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PMC2783367
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10.1038%2Flabinvest.2009.93
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introduction
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Type II diabetes mellitus (T2DM), i.e. non-insulin-dependent diabetes mellitus, represents over 80% of all diabetics and is dramatically increasing in incidence as a result of changes in human behavior and increased body mass index >>1<<. T2DM are often associated with non-alcoholic steatohepatitis (NASH) 2, 3. NASH is characterized by fat accumulation and inflammation in the liver.
n2:mentions
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T2DM are often associated with non-alcoholic steatohepatitis (NASH) >>2<<, 3. NASH is characterized by fat accumulation and inflammation in the liver.
n2:mentions
n3:17919273
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T2DM are often associated with non-alcoholic steatohepatitis (NASH) 2, >>3<<. NASH is characterized by fat accumulation and inflammation in the liver.
n2:mentions
n3:18524692
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Approximate one third of NASH patients develop hepatic fibrosis and even cirrhosis >>4<<. Both T2DM and NASH are most commonly present in obese patients with hypercholesterolemia, i.e. increased levels of plasma low-density lipoprotein (LDL) and oxidized LDL (ox-LDL) 4. However, the role of hypercholesterolemia in hepatic
n2:mentions
n3:16540768
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Both T2DM and NASH are most commonly present in obese patients with hypercholesterolemia, i.e. increased levels of plasma low-density lipoprotein (LDL) and oxidized LDL (ox-LDL) >>4<<. However, the role of hypercholesterolemia in hepatic fibrogenesis remains obscure.
n2:mentions
n3:16540768
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High concentrations of circulating ox-LDL are associated with high incidences of metabolic syndromes, such as type II diabetes and coronary heart disease >>5<<. Cellular uptake of ox-LDL is mediated by binding to its scavenger receptors, such as lectin-like oxidized LDL receptor-1 (LOX-1), leading to the elevation of intracellular levels of ox-LDL and reactive oxygen species (ROS), as well as to
n2:mentions
n3:18492970
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to its scavenger receptors, such as lectin-like oxidized LDL receptor-1 (LOX-1), leading to the elevation of intracellular levels of ox-LDL and reactive oxygen species (ROS), as well as to the activation of intracellular signaling >>6<<, 7. LOX-1 was originally identified as a major scavenger receptor for ox-LDL in endothelial cells, and was subsequently detected in many other cell types 7, 8.
n2:mentions
n3:16324688
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_:vb9301395
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to its scavenger receptors, such as lectin-like oxidized LDL receptor-1 (LOX-1), leading to the elevation of intracellular levels of ox-LDL and reactive oxygen species (ROS), as well as to the activation of intracellular signaling 6, >>7<<. LOX-1 was originally identified as a major scavenger receptor for ox-LDL in endothelial cells, and was subsequently detected in many other cell types 7, 8.
n2:mentions
n3:9052782
Subject Item
_:vb9301396
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LOX-1 was originally identified as a major scavenger receptor for ox-LDL in endothelial cells, and was subsequently detected in many other cell types >>7<<, 8. LOX-1 gene expression is induced by ox-LDL 9 and is up-regulated in obese patients with hyperlipidemia 6.
n2:mentions
n3:9052782
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_:vb9301397
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LOX-1 was originally identified as a major scavenger receptor for ox-LDL in endothelial cells, and was subsequently detected in many other cell types 7, >>8<<. LOX-1 gene expression is induced by ox-LDL 9 and is up-regulated in obese patients with hyperlipidemia 6.
n2:mentions
n3:18092947
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_:vb9301398
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LOX-1 gene expression is induced by ox-LDL >>9<< and is up-regulated in obese patients with hyperlipidemia 6.
n2:mentions
n3:10764682
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LOX-1 gene expression is induced by ox-LDL 9 and is up-regulated in obese patients with hyperlipidemia >>6<<.
n2:mentions
n3:16324688
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_:vb9301400
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Hepatic fibrosis is a progressive disorder characterized by accumulation of extracellular matrix (ECM) components >>10<<, 11. Hepatic stellate cells (HSCs) are the major effector cells during hepatic fibrogenesis and are the primary source of ECM production in the liver 10, 11.
n2:mentions
n3:15690074
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_:vb9301401
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Hepatic fibrosis is a progressive disorder characterized by accumulation of extracellular matrix (ECM) components 10, >>11<<. Hepatic stellate cells (HSCs) are the major effector cells during hepatic fibrogenesis and are the primary source of ECM production in the liver 10, 11.
