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Article ; Online: Reverse translational research of autophagy and metabolism in kidney disease: Oshima Award Address 2018.

Kimura, Tomonori

2019 Volume 23, Issue 6, Page(s) 733–738

Abstract: The management of chronic kidney disease (CKD) has been a great challenge. Focusing on the difficulty to predict the prognosis of CKD, we initially conducted a series of observational studies, and evaluated the prognostic impacts of cardiac, diabetic, ... ...

Abstract	The management of chronic kidney disease (CKD) has been a great challenge. Focusing on the difficulty to predict the prognosis of CKD, we initially conducted a series of observational studies, and evaluated the prognostic impacts of cardiac, diabetic, kidney, as well as senescent profiles, on CKD. Aiming to protect tubular inflammatory lesions, we studied the roles of autophagy, a process of auto-degradation for cellular homeostasis, in kidney diseases. After having determined its protective role, the proceedings of our autophagy studies are now revealing the mechanisms whereby autophagy protects kidney; autophagy protects kidney from DNA damage, and oxidative and metabolic stress. These emerging roles of autophagy converged on the concept that quality control of organelles (mitochondria and lysosomes), as well as the regulation of metabolism, are the key to protect kidney from diseases, ranging from CKD, acute kidney injury (AKI) to aging kidney. To broaden the clinical potential of autophagy, some cellular and molecular studies were followed up to identify the specific targets of autophagy. Having encountered the critical roles of metabolism in kidney diseases, we conducted a subset of clinical studies, and found that D-amino acids, the chiral derivatives of L-amino acids, can predict the prognosis of CKD. D-Amino acids, normally present in only trace amounts in humans, would be potential candidates for the biomarkers in CKD. The intersections between clinical and basic research provided us a potential approach for the better kidney management, reconfirming the aspects that the reverse translational study is an excellent method for the kidney research.
MeSH term(s)	Amino Acids/metabolism ; Autophagy ; Humans ; Observational Studies as Topic ; Prognosis ; Renal Insufficiency, Chronic/diagnosis ; Renal Insufficiency, Chronic/metabolism
Chemical Substances	Amino Acids
Language	English
Publishing date	2019-03-02
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	1338768-6
ISSN	1437-7799 ; 1342-1751
ISSN (online)	1437-7799
ISSN	1342-1751
DOI	10.1007/s10157-019-01717-6
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Article ; Online: Drug repositioning trends in rare and intractable diseases.

Sakate, Ryuichi / Kimura, Tomonori

Drug discovery today

2022 Volume 27, Issue 7, Page(s) 1789–1795

Abstract: Drug repositioning (DR) is an effective way for developing drugs for rare and intractable diseases (RIDs). Preparation of the ontology is essential for drug development in RIDs, in which disease names have been inconsistently used worldwide. Ontology- ... ...

Abstract	Drug repositioning (DR) is an effective way for developing drugs for rare and intractable diseases (RIDs). Preparation of the ontology is essential for drug development in RIDs, in which disease names have been inconsistently used worldwide. Ontology-based analysis of clinical trial data revealed that DR occurs actively in RIDs. Drugs and their target genes are keys to explore repositionable drugs, because shared target genes between diseases indicate a common mechanism of drug action. This approach visualizes a DR landscape that facilitates drug development. Here, we review the current situation of ontology in RIDs, the trends in drug development, and an efficient strategy for DR based on drug target gene information.
MeSH term(s)	Drug Repositioning ; Humans ; Rare Diseases/drug therapy
Language	English
Publishing date	2022-01-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1324988-5
ISSN	1878-5832 ; 1359-6446
ISSN (online)	1878-5832
ISSN	1359-6446
DOI	10.1016/j.drudis.2022.01.013
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Article ; Online: D-Serine as a sensor and effector of the kidney.

