Tomoyoshi Soga

Keio University, Edo, Tōkyō, Japan

Are you Tomoyoshi Soga?

Claim your profile

Publications (158)721.33 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis-mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment. Copyright © 2014 by the American Society of Nephrology.
    Journal of the American Society of Nephrology : JASN. 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Matrix effects influence the accuracy of γ-glutamyl peptide determination by LC–MS/MS.•The developed CE-MS/MS method was minimally affected by matrix effects.•This method was highly selective and sensitive.
    Journal of Chromatography A. 11/2014; 1369.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Quinonoid dihydropteridine reductase (QDPR) catalyzes the regeneration of tetrahydrobiopterin (BH4), a cofactor for monoamine synthesis, phenylalanine hydroxylation and nitric oxide production. Here, we produced and analyzed a transgenic Qdpr(-/-) mouse model. Unexpectedly, the BH4 contents in the Qdpr(-/-) mice were not decreased and even increased in some tissues, whereas those of the oxidized form dihydrobiopterin (BH2) were significantly increased. We demonstrated that unlike the wild-type mice, dihydrofolate reductase regenerated BH4 from BH2 in the mutants. Furthermore, we revealed wide alterations in folate-associated metabolism in the Qdpr(-/-) mice, which suggests an interconnection between folate and biopterin metabolism in the transgenic mouse model.
    FEBS Letters 11/2014; 588(21):3924-3931. · 3.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastric mucosal ulceration and gastric hemorrhage are frequently associated with treatment by non-steroid anti-inflammatory drugs (NSAIDs); however, no convenient biomarker-based diagnostic methods for these adverse reactions are currently available, requiring the use of endoscopic evaluation. We recently reported five biomarker candidates in serum which predict gastric injury induced by NSAIDs in rats, but were unable to clarify the mechanism of change in the levels of these biomarker candidates. In this study, we performed capillary electrophoresis–mass spectrometry-based metabolomic profiling in stomach and serum from rats in which gastric ulcer was induced by aspirin and prevented by co-administration of omeprazole and famotidine. Results showed drug-induced decreases in the levels of citrate, cis-aconitate, succinate, 3-hydroxy butanoic acid, and O-acetyl carnitine in all animals administered aspirin. In contrast, aspirin-induced decreases in the level of 4-hydroxyproline were suppressed by co-administration of omeprazole and famotidine. We consider that these changes were due to the prevention of gastric ulcer and decrease in the amount of collagen in stomach tissue by omeprazole and famotidine, without prevention of the NSAID-induced depression of mitochondrial function. In addition, the decreases in 4-hydroxyproline in the stomach was also detectable as changes in the serum. While further study is needed to clarify limitations of indications and extrapolation to humans, this new serum biomarker candidate of gastric injury may be useful in the monitoring of NSAID-induced tissue damage.
    Metabolomics 10/2014; 10(5). · 4.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Capillary electrophoresis-mass spectrometry (CE-MS) has emerged as a powerful new tool for comprehensive analysis of charged compounds. In this review, we provide a general description of the application of CE-MS in metabolome analysis, including the separation modes of CE, various interfaces and the mass spectrometers used. We also discuss strategies for sample pretreatment, data processing and peak identification, which are important processes in metabolome analysis. In addition, we highlight a number of new techniques to improve metabolite extraction, peak resolution and sensitivity. Finally, we provide some general conclusions and future perspectives.
    TrAC Trends in Analytical Chemistry 10/2014; · 6.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cellular homeostasis is regulated by signals through multiple molecular networks that include protein phosphorylation and metabolites. However, where and when the signal flows through a network and regulates homeostasis has not been explored. We have developed a reconstruction method for the signal flow based on time-course phosphoproteome and metabolome data, using multiple databases, and have applied it to acute action of insulin, an important hormone for metabolic homeostasis. An insulin signal flows through a network, through signaling pathways that involve 13 protein kinases, 26 phosphorylated metabolic enzymes, and 35 allosteric effectors, resulting in quantitative changes in 44 metabolites. Analysis of the network reveals that insulin induces phosphorylation and activation of liver-type phosphofructokinase 1, thereby controlling a key reaction in glycolysis. We thus provide a versatile method of reconstruction of signal flow through the network using phosphoproteome and metabolome data.
