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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

Effects of PLP on serum indices of liver function.Notes: Rats were treated with 60 mg/kg ANIT with different doses of PLP. The following seven liver function markers in the serum were assayed: (A) ALT; (B) AST; (C) TBIL; (D) DBIL; (E) ALP; (F) TBA; (G) γ-GT; and (H) PCA. Data are expressed as 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; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; DBIL, direct bilirubin; TBA, total bile acid; ALP, alkaline phosphatase; γ-GT, γ-glutamyl transpeptidase; PCA, principal component analysis; SD, standard deviation.
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f3-dddt-9-5061: Effects of PLP on serum indices of liver function.Notes: Rats were treated with 60 mg/kg ANIT with different doses of PLP. The following seven liver function markers in the serum were assayed: (A) ALT; (B) AST; (C) TBIL; (D) DBIL; (E) ALP; (F) TBA; (G) γ-GT; and (H) PCA. Data are expressed as 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; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; DBIL, direct bilirubin; TBA, total bile acid; ALP, alkaline phosphatase; γ-GT, γ-glutamyl transpeptidase; PCA, principal component analysis; SD, standard deviation.

Mentions: The serum levels of ALT and AST were measured as the sensitive indices of liver damage. Rats administered with only ANIT displayed remarkable increase in the levels of ALT and AST (Figure 3A and B). The administration of PLP at both 80 g/kg and 40 g/kg significantly reduced the serum levels of ALT and AST, respectively, which is almost equal to the results obtained by administering UDCA. In addition, ALT, but not AST, levels were also altered by PLP at a dosage of 20 g/kg. As shown in Figure 3C–G, the serum levels of TBIL, DBIL, ALP, TBA, and γ-GT levels, which are crucial indices of cholestasis, were significantly higher in the ANIT-treated rats than in the control rats. Furthermore, the levels of ALP, TBIL, γ-GT, and TBA were remarkably decreased in rats treated with 80 g/kg, 40 g/kg, and 20 g/kg of PLP. Moreover, the serum level of DBIL decreased significantly in 80 g/kg and 40 g/kg PLP groups.


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)

Effects of PLP on serum indices of liver function.Notes: Rats were treated with 60 mg/kg ANIT with different doses of PLP. The following seven liver function markers in the serum were assayed: (A) ALT; (B) AST; (C) TBIL; (D) DBIL; (E) ALP; (F) TBA; (G) γ-GT; and (H) PCA. Data are expressed as 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; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; DBIL, direct bilirubin; TBA, total bile acid; ALP, alkaline phosphatase; γ-GT, γ-glutamyl transpeptidase; PCA, principal component analysis; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-9-5061: Effects of PLP on serum indices of liver function.Notes: Rats were treated with 60 mg/kg ANIT with different doses of PLP. The following seven liver function markers in the serum were assayed: (A) ALT; (B) AST; (C) TBIL; (D) DBIL; (E) ALP; (F) TBA; (G) γ-GT; and (H) PCA. Data are expressed as 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; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBIL, total bilirubin; DBIL, direct bilirubin; TBA, total bile acid; ALP, alkaline phosphatase; γ-GT, γ-glutamyl transpeptidase; PCA, principal component analysis; SD, standard deviation.
Mentions: The serum levels of ALT and AST were measured as the sensitive indices of liver damage. Rats administered with only ANIT displayed remarkable increase in the levels of ALT and AST (Figure 3A and B). The administration of PLP at both 80 g/kg and 40 g/kg significantly reduced the serum levels of ALT and AST, respectively, which is almost equal to the results obtained by administering UDCA. In addition, ALT, but not AST, levels were also altered by PLP at a dosage of 20 g/kg. As shown in Figure 3C–G, the serum levels of TBIL, DBIL, ALP, TBA, and γ-GT levels, which are crucial indices of cholestasis, were significantly higher in the ANIT-treated rats than in the control rats. Furthermore, the levels of ALP, TBIL, γ-GT, and TBA were remarkably decreased in rats treated with 80 g/kg, 40 g/kg, and 20 g/kg of PLP. Moreover, the serum level of DBIL decreased significantly in 80 g/kg and 40 g/kg PLP groups.

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