n2:mentions
n3:18471545
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_:vb9301402
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Hepatic stellate cells (HSCs) are the major effector cells during hepatic fibrogenesis and are the primary source of ECM production in the liver >>10<<, 11. During liver injury, quiescent HSCs undergo dramatic phenotypic changes from vitamin A, fat-storing cells to proliferative myofibroblast-like cells with acquisition of fibrogenic properties 10, 11. This process is coupled with
n2:mentions
n3:15690074
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_:vb9301403
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Hepatic stellate cells (HSCs) are the major effector cells during hepatic fibrogenesis and are the primary source of ECM production in the liver 10, >>11<<. During liver injury, quiescent HSCs undergo dramatic phenotypic changes from vitamin A, fat-storing cells to proliferative myofibroblast-like cells with acquisition of fibrogenic properties 10, 11. This process is coupled with activation
n2:mentions
n3:18471545
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_:vb9301404
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During liver injury, quiescent HSCs undergo dramatic phenotypic changes from vitamin A, fat-storing cells to proliferative myofibroblast-like cells with acquisition of fibrogenic properties >>10<<, 11. This process is coupled with activation of signaling pathways for pro-fibrogenic transforming growth factor-beta (TGFβ) 12, pro-mitogenic platelet-derived growth factor-beta (PDGF-β) 13 and Wnt signaling 14-16, as well as the
n2:mentions
n3:15690074
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_:vb9301405
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n2:Context
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During liver injury, quiescent HSCs undergo dramatic phenotypic changes from vitamin A, fat-storing cells to proliferative myofibroblast-like cells with acquisition of fibrogenic properties 10, >>11<<. This process is coupled with activation of signaling pathways for pro-fibrogenic transforming growth factor-beta (TGFβ) 12, pro-mitogenic platelet-derived growth factor-beta (PDGF-β) 13 and Wnt signaling 14-16, as well as the depletion
n2:mentions
n3:18471545
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_:vb9301406
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This process is coupled with activation of signaling pathways for pro-fibrogenic transforming growth factor-beta (TGFβ) >>12<<, pro-mitogenic platelet-derived growth factor-beta (PDGF-β) 13 and Wnt signaling 14-16, as well as the depletion of peroxisome proliferator activated receptor-gamma (PPARγ) 17-19.
n2:mentions
n3:8144642
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This process is coupled with activation of signaling pathways for pro-fibrogenic transforming growth factor-beta (TGFβ) 12, pro-mitogenic platelet-derived growth factor-beta (PDGF-β) >>13<< and Wnt signaling 14-16, as well as the depletion of peroxisome proliferator activated receptor-gamma (PPARγ) 17-19.
n2:mentions
n3:8774134
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_:vb9301408
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This process is coupled with activation of signaling pathways for pro-fibrogenic transforming growth factor-beta (TGFβ) 12, pro-mitogenic platelet-derived growth factor-beta (PDGF-β) 13 and Wnt signaling >>14<<-16, as well as the depletion of peroxisome proliferator activated receptor-gamma (PPARγ) 17-19.
n2:mentions
n3:17544413 n3:18006602 n3:16780995
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_:vb9301409
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for pro-fibrogenic transforming growth factor-beta (TGFβ) 12, pro-mitogenic platelet-derived growth factor-beta (PDGF-β) 13 and Wnt signaling 14-16, as well as the depletion of peroxisome proliferator activated receptor-gamma (PPARγ) >>17<<-19. It is important to note that culturing quiescent HSCs on plastic plates causes spontaneous activation, mimicking the process seen in vivo, which provides a good model for elucidating underlying mechanisms of HSC activation and for
n2:mentions
n3:10613734 n3:10930382 n3:10969082
Subject Item
_:vb9301410
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HSCs on plastic plates causes spontaneous activation, mimicking the process seen in vivo, which provides a good model for elucidating underlying mechanisms of HSC activation and for studying therapeutic intervention of the process >>10<<, 11.
n2:mentions
n3:15690074
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_:vb9301411
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HSCs on plastic plates causes spontaneous activation, mimicking the process seen in vivo, which provides a good model for elucidating underlying mechanisms of HSC activation and for studying therapeutic intervention of the process 10, >>11<<.
n2:mentions
n3:18471545
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_:vb9301412
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underlying mechanisms remain elusive, curcumin has shown diverse and versatile beneficial effects, including anti-inflammatory, anti-oxidative stress, anti-viral, anti-hypercholesterolemic, anti-infective and anti-carcinogenic effects >>20<<. Curcumin has recently received attention as a promising dietary supplement for liver protection 21.
n2:mentions
n3:15116757
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_:vb9301413
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Curcumin has recently received attention as a promising dietary supplement for liver protection >>21<<. We recently reported that curcumin inhibited HSC activation by inhibiting cell proliferation, inducing apoptosis and attenuating oxidative stress in vitro and in vivo 22-27. In addition, we demonstrated that curcumin dramatically induced
n2:mentions
n3:18037917
Subject Item
_:vb9301414
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We recently reported that curcumin inhibited HSC activation by inhibiting cell proliferation, inducing apoptosis and attenuating oxidative stress in vitro and in vivo >>22<<-27. In addition, we demonstrated that curcumin dramatically induced gene expression of endogenous PPARγ and stimulated its activity in activated HSCs in vitro and in vivo, which is required for curcumin to inhibit HSC activation 22-24.
n2:mentions
n3:16306131 n3:12660143 n3:17602960 n3:15320868 n3:18006644 n3:16959952
Subject Item
_:vb9301415
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In addition, we demonstrated that curcumin dramatically induced gene expression of endogenous PPARγ and stimulated its activity in activated HSCs in vitro and in vivo, which is required for curcumin to inhibit HSC activation >>22<<-24. Furthermore, curcumin suppressed gene expression of LDL receptor in activated HSCs in vitro by activating PPARγ and regulating gene expression of the transcription factors sterol regulatory element binding proteins (SREBPs), leading
n2:mentions
n3:12660143 n3:15320868 n3:18006644
Subject Item
_:vb9301416
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n8:Section
dc:title
materials and methods
n8:contains
_:vb9301426 _:vb9301427 _:vb9301424 _:vb9301425 _:vb9301428 _:vb9301418 _:vb9301419 _:vb9301417 _:vb9301422 _:vb9301423 _:vb9301420 _:vb9301421
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Primary HSCs were isolated from male Sprague-Dawley rats (200-250g) as we previously described >>23<<. Passaged HSCs were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (v/v) fetal bovine serum (FBS).
