|
1
|
Kadyrov J, Sala S, Grigoroff L, Minaee N, Masuda R, Lodge S, Ebbels TM, Reily MD, Robertson D, Lehman-McKeeman L, Shockcor J, Car BD, Cantor GH, Lindon JC, Nicholson JK, Holmes E, Wist J. A clinical chemical atlas of xenobiotic toxicity for the Sprague-Dawley rat. Arch Toxicol 2025:10.1007/s00204-025-04008-0. [PMID: 40327081 DOI: 10.1007/s00204-025-04008-0] [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: 12/03/2024] [Accepted: 02/24/2025] [Indexed: 05/07/2025]
Abstract
The Consortium for Metabonomic Toxicology (COMET) studies was designed to model metabolic responses to organ- and mechanism-specific toxins to predict acute drug toxicity in rats. A range of clinical chemical parameters were measured in 7-day toxicology studies for 86 toxins eliciting a range of organ- and mechanism-specific effects. Additionally, 21 surgical or physiological stressors were evaluated to identify physiological or metabolic responses that might confound the interpretation of observed toxicity profiles. From these studies on a total of 3473 rats measured at six pharmaceutical companies, we provide a set of 12 serum and 5 urine physical and clinical chemistry parameters. Samples were collected at 24 h, 48 h and 168 h post-dose for each animal and are presented as a downloadable database file. We also summarise the main observations based on the group response at the level of the individual toxin. We demonstrate that correlations between parameters, such as serum bilirubin and aspartate aminotransferase (AST), provide a more nuanced profile of organ-specific toxicity than consideration of individual parameters alone. In addition, we highlight the variability in the measured parameters across the dataset attributable to inter-laboratory differences, and the heterogeneity of metabolic responses to particular compounds or differences in temporal patterns of response. This clinical chemistry atlas of toxicity serves as a valuable reference tool for evaluating the potential toxicity of novel drug candidates.
Collapse
Affiliation(s)
- Janonna Kadyrov
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia
| | - Samuele Sala
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia
| | - Lucy Grigoroff
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia
| | - Novia Minaee
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia
| | - Reika Masuda
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia
| | - Samantha Lodge
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia
| | - Timothy M Ebbels
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London, W12 0NN, UK
| | | | | | | | - John Shockcor
- Formerly Drug Metabolism and Pharmacokinetics Section, Dupont Pharmaceuticals Company, Stine-Haskell Research Center, Newark, Delaware, USA
| | - Bruce D Car
- Formerly Bristol-Myers-Squibb Company, Princeton, NJ, USA
| | - Glenn H Cantor
- Formerly Bristol-Myers-Squibb Company, Princeton, NJ, USA
| | - John C Lindon
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - Jeremy K Nicholson
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia.
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia.
- Institute of Global Health Innovation, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.
| | - Elaine Holmes
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia.
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia.
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
| | - Julien Wist
- Australian National Phenome Centre, Health Futures Institute, Murdoch University, Perth, WA, Australia.
- Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, Australia.
- Institute of Global Health Innovation, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.
- Chemistry Department, Universidad del Valle, 76001, Cali, Colombia.
| |
Collapse
|
|
2
|
Sun R, Fei F, Jin D, Yang H, Xu Z, Cao B, Li J. The integrated analysis of gut microbiota and metabolome revealed steroid hormone biosynthesis is a critical pathway in liver regeneration after 2/3 partial hepatectomy. Front Pharmacol 2024; 15:1407401. [PMID: 39188944 PMCID: PMC11345278 DOI: 10.3389/fphar.2024.1407401] [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: 03/26/2024] [Accepted: 07/23/2024] [Indexed: 08/28/2024] Open
Abstract
Introduction: The liver is the only organ capable of full regeneration in mammals. However, the exact mechanism of gut microbiota and metabolites derived from them relating to liver regeneration has not been fully elucidated. Methods: To demonstrate how the gut-liver axis contributes to liver regeneration, using an LC-QTOF/MS-based metabolomics technique, we examine the gut microbiota-derived metabolites in the gut content of C57BL/6J mice at various points after 2/3 partial hepatectomy (PHx). Compound identification, multivariate/univariate data analysis and pathway analysis were performed subsequently. The diversity of the bacterial communities in the gastrointestinal content was measured using 16S rRNA gene sequencing. Then, the integration analysis of gut microbiota and metabolome was performed. Results: After 2/3 PHx, the residual liver proliferated quickly in the first 3 days and had about 90% of its initial weight by the seventh day. The results of PLS-DA showed that a significant metabolic shift occurred at 6 h and 36 h after 2/3 PHx that was reversed at the late phase of liver regeneration. The α and β-diversity of the gut microbiota significantly changed at the early stage of liver regeneration. Specifically, Escherichia Shigella, Lactobacillus, Akkermansia, and Muribaculaceae were the bacteria that changed the most considerably during liver regeneration. Further pathway analysis found the most influenced co-metabolized pathways between the host and gut bacteria including glycolysis, the TCA cycle, arginine metabolism, glutathione metabolism, tryptophan metabolism, and purine and pyrimidine metabolism. Specifically, steroid hormone biosynthesis is the most significant pathway of the host during liver regeneration. Discussion: These findings revealed that during liver regeneration, there was a broad modification of gut microbiota and systemic metabolism and they were strongly correlated. Targeting specific gut bacterial strains, especially increasing the abundance of Akkermansia and decreasing the abundance of Enterobacteriaceae, may be a promising beneficial strategy to modulate systemic metabolism such as amino acid and nucleotide metabolism and promote liver regeneration.
Collapse
Affiliation(s)
- Runbin Sun
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fei Fei
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Dandan Jin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Haoyi Yang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhi Xu
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| |
Collapse
|
|
3
|
Weidong L, Liuting C, Xiangcong C, Jianhong P, Xueying Y. Analysis of the relationship of refractory gout between potential biomarkers and diet structure and lifestyle based on 1H-NMR. J Orthop Surg Res 2024; 19:78. [PMID: 38243298 PMCID: PMC10797800 DOI: 10.1186/s13018-024-04540-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/06/2024] [Indexed: 01/21/2024] Open
Abstract
OBJECTIVE We investigated the different life styles among the diet structures and exercise patterns of 100 patients with refractory gout and 79 healthy volunteers; of these, we selected 39 patients and 20 healthy volunteers for serum proton magnetic resonance (1H-NMR) metabolic network detection. We determined the potential biomarkers of refractory gout and attempted to explore the relation between potential biomarkers and diet structures and exercise patterns. METHODS The study employed a questionnaire survey to analyze diet structures and exercise patterns from 100 patients of refractory gout and 79 healthy volunteers. At the same time, using 1H-NMR metabolic technology to analyze the metabolites present in the serum samples obtained from 39 patients of refractory gout (group B) and 20 healthy subjects (group A). Employing MestReNova (Version 8.0.1) to analyze the metabolites maps, collecting the NMR results, further importing into SIMCA-P+ 14.0 software (Umetrics, Sweden) for principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) statistical analysis. Combining patterns recognition and multivariate statistics, potential biomarkers were searched. Other experimental data, including creatinine and adiponectin, were counted by the SPSS21.0. The measurement data were expressed by X ± S and t test. The counting data were expressed in percent and performed by X2 test. RESULTS Our results revealed that patients with gout tended to be obese, and there were differences in their lifestyle with exercise, sleep, and smoking, as well as in their preference for fructose drinks, alcohol, and total and structural distribution of meat, milk, eggs, and so on when compared with the healthy volunteers. Importantly, we found the adiponectin in the gout group was lower as compared to the healthy group. Further, metabolomics in combination with KEGG analysis revealed that the biosynthesis of aminoacyl tRNA, biosynthesis of valine, leucine, and isoleucine, metabolism of alanine, aspartic, and glutamate, metabolism of glycine, serine, and threonine, phenylalanine, glycolysis/gluconeogenesis, ketone body synthesis and degradation, metabolism of D-glutamine, citric acid cycle (TCA cycle), triglyceride metabolism, and others could be used as specific biomarkers of this disease. CONCLUSION Recurrent refractory gout and formation of tophus may be related to the diet structures and lifestyles between the patients and the healthy people, and their abnormal metabolic network may be related to the disorder of mitochondrial energy metabolism, which further results in abnormal metabolism of glucose, lipids, amino acids, and deposition of uric acid in joints, peripheral connective tissue, and kidney, inducing an inflammatory response.
Collapse
Affiliation(s)
- Liang Weidong
- Department of Rheumatology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, 523200, China
| | - Chen Liuting
- Department of Rheumatology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, 523200, China
| | - Cheng Xiangcong
- Dongguan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Peng Jianhong
- Department of Rheumatology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, 523200, China.
| | - Ye Xueying
- Department of Rheumatology, Dongguan Hospital of Traditional Chinese Medicine, Dongguan, 523200, China
| |
Collapse
|
|
4
|
Tressler CM, Ayyappan V, Nakuchima S, Yang E, Sonkar K, Tan Z, Glunde K. A multimodal pipeline using NMR spectroscopy and MALDI-TOF mass spectrometry imaging from the same tissue sample. NMR IN BIOMEDICINE 2023; 36:e4770. [PMID: 35538020 PMCID: PMC9867920 DOI: 10.1002/nbm.4770] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 05/05/2022] [Accepted: 05/07/2022] [Indexed: 06/14/2023]
Abstract
NMR spectroscopy and matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) are both commonly used to detect large numbers of metabolites and lipids in metabolomic and lipidomic studies. We have demonstrated a new workflow, highlighting the benefits of both techniques to obtain metabolomic and lipidomic data, which has realized for the first time the combination of these two complementary and powerful technologies. NMR spectroscopy is frequently used to obtain quantitative metabolite information from cells and tissues. Lipid detection is also possible with NMR spectroscopy, with changes being visible across entire classes of molecules. Meanwhile, MALDI MSI provides relative measures of metabolite and lipid concentrations, mapping spatial information of many specific metabolite and lipid molecules across cells or tissues. We have used these two complementary techniques in combination to obtain metabolomic and lipidomic measurements from triple-negative human breast cancer cells and tumor xenograft models. We have emphasized critical experimental procedures that ensured the success of achieving NMR spectroscopy and MALDI MSI in a combined workflow from the same sample. Our data show that several phospholipid metabolite species were differentially distributed in viable and necrotic regions of breast tumor xenografts. This study emphasizes the power of combined NMR spectroscopy-MALDI imaging to advance metabolomic and lipidomic studies.
Collapse
Affiliation(s)
- Caitlin M. Tressler
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Vinay Ayyappan
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sofia Nakuchima
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ethan Yang
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kanchan Sonkar
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Zheqiong Tan
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kristine Glunde
- The Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
5
|
Yang L, Zhen L, Li Z, Zhu S, Xu W, Luo Q, Peng L, Xie C. Human liver tissue transcriptomics revealed immunometabolic disturbances and related biomarkers in hepatitis B virus-related acute-on-chronic liver failure. Front Microbiol 2022; 13:1080484. [PMID: 36532504 PMCID: PMC9752073 DOI: 10.3389/fmicb.2022.1080484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 11/17/2022] [Indexed: 04/06/2024] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a major cause of liver-related death worldwide, but its key pathological features remain incompletely defined. This study aimed to reveal the molecular basis of hepatitis B virus-related ACLF (HBV-ACLF) by transcriptome sequencing of human liver tissue. A total of 18 human liver tissues from patients with different stages of HBV-related disease were collected for RNA sequencing, and liver tissues from patients and mouse models with ACLF were used for subsequent validation. Specifically, 6,853 differentially expressed genes (DEGs) and 5,038 differentially expressed transcripts were identified in patients with ACLF compared to patients with chronic hepatitis B (CHB) and normal controls (NCs). Investigation of functional by KEGG pathway enrichment analysis revealed prominent immune and metabolic dysregulation at the ACLF stage. We found that the key genes FGF19, ADCY8 and KRT17, which are related to immunometabolic disturbances, were significantly upregulated in the progression of ACLF. The three key genes were validated in human and mouse samples, indicating their prognostic and therapeutic potential in ACLF. In summary, our work reveals that immunometabolic disorder is involved in HBV-ACLF pathogenesis and indicates that FGF19, ADCY8 and KRT17 may be sensitive biomarkers for HBV-related ACLF.
