Identification of urine tauro-β-muricholic acid as a promising biomarker in Polygoni Multiflori Radix-induced hepatotoxicity by targeted metabolomics of bile acids

Dong-sheng, Zhao; Jiang, Li; Fan, Ya-Xi; Dong, Lei-Chi; Ma, Jie; Dong, Xin; Xu, Xiaojun; Li, Ping; Li, Huijun

doi:10.1016/j.fct.2017.02.030

Cited by 25 publications

(17 citation statements)

References 37 publications

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“…However, because of the inhibition of bile acid metabolism and excretion, cholestasis can cause liver and mitochondrial damage and can lead to apoptosis and hepatocyte failure. Therefore, changes in the bile acid metabolic network are of great significance in the study of liver injury mechanisms and the toxicity of TCM [23,24,25,26,27]. Experimental studies have shown that bile acids can be used as biomarkers to characterize hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics of Aurantio-Obtusin-Induced Hepatotoxicity in Rats for Discovery of Potential Biomarkers

Li²,

Tang³

et al. 2019

Molecules

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Aurantio-obtusin is an anthraquinone derived from Cassia obtusifolia (cassiae semen). It is also used as a tool and a detection index for the identification of cassiae semen, as stipulated by the Chinese Pharmacopoeia. Anthraquinones, the main components in cassiae semen, have been reported to show hepatotoxicity. This study investigates the hepatotoxicity of aurantio-obtusin in male Sprague–Dawley rats. We randomly divided the animals into a blank control group and treated three test groups with different doses of aurantio-obtusin: Low dose (4 mg/kg), medium dose (40 mg/kg), and high dose (200 mg/kg). Each group was treated with aurantio-obtusin for 28 days, whereas the control group was administered an equal volume of 0.5% carboxymethyl cellulose sodium salt (CMC-Na) aqueous solution. Subsequently, we conducted biochemical, hematological, and pathological investigations and determined the weight of different organs. We used serum metabolomics to identify possible biomarkers related to hepatotoxicity. The low-dose group showed no significant liver injury, whereas the medium- and high-dose groups manifested obvious liver injury. Compared with the control group, the test groups showed an increase in alanine transaminase, aspartate transaminase, and alkaline phosphatase levels. The liver organ coefficient also significantly increased. Additionally, we found significant changes in the hematological indices. Metabolomics analysis showed that aurantio-obtusin induced 28 endogenous markers related to liver injury. Our data indicate that aurantio-obtusin induces hepatotoxicity in rat liver in a dose-dependent manner and is mediated by pathways involving bile acids, fatty acids, amino acids, and energy metabolism. In particular, changes in bile acid content during treatment with therapeutic agents containing aurantio-obtusin deserve increased attention.

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Section: Discussionmentioning

confidence: 99%

Metabolomics of Aurantio-Obtusin-Induced Hepatotoxicity in Rats for Discovery of Potential Biomarkers

Li²,

Tang³

et al. 2019

Molecules

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“…The long-term use of high doses of PMR can potentially damage the liver [26]. One study identified BAs and urine T-β muricholic acid (MCA) as promising metabolic biomarkers to facilitate the clinical monitoring of PMR-induced hepatotoxicity, and urine T-β MCA served as a potential therapeutic target [36]. The perturbation of nine BAs is associated with PMR-induced liver injury, In addition, glycodeoxycholic acid in bile and hyodeoxycholic acid in serum may be potential biomarkers [37].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics profiling of Polygoni Multiflori Radix and Polygoni Multiflori Radix Preparata extracts using UPLC-Q/TOF-MS

