Publications by authors named "Akihiko Taguchi"

115 Publications

Bone Marrow Mononuclear Cells Transplantation and Training Increased Transplantation of Energy Source Transporters in Chronic Stroke.

J Stroke Cerebrovasc Dis 2021 Jun 17;30(8):105932. Epub 2021 Jun 17.

Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan. Electronic address:

Objectives: Bone marrow mononuclear cells (BM-MNC) show a significant therapeutic effect in combination with training even in the chronic phase of stroke. However, the mechanism of this combination therapy has not been investigated. Here, we examined its effects on brain metabolism in chronic stroke mice.

Materials And Methods: BM-MNC (1x10 cells in 100 µL of phosphate-buffered saline) were intravenously transplanted at 4 weeks (chronic stage) after the middle cerebral artery occlusion. At 3 h and 10 weeks after the administration of BM-MNC, we evaluated transcription changes of the metabolism-related genes, hypoxia inducible factor 1-α (Hif-1α), prolyl hydroxylase 3 (Phd3), pyruvate dehydrogenase kinase 1 (Pdk1), Na+/K+-ATPase (Atp1α1‒3), connexins, glucose transporters, and monocarboxylate transporters, in the brain during chronic phase of stroke using quantitative polymerase chain reaction.

Results: The results showed transcriptional activation of the metabolism-related genes in the contralateral cortex at 3 h after BM-MNC transplantation. Behavioral tests were performed after cell therapy, and the brain metabolism of mice with improved motor function was examined at 10 weeks after cell therapy. The therapeutic efficacy of the combination therapy with BM-MNC transplantation and training was evident in the form of transcriptional activation of ipsilateral anterior cerebral artery (ACA) cortex.

Conclusions: BM-MNC transplantation combined with training for chronic stroke activated gene expression in both the ipsilateral and the contralateral side.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105932DOI Listing
June 2021

Endothelial connexin-integrin crosstalk in vascular inflammation.

Biochim Biophys Acta Mol Basis Dis 2021 Sep 13;1867(9):166168. Epub 2021 May 13.

Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan. Electronic address:

Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment - including vascular stiffness and shear stress - modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2021.166168DOI Listing
September 2021

Gap junction-mediated cell-cell interaction between transplanted mesenchymal stem cells and vascular endothelium in stroke.

Stem Cells 2021 Mar 11. Epub 2021 Mar 11.

Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan.

We have shown previously that transplanted bone marrow mononuclear cells (BM-MNC), which are a cell fraction rich in hematopoietic stem cells, can activate cerebral endothelial cells via gap junction-mediated cell-cell interaction. In the present study, we investigated such cell-cell interaction between mesenchymal stem cells (MSC) and cerebral endothelial cells. In contrast to BM-MNC, for MSC we observed suppression of vascular endothelial growth factor uptake into endothelial cells and transfer of glucose from endothelial cells to MSC in vitro. The transfer of such a small molecule from MSC to vascular endothelium was subsequently confirmed in vivo and was followed by suppressed activation of macrophage/microglia in stroke mice. The suppressive effect was absent by blockade of gap junction at MSC. Furthermore, gap junction-mediated cell-cell interaction was observed between circulating white blood cells and MSC. Our findings indicate that gap junction-mediated cell-cell interaction is one of the major pathways for MSC-mediated suppression of inflammation in the brain following stroke and provides a novel strategy to maintain the blood-brain barrier in injured brain. Furthermore, our current results have the potential to provide a novel insight for other ongoing clinical trials that make use of MSC transplantation aiming to suppress excess inflammation, as well as other diseases such as COVID-19 (coronavirus disease 2019).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.3360DOI Listing
March 2021

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.

Front Aging Neurosci 2021 28;13:623751. Epub 2021 Jan 28.

Unidad de Investigación Neurovascular, Departamento Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid, Spain.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2021.623751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876251PMC
January 2021

Intravenous Bone Marrow Mononuclear Cells Transplantation Improves the Effect of Training in Chronic Stroke Mice.

