Details of a Researcher - Tomita, Masaru

Papers - Tomita, Masaru

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Contribution of developmental changes in energy metabolism to excitation-contraction coupling of a ventricular cell: A simulation study

Sano, I., H., Toki, T., Naito, Y. and Tomita, M.

Computing in Cardiology 41 ( January ) 73 - 76 2014

ISSN 23258861

In fetal guinea pigs, ventricular cells have higher anaerobic glycolytic capacity and lower mitochondrial enzyme activity. Here, we implemented developmental changes in glycolytic enzyme activity, concentrations of glycogen, and total creatine in late embryonic and adult ventricular cell models. We then simulated the effects of hypoxic conditions on dynamic changes in contractile force and ATP concentration. Our model demonstrates that fetal ventricular cells maintain ATP for longer periods of time than adult ventricular cells. This is consistent with reported dynamics of ventricular cells under hypoxic conditions.

Global metabolic network reorganization by adaptive mutations allows fast growth of Escherichia coli on glycerol

Cheng K., Lee B., Masuda T., Ito T., Ikeda K., Hirayama A., Deng L., Dong J., Shimizu K., Soga T., Tomita M., Palsson B., Robert M.

Nature Communications (Nature Communications) 31 3233 2014

Joint Work

Comparative whole-genome sequencing enables the identification of specific mutations during adaptation of bacteria to new environments and allelic replacement can establish their causality. However, the mechanisms of action are hard to decipher and little has been achieved for epistatic mutations, especially at the metabolic level. Here we show that a strain of Escherichia coli carrying mutations in the rpoC and glpK genes, derived from adaptation in glycerol, uses two distinct metabolic strategies to gain growth advantage. A 27-bp deletion in the rpoC gene first increases metabolic efficiency. Then, a point mutation in the glpK gene promotes growth by improving glycerol utilization but results in increased carbon wasting as overflow metabolism. In a strain carrying both mutations, these contrasting carbon/energy saving and wasting mechanisms work together to give an 89% increase in growth rate. This study provides insight into metabolic reprogramming during adaptive laboratory evolution for fast cellular growth.

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Metabolomic profiling of sodium fluoride-induced cytotoxicity in an oral squamous cell carcinoma cell line

Sakagami H., Sugimoto M., Tanaka S., Onuma H., Ota S., Kaneko M., Soga T., Tomita M.

Metabolomics 10 ( 2 ) 270 - 279 2014

Joint Work, ISSN 15733882

Sodium fluoride (NaF) is used in dentistry as a preventive agent for dental caries because of its ability to remineralize the tooth surface and its antibacterial effect. Although one of its target molecules in bacteria is enolase, its site of action in human cells has not been identified. The aim of this study was to identify target metabolites that are coupled to NaF-induced cytotoxicity in the HSC-2 human oral squamous cell carcinoma cell line. Cell viability, membrane integrity and apoptosis induction were analyzed by MTT assay, trypan blue exclusion and caspase-3 activation, respectively. Cells were treated with a minimal cytotoxic concentration of NaF for various times and subjected to comprehensive metabolomics analysis using capillary electrophoresis-mass spectrometry. In the early stages, inhibition of the enolase reaction in glycolysis pathway was observed. This was coupled with rapid inhibition of the progression of TCA cycle. In the later stages, gradual increases in the AMP/ATP ratio (a putative marker of apoptosis) and oxidized products (e.g. GSSH, and methionine sulfoxide), and marginal changes in polyamine levels (putative marker of necrosis) were observed. This manuscript provides the new insight into the global impact of NaF on metabolic pathways in human oral squamous cell carcinoma cells.

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Quantifying periodicity in omics data

Amariei, A., Tomita, M. and Murray, B.D.

