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TGF beta AND Small molecules

Mohammad Massumi, Farzaneh Pourasgari, Amarnadh Nalla, Battsetseg Batchuluun, Kristina Nagy, Eric Neely, Rida Gull, Andras Nagy, Michael B Wheeler
The ability to yield glucose-responsive pancreatic beta-cells from human pluripotent stem cells in vitro will facilitate the development of the cell replacement therapies for the treatment of Type 1 Diabetes. Here, through the sequential in vitro targeting of selected signaling pathways, we have developed an abbreviated five-stage protocol (25-30 days) to generate human Embryonic Stem Cell-Derived Beta-like Cells (ES-DBCs). We showed that Geltrex, as an extracellular matrix, could support the generation of ES-DBCs more efficiently than that of the previously described culture systems...
2016: PloS One
Ying Wang, Yumeng Wan, Guihong Ye, Pu Wang, Xiaowen Xue, Guanzhong Wu, Boping Ye
Adiponectin is an antidiabetic and antiatherogenic adipokine, which plays distinct roles in the balance of energy homoeostasis. As an insulin sensitizing hormone, adiponectin exerts multiple biological effects by the specific receptors (AdipoR1 and AdipoR2), through activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)α pathways. AdipoRon, an orally active synthetic small-molecule AdipoR agonist, shows very similar effects to adiponectin in vitro and in vivo, which could be a promising therapeutic approach for obesity-related disorders...
October 10, 2016: European Journal of Pharmaceutical Sciences
Karen C L Torres, Giselle Lima, Ana C Simões E Silva, Isabela Lubambo, Luiz O Rodrigues, Luiza Rodrigues, Kátia D Silveira, Érica L M Vieira, Marco A Romano-Silva, Débora M Miranda
Neurofibromatosis type 1 (NF1) is a genetic disorder with an early mortality determined mostly by malignancy. Little is known about the immunosurveillance factors in NF1 patients. In this study we evaluated inflammatory markers and their cellular sources in NF1 patients to try understanding the relation of immune factors and the tumorigenesis that characterizes the disease. Using flow cytometry and ELISA, we assayed cytokines, co-stimulatory molecules, the functional state of circulating blood cells and cytokine plasma levels in a case-control transversal study...
June 15, 2016: Journal of Neuroimmunology
B Mondal, V Patil, S D Shwetha, K Sravani, A S Hegde, A Arivazhagan, V Santosh, M Kanduri, K Somasundaram
An integrative functional genomics study of multiple forms of data are vital for discovering molecular drivers of cancer development and progression. Here, we present an integrated genomic strategy utilizing DNA methylation and transcriptome profile data to discover epigenetically regulated genes implicated in cancer development and invasive progression. More specifically, this analysis identified fibromodulin (FMOD) as a glioblastoma (GBM) upregulated gene because of the loss of promoter methylation. Secreted FMOD promotes glioma cell migration through its ability to induce filamentous actin stress fiber formation...
May 23, 2016: Oncogene
Lingling Feng, Brandoch Cook, Su-Yi Tsai, Ting Zhou, Brooke LaFlamme, Todd Evans, Shuibing Chen
Sorely missing from the "toolkit" for directed differentiation of stem/progenitor cells are agonists of the BMP-signaling pathway. Using a high-throughput chemical screen, we discovered that PD407824, a checkpoint kinase 1 (CHK1) inhibitor, increases the sensitivity of cells to sub-threshold amounts of BMP4. We show utility of the compound in the directed differentiation of human embryonic stem cells toward mesoderm or cytotrophoblast stem cells. Blocking CHK1 activity using pharmacological compounds or CHK1 knockout using single guide RNA (sgRNA) confirmed that CHK1 inhibition increases the sensitivity to BMP4 treatment...