Kimura, Tomonori / Sakai, Shinsuke / Isaka, Yoshitaka

Clinical and experimental nephrology

2023 Volume 27, Issue 11, Page(s) 891–900

Abstract: D-Serine, a rare enantiomer of serine, is a biomarker of kidney disease and function. The level of D-serine in the human body is precisely regulated through the urinary clearance of the kidney, and its clearance serves as a new measure of glomerular ... ...

Abstract	D-Serine, a rare enantiomer of serine, is a biomarker of kidney disease and function. The level of D-serine in the human body is precisely regulated through the urinary clearance of the kidney, and its clearance serves as a new measure of glomerular filtration rate with a lower bias than creatinine clearance. D-Serine also has a direct effect on the kidneys and mediates the cellular proliferation of tubular cells via mTOR signaling and induces kidney remodeling as a compensatory reaction to the loss of kidney mass. In living kidney donors, the removal of the kidney results in an increase in blood D-serine level, which in turn accelerates kidney remodeling and augments kidney clearance, thus reducing blood levels of D-serine. This feedback system strictly controls D-serine levels in the body. The function of D-serine as a biomarker and modulator of kidney function will be the basis of precision medicine for kidney diseases.
MeSH term(s)	Humans ; Serine ; Creatinine ; Kidney ; Kidney Diseases/diagnosis ; Glomerular Filtration Rate ; Biomarkers
Chemical Substances	Serine (452VLY9402) ; Creatinine (AYI8EX34EU) ; Biomarkers
Language	English
Publishing date	2023-07-27
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	1338768-6
ISSN	1437-7799 ; 1342-1751
ISSN (online)	1437-7799
ISSN	1342-1751
DOI	10.1007/s10157-023-02384-4
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Article ; Online: Resistant Maltodextrin Suppresses Intestinal Phenols Production by Modifying the Intestinal Environment.

Kanasaki, Akane / Kimura, Tomonori / Kitagawa, Machiko / Kishimoto, Yuka

Journal of nutritional science and vitaminology

2023 Volume 69, Issue 4, Page(s) 268–274

Abstract: Protein is an essential nutrient that plays several roles in the maintenance of the human body. A high-protein diet is also known to play an important role in weight management in obese individuals and in maintaining muscle strength in the elderly. ... ...

Abstract	Protein is an essential nutrient that plays several roles in the maintenance of the human body. A high-protein diet is also known to play an important role in weight management in obese individuals and in maintaining muscle strength in the elderly. However, over-consumption of protein can have negative effects on health, including deterioration of the intestinal environment by the production of amino acid metabolites such as phenols. Interest in the regulation of the intestinal environment to maintain health has gained attention recently. Resistant maltodextrin (RMD) is a prebiotic dietary fiber. Therefore, we investigated whether RMD suppressed the production of amino acid metabolites through intestinal regulation in rats. Wistar rats were fed either an AIN-93G diet or a modified AIN-93G diet containing 5% tyrosine. RMD (2.5% or 5.0%) was provided with drinking water. The rats were fed these diets and water ad libitum for 3 wk. Urine was collected overnight, after which serum, liver, kidneys, and the whole cecum were collected from rats under anesthesia with isoflurane for analysis of phenols and microbiota. RMD decreased the cecal, serum, and urinary levels of phenols, especially phenol. Moreover, the relative abundance of intestinal Romboutsia ilealis showed a significant correlation with the cecal phenols levels, and RMD decreased the abundance of this species. Thus, RMD may suppress phenols production and decrease serum phenols levels by altering the intestinal environment in rats.
MeSH term(s)	Humans ; Aged ; Rats ; Animals ; Phenols/pharmacology ; Rats, Wistar ; Phenol ; Amino Acids
Chemical Substances	Phenols ; maltodextrin (7CVR7L4A2D) ; Phenol (339NCG44TV) ; Amino Acids
Language	English
Publishing date	2023-08-30
Publishing country	Japan
Document type	Journal Article
ZDB-ID	191366-9
ISSN	1881-7742 ; 0301-4800
ISSN (online)	1881-7742
ISSN	0301-4800
DOI	10.3177/jnsv.69.268
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Article ; Online: Drug target gene-based analyses of drug repositionability in rare and intractable diseases.

