Paeoniflorin ameliorates ANIT-induced cholestasis by activating Nrf2 through an PI3K/Akt-dependent pathway in rats.
Cholestasis causes hepatic accumulation of bile acids leading to liver injury, fibrosis and liver failure. Paeoniflorin, the major active compound isolated from the roots of Paeonia lactiflora pall and Paeonia veitchii Lynch, is extensively used for liver diseases treatment in China. However, the mechanism of paeoniflorin's hepatoprotective effect on cholestasis has not been investigated yet. In this study, we administered paeoniflorin to rats for 3 days prior to alpha-naphthylisothiocyanate (ANIT) administration for once, then went on administering paeoniflorin to rats for 3 days. The data demonstrated that paeoniflorin significantly prevented ANIT-induced change in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphates (ALP), serum total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA) and gamma-glutamyl transpeptidase (γ-GT). Histology examination revealed that paeoniflorin treatment rats relieved more liver injury and bile duct proliferation than ANIT-administered rats. Moreover, our data indicated that paeoniflorin could restore glutathione (GSH) and its related synthase glutamate-cysteine ligase catalytic subunit (GCLc) and glutamate-cysteine ligase modifier subunit (GCLm) in ANIT-treated group. In addition, the RNA and protein expression of Akt and nuclear factor-E2-related factor-2 (Nrf2) were also activated by paeoniflorin in ANIT-induced rats. These findings indicated that paeoniflorin protected ANIT-induced cholestasis and increased GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. Therefore, paeoniflorin might be a potential therapeutic agent for cholestasis.
Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.|Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Zhe
Z
Chen
Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.|Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Xiao
X
Ma
Department of Integrative Medical Center, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Yun
Y
Zhu
Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Yanling
Y
Zhao
China Military Institute of Chinese Medicine, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Jiabo
J
Wang
Experimental Laboratory Center, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Ruisheng
R
Li
Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.|Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Chang
C
Chen
Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.|Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Shizhang
S
Wei
China Military Institute of Chinese Medicine, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Wenjuan
W
Jiao
China Military Institute of Chinese Medicine, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Yaming
Y
Zhang
Department of Integrative Medical Center, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Jianyu
J
Li
Department of Integrative Medical Center, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Lifu
L
Wang
Department of Integrative Medical Center, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Ruilin
R
Wang
Department of Integrative Medical Center, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Honghong
H
Liu
China Military Institute of Chinese Medicine, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Honghui
H
Shen
China Military Institute of Chinese Medicine, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Xiaohe
X
Xiao
D015058:1-Naphthylisothiocyanate; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001565:Benzoates / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002681:China; D002779:Cholestasis / Q000188:drug therapy*; D005960:Glucosides / Q000494:pharmacology*; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D039821:Monoterpenes / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000097:blood; D006027:Glycosides
D015058:1-Naphthylisothiocyanate; D000410:Alanine Transaminase; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001219:Aspartate Aminotransferases; D001565:Benzoates; D001647:Bile Acids and Salts; D001663:Bilirubin; D001952:Bridged-Ring Compounds; D005960:Glucosides; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D039821:Monoterpenes; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D005723:gamma-Glutamyltransferase; C015423:peoniflorin; D006027:Glycosides; C546365:GCLM protein, human
Nrf2; PI3K/Akt pathway; cholestasis; glutathione; paeoniflorin