May 31, 2016: Cell Reports
Jessica A Zagory, Marie V Nguyen, William Dietz, Nirmala Mavila, Allison Haldeman, Anatoly Grishin, Kasper S Wang
BACKGROUND: In biliary atresia (BA), epithelial-mesenchymal hepatic progenitor cells (HPC) expressing the stem/progenitor cell marker PROMININ-1 (PROM1) undergo expansion and subsequent transdifferentiation into collagen-producing myofibroblasts within regions of evolving biliary fibrosis under the regulation of Transforming Growth Factor-β (TGFβ) signaling. We hypothesized that pro-inflammatory Toll-like Receptor-3 (TLR3) signal activation promotes the differentiation of PROM1+ HPC via TGFβ pathway activation in vitro...
June 2016: Journal of Pediatric Surgery
Sangeeta Dhawan, Ercument Dirice, Rohit N Kulkarni, Anil Bhushan
Diabetes is associated with loss of functional pancreatic β-cells, and restoration of β-cells is a major goal for regenerative therapies. Endogenous regeneration of β-cells via β-cell replication has the potential to restore cellular mass; however, pharmacological agents that promote regeneration or expansion of endogenous β-cells have been elusive. The regenerative capacity of β-cells declines rapidly with age, due to accumulation of p16(INK4a), resulting in limited capacity for adult endocrine pancreas regeneration...
May 2016: Diabetes
Alessandra Micera, Luciano Quaranta, Graziana Esposito, Irene Floriani, Augusto Pocobelli, Sergio Claudio Saccà, Ivano Riva, Gianluca Manni, Francesco Oddone
INTRODUCTION: Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis. METHODS: TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls...
February 2016: Advances in Therapy
Jarosław Lewandowski, Tomasz J Kolanowski, Maciej Kurpisz
The derivation of pluripotent stem cells from human embryos and the generation of induced pluripotent stem cells (iPSCs) from somatic cells opened a new chapter in studies on the regeneration of the post-infarction heart and regenerative medicine as a whole. Thus, protocols for obtaining iPSCs were enthusiastically adopted and widely used for further experiments on cardiac differentiation. iPSC-mediated cardiomyocytes (iPSC-CMs) under in vitro culture conditions are generated by simulating natural cardiomyogenesis and involve the wingless-type mouse mammary tumour virus integration site family (WNT), transforming growth factor beta (TGF-β) and fibroblast growth factor (FGF) signalling pathways...
January 17, 2016: Journal of Tissue Engineering and Regenerative Medicine
Wan Zhao, Lixia Lu, Pengcheng Yang, Na Cui, Le Kang, Feng Cui
Rice stripe virus (RSV) causes rice stripe disease and is transmitted by the small brown planthopper (Laodelphax striatellus, SBPH) in a persistent, circulative, and propagative manner. The alimentary canal and salivary gland of SBPH play important roles in viral replication and transmission. However, little is known about the underlying molecular functions of these two organs in the interaction between RSV and SBPH. In this study, organ-specific transcriptomes of the alimentary canal and salivary gland were analyzed in viruliferous and naïve SBPH...
March 2016: Insect Biochemistry and Molecular Biology
Jie Chen, Yanqin Li, Haojie Hao, Chonghui Li, Yu Du, Ye Hu, Jian Li, Zhixin Liang, Chunsun Li, Jiejie Liu, Liangan Chen
BACKGROUND/AIMS: Mesenchymal stem cell (MSC) based therapies may be useful for treating acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the impact of human umbilical cord Wharton's jelly-derived MSC (hUC-MSC) secreted factors on alveolar epithelial cells under septic conditions and determined the relevant intracellular signaling pathways. METHODS: Human alveolar epithelial cells (AEC) and primary human small airway epithelial cells (SAEC) were subjected to lipopolysaccharide (LPS) with or without the presence of hUC-MSC-conditioned medium (CM)...
2015: Cellular Physiology and Biochemistry
Yutaka Fujiwara, Hiroshi Nokihara, Yasuhide Yamada, Noboru Yamamoto, Kuniko Sunami, Hirofumi Utsumi, Hiroya Asou, Osamu TakahashI, Ken Ogasawara, Ivelina Gueorguieva, Tomohide Tamura
PURPOSE: Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients...
