研究者詳細 - 曽我　朋義

論文 - 曽我　朋義

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Ketone body 3-hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

Izuta Y., Imada T., Hisamura R., Oonishi E., Nakamura S., Inagaki E., Ito M., Soga T., Tsubota K.

Aging Cell 17 （ 1 ） e12699 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 14749718

Calorie restriction (CR) being the most robust dietary intervention provides various health benefits. D-3-hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), were concomitantly preserved. Importantly, the upregulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a regulator of G6PD, and elevation of the tricarboxylic acid cycle's Nrf2 activator, fumarate, were also shared. Together, our findings suggest that CR provides retinal antioxidative defense by 3HB through the antioxidant Nrf2 pathway via modification of a tricarboxylic acid cycle intermediate during 3HB metabolism.

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Comparative analysis of cerebrospinal fluid metabolites in Alzheimer's disease and idiopathic normal pressure hydrocephalus in a Japanese cohort

Nagata Y., Hirayama A., Ikeda S., Shirahata A., Shoji F., Maruyama M., Kayano M., Bundo M., Hattori K., Yoshida S., Goto Y., Urakami K., Soga T., Ozaki K., Niida S.

Biomark. Res. 6 （ 1 ） 5 2018年01月

研究論文（学術雑誌）, 共著, 査読有り

© 2018 The Author(s).
Background: Alzheimer's disease (AD) is a most common dementia in elderly people. Since AD symptoms resemble those of other neurodegenerative diseases, including idiopathic normal pressure hydrocephalus (iNPH), it is difficult to distinguish AD from iNPH for a precise and early diagnosis. iNPH is caused by the accumulation of cerebrospinal fluid (CSF) and involves gait disturbance, urinary incontinence, and dementia. iNPH is treatable with shunt operation which removes accumulated CSF from the brain ventricles. Methods: We performed metabolomic analysis in the CSF of patients with AD and iNPH with capillary electrophoresis-mass spectrometry. We assessed metabolites to discriminate between AD and iNPH with Welch's t-test, receiver operating characteristic (ROC) curve analysis, and multiple logistic regression analysis. Results: We found significant increased levels of glycerate and N-acetylneuraminate and significant decreased levels of serine and 2-hydroxybutyrate in the CSF of patients with AD compared to the CSF of patients with iNPH. The ROC curve analysis with these four metabolites showed that the area under the ROC curve was 0.90, indicating good discrimination between AD and iNPH. Conclusions: This study identified four metabolites that could possibly discriminate between AD and iNPH, which previous research has shown are closely related to the risk factors, pathogenesis, and symptoms of AD. Analyzing pathway-specific metabolites in the CSF of patients with AD may further elucidate the mechanism and pathogenesis of AD.

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Reliability of plasma polar metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry

Harada S., Hirayama A., Chan Q., Kurihara A., Fukai K., Iida M., Kato S., Sugiyama D., Kuwabara K., Takeuchi A., Akiyama M., Okamura T., Ebbels T., Elliott P., Tomita M., Sato A., Suzuki C., Sugimoto M., Soga T., Takebayashi T.

PLoS One 13 （ 1 ） e0191230 2018年01月

研究論文（学術雑誌）, 単著, 査読有り

Background: Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population.

Methods: Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid.

Results and conclusions: In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies.

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Antioxidant role of autophagy in maintaining the integrity of glomerular capillaries

Matsuda J., Namba T., Takabatake Y., Kimura T., Takahashi A., Yamamoto T., Minami S., Sakai S., Fujimura R., Kaimori J., Matsui I., Hamano T., Fukushima Y., Matsui K., Soga T., Isaka Y.

Autophagy 14 （ 1 ） 53 - 65 2018年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 15548627