Collapse
Affiliation(s)
- Luo Yang
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Limin Zhen
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhihui Li
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shu Zhu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenxiong Xu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiumin Luo
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liang Peng
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, China
- Key Laboratory of Tropical Diseases Control, Ministry of Education, Guangzhou, China
| | - Chan Xie
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong, China
- Key Laboratory of Tropical Diseases Control, Ministry of Education, Guangzhou, China
| |
Collapse
|
|
6
|
Ruan L, Jiang L, Zhao W, Meng H, Zheng Q, Wang J. Hepatotoxicity or hepatoprotection of emodin? Two sides of the same coin by 1H-NMR metabolomics profiling. Toxicol Appl Pharmacol 2021; 431:115734. [PMID: 34606778 DOI: 10.1016/j.taap.2021.115734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 09/17/2021] [Accepted: 09/27/2021] [Indexed: 10/20/2022]
Abstract
Emodin is the major anthraquinone component of many important traditional Chinese herbs, such as Rheum palmatum L. and Polygonum multiflorum Thunb. They have been popular health products but recently aroused concerns about their hepatotoxicity, which are believed to be arising from the contained anthraquinones, such as emodin. However, emodin exerts potent hepatoprotective ability, such as anti-fibrotic, anti-oxidative, and anti-inflammatory effects. In this study, 1H NMR based metabolomics approach, complemented with histopathological observation, biochemical measurements, western blotting analysis and real-time quantitative PCR (RT-qPCR), was applied to interpret the paradox of emodin (30 mg/kg, 10 mg/kg BW) using both healthy mice (male, ICR) and chronic CCl4-injured mice (0.1 mL/kg, 0.35% CCl4, 3 times a week for a month). Emodin exerted a weight loss property associated with its lipid-lowing effects, which helped alleviate CCl4-induced steatosis. Emodin effectively ameliorated CCl4-induced oxidative stress and energy metabolism dysfunction in mice liver via regulating glucose, lipid and amino acid metabolism, and inhibited excessive inflammatory response. In healthy mice, emodin only exhibited hepatoxicity on high-dosage by disturbing hepatic anti-oxidant homeostasis, especially GSH and xanthine metabolism. This integrated metabolomics approach identified the bidirectional potential of emodin, which are important for its rational use.
Collapse
Affiliation(s)
- Lingyu Ruan
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Lei Jiang
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Wenlong Zhao
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Huihui Meng
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Qi Zheng
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| | - Junsong Wang
- Center for Molecular Metabolism, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing 210094, PR China.
| |
Collapse
|
|
7
|
Bottiglieri T, Wang X, Arning E, Fernandez H, Wall A, McKenna G, Ruiz R, Onaca N, Trotter J, Lawrence M, Naziruddin B, Asrani SK, Testa G. Longitudinal profiling of plasma and urine metabolites during liver regeneration in living liver donors. Clin Transplant 2021; 36:e14490. [PMID: 34545967 DOI: 10.1111/ctr.14490] [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: 04/05/2021] [Revised: 09/03/2021] [Accepted: 09/16/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Knowledge of metabolic processes affected by major hepatectomy (MHx), and the metabolic pathways involved in liver regeneration and recovery of function, is limited and mainly derived from animal models. Assessment of restoration of hepatic function is essential in human living liver donors (LD). METHODS We used a targeted metabolomic approach to longitudinally quantify changes in plasma and urine biomarkers from healthy LD. The biomarkers were analyzed before MHx and at scheduled intervals up to 12 months thereafter. RESULTS Marked changes were found in the concentration of 15 primary and secondary plasma bile acids. Most significant changes occurred 2 days after MHx and persisted for up to 3 months. In addition, there were significant changes in acylcarnitine, phospholipid, and amino acid metabolism. The sum of aromatic amino acids and the Fischer ratio, both metabolic markers of liver damage, and the symmetrically demethylated arginine to arginine ratio, a marker of kidney function, were affected. CONCLUSIONS This is the first comprehensive longitudinal study investigating metabolic processes during recovery of liver function after MHx in LD. It provides further evidence of full restoration of metabolic processes 3 months after MHx and supports future investigation to understand how metabolic changes affect donors' hepatic function.
Collapse
Affiliation(s)
- Teodoro Bottiglieri
- Center of Metabolomics, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Xuan Wang
- Department of Statistics and Bioinformatics, Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Erland Arning
- Center of Metabolomics, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Hoylan Fernandez
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Anji Wall
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Greg McKenna
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Richard Ruiz
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Nicholas Onaca
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - James Trotter
- Division of Hepatology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas, USA
| | - Michael Lawrence
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Bashoo Naziruddin
- Islet Cell Laboratory, Baylor Scott and White Research Institute, Dallas, Texas, USA
| | - Sumeet K Asrani
- Division of Hepatology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas, USA
| | - Giuliano Testa
- Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, Texas, USA
| |
Collapse
|
|
8
|
Biochemical and Metabolomic Changes after Electromagnetic Hyperthermia Exposure to Treat Colorectal Cancer Liver Implants in Rats. NANOMATERIALS 2021; 11:nano11051318. [PMID: 34067780 PMCID: PMC8156717 DOI: 10.3390/nano11051318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 01/10/2023]
Abstract
Background: Hyperthermia (HT) therapy still remains relatively unknown, in terms of both its biological and therapeutic effects. This work aims to analyze the effects of exposure to HT, such as that required in anti-tumor magnetic hyperthermia therapies, using metabolomic and serum parameters routinely analyzed in clinical practice. Methods: WAG/RigHsd rats were assigned to the different experimental groups needed to emulate all of the procedures involved in the treatment of liver metastases by HT. Twelve hours or ten days after the electromagnetic HT (606 kHz and 14 kA/m during 21 min), blood samples were retrieved and liver samples were obtained. 1H-nuclear-magnetic-resonance spectroscopy (1H-NMR) was used to search for possible diagnostic biomarkers of HT effects on the rat liver tissue. All of the data obtained from the hydrophilic fraction of the tissues were analyzed and modeled using chemometric tools. Results: Hepatic enzyme levels were significantly increased in animals that underwent hyperthermia after 12 h, but 10 d later they could not be detected anymore. The metabolomic profile (main metabolic differences were found in phosphatidylcholine, taurine, glucose, lactate and pyruvate, among others) also showed that the therapy significantly altered metabolism in the liver within 12 h (with two different patterns); however, those changes reverted to a control-profile pattern after 10 days. Conclusions: Magnetic hyperthermia could be considered as a safe therapy to treat liver metastases, since it does not induce irreversible physiological changes after application.
Collapse
|
|
9
|
Sun L, Zhao M, Zhao Y, Wang M, Man J, Zhao C. Investigation of the therapeutic effect of Shaoyao Gancao decoction on CCL 4 -induced liver injury in rats by metabolomic analysis. Biomed Chromatogr 2020; 34:e4940. [PMID: 32634249 DOI: 10.1002/bmc.4940] [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: 04/18/2020] [Revised: 06/21/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022]
Abstract
Shaoyao Gancao decoction (SGD) is a famous Chinese traditional prescription for treating liver injury. In this research, we investigated the therapeutic effects of SGD on liver injury and its metabolic mechanisms using 1 H NMR and UPLC-MS. Serum biochemical indicators and histopathological methods were used to determine the mechanism of action of SGD in treating liver injury. An orthogonal partial least squares discriminant analysis method was used to screen potential metabolic markers, and the MetaboAnalyst and KEGG PATHWAY databases were used to find relevant metabolic pathways. A total of 26 significant metabolites were identified with significant changes in their abundance levels, and these metabolites are involved in many metabolic pathways such as amino acid and lipid metabolism. The changes in biomarker levels reveal the therapeutic effect of SGD on liver injury, which is of great significance to speculate on possible metabolic mechanisms.
Collapse
Affiliation(s)
- Lin Sun
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Min Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yanhui Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Miao Wang
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Jingyi Man
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
| | - Chunjie Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| |
Collapse
|
|
10
|
Bannuscher A, Hellack B, Bahl A, Laloy J, Herman H, Stan MS, Dinischiotu A, Giusti A, Krause BC, Tentschert J, Roșu M, Balta C, Hermenean A, Wiemann M, Luch A, Haase A. Metabolomics profiling to investigate nanomaterial toxicity in vitro and in vivo. Nanotoxicology 2020; 14:807-826. [DOI: 10.1080/17435390.2020.1764123] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Anne Bannuscher
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
- Adolphe Merkle Institute (AMI), University of Fribourg, Fribourg, Switzerland
| | - Bryan Hellack
- Institute of Energy and Environmental Technology (IUTA) e.V, Duisburg, Germany
- German Environment Agency (UBA), Dessau, Germany
| | - Aileen Bahl
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Julie Laloy
- Department of Pharmacy, Namur Nanosafety Centre, NARILIS, University of Namur, Namur, Belgium
| | - Hildegard Herman
- Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Miruna S. Stan
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Anca Dinischiotu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Anna Giusti
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Benjamin-Christoph Krause
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Jutta Tentschert
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Marcel Roșu
- Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Cornel Balta
- Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
| | - Anca Hermenean
- Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, Arad, Romania
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Martin Wiemann
- IBE R&D Institute for Lung Health gGmbH, Münster, Germany
| | - Andreas Luch
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| | - Andrea Haase
- Department of Chemical and Product Safety, German Federal Institute for Risk Assessment (BfR), Berlin, Germany
| |
Collapse
|
|
11
|
Zhao Y, Chen E, Huang K, Xie Z, Zhang S, Wu D, Ji F, Zhu D, Xu X, Li L. Dynamic Alterations of Plasma Metabolites in the Progression of Liver Regeneration after Partial Hepatectomy. J Proteome Res 2020; 19:174-185. [PMID: 31802674 DOI: 10.1021/acs.jproteome.9b00493] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
To elucidate the dynamic alterations of metabolites in rat plasma during liver regeneration and search for potential biomarkers of liver regeneration, 65 male Sprague-Dawley rats were divided into three groups: 70% partial hepatectomy group (PHx, n = 30), sham-operated group (Sham, n = 30), and pre-PHx group (pre-PHx, n = 5). Rats in the Sham and PHx groups were sacrificed after 30 min (min), 6 h (h), 24, 48, 72, and 168 h of surgery (n = 5 per time point). The gas chromatography-mass spectrometry-based metabolomic approach was used to identify the dynamic metabolites. Liver regeneration in the rats was evidenced by an increase in the liver weight/body weight ratio, expression of proliferating cell nuclear antigen, and yes-associated protein-1. Thirty-four differentially abundant metabolites between the Sham and PHx groups were identified, which were involved in arginine and proline metabolism, aminoacyl-tRNA biosynthesis, and cysteine and methionine metabolism pathways. Of these metabolites, low 1,5-anhydroglucitol may indicate proliferation of liver parenchymal cells during liver regeneration. Thus, a series of metabolic changes occurred with the progression of liver regeneration, and 1,5-anhydroglucitol could function as a novel hallmark of proliferation of liver parenchymal cells.
