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Search Results: 1 - 10 of 473 matches for " Yoshiki Sawa "
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From bench to bedside, work in cell-based myocardial regeneration therapy  [PDF]
Shigeru Miyagawa, Yoshiki Sawa
Journal of Biomedical Science and Engineering (JBiSE) , 2014, DOI: 10.4236/jbise.2014.72012

In clinical cellular cardiomyoplasty, bone marrow cells and myoblasts are introduced mainly to ischemic cardiomyopathy tissue via several cell delivery systems, such as needle injection or catheter. These clinical studies have demonstrated the safety and feasibility of this technique, but its effectiveness for treating heart failure, especially in the long term, is still under discussion. Neither of these cell types can differentiate into cardiomyocytes; rather, they improve the failing heart mainly by the paracrine effects of some cytokines, such as Hepatocyte growth factor (HGF) and Vascular endothelial growth factor (VEGF). Thus, many researchers have a great interest in stem cells, which exist in bone marrow, circulating blood, atrium, and adipose tissue, and can differentiate into cardiomyocytes. Although several stem cells with the potential to differentiate into various cell types have been reported, few can differentiate into cardiomyocytes. Moreover, beating cells that can demonstrate synchronized contraction with native cardiomyocytes are critical for the complete repair of severe heart failure. Therefore, stem cells with a high differentiation capacity should be explored for the goal of completely repairing severely damaged myocardium. In this review, we summarize the clinical protocols and basic experiments for cellular cardiomyoplasty using bone marrow cells, myoblasts, and other stem cells.

Activated Protein C Has a Protective Effect against Myocardial I/R Injury by Improvement of Endothelial Function and Activation of AKT1
Yoshito Maehata, Shigeru Miyagawa, Yoshiki Sawa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038738
Abstract: Objectives Activated protein C (APC) has a protective efficacy against ischemia-reperfusion (I/R) injury in several organs. The objective of this study was to investigate effect of APC in myocardium with possible mechanism. Methods We used regional and global myocardial I/R injury models of rats. They consisted of I/R injuries (1) by ligation of left coronary artery, or (2) using Langendorff apparatus. Langendorff was used to focus the mechanism of APC excluding coagulation cascade in a working heart. Each experiment had an APC group (n = 10) and a control group with normal saline (n = 10). Injections of these solutions into rats were performed 30 minutes before the planned-I/R injury. Cardiac performance after the procedure was evaluated by echocardiography or indices with Langendorff apparatus. Coronary flow (CF) was measured in the global I/R injury model. Western blotting was performed to detect the change of AKT1 signal in myocardium after global I/R injury. Results LV function improved significantly in the APC group: %EF at 2 weeks after procedure, 70.8%±4.5% vs. 56.5%±0.7%; APC vs. control; p<0.01. Percent LV development pressure (LVDP) also improved in the APC group significantly, 88.8%±45.3% vs. 28.1%±15.4%; APC vs. control; p<0.01. In APC group, %CF improved significantly, 88.5%±15.8% vs. 65.0%±13.4%; APC vs. control; p<0.01. It was enhanced significantly when acetylcholine was administered; % CF: 103.5%±9.9% vs. 87.0%±12.1%; APC vs. control; p<0.05. Western blotting revealed that APC significantly induced activation of phosphorylated AKT1 in myocardium (p<0.05). Conclusions APC has a novel effect to protect myocardium and cardiac performance against I/R injury through improvement of endothelial function and activation of AKT1.