n2:mentions
n3:12660143
Subject Item
_:vb9301418
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Nuclear extracts were prepared as we previously described >>28<<. In brief, after washing twice with PBS, cells were evenly re-suspended in Buffer A (10 mM HEPES-KOH pH7.9, 1.5 mM MgCl2, 10 mM KCl, 1 mM DTT, 1 mM PMSF).
n2:mentions
n3:9867824
Subject Item
_:vb9301419
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Mehta (Department of Internal Medicine, University of Arkansas for Medical Sciences) >>29<<. Additional lox-1 promoter luciferase reporter constructs with shorter promoter regions were created by PCR and enzyme ligation using p-2336/+36-Luc as a template (see the following for details). The PDGF-βR promoter luciferase reporter
n2:mentions
n3:16173915
Subject Item
_:vb9301420
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Keiko Funa (Ludwig Institute for Cancer Research, Uppsala, Sweden) >>30<<. The type I TGF-β receptor promoter luciferase reporter plasmid pTβ-RI-Luc (pES1.0) was kindly provided by Dr Michael Centrella (Yale University, New Haven, CT, USA) 31.
n2:mentions
n3:7741738
Subject Item
_:vb9301421
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The type I TGF-β receptor promoter luciferase reporter plasmid pTβ-RI-Luc (pES1.0) was kindly provided by Dr Michael Centrella (Yale University, New Haven, CT, USA) >>31<<. The PPARγ cDNA expression plasmid pPPARγ, containing a full size of PPARγ cDNA, was a gift from Dr. Reed Graves (Department of Medicine, University of Chicago). The dominant negative PPARγ expression construct pdn-PPARγ was a gift from
n2:mentions
n3:8978463
Subject Item
_:vb9301422
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Chatterjee >>32<<. The Wnt signaling luciferase reporter plasmids TOPflash and its mutant FOPflash were kindly provided by Dr.
n2:mentions
n3:10681562
Subject Item
_:vb9301423
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Moon (Department of Pharmacology, School of Medicine, University of Washington) >>33<<. TOPflash contained 8 copies of TCF/LEF binding sites. FOPflash was a counterpart control for TOPflash with site-directed mutations in the TCF/LEF binding sites 33.
n2:mentions
n3:15817814
Subject Item
_:vb9301424
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FOPflash was a counterpart control for TOPflash with site-directed mutations in the TCF/LEF binding sites >>33<<.
n2:mentions
n3:15817814
Subject Item
_:vb9301425
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, as we previously described >>23<<. Each treatment had triplicates in every experiment.
n2:mentions
n3:12660143
Subject Item
_:vb9301426
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Luciferase activity assays were conducted as we previously described >>23<<. Transfection efficiency was determined by co-transfection of a β-galactosidase reporter, pSV-β-gal (Promega, Madison, WI).
n2:mentions
n3:12660143
Subject Item
_:vb9301427
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Real-time PCR was carried out using SYBR green, as previously described >>34<<. Total RNA was treated with DNase I prior to the synthesis of the first strand of cDNA.
n2:mentions
n3:12223099
Subject Item
_:vb9301428
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mRNA levels were expressed as fold changes after normalization with endogenous glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as suggested by Schmittgen et. al. >>35<<. The primers for PCR were presented in Table 3.
n2:mentions
n3:11017702
Subject Item
_:vb9301429
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n8:Section
dc:title
results
n8:contains
_:vb9301438 _:vb9301439 _:vb9301436 _:vb9301437 _:vb9301434 _:vb9301435 _:vb9301432 _:vb9301433 _:vb9301430 _:vb9301431 _:vb9301454 _:vb9301455 _:vb9301452 _:vb9301453 _:vb9301450 _:vb9301451 _:vb9301448 _:vb9301449 _:vb9301446 _:vb9301447 _:vb9301444 _:vb9301445 _:vb9301442 _:vb9301443 _:vb9301440 _:vb9301441 _:vb9301458 _:vb9301459 _:vb9301456 _:vb9301457
Subject Item
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It was previously demonstrated that ox-LDL prompted biosynthesis of ECM components in HSCs, implying ox-LDL being a pro-fibrogenic stimulator >>36<<. We further examined the effect of ox-LDL on expression of genes closely relevant to HSC activation.
n2:mentions
n3:11584369
Subject Item
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Subsequent culture in serum-depleted media excluded the interference from other factors in FBS >>37<<, 38. Total RNA and whole cell protein extracts were prepared from the cells for real-time PCR and Western blotting analyses, respectively. As shown in Fig. 1A & B, ox-LDL increased gene expression of α(I) collagen and alpha-smooth muscle
n2:mentions
n3:18332871
Subject Item
_:vb9301432
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n2:Context
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Subsequent culture in serum-depleted media excluded the interference from other factors in FBS 37, >>38<<. Total RNA and whole cell protein extracts were prepared from the cells for real-time PCR and Western blotting analyses, respectively. As shown in Fig. 1A & B, ox-LDL increased gene expression of α(I) collagen and alpha-smooth muscle
n2:mentions
n3:17372590
Subject Item
_:vb9301433
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LOX-1 has been identified as a specific receptor for ox-LDL, responsible for transporting extracellular ox-LDL into cells >>6<<, 7. LOX-1, as a scavenger receptor, facilitates the accumulation of ox-LDL and stimulates the transformation of smooth muscle cells and monocyte/macrophages into foam cells 39.
n2:mentions
n3:16324688
Subject Item
_:vb9301434
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LOX-1 has been identified as a specific receptor for ox-LDL, responsible for transporting extracellular ox-LDL into cells 6, >>7<<. LOX-1, as a scavenger receptor, facilitates the accumulation of ox-LDL and stimulates the transformation of smooth muscle cells and monocyte/macrophages into foam cells 39.
