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Jimenez G, Foiani L, Figueiredo JT, Sá Alves M, Sá Rodrigues N, Bandeira CM, Alves MGO, Dias Almeida J, da Silva Martinho H. Histine, carbohydrates/polysaccharides, and proteins with β-sheet conformation as promising staging markers for oral squamous cell carcinoma. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 340:126296. [PMID: 40373546 DOI: 10.1016/j.saa.2025.126296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 02/04/2025] [Accepted: 04/23/2025] [Indexed: 05/17/2025]
Abstract
Cancers of the oral cavity and lip ranks 15th cancer mortality being oral squamous cell carcinoma (OSCC) the predominant malignant neoplasm in the head and neck region. Liquid optical biopsy using infrared absorption spectroscopy offers rapid and accurate diagnosis of several diseases, including oral cancer. Here we investigated saliva samples from patients with OSCC and healthy individuals using micro-reflectance Fourier-transform infrared absorption spectroscopy. Partial least squares discriminant (PLSDA) and support vector machine (SVM) analysis were employed to mining the set of data. SVM analysis validated the PLSDA findings and presented excellent results with sensitivity of 98.6%, specificity of 97.3%, and area under ROC curve of 0.965. Interestingly we found that bands assigned to histidine, carbohydrates/polysaccharides, and content of proteins with β-sheet conformation contributed to discrimination among groups. Moreover we found that specific changes in these bands could be related to OSCC staging being promising disease gravity markers.
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Affiliation(s)
- Gabrielle Jimenez
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), Av. dos Estados 5001, Santo André, 09210-580, SP, Brazil
| | - Letícia Foiani
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), Av. dos Estados 5001, Santo André, 09210-580, SP, Brazil
| | - Julia Toledo Figueiredo
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), Av. dos Estados 5001, Santo André, 09210-580, SP, Brazil
| | - Mariana Sá Alves
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University (UNESP), São José dos Campos, São Paulo, Brazil
| | - Nayara Sá Rodrigues
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University (UNESP), São José dos Campos, São Paulo, Brazil
| | - Celso Muller Bandeira
- Núcleo de Pesquisas Tecnológicas, Universidade Mogi das Cruzes, Mogi das Cruzes-SP, 08780-911, Brazil
| | - Mônica Ghislaine Oliveira Alves
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University (UNESP), São José dos Campos, São Paulo, Brazil
| | - Janete Dias Almeida
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University (UNESP), São José dos Campos, São Paulo, Brazil
| | - Herculano da Silva Martinho
- Centro de Ciências Naturais e Humanas, Universidade Federal do ABC (UFABC), Av. dos Estados 5001, Santo André, 09210-580, SP, Brazil.
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Lin S, Yan R, Zhu J, Li B, Zhong Y, Han S, Wang H, Wu J, Chen Z, Jiang Y, Pan A, Huang X, Chen X, Zhu P, Cao S, Liang W, Ye P, Gao Y. Rapid and Noninvasive Early Detection of Lung Cancer by Integration of Machine Learning and Salivary Metabolic Fingerprints Using MS LOC Platform: A Large-Scale Multicenter Study. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2416719. [PMID: 40365752 PMCID: PMC12165017 DOI: 10.1002/advs.202416719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 04/09/2025] [Indexed: 05/15/2025]
Abstract
Most lung cancer (LC) patients are diagnosed at advanced stages due to the lack of effective screening tools. This multicenter study analyzes 1043 saliva samples (334 LC cases and 709 non-LC cases) using a novel high-throughput platform for metabolic fingerprint acquisition. Machine learning identifies 35 metabolic features distinguishing LC from non-LC subjects, enabling the development of a classification model named SalivaMLD. In the validation set and test set, SalivaMLD demonstrates strong diagnostic performance, achieving an area under the curve of 0.849-0.850, a sensitivity of 81.69-83.33%, and a specificity of 74.23-74.39%, outperforming conventional tumor biomarkers. Notably, SalivaMLD exhibits superior accuracy in distinguishing early stage LC patients. Hence, this rapid and noninvasive screening method may be widely applied in clinical practice for LC detection.
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Affiliation(s)
- Shuang Lin
- Department of Thoracic SurgeryThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310006China
| | - Runlan Yan
- Department of GeriatricsZhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People’s HospitalSchool of MedicineWestlake UniversityHangzhou310006China
| | - Junqi Zhu
- Respiratory and Critical Care Medicine DepartmentTongde Hospital of Zhejiang ProvinceHangzhou310012China
| | - Bei Li
- Department of GeriatricsZhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People’s HospitalSchool of MedicineWestlake UniversityHangzhou310006China
| | - Yinyan Zhong
- Pengbu Subdistrict Community Healthcare CenterShangcheng DistrictHangzhou310000China
| | - Shuang Han
- Department of GeriatricsZhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People’s HospitalSchool of MedicineWestlake UniversityHangzhou310006China
| | - Huiting Wang
- Department of Thoracic Oncology and SurgeryChina State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510000China
| | - Jianmin Wu
- Lab of Nanomedicine and Omic‐based DiagnosisDepartment of ChemistryZhejiang UniversityHangzhou310058China
| | - Zhao Chen
- Department of Thoracic SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China
| | - Yuyue Jiang
- Respiratory and Critical Care Medicine DepartmentTongde Hospital of Zhejiang ProvinceHangzhou310012China
| | - Aiwu Pan
- Department of Internal Medicinethe Second Affiliated Hospital Zhejiang University School of MedicineHangzhou310058China
| | - Xuqing Huang
- Respiratory and Critical Care Medicine DepartmentAffiliated Hospital of Hangzhou Normal UniversityHangzhou310000China
| | - Xiaoming Chen
- Well‐healthcare Technologies, Co., Ltd.Hangzhou310012China
- Department of General SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhou310016China
| | - Pingya Zhu
- Well‐healthcare Technologies, Co., Ltd.Hangzhou310012China
| | - Sheng Cao
- Well‐healthcare Technologies, Co., Ltd.Hangzhou310012China
| | - Wenhua Liang
- Department of Thoracic Oncology and SurgeryChina State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510000China
| | - Peng Ye
- Department of Thoracic SurgeryThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310006China
| | - Yue Gao
- Department of GeriatricsZhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People’s HospitalSchool of MedicineWestlake UniversityHangzhou310006China
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Mizukami-Murata S, Tsushima I, Abe S, Kitamura T, Okayasu Y. Effects of laundry-derived microplastic fibers on larval Japanese medaka (Oryzias latipes). THE SCIENCE OF THE TOTAL ENVIRONMENT 2025; 983:179657. [PMID: 40398170 DOI: 10.1016/j.scitotenv.2025.179657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 05/10/2025] [Accepted: 05/10/2025] [Indexed: 05/23/2025]
Abstract
In recent years, laundry-derived microplastic fibers (LMFs) have been reported as one of the major sources of microplastics (MPs) released from wastewater treatment plants into the aquatic environment. Fish are considered to be among the types of aquatic biota most susceptible to ingested MPs; there is thus a need to assess the risk that LMFs pose to fish, although this remains largely unknown. Here, fluorescent LMFs were prepared using a washing machine, after which Oryzias latipes (Japanese medaka) larvae were exposed to them for 21 days to assess their toxicities. Upon exposure of the larvae to LMFs (0.2 and 2 mg/L), the typical yellow fluorescent signal of LMFs was observed mainly in the mouth, gastrointestinal tract, anus, and feces. No mortality was observed in larvae treated with either concentration of LMFs. However, decreases in body length and weight were observed upon the 2 mg/L treatment, which induced metabolites related to nucleotide metabolism. In addition, increased relative amounts of specific flora, Flavobacterium sp. and Burkholderiaceae, were observed in larvae exposed to 2 mg/L LMFs. Overall, 85.6 % of LMFs were ejected from LMF-treated medaka larvae after a 4-day depuration period; however, longer LMFs were more likely to remain in the larval gastrointestinal tract than shorter ones. These findings should deepen our understanding of the ecological effects of LMFs on freshwater fish.
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Affiliation(s)
- Satomi Mizukami-Murata
- Water Quality Team, Water Environment Research Group, Public Works Research Institute, 1-6 Minamihara, Tsukuba, Ibaraki 305-8516, Japan.
| | - Ikuo Tsushima
- Water Quality Team, Water Environment Research Group, Public Works Research Institute, 1-6 Minamihara, Tsukuba, Ibaraki 305-8516, Japan
| | - Shota Abe
- Entex Co., Ltd., 1-2-8 Asahi, Kashiwa, Chiba 277-0852, Japan
| | - Tomokazu Kitamura
- Water Quality Team, Water Environment Research Group, Public Works Research Institute, 1-6 Minamihara, Tsukuba, Ibaraki 305-8516, Japan
| | - Yuji Okayasu
- Water Quality Team, Water Environment Research Group, Public Works Research Institute, 1-6 Minamihara, Tsukuba, Ibaraki 305-8516, Japan
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Aoyama K, Yamamura R, Katsurada T, Shimizu T, Takahashi D, Kondo E, Iwasaki N, Tamakoshi A, Soga T, Fukuda S, Sonoshita M, Sakamoto N. Decreased Fecal Nicotinamide and Increased Bacterial Nicotinamidase Gene Expression in Ulcerative Colitis Patients. Inflamm Bowel Dis 2025:izaf092. [PMID: 40357746 DOI: 10.1093/ibd/izaf092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Indexed: 05/15/2025]
Abstract
BACKGROUND/OBJECTIVE Ulcerative colitis (UC) is significantly linked with gut microbiota, which is essential for maintaining gut health. Their metabolites mitigate gut inflammation and bolster barrier function. Among these metabolites, we focused on vitamin B3, which has been reported to improve the pathogenesis of UC in mice. This study aimed to compare fecal vitamin B3 and gut microbiota between non-UC and UC patients. METHODS We assessed fecal metabolites and gut microbiota in 71 UC patients (UC group) and 72 non-UC patients (non-UC group) matched by sex and age in 10-year intervals. Fecal samples were collected and metabolites were analyzed using capillary electrophoresis time-of-flight mass spectrometry. Bacterial DNA was extracted for 16S rRNA gene sequencing. We analyzed fecal nicotinamide levels and gut microbiota composition, employing statistical adjustments for confounding factors. RESULTS We found that the UC group exhibited significantly lower fecal nicotinamide levels and α-diversity (Shannon index) compared to the non-UC group. The relative abundance of bacterial genera such as Treponema, UCG-002, and Fusicatenibacter was decreased, while Sellimonas, Fournierella, and Oscillospira were increased in the UC group. Moreover, a negative correlation was observed between Sellimonas abundance and fecal nicotinamide levels in the UC group. Additionally, the UC group showed higher expression of a bacterial gene encoding nicotinamidase compared to the non-UC group. CONCLUSIONS These findings suggest that gut microbiota dysbiosis contributes to reduced vitamin B3 metabolism in UC patients. The study highlights the potential of replenishing vitamin B3 metabolic pathways as a novel therapeutic approach for UC treatment.
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Affiliation(s)
- Keiya Aoyama
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Ryodai Yamamura
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Takehiko Katsurada
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Tomohiro Shimizu
- Department of Orthopaedic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Daisuke Takahashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Eiji Kondo
- Center for Sports Medicine, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
| | - Norimasa Iwasaki
- Department of Orthopaedic Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Akiko Tamakoshi
- Department of Public Health, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
- Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Kanagawa, Japan
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Innovative Microbiome Therapy Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
- Metagen, Inc., Tsuruoka, Yamagata, Japan
| | - Masahiro Sonoshita
- Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- FlyWorks, K.K., Sapporo, Hokkaido, Japan
- FlyWorks America Inc., Pittsfield, MA, USA
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
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Pickard JM, Porwollik S, Caballero-Flores G, Caruso R, Fukuda S, Soga T, Inohara N, McClelland M, Núñez G. Dietary amino acids regulate Salmonella colonization via microbiota-dependent mechanisms in the mouse gut. Nat Commun 2025; 16:4225. [PMID: 40335509 PMCID: PMC12058977 DOI: 10.1038/s41467-025-59706-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/30/2025] [Indexed: 05/09/2025] Open
Abstract
The gut microbiota confers host protection against pathogen colonization early after infection. Several mechanisms underlying the protection have been described, but the contributions of nutrient competition versus direct inhibition are controversial. Using an ex vivo model of Salmonella growth in the mouse cecum with its indigenous microbes, we find that nutrient limitation and typical inhibitory factors alone cannot prevent pathogen growth. However, the addition of certain amino acids markedly reverses the microbiota's ability to suppress pathogen growth. Enhanced Salmonella colonization after antibiotic treatment is ablated by exclusion of dietary protein, which requires the presence of the microbiota. Thus, dietary protein and amino acids are important regulators of colonization resistance.
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Affiliation(s)
- Joseph M Pickard
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Steffen Porwollik
- Department of Microbiology and Molecular Genetics, University of California, Irvine, School of Medicine, Irvine, CA, USA
| | - Gustavo Caballero-Flores
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA
| | - Roberta Caruso
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
- Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Kanagawa, Japan
- Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Innovative Microbiome Therapy Research Center, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Naohiro Inohara
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Michael McClelland
- Department of Microbiology and Molecular Genetics, University of California, Irvine, School of Medicine, Irvine, CA, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
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Kakisaka K, Sato T, Wada Y, Abe H, Abe S, Shimodate A, Watanabe T, Sasaki T, Fujiwara Y, Abe T, Suzuki A, Endo K, Yoshida Y, Oikawa T, Sawara K, Miyasaka A, Komaki S, Shimizu A, Ishikawa K, Akasaka M, Kuroda H, Matsumoto T. Dual pathogenic mechanisms in lysinuric protein intolerance: Interplay between hyperammonemia and cellular metabolic dysregulation in astrocyte injury. Mol Genet Metab 2025; 145:109134. [PMID: 40349487 DOI: 10.1016/j.ymgme.2025.109134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 05/02/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Lysinuric protein intolerance (LPI) is a rare genetic disorder characterized by an inherited defect in cationic amino acid transport caused by pathogenic variants in the SLC7A7 gene. While LPI causes systemic complications, the underlying cellular mechanisms remain poorly understood. This study investigated the cellular characteristics of LPI, focusing on intracellular metabolite profiles and astrocyte response to hyperammonemia. OBJECTIVES To examine intracellular metabolite changes in LPI patients and to evaluate the response of patient-derived astrocytes to ammonia exposure. METHODS Peripheral blood mononuclear cells (PBMCs) from three LPI patients and three healthy controls were analyzed for intracellular metabolite profiles using capillary electrophoresis-fourier transform mass spectrometry. Induced pluripotent stem cells were generated from a patient's PBMCs and differentiated into astrocytes. We evaluated LPI-astrocytes and their response to ammonia treatment by RNA sequencing, gene expression profiling, and cell viability assays. RESULTS Metabolite analysis revealed significant intracellular metabolite imbalances in LPI patients, with increases of 21 metabolites including 11 amino acids. LPI-astrocytes exhibited distinct cellular characteristics regarding altered gene expression and enhanced cell cycle progression. When exposed to ammonia, the astrocytes demonstrated markedly lower cell viability and increased reactive oxygen species (ROS) production compared to control astrocytes. N-acetylcysteine supplementation significantly ameliorated ammonia-induced cytotoxicity. CONCLUSIONS SLC7A7 dysfunction leads to intracellular metabolite disturbances and an increase in vulnerability to ammonia toxicity through ROS production of astrocyte, suggesting hyperammonemia and amino acid deficiencies as potential therapeutic targets in LPI patient care.