Sakate, Ryuichi / Kimura, Tomonori

Scientific reports

2021 Volume 11, Issue 1, Page(s) 12338

Abstract: Drug development for rare and intractable diseases has been challenging for decades due to the low prevalence and insufficient information on these diseases. Drug repositioning is increasingly being used as a promising option in drug development. We ... ...

Abstract	Drug development for rare and intractable diseases has been challenging for decades due to the low prevalence and insufficient information on these diseases. Drug repositioning is increasingly being used as a promising option in drug development. We aimed to analyze the trend of drug repositioning and inter-disease drug repositionability among rare and intractable diseases. We created a list of rare and intractable diseases based on the designated diseases in Japan. Drug information extracted from clinical trial data were integrated with information of drug target genes, which represent the mechanism of drug action. We obtained 753 drugs and 551 drug target genes from 8307 clinical trials for 189 diseases or disease groups. Trend analysis of drug sharing between a disease pair revealed that 1676 drug repositioning events occurred in 4401 disease pairs. A score, R
MeSH term(s)	Clinical Trials as Topic ; Computational Biology ; Drug Repositioning/methods ; Drug Repositioning/statistics & numerical data ; Drug Resistance ; Genotype ; Humans ; Molecular Targeted Therapy/methods ; Rare Diseases/drug therapy ; Rare Diseases/genetics
Language	English
Publishing date	2021-06-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-91428-4
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Article ; Online: Demographics and treatment of patients with primary membranoproliferative glomerulonephritis in Japan using a national registry of clinical personal records.

Nakagawa, Naoki / Kimura, Tomonori / Sakate, Ryuichi / Isaka, Yoshitaka / Narita, Ichiei

Clinical and experimental nephrology

2023 Volume 27, Issue 11, Page(s) 928–935

Abstract: Background: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular injury that causes nephrotic syndrome and end-stage kidney disease. The nationwide demographics and treatment of Japanese patients with primary MPGN have not yet been ... ...

Abstract	Background: Membranoproliferative glomerulonephritis (MPGN) is a rare glomerular injury that causes nephrotic syndrome and end-stage kidney disease. The nationwide demographics and treatment of Japanese patients with primary MPGN have not yet been reported. Methods: We collected clinical personal records of patients with primary MPGN between 2015 and 2018 from the national registry organized by the Japanese Ministry of Health, Labour, and Welfare and investigated the characteristics of primary MPGN throughout Japan. Results: Of 258 patients with primary MPGN, 199 and 59 showed nephrotic and non-nephrotic syndrome, respectively. The median age at onset was higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (45 [24-63] vs. 35 [14-53] years, respectively; P = 0.010). The use of oral prednisolone was significantly higher in patients with nephrotic syndrome than in those with non-nephrotic syndrome (73.9% vs. 59.3%, respectively; P = 0.032). When patients were divided into three age groups: adolescent and young adult group (≤ 39 years; n = 80), middle adult group (40-64 years; n = 111), and older adult group (≥ 65 years; n = 67), the use of oral prednisolone, cyclosporine, and mizoribine was significantly higher in the adolescent and young adult group than in the middle adult group. The mean dosage of oral prednisolone and mizoribine showed no differences among the three age groups. Conclusion: The national registry of clinical personal records of primary MPGN could provide an informative insight into the characteristics, clinical features, and treatment approaches for patients with primary MPGN in Japan.
MeSH term(s)	Adolescent ; Young Adult ; Humans ; Aged ; Adult ; Glomerulonephritis, Membranoproliferative/drug therapy ; Glomerulonephritis, Membranoproliferative/epidemiology ; Nephrotic Syndrome/drug therapy ; Nephrotic Syndrome/epidemiology ; Japan/epidemiology ; Prednisolone/therapeutic use ; Registries ; Demography
Chemical Substances	Prednisolone (9PHQ9Y1OLM)
Language	English
Publishing date	2023-07-29
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1338768-6
ISSN	1437-7799 ; 1342-1751
ISSN (online)	1437-7799
ISSN	1342-1751
DOI	10.1007/s10157-023-02387-1
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Article ; Online: GCN2 kinase‐mediated upregulation of ubiquitin C maintains intracellular glutamine level and tRNAGln(CUG) charging under amino acid starvation