Front Med (Lausanne) 2020 26;7:535902. Epub 2020 Nov 26.

Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan.

There is no effective treatment for chronic stroke if the acute or subacute phase is missed. Rehabilitation alone cannot easily achieve a dramatic recovery in function. In contrast to significant therapeutic effects of bone marrow mononuclear cells (BM-MNC) transplantation for acute stroke, mild and non-significant effects have been shown for chronic stroke. In this study, we have evaluated the effect of a combination of BM-MNC transplantation and neurological function training in chronic stroke. The effect of BM-MNC on neurological functional was tested four weeks after permanent middle cerebral artery occlusion (MCAO) insult in mice. BM-MNC (1 × 10cells in 100 μl PBS) were injected into the vein of MCAO model mice, followed by behavioral tests as functional evaluations. Interestingly, there was a significant therapeutic effect of BM-MNC only when repeated training was performed. This suggested that cell therapy alone was not sufficient for chronic stroke treatment; however, training with cell therapy was effective. The combination of these differently targeted therapies provided a significant benefit in the chronic stroke mouse model. Therefore, targeted cell therapy BM-MNC transplantation with appropriate training presents a promising novel therapeutic option for patients in the chronic stroke period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2020.535902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726263PMC
November 2020

Liver-specific dysregulation of clock-controlled output signal impairs energy metabolism in liver and muscle.

Biochem Biophys Res Commun 2021 01 27;534:415-421. Epub 2020 Nov 27.

Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Department of Bio-Signal Analysis, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi, 755-8505, Japan.

The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.11.066DOI Listing
January 2021

Increased migratory and homing abilities of neural and mesenchymal stem cell populations by transient cell modifications: Preclinical progress and clinical relevance.

EBioMedicine 2020 Oct 24;60:103022. Epub 2020 Sep 24.

Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation, Minatojima-Minamimachi 2-2, Kobe 650-0047, Hyogo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.103022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519243PMC
October 2020

A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.

Genes Dev 2020 08 2;34(15-16):1089-1105. Epub 2020 Jul 2.

Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic β cells that are perturbed in and β-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant β cells, including transcripts encoding () and (). Depletion of THRAP3 restores expression of the long isoforms of and , and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in β-cell function across the sleep/wake cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.338178.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397853PMC
August 2020

Intravenous Bone Marrow Mononuclear Cells Transplantation in Aged Mice Increases Transcription of Glucose Transporter 1 and Na/K-ATPase at Hippocampus Followed by Restored Neurological Functions.

Front Aging Neurosci 2020 11;12:170. Epub 2020 Jun 11.

Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan.

We recently reported that intravenous bone marrow mononuclear cell (BM-MNC) transplantation in stroke improves neurological function through improvement of cerebral metabolism. Cerebral metabolism is known to diminish with aging, and the reduction of metabolism is one of the presumed causes of neurological decline in the elderly. We report herein that transcription of glucose transporters, monocarboxylate transporters, and Na/K-ATPase is downregulated in the hippocampus of aged mice with impaired neurological functions. Intravenous BM-MNC transplantation in aged mice stimulated the transcription of glucose transporter 1 and Na/K-ATPase α1 followed by restoration of neurological function. As glucose transporters and Na/K-ATPases are closely related to cerebral metabolism and neurological function, our data indicate that BM-MNC transplantation in aged mice has the potential to restore neurological function by activating transcription of glucose transporter and Na/K-ATPase. Furthermore, our data indicate that changes in transcription of glucose transporter and Na/K-ATPase could be surrogate biomarkers for age-related neurological impairment as well as quantifying the efficacy of therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2020.00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301702PMC
June 2020

Cilostazol, a Phosphodiesterase 3 Inhibitor, Moderately Attenuates Behaviors Depending on Sex in the Ts65Dn Mouse Model of Down Syndrome.

Front Aging Neurosci 2020 21;12:106. Epub 2020 Apr 21.

Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Osaka, Japan.