Frontiers in Cell and Developmental Biology (Frontiers in Cell and Developmental Biology) 2 ( AUG ) 40 2014

Joint Work, ISSN 2296-634X

Oscillations play a significant role in biological systems, with many examples in the fast, ultradian, circadian, circalunar, and yearly time domains. However, determining periodicity in such data can be problematic. There are a number of computational methods to identify the periodic components in large datasets, such as signal-to-noise based Fourier decomposition, Fisher's g-test and autocorrelation. However, the available methods assume a sinusoidal model and do not attempt to quantify the waveform shape and the presence of multiple periodicities, which provide vital clues in determining the underlying dynamics. Here, we developed a Fourier based measure that generates a de-noised waveform from multiple significant frequencies. This waveform is then correlated with the raw data from the respiratory oscillation found in yeast, to provide oscillation statistics including waveform metrics and multi-periods. The method is compared and contrasted to commonly used statistics. Moreover, we show the utility of the program in the analysis of noisy datasets and other high-throughput analyses, such as metabolomics and flow cytometry, respectively.

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Transcriptome-wide variability in single embryonic development cells

Piras V., Tomita M., Selvarajoo K.

Scientific Reports (Scientific Reports) 4 7137 2014

Joint Work

Molecular heterogeneity of individual molecules within single cells has been recently shown to be crucial for cell fate diversifications. However, on a global scale, the effect of molecular variability for embryonic developmental stages is largely underexplored. Here, to understand the origins of transcriptome-wide variability of oocytes to blastocysts in human and mouse, we examined RNA-Seq datasets. Evaluating Pearson correlation, Shannon entropy and noise patterns (•2 vs.μ), our investigations reveal a phase transition from low to saturating levels of diversity and variability of transcriptome-wide expressions through the development stages. To probe the observed behaviour further, we utilised a stochastic transcriptional model to simulate the global gene expressions pattern for each development stage. From the model, we concur that transcriptome-wide regulation initially begins from 2-cell stage, and becomes strikingly variable from 8-cell stage due to amplification and quantal transcriptional activity.

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Genome Analysis Workshop: a Personal Genomics class at Keio SFC

Arakawa, K. and Tomita, M.

KEIO SFC JOURNAL 14 158 - 197 2014

Joint Work

Undesigned selection for replication termination of bacterial chromosomes

Kono, N., Arakawa, K., Mitsuru Sato; Yoshikawa, H., Masaru Tomita, M. and Itaya, M.

Journal of Molecular Biology (Journal of Molecular Biology) 426 ( 16 ) 2918 - 2927 2014

Joint Work, ISSN 00222836

The oriC DNA replication origin in bacterial chromosomes, the location of which appears to be physically identified, is genetically regulated by relevant molecular machinery. In contrast, the location of the terminus remains obscure for many bacterial replicons, except for terC, the proposed and well-studied chromosome termination site in certain bacteria. The terC locus, which is composed of specific sequences for its binding protein, is located at a site opposite from oriC, exhibiting a symmetric structure around the oriC-terC axis. Here, we investigated Bacillus subtilis 168 strains whose axes were hindered and found that the native terC function was robust. However, eradication of terminus region specific binding protein resulted in the natural terC sites not being used for termination; instead, new termini were selected at a location exactly opposite to oriC. We concluded that replication generally terminates at the loci where the two approaching replisomes meet. This site was automatically selected, and two replisomes moving at the same rate supported symmetrical chromosome structures relative to oriC. The rule, which was even validated by artificial chromosomes irrespective of oriC, should be general for replicons administered by two replisomes. © 2014 The Authors.

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Multi-faceted integrated omics analysis revealed parsley (Petroselinum crispum) as a novel dietary intervention in dextran sodium sulphate induced colitic mice

Jia, H., Aw, W., Hanate, M., Takahashi, S., Kenji, S., Tanaka, H., Tomita, M., and Kato, H.