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Affiliation(s)
- Keisuke Kakisaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan.
| | - Takuro Sato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Yasunori Wada
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Hiroaki Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Shizuka Abe
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Ai Shimodate
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Takuya Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Tokio Sasaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Yudai Fujiwara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Tamami Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Akiko Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Kei Endo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Yuichi Yoshida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Takayoshi Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Kei Sawara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Akio Miyasaka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Shohei Komaki
- Division of Biomedical Information Analysis, Iwate Medical University, Yahaba, Japan
| | - Atsushi Shimizu
- Division of Biomedical Information Analysis, Iwate Medical University, Yahaba, Japan
| | - Ken Ishikawa
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Manami Akasaka
- Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan
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Zaripov EA, Khraibah A, Kasyanchyk P, Radchanka A, Hüttmann N, Berezovski MV. CE-MS Metabolomic and LC-MS Proteomic Analyses of Breast Cancer Exosomes Reveal Alterations in Purine and Carnitine Metabolism. J Proteome Res 2025; 24:2505-2516. [PMID: 40036676 DOI: 10.1021/acs.jproteome.4c00795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
A nanosheath-flow capillary electrophoresis mass spectrometry (CE-MS) system with electrospray ionization was used to profile cationic metabolite cargo in exosomes secreted by nontumorigenic MCF-10A and tumorigenic MDA-MB-231 breast epithelial cells. An in-house-produced sheath liquid interface was developed and machined from PEEK to enable nanoflow volumes. Normalization of CE-MS peak areas to the total UV signal was employed to enhance quantitative accuracy and reduce variability. CE-MS-based metabolomics revealed increased purine synthesis intermediates and increased carnitine synthesis metabolites in MDA-MB-231-derived exosomes, with pathway enrichment indicating the activation of de novo purine pathways and upregulation of carnitine metabolism. In addition, nano-LC-MS-based proteomics revealed differential expression of ecto-5'-nucleotidase (NT5E) and mitochondrial aldehyde dehydrogenase (ALDH9A1), demonstrating metabolic alterations in related enzymatic steps. This study demonstrates the application of nanosheath-flow CE-MS for comprehensive and quantitative exosome metabolomics, uncovering metabolic reprogramming in purine and carnitine pathways between normal and cancerous breast cell lines and providing insight into exosome-mediated signaling of breast cancer metabolism.
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Affiliation(s)
- Emil A Zaripov
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Abdullah Khraibah
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Petr Kasyanchyk
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Aliaksandra Radchanka
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
| | - Nico Hüttmann
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
- European Molecular Biology Laboratory, Molecular Systems Biology Unit, Heidelberg 69117, Germany
| | - Maxim V Berezovski
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa K1N 6N5, Canada
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Tanaka S, Sakagami H, Sugimoto M. Age- and Periodontal Disease Independent Correlation of Salivary Amino Acids. In Vivo 2025; 39:1237-1250. [PMID: 40295002 PMCID: PMC12042004 DOI: 10.21873/invivo.13928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 01/25/2025] [Accepted: 01/27/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND/AIM This study explored the relationship between salivary metabolomic profiles, periodontal diseases, and age. PATIENTS AND METHODS Resting whole saliva samples were collected from a cohort comprising 21 women and 30 men aged 20 to 70 years, including healthy volunteers and patients with different stages of periodontal diseases. Hydrophilic metabolites were analyzed using capillary electrophoresis-mass spectrometry. The concentrations were quantified and analyzed using multivariable analysis with or without normalization to eliminate overall differences in salivary concentrations across the samples. RESULTS Metabolomic analysis quantified the absolute concentration of 248 metabolites in saliva samples. The unnormalized metabolomic profiles formed large clusters, with more than half of the detected metabolites showing positive correlations with each other. The absence of such clusters in the normalized data suggests the presence of individual differences in the processed data. The presence of urea, whose concentration increased gradually with the degree of progression of periodontal disease, and leucine, whose concentration decreased gradually, was identified. Highly positive correlations were observed between proline and glycine, which remained consistent regardless of normalization, age, or disease progression. CONCLUSION The metabolomic profiles of salivary samples revealed unique correlations between amino acids that were independent of age and periodontal disease.
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Affiliation(s)
- Shoji Tanaka
- Meikai University School of Dentistry, Sakado, Japan
| | | | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan;
- Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
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Yamaguchi F, Akieda-Asai S, Nakamura E, Uchida H, Yamashita A, Date Y. Continuous Exposure of Nonobese Adult Male Rats to a Soft-Textured, Readily Absorbable Diet Induces Insulin Resistance and Derangements in Hepatic Glucose and Lipid Metabolism. J Nutr 2025; 155:1387-1397. [PMID: 40074175 PMCID: PMC12121407 DOI: 10.1016/j.tjnut.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/12/2025] [Accepted: 03/06/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is characterized by insulin resistance and defective insulin secretion. Previously, we found that rats fed soft pellets (SPs) on a 3-h restricted schedule over 14 wk demonstrated glucose intolerance and insulin resistance with disruption of insulin signaling. OBJECTIVES This study aims to determine 1) the time required for an SP diet to induce insulin resistance, and 2) whether the metabolic derangements in rats fed SPs can be reversed by changing to a standard control diet. METHODS We performed glucose tolerance tests and calculated the homeostasis model assessment of insulin resistance (HOMA-IR) to evaluate the insulinemic response to glucose and assess insulin resistance in nonobese male rats fed control pellets (CPs) or SPs on a 3-h restricted schedule (10:00-13:00) for 4 and 9 wk. At 11 wk, we switched half of the insulin-resistant SP group to CPs [soft-to-control pellets (SCPs)] and after an additional 11 wk evaluated changes in glucose and lipid metabolism across the 3 groups. RESULTS The glucose tolerance test results in the SP and CP rats did not differ at 4 or 9 wk. The insulin levels in the SP group were higher than in the CP group at both time points (P < 0.05). The HOMA-IR was significantly higher in the SP rats at 9 wk compared with the controls (P < 0.05). At 22 wk, the HOMA-IR, blood glucose levels at 30 min after initiating feeding, hepatic glucose metabolism, and lipid synthesis in rats fed SPs continuously were significantly greater than in those fed CPs (P < 0.05); however, these values in the SCP rats did not differ from those in the CP rats. CONCLUSIONS A continuous diet of soft-textured, readily absorbable food may be an important and reversible underlying driver in T2D pathogenesis.
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Affiliation(s)
- Fumitake Yamaguchi
- Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan; School of Nursing, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Sayaka Akieda-Asai
- Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
| | - Eriko Nakamura
- Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Hinano Uchida
- Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
| | - Atsushi Yamashita
- Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yukari Date
- Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
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10
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Nejat Dehkordi A, Maddahi M, Vafa P, Ebrahimi N, Aref AR. Salivary biomarkers: a promising approach for predicting immunotherapy response in head and neck cancers. Clin Transl Oncol 2025; 27:1887-1920. [PMID: 39377974 DOI: 10.1007/s12094-024-03742-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 09/21/2024] [Indexed: 04/27/2025]
Abstract
Head and neck cancers, including cancers of the mouth, throat, voice box, salivary glands, and nose, are a significant global health issue. Radiotherapy and surgery are commonly used treatments. However, due to treatment resistance and disease recurrence, new approaches such as immunotherapy are being explored. Immune checkpoint inhibitors (ICIs) have shown promise, but patient responses vary, necessitating predictive markers to guide appropriate treatment selection. This study investigates the potential of non-invasive biomarkers found in saliva, oral rinses, and tumor-derived exosomes to predict ICI response in head and neck cancer patients. The tumor microenvironment significantly impacts immunotherapy efficacy. Oral biomarkers can provide valuable information on composition, such as immune cell presence and checkpoint expression. Elevated tumor mutation load is also associated with heightened immunogenicity and ICI responsiveness. Furthermore, the oral microbiota may influence treatment outcomes. Current research aims to identify predictive salivary biomarkers. Initial studies indicate that tumor-derived exosomes and miRNAs present in saliva could identify immunosuppressive pathways and predict ICI response. While tissue-based markers like PD-L1 have limitations, combining multiple oral fluid biomarkers could create a robust panel to guide treatment decisions and advance personalized immunotherapy for head and neck cancer patients.
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Affiliation(s)
| | - Moein Maddahi
- Faculty of Density, Yeditepe University, Istanbul, Turkey
| | - Parinaz Vafa
- Faculty of Density, Yeditepe University, Istanbul, Turkey
| | - Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Amir Reza Aref
- Mass General Cancer Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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11
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Oishi K, Yoshida Y, Kaida K, Terai K, Yamamoto H, Toyoda A. Potential non-invasive biomarkers of chronic sleep disorders identified by salivary metabolomic profiling among middle-aged Japanese men. Sci Rep 2025; 15:10980. [PMID: 40258870 PMCID: PMC12012070 DOI: 10.1038/s41598-025-95403-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/20/2025] [Indexed: 04/23/2025] Open
Abstract
Sleep disorders have become a global social problem that increases the risk of developing mental illnesses and metabolic diseases. We aimed to identify biomarkers with which to non-invasively and objectively evaluate chronic sleep disorders. We used capillary electrophoresis-Fourier transform mass spectrometry (CE-FTMS) to analyze metabolomes in saliva collected from 50 persons each with good (≤ 2) and poor (≥ 6) sleep quality scored according to the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) self-report questionnaire. The levels of five metabolites including glycerol and hippuric acid and eight including 2-hydroxybutyric acid (2HB), were respectively decreased and increased in participants with poor sleep quality. We established a random forest model consisting of six metabolites, including glycerol and hippuric acid, with a prediction accuracy of 0.866. Correlations between metabolites and sleep satisfaction were assessed using the Oguri-Shirakawa-Azumi sleep inventory, middle-age and aged version (OSA-MA) questionnaire. The results showed that 2'-deoxyguanosine, N1-acetylspermine, and 2,4-dihydroxybenzoic acid correlated positively, whereas glucosamine 6-phosphate and trimethylamine N-oxide correlated negatively with sleep quality. These findings suggested that changes in salivary metabolites reflect pathophysiological mechanisms of chronic sleep disorders, and that saliva samples could serve as non-invasive and objective diagnostic targets for predicting habitual sleep quality.
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Affiliation(s)
- Katsutaka Oishi
- Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan.
- Department of Applied Biological Science, Graduate School of Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
| | - Yuta Yoshida
- Department of Food and Life Sciences, College of Agriculture, Ibaraki University, Ami, Ibaraki, Japan
| | - Kosuke Kaida
- Institute for Information Technology and Human Factors, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
| | - Kozue Terai
- Human Metabolome Technologies Inc, Tsuruoka, Yamagata, Japan
| | | | - Atsushi Toyoda
- Department of Food and Life Sciences, College of Agriculture, Ibaraki University, Ami, Ibaraki, Japan
- United Graduate School of Agricultural Science, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan
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12
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Iijima H, Imai-Okazaki A, Kishita Y, Sugiura A, Shimura M, Murayama K, Okazaki Y, Ohtake A. Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis. Mol Genet Metab 2025; 145:109113. [PMID: 40273865 DOI: 10.1016/j.ymgme.2025.109113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/26/2025]
Abstract
BOLA3 is one of the proteins involved in the assembly and transport of [4Fe-4S] clusters, which are incorporated into mitochondrial respiratory chain complexes I and II, aconitase, and lipoic acid synthetase. Pathogenic variants in the BOLA3 gene cause a rare condition known as multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, characterized by life-threatening lactic acidosis, nonketotic hyperglycinemia, and hypertrophic cardiomyopathy. The aim of this study was to elucidate the biochemical characteristics of patients with BOLA3 variants and to clarify the role of BOLA3 protein in humans. The characteristics, clinical course, and biochemical data of eight Japanese patients with BOLA3 pathogenic variants were collected. In addition, metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry, blue native polyacrylamide gel electrophoresis (BN-PAGE)/Western blot analysis of mitochondrial respiratory chain complexes, and in-gel enzyme staining of mitochondrial respiratory chain complexes of fibroblasts from all eight patients. Metabolomic data were compared between the eight patients with BOLA3 variants and three control samples using Welch's t-test. In the metabolomic analysis, levels of lactic acid, pyruvic acid, alanine, tricarboxylic acid (TCA) cycle intermediates (such as α-ketoglutaric acid and succinic acid), branched-chain amino acids, and metabolites of lysine and tryptophan were significantly elevated in the BOLA3 group. Data collected during the patients' lives showed increased lactic acid and glycine levels. In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases. These results indicate that BOLA3 variants decrease the activity of lipoic acid-dependent proteins (pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine cleavage system), as well as mitochondrial respiratory chain complexes I and II, but do not affect aconitase. Thus, it is believed that BOLA3 is involved in transporting [4Fe-4S] clusters to respiratory chain complexes I and II and lipoic acid synthetase, but does not interfere with aconitase. These findings suggest that while lipoic acid supplementation or vitamin cocktails may provide benefits, the impaired [4Fe-4S] cluster pathway itself should be targeted for treatment to improve the extensive metabolic abnormalities caused by BOLA3 deficiency.