Tsukamoto, Yusuke / Nakamura, Yumi / Hirata, Makoto / Okuzaki, Daisuke / Sakate, Ryuichi / Kimura, Tomonori

FEBS Letters. 2023 June, v. 597, no. 12 p.1638-1650

2023

Abstract: Each tRNA is aminoacylated (charged) with a genetic codon‐specific amino acid. It remains unclear what factors are associated with tRNA charging and how tRNA charging is maintained. By using the individual tRNA acylation PCR method, we found that the ... ...

Abstract	Each tRNA is aminoacylated (charged) with a genetic codon‐specific amino acid. It remains unclear what factors are associated with tRNA charging and how tRNA charging is maintained. By using the individual tRNA acylation PCR method, we found that the charging ratio of tRNAᴳˡⁿ(CUG) reflects cellular glutamine level. When uncharged tRNAᴳˡⁿ(CUG) increased under amino acid starvation, the kinase GCN2, which is a key stimulator of the integrated stress response, was activated. Activation of GCN2 led to the upregulation of ubiquitin C (UBC) expression. Upregulated UBC, in turn, suppressed the further reduction in tRNAᴳˡⁿ(CUG) charging levels. Thus, tRNA charging is sensitive to intracellular nutrient status and is an important initiator of intracellular signaling.
Keywords	acylation ; glutamine ; starvation ; stress response ; ubiquitin
Language	English
Dates of publication	2023-06
Size	p. 1638-1650.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	JOURNAL ARTICLE
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14628
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Article ; Online: i-tRAP (individual tRNA acylation PCR): A convenient method for selective quantification of tRNA charging.

Tsukamoto, Yusuke / Nakamura, Yumi / Hirata, Makoto / Sakate, Ryuichi / Kimura, Tomonori

RNA (New York, N.Y.)

2022

Abstract: Each transfer RNA (tRNA) is aminoacylated (charged) with a genetic codon-specific amino acid at its 3' end. Charged tRNAs are primarily used for translation, whereas fluctuations in charged tRNA fractions are known to reflect cellular response to stress. ...

Abstract	Each transfer RNA (tRNA) is aminoacylated (charged) with a genetic codon-specific amino acid at its 3' end. Charged tRNAs are primarily used for translation, whereas fluctuations in charged tRNA fractions are known to reflect cellular response to stress. Here we report the development of individual tRNA-acylation using PCR (i-tRAP), a convenient PCR-based method that can specifically quantify individual tRNA charging ratio. In this i-tRAP method, demethylases remove base methylations which are problematic for reverse transcription reaction, and β-elimination reaction specifically removes the 3' end of adenine residue in uncharged tRNA. Subsequent TaqMan MGB qRT-PCR can distinguish between cDNA of charged tRNA and uncharged tRNA. By using this method, we revealed that the charging ratio of tRNAGln(CUG) was changed in response to amino acid starvation and also the charging ratio of tRNAGln(CUG) in senescent cells was lower than in young cells under starvation conditions. i-tRAP can be applicable to the quantification of charging ratio of various tRNAs, and provides a simple and convenient method for analyzing tRNA charging.
Language	English
Publishing date	2022-10-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079323.122
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Article ; Online: A novel in silico scaffold-hopping method for drug repositioning in rare and intractable diseases.