    Cell reports. 08/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thymidine phosphorylase (TP) promotes angiogenesis and metastasis, and confers resistance to anticancer agents in some cancer cell types. We previously reported that TP stimulates the expression of interleukin (IL)-8 in human KB cancer cells by an unknown mechanism. A mutation in the nuclear factor (NF)κB binding site of the IL-8 promoter suppressed promoter activity in KB/TP cells that overexpress TP. Specifically inhibiting NFκB by using BY11-7082 also suppressed TP-induced IL-8 promoter activity and IL-8 expression. Moreover, TP overexpression led to the activation of NFκB and an upregulation in the expression of its target genes, and increased phosphorylated IKKα/β protein levels, while promoting IκBα degradation as well as p65 phosphorylation and nuclear localization. The activation of NFκB in KB/TP cells was suppressed by the antioxidants N-acetylcysteine and EUK-8. In addition, in gastric cancer tissue samples, the expression of the NFκB-regulated genes, including IL-8, IL-6, and fibronectin-1 was positively correlated with TP expression. These findings indicate that reactive oxygen species mediated NFκB activation by TP increases the expression of genes that promote angiogenesis and metastasis in gastric cancer.
    Oncotarget 07/2014; · 6.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tissue damage by oxidative stress is a key pathogenic mechanism in various diseases, including AKI and CKD. Thus, early detection of oxidative tissue damage is important. Using a tRNA-specific modified nucleoside 1-methyladenosine (m1A) antibody, we show that oxidative stress induces a direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation and occurs much earlier than DNA damage. In various models of tissue damage (ischemic reperfusion, toxic injury, and irradiation), the levels of circulating tRNA derivatives increased rapidly. In humans, the levels of circulating tRNA derivatives also increased under conditions of acute renal ischemia, even before levels of other known tissue damage markers increased. Notably, the level of circulating free m1A correlated with mortality in the general population (n=1033) over a mean follow-up of 6.7 years. Compared with healthy controls, patients with CKD had higher levels of circulating free m1A, which were reduced by treatment with pitavastatin (2 mg/d; n=29). Therefore, tRNA damage reflects early oxidative stress damage, and detection of tRNA damage may be a useful tool for identifying organ damage and forming a clinical prognosis.
    Journal of the American Society of Nephrology 05/2014; · 8.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.
    Cell Reports 04/2014; · 7.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Isocitrate dehydrogenase 1 (IDH1), which localizes to the cytosol and peroxisomes, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and in parallel converts NADP(+) to NADPH. IDH1 mutations are frequently detected in grades 2-4 gliomas and in acute myeloid leukemias (AML). Mutations of IDH1 have been identified at codon 132, with arginine being replaced with histidine in most cases. Mutant IDH1 gains novel enzyme activity converting α-KG to D-2-hydroxyglutarate (2-HG) which acts as a competitive inhibitor of α-KG. As a result, the activity of α-KG-dependent enzyme is reduced. Based on these findings, 2-HG has been proposed to be an oncometabolite. In this study, we established HEK293 and U87 cells that stably expressed IDH1-WT and IDH1-R132H and investigated the effect of glutaminase inhibition on cell proliferation with 6-diazo-5-oxo-L-norleucine (DON). We found that cell proliferation was suppressed in IDH1-R132H cells. The addition of α-KG restored cell proliferation. The metabolic features of 33 gliomas with wild type IDH1 (IDH1-WT) and with IDH1-R132H mutation were examined by global metabolome analysis using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). We showed that the 2-HG levels were highly elevated in gliomas with IDH1-R132H mutation. Intriguingly, in gliomas with IDH1-R132H, glutamine and glutamate levels were significantly reduced which implies replenishment of α-KG by glutaminolysis. Based on these results, we concluded that glutaminolysis is activated in gliomas with IDH1-R132H mutation and that development of novel therapeutic approaches targeting activated glutaminolysis is warranted.
