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The hepatoprotective efficacy and biological mechanisms of three phenylethanoid glycosides from cistanches herba and their metabolites based on intestinal bacteria and network pharmacology

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Abstract

Echinacoside (ECH), acteoside (ACT), and isoacteoside (ISAT), the typical phenylethanoid glycosides (PhGs) in cistanches herba, have various pharmacological activities. However, the ECH, ACT and ISAT have extremely low oral bioavailability, which is related to their metabolism under the intestinal flora. Previous studies showed that intestinal metabolites were the hepatoprotective substances in vivo, but the research on whether PhGs has effects without intestinal bacteria has not been studied. In this paper, ECH, ACT and ISAT were incubated with human or rat intestinal bacteria for 36 h. After incubating with human bacteria for 36 h, three prototype compounds were not detected and were mainly biotransformed to 3-HPP and HT. In the network pharmacology, a total of 6 common targets were obtained by analysing the prototypes, the metabolites and the liver injury. It was found that the combinations of three metabolites and common targets were more stable than those of the prototypes and common targets by molecular docking. Meanwhile, hepatocellular apoptosis, proliferation, inflammation and oxidative responses might play important roles in the mechanisms of the metabolites exerting hepatoprotective activities. Then normal and pseudo-sterile mice experiments were adopted to further compare the hepatoprotective activities of prototypes and metabolites. Animal experiment results showed that the prototypes and the metabolites in the normal mice had significantly hepatoprotective activity. Interestingly, in the pseudo-germfree mice, the metabolites showed significant hepatoprotective effect, but the prototypes had not effect. It indicated that the prototype cannot exert liver protective activity without the effect of intestinal bacteria.

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Abbreviations

ACT:

Acteoside

AKR1B1:

Aldo–Keto Reductase Family 1 Member B

AKR1B10:

Aldo–Keto Reductase Family 1 Member B10

ALT:

Aminotransferase

ANOVA:

Analysis of variance

APP:

Amyloid-beta precursor protein

AST:

Aspartate aminotransferase

CA:

Caffeic acid

COMT:

Catechol O-methyltransferase

CYP2C19:

Cytochrome P450 2C19

CYP3A4:

Cytochrome P450 3A4

ECH:

Echinacoside

EGFR:

Epidermal growth factor receptor

ERBB2:

Receptor tyrosine–protein kinase erbB-2

ESR1:

Estrogen receptor

GalN/LPS:

Galactosamine/lipopolysaccharides

GSH:

Glutathione

H&E:

Haematoxylin–eosin

HMGB1:

High mobility group box 1

HT:

Hydroxytyrosol

IL-6:

Interleukin 6

ISAT:

Isoacteoside

MAPK1:

Mitogen-activated protein kinase 1

MDA:

Malondialdehyde

MMP1:

Interstitial collagenase

MMP2:

72 KDa type IV collagenase

MMP9:

Matrix metalloproteinase-9

PhGs:

Phenylethanoid glycosides;

PPI:

Protein–protein interaction

PTGS2:

Prostaglandin G/H synthase 2

RELA:

Transcription factor p65

SOD:

Superoxide dismutase

STAT1:

Signal transducer and activator of transcription 1-alpha/beta

STAT3:

Signal transducer and activator of transcription 3

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor α

TYR:

Tyrosinase

3-HPP:

3-Hydroxyphenylpropionic acid

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Acknowledgements

Our present study is supported by National Natural Science Foundation of China (NSFC Nos. 81773879, 81973465), Overseas Training Project of Liaoning Colleges and Universities (2018LNGXGJWPY-YB024), The Fourth Investigation of Traditional Chinese Medicine resources in Liaoning Province of China (2018017, 2019019).

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Authors and Affiliations

  1. School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China

    Yongli Guo, Qingling Cui, Shumeng Ren, Deguo Hao, Xiaoqiu Liu & Yingni Pan

  2. Pharmaceutical Research and Technology Institute, Joint Research Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan

    Toshio Morikawa

  3. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China

    Dongmei Wang

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  1. Yongli Guo
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Guo, Y., Cui, Q., Ren, S. et al. The hepatoprotective efficacy and biological mechanisms of three phenylethanoid glycosides from cistanches herba and their metabolites based on intestinal bacteria and network pharmacology. J Nat Med 75, 784–797 (2021). https://doi.org/10.1007/s11418-021-01508-y

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