担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Short-chain peptides derived from various protein sources have been shown to exhibit diverse bio-modulatory and health-promoting effects in animal experiments and human trials. We recently reported that the oral administration of the Tyr–Trp (YW) dipeptide to mice markedly enhances noradrenaline metabolism in the brain and ameliorates the working-memory deficits induced by the β-amyloid 25–35 peptide (Aβ25–35). In the current study, we performed multiple bioinformatics analyses of microarray data from Aβ25–35/YW-treated brains to determine the mechanism underlying the action of YW in the brain and to infer the molecular mechanisms and networks involved in the protective effect of YW in the brain. We found that YW not only reversed inflammation-related responses but also activated various molecular networks involving a transcriptional regulatory system, which is mediated by the CREB binding protein (CBP), EGR-family proteins, ELK1, and PPAR, and the calcium-signaling pathway, oxidative stress tolerance, and an enzyme involved in de novo l-serine synthesis in brains treated with Aβ25–35. This study revealed that YW has a neuroprotective effect against Aβ25–35 neuropathy, suggesting that YW is a new functional-food-material peptide.

DOI： 10.3390/nu15122731

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353RLMNA–related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

DOI： 10.1126/sciadv.ade7047

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

Purpose: Here, we investigated expression modules reflecting the reciprocal expression of the cancer microenvironment and immune response-related genes associated with poor prognosis in primary central nervous system lymphoma (PCNSL). Methods: Weighted gene coexpression network analysis revealed representative modules, including neurogenesis, immune response, anti-virus, microenvironment, gene expression and translation, extracellular matrix, morphogenesis, and cell adhesion in the transcriptome data of 31 PCNSL samples. Results : Gene expression networks were also reflected by protein–protein interaction networks. In particular, some of the hub genes were highly expressed in patients with PCNSL with prognoses as follows: AQP4, SLC1A3, GFAP, CXCL9, CXCL10, GBP2, IFI6, OAS2, IFIT3, DCN, LRP1, and LUM with good prognosis; and STAT1, IFITM3, GZMB, ISG15, LY6E, TGFB1, PLAUR, MMP4, FTH1, PLAU, CSF3R, FGR, POSTN, CCR7, TAS1R3, small ribosomal subunit genes, and collagen type 1/3/4/6 genes with poor prognosis. Furthermore, prognosis prediction formulae were constructed using the Cox proportional-hazards regression model, which demonstrated that the IP-10 receptor gene CXCR3 and type I interferon-induced protein gene IFI44L could predict patient survival in PCNSL. Conclusion: These results indicate that the differential expression and balance of immune response and microenvironment genes may be required for PCNSL tumor growth or prognosis prediction, which would help understanding the mechanism of tumorigenesis and potential therapeutic targets in PCNSL.

DOI： 10.1007/s10147-022-02285-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Background: Reliable predictors of treatment efficacy in heart failure have been long awaited. DNA damage has been implicated as a cause of heart failure. Objectives: The purpose of this study was to investigate the association of DNA damage in myocardial tissue with treatment response and prognosis of heart failure. Methods: The authors performed immunostaining of DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in endomyocardial biopsy specimens from 175 patients with heart failure with reduced ejection fraction (HFrEF) of various underlying etiologies. They calculated the percentage of nuclei positive for each DNA damage marker (%PAR and %γ-H2A.X). The primary outcome was left ventricular reverse remodeling (LVRR) at 1 year, and the secondary outcome was a composite of cardiovascular death, heart transplantation, and ventricular assist device implantation. Results: Patients who did not achieve LVRR after the optimization of medical therapies presented with significantly higher %PAR and %γ-H2A.X. The ROC analysis demonstrated good performance of both %PAR and %γ-H2A.X for predicting LVRR (AUCs: 0.867 and 0.855, respectively). There was a negative correlation between the mean proportion of DNA damage marker–positive nuclei and the probability of LVRR across different underlying diseases. In addition, patients with higher %PAR or %γ-H2A.X had more long-term clinical events (PAR HR: 1.63 [95% CI: 1.31-2.01; P < 0.001]; γ-H2A.X HR: 1.48 [95% CI: 1.27-1.72; P < 0.001]). Conclusions: DNA damage determines the consequences of human heart failure. Assessment of DNA damage is useful to predict treatment efficacy and prognosis of heart failure patients with various underlying etiologies.