December 2015: Cancer Chemotherapy and Pharmacology
Stephan Herbertz, J Scott Sawyer, Anja J Stauber, Ivelina Gueorguieva, Kyla E Driscoll, Shawn T Estrem, Ann L Cleverly, Durisala Desaiah, Susan C Guba, Karim A Benhadji, Christopher A Slapak, Michael M Lahn
Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway...
2015: Drug Design, Development and Therapy
Namitha Mohandas, Neil D Young, Abdul Jabbar, Pasi K Korhonen, Anson V Koehler, Parisa Amani, Ross S Hall, Paul W Sternberg, Aaron R Jex, Andreas Hofmann, Robin B Gasser
Parasitic worm proteins that belong to the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 (CAP) superfamily are proposed to play key roles in the infection process and the modulation of immune responses in host animals. However, there is limited information on these proteins for most socio-economically important worms. Here, we review the CAP protein superfamily of Haemonchus contortus (barber's pole worm), a highly significant parasitic roundworm (order Strongylida) of small ruminants...
December 2015: Biotechnology Advances
Laura D Hover, Christian D Young, Neil E Bhola, Andrew J Wilson, Dineo Khabele, Charles C Hong, Harold L Moses, Philip Owens
The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue...
November 1, 2015: Cancer Letters
Jan Vrbsky, Tamas Tereh, Sergiy Kyrylenko, Petr Dvorak, Lumir Krejci
The possibility of replacing the originally discovered and widely used DNA reprogramming transcription factors is stimulating enormous effort to identify more effective compounds that would not alter the genetic information. Here, we describe the generation of induced pluripotent stem cells (iPSc) from head-derived primary culture of mouse embryonic cells using small chemical inhibitors of the MEK and TGF-beta pathways without delivery of exogenous transcription factors. These iPSc express standard pluripotency markers and retain their potential to differentiate into cells of all germ layers...
2015: PloS One
A V Boiko, A R Gevorkov, L E Zavalishina, E A Nosova, R N Plavnik
It is now possible to identify several key factors that determine biological characteristics of squamous cell cancer of the head and neck: genes p53, p16, cyclin D1, P13-K/Akt connected with metastasis proteins (proteases, proteins mesenchymal cells, cell adhesion molecules chemokines), angiogenesis factors (VEGF, PDGF, FGF, TGF-alpha and TGF-beta), IL-8; epidermal growth factor receptors. An important role of tumor cells plays microenvironment. Of course the above mentioned is only a small part of the factors that determine the livelihoods and the activity of cancer cells...
2015: Voprosy Onkologii
Kshemendra Senarath-Yapa, Nathaniel Meyer, Shuli Li, Michael T Longaker, Natalina Quarto
No abstract text is available yet for this article.
March 2014: Plastic and Reconstructive Surgery
Changmei Liu, Fangmei Yang
Ovarian cancers present a mild clinical course when diagnosed early but an aggressive pathway when diagnosed in the peri- and postmenopausal periods. However, the predictability of tumor progression is stochastic and is difficult to predict. In the present study, we hypothesized to examine the key pathways that are dysregulated to promote epithelial-mesenchymal transition in serous ovarian carcinoma. Examination of these steps would help to identify ascitic fluid with cells poised for metastasis or otherwise...
September 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Joanna Domagala-Kulawik
Over a hundred years after the first description of this disease, lung cancer represents one of the major challenges in oncology. Radical treatment cannot be introduced in more than 70% of cases and overall survival rate does not exceed 15%. The immunosurveillance of lung cancer may be effective in early oncogenesis but is inhibited in the course of developing a clinically detectable tumor. Very low and heterogonous antigenicity of lung cancer cells leads to passive escape from anti-cancer immune defense. The cytotoxic lymphocytes (CTLs) that play a main role in the anticancer response are actively suppressed in the tumor environment and following regulatory mechanisms inhibit the recognition of tumor antigens by antigen presenting cells...
April 2015: Translational Lung Cancer Research
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