記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Biochemistry  

Mitochondrial DNA (mtDNA) replication is tightly regulated and necessary for cellular homeostasis; however, its relationship with mitochondrial metabolism remains unclear. Advances in metabolomics integrated with the rapid isolation of mitochondria will allow for remarkable progress in analyzing mitochondrial metabolism. Here, we propose a novel methodology for mitochondria-targeted metabolomics, which employs a quick isolation procedure using a hemolytic toxin from Streptococcus pyogenes streptolysin O (SLO). SLO isolation of mitochondria from cultured HEK293 cells is time- and labor-saving for simultaneous multi-sample processing and has been applied to various other cell lines in this study. Furthermore, our method can detect the time-dependent reduction in mitochondrial ATP in response to a glycolytic inhibitor 2-deoxyglucose, indicating the suitability to prepare metabolite analysis-competent mitochondria. Using this methodology, we searched for specific mitochondrial metabolites associated with mtDNA replication activation, and nucleotides and NAD+ were identified to be prominently altered. Most notably, treatment of β-nicotinamide mononucleotide (β-NMN), a precursor of NAD+, to HEK293 cells activated and improved the rate of mtDNA replication by increasing nucleotides in mitochondria and decreasing their degradation products: nucleosides. Our results suggest that β-NMN metabolism plays a role in supporting mtDNA replication by maintaining the nucleotide pool balance in the mitochondria.

DOI： 10.1093/jb/mvab136

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpsychires.2021.04.009.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jad.2020.09.118.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-75115-4.

記述言語：英語   出版者・発行元：Cellular and Molecular Life Sciences  

This study examines the interplay between ambient temperature, brown adipose tissue (BAT) function, and bone metabolism, emphasizing the effects of cold exposure and BAT mitochondrial activity on bone health. Utilizing ovariectomized (OVX) mice to model primary osteoporosis and BAT-specific mitochondrial dysfunction (BKO) mice, we evaluated the impact of housing temperature on bone density, immune modulation in bone marrow, and the protective role of BAT against bone loss. Cold exposure was found to universally reduce bone mass, enhance osteoclastogenesis, and alter bone marrow T-cell populations, implicating the immune system in bone remodeling under cold stress. The thermogenic function of BAT, driven by mitochondrial oxidative phosphorylation, was crucial in protecting against bone loss. Impaired BAT function, through surgical removal or mitochondrial dysfunction, exacerbated bone loss in cold environments, highlighting BAT’s metabolic role in maintaining bone health. Furthermore, cold-induced changes in BAT function led to systemic metabolic shifts, including elevated long-chain fatty acids, which influenced osteoclast differentiation and activity. These findings suggest a systemic mechanism connecting environmental temperature and BAT metabolism with bone physiology, providing new insights into the metabolic and environmental determinants of bone health. Future research could lead to novel bone disease therapies targeting these pathways.

DOI： 10.1007/s00018-024-05347-4

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記述言語：英語  

DOI： 10.1186/s40170-024-00364-0

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1543209468

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記述言語：英語   出版者・発行元：Genes to Cells  

An autism-associated gene Shank3 encodes multiple splicing isoforms, Shank3a-f. We have recently reported that Shank3a/b-knockout mice were more susceptible to kainic acid-induced seizures than wild-type mice at 4 weeks of age. Little is known, however, about how the N-terminal and ankyrin repeat domains (NT-Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry-based proteomic search for proteins interacting with GFP-tagged NT-Ank. In this study, NT-Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA-binding (n = 102), spliceosome (n = 22), and ribosome-associated molecules (n = 9) were significantly enriched. Among them, an X-linked intellectual disability-associated protein, Nono, was identified as a NT-Ank-binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b-knockout mice aberrantly expressed splicing isoforms of autism-associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA-binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism-associated genes after birth.