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Affiliation(s)
- Hiroyuki Iijima
- Department of Clinical Genomics, Saitama Medical University, Saitama, Japan; Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, Tokyo, Japan.
| | - Atsuko Imai-Okazaki
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yoshihito Kishita
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Life Science, Faculty of Science and Engineering, Kindai University, Osaka, Japan
| | - Ayumu Sugiura
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Masaru Shimura
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Kei Murayama
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yasushi Okazaki
- Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Akira Ohtake
- Department of Clinical Genomics, Saitama Medical University, Saitama, Japan
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13
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Hiraoka N, Imai S, Shioyama S, Yoneyama F, Mase A, Makita Y. Unveiling the effects of metabolites on the material properties of natural rubber by the integration of metabolomics and material characteristics. Sci Rep 2025; 15:11341. [PMID: 40234483 PMCID: PMC12000568 DOI: 10.1038/s41598-025-91631-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 02/21/2025] [Indexed: 04/17/2025] Open
Abstract
Natural rubber (NR) is an important material with excellent physical properties. Unlike synthetic rubber from petroleum, NR contains non-rubber components such as proteins, lipids, and metal ions. The non-rubber components are known to affect the properties of NR. In this study, latex samples of Hevea brasiliensis were collected for nine months and their metabolites were comprehensively analyzed by mass spectrometry. NR was made from the same latex samples used for the mass spectrometry, and their vulcanization, tensile and thermal-aging properties were assessed. By using this approach of integrating metabolite and property data, we aim to clarify the influence of metabolites on the physical properties of NR. These results suggest that the metabolite composition in the latex and the NR properties changed seasonally. Correlation analysis between the metabolites and the properties of NR indicated that different metabolites affected different properties. A regression model of NR properties using metabolites as the explanatory variables suggests that about five metabolites need to be considered when examining the relationship between properties and metabolites. This method, which combines comprehensive analysis and characterization of NR, contributes to studies aimed at elucidating how the superior properties of NR are brought about.
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Affiliation(s)
- Nobuyuki Hiraoka
- Fundamental Material Development Laboratory, Sumitomo Riko Company Ltd, Aichi, 485- 8550, Japan
- Graduate School of Engineering, Maebashi Institute of Technology, Maebashi, Gunma, 371-0816, Japan
| | - Shunsuke Imai
- Fundamental Material Development Laboratory, Sumitomo Riko Company Ltd, Aichi, 485- 8550, Japan
| | - Shintaro Shioyama
- Fundamental Material Development Laboratory, Sumitomo Riko Company Ltd, Aichi, 485- 8550, Japan
| | - Fuminori Yoneyama
- Fundamental Material Development Laboratory, Sumitomo Riko Company Ltd, Aichi, 485- 8550, Japan
| | - Akio Mase
- Fundamental Material Development Laboratory, Sumitomo Riko Company Ltd, Aichi, 485- 8550, Japan
| | - Yuko Makita
- Graduate School of Engineering, Maebashi Institute of Technology, Maebashi, Gunma, 371-0816, Japan.
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14
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Zhou X, Berenger E, Shi Y, Shirokova V, Kochetkova E, Becirovic T, Zhang B, Kaminskyy VO, Esmaeilian Y, Hosaka K, Lindskog C, Hydbring P, Ekman S, Cao Y, Genander M, Iwanicki M, Norberg E, Vakifahmetoglu-Norberg H. Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors. EMBO Mol Med 2025; 17:747-774. [PMID: 40055574 PMCID: PMC11982252 DOI: 10.1038/s44321-025-00210-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 02/05/2025] [Accepted: 02/17/2025] [Indexed: 04/11/2025] Open
Abstract
Tumors often recapitulate programs to acquire invasive and dissemination abilities, during which pro-metastatic proteins are distinctively stabilized in cancer cells to drive further progression. Whether failed protein degradation affects the metastatic programs of cancer remains unknown. Here, we show that the human cancer cell-specific knockout (KO) of LAMP-2A, a limiting protein for chaperone-mediated autophagy (CMA), promotes the aggressiveness of mesenchymal tumors. Deficient CMA resulted in widespread tumor cell dissemination, invasion into the vasculature and cancer metastasis. In clinical samples, metastatic lesions showed suppressed LAMP-2A expression compared to primary tumors from the same cancer patients. Mechanistically, while stimulating TGFβ signaling dampens LAMP-2A levels, genetic suppression of CMA aggravated TGFβ signaling in cancer cells and tumors. Conversely, pharmacological inhibition of TGFβ signaling repressed the growth of LAMP-2A KO-driven tumors. Furthermore, we found that multiple EMT-driving proteins, such as TGFβR2, are degraded by CMA. Our study demonstrates that the tumor suppressive function of CMA involves negative regulation of TGFβ-driven EMT and uncovers a mechanistic link between CMA and a major feature of metastatic invasiveness.
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Affiliation(s)
- Xun Zhou
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Eva Berenger
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Yong Shi
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Vera Shirokova
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Elena Kochetkova
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Tina Becirovic
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Boxi Zhang
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Vitaliy O Kaminskyy
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Yashar Esmaeilian
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Kayoko Hosaka
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Per Hydbring
- Department of Oncology and Pathology, Karolinska Institutet, 171 64, Stockholm, Sweden
| | - Simon Ekman
- Department of Oncology and Pathology, Karolinska Institutet, 171 64, Stockholm, Sweden
- Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, 17176, Stockholm, Sweden
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Maria Genander
- Department of Cell and Molecular Biology, Karolinska Institutet, 171 65, Stockholm, Sweden
| | - Marcin Iwanicki
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA
| | - Erik Norberg
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden.
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15
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Kosho MXF, Ciurli A, Giera M, Neefjes J, Loos BG. Metabolomic Profiles of Oral Rinse Samples to Distinguish Severe Periodontitis Patients From Non-Periodontitis Controls. J Periodontal Res 2025. [PMID: 40083241 DOI: 10.1111/jre.13379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 03/16/2025]
Abstract
AIMS To explore the potential of metabolomic profiles of oral rinse samples to distinguish between patients with severe periodontitis (stage III/IV) and non-periodontitis controls. This is coupled to an analysis of differences in metabolomic profiles between individuals without periodontitis, patients with localized periodontitis, and patients with generalized periodontitis. METHODS Periodontitis patients and controls were recruited, all aged ≥ 40 years. Study participants were asked to rinse vigorously for 30 s with 10 mL phosphate buffered saline. Metabolites were identified using a semi-targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) platform. RESULTS In total, 38 periodontitis patients (18 localized, 20 generalized stage III/IV periodontitis patients) and 16 controls were included. Metabolomic profiles of oral rinse samples were able to distinguish patients with severe periodontitis (stage III/IV) from non-periodontitis controls. Among various variables for the severity of periodontitis, we found that the number of sites with deep pockets (PPD) ≥ 6 mm explained best the differences in metabolomic profiles between controls and patients with severe periodontitis. Subjects with a high number of sites with PPD ≥ 6 mm were characterized by a higher level of phosphorylated nucleotides, amino acids, peptides, and dicarboxylic acids. Metabolomic profiles were also significantly different between controls vs. generalized periodontitis and between localized periodontitis vs. generalized periodontitis (p < 0.05). CONCLUSION Our study demonstrates that simply collected oral rinse samples are suitable for LC-MS/MS based metabolomic analysis. We show that a metabolomic profile with a substantial number of metabolites can distinguish severe periodontitis patients from non-periodontitis controls. These observations can be a basis for further studies into screening to identify subjects with the risk of having severe periodontitis.
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Affiliation(s)
- Madeline X F Kosho
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Alessio Ciurli
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
- Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
| | - Martin Giera
- Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, the Netherlands
| | - Jacques Neefjes
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands
| | - Bruno G Loos
- Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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16
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Zou M, Tanabe K, Amo-Shiinoki K, Kohno D, Kagawa S, Shirasawa H, Ikeda K, Taguchi A, Ohta Y, Okuya S, Yamada T, Kitamura T, Masutani H, Tanizawa Y. Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice. J Biol Chem 2025; 301:108293. [PMID: 39947474 PMCID: PMC11938133 DOI: 10.1016/j.jbc.2025.108293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/29/2024] [Accepted: 11/11/2024] [Indexed: 03/29/2025] Open
Abstract
Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining nonshivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip-/-) mice acclimated to thermoneutrality (30 °C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5 °C), Txnip-/- mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip-/- mice were corrected by acclimation to 16 °C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip-/- mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.
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Affiliation(s)
- Meng Zou
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Katsuya Tanabe
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
| | - Kikuko Amo-Shiinoki
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Daisuke Kohno
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
| | - Syota Kagawa
- Department of Natural Products Chemistry, Daiichi University of Pharmacy, Fukuoka, Japan
| | - Hideki Shirasawa
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Kenji Ikeda
- Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akihiko Taguchi
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yasuharu Ohta
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Shigeru Okuya
- Health Administration Center, Organization for University Education, Yamaguchi University, Yamaguchi, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
| | - Hiroshi Masutani
- Department of Clinical Laboratory Sciences, Faculty of Health Care, Tenri University, Tenri, Nara, Japan
| | - Yukio Tanizawa
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
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17
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Takami N, Okazaki M, Ozeki T, Imaizumi T, Nishibori N, Kurasawa S, Hishida M, Akiyama S, Saito R, Hirayama A, Kasuga H, Kaneda F, Maruyama S. Plasma Metabolite Profiles Between In-Center Daytime Extended-Hours and Conventional Hemodialysis. KIDNEY360 2025; 6:420-431. [PMID: 39652407 PMCID: PMC11970860 DOI: 10.34067/kid.0000000675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 12/03/2024] [Indexed: 03/28/2025]
Abstract
Key Points Significant differences in 39 plasma metabolites were observed between patients on extended-hours hemodialysis and those on conventional hemodialysis. Extended-hours hemodialysis had a lower lactate-to-pyruvate ratio and higher branched-chain amino acids than conventional hemodialysis. Extended-hours hemodialysis may have favorable metabolic and nutritional benefits for patients undergoing maintenance hemodialysis. Background Protein–energy wasting, characterized by disordered body protein catabolism resulting from metabolic and nutritional derangements, is associated with adverse clinical outcomes in patients undergoing hemodialysis. Extended-hours hemodialysis (≥6 hours per treatment session) offers both enhanced removal of uremic solutes and better fluid management, generally allowing more liberalized dietary protein and calorie intake. The aim of this study was to evaluate the difference in plasma metabolite profiles among patients receiving in-center daytime extended-hours hemodialysis and those receiving conventional hemodialysis. Methods Predialysis plasma samples were obtained from 188 patients on extended-hours hemodialysis (21.9 h/wk) and 286 patients on conventional hemodialysis (12.1 h/wk) in Japan in 2020 using capillary electrophoresis-mass spectrometry. Group differences were compared for 117 metabolites using Wilcoxon rank-sum tests with multiple comparisons and partial least squares discriminant analysis. In addition, propensity score–adjusted multiple regression analyses were performed to evaluate group differences for known uremic toxins, branched-chain amino acids, and lactate-to-pyruvate ratio (a possible surrogate marker of mitochondrial dysfunction). Results Significant differences were observed in 39 metabolites, largely consistent with the high variable importance for prediction in partial least squares discriminant analysis. Among known uremic toxins, uridine and hypoxanthine levels were significantly higher in the conventional hemodialysis group than in the extended-hours hemodialysis group, whereas trimethylamine N -oxide levels were higher in the extended-hours hemodialysis group than in the conventional hemodialysis group. Patients on extended-hours hemodialysis had higher levels of all branched-chain amino acids and a lower lactate-to-pyruvate ratio than those on conventional hemodialysis (significant difference of −8.6 [95% confidence interval, −9.8 to −7.4]). Conclusions Extended-hours hemodialysis was associated with a more favorable plasma metabolic and amino acid profile; however, concentrations of most uremic toxins did not significantly differ from those of conventional hemodialysis.
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Affiliation(s)
- Norito Takami
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masaki Okazaki
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takaya Ozeki
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takahiro Imaizumi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Nobuhiro Nishibori
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shimon Kurasawa
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Manabu Hishida
- Department of Nephrology, Kaikoukai Josai Hospital, Nagoya, Japan
| | - Shin'ichi Akiyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Rintaro Saito
- Department of Nephrology, Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Akiyoshi Hirayama
- Department of Nephrology, Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Hirotake Kasuga
- Department of Nephrology, Nagoya Kyoritsu Hospital, Nagoya, Japan
| | | | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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18
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Ishihara C, Sako M, Tsutsumi K, Fujii N, Hashimoto D, Sato A, Ichiba Y, Chikazawa T, Kakizawa Y, Nishinaga E, Uchiyama A. Involvement of propionate, citrulline, homoserine, and succinate in oral microbiome metabolite-driven periodontal disease progression. Sci Rep 2025; 15:7149. [PMID: 40021789 PMCID: PMC11871350 DOI: 10.1038/s41598-025-91105-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/18/2025] [Indexed: 03/03/2025] Open
Abstract
Dysbiosis of the oral microbiome has been implicated in the onset and progression of periodontal diseases. An altered oral microbiome can significantly affect the concentration and composition ratio of bacterial-derived metabolites, thereby contributing to disease development. However, there is limited research on the role of metabolites derived from the oral microbiota. This study aimed to identify specific bacteria-derived metabolites and their contributions to pathogenicity. Mouth-rinsed water was collected from 24 patients with periodontal disease and 22 healthy individuals. We conducted a correlation analysis between periodontal disease-associated bacteria and metabolites present in mouth-rinsed water. We evaluated the effects of these metabolites on human gingival epithelial cells analysis of oral bacteria culture supernatants confirmed the origin of these metabolites. We identified 20 metabolites associated with bacteria that are significantly more prevalent in periodontal disease. Notably, propionate, succinate, citrulline, and homoserine-metabolites derived from the oral microbiome-were identified as being associated with periodontal disease. These results suggested that metabolites derived from the oral microbiota are involved in periodontal disease.
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Affiliation(s)
- Chikako Ishihara
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan.
- Section of Oral Health Promotion and Technology, Division of Oral Health, Technology and Epidemiology, Kyushu University Faculty of Dental Science, Fukuoka, Fukuoka, 812-8582, Japan.
| | - Misato Sako
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Kota Tsutsumi
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Narumi Fujii
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Daiki Hashimoto
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Atsushi Sato
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Yuko Ichiba
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Takashi Chikazawa
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Yasushi Kakizawa
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
| | - Eiji Nishinaga
- Research and Development Headquarters, Lion Corporation, 7-2-1 Hirai, Edogawa-ku, Tokyo, 132-0035, Japan
- Section of Oral Health Promotion and Technology, Division of Oral Health, Technology and Epidemiology, Kyushu University Faculty of Dental Science, Fukuoka, Fukuoka, 812-8582, Japan
| | - Akira Uchiyama
- Section of Oral Health Promotion and Technology, Division of Oral Health, Technology and Epidemiology, Kyushu University Faculty of Dental Science, Fukuoka, Fukuoka, 812-8582, Japan
- The Lion Foundation for Dental Health, 1-3-28 Kuramae, Taito-ku, Tokyo, 111-8644, Japan
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19
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Morishima T, Fakruddin M, Kanamori Y, Masuda T, Ogawa A, Wang Y, Schoonenberg VAC, Butter F, Arima Y, Akaike T, Moroishi T, Tomizawa K, Suda T, Wei FY, Takizawa H. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis. SCIENCE ADVANCES 2025; 11:eadu3011. [PMID: 39983002 PMCID: PMC11844735 DOI: 10.1126/sciadv.adu3011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 01/22/2025] [Indexed: 02/23/2025]
Abstract
Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.
