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https://www.readbyqxmd.com/read/28534941/two-natural-eudesmane-type-sesquiterpenes-from-laggera-alata-inhibit-angiogenesis-and-suppress-breast-cancer-cell-migration-through-vegf-and-angiopoietin-2-mediated-signaling-pathways
#1
Ning Liang, Yaolan Li, Hau Yin Chung
Eudesmane-type sesquiterpenes are natural sesquiterpenes with anti-inflammatory properties, but their anti-angiogenic activities are not known. The present study demonstrated that 5α-hydroxycostic acid and hydroxyisocostic acid, two eudesmane-type sesquiterpenes (ETSs), isolated from the herb Laggera alata, possessed anti-angiogenic effects. Under non-toxic dosage, ETSs suppressed VEGF‑induced proliferation in human umbilical vein endothelial cells (HUVECs) and vessel formation in zebrafish embryos. Moreover, ETSs inhibited VEGF-stimulated HUVEC migration, stress fibers and tube formation...
May 17, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28508859/plastic-roles-of-pericytes-in-the-blood-retinal-barrier
#2
Do Young Park, Junyeop Lee, Jaeryung Kim, Kangsan Kim, Seonpyo Hong, Sangyeul Han, Yoshiaki Kubota, Hellmut G Augustin, Lei Ding, Jin Woo Kim, Hail Kim, Yulong He, Ralf H Adams, Gou Young Koh
The blood-retinal barrier (BRB) consists of tightly interconnected capillary endothelial cells covered with pericytes and glia, but the role of the pericytes in BRB regulation is not fully understood. Here, we show that platelet-derived growth factor (PDGF)-B/PDGF receptor beta (PDGFRβ) signalling is critical in formation and maturation of BRB through active recruitment of pericytes onto growing retinal vessels. Impaired pericyte recruitment to the vessels shows multiple vascular hallmarks of diabetic retinopathy (DR) due to BRB disruption...
May 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28498260/combined-gene-therapy-using-adsvegfr2-and-adstie2-with-chemotherapy-reduces-the-growth-of-human-ovarian-cancer-and-formation-of-ascites-in-mice
#3
Laura Tuppurainen, Hanna Sallinen, Anni Karvonen, Elina Valkonen, Hanne Laakso, Timo Liimatainen, Elisa Hytönen, Kirsi Hämäläinen, Veli-Matti Kosma, Maarit Anttila, Seppo Ylä-Herttuala
OBJECTIVES: Ovarian cancer is highly dependent on tumor microvessels and angiogenesis regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) and angiopoietins (Ang) and their Tie receptors. We studied the efficacy of adenoviral (Ad) gene therapy with soluble VEGFR2 and Tie2 combined with paclitaxel and carboplatin for the treatment of ovarian cancer. METHODS: An intraperitoneal human ovarian cancer xenograft model in nude mice (n = 44) was used in this study...
June 2017: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/28473437/endothelial-myocyte-enhancer-factor-2c-inhibits-migration-of-smooth-muscle-cells-through-fenestrations-in-the-internal-elastic-lamina
#4
Yao Wei Lu, Anthony M Lowery, Li-Yan Sun, Harold A Singer, Guohao Dai, Alejandro P Adam, Peter A Vincent, John J Schwarz
OBJECTIVE: Laminar flow activates myocyte enhancer factor 2 (MEF2) transcription factors in vitro to induce expression of atheroprotective genes in the endothelium. Here we sought to establish the role of Mef2c in the vascular endothelium in vivo. APPROACH AND RESULTS: To study endothelial Mef2c, we generated endothelial-specific deletion of Mef2c using Tie2-Cre or Cdh5-Cre-ER(T2) and examined aortas and carotid arteries by en face immunofluorescence. We observed enhanced actin stress fiber formation in the Mef2c-deleted thoracic aortic endothelium (laminar flow region), similar to those observed in normal aortic inner curvature (disturbed flow region)...