People with Down syndrome, which is a trisomy of chromosome 21, exhibit intellectual disability from infancy and neuropathology similar to Alzheimer's disease, such as amyloid plaques, from an early age. Recently, we showed that cilostazol, a selective inhibitor of phosphodiesterase (PDE) 3, promotes the clearance of amyloid β and rescues cognitive deficits in a mouse model of Alzheimer's disease. The objective of the present study was to examine whether cilostazol improves behaviors in the most widely used animal model of Down syndrome, i.e., Ts65Dn mice. Mice were supplemented with cilostazol from the fetal period until young adulthood. Supplementation significantly ameliorated novel-object recognition in Ts65Dn females and partially ameliorated sensorimotor function as determined by the rotarod test in Ts65Dn females and hyperactive locomotion in Ts65Dn males. Cilostazol supplementation significantly shortened swimming distance in Ts65Dn males in the Morris water maze test, suggesting that the drug improved cognitive function, although it did not shorten swimming duration, which was due to decreased swimming speed. Thus, this study suggests that early supplementation with cilostazol partially rescues behavioral abnormalities seen in Down syndrome and indicates that the effects are sex-dependent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2020.00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186592PMC
April 2020

Bone Marrow Mononuclear Cells Activate Angiogenesis via Gap Junction-Mediated Cell-Cell Interaction.

Stroke 2020 04 19;51(4):1279-1289. Epub 2020 Feb 19.

From the Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan (A.K.-T., Y. Okinaka, Y.T., Y. Ogawa, M.M., J.B., A.T.).

Background and Purpose- Bone marrow mononuclear cells (BM-MNCs) are a rich source of hematopoietic stem cells and have been widely used in experimental therapies for patients with ischemic diseases. Activation of angiogenesis is believed to be one of major BM-MNC mode of actions, but the essential mechanism by which BM-MNCs activate angiogenesis have hitherto been elusive. The objective of this study is to reveal the mechanism how BM-MNCs activate angiogenesis. Methods- We have evaluated the effect of direct cell-cell interaction between BM-MNC and endothelial cell on uptake of VEGF (vascular endothelial growth factor) into endothelial cells in vitro. Cerebral ischemia model was used to evaluate the effects of direct cell-cell interaction with transplanted BM-MNC on endothelial cell at ischemic tissue. Results- The uptake of VEGF into endothelial cells was increased by BM-MNC, while being inhibited by blockading the gap junction. Low-molecular-weight substance was transferred from BM-MNC into endothelial cells via gap junctions in vivo, followed by increased expression of hypoxia-inducible factor-1α and suppression of autophagy in endothelial cells. The concentration of glucose in BM-MNC cytoplasm was significantly higher than in endothelial cells, and transfer of glucose homologue from BM-MNC to endothelial cells was observed. Conclusions- Our findings demonstrated cell-cell interaction via gap junction is the prominent pathway for activation of angiogenesis at endothelial cells after ischemia and provided novel paradigm that energy source supply by stem cell to injured cell is one of the therapeutic mechanisms of cell-based therapy. Visual Overview- An online visual overview is available for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.119.028072DOI Listing
April 2020

Adrenomedullin has a cytoprotective role against endoplasmic reticulum stress for pancreatic β-cells in autocrine and paracrine manners.

J Diabetes Investig 2020 Jul 10;11(4):823-833. Epub 2020 Mar 10.

Division of Endocrinology, Metabolism, Hematological Science and Therapeutics, Department of Bio-Signal Analysis, Graduate School of Medicine, Yamaguchi University, Ube, Japan.

Aims/introduction: Pancreatic β-cells are sensitive to endoplasmic reticulum (ER) stress, which has a major role in the context of β-cell death. Adrenomedullin (ADM) has been shown to exert a cytoprotective effect under various pathophysiological conditions. Several studies have suggested that thiazolidinediones have protective effects on β-cells. During the course to elucidate the molecular mechanisms by which pioglitazone prevents β-cell death, ADM emerged as a candidate. Here, we studied the regulation of ADM expression, including the effects of pioglitazone, and its role in pancreatic islets.

