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Zhu M, Hu Y, Gu Y, Lin X, Jiang X, Gong C, Fang Z. Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer. Am J Cancer Res 2025; 15:233-247. [PMID: 39949925 PMCID: PMC11815375 DOI: 10.62347/zsoo2247] [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: 11/09/2024] [Accepted: 01/15/2025] [Indexed: 02/16/2025] Open
Abstract
This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.
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Affiliation(s)
- Minjing Zhu
- Clinical Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Yanyan Hu
- Clinical Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Yangjia Gu
- Chinese Medicine, Changchun University of Science and TechnologyChangchun 130600, Jilin, China
| | - Xuedan Lin
- Clinical Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Xiang Jiang
- Department of Gastroenterology, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
| | - Chaoju Gong
- Central Laboratory, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical UniversityXuzhou 221000, Jiangsu, China
| | - Zejun Fang
- Central Laboratory, Sanmen People’s HospitalSanmen 317100, Zhejiang, China
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2
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Pranzini E, Muccillo L, Nesi I, Santi A, Mancini C, Lori G, Genovese M, Lottini T, Comito G, Caselli A, Arcangeli A, Sabatino L, Colantuoni V, Taddei ML, Cirri P, Paoli P. Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia. Cell Death Discov 2024; 10:510. [PMID: 39706853 DOI: 10.1038/s41420-024-02271-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/06/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024] Open
Abstract
Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality. Here, we demonstrate that decreased serine availability during tumor progression promotes myotubes diameter reduction in vitro and induces muscle wasting in in vivo mice models. By investigating the metabolic crosstalk between colorectal cancer cells and muscle cells, we found that incubating myotubes with conditioned media from tumor cells relying on exogenous serine consumption triggers pronounced myotubes diameter reduction. Accordingly, culturing myotubes in a serine-free medium induces fibers width reduction and suppresses the activation of the AKT-mTORC1 pathway with consequent impairment in protein synthesis, increased protein degradation, and enhanced expression of the muscle atrophy-related genes Atrogin1 and MuRF1. In addition, serine-starved conditions affect myoblast differentiation and mitochondrial oxidative metabolism, finally inducing oxidative stress in myotubes. Consistently, serine dietary deprivation strongly strengthens cancer-associated weight loss and muscle atrophy in mice models. These findings uncover serine consumption by tumor cells as a previously undisclosed driver in cancer cachexia, opening new routes for possible therapeutic approaches.
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Affiliation(s)
- Erica Pranzini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Livio Muccillo
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
- AREA Science Park, Padriciano, 99, Trieste, Italy
| | - Ilaria Nesi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Alice Santi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Caterina Mancini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Giulia Lori
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Massimo Genovese
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Tiziano Lottini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giuseppina Comito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Anna Caselli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Annarosa Arcangeli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Lina Sabatino
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Vittorio Colantuoni
- Department of Sciences and Technologies, University of Sannio, Benevento, Italy
| | - Maria Letizia Taddei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Paolo Cirri
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Paolo Paoli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
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Deng W, Ye C, Wang W, Huang R, Guo C, Pan Y, Sun C. LC-MS analysis of chiral amino acids in human urine reveals D-amino acids as potential biomarkers for colorectal cancer. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1245:124270. [PMID: 39121519 DOI: 10.1016/j.jchromb.2024.124270] [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: 05/10/2024] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
Colorectal cancer (CRC) is a common malignant tumor in the gastrointestinal tract. Changes in amino acid metabolites have been implicated in tumorigenesis and disease progression. Biomarkers on the basis of chiral amino acids, especially D-amino acids, have not been established for early diagnosis of CRC. Quantification of chiral amino acids, especially very low concentrations of endogenous D-amino acids, is technically challenging. We report here the quantification of L- and D-amino acids in urine samples collected from 115 CRC patients and 155 healthy volunteers, using an improved method. The method of chiral labeling, liquid chromatography, and tandem mass spectrometry enabled separation and detection of 28 amino acids (14 L-amino acids, 13 D-amino acids and Gly). Orthogonal partial least squares discriminant analysis identified 14 targeted variables among these chiral amino acids that distinguished the CRC from the healthy controls. Binary logistic regression analysis revealed that D-α-aminobutyric acid (D-AABA), L-alanine (L-Ala), D-alanine (D-Ala), D-glutamine (D-Gln) and D-serine (D-Ser) could be potential biomarkers for CRC. A receiver operating characteristic curve analysis of combined multi-variables contributed to an area under the curve (AUC) of 0.995 with 98.3 % sensitivity and 96.8 % specificity. A model constructed with D-AABA, D-Ala, D-Gln, and D-Ser achieved an AUC of 0.988, indicating important contributions of D-amino acids to the association with CRC. Further analysis also demonstrated that the metabolic aberration was associated with age and the development of CRC, D-methionine (D-Met) was decreased in CRC patients with age over 50, and D/L-Gln in patients at stage IV was higher than patients at stage I. This study provides the signature of D-amino acids in urine samples and offers a promising strategy for developing non-invasive diagnosis of CRC.
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Affiliation(s)
- Wenchan Deng
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Chundan Ye
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Wei Wang
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Zijingang Campus of Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Rongrong Huang
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
| | - Cheng Guo
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
| | - Yuanjiang Pan
- Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China.
| | - Cuirong Sun
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
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4
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Saleem TH, Rizk MA, Abdelhafez NF, Sabra A, Radwan E. Upregulation of BRCA1 and 2 protein expression is associated with dysregulation in amino acids profiles in breast cancer. Mol Biol Rep 2024; 51:50. [PMID: 38165507 PMCID: PMC10761515 DOI: 10.1007/s11033-023-09028-6] [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: 08/09/2023] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND The prevalence of breast cancer (BC) is high among cancers in Egypt, ranking it the most common cause of cancer mortality in women. BRCA1 and BRCA2 tumor suppressors proteins have a specific relationship with BC. Plasma free amino acids levels (PFAAs) have been reported to exhibit altered profiles among cancer patients. Thus, the present study aims to examine the alteration of the PFAAs profiles and investigate their association with BRCA1 and 2 circulating levels in Egyptian females diagnosed with BC and in females with family history of BC to establish potential early detection strategies for BC. METHODS AND RESULTS This study included 26 BC patients, 22 females with family history of BC (relatives) in addition to 38 healthy females as control group. Quantitative measurement of PFAAs was determined by the ion exchange separation method through high performance liquid chromatography. BRCA1 and BRCA2 concentrations were determined using ELISA. Our results showed PFAAs profiles in BC patients and in females with BC family history with significant upregulation in mean plasma levels of Alanine, Phenylalanine, Glutamate and Cysteine and downregulation of Taurine, Threonine, Serine, Glycine, Valine, Methionine and Histidine levels compared to controls. Also, a significant positive correlation was observed between plasma BRCA1 and Valine levels while a significant negative correlation was observed between BRCA2 and Lysine plasma levels. CONCLUSION PFAAs profile can potentially be used in early screening for BC patients and for susceptible females.
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Affiliation(s)
- Tahia H Saleem
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Rizk
- General Surgery Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nashwa F Abdelhafez
- Anesthesia and Intensive Care Unit, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Sabra
- Medical Biochemistry Department, Faculty of Medicine, Merit University, Sohag, Egypt
| | - Eman Radwan
- Medical Biochemistry Department, Faculty of Medicine, Assiut University, Assiut, Egypt.
- Biochemistry Department, Sphinx University, New Assiut, Assiut, Egypt.
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Santos MD, Barros I, Brandão P, Lacerda L. Amino Acid Profiles in the Biological Fluids and Tumor Tissue of CRC Patients. Cancers (Basel) 2023; 16:69. [PMID: 38201497 PMCID: PMC10778074 DOI: 10.3390/cancers16010069] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/19/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Amino acids are the building blocks of proteins and essential players in pathways such as the citric acid and urea cycle, purine and pyrimidine biosynthesis, and redox cell signaling. Therefore, it is unsurprising that these molecules have a significant role in cancer metabolism and its metabolic plasticity. As one of the most prevalent malign diseases, colorectal cancer needs biomarkers for its early detection, prognostic, and prediction of response to therapy. However, the available biomarkers for this disease must be more powerful and present several drawbacks, such as high costs and complex laboratory procedures. Metabolomics has gathered substantial attention in the past two decades as a screening platform to study new metabolites, partly due to the development of techniques, such as mass spectrometry or liquid chromatography, which have become standard practice in diagnostic procedures for other diseases. Extensive metabolomic studies have been performed in colorectal cancer (CRC) patients in the past years, and several exciting results concerning amino acid metabolism have been found. This review aims to gather and present findings concerning alterations in the amino acid plasma pool of colorectal cancer patients.
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Affiliation(s)
- Marisa Domingues Santos
- Colorectal Unit, Hospital de Santo António, Centro Hospitalar Universitário de Santo António, 4050-651 Porto, Portugal;
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; (I.B.); (L.L.)
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - Ivo Barros
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; (I.B.); (L.L.)
| | - Pedro Brandão
- Colorectal Unit, Hospital de Santo António, Centro Hospitalar Universitário de Santo António, 4050-651 Porto, Portugal;
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; (I.B.); (L.L.)
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - Lúcia Lacerda
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal; (I.B.); (L.L.)
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
- Genetic Laboratory Service, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar Universitário de Santo António, 4050-651 Porto, Portugal
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Bull C, Hazelwood E, Bell JA, Tan V, Constantinescu AE, Borges C, Legge D, Burrows K, Huyghe JR, Brenner H, Castellvi-Bel S, Chan AT, Kweon SS, Le Marchand L, Li L, Cheng I, Pai RK, Figueiredo JC, Murphy N, Gunter MJ, Timpson NJ, Vincent EE. Identifying metabolic features of colorectal cancer liability using Mendelian randomization. eLife 2023; 12:RP87894. [PMID: 38127078 PMCID: PMC10735227 DOI: 10.7554/elife.87894] [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] [Indexed: 12/23/2023] Open
Abstract
Background Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y. Results The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development. Funding This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
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Affiliation(s)
- Caroline Bull
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
- Translational Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Emma Hazelwood
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Joshua A Bell
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Vanessa Tan
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Andrei-Emil Constantinescu
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Carolina Borges
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Danny Legge
- Translational Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer CenterSeattleUnited States
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)HeidelbergGermany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)HeidelbergGermany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
| | - Sergi Castellvi-Bel
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of BarcelonaBarcelonaSpain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical SchoolBostonUnited States
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical SchoolBostonUnited States
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical SchoolBostonUnited States
- Broad Institute of Harvard and MITCambridgeUnited States
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard UniversityBostonUnited States
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard UniversityBostonUnited States
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical SchoolGwangjuRepublic of Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun HospitalHwasunRepublic of Korea
| | | | - Li Li
- Department of Family Medicine, University of VirginiaCharlottesvilleUnited States
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San FranciscoSan FranciscoUnited States
- University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San FranciscoSan FranciscoUnited States
| | - Rish K Pai
- Department of Pathology and Laboratory Medicine, Mayo ClinicScottsdaleUnited States
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterLos AngelesUnited States
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on CancerLyonFrance
| | - Marc J Gunter
- Nutrition and Metabolism Branch, International Agency for Research on CancerLyonFrance
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonLondonUnited Kingdom
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
| | - Emma E Vincent
- MRC Integrative Epidemiology Unit at the University of BristolBristolUnited Kingdom
- Population Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
- Translational Health Sciences, Bristol Medical School, University of BristolBristolUnited Kingdom
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Metri NJ, Butt AS, Murali A, Steiner-Lim GZ, Lim CK. Normative Data on Serum and Plasma Tryptophan and Kynurenine Concentrations from 8089 Individuals Across 120 Studies: A Systematic Review and Meta-Analysis. Int J Tryptophan Res 2023; 16:11786469231211184. [PMID: 38034059 PMCID: PMC10687991 DOI: 10.1177/11786469231211184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/15/2023] [Indexed: 12/02/2023] Open
Abstract
In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 μM and 51.45 ± 10.47 μM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 μM and 1.82 ± 0.54 μM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data.
