Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Daiki Setoyama Last modified date:2021.05.20

Assistant Professor / Clinical Laboratories / Kyushu University Hospital

1. Masanori Honsho, Fabian Dorninger, Yuichi Abe, Daiki Setoyama, Ryohei Ohgi, Takeshi Uchiumi, Dongchon Kang, Johannes Berger, Yukio Fujiki, Impaired plasmalogen synthesis dysregulates liver X receptor-dependent transcription in cerebellum, J Biochem, 10.1093/jb/mvz043, 2019.05.
2. Satoshi Maekawa, Shingo Takada, Hideo Nambu, Takaaki Furihata, Naoya Kakutani, Daiki Setoyama, Yasushi Ueyanagi, Dongchon Kang, Hisataka Sabe, Shintaro Kinugawa, Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure, Cell Communication and Signaling, 10.1186/s12964-019-0445-0, 17, 1, 2019.10, Background: Linoleic acid is the major fatty acid moiety of cardiolipin, which is central to the assembly of components involved in mitochondrial oxidative phosphorylation (OXPHOS). Although linoleic acid is an essential nutrient, its excess intake is harmful to health. On the other hand, linoleic acid has been shown to prevent the reduction in cardiolipin content and to improve mitochondrial function in aged rats with spontaneous hypertensive heart failure (HF). In this study, we found that lower dietary intake of linoleic acid in HF patients statistically correlates with greater severity of HF, and we investigated the mechanisms therein involved. Methods: HF patients, who were classified as New York Heart Association (NYHA) functional class I (n = 45), II (n = 93), and III (n = 15), were analyzed regarding their dietary intakes of different fatty acids during the one month prior to the study. Then, using a mouse model of HF, we confirmed reduced cardiolipin levels in their cardiac myocytes, and then analyzed the mechanisms by which dietary supplementation of linoleic acid improves cardiac malfunction of mitochondria. Results: The dietary intake of linoleic acid was significantly lower in NYHA III patients, as compared to NYHA II patients. In HF model mice, both CI-based and CII-based OXPHOS activities were affected together with reduced cardiolipin levels. Silencing of CRLS1, which encodes cardiolipin synthetase, in cultured cardiomyocytes phenocopied these events. Feeding HF mice with linoleic acid improved both CI-based and CII-based respiration as well as left ventricular function, together with an increase in cardiolipin levels. However, although assembly of the respirasome (i.e., CI/CIII2/CIV complex), as well as assembly of CII subunits and the CIII2/CIV complex statistically correlated with cardiolipin levels in cultured cardiomyocytes, respirasome assembly was not notably restored by dietary linoleic acid in HF mice. Therefore, although linoleic acid may significantly improve both CI-based and CII-based respiration of cardiomyocytes, respirasomes impaired by HF were not easily repaired by the dietary intake of linoleic acid. Conclusions: Dietary supplement of linoleic acid is beneficial for improving cardiac malfunction in HF, but is unable to completely cure HF..