DOI： 10.1111/gtc.13142

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記述言語：英語   出版者・発行元：DMM Disease Models and Mechanisms  

Pathogenic variants in ATP1A3, the gene encoding the α3 subunit of the Na+/K+-ATPase, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerated symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as Eif4g (encoded by Eif4g1), Pabpc1 and Fmrp (encoded by Fmr1), in mouse Neuro2a cells. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C variant of human ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 (encoded by Rps6) and increased susceptibility to heat stress. In agreement with these findings, induced pluripotent stem cells (iPSCs) from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient-derived iPSCs showed lower calcium influxes in responses to stimulation with ATP than those in control iPSCs. These data indicate that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes in patients with the p.R756C variant among a variety of ATP1A3-related disorders.

DOI： 10.1242/dmm.050574

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記述言語：英語   出版者・発行元：Bioscience reports  

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

DOI： 10.1042/BSR20231992

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記述言語：英語   出版者・発行元：International Journal of Molecular Sciences  

Pancreatic ductal adenocarcinoma (PDAC) is a solid-tumor malignancy. To enhance the treatment landscape of PDAC, a 3D model optimized for rigorous drug screening is essential. Within the PDAC tumor microenvironment, a dense stroma comprising a large extracellular matrix and cancer-associated fibroblasts (CAFs) is well-known for its vital role in modulating tumor growth, cellular heterogeneity, bidirectional paracrine signaling, and chemoresistance. In this study, we employed a fibroblast-populated collagen lattice (FPCL) modeling approach that has the ability to replicate fibroblast contractility in the collagenous matrix to build dense stroma. This FPCL model allows CAF differentiation by facilitating multifaceted cell–cell interactions between cancer cells and CAFs, with the differentiation further influenced by mechanical forces and hypoxia carried within the 3D structure. Our FPCL models displayed hallmark features, including ductal gland structures and differentiated CAFs with spindle shapes. Through morphological explorations alongside in-depth transcriptomic and metabolomic profiling, we identified substantial molecular shifts from the nascent to mature model stages and potential metabolic biomarkers, such as proline. The initial pharmacological assays highlighted the effectiveness of our FPCL model in screening for improved therapeutic strategies. In conclusion, our PDAC modeling platform mirrors complex tumor microenvironmental dynamics and offers an unparalleled perspective for therapeutic exploration.

DOI： 10.3390/ijms25073740

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1405207185

CiNii Research

記述言語：英語   出版者・発行元：Life Science Alliance  

Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD+) levels, leading to impaired lysosomal acidification and autophagy. In this study, we investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.

DOI： 10.26508/lsa.202302116

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記述言語：英語   出版者・発行元：Bioengineering  

Pancreatic ductal adenocarcinoma (PDAC) is a refractory tumor with a poor prognosis, and its complex microenvironment is characterized by a fibrous interstitial matrix surrounding PDAC cells. Type I collagen is a major component of this interstitial matrix. Abundant type I collagen promotes its deposition and cross-linking to form a rigid and dense physical barrier, which limits drug penetration and immune cell infiltration and provides drug resistance and metabolic adaptations. In this study, to identify the physical effect of the stroma, type I collagen was used as a 3D matrix to culture Capan-1 cells and generate a 3D PDAC model. Using transcriptome analysis, a link between type I collagen-induced physical effects and the promotion of Capan-1 cell proliferation and migration was determined. Moreover, metabolomic analysis revealed that the physical effect caused a shift in metabolism toward a glycolytic phenotype. In particular, the high expression of proline in the metabolites suggests the ability to maintain Capan-1 cell proliferation under hypoxic and nutrient-depleted conditions. In conclusion, we identified type I collagen-induced physical effects in promoting Capan-1 cells, which cause PDAC progression, providing support for the role of dense stroma in the PDAC microenvironment and identifying a fundamental method for modeling the complex PDAC microenvironment.

DOI： 10.3390/bioengineering10121437

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記述言語：英語   出版者・発行元：Nucleic Acids Research  

The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.