Collapse
Affiliation(s)
| | - Ermei Chen
- Department of Gastroenterology , Zhongshan Hospital Affiliated to Xiamen University , Xiamen 361004 , Fujian Province , China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Bao Q, Yu L, Chen D, Li L. Variation in the gut microbial community is associated with the progression of liver regeneration. Hepatol Res 2020; 50:121-136. [PMID: 31465626 DOI: 10.1111/hepr.13424] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 08/07/2019] [Accepted: 08/08/2019] [Indexed: 12/23/2022]
Abstract
AIM To highlight a potential dynamic interaction between intestinal bacteria (IB) and metabolites that might contribute to liver regeneration (LR). METHODS Male Sprague-Dawley rats were subjected to surgical removal of two-thirds of the liver and samples were collected over a 14-day period. Intestinal community and metabolic profiles were characterized to establish their potential interactions during liver regeneration. RESULTS Partial hepatectomy caused fluctuating changes in the gut microbiome, which paralleled the biological processes of LR. Briefly, the enhanced cell proliferation occurring within 30-48 h was associated with a decreased ratio of Firmicutes to Bacteroidetes reflected by a reduction in Ruminococcaceae and Lachnospiraceae, and an increase in Bacteroidaceae, Rikenellaceae, and Porphyromonadaceae, which was indicative of a lean phenotype. The microbiota derived from rats at 12-24 h and 3-14 days were characterized by elevated F/B ratios, suggesting the differing energy extract behaviors of microbiota during the course of LR. Functional changes of the shifted microbiota revealed by PICRUSt software confirmed the pyrosequencing results. The microbiome derived from hour 12 rats showed overpresentation of metabolism-related modules. In contrast, the microbiome derived from day 2 rats was functionally unique in "replication and repair", "amino acid metabolism," and "nucleoid metabolism." Upon examining the dynamic pattern of metabolic response, the specific pathways, including glycerophospholipid metabolism, taurine, and hypotaurine metabolism, were identified to be attributable to the systemic alterations in LR-related metabolism. Moreover, our data indicated that several key functional bacteria were strongly related to perturbations of the above pathways. CONCLUSION Gut flora could play a central role in manipulating metabolic responses in LR.
Collapse
Affiliation(s)
- Qiongling Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Liang Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Deying Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China
| |
Collapse
|
|
13
|
EL-Hak HN, ELaraby EE, Hassan AK, Abbas OA. Study of the toxic effect and safety of vitamin E supplement in male albino rats after 30 days of repeated treatment. Heliyon 2019; 5:e02645. [PMID: 31667433 PMCID: PMC6812462 DOI: 10.1016/j.heliyon.2019.e02645] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 09/26/2019] [Accepted: 10/09/2019] [Indexed: 02/07/2023] Open
Abstract
The aim of these investigations was to study vitamin E supplement effect in male albino rats after 30 days of repeated treatment. Four groups of six male rats were orally administered distilled water (control), 500, 1000 and 2000 mg/kg body weight vitamin E daily for 30 days. The impact of the treatment on percent body weight and mortality was determined and compared to the control group. Some hematological analysis, biochemical parameters and histological examination of different body organs were assessed. The rats treated with different doses of vitamin E supplement showed no deaths recorded in 30 days. The treatment with higher dose Vitamin E supplementation" caused significant alteration at the hematological, biochemical and histological level. Therefore, oral administration of vitamin E supplement in rats for 30 days was not safe for the liver and kidney and in the other hand, safe for the testes therefore that side effect on the liver and kidney should be considered when recommended vitamin E for therapeutic purpose. Care should be taken in taking high doses of vitamin E.
Collapse
Affiliation(s)
- Heba N.Gad EL-Hak
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Eman E. ELaraby
- Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Ahmed K. Hassan
- Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt
| | - Osama A. Abbas
- Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt
| |
Collapse
|
|
14
|
Chen C, Gao J, Wang TS, Guo C, Yan YJ, Mao CY, Gu LW, Yang Y, Li ZF, Liu A. NMR-based Metabolomic Techniques Identify the Toxicity of Emodin in HepG2 Cells. Sci Rep 2018; 8:9379. [PMID: 29925852 PMCID: PMC6010407 DOI: 10.1038/s41598-018-27359-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 06/01/2018] [Indexed: 01/24/2023] Open
Abstract
Emodin is a natural anthraquinone derivative that is present in various herbal preparations. The pharmacological effects of emodin include anticancer, hepatoprotective, anti-inflammatory, antioxidant and even antimicrobial activities. However, emodin also has been reported to induce hepatotoxicity, nephrotoxicity, genotoxicity and reproductive toxicity. The mechanism of emodin's adverse effects is complicated and currently not well understood. This study aimed to establish a cell metabonomic method to investigate the toxicity of emodin and explore its potential mechanism and relevant targets. In the present study, metabonomic profiles of cell extracts and cell culture media obtained using the 1H NMR technique were used to assess emodin toxicity in HepG2 cells. Multivariate statistical analyses such as partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to characterize the metabolites that differed between the control and emodin groups. The results indicated that emodin resulted in differences in 33 metabolites, including acetate, arginine, aspartate, creatine, isoleucine, leucine and histidine in the cell extract samples and 23 metabolites, including alanine, formate, glutamate, succinate and isoleucine, in the cell culture media samples. Approximately 8 pathways associated with these metabolites were disrupted in the emodin groups. These results demonstrated the potential for using cell metabonomics approaches to clarify the toxicological effects of emodin, the underlying mechanisms and potential biomarkers. Our findings may help with the development of novel strategies to discover targets for drug toxicity, elucidate the changes in regulatory signal networks and explore its potential mechanism of action.
Collapse
Affiliation(s)
- Chang Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jian Gao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.,Beijing University of Chinese Medicine, Beijing, China
| | - Tie-Shan Wang
- Beijing University of Chinese Medicine, Beijing, China
| | - Cong Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu-Jing Yan
- Department of Chemistry, Capital Normal University, Beijing, China
| | - Chao-Yi Mao
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li-Wei Gu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yang Yang
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhong-Feng Li
- Department of Chemistry, Capital Normal University, Beijing, China.
| | - An Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
| |
Collapse
|
|
15
|
Zhou YZ, Yan ML, Gao L, Zhang JQ, Qin XM, Zhang X, Du GH. Metabonomics approach to assessing the metabolism variation and gender gap of Drosophila melanogaster in aging process. Exp Gerontol 2017; 98:110-119. [DOI: 10.1016/j.exger.2017.07.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 07/25/2017] [Accepted: 07/31/2017] [Indexed: 02/06/2023]
|
|
16
|
Zhang P, Zhu W, Wang D, Yan J, Wang Y, Zhou Z, He L. A combined NMR- and HPLC-MS/MS-based metabolomics to evaluate the metabolic perturbations and subacute toxic effects of endosulfan on mice. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2017; 24:18870-18880. [PMID: 28653198 DOI: 10.1007/s11356-017-9534-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 06/13/2017] [Indexed: 06/07/2023]
Abstract
Endosulfan is the newly persistent organic pollutants (POPs) added to the Stockholm Convention as its widespread use, persistence, bioaccumulation, long-range transport, endocrine disruption, and toxicity related to various adverse effects. In the present study, male mice were administrated endosulfan at 0, 0.5, and 3.5 mg/kg by gavage for 2 weeks. 1H-NMR-based urinary metabolomics, HPLC-MS/MS-based targeted serum metabolomics, clinical analysis, and histopathology techniques were employed to evaluate the metabolic perturbations of subacute endosulfan exposure. Endosulfan exposures resulted in weight loss, liver inflammation and necrosis, and alterations in serum amino acids and urine metabolomics. Based on altered metabolites, several significantly perturbed pathways were identified including glycine, serine, and threonine metabolism; TCA cycle; pyruvate metabolism; glycolysis or gluconeogenesis; glycerophospholipid metabolism; and glyoxylate and dicarboxylate metabolism. Such pathways were highly related to amino acid metabolism, energy metabolism, and lipid metabolism. In addition, metabolomic results also demonstrated that gut microbiota was remarkably altered after endosulfan exposure. These observations may provide novel insight into revealing the potential toxic mechanism and evaluating the health risk of endosulfan exposure at metabolomic level.
Collapse
Affiliation(s)
- Ping Zhang
- Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing, 400715, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, China
| | - Wentao Zhu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, China
| | - Dezhen Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, China
| | - Jin Yan
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, China
| | - Yao Wang
- Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing, 400715, China
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, China
| | - Zhiqiang Zhou
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing, China
| | - Lin He
- Key Laboratory of Entomology and Pest Control Engineering, College of Plant Protection, Southwest University, Chongqing, 400715, China.
| |
Collapse
|
|
17
|
Wu F, Zheng H, Yang ZT, Cheng B, Wu JX, Liu XW, Tang CL, Lu SY, Chen ZN, Song FM, Ruan JX, Zhang HY, Liang YH, Song H, Su ZH. Urinary metabonomics study of the hepatoprotective effects of total alkaloids from Corydalis saxicola Bunting on carbon tetrachloride-induced chronic hepatotoxicity in rats using 1 H NMR analysis. J Pharm Biomed Anal 2017; 140:199-209. [DOI: 10.1016/j.jpba.2017.03.031] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 03/08/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023]
|
|
18
|
Sun L, Sun J, Xu Q, Li X, Zhang L, Yang H. Metabolic responses to intestine regeneration in sea cucumbers Apostichopus japonicus. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2017; 22:32-38. [PMID: 28189056 DOI: 10.1016/j.cbd.2017.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/27/2017] [Accepted: 02/02/2017] [Indexed: 02/08/2023]
Abstract
Sea cucumbers are excellent models for studying organ regeneration due to their striking capacity to regenerate most of their viscera after evisceration. In this study, we applied NMR-based metabolomics to determine the metabolite changes that occur during the process of intestine regeneration in sea cucumbers. Partial least-squares discriminant analysis showed that there was significant differences in metabolism between regenerative intestines at 3, 7, and 14days post evisceration (dpe) and normal intestines. Changes in the concentration of 13 metabolites related to regeneration were observed and analyzed. These metabolites included leucine, isoleucine, valine, arginine, glutamate, hypotaurine, dimethylamine, N,N-dimethylglycine, betaine, taurine, inosine, homarine, and histidine. Three important genes (betaine-aldehyde dehydrogenase, betaine-homocysteine S-methyltransferase 1, and dimethylglycine dehydrogenase) were differentially expressed to regulate the levels of betaine and N,N-dimethylglycine during intestine regeneration. These results provide an important basis for studying regenerative mechanisms and developing regenerative matrixes.
Collapse
Affiliation(s)
- Lina Sun
- Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
| | - Jingchun Sun
- Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
| | - Qinzeng Xu
- Key Laboratory of Marine Ecology and Environmental Science and Engineering, First Institute of Oceanography, State Oceanic Administration, Qingdao, China
| | - Xiaoni Li
- Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China
| | - Libin Zhang
- Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.
| | - Hongsheng Yang
- Key Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China
| |
Collapse
|
|
19
|
Zhang P, Zhu W, Wang D, Yan J, Wang Y, He L. Enantioselective Effects of Metalaxyl Enantiomers on Breast Cancer Cells Metabolic Profiling Using HPLC-QTOF-Based Metabolomics. Int J Mol Sci 2017; 18:ijms18010142. [PMID: 28085117 PMCID: PMC5297775 DOI: 10.3390/ijms18010142] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 12/29/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023] Open
Abstract
In this study, an integrative high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF) based metabolomics approach was performed to evaluate the enantioselective metabolic perturbations in MCF-7 cells after treatment with R-metalaxyl and S-metalaxyl, respectively. Untargeted metabolomics profile, multivariate pattern recognition, metabolites identification, and pathway analysis were determined after metalaxyl enantiomer exposure. Principal component analysis (PCA) and partitial least-squares discriminant analysis (PLS-DA) directly reflected the enantioselective metabolic perturbations induced by metalaxyl enantiomers. On the basis of multivariate statistical results, a total of 49 metabolites including carbohydrates, amino acids, nucleotides, fatty acids, organic acids, phospholipids, indoles, derivatives, etc. were found to be the most significantly changed metabolites and metabolic fluctuations caused by the same concentration of R-metalaxyl and S-metalaxyl were enantioselective. Pathway analysis indicated that R-metalaxyl and S-metalaxyl mainly affected the 7 and 10 pathways in MCF-7 cells, respectively, implying the perturbed pathways induced by metalaxyl enantiomers were also enantioselective. Furthermore, the significantly perturbed metabolic pathways were highly related to energy metabolism, amino acid metabolism, lipid metabolism, and antioxidant defense. Such results provide more specific insights into the enantioselective metabolic effects of chiral pesticides in breast cancer progression, reveal the underlying mechanisms, and provide available data for the health risk assessments of chiral environmental pollutants at the molecular level.
