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Activin A

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https://www.readbyqxmd.com/read/29331635/sotatercept-with-long-term-extension-for-the-treatment-of-anaemia-in-patients-with-lower-risk-myelodysplastic-syndromes-a-phase-2-dose-ranging-trial
#1
Rami Komrokji, Guillermo Garcia-Manero, Lionel Ades, Thomas Prebet, David P Steensma, Joseph G Jurcic, Mikkael A Sekeres, Jesus Berdeja, Michael R Savona, Odile Beyne-Rauzy, Aspasia Stamatoullas, Amy E DeZern, Jacques Delaunay, Gautam Borthakur, Robert Rifkin, Thomas E Boyd, Abderrhamane Laadem, Bond Vo, Jennie Zhang, Marie Puccio-Pick, Kenneth M Attie, Pierre Fenaux, Alan F List
BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. METHODS: This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France...
January 10, 2018: Lancet Haematology
https://www.readbyqxmd.com/read/29328402/mir%C3%A2-203%C3%A2-3p-participates-in-the-suppression-of-diabetes%C3%A2-associated-osteogenesis-in-the-jaw-bone-through-targeting-smad1
#2
Yuying Tang, Leilei Zheng, Jie Zhou, Yang Chen, Lan Yang, Feng Deng, Yun Hu
Certain microRNAs (miRs) have important roles in the maintenance of bone development and metabolism, and a variety of miRs are known to be deregulated in diabetes. The present study investigated the role of miR‑203‑3p in the regulation of bone loss by assessing jaw bones of a rat model of type 2 diabetes. The results indicated that miR‑203‑3p inhibited osteogenesis in the jaws of diabetic rats and in rat bone marrow mesenchymal stem cells cultured in high‑glucose medium. A luciferase re-porter assay was used to verify the bioinformatics prediction that miR‑203‑3p targets the 3'‑untranslated region of Smad1, which is an important mediator of the bone morphogenetic protein (BMP)/Smad pathway...
January 9, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29312979/bone-morphogenetic-protein-9-activin-like-kinase-1-axis-a-new-target-for-hepatic-regeneration-and-fibrosis-treatment-in-liver-injury
#3
EDITORIAL
Montserrat Marí, Albert Morales
No abstract text is available yet for this article.
December 2017: Hepatobiliary Surgery and Nutrition
https://www.readbyqxmd.com/read/29311136/pharmacokinetics-and-disposition-of-momelotinib-revealed-a-disproportionate-human-metabolite-%C3%A2-resolution-for-clinical-development
#4
Jim Zheng, Yan Xin, Jingyu Zhang, Raju Subramanian, Bernard P Murray, J Andrew Whitney, Matthew R Warr, John Ling, Lisa Moorehead, Ellen Kwan, Jeffrey Hemenway, Bill J Smith, Jeffrey A Silverman
Momelotinib (MMB) is a small molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route...
January 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29305977/functional-analysis-of-a-novel-eng-variant-in-a-patient-with-hereditary-hemorrhagic-telangiectasia-hht-identifies-a-new-sp1-binding-site
#5
Sara Plumitallo, Lidia Ruiz-Llorente, Carmen Langa, Jacopo Morini, Gabriele Babini, Donata Cappelletti, Laura Scelsi, Alessandra Greco, Cesare Danesino, Carmelo Bernabeu, Carla Olivieri
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease, with an autosomal dominant inheritance and a worldwide incidence of about 1: 5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG or ACVRL1, which code for ENDOGLIN and Activin A Receptor Type II-Like Kinase 1 (ALK1), belonging to the TGF-β/BMP signalling pathway. Typical HHT clinical features are mucocutaneous telangiectases, arteriovenous malformations, spontaneous and recurrent epistaxis, as well as gastrointestinal bleedings...
January 3, 2018: Gene
https://www.readbyqxmd.com/read/29298619/developing-a-cost-effective-and-scalable-production-of-human-hepatic-competent-endoderm-from-size-controlled-pluripotent-stem-cell-aggregates
#6
Zahra Farzaneh, Mostafa Najarasl, Saeed Abbasalizadeh, Massoud Vosough, Hossein Baharvand
Dynamic suspension culture of human pluripotent stem cells (hPSCs) in stirred bioreactors provides a valuable scalable culture platform for integrated differentiation toward different lineages for potential research and therapeutic applications. However, current protocols for scalable and integrated differentiation of hPSCs limited due to high cost of growth factors and technical challenges. Here, hPSCs aggregates primed with 6 and 12 µM of CHIR99021 (CHIR), a Wnt agonist, in combination with different concentrations of high cost Activin A (10, 25, 50, 100 ng/ml)...
January 3, 2018: Stem Cells and Development
https://www.readbyqxmd.com/read/29290529/histone-deacetylase-inhibitor-hdaci-upregulates-activin-a-and-activates-the-smad-signaling-pathway-in-melanomas
#7
Jeeyong Lee, Jiwon Ko, Jae Youn Yi
BACKGROUND: Histone deacetylase (HDAC) is an enzyme that regulates gene expression, cell cycle arrest, apoptosis and modulation of various pathways. HDAC inhibitors (HDACis) can modulate these pathways by hyper-acetylating target proteins, thereby acting as cancer chemotherapeutic agents. OBJECTIVE: One of HDACis, suberoylanilide hydroxamic acid (SAHA), has been found to regulate the Smad signaling pathway, by an as yet unclear mechanism. This study therefore investigated the mechanism by which SAHA regulates Smad signaling in the melanoma cell line SK-Mel-5...
