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Matuda S.,National Institute of Fitness and Sports in Kanoya | Arimura T.,Tokyo Medical and Dental University | Kimura A.,Tokyo Medical and Dental University | Takekura H.,National Institute of Fitness and Sports in Kanoya | And 2 more authors.
Biochimica et Biophysica Acta - General Subjects | Year: 2010

Background: It is not known if the dihydrolipoamide succinyltransferase (DLST) gene, a mitochondrial protein, undergoes alternative splicing. We identified an uncharacterized protein reacting with an anti-DLST antibody in the I bands of myofibrils in rat skeletal muscle. Methods: Immunocytochemical staining with an anti-DLST antibody, the purification and amino acid sequence analysis of the protein, and the isolation and sequencing of the protein's cDNA were carried out to clarify the properties of the protein and its relationship to the DLST gene. Results: A pyrophosphate concentration >10 mM was necessary to extract the protein from myofibrils in the presence of salt with a higher concentration than 0.6 M, at an alkaline pH of 7.5-8.0. The protein corresponded to the amino acid sequence of the C-terminal side of DLST. The cDNAs for this protein were splicing variants of the DLST gene, with deletions of both exons 2 and 3, or only exon 2 or 3. These variants possessed an open reading frame from an initiation codon in exon 8 of the DLST gene to a termination codon in exon 15, generating a protein with a molecular weight of 30 kDa. Conclusions: The DLST gene undergoes alternative splicing, generating the protein isolated from the I bands of myofibrils. General significance: The DLST gene produces two different proteins with quite different functions via alternative splicing. © 2009. Source

Ohta S.,Institute of Development and Aging science
Pharmacology and Therapeutics | Year: 2014

Molecular hydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body. We have turned this concept by demonstrating that H2 reacts with strong oxidants such as hydroxyl radical in cells, and proposed its potential for preventive and therapeutic applications. H2 has a number of advantages exhibiting extensive effects: H 2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species; therefore, there should be no or little adverse effects of H2. There are several methods to ingest or consume H2; inhaling H2 gas, drinking H2-dissolved water (H 2-water), injecting H2-dissolved saline (H 2-saline), taking an H2 bath, or dropping H 2-saline into the eyes. The numerous publications on its biological and medical benefits revealed that H2 reduces oxidative stress not only by direct reactions with strong oxidants, but also indirectly by regulating various gene expressions. Moreover, by regulating the gene expressions, H 2 functions as an anti-inflammatory and anti-apoptotic, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under investigation. Since most drugs specifically act to their targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has promising potential for clinical use against many diseases. © 2014 Elsevier Inc. Source

Cheng A.,U.S. National Institute on Aging | Wan R.,U.S. National Institute on Aging | Yang J.-L.,U.S. National Institute on Aging | Kamimura N.,U.S. National Institute on Aging | And 7 more authors.
Nature Communications | Year: 2012

The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses. © 2012 Macmillan Publishers Limited. All rights reserved. Source

Lee H.,Institute of Development and Aging science | Kiuchi T.,Nippon Medical School | Muto J.,Nippon Sport Science University | Ohta S.,Institute of Development and Aging science | Mikami T.,Nippon Medical School
Gazzetta Medica Italiana Archivio per le Scienze Mediche | Year: 2014

Aim. Much attention to regularly performing exercise at low or moderate intensity has been paid on the stimulation of adult hippocampal neurogenesis. Here, we focused on the contribution of high-intensity exercise to the hippocampal proliferation.Methods. To examine effect of single exercise on the hippocampal proliferation and the brain-derived neurotrophic factor (BDNF) expression, mice were subjected to intense running on a treadmill with gradual increases of treadmill speed until exhaustion or 60 min of moderate running. Additionally, to reveal the involvement of vascular endothelial growth factor (VEGF)-receptor 2 (Flkl) signaling cascade on the hippocampal proliferation and BDNF expression, an Flkl inhibitor, SU1498 was intraperitoneally administered before exercise.Results. A single bout of intense exercise significantly increased expression of BDNF, accompanying the stimulation of the hippocampal proliferation of newborn cells. SU1498 (a specific inhibitor of VEGF receptor 2) suppressed the hippocampal proliferation of newborn cells as well as the BDNF expression. Moreover, a single bout of intense exercise induced the phosphorylations of the Flkl, extracellular signal-regulated kinases (ERKs) and cAMP response element-binding protein (CREB), all of which are involved in the VEGF-Flk1 cascade. On the other hand, a single bout of moderate exercise did not influence the hippocampal proliferation and the BDNF expression.Conclusion. These findings suggest that intense exercise-induced the hippocampal proliferation of newborn cells is regulated by BDNF under the VEGF-Flkl signaling cascade. This study highlights that not only regularly performing moderate exercise but also a single bout of intense exercise also exhibits neurotrophic effects. Source

Kamimura N.,Institute of Development and Aging science | Nishimaki K.,Institute of Development and Aging science | Ohsawa I.,Institute of Development and Aging science | Ohsawa I.,Tokyo Metropolitan University | Ohta S.,Institute of Development and Aging science
Obesity | Year: 2011

Recent extensive studies have revealed that molecular hydrogen (H 2) has great potential for improving oxidative stress-related diseases by inhaling H2 gas, injecting saline with dissolved H 2, or drinking water with dissolved H2 (H 2-water); however, little is known about the dynamic movement of H2 in a body. First, we show that hepatic glycogen accumulates H 2 after oral administration of H2-water, explaining why consumption of even a small amount of H2 over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H2. Next, we examined the benefit of ad libitum drinking H2-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H2-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H2-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H2-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H2-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H2 stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H2 in improving obesity, diabetes, and metabolic syndrome. © 2011 The Obesity Society. Source

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