Autophagy is a lysosomal degradation system by which cytosolic materials and damaged organelles are broken down into basic components. To explore the physiological role of autophagy in glomerular endothelial cells (GEnCs), we compared the autophagic flux among cells in the kidney under starvation. Inhibition of autophagy by chloroquine administration significantly increased the number of autophagosomes or autolysosomes in GEnCs and proximal tubular cells, but not in podocytes, suggesting that the GEnCs exhibit substantial autophagic activity. Next, we analyzed endothelial and hematopoietic cell-specific atg5-deficient mice (atg5-conditional KO [cKO] mice). Glomeruli of 4-wk-old atg5-cKO mice exhibited slightly distended capillary loops accompanied by an accumulation of reactive oxygen species (ROS). Glomeruli of 8-wk-old atg5-cKO mice showed a lobular pattern with thickening of the capillary loops and mesangial matrix expansion; however, the vasculature of other organs was preserved. The atg5-cKO mice died by 12 wk of age, presumably due to pancytopenia resulting from the defect in their hematopoietic lineages. Therefore, we subjected 4-wk atg5-cKO mice to irradiation followed by bone marrow transplantation from normal littermates. Transplanted mice recapitulated the glomerular phenotypes of the atg5-cKO mice with no obvious histological changes in other organs. Twelve-mo-old transplanted mice developed mesangiolysis and glomerulosclerosis with significant deterioration of kidney function. Administration of N-acetyl-l-cysteine, a ROS scavenger, to atg5-cKO mice rescued the glomerular phenotypes. These data suggest that endothelial autophagy protects glomeruli from oxidative stress and maintains the integrity of glomerular capillaries. Enhancing endothelial autophagy may provide a novel therapeutic approach to minimizing glomerular diseases.

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Dynamic metabolomics reveals that insulin primes the adipocyte for glucose metabolism

Krycer, JR., Yugi, K., Hirayama, A., Fazakerley, DJ., Quek, LE., Scalzo, R., Ohno, S., Hodson, MP. Ikeda, S., Shoji, F., Suzuki, K., Domanova, W., Parker, BL.,. Nelson, ME ., Humphrey, SJ., Turner, N., Hoehn, KL., Cooney, GJ., Soga, T., Kuroda, S., James, DE.

Cell Rep. 21 （ 12 ） 3536 - 3547 2017年12月

研究論文（学術雑誌）, 共著, 査読有り

Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to "pull" glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism.

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Cancer-Specific Energy Metabolism in Rhabdomyosarcoma Cells Is Regulated by MicroRNA

Sugito, N., Taniguchi, K., Kuranaga, Y., Ohishi, M., Soga, T., Ito, Y., Miyachi, M., Kikuchi, K., Hosoi, H., Akao, Y.

Nucleic Acid Ther. 27 （ 6 ） 365 - 377 2017年12月

研究論文（学術雑誌）, 査読有り

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma and is most frequently found in children. In RMS, there are two major subtypes, that is, embryonal RMS and alveolar RMS (ARMS). ARMS has exclusively the worse prognosis and is caused by formation of the chimeric PAX3-FOXO1 gene. Regarding cancer, the Warburg effect is known as a feature of cancer-specific metabolism. Polypyrimidine tract-binding protein 1 (PTBP1), a splicer of pyruvate kinase muscle (PKM) mRNA, is a positive regulator of cancer-specific energy metabolism. We investigated the expression and effects of muscle-specific miR-1 and miR-133b on RMS cells (RD, KYM-1, Rh30, and Rh41) from the view of energy metabolism and regulation of the chimeric gene. As a result, downregulated miR-1 and miR-133b/upregulated PTBP1 were found in RMS cell lines as well as in RMS clinical cases. Ectopic expression of either miR in both types of RMS cells induced autophagic cell death through silencing of PTBP1. Interestingly, we validated that miR-133b also knock downed PAX3-FOXO1. Moreover, we found that PAX3-FOXO1 positively regulated the PKM2-dominant expression through enhanced expression of PTBP1. These findings suggest that the miR-1 and miR-133b/PTBP1 axis and miR-133b/PAX3-FOXO1/PTBP1 axis contributed to the maintenance of cancer-specific energy metabolism.

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UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homestasis

Ikeda, K., Kang, Q., Yoneshiro, T., Camporez, J.P., Maki, H., Homma, M., Shinoda, K., Chen, Y., Lu, X., Maretich, P., Tajima, K., Ajuwon, K.M., Soga, T., Kajimura, S.

Nat. Med. 23 （ 12 ） 1454 - 1465 2017年12月

研究論文（学術雑誌）, 共著, 査読有り

Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.

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Genetic, metabolomic and transcriptomic analyses of the de novo L-cysteine biosynthetic pathway in the enteric protozoan parasite Entamoeba histolytica

Jeelani, G., Sato, D., Soga, T., Nozaki, T.