Collapse
Affiliation(s)
- Ping Zhang
- College of Plant Protection, Southwest University, Chongqing 400715, China.
| | - Wentao Zhu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
| | - Dezhen Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
| | - Jin Yan
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
| | - Yao Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
| | - Lin He
- College of Plant Protection, Southwest University, Chongqing 400715, China.
| |
Collapse
|
|
20
|
Robinson O, Toledano MB, Sands C, Beckonert O, J Want E, Goldin R, Hauser ML, Fenwick A, Thursz MR, Coen M. Global metabolic changes induced by plant-derived pyrrolizidine alkaloids following a human poisoning outbreak and in a mouse model. Toxicol Res (Camb) 2016; 5:1594-1603. [PMID: 30090460 PMCID: PMC6060677 DOI: 10.1039/c6tx00221h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2016] [Accepted: 08/11/2016] [Indexed: 11/26/2022] Open
Abstract
Several hundred cases of Hirmi Valley Liver Disease (HVLD), an often fatal liver injury, occurred from 2001 to 2011 in a cluster of rural villages in Tigray, Ethiopia. HVLD is principally caused by contamination of the food supply with plant derived pyrrolizidine alkaloids (PAs), with high exposure to the pesticide DDT among villagers increasing their susceptibility. In an untargeted global approach we aimed to identify metabolic changes induced by PA exposure through 1H NMR spectroscopic based metabolic profiling. We analysed spectra acquired from urine collected from HVLD cases and controls and a murine model of PA exposure and PA/DDT co-exposure, using multivariate partial least squares discriminant analysis. In the human models we identified changes in urinary concentrations of tyrosine, pyruvate, bile acids, N-acetylglycoproteins, N-methylnicotinamide and formate, hippurate, p-cresol sulphate, p-hydroxybenzoate and 3-(3-hydroxyphenyl) propionic acid. Tyrosine and p-cresol sulphate were associated with both exposure and disease. Similar changes to tyrosine, one-carbon intermediates and microbial associated metabolites were observed in the mouse model, with tyrosine correlated with the extent of liver damage. These results provide mechanistic insight and implicate the gut microflora in the human response to challenge with toxins. Pathways identified here may be useful in translational research and as "exposome" signals.
Collapse
Affiliation(s)
- Oliver Robinson
- MRC-PHE Centre for Environment and Health , School of Public Health , Imperial College London , UK
- ISGlobal , Centre for Research in Environmental Epidemiology (CREAL) , Spain
- Hospital del Mar Medical Research Institute (IMIM) , Barcelona , Spain
- CIBER Epidemiología y Salud Pública (CIBERESP) , Spain
| | - Mireille B Toledano
- MRC-PHE Centre for Environment and Health , School of Public Health , Imperial College London , UK
| | - Caroline Sands
- Computational and Systems Medicine , Department of Surgery & Cancer , Faculty of Medicine , Imperial College London , UK .
| | - Olaf Beckonert
- Computational and Systems Medicine , Department of Surgery & Cancer , Faculty of Medicine , Imperial College London , UK .
| | - Elizabeth J Want
- Computational and Systems Medicine , Department of Surgery & Cancer , Faculty of Medicine , Imperial College London , UK .
| | - Rob Goldin
- Department of Medicine , Imperial College London , UK
| | - Michael L Hauser
- One Health Foundation , Switzerland
- Schistosomiasis Control Initiative , School of Public Health, Imperial College , London , UK
| | - Alan Fenwick
- Schistosomiasis Control Initiative , School of Public Health, Imperial College , London , UK
| | - Mark R Thursz
- Department of Medicine , Imperial College London , UK
| | - Muireann Coen
- Computational and Systems Medicine , Department of Surgery & Cancer , Faculty of Medicine , Imperial College London , UK .
| |
Collapse
|
|
21
|
Shariff MI, Kim JU, Ladep NG, Crossey MM, Koomson LK, Zabron A, Reeves H, Cramp M, Ryder S, Greer S, Cox IJ, Williams R, Holmes E, Nash K, Taylor-Robinson SD. Urinary Metabotyping of Hepatocellular Carcinoma in a UK Cohort Using Proton Nuclear Magnetic Resonance Spectroscopy. J Clin Exp Hepatol 2016; 6:186-194. [PMID: 27746614 PMCID: PMC5052404 DOI: 10.1016/j.jceh.2016.03.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/20/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Discriminatory metabolic profiles have been described in urinary 1H nuclear magnetic resonance (NMR) spectroscopy studies of African patients with hepatocellular carcinoma (HCC). This study aimed to assess similarities in a UK cohort, where there is a greater etiological diversity. METHODS Urine from cirrhosis and HCC patients was analyzed using a 600 MHz 1H NMR system. Multivariate analysis and median group MR spectra comparison identified metabolite alterations between groups. Metabolite identification was achieved through literature reference and statistical total correlation spectroscopy. Diagnostic accuracy was compared to serum alpha-fetoprotein (AFP). RESULTS Of the 52 patients recruited, 13 samples from HCC and 25 from cirrhosis patients were selected. At 200 IU mL-1, diagnostic sensitivity of AFP was 27%. Multivariate analysis of urinary spectra generated diagnostic models with a sensitivity/specificity of 53.6%/96%. p-Cresol sulfate (P = 0.04), creatinine (P = 0.03), citrate (P = 0.21) and hippurate (P = 0.52) were reduced in the HCC patients. Carnitine (P = 0.31) and formate (P = 0.44) were elevated. CONCLUSION Diagnostic sensitivity was lower than previous African studies, but still outperformed serum AFP. Reduced creatinine, citrate and hippurate and elevated carnitine are comparable with the African studies. p-Cresol sulfate alteration is a novel finding and may indicate an altered sulfonation capacity of the liver in patients with HCC.
Collapse
Key Words
- 1H NMR
- 1H NMR, proton nuclear magnetic resonance
- AFP, alpha-fetoprotein
- ALT, alanine transaminase
- BCLC, Barcelona Clinic Liver Cancer
- BMI, body mass index
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HIV, human immunodeficiency virus
- INR, International Normalized Ratio
- NASH, non-alcoholic steatohepatitis
- PCA, principal component analysis
- PLS-DA, partial least squares discriminant analysis
- SEER, surveillance Epidemiology and End Results
- STOCSY, statistical total correlation spectroscopy
- TSP, trimethyl-silyl phosphate
- US, ultrasonography
- biomarkers
- hepatocellular carcinoma
- metabonomics
Collapse
Affiliation(s)
- Mohamed I.F. Shariff
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom
| | - Jin U. Kim
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom,Address for correspondence: Jin Un Kim, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom.Division of Digestive Health, Department of Surgery and Cancer, Imperial College LondonSt Mary's Campus, South Wharf RoadLondonW2 1NYUnited Kingdom
| | - Nimzing G. Ladep
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom
| | - Mary M.E. Crossey
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom,Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, United Kingdom
| | - Larry K. Koomson
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom
| | - Abigail Zabron
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom
| | - Helen Reeves
- Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom
| | - Matthew Cramp
- Liver Unit, Derriford Hospital, Derriford Road, Crownhill, Plymouth, Devon PL6 8DH, United Kingdom
| | - Stephen Ryder
- Nottingham Digestive Diseases Centre, University of Nottingham and NIHR Biomedical Research Unit, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom
| | - Shaun Greer
- Department of Gastroenterology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom
| | - I. Jane Cox
- The Foundation for Liver Research, Institute of Hepatology, 69-75 Chenies Mews, London WC1E 6HX, United Kingdom
| | - Roger Williams
- The Foundation for Liver Research, Institute of Hepatology, 69-75 Chenies Mews, London WC1E 6HX, United Kingdom
| | - Elaine Holmes
- Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, United Kingdom
| | - Kathryn Nash
- Liver Unit, Southampton General Hospital, Tremona Rd, Southampton, Hampshire SO16 6YD, United Kingdom
| | - Simon D. Taylor-Robinson
- Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, United Kingdom
| |
Collapse
|
|
22
|
Del Carratore F, Lussu M, Kowalik MA, Perra A, Griffin JL, Atzori L, Grosso M. Statistical Health Monitoring Applied to a Metabolomic Study of Experimental Hepatocarcinogenesis: An Alternative Approach to Supervised Methods for the Identification of False Positives. Anal Chem 2016; 88:7921-9. [PMID: 27437557 DOI: 10.1021/acs.analchem.5b03078] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
In a typical metabolomics experiment, two or more conditions (e.g., treated versus untreated) are compared, in order to investigate the potential differences in the metabolic profiles. When dealing with complex biological systems, a two-class classification is often unsuitable, since it does not consider the unpredictable differences between samples (e.g., nonresponder to treatment). An approach based on statistical process control (SPC), which is able to monitor the response to a treatment or the development of a pathological condition, is proposed here. Such an approach has been applied to an experimental hepatocarcinogenesis model to discover early individual metabolic variations associated with a different response to the treatment. Liver study was performed by nuclear magnetic resonance (NMR) spectroscopy, followed by multivariate statistical analysis. By this approach, we were able to (1) identify which treated samples have a significantly different metabolic profile, compared to the control (in fact, as confirmed by immunohistochemistry, the method correctly classified 7 responders and 3 nonresponders among the 10 treated animals); (2) recognize, for each individual sample, the metabolites that are out of control (e.g., glutathione, acetate, betaine, and phosphocholine). The first point could be used for classification purposes, and the second point could be used for a better understanding of the mechanisms underlying the early phase of carcinogenesis. The statistical control approach can be used for diagnosis (e.g., healthy versus pathological, responder versus nonresponder) and for generation of an individual metabolic profile, leading to a better understanding of the individual pathological processes and to a personalized diagnosis and therapy.
Collapse
Affiliation(s)
| | - Milena Lussu
- Department of Biomedical Sciences, University of Cagliari , Cagliari, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari , Cagliari, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari , Cagliari, Italy
| | | | - Luigi Atzori
- Department of Biomedical Sciences, University of Cagliari , Cagliari, Italy
| | - Massimiliano Grosso
- Department of Mechanical, Chemical and Materials Engineering, University of Cagliari , Cagliari, Italy
| |
Collapse
|
|
23
|
McPhail MJW, Shawcross DL, Lewis MR, Coltart I, Want EJ, Antoniades CG, Veselkov K, Triantafyllou E, Patel V, Pop O, Gomez-Romero M, Kyriakides M, Zia R, Abeles RD, Crossey MME, Jassem W, O'Grady J, Heaton N, Auzinger G, Bernal W, Quaglia A, Coen M, Nicholson JK, Wendon JA, Holmes E, Taylor-Robinson SD. Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis. J Hepatol 2016; 64:1058-1067. [PMID: 26795831 PMCID: PMC4876170 DOI: 10.1016/j.jhep.2016.01.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 12/07/2015] [Accepted: 01/06/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival. METHODS Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)). RESULTS (1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC. CONCLUSION Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.
Collapse
Affiliation(s)
- Mark J W McPhail
- Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom; Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Debbie L Shawcross
- Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom
| | - Matthew R Lewis
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Iona Coltart
- Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom
| | - Elizabeth J Want
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Charalambos G Antoniades
- Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom; Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Kiril Veselkov
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Evangelos Triantafyllou
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Vishal Patel
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Oltin Pop
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Maria Gomez-Romero
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Michael Kyriakides
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Rabiya Zia
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Robin D Abeles
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Mary M E Crossey
- Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom
| | - Wayel Jassem
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - John O'Grady
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Nigel Heaton
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Georg Auzinger
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - William Bernal
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Alberto Quaglia
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Muireann Coen
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Jeremy K Nicholson
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom
| | - Julia A Wendon
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom
| | - Elaine Holmes
- Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
| | - Simon D Taylor-Robinson
- Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom
| |
Collapse
|
|
24
|
Cox IJ, Aliev AE, Crossey MME, Dawood M, Al-Mahtab M, Akbar SM, Rahman S, Riva A, Williams R, Taylor-Robinson SD. Urinary nuclear magnetic resonance spectroscopy of a Bangladeshi cohort with hepatitis-B hepatocellular carcinoma: A biomarker corroboration study. World J Gastroenterol 2016; 22:4191-4200. [PMID: 27122669 PMCID: PMC4837436 DOI: 10.3748/wjg.v22.i16.4191] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 02/19/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish if a distinct urinary metabolic profile could be identified in Bangladeshi hepatitis-B hepatocellular carcinoma (HCC) patients compared to cirrhosis patients and controls.