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Affiliation(s)
- Najwa-Joelle Metri
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
| | - Ali S Butt
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
| | - Ava Murali
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Macquarie Park, NSW, Australia
| | - Genevieve Z Steiner-Lim
- NICM Health Research Institute, Western Sydney University, Penrith, NSW, Australia
- Translational Health Research Institute (THRI), Western Sydney University, Penrith, NSW, Australia
| | - Chai K Lim
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Macquarie Park, NSW, Australia
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8
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Bull CJ, Hazelwood E, Bell JA, Tan VY, Constantinescu AE, Borges MC, Legge DN, Burrows K, Huyghe JR, Brenner H, Castellví-Bel S, Chan AT, Kweon SS, Marchand LL, Li L, Cheng I, Pai RK, Figueiredo JC, Murphy N, Gunter MJ, Timpson NJ, Vincent EE. Identifying metabolic features of colorectal cancer liability using Mendelian randomization. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.10.23287084. [PMID: 36945480 PMCID: PMC10029059 DOI: 10.1101/2023.03.10.23287084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
Background Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. Results The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development. Funding This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
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Affiliation(s)
- Caroline J. Bull
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Translational Health Sciences, Bristol Medical School, University of Bristol, UK
| | - Emma Hazelwood
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Joshua A. Bell
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Vanessa Y. Tan
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Andrei-Emil Constantinescu
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Maria Carolina Borges
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Danny N. Legge
- Translational Health Sciences, Bristol Medical School, University of Bristol, UK
| | - Kimberly Burrows
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Jeroen R. Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sergi Castellví-Bel
- Gastroenterology Department, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea
- Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | | | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Iona Cheng
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA
- University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, San Francisco, California, USA
| | - Rish K. Pai
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Arizona, Scottsdale, Arizona, USA
| | - Jane C. Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Marc J. Gunter
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom
| | - Nicholas J. Timpson
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Emma E. Vincent
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Translational Health Sciences, Bristol Medical School, University of Bristol, UK
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9
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Bui TT, Jang E, Shin JH, Kim TH, Kim H, Choi D, Vu TD, Chung H. Feasibility of Raman spectroscopic identification of gall bladder cancer using extracellular vesicles extracted from bile. Analyst 2023; 148:4156-4165. [PMID: 37501647 DOI: 10.1039/d3an00806a] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Extracellular vesicles (EVs), which are heterogeneous membrane-based vesicles with bilayer cell membrane structures, could be versatile biomarkers for the identification of diverse diseases including cancers. With this potential, this study has attempted the Raman spectroscopic identification of gall bladder (GB) cancer by directly measuring the EV solution extracted from human bile without further sample drying. For this purpose, bile samples were obtained from four normal individuals and 21 GB polyp, eight hepatocellular carcinoma (HCC), and five GB cancer patients, and EVs were extracted from each of the bile samples. The Raman peak shapes of the EVs extracted from the GB cancer samples, especially the relative intensities of peaks in the 1560-1340 cm-1 range, were dissimilar to those of the samples from the normal, GB polyp, and HCC groups. The intensity ratios of peaks at 1537 and 1453 cm-1 and at 1395 and 1359 cm-1 of the GB cancer samples were lower and higher, respectively, than those of the samples of the remaining three groups. The differences of peak intensity ratios were statistically significant based on the Mann-Whitney U test. DNA/RNA bases, amino acids, and bile salts contributed to the spectra of EVs, and their relative abundances seemed to vary according to the occurrence of GB cancer. The varied metabolite compositions and/or structures of EVs were successfully demonstrated by the dissimilar peak intensity ratios in the Raman spectra, thereby enabling the discrimination of GB cancer.
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Affiliation(s)
- Thu Thuy Bui
- Department of Chemistry and Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea.
| | - Eunjin Jang
- Department of Chemistry and Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea.
| | - Ji Hyun Shin
- Department of Surgery, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Tae Hun Kim
- Department of Surgery, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Hayoon Kim
- Department of Surgery, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Dongho Choi
- Department of Surgery, College of Medicine, Hanyang University, Seoul 04763, Republic of Korea
| | - Tung Duy Vu
- Faculty of Chemistry, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Hoeil Chung
- Department of Chemistry and Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea.
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10
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Cutshaw G, Uthaman S, Hassan N, Kothadiya S, Wen X, Bardhan R. The Emerging Role of Raman Spectroscopy as an Omics Approach for Metabolic Profiling and Biomarker Detection toward Precision Medicine. Chem Rev 2023; 123:8297-8346. [PMID: 37318957 PMCID: PMC10626597 DOI: 10.1021/acs.chemrev.2c00897] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Omics technologies have rapidly evolved with the unprecedented potential to shape precision medicine. Novel omics approaches are imperative toallow rapid and accurate data collection and integration with clinical information and enable a new era of healthcare. In this comprehensive review, we highlight the utility of Raman spectroscopy (RS) as an emerging omics technology for clinically relevant applications using clinically significant samples and models. We discuss the use of RS both as a label-free approach for probing the intrinsic metabolites of biological materials, and as a labeled approach where signal from Raman reporters conjugated to nanoparticles (NPs) serve as an indirect measure for tracking protein biomarkers in vivo and for high throughout proteomics. We summarize the use of machine learning algorithms for processing RS data to allow accurate detection and evaluation of treatment response specifically focusing on cancer, cardiac, gastrointestinal, and neurodegenerative diseases. We also highlight the integration of RS with established omics approaches for holistic diagnostic information. Further, we elaborate on metal-free NPs that leverage the biological Raman-silent region overcoming the challenges of traditional metal NPs. We conclude the review with an outlook on future directions that will ultimately allow the adaptation of RS as a clinical approach and revolutionize precision medicine.
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Affiliation(s)
- Gabriel Cutshaw
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50012, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Saji Uthaman
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50012, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Nora Hassan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50012, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Siddhant Kothadiya
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50012, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
| | - Xiaona Wen
- Biologics Analytical Research and Development, Merck & Co., Inc., Rahway, NJ, 07065, USA
| | - Rizia Bardhan
- Department of Chemical and Biological Engineering, Iowa State University, Ames, IA 50012, USA
- Nanovaccine Institute, Iowa State University, Ames, IA 50012, USA
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11
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Yi Y, Wang J, Liang C, Ren C, Lian X, Han C, Sun W. LC-MS-based serum metabolomics analysis for the screening and monitoring of colorectal cancer. Front Oncol 2023; 13:1173424. [PMID: 37448516 PMCID: PMC10338013 DOI: 10.3389/fonc.2023.1173424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
Background Colorectal Cancer (CRC) is a prevalent digestive system tumour with significant mortality and recurrence rates. Serum metabolomics, with its high sensitivity and high throughput, has shown potential as a tool to discover biomarkers for clinical screening and monitoring of the CRC patients. Methods Serum metabolites of 61 sex and age-matched healthy controls and 62 CRC patients (before and after surgical intervention) were analyzed using a ultra-performance liquid chromatography-high resolution mass spectrometer (UPLC-MS). Statistical methods and pathway enrichment analysis were used to identify potential biomarkers and altered metabolic pathways. Results Our analysis revealed a clear distinction in the serum metabolic profile between CRC patients and healthy controls (HCs). Pathway analysis indicated a significant association with arginine biosynthesis, pyrimidine metabolism, pantothenate, and CoA biosynthesis. Univariate and multivariate statistical analysis showed that 9 metabolites had significant diagnostic value for CRC, among them, Guanosine with Area Under the Curve (AUC) values of 0.951 for the training group and0.998 for the validation group. Furthermore, analysis of four specific metabolites (N-Phenylacetylasparticacid, Tyrosyl-Gamma-glutamate, Tyr-Ser and Sphingosine) in serum samples of CRC patients before and after surgery indicated a return to healthy levels after an intervention. Conclusion Our results suggest that serum metabolomics may be a valuable tool for the screening and monitoring of CRC patients.
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Affiliation(s)
- Yanan Yi
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Jianjian Wang
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chengtong Liang
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chuanli Ren
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Xu Lian
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Chongxu Han
- Department of Laboratory Medicine, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Wei Sun
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
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12
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Hu S, Zhao C, Wang Z, Li Z, Kong X. Clinical diagnostic value of amino acids in laryngeal squamous cell carcinomas. PeerJ 2023; 11:e15469. [PMID: 37283897 PMCID: PMC10239616 DOI: 10.7717/peerj.15469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/05/2023] [Indexed: 06/08/2023] Open
Abstract
Background Early diagnosis and treatment can improve the survival rates of patients with laryngeal squamous cell carcinoma (LSCC). Therefore, it is necessary to discover new biomarkers for laryngeal cancer screening and early diagnosis. Methods We collected fasting plasma from LSCC patients and healthy volunteers, as well as cancer and para-carcinoma tissues from LSCC patients, and performed quantitative detection of amino acid levels using liquid chromatography-mass spectrometry. We used overall analysis and multivariate statistical analysis to screen out the statistically significant differential amino acids in the plasma and tissue samples, conducted receiver operating characteristic (ROC) analysis of the differential amino acids to evaluate the sensitivity and specificity of the differential amino acids, and finally determined the diagnostic value of amino acids for laryngeal cancer. Additionally, we identified amino acids in the plasma and tissue samples that are valuable for the early diagnosis of laryngeal cancer classified according to the tumor-node-metastasis (TNM) classification. Results Asparagine (Asp) and homocysteine (Hcy) were two amino acids of common significance in plasma and tissue samples, and their specificity and sensitivity analysis showed that they may be new biomarkers for the diagnosis and treatment of LSCC. According to the TNM staging system, phenylalanine (Phe) and isoleucine (Ile) were screened out in the plasma of LSCC patients at early (I and II) and advanced (III and IV) stages; ornithine hydrochloride (Orn), glutamic acid (Glu), and Glycine (Gly) were selected in the tissue. These dysregulated amino acids found in LSCC patients may be useful as clinical biomarkers for the early diagnosis and screening of LSCC.
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Affiliation(s)
- Shousen Hu
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chang Zhao
- Department of Otorhinolaryngology, Zhengzhou Seventh People’s Hospital, Zhengzhou, China
| | - Zi’an Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Zeyun Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xiangzhen Kong
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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13
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Wu S, Wang J, Fu Z, Familiari G, Relucenti M, Aschner M, Li X, Chen H, Chen R. Matairesinol Nanoparticles Restore Chemosensitivity and Suppress Colorectal Cancer Progression in Preclinical Models: Role of Lipid Metabolism Reprogramming. NANO LETTERS 2023; 23:1970-1980. [PMID: 36802650 DOI: 10.1021/acs.nanolett.3c00035] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Oncogenic-driven lipogenic metabolism is a common hallmark of colorectal cancer (CRC) progression. Therefore, there is an urgent need to develop novel therapeutic strategies for metabolic reprogramming. Herein, the metabolic profiles in the plasma between CRC patients and paired healthy controls were compared using metabolomics assays. Matairesinol downregulation was evident in CRC patients, and matairesinol supplementation significantly represses CRC tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS) colitis-associated CRC mice. Matairesinol rewired lipid metabolism to improve the therapeutic efficacy in CRC by inducing mitochondrial damage and oxidative damage and blunting ATP production. Finally, matairesinol-loaded liposomes significantly promoted the enhanced antitumor activity of 5-Fu/leucovorin combined with oxaliplatin (FOLFOX) in CDX and PDX mouse models by restoring chemosensitivity to the FOLFOX regimen. Collectively our findings highlight matairesinol-mediated lipid metabolism reprogramming as a novel druggable strategy to restore CRC chemosensitivity, and this nanoenabled approach for matairesinol will improve the chemotherapeutic efficacy with good biosafety.