Sci. Rep. 7 （ 1 ） 15649 2017年11月

研究論文（学術雑誌）, 共著, 査読有り

The de novo L-cysteine biosynthetic pathway is critical for the growth, antioxidative stress defenses, and pathogenesis of bacterial and protozoan pathogens, such as Salmonella typhimurium and Entamoeba histolytica. This pathway involves two key enzymes, serine acetyltransferase (SAT) and cysteine synthase (CS), which are absent in mammals and therefore represent rational drug targets. The human parasite E. histolytica possesses three SAT and CS isozymes; however, the specific roles of individual isoforms and significance of such apparent redundancy remains unclear. In the present study, we generated E. histolytica cell lines in which CS and SAT expression was knocked down by transcriptional gene silencing. The strain in which CS1, 2 and 3 were simultaneously silenced and the SAT3 gene-silenced strain showed impaired growth when cultured in a cysteine lacking BI-S-33 medium, whereas silencing of SAT1 and SAT2 had no effects on growth. Combined transcriptomic and metabolomic analyses revealed that, CS and SAT3 are involved in S-methylcysteine/cysteine synthesis. Furthermore, silencing of the CS1-3 or SAT3 caused upregulation of various iron-sulfur flavoprotein genes. Taken together, these results provide the first direct evidence of the biological importance of SAT3 and CS isoforms in E. histolytica and justify the exploitation of these enzymes as potential drug targets.

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ACSL3 promotes intratumoral steroidogenesis in prostate cancer cells

Migita, T., Takayama, K., Urano, T., Obinata, D., Ikeda, K., Soga, T., Takahashi, S., Inoue, S.

Cancer Sci. 108 （ 10 ） 2011 - 2021 2017年10月

研究論文（学術雑誌）, 共著, 査読有り

Long-chain acyl-coenzyme A (CoA) synthetase 3 (ACSL3) is an androgen-responsive gene involved in the generation of fatty acyl-CoA esters. ACSL3 is expressed in both androgen-sensitive and castration-resistant prostate cancer (CRPC). However, its role in prostate cancer remains elusive. We overexpressed ACSL3 in androgen-dependent LNCaP cells and examined the downstream effectors of ACSL3. Furthermore, we examined the role of ACSL3 in the androgen metabolism of prostate cancer. ACSL3 overexpression led to upregulation of several genes such as aldo-keto reductase 1C3 (AKR1C3) involved in steroidogenesis, which utilizes adrenal androgen dehydroepiandrosterone sulfate (DHEAS) as substrate, and downregulated androgen-inactivating enzyme UDP-glucuronosyltransferase 2 (UGT2B). Exposure to DHEAS significantly increased testosterone levels and cell proliferative response in ACSL3-overexpressing cells when compared to that in control cells. A public database showed that ACSL3 level was higher in CRPC than in hormone-sensitive prostate cancer. CRPC cells showed an increased expression of ACSL3 and an expression pattern of AKR1C3 and UGT2B similar to ACSL3-overexpressing cells. DHEAS stimulation significantly promoted the proliferation of CRPC cells when compared to that of LNCaP cells. These findings suggest that ACSL3 contributes to the growth of CRPC through intratumoral steroidogenesis (i.e. promoting androgen synthesis from DHEAS and preventing the catabolism of active androgens).

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Fumarate hydratase deletion in pancreatic β cells leads to progressive diabetes

Adam, J., Ramracheya, R., Chibalina, M.V., Ternette, N., Hamilton, A., Tarasov, A.I., Zhang, Q., Rebelato, E., Rorsman, N.J.G., Martin-del-Rio, R., Lewis, A., Ozkan, G., Do, H.W., Spegal, P., Saitoh, K., Kato, K., Igarashi, K., Kessler, B.M., Pugh, C.W., Tamarit-Rodriques, J., Mulder, H., Clark, A., Fizzell, N., Soga, T., Ashcroft, F.M., Silver, A., Pollard, P.J., Rorsman, P.

Cell Rep. 20 （ 13 ） 3135 - 3148 2017年09月

研究論文（学術雑誌）, 共著, 査読有り

We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic β cells (Fh1βKO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1α or Nrf2. Progressive hyperglycemia in Fh1βKO mice led to dysregulated metabolism in β cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+]i elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.

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Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

Satoh, K., Yachida, S., Sugimoto, M., Oshima, M., Nakagawa, T., Akamoto, S., Tabata, S., Saitoh, K., Kato, K., Sato, S., Igarashi, K., Aizawa, Y., Kajino-Sakamoto, R., Kojima, Y., Fujishita, T., Enomoto, A., Hirayama, A., Ishikawa, T., Taketo, M.M., Kushida, Y., Haba, R., Okano, K., Tomita, M., Suzuki, Y., Fukuda, S., Aoki, M., Soga, T.