DOI： 10.1093/nar/gkad591

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

マウスの生後早期の視床機能の発達におけるShank3a/bアイソフォームの役割について検討した。WTマウスとShank3a/bノックアウトを使用した。評価項目は脳の各領域における定量PCR、カイニン酸治療、免疫蛍光染色、ウェスタンブロット法などとした。その結果、マウスShank3スプライシングアイソフォームShank3a/bは視床核で特異的に発現し、生後2～4週間でピークに達することが示された。また、Shank3a/bノックアウトマウスでは視床核のパルブアルブミンが低かった。一貫して、Shank3a/bノックアウトマウスは、カイニン酸処理後、WTマウスと比較して全般発作を起こしやすいことが示された。以上から、Shank3a/bのNT-Ankドメインは、マウス生後早期において、視床皮質ニューロンを過剰興奮から守る分子経路を制御していることが示された。

記述言語：英語   出版者・発行元：JACC: Basic to Translational Science  

Doxorubicin (DOX)-induced cardiomyopathy has poor prognosis, and myocardial inflammation is intimately involved in its pathophysiology. The role of invariant natural killer T (iNKT) cells has not been fully determined in this disease. We here demonstrated that activation of iNKT cells by α-galactosylceramide (GC) attenuated DOX-induced cardiomyocyte death and cardiac dysfunction. αGC increased interferon (IFN)-γ and phosphorylation of signal transducers and activators of transcription 1 (STAT1) and extracellular signal-regulated kinase (ERK). Administration of anti-IFN-γ neutralizing antibody abrogated the beneficial effects of αGC on DOX-induced cardiac dysfunction. These findings emphasize the protective role of iNKT cells in DOX-induced cardiomyopathy via the IFN-γ-STAT1-ERK pathway.

DOI： 10.1016/j.jacbts.2023.02.014

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記述言語：英語   出版者・発行元：International Journal of Molecular Sciences  

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis, largely due to its unique tumor microenvironment (TME) and dense fibrotic stroma. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor growth and metastasis, contributing to the metabolic adaptation of PDAC cells. However, the metabolic interactions between PDAC cells and CAFs are not well-understood. In this study, an in vitro co-culture model was used to investigate these metabolic interactions. Metabolomic analysis was performed under monoculture conditions of Capan−1 PDAC cells and CAF precursor cells, as well as co-culture conditions of PDAC cells and differentiated inflammatory CAF (iCAF). Co-cultured Capan−1 cells displayed significant metabolic changes, such as increased 2-oxoglutaric acid and lauric acid and decreased amino acids. The metabolic profiles of co-cultured Capan−1 and CAFs revealed differences in intracellular metabolites. Analysis of extracellular metabolites in the culture supernatant showed distinct differences between Capan−1 and CAF precursors, with the co-culture supernatant exhibiting the most significant changes. A comparison of the culture supernatants of Capan−1 and CAF precursors revealed different metabolic processes while co-culturing the two cell types demonstrated potential metabolic interactions. In conclusion, this study emphasizes the importance of metabolic interactions between cancer cells and CAFs in tumor progression and highlights the role of TME in metabolic reprogramming.

DOI： 10.3390/ijms241311015

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

DOI： 10.1073/pnas.2203628119

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neuroscience Research  

Epileptic seizures are distinct but frequent comorbidities in children with autism spectrum disorder (ASD). The hyperexcitability of cortical and subcortical neurons appears to be involved in both phenotypes. However, little information is available concerning which genes are involved and how they regulate the excitability of the thalamocortical network. In this study, we investigate whether an ASD-associated gene, SH3 and multiple ankyrin repeat domains 3 (Shank3), plays a unique role in the postnatal development of thalamocortical neurons. We herein report that Shank3a/b, the splicing isoforms of mouse Shank3, were uniquely expressed in the thalamic nuclei, peaking from two to four weeks after birth. Shank3a/b-knockout mice showed lower parvalbumin signals in the thalamic nuclei. Consistently, Shank3a/b-knockout mice were more susceptible to generalized seizures than wild-type mice after kainic acid treatments. Together, these data indicate that NT-Ank domain of Shank3a/b regulates molecular pathways that protect thalamocortical neurons from hyperexcitability during the early postnatal period of mice.

