Metabolomics combined with network pharmacology exploration reveals the modulatory properties of  Astragali Radix  extract in the treatment of liver fibrosis

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Abstract

Background

Astragali Radix (AR) is widely-used for improving liver fibrosis, but, the mechanism of action has not been systematically explained. This study aims to investigate the mechanism of AR intervention in liver fibrosis based on comprehensive metabolomics combined with network pharmacology approach.

Materials and methods

UPLC–Q-TOF/MS based metabolomics technique was used to explore the specific metabolites and possible pathways of AR affecting the pathological process of liver fibrosis. Network pharmacology analysis was introduced to explore the key targets of AR regarding the mechanisms on liver fibrosis.

Results

AR significantly reduced the levels of ALT, AST and AKP in serum, and improved pathological characteristics. Metabolomics analysis showed that the therapeutic effect of AR was mainly related to the regulation of nine metabolites, including sphingosine, 6-keto-prostaglandin F1a, LysoPC (O-18:0), 3-dehydrosphinganine, 5,6-epoxy-8,11,14-eicosatrienoic acid, leukotriene C4, taurochenodesoxycholic acid, LysoPC (18:1 (9Z)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine. Pathway analysis indicated that the treatment of AR on liver fibrosis was related to arachidonic acid metabolism, ether lipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism and primary bile acid biosynthesis. Validation of the key targets by network pharmacology analysis of potential metabolic markers showed that AR significantly down-regulated the expression of CYP1B1 and up-regulated the expression of CYP1A2 and PCYT1A.

Conclusion

Metabolomics combined with network pharmacology was used for the first time to clarify that the treatment of AR on liver fibrosis, which is related to the regulation of arachidonic acid metabolism and ether lipid metabolism by modulating the expression of CYP1A2, CYP1B1 and PCYT1A. And the integrated approach can provide new strategies and ideas for the study of molecular mechanisms of traditional Chinese medicines in the treatment of liver fibrosis.

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Most cited references 41

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PCA as a practical indicator of OPLS-DA model reliability.

Bradley Worley, Robert Powers (2016)

Principal Component Analysis (PCA) and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) are powerful statistical modeling tools that provide insights into separations between experimental groups based on high-dimensional spectral measurements from NMR, MS or other analytical instrumentation. However, when used without validation, these tools may lead investigators to statistically unreliable conclusions. This danger is especially real for Partial Least Squares (PLS) and OPLS, which aggressively force separations between experimental groups. As a result, OPLS-DA is often used as an alternative method when PCA fails to expose group separation, but this practice is highly dangerous. Without rigorous validation, OPLS-DA can easily yield statistically unreliable group separation.

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Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.

Steven Barr, J Caballería, I Martínez-Arranz … (2012)

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

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Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation

Gregory Norris, Christopher Blesso (2017)

Chronic inflammation is a common underlying factor in many major metabolic diseases afflicting Western societies. Sphingolipid metabolism is pivotal in the regulation of inflammatory signaling pathways. The regulation of sphingolipid metabolism is in turn influenced by inflammatory pathways. In this review, we provide an overview of sphingolipid metabolism in mammalian cells, including a description of sphingolipid structure, biosynthesis, turnover, and role in inflammatory signaling. Sphingolipid metabolites play distinct and complex roles in inflammatory signaling and will be discussed. We also review studies examining dietary sphingolipids and inflammation, derived from in vitro and rodent models, as well as human clinical trials. Dietary sphingolipids appear to influence inflammation-related chronic diseases through inhibiting intestinal lipid absorption, altering gut microbiota, activation of anti-inflammatory nuclear receptors, and neutralizing responses to inflammatory stimuli. The anti-inflammatory effects observed with consuming dietary sphingolipids are in contrast to the observation that most cellular sphingolipids play roles in augmenting inflammatory signaling. The relationship between dietary sphingolipids and low-grade chronic inflammation in metabolic disorders is complex and appears to depend on sphingolipid structure, digestion, and metabolic state of the organism. Further research is necessary to confirm the reported anti-inflammatory effects of dietary sphingolipids and delineate their impacts on endogenous sphingolipid metabolism.

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Author and article information

Contributors

Jian Wang:

ORCID: http://orcid.org/0000-0001-5131-9351

jianwang08@163.com

Yanling Zhao: zhaoyl2855@126.com

Journal

Journal ID (nlm-ta): Chin Med

Journal ID (iso-abbrev): Chin Med

Title: Chinese Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1749-8546

Publication date (Electronic): 28 August 2019

Publication date PMC-release: 28 August 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 30

Affiliations

[1 ]ISNI 0000 0001 0376 205X, GRID grid.411304.3, Provincial and State Key Laboratory Breeding Base of System Research, Development and Utilization of Chinese Herbal Medicine Resources, College of Pharmacy, , Chengdu University of Traditional Chinese Medicine, ; Chengdu, 611137 China

[2 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Department of Pharmacy, , The Fifth Medical Center of PLA General Hospital, ; Beijing, 100039 China

[3 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Research Center for Clinical and Translational Medicine, , The Fifth Medical Center of PLA General Hospital, ; Beijing, 100039 China

[4 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Integrative Medical Center, , The Fifth Medical Center of PLA General Hospital, ; Beijing, 100039 China

[5 ]ISNI 0000 0004 1761 8894, GRID grid.414252.4, Department of Traditional Chinese Medicine, , The Fifth Medical Center of PLA General Hospital, ; Beijing, 100039 China

Author information

Jian Wang http://orcid.org/0000-0001-5131-9351

Article

Publisher ID: 251

DOI: 10.1186/s13020-019-0251-z

PMC ID: 6712842

PubMed ID: 31467589

SO-VID: c597ddad-6a33-41d1-93c6-0de124e19bae

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 25 June 2019

Date accepted : 14 August 2019

Funding

Funded by: the project of Capital’s Funds for Health Improvement and Research

Award ID: No. 2018-2-5031

Award Recipient : Yanling Zhao

Custom metadata

ScienceOpen disciplines: Complementary & Alternative medicine

Keywords: astragali radix,liver fibrosis,metabolomics,network pharmacology,modulatory properties,molecular mechanisms

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ScienceOpen disciplines: Complementary & Alternative medicine

Keywords: astragali radix, liver fibrosis, metabolomics, network pharmacology, modulatory properties, molecular mechanisms

Metabolomics combined with network pharmacology exploration reveals the modulatory properties of Astragali Radix extract in the treatment of liver fibrosis

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Most cited references 41

PCA as a practical indicator of OPLS-DA model reliability.

Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.

Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation

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