DOI： 10.1016/j.jchf.2023.09.027

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）

記述言語：英語   掲載種別：研究論文（学術雑誌）

Motivation: Direct reprogramming involves the direct conversion of fully differentiated mature cell types into various other cell types while bypassing an intermediate pluripotent state (e.g. induced pluripotent stem cells). Cell differentiation by direct reprogramming is determined by two types of transcription factors (TFs): Pioneer factors (PFs) and cooperative TFs. PFs have the distinct ability to open chromatin aggregations, assemble a collective of cooperative TFs and activate gene expression. The experimental determination of two types of TFs is extremely difficult and costly. Results: In this study, we developed a novel computational method, TRANSDIRE (TRANS-omics-based approach for DIrect REprogramming), to predict the TFs that induce direct reprogramming in various human cell types using multiple omics data. In the algorithm, potential PFs were predicted based on low signal chromatin regions, and the cooperative TFs were predicted through a trans-omics analysis of genomic data (e.g. enhancers), transcriptome data (e.g. gene expression profiles in human cells), epigenome data (e.g. chromatin immunoprecipitation sequencing data) and interactome data. We applied the proposed methods to the reconstruction of TFs that induce direct reprogramming from fibroblasts to six other cell types: Hepatocytes, cartilaginous cells, neurons, cardiomyocytes, pancreatic cells and Paneth cells. We demonstrated that the methods successfully predicted TFs for most cell conversions with high accuracy. Thus, the proposed methods are expected to be useful for various practical applications in regenerative medicine.

DOI： 10.1093/bioinformatics/btac209

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

L-Serine (Ser) is synthesized de novo from 3-phosphoglycerate via the phosphorylated pathway committed by phosphoglycerate dehydrogenase (Phgdh). A previous study reported that feeding a protein-free diet increased the enzymatic activity of Phgdh in the liver and enhanced Ser synthesis in the rat liver. However, the nutritional and physiological functions of Ser synthesis in the liver remain unclear. To clarify the physiological significance of de novo Ser synthesis in the liver, we generated liver hepatocyte-specific Phgdh KO (LKO) mice using an albumin-Cre driver. The LKO mice exhibited a significant gain in body weight compared to Floxed controls at 23 weeks of age and impaired systemic glucose metabolism, which was accompanied by diminished insu-lin/IGF signaling. Although LKO mice had no apparent defects in steatosis, the molecular signatures of inflammation and stress responses were evident in the liver of LKO mice. Moreover, LKO mice were more vulnerable to protein starvation than the Floxed mice. These observations demonstrate that Phgdh-dependent de novo Ser synthesis in liver hepatocytes contributes to the maintenance of systemic glucose tolerance, suppression of inflammatory response, and resistance to protein starva-tion.

DOI： 10.3390/nu13103468

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Mouse embryonic fibroblasts lacking D-3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step of de novo synthesis of l-serine, are particularly sensitive to depletion of extracellular L-serine. In these cells, depletion of l-serine leads to a rapid reduction of intracellular L-serine, cell growth arrest, and altered expression of a wide variety of genes. However, it remains unclear whether reduced availability of extracellular l-serine elicits such responses in other cell types expressing Phgdh. Here, we show in the mouse hepatoma cell line Hepa1-6 that extracellular l-serine depletion transiently induced transcriptional activation of Atf4-target genes, including cation transport regulator-like protein 1 (Chac1). Expression levels of these genes returned to normal 24 h after l-serine depletion, and were suppressed by the addition of l-serine or glycine in the medium. Extracellular l-serine depletion caused a reduction of extracellular and intracellular glycine levels but maintained intracellular l-serine levels in the cells. Further, Phgdh and serine hydroxymethyltransferase 2 (Shmt2) were upregulated after l-serine depletion. These results led us to conclude that the Atf4-mediated gene expression program is activated by extracellular l-serine depletion in Hepa1-6 cells expressing Phgdh, but is antagonized by the subsequent upregulation of l-serine synthesis, mainly from autonomous glycine consumption.

DOI： 10.3390/nu12103018

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記述言語：英語   掲載種別：研究論文（学術雑誌）

Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin’s B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. These results suggest that the GSEA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances.