n2:mentions
n3:9052782
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LOX-1, as a scavenger receptor, facilitates the accumulation of ox-LDL and stimulates the transformation of smooth muscle cells and monocyte/macrophages into foam cells >>39<<. LOX-1 gene expression is induced by ox-LDL 9. We assumed that LOX-1 mediated the stimulatory effects of ox-LDL on HSC activation and fibrogenesis. To elucidate the link role of LOX-1 in ox-LDL-induced HSC activation, serum-starved HSCs
n2:mentions
n3:9933026
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LOX-1 gene expression is induced by ox-LDL >>9<<. We assumed that LOX-1 mediated the stimulatory effects of ox-LDL on HSC activation and fibrogenesis.
n2:mentions
n3:10764682
Subject Item
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To elucidate the link role of LOX-1 in ox-LDL-induced HSC activation, serum-starved HSCs were pre-treated with or without κ-carrageenan (250 μg/ml), a LOX-1 antagonist >>40<<, 41, for 1 hr prior to the stimulation with ox-LDL (10 μg/ml) for additional 24 hr.
n2:mentions
n3:16690797
Subject Item
_:vb9301438
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To elucidate the link role of LOX-1 in ox-LDL-induced HSC activation, serum-starved HSCs were pre-treated with or without κ-carrageenan (250 μg/ml), a LOX-1 antagonist 40, >>41<<, for 1 hr prior to the stimulation with ox-LDL (10 μg/ml) for additional 24 hr.
n2:mentions
n3:14656932
Subject Item
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This plasmid contained a 5′-flanking fragment (2336 bp) of the LOX-1 gene promoter, subcloned in a luciferase reporter plasmid >>29<<. After overnight recovery, cells were treated with curcumin at various concentrations (0-30 μM) for 24 hr. As shown in Fig. 3A by luciferase activity assays, curcumin caused a dose-dependent reduction in luciferase activities, suggesting
n2:mentions
n3:16173915
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_:vb9301440
rdf:type
n2:Context
rdf:value
We have previously reported that curcumin induces expression of endogenous PPARγ gene and stimulates its activity in activated HSCs, which is a prerequisite for curcumin to inhibit HSC activation in vitro>>23<<, 24. To elucidate the mechanisms by which curcumin suppressed gene expression of LOX-1 in HSCs, we postulated that PPARγ mediated the inhibitory effect of curcumin on lox-1 expression.
n2:mentions
n3:12660143
Subject Item
_:vb9301441
rdf:type
n2:Context
rdf:value
We have previously reported that curcumin induces expression of endogenous PPARγ gene and stimulates its activity in activated HSCs, which is a prerequisite for curcumin to inhibit HSC activation in vitro23, >>24<<. To elucidate the mechanisms by which curcumin suppressed gene expression of LOX-1 in HSCs, we postulated that PPARγ mediated the inhibitory effect of curcumin on lox-1 expression.
n2:mentions
n3:15320868
Subject Item
_:vb9301442
rdf:type
n2:Context
rdf:value
The cDNA expression plasmid pPPARγ contained a full size of wild-type PPARγ cDNA >>24<<. pdn-PPARγ contained a full length of cDNA encoding dominant negative PPARγ (dn-PPARγ) 32. A total of 4.5 μg of plasmid DNA per well was used for co-transfection of HSCs in 6-well culture plates. It included 2 μg of pLOX-1-Luc, 0.5 μg of
n2:mentions
n3:15320868
Subject Item
_:vb9301443
rdf:type
n2:Context
rdf:value
pdn-PPARγ contained a full length of cDNA encoding dominant negative PPARγ (dn-PPARγ) >>32<<. A total of 4.5 μg of plasmid DNA per well was used for co-transfection of HSCs in 6-well culture plates. It included 2 μg of pLOX-1-Luc, 0.5 μg of pSV-β-gal, and 2.0 μg of pPPARγ, or pdn-PPARγ, at indicated doses plus the empty vector
n2:mentions
n3:10681562
Subject Item
_:vb9301444
rdf:type
n2:Context
rdf:value
Prior experiments have suggested that 10% of FBS in the medium contains enough agonists to activate PPARγ in HSCs >>19<<, 23, 24. Luciferase activity assays demonstrated that forced expression of wild-type PPARγ cDNA dose-dependently reduced luciferase activities (Fig. 5A). In contrast, forced expression of dn-PPARγ dose-dependently abrogated the inhibitory
n2:mentions
n3:10969082
Subject Item
_:vb9301445
rdf:type
n2:Context
rdf:value
Prior experiments have suggested that 10% of FBS in the medium contains enough agonists to activate PPARγ in HSCs 19, >>23<<, 24. Luciferase activity assays demonstrated that forced expression of wild-type PPARγ cDNA dose-dependently reduced luciferase activities (Fig. 5A). In contrast, forced expression of dn-PPARγ dose-dependently abrogated the inhibitory
n2:mentions
n3:12660143
Subject Item
_:vb9301446
rdf:type