DOI： 10.1016/j.neures.2023.03.001

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Communications Biology  

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor developed, has been shown to reduce cardiovascular events in patients with type 2 diabetes and established cardiovascular disease. Several studies have suggested that empagliflozin improves the cardiac energy state which is a partial cause of its potency. However, the detailed mechanism remains unclear. To address this issue, we used a mouse model that enabled direct measurement of cytosolic and mitochondrial ATP levels. Empagliflozin treatment significantly increased cytosolic and mitochondrial ATP levels in the hearts of db/db mice. Empagliflozin also enhanced cardiac robustness by maintaining intracellular ATP levels and the recovery capacity in the infarcted area during ischemic-reperfusion. Our findings suggest that empagliflozin enters cardiac mitochondria and directly causes these effects by increasing mitochondrial ATP via inhibition of NHE1 and Nav1.5 or their common downstream sites. These cardioprotective effects may be involved in the beneficial effects on heart failure seen in clinical trials.

DOI： 10.1038/s42003-023-04663-y

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：eNeuro  

Wallerian degeneration (WD) occurs in the early stages of numerous neurologic disorders, and clarifying WD pathology is crucial for the advancement of neurologic therapies. ATP is acknowledged as one of the key pathologic substances in WD. The ATP-related pathologic pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. However, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. But little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.

DOI： 10.1523/ENEURO.0353-22.2023

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記述言語：日本語   出版者・発行元：日本生物学的精神医学会  

うつ病など精神疾患をもつ患者が発症初期から精神医療機関を受診することはまれであり，適切な精神医療の導入は遅れがちである。他方，こうした患者は身体症状のために身体科を受診していることがまれではない。しかるに，筆者らは精神科以外でも実施可能な採血による血液バイオマーカーの開発が，精神疾患の早期発見・早期介入につながることを期待して，血液を用いた精神疾患の客観的バイオマーカー開発を進めている。本稿では，血液メタボローム解析について概説し，うつ病やひきこもりに関連した研究の成果を紹介する。筆者らはこれまで抑うつ重症度と3ヒドロキシ酪酸，自殺とキヌレニン経路代謝物，ひきこもりとアシルカルニチン／アルギニンとの関連を萌芽的に見いだしてきた。こうした研究の発展により精神疾患を採血で客観的に生物学的に評価できるシステムが構築されることで，精神疾患の早期発見・早期介入の実現に加えて精神疾患への偏見解消が期待される。

DOI： 10.11249/jsbpjjpp.34.1_7

CiNii Research

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：iScience  

The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.

DOI： 10.1016/j.isci.2022.104889

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cellular and Molecular Life Sciences  

Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient’s quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP. However, little is known about whether or not extracellular ATP cause NP-SCI. We found in the present study that excess of intracellular ATP at the lesion site evokes at-level NP-SCI. No significant differences in the body weight, locomotor function, or motor behaviors were found in groups that were negative and positive for at-level allodynia. The intracellular ATP level at the lesion site was significantly higher in the allodynia-positive mice than in the allodynia-negative mice. A metabolome analysis revealed that there were no significant differences in the ATP production or degradation between allodynia-negative and allodynia-positive mice. Dorsal horn neurons in allodynia mice were found to be inactivated in the resting state, suggesting that decreased ATP consumption due to neural inactivity leads to a build-up of intracellular ATP. In contrast to the findings in the resting state, mechanical stimulation increased the neural activity of dorsal horn and extracellular ATP release at lesion site. The forced production of intracellular ATP at the lesion site in non-allodynia mice induced allodynia. The inhibition of P2X4 receptors in allodynia mice reduced allodynia. These results suggest that an excess buildup of intracellular ATP in the resting state causes at-level NP-SCI as a result of the extracellular release of ATP with mechanical stimulation.

DOI： 10.1007/s00018-022-04510-z

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記述言語：英語   出版者・発行元：Scientific Reports  

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations including pathogenic missense mutation of DPYD gene encoding dihydropyrimidine dehydrogenase (DPD). Conversely, high DPYD and DPD expression were associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells sensitive to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.

