PMID- 23004355
OWN - NLM
STAT- MEDLINE
DCOM- 20130716
LR  - 20211203
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 168
IP  - 4
DP  - 2013 Feb
TI  - Silibinin inhibits VEGF secretion and age-related macular degeneration in a 
      hypoxia-dependent manner through the PI-3 kinase/Akt/mTOR pathway.
PG  - 920-31
LID - 10.1111/j.1476-5381.2012.02227.x [doi]
AB  - BACKGROUND AND PURPOSE: Hypoxia-mediated neovascularization plays an important 
      role in age-related macular degeneration (AMD). There are few animal models or 
      effective treatments for AMD. Here, we investigated the effects of the flavonoid 
      silibinin on hypoxia-induced angiogenesis in a rat AMD model. EXPERIMENTAL 
      APPROACH: Retinal pigmented epithelial (RPE) cells were subjected to hypoxia in 
      vitro and the effects of silibinin on activation of key hypoxia-induced pathways 
      were examined by elucidating the hypoxia-inducible factor-1 alpha (HIF-1alpha) 
      protein level by Western blot. A rat model of AMD was developed by intravitreal 
      injection of VEGF in Brown Norway rats, with or without concomitant exposure of 
      animals to hypoxia. Animals were treated with oral silibinin starting at day 7 
      post-VEGF injection and AMD changes were followed by fluorescein angiography on 
      days 14 and 28 post-injection. KEY RESULTS: Silibinin pretreatment of RPE cells 
      increased proline hydroxylase-2 expression, inhibited HIF-1alpha subunit 
      accumulation, and inhibited VEGF secretion. Silibinin-induced HIF-1alpha and VEGF 
      down-regulation required suppression of hypoxia-induced phosphatidylinositol 
      3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. In the rat model of 
      AMD, silibinin administration prevented VEGF- and VEGF plus hypoxia-induced 
      retinal oedema and neovascularization. CONCLUSION AND IMPLICATIONS: The effects 
      of silibinin, both in vitro and in vivo, support its potential as a therapeutic 
      for the prevention of neovascular AMD.
CI  - (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British 
      Pharmacological Society.
FAU - Lin, C H
AU  - Lin CH
AD  - School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 
      Taiwan.
FAU - Li, C H
AU  - Li CH
FAU - Liao, P L
AU  - Liao PL
FAU - Tse, L S
AU  - Tse LS
FAU - Huang, W K
AU  - Huang WK
FAU - Cheng, H W
AU  - Cheng HW
FAU - Cheng, Y W
AU  - Cheng YW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Silymarin)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 4RKY41TBTF (Silybin)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Angiogenesis Inhibitors/administration & dosage/*therapeutic use
MH  - Animals
MH  - Autophagy/drug effects
MH  - Blotting, Western
MH  - Cell Hypoxia/physiology
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Epithelial Cells/drug effects/metabolism
MH  - Humans
MH  - Hypoxia/complications/enzymology/*metabolism
MH  - Hypoxia-Inducible Factor 1/biosynthesis/metabolism
MH  - Macular Degeneration/enzymology/metabolism/*prevention & control
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Rats
MH  - Rats, Inbred BN
MH  - Retinal Pigment Epithelium/cytology/drug effects
MH  - Signal Transduction
MH  - Silybin
MH  - Silymarin/administration & dosage/*therapeutic use
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Vascular Endothelial Growth Factor A/administration & 
      dosage/biosynthesis/*metabolism
PMC - PMC3631380
EDAT- 2012/09/26 06:00
MHDA- 2013/07/17 06:00
PMCR- 2014/02/01
CRDT- 2012/09/26 06:00
PHST- 2012/03/07 00:00 [received]
PHST- 2012/08/19 00:00 [revised]
PHST- 2012/09/06 00:00 [accepted]
PHST- 2012/09/26 06:00 [entrez]
PHST- 2012/09/26 06:00 [pubmed]
PHST- 2013/07/17 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.2012.02227.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2013 Feb;168(4):920-31. doi: 10.1111/j.1476-5381.2012.02227.x.