Juntendo Medical Journal
Online ISSN : 2188-2134
Print ISSN : 0022-6769
ISSN-L : 0022-6769
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Volume 54, Issue 4
Displaying 1-24 of 24 articles from this issue
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Contents
  • [title in Japanese]
    AKIMICHI OHSAKA
    2008 Volume 54 Issue 4 Pages 432
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.432
    JOURNAL FREE ACCESS
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  • Elucidating the mechanisms system of angiogenesis in regenerative medicine
    KOICHI HATTORI, MAKIKO OHKI
    2008 Volume 54 Issue 4 Pages 433-440
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.433
    JOURNAL FREE ACCESS
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    Vascular endothelial growth factor (VEGF) regulates vasculogenesis and angiogenesis by signaling mediated through two tyrosine kinase receptors, VEGF receptor-1 (VEGFR1) and VEGFR2. While VEGF /VEGFR2 signaling contributes to the regulation of endothelial cell lineage differentiation and proliferation, VEGF /VEGFR1 signaling in hematopoietic lineage cells can promote the mobilization of hematopoietic stem cells and induce bone marrow regeneration. These data suggest that there is a significant interaction between post-natal angiogenesis and hematopoiesis. We reported that the activation of VEGF/VEGFR and chemokine stromal cell-derived factor-1 (CXCL12)/CXCR4 signal pathways induce the mobilization of bone marrow-derived hematopoietic lineage cells. It was shown that these pathways regulate bone marrow cell differentiation and proliferation by activating matrix metalloproteinases (MMP) causing MMP-mediated hematopoietic factor, Kit ligand processing. Moreover, we have also reported that CXCL12 and VEGF are released from bone marrow-derived inflammatory cells like neutrophils or platelets. It was demonstrated that CXCR4 positive and VEGFR1 positive lineage cells, also called hemangiocytes, can produce Angiopoetin-2 which can recruit hematopoietic stem cells from bone marrow and function as molecular HUB by augmenting revascularization in the “neovascular niche”. Recently, we showed that activation of the fibrinolytic system resulted in the constitutive activation of MMPs causing Kit ligand release, which promoted bone marrow regeneration after myelosuppression. These data imply that the fibrinolytic system might also play a role in regulating neoangiogenesis during tissue regeneration. Here, we will present recent studies from our group and several novel concepts in our current understanding of the regulation of angiogenesis.
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  • Regenerative Medicine for Cardiovascular Disease
    YOUICHI KATOH
    2008 Volume 54 Issue 4 Pages 441-446
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.441
    JOURNAL FREE ACCESS
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    Since the existence of adult cardiac stem cells in the human heart and cardiomyocyte-differentiation potential of mesenchymal stem cells were reported, various clinical trials on regeneration and neovascularization of the cardiovascular system have been performed. Although direct injection of skeletal myoblasts into myocardium improved the left ventricular ejection fraction (LVEF) in patients with myocardial infarction, some of these patients demonstrated fatal ventricular arrhythmias. Intracoronary administration of bone marrow mononuclear cells or endothelial progenitor cells (EPC) also tended to improve LVEF in patients with myocardial infarction, most of the outcomes indicated that improvements in LVEF were less than 5%, and the differences could not reach significance. Several reports suggested that the number of cells, timing of cell administration, and methods of cell preparation were critically important in order to achieve good results. Future application of cardiomyocytes obtained from embryonic stem (ES) cells or inducible pluripotent stem (iPS) cells are awaited.