Proc. Natl. Acad. Sci. USA 114 （ 37 ） E7697 - E7706 2017年09月

研究論文（学術雑誌）, 共著, 査読有り

Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.

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Evaluation of the impact of gut microbiota on uremic solute accumulation by CE-TOFMS-based metabolomics approach

Mishima, E., Fukuda, S. (equally contributed), Mukawa, C., Yuri, A., Kanemitsu, Y., Matsumoto, Y., Akiyama, Y., Fukuda, NN., Tsukamoto, H., Asaji, K., Shima, H., Kikuchi, K., Suzuki, T., Tomioka, Y., Soga, T., Ito, S., Abe, T.

Kidney Int. 92 （ 3 ） 634 - 645 2017年09月

研究論文（学術雑誌）, 共著

Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.

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Effect of masticatory stimulation on the quantity and quality of saliva and the salivary metabolomic profile

Okuma, N., Saita, M., Hoshi, N., Soga, T., Tomita, M., Sugimoto, M., Kimoto, K.

PLoS One 12 （ 8 ） e0183109 2017年08月

研究論文（学術雑誌）, 共著, 査読有り

Background: This study characterized the changes in quality and quantity of saliva, and changes in the salivary metabolomic profile, to understand the effects of masticatory stimulation.
Methods: Stimulated and unstimulated saliva samples were collected from 55 subjects and salivary hydrophilic metabolites were comprehensively quantified using capillary electrophoresis-time-of-flight mass spectrometry.
Results: In total, 137 metabolites were identified and quantified. The concentrations of 44 metabolites in stimulated saliva were significantly higher than those in unstimulated saliva. Pathway analysis identified the upregulation of the urea cycle and synthesis and degradation pathways of glycine, serine, cysteine and threonine in stimulated saliva. A principal component analysis revealed that the effect of masticatory stimulation on salivary metabolomic profiles was less dependent on sample population sex, age, and smoking. The concentrations of only 1 metabolite in unstimulated saliva, and of 3 metabolites stimulated saliva, showed significant correlation with salivary secretion volume, indicating that the salivary metabolomic profile and salivary secretion volume were independent factors.
Conclusions: Masticatory stimulation affected not only salivary secretion volume, but also metabolite concentration patterns. A low correlation between the secretion volume and these patterns supports the conclusion that the salivary metabolomic profile may be a new indicator to characterize masticatory stimulation.

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Inhibition of dipeptidyl peptidase-4 ameliorates cardiac ischemia and systolic dysfunction by up-regulating the FGF-2/EGR-1 pathway

Suda, M., Shimizu, I. , Yoshida, Y., Hayashi, Y., Ikegami, R., Katsuumi, G., Wakasugi, T., Yoshida, Y., Okuda, S., Soga, T., Minamino, T.

PLoS One 12 （ 8 ） e0182422 2017年08月

研究論文（学術雑誌）, 共著

Dipeptidyl peptidase 4 inhibitors are used worldwide in the management of diabetes, but their role in the prevention or treatment of cardiovascular disorders has yet to be defined. We found that linagliptin, a DPP-4 inhibitor, suppressed capillary rarefaction in the hearts of mice with dietary obesity. Metabolomic analysis performed with capillary electrophoresis/mass spectrometry (LC-MS/MS) showed that linagliptin promoted favorable metabolic remodeling in cardiac tissue, which was characterized by high levels of citrulline and creatine. DNA microarray analysis revealed that the cardiac tissue level of early growth response protein 1 (EGR-1), which activates angiogenesis, was significantly reduced in untreated mice with dietary obesity, while this decrease was inhibited by administration of linagliptin. Mature fibroblast growth factor 2 (FGF-2) has a putative truncation site for DPP-4 at the NH2-terminal, and LC-MS/MS showed that recombinant DPP-4 protein cleaved the NH2-terminal dipeptides of mature FGF-2. Incubation of cultured neonatal rat cardiomyocytes with FGF-2 increased Egr1 expression, while it was suppressed by recombinant DPP-4 protein. Furthermore, vascular endothelial growth factor-A had a critical role in mediating FGF-2/EGR-1 signaling. In conclusion, pharmacological inhibition of DPP-4 suppressed capillary rarefaction and contributed to favorable remodeling of cardiac metabolism in mice with dietary obesity.

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Distinct requirements for energy metabolism in mouse primordial germ cells and their reprogramming to embryonic germ cells

Hayashi, Y., Otsuka, K., Ebina, M., Igarashi, K., Takehara, A., Matsumoto, M., Kanai, A., Igarashi, K., Soga, T., Matsui, Y.

