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https://www.readbyqxmd.com/read/28973643/tacrolimus-rescues-the-signaling-and-gene-expression-signature-of-endothelial-alk1-loss-of-function-and-improves-hht-vascular-pathology
#1
Santiago Ruiz, Pallavi Chandakkar, Haitian Zhao, Julien Papoin, Prodyot K Chatterjee, Erica Christen, Christine N Metz, Lionel Blanc, Fabien Campagne, Philippe Marambaud
Hereditary hemorrhagic telangiectasia (HHT) is a highly debilitating and life-threatening genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in BMP9-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. We interrogated the whole-transcriptome in human umbilical vein ECs (HUVECs) and found that ALK1 signaling inhibition was associated with a specific pro-angiogenic gene expression signature, which included a significant elevation of DLL4 expression...
September 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28916158/pyrrolizines-design-synthesis-anticancer-evaluation-and-investigation-of-the-potential-mechanism-of-action
#2
Ahmed M Gouda, Ahmed H Abdelazeem, Hany A Omar, Ashraf N Abdalla, Mohammed A S Abourehab, Hamed I Ali
A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28910869/-lymphomatoid-papulosis-a-clinicopathologic-analysis-and-whole-exome-sequencing
#3
T T Wang, Y Xie, L Li, L Wang
Objective: To study the clinicopathologic characteristics and immunophenotype of lymphomatoid papulosis(LyP), followed by exon mutation analysis with focus on gene mutations involved in apoptosis pathway and other possible pathogenic genes. Methods: Clinical data analysis and immunohistochemical staining were carried out in 20 cases of LyP. Whole exome sequencing technology was employed in 2 cases of type C of LyP. Results: Of the 20 cases, there were 9 males and 11 females with a median age of 28.6 years. Nineteen patients presented with multiple papules and nodules, and one case presented with only one tumor nodule...
September 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28871312/alk1-signaling-in-development-and-disease-new-paradigms
#4
REVIEW
Beth L Roman, Andrew P Hinck
Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels...
September 4, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28820968/reduced-activin-receptor-like-kinase-1-activity-promotes-cardiac-fibrosis-in-heart-failure
#5
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, S Paul Oh, Richard H Karas, Navin K Kapur
INTRODUCTION: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. HYPOTHESIS: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. METHODS AND RESULTS: In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure...
July 18, 2017: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
https://www.readbyqxmd.com/read/28796572/endoglin-and-alk1-as-therapeutic-targets-for-hereditary-hemorrhagic-telangiectasia
#6
REVIEW
Lidia Ruiz-Llorente, Eunate Gallardo-Vara, Elisa Rossi, David M Smadja, Luisa M Botella, Carmelo Bernabeu
Hereditary Haemorrhagic Telangiectasia (HHT) is as an autosomal dominant trait characterized by frequent nose bleeds, mucocutaneous telangiectases, arteriovenous malformations (AVMs) of the lung, liver and brain, and gastrointestinal bleedings due to telangiectases. HHT is originated by mutations in genes whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signalling of vascular endothelial cells. In spite of the great advances in the diagnosis as well as in the molecular, cellular and animal models of HHT, the current treatments remain just at the palliative level...
October 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28794048/hepatitis-c-virus-core-protein-modulates-endoglin-cd105-signaling-pathway-for-liver-pathogenesis
#7
Young-Chan Kwon, Reina Sasaki, Keith Meyer, Ranjit Ray
Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28782519/identification-of-novel-alk2-inhibitors-and-their-effect-on-cancer-cells
#8
Minsung Kim, Okran Choi, Suhkneung Pyo, Sang Un Choi, Chi Hoon Park
Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, is considered a regulator of glucose homeostasis as well as a neuronal differentiation factor. BMP9 induces phosphorylation of Smad1/5 through activin receptor-like kinase 1 and 2 (ALK1 and ALK2). Recently, many studies have shown that BMP9 contributes to tumorigenesis, and aberrant ALK2 expression is involved in many diseases. To investigate the role of BMP9-ALK2 signaling in cancer cells, we used TF-1 cells that require granulocyte-macrophage colony-stimulating factor (GM-CSF) for cell proliferation...