Sustained-Release Delivery of Prostacyclin Analogue Enhances Bone Marrow-Cell Recruitment and Yields Functional Benefits for Acute Myocardial Infarction in Mice
Yukiko Imanishi, Shigeru Miyagawa, Satsuki Fukushima, Kazuhiko Ishimaru, Nagako Sougawa, Atsuhiro Saito, Yoshiki Sakai, Yoshiki Sawa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069302
Abstract: Background A prostacyclin analogue, ONO-1301, is reported to upregulate beneficial proteins, including stromal cell derived factor-1 (SDF-1). We hypothesized that the sustained-release delivery of ONO-1301 would enhance SDF-1 expression in the acute myocardial infarction (MI) heart and induce bone marrow cells (BMCs) to home to the myocardium, leading to improved cardiac function in mice. Methods and Results ONO-1301 significantly upregulated SDF-1 secretion by fibroblasts. BMC migration was greater to ONO-1301-stimulated than unstimulated conditioned medium. This increase was diminished by treating the BMCs with a CXCR4-neutralizing antibody or CXCR4 antagonist (AMD3100). Atelocollagen sheets containing a sustained-release form of ONO-1301 (n = 33) or ONO-1301-free vehicle (n = 48) were implanted on the left ventricular (LV) anterior wall immediately after permanent left-anterior descending artery occlusion in C57BL6/N mice (male, 8-weeks-old). The SDF-1 expression in the infarct border zone was significantly elevated for 1 month in the ONO-1301-treated group. BMC accumulation in the infarcted hearts, detected by in vivo imaging after intravenous injection of labeled BMCs, was enhanced in the ONO-1301-treated hearts. This increase was inhibited by AMD3100. The accumulated BMCs differentiated into capillary structures. The survival rates and cardiac function were significantly improved in the ONO-1301-treated group (fractional area change 23±1%; n = 22) compared to the vehicle group (19±1%; n = 20; P = 0.004). LV anterior wall thinning, expansion of infarction, and fibrosis were lower in the ONO-1301-treated group. Conclusions Sustained-release delivery of ONO-1301 promoted BMC recruitment to the acute MI heart via SDF-1/CXCR4 signaling and restored cardiac performance, suggesting a novel mechanism for ONO-1301-mediated acute-MI heart repair.
Recent Clinical and Experimental Advances in Atrial Fibrillation
Shigeru Miyagawa,Taichi Sakaguchi,Hiroyuki Nishi,Yasushi Yoshikawa,Satsuki Fukushima,Shunsuke Saito,Yoshiki Sawa
ISRN Cardiology , 2011, DOI: 10.5402/2011/958189
Abstract: Atrial fibrillation (AF) is the most common arrhythmia in clinical settings (Fuster et al., 2001), and it is often associated with congestive heart diseases (Issac et al., 2007). Many studies in both laboratory and clinical settings have sought to analyze the mechanisms of AF, develop treatments based on these mechanisms, and examine atrial remodeling in chronic AF. The aim of this paper is to analyze recent findings regarding the atrial remodeling that occurs in AF. In particular, we will describe the electrical and structural changes that involve atrial myocytes and the extracellular matrix. We will also describe the general classification and basic pathophysiology of AF and its surgical treatments. 1. Classification of AF The joint American College of Cardiology/American Heart Association/European Society of Cardiology proposed a classification system for AF to simplify its heterogeneous clinical aspects and clarify its clinical states [1]. Patients are initially classified as having a “first detected episode of AF,” when AF is confirmed by clinicians. If a patient has two or more episodes, the AF is classified as recurrent. Recurrent AF is designated as paroxysmal or persistent. Paroxysmal AF is an episode that generally continues for 7 or fewer days and terminates on its own. Persistent AF usually continues for more than 7 days without self-terminating and requires clinicians to terminate it using pharmacological treatment or electrical cardioversion to restore the sinus rhythm. Permanent AF is a situation in which the sinus rhythm cannot be sustained after cardioversion, and further medical efforts are required to restore it. 2. Pathophysiology of AF 2.1. The Basic Mechanisms of AF Many researchers agree that inflammation [2], neurohormonal disorders [3], cardiovascular diseases such as valvular diseases [4], diabetes, hypertension, congestive heart failure, myocardial infarction [5], and genetic factors [6] are “modulating factors” that can induce AF. Classically, AF mechanisms are described by the concept of atrial ectopic foci [7], which fire spontaneously in the atrium, a single reentry circuit, or multiple reentry circuits [8, 9]. The surgical maze procedure is designed to block the multiple reentry circuits and create an isolated electrical lesion in the atrium [10]. Haissaguerre et al. reported that triggers located in the pulmonary veins initiate most cases of paroxysmal AF [7], while in some cases the trigger, such as a venous remnant in the left atrium (LA) and superior vena cavae, occurs outside the pulmonary vein. This finding supports
