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Paeonia lactiflora Pall. protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway.

Ma X, Zhao YL, Zhu Y, Chen Z, Wang JB, Li RY, Chen C, Wei SZ, Li JY, Liu B, Wang RL, Li YG, Wang LF, Xiao XH - Drug Des Devel Ther (2015)

Bottom Line: Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed.It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression.The putative targets network validation also confirmed the important role of PLP in activating Akt expression.

View Article: PubMed Central - PubMed

Affiliation: Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China ; Department of Pharmacy, 302 Military Hospital of People's Liberation Army, Beijing, People's Republic of China.

ABSTRACT

Background: Paeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.

Materials and methods: Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico.

Results: Four major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression.

Conclusion: The potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.

No MeSH data available.


Related in: MedlinePlus

Positive ES mode of LC–MS of PLP aqueous extract.Notes: Four major compounds were identified. The sequence of tR was oxypaeoniflorin, albiflorin, paeoniflorin, and benzoylpaeoniflorin.Abbreviations: ES, electron spray; PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; tR, retention time.
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f2-dddt-9-5061: Positive ES mode of LC–MS of PLP aqueous extract.Notes: Four major compounds were identified. The sequence of tR was oxypaeoniflorin, albiflorin, paeoniflorin, and benzoylpaeoniflorin.Abbreviations: ES, electron spray; PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; tR, retention time.

Mentions: Both negative and positive electron spray (ES) modes were applied to analyze and identify the chemical components in the aqueous extract of PLP. The total current chromatogram at the positive ES mode is shown in Figure 2. Four compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were detected and identified by comparing the MS fragments, characteristics of the compounds, with previous reference records and database (provided by Agilent) connected to Agilent MassHunter software (Figure S1).17–19 The analyzed and identified compounds are listed in Table 2.


Paeonia lactiflora Pall. protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway.

Ma X, Zhao YL, Zhu Y, Chen Z, Wang JB, Li RY, Chen C, Wei SZ, Li JY, Liu B, Wang RL, Li YG, Wang LF, Xiao XH - Drug Des Devel Ther (2015)

Positive ES mode of LC–MS of PLP aqueous extract.Notes: Four major compounds were identified. The sequence of tR was oxypaeoniflorin, albiflorin, paeoniflorin, and benzoylpaeoniflorin.Abbreviations: ES, electron spray; PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; tR, retention time.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562737&req=5

f2-dddt-9-5061: Positive ES mode of LC–MS of PLP aqueous extract.Notes: Four major compounds were identified. The sequence of tR was oxypaeoniflorin, albiflorin, paeoniflorin, and benzoylpaeoniflorin.Abbreviations: ES, electron spray; PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; tR, retention time.
Mentions: Both negative and positive electron spray (ES) modes were applied to analyze and identify the chemical components in the aqueous extract of PLP. The total current chromatogram at the positive ES mode is shown in Figure 2. Four compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were detected and identified by comparing the MS fragments, characteristics of the compounds, with previous reference records and database (provided by Agilent) connected to Agilent MassHunter software (Figure S1).17–19 The analyzed and identified compounds are listed in Table 2.

Bottom Line: Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed.It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression.The putative targets network validation also confirmed the important role of PLP in activating Akt expression.

View Article: PubMed Central - PubMed

Affiliation: Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China ; Department of Pharmacy, 302 Military Hospital of People's Liberation Army, Beijing, People's Republic of China.

ABSTRACT

Background: Paeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway.

Materials and methods: Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico.

Results: Four major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression.

Conclusion: The potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.

No MeSH data available.


Related in: MedlinePlus