研究者詳細 - 曽我　朋義

論文 - 曽我　朋義

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Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells

Kawano, G., Ikeda, R., Ishihara, D., Shima, T., Sakoda, T., Yamamoto, S., Kochi, Y., Semba, Y., Ashitani, S., Mori, Y., Kato K., Maeda, T., Miyamoto, T., Soga, T., Akashi, K., Kikushige, Y.

Blood online 2025年11月

共著, 査読有り

Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly due to the persistence of leukemia stem cells (LSCs) capable of metabolic adaptation. While venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSCs undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. Inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSCs.

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Decreased Fecal Nicotinamide and Increased Bacterial Nicotinamidase Gene Expression in Ulcerative Colitis Patients

Aoyama, K., Yamamura, R., Katsurada, T., Shimizu, T., Takahashi, D., Kondo, E., Iwasaki, N., Tamakoshi, A., Soga, T., Fukuda, S., Sonoshita, M., Sakamoto, N.

Inflamm. Bowel Dis. 31 （ 10 ） 2815 - 2825 2025年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10780998

Background/objective: Ulcerative colitis (UC) is significantly linked with gut microbiota, which is essential for maintaining gut health. Their metabolites mitigate gut inflammation and bolster barrier function. Among these metabolites, we focused on vitamin B3, which has been reported to improve the pathogenesis of UC in mice. This study aimed to compare fecal vitamin B3 and gut microbiota between non-UC and UC patients.

Methods: We assessed fecal metabolites and gut microbiota in 71 UC patients (UC group) and 72 non-UC patients (non-UC group) matched by sex and age in 10-year intervals. Fecal samples were collected and metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Bacterial DNA was extracted for 16S rRNA gene sequencing. We analyzed fecal nicotinamide levels and gut microbiota composition, employing statistical adjustments for confounding factors.

Results: We found that the UC group exhibited significantly lower fecal nicotinamide levels and α-diversity (Shannon index) compared to the non-UC group. The relative abundance of bacterial genera such as Treponema, UCG-002, and Fusicatenibacter was decreased, while Sellimonas, Fournierella, and Oscillospira were increased in the UC group. Moreover, a negative correlation was observed between Sellimonas abundance and fecal nicotinamide levels in the UC group. Additionally, the UC group showed higher expression of a bacterial gene encoding nicotinamidase compared to the non-UC group.

Conclusions: These findings suggest that gut microbiota dysbiosis contributes to reduced vitamin B3 metabolism in UC patients. The study highlights the potential of replenishing vitamin B3 metabolic pathways as a novel therapeutic approach for UC treatment.

Keywords: gut microbiota; inflammatory bowel disease; nicotinamide; ulcerative colitis; vitamin B3.

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Dysregulated Anaerobic Glycolysis in Podocytes is Relevant to the Progression of Focal Segmental Glomerulosclerosis

Sugimura, M., Maeda, K., Shibata, K., Seko, H., Kozaki, Y., Hirayama, A., Soga, T., Ozeki, T., Sato, Y., Kato, N., Kosugi, T., Kadomatsu, K., Maruyama, S.

Kidney Int. Rep. 10 （ 9 ） 3239 - 3254 2025年09月

研究論文（学術雑誌）, 共著, 査読有り

Introduction
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies with varying clinical courses and therapeutic responses. FSGS often leads to end-stage renal disease. Consequently, their heterogeneity requires case stratification and pathophysiological elucidation. The involvement of energy metabolism in FSGS pathogenesis and stratification has not been clarified. Therefore, this study aimed to verify whether evaluating energy kinetics can be a new approach to MCD or FSGS stratification and explore the role of energy metabolism in MCD or FSGS.
Methods
Cultured human podocytes were treated with sera from patients with biopsy-confirmed MCD or FSGS. Serum-treated podocytes were analyzed for apoptosis using flow cytometry, metabolomics via mass spectrometry, and real-time adenosine triphosphate (ATP) production rates using an extracellular flux analyzer. Adriamycin-induced nephropathy was induced in podocyte-specific lactate dehydrogenase (LDH) A (LDHA)-deficient and control mice.
Results
The sera from patients with FSGS significantly induced apoptosis in human podocytes compared with those from individuals with MCD. Apoptosis severity was associated with segmental obliteration and corticosteroid resistance. Metabolomic analysis revealed differences in anaerobic glycolysis and tricarboxylic acid cycle (TCA)-related metabolites in podocytes exposed to the sera of patients with MCD and FSGS. In the podocytes treated with sera from patients with FSGS, glycolytic ATP production significantly decreased in cases with high apoptosis rates. The sera from patients with FSGS suppressed LDHA activity, suppressed α-actinin 4 (ACTN4) expression, and promoted actin remodeling of podocytes. Segmental sclerosis was more prominent in podocyte-specific LDHA-deficient mice with adriamycin-induced nephropathy than in control mice.
Conclusion
FSGS progression was associated with decreased anaerobic glycolysis in podocytes.