Materials And Methods: We analyzed ADM expression in islet cell lines treated with pioglitazone. The effects of ER stress on ADM and ADM receptor expressions were investigated by analyzing thapsigargin-treated MIN6 cells and islets isolated from Wfs1 and db/db mice. To study the anti-apoptotic effect of ADM, ER stress-exposed MIN6 cells were treated with ADM peptides or transfected with ADM expression plasmid.

Results: Pioglitazone increased the production and secretion of ADM in islets through peroxisome-proliferator activated receptor-γ-dependent mechanisms. Thapsigargin treatment increased expressions of both ADM and ADM receptor, composed of Ramp2, Ramp3 and Crlr, in MIN6 cells. ADM and ADM receptor expressions were also increased in isolated islets from Wfs1 and db/db mice. ADM peptides and ADM overexpression protected MIN6 cells from thapsigargin-induced apoptosis.

Conclusions: ER stress stimulates ADM production and secretion in islets. ADM signaling might protect β-cells from ER stress-induced apoptosis, and might be one of the self-protective mechanisms. β-Cell protection by pioglitazone is partly through induction of ADM. ADM-based therapy could be a novel strategy for treating diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.13218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378419PMC
July 2020

Stem Cells as an Emerging Paradigm in Stroke 4: Advancing and Accelerating Preclinical Research.

Stroke 2019 11 17;50(11):3299-3306. Epub 2019 Oct 17.

Institute for Stroke and Cerebrovascular Disease, UTHealth, Houston, TX (S.I.S.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.119.025436DOI Listing
November 2019

Circulating levels of CD34+ cells predict long-term cardiovascular outcomes in patients on maintenance hemodialysis.

PLoS One 2019 4;14(10):e0223390. Epub 2019 Oct 4.

Department of Nephrology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

CD34+ cells maintain vascular homeostasis and predict cardiovascular outcomes. We previously evaluated the association of CD34+ cells with cardiovascular disease (CVD) events over 23 months, but long-term CVD outcomes in relation to levels of CD34+ cells in patients on maintenance hemodialysis are unclear. Herein, we analyzed the long-term predictive potential levels of CD34+ cells for CVD outcomes and all-cause mortality. Between March 2005 and May 2005, we enrolled 215 patients on maintenance hemodialysis at Nagoya Kyoritsu Hospital and followed them up to 12.8 years. According to the CD34+ cell counts, patients were classified into the lowest, medium, and highest tertiles. Levels of CD34+ cells were analyzed in association with four-point major adverse CV events (MACEs), CVD death, and all-cause mortality. In univariate analysis age, smoking habit, lower geriatric nutrition risk index, lower calcium × phosphate product, and lower intact parathyroid hormone were significantly associated with the lowest tertile. Whereas, in multivariate analysis, age and smoking habit were significantly associated with the lowest tertile. Among 139 (64.7%) patients who died during a mean follow-up period of 8.0 years, 39 (28.1%) patients died from CVD. Patients in the lowest tertile had a significantly lower survival rate than those in the medium and highest tertiles (p ≤ 0.001). Using multivariable analyses, the lowest tertile was significantly associated with four-point MACEs (hazard ratio 1.80, p = 0.023) and CVD death (hazard ratio 2.50, p = 0.011). In conclusion, our long-term observational study revealed that a low level of CD34+ cells in the circulation predicts CVD outcomes among patients on maintenance hemodialysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223390PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777758PMC
March 2020

Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke.

Stroke 2019 10 12;50(10):2883-2891. Epub 2019 Sep 12.

From the Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan (Y.O., A.K.-T., Y.T., Y.O., J.B., A.T.).

Background and Purpose- The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies. Methods- To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used. Results- We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation. Conclusions- Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants. Visual Overview- An online visual overview is available for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.119.026669DOI Listing
October 2019

Amyloid β deposition in subcortical stroke patients and effects of educational achievement: A pilot study.

Int J Geriatr Psychiatry 2019 11 31;34(11):1651-1657. Epub 2019 Jul 31.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.