Journal of Functional Foods 11 ( C ) 438 - 448 2014

Joint Work, ISSN 17564646

Here we describe our unprecedented approach in proposing parsley as a nutraceutical intervention in inflammatory bowel disease (IBD) via multi-omics evaluation using dextran sodium sulphate (DSS)-induced colitis. Seven-week-old male C57BL/6J mice were fed either 2% parsley or basal diet and drank normal-drinking-water for 1 week after which colitis was induced by administering 1.5% (w/v) DSS-drinking-water for 9 days. Parsley supplementation significantly improved colon shortening and increased disease activity index. Colonic transcriptome revealed down-regulation of inflammatory cytokines, hepatic transcriptome and metabolome revealed up-regulation of fatty-acid synthesis genes, thereby improving body weight loss. Down-regulated cancer markers were observed in the hepatic transcriptome and proteome. Plasma metabolite analysis indicated shifts in the citric and urea cycle, implicating improved impaired glycolysis and oxidative stress. Parsley's role in preventing against IBD was highlighted by this pioneering multi-integrated-omics which is expected to be useful and informative, and shape the future of nutraceutical and functional food research.

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Hybridization between Japanese and North American Chlamydomonas reinhardtii (Volvocales, Chlorophyceae)

Nakada T, Tsuchida Y, Arakawa K, Ito T and Tomita M.

Phycological Research 62 ( 3 ) 232 - 266 2014

Joint Work, ISSN 13220829

The microalga Chlamydomonas reinhardtii is a model organism whose whole genome has been sequenced. Although considered a cosmopolitan species, only eastern North American isolates of C. reinhardtii were available before 2010, when new Japanese isolates were reported. In the study describing the new Japanese isolates, zygote formation between Japanese and North American strains was shown, but germination was not demonstrated. In this study, the germination of intercontinental hybrid zygotes was examined using wild-type Japanese strains and mutant American strains that cannot utilize nitrate. Several clonal progeny strains were established, and the progeny strains were screened based on mating type and nitrate utilization to confirm their hybrid nature. The establishment of four intercontinental hybrid strains with different phenotypic combinations was confirmed by sequencing mating type-specific and nitrate reductase-related genes. The potential for hybrid formation between Japanese and North American strains suggests the existence of a worldwide mating population of C. reinhardtii. © 2014 Japanese Society of Phycology.

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Effect of codon adaptation on codon-level and gene-level translation efficiency in vivo

Nakahigashi, K., Takai, Y., Shiwa, Y., Wada, M., Honma, M., Yoshikawa, H., Tomita, M., Kanai, A. and Mori, H

BMC Genomics (BMC Genomics) 15 ( 1 ) 1115 2014

Joint Work

Background: There is a significant difference between synonymous codon usage in many organisms, and it is known that codons used more frequently generally showed efficient decoding rate. At the gene level, however, there are conflicting reports on the existence of a correlation between codon adaptation and translation efficiency, even in the same organism. Results: To resolve this issue, we cultured Escherichia coli under conditions designed to maintain constant levels of mRNA and protein and subjected the cells to ribosome profiling (RP) and mRNA-seq analyses. We showed that the RP results correlated more closely with protein levels generated under similar culture conditions than with the mRNA abundance from the mRNA-seq. Our result indicated that RP/mRNA ratio could be used as a measure of translation efficiency at gene level. On the other hand, the RP data showed that codon-specific ribosome density at the decoding site negatively correlated with codon usage, consistent with the hypothesis that preferred codons display lower ribosome densities due to their faster decoding rate. However, highly codon-adapted genes showed higher ribosome densities at the gene level, indicating that the efficiency of translation initiation, rather than higher elongation efficiency of preferred codons, exerted a greater effect on ribosome density and thus translation efficiency. Conclusions: These findings indicate that evolutionary pressure on highly expressed genes influenced both codon bias and translation initiation efficiency and therefore explains contradictory findings that codon usage bias correlates with translation efficiency of native genes, but not with the artificially created gene pool, which was not subjected to evolution pressure.