DOI： 10.1038/s41598-022-12528-3

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記述言語：日本語   出版者・発行元：公益社団法人日本生化学会  

細胞小器官の一つであるミトコンドリアは，「細胞のエネルギー発電所（powerhouse）」と呼ばれる．もちろん，エネルギーとはATPのことであり，「発電所」とは内膜に存在する酸化的リン酸化システム（OXPHOS）を指すことは常識であろう．ミトコンドリアの機能を一言でまとめると「ATPをよく産生する」ことになる．しかし当然ながら，これはミトコンドリア機能の一側面にすぎない．事実，ミトコンドリアはエネルギー産生以外にも数多くの代謝反応の場として，細胞機能を維持する上できわめて重要な役割を果たしている．本稿では，ミトコンドリアを場とする「代謝」の重要性を二つのファクトから浮き彫りにし，次にその代謝経路のいくつかを点描した後，最後にその活性を「代謝産物の変動」として正確に捉えるための方法論，すなわち，ミトコンドリア-メタボロミクスについて筆者らが開発した内容の一部を解説する．

DOI： 10.14952/seikagaku.2022.940159

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CiNii Research

記述言語：日本語   出版者・発行元：大道学館出版部  

82歳女性。糖尿病に対する即効性インスリン、持効性インスリン、SGLT-2阻害薬服用中に気尿が出現した。精査結果から、本症例ではSGLT-2阻害薬による尿糖排泄量増加に伴う尿内発酵症候群が考えられ、膀胱内にはエタノール産生が確認された。SGLT-2阻害薬を一時中止したが、血糖コントロールが不安定となったため再開し、その後は慎重に経過観察しながら投与を継続している。

記述言語：英語   出版者・発行元：(公社)日本生化学会  

化膿レンサ球菌ストレプトリジンO(SLO)の溶血毒素を用いた迅速分離法によるミトコンドリア(MT)標的メタボロミクスの新手法を提案した。培養HEK293細胞からのMT-SLO分離は時間・労力を節約でき、他の細胞株にも適用しえた。更に、本手法は解糖阻止薬に応答してMT-ATPの時間依存性の低下を検出でき、代謝物分析能力保有MTの調製に適していた。本手法を用いて、MT-DNA複製活性化に関連する特異的MT代謝物を探索し、ヌクレオチドとNAD+が顕著に変化していた。HEK293細胞をNAD+前駆体のβ-ニコチンアミドモノヌクレオチド(β-NMN)で処理すると、MT内のヌクレオチドが増加し、分解生成物のヌクレオシドが減少して、MT-DNA複製の速度が活性化・改善された。

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fimmu.2021.714897. eCollection 2021.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s42003-021-02498-z.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.15252/embj.2020105268.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/braincomms/fcab058

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1096/fj.202001113R.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-78410-2.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-020-73918-z

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.isci.2020.101654.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12964-019-0445-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/jb/mvz043

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fncel.2019.00031

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/pcn.12842

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.celrep.2018.10.057

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1016/j.jad.2018.01.014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2018.01.012

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-017-15414-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-017-14440-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41389-017-0009-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/cvr/cvx095

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0165267

記述言語：日本語   掲載種別：研究論文（大学，研究機関等紀要）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

開催年月日： 2021年10月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：横浜市   国名：日本国  

開催年月日： 2021年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2020年10月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2019年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2019年10月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2019年9月

記述言語：日本語  

開催地：仙台国際センター   国名：日本国  

開催年月日： 2019年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：日本臨床衛生検査技師会館   国名：日本国  

開催年月日： 2019年7月

記述言語：日本語  

国名：日本国  

開催年月日： 2019年2月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡県保健環境研究所   国名：日本国  

開催年月日： 2018年11月

記述言語：日本語  

開催地：横浜   国名：日本国  

開催年月日： 2018年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

開催年月日： 2018年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸   国名：日本国  

開催年月日： 2018年9月

記述言語：英語   会議種別：口頭発表（一般）  

国名：日本国  

開催年月日： 2018年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋国際会議場   国名：日本国  

開催年月日： 2018年8月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：名古屋国際会議場   国名：日本国  

開催年月日： 2018年7月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：九州大学医学部保健学科   国名：日本国  