3. Takahiro A. Kato, Ryoko Katsuki, Hiroaki Kubo, Norihiro Shimokawa, Mina Sato-Kasai, Kohei Hayakawa, Nobuki Kuwano, Wakako Umene-Nakano, Masaru Tateno, Daiki Setoyama, Dongchon Kang, Motoki Watabe, Shinji Sakamoto, Alan R. Teo, Shigenobu Kanba, Development and validation of the 22-item Tarumi's Modern-Type Depression Trait Scale
Avoidance of Social Roles, Complaint, and Low Self-Esteem (TACS-22), Psychiatry and clinical neurosciences, 10.1111/pcn.12842, 73, 8, 448-457, 2019.01, Aim: Understanding premorbid personality is important, especially when considering treatment selection. Historically, the premorbid personality of patients with major depression in Japan was described as Shuchaku-kishitsu [similar to Typus melancholicus], as proposed by Shimoda in the 1930s. Since around 2000, there have been increased reports in Japan of young adults with depression who have had premorbid personality differing from the traditional type. In 2005, Tarumi termed this novel condition ‘dysthymic-type depression,’ and more recently the condition has been called Shin-gata/Gendai-gata Utsu-byo [modern-type depression (MTD)]. We recently developed a semi-structured diagnostic interview to evaluate MTD. Development of a tool that enables understanding of premorbid personality in a short time, especially at the early stage of treatment, is desirable. The object of this study was to develop a self-report scale to evaluate the traits of MTD, and to assess the scale's psychometric properties, diagnostic accuracy, and biological validity. Methods: A sample of 340 participants from clinical and community settings completed measures. Psychometric properties were assessed with factor analysis. Diagnostic accuracy of the MTD traits was compared against a semi-structured interview. Results: The questionnaire contained 22 items across three subscales, thus we termed it the 22-item Tarumi's Modern-Type Depression Trait Scale: Avoidance of Social Roles, Complaint, and Low Self-Esteem (TACS-22). Internal consistency, test–retest reliability, and convergent validity were all satisfactory. Among patients with major depression, the area under the curve was 0.757 (sensitivity of 63.1% and specificity of 82.9%) and the score was positively correlated with plasma tryptophan. Conclusion: The TACS-22 possessed adequate psychometric properties and diagnostic accuracy in an initial sample of Japanese adults. Additional research on its ability to support clinical assessment of MTD is warranted..
4. Hisaomi Suzuki, Masahiro Ohgidani, Nobuki Kuwano, Fabrice Chrétien, Geoffroy Lorin de la Grandmaison, Mitsumoto Onaya, Itaru Tominaga, Daiki Setoyama, Dongchon Kang, Masaru Mimura, Shigenobu Kanba, Takahiro A. Kato, Suicide and microglia
Recent findings and future perspectives based on human studies, Frontiers in Cellular Neuroscience, 10.3389/fncel.2019.00031, 13, 1-10, 2019.01, Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims..
5. Kazuhito Gotoh, Takafumi Morisaki, Daiki Setoyama, Katsuhiko Sasaki, Mikako Yagi, Ko Igami, Soichi Mizuguchi, Takeshi Uchiumi, Yoshinori Fukui, Dongchon Kang, Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation, Cell Reports, 10.1016/j.celrep.2018.10.057, 25, 7, 1800-1815.e4, 2018.11, Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial p32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial p32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo..
6. Nobuki Kuwano, Takahiro A. Kato, Daiki Setoyama, Mina Sato-Kasai, Norihiro Shimokawa, Kohei Hayakawa, Masahiro Ohgidani, Noriaki Sagata, Hiroaki Kubo, Junji Kishimoto, Dongchon Kang, Shigenob Kanba, Tryptophan-kynurenine and lipid related metabolites as blood biomarkers for first-episode drug-naïve patients with major depressive disorder
An exploratory pilot case-control study, Journal of Affective Disorders, 10.1016/j.jad.2018.01.014, 231, 74-82, 2018.04, Background: Early intervention in depression has been critical to prevent its negative impact including suicide. Recent blood biomarker studies for major depressive disorder (MDD) have suggested that tryptophan-kynurenine and lipid related metabolites are involved in the pathophysiology of MDD. However, there have been limited studies investigating these blood biomarkers in first-episode drug-naïve MDD, which are particularly important for early intervention in depression. Methods: As an exploratory pilot case-control study, we examined the above blood biomarkers, and analyzed how these biomarkers are associated with clinical variables in first-episode drug-naïve MDD patients, based on metabolome/lipidome analysis. Results: Plasma tryptophan and kynurenine levels were significantly lower in MDD group (N = 15) compared to healthy controls (HC) group (N = 19), and plasma tryptophan was the significant biomarker to identify MDD group (area under the curve = 0.740). Lower serum high density lipoprotein-cholesterol (HDL-C) was the predictive biomarker for severity of depression in MDD group (R2 = 0.444). Interestingly, depressive symptoms were variously correlated with plasma tryptophan-kynurenine and lipid related metabolites. Moreover, plasma tryptophan-kynurenine metabolites and cholesteryl esters (CEs) were significantly correlated in MDD group, but not in HC group. Limitations: This study had small sample size, and we did not use the multiple test correction. Conclusions: This is the first study to suggest that not only tryptophan-kynurenine metabolites but also HDL-C and CEs are important blood biomarkers for first-episode drug-naïve MDD patients. The present study sheds new light on early intervention in clinical practice in depression, and further clinical studies especially large-scale prospective studies are warranted..