METHODS: Urine samples from 42 Bangladeshi patients with HCC (39 patients with hepatitis-B HCC), 47 with cirrhosis on a background of hepatitis B, 46 with chronic hepatitis B, and seven ethnically-matched healthy controls were analyzed using nuclear magnetic resonance (NMR) spectroscopy. A full dietary and medication history was recorded for each subject. The urinary NMR data were analyzed using principal component analysis (PCA) and orthogonal partial least squared discriminant analysis (OPLS-DA) techniques. Differences in relative signal levels of the most discriminatory metabolites identified by PCA and OPLS-DA were compared between subject groups using an independent samples Kruskal-Wallis one-way analysis of variance (ANOVA) test with all pairwise multiple comparisons. Within the patient subgroups, the Mann-Whitney U test was used to compare metabolite levels depending on hepatitis B e-antigen (HBeAg) status and treatment with anti-viral therapy. A Benjamini-Hochberg adjustment was applied to acquire the level of significance for multiple testing, with a declared level of statistical significance of P < 0.05.
RESULTS: There were significant differences in age (P < 0.001), weight (P < 0.001), and body mass index (P < 0.001) across the four clinical subgroups. Serum alanine aminotransferase (ALT) was significantly higher in the HCC group compared to controls (P < 0.001); serum α-fetoprotein was generally markedly elevated in HCC compared to controls; and serum creatinine levels were significantly reduced in the HCC group compared to the cirrhosis group (P = 0.004). A three-factor PCA scores plot showed clustering of the urinary NMR spectra from the four subgroups. Metabolites that contributed to the discrimination between the subgroups included acetate, creatine, creatinine, dimethyamine (DMA), formate, glycine, hippurate, and trimethylamine-N-oxide (TMAO). A comparison of relative metabolite levels confirmed that carnitine was significantly increased in HCC; and creatinine, hippurate, and TMAO were significantly reduced in HCC compared to the other subgroups. HBeAg negative patients showed a significant increase in creatinine (P = 0.001) compared to HBeAg positive patients in the chronic hepatitis B subgroup, whilst HBeAg negative patients showed a significant decrease in DMA (P = 0.004) in the cirrhosis subgroup compared to HBeAg positive patients. There were no differences in metabolite levels in HCC patients who did or did not receive antiviral treatment.
CONCLUSION: Urinary NMR changes in Bangladeshi HCC were identified, corroborating previous findings from Egypt and West Africa. These findings could form the basis for the development of a cost-effective HCC dipstick screening test.
Collapse
|
|
25
|
Goossens C, Nahon P, Le Moyec L, Triba MN, Bouchemal N, Amathieu R, Ganne-Carrié N, Ziol M, Trinchet JC, Sellier N, Diallo A, Seror O, Savarin P. Sequential Serum Metabolomic Profiling after Radiofrequency Ablation of Hepatocellular Carcinoma Reveals Different Response Patterns According to Etiology. J Proteome Res 2016; 15:1446-54. [PMID: 27015127 DOI: 10.1021/acs.jproteome.5b01032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Radiofrequency ablation (RFA) is commonly performed as a curative approach in patients with hepatocellular carcinoma (HCC); however, the risk of tumor recurrence is difficult to predict due to a lack of reliable clinical and biological markers, and identification of new biomarkers poses a major challenge for improving prognoses. Metabolomics is a promising technique that may lead to the identification and characterization of new disease fingerprints. The objective of the present study was to explore, preoperatively and at various time points post-RFA, the metabolic profile of serum samples from HCC patients to identify factors associated with treatment response and recurrence. Sequential sera obtained before and after RFA procedures for 120 patients with HCC due to cirrhosis were investigated using nuclear magnetic resonance metabolomics. A multilevel orthogonal projection to latent structure analysis was used to discriminate intraindividual metabolic changes in response to RFA treatment. Recurrence-free survival differed depending on the underlying cause of cirrhosis. The statistical model showed significant differences depending on whether the liver disease had a viral or nonviral etiology before RFA intervention (explained variance of R(2)Y = 0.89 and predictability of Q(2)Y = 0.34). These profiles were also associated with specific and distinct metabolic responses after RFA.
Collapse
Affiliation(s)
- Corentine Goossens
- Université Paris 13 , Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| | - Pierre Nahon
- Groupe Hospitalier Paris Seine-Saint-Denis, Pôle d'Activités Cancérologiques Spécialisées, APHP, Hôpital Jean Verdier, Bondy et Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.,INSERM U1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris 5 , Paris, France
| | | | - Mohamed Nawfal Triba
- Université Paris 13 , Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| | - Nadia Bouchemal
- Université Paris 13 , Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| | - Roland Amathieu
- Université Paris 13 , Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France.,Service d'Anesthésie-Réanimation, GHU PSSD, Hôpital Jean Verdier, Bondy et Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France
| | - Nathalie Ganne-Carrié
- Groupe Hospitalier Paris Seine-Saint-Denis, Pôle d'Activités Cancérologiques Spécialisées, APHP, Hôpital Jean Verdier, Bondy et Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.,INSERM U1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris 5 , Paris, France
| | - Marianne Ziol
- APHP, Service d'Anatomie Pathologique, Hôpital Jean Verdier, Bondy et Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.,BB-0033-00027, Centre de Ressources Biologiques Maladies du Foie, Groupe Hospitalier Paris-Seine-Saint-Denis, Bondy, France
| | - Jean-Claude Trinchet
- Groupe Hospitalier Paris Seine-Saint-Denis, Pôle d'Activités Cancérologiques Spécialisées, APHP, Hôpital Jean Verdier, Bondy et Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.,INSERM U1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris 5 , Paris, France.,BB-0033-00027, Centre de Ressources Biologiques Maladies du Foie, Groupe Hospitalier Paris-Seine-Saint-Denis, Bondy, France
| | - Nicolas Sellier
- APHP, Service de Radiologie, Hôpital Jean Verdier, Bondy, France
| | - Abou Diallo
- Service d'Information Médicale, GHU PSSD, Hôpital Jean Verdier, Bondy, France
| | - Olivier Seror
- INSERM U1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris 5 , Paris, France.,APHP, Service de Radiologie, Hôpital Jean Verdier, Bondy, France
| | - Philippe Savarin
- Université Paris 13 , Sorbonne Paris Cité, CSPBAT, UMR 7244, CNRS, Bobigny, France
| |
Collapse
|
|
26
|
Wang H, Su G, Chen G, Bai J, Pei Y. 1H NMR-based metabonomics of the protective effect of Curcuma longa and curcumin on cinnabar-induced hepatotoxicity and nephrotoxicity in rats. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.04.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
|
|
27
|
Abstract
This paper aims to review the progress and problems in research of liver regeneration regulation in recent years and to explore the solutions to these problems by performing a systematic literature review combined with the author's work. In recent years, great progress has been made in preventing and treating liver diseases by regulating liver regeneration, for example, the coordination of promotion and inhibition, the reverse inhibition and positive induction, slight adjustment and preconditioning, and overall dynamic control. Current key scientific problems in this field include distinguishing between abnormal and normal liver regeneration, mechanisms underlying their mutual transformation, objective criteria for clinical application, and quantitative indicators for judging the efficacy. The regulation of liver regeneration for preventing and treating liver diseases has become a hot research topic, and the clinical translation and application of studies remain to be promoted on the basis of further in-depth research.
Collapse
|
|
28
|
Yang Y, Zheng L, Wang L, Wang S, Wang Y, Han Z. Effects of high fructose and salt feeding on systematic metabonome probed via (1) H NMR spectroscopy. MAGNETIC RESONANCE IN CHEMISTRY : MRC 2015; 53:295-303. [PMID: 25641270 DOI: 10.1002/mrc.4198] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/01/2014] [Accepted: 11/15/2014] [Indexed: 06/04/2023]
Abstract
Diets rich in high fructose and salt are increasingly popular in our daily life. A combination consumption of excessive fructose and salt can induce insulin resistance (IR) and hypertension (HT), which are major public health problems around the world. However, the effects of high fructose and salt on systematic metabonome remain unknown, which is very important for revealing the molecular mechanism of IR and HT induced by this dietary pattern. The metabolic profiling in urine, plasma, and fecal extracts from high fructose and salt-fed rats was investigated by use of (1) H nuclear magnetic resonance (NMR)-based metabonomics approach in this study. Multivariate analysis of NMR data showed the effects of high fructose and salt on the global metabonome. The metabolite analysis in urine and fecal extracts showed the time-dependent metabolic changes, which displayed metabonomic progression axes from normal to IR and HT status. The changes of 2-oxoglutarate, creatine and creatinine, citrate, hippurate, trimethylamine N-oxide (TMAO), and betaine in urine, together with gut microbiota disorder in feces, were observed at the preliminary formation stage of IR and HT (fourth week). At the severe stage (eighth week), the previously mentioned metabolic changes were aggravated, and the changes of lipid and choline metabolism in plasma suggested the increased risk of cardiovascular diseases. These findings provide an overview of biochemistry consequences of high fructose and salt feeding and comprehensive insights into the progression of systematic metabonome for IR and HT induced by this dietary pattern.
Collapse
Affiliation(s)
- Yongxia Yang
- School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | | | | | | | | | | |
Collapse
|
|
29
|
Wang P, Wang HP, Xu MY, Liang YJ, Sun YJ, Yang L, Li L, Li W, Wu YJ. Combined subchronic toxicity of dichlorvos with malathion or pirimicarb in mice liver and serum: A metabonomic study. Food Chem Toxicol 2014; 70:222-30. [DOI: 10.1016/j.fct.2014.05.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 05/15/2014] [Accepted: 05/19/2014] [Indexed: 01/08/2023]
|
|
30
|
Ginanni Corradini S, Siciliano M, Parlati L, Molinaro A, Cantafora A, Poli E, Mennini G, Melandro F, Vestri AR, Merli M, Bianco P, Corsi A, Toniutto P, Bitetto D, Falleti E, Attili AF, Berloco P, Rossi M. Recipient perioperative cholesterolaemia and graft cholesterol metabolism gene expression predict liver transplant outcome. Liver Int 2014; 34:e290-301. [PMID: 24256518 DOI: 10.1111/liv.12351] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 09/25/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS We analysed for the first time whether recipient perioperative serum total cholesterol (sTC) concentration is associated with liver transplantation outcome. METHODS We studied noncholestatic cirrhotics submitted to primary deceased-donor liver transplantation in a prospective group (n=140) from Rome and in a validation retrospective cohort (n=157) from Udine, Italy. Pre-ischaemia and post-reperfusion cholesterol metabolism gene mRNA was measured by RT-PCR in 74 grafts of the study group. RESULTS At Cox regression analysis, independently from confounders including recipient MELD score, the recipient pre-operative sTC pooled quintiles 2-5, compared with the lowest quintile showed HR (95% CI) and significances for overall graft loss (GL) of 0.215 (0.104-0.444) P<0.001 in the study group and 0.319 (0.167-0.610) P=0.001 in the validation cohort. Analysing sTC as a continuous variable, the risk of overall GL for every 10-mg/dl decrease in pre-operative sTC increased by 13% and by 9% in the study group and in the validation cohort respectively. In the study group, independent associations at multivariate analyses were: (a) high graft pre-ischaemia expression of INSIG-1, which indicates hepatocellular cholesterol depletion, with post-reperfusion graft necrosis; (b) GL with inadequate graft post-reperfusion response to cholesterol depletion, shown by a failure to reduce the PCSK9 to LDLR expression ratio; (c) GL with a relative increase of sTC on post-operative day-7, selectively because of the LDL fraction, which indirectly suggests poor cholesterol uptake from blood. CONCLUSIONS Low recipient pre-transplant sTC concentration, its post-operative day-7 increase and a genetically determined low graft cholesterol availability predict poor liver transplant outcome.