n2:Context
rdf:value
Prior experiments have suggested that 10% of FBS in the medium contains enough agonists to activate PPARγ in HSCs 19, 23, >>24<<. Luciferase activity assays demonstrated that forced expression of wild-type PPARγ cDNA dose-dependently reduced luciferase activities (Fig. 5A). In contrast, forced expression of dn-PPARγ dose-dependently abrogated the inhibitory effect
n2:mentions
n3:15320868
Subject Item
_:vb9301447
rdf:type
n2:Context
rdf:value
TCF/LEF binding sites are targets of canonical Wnt signaling and bound by a complex of β-catenin with TCF/LEF, mediating the regulation of target gene transcription >>42<<, 43. The plasmid pLOX-1(mut)-Luc with site-directed mutation in the TCF/LEF-1 binding site was generated from the parental plasmid pLOX-1-Luc. Passaged HSCs were transfected with pLOX-1-Luc or pLOX-1(mut)-Luc and subsequently treated with
n2:mentions
n3:18177486
Subject Item
_:vb9301448
rdf:type
n2:Context
rdf:value
TCF/LEF binding sites are targets of canonical Wnt signaling and bound by a complex of β-catenin with TCF/LEF, mediating the regulation of target gene transcription 42, >>43<<. The plasmid pLOX-1(mut)-Luc with site-directed mutation in the TCF/LEF-1 binding site was generated from the parental plasmid pLOX-1-Luc. Passaged HSCs were transfected with pLOX-1-Luc or pLOX-1(mut)-Luc and subsequently treated with or
n2:mentions
n3:18160255
Subject Item
_:vb9301449
rdf:type
n2:Context
rdf:value
After recovery, cells were cultured for 24 hr in DMEM with FBS (10%), which contained enough agonists to activate PPARγ in HSCs >>19<<, 23, 24. Luciferase activity assays in Fig. 7A demonstrated that forced expression of PPARγ from pPPARγ significantly reduced luciferase activity by 63.4% in cells co-transfected with the wild-type plasmid pLOX-1-Luc (the upper black
n2:mentions
n3:10969082
Subject Item
_:vb9301450
rdf:type
n2:Context
rdf:value
After recovery, cells were cultured for 24 hr in DMEM with FBS (10%), which contained enough agonists to activate PPARγ in HSCs 19, >>23<<, 24. Luciferase activity assays in Fig. 7A demonstrated that forced expression of PPARγ from pPPARγ significantly reduced luciferase activity by 63.4% in cells co-transfected with the wild-type plasmid pLOX-1-Luc (the upper black column),
n2:mentions
n3:12660143
Subject Item
_:vb9301451
rdf:type
n2:Context
rdf:value
After recovery, cells were cultured for 24 hr in DMEM with FBS (10%), which contained enough agonists to activate PPARγ in HSCs 19, 23, >>24<<. Luciferase activity assays in Fig. 7A demonstrated that forced expression of PPARγ from pPPARγ significantly reduced luciferase activity by 63.4% in cells co-transfected with the wild-type plasmid pLOX-1-Luc (the upper black column),
n2:mentions
n3:15320868
Subject Item
_:vb9301452
rdf:type
n2:Context
rdf:value
TOPflash was a canonical Wnt signaling luciferase reporter, which contained 8 copies of TCF/LEF binding sites >>33<<. FOPflash was used as a control luciferase reporter, which contained 8 copies of mutant TCF/LEF binding sites 33. After recovery, cells were treated with curcumin at various concentrations (0-30 μM) in DMEM with FBS (10%) for 24 hr.
n2:mentions
n3:15817814
Subject Item
_:vb9301453
rdf:type
n2:Context
rdf:value
FOPflash was used as a control luciferase reporter, which contained 8 copies of mutant TCF/LEF binding sites >>33<<. After recovery, cells were treated with curcumin at various concentrations (0-30 μM) in DMEM with FBS (10%) for 24 hr. Luciferase activity assays in Fig. 9A demonstrated that curcumin caused a dose-dependent reduction in luciferase
n2:mentions
n3:15817814
Subject Item
_:vb9301454
rdf:type
n2:Context
rdf:value
Canonical Wnt signaling is activated only when dephosphorylated β-catenin is translocated into the nucleus >>42<<. To verify the effect of curcumin on interrupting the Wnt signaling pathway, HSCs were treated with curcumin at various concentrations (0-30 μM) for 24 hr.
n2:mentions
n3:18177486
Subject Item
_:vb9301455
rdf:type
n2:Context
rdf:value
Nuclear β-catenin forms a complex with the transcription factor TCF/LEF to bind to the promoter of target genes and to stimulate target gene transcription >>42<<, 43. EMSA were conducted to further verify the effect of curcumin on interrupting canonical Wnt signaling.
n2:mentions
n3:18177486
Subject Item
_:vb9301456
rdf:type
n2:Context
rdf:value
Nuclear β-catenin forms a complex with the transcription factor TCF/LEF to bind to the promoter of target genes and to stimulate target gene transcription 42, >>43<<. EMSA were conducted to further verify the effect of curcumin on interrupting canonical Wnt signaling.
