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https://www.readbyqxmd.com/read/28068599/discovery-of-novel-anti-angiogenesis-agents-part-6-multi-targeted-rtk-inhibitors
#1
Lin Zhang, Yuanyuan Shan, Chuansheng Li, Ying Sun, Ping Su, Jinfeng Wang, Lisha Li, Xiaoyan Pan, Jie Zhang
Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4...
January 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28041961/expression-of-angiopoietins-in-central-nervous-system-hemangioblastomas-is-associated-with-cyst-formation
#2
Xiang Li, Wenke Liu, Jianping Liu, Weiya Wang, Si Zhang, Jian Chen, Xuhui Hui
PURPOSE: This study aimed to determine the expression of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and endothelial tyrosine kinase receptor (Tie-2) in central nervous system (CNS) hemangioblastomas (HBs) and explore the correlation with peritumoral cyst formation. METHOD: A total of 22 paraffin-embedded specimens derived from 11 cyst-associated and 11 solid solitary CNS HBs were collected for streptavidin-peroxidase immunohistochemical staining. The expression levels of Ang-1, Ang-2 and Tie-2 in cystic and solid HBs were estimated and compared according to the integrated optical density (IOD) of staining in the sections...
December 29, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/28034894/the-osmopressor-induced-angiopoietin-1-secretion-in-plasma-and-subsequent-activation-of-the-tie-2-akt-enos-signaling-pathway-in-red-blood-cell
#3
You-Hsiang Chu, Chih-Cherng Lu, Tso-Chou Lin, Mei-Yung Tsou, Yu-Juei Hsu, Shung-Tai Ho, Che-Se Tung, Ching-Jiunn Tseng, Min-Hui Li, Herng-Sheng Lee
BACKGROUND: Water ingestion induces the osmopressor response, which typically presents as increased total peripheral vascular resistance in young healthy subjects. A previous study has suggested that the RBC membrane receptor is involved in osmopressor stress. Recent studies have indicated nitric oxide synthase phosphorylation in RBCs. However, the main process in signaling pathway activation to elicit such a response is unknown. Herein, we hypothesized that hypo-osmotic stress following water ingestion modulates the eNOS/NO pathway, thereby alternating vascular resistance...
December 29, 2016: American Journal of Hypertension
https://www.readbyqxmd.com/read/28010758/double-jeopardy-the-rubber-ball-bounces-twice
#4
Jack L Arbiser, Linda C Gilbert
Soblet et al. describe cis mutations in TEK/Tie-2 in blue rubber bleb nevus and sporadic vascular malformations. This suggests that the remaining normal allele is required for the phenotype. Second, it suggests therapeutic approaches to treatment signal transduction inhibition.
January 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28002269/efficacy-of-intravitreal-aflibercept-in-macular-telangiectasia-type-1-is-linked-to-the-ocular-angiogenic-profile
#5
Laura Kowalczuk, Alexandre Matet, Ali Dirani, Alejandra Daruich, Aude Ambresin, Irmela Mantel, Richard F Spaide, Natacha Turck, Francine Behar-Cohen
PURPOSE: To evaluate intravitreal aflibercept in macular telangiectasia Type 1 (MacTel 1) patients and measure their ocular angiogenic profile. METHODS: Eight subjects with MacTel 1 refractory to bevacizumab, ranibizumab, or laser therapy and switched to aflibercept were included. Best-corrected visual acuity, central macular thickness, and cystic areas quantified on optical coherence tomography B-scans were assessed during 12 months. Perifoveal capillary densities were measured on optical coherence tomography angiography...
December 20, 2016: Retina
https://www.readbyqxmd.com/read/27918469/dietary-compound-chrysin-inhibits-retinal-neovascularization-with-abnormal-capillaries-in-db-db-mice
#6
Min-Kyung Kang, Sin-Hye Park, Yun-Ho Kim, Eun-Jung Lee, Lucia Dwi Antika, Dong Yeon Kim, Yean-Jung Choi, Young-Hee Kang
Diabetic retinopathy (DR) develops in a significant proportion of patients with chronic diabetes, characterized by retinal macular edema and abnormal retinal vessel outgrowth leading to vision loss. Chrysin, a naturally-occurring flavonoid found in herb and honeycomb, has anti-inflammatory, antioxidant, and anti-cancer properties. This study sought to determine the protective effects of chrysin on retinal neovascularization with abnormal vessels and blood-retinal barrier (BRB) breakdown in 33 mM glucose-exposed human retinal endothelial cells and in db/db mouse eyes...