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Affiliation(s)
- Tatsuya Morishima
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMS, Kumamoto University, Kumamoto, Japan
| | - Md. Fakruddin
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Laboratory of Hematopoietic Stem Cell Engineering, IRCMS, Kumamoto University, Kumamoto, Japan
| | - Yohei Kanamori
- Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takeshi Masuda
- Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Akiko Ogawa
- Department of Modomics Biology and Medicine, IDAC, Tohoku University, Sendai, Japan
| | - Yuxin Wang
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
| | | | - Falk Butter
- Quantitative Proteomics, Institute of Molecular Biology, 55128 Mainz, Germany
| | - Yuichiro Arima
- Laboratory of Developmental Cardiology, IRCMS, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Takaaki Akaike
- Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toshiro Moroishi
- Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
| | - Kazuhito Tomizawa
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Toshio Suda
- Laboratory of Stem Cell Regulation, IRCMS, Kumamoto University, Kumamoto, Japan
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Fan-Yan Wei
- Department of Modomics Biology and Medicine, IDAC, Tohoku University, Sendai, Japan
| | - Hitoshi Takizawa
- Laboratory of Stem Cell Stress, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging (CMHA), Kumamoto University, Kumamoto, Japan
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20
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Ramsay S, Hyvärinen E, González-Arriagada W, Salo T, Ajudarte Lopes M, Mikkonen JJW, Kashyap B, Kullaa AM. Radiation-induced changes in salivary metabolite profile and pathways in head and neck cancer patients. Clin Oral Investig 2025; 29:145. [PMID: 39982563 PMCID: PMC11845554 DOI: 10.1007/s00784-025-06225-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 02/09/2025] [Indexed: 02/22/2025]
Abstract
INTRODUCTION This longitudinal study assessed the salivary metabolic profile in patients with head and neck cancer (HNC) treated with radiotherapy (RT). This study aims to investigate salivary metabolites and biological oral pathways induced by RT. METHODS Clinical data and unstimulated whole-mouth saliva (USWMS) were obtained from 45 HNC patients before, during, and one week after the RT. Data was also collected from 30 healthy controls. NMR spectroscopy identified and quantified 24 metabolites. Spearman's rank correlation analysis and pathway enrichment analysis (MetaboAnalyst 6.0) was performed to check the effect of cancer therapy on the correlation and pathways of different salivary metabolites. RESULTS Of 24 metabolites identified, 17 salivary metabolites showed a consistent decrease in the concentration during and after treatment of HNC patients. The metabolite proline decreased, whereas fucose and 1,2-Propanediol were increased in the saliva causing altered redox balance and abnormal fucosylation in HNC patients compared to controls. Spearman correlation analysis indicated changes between pyruvate and some other metabolites, including alanine, trimethylamine, choline, taurine, and succinate, during RT. Five pathways (Pyruvate metabolism; Glycolysis / Gluconeogenesis; Glycine, serine, and threonine metabolism; Glyoxylate and dicarboxylate metabolism; and Alanine, aspartate and glutamate metabolism) are affected, demonstrating the metabolic dysregulation due to RT. The pyruvate metabolism was overpresented with the high Pathway Impact score. CONCLUSION Salivary metabolomics analysis revealed significant alterations in the metabolic profile of HNC patients undergoing RT, providing valuable insights into treatment-induced oral pathobiological changes. Alterations in salivary pathways during RT suggest disturbances in redox homeostasis, oxidative stress, and inflammation. The ability to monitor salivary metabolites and pathways non-invasively holds promise to personalized medicine in HNC treatment by enabling early detection of treatment-related toxicities, monitoring treatment response, and tailoring interventions to patient needs.
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Affiliation(s)
- Saga Ramsay
- Institute of Dentistry, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70210, Finland
- Educational Dental Clinic, Kuopio University Hospital, The Wellbeing Services County of North Savo, Kuopio, Finland
| | - Eelis Hyvärinen
- Institute of Dentistry, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70210, Finland
- Educational Dental Clinic, Kuopio University Hospital, The Wellbeing Services County of North Savo, Kuopio, Finland
| | - Wilfredo González-Arriagada
- Facultad de Odontología, Universidad de los Andes, Santiago, Chile
- Centro de Investigación E Innovación Biomédica, Universidad de los Andes, Santiago, Chile
- IMPACT-Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Tuula Salo
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Department of Oral and Maxillofacial Diseases, Faculty of Medicine, University of Helsinki, Helsinki University Hospital, ClinicumHelsinki, Finland
- Translational Immunology Research Program (TRIMM), University of Helsinki, Helsinki, Finland
- CAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Marcio Ajudarte Lopes
- Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Sao Paulo, CEP, 13414-018, Brazil
| | - Jopi J W Mikkonen
- Institute of Dentistry, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70210, Finland
| | - Bina Kashyap
- Institute of Dentistry, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70210, Finland
| | - Arja M Kullaa
- Institute of Dentistry, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, 70210, Finland.
- Educational Dental Clinic, Kuopio University Hospital, The Wellbeing Services County of North Savo, Kuopio, Finland.
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21
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Amo-Shiinoki K, Tanabe K, Nishimura W, Hatanaka M, Kondo M, Kagawa S, Zou M, Morikawa S, Sato Y, Komatsu M, Mizukami H, Nishida N, Asahara SI, Masutani H, Tanizawa Y. β cell dedifferentiation, the underlying mechanism of diabetes in Wolfram syndrome. Sci Transl Med 2025; 17:eadp2332. [PMID: 39970233 DOI: 10.1126/scitranslmed.adp2332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 09/06/2024] [Accepted: 01/24/2025] [Indexed: 02/21/2025]
Abstract
Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by WFS1 gene mutations. However, the pathological process of ER stress-associated β cell failure remains to be fully elucidated. Our results indicate loss of β cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of β cells and subsequent decrease in α cells, suggesting loss of endocrine function. Wfs1-deficient mice displayed dysfunction, gradual loss, and dedifferentiation of β cells, leading to permanent hyperglycemia. Impairment of the β cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced β cells. Islets of Wfs1-deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically, Wfs1-null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS β cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress-induced protein up-regulated in Wfs1 deficiency. Txnip deletion preserved functional β cells and prevented diabetes progression in Wfs1-deficient mice. Together, this study deciphered pathological mechanisms of β cell dedifferentiation in β cell failure and has implications for Txnip inhibition in WS therapy.
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Affiliation(s)
- Kikuko Amo-Shiinoki
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
- Department of Diabetes Research, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Katsuya Tanabe
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Wataru Nishimura
- Department of Molecular Biology, International University of Health and Welfare School of Medicine, Narita, Chiba 286-8686, Japan
- Department of Anatomy, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan
| | - Masayuki Hatanaka
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Manabu Kondo
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Syota Kagawa
- Department of Natural Products Chemistry, Daiichi University of Pharmacy, Fukuoka, Fukuoka 815-8511, Japan
| | - Meng Zou
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
| | - Shuntaro Morikawa
- Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan
| | - Yoshihiko Sato
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan
- Department of Internal Medicine, Matsumoto City Hospital, Matsumoto, Nagano 390-1401, Japan
| | - Mitsuhisa Komatsu
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Naoki Nishida
- Department of Legal Medicine, Faculty of Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan
| | - Shun-Ichiro Asahara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Hiroshi Masutani
- Department of Clinical Laboratory Sciences, Faculty of Health Care, Tenri University, Tenri, Nara 632-0018, Japan
| | - Yukio Tanizawa
- Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan
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22
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Alusta P, Paredes A, Azevedo M, Mullis L, Buzatu D. Direct detection and identification of viruses in saliva using a SpecID ionization modified mass spectrometer. PLoS One 2025; 20:e0316368. [PMID: 39919111 PMCID: PMC11805448 DOI: 10.1371/journal.pone.0316368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/09/2024] [Indexed: 02/09/2025] Open
Abstract
The COVID-19 (SARS-CoV-2) pandemic has led to a significant mortality globally and persistent health challenges in many survivors. Early accurate diagnosis, surveillance, identification of cohorts, and prophylaxis are considered essential measures to reduce the spread of infectious viral pathogens such as SARS-CoV-2. A reliable, fast, high-throughput screening method that can detect viral particles and identify the pathogenic virus in infected individuals could help to reduce the spread of the next viral threat through quick knowledge and implementation of appropriate prevention strategies. Since respiratory viruses are typically present in nasal and oral secretions, saliva is a good target for testing for viral infections. Saliva testing has slowly gained popularity in the diagnostics based on biomarkers and other constituents ranging from organic compounds (e.g., food additives), peptides, and even microorganisms. Polymerase chain reaction (PCR) remains the gold standard for sensitive detection of SARS-CoV-2 infection in biological samples. However, while PCR testing for COVID is sensitive and widely used by hospitals, the method has a false-negative rate of 15-20% and is kit-based necessitating the development of alternative methods of detection that provide higher accuracy. This paper describes the use of a SpecID Mass Spectrometer that can detect the presence of viral particles in saliva at very low levels (<500 virions/0.5 ml). The main goal of this study was to demonstrate that our previously developed, portable, mass spectrometry based method, SpecID, could also be sued for detecting viruses in saliva, including but not limited to SARS-CoV-2; the SpecID method has the potential to provide a reliable solution that overcomes some of the challenges with molecular testing like PCR.
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Affiliation(s)
- Pierre Alusta
- Systems Biology Division, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, Jefferson, AR, United States of America
| | - Angel Paredes
- NCTR / ORA Nanotechnology Facility, Office of Scientific Coordination, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, Jefferson, AR, United States of America
| | - Marli Azevedo
- Division of Microbiology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, Jefferson, AR, United States of America
| | - Lisa Mullis
- Division of Microbiology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, Jefferson, AR, United States of America
| | - Dan Buzatu
- Systems Biology Division, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration, Jefferson, AR, United States of America
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23
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Parize G, Luana Jimenez G, Shibli JA, Siroma R, Caetano MW, Kim YJ, Braz-Silva PH, da Silva Martinho H, Pallos D. Evaluation of Peri-Implantitis through Fourier-Transform Infrared Spectroscopy on Saliva. J Proteome Res 2025; 24:639-648. [PMID: 39792796 PMCID: PMC11812000 DOI: 10.1021/acs.jproteome.4c00707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/26/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
BACKGROUND Peri-implantitis is characterized as a pathological change in the tissues around dental implants. Fourier-transform infrared spectroscopy (FTIR) provides molecular information from optical phenomena observed by the vibration of molecules, which is used in biological studies to characterize changes and serves as a form of diagnosis. AIMS this case-control study evaluated the peri-implant disease by using FTIR spectroscopy with attenuated total reflectance in the fingerprint region. METHODS 38 saliva samples were evaluated, 17 from the control group and 21 from the peri-implantitis group. Clinical data such as plaque index (PI), gingival index, probing depth (PS), and attachment level were assessed. RESULTS The results of clinical parameters showed a statistical difference between the two groups regarding an excess of the PI. In the FTIR-ATR analysis, the main components revealed vibrational modes of fatty acids, histidine, lipid esters, nucleic acids, and tryptophan, with the main molecules contributing to spectral discrimination. The five-component partial least-squares discriminant analysis classification model had an accuracy of 81%, showing differences between healthy and diseased implants. CONCLUSION the FTIR spectroscopy provides important molecular characteristics of the samples and the results in association with clinical data show the effectiveness of using this tool for diagnosing the disease.
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Affiliation(s)
- Graziele Parize
- University
of Santo Amaro (UNISA), Rua Isabel Schmidt 349, São Paulo 04743-030, Brazil
| | - Gabrielle Luana Jimenez
- Centro
de Ciências Naturais e Humanas, Universidade
Federal Do ABC (UFABC), Santo
André, São Paulo 09280-560, Brazil
| | - Jamil Awad Shibli
- Department
of Periodontology, Dental Research Division, Guarulhos Univeristy, Guarulhos, São Paulo 07023-070, Brazil
| | - Rafael Siroma
- Department
of Periodontology, Dental Research Division, Guarulhos Univeristy, Guarulhos, São Paulo 07023-070, Brazil
| | - Matheus Willian Caetano
- Department
of Stomatology, School of Dentistry, University
of São Paulo, Sao Paulo 05508-000, Brazil
| | - Yeon Jung Kim
- University
of Santo Amaro (UNISA), Rua Isabel Schmidt 349, São Paulo 04743-030, Brazil
| | - Paulo Henrique Braz-Silva
- Department
of Stomatology, School of Dentistry, University
of São Paulo, Sao Paulo 05508-000, Brazil
- Laboratory
of Virology (LIM-52-HCFMUSP), Institute
of Tropical Medicine of São Paulo, University of São
Paulo School of Medicine, São
Paulo 05403-000, Brazil
| | - Herculano da Silva Martinho
- Centro
de Ciências Naturais e Humanas, Universidade
Federal Do ABC (UFABC), Santo
André, São Paulo 09280-560, Brazil
| | - Debora Pallos
- University
of Santo Amaro (UNISA), Rua Isabel Schmidt 349, São Paulo 04743-030, Brazil
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24
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Sarmiento-Mañús R, Fontcuberta-Cervera S, Kawade K, Oikawa A, Tsukaya H, Quesada V, Micol JL, Ponce MR. Functional conservation and divergence of arabidopsis VENOSA4 and human SAMHD1 in DNA repair. Heliyon 2025; 11:e41019. [PMID: 39801971 PMCID: PMC11720913 DOI: 10.1016/j.heliyon.2024.e41019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 11/28/2024] [Accepted: 12/05/2024] [Indexed: 01/16/2025] Open
Abstract
The human deoxyribonucleoside triphosphatase (dNTPase) Sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) has a dNTPase-independent role in repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). Here, we show that VENOSA4 (VEN4), the probable Arabidopsis thaliana ortholog of SAMHD1, also functions in DSB repair by HR. The ven4 loss-of-function mutants showed increased DNA ploidy and deregulated DNA repair genes, suggesting DNA damage accumulation. Hydroxyurea, which blocks DNA replication and generates DSBs, induced VEN4 expression. The ven4 mutants were hypersensitive to hydroxyurea, with decreased DSB repair by HR. Metabolomic analysis of the strong ven4-0 mutant revealed depletion of metabolites associated with DNA damage responses. In contrast to SAMHD1, VEN4 showed no evident involvement in preventing R-loop accumulation. Our study thus reveals functional conservation in DNA repair by VEN4 and SAMHD1.