n2:mentions
n3:18160255
Subject Item
_:vb9301457
rdf:type
n2:Context
rdf:value
Transfected cells were cultured for 24 hr in media with 10% FBS, which contains enough agonists to activate PPARγ in HSCs >>19<<, 23, 24. Luciferase activity assays in Fig. 10B revealed that forced expression of PPARγ dose-dependently reduced luciferase activities in cells transfected with TOPflash, but not in cells transfected with FOPflash, confirming that the
n2:mentions
n3:10969082
Subject Item
_:vb9301458
rdf:type
n2:Context
rdf:value
Transfected cells were cultured for 24 hr in media with 10% FBS, which contains enough agonists to activate PPARγ in HSCs 19, >>23<<, 24. Luciferase activity assays in Fig. 10B revealed that forced expression of PPARγ dose-dependently reduced luciferase activities in cells transfected with TOPflash, but not in cells transfected with FOPflash, confirming that the
n2:mentions
n3:12660143
Subject Item
_:vb9301459
rdf:type
n2:Context
rdf:value
Transfected cells were cultured for 24 hr in media with 10% FBS, which contains enough agonists to activate PPARγ in HSCs 19, 23, >>24<<. Luciferase activity assays in Fig. 10B revealed that forced expression of PPARγ dose-dependently reduced luciferase activities in cells transfected with TOPflash, but not in cells transfected with FOPflash, confirming that the activation
n2:mentions
n3:15320868
Subject Item
_:vb9301460
rdf:type
n8:Section
dc:title
discussion
n8:contains
_:vb9301482 _:vb9301483 _:vb9301480 _:vb9301481 _:vb9301486 _:vb9301487 _:vb9301484 _:vb9301485 _:vb9301474 _:vb9301475 _:vb9301472 _:vb9301473 _:vb9301478 _:vb9301479 _:vb9301476 _:vb9301477 _:vb9301496 _:vb9301490 _:vb9301491 _:vb9301488 _:vb9301489 _:vb9301494 _:vb9301495 _:vb9301492 _:vb9301493 _:vb9301466 _:vb9301467 _:vb9301464 _:vb9301465 _:vb9301470 _:vb9301471 _:vb9301468 _:vb9301469 _:vb9301462 _:vb9301463 _:vb9301461
Subject Item
_:vb9301461
rdf:type
n2:Context
rdf:value
NASH patients are often associated with high levels of lipid peroxidation products, such as ox-LDL >>44<<. It has been suggested that the elevated levels of lipid peroxidation might make an important contribution to the pathogenesis of NASH 45, leading to hepatic fibrosis.
n2:mentions
n3:15307867
Subject Item
_:vb9301462
rdf:type
n2:Context
rdf:value
It has been suggested that the elevated levels of lipid peroxidation might make an important contribution to the pathogenesis of NASH >>45<<, leading to hepatic fibrosis.
n2:mentions
n3:10335777
Subject Item
_:vb9301463
rdf:type
n2:Context
rdf:value
Prior studies suggested that oxidized LDL was only a minor fraction of LDL ranging from 0.001% in healthy controls >>46<< to approximately 5% in patients with acute coronary events 47.
n2:mentions
n3:10580183
Subject Item
_:vb9301464
rdf:type
n2:Context
rdf:value
Prior studies suggested that oxidized LDL was only a minor fraction of LDL ranging from 0.001% in healthy controls 46 to approximately 5% in patients with acute coronary events >>47<<. A recent report indicated that the level of ox-LDL in healthy human was in 0.58 ± 0.23 ng/5 μg LDL protein 48. However, it bears emphasis that because the in vivo system is multi-factorial, directly extrapolating in vitro conditions and
n2:mentions
n3:9769301
Subject Item
_:vb9301465
rdf:type
n2:Context
rdf:value
A recent report indicated that the level of ox-LDL in healthy human was in 0.58 ± 0.23 ng/5 μg LDL protein >>48<<. However, it bears emphasis that because the in vivo system is multi-factorial, directly extrapolating in vitro conditions and results, e.g. effective concentrations, to the in vivo system might be misleading. ox-LDL at 10 μg/ml was
n2:mentions
n3:11306523
Subject Item
_:vb9301466
rdf:type
n2:Context
rdf:value
It showed no apparent cytotoxicity to cultured HSCs (data not presented here), though higher concentrations (>25 μg/ml) of ox-LDL might result in the reduction in the production of ECM components and even cytotoxicity to cultured HSCs >>36<<.
n2:mentions
n3:11584369
Subject Item
_:vb9301467
rdf:type
n2:Context
rdf:value
Uptake and transport of ox-LDL into cells is mediated by a variety of scavenger receptors, including LOX-1, SR-AI/II, CD36 and SR-BI >>49<<. Depending on cell types, these scavenger receptors display distinct expression profiles.
n2:mentions
n3:10511292
Subject Item
_:vb9301468
rdf:type
n2:Context
rdf:value
For example, CD36 is highly expressed in macrophages, and plays a fundamental role in uptake of ox-LDL into macrophages >>50<<, while LOX-1 is the principal ox-LDL receptor in epithelia cells 7.