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Affiliation(s)
- Shenshen Wu
- School of Public Health, Capital Medical University, Beijing 100069, P.R. China
| | - Jiajia Wang
- School of Public Health, Capital Medical University, Beijing 100069, P.R. China
| | - Zan Fu
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P.R. China
| | - Giuseppe Familiari
- Department of Anatomical, Histological, Medical and Legal Locomotive Apparatus, Section of Human Anatomy Via Alfonso Borelli, Sapienza University of Rome, Roma 5000161, Italia
| | - Michela Relucenti
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Science, Sapienza University of Rome, Roma 5000161, Italia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, New York 10461, United States
| | - Xiaobo Li
- School of Public Health, Capital Medical University, Beijing 100069, P.R. China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, P.R. China
| | - Hanqing Chen
- Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510180, P.R. China
| | - Rui Chen
- School of Public Health, Capital Medical University, Beijing 100069, P.R. China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, P. R. China
- Beijing Laboratory of Allergic Diseases, Capital Medical University, Beijing 100069, P.R. China
- Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou 511436, P.R. China
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14
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Shen QM, Tan YT, Wang J, Fang J, Liu DK, Li HL, Xiang YB. Cross-sectional relationships between general and central adiposity and plasma amino acids in Chinese adults. Amino Acids 2023:10.1007/s00726-023-03258-5. [PMID: 36881189 DOI: 10.1007/s00726-023-03258-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 02/23/2023] [Indexed: 03/08/2023]
Abstract
Adiposity is an important determinant of blood metabolites, but little is known about the variations of blood amino acids according to general and central adiposity status among Chinese population. This study included 187 females and 322 males who were cancer-free subjects randomly selected from two cohorts in Shanghai, China. Participants' plasma concentrations of amino acids were measured by ultra-performance liquid chromatography coupled to tandem mass spectrometry. Linear regression models were used to examine the cross-sectional correlations between general and central adiposity and amino acid levels. A total of 35 amino acids in plasma were measured in this study. In females, alanine, aspartic acid and pyroglutamic acid were positively correlated with general adiposity. In males, glutamic acid, aspartic acid, valine and pyroglutamic acid showed positive correlations, and glutamine, serine and glycine showed negative correlations with both general and central adiposity; phenylalanine, isoleucine and leucine were positively correlated and N-phenylacetylglutamine was negatively correlated with general adiposity; asparagine was negatively correlated with central adiposity. In summary, general adiposity and central adiposity were correlated with the concentrations of specific plasma amino acids among cancer-free female and male adults in China. Adiposity-metabolite characteristics and relationships should be considered when studying blood biomarkers for adiposity-related health outcomes.
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Affiliation(s)
- Qiu-Ming Shen
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China
| | - Yu-Ting Tan
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China
| | - Jing Wang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China
| | - Jie Fang
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China
| | - Da-Ke Liu
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China
| | - Hong-Lan Li
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China
| | - Yong-Bing Xiang
- School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25, Lane 2200, Xie Tu Road, Shanghai, 200032, China.
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15
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Di Cesare F, Vignoli A, Luchinat C, Tenori L, Saccenti E. Exploration of Blood Metabolite Signatures of Colorectal Cancer and Polyposis through Integrated Statistical and Network Analysis. Metabolites 2023; 13:metabo13020296. [PMID: 36837915 PMCID: PMC9965766 DOI: 10.3390/metabo13020296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/07/2023] [Accepted: 02/12/2023] [Indexed: 02/19/2023] Open
Abstract
Colorectal cancer (CRC), one of the most prevalent and deadly cancers worldwide, generally evolves from adenomatous polyps. The understanding of the molecular mechanisms underlying this pathological evolution is crucial for diagnostic and prognostic purposes. Integrative systems biology approaches offer an optimal point of view to analyze CRC and patients with polyposis. The present study analyzed the association networks constructed from a publicly available array of 113 serum metabolites measured on a cohort of 234 subjects from three groups (66 CRC patients, 76 patients with polyposis, and 92 healthy controls), which concentrations were obtained via targeted liquid chromatography-tandem mass spectrometry. In terms of architecture, topology, and connectivity, the metabolite-metabolite association network of CRC patients appears to be completely different with respect to patients with polyposis and healthy controls. The most relevant nodes in the CRC network are those related to energy metabolism. Interestingly, phenylalanine, tyrosine, and tryptophan metabolism are found to be involved in both CRC and polyposis. Our results demonstrate that the characterization of metabolite-metabolite association networks is a promising and powerful tool to investigate molecular aspects of CRC.
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Affiliation(s)
- Francesca Di Cesare
- Magnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, Italy
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy
- Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (C.I.R.M.M.P.), 50019 Sesto Fiorentino, Italy
| | - Alessia Vignoli
- Magnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, Italy
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy
- Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (C.I.R.M.M.P.), 50019 Sesto Fiorentino, Italy
| | - Claudio Luchinat
- Magnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, Italy
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy
- Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (C.I.R.M.M.P.), 50019 Sesto Fiorentino, Italy
| | - Leonardo Tenori
- Magnetic Resonance Center (CERM), University of Florence, 50019 Sesto Fiorentino, Italy
- Department of Chemistry “Ugo Schiff”, University of Florence, 50019 Sesto Fiorentino, Italy
- Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (C.I.R.M.M.P.), 50019 Sesto Fiorentino, Italy
- Correspondence: (L.T.); (E.S.)
| | - Edoardo Saccenti
- Laboratory of Systems and Synthetic Biology, Wageningen University & Research, 6708 WE Wageningen, The Netherlands
- Correspondence: (L.T.); (E.S.)
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16
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Costantini S, Di Gennaro E, Capone F, De Stefano A, Nasti G, Vitagliano C, Setola SV, Tatangelo F, Delrio P, Izzo F, Avallone A, Budillon A. Plasma metabolomics, lipidomics and cytokinomics profiling predict disease recurrence in metastatic colorectal cancer patients undergoing liver resection. Front Oncol 2023; 12:1110104. [PMID: 36713567 PMCID: PMC9875807 DOI: 10.3389/fonc.2022.1110104] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/22/2022] [Indexed: 01/13/2023] Open
Abstract
Purpose In metastatic colorectal cancer (mCRC) patients (pts), treatment strategies integrating liver resection with induction chemotherapy offer better 5-year survival rates than chemotherapy alone. However, liver resection is a complex and costly procedure, and recurrence occurs in almost 2/3rds of pts, suggesting the need to identify those at higher risk. The aim of this work was to evaluate whether the integration of plasma metabolomics and lipidomics combined with the multiplex analysis of a large panel of plasma cytokines can be used to predict the risk of relapse and other patient outcomes after liver surgery, beyond or in combination with clinical morphovolumetric criteria. Experimental design Peripheral blood metabolomics and lipidomics were performed by 600 MHz NMR spectroscopy on plasma from 30 unresectable mCRC pts treated with bevacizumab plus oxaliplatin-based regimens within the Obelics trial (NCT01718873) and subdivided into responder (R) and non-R (NR) according to 1-year disease-free survival (DFS): ≥ 1-year (R, n = 12) and < 1-year (NR, n = 18). A large panel of cytokines, chemokines, and growth factors was evaluated on the same plasma using Luminex xMAP-based multiplex bead-based immunoassay technology. A multiple biomarkers model was built using a support vector machine (SVM) classifier. Results Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing metabolomics profiles of samples collected at the time of response evaluation when resectability was established showed significantly different levels of metabolites between the two groups. Two metabolites, 3-hydroxybutyrate and histidine, significantly predicted DFS and overall survival. Lipidomics analysis confirmed clear differences between the R and NR pts, indicating a statistically significant increase in lipids (cholesterol, triglycerides and phospholipids) in NR pts, reflecting a nonspecific inflammatory response. Indeed, a significant increase in proinflammatory cytokines was demonstrated in NR pts plasma. Finally, a multiple biomarkers model based on the combination of presurgery plasma levels of 3-hydroxybutyrate, cholesterol, phospholipids, triglycerides and IL-6 was able to correctly classify patients by their DFS with good accuracy. Conclusion Overall, this exploratory study suggests the potential of these combined biomarker approaches to predict outcomes in mCRC patients who are candidates for liver metastasis resection after induction treatment for defining personalized management and treatment strategies.
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Affiliation(s)
- Susan Costantini
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Francesca Capone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Alfonso De Stefano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Guglielmo Nasti
- Innovative Therapy for Abdominal Metastases Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Carlo Vitagliano
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Sergio Venanzio Setola
- Radiology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Fabiana Tatangelo
- Pathology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Paolo Delrio
- Colorectal Oncological Surgery Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Francesco Izzo
- Hepatobiliary Surgery Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy,*Correspondence: Alfredo Budillon,
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Singh P, Yadav R, Verma M, Chhabra R. Antileukemic Activity of hsa-miR-203a-5p by Limiting Glutathione Metabolism in Imatinib-Resistant K562 Cells. Curr Issues Mol Biol 2022; 44:6428-6438. [PMID: 36547099 PMCID: PMC9777165 DOI: 10.3390/cimb44120438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Imatinib has been the first and most successful tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML), but many patients develop resistance to it after a satisfactory response. Glutathione (GSH) metabolism is thought to be one of the factors causing the emergence of imatinib resistance. Since hsa-miR-203a-5p was found to downregulate Bcr-Abl1 oncogene and also a link between this oncogene and GSH metabolism is reported, the present study aimed to investigate whether hsa-miR-203a-5p could overcome imatinib resistance by targeting GSH metabolism in imatinib-resistant CML cells. After the development of imatinib-resistant K562 (IR-K562) cells by gradually exposing K562 (C) cells to increasing doses of imatinib, resistant cells were transfected with hsa-miR-203a-5p (R+203). Thereafter, cell lysates from various K562 cell sets (imatinib-sensitive, imatinib-resistant, and miR-transfected imatinib-resistant K562 cells) were used for GC-MS-based metabolic profiling. L-alanine, 5-oxoproline (also known as pyroglutamic acid), L-glutamic acid, glycine, and phosphoric acid (Pi)-five metabolites from our data, matched with the enumerated 28 metabolites of the MetaboAnalyst 5.0 for the GSH metabolism. All of these metabolites were present in higher concentrations in IR-K562 cells, but intriguingly, they were all reduced in R+203 and equated to imatinib-sensitive K562 cells (C). Concludingly, the identified metabolites associated with GSH metabolism could be used as diagnostic markers.
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Affiliation(s)
- Priyanka Singh
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda 151401, India
| | - Radheshyam Yadav
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda 151401, India
| | - Malkhey Verma
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda 151401, India
- School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi 221005, India
- Correspondence: or (M.V.); or (R.C.); Tel.: +91-7589489833 (M.V.); +91-9478723446 (R.C.)
| | - Ravindresh Chhabra
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda 151401, India
- Correspondence: or (M.V.); or (R.C.); Tel.: +91-7589489833 (M.V.); +91-9478723446 (R.C.)
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18
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Savva KV, Das B, Antonowicz S, Hanna GB, Peters CJ. Progress with Metabolomic Blood Tests for Gastrointestinal Cancer Diagnosis-An Assessment of Biomarker Translation. Cancer Epidemiol Biomarkers Prev 2022; 31:2095-2105. [PMID: 36215181 DOI: 10.1158/1055-9965.epi-22-0307] [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: 03/28/2022] [Revised: 06/27/2022] [Accepted: 09/30/2022] [Indexed: 12/30/2022] Open
Abstract
There is an urgent need for cost-effective, non-invasive tools to detect early stages of gastrointestinal cancer (colorectal, gastric, and esophageal cancers). Despite many publications suggesting circulating metabolites acting as accurate cancer biomarkers, few have reached the clinic. In upper gastrointestinal cancer this is critically important, as there is no test to complement gold-standard endoscopic evaluation in patients with mild symptoms that do not meet referral criteria. Therefore, this study aimed to describe and solve this translational gap. Studies reporting diagnostic accuracy of metabolomic blood-based gastrointestinal cancer biomarkers from 2007 to 2020 were systematically reviewed and progress of each biomarker along the discovery-validation-adoption pathway was mapped. Successful biomarker translation was defined as a composite endpoint, including patent protection/FDA approval/recommendation in national guidelines. The review found 77 biomarker panels of gastrointestinal cancer, including 25 with an AUROC >0.9. All but one was stalled at the discovery phase, 9.09% were patented and none were clinically approved, confirming the extent of biomarker translational gap. In addition, there were numerous "re-discoveries," including histidine, discovered in 7 colorectal studies. Finally, this study quantitatively supports the presence of a translational gap between discovery and clinical adoption, despite clear evidence of highly performing biomarkers with significant potential clinical value.