Collapse
Affiliation(s)
- Stefano Ginanni Corradini
- Division of Gastroenterology, Department of Clinical Medicine, University "Sapienza" of Rome, Rome, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Zou X, Holmes E, Nicholson JK, Loo RL. Statistical HOmogeneous Cluster SpectroscopY (SHOCSY): an optimized statistical approach for clustering of ¹H NMR spectral data to reduce interference and enhance robust biomarkers selection. Anal Chem 2014; 86:5308-15. [PMID: 24773160 PMCID: PMC4110102 DOI: 10.1021/ac500161k] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 04/28/2014] [Indexed: 12/24/2022]
Abstract
We propose a novel statistical approach to improve the reliability of (1)H NMR spectral analysis in complex metabolic studies. The Statistical HOmogeneous Cluster SpectroscopY (SHOCSY) algorithm aims to reduce the variation within biological classes by selecting subsets of homogeneous (1)H NMR spectra that contain specific spectroscopic metabolic signatures related to each biological class in a study. In SHOCSY, we used a clustering method to categorize the whole data set into a number of clusters of samples with each cluster showing a similar spectral feature and hence biochemical composition, and we then used an enrichment test to identify the associations between the clusters and the biological classes in the data set. We evaluated the performance of the SHOCSY algorithm using a simulated (1)H NMR data set to emulate renal tubule toxicity and further exemplified this method with a (1)H NMR spectroscopic study of hydrazine-induced liver toxicity study in rats. The SHOCSY algorithm improved the predictive ability of the orthogonal partial least-squares discriminatory analysis (OPLS-DA) model through the use of "truly" representative samples in each biological class (i.e., homogeneous subsets). This method ensures that the analyses are no longer confounded by idiosyncratic responders and thus improves the reliability of biomarker extraction. SHOCSY is a useful tool for removing irrelevant variation that interfere with the interpretation and predictive ability of models and has widespread applicability to other spectroscopic data, as well as other "omics" type of data.
Collapse
Affiliation(s)
- Xin Zou
- Medway
School of Pharmacy, Universities of Kent
and Greenwich, Anson
Building, Central Avenue, Chatham, Kent ME4 4TB, U.K.
| | - Elaine Holmes
- Section
of Biomolecular Medicine, Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
- MRC-HPA
Centre for Environment and Health, Imperial
College London, 150 Stamford
Street, London SE1 9NH, U.K.
| | - Jeremy K. Nicholson
- Section
of Biomolecular Medicine, Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
- MRC-HPA
Centre for Environment and Health, Imperial
College London, 150 Stamford
Street, London SE1 9NH, U.K.
| | - Ruey Leng Loo
- Medway
School of Pharmacy, Universities of Kent
and Greenwich, Anson
Building, Central Avenue, Chatham, Kent ME4 4TB, U.K.
- Section
of Biomolecular Medicine, Department of Surgery and Cancer, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.
| |
Collapse
|
|
32
|
Guan Q, Liang S, Wang Z, Yang Y, Wang S. ¹H NMR-based metabonomic analysis of the effect of optimized rhubarb aglycone on the plasma and urine metabolic fingerprints of focal cerebral ischemia-reperfusion rats. JOURNAL OF ETHNOPHARMACOLOGY 2014; 154:65-75. [PMID: 24685586 DOI: 10.1016/j.jep.2014.03.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 01/19/2014] [Accepted: 03/01/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The ischemia cerebrovascular disease is one of leading causes of death and long-term disability in modern society. Rhubarb is one of the common traditional Chinese medicine with many effects, and the main pharmacodynamic ingredients are aloe-emodin, rhein, emodin, chrysophanol and physcion. The five components are also known as rhubarb aglycone. Rhubarb aglycone has been confirmed to play a remarkable curative effect on cerebral ischemia, but the mechanism is not clear. In this study, (1)H NMR-based metabonomics approach has been used to investigate the protective effect of the optimized rhubarb aglycone on rats of cerebral ischemia-reperfusion. MATERIALS AND METHODS Male Wistar rats were divided into four groups: sham operation group, model group, Nimodipine group and the optimized rhubarb aglycone group. Based on (1)H-NMR spectra of plasma and urine, principal component analyses were performed to identify different metabolic markers and explore the changes of associated biochemical pathways. Behavior research and brain histopathology examinations were also performed. RESULTS It was showed that the optimized rhubarb aglycone treatment improved neurological deficits, cerebral infarction and neuronal apoptosis. Principal component analysis scores plots demonstrated that the cluster of model rats was separated from those of sham operation group; rats of the optimized rhubarb aglycone group were classified from model group, but the optimized rhubarb aglycone group closed to the sham operation group. Optimized rhubarb aglycone regulated the associated amino acid, energy and lipid metabolisms disturbed in model rats. CONCLUSION Our results suggested that the optimized rhubarb aglycone had protective effect on rats of cerebral ischemia-reperfusion and explored the metabolic regulation mechanism. This work showed that the NMR-based metabonomics approach might be a promising approach to study mechanisms of traditional Chinese medicines.
Collapse
Affiliation(s)
- Qinxiao Guan
- Department of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Shengwang Liang
- Department of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Zhanhong Wang
- Department of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | - Yongxia Yang
- School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
| | - Shumei Wang
- Department of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
| |
Collapse
|
|
33
|
Zhang Y, Deng Y, Zhao Y, Ren H. Using combined bio-omics methods to evaluate the complicated toxic effects of mixed chemical wastewater and its treated effluent. JOURNAL OF HAZARDOUS MATERIALS 2014; 272:52-58. [PMID: 24675614 DOI: 10.1016/j.jhazmat.2014.02.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Revised: 02/27/2014] [Accepted: 02/28/2014] [Indexed: 06/03/2023]
Abstract
Mixed chemical wastewaters (MCWW) from industrial park contain complex mixtures of trace contaminants, which cannot be effectively removed by wastewater treatment plants (WWTP) and have become an unignored threat to ambient environment. However, limited information is available to evaluate the complicated toxic effects of MCWW and its effluent from wastewater treatment plant (WTPE) from the perspective of bio-omics. In this study, mice were exposed to the MCWW and WTPE for 90 days and distinct differences in the hepatic transcriptome and serum metabolome were analyzed by digital gene expression (DGE) and proton nuclear magnetic resonance ((1)H-NMR) spectra, respectively. Our results indicated that disruption of lipid metabolism in liver and hepatotoxicity were induced by both MCWW and WTPE exposure. WTPE is still a health risk to the environment, which is in need of more attention. Furthermore, we demonstrated the potential ability of bio-omics approaches for evaluating toxic effects of MCWW and WTPE.
Collapse
Affiliation(s)
- Yan Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, Jiangsu, China
| | - Yongfeng Deng
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, Jiangsu, China
| | - Yanping Zhao
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, Jiangsu, China
| | - Hongqiang Ren
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, Jiangsu, China.
| |
Collapse
|
|
34
|
Miettinen TP, Pessa HKJ, Caldez MJ, Fuhrer T, Diril MK, Sauer U, Kaldis P, Björklund M. Identification of transcriptional and metabolic programs related to mammalian cell size. Curr Biol 2014; 24:598-608. [PMID: 24613310 PMCID: PMC3991852 DOI: 10.1016/j.cub.2014.01.071] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/20/2013] [Accepted: 01/30/2014] [Indexed: 12/16/2022]
Abstract
Background Regulation of cell size requires coordination of growth and proliferation. Conditional loss of cyclin-dependent kinase 1 in mice permits hepatocyte growth without cell division, allowing us to study cell size in vivo using transcriptomics and metabolomics. Results Larger cells displayed increased expression of cytoskeletal genes but unexpectedly repressed expression of many genes involved in mitochondrial functions. This effect appears to be cell autonomous because cultured Drosophila cells induced to increase cell size displayed a similar gene-expression pattern. Larger hepatocytes also displayed a reduction in the expression of lipogenic transcription factors, especially sterol-regulatory element binding proteins. Inhibition of mitochondrial functions and lipid biosynthesis, which is dependent on mitochondrial metabolism, increased the cell size with reciprocal effects on cell proliferation in several cell lines. Conclusions We uncover that large cell-size increase is accompanied by downregulation of mitochondrial gene expression, similar to that observed in diabetic individuals. Mitochondrial metabolism and lipid synthesis are used to couple cell size and cell proliferation. This regulatory mechanism may provide a possible mechanism for sensing metazoan cell size.
Gene expression and metabolites levels relative to cell size are analyzed in liver Mitochondrial gene expression is repressed cell-autonomously in larger cells Cell size can be modulated by targeting mitochondria functions and lipid synthesis Lipids are negative regulators of cell size because they promote cell proliferation
Collapse
Affiliation(s)
- Teemu P Miettinen
- Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Heli K J Pessa
- Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Matias J Caldez
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos #03-09, Singapore 138673, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore
| | - Tobias Fuhrer
- Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Wolfgang-Pauli Strasse 16, 8093 Zürich, Switzerland
| | - M Kasim Diril
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos #03-09, Singapore 138673, Singapore
| | - Uwe Sauer
- Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, Wolfgang-Pauli Strasse 16, 8093 Zürich, Switzerland
| | - Philipp Kaldis
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Proteos #03-09, Singapore 138673, Singapore; Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore
| | - Mikael Björklund
- Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
| |
Collapse
|
|
35
|
Bouhifd M, Hartung T, Hogberg HT, Kleensang A, Zhao L. Review: toxicometabolomics. J Appl Toxicol 2013; 33:1365-83. [PMID: 23722930 PMCID: PMC3808515 DOI: 10.1002/jat.2874] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 02/10/2013] [Accepted: 02/11/2013] [Indexed: 12/19/2022]
Abstract
Metabolomics use in toxicology is rapidly increasing, particularly owing to advances in mass spectroscopy, which is widely used in the life sciences for phenotyping disease states. Toxicology has the advantage of having the disease agent, the toxicant, available for experimental induction of metabolomics changes monitored over time and dose. This review summarizes the different technologies employed and gives examples of their use in various areas of toxicology. A prominent use of metabolomics is the identification of signatures of toxicity - patterns of metabolite changes predictive of a hazard manifestation. Increasingly, such signatures indicative of a certain hazard manifestation are identified, suggesting that certain modes of action result in specific derangements of the metabolism. This might enable the deduction of underlying pathways of toxicity, which, in their entirety, form the Human Toxome, a key concept for implementing the vision of Toxicity Testing for the 21st century. This review summarizes the current state of metabolomics technologies and principles, their uses in toxicology and gives a thorough overview on metabolomics bioinformatics, pathway identification and quality assurance. In addition, this review lays out the prospects for further metabolomics application also in a regulatory context.
Collapse
Affiliation(s)
| | - Thomas Hartung
- Correspondence to: T. Hartung, Johns Hopkins Bloomberg School of Public Health, Environmental Health Sciences, Chair for Evidence-based Toxicology, Center for Alternatives to Animal Testing, 615 N. Wolfe St., Baltimore, MD, 21205, USA.
| | | | | | | |
Collapse
|
|
36
|
Pauta M, Rotllan N, Vales F, Allen RM, Ford DA, Marí M, Jiménez W, Baldán Á, Morales-Ruiz M, Fernández-Hernando C, Fernández-Hernando C. Impaired liver regeneration in Ldlr-/- mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids. J Hepatol 2013; 59:731-7. [PMID: 23712050 PMCID: PMC4145584 DOI: 10.1016/j.jhep.2013.05.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 04/23/2013] [Accepted: 05/14/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS It is widely recognized that in the early stages of liver regeneration after partial hepatectomy, the hepatocytes accumulate a significant amount of lipids. The functional meaning of this transient steatosis and its effect on hepatocellular proliferation are not well defined. In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr). METHODS To address these questions, we studied the process of liver regeneration in Ldlr null mice and wild type mice following partial hepatectomy. RESULTS Ldlr deficiency was associated with a significant decrease in serum albumin concentration, during early stages of liver regeneration, and a delayed hepatic regeneration. Remnant livers of Ldlr(-)(/)(-) showed a time-shifted expression of interleukin-6 (IL6) and a defective activation of tumor necrosis factor-α (TNFα) and hepatocyte growth factor (HGF) expression in early phases of liver regeneration. Unexpectedly, Ldlr(-)(/)(-) showed no significant differences in the content of lipid droplets after partial hepatectomy compared to wild type mice. However, lipidomic analysis of the regenerating liver from Ldlr(-)(/)(-) revealed a lipid profile compatible with liver quiescence: high content of cholesterol esters and ceramide, and low levels of phosphatidylcholine. CONCLUSIONS Ldlr deficiency is associated with significant changes in the hepatic lipidome that affect cytokine-growth factor signaling and impair liver regeneration. These results suggest that the analysis of the hepatic lipidome may help predict the success of liver regeneration in the clinical environment, specifically in the context of pre-existing liver steatosis.