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Affiliation(s)
- Raquel Sarmiento-Mañús
- Instituto de Bioingeniería, Universidad Miguel Hernández, Campus de Elche, 03202, Elche, Spain
| | | | - Kensuke Kawade
- Graduate School of Science and Engineering, Saitama University, Saitama City, 338-8570, Saitama, Japan
- Center for Sustainable Resource Science, RIKEN, Yokohama, 230-0045, Kanagawa, Japan
- Exploratory Research Center on Life and Living Systems, Okazaki, 444-8787, Aichi, Japan
| | - Akira Oikawa
- Center for Sustainable Resource Science, RIKEN, Yokohama, 230-0045, Kanagawa, Japan
- Graduate School of Agriculture, Kyoto University, 606-8502, Kyoto, Japan
| | - Hirokazu Tsukaya
- Exploratory Research Center on Life and Living Systems, Okazaki, 444-8787, Aichi, Japan
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Bunkyo-ku, 113-0033, Tokyo, Japan
| | - Víctor Quesada
- Instituto de Bioingeniería, Universidad Miguel Hernández, Campus de Elche, 03202, Elche, Spain
| | - José Luis Micol
- Instituto de Bioingeniería, Universidad Miguel Hernández, Campus de Elche, 03202, Elche, Spain
| | - María Rosa Ponce
- Instituto de Bioingeniería, Universidad Miguel Hernández, Campus de Elche, 03202, Elche, Spain
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25
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Maruyama Y, Fujii N, Kawamata R, Yamada K, Ichiba Y, Kakizawa Y, Sugimoto M, Hirayama A. Intra- and inter-day variations in oral metabolites from mouth-rinsed water determined using capillary electrophoresis-mass spectrometry metabolomics. Clin Chim Acta 2025; 565:119965. [PMID: 39284378 DOI: 10.1016/j.cca.2024.119965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 09/08/2024] [Accepted: 09/09/2024] [Indexed: 11/22/2024]
Abstract
BACKGROUND AND AIMS Collecting clinical samples without inconveniencing participants is desirable. The profile of metabolites in mouth-rinsed water is similar to that in saliva. However, the intra- and inter-day variations in unstimulated or stimulated saliva metabolites from mouth-rinsed water have yet to be clarified. Thus, we aimed to fill this research gap using capillary electrophoresis-mass spectrometry metabolomics. MATERIALS AND METHODS We collected mouth-rinsed water from 15 healthy participants at 9:00, 11:30, 14:00, and 16:30 daily for 3 days. In total, 509 metabolite concentrations from 180 samples were obtained using capillary electrophoresis time-of-flight mass spectrometry. Variations in each metabolite were evaluated using the Wilcoxon signed-rank test to determine at which time/day significant differences occurred after removing metabolites without significant changes using the Friedman test. RESULTS Of 167 frequently detected metabolites, 100 exhibited intra-day variations, and none exhibited inter-day variations. Intra-day variations were classified into four patterns, and the intra-day variation in each metabolite was assessed. The variations may reflect elapsed time after meals, oral cleaning, or circadian rhythms. CONCLUSION This study could serve as a reference for improving the design of future clinical trials and the accuracy of metabolome analysis of mouth-rinsed water samples collected at different dates and times.
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Affiliation(s)
- Yuki Maruyama
- Research and Development Headquarters, Lion Corporation. 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan; Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa 252-0882, Japan.
| | - Narumi Fujii
- Research and Development Headquarters, Lion Corporation. 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan
| | - Ryosuke Kawamata
- Research and Development Headquarters, Lion Corporation. 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan
| | - Kaoru Yamada
- Research and Development Headquarters, Lion Corporation. 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan
| | - Yuko Ichiba
- Research and Development Headquarters, Lion Corporation. 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan
| | - Yasushi Kakizawa
- Research and Development Headquarters, Lion Corporation. 7-2-1 Hirai, Edogawa-ku, Tokyo 132-0035, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa 252-0882, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan; Systems Biology Program, Graduate School of Media and Governance, Keio University, Fujisawa, Kanagawa 252-0882, Japan
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26
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Helmeczi E, Kroezen Z, Shanmuganathan M, Stanciu AR, Martinez V, Kurysko N, Normando P, Castro IRRD, Schincaglia RM, Kac G, Britz-McKibbin P. A Software Tool for Rapid and Automated Preprocessing of Large-Scale Serum Metabolomic Data by Multisegment Injection-Capillary Electrophoresis-Mass Spectrometry. Anal Chem 2025; 97:175-184. [PMID: 39729551 PMCID: PMC11740174 DOI: 10.1021/acs.analchem.4c03513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 12/13/2024] [Accepted: 12/14/2024] [Indexed: 12/29/2024]
Abstract
Mass spectrometry (MS)-based metabolomics often rely on separation techniques when analyzing complex biological specimens to improve method resolution, metabolome coverage, quantitative performance, and/or unknown identification. However, low sample throughput and complicated data preprocessing procedures remain major barriers to affordable metabolomic studies that are scalable to large populations. Herein, we introduce PeakMeister as a new software tool in the R statistical environment to enable standardized processing of serum metabolomic data acquired by multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS), a high-throughput separation platform (<4 min/sample) which takes advantage of a serial injection format of 13 samples within a single analytical run. We performed a rigorous validation of PeakMeister by analyzing 47 cationic metabolites consistently measured in 5,000 serum and 420 quality control samples from the Brazilian National Survey on Child Nutrition (ENANI-2019) comprising a total of 224,983 metabolite peaks acquired in 40 days across three batches over an eight-month period. A migration time index using a panel of 11 internal standards was introduced to correct for large variations in migration times, which allowed for reliable peak annotation, peak integration, and sample position assignment for serum metabolites having two flanking internal standards or a single comigrating stable-isotope internal standard. PeakMeister accelerated data preprocessing times by 30-fold compared to manual processing of MSI-CE-MS data by an experienced analyst using vendor software, while also achieving excellent peak annotation fidelity (median accuracy >99.9%), acceptable intermediate precision (median CV = 16.0%), consistent metabolite peak integration (mean bias = -2.1%), and good mutual agreement when quantifying 16 plasma metabolites from NIST SRM-1950 (mean bias = -1.3%). Reference ranges are also reported for 40 serum metabolites in a national nutritional survey of Brazilian children under 5 years of age from the ENANI-2019 study. MSI-CE-MS in conjunction with PeakMeister allows for rapid and automated processing of large-scale metabolomic studies that tolerate nonlinear migration time shifts without complicated dynamic time warping or effective mobility scale transformations.
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Affiliation(s)
- Erick Helmeczi
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
| | - Zachary Kroezen
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
| | - Meera Shanmuganathan
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
| | - Ana Ruxandra Stanciu
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
| | - Vanessa Martinez
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
| | - Natasia Kurysko
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
| | - Paula Normando
- Nutritional
Epidemiology Observatory, Josué de
Castro Nutrition Institute, Rio de Janeiro Federal University, Rio de Janeiro 21941-902, Brazil
| | | | | | - Gilberto Kac
- Nutritional
Epidemiology Observatory, Josué de
Castro Nutrition Institute, Rio de Janeiro Federal University, Rio de Janeiro 21941-902, Brazil
| | - Philip Britz-McKibbin
- Department
of Chemistry and Chemical Biology, McMaster
University, Hamilton, Ontario L8S 4M1, Canada
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27
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Nishida S, Ishima T, Iwami D, Nagai R, Aizawa K. Whole Blood Metabolomic Profiling of Mice with Tacrolimus-Induced Chronic Nephrotoxicity: NAD + Depletion with Salvage Pathway Impairment. Antioxidants (Basel) 2025; 14:62. [PMID: 39857396 PMCID: PMC11760425 DOI: 10.3390/antiox14010062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/02/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) is a serious issue for long-term graft survival in kidney transplantation. However, the pathophysiology of TAC nephrotoxicity remains unclear. In this study, we analyzed whole blood samples from mice that developed TAC nephrotoxicity in order to discover its mechanism. Mice were divided into a TAC group and a control group (n = 5 per group). The TAC group received TAC subcutaneously (1 mg/kg/day for 28 days), while the control group received normal saline instead. After the administration period, whole blood was collected and metabolomic analysis was performed, revealing significant changes in 56 metabolites. The major metabolic changes were related to uremic toxins, vascular damage, and NAD+. NAD+ levels were significantly lower in the TAC group, and ADP-ribose, nicotinamide, and nicotinamide N-oxide, which are degradation products of NAD+, were significantly higher, suggesting impairment of the NAD+ salvage pathway. NAD+ deficiency suggests cellular aging and mitochondrial dysfunction, which may induce vascular damage and chronic kidney disease. Our study demonstrated a correlation between low NAD+ levels and the pathophysiology of TAC nephrotoxicity.
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Affiliation(s)
- Sho Nishida
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Japan
- Division of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University, Shimotsuke 329-0498, Japan
| | - Tamaki Ishima
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Japan
| | - Daiki Iwami
- Division of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University, Shimotsuke 329-0498, Japan
| | - Ryozo Nagai
- Jichi Medical University, Shimotsuke 329-0498, Japan
| | - Kenichi Aizawa
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Shimotsuke 329-0498, Japan
- Clinical Pharmacology Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan
- Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Shimotsuke 329-0498, Japan
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28
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Negishi H, Ichikawa A, Takahashi S, Kano H, Makino S. Targeted prebiotic application of gluconic acid-containing oligosaccharides promotes Faecalibacterium growth through microbial cross-feeding networks. THE ISME JOURNAL 2025; 19:wraf027. [PMID: 39936592 PMCID: PMC11922316 DOI: 10.1093/ismejo/wraf027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/19/2024] [Accepted: 02/10/2025] [Indexed: 02/13/2025]
Abstract
The gut microbiome plays a crucial role in human health, and certain bacterial species, such as Faecalibacterium prausnitzii, are particularly beneficial. This study conducted a comprehensive investigation of prebiotic compounds that showed potential for specifically promoting beneficial gut bacteria. Using in vitro fecal cultures and a human intervention study, we identified maltobionic acid and lactobionic acid as compounds that specifically promoted Faecalibacterium growth both in vitro and in vivo without significantly affecting Bifidobacterium, which is typically increased by traditional prebiotics. In a human intervention study (n = 27), a significant increase was observed in Faecalibacterium abundance following maltobionic acid supplementation, with effectiveness correlating with the initial Parabacteroides abundance. Mechanistic investigations revealed a cross-feeding pathway between gut bacteria. In this pathway, Parabacteroides species converted the gluconic acid moiety of maltobionic and lactobionic acids to glucuronic acid, which was then preferentially utilized by Faecalibacterium. These findings suggest that gluconic acid-containing oligosaccharides are promising prebiotics for the targeted enhancement of beneficial Faecalibacterium and underscore the importance of microbial interactions in prebiotic research, offering new avenues for personalized microbiome modulation strategies.
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Affiliation(s)
- Hiroki Negishi
- Wellness Science Labs, Meiji Holdings Co., Ltd., Tokyo 192-0919, Japan
| | - Ayumi Ichikawa
- Wellness Science Labs, Meiji Holdings Co., Ltd., Tokyo 192-0919, Japan
| | - Saori Takahashi
- Wellness Science Labs, Meiji Holdings Co., Ltd., Tokyo 192-0919, Japan
| | - Hiroshi Kano
- Wellness Science Labs, Meiji Holdings Co., Ltd., Tokyo 192-0919, Japan
| | - Seiya Makino
- Wellness Science Labs, Meiji Holdings Co., Ltd., Tokyo 192-0919, Japan
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29
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Miyake M, Iida K, Nishimura N, Ohnishi S, Owari T, Fujii T, Oda Y, Miyamoto T, Shimizu T, Ohnishi K, Hori S, Morizawa Y, Gotoh D, Nakai Y, Tanaka N, Fujimoto K. Serum metabolomic analysis identified serum biomarkers predicting tumour recurrence after Bacillus Calmette-Guérin therapy in patients with non-muscle invasive bladder cancer. Bladder Cancer 2025; 11:23523735251325100. [PMID: 40109498 PMCID: PMC11921002 DOI: 10.1177/23523735251325100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 02/11/2025] [Indexed: 03/22/2025]
Abstract
Background Metabolomic research and metabolomics-based biomarkers predicting treatment outcomes in bladder cancer remain limited. Objective We explored the serum metabolites potentially associated with the risk of recurrence after intravesical Bacillus Calmette-Guérin (BCG) therapy. Methods Two independent cohorts, a discovery cohort (n = 23) and a validation cohort (n = 40), were included in this study. Blood was collected before the induction of BCG therapy (pre-BCG blood; both discovery and validation cohorts) and after six doses of BCG (post-BCG blood; only discovery cohort). Metabolome analysis of serum samples was conducted using capillary electrophoresis time-of-flight mass spectrometry. The endpoint was intravesical recurrence-free survival, which was analysed using Kaplan-Meier estimates, the log-rank test, and the Cox proportional hazard model. Results Of the 353 metabolites quantified, nine (2.5%) and four (1.1%) were significantly upregulated and downregulated, respectively. The heatmap of hierarchical clustering analysis and principal coordinate analysis for the fold changes and in serum metabolites differentiated 10 recurrent cases and 13 non-recurrent cases in the discovery cohort. A metabolome response-based scoring model using 16 metabolites, including threonine and N6,N6,N6-trimethyl-lysine effectively stratified the risk of post-BCG recurrence. Additionally, pre-BCG metabolome-based score models using six metabolites, octanoylcarnitine, S-methylcysteine-S-oxide, theobromine, carnitine, indole-3-acetic acid, and valeric acid, were developed from the discovery cohort. Univariate and multivariate analyses confirmed a high predictive accuracy in the validation and combination cohorts. Conclusions We demonstrated that numerous types of serum metabolites were altered in response to intravesical BCG and developed high-performance score models which might effectively differentiated the risk of post-BCG tumour recurrence.