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Affiliation(s)
- Katerina-Vanessa Savva
- Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London, United Kingdom
| | - Bibek Das
- Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London, United Kingdom
| | - Stefan Antonowicz
- Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London, United Kingdom
| | - George B Hanna
- Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London, United Kingdom
| | - Christopher J Peters
- Department of Surgery and Cancer, Imperial College London, St. Mary's Hospital, London, United Kingdom
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19
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Imajo M, Norikane T, Yamamoto Y, Maeda Y, Saitoh K, Kato K, Soga T, Okano K, Nishiyama Y. Relationship between [ 18F]FDG PET/CT and metabolomics in patients with colorectal cancer. Metabolomics 2022; 18:91. [PMID: 36367606 PMCID: PMC9652241 DOI: 10.1007/s11306-022-01952-1] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 10/30/2022] [Indexed: 11/13/2022]
Abstract
INTRODUCTION Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis. OBJECTIVES To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC). METHODS The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors. RESULTS The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor. CONCLUSIONS Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.
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Affiliation(s)
- Masashi Imajo
- Department of Radiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan
| | - Takashi Norikane
- Department of Radiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan
| | - Yuka Yamamoto
- Department of Radiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan.
| | - Yukito Maeda
- Department of Clinical Radiology, Kagawa University Hospital, Miki-Cho, Kagawa, Japan
| | - Kaori Saitoh
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Keiko Kato
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-Cho, Kagawa, Japan
| | - Yoshihiro Nishiyama
- Department of Radiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan
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20
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Gao R, Wu C, Zhu Y, Kong C, Zhu Y, Gao Y, Zhang X, Yang R, Zhong H, Xiong X, Chen C, Xu Q, Qin H. Integrated Analysis of Colorectal Cancer Reveals Cross-Cohort Gut Microbial Signatures and Associated Serum Metabolites. Gastroenterology 2022; 163:1024-1037.e9. [PMID: 35788345 DOI: 10.1053/j.gastro.2022.06.069] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 06/19/2022] [Accepted: 06/27/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Studies have reported abnormal gut microbiota or circulating metabolome associated with colorectal cancer (CRC), but it remains a challenge to capture the CRC-relevant features consistent across geographic regions. This is particularly the problem for metabolic traits of CRC because the analyses generally use different platforms and laboratory methods, which poses a barrier to cross-dataset examination. In light of this, we sought to elucidate the microbial and metabolic signatures of CRC with broad population relevance. METHODS In this integrated metagenomic (healthy controls [HC], n = 91; colorectal adenoma [CRA], n = 63; CRC, n = 71) and metabolomic (HC, n = 34; CRA, n = 31; CRC, n = 35) analysis, CRC-associated features and microbe-metabolite correlations were first identified from a Shanghai cohort. A gut microbial panel was trained in the in-house cohort and cross-validated in 7 published metagenomic datasets of CRC. The in-house metabolic connections to the cross-cohort microbial signatures were used as evidence to infer serum metabolites with potentially external relevance. In addition, a combined microbe-metabolite panel was produced for diagnosing CRC or adenoma. RESULTS CRC-associated alterations were identified in the gut microbiome and serum metabolome. A composite microbe-metabolite diagnostic panel was developed and yielded an area under the curve of 0.912 for adenoma and 0.994 for CRC. We showed that many CRC-associated metabolites were linked to cross-cohort gut microbiome signatures of the disease, including CRC-enriched leucylalanine, serotonin, and imidazole propionate; and CRC-depleted perfluorooctane sulfonate, 2-linoleoylglycerol (18:2), and sphingadienine. CONCLUSIONS We generated cross-cohort metagenomic signatures of CRC, some of which linked to in-house CRC-associated serum metabolites. The microbial and metabolic shifts may have wide population relevance.
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Affiliation(s)
- Renyuan Gao
- Diagnostic and Treatment Center for Refractory Diseases of Abdomen Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Chunyan Wu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China; Realbio Genomics Institute, Shanghai, China
| | - Yefei Zhu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Cheng Kong
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yin Zhu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yaohui Gao
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Xiaohui Zhang
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Rong Yang
- Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hui Zhong
- Department of Pediatrics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiao Xiong
- Realbio Genomics Institute, Shanghai, China
| | - Chunqiu Chen
- Diagnostic and Treatment Center for Refractory Diseases of Abdomen Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qian Xu
- Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China
| | - Huanlong Qin
- Diagnostic and Treatment Center for Refractory Diseases of Abdomen Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Institute for Intestinal Diseases, Tongji University School of Medicine, Shanghai, China; Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
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21
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Kuwabara H, Katsumata K, Iwabuchi A, Udo R, Tago T, Kasahara K, Mazaki J, Enomoto M, Ishizaki T, Soya R, Kaneko M, Ota S, Enomoto A, Soga T, Tomita M, Sunamura M, Tsuchida A, Sugimoto M, Nagakawa Y. Salivary metabolomics with machine learning for colorectal cancer detection. Cancer Sci 2022; 113:3234-3243. [PMID: 35754317 PMCID: PMC9459332 DOI: 10.1111/cas.15472] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 11/29/2022] Open
Abstract
As the worldwide prevalence of colorectal cancer (CRC) increases, it is vital to reduce its morbidity and mortality through early detection. Saliva‐based tests are an ideal noninvasive tool for CRC detection. Here, we explored and validated salivary biomarkers to distinguish patients with CRC from those with adenoma (AD) and healthy controls (HC). Saliva samples were collected from patients with CRC, AD, and HC. Untargeted salivary hydrophilic metabolite profiling was conducted using capillary electrophoresis–mass spectrometry and liquid chromatography–mass spectrometry. An alternative decision tree (ADTree)‐based machine learning (ML) method was used to assess the discrimination abilities of the quantified metabolites. A total of 2602 unstimulated saliva samples were collected from subjects with CRC (n = 235), AD (n = 50), and HC (n = 2317). Data were randomly divided into training (n = 1301) and validation datasets (n = 1301). The clustering analysis showed a clear consistency of aberrant metabolites between the two groups. The ADTree model was optimized through cross‐validation (CV) using the training dataset, and the developed model was validated using the validation dataset. The model discriminating CRC + AD from HC showed area under the receiver‐operating characteristic curves (AUC) of 0.860 (95% confidence interval [CI]: 0.828‐0.891) for CV and 0.870 (95% CI: 0.837‐0.903) for the validation dataset. The other model discriminating CRC from AD + HC showed an AUC of 0.879 (95% CI: 0.851‐0.907) and 0.870 (95% CI: 0.838‐0.902), respectively. Salivary metabolomics combined with ML demonstrated high accuracy and versatility in detecting CRC.
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Affiliation(s)
- Hiroshi Kuwabara
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kenji Katsumata
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Atsuhiro Iwabuchi
- Center for Health Surveillance and Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan
| | - Ryutaro Udo
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Tomoya Tago
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Kenta Kasahara
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Junichi Mazaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Masanobu Enomoto
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Tetsuo Ishizaki
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Ryoko Soya
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Miku Kaneko
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Sana Ota
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Ayame Enomoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Masaru Tomita
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan
| | - Makoto Sunamura
- Digestive Surgery and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
| | - Akihiko Tsuchida
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Masahiro Sugimoto
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.,Research and Development Center for Minimally Invasive Therapies Health Promotion and Preemptive Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
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22
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Luu HN, Paragomi P, Wang R, Huang JY, Adams-Haduch J, Midttun Ø, Ulvik A, Nguyen TC, Brand RE, Gao Y, Ueland PM, Yuan JM. The Association between Serum Serine and Glycine and Related-Metabolites with Pancreatic Cancer in a Prospective Cohort Study. Cancers (Basel) 2022; 14:2199. [PMID: 35565328 PMCID: PMC9105477 DOI: 10.3390/cancers14092199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 12/24/2022] Open
Abstract
Background. Serine and glycine play an important role in the folate-dependent one-carbon metabolism. The metabolism of serine and glycine has been shown to be associated with cancer cell proliferation. No prior epidemiologic study has investigated the associations for serum levels of serine and glycine with pancreatic cancer risk. Methods. We conducted a nested case-control study involved 129 incident pancreatic cancer cases and 258 individually matched controls within a prospective cohort study of 18,244 male residents in Shanghai, China. Glycine and serine and related metabolites in pre-diagnostic serum were quantified using gas chromatography-tandem mass spectrometry. A conditional logistic regression method was used to evaluate the associations for serine, glycine, and related metabolites with pancreatic cancer risk with adjustment for potential confounders. Results: Odds ratios (95% confidence intervals) of pancreatic cancer for the highest quartile of serine and glycine were 0.33 (0.14−0.75) and 0.25 (0.11−0.58), respectively, compared with their respective lowest quartiles (both p’s < 0.01). No significant association with risk of pancreatic cancer was observed for other serine- or glycine related metabolites including cystathionine, cysteine, and sarcosine. Conclusion. The risk of pancreatic cancer was reduced by more than 70% in individuals with elevated levels of glycine and serine in serum collected, on average, more than 10 years prior to cancer diagnosis in a prospectively designed case-control study. These novel findings support a protective role of serine and glycine against the development of pancreatic cancer in humans that might have an implication for cancer prevention.
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Affiliation(s)
- Hung N. Luu
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
- Department of Epidemiology, School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA 15261, USA
| | - Pedram Paragomi
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
| | - Renwei Wang
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
| | - Joyce Y. Huang
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
- Department of Epidemiology, School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA 15261, USA
| | - Jennifer Adams-Haduch
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
| | - Øivind Midttun
- Bevital A/S, Jonas Lies Veg 87, 5021 Bergen, Norway; (Ø.M.); (P.M.U.)
| | - Arve Ulvik
- Department of Clinical Science, University of Bergen, Postboks 7804, 5020 Bergen, Norway;
| | - Tin C. Nguyen
- Department of Computer Science and Engineering, University of Nevada at Reno, Reno, NV 89557, USA;
| | - Randall E. Brand
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Yutang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201112, China;
| | - Per Magne Ueland
- Bevital A/S, Jonas Lies Veg 87, 5021 Bergen, Norway; (Ø.M.); (P.M.U.)
- Laboratory of Clinical Biochemistry, Haukeland University Hospital, 5021 Bergen, Norway
| | - Jian-Min Yuan
- UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, 5150 Centre Avenue, Suite 4C, Pittsburgh, PA 15232, USA; (P.P.); (R.W.); (J.Y.H.); (J.A.-H.); (R.E.B.); (J.-M.Y.)
- Department of Epidemiology, School of Public Health, University of Pittsburgh, 130 De Soto St, Pittsburgh, PA 15261, USA
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23
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Zhu C, Huang F, Li Y, Zhu C, Zhou K, Xie H, Xia L, Xie G. Distinct Urinary Metabolic Biomarkers of Human Colorectal Cancer. DISEASE MARKERS 2022; 2022:1758113. [PMID: 35521635 PMCID: PMC9064491 DOI: 10.1155/2022/1758113] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 02/26/2022] [Accepted: 03/08/2022] [Indexed: 11/30/2022]
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with high mortality rate due to its poor diagnosis in the early stage. Here, we report a urinary metabolomic study on a cohort of CRC patients (n =67) and healthy controls (n =21) using ultraperformance liquid chromatography triple quadrupole mass spectrometry. Pathway analysis showed that a series of pathways that belong to amino acid metabolism, carbohydrate metabolism, and lipid metabolism were dysregulated, for instance the glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, glycolysis, and TCA cycle. A total of 48 differential metabolites were identified in CRC compared to controls. A panel of 12 biomarkers composed of chenodeoxycholic acid, vanillic acid, adenosine monophosphate, glycolic acid, histidine, azelaic acid, hydroxypropionic acid, glycine, 3,4-dihydroxymandelic acid, 4-hydroxybenzoic acid, oxoglutaric acid, and homocitrulline were identified by Random Forest (RF), Support Vector Machine (SVM), and Boruta analysis classification model and validated by Gradient Boosting (GB), Logistic Regression (LR), and Random Forest diagnostic model, which were able to discriminate CRC subjects from healthy controls. These urinary metabolic biomarkers provided a novel and promising molecular approach for the early diagnosis of CRC.