December 21, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/29287776/activin-a-causes-hepatic-stellate-cell-activation-via-the-induction-of-tnf%C3%AE-%C3%AE%C2%BA%C3%AE-%C3%AE-tgf%C3%AE-in-kupffer-cells
#8
Foteini Kiagiadaki, Marilena Kampa, Argyro Voumvouraki, Elias Castanas, Elias Kouroumalis, George Notas
Background&Aims. TGFβ superfamily member Activin-A is a multifunctional hormone/cytokine expressed in multiple tissues and cells., where it regulates cellular differentiation, proliferation, inflammation and tissue architecture. High activin-A levels have been reported in alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH). Our aim was to identify the cell types involved in the fibrotic processes induced by activin-A in liver and verify the liver diseases that this molecule can be found increased...
December 26, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29286116/bambi-promotes-macrophage-proliferation-and-differentiation-in-gliomas
#9
Dan Wang, Xiaolai Chen, Ran Zhang
The present study investigated the capacity of Bone morphogenic protein and activin membrane‑bound inhibitor homolog (BAMBI) to regulate the migration and differentiation of macrophages in gliomas. Using a migration assay, it was determined that BAMBI stimulated monocytes migration in a dose‑dependent effect. When induced by phorbol myristate acetate (PMA) the monocytes differentiated into macrophages, and BAMBI also increased the migration of PMA‑induced macrophages compared with control cells. The expression of CD68 and BAMBI protein and mRNA in glioma and normal specimens were detected using immunohistochemistry and reverse transcription‑quantitative polymerase chain reaction, respectively...
December 20, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29261154/the-role-of-par2-in-tgf-%C3%AE-1-induced-erk-activation-and-cell-motility
#10
Hendrik Ungefroren, David Witte, Christian Fiedler, Thomas Gädeken, Roland Kaufmann, Hendrik Lehnert, Frank Gieseler, Bernhard H Rauch
BACKGROUND: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell migration by transforming growth factor (TGF)-β1. However, it is not known whether activation of non-SMAD TGF-β signaling (e.g., RAS-RAF-MEK-extracellular signal-regulated kinase (ERK) signaling) is required for cell migration and whether it is also dependent on PAR2. METHODS: RNA interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation to detect a PAR2-ALK5 physical interaction...
December 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29259971/alk1fc-suppresses-the-human-prostate-cancer-growth-in-in-vitro-and-in-vivo-preclinical-models
#11
Letizia Astrologo, Eugenio Zoni, Sofia Karkampouna, Peter C Gray, Irena Klima, Joël Grosjean, Marie J Goumans, Lukas J A C Hawinkels, Gabri van der Pluijm, Martin Spahn, George N Thalmann, Peter Ten Dijke, Marianna Kruithof-de Julio
Prostate cancer is the second most common cancer in men and lethality is normally associated with the consequences of metastasis rather than the primary tumor. Therefore, targeting the molecular pathways that underlie dissemination of primary tumor cells and the formation of metastases has a great clinical value. Bone morphogenetic proteins (BMPs) play a critical role in tumor progression and this study focuses on the role of BMP9- Activin receptor-Like Kinase 1 and 2 (ALK1 and ALK2) axis in prostate cancer...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29243844/in-vitro-improvement-of-quail-primordial-germ-cell-expansion-through-activation-of-tgf-beta-signaling-pathway
#12
Saeed Yakhkeshi, Shaban Rahimi, Mohsen Sharafi, Seyedeh-Nafiseh Hassani, Sara Taleahmad, Abdolhossein Shahverdi, Hossein Baharvand
Avian primordial germ cells (PGCs) have valuable potentials to cell-based approaches for transgenic bird production. In this regard, improvement of avian PGC expansion in vitro is necessary. Among experimental avian species, quail is a good model for transgenic technology, especially due to its short generation time. In the present study, we have examined the proliferative effects of transforming growth factor β (TGF-β) on the quail PGCs. After isolation of quail PGCs from blood [Hamburger-Hamilton (HH stages 13-15)] and gonads (HH stages 28-30), these cells were cultured on quail embryonic fibroblasts (QEF)...
December 15, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29243365/vitamin-a-coupled-liposome-system-targeting-free-cholesterol-accumulation-in-hepatic-stellate-cells-offers-a-beneficial-therapeutic-strategy-for-liver-fibrosis
#13
Hirotaka Furuhashi, Kengo Tomita, Toshiaki Teratani, Motonori Shimizu, Makoto Nishikawa, Masaaki Higashiyama, Takeshi Takajo, Kazuhiko Shirakabe, Koji Maruta, Yoshikiyo Okada, Chie Kurihara, Chikako Watanabe, Shunsuke Komoto, Suefumi Aosasa, Shigeaki Nagao, Junji Yamamoto, Soichiro Miura, Ryota Hokari
AIM: Liver fibrosis is a life-threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation partly by enhancing signaling via sterol regulatory element-binding protein 2 (SREBP2) and microRNA-33a (miR-33a), which resulted in HSC sensitization to transforming growth factor-β (TGFβ)-induced activation in a 'vicious cycle' of liver fibrosis. METHODS: Human HSCs were isolated from surgical liver specimens from the control patients and patients with liver fibrosis...