開催年月日： 2018年6月

記述言語：英語  

国名：アメリカ合衆国  

開催年月日： 2018年3月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：九州大学稲盛財団記念館 A会議室   国名：日本国  

開催年月日： 2017年10月

記述言語：日本語  

開催地：札幌   国名：日本国  

開催年月日： 2017年9月

記述言語：日本語  

開催地：横浜   国名：日本国  

開催年月日： 2017年6月

記述言語：英語  

国名：ドイツ連邦共和国  

開催年月日： 2015年9月 - 2015年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：静岡県三島市三島文化会館   国名：日本国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：鹿児島   国名：日本国  

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡   国名：日本国  

開催年月日： 2016年11月 - 2016年12月

記述言語：日本語  

開催地：パシフィコ横浜   国名：日本国  

開催年月日： 2016年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸国際展示場   国名：日本国  

開催年月日： 2015年11月 - 2016年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：岐阜   国名：日本国  

開催年月日： 2015年9月 - 2015年10月

記述言語：日本語  

開催地：静岡県三島市三島文化会館   国名：日本国  

開催年月日： 2015年9月 - 2015年10月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：静岡県三島市三島文化会館   国名：日本国  

記述言語：日本語  

開催地：神戸   国名：日本国  

記述言語：日本語  

開催地：福岡   国名：日本国  

記述言語：日本語  

開催地：福岡   国名：日本国  

記述言語：英語  

国名：グレートブリテン・北アイルランド連合王国(英国)  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語   出版者・発行元：日本生物学的精神医学会  

うつ病など精神疾患をもつ患者が発症初期から精神医療機関を受診することはまれであり,適切な精神医療の導入は遅れがちである。他方,こうした患者は身体症状のために身体科を受診していることがまれではない。しかるに,筆者らは精神科以外でも実施可能な採血による血液バイオマーカーの開発が,精神疾患の早期発見・早期介入につながることを期待して,血液を用いた精神疾患の客観的バイオマーカー開発を進めている。本稿では,血液メタボローム解析について概説し,うつ病やひきこもりに関連した研究の成果を紹介する。筆者らはこれまで抑うつ重症度と3ヒドロキシ酪酸,自殺とキヌレニン経路代謝物,ひきこもりとアシルカルニチン/アルギニンとの関連を萌芽的に見いだしてきた。こうした研究の発展により精神疾患を採血で客観的に生物学的に評価できるシステムが構築されることで,精神疾患の早期発見・早期介入の実現に加えて精神疾患への偏見解消が期待される。(著者抄録)

記述言語：日本語   出版者・発行元：(一社)日本臨床化学会  

記述言語：日本語   出版者・発行元：(株)アークメディア  

記述言語：日本語   出版者・発行元：(一社)日本臨床化学会  

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

細胞小器官の一つであるミトコンドリアは,「細胞のエネルギー発電所(powerhouse)」と呼ばれる.もちろん,エネルギーとはATPのことであり,「発電所」とは内膜に存在する酸化的リン酸化システム(OXPHOS)を指すことは常識であろう.ミトコンドリアの機能を一言でまとめると「ATPをよく産生する」ことになる.しかし当然ながら,これはミトコンドリア機能の一側面にすぎない.事実,ミトコンドリアはエネルギー産生以外にも数多くの代謝反応の場として,細胞機能を維持する上できわめて重要な役割を果たしている.本稿では,ミトコンドリアを場とする「代謝」の重要性を二つのファクトから浮き彫りにし,次にその代謝経路のいくつかを点描した後,最後にその活性を「代謝産物の変動」として正確に捉えるための方法論,すなわち,ミトコンドリア-メタボロミクスについて筆者らが開発した内容の一部を解説する.(著者抄録)

種別：大会・シンポジウム等 

参加者数：3,000

種別：大会・シンポジウム等 

参加者数：70

種別：大会・シンポジウム等 

参加者数：3,000

種別：大会・シンポジウム等 

参加者数：300

福岡県保健環境研究所主催の研究セミナーの講師を務めた
「Rで広がるデータ解析の地平」

機械学習の臨床検査応用に関する自主勉強会を主催している