May 4, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28473248/endothelial-deletion-of-mtorc1-protects-against-hindlimb-ischemia-in-diabetic-mice-via-activation-of-autophagy-attenuation-of-oxidative-stress-and-alleviation-of-inflammation
#5
Wensi Fan, Dong Han, Zhongchan Sun, Sai Ma, Lei Gao, Jiangwei Chen, Xiang Li, Xiujuan Li, Miaomiao Fan, Congye Li, Dahai Hu, Yabin Wang, Feng Cao
Peripheral arterial disease (PAD) complicated with diabetes mellitus (DM) still remains a thorny issue due to lack of effective strategies. Our previous study has demonstrated that inhibition of mTORC1 protected adipose-derived stromal cells from hindlimb ischemic injury in PAD mice. However, whether inhibition of mTORC1 could protect against PAD in diabetes mellitus and the underlying mechanisms remained elusive. In this study, we employed endothelial-specific raptor (an essential component of the mTORC1 signaling complex) knockout (KO) mice (Tie2-mTORC1(ko)) to investigate whether and how mTORC1 downregulation could alleviate hindlimb ischemic injury in diabetic mice...
May 1, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28465380/the-angiopoietin-tie2-signaling-axis-in-systemic-inflammation
#6
Samir M Parikh
Systemic inflammation is a hallmark of commonly encountered diseases ranging from bacterial sepsis to sterile syndromes such as major trauma. Derangements in the host vasculature contribute to the cardinal manifestations of sepsis in profound ways. Recent studies of control pathways regulating the vascular endothelium have illuminated how this single cell layer toggles between quiescence and activation to affect the development of shock and multiorgan dysfunction. This article focuses on one such control pathway, the Tie2 receptor and its ligands the angiopoietins, to describe a growing body of genetic, biochemical, mechanistic, and human studies that implicate Tie2 as a critical switch...
May 2, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28464467/elevated-expression-of-tie1-is-accompanied-by-acquisition-of-cancer-stemness-properties-in-colorectal-cancer
#7
Miku Torigata, Daishi Yamakawa, Nobuyuki Takakura
The Tie receptors 1 and 2 (Tie1/2) play crucial roles in embryonic angiogenesis. Recent studies suggest enhanced expression of Tie1 in several types of cancer and negative correlations between Tie1 levels and clinical outcome. These observations suggest important functions of Tie1 not only for vascular formation but also in tumorigenesis. Ligands for Tie2, that is angiopoietins 1-4, have been identified, but not for Tie1. To determine the molecular functions of Tie1, its detailed characterization in tumors would be helpful...
May 2, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28460436/rab10-overexpression-promotes-tumor-growth-and-indicates-poor-prognosis-of-hepatocellular-carcinoma
#8
Wei Wang, Wei-Dong Jia, Bing Hu, Yue-Yin Pan
Hepatocellular carcinoma (HCC), one of the most common and lethal cancers worldwide, has a high recurrence rate with current treatment modalities. Identifying biomarkers for early diagnosis and discovering new sufficient molecular targets for the development of targeted therapies are urgently needed. RAB10, a member of the RAS family, has been shown to be highly expressed in HCC. However, the function of RAB10 in HCC is less studied. Here we report that RAB10 acts as an oncogene in HCC. The shRNA-mediated knockdown of RAB10 significantly reduced the proliferation of HCC cells and colony formation, induced cell cycle arrest at G0/G1 phase and increased apoptosis in vitro...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28454094/proteolytic-cleavages-in-the-extracellular-domain-of-receptor-tyrosine-kinases-by-membrane-associated-serine-proteases
#9
Li-Mei Chen, Karl X Chai
The epithelial extracellular membrane-associated serine proteases matriptase, hepsin, and prostasin are proteolytic modifying enzymes of the extracellular domain (ECD) of the epidermal growth factor receptor (EGFR). Matriptase also cleaves the ECD of the vascular endothelial growth factor receptor 2 (VEGFR2) and the angiopoietin receptor Tie2. In this study we tested the hypothesis that these serine proteases may cleave the ECD of additional receptor tyrosine kinases (RTKs). We co-expressed the proteases in an epithelial cell line with Her2, Her3, Her4, insulin receptor (INSR), insulin-like growth factor I receptor (IGF-1R), the platelet-derived growth factor receptors (PDGFRs) α and β, or nerve growth factor receptor A (TrkA)...
April 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28453727/endothelial-glycocalyx-breakdown-is-mediated-by-angiopoietin-2
#10
Alexander Lukasz, Carina Hillgruber, Hans Oberleithner, Kristina Kusche-Vihrog, Hermann Pavenstädt, Alexandros Rovas, Bettina Hesse, Tobias Goerge, Philipp Kümpers
Aims: The endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal surface of the endothelium, provides a first vasoprotective barrier against vascular leakage and adhesion in sepsis and vessel inflammation. Angiopoietin-2 (Angpt-2), an antagonist of the endothelium-stabilizing receptor Tie2 secreted by endothelial cells, promotes vascular permeability through cellular contraction and junctional disintegration. We hypothesized that Angpt-2 might also mediate the breakdown of the eGC...
