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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

mRNA expessions of GLCc, GLCm, Nqo1, HO-1, Akt, and Nrf2 (%).Notes: Rats were treated with different doses of PLP. (A) GCLm; (B) GCLc; (C)Nqo1; (D) HO-1; (E) Akt; (F) Nrf2. Data are expressed as the mean ± SD. ##P<0.01 compared with control group; **P<0.01 compared with ANIT group.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; Nrf2, NF-E2-related factor 2; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; NQO1, NAD(P)H/quinone oxidoreductase 1; SD, standard deviation.
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f6-dddt-9-5061: mRNA expessions of GLCc, GLCm, Nqo1, HO-1, Akt, and Nrf2 (%).Notes: Rats were treated with different doses of PLP. (A) GCLm; (B) GCLc; (C)Nqo1; (D) HO-1; (E) Akt; (F) Nrf2. Data are expressed as the mean ± SD. ##P<0.01 compared with control group; **P<0.01 compared with ANIT group.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; Nrf2, NF-E2-related factor 2; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; NQO1, NAD(P)H/quinone oxidoreductase 1; SD, standard deviation.

Mentions: As shown in Figure 6A and B, we examined the effect of PLP on ANIT-reduced mRNA expressions of GCLc and GCLm. The results showed that PLP increased the mRNA expressions of GCLc and GCLm in a concentration-dependent manner. The downstream signaling of Nrf2, such as mRNA expressions of Nqo1 and HO-1, was not significantly altered by ANIT, but was upregulated by PLP at doses of 80 g/kg and 40 g/kg (Figure 6C and D). This indicated that PLP possibly affects Nqo1 and HO-1 upstream gene expression such as Nrf2. To elucidate the regulation of PI3K/Akt pathway and Nrf2, we further examined the effect of PLP on mRNA expressions of Akt and Nrf2 (Figure 6E and F). We observed that PLP could increase the mRNA expression of Nrf2 at all doses, and there was a significant increase in regulation of Akt in the group treated with PLP at doses of 80 g/kg and 40 g/kg.


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)

mRNA expessions of GLCc, GLCm, Nqo1, HO-1, Akt, and Nrf2 (%).Notes: Rats were treated with different doses of PLP. (A) GCLm; (B) GCLc; (C)Nqo1; (D) HO-1; (E) Akt; (F) Nrf2. Data are expressed as the mean ± SD. ##P<0.01 compared with control group; **P<0.01 compared with ANIT group.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; Nrf2, NF-E2-related factor 2; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; NQO1, NAD(P)H/quinone oxidoreductase 1; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

f6-dddt-9-5061: mRNA expessions of GLCc, GLCm, Nqo1, HO-1, Akt, and Nrf2 (%).Notes: Rats were treated with different doses of PLP. (A) GCLm; (B) GCLc; (C)Nqo1; (D) HO-1; (E) Akt; (F) Nrf2. Data are expressed as the mean ± SD. ##P<0.01 compared with control group; **P<0.01 compared with ANIT group.Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; Nrf2, NF-E2-related factor 2; GCLc, glutamate-cysteine ligase catalytic subunit; GCLm, glutamate-cysteine ligase modulatory subunit; HO-1, heme oxygenase-1; NQO1, NAD(P)H/quinone oxidoreductase 1; SD, standard deviation.
Mentions: As shown in Figure 6A and B, we examined the effect of PLP on ANIT-reduced mRNA expressions of GCLc and GCLm. The results showed that PLP increased the mRNA expressions of GCLc and GCLm in a concentration-dependent manner. The downstream signaling of Nrf2, such as mRNA expressions of Nqo1 and HO-1, was not significantly altered by ANIT, but was upregulated by PLP at doses of 80 g/kg and 40 g/kg (Figure 6C and D). This indicated that PLP possibly affects Nqo1 and HO-1 upstream gene expression such as Nrf2. To elucidate the regulation of PI3K/Akt pathway and Nrf2, we further examined the effect of PLP on mRNA expressions of Akt and Nrf2 (Figure 6E and F). We observed that PLP could increase the mRNA expression of Nrf2 at all doses, and there was a significant increase in regulation of Akt in the group treated with PLP at doses of 80 g/kg and 40 g/kg.

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