Metabolomics Coupled with Multivariate Data and Pathway Analysis on Potential Biomarkers in Cholestasis and Intervention Effect of Paeonia lactiflora Pall.

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Abstract

Background: The dried root of Paeonia lactiflora Pall. (PLP) is a classical Chinese herbal medicine that has been used to treat hepatic disease for 1000s of years. Our previous work suggested that PLP can be used to treat hepatitis with severe cholestasis. This study explored the mechanism by which PLP affects ANIT-induced cholestasis in rats using a metabolomics approach.

Methods: The effects of PLP on serum indices (TBIL, DBIL, AST, ALT, ALP, and TBA) and the histopathology of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to identify the possible effect of PLP on metabolites. The pathway analysis was conducted to illustrate the pathways and network by which PLP treats cholestasis.

Result: High-dose PLP remarkably down-regulated the serum indices and alleviated histological damage to the liver. Metabolomics analyses showed that the therapeutic effect of high-dose PLP is mainly associated with the regulation of several metabolites, such as glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, L( D)-arginine, and L-tryptophan. A pathway analysis showed that the metabolites were related to bile acid secretion and amino acid metabolism. In addition, the significant changes in bile acid transporters also indicated that bile acid metabolism might be involved in the therapeutic effect of PLP on cholestasis. Moreover, a principal component analysis indicated that the metabolites in the high-dose PLP group were closer to those of the control, whereas those of the moderate dose or low-dose PLP group were closer to those of the ANIT group. This finding indicated that metabolites may be responsible for the differences between the effects of low-dose and moderate-dose PLP.

Conclusion: The therapeutic effect of high-dose PLP on cholestasis is possibly related to regulation of bile acid secretion and amino acid metabolism. Moreover, these findings may help better understand the mechanisms of disease and provide a potential therapy for cholestasis.

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Most cited references 33

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Understanding ZHENG in traditional Chinese medicine in the context of neuro-endocrine-immune network.

Yulan Wang, Jennifer Wu, Guangzhao Zhang … (2006)

Traditional Chinese medicine uses ZHENG as the key pathological principle to understand the human homeostasis and guide the applications of Chinese herbs. Here, a systems biology approach with the combination of computational analysis and animal experiment is used to investigate this complex issue, ZHENG, in the context of the neuro-endocrine-immune (NEI) system. By using the methods of literature mining, network analysis and topological comparison, it is found that hormones are predominant in the Cold ZHENG network, immune factors are predominant in the Hot ZHENG network, and these two networks are connected by neuro-transmitters. In addition, genes related to Hot ZHENG-related diseases are mainly present in the cytokine-cytokine receptor interaction pathway, whereas genes related to both the Cold-related and Hot-related diseases are linked to the neuroactive ligand-receptor interaction pathway. These computational findings were subsequently verified by experiments on a rat model of collagen-induced arthritis, which indicate that the Cold ZHENG-oriented herbs tend to affect the hub nodes in the Cold ZHENG network, and the Hot ZHENG-oriented herbs tend to affect the hub nodes in the Hot ZHENG network. These investigations demonstrate that the thousand-year-old concept of ZHENG may have a molecular basis with NEI as background.

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New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.

Ulrich Beuers, Michael Trauner, Jan-Peter Jansen … (2015)

Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases.

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Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer.

Udayan Apte, Tiangang Li (2015)

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid-soluble vitamins. Bile acid synthesis, transport, and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis, and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug, and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport, and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration, and carcinogenesis.

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Author and article information

Contributors

Xiao Ma: URI : http://loop.frontiersin.org/people/287886/overview

Jia-Bo Wang: URI : http://loop.frontiersin.org/people/110962/overview

Cong-En Zhang: URI : http://loop.frontiersin.org/people/298413/overview

Lu Zhang: URI : http://loop.frontiersin.org/people/311370/overview

Xiao-He Xiao: URI : http://loop.frontiersin.org/people/122769/overview

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 04 February 2016

Publication date Collection: 2016

Volume: 7

Electronic Location Identifier: 14

Affiliations

[1] ¹Department of Pharmacy, 302 Military Hospital of China Beijing, China

[2] ²Pharmacy College, Chengdu University of Traditional Chinese Medicine Chengdu, China

[3] ³Cardiology Department, Beijing Chao-Yang Hospital, Capital Medical University Beijing, China

[4] ⁴China Military Institute of Chinese Medicine, 302 Military Hospital of China Beijing, China

[5] ⁵Department of Integrative Medical Center, 302 Military Hospital of China Beijing, China

Author notes

Edited by: Adolfo Andrade-Cetto, Universidad Nacional Autónoma de México, Mexico

Reviewed by: Xiao Yu Tian, Chinese University of Hong Kong, China; Rene Cardenas, Universidad Nacional Autónoma de México, Mexico

*Correspondence: Yan-Ling Zhao, zhaoyl2855@ 123456126.com ; Xiao-He Xiao, xiaoxiaohe302@ 123456126.com

^†These authors have contributed equally to this work.

This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology

Article

DOI: 10.3389/fphar.2016.00014

PMC ID: 4740759

PubMed ID: 26869930

SO-VID: d9f0e125-62d3-470b-bfa2-7632dbd68d13

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 04 November 2015

Date accepted : 13 January 2016

Page count

Figures: 8, Tables: 2, Equations: 0, References: 44, Pages: 12, Words: 0

Funding

Funded by: National Natural Science Foundation of China 10.13039/501100001809

Award ID: 81303120, 81173571

Funded by: China People’s Liberation Army

Award ID: CWS11C164

Funded by: the National Science and Technology

Award ID: 2012ZX10005010-002-002

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Metabolomics Coupled with Multivariate Data and Pathway Analysis on Potential Biomarkers in Cholestasis and Intervention Effect of Paeonia lactiflora Pall.

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Journal of Circulating Biomarkers

Most cited references 33

Understanding ZHENG in traditional Chinese medicine in the context of neuro-endocrine-immune network.

New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.

Bile Acid Metabolism and Signaling in Cholestasis, Inflammation, and Cancer.

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Cited by 25

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