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Comparative metabolite profiling of foxglove aphids (Aulacorthum solani Kaltenbach) on leaves of resistant and susceptible soybean strains

Sato D., Sugimoto M., Akashi H., Tomita M., Soga T.

Molecular BioSystems (Molecular BioSystems) 10 ( 4 ) 909 - 915 2014

ISSN 1742206X

Aphid infestations can cause severe decreases in soybean (Glycine max [L.] Merr.) yield. Since planting aphid-resistant soybean strains is a promising approach for pest control, understanding the resistance mechanisms employed by aphids is of considerable importance. We compared aphid resistance in seven soybean strains and found that strain Tohoku149 was the most resistant to the foxglove aphid, Aulacorthum solani Kaltenbach. We subsequently analyzed the metabolite profiles of aphids cultured on the leaves of resistant and susceptible soybean strains using capillary electrophoresis-time-of-flight mass spectrometry. Our findings showed that the metabolite profiles of several amino acids, glucose 6-phosphate, and components of the tricarboxylic acid cycle were similar in aphids reared on Tohoku149 leaves and in aphids maintained under conditions of starvation, suggesting that Tohoku149 is more resistant to aphid feeding. Compared to susceptible strains, we also found that two methylated metabolites, S-methylmethionine and trigonelline, were either not detected or decreased in aphids reared on Tohoku149 plants. Since these metabolites function as important sulfur transporters in phloem sap and osmoprotectants involved in salt and drought stress, respectively, aphid-resistance is considered to be related to sulfur metabolism and methylation. These results contribute to an increase in our understanding of soybean aphid resistance mechanisms at the molecular level. © 2014 The Royal Society of Chemistry.

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Exceptional Evolutionary Divergence of Human Muscle and Brain Metabolomes Parallels Human Cognitive and Physical Uniqueness

Bozek K., Wei Y., Yan Z., Liu X., Xiong J., Sugimoto M., Tomita M., Pääbo S., Pieszek R., Sherwood C.C., Hof P.R., Ely J.J., Steinhauser D., Willmitzer L., Bangsbo J., Hansson O., Call J., Giavalisco P., Khaitovich P.

PLoS Biology (PLoS Biology) 12 ( 5 ) e1001871 2014

ISSN 15449173

Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys. © 2014 Bozek et al.

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Light microscopy and phylogenetic analyses of Chlamydomonas species (volvocales, chlorophyceae). II. molecular phylogeny, secondary structure of ITS-2, cell morphology, and nomenclature of Microglena opisthopyren, and m. media, comb. nov.

Nakada T., Tomita M.

Acta Phytotaxonomica et Geobotanica 65 ( 2 ) 67 - 73 2014

ISSN 13467565

Two species of Chlamydomonas Ehrenb. in the clade Monadinia, Chlamydomonas pseudomacrostigma L. Ş. Péterfi ex H. Ettl and C. media G. A. Klebs, were recently reported from Japan. However, several species in the clade were transferred to the genus Microglena Ehrenb. by different authors, and therefore the taxonomic treatment of these two species should be revisited. Here, their identifications were re-examined based on 18S rRNA gene phylogeny, secondary structure comparisons of ITS-2 rDNA, and vegetative cell morphology. Based on these comparisons, C. pseudomacrostigma and C. media were treated as a later synonym of Microglena opisthopyren (Skuja) Demchenko, Mikhailyuk & Pröschold and an earlier synonym of M. skujae Demchenko, Mikhailyuk & Pröschold, respectively. A new combination, Microglena media (G.A. Klebs) Nakada, comb. nov., is proposed for the latter.

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Dynamics of serum metabolites in patients with chronic hepatitis C receiving pegylated interferon plus ribavirin: a metabolomics analysis

Saito T, Sugimoto M, Igarashi K, Saito K, Shao L, Katsumi T, Tomita K, Sato C, Okumoto K, Nishise Y, Watanabe H, Tomita M, Ueno Y, Soga T.

