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Cancer
脂肪肝會增加罹患肝癌的危險達2.5至3倍
(1) Non-alcoholic
fatty liver to HCC;
(2) HCV HCC
(3) HBV HCC
Cancer
Science 332(24), p1519, 2011
Liver fatty change in the HBx transgenic livers
H & E stain
Oil red-O staining
3
Metabolic syndrome increases the risk of HCC
Metabolic syndrome was associated with a significant 2.13-fold increased risk of HCC
Hepatology, Volume 54, Issue 2, pages 463–471, August 2011
4
Type I GGHs
Type II GGHs
ER
5
pre-S Mutants
PreS1+PreS2
1
PreS2
ER stress dependent
ER stress independent
JAB1
pp38
VEGF
p27
6
Cdk2
NF-kB
3
Akt
COX-2
Rb
mTOR
Cyclin A
Genomic
instability
HCC
YY
1
2
7
ROI
Oxidative DNA
damages
4
Hepatocyte
proliferation
Ca2+
1
Wang HC et al., 2003
2
Hsieh YH et al., 2004
3
Hung JH et al., 2004
4
Wang HC et al., 2005
5
Hsieh YH et al., 2007
6
Yang JC et al., 2009
7
Teng CF et al., 2011
mTOR signal pathway is a chemoprevention target
Pre-S2
mutant
VEGF-A
ER
stress
HBV
Akt
mTOR
SREBP-1
4E-BP1
ACLY
Citrate
Acetyl-CoA
De novo
lipogenesis
Triglycerides,
Cholesterols
Growth
advantage
HCC
mRNA
translation
YY1
c-myc
GLUT1
Glucose
uptake
1.
2.
3.
4.
5.
6.
Aerobic
glycolysis
Pyruvate,
lactate
TCA cycle,
citrate
HBV pre-S2 mutant activated mTOR through ER stress-dependent VEGF-A/Akt signaling.
Activated mTOR signal upragulated YY1 through phosphorylating and inactivating 4E-BP1, a repressor of mRNA translation.
The YY1/c-myc/GLUT1 signaling cascade stimulated glucose uptake and aerobic glycolysis.
Activated mTOR signal could additionally increase ACLY expression through SREBP-1 mediation.
ACLY converted cytosolic citrate to acetyl-CoA, a vital building block for triglycerides and cholesterols, therefore promoting de novo lipogenesis.
Converged effects of aerobic glycolysis and de novo lipogenesis contributed to growth advantages of hepatocytes and HCC development.
mTOR signals –
Target for drug development
Everolismus
Natural products for chemoprevention:
Resveratrol: Red Grape Magic
• Red wine 5mg/bottle
Resveratraol
Science 1997: Resveratrol is effective for tumor
control at the stages of tumor
initiation, promotion, and
prevention
Resveratrol ( grape skin ) inhibits AKT/mTOR
signaling
Synergistic effect of resveratrol combined with silymarin on PPAR-g activity, p-mTOR
inhibition, and enhanced PGC-1a
mTOR, PPARs
Proposed model for chemoprevention
Targeting at PPAR and mTOR signaling pathway
Chemoprevention
11
Resveratrol combined with silymarin reduce the HCC
in HBx-transgenic mice model
12
阿茲海默症Alzheimer’s disease (AD) is a
progressive neurodegenerative disease and
the most common cause of dementia
 Alzheimer’s disease
-- Neuronal loss and atrophy
-- Age 65 and up at risk
-- Estimated 37 million people
worldwide affected (1 in 200)
-- 6th leading cause of death in
the United States
-- Memory loss, speech defect
-- Loss ability to do normal tasks,
recognize relatives, and take
care of themselves
阿茲海默症的學理基礎:
異常構造的β類澱粉蛋白(β -amyloid)無法清除，而累積在神
經細胞中形成細纖維團(fibrillary tangle)或細胞外的斑塊
(plague)，引起神經細胞傷害或死亡，導致傳導功能、發炎等
病變。
Oxidative stress, inflammation, amyloid-b (Ab) peptide, and
phosphorylated tau play important role in AD pathogenesis
(g-secretase)
(b-secretase)
(3)
Ab40
Ab42
Amyloid
plaque
Ab
aggregation
APP (amyloid precursor
protein)
(Nature Reviews Neuroscience 8, 499-509, 2007)
(4)
Neurofibrillary
tangle (NFT)
(1)
(2)
Hyperphosphrylated
tau
(Nature Reviews Drug Discovery 8, 783-793, 2009)
The flux of Aβ/cholesterol/ApoE through the cell
and the potential regulation by PPAR/RXR/LXR
PPAR
(Wolozin B, Neuron 41, 7-10, 2004)
如何治療或改善AD
• 治本:
瞭解β–amyloid異常調控的機制，並予以抑
制或分解，最好是在臨床症狀發生前。
我們目前對AD致病機制瞭解多少呢?