Objective: A direct causal relationship of cerebrovascular risk factors/stroke to amyloid β (Aβ) deposition has yet to be shown. We conducted [ C] Pittsburgh compound B (PiB)-positron emission tomography (PET) analysis on subacute ischemic stroke patients and healthy controls. We hypothesized that subacute ischemic stroke patients would show focal Aβ accumulation in cortical regions, which would increase and extend over time during the chronic phase after stroke onset.

Methods: Patients were recruited 14 to 28 days after acute subcortical ischemic stroke and examined with [ C]PiB-PET scans. Regional time-activity data were analyzed with the Logan graphical method. Whole brain voxel-based analysis was conducted to compare stroke patients with healthy controls. We also performed longitudinal comparison of patients with successive [ C]PiB-PET scans 1 year after stroke.

Results: Voxel-based analysis revealed a significant increase of [ C]PiB-BP of the precuneus/posterior cingulate cortex (PCu/PCC) in stroke patients at the subacute stage. Based on stepwise multiple regression analysis of [ C]PiB-BP changes during follow-up as the dependent variable, years of education was the best independent correlate. There was a significant negative relationship between changes in [ C]PiB-BP and years of education.

Conclusions: Our results suggest that processes before and after the onset of ischemic stroke may trigger Aβ deposition in the PCu/PCC, whereby amyloid deposition begins at an early stage of Alzheimer's disease (AD). Our findings support the existence of a cooperative association between vascular risk factors/stroke and AD progression. Further, educational achievement had a protective effect against the increase in Aβ accumulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.5178DOI Listing
November 2019

Accelerating Cell Therapy for Stroke in Japan: Regulatory Framework and Guidelines on Development of Cell-Based Products.

Stroke 2018 04 16;49(4):e145-e152. Epub 2018 Mar 16.

From the Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan (K.H., H.S.); Division of Clinical Research Administration, Hokkaido University Hospital, Sapporo, Japan (H.S.); Department of Neurology, Okayama University Medical School, Japan (K.A., T. Yamashita); Hokkaido University Hospital Clinical Research and Medical Innovation Center, Sapporo, Japan (T.A., N.S.); Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan (M.D.); Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Japan (O.H., M.S.); Department of Neurosurgery, Nagasaki University Hospital, Japan (N.H., I.N.); Department of Neurology and Stroke Center, Tokyo General Hospital, Japan (Y.K.); Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan (Y.K., S.S.); Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital, Sapporo, Japan (K.K.); Department of Neurosurgery, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan (S.K.); Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan (T.M.); Neurorehabilitation Research Institute, Morinomiya Hospital, Osaka, Japan (I.M.); Department of Neurosurgery, Kokura Memorial Hospital, Kitakyushu, Japan (I.N.); Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (K.N., T.T.); Office of Cellular and Tissue-Based Products, Pharmaceuticals and Medical Devices Agency (PMDA), Tokyo, Japan (K. Sakushima, K. Sawanobori); Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan (A.T.); Center for Advancing Clinical and Translational Sciences, National Cerebral and Cardiovascular Center, Suita, Japan (H.Y.); Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan (T. Yoshimine); and Center for Information and Neural Networks, Osaka University, Suita, Japan (T. Yoshimine).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.117.019216DOI Listing
April 2018

Molecular clock as a regulator of β-cell function.

J Diabetes Investig 2018 Mar 15. Epub 2018 Mar 15.

Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.

Molecular clocks are important for the circadian regulation of ß-cell function. DBP/E4BP4 plays central roles among clock-related genes in the metabolic regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jdi.12835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934260PMC
March 2018

Treatment evaluation of acute stroke for using in regenerative cell elements (TREASURE) trial: Rationale and design.

Int J Stroke 2018 06 14;13(4):444-448. Epub 2017 Nov 14.

