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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

Effect of PLP on histological changes in the liver tissue of ANIT-induced rats.Notes: Rats were treated with different doses of PLP. It represented different effects with histological changes. Damage to hepatocytes is pointed by black arrows. (A) Control; (B) ANIT; (C) UDCA; (D) PLP 20 g/kg; (E) PLP 40 g/kg; and (F) PLP 80 g/kg. (HE stained, 200× magnification).Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; HE, hematoxylin-eosin.
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f4-dddt-9-5061: Effect of PLP on histological changes in the liver tissue of ANIT-induced rats.Notes: Rats were treated with different doses of PLP. It represented different effects with histological changes. Damage to hepatocytes is pointed by black arrows. (A) Control; (B) ANIT; (C) UDCA; (D) PLP 20 g/kg; (E) PLP 40 g/kg; and (F) PLP 80 g/kg. (HE stained, 200× magnification).Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; HE, hematoxylin-eosin.

Mentions: Histological evaluations provided the direct evidence for protective effect of PLP on ANIT-induced cholestasis. The liver tissue of control group exhibited normal structure with no abnormal morphological changes (Figure 4A). The specimens in the ANIT group showed acute infiltration with polymorphonuclear neutrophils, edema, sinusoid congestion, severe demolition or loss of the interlobular ducts, and hepatic necrosis (Figure 4B). Administration of UDCA and 80 g/kg PLP both exhibited a mild degree of bile duct epithelial damage and hepatocyte hydropic degeneration with less neutrophil infiltration (Figure 4C and F), which was almost similar to the control group. The specimens treated with 40 g/kg PLP displayed a moderately reduced severity of inflammatory cell infiltration and histological damage (Figure 4E). The liver damage in the specimens treated with 20 g/kg PLP was similar to that observed in ANIT-treated rats. PLP at 20 g/kg did not attenuate any portal tract edema, cholangitis, and bile duct epithelial damage (Figure 4D).


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)

Effect of PLP on histological changes in the liver tissue of ANIT-induced rats.Notes: Rats were treated with different doses of PLP. It represented different effects with histological changes. Damage to hepatocytes is pointed by black arrows. (A) Control; (B) ANIT; (C) UDCA; (D) PLP 20 g/kg; (E) PLP 40 g/kg; and (F) PLP 80 g/kg. (HE stained, 200× magnification).Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; HE, hematoxylin-eosin.
© Copyright Policy
Related In: Results  -  Collection

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

f4-dddt-9-5061: Effect of PLP on histological changes in the liver tissue of ANIT-induced rats.Notes: Rats were treated with different doses of PLP. It represented different effects with histological changes. Damage to hepatocytes is pointed by black arrows. (A) Control; (B) ANIT; (C) UDCA; (D) PLP 20 g/kg; (E) PLP 40 g/kg; and (F) PLP 80 g/kg. (HE stained, 200× magnification).Abbreviations: PLP, Paeonia lactiflora Pall.; ANIT, alpha-naphthylisothiocyanate; UDCA, ursodeoxycholic acid; HE, hematoxylin-eosin.
Mentions: Histological evaluations provided the direct evidence for protective effect of PLP on ANIT-induced cholestasis. The liver tissue of control group exhibited normal structure with no abnormal morphological changes (Figure 4A). The specimens in the ANIT group showed acute infiltration with polymorphonuclear neutrophils, edema, sinusoid congestion, severe demolition or loss of the interlobular ducts, and hepatic necrosis (Figure 4B). Administration of UDCA and 80 g/kg PLP both exhibited a mild degree of bile duct epithelial damage and hepatocyte hydropic degeneration with less neutrophil infiltration (Figure 4C and F), which was almost similar to the control group. The specimens treated with 40 g/kg PLP displayed a moderately reduced severity of inflammatory cell infiltration and histological damage (Figure 4E). The liver damage in the specimens treated with 20 g/kg PLP was similar to that observed in ANIT-treated rats. PLP at 20 g/kg did not attenuate any portal tract edema, cholangitis, and bile duct epithelial damage (Figure 4D).

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