Details of a Researcher - Soga, Tomoyoshi

Papers - Soga, Tomoyoshi

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Metabolomic profiling as a possible reverse engineering tool for estimating processing conditions of dry-cured hams

Sugimoto, M., Obiya, S., Kaneko, M., Enomoto, A., Honma, M., Wakayama, M., Soga, T., Tomita, M.

J. Agric. Food Chem 65 ( 2 ) 402 - 410 2017.01

Research paper (scientific journal), Joint Work, Accepted

Dry-cured hams are popular among consumers. To increase the attractiveness of the product, objective analytical methods and algorithms to evaluate the relationship between observable properties and consumer acceptability are required. In this study, metabolomics, which is used for quantitative profiling of hundreds of small molecules, was applied to 12 kinds of dry-cured hams from Japan and Europe. In total, 203 charged metabolites, including amino acids, organic acids, nucleotides, and peptides, were successfully identified and quantified. Metabolite profiles were compared for the samples with different countries of origin and processing methods (e.g., smoking or use of a starter culture). Principal component analysis of the metabolite profiles with sensory properties revealed significant correlations for redness, homogeneity, and fat whiteness. This approach could be used to design new ham products by objective evaluation of various features.

Stimulating S-adenosyl-L-methionine synthesis extends lifespan via activation of AMPK

Ogawa, T., Tsubakiyama, R., Kanai, M., Koyama , T., Fujii, T., Iefuji, H., Soga, T., Kume, K., Miyakawa, T., Hirata, D., Mizunuma, M.

Proc. Natl. Acad. Sci. USA 113 ( 42 ) 11913 - 11918 2016.10

Research paper (scientific journal), Joint Work, Accepted

Dietary restriction (DR), such as calorie restriction (CR) or methionine (Met) restriction, extends the lifespan of diverse model organisms. Although studies have identified several metabolites that contribute to the beneficial effects of DR, the molecular mechanism underlying the key metabolites responsible for DR regimens is not fully understood. Here we show that stimulating S-adenosyl-l-methionine (AdoMet) synthesis extended the lifespan of the budding yeast Saccharomyces cerevisiae The AdoMet synthesis-mediated beneficial metabolic effects, which resulted from consuming both Met and ATP, mimicked CR. Indeed, stimulating AdoMet synthesis activated the universal energy-sensing regulator Snf1, which is the S. cerevisiae ortholog of AMP-activated protein kinase (AMPK), resulting in lifespan extension. Furthermore, our findings revealed that S-adenosyl-l-homocysteine contributed to longevity with a higher accumulation of AdoMet only under the severe CR (0.05% glucose) conditions. Thus, our data uncovered molecular links between Met metabolites and lifespan, suggesting a unique function of AdoMet as a reservoir of Met and ATP for cell survival.

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Metabolic Profiling of Total Physical Activity and Sedentary Behavior in Community-Dwelling Men

Fukai, K., Harada, S., Iida, M., Kuriara, A., Takeuchi, A., Kuwabara, K., Sugiyama, D., Okamura, T., Akiyama, M., Nishiwaki, Y., Oguma, Y., Suzuki, A., Suzuki, C, Hirayama, A., Sugimoto, M., Soga, T.,c Tomita, M., Takebayashi, T.

PLoS One 11 ( 10 ) e0164877 2016.10

Research paper (scientific journal), Joint Work, Accepted

Objective: Physical activity is known to be preventive against various non-communicable diseases. We investigated the relationship between daily physical activity level and plasma metabolites using a targeted metabolomics approach in a population-based study.
Methods: A total of 1,193 participants (male, aged 35 to 74 years) with fasting blood samples were selected from the baseline survey of a cohort study. Information on daily total physical activity, classified into four levels by quartile of metabolic equivalent scores, and sedentary behavior, defined as hours of sitting per day, was collected through a self-administered questionnaire. Plasma metabolite concentrations were quantified by capillary electrophoresis mass spectrometry method. We performed linear regression analysis models with multivariable adjustment and corrected p-values for multiple testing in the original population (n = 808). The robustness of the results was confirmed by replication analysis in a separate population (n = 385) created by random allocation.
Results: Higher levels of total physical activity were associated with various metabolite concentrations, including lower concentrations of amino acids and their derivatives, and higher concentrations of pipecolate (FDR p <0.05 in original population). The findings persisted after adjustment for age, body mass index, smoking, alcohol intake, and energy intake. Isoleucine, leucine, valine, 4-methyl-2-oxoisopentanoate, 2-oxoisopentanoate, alanine, and proline concentrations were lower with a shorter sitting time.
Conclusions: Physical activity is related to various plasma metabolites, including known biomarkers for future insulin resistance or type 2 diabetes. These metabolites might potentially play a key role in the protective effects of higher physical activity and/or less sedentary behavior on non-communicable diseases.

