Cancer

Science 332(24), p1519, 2011

Cancer

(1) Non-alcoholic fatty liver to HCC;(2) HCV HCC(3) HBV HCC

脂肪肝會增加罹患肝癌的危險達 2.5 至 3 倍

Liver fatty change in the HBx transgenic livers

3

H & E stain Oil red-O staining

4

Metabolic syndrome increases the risk of HCC

Hepatology, Volume 54, Issue 2, pages 463–471, August 2011

Metabolic syndrome was associated with a significant 2.13-fold increased risk of HCC

ER pre-S Mutants

ER stress dependent

pp38 NF-kB

COX-2

Hepatocyte proliferation

Akt

VEGF

mTOR

Genomic instability

Ca2+

ROI

Oxidative DNA damagesCyclin A

JAB1

p27

Cdk2

Rb

ER stress independent

HCC

1

23

4

5 PreS1+PreS2PreS2

6

Wang HC et al., 2003

Hsieh YH et al., 2004

Hung JH et al., 2004

Wang HC et al., 2005

1

2

4

3

5 Hsieh YH et al., 2007

6 Yang JC et al., 2009

Type I GGHsType II GGHs

YY1

YY1

7

7 Teng CF et al., 2011

mTOR

ER stress

mRNA translation

Growth advantage

VEGF-A

Akt

4E-BP1

YY1 c-myc

SREBP-1 ACLYDe novo

lipogenesis

Aerobic glycolysis

HCC

GLUT1

HBV

Pre-S2mutant

Citrate Acetyl-CoA Triglycerides,Cholesterols

Glucoseuptake

Pyruvate,lactate

TCA cycle,citrate

mTOR signal pathway is a chemoprevention target

1. HBV pre-S2 mutant activated mTOR through ER stress-dependent VEGF-A/Akt signaling.2. Activated mTOR signal upragulated YY1 through phosphorylating and inactivating 4E-BP1, a repressor of mRNA translation.3. The YY1/c-myc/GLUT1 signaling cascade stimulated glucose uptake and aerobic glycolysis.4. Activated mTOR signal could additionally increase ACLY expression through SREBP-1 mediation.5. ACLY converted cytosolic citrate to acetyl-CoA, a vital building block for triglycerides and cholesterols, therefore promoting de novo lipogenesis.6. Converged effects of aerobic glycolysis and de novo lipogenesis contributed to growth advantages of hepatocytes and HCC development.

mTOR signals –Target for drug developmentEverolismus

Natural products for chemoprevention:Resveratrol: Red Grape Magic

• Red wine 5mg/bottleResveratraol

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

11

Chemoprevention

Targeting at PPAR and mTOR signaling pathway

Proposed model for chemoprevention

12

Resveratrol combined with silymarin reduce the HCC in HBx-transgenic mice model

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

APP (amyloid precursor protein)

(b-secretase)

(g-secretase)

(Nature Reviews Drug Discovery 8, 783-793, 2009)

Amyloid plaque

Ab40

Ab42

Ab aggregation

(1)

(2)

(3)

Neurofibrillary tangle (NFT)

Hyperphosphrylated tau

(4)(Nature Reviews Neuroscience 8, 499-509, 2007)

PPAR

The flux of Aβ/cholesterol/ApoE through the cell and the potential regulation by PPAR/RXR/LXR

(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。

前述治本、治標方案皆可以食療改善

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 )

( 薑黃素 )

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

The mechanism by which curcumin inhibits Ab deposition

remains to be clarified

(CNS Neuroscience&Therapeutics 16, 285-297, 2010)

Question

Capsicum annumRed chilli

Capsaicin

Curcuma longaTurmeric

Curcumin

H3CO

OH

O O

OCH3

OH

DiosgeninT. foenum-graecumFenugreek

Foeniculum vulgare AnetholeFennel

OCH3

CH

CH

CH3

Eugenia caryophyllataCloves

Spices as NF-B Inhibitors

Eugenol

Ursolic AcidOcimum sanctumHoli basil

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

( 內質網壓力）

Oxidative Stress

( 氧化壓力 )

Inflammation ( 發炎 )

Metabolic Syndrome ( 代謝症候群 )

Oxidative DNA damage ( 氧化 DNA 傷害 )

Repair ( 修護 DNA)

Genomic instability

Aging ( AD )

Cancer 癌

①

Diet & Exercise

節食進康飲食

運動

②Omega-3,-6

Antioxidants Resveratrol

Curcumin

③Anti-oxidants PPAR agonists Resveratrol

Curcumin

④

Anti-oxidants PPAR

agonists Curcumin

Resveratrol

⑤

C / T

Target supplements

Toward the Amelioration of Health and Disease Prevention by Taking Natural Products in the 21st Century

DMSO - + - + + + + +

Rapamycin 200

3D 300

Resveratrol 20

3DR 400

400

Curcumin 15 15

μg/mL

p-Akt

SIRT1PGC-1α

PPARα

PPARγ

Apo E

μg/mL

μM

μg/mL

actin

p-mTOR

DMSO - + - + + + + +

Rapamycin 400

3D 300

Resveratrol 20

3DR 400

400

Curcumin 15 15

μg/mL

p-Akt

PGC-1α

PPARα

PPARγ

Apo E

μg/mL

μg/mL

μg/mL

nM

actin

p-mTOR

SIRT1

Huh7 HepG2

** Resveratrol (pure compound, merck) Curcumin (pure compound, sigma)

** 3D ( 統一 ) 3DR ( 統一 )

Validation of combined natural products for PPARs, mTOR, and Apo E by Western blot Hybridization

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

28

Component FingerprintHPLC/GC-MS

Biological Function Monitoring

PPARs activities (Reporter assay)mTOR inhibition (Western blot)

cDNA arrayComparative Proteomics

Stability

Animal Toxicology(Safety)

Human/Animal Studies(Efficacy)

0.0

3.0

1.5

Intensity

(lo

g)

Absorbance

(%

)

0

50

100

Thank you for your attention