7. Miho Irie, Eisuke Hayakawa, Yoshinori Fujimura, Youhei Honda, Daiki Setoyama, Hiroyuki Wariishi, Fuminori Hyodo, Daisuke Miura, Analysis of spatiotemporal metabolomic dynamics for sensitively monitoring biological alterations in cisplatin-induced acute kidney injury, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2018.01.012, 496, 1, 140-146, 2018.01, Clinical application of the major anticancer drug, cisplatin, is limited by severe side effects, especially acute kidney injury (AKI) caused by nephrotoxicity. The detailed metabolic mechanism is still largely unknown. Here, we used an integrated technique combining mass spectrometry imaging (MSI) and liquid chromatography–mass spectrometry (LC–MS) to visualize the diverse spatiotemporal metabolic dynamics in the mouse kidney after cisplatin dosing. Biological responses to cisplatin was more sensitively detected within 24 h as a metabolic alteration, which is much earlier than possible with the conventional clinical chemistry method of blood urea nitrogen (BUN) measurement. Region-specific changes (e.g., medulla and cortex) in metabolites related to DNA damage and energy generation were observed over the 72-h exposure period. Therefore, this metabolomics approach may become a novel strategy for elucidating early renal responses to cisplatin, prior to the detection of kidney damage evaluated by conventional method..
8. Noriaki Sagata, Takahiro A. Kato, Shin Ichi Kano, Masahiro Ohgidani, Norihiro Shimokawa, Mina Sato-Kasai, Kohei Hayakawa, Nobuki Kuwano, Ashley M. Wilson, Koko Ishizuka, Shiori Kato, Takeshi Nakahara, Makiko Nakahara-Kido, Daiki Setoyama, Yasunari Sakai, Shouichi Ohga, Masutaka Furue, Akira Sawa, Shigenobu Kanba, Dysregulated gene expressions of MEX3D, FOS and BCL2 in human induced-neuronal (iN) cells from NF1 patients
A pilot study, Scientific reports, 10.1038/s41598-017-14440-7, 7, 1, 2017.12, Direct conversion technique to produce induced-neuronal (iN) cells from human fibroblasts within 2 weeks is expected to discover unknown neuronal phenotypes of neuropsychiatric disorders. Here, we present unique gene expression profiles in iN cells from patients with neurofibromatosis type 1 (NF1), a single-gene multifaceted disorder with comparatively high co-occurrence of autism spectrum disorder (ASD). Microarray-based transcriptomic analysis on iN cells from male healthy controls and male NF1 patients (NF1-iN cells) revealed that 149 genes expressions were significantly different (110 upregulated and 39 downregulated). We validated that mRNA of MEX3D (mex-3 RNA binding family member D) was lower in NF1-iN cells by real-time PCR with 12 sex-mixed samples. In NF1-iN cells on day 14, higher expression of FOS mRNA was observed with lower expression of MEX3D mRNA. Interestingly, BCL2 mRNA was higher in NF1-iN cells on day 5 (early-period) but not on day 14. Our data suggest that aberrant molecular signals due to NF1 mutations may disturb gene expressions, a subset of which defines continuum of the neuronal phenotypes of NF1 with ASD. Further translational studies using induced pluripotent stem (iPS) cell-derived neuronal cells are needed to validate our preliminary findings especially confirming meanings of analysis using early-period iN cells..
