Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti-fibrosis effect by inhibition of mammalian target of rapamycin.
A previous study has demonstrated that Ganshuang granule (GSG) plays an anti-fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)-autophagy plays an important role. We attempted to investigate the role of mTOR-autophagy in anti-fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti-fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti-fibrotic effect. 3-methyladenine (3-MA) and Insulin-like growth factor-1 (IGF-1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti-fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3-MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF-1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti-fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.
Beijing Youan Hospital, Capital Medical University, Beijing, China.|Beijing Institute of Hepatology, Beijing, China.
Hongbo
H
Shi
Beijing Youan Hospital, Capital Medical University, Beijing, China.|Beijing Institute of Hepatology, Beijing, China.
Honglin
H
Shi
Beijing Youan Hospital, Capital Medical University, Beijing, China.|Beijing Institute of Hepatology, Beijing, China.
Feng
F
Ren
Beijing Youan Hospital, Capital Medical University, Beijing, China.|Beijing Institute of Hepatology, Beijing, China.
Dexi
D
Chen
Beijing Youan Hospital, Capital Medical University, Beijing, China.
Yu
Y
Chen
Beijing Youan Hospital, Capital Medical University, Beijing, China.|Beijing Institute of Hepatology, Beijing, China.
Zhongping
Z
Duan
D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008516:Medicine, Chinese Traditional / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D004365:Drugs, Chinese Herbal; D044950:Flavanones; C025946:3-methyladenine; D007334:Insulin-Like Growth Factor I; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; C005274:naringin
autophagy; hepatic stellate cells; mammalian target of rapamycin; naringin
J Biol Chem. 2010 Oct 1;285(40):30463-71
20663865
Autophagy. 2016 Jul 2;12(7):1094-104
27158844
PLoS One. 2014 Jan 03;9(1):e83908
24404143
Oncotarget. 2016 Aug 2;7(31):50805-50813
27177330
Liver Int. 2015 Apr;35(4):1222-33
25040634
Biomed Res Int. 2014;2014:436242
24779010
World J Hepatol. 2015 Aug 8;7(16):1982-6
26261688
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2324-9
23345421
PLoS One. 2016 Apr 13;11(4):e0153241
27073901
Chin J Integr Med. 2015 Nov 5;:null
26542309
Hepatology. 2012 Apr;55(4):1271-81
22095555
Int J Oncol. 2015 Sep;47(3):1061-9
26201693
J Hepatol. 2010 Dec;53(6):1123-34
20810185
Hepatology. 2006 Feb;43(2 Suppl 1):S82-8
16447275
Autophagy. 2010 Aug;6(6):764-76
20639694
Hepatology. 2006 Feb;43(2 Suppl 1):S99-S112
16447287
Nat Commun. 2015 Apr 16;6:6808
25879755
FEBS Lett. 2016 Mar;590(5):672-82
26848942
Am J Physiol Gastrointest Liver Physiol. 2011 Aug;301(2):G210-9
21252047
Gastroenterology. 2012 Apr;142(4):938-46
22240484
Sci Rep. 2016 Apr 25;6:24562
27109829