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EML4-ALK Rearrangement Creates a Distinctive Myeloid Cell-Dominant Immunosuppressive Microenvironment in Lung Cancer

Arai K., Nishito Y., Mizuno H., Motoi N., Hiraoka N., Fuse M., Arai Y., Shibata T., Sonobe Y., Kayukawa Y., Maruyama T., Fukuda H., Mizoguchi Y., Aikawa Y., Yoshida Y., Watanabe S.I., Sakamoto H., Yamashita M., Kitano S., Nagata Y., Mitsumori R., Ozaki K., Niida S., Kanai Y., Hirayama A., Soga T., Yoshida T., Yasuda K., Ochiai A., Tsunoda H., Aoki K.

Cancer Immunol. Res. 13 （ 9 ） 1435 - 1452 2025年09月

研究論文（学術雑誌）, 共著, ISSN 23266066

Tyrosine kinase inhibitors are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma, but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for tyrosine kinase inhibitor-resistant cases. Although the use of immune checkpoint inhibitors (ICI) has improved the prognosis of patients with lung cancer, patients with ALK+ lung adenocarcinoma exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. In this study, we explored the immunologic status of the tumor microenvironment (TME) in ALK+ lung adenocarcinoma tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSC) relative to ALK- lung adenocarcinoma cases, indicating that ALK+ lung adenocarcinoma has a myeloid cell-dominant immunosuppressive TME. Single-cell RNA sequencing analysis identified a subset of macrophages that expressed most T cell-attractant chemokines (CXCL9, CXCL10, and CXCL11), and the macrophages were inactivated in ALK+ lung adenocarcinoma. In contrast, ALK+ lung adenocarcinoma expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ lung adenocarcinoma showed higher levels of IL6, an MDSC-inducing cytokine, than ALK- lung adenocarcinoma. An IL6R inhibitor transformed the TME in a murine ALK+ lung adenocarcinoma model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL6R inhibitor had significant antitumor effects in mice. Our findings illustrate the molecular basis of fusion gene-mediated immunosuppressive TMEs, providing a rationale for a novel combination immunotherapy for ALK+ lung adenocarcinoma. See related Spotlight by Vitale and Bria, p.1326.

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Lubiprostone in chronic kidney disease: Insights into mitochondrial function and polyamines from a randomized phase 2 clinical trial

Watanabe S., Nakayama M., Yokoo T., Sanada S., Ubara Y., Komatsuda A., Asanuma K., Suzuki Y., Konta T., Kazama J.J., Suzuki T., Fukuda S., Soga T., Yamada T., Mizutani S., Matsumoto M., Naito Y., Taguchi K., Fukami K., Kashiwagi H., Kikuchi K., Suzuki C., Tokuno H., Urasato M., Kujirai R., Matsumoto Y., Akiyama Y., Tomioka Y., Itai S., Tongu Y., Mishima E., Kawabe C., Kasahara T., Ogata Y., Toyohara T., Sato T., Tanaka T., Abe T.