n2:mentions
n3:7560077
Subject Item
_:vb9301469
rdf:type
n2:Context
rdf:value
For example, CD36 is highly expressed in macrophages, and plays a fundamental role in uptake of ox-LDL into macrophages 50, while LOX-1 is the principal ox-LDL receptor in epithelia cells >>7<<. CD36 is a multiligand scavenger receptor that recognizes and binds many ligands, including ox-LDL and long-chain free fatty acids 51. Our preliminary experiments indicated that compared to that of CD36, the expression of LOX-1 in
n2:mentions
n3:9052782
Subject Item
_:vb9301470
rdf:type
n2:Context
rdf:value
CD36 is a multiligand scavenger receptor that recognizes and binds many ligands, including ox-LDL and long-chain free fatty acids >>51<<. Our preliminary experiments indicated that compared to that of CD36, the expression of LOX-1 in activated HSCs is more inducible and highly expressed at both transcript and protein levels (unpublished observations), suggesting that LOX-1
n2:mentions
n3:16712941
Subject Item
_:vb9301471
rdf:type
n2:Context
rdf:value
We have previously shown that curcumin dramatically induces expression of endogenous PPARγ gene and its activity in cultured HSCs, which is required for curcumin to inhibit HSC activation >>23<<, 24, 27. We have also observed that although significantly reduced, PPARγ is still detectable in cultured HSCs and responds to the stimulation with PGJ2, a natural PPARγ agonist 23, 38. To evaluate the role of PPARγ activation in the
n2:mentions
n3:12660143
Subject Item
_:vb9301472
rdf:type
n2:Context
rdf:value
We have previously shown that curcumin dramatically induces expression of endogenous PPARγ gene and its activity in cultured HSCs, which is required for curcumin to inhibit HSC activation 23, >>24<<, 27. We have also observed that although significantly reduced, PPARγ is still detectable in cultured HSCs and responds to the stimulation with PGJ2, a natural PPARγ agonist 23, 38. To evaluate the role of PPARγ activation in the
n2:mentions
n3:15320868
Subject Item
_:vb9301473
rdf:type
n2:Context
rdf:value
We have previously shown that curcumin dramatically induces expression of endogenous PPARγ gene and its activity in cultured HSCs, which is required for curcumin to inhibit HSC activation 23, 24, >>27<<. We have also observed that although significantly reduced, PPARγ is still detectable in cultured HSCs and responds to the stimulation with PGJ2, a natural PPARγ agonist 23, 38. To evaluate the role of PPARγ activation in the
n2:mentions
n3:17602960
Subject Item
_:vb9301474
rdf:type
n2:Context
rdf:value
We have also observed that although significantly reduced, PPARγ is still detectable in cultured HSCs and responds to the stimulation with PGJ2, a natural PPARγ agonist >>23<<, 38. To evaluate the role of PPARγ activation in the curcumin-caused inhibition of LOX-1 gene expression in cultured HSCs, PPARγ activation was blocked by its specific antagonist PD68235. Our results in Fig. 4 indicated that the blockade
n2:mentions
n3:12660143
Subject Item
_:vb9301475
rdf:type
n2:Context
rdf:value
We have also observed that although significantly reduced, PPARγ is still detectable in cultured HSCs and responds to the stimulation with PGJ2, a natural PPARγ agonist 23, >>38<<. To evaluate the role of PPARγ activation in the curcumin-caused inhibition of LOX-1 gene expression in cultured HSCs, PPARγ activation was blocked by its specific antagonist PD68235. Our results in Fig. 4 indicated that the blockade of
n2:mentions
n3:17372590
Subject Item
_:vb9301476
rdf:type
n2:Context
rdf:value
Our current observations are consistent with prior other reports >>6<<, 52. The activation of PPARγ by its ligand pioglitazone inhibited LOX-1 expression in coronary artery endothelial cells and fibroblasts 6, 52.
n2:mentions
n3:16324688
Subject Item
_:vb9301477
rdf:type
n2:Context
rdf:value
Our current observations are consistent with prior other reports 6, >>52<<. The activation of PPARγ by its ligand pioglitazone inhibited LOX-1 expression in coronary artery endothelial cells and fibroblasts 6, 52.
n2:mentions
n3:12958047
Subject Item
_:vb9301478
rdf:type
n2:Context
rdf:value
The activation of PPARγ by its ligand pioglitazone inhibited LOX-1 expression in coronary artery endothelial cells and fibroblasts >>6<<, 52. In addition, PPARγ activation inhibited TNF-α-induced LOX-1 expression in aortic endothelial cells 53. On the other hand, the stimulatory effect of PPARγ on lox-1 expression was also reported 54. PPARγ bound to the peroxisome
n2:mentions
n3:16324688
Subject Item
_:vb9301479
rdf:type
n2:Context
rdf:value
The activation of PPARγ by its ligand pioglitazone inhibited LOX-1 expression in coronary artery endothelial cells and fibroblasts 6, >>52<<. In addition, PPARγ activation inhibited TNF-α-induced LOX-1 expression in aortic endothelial cells 53. On the other hand, the stimulatory effect of PPARγ on lox-1 expression was also reported 54. PPARγ bound to the peroxisome
n2:mentions
n3:12958047
Subject Item
_:vb9301480
rdf:type
n2:Context
rdf:value
In addition, PPARγ activation inhibited TNF-α-induced LOX-1 expression in aortic endothelial cells >>53<<. On the other hand, the stimulatory effect of PPARγ on lox-1 expression was also reported 54. PPARγ bound to the peroxisome proliferator response elements (PPREs) in the lox-1 promoter and stimulated LOX-1 gene transcription and
n2:mentions
n3:11511093
Subject Item
_:vb9301481
rdf:type
n2:Context
rdf:value
On the other hand, the stimulatory effect of PPARγ on lox-1 expression was also reported >>54<<. PPARγ bound to the peroxisome proliferator response elements (PPREs) in the lox-1 promoter and stimulated LOX-1 gene transcription and expression in adipocytes 54. These observations indicate that the roles of PPARγ in the regulation of
n2:mentions
n3:16007265
Subject Item
_:vb9301482
rdf:type
n2:Context
rdf:value
PPARγ bound to the peroxisome proliferator response elements (PPREs) in the lox-1 promoter and stimulated LOX-1 gene transcription and expression in adipocytes >>54<<. These observations indicate that the roles of PPARγ in the regulation of lox-1 expression are divergent and might greatly depend on cell types. Additional experiments are necessary to clarify the underlying mechanisms.