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Affiliation(s)
- Chang Zhu
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
- Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
| | - Fengjie Huang
- Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
| | - Yang Li
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
- Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
| | - Chaowei Zhu
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
- Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
| | - Kejun Zhou
- Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
| | - Haihui Xie
- Department of Gynaecology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
| | - Ligang Xia
- Department of Gastrointestinal Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
- Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020 Guangdong, China
| | - Guoxiang Xie
- Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
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24
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Li Z, Deng X, Luo J, Lei Y, Jin X, Zhu J, Lv G. Metabolomic Comparison of Patients With Colorectal Cancer at Different Anticancer Treatment Stages. Front Oncol 2022; 11:574318. [PMID: 35186705 PMCID: PMC8855116 DOI: 10.3389/fonc.2021.574318] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 11/05/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The difficulties of early diagnosis of colorectal cancer (CRC) result in a high mortality rate. The ability to predict the response of a patient to surgical resection or chemotherapy may be of great value for clinicians when planning CRC treatments. Metabolomics is an emerging tool for biomarker discovery in cancer research. Previous reports have indicated that the metabolic profile of individuals can be significantly altered between CRC patients and healthy controls. However, metabolic changes in CRC patients at different treatment stages have not been explored. METHODS To this end, we performed nuclear magnetic resonance (NMR)-based metabolomic analysis to determine metabolite aberrations in CRC patients before and after surgical resection or chemotherapy. In general, a total of 106 urine samples from four clinical groups, namely, healthy volunteers (n = 31), presurgery CRC patients (n = 25), postsurgery CRC patients (n = 25), and postchemotherapy CRC patients (n = 25), were collected and subjected to further analysis. RESULTS In the present study, we identified five candidate metabolites, namely, N-phenylacetylglycine, succinate, 4-hydroxyphenylacetate, acetate, and arabinose, in CRC patients compared with healthy individuals, three of which were reported for the first time. Furthermore, approximately ten metabolites were uniquely identified at each stage of CRC treatment, serving as good candidates for biomarker panel selection. CONCLUSION In summary, these potential metabolite candidates may provide promising early diagnostic and monitoring approaches for CRC patients at different anticancer treatment stages.
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Affiliation(s)
| | | | | | | | | | | | - Guoqing Lv
- Department of Gastroinerstinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China
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25
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Atila A, Alay H, Yaman ME, Akman TC, Cadirci E, Bayrak B, Celik S, Atila NE, Yaganoglu AM, Kadioglu Y, Halıcı Z, Parlak E, Bayraktutan Z. The serum amino acid profile in COVID-19. Amino Acids 2021; 53:1569-1588. [PMID: 34605988 PMCID: PMC8487804 DOI: 10.1007/s00726-021-03081-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023]
Abstract
The pandemic of the coronavirus disease (COVID-19) caused by SARS-CoV-2 affects millions of people worldwide. There are still many unknown aspects to this infection which affects the whole world. In addition, the potential impacts caused by this infection are still unclear. Amino acid metabolism, in particular, contains significant clues in terms of the development and prevention of many diseases. Therefore, this study aimed to compare amino acid profile of COVID-19 and healthy subject. In this study, the amino acid profiles of patients with asymptomatic, mild, moderate, and severe/critical SARS-CoV-2 infection were scanned with LC–MS/MS. The amino acid profile encompassing 30 amino acids in 142 people including 30 control and 112 COVID-19 patients was examined. 20 amino acids showed significant differences when compared to the control group in COVID-19 patient groups with different levels of severity in the statistical analyses conducted. It was detected that the branched-chain amino acids (BCAAs) changed in correlation with one another, and l-2-aminobutyric acid and l-phenylalanine had biomarker potential for COVID-19. Moreover, it was concluded that l-2-aminobutyric acid could provide prognostic information about the course of the disease. We believe that a new viewpoint will develop regarding the diagnosis, treatment, and prognosis as a result of the evaluation of the serum amino acid profiles of COVID-19 patients. Determining l-phenylalanine and l-2-aminobutyric levels can be used in laboratories as a COVID-19-biomarker. Also, supplementing COVID patients with taurine and BCAAs can be beneficial for treatment protocols.
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Affiliation(s)
- Alptug Atila
- Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, 25240 Erzurum, Turkey
| | - Handan Alay
- Department of Infectious Diseases and Clinical Microbiology, Ataturk University Faculty of Medicine, 25240 Erzurum, Turkey
| | - Mehmet Emrah Yaman
- Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, 25240 Erzurum, Turkey
| | - Tugrul Cagri Akman
- Department of Analytical Chemistry, Faculty of Pharmacy, Erzincan Binali Yildirim University, 25240 Erzurum, Turkey
| | - Elif Cadirci
- Department of Pharmacology, Ataturk University Faculty of Medicine, 25240 Erzurum, Turkey
| | - Burak Bayrak
- Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, 25240 Erzurum, Turkey
| | - Saffet Celik
- Technology Research and Development Application and Research Center, Trakya University, 22030 Edirne, Turkey
| | - Nihal Efe Atila
- Department of Otorhinolaryngology, Erzurum Regional Training and Research Hospital, 25240 Erzurum, Turkey
| | - Aycan Mutlu Yaganoglu
- Department of Animal Science, College of Agriculture, Ataturk University, 25240 Erzurum, Turkey
| | - Yucel Kadioglu
- Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, 25240 Erzurum, Turkey
| | - Zekai Halıcı
- Department of Pharmacology, Ataturk University Faculty of Medicine, 25240 Erzurum, Turkey
| | - Emine Parlak
- Department of Infectious Diseases and Clinical Microbiology, Ataturk University Faculty of Medicine, 25240 Erzurum, Turkey
| | - Zafer Bayraktutan
- Department of Biochemistry, Ataturk University Faculty of Medicine, 25240 Erzurum, Turkey
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26
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Jhanji M, Rao CN, Sajish M. Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation. GeroScience 2021; 43:1171-1200. [PMID: 33244652 PMCID: PMC7690980 DOI: 10.1007/s11357-020-00295-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023] Open
Abstract
Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADP-ribose polymerase 1 (PARP1), a major determinant of cellular NAD+-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the auto-poly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1-mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention.
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Affiliation(s)
- Megha Jhanji
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Chintada Nageswara Rao
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA
| | - Mathew Sajish
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
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27
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Fu J, Zhang Y, Liu J, Lian X, Tang J, Zhu F. Pharmacometabonomics: data processing and statistical analysis. Brief Bioinform 2021; 22:6236068. [PMID: 33866355 DOI: 10.1093/bib/bbab138] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/09/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
Individual variations in drug efficacy, side effects and adverse drug reactions are still challenging that cannot be ignored in drug research and development. The aim of pharmacometabonomics is to better understand the pharmacokinetic properties of drugs and monitor the drug effects on specific metabolic pathways. Here, we systematically reviewed the recent technological advances in pharmacometabonomics for better understanding the pathophysiological mechanisms of diseases as well as the metabolic effects of drugs on bodies. First, the advantages and disadvantages of all mainstream analytical techniques were compared. Second, many data processing strategies including filtering, missing value imputation, quality control-based correction, transformation, normalization together with the methods implemented in each step were discussed. Third, various feature selection and feature extraction algorithms commonly applied in pharmacometabonomics were described. Finally, the databases that facilitate current pharmacometabonomics were collected and discussed. All in all, this review provided guidance for researchers engaged in pharmacometabonomics and metabolomics, and it would promote the wide application of metabolomics in drug research and personalized medicine.
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Affiliation(s)
- Jianbo Fu
- College of Pharmaceutical Sciences in Zhejiang University, China
| | - Ying Zhang
- College of Pharmaceutical Sciences in Zhejiang University, China
| | - Jin Liu
- College of Pharmaceutical Sciences in Zhejiang University, China
| | - Xichen Lian
- College of Pharmaceutical Sciences in Zhejiang University, China
| | - Jing Tang
- Department of Bioinformatics in Chongqing Medical University, China
| | - Feng Zhu
- College of Pharmaceutical Sciences in Zhejiang University, China
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Horala A, Plewa S, Derezinski P, Klupczynska A, Matysiak J, Nowak-Markwitz E, Kokot ZJ. Serum Free Amino Acid Profiling in Differential Diagnosis of Ovarian Tumors-A Comparative Study with Review of the Literature. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18042167. [PMID: 33672144 PMCID: PMC7926859 DOI: 10.3390/ijerph18042167] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/11/2021] [Accepted: 02/16/2021] [Indexed: 12/21/2022]
Abstract
Proper preoperative ovarian cancer (OC) diagnosis remains challenging. Serum free amino acid (SFAA) profiles were investigated to identify potential novel biomarkers of OC and assess their performance in ovarian tumor differential diagnosis. Serum samples were divided based on the histopathological result: epithelial OC (n = 38), borderline ovarian tumors (n = 6), and benign ovarian tumors (BOTs) (n = 62). SFAA profiles were evaluated using aTRAQ methodology based on high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Levels of eleven amino acids significantly differed between OC+borderline and BOTs. The highest area under the receiver operating characteristic curve (AUC of ROC) (0.787) was obtained for histidine. Cystine and histidine were identified as best single markers for early stage OC/BOT and type I OC. For advanced stage OC, seven amino acids differed significantly between the groups and citrulline obtained the best AUC of 0.807. Between type II OC and BOTs, eight amino acids differed significantly and the highest AUC of 0.798 was achieved by histidine and citrulline (AUC of 0.778). Histidine was identified as a potential new biomarker in differential diagnosis of ovarian tumors. Adding histidine to a multimarker panel together with CA125 and HE4 improved the differential diagnosis between OC and BOTs.
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Affiliation(s)
- Agnieszka Horala
- Gynecologic Oncology Department, Poznan University of Medical Sciences, Polna 33 Street, 60-535 Poznan, Poland;
- Correspondence:
| | - Szymon Plewa
- Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland; (S.P.); (P.D.); (A.K.); (J.M.)
| | - Pawel Derezinski
- Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland; (S.P.); (P.D.); (A.K.); (J.M.)
| | - Agnieszka Klupczynska
- Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland; (S.P.); (P.D.); (A.K.); (J.M.)
| | - Jan Matysiak
- Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland; (S.P.); (P.D.); (A.K.); (J.M.)
| | - Ewa Nowak-Markwitz
- Gynecologic Oncology Department, Poznan University of Medical Sciences, Polna 33 Street, 60-535 Poznan, Poland;
| | - Zenon J. Kokot
- Faculty of Health Sciences, Calisia University, 13 Kaszubska Street, 62-800 Kalisz, Poland;
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29
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Fan M, Gao X, Li L, Ren Z, Lui LMW, McIntyre RS, Teopiz KM, Deng P, Cao B. The Association Between Concentrations of Arginine, Ornithine, Citrulline and Major Depressive Disorder: A Meta-Analysis. Front Psychiatry 2021; 12:686973. [PMID: 34867503 PMCID: PMC8636832 DOI: 10.3389/fpsyt.2021.686973] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 10/19/2021] [Indexed: 11/29/2022] Open
Abstract
Alterations in the peripheral (e.g., serum, plasma, platelet) concentrations of arginine and its related catabolic products (i.e., ornithine, citrulline) in the urea and nitric oxide cycles have been reported to be associated with major depressive disorder (MDD). The meta-analysis herein aimed to explore the association between the concentration of peripheral arginine, its catabolic products and MDD, as well as to discuss the possible role of arginine catabolism in the onset and progression of MDD. PubMed, EMBASE, PsycINFO and Web of Science were searched from inception to June 2020. The protocol for the meta-analysis herein has been registered at the Open Science Framework [https://doi.org/10.17605/osf.io/7fn59]. In total, 745 (47.5%) subjects with MDD and 823 (52.5%) healthy controls (HCs) from 13 articles with 16 studies were included. Fifteen of the included studies assessed concentrations of peripheral arginine, eight assessed concentrations of ornithine, and six assessed concentrations of citrulline. Results indicated that: (1) the concentrations of arginine, ornithine, and citrulline were not significantly different between individuals with MDD and HCs when serum, plasma and platelet are analyzed together, (2) in the subgroups of serum samples, the concentrations of arginine were lower in individuals with MDD than HCs, and (3) concurrent administration of psychotropic medications may be a confounding variable affecting the concentrations of arginine, ornithine, and citrulline. Our findings herein do not support the hypothesis that arginine catabolism between individuals with MDD and HCs are significantly different. The medication status and sample types should be considered as a key future research avenue for assessing arginine catabolism in MDD.