Proc. Natl. Acad. Sci. USA 114 （ 31 ） 8289 - 8294 2017年08月

研究論文（学術雑誌）, 共著, 査読有り

Primordial germ cells (PGCs), undifferentiated embryonic germ cells, are the only cells that have the ability to become gametes and to reacquire totipotency upon fertilization. It is generally understood that the development of PGCs proceeds through the expression of germ cell-specific transcription factors and characteristic epigenomic changes. However, little is known about the properties of PGCs at the metabolite and protein levels, which are directly responsible for the control of cell function. Here, we report the distinct energy metabolism of PGCs compared with that of embryonic stem cells. Specifically, we observed remarkably enhanced oxidative phosphorylation (OXPHOS) and decreased glycolysis in embryonic day 13.5 (E13.5) PGCs, a pattern that was gradually established during PGC differentiation. We also demonstrate that glycolysis and OXPHOS are important for the control of PGC reprogramming and specification of pluripotent stem cells (PSCs) into PGCs in culture. Our findings about the unique metabolic property of PGCs provide insights into our understanding of the importance of distinct facets of energy metabolism for switching PGC and PSC status.

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Metabolomics of an in vitro liver model containing primary hepatocytes assembling around an endothelial cell network: comparative study on the metabolic stability and the effect of acetaminophen treatment

Toyoda, Y., Kashikura, K., Soga, T., Tagawa, Y.

J. Toxicol. Sci. 42 （ 4 ） 445 - 454 2017年08月

研究論文（学術雑誌）, 共著, 査読有り

Recently, a novel culture system consisting of primary hepatocytes structured over a network of endothelial cells on the Engelbreth-Holm-Swarm (EHS) gel has been reported. This in vitro liver model on the EHS gel (IVLEHS) has been shown to maintain the expression of hepatic genes and their functional activity. Moreover, the IVLEHS was more sensitive to xenobiotics than hepatocyte monocultures, suggesting the potential utility of this culture system for compound hepatotoxicity screening. However, the effect of this three-dimensional structure formation on the cellular metabolic profile of hepatocytes in the IVLEHS is not well understood. To address this concern, we performed metabolome analysis using capillary electrophoresis-time of flight mass spectrometry. Between the IVLEHS and mono-cultured hepatocytes on the EHS gel, there was no significant difference in the levels of metabolites of the urea cycle and the tricarboxylic acid cycle, essential amino acids, and adenylate energy charge (AEC) which is an important indicator of cellular energy status. On the other hand, acetaminophen-dependent decrease of the AEC in the IVLEHS was greater than that in the monoculture, suggesting the higher sensitivity of IVLEHS to acetaminophen-induced hepatotoxicity which is caused by metabolic activation of this drug. Further analysis showed that the levels of taurocholate, one of the major conjugated bile acids, were higher in the IVLEHS than in the monoculture. Considering that the construction of the IVLEHS did not seem to disturb the major cellular metabolism, our findings would strengthen the concept that IVLEHS would have beneficial effects on the maintenance of hepatic functions.

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Cancer with low cathepsin D levels is susceptible to vacuolar (H+)-ATPase inhibition

Kitazawa, S., Nishizawa, S., Nakagawa, H., Funata, M., Nishimura, K., Soga, T., Hara,T.

Cancer Sci. 108 （ 6 ） 1185 - 1193 2017年06月

研究論文（学術雑誌）, 共著, 査読有り

Vacuolar (H+ )-ATPases (V-ATPases) have important roles in the supply of nutrients to tumors by mediating autophagy and the endocytic uptake of extracellular fluids. Accordingly, V-ATPases are attractive therapeutic targets for cancer. However, the clinical use of V-ATPase inhibitors as anticancer drugs has not been realized, possibly owing to their high toxicity in humans. Inhibition of V-ATPase may be an appropriate strategy in highly susceptible cancers. In this study, we explored markers of V-ATPase inhibitor sensitivity. V-ATPase inhibitors led to pH impairment in acidic intracellular compartments, suppression of macropinocytosis, and decreased intracellular amino acid levels. The sensitivity of cells to V-ATPase inhibitors was correlated with low cathepsin D expression, and cancer cells showed increased sensitivity to V-ATPase inhibitors after pretreatment with a cathepsin D inhibitor and siRNA targeting the cathepsin D gene (CTSD). In addition, V-ATPase inhibitor treatment led to the induction of the amino acid starvation response, upregulation of endoplasmic reticulum stress markers, and suppression of mammalian target of rapamycin (mTOR) signaling in cells expressing low levels of cathepsin D. Some colorectal cancer patients showed the downregulation of cathepsin D in tumor tissues compared with matched normal tissues. These findings indicate that V-ATPase inhibitors are promising therapeutic options for cancers with downregulated cathepsin D.