1 Department of Neurosurgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Japan.

Rationale MultiStem® (HLM051) is one of the promising allogenic cell products for acute ischemic stroke with strong evidence. A previous phase 2 randomized, double-blind, placebo-controlled, multicenter dose-escalation trial showed the safety of MultiStem® for acute ischemic stroke, with a time window beyond that of rt-PA and endovascular thrombectomy. We aim to obtain stronger evidence and to show the efficacy of the MultiStem® for treatment of ischemic stroke. Sample size Estimated sample size is 220 (110 patients per group), which has 90% power at 5% significance level. Methods and design TREASURE is a randomized, double-blind, placebo-controlled, multicenter phase 2/3 trial. The trial will be done at 31 medical centers in Japan. Patients with acute ischemic stroke including motor or speech deficit defined by a National Institution of Health Stroke Scale (NIHSS) score of 8-20 at baseline will be randomized 1:1 to receive a single intravenous infusion of MultiStem® or placebo within 18-36 h of stroke onset. Study outcomes Primary outcome in this study is the proportion of patients with an excellent outcome at day 90 defined by the functional assessment. Trial registration ClinicalTrials.gov (NCT02961504). Conclusion The TREASURE trial will provide a novel treatment option and expand the therapeutic window for patients with stroke if the results are positive.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1747493017743057DOI Listing
June 2018

Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function.

EBioMedicine 2017 Apr 30;18:146-156. Epub 2017 Mar 30.

Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan. Electronic address:

In Wfs1A/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2017.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405175PMC
April 2017

Mutual effect of cerebral amyloid β and peripheral lymphocytes in cognitively normal older individuals.

Int J Geriatr Psychiatry 2017 12 23;32(12):e93-e99. Epub 2017 Jan 23.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.

Objective: We hypothesized that cerebral amyloid accumulation is reflected in the periphery in the pre-dementia stage and used flow cytometry to investigate the peripheral lymphocytes as an easily accessible biomarker to observe neuro-inflammation. We aimed to determine whether peripheral lymphocytes are related to the cortical amyloid burden or vice versa in cognitively normal older subjects.

Methods: We applied [ C] Pittsburgh compound B (PiB)-positron emission tomography to 36 cognitively normal older individuals, and Aβ deposition was quantified by cortical binding potential (PiB-BP ). Blood samples were obtained, and lymphocyte subsets were evaluated. We examined differences between low and high PiB-BP groups in the percentage of B cells, T cells, helper T cells, cytotoxic T cells, regulatory T cells, and natural killer cells RESULTS: Subjects with high PiB-BP showed significantly higher percentage of cytotoxic T cells (%CD3 ). Correlation analysis revealed a significant relationship between the percentage of cytotoxic T cells and global cortical mean PiB-BP . Hierarchical regression analyses showed that cytotoxic T cells were significantly related to the value of global cortical mean PiB-BP and vice versa.

Conclusions: Our results indicated that a specific peripheral immune response, reflected in the increased ratio of cytotoxic T cells, could be regarded as a preclinical sign of AD and could be attributed to the Aβ neuropathological mechanism. Copyright © 2017 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gps.4660DOI Listing
December 2017

Evaluations of Intravenous Administration of CD34+ Human Umbilical Cord Blood Cells in a Mouse Model of Neonatal Hypoxic-Ischemic Encephalopathy.

Dev Neurosci 2016 20;38(5):331-341. Epub 2017 Jan 20.

Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Japan.

Several cell therapies have been explored as novel therapeutic strategies for neonatal encephalopathy because the benefits of current treatments are limited. We previously reported that intravenous administration of human umbilical cord blood (hUCB) CD34+ cells (hematopoietic stem cells/endothelial progenitor cells) at 48 h after insult exerts therapeutic effects in neonatal mice with stroke, i.e., permanent middle cerebral artery occlusion. Although neonatal stroke and hypoxic-ischemic encephalopathy (HIE) are grouped under the term "neonatal encephalopathy," their pathogenesis differs. However, little is known about the differences in the effects of the same treatment between these 2 diseases. In this study, we investigated whether the same treatment protocol exerts therapeutic effects in neonatal mice with HIE. The treatment significantly ameliorated the decreased cerebral blood flow in the ischemic penumbra. Although the cylinder and rotarod tests showed a trend of amelioration of behavioral impairments from the treatment, these were not statistically significant. Morphological brain injuries were not altered by treatment. The cell administration did not cause any adverse effects apart from hyperactivity in the open-field test. Some of these findings are consistent with the results obtained in our previous study using a stroke model, but others are not. This study suggests that the treatment protocol needs to be optimized for each pathological condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000454830DOI Listing
January 2018

Use of T1-weighted/T2-weighted magnetic resonance ratio to elucidate changes due to amyloid β accumulation in cognitively normal subjects.