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Affiliation(s)
- Mingyue Fan
- Department of Public Health and Management, Chongqing Three Gorges Medical College, Chongqing, China
| | - Xiao Gao
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China.,National Demonstration Center for Experimental Psychology Education, Southwest University, Chongqing, China
| | - Li Li
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China
| | - Zhongyu Ren
- College of Physical Education, Southwest University, Chongqing, China
| | - Leanna M W Lui
- Mood Disorders Psychopharmacology Unit, Toronto, ON, Canada
| | | | - Kayla M Teopiz
- Mood Disorders Psychopharmacology Unit, Toronto, ON, Canada
| | - Peng Deng
- Yubei Center for Disease Control and Prevention, Chongqing, China
| | - Bing Cao
- Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, Southwest University, Chongqing, China.,National Demonstration Center for Experimental Psychology Education, Southwest University, Chongqing, China
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30
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Oz O, Koyuncu I, Gonel A. A Pilot Study for Investigation of Plasma Amino Acid Profile in Neurofibromatosis Type 1 Patients. Comb Chem High Throughput Screen 2020; 25:114-122. [PMID: 33280590 DOI: 10.2174/1386207323666201204143206] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 11/01/2020] [Accepted: 11/09/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Neurofibromatosis, also known as Von Recklinghausen disease, is a systemic and progressive genetic disease that primarily affects the skin, eyes, nervous system and bones. The disease can occur in a variety of ways and can vary from individuals. Metabolomic-based research using blood samples has enabled new diagnostic methods to be used in the diagnosis of various diseases, especially cancer. Among metabolites, profiling of plasma free amino acids (PFAA) is a promising approach because PFAAs bind all organ systems and play an important role in metabolism. OBJECTIVE This study aimed to determine the characteristics of PFAA profiles in neurofibromatosis patients and the possibility of using them for early detection and treatment of the disease. METHOD Patients with a diagnosis of Neurofibromatosis Type I confirmed by genetic analysis and healthy individuals of the same age group without any disease were included in the study. We analysed the nineteen plasma free amino acids (phenylalanine, proline, threonine, arginine, asparagine, cystine, valine, glutamate, tyrosine, serine, glutamine, glycine, tryptophane, leucine, lysine, methionine, isoleucine, aspartate and alanine) from neurofibromatosis Type I patients and control group by liquid chromatography tandem mass spectrometry (LC-MS/MS) in Metabolism Laboratory of Harran University Research and Application Hospital. The results of the plasma free amino acid levels were divided into 3 groups as essential, semi-essential and non-essential. The differences of amino acid levels between groups were determined. RESULTS Eight amino acid levels (methionine, arginine, cystine, glutamine, proline, asparagine, serine, aspartate) were significantly altered in patients with neurofibromatosis type 1. In essential amino acids, methionine levels were significantly higher in the patient group than the control group. While the levels of arginine and glutamine in semi-essential amino acids were statistically significantly higher in the patient group, a significant decrease was observed in cystine and proline levels compared to the control group's amino acid levels. In non-essential amino acids group, asparagine, serine and aspartate amino acid levels were significantly higher in the patient group compared to the control group. CONCLUSION The current research predicates that eight amino acids, nsmely methionine, arginine, cystine, glutamine, proline, asparagine, serine, aspartate can be considered to be valuable biomarkers for neurofibromatosis type I. This present study is the first to build models for neurofibromatosis Type I screening using plasma free amino acids and the amino acid profile will guide the predicting of the complications that may occur during the course of the disease.
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Affiliation(s)
- Ozlem Oz
- Department of Medical Genetics, Harran University. Turkey
| | - Ismail Koyuncu
- Department of Medicinal Biochemistry, Harran University. Turkey
| | - Ataman Gonel
- Department of Medicinal Biochemistry, Harran University. Turkey
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31
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Flux variability analysis reveals a tragedy of commons in cancer cells. SN APPLIED SCIENCES 2020. [DOI: 10.1007/s42452-020-03762-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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32
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The free amino acid profiles and metabolic biomarkers of predicting the chemotherapeutic response in advanced sarcoma patients. Clin Transl Oncol 2020; 22:2213-2221. [PMID: 32948983 DOI: 10.1007/s12094-020-02494-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 09/03/2020] [Indexed: 12/27/2022]
Abstract
PURPOSE Metabolomics is an emerging field in cancer research. Plasma free amino acid profiles (PFAAs) have shown different features in various cancers, but the characteristic in advanced sarcoma remains unclear. We aimed to uncover the specific PFAAs in advanced sarcoma and to find the relationship between the altering of PFAAs and response to chemotherapy. PATIENTS AND METHODS We analyzed the differences in PFAAs between 23 sarcoma patients and 30 healthy subjects basing on liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, we compared the dynamics of PFAAs after chemotherapy between improvement group and deterioration group. RESULTS We identified seven biological differential amino acids and four pathways which were perturbed in the sarcoma patients compared with healthy subjects. After one cycle chemotherapy, the levels of γ-aminobutyric acid (GABA) and carnosine (Car) decreased significantly in the improvement group but not in deterioration group. The levels of α-aminobutyric acid (Abu) increased significantly in the deterioration group but not in the improvement group. CONCLUSION Our study suggests the potential specific PFAAs in sarcoma patients. The unusual amino acids and metabolic pathways may provide ideas for clinical drugs targeting therapy. Three amino acids including Car, GABA and Abu may be metabolic biomarkers playing a role in dynamic monitoring of the therapeutic effect.
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33
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Franco-Pereira AM, Nakas CT, Pardo MC. Biomarker assessment in ROC curve analysis using the length of the curve as an index of diagnostic accuracy: the binormal model framework. ASTA ADVANCES IN STATISTICAL ANALYSIS 2020. [DOI: 10.1007/s10182-020-00371-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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34
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Nannini G, Meoni G, Amedei A, Tenori L. Metabolomics profile in gastrointestinal cancers: Update and future perspectives. World J Gastroenterol 2020; 26:2514-2532. [PMID: 32523308 PMCID: PMC7265149 DOI: 10.3748/wjg.v26.i20.2514] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/11/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Despite recent progress in diagnosis and therapy, gastrointestinal (GI) cancers remain one of the most important causes of death with a poor prognosis due to late diagnosis. Serum tumor markers and detection of occult blood in the stool are the current tests used in the clinic of GI cancers; however, these tests are not useful as diagnostic screening since they have low specificity and low sensitivity. Considering that one of the hallmarks of cancer is dysregulated metabolism and metabolomics is an optimal approach to illustrate the metabolic mechanisms that belong to living systems, is now clear that this -omics could open a new way to study cancer. In the last years, nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for diseases' diagnosis nevertheless a few studies focus on the NMR capability to find new biomarkers for early diagnosis of GI cancers. For these reasons in this review, we will give an update on the status of NMR metabolomic studies for the diagnosis and development of GI cancers using biological fluids.
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Affiliation(s)
- Giulia Nannini
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gaia Meoni
- Giotto Biotech Srl, and CERM (University of Florence), Florence 50019, Italy
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
- SOD of Interdisciplinary Internal Medicine, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Leonardo Tenori
- Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine, Florence 50019, Italy
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35
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Yang XH, Jing Y, Wang S, Ding F, Zhang XX, Chen S, Zhang L, Hu QG, Ni YH. Integrated Non-targeted and Targeted Metabolomics Uncovers Amino Acid Markers of Oral Squamous Cell Carcinoma. Front Oncol 2020; 10:426. [PMID: 32351881 PMCID: PMC7174902 DOI: 10.3389/fonc.2020.00426] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/10/2020] [Indexed: 12/11/2022] Open
Abstract
Purpose: It is very important to develop potential molecular associated with oral squamous cell carcinoma (OSCC) malignant transformation and progression. Thus, the aim of our study was to determine the amino acid metabolic characteristics of OSCC patients and test their diagnostic value. Experimental Design: Eight pairs of matched tumor and normal samples were collected for gas chromatography–mass spectrometry (GC-MS) high-throughput untargeted analysis. Another 20 cases (each case including tumor and normal tissues) were also enrolled for ultrahigh-performance liquid chromatography–tandem mass spectrometer (UHPLC-MS/MS) amino acid quantitative analysis. T-test and receiver operating characteristic (ROC) curve analysis were used to determine candidate markers. Principal component analysis, partial least squares discriminant analysis, and heat map analysis were used to verify the ability of candidate markers to distinguish tumors from normal tissues. Results: A total of 10 amino acids biomarker were selected as OSCC candidate diagnostic biomarkers by GC-MS high-throughput untargeted metabolomics analyses [area under the curve (AUC) >0.80]. We further measured the specific concentration of these candidate amino acids biomarkers in another batch of 20 cases by UHPLC-MS/MS quantitative analysis. The result validated that nine amino acids had been detected, which had statistically significant difference (t-test, p < 0.05). Moreover, three of nine amino acid markers (glutamate, aspartic acid, and proline) displayed high sensitivity and specificity (AUC >0.90) by ROC curve analysis and obtained optimal sensitivity and specificity by binary logistic regression in the Glmnet package (AUC = 0.942). Conclusions: In conclusion, a panel including three amino acids (glutamate, aspartic acid, and proline) was identified as potential diagnostic biomarkers of OSCC by a combination of non-targeted and targeted metabolomics methods.
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Affiliation(s)
- Xi-Hu Yang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yue Jing
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Shuai Wang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feng Ding
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Xiao-Xin Zhang
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Sheng Chen
- Department of Oral Pathology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lei Zhang
- Department of Oral Pathology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Qin-Gang Hu
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yan-Hong Ni
- Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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Nizioł J, Sunner J, Beech I, Ossoliński K, Ossolińska A, Ossoliński T, Płaza A, Ruman T. Localization of Metabolites of Human Kidney Tissue with Infrared Laser-Based Selected Reaction Monitoring Mass Spectrometry Imaging and Silver-109 Nanoparticle-Based Surface Assisted Laser Desorption/Ionization Mass Spectrometry Imaging. Anal Chem 2020; 92:4251-4258. [PMID: 32083846 PMCID: PMC7497619 DOI: 10.1021/acs.analchem.9b04580] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
![]()
Infrared (IR) laser
ablation-remote-electrospray ionization (LARESI)
platform coupled to a tandem mass spectrometer (MS/MS) operated in
selected reaction monitoring (SRM) or multiple reaction monitoring
(MRM) modes was developed and employed for imaging of target metabolites
in human kidney cancer tissue. SRM or MRM modes were employed to avoid
artifacts that are present in full scan MS mode. Four tissue samples
containing both cancerous and noncancerous regions, obtained from
three patients with renal cell carcinoma (RCC), were imaged. Sixteen
endogenous metabolites that were reported in the literature as varying
in abundance between cancerous and noncancerous areas in various human
tissues were selected for analysis. Target metabolites comprised ten
amino acids, four nucleosides and nucleobases, lactate, and vitamin
E. For comparison purposes, images of the same metabolites were obtained
with ultraviolet (UV) desorption/ionization mass spectrometry imaging
(UV-LDI-MSI) using monoisotopic silver-109 nanoparticle-enhanced target
(109AgNPET) in full-scan MS mode. The acquired MS images
revealed differences in abundances of selected metabolites between
cancerous and noncancerous regions of the kidney tissue. Importantly,
the two imaging methods offered similar results. This study demonstrates
the applicability of the novel ambient LARESI SRM/MRM MSI method to
both investigating and discovering cancer biomarkers in human tissue.