December 15, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/29241827/prevalence-and-risk-factors-for-kidney-stones-in-fibrodysplasia-ossificans-progressiva
#14
REVIEW
Rishi R Gupta, Patricia L R Delai, David L Glaser, David M Rocke, Mona Al Mukaddam, Robert J Pignolo, Frederick S Kaplan
The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7...
December 11, 2017: Bone
https://www.readbyqxmd.com/read/29232368/ascorbic-acid-promotes-cardiomyogenesis-through-smad1-signaling-in-differentiating-mouse-embryonic-stem-cells
#15
Maria Grazia Perino, Satoshi Yamanaka, Daniel R Riordon, Yelena Tarasova, Kenneth R Boheler
Numerous groups have documented that Ascorbic Acid (AA) promotes cardiomyocyte differentiation from both mouse and human ESCs and iPSCs. AA is now considered indispensable for the routine production of hPSC-cardiomyocytes (CMs) using defined media; however, the mechanisms involved with the inductive process are poorly understood. Using a genetically modified mouse embryonic stem cell (mESC) line containing a dsRED transgene driven by the cardiac-restricted portion of the ncx1 promoter, we show that AA promoted differentiation of mESCs to CMs in a dose- and time-dependent manner...
2017: PloS One
https://www.readbyqxmd.com/read/29230965/prevention-of-chemotherapy-induced-cachexia-by-acvr2b-ligand-blocking-has-different-effects-on-heart-and-skeletal-muscle
#16
Juha J Hulmi, Tuuli A Nissinen, Markus Räsänen, Joni Degerman, Juulia H Lautaoja, Karthik Amudhala Hemanthakumar, Janne T Backman, Olli Ritvos, Mika Silvennoinen, Riikka Kivelä
BACKGROUND: Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown. METHODS: The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated...
December 11, 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/29222466/deciphering-transcriptional-regulation-in-human-embryonic-stem-cells-specified-towards-a-trophoblast-fate
#17
Ashish Jain, Toshihiko Ezashi, R Michael Roberts, Geetu Tuteja
Differentiated human embryonic stem cells (hESC) continue to provide a model for studying early trophoblast cells (TB), but many questions have been raised regarding their true identity. Therefore, we carried out a global and unbiased analysis on previously published transcriptomic profiles for hESC differentiated to TB by means of bone morphogenetic protein-4 and inhibitors of activin A and fibroblast growth factor-2 signaling (BAP treatment). Our results confirm that BAP treated hESC (ESCd) lack a mesoderm signature and are a subtype of placental cells unlike those present at term...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29222267/new-therapeutic-targets-in-transfusion-dependent-and-independent-thalassemia
#18
REVIEW
M Domenica Cappellini, Irene Motta
β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin-heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29221447/disruption-of-postnatal-folliculogenesis-and-development-of-ovarian-tumor-in-a-mouse-model-with-aberrant-transforming-growth-factor-beta-signaling
#19
Yang Gao, Xin Fang, David F Vincent, David W Threadgill, Laurent Bartholin, Qinglei Li
BACKGROUND: Transforming growth factor beta (TGFB) superfamily signaling is implicated in the development of sex cord-stromal tumors, a category of poorly defined gonadal tumors. The aim of this study was to determine potential effects of dysregulated TGFB signaling in the ovary using Cre recombinase driven by growth differentiation factor 9 (Gdf9) promoter known to be expressed in oocytes. METHODS: A mouse model containing constitutively active TGFBR1 (TGFBR1CA) using Gdf9-iCre (termed TGFBR1-CAG9Cre) was generated...
December 8, 2017: Reproductive Biology and Endocrinology: RB&E
https://www.readbyqxmd.com/read/29208243/resveratrol-mitigates-trophoblast-and-endothelial-dysfunction-partly-via-activation-of-nuclear-factor-erythroid-2-related-factor-2
#20
Seshini Gurusinghe, Annie G Cox, Rahana Rahman, Siow T Chan, Ruth Muljadi, Harmeet Singh, Bryan Leaw, Joanne C Mockler, Sarah A Marshall, Padma Murthi, Rebecca Lim, Euan M Wallace
INTRODUCTION: Maternal endothelial dysfunction underlying preeclampsia arises from excessive placental release of anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng) and activin A. Resveratrol, an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, mediates the gene expression of antioxidant and vasoprotective factors that may counter the endothelial damage imposed by these anti-angiogenic factors. The objective of this study was to assess whether resveratrol could reduce placental oxidative stress and production of anti-angiogenic factors in vitro and/or improve in vitro markers of endothelial dysfunction via Nrf2 activation...
December 2017: Placenta
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