MicroRNA134 Mediated Upregulation of JNK and Downregulation of NFkB Signalings Are Critically Involved in Dieckol Induced Antihepatic Fibrosis.
Though Dieckol, a phlorotannin of Ecklonia cava, was known to have antioxidant, anticancer, antidiabetic, and anti-inflammatory effects, the underlying antifibrotic mechanism of Dieckol still remains unclear until now. Thus, in the current study, the inhibitory mechanism of Dieckol on liver fibrosis was elucidated mainly in hepatic stellate cells (HSCs). Dieckol exerted cytotoxicity in LX-2, HSC-T6, and HepG2 cells with the reduced fibrosis features of large, spread out, and flattened polygonal shapes in LX-2 cells compared to untreated control. Dieckol attenuated the expression of α-SMA and TGF-β1, increased sub-G1 phase population, and induced caspase-3 activation and cleavages of PARP in HSCs. Furthermore, Dieckol decreased phosphorylation of ERK, p38, AKT, NF-kB, and IkB and activated the microRNA(miR)134 level and JNK phosphorylation in HSCs. Conversely, JNK inhbitor SP600125 reversed the effect of Dieckol on PARP, p-NF-kB, α -SMA, and p-JNK in LX-2 cells. Likewise, miR134 overexpression mimic enhanced phosphorylation of JNK and NF-kB and reduced the expression of α-SMA and PARP cleavage, while miR134 inhibitor reversed the ability of Dieckol to cleave PARP and attenuate the expression of α-SMA in LX-2 cells. Overall, our findings suggest that Dieckol suppresses liver fibrosis via caspase activation and miR134 mediated JNK activation and NF-kB inhibition.
Sang Yoon
SY
Lee
College of Korean Medicine, Kyung Hee University , Seoul 131-701, South Korea.
Jihyun
J
Lee
College of Korean Medicine, Kyung Hee University , Seoul 131-701, South Korea.
HyoJung
H
Lee
College of Korean Medicine, Kyung Hee University , Seoul 131-701, South Korea.
Bonglee
B
Kim
Jaehwan
J
Lew
Namin
N
Baek
College of Korean Medicine, Kyung Hee University , Seoul 131-701, South Korea.
Sung-Hoon
SH
Kim
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D000459:Phaeophyceae / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D001572:Benzofurans; C569273:MIRN134 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D010936:Plant Extracts; C503840:dieckol; D048670:MAP Kinase Kinase 4
Dieckol; JNK; NF-kB; apoptosis; liver fibrosis; miR134