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Affiliation(s)
- Makito Miyake
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Kota Iida
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | | | - Sayuri Ohnishi
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Takuya Owari
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
- Division of Cancer Immunology, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan
| | - Tomomi Fujii
- Division of Fostering Required Medical Human Resources, Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Yuki Oda
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Tatsuki Miyamoto
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Takuto Shimizu
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Kenta Ohnishi
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Shunta Hori
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Yosuke Morizawa
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Daisuke Gotoh
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Yasushi Nakai
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
| | - Nobumichi Tanaka
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
- Department of Prostate Brachytherapy, Nara Medical University, Kashihara, Nara, Japan
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University, Kashihara, Nara, Japan
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Okuda K, Nagano N, Nakazaki K, Matsuda K, Tokunaga W, Fuwa K, Aoki R, Okahashi A, Morioka I. Metabolomic profiles of preterm small-for-gestational age infants. Pediatr Neonatol 2025; 66:50-54. [PMID: 38789293 DOI: 10.1016/j.pedneo.2023.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/06/2023] [Accepted: 11/19/2023] [Indexed: 05/26/2024] Open
Abstract
We aimed to characterize the metabolomic profiles in preterm small-for-gestational age (SGA) infants using cord blood. We conducted a gestational age (GA)-matched case-control study that included 30 preterm infants who were categorized into two groups: SGA infants, with a birth weight (BW) < 10th percentile for GA (n = 15) and non-SGA infants, with BW ≥ 10th percentile for GA (n = 15). SGA infants with chromosomal or genetic abnormalities were excluded. At birth, the umbilicus was double-clamped, and the cord blood was sampled from the umbilical vein. Metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry. The median GA at birth was not significantly different between the two groups [SGA, 32 (26-36) weeks; non-SGA, 32 (25-35) weeks; p = 0.661)]. Of the 255 metabolites analyzed, 19 (7.5%) showed significant differences between SGA and non-SGA infants. There were significant reductions in the carnosine, hypotaurine, and S-methylcysteine levels in SGA infants as compared to non-SGA infants (p < 0.05). Carnosine was correlated with gestational age, BMI before pregnancy, body weight gain during pregnancy (p = 0.002, p = 0.023, and p = 0.020, respectively). In conclusion, preterm SGA infants have low levels of cord blood antioxidative- and antiglycation-related metabolites, making them vulnerable to oxidative stress.
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Affiliation(s)
- Koh Okuda
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Nobuhiko Nagano
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.
| | - Kimitaka Nakazaki
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Kengo Matsuda
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Wataru Tokunaga
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Kazumasa Fuwa
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Ryoji Aoki
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Aya Okahashi
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
| | - Ichiro Morioka
- Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan
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31
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Kaur R, Gupta S, Kulshrestha S, Khandelwal V, Pandey S, Kumar A, Sharma G, Kumar U, Parashar D, Das K. Metabolomics-Driven Biomarker Discovery for Breast Cancer Prognosis and Diagnosis. Cells 2024; 14:5. [PMID: 39791706 PMCID: PMC11720085 DOI: 10.3390/cells14010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 01/12/2025] Open
Abstract
Breast cancer is a cancer with global prevalence and a surge in the number of cases with each passing year. With the advancement in science and technology, significant progress has been achieved in the prevention and treatment of breast cancer to make ends meet. The scientific intradisciplinary subject of "metabolomics" examines every metabolite found in a cell, tissue, system, or organism from different sources of samples. In the case of breast cancer, little is known about the regulatory pathways that could be resolved through metabolic reprogramming. Evidence related to the significant changes taking place during the onset and prognosis of breast cancer can be obtained using metabolomics. Innovative metabolomics approaches identify metabolites that lead to the discovery of biomarkers for breast cancer therapy, diagnosis, and early detection. The use of diverse analytical methods and instruments for metabolomics includes Magnetic Resonance Spectroscopy, LC/MS, UPLC/MS, etc., which, along with their high-throughput analysis, give insights into the metabolites and the molecular pathways involved. For instance, metabolome research has led to the discovery of the glutamate-to-glutamate ratio and aerobic glycolysis as biomarkers in breast cancer. The present review comprehends the updates in metabolomic research and its processes that contribute to breast cancer prognosis and metastasis. The metabolome holds a future, and this review is an attempt to amalgamate the present relevant literature that might yield crucial insights for creating innovative therapeutic strategies aimed at addressing metastatic breast cancer.
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Affiliation(s)
- Rasanpreet Kaur
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India; (R.K.); (S.K.); (V.K.); (S.P.)
| | - Saurabh Gupta
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India; (R.K.); (S.K.); (V.K.); (S.P.)
| | - Sunanda Kulshrestha
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India; (R.K.); (S.K.); (V.K.); (S.P.)
| | - Vishal Khandelwal
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India; (R.K.); (S.K.); (V.K.); (S.P.)
| | - Swadha Pandey
- Department of Biotechnology, Institute of Applied Sciences & Humanities, GLA University, Chaumuhan, Mathura 281406, Uttar Pradesh, India; (R.K.); (S.K.); (V.K.); (S.P.)
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Anil Kumar
- National Institute of Immunology, New Delhi 110067, India;
| | - Gaurav Sharma
- Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
- Advanced Imaging Research Center (AIRC), University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Umesh Kumar
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), Ghaziabad 201015, Uttar Pradesh, India;
| | - Deepak Parashar
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA;
| | - Kaushik Das
- Biotechnology Research and Innovation Council-National Institute of Biomedical Genomics, Kalyani 741251, West Bengal, India
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Maiti A, Mondal S, Choudhury S, Bandopadhyay A, Mukherjee S, Sikdar N. Oncometabolites in pancreatic cancer: Strategies and its implications. World J Exp Med 2024; 14:96005. [PMID: 39713078 PMCID: PMC11551704 DOI: 10.5493/wjem.v14.i4.96005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 08/24/2024] [Accepted: 09/14/2024] [Indexed: 10/31/2024] Open
Abstract
Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
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Affiliation(s)
- Arunima Maiti
- Suraksha Diagnostics Pvt Ltd, Newtown, Rajarhat, Kolkata 700156, West Bengal, India
| | - Susmita Mondal
- Department of Zoology, Diamond Harbour Women’s University, Diamond Harbour 743368, West Bengal, India
| | - Sounetra Choudhury
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, West Bengal, India
| | | | - Sanghamitra Mukherjee
- Department of Pathology, RG Kar Medical College and Hospital, Kolkata 700004, West Bengal, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, West Bengal, India
- Scientist G, Estuarine and Coastal Studies Foundation, Howrah 711101, West Bengal, India
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Mohd Faizal NF, Vincent-Chong VK, Ramanathan A, Paterson IC, Karen-Ng LP, Zaini ZM. Metabolomic Profiling of Oral Potentially Malignant Disorders and Its Clinical Values. Biomedicines 2024; 12:2899. [PMID: 39767805 PMCID: PMC11726734 DOI: 10.3390/biomedicines12122899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Revised: 11/17/2024] [Accepted: 11/21/2024] [Indexed: 01/16/2025] Open
Abstract
Oral potentially malignant disorders (OPMD) are a group of lesions carrying the risk of developing into cancer. The gold standard to predict which lesions are more likely to undergo malignant transformation is the presence of dysplasia histologically. However, not all dysplastic lesions progress, and non-dysplastic lesions may also undergo malignant transformation. Oral carcinogenesis is a complex molecular process that involves somatic alterations and the deregulation of transcriptions, protein expression, and metabolite levels. Metabolomics, which is the scientific study of metabolites, has emerged as a promising high-throughput approach to investigate the metabolic changes of small molecules in biological pathways. In this review, we summarize the data relating to the metabolomic profiling of OPMDs, which will help elucidate the complex process of oral carcinogenesis. Furthermore, we identify that among all metabolites, citrate, pyruvate, and glutamate may serve as potential biomarkers for oral leukoplakia (OLK). Notably, metformin and gluconate have been shown to target glutamate and citrate, respectively, in cancer cells. Based on these findings, we propose that targeting these metabolites in patients with OPMD could be a promising therapeutic strategy to mitigate OPMD progression and potentially reduce the risk of malignant transformation. We also discuss the limitations and future directions of metabolomics in OPMD. Understanding these important metabolites is crucial for early detection and monitoring of oral cancer progression.
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Affiliation(s)
- Nur Fatinazwa Mohd Faizal
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (N.F.M.F.); (A.R.)
| | - Vui King Vincent-Chong
- Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Anand Ramanathan
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (N.F.M.F.); (A.R.)
- Oral Cancer Research and Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Ian C. Paterson
- Oral Cancer Research and Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Lee Peng Karen-Ng
- Oral Cancer Research and Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Zuraiza Mohamad Zaini
- Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (N.F.M.F.); (A.R.)
- Oral Cancer Research and Coordinating Centre (OCRCC), Faculty of Dentistry, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
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34
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Rashid S, Puttagunta P, Pamulapati S, Yang J, Pocha S, Saba NF, Teng Y. Leveraging Saliva for Insights into Head and Neck Cancer. Int J Mol Sci 2024; 25:13514. [PMID: 39769275 PMCID: PMC11678725 DOI: 10.3390/ijms252413514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/13/2024] [Accepted: 12/14/2024] [Indexed: 01/11/2025] Open
Abstract
Head and neck cancer (HNC) represents a heterogeneous group of malignancies with increasing global incidence and notable mortality. Early detection is essential for improving survival rates and minimizing recurrence; however, existing diagnostic methods are often invasive and complex. There is a need for noninvasive and more effective approaches for early detection and real-time monitoring of HNC. Saliva contains various biomolecules that may serve as indicators of HNC. As a result, saliva-based biomarkers have emerged as a transformative approach in the diagnosis and treatment of HNC due to their ease of collection, non-invasiveness, and potential to provide details about biomolecular changes associated with cancer progression. This narrative review synthesizes the current literature on the potential of saliva as a noninvasive diagnostic tool for HNC. It highlights various biomarkers found in saliva, including cell-free DNA, RNA, proteins, and metabolites, and explores emerging technologies in saliva detection that could transform the future of HNC management. Continued research efforts and larger-scale validation studies are essential to fully realize the potential of saliva-based biopsy and help pinpoint notable biomarkers to improve patient outcomes and reduce mortality associated with HNC worldwide.
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Affiliation(s)
- Saad Rashid
- Internal Medicine Program, Mercyhealth Graduate Medical Education Consortium, Rockford, IL 61114, USA; (S.R.); (S.P.)
| | - Prashant Puttagunta
- Medical Education, University of Michigan Medical School, Ann Arbor, MI 48105, USA;
| | - Saagar Pamulapati
- Hematology-Oncology, Advocate Lutheran General Hospital, Park Ridge, IL 60068, USA;
| | - Jianqiang Yang
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; (J.Y.)
- Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | - Suneha Pocha
- Internal Medicine Program, Mercyhealth Graduate Medical Education Consortium, Rockford, IL 61114, USA; (S.R.); (S.P.)
| | - Nabil F. Saba
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; (J.Y.)
- Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
| | - Yong Teng
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA; (J.Y.)
- Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA 30322, USA
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Vitale F, Zileri Dal Verme L, Paratore M, Negri M, Nista EC, Ainora ME, Esposto G, Mignini I, Borriello R, Galasso L, Alfieri S, Gasbarrini A, Zocco MA, Nicoletti A. The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer. Biomedicines 2024; 12:2840. [PMID: 39767746 PMCID: PMC11673965 DOI: 10.3390/biomedicines12122840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/30/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
Pancreatic cancer is one of the most aggressive cancers with a very poor 5-year survival rate and reduced therapeutic options when diagnosed in an advanced stage. The dismal prognosis of pancreatic cancer has guided significant efforts to discover novel biomarkers in order to anticipate diagnosis, increasing the population of patients who can benefit from curative surgical treatment. CA 19-9 is the reference biomarker that supports the diagnosis and guides the response to treatments. However, it has significant limitations, a low specificity, and is inefficient as a screening tool. Several potential biomarkers have been discovered in the serum, urine, feces, and pancreatic juice of patients. However, most of this evidence needs further validation in larger cohorts. The advent of advanced omics sciences and liquid biopsy techniques has further enhanced this field of research. The aim of this review is to analyze the historical evolution of the research on novel biomarkers for the early diagnosis of pancreatic cancer, focusing on the current evidence for the most promising biomarkers from different body fluids and the novel trends in research, such as omics sciences and liquid biopsy, in order to favor the application of modern personalized medicine.
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Affiliation(s)
- Federica Vitale
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Lorenzo Zileri Dal Verme
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Mattia Paratore
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Marcantonio Negri
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Enrico Celestino Nista
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Maria Elena Ainora
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Giorgio Esposto
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Irene Mignini
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Raffaele Borriello
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Linda Galasso
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Sergio Alfieri
- Centro Pancreas, Chirurgia Digestiva, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy;
| | - Antonio Gasbarrini
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Maria Assunta Zocco
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Alberto Nicoletti
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
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Dolińska E, Wiśniewski P, Pietruska M. Periodontal Molecular Diagnostics: State of Knowledge and Future Prospects for Clinical Application. Int J Mol Sci 2024; 25:12624. [PMID: 39684335 DOI: 10.3390/ijms252312624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/21/2024] [Accepted: 11/23/2024] [Indexed: 12/18/2024] Open
Abstract
Periodontitis leads to immunologically mediated loss of periodontium and, if untreated, can result in tooth loss. Periodontal diseases are the most prevalent in the world and have a very strong impact on patients' well-being and general health. Their treatment generates enormous costs. Given the above, precise, prompt, and predictive diagnosis of periodontal disease is of paramount importance for clinicians. The aim of the study was to summarize the state-of-the-art knowledge of molecular periodontal diagnostics and the utility of its clinical application. There is a great need to have diagnostic tests that not only describe the periodontal destruction that has occurred in the tissues but also allow clinicians to detect disease at a subclinical level before the changes occur. A test that would enable clinicians to follow the course of the disease and detect areas prone to exacerbation could be used to evaluate the effectiveness of ongoing periodontal therapies. Unfortunately, there is no such diagnostic method yet. A hopeful prospect is molecular diagnostics. There are numerous studies on biomarkers of periodontal disease. Point-of-care tests are also emerging. There are possibilities for processing large biological datasets (omics data). However, all of the above have a minor role in the overall single-patient diagnostics process. Despite advances in microbiological, molecular, and genetic research, the basis of periodontal diagnosis is still clinical examination enriched by the evaluation of radiological images.