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Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles

Yamano, E., Sugimoto, M., Hirayama, A., Kume, S., Yamato, M., Jin, G., Tajima, S., Goda, N., Iwai, K., Fukuda, S., Yamaguti, K, Kuratsune, H., Soga, T., Watanabe, Y., Kataoka, Y.

Sci Rep. 6 34990 2016.10

Research paper (scientific journal), Joint Work, Accepted

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Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis

Bardella C, Al-Dalahmah O, Krell D, Brazauskas P, Al-Qahtani K, Tomkova M, Adam J, Serres S, Lockstone H, Freeman-Mills L, Pfeffer I, Sibson N, Goldin R, Schuster-Böeckler B, Pollard, PJ, Soga T, McCullagh JS, Schofield CJ, Mulholland P, Ansorge O, Kriaucionis S, Ratcliffe PJ, Szele, FG, Tomlinson I

Cancer Cell 30 ( 4 ) 578 - 594 2016.10

Research paper (scientific journal), Joint Work

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

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Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance

Hegazy, A.M., Yamada, D., Kobayashi, M., Kohno, S., Ueno, M., Ali, MA., Ohta, K., Tadokoro, Y., Ino, Y., Todo, T., Soga, T., Takahashi, C., Hirao, A.

J. Biol. Chem. 291 ( 41 ) 21496 - 21509 2016.10

Research paper (scientific journal), Joint Work, Accepted

Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients.

Identification of salivary metabolomic biomarkers for oral cancer screening

Ishikawa, S., Sugimoto, M., Kitabatake, K., Sugano, A., Nakamura, M., Kaneko, M., Ota, S., Hiwatari, K., Enomoto, A., Soga, T., Tomita, M., Iino, M.

Sci. Rep. 6 ( - ) 31520 - - 2016.08

Research paper (scientific journal), Joint Work, Accepted

The objective of this study was to explore salivary metabolite biomarkers by profiling both saliva and tumor tissue samples for oral cancer screening. Paired tumor and control tissues were obtained from oral cancer patients and whole unstimulated saliva samples were collected from patients and healthy controls. The comprehensive metabolomic analysis for profiling hydrophilic metabolites was conducted using capillary electrophoresis time-of-flight mass spectrometry. In total, 85 and 45 metabolites showed significant differences between tumor and matched control samples, and between salivary samples from oral cancer and controls, respectively (P < 0.05 correlated by false discovery rate); 17 metabolites showed consistent differences in both saliva and tissue-based comparisons. Of these, a combination of only two biomarkers yielded a high area under receiver operating characteristic curves (0.827; 95% confidence interval, 0.726-0.928, P < 0.0001) for discriminating oral cancers from controls. Various validation tests confirmed its high generalization ability. The demonstrated approach, integrating both saliva and tumor tissue metabolomics, helps eliminate pseudo-molecules that are coincidentally different between oral cancers and controls. These combined salivary metabolites could be the basis of a clinically feasible method of non-invasive oral cancer screening.

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p38α activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling in response to stress

Karigane, D., Kobayashi, H., Morikawa, T., Ootomo, Y., Sakai, M., Nagamatsu, G., Kubota, Y., Goda, N., Matsumoto, M., Nishimura, E. K., Soga, T., Otsu, K., Suematsu, M., Okamoto, S., Suda, T., Takubo, K.

Cell Stem Cell 19 ( 2 ) 192 - 204 2016.08

Research paper (scientific journal), Joint Work

Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. We do not yet have a clear understanding of how this metabolic activity changes during stress hematopoiesis, such as bone marrow transplantation. Here, we report a critical role for the p38MAPK family isoform p38α in initiating hematopoietic stem and progenitor cell (HSPC) proliferation during stress hematopoiesis in mice. We found that p38MAPK is immediately phosphorylated in HSPCs after a hematological stress, preceding increased HSPC cycling. Conditional deletion of p38α led to defective recovery from hematological stress and a delay in initiation of HSPC proliferation. Mechanistically, p38α signaling increases expression of inosine-5'-monophosphate dehydrogenase 2 in HSPCs, leading to altered levels of amino acids and purine-related metabolites and changes in cell-cycle progression in vitro and in vivo. Our studies have therefore uncovered a p38α-mediated pathway that alters HSPC metabolism to respond to stress and promote recovery.