October 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28751863/bone-morphogenetic-protein-9-protects-against-neonatal-hyperoxia-induced-impairment-of-alveolarization-and-pulmonary-inflammation
#9
Xueyu Chen, Mar Orriols, Frans J Walther, El Houari Laghmani, Annemarie M Hoogeboom, Anne C B Hogen-Esch, Pieter S Hiemstra, Gert Folkerts, Marie-José T H Goumans, Peter Ten Dijke, Nicholas W Morrell, Gerry T M Wagenaar
Aim: Effective treatment of premature infants with bronchopulmonary dysplasia (BPD) is lacking. We hypothesize that bone morphogenetic protein 9 (BMP9), a ligand of the TGF-β family that binds to the activin receptor-like kinase 1 (ALK1)-BMP receptor type 2 (BMPR2) receptor complex, may be a novel therapeutic option for BPD. Therefore, we investigated the cardiopulmonary effects of BMP9 in neonatal Wistar rats with hyperoxia-induced BPD. Methods: Directly after birth Wistar rat pups were exposed to 100% oxygen for 10 days...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28733640/interleukin-37-promotes-angiogenesis-through-tgf-%C3%AE-signaling
#10
Mengmeng Zhao, Yongguang Hu, Jiayi Jin, Ying Yu, Shanshan Zhang, Jingjing Cao, Yuanfen Zhai, Rongbin Wei, Juanjuan Shou, Wenping Cai, Shangfeng Liu, Xiaoping Yang, Guo-Tong Xu, Jianhua Yang, David B Corry, Shao Bo Su, Xialin Liu, Tianshu Yang
IL-37 is a novel pro-angiogenic cytokine that potently promotes endothelial cell activation and pathological angiogenesis in our previous study, but the mechanisms behind the pro-angiogenic effect of IL-37 are less well understood. Extending our observations, we found that TGF-β interacts with IL-37, and potently enhances the binding affinity of IL-37 to the ALK1 receptor complex, thus allowing IL-37 to signal through ALK1 to activate pro-angiogenic responses. We further show that TGF-β and ALK1 are required in IL-37 induced pro-angiogenic response in ECs and in the mouse model of Matrigel plug and oxygen-induced retinopathy...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28733457/role-of-bone-morphogenetic-proteins-in-sprouting-angiogenesis-differential-bmp-receptor-dependent-signaling-pathways-balance-stalk-vs-tip-cell-competence
#11
Andreas Benn, Christian Hiepen, Marc Osterland, Christof Schütte, An Zwijsen, Petra Knaus
Before the onset of sprouting angiogenesis, the endothelium is prepatterned for the positioning of tip and stalk cells. Both cell identities are not static, as endothelial cells (ECs) constantly compete for the tip cell position in a dynamic fashion. Here, we show that both bone morphogenetic protein 2 (BMP2) and BMP6 are proangiogenic in vitro and ex vivo and that the BMP type I receptors, activin receptor-like kinase 3 (ALK3) and ALK2, play crucial and distinct roles in this process. BMP2 activates the expression of tip cell-associated genes, such as delta-like ligand 4 (DLL4) and kinase insert domain receptor (KDR), and p38-heat shock protein 27 (HSP27)-dependent cell migration, thereby generating tip cell competence...
July 21, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28695967/expression-of-the-alk1-family-of-type-i-bmp-admp-receptors-during-gastrula-stages-in-xenopus-embryos
#12
Avi Leibovich, Herbert Steinbeißer, Abraham Fainsod
Multiple members of the transforming growth factor beta (TGFβ) family of secreted factors play central inductive and patterning roles during embryogenesis. During gastrulation in vertebrates, the bone morphogenetic protein (BMP) sub-family is linked to formation of the embryonic organizer, Spemann's organizer in Xenopus, and dorsal-ventral mesoderm patterning. Our knowledge regarding the BMP receptors mediating this signaling is still very incomplete. The BMPR1A (ALK3) and BMPR1B (ALK6) receptors are known to mediate the BMP4 signal...
2017: International Journal of Developmental Biology
https://www.readbyqxmd.com/read/28646109/bone-morphogenetic-protein-9-bmp9-and-bmp10-enhance-tumor-necrosis-factor-%C3%AE-induced-monocyte-recruitment-to-the-vascular-endothelium-mainly-via-activin-receptor-like-kinase-2
#13
Claudia-Gabriela Mitrofan, Sarah L Appleby, Gerard B Nash, Ziad Mallat, Edwin R Chilvers, Paul D Upton, Nicholas W Morrell
Bone morphogenetic proteins 9 and 10 (BMP9/BMP10) are circulating cytokines with important roles in endothelial homeostasis. The aim of this study was to investigate the roles of BMP9 and BMP10 in mediating monocyte-endothelial interactions using an in vitro flow adhesion assay. Herein, we report that whereas BMP9/BMP10 alone had no effect on monocyte recruitment, at higher concentrations both cytokines synergized with tumor necrosis factor-α (TNFα) to increase recruitment to the vascular endothelium. The BMP9/BMP10-mediated increase in monocyte recruitment in the presence of TNFα was associated with up-regulated expression levels of E-selectin, vascular cell adhesion molecule (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells...
August 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28642261/transforming-growth-factor-%C3%AE-stimulates-smad1-5-signaling-in-pulmonary-artery-smooth-muscle-cells-and-fibroblasts-of-the-newborn-mouse-through-alk1
#14
Huili Zhang, Lili Du, Ying Zhong, Kathleen C Flanders, Jesse D Roberts
The intracellular signaling mechanisms through which TGF-β regulates pulmonary development are incompletely understood. Canonical TGF-β signaling involves Smad2/3 phosphorylation, Smad2/3·Smad4 complex formation and nuclear localization, and gene regulation. Here, we show that physiologically relevant TGF-β1 levels also stimulate Smad1/5 phosphorylation, which is typically a mediator of bone morphogenetic protein (BMP) signaling, in mouse pup pulmonary artery smooth muscle cells (mPASMC) and lung fibroblasts and other interstitial lung cell lines...