    Tumor Biology 03/2014; · 2.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Molecular BioSystems 02/2014; · 3.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adult haematopoiesis depends on rare multipotent hematopoietic stem cells (HSCs) that self-renew and give rise to progenitor cells, which differentiate to all blood lineages. The strict regulation of the fine balance between self-renewal and differentiation is essential for normal haematopoiesis and suppression of leukaemia development. HSCs and progenitor cells are commonly assumed to reside within the hypoxic BM microenvironment, however, there is no direct evidence supporting this notion. Nevertheless, HSCs and progenitors do exhibit a hypoxic profile and strongly express Hif-1α. Although hypoxia signalling pathways are thought to play important roles in adult HSC maintenance and leukaemogenesis, the precise function of Hif-dependent signalling in HSCs remains to be uncovered. Here we discuss recent gain-of-function and loss-of-function studies that shed light on the complex roles of hypoxia-signalling pathways in HSCs and their niches in normal and malignant haematopoiesis. Importantly, we comment on the current and often contrasting interpretations of the role of Hif-dependent signalling in stem cell functions. Stem Cells 2014.
    Stem Cells 02/2014; · 7.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Nature Communications 01/2014; 5:3233. · 10.74 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gastrointestinal symptoms are a common manifestation of adverse drug effects. Non-steroid anti-inflammatory drugs (NSAIDs) are widely prescribed drugs that induce the serious side effect of gastric mucosal ulceration. Biomarkers for these side effects have not been identified and ulcers are now only detectable by endoscopy. We previously identified five metabolites as biomarker candidates for NSAID-induced gastric ulcer using capillary electrophoresis-mass spectrometry (CE-MS)-based metabolomic analysis of serum and stomach from rats. Here, to clarify mechanism of changes and limitations of indications of biomarker candidates, we performed CE-MS-based metabolomic profiling in stomach and serum from rats with gastric ulcers induced by ethanol, stress, and aspirin. The results suggest that a decrease in hydroxyproline reflects the induction of gastric injury and may be useful in identifying gastric ulcer induced by multiple causes. While extrapolation to humans requires further study, hydroxyproline can be a new serum biomarker of gastric injury regardless of cause.
    Biomarker insights 01/2014; 9:61-6.
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Metabolomics 01/2014; 10(2):270-279. · 4.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ezrin is a membrane-associated cytoplasmic protein that serves to link cell-membrane proteins with the actin-based cytoskeleton, and also plays a role in regulation of the functional activities of some transmembrane proteins. It is expressed in placental trophoblasts. We hypothesized that placental ezrin is involved in the supply of nutrients from mother to fetus, thereby influencing fetal growth. The aim of this study was firstly to clarify the effect of ezrin on fetal growth and secondly to determine whether knockout of ezrin is associated with decreased concentrations of serum and placental nutrients. Ezrin knockout mice (Ez-/-) were confirmed to exhibit fetal growth retardation. Metabolome analysis of fetal serum and placental extract of ezrin knockout mice by means of capillary electrophoresis-time-of-flight mass spectrometry revealed a markedly decreased concentration of hypotaurine, a precursor of taurine. However, placental levels of cysteine and cysteine sulfinic acid (precursors of hypotaurine) and taurine were not affected. Lack of hypotaurine in Ez-/- mice was confirmed by liquid chromatography with tandem mass spectrometry. Administration of hypotaurine to heterogenous dams significantly decreased the placenta-to-maternal plasma ratio of hypotaurine in wild-type fetuses but only slightly decreased it in ezrin knockout fetuses, indicating that the uptake of hypotaurine from mother to placenta is saturable and that disruption of ezrin impairs the uptake of hypotaurine by placental trophoblasts. These results indicate that ezrin is required for uptake of hypotaurine from maternal serum by placental trophoblasts, and plays an important role in fetal growth.
    PLoS ONE 01/2014; 9(8):e105423. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: l-Cysteine is essential for virtually all living organisms, from bacteria to higher eukaryotes. Besides having a role in the synthesis of virtually all proteins and of taurine, cysteamine, glutathione, and other redox-regulating proteins, l-cysteine has important functions under anaerobic/microaerophilic conditions. In anaerobic or microaerophilic protozoan parasites, such as Entamoeba histolytica, l-cysteine has been implicated in growth, attachment, survival, and protection from oxidative stress. However, a specific role of this amino acid or related metabolic intermediates is not well understood. In this study, using stable-isotope-labeled l-cysteine and capillary electrophoresis-time of flight mass spectrometry, we investigated the metabolism of l-cysteine in E. histolytica. [U-(13)C3, (15)N]l-cysteine was rapidly metabolized into three unknown metabolites, besides l-cystine and l-alanine. These metabolites were identified as thiazolidine-4-carboxylic acid (T4C), 2-methyl thiazolidine-4-carboxylic acid (MT4C), and 2-ethyl-thiazolidine-4-carboxylic acid (ET4C), the condensation products of l-cysteine with aldehydes. We demonstrated that these 2-(R)-thiazolidine-4-carboxylic acids serve for storage of l-cysteine. Liberation of l-cysteine occurred when T4C was incubated with amebic lysates, suggesting enzymatic degradation of these l-cysteine derivatives. Furthermore, T4C and MT4C significantly enhanced trophozoite growth and reduced intracellular reactive oxygen species (ROS) levels when it was added to cultures, suggesting that 2-(R)-thiazolidine-4-carboxylic acids are involved in the defense against oxidative stress.
