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TGF beta inhibitors

Long-Xing Xue, Zhong-Hang Xu, Jiao-Qi Wang, Cui Yang, Hong-Yu Liu, Wen-Zhao Liang, Qiu-Ye Ji, Jin-Ting He, Yan-Kun Shao, Jing Mang, Zhong-Xin Xu
Activin A (Act A), a member of the transforming growth factor-beta (TGF-β), reduces neuronal apoptosis during cerebral ischemia through Act A/Smads signaling pathway. However, little is known about the effect of Act A/Smads pathway on autophagy in neurons. Here, we found that oxygen-glucose deprivation (OGD)-induced autophagy was suppressed by exogenous Act A in a concentration-dependent manner and enhanced by Act A/Smads pathway inhibitor (ActRIIA-Ab) in neuronal PC12 cells. These results indicate that Act A/Smads pathway negatively regulates autophagy in OGD-treated PC12 cells...
October 18, 2016: Biochemical and Biophysical Research Communications
Jun Li, Jie Ao, Kai Li, Jie Zhang, Yanyan Li, Le Zhang, Yuyan Wei, Di Gong, Junping Gao, Weiwei Tan, Lugang Huang, Lunxu Liu, Ping Lin, Yuquan Wei
Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells...
October 20, 2016: Cell Death & Disease
Piero Pingitore, Paola Dongiovanni, Benedetta Maria Motta, Marica Meroni, Saverio Massimo Lepore, Rosellina Margherita Mancina, Serena Pelusi, Cristina Russo, Andrea Caddeo, Giorgio Rossi, Tiziana Montalcini, Arturo Pujia, Olov Wiklund, Luca Valenti, Stefano Romeo
Liver fibrosis is a pathological scarring response to chronic hepatocellular injury and hepatic stellate cells (HSCs) are key players in this process. PNPLA3 I148M is a common variant robustly associated with liver fibrosis but the mechanisms underlying this association are unknown.We aimed to examine a) the effect of fibrogenic and proliferative stimuli on PNPLA3 levels in HSCs and b) the role of wild type and mutant PNPLA3 overexpression on markers of HSC activation and fibrosis.Here we show that PNPLA3 is upregulated by the fibrogenic cytokine transforming growth factor-beta (TGF-β), but not by platelet-derived growth factor (PDGF), and is involved in the TGF-β-induced reduction in lipid droplets in primary human HSCs...
October 13, 2016: Human Molecular Genetics
Po-Shuen Lin, Hsiao-Hua Chang, Chien-Yang Yeh, Mei-Chi Chang, Chiu-Po Chan, Han-Yueh Kuo, Hsin-Cheng Liu, Wan-Chuen Liao, Po-Yuan Jeng, Sin-Yuet Yeung, Jiiang-Huei Jeng
BACKGROUND/PURPOSE: In order to clarify the role of transforming growth factor beta 1 (TGF-β1) in pulp repair/regeneration responses, we investigated the differential signaling pathways responsible for the effects of TGF-β1 on collagen turnover, matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of metalloproteinase-1 (TIMP-1) production in human dental pulp cells. METHODS: Pulp cells were exposed to TGF-β1 with/without pretreatment and coincubation by 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenyl mercapto)butadiene (U0126; a mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] inhibitor) and 4-(5-benzol[1,3]dioxol-5-yl-4-pyrldin-2-yl-1H- imidazol-2-yl)-benzamide hydrate (SB431542; an activin receptor-like kinase-5/Smad signaling inhibitor)...
October 6, 2016: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Daniele Pereira Jardim, Paula Cristina Eiras Poço, Alexandre Holthausen Campos
Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of men and women of all ages and racial groups. Loss of mesangial cells (MC) represents an early common feature in the pathogenesis of CKD. Transforming growth factor-β1 (TGF-β1) is a key inducer of kidney damage and triggers several pathological changes in renal cells, notably MC apoptosis. However, the mechanism of MC apoptosis induced by TGF-β1 remains elusive. Here we demonstrate for the first time a novel regulatory pathway in which the disheveled-binding antagonist of beta-catenin 1 (Dact1) gene is upregulated by TGF-β1, inducing MC apoptosis...
October 7, 2016: Journal of Cellular Physiology
Chao Zhu, Changchun Cao, Xiaofei Wang, Jie Yuan, Lai Jin, Shengnan Li
Urocortins (UCNs) and transforming growth factor-beta (TGF-beta) have been demonstrated to participate in various cardiovascular diseases, many of which involve vascular smooth muscle cells (VSMCs) proliferation. Cytosolic phospholipase A2 (cPLA2)-mediated arachidonic acid (AA) release is an important cause of VSMCs proliferation. The work was to investigate the regulation of VSMCs proliferation by UCN/TGF-beta and whether cPLA2 was a link between their signaling pathways. VSMCs proliferation was measured by colorimetric assay and immunofluorescence microscopy...