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The metabolic profile of a rat model of chronic kidney disease

Tanada, Y., Okuda, J., Kato, T., Minamino-Muta, E., Murata, I., Soga, T., Shioi, T., Kimura, T.

Peer J. 5 e3352 2017年05月

研究論文（学術雑誌）, 共著, 査読有り

Background: The kidney is always subjected to high metabolic demand. The aim of this study was to characterize metabolic profiles of a rat model of chronic kidney disease (CKD) with cardiorenal syndrome (CRS) induced by prolonged hypertension.
Methods: We used inbred male Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from six weeks of age (high-salt; HS group) or a 0.3% NaCl diet as controls (low-salt; LS group). We analyzed function, pathology, metabolome, and the gene expression related to energy metabolism of the kidney.
Results: DS rats with a high-salt diet showed hypertension at 11 weeks of age and elevated serum levels of creatinine and blood urea nitrogen with heart failure at 21 weeks of age. The fibrotic area in the kidneys increased at 21 weeks of age. In addition, gene expression related to mitochondrial function was largely decreased. The levels of citrate and isocitrate increased and the gene expression of alpha-ketoglutaratedehydrogenase and succinyl-CoA synthetase decreased; these are enzymes that metabolize citrate and isocitrate, respectively. In addition, the levels of succinate and acetyl Co-A, both of which are metabolites of the tricarboxylic acid (TCA) cycle, decreased.
Conclusions: DS rats fed a high-salt diet were deemed a suitable model of CKD with CRS. Gene expression and metabolites related to energy metabolism and mitochondria in the kidney significantly changed in DS rats with hypertension in accordance with the progression of renal injury.

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Synthetic Biomarker Design by Using Analyte-Responsive Acetaminophen

Nishihara, T., Inoue, J., Tabata, S., Murakami, S., Ishikawa, T., Saito, N., Fukuda, S., Tomita, M., Soga, T.

Chembiochem 18 （ 10 ） 910 - 913 2017年05月

研究論文（学術雑誌）, 共著, 査読有り

The use of synthetic biomarkers is an emerging technique to improve disease diagnosis. Here, we report a novel design strategy that uses analyte-responsive acetaminophen (APAP) to expand the catalogue of analytes available for synthetic biomarker development. As proof-of-concept, we designed hydrogen peroxide (H2 O2 )-responsive APAP (HR-APAP) and succeeded in H2 O2 detection with cellular and animal experiments. In fact, for blood samples following HR-APAP injection, we demonstrated that the plasma concentration ratio [APAP+APAP conjugates]/[HR-APAP] accurately reflects in vivo differences in H2 O2 levels. We anticipate that our practical methodology will be broadly useful for the preparation of various synthetic biomarkers.

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Thymidine Catabolism as a Metabolic Strategy for Cancer Survival

Tabata, S., Yamamoto, M., Goto, H., Hirayama, A., Ohishi, M., Kuramoto, T., Mitsuhashi, A., Ikeda, R., Haraguchi, M., Kawahara, K., Shinsato, Y., Minami, K., Saijo, A., Hanibuchi, M., Nishioka, Y., Sone, S., Esumi, H., Tomita, M., Soga, T., Furukawa, T., Akiyama, S.

Cell Rep. 19 （ 7 ） 1313 - 1321 2017年05月

研究論文（学術雑誌）, 共著, 査読有り

Thymidine phosphorylase (TP), a rate-limiting enzyme in thymidine catabolism, plays a pivotal role in tumor progression; however, the mechanisms underlying this role are not fully understood. Here, we found that TP-mediated thymidine catabolism could supply the carbon source in the glycolytic pathway and thus contribute to cell survival under conditions of nutrient deprivation. In TP-expressing cells, thymidine was converted to metabolites, including glucose 6-phosphate, lactate, 5-phospho-α-D-ribose 1-diphosphate, and serine, via the glycolytic pathway both in vitro and in vivo. These thymidine-derived metabolites were required for the survival of cells under low-glucose conditions. Furthermore, activation of thymidine catabolism was observed in human gastric cancer. These findings demonstrate that thymidine can serve as a glycolytic pathway substrate in human cancer cells.

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