DOI： 10.1038/s41598-020-65463-6

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記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）

Motivation: Genome-wide identification of the transcriptomic responses of human cell lines to drug treatments is a challenging issue in medical and pharmaceutical research. However, drug-induced gene expression profiles are largely unknown and unobserved for all combinations of drugs and human cell lines, which is a serious obstacle in practical applications. Results: Here, we developed a novel computational method to predict unknown parts of drug-induced gene expression profiles for various human cell lines and predict new drug therapeutic indications for a wide range of diseases. We proposed a tensor-train weighted optimization (TT-WOPT) algorithm to predict the potential values for unknown parts in tensor-structured gene expression data. Our results revealed that the proposed TT-WOPT algorithm can accurately reconstruct drug-induced gene expression data for a range of human cell lines in the Library of Integrated Network-based Cellular Signatures. The results also revealed that in comparison with the use of original gene expression profiles, the use of imputed gene expression profiles improved the accuracy of drug repositioning. We also performed a comprehensive prediction of drug indications for diseases with gene expression profiles, which suggested many potential drug indications that were not predicted by previous approaches. Supplementary information: Supplementary data are available at Bioinformatics online.

DOI： 10.1093/bioinformatics/btz313

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. l-Serine (l-Ser) is a necessary precursor for the synthesis of proteins, lipids, glycine, cysteine, d-serine, and tetrahydrofolate metabolites. Low l-Ser availability activates stress responses and cell death; however, the underlying molecular mechanisms remain unclear. l-Ser is synthesized de novo from 3-phosphoglycerate with 3-phosphoglycerate dehydrogenase (Phgdh) catalyzing the first reaction step. Here, we show that l-Ser depletion raises intracellular H2O2 levels and enhances vulnerability to oxidative stress in Phgdh-deficient mouse embryonic fibroblasts. These changes were associated with reduced total glutathione levels. Moreover, levels of the inflammatory markers thioredoxin-interacting protein and prostaglandin-endoperoxide synthase 2 were upregulated under l-Ser-depleted conditions; this was suppressed by the addition of N-acetyl-l-cysteine. Thus, intracellular l-Ser deficiency triggers an inflammatory response via increased oxidative stress, and de novo l-Ser synthesis suppresses oxidative stress damage and inflammation when the external l-Ser supply is restricted.

DOI： 10.1002/2211-5463.12429

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）

DOI： 10.1016/j.dib.2016.04.052

記述言語：英語   掲載種別：研究論文（学術雑誌）

© 2016 Federation of European Biochemical Societies. Reduced availability of l-serine limits cell proliferation and leads to an adaptation to l-serine-deficient environment, the underlying molecular mechanism of which remain largely unexplored. Genetic ablation of 3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step of de novo l-serine synthesis, led to diminished cell proliferation and the activation of p38 MAPK and stress-activated protein kinase/Jun amino-terminal kinase in mouse embryonic fibroblasts under l-serine depletion. The resultant l-serine deficiency induced cyclin-dependent kinase inhibitor 1a (Cdkn1a; p21) expression, which was mediated by p38 MAPK. Survival of the Phgdh-deficient mouse embryonic fibroblasts was markedly reduced by p38 MAPK inhibition under l-serine depletion, whereas p38 MAPK could be activated by 1-deoxysphinganine, an atypical alanine-derived sphingoid base that was found to accumulate in l-serine-depleted mouse embryonic fibroblasts. These observations provide persuasive evidence that when the external l-serine supply is limited, l-serine synthesized de novo in proliferating cells serves as a metabolic gatekeeper to maintain cell survival and the functions necessary for executing cell cycle progression. Database: Gene Expression Omnibus, accession number GSE55687. Using 3-phosphoglycerate dehydrogenase (Phgdh)-deficient mouse embryonic fibroblasts, we explored l-serine deficiency. Cell proliferation was reduced, but Cdkn1a/p21 expression was induced, mediated by p38 MAPK. These observations suggest that when the external l-serine supply is limited, l-serine synthesized de novo in proliferating cells serves as a metabolic gatekeeper to maintain cell survival and the functions necessary for executing cell cycle progression.

DOI： 10.1002/2211-5463.12038

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