September 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28569204/tgf%C3%AE-1-induced-smad2-3-and-smad1-5-phosphorylation-are-both-alk5-kinase-dependent-in-primary-chondrocytes-and-mediated-by-tak1-kinase-activity
#15
Arjan van Caam, Wojciech Madej, Amaya Garcia de Vinuesa, Marie-José Goumans, Peter Ten Dijke, Esmeralda Blaney Davidson, Peter van der Kraan
BACKGROUND: Dysregulated transforming growth factor β (TGFβ) signaling is implicated in osteoarthritis development, making normalizing TGFβ signaling a possible therapy. Theoretically, this can be achieved with small molecule inhibitors specifically targeting the various TGFβ receptors and downstream mediators. In this study we explore in primary chondrocytes the use of small molecule inhibitors to target TGFβ-induced pSmad1/5/9-, pSmad2/3- and TGFβ-activated kinase 1 (TAK1)-dependent signaling...
May 31, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28565818/transforming-growth-factor-%C3%AE-and-its-role-in-heart-disease
#16
Guangwang Liu, Chao Ma, Huilin Yang, Pei-Ying Zhang
Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor β (TGFβ) and its signaling pathways. TGFβ appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy...
May 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28475519/genomic-assessment-of-blitz-nevi-suggests-classification-as-a-subset-of-blue-nevus-rather-than-spitz-nevus-clinical-histopathologic-and-molecular-analysis-of-18-cases
#17
Maria C Isales, Alexandra M Haugh, Jeffrey Bubley, Anna E Verzì, Bin Zhang, Emily Kudalkar, Christina Y Lee, Pedram Yazdan, Joan Guitart, Pedram Gerami
Blitz nevi/tumors are a distinct subset of melanocytic neoplasia which show mixed morphologic features of Spitz and blue nevus. Genomically, most blue nevi have GNAQ or GNA11 mutations while most Spitzoid neoplasms have either an HRAS mutation or translocations involving MET, ROS, BRAF, ALK1, NTRK1, and RET. The criteria used for the assessment of malignancy in blue and Spitzoid lesions are different, and these lesions have different prognostic markers. In this study, we assess the clinical, morphological, and genomic changes in 18 cases of Blitz nevi/tumors to better characterize this subset of neoplasms and determine their optimal genomic classification...
April 27, 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28468941/aberrant-caveolin-1-mediated-smad-signaling-and-proliferation-identified-by-analysis-of-adenine-474-deletion-mutation-c-474dela-in-patient-fibroblasts-a-new-perspective-on-the-mechanism-of-pulmonary-hypertension
#18
Glenn Marsboom, Zhenlong Chen, Yang Yuan, Yanmin Zhang, Chinnaswamy Tiruppathi, James E Loyd, Eric D Austin, Roberto F Machado, Richard D Minshall, Jalees Rehman, Asrar B Malik
A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum...
May 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28445989/tmprss2-erg-gene-fusion-variants-induce-tgf-%C3%AE-signaling-and-epithelial-to-mesenchymal-transition-in-human-prostate-cancer-cells
#19
Leonie Ratz, Mark Laible, Lukasz A Kacprzyk, Stephanie M Wittig-Blaich, Yanis Tolstov, Stefan Duensing, Peter Altevogt, Sabine M Klauck, Holger Sültmann
TMPRSS2:ERG (T/E) gene fusions are present in approximately 50% of all prostate cancer (PCa) cases. The expression of fusion mRNAs from distinct T/E variants is associated with clinicopathological parameters, while the underlying molecular processes remain unclear. We characterized the molecular mechanisms and functional implications caused by doxycycline (Dox)-inducible overexpression of the frequent T/E III and VI fusion variants in LNCaP cells. Induction of T/E expression resulted in increased cellular migratory and invasive potential, and reduced proliferation and accumulation in G1 phase...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427693/a-case-of-cd30-alk1-anaplastic-large-cell-lymphoma-resembling-acute-disseminated-encephalomyelitis
#20
T Afrantou, K S Natsis, G Papadopoulos, R Lagoudaki, C Poulios, D Mamouli, I Kostopoulos, N Grigoriadis
Central nervous system involvement is an uncommon complication of systemic non-Hodgkin lymphomas. The majority of these cases concern B-cell lymphomas. We report a case of systemic T-cell anaplastic large cell lymphoma CD30+ ALK- with CNS involvement at the time of diagnosis and unusual MRI characteristics resembling acute disseminated encephalomyelitis.
April 2017: Multiple Sclerosis and related Disorders
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