    mBio 01/2014; 5(6). · 6.88 Impact Factor
  • Hypoxia. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: De novo lipogenesis is activated in most cancers, and several lipogenic enzymes have been implicated as therapeutic targets. Here, we demonstrate a novel function of the lipogenic enzyme, ATP citrate lyase (ACLY), in lipid metabolism in cancer cells. ACLY depletion by small interfering RNAs caused growth suppression and/or apoptosis in a subset of cancer cell lines. To investigate the effect of ACLY inhibition on lipid metabolism, metabolome and transcriptome analysis was performed. ACLY depletion blocks the fatty acid chain elongation from C16 to C18 in triglyceride (TG), but not in other lipid classes. Meanwhile, wild type ACLY overexpression enhanced fatty acid elongation of TG, whereas an inactive mutant ACLY did not change it. ACLY depletion-mediated blockade of fatty acid elongation was coincident with down-regulation of long-chain fatty acid elongase ELOVL6, which resides in endoplasmic reticulum (ER). Paradoxically, ACLY depletion-mediated growth suppression was associated with TG accumulation. ACLY depletion down-regulated the expression of carnitine palmitoyltransferase 1A (CPT1A), which is a mitochondrial fatty acid transporter. Consistent with this finding, metabolome analysis revealed that ACLY positively regulates the carnitine system, which plays as an essential cofactor for fatty acid transport across mitochondrial membrane. AICAR, an activator of mitochondrial fatty acid oxidation, significantly reduced ACLY depletion-mediated TG accumulation. These data indicate that inhibition of ACLY might affect both fatty acid elongation in ER and fatty acid oxidation in mitochondria, thereby explaining the TG accumulation with altered fatty acid composition. This phenotype may be a hallmark of growth suppression mediated by ACLY inhibition. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 12/2013; · 6.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite increasing global prevalence, the precise pathogenesis and terms for objective diagnosis of neurodegenerative dementias remain controversial, and comprehensive understanding of the disease remains lacking. Here, we conducted metabolomic analysis of serum and saliva obtained from patients with neurodegenerative dementias (n = 10), including Alzheimer's disease, frontotemporal lobe dementia, and Lewy body disease, as well as from age-matched healthy controls (n = 9). Using CE-TOF-MS, six metabolites in serum (β-alanine, creatinine, hydroxyproline, glutamine, iso-citrate, and cytidine) and two in saliva (arginine and tyrosine) were significantly different between dementias and controls. Using multivariate analysis, serum was confirmed as a more efficient biological fluid for diagnosis compared to saliva; additionally, 45 metabolites in total were identified as candidate markers that could discriminate at least one pair of diagnostic groups from the healthy control group. These metabolites possibly provide an objective method for diagnosing dementia-type by multiphase screening. Moreover, diagnostic-type-dependent differences were observed in several tricarboxylic acid cycle compounds detected in serum, indicating that some pathways in glucose metabolism may be altered in dementia patients. This pilot study revealed novel alterations in metabolomic profiles between various neurodegenerative dementias, which would contribute to etiological investigations.
    Electrophoresis 10/2013; 34(19). · 3.26 Impact Factor

Publication Stats

3k Citations
721.33 Total Impact Points

Institutions

  • 2001–2014
    • Keio University
      • • Institute for Advanced Biosciences
      • • Department of Biochemistry and Integrative Medical Biology
      Edo, Tōkyō, Japan
  • 2013
    • The University of Tokyo
      Tōkyō, Japan
    • Tokyo Metropolitan Institute of Medical Science
      Edo, Tōkyō, Japan
    • Yamagata University
      • Department of Gastroenterology
      Ямагата, Yamagata, Japan
  • 2011–2013
    • University of Oxford
      • Nuffield Department of Clinical Medicine
      Oxford, England, United Kingdom
  • 2012
    • Meikai University
      • Department of Diagnostic and Therapeutic Sciences
      Saitama, Saitama, Japan
    • Tohoku University
      Japan
  • 2010–2012
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2010–2011
    • Kyoto University
      • Department of Cardiovascular Medicine
      Kyoto, Kyoto-fu, Japan
  • 2005
    • National Institute of Advanced Industrial Science and Technology
      Tsukuba, Ibaraki, Japan