May 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28438786/vegfr2-but-not-vegfr3-governs-integrity-and-remodeling-of-thyroid-angiofollicular-unit-in-normal-state-and-during-goitrogenesis
#11
Jeon Yeob Jang, Sung Yong Choi, Intae Park, Do Young Park, Kibaek Choe, Pilhan Kim, Young Keum Kim, Byung-Joo Lee, Masanori Hirashima, Yoshiaki Kubota, Jeong-Won Park, Sheue-Yann Cheng, Andras Nagy, Young Joo Park, Kari Alitalo, Minho Shong, Gou Young Koh
Thyroid gland vasculature has a distinguishable characteristic of endothelial fenestrae, a critical component for proper molecular transport. However, the signaling pathway that critically governs the maintenance of thyroid vascular integrity, including endothelial fenestrae, is poorly understood. Here, we found profound and distinct expression of follicular epithelial VEGF-A and vascular VEGFR2 that were precisely regulated by circulating thyrotropin, while there were no meaningful expression of angiopoietin-Tie2 system in the thyroid gland...
April 24, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28436588/reduced-erg-dosage-impairs-survival-of-hematopoietic-stem-and-progenitor-cells
#12
Ying Xie, Mia Lee Koch, Xin Zhang, Melanie J Hamblen, Frank J Godinho, Yuko Fujiwara, Huafeng Xie, Jan-Henning Klusmann, Stuart H Orkin, Zhe Li
ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Erg(kd) ) in which Erg expression can be conditionally restored by Cre recombinase. Erg(kd/kd) animals die at E10.5-E11...
April 24, 2017: Stem Cells
https://www.readbyqxmd.com/read/28436498/integrative-meta-modeling-identifies-endocytic-vesicles-late-endosome-and-the-nucleus-as-the-cellular-compartments-primarily-directing-rtk-signaling
#13
Jared C Weddell, Princess I Imoukhuede
Recently, intracellular receptor signaling has been identified as a key component mediating cell responses for various receptor tyrosine kinases (RTKs). However, the extent each endocytic compartment (endocytic vesicle, early endosome, recycling endosome, late endosome, lysosome and nucleus) contributes to receptor signaling has not been quantified. Furthermore, our understanding of endocytosis and receptor signaling is complicated by cell- or receptor-specific endocytosis mechanisms. Therefore, towards understanding the differential endocytic compartment signaling roles, and identifying how to achieve signal transduction control for RTKs, we delineate how endocytosis regulates RTK signaling...
May 22, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/28422724/utilizing-combinatorial-engineering-to-develop-tie2-targeting-antagonistic-angiopoetin-2-ligands-as-candidates-for-anti-angiogenesis-therapy
#14
Tomer Shlamkovich, Lidan Aharon, William A Barton, Niv Papo
In many human cancers, the receptor tyrosine kinase (RTK) Tie2 plays important roles in mediating proliferation, survival, migration and angiogenesis. Thus, molecules that could potently inhibit activation of the Tie2 receptor would have a significant impact on cancer therapy. Nevertheless, attempts to develop Tie2-targeted inhibitors have met with little success, and there is currently no FDA-approved therapeutic selectively targeting Tie2. We used a combinatorial protein engineering approach to develop a new generation of angiopoietin (Ang)2-derived Tie2 antagonists as potential cancer therapeutics and as tools to study angiogenesis...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28396439/structural-basis-of-tie2-activation-and-tie2-tie1-heterodimerization
#15
Veli-Matti Leppänen, Pipsa Saharinen, Kari Alitalo
The endothelial cell (EC)-specific receptor tyrosine kinases Tie1 and Tie2 are necessary for the remodeling and maturation of blood and lymphatic vessels. Angiopoietin-1 (Ang1) growth factor is a Tie2 agonist, whereas Ang2 functions as a context-dependent agonist/antagonist. The orphan receptor Tie1 modulates Tie2 activation, which is induced by association of angiopoietins with Tie2 in cis and across EC-EC junctions in trans Except for the binding of the C-terminal angiopoietin domains to the Tie2 ligand-binding domain, the mechanisms for Tie2 activation are poorly understood...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28396397/dimerization-of-tie2-mediated-by-its-membrane-proximal-fniii-domains
