Matsuzaki K.,Kansai Medical University
Cytokine and Growth Factor Reviews | Year: 2013
Better understanding of TGF-β signaling has deepened our appreciation of normal epithelial cell homeostasis and its dysfunction in such human disorders as cancer and fibrosis. Smad proteins, which convey signals from TGF-β receptors to the nucleus, possess intermediate linker regions connecting Mad homology domains. Membrane-bound, cytoplasmic, and nuclear protein kinases differentially phosphorylate Smad2 and Smad3 to create C-tail (C), the linker (L), or dually (L/C) phosphorylated (p, phospho-) isoforms. According to domain-specific phosphorylation, distinct transcriptional responses, and selective metabolism, Smad phospho-isoform pathways can be grouped into 4 types: cytostatic pSmad3C signaling, mitogenic pSmad3L (Ser-213) signaling, invasive/fibrogenic pSmad2L (Ser-245/250/255)/C or pSmad3L (Ser-204)/C signaling, and mitogenic/migratory pSmad2/3L (Thr-220/179)/C signaling. We outline how responses to TGF-β change through the multiple Smad phospho-isoforms as normal epithelial cells mature from stem cells through progenitors to differentiated cells, and further reflect upon how constitutive Ras-activating mutants favor the Smad phospho-isoform pathway promoting tumor progression. Finally, clinical analyses of reversible Smad phospho-isoform signaling during human carcinogenesis could assess effectiveness of interventions aimed at reducing human cancer risk. Spatiotemporally separate, functionally different Smad phospho-isoforms have been identified in specific cells and tissues, answering long-standing questions about context-dependent TGF-β signaling. © 2013 Elsevier Ltd.
Nomura S.,Kansai Medical University
Journal of Atherosclerosis and Thrombosis | Year: 2016
Microparticles (MPs) are small membrane vesicles that are released from many different cell types by exocytotic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may be involved in both physiological processes and clinical treatments because they express phospholipids, which function as procoagulants. Elevated levels of platelet-derived MPs, endothelial cell-derived MPs, and monocyte-derived MPs are observed in almost all thrombotic diseases occurring in venous and arterial beds. Several studies have shown that the quantity, cellular origin, and composition of circulating MPs depend on the type of disease, the disease state, and medical treatment. Although MPs were initially thought to be small particles with only procoagulant activity, they are now known to have many different functions. An increasing number of studies have identified new implications of elevated MPs in clinical disorders. On the basis of evidence available till date, the present review suggests that MPs may be a useful biomarker in identifying atherothrombosis. © 2016, Japan Atherosclerosis Society. All rights reserved.
Matsuzaki K.,Kansai Medical University
Cell and Tissue Research | Year: 2012
Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage, hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing mesenchymal cells. Concomitantly, perturbation of transforming growth factor (TGF)-β signaling by pro-inflammatory cytokines in the epithelial cells of the liver (hepatocytes) promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both (L/C) regions. After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory cytokine-mediated mitogenic pSmad3L pathway; TGF-β and proinflammatory cytokines synergistically enhance collagen synthesis by activated hepatic stellate cells via pSmad2L/C and pSmad3L/C pathways. During chronic liver disease progression, pre-neoplastic hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic (mitogenic) pSmad3L and fibrogenic pSmad2L/C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention of fibro-carcinogenesis. © The Author(s) 2011.
Matsuzaki K.,Kansai Medical University
Carcinogenesis | Year: 2011
Transforming growth factor (TGF)-β antagonizes mitogenic Ras signaling during epithelial regeneration, but TGF-β and Ras act synergistically in driving tumor progression. Insights into these apparently contradictory effects have come from recent detailed analyses of the TGF-β signaling process. Here, we summarize the different modes of TGF-β/Ras signaling in normal epithelium and neoplasms and show how perturbation of TGF-β signaling by Ras may contribute to a shift from tumor-suppressive to protumorigenic TGF-β activity during tumor progression. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β Type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. In epithelial homeostasis, TGF-β-mediated pSmad3C signaling opposes proliferative responses induced by mitogenic signals. During carcinogenesis, activation of cytoplasmic Ras-associated kinases including mitogen-activated protein kinase confers a selective advantage on benign tumors by shifting Smad3 signaling from a tumor-suppressive pSmad3C to an oncogenic pSmad3L pathway, leading to carcinoma in situ. Finally, at the edges of advanced carcinomas invading adjacent tissues, nuclear Ras-associated kinases such as cyclin-dependent kinases, together with cytoplasmic kinases, alter TGF-β signals to more invasive and proliferative pSmad2L/C and pSmad3L/C signaling. Taken together, TGF-β signaling specificity arises from spatiotemporal dynamics of Smad phosphoisoforms. Based on these findings, we have reason to hope that pharmacologic inhibition of linker phosphorylation might suppress progression to human advanced carcinomas by switching from protumorigenic to tumor-suppressive TGF-β signaling. © The Author 2011. Published by Oxford University Press.