Metabolism (Metabolism: Clinical and Experimental) 62 ( 11 ) 1577 - 1586 2013.11

Joint Work, ISSN 00260495

Objectives Serum samples from patients with chronic hepatitis C were subjected to metabolomics analysis to clarify the pretreatment characteristics of their metabolites and also changes in specific metabolites resulting from antiviral therapy with pegylated interferon plus ribavirin (PegIFN/RBV). Materials/Methods The serum levels of low-molecular-weight metabolites in the twenty patients before and 24 weeks after completion of PegIFN/RBV therapy were analyzed using capillary electrophoresis and liquid chromatography-mass spectrometry. Results Ten patients showed a non-virological response (NVR) and 10 achieved a sustained virological response (SVR) with eradication of viremia. The pretreatment levels of tryptophan were significantly higher in the patients of SVR than in those of NVR (p = 0.010). The area under the curve (AUC) value of tryptophan calculated from the receiver operating characteristic (ROC) curve for discriminating SVR from NVR was 0.84 (95% confidential interval, 0.66-1.02, p = 0.010). The ROC curve of multiple logistic regression model incorporating the pretreatment levels of tryptophan and γ-glutamate-arginine showed that the AUC value was highly significant (AUC = 0.92, 95% confidential interval, 0.79-1.05, p = 0.002). Twenty four weeks after completion of treatment, the levels of γ-glutamyl dipeptides, glutamic acid, 5-oxoproline, glucosamine and methionine sulfoxide were decreased, whereas those of 5-methoxy-3- indoleacetate, glutamine, kynurenine and lysine were increased significantly (p < 0.05) in both the NVR and SVR patients. Conclusions The pretreatment serum levels of certain metabolites including tryptophan are associated with the response to PegIFN/RBV therapy. PegIFN/RBV therapy can ameliorate the oxidative stress responsible for glutathione metabolism. © 2013 Elsevier Inc.

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The dynamics of cellular energetics during continuous yeast culture

Amariei C., Machne R., Sasidharan K., Gottstein W., Tomita M., Soga T., Lloyd D., Murray D.B.

Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS (Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS) 2013 2708 - 2711 2013.10

ISSN 1557170X

A plethora of data is accumulating from high throughput methods on metabolites, coenzymes, proteins, and nucleic acids and their interactions as well as the signalling and regulatory functions and pathways of the cellular network. The frozen moment viewed in a single discrete time sample requires frequent repetition and updating before any appreciation of the dynamics of component interaction becomes possible. Even then in a sample derived from a cell population, time-averaging of processes and events that occur in out-of-phase individuals blur the detailed complexity of single cell organization. Continuously-grown cultures of yeast can become spontaneously self-synchronized, thereby enabling resolution of far more detailed temporal structure. Continuous on-line monitoring by rapidly responding sensors (O 2 electrode and membrane-inlet mass spectrometry for O2, CO2 and H2S; direct fluorimetry for NAD(P)H and flavins) gives dynamic information from time-scales of minutes to hours. Supplemented with capillary electophoresis and gas chromatography mass spectrometry and transcriptomics the predominantly oscillatory behaviour of network components becomes evident, with a 40 min cycle between a phase of increased respiration (oxidative phase) and decreased respiration (reductive phase). Highly pervasive, this ultradian clock provides a coordinating function that links mitochondrial energetics and redox balance to transcriptional regulation, mitochondrial structure and organelle remodelling, DNA duplication and cell division events. Ultimately, this leads to a global partitioning of anabolism and catabolism and the enzymes involved, mediated by a relatively simple ATP feedback loop on chromatin architecture. © 2013 IEEE.

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Time-resolved metabolomics of a novel trebouxiophycean alga using 13CO2 feeding

Ito T., Sugimoto M., Toya Y., Ano Y., Kurano N., Soga T., Tomita M.