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Mitochondrial Mg2+ homeostasis decides cellular energy metabolism and vulnerability to stress

Yamanaka, R., Tabata, S., Shindo, Y., Hotta, K., Suzuki, K., Soga, T., Oka, K.

Sci. Rep. 6 30027 2016.07

Research paper (scientific journal), Joint Work, Accepted

Cellular energy production processes are composed of many Mg(2+) dependent enzymatic reactions. In fact, dysregulation of Mg(2+) homeostasis is involved in various cellular malfunctions and diseases. Recently, mitochondria, energy-producing organelles, have been known as major intracellular Mg(2+) stores. Several biological stimuli alter mitochondrial Mg(2+) concentration by intracellular redistribution. However, in living cells, whether mitochondrial Mg(2+) alteration affect cellular energy metabolism remains unclear. Mg(2+) transporter of mitochondrial inner membrane MRS2 is an essential component of mitochondrial Mg(2+) uptake system. Here, we comprehensively analyzed intracellular Mg(2+) levels and energy metabolism in Mrs2 knockdown (KD) cells using fluorescence imaging and metabolome analysis. Dysregulation of mitochondrial Mg(2+) homeostasis disrupted ATP production via shift of mitochondrial energy metabolism and morphology. Moreover, Mrs2 KD sensitized cellular tolerance against cellular stress. These results indicate regulation of mitochondrial Mg(2+) via MRS2 critically decides cellular energy status and cell vulnerability via regulation of mitochondrial Mg(2+) level in response to physiological stimuli.

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Serum metabolome profiles characterized by patients with hepatocellular carcinoma associated with hepatitis B and C

Saito, T., Sugimoto, M., Okumoto, K., Haga, H., Katsumi, T., Mizuno, K., Nishina, T., Sato, S., Igarashi, K., Maki, H., Tomita, M., Ueno, Y., Soga, T.

World J. Gastroenterol. 22 ( 27 ) 6224 - 6234 2016.07

Research paper (scientific journal), Joint Work

Aim: To clarify the characteristics of metabolite profiles in virus-related hepatocellular carcinoma (HCC) patients using serum metabolome analysis.
Methods: The serum levels of low-molecular-weight metabolites in 68 patients with HCC were quantified using capillary electrophoresis chromatography and mass spectrometry. Thirty and 38 of the patients suffered from hepatitis B virus-related HCC (HCC-B) and hepatitis C virus-related HCC (HCC-C), respectively.
Results: The main metabolites characteristic of HCC were those associated with glutathione metabolism, notably 13 γ-glutamyl peptides, which are by-products of glutathione induction. Two major profiles, i.e., concentration patterns, of metabolites were identified in HCC patients, and these were classified into two groups: an HCC-B group and an HCC-C group including some of the HCC-B cases. The receiver operating characteristic curve for the multiple logistic regression model discriminating HCC-B from HCC-C incorporating the concentrations of glutamic acid, methionine and γ-glutamyl-glycine-glycine showed a highly significant area under the curve value of 0.94 (95%CI: 0.89-1.0, P < 0.0001).

Conclusion: The serum levels of γ-glutamyl peptides, as well as their concentration patterns, contribute to the development of potential biomarkers for virus-related HCC. The difference in metabolite profiles between HCC-B and HCC-C may reflect the respective metabolic reactions that underlie the different pathogeneses of these two types of HCC.

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Profiling of plasma metabolites in postmenopausal women with metabolic syndrome

Iida, M., Harada, S., Kurihara, A., Fukai, K., Kuwabara, K., Sugiyama, D., Takeuchi, A., Okamura, T., Akiyama, M., Nishiwaki, Y., Suzuki, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Banno, K., Aoki, D., Takebayashi, T.

Menopause 23 ( 7 ) 749 - 758 2016.07

Research paper (scientific journal), Joint Work, Accepted

Objective: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population.
Methods: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation.
Results: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0 kg/m, 72.1 mg/dL, and 126.1 mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased.
Conclusions: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.