Impact of microRNA Expression in Human Atrial Tissue in Patients with Atrial Fibrillation Undergoing Cardiac Surgery
Hiroyuki Nishi, Taichi Sakaguchi, Shigeru Miyagawa, Yasushi Yoshikawa, Satsuki Fukushima, Shunsuke Saito, Takayoshi Ueno, Toru Kuratani, Yoshiki Sawa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073397
Abstract: Background Although microRNA (miRNA) regulates initiation and/or progression of atrial fibrillation (AF) in canine AF models, the underlying mechanism in humans remains unclear. We speculated that certain miRNAs in atrial tissue are related to AF, and evaluated the relationship of miRNA expression in human atrial tissue in cardiac surgery patients. Methods Right atrial tissues from 29 patients undergoing cardiovascular surgery were divided into 3 groups [A: chronic AF or unsuccessful maze, n=6; B: successful maze, n=10; C: sinus rhythm (SR) n=13]. miRNA expression was determined using high density microarrays and with Reverse transcriptase-polymerase chain reaction (RT-PCR). Fibrosis was examined using Masson trichrome staining. Results miRNA microarray analysis showed elevated miRNA-21, miRNA-23b, miRNA-199b, and miRNA-208b in AF as compared to SR groups. RT-PCR showed elevated miRNA-21 (1.9-fold) and miRNA-208b (4.2-fold) in AF as compared to the SR groups. miRNA-21 expression increased from Group C to A (A: 2.1-fold, B: 1.8-fold, C: 1.0-fold). Fibrosis increased from C to A (A: 43.0±12.9%, B: 21.3±6.1%, C: 11.9±3.1%). Percent fibrosis and miRNA-21 expression were correlated (r=0.508, p<0.05). The plasma levels of miRNA-21 in AF patients was significantly decreased as compared to the healthy volunteers (p<0.05). Conclusion The expression of miRNA-21 in human atrial tissue was found to be related to atrial fibrosis and might affect AF occurrence, indicating its usefulness as a biomarker for cardiac surgery management.
CD34+ Cells Represent Highly Functional Endothelial Progenitor Cells in Murine Bone Marrow
Junjie Yang, Masaaki Ii, Naosuke Kamei, Cantas Alev, Sang-Mo Kwon, Atsuhiko Kawamoto, Hiroshi Akimaru, Haruchika Masuda, Yoshiki Sawa, Takayuki Asahara
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020219
Abstract: Background Endothelial progenitor cells (EPCs) were shown to have angiogenic potential contributing to neovascularization. However, a clear definition of mouse EPCs by cell surface markers still remains elusive. We hypothesized that CD34 could be used for identification and isolation of functional EPCs from mouse bone marrow. Methodology/Principal Findings CD34+ cells, c-Kit+/Sca-1+/Lin? (KSL) cells, c-Kit+/Lin? (KL) cells and Sca-1+/Lin? (SL) cells were isolated from mouse bone marrow mononuclear cells (BMMNCs) using fluorescent activated cell sorting. EPC colony forming capacity and differentiation capacity into endothelial lineage were examined in the cells. Although CD34+ cells showed the lowest EPC colony forming activity, CD34+ cells exhibited under endothelial culture conditions a more adherent phenotype compared with the others, demonstrating the highest mRNA expression levels of endothelial markers vWF, VE-cadherin, and Flk-1. Furthermore, a dramatic increase in immediate recruitment of cells to the myocardium following myocardial infarction and systemic cell injection was observed for CD34+ cells comparing with others, which could be explained by the highest mRNA expression levels of key homing-related molecules Integrin β2 and CXCR4 in CD34+ cells. Cell retention and incorporation into the vasculature of the ischemic myocardium was also markedly increased in the CD34+ cell-injected group, giving a possible explanation for significant reduction in fibrosis area, significant increase in neovascularization and the best cardiac functional recovery in this group in comparison with the others. Conclusion These findings suggest that mouse CD34+ cells may represent a functional EPC population in bone marrow, which could benefit the investigation of therapeutic EPC biology.
hHGF Overexpression in Myoblast Sheets Enhances Their Angiogenic Potential in Rat Chronic Heart Failure
Antti Siltanen,Katsukiyo Kitabayashi,P?ivi Lakkisto,Johanna M?kel?,Tommi P?til?,Masamichi Ono,Ilkka Tikkanen,Yoshiki Sawa,Esko Kankuri,Ari Harjula
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019161
Abstract: After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6-HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression.