n2:mentions
n3:16007265
Subject Item
_:vb9301483
rdf:type
n2:Context
rdf:value
β-catenin-independent Wnt signaling, canonical Wnt signaling involves a series of events that is initiated by binding an extracellular Wnt protein, including Wnt3a, to a member of the family of Frizzled transmembrane receptors >>42<<, 43. This interaction activates the Dishevelled protein by hyper-phosphorylation, which results in the prevention of the phosphorylation of β-catenin by the degradation complex (GSK-3, APC, and Axin) and the release of β-catenin from the
n2:mentions
n3:18177486
Subject Item
_:vb9301484
rdf:type
n2:Context
rdf:value
β-catenin-independent Wnt signaling, canonical Wnt signaling involves a series of events that is initiated by binding an extracellular Wnt protein, including Wnt3a, to a member of the family of Frizzled transmembrane receptors 42, >>43<<. This interaction activates the Dishevelled protein by hyper-phosphorylation, which results in the prevention of the phosphorylation of β-catenin by the degradation complex (GSK-3, APC, and Axin) and the release of β-catenin from the
n2:mentions
n3:18160255
Subject Item
_:vb9301485
rdf:type
n2:Context
rdf:value
Free β-catenin forms a complex with TCF/LEF and translocates into the nucleus, stimulating target gene transcription >>42<<, 43. Although its effects remain controversial 55, accumulating evidence has indicated that activation of the canonical Wnt signaling pathway stimulates HSC activation and hepatic fibrogenesis 56, 57. We demonstrated in this report that
n2:mentions
n3:18177486
Subject Item
_:vb9301486
rdf:type
n2:Context
rdf:value
Free β-catenin forms a complex with TCF/LEF and translocates into the nucleus, stimulating target gene transcription 42, >>43<<. Although its effects remain controversial 55, accumulating evidence has indicated that activation of the canonical Wnt signaling pathway stimulates HSC activation and hepatic fibrogenesis 56, 57. We demonstrated in this report that
n2:mentions
n3:18160255
Subject Item
_:vb9301487
rdf:type
n2:Context
rdf:value
Although its effects remain controversial >>55<<, accumulating evidence has indicated that activation of the canonical Wnt signaling pathway stimulates HSC activation and hepatic fibrogenesis 56, 57.
n2:mentions
n3:18158920
Subject Item
_:vb9301488
rdf:type
n2:Context
rdf:value
Although its effects remain controversial 55, accumulating evidence has indicated that activation of the canonical Wnt signaling pathway stimulates HSC activation and hepatic fibrogenesis >>56<<, 57. We demonstrated in this report that curcumin significantly reduced the level of nuclear β-catenin in HSCs. In addition, the activation of PPARγ by curcumin interrupted Wnt signaling, leading to the suppression of lox-1 expression and
n2:mentions
n3:17464972
Subject Item
_:vb9301489
rdf:type
n2:Context
rdf:value
Although its effects remain controversial 55, accumulating evidence has indicated that activation of the canonical Wnt signaling pathway stimulates HSC activation and hepatic fibrogenesis 56, >>57<<. We demonstrated in this report that curcumin significantly reduced the level of nuclear β-catenin in HSCs. In addition, the activation of PPARγ by curcumin interrupted Wnt signaling, leading to the suppression of lox-1 expression and the
n2:mentions
n3:16958658
Subject Item
_:vb9301490
rdf:type
n2:Context
rdf:value
Our results are supported by prior observations that the activation of PPARγ antagonistically interrupted Wnt signaling by inducing the degradation of β-catenin >>58<<-60. In addition, the interruption of Wnt signaling inhibited HSC activation 15, 16. Other studies also showed the roles of the Wnt signaling pathway and the transcription factor TCF/LEF-1 in mediating curcumin actions. For example,
n2:mentions
n3:15711576 n3:16847334 n3:12954078
Subject Item
_:vb9301491
rdf:type
n2:Context
rdf:value
In addition, the interruption of Wnt signaling inhibited HSC activation >>15<<, 16. Other studies also showed the roles of the Wnt signaling pathway and the transcription factor TCF/LEF-1 in mediating curcumin actions.
n2:mentions
n3:16780995
Subject Item
_:vb9301492
rdf:type
n2:Context
rdf:value
In addition, the interruption of Wnt signaling inhibited HSC activation 15, >>16<<. Other studies also showed the roles of the Wnt signaling pathway and the transcription factor TCF/LEF-1 in mediating curcumin actions.
n2:mentions
n3:17544413
Subject Item
_:vb9301493
rdf:type
n2:Context
rdf:value
caused a caspase-3-mediated cleavage of β-catenin, decreased trans-activation of β-catenin/TCF, decreased promoter DNA binding activity of the β-catenin/TCF complex, and decreased levels of c-Myc protein in the colon cancer cells >>61<<. Studies also indicated that curcumin and its derivatives attenuated the Wnt/β-catenin pathway through down-regulation of the transcriptional coactivator p300 62.
n2:mentions
n3:12466962
Subject Item
_:vb9301494
rdf:type
n2:Context
rdf:value
Studies also indicated that curcumin and its derivatives attenuated the Wnt/β-catenin pathway through down-regulation of the transcriptional coactivator p300 >>62<<. It was even suggested that curcumin and its derivative were excellent inhibitors of β-catenin/TCF signaling in cancer cell lines 63. The reduced β-catenin/TCF transcriptional activity was due to the decreased nuclear β-catenin and TCF-4
n2:mentions
n3:19000900
Subject Item
_:vb9301495
rdf:type
n2:Context
rdf:value
It was even suggested that curcumin and its derivative were excellent inhibitors of β-catenin/TCF signaling in cancer cell lines >>63<<. The reduced β-catenin/TCF transcriptional activity was due to the decreased nuclear β-catenin and TCF-4 63.
n2:mentions
n3:15893313
Subject Item
_:vb9301496
rdf:type
n2:Context
rdf:value
The reduced β-catenin/TCF transcriptional activity was due to the decreased nuclear β-catenin and TCF-4 >>63<<.
n2:mentions
n3:15893313
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