December 3, 2016: Nutrients
https://www.readbyqxmd.com/read/27894114/hydroxysafflor-yellow-a-promotes-angiogenesis-via-the-angiopoietin-1-tie-2-signaling-pathway
#7
Tangting Chen, Ni Chen, Ningbo Pang, Lamei Xiao, Yongjie Li, Rong Li, Mao Luo, Xin Deng, Meiping Ren, Jianbo Wu, Liqun Wang
BACKGROUND: The flowers of Carthamus tinctorius L. are widely used in traditional Chinese medicine to treat cerebrovascular and cardiovascular diseases. Hydroxysafflor yellow A (HSYA), the main constituent of C. tinctorius L. flowers, is known for its multiple biological activities. The present study investigated the effects of HSYA on angiogenesis in vitro and in a mouse hindlimb ischemia model. METHODS: Using human umbilical vein endothelial cells (HUVEC) in vitro and a mouse hindlimb ischemia model in vivo, the angiogenic role of HSYA was evaluated...
November 29, 2016: Journal of Vascular Research
https://www.readbyqxmd.com/read/27893762/circulating-angiopoietin-2-and-its-soluble-receptor-tie-2-concentrations-are-related-to-renal-function-in-two-population-based-cohorts
#8
Anna Hennings, Anke Hannemann, Rainer Rettig, Marcus Dörr, Matthias Nauck, Henry Völzke, Markus M Lerch, Wolfgang Lieb, Nele Friedrich
BACKGROUND: An intact angiopoietin/Tie-2 ligand receptor system is indispensable for life. High circulating angiopoietin-2 (Ang-2) concentrations are strongly associated with kidney disease involving the progressive loss of glomerular filtration. The aim of our study was to investigate the associations between renal function and serum Ang-2 or serum Tie-2 concentrations in the general population. METHODS: Data of 3081 and 4088 subjects from two population-based studies, the Study of Health in Pomerania (SHIP-1) and SHIP-Trend, were used...
2016: PloS One
https://www.readbyqxmd.com/read/27885577/distinct-expression-of-various-angiogenesis-factors-in-mice-brain-after-whole-brain-irradiation-by-x-ray
#9
Zhezhi Deng, Haiwei Huang, Xiaohong Wu, Mengmeng Wu, Guoyong He, Junjie Guo
Radiation-induced brain injury (RBI) is the most serious complication after radiotherapy. However, the etiology of RBI remains elusive. In order to evaluate the effect of X-rays on normal brain tissue, adult male BALB/C mice were subjected to whole-brain exposure with a single dose of 10 Gy or sham radiation. The structure and number of mice brain vessels were investigated 1, 7, 30, 90 and 180 days after irradiation by H&E staining and immune-fluorescence staining. Compared with sham control mice, in addition to morphological changes, a significant reduction of microvascular density was detected in irradiated mice brains...
November 25, 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27876862/in-silico-exploration-for-novel-type-i-inhibitors-of-tie-2-tek-the-performance-of-different-selection-strategy-in-selecting-virtual-screening-candidates
#10
Peichen Pan, Huiyong Sun, Hui Liu, Dan Li, Wenfang Zhou, Xiaotian Kong, Youyong Li, Huidong Yu, Tingjun Hou
The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27863496/evaluation-of-anti-tumorigenic-activity-of-bp3b-against-colon-cancer-with-patient-derived-tumor-xenograft-model
#11
Hye-Youn Kim, Jinhee Kim, Huyen Trang Ha Thi, Ok-Sun Bang, Won-Suk Lee, Suntaek Hong
BACKGROUND: KIOM-CRC#BP3B (BP3B) is a novel herbal prescription that is composed of three plant extracts. Our preliminary study identified that BP3B exhibited potent anti-proliferative activity against various types of cancer cell lines in vitro. Because the in vivo anti-tumor effect of BP3B is not evaluated before clinical trial, we want to test it using patient's samples. METHODS: To confirm the in vivo anti-cancer effect of BP3B, we used genetically characterized patient-derived colon tumor xenograft (PDTX) mouse model...