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  • Current state of regenerative medicine following brain infarction
    TAKAO URABE
    2008 Volume 54 Issue 4 Pages 447-455
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.447
    JOURNAL FREE ACCESS
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    Regenerative medicine for cerebral ischemia includes the activation of proliferation, migration, and differentiation of endogenous neuronal stem cell, as well as transplantation of stem cell. Neurogenesis is well described in the subventricular zone (SVZ) and subgranular cell layer (SGL) in the dentate gyrus of the hippocampus in adult mammals. Recent studies have shown the existence of neuronal stem cells in the SVZ and in the dentate gyrus of the hippocampus throughout life. To date, it has been shown that ischemic stress activates regeneration of newborn neurons in the SGL and SVZ in several animal stroke models. A previous study showed that transient forebrain ischemia in rats was followed by replacement of hippocampal CA1 pyramidal neurons by recruitment of endogenous neural progenitor cells, and its recruitment is increased by neurotrophic factors. In a recent study, we visualized the proliferation, migration and differentiation of neuronal progenitor cells in the dentate gyrus induced by ischemic stress using improved retroviral vector. Furthermore, we showed that ischemic stress promoted the proliferation and normal development of neurons at this site. Considerable basic research on regenerative treatment using neuronal stem cell transplantation has been reported. Part of the regenerative treatment by stem cell transplantation has progressed to clinical trials. Recently, it has been reported that transplantation of bone marrow stem cells into areas of cerebral infarction merits further attention. Recent studies have shown that the hematopoietic cytokine, granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect through the signaling pathway for anti-apoptotic cascade. We tested the hypothesis that G-CSF has neuroprotective effects in cerebral ischemia and that such an effect is mediated through the anti-apoptotic pathway by activating the JAK/STAT pathway, in addition to the reduction of iNOS activity. Our findings indicate that G-CSF exerts a neuroprotective effect through direct activation of the anti-apoptotic pathway, and suggested that G-CSF is important for expansion of the therapeutic time window in patients with cerebral ischemia. Some research groups reported that various cytokines appear to play roles in neurogenesis and neuronal regeneration. Another recent study showed that administration of G-CSF and stem cell factor in the subacute phase after focal cerebral ischemia effectively promotes cytokine-induced generation of neuronal cells from bone marrow-derived cells. However, there are many problems to be resolved before clinical application as a real regenerative treatment using stem cells in ischemic stroke.
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  • Beta-cell regeneration therapy as a cure for diabetes mellitus
    HIROTAKA WATADA
    2008 Volume 54 Issue 4 Pages 456-463
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.456
    JOURNAL FREE ACCESS
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    Diabetes Mellitus is a disease caused by absolute or relative reduction of insulin action. The resultant hyperglycemia plays a central role in the pathogenesis of various diabetic complications. Thus, for a true cure for diabetes, it is essential to establish a method of augmenting the pancreatic beta cell function. Regeneration therapy for pancreatic beta cells is one of the efficient strategies. In this review, we summarized progress in research on beta cell regeneration therapy mainly focusing on methods using embryogenic stem cells and those using tissue stem cells. Understanding of the whole process of beta cell differentiation seems to be a key to establish the method to generate pancreatic beta cells from embryogenic stems cells. However, the progression of research in this area is expected to provide a method of enhancing differentiation from tissue stem cells to pancreatic beta cells.
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  • Recent advances in regenerative medicine in the dermatological field
    SHIGAKU IKEDA
    2008 Volume 54 Issue 4 Pages 464-467
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.464
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    This report summarizes recent advances in regenerative medicine in the dermatological field. The possibility of utilizing iPS cells to establish a novel therapeutic option for dermatological diseases is also discussed. In addition to the knowledge and technology required to construct a cultured skin equivalent using cultured epidermal keratinocytes, dermal fibroblasts and melanocytes, iPS cell technology is expected to provide considerable information promoting our understanding of various pathomechanisms as well as establishing “ordermade” treatments for skin diseases.
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  • Clinical study of psychiatric inpatients in Juntendo Tokyo Koto Geriatric Medical Center
    RYO KUMAGAI, RYO HANZAWA, YUSHI UTSUMI, HIROYUKI KOMATSU, MOTOHIRO NOZ ...