October 1, 2016: International Journal of Biochemistry & Cell Biology
John A D'Elia, George Bayliss, Ray E Gleason, Larry A Weinrauch
Since angiotensin increases the expression of plasminogen activator inhibitor (PAI), mechanisms associated with an actively functioning renin-angiotensin-aldosterone system can be expected to be associated with increased PAI-1 expression. These mechanisms are present not only in common conditions resulting in glomerulosclerosis associated with aging, diabetes or genetic mutations, but also in autoimmune disease (like scleroderma and lupus), radiation injury, cyclosporine toxicity, allograft nephropathy and ureteral obstruction...
October 2016: Clinical Kidney Journal
Rui-Fang Li, Shan-Shan Cao, Wei-Jin Fang, Ying Song, Xue-Ting Luo, Hong-Yun Wang, Jian-Gang Wang
Recent studies indicate that histone deacetylases (HDACs) activity is associated with the development and progression of cardiac hypertrophy. In this study, we investigated the effects of a HDACs inhibitor, valproic acid sodium (VPA), on cardiac remodeling and the differential expression of HDACs in left ventricles (LVs) of renovascular hypertensive rats. Renovascular hypertension was induced in rats by the two-kidney two-clip (2K2C) method. Cardiac remodeling, heart function and the differential expression of HDACs were examined at different weeks after 2K2C operation...
September 27, 2016: Pharmacology
Katja Walpurgis, Andreas Thomas, Matthias Vogel, Christian Reichel, Hans Geyer, Wilhelm Schänzer, Mario Thevis
Sotatercept (formerly ACE-011) is a glycosylated, dimeric fusion protein composed of the extracellular domain of the human activin receptor type IIA (ActRIIA) and the Fc region of human IgG1. The protein-based drug candidate acts as a ligand trap which competitively binds to activin A and other members of the transforming growth factor beta superfamily, thus blocking signalling through ActRIIA. Since the inhibition of activin A was found to significantly increase bone formation and quality, Sotatercept was originally developed for the treatment of diseases involving bone loss...
September 20, 2016: Drug Testing and Analysis
S Khanizadeh, M Ravanshad, S Y Hosseini, P Davoodian, A N Zadeh, F Sabahi, J Sarvari, Z Khanlari, M Hasani-Azad
The various roles of hepatitis C virus (HCV) NS3 protein in viral pathogenesis are emphasized, especially in the progression of fibrosis and tumors. The levels of miR-122 have been widely accepted as a critical factor in viral pathogenesis and disease progression. However, the possible correlation between miR-122 levels and fibrosis state has been less investigated. Therefore, in this study, plasmids expressing protease competent and protease mutated non-structural proteins 3 (NS3) were transfected into LX-2 cell line...
2016: Acta Virologica
Xiaofan Guo, Hao Xue, Qianqian Shao, Jian Wang, Xing Guo, Xi Chen, Jinsen Zhang, Shugang Xu, Tong Li, Ping Zhang, Xiao Gao, Wei Qiu, Qinglin Liu, Gang Li
Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of a correlation between the density of M2-polarized TAMs and hypoxic areas suggests that hypoxia plays a supportive role during TAM recruitment and induction. Here, we investigated the effects of hypoxia on human macrophage recruitment and M2 polarization...
September 2, 2016: Oncotarget
X H Chang, A Zhu, F F Liu, L Y Zou, L Su, S K Liu, H H Zhou, Y Y Sun, A J Han, Y F Sun, S Li, J Li, Y B Sun
Nano nickel oxide (NiO), widely used in industry, has recently been discovered to have pulmonary toxicity. However, no subchronic exposure studies about nano NiO-induced pulmonary fibrosis have been reported. The objective of this study was to investigate pulmonary fibrosis induced by nano NiO and its potential mechanism in rats. Male Wistar rats (n = 40, 200-240 g) were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg/kg), and micro NiO group (0.024 mg/kg). All rats were killed to collect lung tissue after intratracheal instillation of NiO particles twice a week for 6 weeks...
September 5, 2016: Human & Experimental Toxicology
Venkatachalam Sukumaran, Se Chang Park, Sib Sankar Giri
This study evaluated the effects of ginger (Zingiber officinale) as a feeding supplement on the growth, skin mucus immune parameters, and cytokine-related gene expression of Labeo rohita, and its susceptibility to Aeromonas hydrophila infection. Diets containing six different concentrations of dried ginger (0% [basal diet], 0.2% [G2], 0.4% [G4], 0.6% [G6], 0.8% [G8], and 1.0% [G10] were fed to fish (average weight: 12.3 g) for 60 days. Growth parameters were examined at 30 and 60 days post-feeding. Skin mucosal immune responses and gene expression were examined 60 days post-feeding...