Sci. Adv. 11 （ 35 ） eadw3934 2025年08月

研究論文（学術雑誌）, 査読有り

Chronic kidney disease (CKD) is a life-threatening condition, and constipation is a progressive risk factor. We evaluated changes in uremic toxins, renal function, and the safety of lubiprostone, a selective chloride channel activator, in patients with CKD. In this phase 2, randomized, double-blind, placebo-controlled trial across nine centers in Japan, 150 patients with stage IIIb–IV CKD received lubiprostone (8 or 16 micrograms) or placebo for 24 weeks. The primary end point was change in indoxyl sulfate levels. Secondary end points included other uremic toxins and renal function markers. Lubiprostone did not alter uremic toxin levels but improved or preserved estimated glomerular filtration rate and its slope in the 16-microgram group. Mild-to-moderate gastrointestinal events occurred in the placebo and 16-microgram groups. Multiomics analysis revealed that lubiprostone modulated the gut microbial agmatine pathway and increased spermidine levels, thereby improving renal mitochondrial function. Lubiprostone is a previously unknown and safe therapeutic option to mitigate renal decline in CKD.

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Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling

Yang, C., Arai, M., Fuji Ariyanto, E., Zhang, J., Mirani Lubis D., Ito, R., Xie, S., Nitta, M., Kawashima, F., Ishitsuka, T., Yang, C., Suzuki, T., Komatsu, T., Sagae, H., Jin, H., Takahashi, H., Kobayashi, E., Wei, Y., Liu, B., Choi, H., Wada, Y., Tanaka T., Osawa, T., Kimura, H., Kodama, T., Aburatani, H., Tachibana, M., Shinkai, Y., Inagaki, T., Soga, T., Osbome, T.F., Yoneshiro, T., Matsumura, Y., Sakai, J.

Cell Rep. 44 （ 8 ） 116060 2025年08月

研究論文（学術雑誌）, 共著, 査読有り

Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.

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2,3-Pyridinedicarboxylate Is Associated with Shorter Recurrence-Free Survival in Patients with Hypopharyngeal Squamous Cell Carcinoma

Takase, H., Fujisawa, T., Hayashi, R., Makinoshima, H., Suzuki, Y., Soga, T., Fujii, S.

Pathobiology online 1 - 15 2025年08月

研究論文（学術雑誌）, 査読有り, ISSN 10152008

Introduction: Metabolites are associated with the biology of cancer; however, no metabolites related to prognosis have been identified in head and neck cancer. This study aimed to identify metabolites associated with prognosis in patients with hypopharyngeal squamous cell carcinoma (HPSCC).

Methods: Fifty-two patients who underwent surgery for HPSCC were included and randomly divided into test and validation cohorts of 26 patients each for further metabolome analysis using capillary electrophoresis/mass spectrometry on tumor and non-tumor tissues of the hypopharynx. Twenty-two patients who received adjuvant therapy after surgery were included. The receiver operating characteristic (ROC) and univariate and multivariate analyses were used to explore the relationship between recurrence-free survival (RFS), clinicopathological factors, and differentiated metabolites.

Results: ROC analysis revealed six metabolites significantly associated with RFS in both cohorts, and multivariate analysis indicated that 2,3-pyridinedicarboxylate was a significantly independent poorer prognostic factor in the cohorts including patients with HPSCC without any adjuvant therapies (p = 0.017).

Conclusion: 2,3-Pyridinedicarboxylate, involved in NAD+ metabolism and genomic stability, suggests the possibility of developing molecular-targeted drugs for the production of metabolites related to prognosis. This study identifies novel prognostic metabolites and their associated metabolic pathways in HPSCC, highlighting potential therapeutic targets for treatment.

Keywords: 2,3-Pyridinedicarboxylate; Hypopharyngeal squamous cell carcinoma; Metabolites; Recurrence-free survival.

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Dietary amino acids regulate Salmonella colonization via microbiota-dependent mechanisms in the mouse gut

Pickard, J., Porwollik, S., Caballero-Flores, G., Caruso, R., Fukuda, S., Soga, T., Inohara, N., McClelland, M., Nunez, G.

Nat. Commun. 16 （ 1 ） 4225 2025年05月

研究論文（学術雑誌）, 共著

The gut microbiota confers host protection against pathogen colonization early after infection. Several mechanisms underlying the protection have been described, but the contributions of nutrient competition versus direct inhibition are controversial. Using an ex vivo model of Salmonella growth in the mouse cecum with its indigenous microbes, we find that nutrient limitation and typical inhibitory factors alone cannot prevent pathogen growth. However, the addition of certain amino acids markedly reverses the microbiota's ability to suppress pathogen growth. Enhanced Salmonella colonization after antibiotic treatment is ablated by exclusion of dietary protein, which requires the presence of the microbiota. Thus, dietary protein and amino acids are important regulators of colonization resistance.

