A5005137443- Liver physiology and pathology
- Liver Disease Diagnosis and Treatment
- TGF-β signaling in diseases
- Connective Tissue Growth Factor Research
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Liver Diseases and Immunity
- Liver Disease and Transplantation
- Cell Adhesion Molecules Research
- Pancreatic function and diabetes
- MicroRNA in disease regulation
- Hepatitis B Virus Studies
- Pediatric Hepatobiliary Diseases and Treatments
- Genetic factors in colorectal cancer
- Pancreatitis Pathology and Treatment
- Hepatitis C virus research
- Hepatocellular Carcinoma Treatment and Prognosis
- Organ Transplantation Techniques and Outcomes
- Renal function and acid-base balance
- Fibroblast Growth Factor Research
- Medical Imaging and Pathology Studies
- Wound Healing and Treatments
- Immune Cell Function and Interaction
- Wnt/β-catenin signaling in development and cancer
- Neonatal Respiratory Health Research
- CRISPR and Genetic Engineering
Tokai University
2015-2024
Institute of Medical Sciences
2009-2024
Tokushima University
2012-2021
Juntendo University
2021
Japan Agency for Medical Research and Development
2015-2019
Japan Science and Technology Agency
2013-2016
Matrix Research (United States)
2015-2016
Science Oxford
2016
University of Oxford
2016
Tokyo Institute of Technology
2013
Conditional knockout mice and transgenic expressing recombinases, reporters, inducible transcriptional activators are key for many genetic studies comprise over 90% of mouse models created. generated using labor-intensive methods homologous recombination in embryonic stem cells available only ~25% all genes. Transgenic by random genomic insertion approaches pose problems unreliable expression, thus there is a need targeted-insertion models. Although CRISPR-based strategies were reported to...
Transforming growth factor-pl (TGF-P) is a strong and rapid inducer of several genes coding for extracellular matrix components, such as type I collagen.W e report here that TGF-P stimulates transcription the human (u2(I) collagen gene (COLlA2) promoter by increasing affinity an Spl-containing protein complex its cognate DNA-binding site.Cell transfection experiments mapped TGF-P-responsive element (TbRE) COLlA2 to 131 bp region contains at least two cis-acting elements.Insertion TbRE...
Liver fibrosis is usually progressive, but it can occasionally be reversible if the causative agents are adequately removed or patients treated effectively. However, molecular mechanisms responsible for this reversibility of liver have been poorly understood. To reveal contribution bone marrow (BM)-derived cells to spontaneous regression fibrosis, mice were with repeated carbon tetrachloride injections after hematopoietic reconstitution enhanced green fluorescent protein (EGFP)-expressing BM...
Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB)–phenotype on plastic dishes. This response recapitulates the features of activation in vivo. Transforming growth factor β (TGF–β) plays a prominent role stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF–β signaling involves type I receptor (TβRI)–mediated phosphorylation serine residues within conserved SSXS motif at C–terminus Smad2 and Smad3. The middle linker regions Smad3 also are...
Transforming growth factor-β1 (TGFβ) is a strong activator of extracellular matrix accumulation. TGFβ stimulates the gene coding for human α2(I)-collagen (COL1A2) by inducing binding an Sp1-containing complex to upstream promoter element (TGFβ responsive or TbRE) that contains CAGA box. Here we report box TbRE site Smad3/Smad4 complex, and required TGFβ-induced COL1A2 up-regulation. Recombinant Smad3 Smad4 bind <i>in vitro</i> COL1A2; treatment cultured fibroblasts induces TbRE; transient...
Abstract Cancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since in most solid tumours are subjected severe microenvironmental stresses including low nutrient oxygen availability, such cancer must develop mechanisms overcome these unfavourable conditions by metabolic adaptation. Although liver kinase B1 (LKB1)-adenosine monophosphate-activated (AMPK) signalling plays a pivotal role maintaining energy homeostasis under of stress, LKB1-AMPK aiding...
During chronic liver injury, transforming growth factor β (TGF-β) plays a prominent role in stimulating fibrogenesis by myofibroblast-like cells derived from hepatic stellate (HSCs). On the other hand, Smad 7 was recently shown to antagonize TGF-β-induced activation of signal-transducing Smads (2 and 3). In this study, we investigated regulatory mechanisms TGF-β signals rat HSCs during acute injury myofibroblasts (MFBs) focusing on roles 2 antagonistic 7. HSC-derived increased plasminogen...
It is currently debated whether AP1 or Sp1 the factor that mediates transforming growth beta1 (TGF-beta) stimulation of human alpha2(I) collagen (COL1A2) gene by binding to an upstream promoter element (TbRE). The present study was designed resolve this controversy correlating expression COL1A2, AP1, and in same cell line under different experimental conditions. results strongly indicate required for immediate early response COL1A2 TGF-beta not. inhibitor mithramycin blocked mRNA...
Transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ) exert antagonistic effects on collagen synthesis in human dermal fibroblasts. We have recently shown that Y box-binding protein YB-1 mediates the inhibitory of IFN-γ α2(I) procollagen gene (COL1A2) transcription through response element located between –161 –150. Here we report counter-represses TGF-β-stimulated COL1A2 by interfering with Smad3 bound to upstream sequence around –265 subsequently interrupting Smad3-p300...
<b>Background:</b> Liver cirrhosis, which is caused by the accumulation of extracellular matrix materials, a serious clinical problem that can progress to hepatic failure. Transforming growth factor-β (TGFβ) plays pivotal role in production, but bone morphogenetic protein (BMP)-7, member TGFβ superfamily, antagonise fibrogenic activity TGFβ. <b>Aim:</b> In this study, we examined whether adenovirus-mediated overexpression BMP-7 (Ad-BMP-7) antagonised effect vitro and vivo. <b>Methods...
The equilibrium between the production and degradation of collagen is rigorously controlled by a number growth factors cytokines. Interferon alfa (IFN-alpha) now widely used for treatment chronic hepatitis C, which can improve serum levels fibrotic markers degree hepatic fibrosis, not only in patients who responded to therapy but also those whom it ineffective. These findings may suggest that IFN-alpha possesses direct antifibrotic effects addition its antiviral activity. However, contrast...
Background and Aims Hepatic stellate cells (HSCs), a key player in the progression of liver fibrosis, are activated by various inflammatory stimuli converted to myofibroblast‐like with excessive collagen production. Despite many attempts suppress activation HSCs or inhibit production HSCs, their clinical applications have not been established yet. Recently, deactivation has reported as mechanism underlying reversibility experimental fibrosis. In present study, we sought for factors that...
Abstract Increases in adhesive and invasive commensal bacteria, such as Escherichia coli , subsequent disruption of the epithelial barrier is implicated pathogenesis inflammatory bowel disease (IBD). However, protective systems against are not fully understood. Here, we show that secretion luminal glycoprotein 2 (GP2) from pancreatic acinar cells induced a TNF–dependent manner mice with chemically colitis. Fecal GP2 concentration also increased Crohn’s diease patients. Furthermore,...
Epithelial cells require attachment to a support, such as the extracellular matrix, for survival. During cancer progression and metastasis, cancerous epithelial must overcome their dependence on adhesion signals. Dependence glucose metabolism is hallmark of cells, but nutrient requirements under anchorage-deficient conditions remain uncharacterized. Here, we report that prioritize glutamine-derived tricarboxylic acid cycle energy over glycolysis sustain anchorage-independent Moreover,...
Abstract Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive production of extracellular matrix (ECM) and understood to develop under the influence certain growth factors. Connective tissue factor (CTGF) is a cysteine‐rich mitogenic peptide that implicated in various induced fibroblasts after activation with transforming factor‐β (TGF‐β). To better understand mechanisms persistent fibrosis seen SSc, we previously established animal model skin exogenous...
The equilibrium between the production and degradation of collagen is rigorously controlled by a number growth factors cytokines. Interferon alfa (IFN-α) now widely used for treatment chronic hepatitis C, which can improve serum levels fibrotic markers degree hepatic fibrosis, not only in patients who responded to therapy but also those whom it ineffective. These findings may suggest that IFN-α possesses direct antifibrotic effects addition its antiviral activity. However, contrast IFN-γ,...
Hepatic stellate cells (HSC) are the main producers of type I collagen in fibrotic liver, and transforming growth factor-β (TGF-β) plays critical roles stimulating gene expression mainly at level transcription. We have previously identified an upstream sequence α2(I) (COL1A2) that is essential for its basal TGF-β-stimulated transcription skin fibroblasts HSC. designated this region TGF-β-responsive element (TbRE). Recently Smad3, intracellular mediator TGF-β signal transduction, has been...
Transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) are multifunctional peptides intimately involved in the process of extracellular matrix remodeling. We recently showed that TGF-β stimulates human α2(I) collagen gene by increasing affinity an Sp1-containing transcriptional complex bound to upstream sequence termed TbRE (Inagaki, Y., Truter, S. Ramirez, F.(1994) J. Biol. Chem. 269, 14828-14834). Here, we report TbRE-bound also mediates inhibitory signal TNF-α. Nuclear...
Mesenchymal cells, primarily fibroblasts and myofibroblasts, are the principal matrix-producing cells during pulmonary fibrogenesis. Transforming growth factor (TGF)-β signaling plays an important role in stimulating expression of type I collagen these cells. Bone morphogenetic protein (BMP)-7, a member TGF-β superfamily, has been reported to oppose fibrogenic activity TGF-β1. Here, we have addressed effects BMP-7 on myofibroblasts. We first established cell lines from lungs transgenic mice...