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Affiliation(s)
- Ewa Dolińska
- Department of Periodontal and Oral Mucosa Diseases, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
| | - Patryk Wiśniewski
- Student's Research Group at the Department of Periodontal and Oral Mucosa Diseases, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
| | - Małgorzata Pietruska
- Department of Periodontal and Oral Mucosa Diseases, Medical University of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok, Poland
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Uchimido R, Kami K, Yamamoto H, Yokoe R, Tsuchiya I, Nukui Y, Goto Y, Hanafusa M, Fujiwara T, Wakabayashi K. Longitudinal Metabolomics Reveals Metabolic Dysregulation Dynamics in Patients with Severe COVID-19. Metabolites 2024; 14:656. [PMID: 39728437 DOI: 10.3390/metabo14120656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/17/2024] [Accepted: 11/22/2024] [Indexed: 12/28/2024] Open
Abstract
Background/Objective: A dysregulated metabolism has been studied as a key aspect of the COVID-19 pathophysiology, but its longitudinal progression in severe cases remains unclear. In this study, we aimed to investigate metabolic dysregulation over time in patients with severe COVID-19 requiring mechanical ventilation (MV). Methods: In this single-center, prospective, observational study, we obtained 236 serum samples from 118 adult patients on MV in an ICU. The metabolite measurements were performed using capillary electrophoresis Fourier transform mass spectrometry, and we categorized the sampling time points into three time zones to align them with the disease progression: time zone 1 (T1) (the hyperacute phase, days 1-3 post-MV initiation), T2 (the acute phase, days 4-14), and T3 (the chronic phase, days 15-30). Using volcano plots and enrichment pathway analyses, we identified the differential metabolites (DMs) and enriched pathways (EPs) between the survivors and non-survivors for each time zone. The DMs and EPs were further grouped into early-stage, late-stage, and consistent groups based on the time zones in which they were detected. Results: With the 566 annotated metabolites, we identified 38 DMs and 17 EPs as the early-stage group, which indicated enhanced energy production in glucose, amino acid, and fatty acid metabolisms in non-survivors. As the late-stage group, 84 DMs and 10 EPs showed upregulated sphingolipid, taurine, and tryptophan-kynurenine metabolisms with downregulated steroid hormone synthesis in non-survivors. Three DMs and 23 EPs in the consistent group showed more pronounced dysregulation in the dopamine and arachidonic acid metabolisms across all three time zones in non-survivors. Conclusions: This study elucidated the temporal differences in metabolic dysregulation between survivors and non-survivors of severe COVID-19, offering insights into its longitudinal progression and disease mechanisms.
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Affiliation(s)
- Ryo Uchimido
- Department of Intensive Care Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo City 113-8510, Japan
| | - Kenjiro Kami
- Human Metabolome Technologies, Inc., 246-2 Mizukami Kakuganji, Tsuruoka City 997-0052, Japan
| | - Hiroyuki Yamamoto
- Human Metabolome Technologies, Inc., 246-2 Mizukami Kakuganji, Tsuruoka City 997-0052, Japan
| | - Ryo Yokoe
- Department of Intensive Care Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo City 113-8510, Japan
| | - Issei Tsuchiya
- Department of Intensive Care Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo City 113-8510, Japan
| | - Yoko Nukui
- Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku Kajii-cho, Kawaramachi-Hirokoji, Kyoto 602-8566, Japan
| | - Yuki Goto
- Department of Tokyo Metropolitan Health Policy Advisement, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo City 113-8519, Japan
| | - Mariko Hanafusa
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo 104-0045, Japan
| | - Takeo Fujiwara
- Department of Public Health, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo City 113-8519, Japan
| | - Kenji Wakabayashi
- Department of Intensive Care Medicine, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo City 113-8510, Japan
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Sekiya M, Sakakibara Y, Hirota Y, Ito N, Chikamatsu S, Takei K, Nishijima R, Iijima KM. Decreased plasma nicotinamide and altered NAD + metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease. Neurobiol Dis 2024; 202:106694. [PMID: 39374707 DOI: 10.1016/j.nbd.2024.106694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 10/09/2024] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of Aβ accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by Aβ pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (AppNLGF) mouse model of Aβ amyloidosis. The CE-TOFMS analysis of plasma samples from female wild-type (WT) and AppNLGF mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in AppNLGF mice, and altered metabolite profiles were enriched for nicotinate/nicotinamide metabolism. In AppNLGF mouse brains, NAD+ levels were unaltered, but mRNA levels of NAD+-synthesizing nicotinate phosphoribosyltransferase (Naprt) and NAD+-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding Aβ plaques in the cortex and hippocampus of female AppNLGF mouse brains, suggesting neuroinflammation increases NAD+ metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection.
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Affiliation(s)
- Michiko Sekiya
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
| | - Yasufumi Sakakibara
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Yu Hirota
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Reseach Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Naoki Ito
- Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Sachie Chikamatsu
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Kimi Takei
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Risa Nishijima
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
| | - Koichi M Iijima
- Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
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Carvalho BFDC, Faria NDC, Silva KCS, Greenfield E, Alves MGO, Dias M, Mendes MA, Pérez-Sayáns M, Almeida JD. Salivary Metabolic Pathway Alterations in Brazilian E-Cigarette Users. Int J Mol Sci 2024; 25:11750. [PMID: 39519301 PMCID: PMC11546306 DOI: 10.3390/ijms252111750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/22/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
In recent years, the use of electronic cigarettes (e-cigs) has increased. However, their long-term effects on oral health and saliva remain poorly understood. Therefore, this study aimed to evaluate the saliva of e-cig users and investigate possible biomarkers. Participants were divided into two groups: the Electronic Cigarette Group (EG)-25 regular and exclusive e-cig users-and Control Group (CG)-25 non-smokers and non-e-cig users, matched in sex and age to the EG. The clinical analysis included the following parameters: age, sex, heart rate, oximetry, capillary blood glucose, carbon monoxide (CO) concentration in exhaled air, and alcohol use disorder identification test (AUDIT). Qualitative and quantitative analyses of saliva included sialometry, viscosity, pH, and cotinine concentrations. Furthermore, the EG and CG salivary metabolomes were compared using gas chromatography coupled with mass spectrometry (GC-MS). Data were analyzed using the Mann-Whitney test. The MetaboAnalyst 6.0 software was used for statistical analysis and biomarker evaluation. The EG showed high means for exhaled CO concentration and AUDIT but lower means for oximetry and salivary viscosity. Furthermore, 10 metabolites (isoleucine, 2-hydroxyglutaric acid, 3-phenyl-lactic acid, linoleic acid, 3-hydroxybutyric acid, 1,6-anhydroglucose, glucuronic acid, valine, stearic acid, and elaidic acid) were abundant in EG but absent in CG. It was concluded that e-cig users had high rates of alcohol consumption and experienced significant impacts on their general health, including increased cotinine and CO concentration in exhaled air, decreased oximetry, and low salivary viscosity. Furthermore, they showed a notable increase in salivary metabolites, especially those related to inflammation, xenobiotic metabolism, and biomass-burning pathways.
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Affiliation(s)
- Bruna Fernandes do Carmo Carvalho
- Instituto de Ciência e Tecnologia, Universidade Estadual Paulista (UNESP), Câmpus São José dos Campos, Av. Eng. Francisco José Longo, 777, São Dimas, São José dos Campos 12245-000, São Paulo, Brazil; (B.F.d.C.C.)
| | - Natalia de Carvalho Faria
- Instituto de Ciência e Tecnologia, Universidade Estadual Paulista (UNESP), Câmpus São José dos Campos, Av. Eng. Francisco José Longo, 777, São Dimas, São José dos Campos 12245-000, São Paulo, Brazil; (B.F.d.C.C.)
| | - Kethilyn Chris Sousa Silva
- Instituto de Ciência e Tecnologia, Universidade Estadual Paulista (UNESP), Câmpus São José dos Campos, Av. Eng. Francisco José Longo, 777, São Dimas, São José dos Campos 12245-000, São Paulo, Brazil; (B.F.d.C.C.)
| | - Ellen Greenfield
- Technology Research Center (NPT), Universidade Mogi das Cruzes, Mogi das Cruzes 08780-911, São Paulo, Brazil
| | - Mônica Ghislaine Oliveira Alves
- Instituto de Ciência e Tecnologia, Universidade Estadual Paulista (UNESP), Câmpus São José dos Campos, Av. Eng. Francisco José Longo, 777, São Dimas, São José dos Campos 12245-000, São Paulo, Brazil; (B.F.d.C.C.)
| | - Meriellen Dias
- Dempster MS Lab, Department of Chemical Engineering, Polytechnic School, University of São Paulo, São Paulo 05508-040, São Paulo, Brazil
| | - Maria Anita Mendes
- Dempster MS Lab, Department of Chemical Engineering, Polytechnic School, University of São Paulo, São Paulo 05508-040, São Paulo, Brazil
| | - Mario Pérez-Sayáns
- Oral Medicine, Oral Surgery and Implantology Unit (MedOralRes), Faculty of Medicine and Dentistry, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
- ORALRES Group, Instituto de Investigación Sanitaria de Santiago (IDIS), 15782 Santiago de Compostela, Spain
- Instituto de los Materiales de Santiago de Compostela (iMATUS), 15782 Santiago de Compostela, Spain
| | - Janete Dias Almeida
- Instituto de Ciência e Tecnologia, Universidade Estadual Paulista (UNESP), Câmpus São José dos Campos, Av. Eng. Francisco José Longo, 777, São Dimas, São José dos Campos 12245-000, São Paulo, Brazil; (B.F.d.C.C.)
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Togawa N, Yamada R, Aoki Y, Suehiro S, Uchida N, Haseda A, Kagami-Katsuyama H, Honma N, Nishihira J. Improvement of skin condition and intestinal microbiota via Heyndrickxia coagulans SANK70258 intake: A placebo-controlled, randomized, double-blind, parallel-group comparative study. Nutrition 2024; 126:112533. [PMID: 39127017 DOI: 10.1016/j.nut.2024.112533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 07/04/2024] [Accepted: 07/12/2024] [Indexed: 08/12/2024]
Abstract
OBJECTIVE Heyndrickxia coagulans SANK70258, a representative probiotic, is known for alleviating inflammation caused by cedar pollen, improving the intestinal environment and bowel movements. A previous study on consuming H. coagulans SANK70258 together with galactooligosaccharides showed a trend toward improvement in skin scaliness scores and subjective assessments of skin roughness. However, the effect of H. coagulans SANK70258 alone on the skin remains unclear. Thus, we aimed to re-evaluate the effects of the intake of H. coagulans SANK70258 alone on skin conditions and the intestinal environment through a clinical trial. METHODS This placebo-controlled, double-blind clinical trial involved 80 Japanese women aged 30 to 65 with perceived skin roughness. Participants were divided into placebo and test groups. Over eight weeks, the test group consumed H. coagulans SANK70258, and its effects on skin condition and intestinal health were examined. RESULTS The probiotic group showed significant intestinal improvements, with reduced fecal phenol levels (p = 0.044) and pH (p = 0.022), as well as enhanced skin lightness (L* value) (p = 0.040) and liver function tests. Metabolic analyses revealed decreases in fecal Nε-(carboxymethyl)lysine and plasma hydroxyproline, suggesting skin health benefits. There were also significant improvements in skin scaliness (p = 0.015) and bowel movement frequency (p = 0.032) in subgroup analysis. CONCLUSIONS H. coagulans SANK70258 can improve skin health by improving the intestinal lining. This probiotic reduces the levels of intestinal putrefactive products and advanced glycation end-product levels in feces, suggesting that it may affect not only skin health but also systemic tissues such as the liver.
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Affiliation(s)
- Naoyuki Togawa
- Food & Healthcare Group, Wellness Technology Department, Mitsubishi Chemical Corporation, Yokohama-shi, Japan.
| | - Ryouichi Yamada
- Food & Healthcare Group, Wellness Technology Department, Mitsubishi Chemical Corporation, Yokohama-shi, Japan
| | | | | | | | - Akane Haseda
- Department of Medical Management and Informatics, Hokkaido Information University, Hokkaido, Japan
| | - Hiroyo Kagami-Katsuyama
- Department of Medical Management and Informatics, Hokkaido Information University, Hokkaido, Japan
| | - Naoyuki Honma
- Department of Medical Management and Informatics, Hokkaido Information University, Hokkaido, Japan
| | - Jun Nishihira
- Department of Medical Management and Informatics, Hokkaido Information University, Hokkaido, Japan
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Chu S, Chan AKY, Chu CH. Polyamines in Dysbiotic Oral Conditions of Older Adults: A Scoping Review. Int J Mol Sci 2024; 25:10596. [PMID: 39408925 PMCID: PMC11477423 DOI: 10.3390/ijms251910596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/21/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Polyamines modulate cellular proliferation and function. Their dysregulation results in inflammatory and oncological repercussions. This study aims to map the current literature and provide an overview of polyamines in dysbiotic oral conditions among older adults. English publications indexed in MEDLINE, Scopus, and Web of Science from January 2000 to May 2024 were screened. Eligibility criteria included clinical and laboratory studies using samples from adults aged 65 or above. This scoping review identified 2725 publications and included 19 publications. Ten studies detected that older adults with oral carcinoma had increased levels of polyamines such as spermidine in saliva and tumour-affected tissues. Eight studies reported older adults suffering from periodontal infection had increased levels of polyamines such as putrescine in saliva, gingival crevicular fluid, and biofilm from the gingival crevice. Two studies showed polyamine levels could reflect the success of periodontal therapy. Three studies found older adults with halitosis had increased levels of polyamines such as cadaverine in saliva and tongue biofilm. Polyamines were suggested as biomarkers for these oral conditions. In conclusion, certain polyamine levels are elevated in older adults with oral cancer, periodontal infections, and halitosis. Polyamines may be used as a simple and non-invasive tool to detect dysbiotic oral conditions and monitor treatment progress in older adults (Open Science Framework registration).
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Affiliation(s)
| | | | - Chun Hung Chu
- Faculty of Dentistry, The University of Hong Kong, Hong Kong 999077, China
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Mio K, Goto Y, Matsuoka T, Komatsu M, Ishii C, Yang J, Kobayashi T, Aoe S, Fukuda S. Barley β-glucan consumption improves glucose tolerance by increasing intestinal succinate concentrations. NPJ Sci Food 2024; 8:69. [PMID: 39349520 PMCID: PMC11444033 DOI: 10.1038/s41538-024-00311-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 09/15/2024] [Indexed: 10/02/2024] Open
Abstract
Barley is rich in β-glucan, which can alter gut microbiota and metabolome profiles, potentially affecting host metabolism. However, the microbiota and metabolites increased by barley β-glucan remain unclear. In this study, we focused on the gut-microbiota-derived metabolite succinate and investigated the microbiome and metabolome profiles altered by barley β-glucan intake. C57BL/6 J mice were fed a standard or middle-fat diet containing barley flour rich in β-glucan or barley flour without β-glucan, and their gut microbiota and metabolome profiles were analyzed. The results showed increased Bacteroides, Parasutterella, and succinate due to barley β-glucan intake independent of diet differences. Next, we used mice lacking slc13a2, a gene that is involved in the cellular uptake of succinate. Wild-type mice showed improved glucose tolerance after the intake of barley β-glucan, but this effect was attenuated in the slc13a2-deficient mice. These results suggest that barley β-glucan intake increases succinate and succinate-producing bacteria and affects glucose metabolism.
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Affiliation(s)
- Kento Mio
- Research and Development Department, Hakubaku co., Ltd., Yamanashi, Japan.
| | - Yuka Goto
- Research and Development Department, Hakubaku co., Ltd., Yamanashi, Japan
| | - Tsubasa Matsuoka
- Research and Development Department, Hakubaku co., Ltd., Yamanashi, Japan
| | - Mitsuko Komatsu
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Chiharu Ishii
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Jiayue Yang
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Toshiki Kobayashi
- Research and Development Department, Hakubaku co., Ltd., Yamanashi, Japan
| | - Seiichiro Aoe
- Graduate School of Studies in Human Culture, Otsuma Women's University, Tokyo, Japan.