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MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes

Nishio M., Yamaguchi K., Otani J., Yuguchi K., Kohno D., Sasaki T., Kitamura T., Shinohara M., Soga T., Kawamura K., Sasaki A.T., Oshima M., Hikasa H., Woo M., Sasaki T., Nishina H., Nakao K., Maehama T., Suzuki A.

Proc Natl Acad Sci USA 122 （ 17 ） e2424741122 2025年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00278424

There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/ TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of Mob1a/b specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, “beiging,” and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.

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Genome-wide association study of plasma amino acids and Mendelian randomization for cardiometabolic traits

Toki R., Fushiki S., Kojima S., Sutoh Y., Otsuka-Yamasaki Y., Harada S., Iida M., Hirata A., Miyagawa N., Matsumoto M., Edagawa S., Miyake A., Kuwabara K., Hirayama A., Sugimoto M., Sato A., Amano K., Soga T., Tomita M., Arakawa K., Kinoshita K., Sakurai-Yageta M., Tamiya G., Ohmomo H., Shimizu A., Okamura T., Takebayashi T.

Sci. Rep. 15 （ 1 ） 14569 2025年04月

研究論文（学術雑誌）, 査読有り

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = − 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

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Structural robustness and temporal vulnerability of the starvation-responsive metabolic network in healthy and obese mouse liver

Morita K., Hatano A., Kokaji T., Sugimoto H., Tsuchiya T., Ozaki H., Egami R., Li D., Terakawa A., Ohno S., Inoue H., Inaba Y., Suzuki Y., Matsumoto M., Takahashi M., Izumi Y., Bamba T., Hirayama A., Soga T., Kuroda S.

Sci. Signal. 18 （ 883 ） eads2547 2025年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 19450877

Adaptation to starvation is a multimolecular and temporally ordered process. We sought to elucidate how the healthy liver regulates various molecules in a temporally ordered manner during starvation and how obesity disrupts this process. We used multiomic data collected from the plasma and livers of wild-type and leptin-deficient obese (ob/ob) mice at multiple time points during starvation to construct a starvation-responsive metabolic network that included responsive molecules and their regulatory relationships. Analysis of the network structure showed that in wild-type mice, the key molecules for energy homeostasis, ATP and AMP, acted as hub molecules to regulate various metabolic reactions in the network. Although neither ATP nor AMP was responsive to starvation in ob/ob mice, the structural properties of the network were maintained. In wild-type mice, the molecules in the network were temporally ordered through metabolic processes coordinated by hub molecules, including ATP and AMP, and were positively or negatively coregulated. By contrast, both temporal order and coregulation were disrupted in ob/ob mice. These results suggest that the metabolic network that responds to starvation was structurally robust but temporally disrupted by the obesity-associated loss of responsiveness of the hub molecules. In addition, we propose how obesity alters the response to intermittent fasting.

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Lysine-arginine imbalance overcomes therapeutic tolerance governed by the transcription factor E3-lysosome axis in glioblastoma

Jing Y., Kobayashi M., Shoulkamy M.I., Zhou M., Thi Vu H., Arakawa H., Sabit H., Iwabuchi S., Quang Vu C., Kasahara A., Ueno M., Tadokoro Y., Kurayoshi K., Chen X., Yan Y., Arai S., Hashimoto S., Soga T., Todo T., Nakada M., Hirao A.

Nat. Commun. 16 （ 1 ） 2876 - 2876 2025年04月

研究論文（学術雑誌）, 共著, 査読有り

Recent advances in cancer therapy have underscored the importance of targeting specific metabolic pathways. In this study, we propose a precision nutrition approach aimed at lysosomal function in glioblastoma multiforme (GBM). Using patient-derived GBM cells, we identify lysosomal activity as a unique metabolic biomarker of tumorigenesis, controlling the efficacy of temozolomide (TMZ), a standard GBM therapy. Employing combined analyses of clinical patient samples and xenograft models, we further elucidate the pivotal role of Transcription Factor Binding To IGHM Enhancer 3 (TFE3), a master regulator of lysosomal biogenesis, in modulating malignant properties, particularly TMZ tolerance, by regulating peroxisome proliferator-activated receptor-gamma coactivator 1−alpha (PGC1α)-mediated mitochondrial activity. Notably, we find that lysine protects GBM cells from lysosomal stress by counteracting arginine’s effects on nitric oxide production. The lysine restriction mimetic, homoarginine administration, significantly enhances the efficacy of anticancer therapies through lysosomal dysfunction. This study underscores the critical role of lysosomal function modulated by amino acid metabolism in GBM pathogenesis and treatment.

