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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

Work flow of present study.Abbreviations: PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; Nrf2, NF-E2-related factor 2; ANIT, alpha-naphthylisothiocyanate; PI3K, phosphatidylinositol 3-kinase.
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f1-dddt-9-5061: Work flow of present study.Abbreviations: PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; Nrf2, NF-E2-related factor 2; ANIT, alpha-naphthylisothiocyanate; PI3K, phosphatidylinositol 3-kinase.

Mentions: Complementary and alternative medicine displays its unique role in the treatment of cholestasis along with the development of medical science. In the traditional Chinese medicine, the dried root of Paeonia lactiflora Pall. (PLP, Chishao in Chinese) has been used for the treatment of hepatic diseases for over thousands of years.12 In our previous meta-analysis, PLP was shown to demonstrate excellent therapeutic effect on hepatitis associated with severe cholestasis.6 However, the protective mechanism of PLP on cholestasis seems to be inadequate compared with clinical application. Current studies indicate that PLP might exhibit protective effect against liver diseases through antioxidation and free radicals scavenging mechanisms,13 but the potential pathway still remains to be clarified. Therefore, in the current study, we aimed to investigate the role of PLP in alleviating alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. To further explore its mechanism of antioxidative action in depth, we specifically investigated the PI3K/Akt and Nrf2 signaling pathways, which might provide a novel insight into improving the treatment for cholestatic liver injury (Figure 1).


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)

Work flow of present study.Abbreviations: PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; Nrf2, NF-E2-related factor 2; ANIT, alpha-naphthylisothiocyanate; PI3K, phosphatidylinositol 3-kinase.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-5061: Work flow of present study.Abbreviations: PLP, Paeonia lactiflora Pall.; LC–MS, liquid chromatography–mass spectrometry; Nrf2, NF-E2-related factor 2; ANIT, alpha-naphthylisothiocyanate; PI3K, phosphatidylinositol 3-kinase.
Mentions: Complementary and alternative medicine displays its unique role in the treatment of cholestasis along with the development of medical science. In the traditional Chinese medicine, the dried root of Paeonia lactiflora Pall. (PLP, Chishao in Chinese) has been used for the treatment of hepatic diseases for over thousands of years.12 In our previous meta-analysis, PLP was shown to demonstrate excellent therapeutic effect on hepatitis associated with severe cholestasis.6 However, the protective mechanism of PLP on cholestasis seems to be inadequate compared with clinical application. Current studies indicate that PLP might exhibit protective effect against liver diseases through antioxidation and free radicals scavenging mechanisms,13 but the potential pathway still remains to be clarified. Therefore, in the current study, we aimed to investigate the role of PLP in alleviating alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. To further explore its mechanism of antioxidative action in depth, we specifically investigated the PI3K/Akt and Nrf2 signaling pathways, which might provide a novel insight into improving the treatment for cholestatic liver injury (Figure 1).

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