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p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

Saito, T., Ichimura, Y., Taguchi, K., Suzuki, T., Mizushima, T., Takagi, K., Hirose, Y., Nagahashi, M., Iso, T., Fukutomi, T., Ohishi, M., Endo, K., Uemura, T., Nishito, Y., Okuda, S., Obata, M., Kouno, T., Imamura, R., Tada, Y., Obata, R., Yasuda, D., Takahashi, K., Fujimura, T., Pi, J., Lee, MS., Ueno, T., Ohe, T., Mashino, T., Wakai, T., Kojima, H., Okabe, T., Nagano, T., Motohashi, H., Waguri, S., Soga, T., Yamamoto, M., Tanaka, K., Komatsu, M.

Nat. Commun. 7 12030 2016.06

Research paper (scientific journal), Joint Work

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

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Smad2/3 are required for immobilization-induced skeletal muscle atrophy

Tando, T., Hirayama, A., Furukawa, M., Sato, Y., Kobayashi, T., Funayama1, A., Kanaji, A., Hao, W., Watanabe, R., Morita, M., Oike, T., Miyamoto, K., Soga, T., Nomura, M., Yoshimura, A., Tomita, M., Matsumoto, M., Nakamura, M., Toyama, Y., Miyamoto, T.

J. Biol. Chem. 291 ( 23 ) 12184 - 12194 2016.06

Research paper (scientific journal), Joint Work, Accepted

Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.

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Effects of fractionated radiation on murine glioma stem cell metabolism

Fujita, S., Osuka, S. Shibao, S., Igarashi, K., Soga, T., Sampetrean, O.

Toho J. Med. 2 ( 2 ) 45 - 52 2016.06

Research paper (scientific journal), Joint Work, Accepted

Background: Glioma stem cells (GSCs) have an important role in tumor recurrence after treatment. We recently showed that, in a mouse model of glioma, GSCs adapt to repeated radiation exposures by changing
their secretory profile and modulating survival signaling. Irradiated GSCs also reduce their rate of proliferation. In the present study we examined whether these changes require a specific adaptation of GSC energy
metabolism.
Methods: Initial tumors were established in mice by orthotopic implantation of Ink4a/Arf-null neural stem
cells transduced with human HRASV12. GSCs isolated from the tumors were exposed (or not) to fractionated
radiation (12 fractions of 5 Gy), and five clones in each group of cells were assessed for glucose consumption,
lactate production, and content of intracellular metabolites.
Results: Rates of glucose consumption and lactate production were lower in clones exposed to radiation
than in nonirradiated clones, which suggests a reduction in glycolysis. Among intracellular metabolites, the
high concentrations of intermediates of glycolysis and nucleoside metabolism were reduced in irradiated
clones, whereas levels of essential amino acids were largely unchanged.
Conclusions: Repeated radiation changes the metabolic preferences of GSCs, in conjunction with their
slowed proliferation. Future studies should thus investigate intra- and extracellular metabolites, to identify
potential diagnostic and therapeutic targets for glioma recurrence.

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Identification of biomarkers for development of end-stage kidney disease in chronic kidney disease by metabolomic profiling

Kimura, T., Yasuda, K., Yamamoto, R., Soga, T., Rakugi, H., Hayashi, T., Isaka, Y.

Sci. Rep. 6 ( - ) 26138 - - 2016.05

Research paper (scientific journal), Joint Work

A critical issue in the management of chronic kidney disease (CKD) is to prevent patients from the progression to end-stage kidney disease (ESKD), however, there is only limited number of biomarkers for the discrimination of the high-risk CKD patients. We aimed to identify the metabolites which possess the ability to predict the earlier kidney deterioration. We performed capillary electrophoresis and liquid chromatography mass spectrometry (CE-MS)-based metabolic profiling in a prospective cohort, which consisted of referred 112 CKD patients with median follow-up period of 4.4 years. The association between the levels of candidate metabolites and the outcomes (progression to ESKD alone or in combination with death before ESKD) were assessed by multivariate Cox proportional hazard models after adjusting for the baseline covariates. A total of 218 metabolites were detected in the plasma of CKD patients. We identified 16 metabolites which have predictive values for the composite outcome: The risk for composite outcome was elevated from 2.0- to 8.0-fold in those with higher levels of 16 plasma metabolites. Our results suggest that the measurement of these metabolites may facilitate CKD management by predicting the risk of progression to ESKD.