Otani H.,Kansai Medical University
Antioxidants and Redox Signaling | Year: 2011
Metabolic syndrome (MetS) is characterized by accumulation of visceral fat associated with the clustering of metabolic and pathophysiological cardiovascular risk factors: impaired glucose tolerance, dyslipidemia, and hypertension. Although the definition of MetS is different among countries, visceral obesity is an indispensable component of MetS. A growing body of evidence suggests that increased oxidative stress to adipocytes is central to the pathogenesis of cardiovascular disease in MetS. Increased oxidative stress to adipocytes causes dysregulated expression of inflammation-related adipocytokines in MetS, which contributes to obesity-associated vasculopathy and cardiovascular risk primarily through endothelial dysfunction. The purpose of present review is to unravel the mechanistic link between oxidative stress and cardiovascular risk in MetS, focusing on insulin resistance, hypertension, and atherosclerosis. Then, therapeutic opportunities translated from the bench to bedside will be provided to develop novel strategies to cardiovascular risk factors in MetS. © 2011 Mary Ann Liebert, Inc.
Asai T.,Kansai Medical University
British Journal of Anaesthesia | Year: 2010
In patients with unstable necks and at risk of pulmonary aspiration, awake fibreoptic intubation is often appropriate. However, stabilization of the neck can make fibreoptic intubation more difficult. I report the use of awake nasal intubation using the Pentax-Aiway Scope (AWS) in three patients with restricted neck movement, in whom awake fibreoptic intubation had failed. Case 1: a 59-yr-old man, at risk of aspiration, required an emergency cervical laminectomy. Awake fibreoptic intubation was attempted while a Halo vest was being applied, but it was impossible to see the glottis, mainly due to pharyngeal and laryngeal oedema. The Pentax-AWS was easily inserted orally, and nasotracheal intubation was achieved within 20 s. Case 2: an 85-yr-old woman with neck injury required emergency surgical stabilization. A retropharyngeal haematoma prevented a fibreoptic bronchoscope from being advanced beyond the epiglottis. Nasotracheal intubation using the Pentax-AWS (with the aid of a gum elastic bougie) was achieved within 1 min. Case 3: a 22-yr-old man, with partial spinal cord damage, was undergoing cervical laminoplasty. He was at risk of aspiration and had an oedematous larynx. Although it was possible to insert a fibreoptic bronchoscope into the trachea while the neck was stabilized with a Halo vest, it was impossible to advance a tube over the fibrescope. Awake nasotracheal intubation using the Pentax-AWS was achieved within 15 s. The Pentax-AWS may be useful for nasotracheal intubation in awake patients with restricted necks.
Katakai T.,Kansai Medical University
Frontiers in Immunology | Year: 2012
The architecture of secondary lymphoid organs (SLOs) is supported by several non-hematopoietic stromal cells. Currently it is established that two distinct stromal subsets, follicular dendritic cells and fibroblastic reticular cells, play crucial roles in the formation of tissue compartments within SLOs, i.e., the follicle andT zone, respectively. Although stromal cells in the anlagen are essential for SLO development, the relationship between these primordial cells and the subsets in adulthood remains poorly understood. In addition, the roles of stromal cells in the entry of antigens into the compartments through some tissue structures peculiar to SLOs remain unclear. A recently identified stromal subset, marginal reticular cells (MRCs), covers the margin of SLOs that are primarily located in the outer edge of follicles and construct a unique reticulum. MRCs are closely associated with specialized endothelial or epithelial structures for antigen transport. The similarities in marker expression profiles and successive localization during development suggest that MRCs directly descend from organizer stromal cells in the anlagen. Therefore, MRCs are thought to be a crucial stromal component for the organization and function of SLOs. © 2012 Katakai.
Kansai Medical University and Amino Up Chemical Co. | Date: 2013-02-19
The invention relates to a method of intracellularly controlling amounts of gene products, which can increase an amount of gene product intracellularly, comprising a step of introducing into the cell a substance having a sequence complementary to the base sequence of mRNA corresponding to the gene product, its precursor or another substance which can have equivalent action in the cell.
Kansai Medical University and Terumo Kabushiki Kaisha | Date: 2015-03-19
A long-lasting, controlled-release local anesthetic liposome preparation is produced by: providing a liposome composition, which is obtained by mixing, in a water-miscible organic solvent, a first aqueous phase solution with a water-miscible organic solution, in which a phospholipid and cholesterol are contained at a defined total concentration, at a defined ratio by volume thereby obtaining an emulsion wherein a total concentration of the phospholipid and cholesterol in the mixed phase is at 15 w/v % to 50 w/v %, followed by subjecting the emulsion to external solution exchange with a second aqueous phase solution to obtain a liposome composition wherein an ion gradient is formed between an internal-region aqueous phase of a liposome membrane made of the first aqueous phase solution and an external-region aqueous phase of the liposome membrane made of the second aqueous phase solution; and encapsulating a local anesthetic in the internal-region aqueous phase according to a remote loading method.
Amino Up Chemical Co. and Kansai Medical University | Date: 2014-12-12
The invention relates to sense oligonucleotide having a sequence complementary to a single-stranded RNA (antisense transcript) having a sequence complementary to mRNA of iNOS gene in order to control expression of iNOS (inducible nitric oxide synthase). The sense oligonucleotide of the present invention can control expression of iNOS and is useful for biological defense and treatment and prevention of diseases related to excessive production of NO, such as cancerogenesis, inflammatory disease, endotoxin shock by bacterial infection and the like.