November 18, 2016: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/27852330/appearance-of-claudin-5-leukocytes-in-the-central-nervous-system-during-neuroinflammation-a-novel-role-for-endothelial-derived-extracellular-vesicles
#12
Debayon Paul, Valentina Baena, Shujun Ge, Xi Jiang, Evan R Jellison, Timothy Kiprono, Dritan Agalliu, Joel S Pachter
BACKGROUND: The mechanism of leukocyte transendothelial migration (TEM) across the highly restrictive blood-brain barrier (BBB) remains enigmatic, with paracellular TEM thought to require leukocytes to somehow navigate the obstructive endothelial tight junctions (TJs). Transient interactions between TJ proteins on the respective leukocyte and endothelial surfaces have been proposed as one mechanism for TEM. Given the expanding role of extracellular vesicles (EVs) in intercellular communication, we investigated whether EVs derived from brain microvascular endothelial cells (BMEC) of the BBB may play a role in transferring a major TJ protein, claudin-5 (CLN-5), to leukocytes as a possible basis for such a mechanism during neuroinflammation...
November 16, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27828873/elevated-markers-of-vascular-remodeling-and-arterial-stiffness-are-associated-with-neurocognitive-function-in-older-hiv-adults-on-suppressive-antiretroviral-therapy
#13
Jessica L Montoya, Jennifer Iudicello, Pariya L Fazeli, Suzi Hong, Michael Potter, Ronald J Ellis, Igor Grant, Scott L Letendre, David J Moore
BACKGROUND: HIV is associated with elevated markers of vascular remodeling that may contribute to arterial fibrosis and stiffening and changes in pulse pressure (PP). These changes may, in turn, deleteriously affect autoregulation of cerebral blood flow and neurocognitive function. METHODS: To evaluate these mechanisms, we studied markers of vascular remodeling, PP, and neurocognitive function among older (≥50 years of age) HIV-infected (HIV+, n = 72) and HIV-seronegative (HIV-, n = 36) adults...
February 1, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/27821605/a-phase-i-ii-multicenter-study-of-single-agent-foretinib-as-first-line-therapy-in-patients-with-advanced-hepatocellular-carcinoma
#14
Thomas Cc Yau, Riccardo Lencioni, Wattana Sukeepaisarnjaroen, Yee Chao, Chia-Jui Yen, Wirote Lausoontornsiri, Pei-Jer Chen, Theeranun Sanpajit, Aaron Camp, Donna S Cox, Robert C Gagnon, Yuan Liu, Kristen E Raffensperger, Diptee A Kulkarni, Howard Kallender, Lone Harild Ottesen, Ronnie Tp Poon, Donald P Bottaro
PURPOSE: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma (HCC) patients. EXPERIMENTAL DESIGN: In the phase I part, advanced HCC patients were dose-escalated on foretinib (30-60 mg) once daily (QD) using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety...
November 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27787897/novel-tie-2-inhibitor-bay-826-displays-in%C3%A2-vivo-efficacy-in-experimental-syngeneic-murine-glioma-models
#15
Hannah Schneider, Emese Szabo, Raquel A C Machado, Angela Broggini-Tenzer, Alexander Walter, Mario Lobell, Dieter Heldmann, Frank Süssmeier, Sylvia Grünewald, Michael Weller
Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models...