Journal of Bioscience and Bioengineering (Journal of Bioscience and Bioengineering) 116 ( 3 ) 408 - 415 2013.09

ISSN 13891723

Oil-rich algae are potentially promising as next-generation biofuel feedstock. However, the productivity of oil needs to be improved for industrial use. The biosynthesis of oil and its control mechanism have not been characterized in any algae, and understanding the metabolic network is vital to achieve the precise engineering of algae metabolic pathways. "Pseudochoricystis ellipsoidea" MBIC 11204, a novel microalgal strain, accumulates a large amount of lipids in nitrogen-deficient conditions. In this study, "P.ellipsoidea" was grown in flat flasks with continuous illumination and aeration with 1% CO2 at 25°C. During the exponential growth phase, CO2 was switched to 13C-labeled CO2 and samples were collected for time-course experiments. Seventy-eight pairs of unlabeled and uniformly 13C-labeled metabolites were quantified using a capillary electrophoresis- and liquid chromatography-mass spectrometry for ionic primary metabolites and lipids, respectively. The 13C-exchange indices of the metabolites were calculated from a concentration of unlabeled and uniformly-labeled metabolites. A hierarchical clustering analysis of the dynamics of the indices revealed 4 characteristic clusters, two of which represented rapidly-labeled metabolites, mainly composed of primary metabolites, while the two other clusters represented slowly-labeled metabolites, mainly composed of lipids. Moreover, the labeling order of these clusters was mainly matched to the metabolic process of Chlamydomonas reinhardtii, a model organism of green algae. In TCA cycle, anomalistically different of the labeling order was found. To the author's knowledge, this study for the first time in literature, characterize the features of global metabolism in "P.ellipsoidea.". © 2013 The Society for Biotechnology, Japan.

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Dynamic Simulation and Metabolome Analysis of Long-Term Erythrocyte Storage in Adenine-Guanosine Solution

Nishino T., Yachie-Kinoshita A., Hirayama A., Soga T., Suematsu M., Tomita M.

PLoS ONE (PLoS ONE) 8 ( 8 ) e71060 2013.08

Although intraerythrocytic ATP and 2,3-bisphophoglycerate (2,3-BPG) are known as direct indicators of the viability of preserved red blood cells and the efficiency of post-transfusion oxygen delivery, no current blood storage method in practical use has succeeded in maintaining both these metabolites at high levels for long periods. In this study, we constructed a mathematical kinetic model of comprehensive metabolism in red blood cells stored in a recently developed blood storage solution containing adenine and guanosine, which can maintain both ATP and 2,3-BPG. The predicted dynamics of metabolic intermediates in glycolysis, the pentose phosphate pathway, and purine salvage pathway were consistent with time-series metabolome data measured with capillary electrophoresis time-of-flight mass spectrometry over 5 weeks of storage. From the analysis of the simulation model, the metabolic roles and fates of the 2 major additives were illustrated: (1) adenine could enlarge the adenylate pool, which maintains constant ATP levels throughout the storage period and leads to production of metabolic waste, including hypoxanthine; (2) adenine also induces the consumption of ribose phosphates, which results in 2,3-BPG reduction, while (3) guanosine is converted to ribose phosphates, which can boost the activity of upper glycolysis and result in the efficient production of ATP and 2,3-BPG. This is the first attempt to clarify the underlying metabolic mechanism for maintaining levels of both ATP and 2,3-BPG in stored red blood cells with in silico analysis, as well as to analyze the trade-off and the interlock phenomena between the benefits and possible side effects of the storage-solution additives. © 2013 Yachie-Kinoshita et al.

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GEMBASSY: An EMBOSS associated software package for comprehensive genome analyses

Itaya H, Oshita K, Arakawa K, Tomita M.

