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      Metabonomics window into plateau hypoxia

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          Abstract

          Oxygen deficiency in the plateau environment weakens aerobic metabolism and reduces the energy supply, leading to high-altitude diseases including decreased circulatory function, decreased nutrient and energy supply to tissues and organs, and decreased waste discharge. The involvement of many metabolic pathways is reflected in dramatic changes in levels of endogenous small molecule metabolites. Metabolomics represents a promising technique for mechanistic studies and drug screening, and metabonomics, or quantitative metabolomics, has been increasingly applied to the study of hypoxic diseases and their pathogenesis, as well as to pharmacodynamics at high altitudes. In this article, we review the recent literature on the pathogenesis of altitude hypoxia and the clinical and preclinical metabonomics of drug interventions. Endogenous metabolites and metabolic pathways change significantly under high-altitude hypoxia. Some drug interventions have also been shown to regulate pathway metabolism, and the problems of applying metabonomics to hypoxic diseases at high altitude and the prospects for its future application are summarized.

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          Most cited references39

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          Opinion: understanding 'global' systems biology: metabonomics and the continuum of metabolism.

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            Pharmaco-metabonomic phenotyping and personalized drug treatment.

            There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.
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              AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.

              Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.
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                Author and article information

                Journal
                J Int Med Res
                J. Int. Med. Res
                IMR
                spimr
                The Journal of International Medical Research
                SAGE Publications (Sage UK: London, England )
                0300-0605
                1473-2300
                09 October 2019
                November 2019
                : 47
                : 11
                : 5441-5452
                Affiliations
                [1 ]Department of Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People’s Armed Police Force, Tianjin, China
                [2 ]Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment, Tianjin, China
                [3 ]Division of Gastroenterology and Hepatology, Tianjin Xiqing Hospital, Tianjin, China
                Author notes
                [*]Hai Li, Division of Gastroenterology and Hepatology, Tianjin Xiqing Hospital, No. 403 Xiqing Road, Xiqing District, Tianjin 300380, China. Email: haili_tj@ 123456sina.com Shihai Xia, Department of Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People’s Armed Police Force, Tianjin 300162, China. Email: xiash@ 123456163.com
                Author information
                https://orcid.org/0000-0001-9563-6842
                Article
                10.1177_0300060519879323
                10.1177/0300060519879323
                6862876
                31594434
                f0120fac-60db-4acd-b7f0-2ec15f717a4e
                © The Author(s) 2019

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 29 June 2019
                : 9 September 2019
                Funding
                Funded by: Tianjin Science and Technology Project;
                Award ID: 15ZXLCSY00040
                Funded by: National Major Science and Technology Projects in the 13th Five-Year Plan ;
                Award ID: 2018ZX10732-202-004-005
                Categories
                Review

                high altitude,hypoxia,metabonomics,metabolic pathway,drug intervention,metabolite

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