Neuroimage Clin 2017 2;13:209-214. Epub 2016 Dec 2.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.

The ratio of signal intensity in T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) was recently proposed to enhance the sensitivity of detecting changes in disease-related signal intensity. The objective of this study was to test the effectiveness of T1w/T2w image ratios as an easily accessible biomarker for amyloid beta (Aβ) accumulation. We performed the T1w/T2w analysis in cognitively normal elderly individuals. We applied [C] Pittsburgh Compound B (PiB)-PET to the same individuals, and Aβ deposition was quantified by its binding potential (PiB-BP). The subjects were divided into low and high PiB-BP groups, and group differences in regional T1w/T2w values were evaluated. In the regions where we found a significant group difference, we conducted a correlation analysis between regional T1w/T2w values and PiB-BP. Subjects with high global cortical PiB-BP showed a significantly higher regional T1w/T2w ratio in the frontal cortex and anterior cingulate cortex We found a significant positive relationship between the regional T1w/T2w ratio and Aβ accumulation. Moreover, with a T1w/T2w ratio of 0.55 in the medial frontal regions, we correctly discriminated subjects with high PiB-BP from the entire subject population with a sensitivity of 84.6% and specificity of 80.0%. Our results indicate that early Aβ-induced pathological changes can be detected using the T1w/T2w ratio on MRI. We believe that the T1w/T2w ratio is a prospective stable biological marker of early Aβ accumulation in cognitively normal individuals. The availability of such an accessible marker would improve the efficiency of clinical trials focusing on the initial disease stages by reducing the number of subjects who require screening by Aβ-PET scan or lumbar puncture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2016.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157788PMC
November 2017

Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle.

Cell Metab 2017 01 20;25(1):86-92. Epub 2016 Oct 20.

Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address:

Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1 myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia. HIF1α bound directly to core clock gene promoters, and, when co-expressed with BMAL1, led to transactivation of PER2-LUC and HRE-LUC reporters. Further, genetic stabilization of HIF1α in Vhl cells altered circadian transcription. Finally, induction of clock and HIF1α target genes in response to strenuous exercise varied according to the time of day in wild-type mice. Collectively, our results reveal bidirectional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226863PMC
January 2017

Transplantation of hematopoietic stem cells: intra-arterial versus intravenous administration impacts stroke outcomes in a murine model.

Transl Res 2016 10 18;176:69-80. Epub 2016 Apr 18.

Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan. Electronic address:

Based on results of hematopoietic stem cell transplantation in animal models of stroke, clinical trials with hematopoietic stem cells administered intra-arterially or intravenously have been initiated in patients. Although intra-arterial injection is expected to deliver transplanted cells more directly to the ischemic tissue, the optimal route for enhancing clinical outcomes has not been identified in the setting of stroke. In this study, we compared the therapeutic potential of intra-arterial versus intravenous injection of bone marrow derived-mononuclear cells (BM-MNCs) and CD133-positive (CD133(+)) cells in a murine stroke model. We have found that intra-arterial injection of BM-MNCs exaggerates inflammation with accompanying loss of microvascular structures in poststroke brain and no improvement in cortical function. In contrast, intravenous injection of BM-MNCs did not similarly enhance inflammation and improved cortical function. Our results indicate that the optimal route of cell transplantation can vary with different cell populations and highlight possible issues that might arise with intra-arterial cell administration for acute ischemic cerebrovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trsl.2016.04.003DOI Listing
October 2016