Source Code for Biology and Medicine (Source Code for Biology and Medicine) 8 ( 17 ) 17 2013.08

Joint Work, ISSN 1751-0473

The popular European Molecular Biology Open Software Suite (EMBOSS) currently contains over 400 tools used in various bioinformatics researches, equipped with sophisticated development frameworks for interoperability and tool discoverability as well as rich documentations and various user interfaces. In order to further strengthen EMBOSS in the fields of genomics, we here present a novel EMBOSS associated software (EMBASSY) package named GEMBASSY, which adds more than 50 analysis tools from the G-language Genome Analysis Environment and its Representational State Transfer (REST) and SOAP web services. GEMBASSY basically contains wrapper programs of G-language REST/SOAP web services to provide intuitive and easy access to various annotations within complete genome flatfiles, as well as tools for analyzing nucleic composition, calculating codon usage, and visualizing genomic information. For example, analysis methods such as for calculating distance between sequences by genomic signatures and for predicting gene expression levels from codon usage bias are effective in the interpretation of meta-genomic and meta-transcriptomic data. GEMBASSY tools can be used seamlessly with other EMBOSS tools and UNIX command line tools. The source code written in C is available from GitHub (https://github.com/celery-kotone/GEMBASSY/) and the distribution package is freely available from the GEMBASSY web site (http://www.g-language.org/gembassy/). © 2013 Itaya et al.; licensee BioMed Central Ltd.

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Global microRNA elevation by inducible Exportin 5 regulates cell cycle entry

Iwasaki Y.W., Kiga K., Kayo H., Fukuda-Yuzawa Y., Weise J., Inada T., Tomita M., Ishihama Y., Fukao T.

RNA (RNA) 19 ( 4 ) 490 - 497 2013.04

ISSN 13558382

Proper regulation of gene expression during cell cycle entry ensures the successful completion of proliferation, avoiding risks such as carcinogenesis. The microRNA (miRNA) network is an emerging molecular system regulating multiple genetic pathways. We demonstrate here that the global elevation of miRNAs is critical for proper control of gene expression program during cell cycle entry. Strikingly, Exportin 5 (XPO5) is promptly induced during cell cycle entry by a PI3K-dependent post-transcriptional mechanism. Inhibition of XPO5 induction interfered with global miRNA elevation and resulted in a proliferation defect associated with delayed G1/S transition. During cell cycle entry, XPO5 therefore plays a paramount role as a critical molecular hub controlling the gene expression program through global regulation of miRNAs. Our data suggest that XPO5-mediated global miRNA elevation might be involved in a broad range of cellular events associated with cell cycle control. Copyright © 2013 RNA Society.

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Changes of metabolic profiles in an oral squamous cell carcinoma cell line induced by eugenol

Koh T, Murakami Y, Tanaka S, Machino M, Onuma H, Kaneko M, Sugimoto M, Soga T, Tomita M, Sakagami H.

In Vivo (In Vivo) 27 ( 2 ) 233 - 243 2013.03

Joint Work, ISSN 0258851X

Background: We have recently reported that eugenol exerted indiscriminate cytotoxicity towards normal oral cells and oral squamous cell carcinoma (OSCC) cell lines without induction of apoptosis markers. In order to investigate the underlying mechanisms of cytotoxicity induction, we investigated the effect of short-term treatment with eugenol on the metabolic profiles of a human OSCC cell line (HSC-2). Materials and Methods: The viable cell number was determined by direct cell counting with a hemocytometer after trypsinization. After washing with 5% D-mannitol solution (found to retain the highest amounts of intracellular metabolites among several washing conditions), cellular metabolites were extracted with methanol with internal markers and then subjected to metabolomic analysis. Results: Cytotoxic concentrations of eugenol induced the reduction of ATP utilization (assessed by a significant reduction of the AMP/ATP and ADP/ATP ratio), of oxidative stress (assessed by the increase in oxidized form of glutathione, cysteine-glutathione disulfide and methionine sulfoxide), and an increase in the polyamines and glycolytic metabolites. Conclusion: The metabolic changes observed in this study suggest the induction of non-apoptotic cell death by eugenol.

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