October 2016: Fish & Shellfish Immunology
Jennifer M Hahn, Kevin L McFarland, Kelly A Combs, Dorothy M Supp
BACKGROUND: Keloids are an extreme form of abnormal scarring that result from a pathological fibroproliferative wound healing process. The molecular mechanisms driving keloid pathology remain incompletely understood, hindering development of targeted, effective therapies. Recent studies in our laboratory demonstrated that keloid keratinocytes exhibit adhesion abnormalities and display a transcriptional signature reminiscent of cells undergoing epithelial-mesenchymal transition (EMT), suggesting a role for EMT in keloid pathology...
2016: Burns and trauma
Anjali Shukla, Yihan Yang, Sara Madanikia, Yan Ho, Mangmang Li, Vanesa Sanchez, Christophe Cataisson, Jing Huang, Stuart H Yuspa
CLIC4 (Chloride intracellular channel 4) belongs to a family of putative intracellular chloride channel proteins expressed ubiquitously in multiple tissues. CLIC4 is predominantly soluble and traffics between the cytoplasm and nucleus and participates in cell cycle control and differentiation. Transforming growth factor beta (TGF-β) elevates CLIC4, which enhances TGF-β signaling through CLIC4 mediated stabilization of phospho-Smad2/3. CLIC4 is essential for TGF-β induced conversion of fibroblasts to myofibroblasts and expression of matrix proteins, signaling via the p38MAPK pathway...
2016: PloS One
Amaya García de Vinuesa, Matteo Bocci, Kristian Pietras, Peter Ten Dijke
Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs)...
August 15, 2016: Biochemical Society Transactions
Mohamed G Elsakkar, Maha M Eissa, Wafaa A Hewedy, Rasha M Nassra, Soha F Elatrebi
AIMS: This study explores the potential antifibrotic effect of sodium valproate (SV), an inhibitor of class I histone deacetylase (HDAC) enzymes, and/or praziquantel (PZQ) on Schistosoma mansoni (S. mansoni)-induced liver fibrosis in mice. MAIN METHODS: Male Swiss albino mice were divided into nine groups: group I- normal control (NC); group II- uninfected gum mucilage (GM) treated; group III- uninfected PZQ- treated; group IV- uninfected SV-treated; group V- control S...
October 1, 2016: Life Sciences
Lucia Centurione, Francesca B Aiello
Double strand breaks (DSBs) induced by radiotherapy are highly cytotoxic lesions, leading to chromosomal aberrations and cell death. Ataxia-telangiectasia-mutated (ATM)-dependent DNA-damage response, non-homologous end joining, and homologous recombination pathways coordinately contribute to repairing DSBs in higher eukaryotes. It is known that the expression of DSB repair genes is increased in tumors, which is one of the main reasons for radioresistance. The inhibition of DSB repair pathways may be useful to increase tumor cell radiosensitivity and may target stem cell-like cancer cells, known to be the most radioresistant tumor components...
2016: Frontiers in Oncology
Gabriel Gallo-Oller, Arabel Vollmann-Zwerenz, Bárbara Meléndez, Juan A Rey, Peter Hau, Javier Dotor, Javier S Castresana
Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 60-70% of all gliomas. Current median patient survival time is 14-16 months after diagnosis. Numerous efforts in therapy have not significantly altered the nearly uniform lethality of this malignancy. The Transforming Growth Factor beta (TGF-β) signaling pathway plays a key role in GBM and is implicated in proliferation, invasion and therapy resistance. Several inhibitors of the TGF-β pathway have entered clinical trials or are under development...
October 10, 2016: Cancer Letters
A R Garcia-Rendueles, J S Rodrigues, M E R Garcia-Rendueles, M Suarez-Fariña, S Perez-Romero, F Barreiro, I Bernabeu, J Rodriguez-Garcia, L Fugazzola, T Sakai, F Liu, J Cameselle-Teijeiro, S B Bravo, C V Alvarez
Papillary thyroid carcinoma (PTC), the most frequent thyroid cancer, is characterized by low proliferation but no apoptosis, presenting frequent lymph-node metastasis. Papillary thyroid carcinoma overexpress transforming growth factor-beta (TGF-β). In human cells, TGF-β has two opposing actions: antitumoral through pro-apoptotic and cytostatic activities, and pro-tumoral promoting growth and metastasis. The switch converting TGF-β from a tumor-suppressor to tumor-promoter has not been identified. In the current study, we have quantified a parallel upregulation of TGF-β and nuclear p27, a CDK2 inhibitor, in samples from PTC...
July 25, 2016: Oncogene
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