9. Mikako Yagi, Takeshi Uchiumi, Noriaki Sagata, Daiki Setoyama, Rie Amamoto, Yuichi Matsushima, Dongchon Kang, Neural-specific deletion of mitochondrial p32/C1qbp leads to leukoencephalopathy due to undifferentiated oligodendrocyte and axon degeneration, Scientific reports, 10.1038/s41598-017-15414-5, 7, 1, 2017.12, Mitochondrial dysfunction is a critical step in the pathogenesis of many neurodegenerative diseases. The p32/ C1qbp gene functions as an essential RNA and protein chaperone in mitochondrial translation, and is indispensable for embryonic development. However, little is known about the consequences of mitochondrial dysfunction of p32 deletion in the brain development. Here, we found that mice lacking p32 in the central nervous system (p32cKO mice) showed white matter degeneration accompanied by progressive oligodendrocyte loss, axon degeneration and vacuolation in the mid brain and brain stem regions. Furthermore, p32cKO mice died within 8 weeks of birth. We also found that p32-deficient oligodendrocytes and neurons showed reduced oligodendrocyte differentiation and axon degeneration in primary culture. We show that mitochondrial disruption activates an adaptive program known as the integrated stress response (ISR). Mitochondrial respiratory chain function in oligodendrocytes and neurons is, therefore, essential for myelination and axon maintenance, respectively, suggesting that mitochondrial respiratory chain dysfunction in the central nervous system contributes to leukoencephalopathy..
10. Takashi Matsumoto, Takeshi Uchiumi, Keisuke Monji, Mikako Yagi, Daiki Setoyama, Rie Amamoto, Yuichi Matsushima, Masaki Shiota, Masatoshi Eto, Dongchon Kang, Doxycycline induces apoptosis via ER stress selectively to cells with a cancer stem cell-like properties
Importance of stem cell plasticity, Oncogenesis, 10.1038/s41389-017-0009-3, 6, 11, 2017.11, Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency..
11. Toshiro Saito, Takeshi Uchiumi, Mikako Yagi, Rie Amamoto, Daiki Setoyama, Yuichi Matsushima, Dongchon Kang, Cardiomyocyte-specific loss of mitochondrial p32/C1qbp causes cardiomyopathy and activates stress responses, Cardiovascular research, 10.1093/cvr/cvx095, 113, 10, 1173-1185, 2017.08, Aims Mitochondria are important organelles, dedicated to energy production. Mitochondrial p32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of p32/C1qbp in vivo is poorly understood because of embryonic lethality in the systemic p32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial p32/C1qbp in the heart. Methods and results We investigated the role of p32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against p32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of p32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by p32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific p32-deficient mice. The mice died beginning at 12 months and their median lifespan was ∼14 months. Cardiac mitochondria in the p32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in p32-deficient compared with control myocytes, AMPKI' was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the p32-deficient hearts. Conclusion These findings support a key role for mitochondrial p32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival..
12. Setoyama D, Plasma Metabolites Predict Severity of Depression and Suicidal Ideation in Psychiatric Patients-A Multicenter Pilot Analysis., PLoS One, 10.1371/journal.pone.0165267, 2016.12, Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings..
13. Setoyama D, Ohgidani M, Sagata N, Kato TA, Hashimoto R, Yoshida T, Hayakawa K, Shimokawa N, Shigenobu Kanba, Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease., Scientific Reports, 10.1038, 14, 4, 4957, 2014.05.
14. 瀬戸山 大樹, Metabolomics reveals that carnitine-palmitoyltransferase-1 is a novel target for oxidative inactivation in human cells, Genes to Cells, 18, 12, 1107-1119, 2013.12.
15. 瀬戸山 大樹, High-throughput metabolic profiling of diverse green Coffea arabica beans identified tryptophan as a universal discrimination factor for immature beans, PLoS ONE, 8, 8, e70098, 2013.08.