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Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men

Harada S., Takebayashi T., Kurihara A., Akiyama M., Suzuki A., Hatakeyama Y., Sugiyama D., Kuwabara K., Takeuchi A., Okamura T., Nishiwaki Y., Tanaka T., Hirayama A., Sugimoto M., Soga T., Tomita M.

Environ. Health Prev. Med. 21 ( 1 ) 18(283) - 26(284) 2016.01

Research paper (scientific journal), Joint Work, Accepted

Objective: Metabolomics is a promising approach to the identification of biomarkers in plasma. Here, we performed a population-based, cross-sectional study to identify potential biomarkers of alcohol intake and alcohol-induced liver injury by metabolomic profiling using capillary electrophoresis-mass spectrometry (CE-MS).
Methods: Fasting plasma samples were collected from 896 Japanese men who participated in the baseline survey of the Tsuruoka Metabolomics Cohort Study, and 115 polar metabolites were identified and absolutely quantified by CE-MS. Information on daily ethanol intake was collected through a standardized, self-administered questionnaire. The associations between ethanol intake and plasma concentration of metabolites were examined. Relationships between metabolite concentrations or their ratios and serum liver enzyme levels in the highest ethanol intake group (>46.0 g/day) were then examined by linear regression analysis. Replication analysis was conducted in 193 samples collected from independent population of this cohort.
Results: Nineteen metabolites were identified to have an association with daily alcohol consumption both in the original and replication population. Three of these metabolites (threonine, glutamine, and guanidinosuccinate) were found to associate well with elevated levels of serum liver enzymes in the highest ethanol intake group, but not in the non-drinker group. We also found that the glutamate/glutamine ratio had a much stronger relation to serum γ-glutamyltransferase, aspartate transaminase, and alanine transaminase than glutamate or glutamine alone (standardized beta = 0.678, 0.558, 0.498, respectively).
Conclusions: We found 19 metabolites associated with alcohol intake, and three biomarker candidates (threonine, guanidinosuccinate and glutamine) of alcohol-induced liver injury. Glutamate/glutamine ratio might also be good biomarker.

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Effects of 3-styrylchromones on metabolic profiles and cell death in oral squamous cell carcinoma cells

Sakagami, H., Shimada, C., Kanda, Y., Amano, O., Sugimoto, M., Ota S., Soga, T., Tomita, M., Sato, A., Tanuma, S., Takao, K., Sugita, Y.

Toxicol. Rep. 2 1281 - 1290 2015.12

Research paper (scientific journal), Joint Work, Accepted

4H-1-benzopyran-4-ones (chromones) are important naturally-distributing compounds. As compared with flavones, isoflavones and 2-styrylchromones, there are only few papers of 3-styrylchromones that have been published. We have previously reported that among fifteen 3-styrylchromone derivatives, three new synthetic compounds that have OCH3 group at the C-6 position of chromone ring, (E)-3-(4-hydroxystyryl)-6-methoxy-4H-chromen-4-one (compound 11), (E)-6-methoxy-3-(4-methoxystyryl)-4H-chromen-4-one (compound 4), (E)-6-methoxy-3-(3,4,5-trimethoxystyryl)-4H-chromen-4-one (compound 6) showed much higher cytotoxicities against four epithelial human oral squamous cell carcinoma (OSCC) lines than human normal oral mesenchymal cells. In order to further confirm the tumor specificities of these compounds, we compared their cytotoxicities against both human epithelial malignant and non-malignant cells, and then investigated their effects on fine cell structures and metabolic profiles and cell death in human OSCC cell line HSC-2. Cytotoxicities of compounds 4, 6, 11 were assayed with MTT method. Fine cell structures were observed under transmission electron microscope. Cellular metabolites were extracted with methanol and subjected to CE-TOFMS analysis. Compounds 4, 6, 11 showed much weaker cytotoxicity against human oral keratinocyte and primary human gingival epithelial cells, as compared with HSC-2, confirming their tumor-specificity, whereas doxorubicin and 5-FU were highly cytotoxic to these normal epithelial cells, giving unexpectedly lower tumor-specificity. The most cytotoxic compound 11, induced the mitochondrial vacuolization, autophagy suppression followed by apoptosis induction, and changes in the metabolites involved in amino acid and glycerophospholipid metabolisms. Chemical modification of lead compound 11 may be a potential choice for designing new type of anticancer drugs.

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Effects of processing and storage conditions on charged metabolomic profiles in blood

Hirayama, A., Sugimoto, M., Suzuki, A., Hatakeyama, Y., Enomoto, A., Harada, S., Soga, T., Tomita, M., Takebayashi, T.

