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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

PLP putative targets network validation and its possible mechanism.Notes: (A) The relationship between 33 putative targets and five ingredients of PLP in silico validation. (B) Top 20 gene functions of the putative targets. (C) The possible mechanism of PLP on cholestasis via Nrf2/PI3K/Akt pathway. (D) Top 20 pathways of the putative targets.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; Nrf2, NF-E2-related factor 2; GSH, Glutathione; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit.
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f7-dddt-9-5061: PLP putative targets network validation and its possible mechanism.Notes: (A) The relationship between 33 putative targets and five ingredients of PLP in silico validation. (B) Top 20 gene functions of the putative targets. (C) The possible mechanism of PLP on cholestasis via Nrf2/PI3K/Akt pathway. (D) Top 20 pathways of the putative targets.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; Nrf2, NF-E2-related factor 2; GSH, Glutathione; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit.

Mentions: Based on Herbal Ingredients’ Targets Database and ChEMBL, five main ingredients of PLP and 33 known targets of these similar ingredients as putative targets for PLP were identified (Table S1, Figure 7A). As shown in Figure 7B and D, the putative targets were analyzed by David 6.7 information tool to obtain the gene annotation. Figure 7B demonstrates the top 20 gene functions of the putative targets. The top gene function was related to cell death or apoptosis, which occupied approximately 42.4% of the total genes. Figure 7D displays the top 20 pathways of the putative targets. The results indicated that cancer (27.3%), Toll-like receptor (24.2%), neurotrophin (21.2%), T-cell receptor (21.2%), and prostate cancer (21.2%) signaling pathways were relatively important of these 33 putative targets. Moreover, according to the annotation of KEGG, Akt was regulated in all the top five pathways, which indicated that Akt played an important role in PLP’s putative targets (Figure 7C).


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)

PLP putative targets network validation and its possible mechanism.Notes: (A) The relationship between 33 putative targets and five ingredients of PLP in silico validation. (B) Top 20 gene functions of the putative targets. (C) The possible mechanism of PLP on cholestasis via Nrf2/PI3K/Akt pathway. (D) Top 20 pathways of the putative targets.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; Nrf2, NF-E2-related factor 2; GSH, Glutathione; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit.
© Copyright Policy
Related In: Results  -  Collection

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

f7-dddt-9-5061: PLP putative targets network validation and its possible mechanism.Notes: (A) The relationship between 33 putative targets and five ingredients of PLP in silico validation. (B) Top 20 gene functions of the putative targets. (C) The possible mechanism of PLP on cholestasis via Nrf2/PI3K/Akt pathway. (D) Top 20 pathways of the putative targets.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; Nrf2, NF-E2-related factor 2; GSH, Glutathione; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit.
Mentions: Based on Herbal Ingredients’ Targets Database and ChEMBL, five main ingredients of PLP and 33 known targets of these similar ingredients as putative targets for PLP were identified (Table S1, Figure 7A). As shown in Figure 7B and D, the putative targets were analyzed by David 6.7 information tool to obtain the gene annotation. Figure 7B demonstrates the top 20 gene functions of the putative targets. The top gene function was related to cell death or apoptosis, which occupied approximately 42.4% of the total genes. Figure 7D displays the top 20 pathways of the putative targets. The results indicated that cancer (27.3%), Toll-like receptor (24.2%), neurotrophin (21.2%), T-cell receptor (21.2%), and prostate cancer (21.2%) signaling pathways were relatively important of these 33 putative targets. Moreover, according to the annotation of KEGG, Akt was regulated in all the top five pathways, which indicated that Akt played an important role in PLP’s putative targets (Figure 7C).

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