    2008 Volume 54 Issue 4 Pages 468-473
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.468
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    Objective : To study the roles of psychiatric wards for the elderly, we assessed the clinical data of psycho-geriatric inpatients in Juntendo Tokyo Koto Geriatric Medical Center and compared findings with those of our previous report at the opening of this center. Materials and Methods : The subjects were 394 psycho-geriatric inpatients admitted to the psychiatric ward of Juntendo Tokyo Koto Geriatric Medical Center between April 2007 and March 2008, and the clinical data (sex, age, clinical diagnose and reasons for admission) were collected. Results : The gender ratio was 178 males to 216 females, and the ages of inpatients ranged between 44 and 100 years (mean age ; 78.8 years). Overall, 74 % of inpatients were diagnosed as having dementia, and the clinical diagnoses of dementia included Alzheimer's disease (201 cases ; 51 %), dementia with Lewy bodies (33 cases ; 8 %), vascular dementia (29 cases ; 7 %), front-temporal dementia (16 cases ; 4 %), mixed type dementia (12cases ; 3 %) and mild cognitive impairment (4 cases ; 1%). In addition, clinical diagnoses of other geriatric psychiatry included mood disorder (30 cases ; 8%), schizophrenia (11 cases ; 3 %), delirium (11 cases ; 3 %) and alcoholism (7 cases ; 2 %). The reasons for admission were treatment of physical complications (185 cases ; 46 %), treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) (100 cases ; 25 %), treatment of other psychiatric symptoms (58 cases ; 15 %), improvement of fatigue for care givers (26 cases ; 7%), diagnostic work-up (7cases ; 2 %) and other reasons. Physical complications that required admission were pneumonia (21 %), fractured femur (11 %), dehydration or malnutrition (9 %), cerebral apoplexy (8 %), malignant tumors (6 %) and so on. Conclusion : Compared with the data of our previous report, the variety of psychiatric diseases had increased during this period. It seemed that these findings were dependent on the adoption of a new examination method and a new conception of dementia, resistance to medication with aging and changes in the residential environment. Furthermore, the number of inpatients admitted for treatment of physical complications increased. This suggests a deficiency of general hospitals with a psychiatric ward that can support such patients with physical diseases. In the future, improvement of the medical system is needed as well as cooperation with the physical therapy department and community medicine.
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  • Multiple Genetic Aberrations in Active Systemic Lupus Erythematosus are Influenced by DNA Methylation but not by DNA Acetylation
    MICHIAKI KAGEYAMA, HITOSHI OGASAWARA, KEN YAMAJI, YOSHINARI TAKASAKI
    2008 Volume 54 Issue 4 Pages 474-479
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.474
    JOURNAL FREE ACCESS
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    Genetic factors are important in the development of systemic lupus erythematosus (SLE), and various hypotheses have been suggested to relate the aberrant expression of certain genes to the pathogenesis of SLE. Although it is clear that genetic factors can trigger SLE, the regulatory mechanisms underlying the expression of these genes remains unclear. Since knowledge of these mechanisms would contribute to a better understanding of the pathogenesis of SLE, this is an important area of research. It is now widely accepted that methylation of DNA and acetylation of histones, so-called epigenetic mechanisms, are related to gene expression. This study investigated whether the methylation and acetylation mechanisms affect the pathogenesis of SLE. For clarity, we focused on the DNMT1 (DNA (cytosine-5) -methyltransferase 1), DNMT3b DNA (cytosine-5) -methyltransferase 3beta), PCAF (p300/CBP-associated factor) and GCN5 genes. DNMT1 and DNMT3b are associated with methylation of DNA, and PCAF and GCN5 are associated with histone acetylation. Quantitative analysis of mRNA for these genes in PBMC from 20 SLE patients and 20 healthy persons was performed using TaqMan PCR. Decreased mRNA expression of DNMT1 was confirmed in lymphocytes from SLE patients, compared with that in those from healthy subjects. In contrast, there were no differences in mRNA expression levels for DNMT3b, PCAF and GCN5 in the two groups. Our findings suggest that aberrant gene expression in SLE may occur through abnormal DNA methylation caused by a decreased level of DNMT1 mRNA.