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
- Laboratory for Regenerative Microbiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
- Gut Environmental Design Group, Kanagawa Institute of Industrial Science and Technology, Kawasaki, Kanagawa, Japan.
- Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki, Japan.
- Metagen Inc., Tsuruoka, Yamagata, Japan.
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Ohta T, Sugimoto M, Ito Y, Horikawa S, Okui Y, Sakaki H, Seino M, Sunamura M, Nagase S. Profiling of metabolic dysregulation in ovarian cancer tissues and biofluids. Sci Rep 2024; 14:21555. [PMID: 39285238 PMCID: PMC11405878 DOI: 10.1038/s41598-024-72938-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 09/11/2024] [Indexed: 09/22/2024] Open
Abstract
Ovarian cancer (OC) is the most lethal gynecologic cancer, mainly due to late diagnosis with widespread peritoneal spread at first presentation. We performed metabolomic analyses of ovarian and paired control tissues using capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry to understand its metabolomic dysregulation. Of the 130 quantified metabolites, 96 metabolites of glycometabolism, including glycolysis, tricarboxylic acid cycles, urea cycles, and one-carbon metabolites, showed significant differences between the samples. To evaluate the local and systemic metabolomic differences in OC, we also analyzed low or non-invasively available biofluids, including plasma, urine, and saliva collected from patients with OC and benign gynecological diseases. All biofluids and tissue samples showed consistently elevated concentrations of N1,N12-diacetylspermine compared to controls. Four metabolites, polyamines, and betaine, were significantly and consistently elevated in both plasma and tissue samples. These data indicate that plasma metabolic dysregulation, which the most reflected by those of OC tissues. Our metabolomic profiles contribute to our understanding of metabolomic abnormalities in OC and their effects on biofluids.
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Affiliation(s)
- Tsuyoshi Ohta
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan.
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0052, Japan
| | - Yasufumi Ito
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan
| | - Shota Horikawa
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan
| | - Yosuke Okui
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan
| | - Hirotsugu Sakaki
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan
| | - Manabu Seino
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan
| | - Makoto Sunamura
- Department of Intestinal Surgery Medical Center, Tokyo Medical University, Hachioji, Tokyo, 193-0998, Japan
| | - Satoru Nagase
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, 990-9585, Japan
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Vats R, Yadav P, Bano A, Wadhwa S, Bhardwaj R. Salivary biomarkers in non-invasive oral cancer diagnostics: a comprehensive review. J Appl Oral Sci 2024; 32:e20240151. [PMID: 39258715 PMCID: PMC11464085 DOI: 10.1590/1678-7757-2024-0151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/18/2024] [Accepted: 07/10/2024] [Indexed: 09/12/2024] Open
Abstract
OBJECTIVE This review aims to provide a comprehensive analysis of the effectiveness of saliva as a non-invasive diagnostic marker for oral cancer. Despite progress in oral cancer diagnosis and prognosis, the 5-year survival rate remains low due to the resistance to treatment and delayed diagnosis, which can be attributed to various factors including tobacco and alcohol consumption, genetic damage, and human papillomavirus (HPV). The potential use of saliva as an easily accessible non-invasive screening and diagnostic method arises from its direct contact with the lesion site. METHODOLOGY Data for this study were gathered via a comprehensive literature evaluation using search engines such as the PubMed, Web of Science, Google Scholar, and SciFinder. RESULTS Identifying salivary biomarkers shows potential to transform oral cancer diagnostics by offering a reliable alternative to the traditional invasive methods. Saliva is an abundant reservoir for both cell-bound and cell-free organic and inorganic constituents. Thus, saliva is an appropriate field for research in proteomics, genomics, metagenomics, and metabolomics. CONCLUSION This review provides a comprehensive elucidation of salivary biomarkers and their function in non-invasive oral cancer diagnosis, demonstrating their potential to enhance patient outcomes and reduce the impact of this devastating disease.
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Affiliation(s)
- Ravina Vats
- Maharshi Dayanand University, Centre for Medical Biotechnology, Rohtak, Haryana, India
| | - Pooja Yadav
- Maharshi Dayanand University, Centre for Medical Biotechnology, Rohtak, Haryana, India
| | - Afsareen Bano
- Maharshi Dayanand University, Centre for Medical Biotechnology, Rohtak, Haryana, India
| | - Sapna Wadhwa
- Maharshi Dayanand University, Centre for Medical Biotechnology, Rohtak, Haryana, India
| | - Rashmi Bhardwaj
- Maharshi Dayanand University, Centre for Medical Biotechnology, Rohtak, Haryana, India
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Harada S, Ohmomo H, Matsumoto M, Sata M, Iida M, Hirata A, Miyagawa N, Kuwabara K, Kato S, Toki R, Edagawa S, Sugiyama D, Sato A, Hirayama A, Sugimoto M, Soga T, Tomita M, Shimizu A, Okamura T, Takebayashi T. Metabolomics Profiles Alterations in Cigarette Smokers and Heated Tobacco Product Users. J Epidemiol 2024; 34:403-410. [PMID: 37926518 PMCID: PMC11330708 DOI: 10.2188/jea.je20230170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/28/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment. METHODS Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey. RESULTS Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels. CONCLUSION Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.
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Affiliation(s)
- Sei Harada
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Hideki Ohmomo
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Minako Matsumoto
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Mizuki Sata
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Miho Iida
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Aya Hirata
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Naoko Miyagawa
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Kazuyo Kuwabara
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Suzuka Kato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Ryota Toki
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Shun Edagawa
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Sugiyama
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Asako Sato
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Masaru Tomita
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Atsushi Shimizu
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Tomonori Okamura
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Toru Takebayashi
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
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Kobayashi K, Takada N, Matsubara Y, Okuhara H, Oosaka M. Lactic acid fermentation of kamaboko, a heated Alaska pollock surimi, enhances angiotensin I-converting enzyme inhibitory activity via fish protein hydrolysis. J GEN APPL MICROBIOL 2024; 70:n/a. [PMID: 38281752 DOI: 10.2323/jgam.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2024]
Abstract
To enhance the value of surimi, efforts have been made to develop a fermentation method with lactic acid bacteria (LAB) to proteolyze fish protein. However, fermenting unheated surimi poses a spoilage risk due to its high bacterial content. Surimi heat treatment can prevent spoilage, but gel formation induced by heating introduces another technical issue: it hinders uniform fermentation. Thus, this study aims to observe the proteolysis and enhance the functionality of seafood product through lactic acid fermentation of kamaboko, a heated surimi. Upon analyzing the kamaboko fermented with Lactobacillus helveticus JCM1004, we observed that LAB produced protease, resulting in the degradation of myosin heavy chain and actin during fermentation. Lactic acid fermentation significantly augmented the peptide content of kamaboko, subsequently elevating the angiotensin Ⅰ-converting enzyme (ACE) inhibitory activity in 200-fold diluted extract of fermented kamaboko to approximately 70% and higher. Notably, our investigation revealed that proteolysis was confined to the surface of kamaboko, as evidenced by SDS-PAGE analysis. This observation implies that the surface area of kamaboko influences the ACE inhibitory activity. Through a comparative analysis of various bacterial strains, we demonstrated that the increase in ACE inhibitory activity is contingent on the protease generated by LAB. These results suggest that LAB-mediated proteolysis of fish proteins liberates bioactive peptides, thereby manifesting in the ACE inhibitory activity. In summary, this study underscores that the fermentation of kamaboko employing proteolytic LAB holds promise in the development of novel functional seafood products.
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Affiliation(s)
| | | | - Yuki Matsubara
- Food Research Center, Niigata Agricultural Research Institute
| | - Hiroaki Okuhara
- Food Research Center, Niigata Agricultural Research Institute
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Ishizaki T, Sugimoto M, Kuboyama Y, Mazaki J, Kasahara K, Tago T, Udo R, Iwasaki K, Hayashi Y, Nagakawa Y. Stage-Specific Plasma Metabolomic Profiles in Colorectal Cancer. J Clin Med 2024; 13:5202. [PMID: 39274416 PMCID: PMC11396754 DOI: 10.3390/jcm13175202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/16/2024] Open
Abstract
Background/Objectives: The objective of this study was to investigate the metabolomic profiles of patients with colorectal cancer (CRC) across various stages of the disease. Methods: The plasma samples were obtained from 255 subjects, including patients with CRC in stages I-IV, polyps, and controls. We employed capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography triple quadrupole mass spectrometry to analyze hydrophilic metabolites comprehensively. The data were randomly divided into two groups, and consistent differences observed in both groups were analyzed. Results: Acetylated polyamines, such as N1-acetylspermine and N1, N12-diacetylspermine, consistently showed elevated concentrations in stage IV compared to stages I-III. Non-acetylated polyamines, including spermine and spermidine, exhibited increasing trends from polyp to stage IV. Other metabolites, such as histidine and o-acetylcarnitine, showed decreasing trends across stages. While acetylated polyamines have been reported as CRC detection markers, our findings suggest that they also possess diagnostic potential for distinguishing stage IV from other stages. Conclusions: This study showed stage-specific changes in metabolic profiles, including polyamines, of colorectal cancer.
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Affiliation(s)
- Tetsuo Ishizaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Masahiro Sugimoto
- Institute of Medical Science, Tokyo Medical University, Shinjuku 160-8402, Tokyo, Japan
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Yamagata, Japan
| | - Yu Kuboyama
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Junichi Mazaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Kenta Kasahara
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Tomoya Tago
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Ryutaro Udo
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Kenichi Iwasaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Yutaka Hayashi
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku 160-0023, Tokyo, Japan
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Steimle A, Neumann M, Grant ET, Willieme S, De Sciscio A, Parrish A, Ollert M, Miyauchi E, Soga T, Fukuda S, Ohno H, Desai MS. Gut microbial factors predict disease severity in a mouse model of multiple sclerosis. Nat Microbiol 2024; 9:2244-2261. [PMID: 39009690 PMCID: PMC11371644 DOI: 10.1038/s41564-024-01761-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 06/14/2024] [Indexed: 07/17/2024]
Abstract
Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.
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Affiliation(s)
- Alex Steimle
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Mareike Neumann
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Erica T Grant
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Stéphanie Willieme
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Alessandro De Sciscio
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
| | - Amy Parrish
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Markus Ollert
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
- Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark
| | - Eiji Miyauchi
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Shinji Fukuda
- Institute for Advanced Biosciences, Keio University, Yamagata, Japan
| | - Hiroshi Ohno
- RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan
| | - Mahesh S Desai
- Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
- Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark.
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Yamada M, Jinno H, Naruse S, Isono Y, Maeda Y, Sato A, Matsumoto A, Ikeda T, Sugimoto M. Predictive analysis of breast cancer response to neoadjuvant chemotherapy through plasma metabolomics. Breast Cancer Res Treat 2024; 207:393-404. [PMID: 38740665 DOI: 10.1007/s10549-024-07370-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
PURPOSE Preoperative chemotherapy is a critical component of breast cancer management, yet its effectiveness is not uniform. Moreover, the adverse effects associated with chemotherapy necessitate the identification of a patient subgroup that would derive the maximum benefit from this treatment. This study aimed to establish a method for predicting the response to neoadjuvant chemotherapy in breast cancer patients utilizing a metabolomic approach. METHODS Plasma samples were obtained from 87 breast cancer patients undergoing neoadjuvant chemotherapy at our facility, collected both before the commencement of the treatment and before the second treatment cycle. Metabolite analysis was conducted using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry (LC-MS). We performed comparative profiling of metabolite concentrations by assessing the metabolite profiles of patients who achieved a pathological complete response (pCR) against those who did not, both in initial and subsequent treatment cycles. RESULTS Significant variances were observed in the metabolite profiles between pCR and non-pCR cases, both at the onset of preoperative chemotherapy and before the second cycle. Noteworthy distinctions were also evident between the metabolite profiles from the initial and the second neoadjuvant chemotherapy courses. Furthermore, metabolite profiles exhibited variations associated with intrinsic subtypes at all assessed time points. CONCLUSION The application of plasma metabolomics, utilizing CE-MS and LC-MS, may serve as a tool for predicting the efficacy of neoadjuvant chemotherapy in breast cancer in the future after all necessary validations have been completed.
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Affiliation(s)
- Miki Yamada
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Hiromitsu Jinno
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan.
| | - Saki Naruse
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Yuka Isono
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Yuka Maeda
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Ayana Sato
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Akiko Matsumoto
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Tatsuhiko Ikeda
- Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan
- Institute of Medical Science, Tokyo Medical University, Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
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50
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Nakasuka F, Hirayama A, Makinoshima H, Yano S, Soga T, Tabata S. The role of cytidine 5'-triphosphate synthetase 1 in metabolic rewiring during epithelial-to-mesenchymal transition in non-small-cell lung cancer. FEBS Open Bio 2024; 14:1570-1583. [PMID: 39030877 PMCID: PMC11492420 DOI: 10.1002/2211-5463.13860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 05/30/2024] [Accepted: 06/25/2024] [Indexed: 07/22/2024] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti-cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor-β (TGF-β)-induced EMT in non-small-cell lung cancer. Our study revealed that TGF-β plays a role in EMT functions by upregulation of cytidine 5'-triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF-β-induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF-β-mediated downregulation of UDP-glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non-small-cell lung cancer.
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Affiliation(s)
- Fumie Nakasuka
- Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
- Systems Biology Program, Graduate School of Media and GovernanceKeio UniversityFujisawaJapan
- Department of Molecular Pathology, Graduate School of MedicineThe University of TokyoJapan
| | - Akiyoshi Hirayama
- Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
- Systems Biology Program, Graduate School of Media and GovernanceKeio UniversityFujisawaJapan
| | - Hideki Makinoshima
- Tsuruoka Metabolomics LaboratoryNational Cancer CenterTsuruokaJapan
- Shonai Regional Industry Promotion CenterTsuruokaJapan
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
| | - Seiji Yano
- Department of Medical Oncology, Kanazawa University Cancer Research InstituteKanazawa UniversityJapan
| | - Tomoyoshi Soga
- Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
- Systems Biology Program, Graduate School of Media and GovernanceKeio UniversityFujisawaJapan
| | - Sho Tabata
- Institute for Advanced BiosciencesKeio UniversityTsuruokaJapan
- Tsuruoka Metabolomics LaboratoryNational Cancer CenterTsuruokaJapan
- Shonai Regional Industry Promotion CenterTsuruokaJapan
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial CenterNational Cancer CenterKashiwaJapan
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