January 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27784306/angiopoietin-2-impairs-collateral-artery-growth-associated-with-the-suppression-of-the-infiltration-of-macrophages-in-mouse-hindlimb-ischaemia
#16
Xiaoyong Tan, Kai Yan, Meiping Ren, Ni Chen, Yongjie Li, Xin Deng, Liqun Wang, Rong Li, Mao Luo, Yong Liu, Yan Liu, Jianbo Wu
BACKGROUND: Angiopoietin-2 (Ang-2), a ligand of the Tie-2 receptor, plays an important role in maintaining endothelial cells and in destabilizing blood vessels. Collateral artery growth (arteriogenesis) is a key adaptive response to arterial occlusion. It is unknown whether the destabilization of blood vessels by Ang-2 can affect arteriogenesis and modulate mononuclear cell function. This study aimed to investigate the effects of Ang-2 on collateral artery growth. METHODS: Hindlimb ischaemia model was produced in C57BL/6 mice by femoral artery ligation...
October 26, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27777694/a-reversal-of-age-dependent-proliferative-capacity-of-endothelial-progenitor-cells-from-different-species-origin-in-in-vitro-condition
#17
Mehdi Hassanpour, Omid Cheraghi, Vahid Siavashi, Reza Rahbarghazi, Mohammad Nouri
Introduction: A large number of cardiovascular disorders and abnormalities, notably accelerated vascular deficiencies could be related to aging changes and increased length of life. During the past decades, the discovery of different stem cells facilitates ongoing attempts for attenuating many disorders, especially in vascular beds. Endothelial progenitor cells (EPCs) are a subtype of stem cells that have potent capacity to differentiate into mature endothelial cells (ECs). However, some documented studies reported an age-related decline in proliferation and function of many stem cells...
2016: Journal of Cardiovascular and Thoracic Research
https://www.readbyqxmd.com/read/27754175/sy-15-1-mechanism-of-endothelin-1-regulation-in-hypertension-the-role-of-endothelin-type-a-receptors
#18
Ernesto Schiffrin
For many years we have studied models of hypertension in which endothelin-1 (ET-1) is overexpressed. These include DOCA-salt hypertensive rats, Dahl-salt sensitive rats, and stroke prone SHR, in all of which ET-1-mediated mechanisms play a role in blood pressure elevation and vascular injury. In humans we demonstrated overexpression of ET-1 in the endothelium of small arteries from stage 2 hypertensive patients. We have also produced a mouse that overexpresses human ET-1 in the endothelium using a Tie-2 promoter, which exhibited increased oxidative stress and inflammation, hypertrophic remodeling and endothelial dysfunction of small arteries but only slight blood pressure elevation...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27683553/dysregulation-of-angiopoietin-1-plays-a-mechanistic-role-in-the-pathogenesis-of-cerebral-malaria
#19
Sarah J Higgins, Lisa A Purcell, Karlee L Silver, Vanessa Tran, Valerie Crowley, Michael Hawkes, Andrea L Conroy, Robert O Opoka, John G Hay, Susan E Quaggin, Gavin Thurston, W Conrad Liles, Kevin C Kain
Cerebral malaria is a leading cause of global morbidity and mortality. Interventions targeting the underlying pathophysiology of cerebral malaria may improve outcomes compared to treatment with antimalarials alone. Microvascular leak plays an important role in the pathogenesis of cerebral malaria. The angiopoietin (Ang)-Tie-2 system is a critical regulator of vascular function. We show that Ang-1 expression and soluble Tie-2 expression were associated with disease severity and outcome in a prospective study of Ugandan children with severe malaria and in a preclinical murine model of experimental cerebral malaria...
September 28, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27643132/sy-15-1-mechanism-of-endothelin-1-regulation-in-hypertension-the-role-of-endothelin-type-a-receptors
#20
Ernesto Schiffrin
For many years we have studied models of hypertension in which endothelin-1 (ET-1) is overexpressed. These include DOCA-salt hypertensive rats, Dahl-salt sensitive rats, and stroke prone SHR, in all of which ET-1-mediated mechanisms play a role in blood pressure elevation and vascular injury. In humans we demonstrated overexpression of ET-1 in the endothelium of small arteries from stage 2 hypertensive patients. We have also produced a mouse that overexpresses human ET-1 in the endothelium using a Tie-2 promoter, which exhibited increased oxidative stress and inflammation, hypertrophic remodeling and endothelial dysfunction of small arteries but only slight blood pressure elevation...
September 2016: Journal of Hypertension
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