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PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover

Ono T., Taketomi Y., Higashi T., Sato H., Mochizuki-Ono C., Nagasaki Y., Ueta T., Miyai T., Tokuoka S.M., Oda Y., Nishito Y., Ono T., Taya C., Arata S., Watanabe S., Soga T., Hirabayashi T., Aihara M., Murakami M.

Nat. Commun. 16 （ 1 ） 2221 - 2221 2025年03月

研究論文（学術雑誌）, 共著, 査読有り

Although mutations in human patatin-like phospholipase PNPLA6 are associated with hereditary retinal degenerative diseases, its mechanistic action in the retina is poorly understood. Here, we uncover the molecular mechanism by which PNPLA6 dysfunction disturbs retinal homeostasis and visual function. PNPLA6, by acting as a phospholipase B, regulates choline mobilization from phosphatidylcholine and subsequent choline turnover for phosphatidylcholine regeneration in retinal pigment epithelial cells. PNPLA6-driven choline is supplied from retinal pigment epithelial cells to adjacent photoreceptor cells to support their survival. Inhibition of this pathway results in abnormal morphology, proliferation, metabolism, and functions of retinal pigment epithelial and photoreceptor cells, and mice with retina-specific PNPLA6 deletion exhibit retinitis pigmentosa-like retinal degeneration. Notably, these abnormalities are entirely rescued by choline supplementation. Thus, PNPLA6 plays an essential role in retinal homeostasis by controlling choline availability for phospholipid recycling and provide a framework for the development of an ophthalmic drug target for retinal degeneration.

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Time and dose selective glucose metabolism for glucose homeostasis and energy conversion in the liver

Pan, Y., Hatano, A., Ohno, S., Morita, K., Kokaji, T., Bai, Y., Sugimoto, H., Egami, R., Terakawa, A., Li, D., Uematsu, S., Maehara, H., Fujita, S., Inoue, H., Inaba, Y., Nagano, A., Hirayama, A., Soga, T., Kuroda, S.

npj Syst. Biol. Appl. 10 （ 1 ） 107 - 107 2024年09月

研究論文（学術雑誌）, 共著, 査読有り

Hepatic glucose metabolism serves dual purposes: maintaining glucose homeostasis and converting glucose into energy sources; however, the underlying mechanisms are unclear. We quantitatively measured liver metabolites, gene expression, and phosphorylated insulin signaling molecules in mice orally administered varying doses of glucose, and constructed a transomic network. Rapid phosphorylation of insulin signaling molecules in response to glucose intake was observed, in contrast to the more gradual changes in gene expression. Glycolytic and gluconeogenic metabolites and expression of genes involved in glucose metabolism including glucose-6-phosphate, G6pc, and Pck1, demonstrated high glucose dose sensitivity. Whereas, glucokinase expression and glycogen accumulation showed low glucose dose sensitivity. During the early phase after glucose intake, metabolic flux was geared towards glucose homeostasis regardless of the glucose dose but shifted towards energy conversion during the late phase at higher glucose doses. Our research provides a comprehensive view of time- and dose-dependent selective glucose metabolism.

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A Supramolecular Biosensor for Rapid and High-ThroughputQuantification of a Disease-Associated Niacin Metabolite

Ueno, M., Sugiyama, H., Li, F., Nishimura, T., Arakawa, H., Chen, X., Cheng, X., Takeuchi,, S., Takeshita, Y., Takamura, T., Miyagi, S., Toyama, T., Soga, T., Masuo, Y., Kato, Y., Nakamura, H., Tsujiguchi, H., Hara, A., Tajima, A., Noguchi-Shinohara, M., Ono, K., Kurayoshi, K., Kobayashi, M., Tadokoro, Y., Kasahara, A., Shoulkamy, M.I., Maeda, K., Ogoshi, T., Hirao, A.