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Affiliation(s)
- Joanna Nizioł
- Rzeszów University of Technology, Faculty of Chemistry, 6 Powstańców Warszawy Ave., Rzeszów, 35-959, Poland
| | - Jan Sunner
- Center for Biofilm Engineering, Montana State University, 366 Barnard Hall, Bozeman, Montana 59717-3980, United States
| | - Iwona Beech
- Center for Biofilm Engineering, Montana State University, 366 Barnard Hall, Bozeman, Montana 59717-3980, United States
| | - Krzysztof Ossoliński
- Department of Urology, John Paul II Hospital, Grunwaldzka 4 St., Kolbuszowa, 36-100, Poland
| | - Anna Ossolińska
- Department of Urology, John Paul II Hospital, Grunwaldzka 4 St., Kolbuszowa, 36-100, Poland
| | - Tadeusz Ossoliński
- Department of Urology, John Paul II Hospital, Grunwaldzka 4 St., Kolbuszowa, 36-100, Poland
| | - Aneta Płaza
- Doctoral School of Engineering and Technical Sciences at the Rzeszów University of Technology, 8 Powstańców Warszawy Ave., Rzeszów, 35-959, Poland
| | - Tomasz Ruman
- Rzeszów University of Technology, Faculty of Chemistry, 6 Powstańców Warszawy Ave., Rzeszów, 35-959, Poland
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Zhang F, Li C, Deng K, Wang Z, Zhao W, Yang K, Yang C, Rong Z, Cao L, Lu Y, Huang Y, Han P, Li K. Metabolic phenotyping to monitor chronic enteritis canceration. Metabolomics 2020; 16:29. [PMID: 32095917 DOI: 10.1007/s11306-020-1651-x] [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: 09/17/2019] [Accepted: 02/12/2020] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) remains an incurable disease. Previous metabolomic studies show that metabolic signatures in plasma distinguish CRC patients from healthy controls. Chronic enteritis (CE) represents a risk factor for CRC, with a 20 fold greater incidence than in healthy individuals. However, no studies have performed metabolomic profiling to investigate CRC biomarkers in CE. OBJECTIVE Our aims were to identify metabolomic signatures in CRC and CE and to search for blood-derived metabolite biomarkers distinguishing CRC from CE, especially early-stage biomarkers. METHODS In this case-control study, 612 subjects were prospectively recruited between May 2015 and May 2016, and including 539 CRC patients (stage I, 102 cases; stage II, 259 cases; stage III, 178 cases) and 73 CE patients. Untargeted metabolomics was performed to identify CRC-related metabolic signatures in CE. RESULTS Five pathways were significantly enriched based on 153 differential metabolites between CRC and CE. 16 biomarkers were identified for diagnosis of CRC from CE and for guiding CRC staging. The AUC value for CRC diagnosis in the external validation set was 0.85. Good diagnostic performances were also achieved for early-stage CRC (stage I and stage II), with an AUC value of 0.84. The biomarker panel could also stage CRC patients, with an AUC of 0.72 distinguishing stage I from stage II CRC and AUC of 0.74 distinguishing stage II from stage III CRC. CONCLUSIONS The identified metabolic biomarkers exhibit promising properties for CRC monitoring in CE patients and are superior to commonly used clinical biomarkers (CEA and CA19-9).
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Affiliation(s)
- Fan Zhang
- Laboratory of Hematology Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Chunbo Li
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150086, China
| | - Kui Deng
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Zhuozhong Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Weiwei Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Kai Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Chunyan Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Zhiwei Rong
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Lei Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Yaxin Lu
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Yue Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China
| | - Peng Han
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150086, China.
| | - Kang Li
- Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, 150086, China.
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Barberini L, Restivo A, Noto A, Deidda S, Fattuoni C, Fanos V, Saba L, Zorcolo L, Mussap M. A gas chromatography-mass spectrometry (GC-MS) metabolomic approach in human colorectal cancer (CRC): the emerging role of monosaccharides and amino acids. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:727. [PMID: 32042743 DOI: 10.21037/atm.2019.12.34] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Background Colorectal cancer (CRC) has been confirmed to be the third most commonly diagnosed cancer in males and the second in females. We investigated the blood plasma metabolome in CRC patients and in healthy adults to elucidate the role of monosaccharides, amino acids, and their respective metabolic pathways as prognostic factors in patients with CRC. Methods Fifteen patients with CRC and nine healthy adults were enrolled in the study and their blood plasma samples analyzed by gas chromatography-mass spectrometry (GC-MS). Univariate Student's t-test, multivariate principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA) were conducted on MetaboAnalyst 4.0. The analysis of metabolic profiles was carried out by the web-based extension Metabolite Sets Enrichment Analysis (MSEA). Results Overall, 125 metabolites were identified in plasma samples by GC-MS. In CRC patient samples, nine metabolites, including D-mannose and fructose, were significantly more abundant than in controls; conversely, eleven amino derivatives were less abundant, including methionine, valine, lysine, and proline. Methionine was significantly less abundant in died patients compared with survivors. The most significantly altered metabolic pathways in CRC patients are those involving monosaccharides (primarily the catabolic pathway of fructose and D-mannose), and amino acids (primarily methionine, valine, leucine, and isoleucine). Conclusions The abundance of D-mannose in CRC patient samples contributes to inhibiting the growth of cancer cells, while the abundance of fructose may be consistent either with low consumption of fructose by aerobic glycolysis within cancer cells or with a high bioavailability of fructose from diet. The reduction in methionine concentration may be related to increased activity of the threonine and methionine catabolic pathways, confirmed by high levels of α-hydroxybutyrate.
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Affiliation(s)
- Luigi Barberini
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Angelo Restivo
- Colorectal Surgery Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - Antonio Noto
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Simona Deidda
- Colorectal Surgery Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - Claudia Fattuoni
- Department of Chemical and Geological Sciences, University of Cagliari, Cagliari, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Neonatal Pathology and Neonatal Section, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - Luca Saba
- Colorectal Surgery Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - Luigi Zorcolo
- Department of Radiology, Azienda Ospedaliero Universitaria (AOU), Cagliari, Italy
| | - Michele Mussap
- Laboratory Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
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Oxaliplatin-Fluoropyrimidine Combination (XELOX) Therapy Does Not Affect Plasma Amino Acid Levels and Plasma Markers of Oxidative Stress in Colorectal Cancer Surgery Patients: A Pilot Study. Nutrients 2019; 11:nu11112667. [PMID: 31694176 PMCID: PMC6893861 DOI: 10.3390/nu11112667] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/25/2019] [Accepted: 10/31/2019] [Indexed: 12/31/2022] Open
Abstract
Chemotherapy for colorectal cancer may lower muscle protein synthesis and increase oxidative stress. We hypothesize that chemotherapy may worsen plasma amino acids (AAs) and markers of oxidative stress (MOS). Therefore, this study aimed to document plasma AAs and MOS before, during and after chemotherapy in colorectal cancer (CRC) surgery patients. Fourteen normal-weight CRC patients were enrolled one month after surgery and scheduled for oxaliplatin-fluoropyrimidine combination (XELOX) therapy. Venous blood samples for AA and MOS (malondialdehyde, MDA; 8-hydroxy-2’-deoxyguanosine, 8-OHdG) measurements were drawn in fasting patients before each oxaliplatin infusion at initiation (A), 1 month (B) and 3 months (C) of the therapy, and after XELOX had finished (6 months, D). The results showed that during XELOX therapy (from phase B to phase D), in comparison to baseline (phase A), the branched chain amino acid/essential amino acid ratio, branched chain amino acids expressed as a percentage of total AAs, and arginine expressed as a percentage of total AAs significantly decreased (p = 0.017, p = 0.028, p = 0.028, respectively). Plasma levels of MOS did not change significantly. This study indicates that XELOX therapy does not affect plasma AA levels or worsen oxidative stress.
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40
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Cheung PK, Ma MH, Tse HF, Yeung KF, Tsang HF, Chu MKM, Kan CM, Cho WCS, Ng LBW, Chan LWC, Wong SCC. The applications of metabolomics in the molecular diagnostics of cancer. Expert Rev Mol Diagn 2019; 19:785-793. [PMID: 31414918 DOI: 10.1080/14737159.2019.1656530] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 08/13/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Metabolomics, the study of metabolites, is a promising research field for cancers. The metabolic pathway in a tumor cell is different from a normal tissue cell. There are two approaches to study the metabolism, targeted and untargeted. The general approach is that metabolomic data are interpreted by bioinformatics tools correlating with metabolomic databases to obtain significant findings. With the use of specific analysis tools, such as nuclear magnetic resonance (NMR) and mass spectrometer (MS) combined with chromatography, metabolic profile or metabolic fingerprint of various biological specimens could be obtained. The applications of metabolomics are used to discover potential cancer biomarkers and monitor the metastatic state, therapeutic and drug response for better patient management. Areas covered: In this review, the author introduce metabolomics and discuss the use of metabolomics approaches in different cancers, including the study of colorectal cancer, prostate cancer, liver cancer, pancreatic cancer and breast cancer using NMR and MS. Expert opinion: Knowledge on the molecular basis of cancer metabolism and its potential clinical applications has been improving recently. However, there are still many challenges for the technological development and integration of metabolomics with other omics spaces such as genomics. In the near future, it is expected that metabolomics will play an important role in cancer molecular diagnostics.
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Affiliation(s)
- Pro Kit Cheung
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - Man Hin Ma
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - Hing Fung Tse
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - Ka Fai Yeung
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - Hin Fung Tsang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - Man Kee Maggie Chu
- Department of Life Science, The Hong Kong University of Science and Technology , Clear Water Bay , Hong Kong Special Administrative Region , China
| | - Chau Ming Kan
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - William Chi Shing Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital , Kowloon , Hong Kong Special Administrative Region , China
| | - Lawrence Bo Wah Ng
- Department of Pathology, Queen Elizabeth Hospital , Kowloon , Hong Kong Special Administrative Region , China
| | - Lawrence Wing Chi Chan
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
| | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon , Hong Kong Special Administrative Region , China
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Li J, Li J, Wang H, Qi LW, Zhu Y, Lai M. Tyrosine and Glutamine-Leucine Are Metabolic Markers of Early-Stage Colorectal Cancers. Gastroenterology 2019; 157:257-259.e5. [PMID: 30885779 DOI: 10.1053/j.gastro.2019.03.020] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/11/2019] [Accepted: 03/12/2019] [Indexed: 02/08/2023]
Affiliation(s)
- Jiankang Li
- State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Jing Li
- The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, Jiangsu, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Huan Wang
- State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Lian-Wen Qi
- The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, Jiangsu, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Yimin Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Maode Lai
- State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Key Laboratory of Disease Proteomics of Zhejiang Province and Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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42
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Hong JT, Kim ER. Current state and future direction of screening tool for colorectal cancer. World J Meta-Anal 2019; 7:184-208. [DOI: 10.13105/wjma.v7.i5.184] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/25/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023] Open
Abstract
As the second-most-common cause of cancer death, colorectal cancer (CRC) has been recognized as one of the biggest health concerns in advanced countries. The 5-year survival rate for patients with early-stage CRC is significantly better than that for patients with CRC detected at a late stage. The primary target for CRC screening and prevention is advanced neoplasia, which includes both CRC itself, as well as benign but histologically advanced adenomas that are at increased risk for progression to malignancy. Prevention of CRC through detection of advanced adenomas is important. It is, therefore, necessary to develop more efficient detection methods to enable earlier detection and therefore better prognosis. Although a number of CRC diagnostic methods are currently used for early detection, including stool-based tests, traditional colonoscopy, etc., they have not shown optimal results due to several limitations. Hence, development of more reliable screening methods is required in order to detect the disease at an early stage. New screening tools also need to be able to accurately diagnose CRC and advanced adenoma, help guide treatment, and predict the prognosis along with being relatively simple and non-invasive. As part of such efforts, many proposals for the early detection of colorectal neoplasms have been introduced. For example, metabolomics, referring to the scientific study of the metabolism of living organisms, has been shown to be a possible approach for discovering CRC-related biomarkers. In addition, a growing number of high-performance screening methodologies could facilitate biomarker identification. In the present, evidence-based review, the authors summarize the current state as recognized by the recent guideline recommendation from the American Cancer Society, US Preventive Services Task Force and the United States Multi-Society Task Force and discuss future direction of screening tools for colorectal cancer. Further, we highlight the most interesting publications on new screening tools, like molecular biomarkers and metabolomics, and discuss these in detail.