Collapse
Affiliation(s)
- Montse Pauta
- Centro Esther Koplowitz, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Noemi Rotllan
- Departments of Medicine, Leon H. Charney Division of Cardiology, and Cell Biology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
| | - Frances Vales
- Departments of Medicine, Leon H. Charney Division of Cardiology, and Cell Biology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
| | - Ryan M. Allen
- EdwardA. Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO, USA
| | - David A. Ford
- EdwardA. Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO, USA
| | - Montserrat Marí
- Department of Cell Death and Proliferation, IIBB-CSIC, Liver Unit-Hospital Clínic-IDIBAPS, CIBERehd, Barcelona, Spain
| | - Wladimiro Jiménez
- Centro Esther Koplowitz, IDIBAPS, CIBERehd, Barcelona, Spain,Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Barcelona, Spain,Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain
| | - Ángel Baldán
- EdwardA. Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO, USA
| | - Manuel Morales-Ruiz
- Centro Esther Koplowitz, IDIBAPS, CIBERehd, Barcelona, Spain,Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Carlos Fernández-Hernando
- Departments of Medicine, Leon H. Charney Division of Cardiology, and Cell Biology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
| | | |
Collapse
|
|
37
|
Xu W, Wang H, Chen G, Li W, Xiang R, Pei Y. (1)H NMR-based metabonomics study on the toxicity alleviation effect of other traditional Chinese medicines in Niuhuang Jiedu tablet to realgar (As2S2). JOURNAL OF ETHNOPHARMACOLOGY 2013; 148:88-98. [PMID: 23583735 DOI: 10.1016/j.jep.2013.03.073] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 03/24/2013] [Accepted: 03/25/2013] [Indexed: 05/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Niuhuang Jiedu Tablet (NJT) is an effective prescription of traditional Chinese medicine (TCM) used in treating acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. NJT is prepared from Xionghuang (Realgar, As2S2), Rengong Niuhuang (Bovis Calculus Artificialis), Bingpian (Borneolum Synthcticum), Shigao (Gypsum Fibrosum), Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix) and Gancao (Glycyrrhizae Radix et Rhizoma). In the prescription, significant level of realgar (As2S2) as a potentially toxic element is contained. AIM OF THE STUDY In this study, (1)H NMR-based metabonomics approach has been used to investigate the toxicity of realgar (As2S2) after being counterbalanced by other TCMs in NJT. MATERIALS AND METHODS Male Wistar rats were divided into five groups: control, group I (treated with Realgar), group II (treated with Realgar, Bovis Calculus Artificialis, Borneolum Synthcticum, Gypsum Fibrosum, Rhei Radix et Rhizoma, Scutellariae Radix, Platycodonis Radix and Glycyrrhizae Radix et Rhizoma), group III (treated with Realgar, Bovis Calculus Artificialis, Borneolum Synthcticum and Gypsum Fibrosum) and group IV (treated with Realgar, Rhei Radix et Rhizoma, Scutellariae Radix, Platycodonis Radix and Glycyrrhizae Radix et Rhizoma). Based on (1)H-NMR spectra of urine and serum from rats, PCA and PLS-DA were performed to identify different metabolic profiles. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed. RESULTS PLS-DA scores plots demonstrated that the cluster of group I was separated from that of control rats, while group II was located close to control rats, indicating that metabolic profiles of group II were restored toward those of control rats. The metabolic profiles of group III were similar to those of group I, while the metabolic profiles of group II were almost in line with those of group II. Statistics results were confirmed by the histopathological examination and biochemical assay. CONCLUSION Our results indicated that it was more secure and much less toxic for counterbalanced realgar (As2S2) in NJT. The effective material bases of toxicity alleviation to realgar (As2S2) were Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix) and Gancao (Glycyrrhizae Radix et Rhizoma), which regulated energy metabolism, choline metabolism, amino acid metabolism and gut flora disorder affected by realgar (As2S2) exposure.
Collapse
Affiliation(s)
- Wenfeng Xu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | | | | | | | | | | |
Collapse
|
|
38
|
Wang HP, Liang YJ, Sun YJ, Chen JX, Hou WY, Long DX, Wu YJ. 1H NMR-based metabonomic analysis of the serum and urine of rats following subchronic exposure to dichlorvos, deltamethrin, or a combination of these two pesticides. Chem Biol Interact 2013; 203:588-96. [PMID: 23566885 DOI: 10.1016/j.cbi.2013.03.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Revised: 03/25/2013] [Accepted: 03/28/2013] [Indexed: 12/27/2022]
Abstract
Metabonomic analysis, clinical chemical analysis and histopathology were used to investigate the toxic effects of subchronic exposure to dichlorvos, deltamethrin, and a combination of these two pesticides, in rats. Weight loss, hind limb weakness and histopathological changes in kidney tissue were only observed in rats exposed to high doses of deltamethrin, or a combination of deltamethrin and dichlorvos. Urinary metabonomic analysis indicated that exposure to a mixture of dichlorvos and deltamethrin was followed by increases in urinary lactate, dimethylamine, N-glycoprotein (NAC) and glycine similar to those observed in rats treated with either dichlorvos or deltamethrin alone. Serum metabonomic analysis suggests that dichlorvos induced an increase in lactate and alanine and a decrease in dimethylglycine (DMG), NAC and very low- and low-density lipoprotein (VLDL/LDL). High levels of lactate and low levels of NAC and VLDL/LDL were observed in the deltamethrin treatment group. Treating rats with a mixture of dichlorvos and deltamethrin caused an increase in serum lactate, trimethylamine-N-oxide (TMAO), choline and alanine, with the highest levels of these metabolites observed in those that received the highest dose. Exposure to a mixture of dichlorvos and deltamethrin also resulted in a decrease in serum acetone, DMG, NAC, and VLDL/LDL. Changes in serum TMAO, alanine, choline and acetone in this treatment group were higher than in rats treated with either dichlorvos or deltamethrin. These results suggest that exposing rats to subchronic doses of dichlorvos, deltamethrin, or a combination of these pesticides, disrupted the energy metabolism of the liver and reduced kidney function.
Collapse
Affiliation(s)
- Hui-Ping Wang
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beichenxi Road, Beijing 100101, PR China
| | | | | | | | | | | | | |
Collapse
|
|
39
|
Samino S, Revuelta-Cervantes J, Vinaixa M, Rodríguez MÁ, Valverde AM, Correig X. A (1)H NMR metabolic profiling to the assessment of protein tyrosine phosphatase 1B role in liver regeneration after partial hepatectomy. Biochimie 2012; 95:808-16. [PMID: 23246914 DOI: 10.1016/j.biochi.2012.11.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 11/28/2012] [Indexed: 11/24/2022]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the tyrosine kinase growth factor signaling pathway, which is involved in major physiological mechanisms such as liver regeneration. We investigate early hepatic metabolic events produced by partial hepatectomy (PHx) for PTP1B deficient (PTP1B KO) and wild type (WT) mice using proton nuclear magnetic resonance spectroscopy. Metabolic response of the two genotypes produced 24 h upon PHx is compared using magic angle spinning high-resolution nuclear magnetic resonance ((1)H-HR-MAS-NMR) on intact liver tissues. In addition, genotype-associated metabolic profile changes were monitored during the first 48 h after PHx using high-resolution nuclear magnetic resonance ((1)H-HR-NMR) on liver extracts. A marked increase of lipid-related signals in regenerating livers was observed after 24 h PHx in either intact tissues or liver extracts studies. In spite of this common initial metabolic response, results obtained 48 h after PHx on liver extracts indicate a genotype-differential metabolic pattern. This metabolic pattern resulted in line with well known regenerative features such as more sustained cell proliferation, a better management of lipids as energy fuel and lessened liver injury for PTP1B KO mice as compared to WT. Taken together, these findings suggest the metabolic basis to the pivotal role of PTP1B in liver regeneration.
Collapse
Affiliation(s)
- Sara Samino
- Metabolomics Platform, IISPV, Universitat Rovira i Virgili, Avda. Països Catalans, 26, 43007 Tarragona, Spain
| | | | | | | | | | | |
Collapse
|
|
40
|
Zira A, Kostidis S, Theocharis S, Sigala F, Engelsen SB, Andreadou I, Mikros E. 1H NMR-based metabonomics approach in a rat model of acute liver injury and regeneration induced by CCl4 administration. Toxicology 2012; 303:115-24. [PMID: 23146765 DOI: 10.1016/j.tox.2012.10.015] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Revised: 10/12/2012] [Accepted: 10/13/2012] [Indexed: 11/28/2022]
Abstract
The administration of carbon tetrachloride (CCl(4)) has been established as a model of toxin-induced acute and chronic liver injury. In the present study, we investigate the progression of the biochemical response to acute CCl(4)-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma. A single dose of CCl(4) (1 mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12h up to 72 h post treatment, while healthy animals served as controls. Acquired (1)H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury. The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36 h) and those at the regenerative phase (peaked at 48 h). At 72 h normalization of liver's pathology similar to the controls group was apparent. Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state. A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl(4) induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions. The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl(4) metabolism.
Collapse
Affiliation(s)
- Athina Zira
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimioupolis Zografou, 15771 Athens, Greece
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Coen M, Rademacher PM, Zou W, Scott M, Ganey PE, Roth R, Nelson SD. Comparative NMR-Based Metabonomic Investigation of the Metabolic Phenotype Associated with Tienilic Acid and Tienilic Acid Isomer. Chem Res Toxicol 2012; 25:2412-22. [DOI: 10.1021/tx3002803] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Muireann Coen
- Biomolecular
Medicine, Department
of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom
| | - Peter M. Rademacher
- Department of Medicinal Chemistry, University of Washington, 1959 NE Pacific Street, Health
Sciences Building, Seattle, Washington 98195-7610, United States
| | - Wei Zou
- Department of Microbiology and
Molecular Genetics, 2215 Biomedical Physical Sciences, Michigan State University, East Lansing, Michigan 48824-1302,
United States
| | - Michael Scott
- Department
of Pathobiology and
Diagnostic Investigation, G-347 Veterinary Medical Center, Michigan State University, East Lansing, Michigan 48824-1314,
United States
| | - Patricia E. Ganey
- Department
of Pharmacology and
Toxicology, 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, Michigan 48824-1302,
United States
| | - Robert Roth
- Department
of Pharmacology and
Toxicology, 221 Food Safety and Toxicology Building, Michigan State University, East Lansing, Michigan 48824-1302,
United States
| | - Sidney D. Nelson
- Department of Medicinal Chemistry, University of Washington, 1959 NE Pacific Street, Health
Sciences Building, Seattle, Washington 98195-7610, United States
| |
Collapse
|
|
42
|
Tang B, Ding J, Wu F, Chen L, Yang Y, Song F. 1H NMR-based metabonomics study of the urinary biochemical changes in Kansui treated rat. JOURNAL OF ETHNOPHARMACOLOGY 2012; 141:134-142. [PMID: 22406398 DOI: 10.1016/j.jep.2012.02.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 01/09/2012] [Accepted: 02/07/2012] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The dried root of Kansui (Euphorbia kansui L.) is a commonly used and effective traditional Chinese medicine (TCM). AIM OF THE STUDY We combined the urinary metabolites alteration and traditional assays of Kansui-induced rats to discuss the mechanism of toxicity of Kansui. MATERIALS AND METHODS The Sprague-Dawley rats were dosed with 7.875g Kansui/kg weight and 15.75g Kansui/kg weight. Urine samples were collected at day -1 (before treatment), and days 7, 14 and 21 for NMR analysis. Plasma and liver and kidney tissues were collected at day 14 for biochemical assays and histopathological examination, respectively. RESULTS The metabonome of rats treated with Kansui differed markedly from that of the controls. This was confirmed by the histopathology of liver and kidney tissue and clinical biochemistry analysis. The toxicity of Kansui accumulated with dosing time, and persisted even when treatment was stopped. The corresponding biochemical pathways alterations included inhibited TCA cycle, increased anaerobic glycolysis, and perturbed amino acids metabolism. CONCLUSION The biochemical pathways disorder conjunction with histopathology changes provides new clues to evaluate the toxicity of Kansui from a systematic and holistic view.
