: The prolonged duration of response that we observed indicates that an interaction between the EGF pathway and the angiogenesis pathway requires further clinical investigations. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of 8-(2-tetrahydropyranyl)-12,13-dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazoles (THP-DHI) was synthesized and evaluated as dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors. Development of the structure–activity relationships (SAR) with the support of X-ray crystallography led to identification of 7f and 7g as potent, selective dual TIE-2/VEGF-R2 inhibitors with excellent cellular potency and acceptable pharmacokinetic properties. Compounds 7f and 7g were orally active in tumor models with no observed toxicity. [Copyright &y& Elsevier]

Abstract: Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure–activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity. [Copyright &y& Elsevier]

Abstract: A novel series of 4-aryl-5-cyano-2-aminopyrimidines were synthesized and found to have potent VEGF-R2 kinase inhibitory activity. Structure–activity relationships were investigated and compound 14a was shown to be efficacious in a mouse model of corneal neovascularization. [Copyright &y& Elsevier]

Pigment epithelium derived factor (PEDF), an endogenous inhibitor of angiogenesis, targets the growth of aberrant blood vessels in many tissues, including the eye. In this study we show that PEDF prevented early mitogenic signals of vascular endothelial growth factor (VEGF-A) in primate retinal endothelial cells, blocking proliferation, migration and tube formation. PEDF inhibited the phosphorylation and activation of five major downstream VEGF-A signaling partners, namely phosphoinositide-3-OH Kinase (PI3K), AKT, FAK, Src (Y416), and PLC-γ. It did so by binding to the extracellular domain of VEGF-R2, blocking VEGF-A-induced tyrosine phosphorylation (Tyr 951 and Tyr 1175), and inhibiting VEGF-R2 receptor kinase activity. PEDF had no effect on the transcription or translation of VEGF-R2 in cultured HUVECs. PEDF also bound to the extracellular domain of VEGF-R1. We conclude that PEDF blocks the growth of new blood vessels, in part, by reducing VEGF-A activation of its key mitogenic receptor, VEGF-R2, and by preventing its downstream signals in endothelial cells. • Physiological levels of PEDF block the proliferation, migration and vessel formation by retinal endothelial cells. • PEDF inhibited phosphorylation of VEGF downstream signaling partners, including PI3Kinase, AKT, FAK, Src (Y416), and PLC-γ. • PEDF binds to the extracellular domain of VEGF-R2 and VEGF-R1. • By blocking VEGF-induced tyrosine phosphorylation (Tyr 951 and Tyr 1175) PEDF effectively reduces VEGF-R2 activation. [ABSTRACT FROM AUTHOR]

Mountain ginseng (Panax ginseng) has been used for cancer patient therapy in Northeast Asia. Although it is well known that cancer cells are able to induce angiogenesis, the effect of mountain ginseng on angiogenesis is still unknown. In the present study, we investigated whether ethanolic extract of mountain ginseng (MGE) could inhibit angiogenesis in in vitro and in vivo models. In comparison with farm-cultivated ginseng extract (FGE), MGE more strongly inhibited cell migration and formation of capillary-like network within non-cytotoxic ranges in SVEC4-10 cells. In addition, MGE dose-dependently suppressed Transwell cell migration of the cells. Moreover, MGE reduced the phosphorylation and expression of VEGF-R2 as well as the phosphorylation of FAK, Src, Akt and ERK, the intermediate proteins in the VEGF-R2 signaling cascade, in the cells. As expected, MGE dramatically decreased hemoglobin content in Matrigel plugs in mice. In conclusion, MGE possesses stronger anti-angiogenic properties than FGE in vascular endothelial cells. Such effect of MGE is correlated with inhibition of activation of the VEGF-R2 signaling pathway. Therefore, the novel features of MGE may be helpful for understanding its anticancer mechanism for the treatment of cancer patients. [ABSTRACT FROM AUTHOR]

We previously reported that blood-brain barrier (BBB) disruption was associated with a pathologic angiogenesis in patients with intractable temporal lobe epilepsy (TLE) and in vivo models. This was confirmed by the overexpression of vascular endothelial growth factor (VEGF) in neurons and astrocytes and of its receptor vascular endothelial growth factor-2 (VEGF-R2) (or flk1) in endothelial cells. Using an original in vitro model, we showed that seizures were sufficient to activate the VEGF/VEGF-R2 system, which promotes vascularization and tight junction disassembly. Such a BBB dysfunction was shown to contribute to epileptogenesis. Therefore, we postulate that drugs that target the specific VEGF-R2 pathways involved in permeability are able to repair the BBB, and, therefore, could reduce epileptogenicity. [ABSTRACT FROM AUTHOR]