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Affiliation(s)
- Ji Taek Hong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24253, South Korea
| | - Eun Ran Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
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43
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The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer. Int J Mol Sci 2019; 20:ijms20102428. [PMID: 31100853 PMCID: PMC6566973 DOI: 10.3390/ijms20102428] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/10/2019] [Accepted: 05/14/2019] [Indexed: 12/11/2022] Open
Abstract
Chronic proliferation is a major hallmark of tumor cells. Rapidly proliferating cancer cells are highly dependent on nutrients in order to duplicate their cell mass during each cell division. In particular, essential amino acids are indispensable for proliferating cancer cells. Their uptake across the cell membrane is tightly controlled by membrane transporters. Among those, the L-type amino acid transporter LAT1 (SLC7A5) has been repeatedly found overexpressed in a vast variety of cancers. In this review, we summarize the most recent advances in our understanding of the role of LAT1 in cancer and highlight preclinical studies and drug developments underlying the potential of LAT1 as therapeutic target.
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44
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Sun L, Kang Q, Pan Y, Li N, Wang X, He Y, Wang H, Yu D, Xie H, Yang L, Lu Y, Jin P, Sheng J. Serum metabolite profiling of familial adenomatous polyposis using ultra performance liquid chromatography and tandem mass spectrometry. Cancer Biol Ther 2019; 20:1017-1028. [PMID: 30983515 DOI: 10.1080/15384047.2019.1595277] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited intestinal polyposis syndrome accounting for about 1% of colorectal cancers (CRC). Despite increasing researches on the molecular pathogenesis of CRC, we are still unclear about metabolic pathways and alterations probably involved in the development of CRC. To obtain new insights into the mechanisms underlying APC mutation and to elucidate the mechanisms of CRC development, we performed to identify the potential metabolites in FAP based on metabolomic strategy. Serum metabolites from FAP patients (n = 30) and healthy individuals (n = 34) were detected and qualified using Ultra Performance Liquid Chromatography and Tandem Mass Spectrometry (UPLC- MS/MS). 118 metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (OPLS-DA), with the conditions of variable importance in projection (VIP) >1, p < 0.05 using the Mann-Whitney U test, and fold change (FC) ≥2 or ≤0.5. OPLS-DA model was useful for distinguishing FAP patients from healthy controls. Unique metabolic signatures were pooled in FAP patients covering tricarboxylic acid (TCA) cycle, amino acids metabolism, vitamin D, fatty acids metabolism, and bile acids (BAs) metabolism. Our results demonstrated that metabolites alterations in FAP can be helpful for further analysis of metabonomics induced by APC mutation, and these alterations might be involved in the progress of intestinal carcinogenesis.
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Affiliation(s)
- Liyan Sun
- a Medical School of Chinese PLA , Chinese PLA General Hospital , Beijing , China
| | - Qian Kang
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Yuanming Pan
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Na Li
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Xin Wang
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Yuqi He
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Haihong Wang
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Dongliang Yu
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Hui Xie
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Lang Yang
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Youyong Lu
- c Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing Cancer Hospital/Institute, School of Oncology , Peking University , Beijing , China
| | - Peng Jin
- b Department of Gastroenterology , The Seventh Medical Center of Chinese PLA General Hospital , Beijing , China
| | - Jianqiu Sheng
- a Medical School of Chinese PLA , Chinese PLA General Hospital , Beijing , China
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45
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Kartsova LA, Solov’eva SA. Application of Chromatographic and Electrophoretic Techniques to Metabolomic Studies. JOURNAL OF ANALYTICAL CHEMISTRY 2019. [DOI: 10.1134/s1061934819040051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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46
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Wang Z, Cui B, Zhang F, Yang Y, Shen X, Li Z, Zhao W, Zhang Y, Deng K, Rong Z, Yang K, Yu X, Li K, Han P, Zhu ZJ. Development of a Correlative Strategy To Discover Colorectal Tumor Tissue Derived Metabolite Biomarkers in Plasma Using Untargeted Metabolomics. Anal Chem 2018; 91:2401-2408. [DOI: 10.1021/acs.analchem.8b05177] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Zhuozhong Wang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.R. China
| | | | | | | | - Xiaotao Shen
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.R. China
- University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | | | | | | | | | | | | | | | | | | | - Zheng-Jiang Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P.R. China
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47
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Sirniö P, Väyrynen JP, Klintrup K, Mäkelä J, Karhu T, Herzig KH, Minkkinen I, Mäkinen MJ, Karttunen TJ, Tuomisto A. Alterations in serum amino-acid profile in the progression of colorectal cancer: associations with systemic inflammation, tumour stage and patient survival. Br J Cancer 2018; 120:238-246. [PMID: 30563990 PMCID: PMC6342921 DOI: 10.1038/s41416-018-0357-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 11/15/2018] [Accepted: 11/22/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Cancer cachexia is a complex wasting syndrome affecting patients with advanced cancer, with systemic inflammation as a key component in pathogenesis. Protein degradation and release of amino acids (AAs) in skeletal muscle are stimulated in cachexia. Here, we define factors contributing to serum AA levels in colorectal cancer (CRC). METHODS Serum levels of nine AAs were characterised in 336 CRC patients and their relationships with 20 markers of systemic inflammatory reaction, clinicopathological features of cancers and patient survival were analysed. RESULTS Low serum glutamine and histidine levels and high phenylalanine levels associated with indicators of systemic inflammation, including high modified Glasgow Prognostic Score, high blood neutrophil/lymphocyte ratio and high serum levels of CRP, IL-6 and IL-8. Low levels of serum glutamine, histidine, alanine and high glycine levels also associated with advanced cancer stage and with poor cancer-specific survival in univariate analysis. CONCLUSIONS In CRC, serum AA levels are associated with systemic inflammation and disease stage. These findings may reflect muscle catabolism induced by systemic inflammation in CRC.
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Affiliation(s)
- Päivi Sirniö
- Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland.,Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland
| | - Juha P Väyrynen
- Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland.,Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland
| | - Kai Klintrup
- Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland.,Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, POB 5000, 90014, Oulu, Finland
| | - Jyrki Mäkelä
- Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland.,Research Unit of Surgery, Anesthesia and Intensive Care, University of Oulu, POB 5000, 90014, Oulu, Finland
| | - Toni Karhu
- Department of Physiology, Research Unit of Biomedicine and Biocenter Oulu, University of Oulu, POB 5000, 90014, Oulu, Finland
| | - Karl-Heinz Herzig
- Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland.,Department of Physiology, Research Unit of Biomedicine and Biocenter Oulu, University of Oulu, POB 5000, 90014, Oulu, Finland.,Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, ul. Szpitalna 27/33, 60-572, Poznan, Poland
| | - Ilkka Minkkinen
- Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland.,Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland
| | - Markus J Mäkinen
- Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland.,Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland
| | - Tuomo J Karttunen
- Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland.,Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland
| | - Anne Tuomisto
- Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland. .,Oulu University Hospital and Medical Research Center Oulu, POB 21, 90029, Oulu, Finland.
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Arya M, Singh P, Tripathi CB, Parashar P, Singh M, Kanoujia J, Guleria A, Kaithwas G, Gupta KP, Saraf SA. Pectin-encrusted gold nanocomposites containing phytic acid and jacalin: 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar rats, PI3K/Akt, COX-2, and serum metabolomics as potential targets. Drug Deliv Transl Res 2018; 9:53-65. [DOI: 10.1007/s13346-018-00605-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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49
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Qi Y, Wang R, Zhao L, Lv L, Zhou F, Zhang T, Lu F, Yan H, Duan G. Celastrol Suppresses Tryptophan Catabolism in Human Colon Cancer Cells as Revealed by Metabolic Profiling and Targeted Metabolite Analysis. Biol Pharm Bull 2018; 41:1243-1250. [PMID: 30068874 DOI: 10.1248/bpb.b18-00171] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Celastrol is well known for its anti-cancer effects, yet its specific mechanisms against colon cancer are still not fully elucidated. In this study, cytotoxic effect of celastrol against HCT116 colon cancer cells was investigated based on cell viability assay and flow cytometry assay, and the possible mechanism was explored using a strategy combining metabolic profiling and targeted metabolite analysis based on ultra performance liquid chromatography (UPLC)/MS. Celastrol was found to inhibit the growth of colon cancer cells and induce apoptosis. Metabolomics analysis revealed characteristic changes in metabolic profiles of the colon cancer cells, revealing altered levels of amino acids, carnitine, and lipid markers. Most interestingly, with the assistance of targeted metabolite analysis, tryptophan (Trp) level was significantly increased whereas kynurenine (Kyn) level was decreased in colon cancer cells after celastrol treatment, together with markedly declined Kyn/Trp ratios. Western blot analysis revealed that expression of indoleamine 2,3-dioxygenase (IDO), the enzyme catalyzing Trp to generate Kyn, was dramatically inhibited in colon cancer cells after celastrol treatment, with a dose-dependent manner. These results suggest that suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells. This study provided scientific basis for further development of celastrol on treating colon cancer.
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Affiliation(s)
- Yunpeng Qi
- School of Pharmacy, Fudan University.,School of Pharmacy, Second Military Medical University
| | - Renping Wang
- School of Pharmacy, Second Military Medical University
| | - Liang Zhao
- Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University
| | - Lei Lv
- Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University
| | - Fan Zhou
- Nanjing Drum Tower Hospital affiliated to Medical School of Nanjing University
| | - Tian Zhang
- School of Pharmacy, Second Military Medical University
| | - Feng Lu
- School of Pharmacy, Second Military Medical University
| | - Hongli Yan
- Department of Laboratory Medicine, Changhai Hospital, Second Military Medical University
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Serum free amino acid levels in rheumatoid arthritis according to therapy and physical disability. Cytokine 2018; 113:332-339. [PMID: 30337216 DOI: 10.1016/j.cyto.2018.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 08/07/2018] [Accepted: 10/01/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND In presented study the amino acid analysis was performed in serum derived from rheumatoid arthritis patients (RA) according to undertaken therapy and classification of physical disability. The results were compared with previously published data. METHODS The levels of 31 free amino acids were determined in 50 serum samples derived from RA subjects and 51 controls. The RA patients were divided into two groups according to the therapy (methotrexate/leflunomide, infliximab/adalimumab/etanercept/tocilizumab, prednisolone/NSAID) and classification of physical disability of the patients. Levels of amino acids were measured by LC-MS/MS. The obtained results were subjected to multivariate statistical tests. RESULTS According to the therapy that was being used, threonine differentiated RA patients treated with methotrexate/leflunomide - infliximab/adalimumab/etanercept/tocilizumab (p = 0.00954) and infliximab/adalimumab/etanercept/tocilizumab - prednisolone/NSAID (p = 0.03109), while tryptophan differentiated RA patients treated with methotrexate/leflunomide - infliximab/adalimumab/etanercept/tocilizumab (p = 0.01723). In the functional classification, arginine differentiated RA samples between class III and IV (p = 0.02332), while glycine differentiated them between class I+II and III of the Steinbrocker functional classification (p = 0.03366). CONCLUSIONS An analysis of the metabolome profile requires the use of validated bioanalytical methods that are strictly dedicated for this purpose. The obtained results are not accidental (p value less than 0.05), and all of the selected amino acids play an important role in inflammation and immune response. It is suggested that studied amino acids can be considered as a markers for diagnosis of RA and monitoring pharmacotherapy of the disease.
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