Collapse
Affiliation(s)
- Bingwen Tang
- Department of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
| | | | | | | | | | | |
Collapse
|
|
43
|
Cantor GH, Beckonert O, Bollard ME, Keun HC, Ebbels TMD, Antti H, Wijsman JA, Bible RH, Breau AP, Cockerell GL, Holmes E, Lindon JC, Nicholson JK. Integrated Histopathological and Urinary Metabonomic Investigation of the Pathogenesis of Microcystin-LR Toxicosis. Vet Pathol 2012; 50:159-71. [DOI: 10.1177/0300985812443839] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Patterns of change of endogenous metabolites may closely reflect systemic and organ-specific toxic changes. The authors examined the metabolic effects of the cyanobacterial (blue-green algal) toxin microcystin-LR by 1H-nuclear magnetic resonance (NMR) analysis of urinary endogenous metabolites. Rats were treated with a single sublethal dose, either 20 or 80 µg/kg intraperitoneally, and sacrificed at 2 or 7 days post dosing. Changes in the high-dose, 2-day sacrifice group included centrilobular hepatic necrosis and congestion, accompanied in some animals by regeneration and neovascularization. By 7 days, animals had recovered, the necrotizing process had ended, and the centrilobular areas had been replaced by regenerative, usually hypertrophic hepatocytes. There was considerable interanimal variation in the histologic process and severity, which correlated with the changes in patterns of endogenous metabolites in the urine, thus providing additional validation of the biomarker and biochemical changes. Similarity of the shape of the metabolic trajectories suggests that the mechanisms of toxic effects and recovery are similar among the individual animals, albeit that the magnitude and timing are different for the individual animals. Initial decreases in urinary citrate, 2-oxoglutarate, succinate, and hippurate concentrations were accompanied by a temporary increase in betaine and taurine, then creatine from 24 to 48 hours. Further changes were an increase in guanidinoacetate, dimethylglycine, urocanic acid, and bile acids. As a tool, urine can be repeatedly and noninvasively sampled and metabonomics utilized to study the onset and recovery after toxicity, thus identifying time points of maximal effect. This can help to employ histopathological examination in a guided and effective fashion.
Collapse
Affiliation(s)
- G. H. Cantor
- Discovery Toxicology, Bristol-Myers Squibb Co., Princeton, NJ, USA
| | - O. Beckonert
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| | - M. E. Bollard
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| | - H. C. Keun
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| | - T. M. D. Ebbels
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| | - H. Antti
- Department of Chemistry, Umeå, Sweden
| | | | - R. H. Bible
- Global Drug Metabolism, Pharmacia Corp., Skokie IL, USA
- Deceased
| | - A. P. Breau
- Biologics Development Services, Sarasota, FL, USA
| | | | - E. Holmes
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| | - J. C. Lindon
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| | - J. K. Nicholson
- Department of Surgery and Cancer, Biomolecular Medicine, Faculty of Medicine, Imperial College London, South Kensington, London, UK
| |
Collapse
|
|
44
|
Li F, Gonzalez FJ, Ma X. LC–MS-based metabolomics in profiling of drug metabolism and bioactivation. Acta Pharm Sin B 2012. [DOI: 10.1016/j.apsb.2012.02.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
|
|
45
|
Zhang Y, Zhang X, Wu B, Cheng S. Evaluating the transcriptomic and metabolic profile of mice exposed to source drinking water. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2012; 46:78-83. [PMID: 21793498 DOI: 10.1021/es201369x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Transcriptomic and metabonomic methods were used to investigate mice's responses to drinking source water (DSW) exposure. After mice were fed with DSW for 90 days, hepatic transcriptome was characterized by microarray and serum metabonome were determined by (1)H nuclear magnetic resonance (NMR) spectroscopy. A total of 243 differentially expressed genes (DEGs) were identified, among which 141 genes were up-regulated and 102 genes were down-regulated. Metabonomics revealed significant changes in concentrations of creatine, pyruvate, glutamine, lysine, choline, acetate, lipids, taurine, and trimethylamine oxide. Four biological pathways were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis where both gene expression and metabolite concentrations were altered in response to DSW exposure. These results highlight the significance of combined use of transcriptomic and metabonomic approaches in evaluating potential health risk induced by DSW contaminated with various hazardous materials.
Collapse
Affiliation(s)
- Yan Zhang
- State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, Jiangsu 210046, China
| | | | | | | |
Collapse
|
|
46
|
Zhang H, Jia J, Cheng J, Ye F, Li X, Gao H. 1H NMR-based metabonomics study on serum of renal interstitial fibrosis rats induced by unilateral ureteral obstruction. ACTA ACUST UNITED AC 2012; 8:595-601. [DOI: 10.1039/c1mb05311f] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
|
|
47
|
Feng J, Liu H, Bhakoo KK, Lu L, Chen Z. A metabonomic analysis of organ specific response to USPIO administration. Biomaterials 2011; 32:6558-69. [PMID: 21641028 DOI: 10.1016/j.biomaterials.2011.05.035] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 05/10/2011] [Indexed: 02/08/2023]
Abstract
As ultrasmall superparamagnetic particles of iron oxides (USPIO) have been widely used in clinical medicine as MRI contrast agents, hence their potential toxicity and adverse effects following administration have attracted particular attention. In the present study, high resolution magic-angle-spinning (1)H NMR spectroscopy coupled with multivariate statistical analysis was used to directly determine the metabolic consequences of specific-tissues, including kidney, liver and spleen following the intravenous administration of USPIO. Alterations of renal, hepatic and splenic function were reflected by changes in a number of metabolic pathways including small molecules involved in energy, lipid, glucose, and amino acids metabolism. The toxicological potential and metabolic fate of USPIO seems to be linked to their surface chemistry and particle size. Hierarchical principal component analysis was used to explore the multidimensional metabolic relationships between various biological matrices such as kidney, liver, spleen, plasma and urine. Information on the involvement of USPIO in transportation, absorption, biotransformation, biodistribution and secretion was derived from metabolic correlation analysis between different organs and biofluids. Such a metabonomic strategy provides methodology for investigating the potential adverse biological effects of similar nanoparticles on the environmental and human health and assessing the drug interventions on the targeted organ.
Collapse
Affiliation(s)
- Jianghua Feng
- Department of Electronic Science, Fujian Key Laboratory of Plasma and Magnetic Resonance, State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, China.
| | | | | | | | | |
Collapse
|
|
48
|
Delgado-Coello B, Briones-Orta MA, Macías-Silva M, Mas-Oliva J. Cholesterol: recapitulation of its active role during liver regeneration. Liver Int 2011; 31:1271-84. [PMID: 21745289 DOI: 10.1111/j.1478-3231.2011.02542.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Liver regeneration is a compensatory hyperplasia produced by several stimuli that promotes proliferation in order to provide recovery of the liver mass and architecture. This process involves complex signalling cascades that receive feedback from autocrine and paracrine pathways, recognized by parenchymal as well as non-parenchymal cells. Nowadays the dynamic role of lipids in biological processes is widely recognized; however, a systematic analysis of their importance during liver regeneration is still missing. Therefore, in this review we address the role of lipids including the bioactive ones such as sphingolipids, but with special emphasis on cholesterol. Cholesterol is not only considered as a structural component but also as a relevant lipid involved in the control of the intermediate metabolism of different liver cell types such as hepatocytes, hepatic stellate cells and Kupffer cells. Cholesterol plays a significant role at the level of specific membrane domains, as well as modulating the expression of sterol-dependent proteins. Moreover, several enzymes related to the catabolism of cholesterol and whose activity is down regulated are related to the protection of liver tissue from toxicity during the process of regeneration. This review puts in perspective the necessity to study and understand the basic mechanisms involving lipids during the process of liver regeneration. On the other hand, the knowledge acquired in this area in the past years, can be considered invaluable in order to provide further insights into processes such as general organogenesis and several liver-related pathologies, including steatosis and fibrosis.
Collapse
Affiliation(s)
- Blanca Delgado-Coello
- Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México, DF Mexico
| | | | | | | |
Collapse
|
|
49
|
Xu C, Chen X, Chang C, Wang G, Wang W, Zhang L, Zhu Q, Wang L, Zhang F. Genome-wide expression profiling of hepatic oval cells after partial hepatectomy in rats. Tissue Cell 2011; 43:291-303. [PMID: 21764095 DOI: 10.1016/j.tice.2011.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Revised: 06/03/2011] [Accepted: 06/06/2011] [Indexed: 11/15/2022]
Abstract
To examine the changes of biological activities in hepatic oval cells (HOCs) elicited by 70% partial hepatectomy (PH) and understand the relationship between this cell and liver regeneration (LR), this study isolated and obtained the high purity HOCs (≥ 95%) from rat regenerating livers, and then monitored gene expression profiling of rat hepatic oval cells following surgical operation. Results showed that there were LR-related 1059 genes. These genes were grossly classified into three groups using a fold change cut-off threshold of three-fold: up-regulation, down-regulation and up/down regulation. Analyses of gene expression patterns combined with gene functional categorization suggested that genes in the categories "nucleic acid metabolism" and "cell cycle" were dominated by up-regulated expression. Genes in the functional groups "cell metabolism" and "oxidation reduction" were significantly enriched in expression pattern characterized by down-regulation. According to above mentioned results, the synchronized induction of DNA replication and cell proliferation-involved genes suggested that the peak of oval cell proliferation might occur between 30 and 36 h post-PH. The amino acid transformation-involved genes were down-regulated at the early phase of LR, which perhaps trigger the storage of those amino acids essential for protein synthesis. Reduced oxidative-reduction activity at early phase might be related to negative influence of surgical operation on its detoxification capacity. Conclusively, the genome-wide transcriptional analysis of oval cells would contribute to our understanding of the nature of LR at cell level.
Collapse
Affiliation(s)
- Cunshuan Xu
- College of Life Science, Henan Normal University, Xinxiang 453007, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Aoki M, Konya Y, Takagaki T, Umemura K, Sogame Y, Katsumata T, Komuro S. Metabolomic investigation of cholestasis in a rat model using ultra-performance liquid chromatography/tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2011; 25:1847-1852. [PMID: 21638360 DOI: 10.1002/rcm.5072] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Metabolomics follows the changes in concentrations of endogenous metabolites, which may reflect various disease states as well as systemic responses to environmental, therapeutic, or genetic interventions. In this study, we applied metabolomic approaches to monitor dynamic changes in plasma and urine metabolites, and compared these metabolite profiles in Eisai hyperbilirubinemic rats (EHBR, an animal model of cholestasis) with those in the parent strain of EHBR - Sprague-Dawley (SD) rats - in order to characterize cholestasis pathophysiologically. Ultra-performance liquid chromatography/tandem mass spectrometry-based analytical methods were used to assay metabolite levels. More than 250 metabolites were detected in both plasma and urine, and metabolite profiles of EHBR differed from those of SD rats. The levels of antioxidative and cytoprotective metabolites, taurine and hypotaurine, were markedly increased in urine of EHBR. The levels of many bile acids were also elevated in plasma and urine of EHBR, but the extent of elevation depended on the particular bile acid. The levels of cytoprotective ursodeoxycholic acid and its conjugates were markedly elevated, while that of cytotoxic chenodeoxycholic acid remained unchanged, suggesting the balance of bile acids had shifted resulting in decreased toxicity. In EHBR, reduced biliary excretion leads to increased systemic exposure to harmful compounds including some endogenous metabolites. Our metabolomic data suggest that mechanisms exist in EHBR that compensate for cholestasis-related damage.
Collapse
Affiliation(s)
- Masayo Aoki
- Pharmacokinetics Research Laboratories, Dainippon Sumitomo Pharma. Co., Ltd., 3-1-98 Kasugade-naka, Osaka 554-0022, Japan.
| | | | | | | | | | | | | |
Collapse
|