Tanabe, Mao / Sakate, Ryuichi / Nakabayashi, Jun / Tsumura, Kyosuke / Ohira, Shino / Iwato, Kaoru / Kimura, Tomonori

Scientific reports

2023 Volume 13, Issue 1, Page(s) 19358

Abstract: In the field of rare and intractable diseases, new drug development is difficult and drug repositioning (DR) is a key method to improve this situation. In this study, we present a new method for finding DR candidates utilizing virtual screening, which ... ...

Abstract	In the field of rare and intractable diseases, new drug development is difficult and drug repositioning (DR) is a key method to improve this situation. In this study, we present a new method for finding DR candidates utilizing virtual screening, which integrates amino acid interaction mapping into scaffold-hopping (AI-AAM). At first, we used a spleen associated tyrosine kinase inhibitor as a reference to evaluate the technique, and succeeded in scaffold-hopping maintaining the pharmacological activity. Then we applied this method to five drugs and obtained 144 compounds with diverse structures. Among these, 31 compounds were known to target the same proteins as their reference compounds and 113 compounds were known to target different proteins. We found that AI-AAM dominantly selected functionally similar compounds; thus, these selected compounds may represent improved alternatives to their reference compounds. Moreover, the latter compounds were presumed to bind to the targets of their references as well. This new "compound-target" information provided DR candidates that could be utilized for future drug development.
MeSH term(s)	Drug Repositioning ; Drug Development ; Amino Acids ; Protein Kinase Inhibitors ; Spleen
Chemical Substances	Amino Acids ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-11-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-46648-1
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Article ; Online: Profiling of kidney involvement in systemic lupus erythematosus by deep learning using the National Database of Designated Incurable Diseases of Japan.

Kimura, Tomonori / Ikeuchi, Hidekazu / Yoshino, Mitsuaki / Sakate, Ryuichi / Maruyama, Shoichi / Narita, Ichiei / Hiromura, Keiju

Clinical and experimental nephrology

2023 Volume 27, Issue 6, Page(s) 519–527

Abstract: Background: Kidney involvement frequently occurs in systemic lupus erythematosus (SLE), and its clinical manifestations are complicated. We profiled kidney involvement in SLE patients using deep learning based on data from the National Database of ... ...

Abstract	Background: Kidney involvement frequently occurs in systemic lupus erythematosus (SLE), and its clinical manifestations are complicated. We profiled kidney involvement in SLE patients using deep learning based on data from the National Database of Designated Incurable Diseases of Japan. Methods: We analyzed the cross-sectional data of 1655 patients with SLE whose Personal Clinical Records were newly registered between 2015 and 2017. We trained an artificial neural network using clinical data, and the extracted characteristics were evaluated using an autoencoder. We tested the difference of population proportions to analyze the correlation between the presence or absence of kidney involvement and that of other clinical manifestations. Results: Data of patients with SLE were compressed in a feature space in which the anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody titer, antinuclear antibody titer, or white blood cell count contributed significantly to distinguishing patients. Many SLE manifestations were accompanied by kidney involvement, whereas in a subgroup of patients with high anti-dsDNA antibody titers and low antinuclear antibody titers, kidney involvement was positively and negatively correlated with hemolytic anemia and inflammatory manifestations, respectively. Conclusion: Although there are various combinations of SLE manifestations, our study revealed that some of them are specific to kidney involvement. SLE profiles extracted from the objective analysis will be useful for categorizing SLE manifestations.
MeSH term(s)	Humans ; Antibodies, Antinuclear ; Japan/epidemiology ; Cross-Sectional Studies ; Deep Learning ; Lupus Erythematosus, Systemic/complications ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/epidemiology ; Kidney
Chemical Substances	Antibodies, Antinuclear
Language	English
Publishing date	2023-03-16
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1338768-6
ISSN	1437-7799 ; 1342-1751
ISSN (online)	1437-7799
ISSN	1342-1751
DOI	10.1007/s10157-023-02337-x
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