Cationized gelatin-HVJ envelope with sodium borocaptate improved the BNCT efficacy for liver tumors in vivo
Hitoshi Fujii, Akifumi Matsuyama, Hiroshi Komoda, Masao Sasai, Minoru Suzuki, Tomoyuki Asano, Yuichiro Doki, Mitsunori Kirihata, Koji Ono, Yasuhiko Tabata, Yasufumi Kaneda, Yoshiki Sawa, Chun Man Lee
Radiation Oncology , 2011, DOI: 10.1186/1748-717x-6-8
Abstract: Hemagglutinating Virus of Japan Envelope (HVJ-E) is used as a vehicle for gene delivery because of its high ability to fuse with cells. However, its strong hemagglutination activity makes HVJ-E unsuitable for systemic administration.In this study, we developed a novel vector for 10B (sodium borocaptate: BSH) delivery using HVJ-E and cationized gelatin for treating multiple liver tumors with BNCT without severe adverse events.We developed cationized gelatin conjugate HVJ-E combined with BSH (CG-HVJ-E-BSH), and evaluated its characteristics (toxicity, affinity for tumor cells, accumulation and retention in tumor cells, boron-carrying capacity to multiple liver tumors in vivo, and bio-distribution) and effectiveness in BNCT therapy in a murine model of multiple liver tumors.CG-HVJ-E reduced hemagglutination activity by half and was significantly less toxic in mice than HVJ-E. Higher 10B concentrations in murine osteosarcoma cells (LM8G5) were achieved with CG-HVJ-E-BSH than with BSH. When administered into mice bearing multiple LM8G5 liver tumors, the tumor/normal liver ratios of CG-HVJ-E-BSH were significantly higher than those of BSH for the first 48 hours (p < 0.05). In suppressing the spread of tumor cells in mice, BNCT treatment was as effective with CG-HVJ-E-BSH as with BSH containing a 35-fold higher 10B dose. Furthermore, CG-HVJ-E-BSH significantly increased the survival time of tumor-bearing mice compared to BSH at a comparable dosage of 10B.CG-HVJ-E-BSH is a promising strategy for the BNCT treatment of visceral tumors without severe adverse events to surrounding normal tissues.Boron neutron capture therapy (BNCT) is a cell-selective radiation therapy that uses alpha particles and lithium nuclei produced by the boron neutron capture reaction. These particles cause cell destruction, bouncing out to a maximum distance of 10 μm from the target, a distance that corresponds to the size of a cell. These particles only destroy the cells that take up 10Boron (10B) [1]
Shape and Chirality Transitions in Off-Axis Twist Nematic Elastomer Ribbons
Yoshiki Sawa,Kenji Urayama,Toshikazu Takigawa,Vianney Gimenez-Pinto,Badel L. Mbanga,Fangfu Ye,Jonathan V. Selinger,Robin L. B. Selinger
Physics , 2013, DOI: 10.1103/PhysRevE.88.022502
Abstract: Using both experiments and finite element simulations, we explore the shape evolution of off-axis nematic elastomer ribbons as a function of temperature. The elastomers are prepared by cross-linking the mesogens with planar anchoring of the director at top and bottom surfaces with a 90 degree left-handed twist. Shape evolution depends sensitively on the off-axis director orientation at the sample mid-plane. When the director at midplane is parallel to either the ribbon's long or short axes, ribbons form either helicoids or spirals depending on the aspect ratio and temperature. If the director at midplane is more than 5 degrees off-axis, then they form only spiral ribbons. Samples in all these geometries show a remarkable transition from right- to left-handed chiral shapes on change of temperature. Simulation studies provide insight into the mechanisms driving shape evolution and enable engineering design of these materials for future applications.
Determination of the velocity of an emitter in spaces with affine connections and metrics
Sawa Manoff
Physics , 2004,
Abstract: Doppler effect and Hubble effect in different models of space-time related to the space-time velocity of an observer are considered. The Doppler effect and Doppler shift frequency parameter are connected with the kinematic characteristics of the relative velocity and the relative acceleration of the emitter with respect to the observer (detector). The Hubble effect and Hubble shift frequency parameter are considered in analogous way. It is shown that by the use of the variation of the shift frequency parameter during a time period, considered locally in the proper frame of reference of an observer, one can directly determine the radial (centrifugal, centripetal) relative velocity and acceleration as well as the tangential (Coriolis) relative velocity and acceleration of an astronomical object moving relatively to the observer. All results are obtained on purely kinematic basis without taking into account the dynamic reasons for the considered effect. PACS numbers: 98.80.Jk; 98.62.Py; 04.90.+e; 04.80.Cc
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