• 治標:
1. 增加神經傳導功能－多動腦、藥物。
2. 降低神經細胞內的內質網(ER)壓力及氧化壓力
(ROI)，減輕神經細胞傷害並延遲神經細胞死亡－抗
氧化。
3. 改善發炎環境。
4. 降低膽固醇。
Cramer PE., et. al. Science 2012, 335: 1503-1506.
Curcumin has antioxidant, anti-inflammatory, and
anti-amyloid activity and is a promising compound
for the development of AD therapies
Curcuma longa (薑黃)
 In vitro studies with curcumin
-- Antioxidant effect
-- Anti-inflammatory effect
-- Inhibition of b-secretase
-- Inhibition of Ab aggregation
 In vivo studies with curcumin
-- Inhibition of Ab deposition
-- Inhibition of Ab oligomerization
(薑黃素)
(CNS Neuroscience&Therapeutics 16, 285-297, 2010
Question
The mechanism by which
curcumin inhibits Ab deposition
remains to be clarified
Spices as NF-B Inhibitors
OCH 3
O
O
H3CO
OCH 3
CH
OH
OH
CH
CH3
Curcuma longa
Curcumin
Turmeric
Foeniculum vulgare
Anethole
Fennel
Capsicum annum
Capsaicin
Cloves
Red chilli
T. foenum-graecum
Fenugreek
Eugenia caryophyllata Eugenol
Diosgenin
Ocimum sanctum
Holi basil
Ursolic Acid
中草藥及蔬果中的有效成分皆可活化PPAR分
子而抗發炎、抑制三高、防老化、與抗癌
（君臣佐使）
（Ⅰ）類胡蘿蔔素（ Carotenoids）：
植物色素—葉綠素、葉黃素（Lutein） 、茄紅素(Lycopene).
胡蘿蔔素（Carotene）
（Ⅱ）類黃酮（Flavonoids）：
柑橘槲黃素、兒茶素（Catechin）
（Ⅲ）三萜類（Triterpenoids）：
牛樟芝、 靈芝
其他：白藜蘆醇（resveratrol）、薑黃素（curcumin）
Combination of the L,B,C,S showed the best
synergistic activation of PPARα and PPARγ
中醫藥典籍中至少30%的上品藥材是PPAR活化
劑，且複方與君臣佐使理念是二十一世紀藥物發
展與養生的主軸
Health promotion and disease prevention through
functional and medical food use
Protein
(蛋白質）
Glucose
（葡萄糖）
Lipid
(脂
肪)
Overnutrition
(過度飲食）
ER Stress
Inflammation (發炎)
(內質網壓力）
Metabolic Syndrome
(代謝症候群)
Oxidative DNA damage
(氧化DNA傷害)
Oxidative
Stress
Genomic
instability
Cancer
癌
Aging
( AD )
Repair (修護DNA)
(氧化壓力)
①
②
③
Diet & Exercise
節食
Omega-3,-6
Antioxidants
Resveratrol
Anti-oxidants
PPAR agonists
Resveratrol
進康飲食
Curcumin
Curcumin
運動
④
⑤
Anti-oxidants
C/T
PPAR
Target
agonists
supplements
Curcumin
Resveratrol
Toward the Amelioration of Health and Disease
Prevention by Taking Natural Products in the 21st Century
Validation of combined natural products for PPARs,
mTOR, and Apo E by Western blot Hybridization
DMSO
Huh7
Rapamycin
3D
Resveratrol
3DR
Curcumin
-
+
-
+
+
+
+
DMSO
HepG2
+
20
0
Rapamycin
nM
30
0
20
40
0
15
μg/mL
3D
μg/mL
μg/mL
μM
Resveratrol
μg/mL
3DR
μg/mL
40
0
μg/mL
15
μg/mL
Curcumin
p-mTOR
p-mTOR
p-Akt
p-Akt
SIRT1
PGC-1α
SIRT1
PGC-1α
PPARα
PPARα
PPARγ
PPARγ
Apo E
actin
Apo E
+
-
+
+
+
+
40
0
30
0
20
40
0
40
0
15
actin
** 3D (統一)
3DR (統一)
+
** Resveratrol (pure compound, merck)
Curcumin (pure compound, sigma)
15
Nature 2011
南臺科技大學 生物科技中心
生技藥物開發平台的建立
Biological Function
Monitoring
PPARs activities (Reporter assay)
mTOR inhibition (Western blot)
cDNA array
Comparative Proteomics
100
3.0
50
1.5
0
0.0
90
0
72
0
Ma
s
54
0
a.m
3
.u.) 60
Intensity (log)
Absorbance (%)
Component Fingerprint
HPLC/GC-MS
32
s(
28
24
18
0
20
16
ntion
Rete
Time
)
(min
Stability
Animal Toxicology
(Safety)
Human/Animal Studies
(Efficacy)
28
Thank you for your attention