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      Comparative metabonomics of Wenxin Keli and Verapamil reveals differential roles of gluconeogenesis and fatty acid β-oxidation in myocardial injury protection

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          Abstract

          Metabonomics/metabolomics is a rapid technology for comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, the application of which has led to understanding pathophysiologic mechanisms of cardiometabolic diseases, defining predictive biomarkers for those diseases, and also assessing the efficacious effects of incident drugs. In this study, proton nuclear magnetic resonance (NMR)-based metabonomics was employed to identify the metabolic changes in rat plasma caused by myocardial ischemia-reperfusion injury (MIRI), and to compare the metabolic regulatory differences between traditional Chinese medicine Wenxin Keli (WXKL) and Western medicine verapamil. The results revealed that energy-substrate metabolism were significantly disturbed by ischemia-reperfusion (I/R) in myocardium and bulk of the key metabolites could be further modulated by verapamil and/or WXKL. Lipid metabolism and amino acid transamination occurred mainly following the treatment of verapamil, whereas glucose oxidation and BCAA degradation were prominently ameliorated by WXKL to content the energy demands of heart. Moreover, both WXKL and verapamil improved the secretions of taurine and ketone bodies to overcome the oxidative stress and the shortage of energy sources induced by ischemia-reperfusion.

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          Myocardial fatty acid metabolism in health and disease.

          There is a constant high demand for energy to sustain the continuous contractile activity of the heart, which is met primarily by the beta-oxidation of long-chain fatty acids. The control of fatty acid beta-oxidation is complex and is aimed at ensuring that the supply and oxidation of the fatty acids is sufficient to meet the energy demands of the heart. The metabolism of fatty acids via beta-oxidation is not regulated in isolation; rather, it occurs in response to alterations in contractile work, the presence of competing substrates (i.e., glucose, lactate, ketones, amino acids), changes in hormonal milieu, and limitations in oxygen supply. Alterations in fatty acid metabolism can contribute to cardiac pathology. For instance, the excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. Furthermore, alterations in fatty acid beta-oxidation both during and after ischemia and in the failing heart can also contribute to cardiac pathology. This paper reviews the regulation of myocardial fatty acid beta-oxidation and how alterations in fatty acid beta-oxidation can contribute to heart disease. The implications of inhibiting fatty acid beta-oxidation as a potential novel therapeutic approach for the treatment of various forms of heart disease are also discussed.
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            Taurine: new implications for an old amino acid.

            Taurine is a semi-essential amino acid and is not incorporated into proteins. In mammalian tissues, taurine is ubiquitous and is the most abundant free amino acid in the heart, retina, skeletal muscle, brain, and leukocytes. In fact, taurine reaches up to 50 mM concentration in leukocytes. Taurine has been shown to be tissue-protective in many models of oxidant-induced injury. One possibility is that taurine reacts with hypochlorous acid, produced by the myeloperoxidase pathway, to produce the more stable but less toxic taurine chloramine (Tau-Cl). However, data from several laboratories demonstrate that Tau-Cl is a powerful regulator of inflammation. Specifically, Tau-Cl has been shown to down-regulate the production of pro-inflammatory mediators in both rodent and human leukocytes. Taurolidine, a derivative of taurine, is commonly used in Europe as an adjunctive therapy for various infections as well as for tumor therapy. Recent molecular studies on the function of taurine provide evidence that taurine is a constituent of biologic macromolecules. Specifically, two novel taurine-containing modified uridines have been found in both human and bovine mitochondria. Studies investigating the mechanism of action of Tau-Cl have shown that it inhibits the activation of NF-kappaB, a potent signal transducer for inflammatory cytokines, by oxidation of IkappaB-alpha at Met45. Key enzymes for taurine biosynthesis have recently been cloned. Cysteine sulfinic acid decarboxylase, a rate-limiting enzyme for taurine biosynthesis, has been cloned and sequenced in the mouse, rat and human. Another key enzyme for cysteine metabolism, cysteine dioxygenase (CDO), has also been cloned from rat liver. CDO has a critical role in determining the flux of cysteine between cysteine catabolism/taurine synthesis and glutathione synthesis. Taurine transporter knockout mice show reduced taurine, reduced fertility, and loss of vision due to severe apoptotic retinal degeneration. Apoptosis induced by amino chloramines is a current and important finding since oxidants derived from leukocytes play a key role in killing pathogens. The fundamental importance of taurine in adaptive and acquired immunity will be unveiled using genetic manipulation.
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              Ketone body metabolism and its defects.

              Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total ketone body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of ketone body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with "mild" SCOT mutations may have nonketotic periods. T2-deficient patients with "mild" mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.
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                Author and article information

                Contributors
                fgw1005@163.com
                yanzhu.harvard@gmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                18 August 2017
                18 August 2017
                2017
                : 7
                : 8739
                Affiliations
                [1 ]ISNI 0000 0001 1816 6218, GRID grid.410648.f, Tianjin State Key Laboratory of Modern Chinese Medicine, , Tianjin University of Traditional Chinese Medicine, ; Tianjin, China
                [2 ]ISNI 0000 0004 1799 2712, GRID grid.412635.7, , First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, ; Tianjin, China
                [3 ]ISNI 0000 0001 0662 3178, GRID grid.12527.33, Institute of Materia Medica, , Chinese Academy of Medical Sciences & Peking Union Medical College, ; Beijing, China
                Article
                9547
                10.1038/s41598-017-09547-w
                5562700
                28821850
                b4eba947-9be3-4c05-86c2-8ba7402ad498
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 25 January 2017
                : 24 July 2017
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