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  • The effects of antibiotics on the production of Panton-Valentine leukocidin (PVL).
    YUH MORIMOTO, TERUYO ITO, YUKI KATAYAMA, TADASHI BABA, TOMOMI UCHIKAWA ...
    2008 Volume 54 Issue 4 Pages 480-491
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.480
    JOURNAL FREE ACCESS
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    The spread of community-acquired MRSA (CA-MRSA) is of great concern all over the world. The majority of CA-MRSA strains isolated in the United States and European countries are reported to produce Panton-Valentine leukocidin (PVL), which is considered the major virulence determinant of CA-MRSA strains. In this study, we examined the effects of antibiotics on the production of PVL as well as the induction of PVL phages lysogenized in S. aureus chromosome. Our findings indicated that antibiotics that inhibit DNA synthesis tend to induce PVL phages and increase PVL toxin production, although an increase in PVL production was not observed in all of the tested strains. In contrast, linezolid was found to reduce the induction of PVL as well as the of PVL.
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  • Prevention of glomerular injury by tubular L-FABP overexpression in immune-mediated glomerulonephritis
    YASUHIKO KANAGUCHI, YUSUKE SUZUKI, TAKESHI SUGAYA, SATOSHI HORIKOSHI, ...
    2008 Volume 54 Issue 4 Pages 492-500
    Published: December 26, 2008
    Released on J-STAGE: November 12, 2014
    DOIhttps://doi.org/10.14789/pjmj.54.492
    JOURNAL FREE ACCESS
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    Objective : Proteinuria in chronic glomerulonephritis is not only the result of glomerular damage, but also the main cause of tubulointerstitial damage. The unsaturated fatty acid contained in proteinuria generates oxidant stress during the resorptive process in the proximal tubules and is a cause of tubulointerstitial damage. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of fatty acid that is expressed in the proximal tubules of human kidney. Tubulointerstitial damage induced by fatty acid is prevented by L-FABP, which binds to the excessively loaded fatty acid and is then excreted into urine. Furthermore, L-FABP is activated and plays an important protective role in tubular ischemia. The present study investigated whether tubulary protection in glomerulonephritis may prevent the progression of glomerular damage. Since L-FABP is not expressed in rodents, transgenic mice (L-FABPTg were established by introducing the human chromosome gene including the transcript adjustment area only into the proximal tubules. Then these animals were employed for this study. Materials and Methods : We induced anti-glomerular basement membrane antibody-mediated glomerulonephritis (Anti-GBM GN) in L-FABPTg mice and wild type littermates (WT), and evaluated the kinetics of proteinuria, polymorphonuclear (PMN) influx, urinary L-FABP concentration, a marker whose lack indicates fibrosis (α-SMA), oxidative stress (HNE) and tubular ischemia (KIM-1), and glomerular histology. In addition, we also orally administered angiotensin II type 1 receptor blocker (ARB : Olmesartan, 6mg/kg body wt/ day) in L-FABPTg mice with Anti-GBM GN. Results : Glomerular injury and proteinuria before day 3 were significantly prevented in L-FABPTg mice showing a lack of PMN influx at 3 and 6 hours. Proteinuria in L-FABPTg mice gradually increased after day 3 and reached the level shown in WT mice at day 7. WT mice showed glomerular damage with severe endothelial injury, while L-FABPTg differently showed mesangial proliferative glomerulonephritis. Despite the same degree of proteinuria at day 7, tubular expressions of a-SMA, HNE and KIM-1 were clearly decreased. Proteinuria and glomerular damage in L-FABPTg mice were significantly inhibited by ARB. Conclusions : These present findings suggest that the enhancement of tubular L-FABP expression may prevent not only tubulointerstitial damage but also the progression of glomerular damage.
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