2019

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BackgroundThe side effects caused by Polygoni Multiflori Radix (PMR) and Polygoni Multiflori Radix Praeparata (PMRP) have often appeared globally. There is no research on the changes of endogenous metabolites among PMR- and PMRP-treated rats. The aim of this study was to evaluate the varying metabolomic effects between PMR- and PMRP-treated rats. We tried to discover relevant differences in biomarkers and endogenous metabolic pathways.MethodsHematoxylin and eosin staining and immunohistochemistry staining were performed to find pathological changes. Biochemical indicators were also measured, one-way analysis of variance with Dunnett’s multiple comparison test was used for biochemical indicators comparison among various groups. Metabolomics analysis based on ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UPLC-Q/TOF-MS) was performed to find the changes in metabolic biomarkers. Multivariate statistical approaches such as principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA) were applied to reveal group clustering trend, evaluate and maximize the discrimination between the two groups. MetaboAnalyst 4.0 was performed to find and confirm the pathways.ResultsPMR extracts exhibited slight hepatotoxic effects on the liver by increasing aspartate and alanine aminotransferase levels. Twenty-nine metabolites were identified as biomarkers, belonging to five pathways, including alpha-linolenic acid metabolism, taurine and hypotaurine metabolism, glycerophospholipid metabolism, arginine and proline metabolism, and primary bile acid biosynthesis.ConclusionThis study provided a comprehensive description of metabolomic changes between PMR- and PMRP-treated rats. The underlying mechanisms require further research.

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“…Schott Ariseammatic Rhizoma induced nephrotoxicity [ 49 ] Butea monosperma Butea monosperma The safety of Butea monosperma can be used as potential anti-diabetic phytopharmaceuticals [ 51 ] Euphorbia fischeriana Steud Euphorbia fischeriana Steud Metabolic profiles contribute to a better understanding of its adverse effects [ 61 ] Polygoni Multiflori Radix Polygonum multiflorum Thunb. Polygoni Multiflori Radix induces hepatotoxicity [ 47 ] Cocaine Erythroxylum novogranatense (Morris) Hier. Disrupt amino acid and fatty acid metabolism [ 17 , 62 ] Activity Schisandrol B Schisandra sphenanthera Schisandrol B protects lithocholic acid-induced cholestasis [ 63 ] Osthole Cnidium moonieri (L.) Cussion/ Angelica pubescens Lipid-lowering potential [ 5 ] Dehydrodiisoeugenol Myristica fragrans Houtt.…”

Section: Metabolic Profile Of Nature Productsmentioning

confidence: 99%

“…(II) The altered endogenous metabolites might include bile acids, acylcarnitines, lipids, amino acids, long chain fatty acids, and dicarboxylic acids. Metabolomics can be used to evaluate hepatotoxicity [ 47 ], cerebral lesion [ 48 ], and nephrotoxicity [ 49 ], and evaluate the safety of natural products, such as noscapine and Butea monosperma extract (Table 1 ) [ 50 , 51 ]. Using the powerful technology, the toxicity and safety of various natural products have been evaluated, such as noscapine [ 50 ], bupleurotoxin [ 48 ], celastrol [ 52 ], TP [ 5 ], and various extracts of natural products (Table 1 and Fig.…”

Section: Metabolomics Explores the Toxicity Of Natural Productsmentioning

confidence: 99%

Application of Metabolomics in the Study of Natural Products

Zhao

Zhang

2018

Nat. Prod. Bioprospect.

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LC–MS-based metabolomics could have a major impact in the study of natural products, especially in its metabolism, toxicity and activity. This review highlights recent applications of metabolomics approach in the study of metabolites and toxicity of natural products, and the understanding of their effects on various diseases. Metabolomics has been employed to study the in vitro and in vivo metabolism of natural compounds, such as osthole, dehydrodiisoeugenol, and myrislignan. The pharmacological effects of natural compounds and extracts were determined using metabolomics technology combined with diseases models in animal, including osthole and nutmeg extracts. It has been demonstrated that metabolomics is a powerful technology for the investigation of xenobiotics-induced toxicity. The metabolism of triptolide and its hepatotoxicity were discussed. LC–MS-based metabolomics has a great potential in the druggability of natural products. The application of metabolomics should be broadened in the field of natural products in the future.Graphical Abstract

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Identification of urine tauro-β-muricholic acid as a promising biomarker in Polygoni Multiflori Radix-induced hepatotoxicity by targeted metabolomics of bile acids

Cited by 25 publications

References 37 publications

Metabolomics of Aurantio-Obtusin-Induced Hepatotoxicity in Rats for Discovery of Potential Biomarkers

Metabolomics of Aurantio-Obtusin-Induced Hepatotoxicity in Rats for Discovery of Potential Biomarkers

Metabolomics profiling of Polygoni Multiflori Radix and Polygoni Multiflori Radix Preparata extracts using UPLC-Q/TOF-MS

Application of Metabolomics in the Study of Natural Products

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