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      Metabonomics delineates allergic reactions induced by Shuang-huang-lian injection in rats using ultra performance liquid chromatography-mass spectrometry

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          Abstract

          Shuang-huang-lian Injection (SHLI) is the first successfully developed drug from traditional Chinese medicine (TCM) powder for injection, since its use for the treatment of acute respiratory tract infection, pneumonia, influenza, etc. At the same time, its allergic reactions have also emerged, which limits clinical applications. However, few scholars pay attention to the mechanism of allergic reactions. In this present study, metabonomics technology was used to explore the changes in endogenous metabolites in urine of the rat model of SHLI induced allergic reaction; we and analyzed the metabolites, metabolic pathway, and the mechanism which were closely related to the allergic reactions. The levels of serum histamine and tryptase were examined and changes in histomorphol-ogy were also observed. Based on the UPLC-Q-TOF/MS metabonomics, we carried out the pattern recognition analysis, selected potential biomarkers associated with allergic reactions, and explored the pathological mechanism for SHLI induced allergic reaction, which laid the foundation for the safety research of SHLI. Our results showed that SHLI increased the levels of serum histamine and tryptase in rats with allergic reaction; we determined 15 biomarkers in rat allergic reaction model induced by SHLI and found multiple metabolic pathways involved, such as metabolism of linolenic acid, phenylalanine, amino acid, 2-oxo acid, and purine and other metabolic pathways.

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          Most cited references 48

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          Intrarenal metabolomic investigation of chronic kidney disease and its TGF-β1 mechanism in induced-adenine rats using UPLC Q-TOF/HSMS/MS(E).

          Chronic kidney disease (CKD) is becoming a worldwide public health problem. In this study, a kidney metabonomics method based on the ultra performance liquid chromatography/high-sensitivity mass spectrometry with MS(E) data collection technique was undertaken to explore the excretion pattern of low molecular mass metabolites in rat model of adenine-induced chronic renal failure (CRF). Coupled with blood biochemistry and kidney histopathology results, the significant difference in metabolic profiling between the adenine-induced CRF group and the control group by using pattern recognition analysis indicated that changes in global tissue metabolites were occurred. Some significantly changed metabolites like fatty acids, p-cresol sulfate, and indoxyl sulfate have been identified. The results showed that the most important CRF-related metabolites were polyunsaturated fatty acids, indoxyl sulfate, and p-cresyl sulfate. Indoxyl sulfate and p-cresyl sulfate (uremic toxins) were significantly increased in CRF rats. Indoxyl sulfate and p-cresyl sulfate stimulate progressive tubulointerstitial fibrosis by increasing the expression of transforming growth factor-β1 (TGF-β1). These biochemical changes in tissue metabolites are related to the perturbations of fatty acid metabolism and amino metabolism, which may be helpful to further understand the TGF-β1 mechanisms of tubulointerstitial fibrosis. This work shows that the metabonomics method is a valuable tool for studying the essence of CKD.
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            Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression

            Early detection is critical in prevention and treatment of kidney disease. However currently clinical laboratory and histopathological tests do not provide region-specific and accurate biomarkers for early detection of kidney disease. The present study was conducted to identify sensitive biomarkers for early detection and progression of tubulo-interstitial nephropathy in aristolochic acid I-induced rats at weeks 4, 8 and 12. Biomarkers were validated using aristolochic acid nephropathy (AAN) rats at week 24, adenine-induced chronic kidney disease (CKD) rats and CKD patients. Compared with control rats, AAN rats showed anemia, increased serum urea and creatinine, progressive renal interstitial fibrosis, activation of nuclear factor-kappa B, and up-regulation of pro-inflammatory, pro-oxidant, and pro-fibrotic proteins at weeks 8 and 12. However, no significant difference was found at week 4. Metabolomics identified 12-ketodeoxycholic acid, taurochenodesoxycholic acid, LPC(15:0) and docosahexaenoic acid as biomarkers for early detection of tubulo-interstitial nephropathy. With prolonging aristolochic acid I exposure, LPE(20:2), cholic acid, chenodeoxycholic acid and LPC(17:0) were identified as biomarkers for progression from early to advanced AAN and lysoPE(22:5), indoxyl sulfate, uric acid and creatinine as biomarkers of advanced AAN. These biomarkers were reversed by treatment of irbesartan and ergone in AAN rats at week 24 and adenine-induced CKD rats. In addition, these biomarkers were also reversed by irbesartan treatment in CKD patients.
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              Urinary metabonomics study on biochemical changes in an experimental model of chronic renal failure by adenine based on UPLC Q-TOF/MS.

              Chronic renal failure (CRF) is a serious clinical symptom, occurring as the end result of all kinds of chronic kidney disease and its pathophysiological mechanism is not yet well understood. We investigated the metabolic profiling of urine samples from CRF model rats to find potential disease biomarkers and research pathology of CRF. An animal model of CRF was produced by adenine. Metabolic profiling of the urine was performed by using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC Q-TOF/MS). Acquired data were subjected to principal component analysis (PCA) for differentiating the CRF and the normal control groups. Potential biomarkers were screened by using S-plot and were identified by the accurate mass, isotopic pattern and MS(E) fragments information obtained from UPLC Q-TOF/MS analysis. 12 metabolites in urine were identified as potential biomarkers. Adenine-induced CRF rats were characterized by the increase of phytosphingosine, adrenosterone, tryptophan, 2,8-dihydroxyadenine, creatinine, and dihydrosphingosine together with the decrease of N-acetylleucine, 3-O-methyldopa, ethyl-N2-acetyl-L-argininate, dopamine, phenylalanine and kynurenic acid in urine. The altered metabolites demonstrated perturbations of amino acids metabolism, phospholipids metabolism and creatinine metabolism in CRF rats. This work shows that metabonomics method is a valuable tool in CRF mechanism study and assists in clinical diagnosis of CRF. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                CJNM
                Chinese Journal of Natural Medicines
                Elsevier
                1875-5364
                20 August 2018
                : 16
                : 8
                : 628-640
                Affiliations
                1Research Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin 150040, China
                2First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin 150040, China
                Author notes
                *Corresponding author: CHEN Da-Zhong, Tel: 86-451-87266836, E-mail: 1259779868@ 123456qq.com

                These authors have no conflict of interest to declare.

                Article
                S1875-5364(18)30101-8
                10.1016/S1875-5364(18)30101-8
                Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
                Funding
                Funded by: Research and Development Projects of Application of Technology of Heilongjiang Province in China
                Award ID: GC13C109
                Funded by: Major Projects of Science and Technology ”Significant Drug Discovery ”-Transformation of SHL Powder for Injection, (China)
                Award ID: 2011ZX09201-201-15
                Funded by: Science and Technology Projects on Heilongjiang Province of traditional Chinese Medicine (China)
                Award ID: ZHY16-099
                The work was supported by the Research and Development Projects of Application of Technology of Heilongjiang Province in China (No. GC13C109) and Major Projects of Science and Technology ”Significant Drug Discovery ”-Transformation of SHL Powder for Injection, (China) (No. 2011ZX09201-201-15), and Science and Technology Projects on Heilongjiang Province of traditional Chinese Medicine (China) (No. ZHY16-099).

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