%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Bisdemethoxycurcumin Induces Apoptosis in Activated Hepatic Stellate Cells via Cannabinoid Receptor 2
Phil Jun Lee, Seung Je Woo, Jun-Goo Jee, Sang Hyun Sung, Hong Pyo Kim
Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.
bisdemethoxycurcumin (BDMC)
curcumin
hepatic stellate cells (HSCs)
liver fibrosis
cannabinoid receptor (CBR) 2
death-inducing signaling complex (DISC)
adenosine triphosphate (ATP)
endstream
endobj
3 0 obj
<>
endobj
4 0 obj
<>
endobj
5 0 obj
<>stream
q
endstream
endobj
6 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi1 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
7 0 obj
<>stream
q
endstream
endobj
8 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi2 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
9 0 obj
<>stream
q
endstream
endobj
10 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi3 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
11 0 obj
<>stream
q
endstream
endobj
12 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi4 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
13 0 obj
<>stream
q
endstream
endobj
14 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi5 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
15 0 obj
<>stream
q
endstream
endobj
16 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi6 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
17 0 obj
<>stream
q
endstream
endobj
18 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi7 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
19 0 obj
<>stream
q
endstream
endobj
20 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi8 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
21 0 obj
<>stream
q
endstream
endobj
22 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi9 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
23 0 obj
<>stream
q
endstream
endobj
24 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi10 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
25 0 obj
<>stream
q
endstream
endobj
26 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi11 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
27 0 obj
<>stream
q
endstream
endobj
28 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi12 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
29 0 obj
<>stream
q
endstream
endobj
30 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi13 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
31 0 obj
<>stream
q
endstream
endobj
32 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi14 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
33 0 obj
<>stream
q
endstream
endobj
34 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi15 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
35 0 obj
<>stream
q
endstream
endobj
36 0 obj
<>stream
Q
q
q
0.57765 0.81629 -0.81629 0.57765 322.27 403.53 cm
BT
1 0 0 1 -412.45 0 Tm
/Xi16 86.43 Tf
1 Tr
0.86431 w
0.75294 0.75294 0.75294 RG
0 0 1 rg
(www.science-truth.com)Tj
0 g
0 Tr
0 G
1 w
ET
Q
Q
endstream
endobj
37 0 obj
<>
endobj
38 0 obj
<>
endobj
39 0 obj
<>stream
q
endstream
endobj
40 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi0 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
41 0 obj
<>stream
q
endstream
endobj
42 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi1 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
43 0 obj
<>stream
q
endstream
endobj
44 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi2 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
45 0 obj
<>stream
q
endstream
endobj
46 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi3 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
47 0 obj
<>stream
q
endstream
endobj
48 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi4 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
49 0 obj
<>stream
q
endstream
endobj
50 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi5 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
51 0 obj
<>stream
q
endstream
endobj
52 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi6 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
53 0 obj
<>stream
q
endstream
endobj
54 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi7 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
55 0 obj
<>stream
q
endstream
endobj
56 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi8 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
57 0 obj
<>stream
q
endstream
endobj
58 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi9 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
59 0 obj
<>stream
q
endstream
endobj
60 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi10 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
61 0 obj
<>stream
q
endstream
endobj
62 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi11 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
63 0 obj
<>stream
q
endstream
endobj
64 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi12 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
65 0 obj
<>stream
q
endstream
endobj
66 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi13 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
67 0 obj
<>stream
q
endstream
endobj
68 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi14 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
69 0 obj
<>stream
q
endstream
endobj
70 0 obj
<>stream
Q
q
q
BT
1 0 0 1 7.2 825.74 Tm
/Xi15 12 Tf
0 0 1 rg
(SOURCE: http://www.science-truth.com)Tj
0 g
ET
Q
Q
endstream
endobj
71 0 obj
<>/ProcSet[/PDF/Text/ImageB/ImageC/ImageI]>>/CropBox[0 0 595.62 841.68]/Parent 76 0 R/Type/Page>>
endobj
72 0 obj
<>stream
x[[:r~w