Electrophoresis 36 ( 18 ) 2148 - 2155 2015.09

Research paper (scientific journal), Joint Work, Accepted

The development of high-throughput metabolite measurement technologies has enabled the use of metabolomics for epidemiologic studies by profiling metabolite concentrations in large cohorts of human blood samples. Standard protocols are necessary to obtain unbiased profiles through multiple runs over long periods of time and to allow reliable statistical analyses. This study assessed the effects of sampling procedures and storage conditions on the stability of metabolomic profiles in plasma and serum. Charged metabolomic profiles were determined by capillary electrophoresis-mass spectrometry (CE-MS) and compared by multivariate analyses. The effects of pre-analytical procedures, including times for clotting and incubation of serum and plasma, respectively; incubation temperatures; and number of freeze-thaw cycles, were assessed. Overall, inter-individual differences in profiles were larger than intra-individual differences, and profiles in plasma showed better stability than those in serum. These quantified datasets of metabolites, along with their stability and variation, may help in interpreting data from long-term cohort studies.

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Metabolomic alterations in human cancer cells by vitamin C-induced oxidative stress

Uetaki, M., Tabata, S., Nakasuka, F., Soga, T., Tomita, M.

Sci. Rep. 5 ( - ) 13896 - - 2015.09

Research paper (scientific journal), Joint Work, Accepted

Intravenous administration of high-dose vitamin C has recently attracted attention as a cancer therapy. High-dose vitamin C induces pro-oxidant effects and selectively kills cancer cells. However, the anticancer mechanisms of vitamin C are not fully understood. Here, we analyzed metabolic changes induced by vitamin C in MCF7 human breast adenocarcinoma and HT29 human colon cancer cells using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The metabolomic profiles of both cell lines were dramatically altered after exposure to cytotoxic concentrations of vitamin C. Levels of upstream metabolites in the glycolysis pathway and tricarboxylic acid (TCA) cycle were increased in both cell lines following treatment with vitamin C, while adenosine triphosphate (ATP) levels and adenylate energy charges were decreased concentration-dependently. Treatment with N-acetyl cysteine (NAC) and reduced glutathione (GSH) significantly inhibited vitamin C-induced cytotoxicity in MCF7 cells. NAC also suppressed vitamin C-dependent metabolic changes, and NAD treatment prevented vitamin C-induced cell death. Collectively, our data suggests that vitamin C inhibited energy metabolism through NAD depletion, thereby inducing cancer cell death.

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Acquisition of chemoresistance to gemcitabine is induced by a loss-of-function missense mutation of DCK

Nakano, T., Saiki, Y., Kudo, C., Hirayama, A., Mizuguchi, Y., Fujiwara, S., Soga, T., Sunamura, M., Matsumura, N., Motoi, F., Unno, M., Horii, A.

Biochem. Biophys. Res. Commun. 464 ( 4 ) 1084 - 1089 2015.09

Research paper (scientific journal), Joint Work, Accepted

The anti-tumor activity of gemcitabine (GEM) has been clinically proven in several solid tumors, including pancreatic cancer, biliary tract cancer, urinary bladder cancer, and non-small cell lung cancer. However, problems remain with issues such as acquisition of chemoresistance against GEM. GEM is activated after phosphorylation by deoxycytidine kinase (DCK) inside of the cell; thus, DCK inactivation is one of the important mechanisms for acquisition of GEM resistance. We previously investigated the DCK gene in multiple GEM resistant cancer cell lines and identified frequent inactivating mutations. In this study, we identified two crucial genetic alteration in DCK. (1) A total deletion of DCK in RTGBC1-TKB, an acquired GEM resistant cell line derived from a gall bladder cancer cell line TGBC1-TKB. (2) An E197K missense alteration of DCK in MKN28, a gastric cancer cell line; its acquired GEM resistant cancer cell line, RMKN28, showed a loss of the normal E197 allele. We introduced either normal DCK or altered DCK_E197K into RMKN28 and proved that only the introduction of normal DCK restored GEM sensitivity. Furthermore, we analyzed 104 healthy volunteers and found that none of them carried the same base substitution observed in MKN28. These results strongly suggest that (1) the E197K alteration in DCK causes inactivation of DCK, and that (2) loss of the normal E197 allele is the crucial mechanism in acquisition of GEM resistance in RMKN28.

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