Anal. Chem. 96 （ 36 ） 14499 - 14507 2024年09月

研究論文（学術雑誌）, 共著, 査読有り

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

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Metabolomics Profiles Alterations in Cigarette Smokers and Heated Tobacco Product Users

Harada, S., Ohmomo, H., Matsumoto, M., Sata, M., Iida, M., Hirata, A., Miyagawa, N., Kuwabara, K., Kato, S., Toki, R., Edagawa, S., Sugiyama, D., Sato, A., Hirayama, A., Sugimoto, M., Soga, T., Tomita, M., Shimizu, A., Okamura, T., Takebayashi, T.

J. Epidemiol. 34 （ 9 ） 403 - 410 2024年09月

研究論文（学術雑誌）, 共著, 査読有り

Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment.

Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey.

Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels.

Conclusions: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

Keywords: electronic nicotine delivery devices; heated tobacco products; metabolomics; prevention; smoking-induced disease.

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The role of cytidine 5'-triphosphate synthetase 1 in metabolic rewiring during epithelial-to-mesenchymal transition in non-small-cell lung cancer

Nakasuka, F., Hirayama, A., Mkinoshima, H., Yano, S., Soga, T., Tabata, S.

FEBS Open Bio 14 （ 9 ） 1570 - 1583 2024年09月

研究論文（学術雑誌）, 共著, 査読有り

Epithelial-to-mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti-cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor-β (TGF-β)-induced EMT in non-small-cell lung cancer. Our study revealed that TGF-β plays a role in EMT functions by upregulation of cytidine 5'-triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF-β-induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF-β-mediated downregulation of UDP-glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non-small-cell lung cancer.

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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis

Steimle, A., Neumann, M., Grant, E.T., Willieme, S., Sciscio, A.D., Parrish, A., Ollert, M., Miyauchi, E., Soga, T., Fukuda, S., Ohno, H., Desai, M.S.

Nat. Microbiol. 9 （ 9 ） 2244 - 2261 2024年09月

研究論文（学術雑誌）, 共著, 査読有り

Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.

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FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells

Miyahara, S., Ohuchi, M., Nomura, M., Hashimoto, E., Soga, T., Saito, R., Hayashi, K., Sato, T., Saito, M., Yamashita, Y., Shimada, M., Yaegashi, N., Yamada, H., Tanuma, N.

J. Biol. Chem. 300 （ 9 ） 107678 - 107678 2024年09月

研究論文（学術雑誌）, 査読有り

Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, apoptosis, or ferroptosis, depending on cell context. To assess these outcomes in cancer, we developed an ovarian cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global downregulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53 deficiency augmented DNA damage responses upon FDX2 loss, resulting in apoptosis rather than senescence. FDX2 loss also sensitized cells to ferroptosis, as evidenced by compromised redox homeostasis of membrane phospholipids. Our results suggest that p53 status and phospholipid homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in cancer cells.

Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS)

Harada S., Iida M., Miyagawa N., Hirata A., Kuwabara K., Matsumoto M., Okamura T., Edagawa S., Kawada Y., Miyake A., Toki R., Akiyama M., Kawai A., Sugiyama D., Sato Y., Takemura R., Fukai K., Ishibashi Y., Kato S., Kurihara A., Sata M., Shibuki T., Takeuchi A., Kohsaka S., Sawano M., Shoji S., Izawa Y., Katsumata M., Oki K., Takahashi S., Takizawa T., Maruya H., Nishiwaki Y., Kawasaki R., Hirayama A., Ishikawa T., Saito R., Sato A., Soga T., Sugimoto M., Tomita M., Komaki S., Ohmomo H., Ono K., Otsuka-Yamasaki Y., Shimizu A., Sutoh Y., Hozawa A., Kinoshita K., Koshiba S., Kumada K., Ogishima S., Sakurai-Yageta M., Tamiya G., Takebayashi T.

J. Epidemiol. 34 （ 8 ） 393 - 401 2024年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09175040

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

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