#16
Jason O Moore, Mark A Lemmon, Kathryn M Ferguson
Tie1 and Tie2, members of the tyrosine kinase family with immunoglobulin and EGF homology domains, are receptor tyrosine kinases found primarily in endothelial cells with key roles in development and maintenance of the vasculature and in angiogenesis. They are attractive targets for therapeutic intervention in tumor angiogenesis, inflammation, and sepsis. Tie2 is regulated directly by the multimeric angiopoietin (Ang) ligands, with Ang1 being its primary activator. Structural studies have shown how Angs bind to the Tie2 ligand-binding region, but do not explain Tie2 activation and suggest a passive role for the Tie2 extracellular region (ECR) in ligand-induced receptor dimerization...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28387902/angiogenesis-characteristics-of-infantile-hemangioma-and-feasibility-observation-of-transplantation-model-of-human-hemangioma-on-mice
#17
Y Fu, Z-G Yang, L-Y Zhao
OBJECTIVE: To study pathogenic features of pediatric hemangiomas, we successfully established a model in mice, by transplanting human hemangioma tissues. MATERIALS AND METHODS: The hemangioma from the leg of a two-month-old infant was dissected and sliced into several pieces. During a careful surgical procedure, the hemangioma tissues were individually transplanted into skin incisions in anesthetized mice. The volume of the transplanted tumors was measured and the changes in shape recorded at 1 day, and at 1, 2, 3, 4, 5 and 6 months after the transplantation...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28372817/angiopoietin-2-in-placentation-and-tumor-biology-the-yin-and-yang-of-vascular-biology
#18
Qiong Wang, Gendie E Lash
There are several parallels between placental and tumor biology. Both require rapid acquisition of a blood supply to supply oxygen and nutrients, the placenta through neoangiogenesis and tumors by co-opting the existing vasculature. In addition, successful pregnancy also requires remodeling of the maternal uterine spiral arteries. Angiopoietins (Angs) are a family of angiogenic growth factors, the best studied being Ang-1 and Ang-2, which signal through the membrane tyrosine kinase receptor Tie2, and in simple terms have opposite effects with Ang-1 acting to stabilize newly formed blood vessels and Ang-2 having a destabilizing effect...
March 30, 2017: Placenta
https://www.readbyqxmd.com/read/28369068/all-trans-retinoic-acid-suppresses-the-angiopoietin-tie2-pathway-and-inhibits-angiogenesis-and-metastasis-in-esophageal-squamous-cell-carcinoma
#19
Na Li, Yanjuan Lu, Daoming Li, Xiangyu Zheng, Jingyao Lian, Shanshan Li, Huijuan Cui, Linda Zhang, Luqian Sang, Ying Wang, Jane J Yu, Taiying Lu
Esophageal squamous cell carcinoma (ESCC) is the second common cancer in Henan province and is well-known for aggressiveness and dismal prognosis. Adjuvant therapies, chemotherapy, radiotherapy and endoscopic treatment have not improved survival rates in patients with late stage esophageal carcinoma. All-trans retinoic acid (ATRA) is the active ingredient of Vitamin A and affects a wide spectrum of biological processes including development, growth, neural function, immune function, reproduction, and vision...
2017: PloS One
https://www.readbyqxmd.com/read/28334876/pdgfrb-gain-of-function-mutations-in-sporadic-infantile-myofibromatosis
#20
Florence A Arts, Raf Sciot, Bénédicte Brichard, Marleen Renard, Audrey de Rocca Serra, Guillaume Dachy, Laura A Noël, Amélie I Velghe, Christine Galant, Maria Debiec-Rychter, An Van Damme, Miikka Vikkula, Raphaël Helaers, Nisha Limaye, Hélène A Poirel, Jean-Baptiste Demoulin
Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. Multifocal nodules with visceral lesions are associated with a poor prognosis. A few familial cases have been linked to mutations in various genes including PDGFRB. In this study, we sequenced PDGFRB, which encodes a receptor tyrosine kinase, in 16 cases of myofibromatosis or solitary myofibroma. Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma...
May 15, 2017: Human Molecular Genetics
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