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TGF beta AND Small molecules

Shibnath Ghatak, Vincent C Hascall, Roger R Markwald, Carol Feghali-Bostwick, Carol M Artlett, Monika Gooz, Galina S Bogatkevich, Ilia Atanelishvili, Richard M Silver, Jeanette Wood, Victor J Thannickal, Suniti Misra
Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblasts phenotype has prevented the development of targeted therapies for IPF. Our previous study (1) showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44v6 (CD44-variants containing exon-6), which enhances the TGF-beta-1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts...
April 7, 2017: Journal of Biological Chemistry
Michael W Epperly, Byung-Han Rhieu, Darcy Franicola, Tracy Dixon, Shaonan Cao, Xichen Zhang, Donna Shields, Hong Wang, Peter Wipf, Joel S Greenberger
BACKGROUND/AIM: Total-body irradiation and/or administration of chemotherapy drugs in bone marrow transplantation induce cytokines that can suppress engraftment. Fanconi Anemia (FA) patients have a hyperactive responsiveness to the inhibitory cytokine, transforming growth factor-beta (TGF-β). Small molecule radiation mitigator drugs, JP4-039 and MMS350, were evaluated for suppression of irradiation or drug-induced TGF-β. MATERIALS AND METHODS: In vivo induction of TGF-β by total-body ionizing irradiation (TBI), L-phenylalanine mustard (L-PAM), busulfan or fludarabine, was quantified...
March 2017: In Vivo
Yuan Cao, Rahul Agarwal, Francesco Dituri, Luigi Lupo, Paolo Trerotoli, Serena Mancarella, Peter Winter, Gianluigi Giannelli
Transforming growth factor-beta (TGF-β) signaling has gained extensive interest in hepatocellular carcinoma (HCC). The small molecule kinase inhibitor galunisertib, targeting the TGF-β receptor I (TGF-βRI), blocks HCC progression in preclinical models and shows promising effects in ongoing clinical trials. As the drug is not similarly effective in all patients, this study was aimed at identifying new companion diagnostics biomarkers for patient stratification. Next-generation sequencing-based massive analysis of cDNA ends was used to investigate the transcriptome of an invasive HCC cell line responses to TGF-β1 and galunisertib...
February 23, 2017: Cell Death & Disease
David J Duffy, Aleksandar Krstic, Melinda Halasz, Thomas Schwarzl, Anja Konietzny, Kristiina Iljin, Desmond G Higgins, Walter Kolch
BACKGROUND: Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance...
February 10, 2017: Genome Medicine
Hiroshi Yokouchi, Hiroshi Nishihara, Toshiyuki Harada, Takashi Ishida, Shigeo Yamazaki, Hajime Kikuchi, Satoshi Oizumi, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Aya Goto, Hiroyuki Suzuki, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura, Mitsuru Munakata
The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC)...
December 31, 2016: Oncotarget
Chaoming Zhou, Fang Liu, Phillip H Gallo, Mark E Baratz, Sandeep Kathju, Latha Satish
BACKGROUND: Dupuytren's disease (DD) is a complex fibro-proliferative disorder of the hand that is often progressive and eventually can cause contractures of the affected fingers. Transforming growth factor beta (TGF-β1) has been implicated as a key stimulator of myofibroblast activity and fascial contraction in DD. Pirfenidone (PFD) is an active small molecule shown to inhibit TGF-β1-mediated action in other fibrotic disorders. This study investigates the efficacy of PFD in vitro in inhibiting TGF-β1-mediated cellular functions leading to Dupuytren's fibrosis...
November 11, 2016: BMC Musculoskeletal Disorders
Huiyun Xu, Dandan Ning, Dezhi Zhao, Yunhe Chen, Dongdong Zhao, Sumin Gu, Jean Xin Jiang, Peng Shang
Osteocytes, the most abundant cells in bone, are highly responsive to external environmental changes. We tested how Cx43 hemichannels which mediate the exchange of small molecules between cells and extracellular environment impact genome wide gene expression under conditions of abnormal gravity and magnetic field. To this end, we subjected osteocytic MLO-Y4 cells to a high magneto-gravitational environment and used microarray to examine global gene expression and a specific blocking antibody was used to assess the role of Cx43 hemichannels...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
Maria D Castellone, Mikko O Laukkanen
Activation of resting fibroblasts to myofibroblasts characterizes several physiological and pathological conditions, from wound healing to aggressive metastatic cancers. In tissue damage, including wound healing, fibroblasts are activated in response to injury for a limited period of time to stimulate the healing process. Similar biological mechanisms are maintained in pathological conditions, e.g., scleroderma and cancer, where myofibroblasts persist in producing cytokines and growth factors to drive the development of fibrosis and the progression of disease...
January 1, 2017: Frontiers in Bioscience (Scholar Edition)
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
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