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Nutrigenomics Definition
Analyzing the effects of diet on the activity of on
individuals genes and health and the effect of an
individuals genes on metabolism of dietary chemicals
Diet = nutritional science
Activity of genes = molecular biology
Individual = genetics/genomics
Health = physiology
A systems biology science : Multi - disciplinary
Nutrient is independent variable
Nutrient
Gene Expression
Nutrigenetics Definition
Effects of individual genetic variation in
response to nutrient
Any two individuals share 99% of their DNA sequence
Most common form of variation
Single nucleotide polymorphism (SNP)
Changes in single base pair
Occur ~ 1 in every 1000bp of human genome
(~ 3 million in human genome)
Molekul mechanisms of
genetic variation Linked diet
Ancestral diet
Modern diet
Macronutrients
Transduction of
signal via sensory
mechanisms
Metabolism
NUTRIGENOMICS
Genomics
Transcriptomics
DNA
mRNA
Sequencing
and Genotyping
Pattens of
Gene expression
Proteomics
Protein
Metabolomics
Metabolites
Gene
MTHFR
APOE
APOA 1
GPX4
HFE
SNP/Isoform
C677T
E2+ , E3+ , E4
-75 (G/A)
3 UTR
C282Y, H63D, S65C
Nutrient
Folate, alcohol
- 3 PUFA
PUFA
Selenium
Iron
Nutrigenetics
Genetic variation (SNP) may contribute to disease
differentials
Several alterations will be diet responsive and can
be rendered harmless
Challenge
Defining the right diet for the right population
Tailoring dietary recommendation based on genetic when
appropriate
Smoking
Protective
SNP1
Good
Nutrition
In utero
Health
pendulum
Food
Component 2
Physical
activity
Time
Health
Disease
Iron
Carbohydrates
i.e., glucose
Vitamin D
VDR
Nutrient ligand
Bioflavonoids
Estrogen receptors
Nuclear factor xB
Vitamin A
Xenobiotics
RAR
RXR
Trancription factor
Protein &
amino acid
CCAAT/enhancer-biding protein
Cholesterol
Fatty acids
Calcium
Liver X receptor
Farnesoid X receptor
Pregnane X receptor
Vitamin E
PHENOTYPIC STABILITY
Health
Reproductive efficiency
Enhanced competitiveness
A more robust
cellular integrity
Desease
Reproductive inefficiency
Reduced competitiveness
A lessrobust
cellular integrity
PHENOTYPIC INSTABILITY
The Balances between phenotypic outcomes with respect to nutrition and
genetic buffering
Background
Information
Binds either RXR or RAR nuclear retionoid receptor and enhances transcription,
although in absence of
retinoic acid, heterodimers repress gene expression
Pyridoxal
Phosphate
(vitamin B6)
Modulates responsiveness of
steroid hormone receptor
Attenuates transcription
Riboflavin
(vitamin B2)
May interact with cellular folate to influence elaboration of DNA (1-C unit from
folate donated to thymine)
Folic acid
May modulate both expression of DNA via CpG methylation pattern and
elaboration of DNA via provision of thymine. If 1-C shortage, uracil is
misincorporated and DNA becomes unstable
Vitamin D
Vitamin K
Regulates apoptosis, but it does not interact directly with genomic machinery
-Tocopherol
(vitamin E)
Iron
Magnesium
Ascorbic acid
(vitamin C)
Calcium
Potassium
Selenium
Zinc
APPLICATIONS
Screening and development of new
antioxidants
Assessing potential effects of
antioxidants
Defining biomarkers of oxidative stress
Evaluating the bioavailability of
antioxidants
Studying redox sensitive signal
transduction pathways
TECHNIQUES
Differential display
cDNA arrays and Gene chips
Serial Analysis of Gene Expression
RT-PCR
Northern blotting
Free
radikal
Radical generated
Lipid peroxides
NADP+
Glutathione reductase
NADPH
Glutathione peroxidase
enzyme protein with a
selenocysteine residu at
the catalytic site
CH2
H3N CH
C=0
SeH
S-Adenosylhomocysteine Homocysteine
S-Adenosylmethionine
methionine
Genomic
methyiations
B12
5-Methylenetetrahydrofolate
Methyionine
synthase
Equlibrium in
favor of 677C
allele
Methyionine biosynthesis
Equlibrium in
favor of 677T
allele
dUMP
Thymidylate synhase
dTMP
Nucleotide biosynthesis and the elaboration of DNA
Pertubations may influence embryogenesis; inadequate folate due to a poor diet and 677MTHFR might lead to uracil misincorparation in DNA, genomic instability, and loss of the
developing embryo. It may also promote cancer
Vitamin
C
Vitamin
B12
Vitamin
B6
Vitamin
E
Vitamin
B3
Folic
acid
Vitamin
B2
Vitamin
D
Zn,Se,Fe
Mg, Cu
Membrane Damage
Free
radicals
+
O2
Mitochhondrial
DNA Damage
l
ica
ad
e r gy
xid er
ro en
pe P
Su AT
Superoxide
dismutase
H2O2
Catalase
O2 + Glucose
H2O and
O2
Reduce NO
Reduce tetrahydro
biopterin
Metionin
sintase
Low methylation
5 metilTHF
5,10 metilen THF
MTHFR:
C677C (normal)
C677T (akt rendah)
Cellular genomic and nongenomic effects of isoflavones. The effects differ according to the
type of tissue and the number of estrogen receptors within that tissue. The effect on reproductive tissue
is of particular interest and may influence reproductive efficiency.
Pollution
Food
Lack of
Exercise
Oxidative
Activities
Toxine
Cholesterol
Diabetes Bacteria
Gene
Germ
Lack of
enzyme
Enviroment
INSULIN RESISTANCE
Production of
Oxidant molecules
Acute phase
protein
Fever
Glucose Synthesis
Effect of
cytokines TNF,
IL 1 and IL6
Appetite
Loss and
lethargy
Plasma copper
Plasma Zn
Plasma Iron
Loss of lean
Tissue and
fat
Increased urinary
Nitrogen sulphur
And mineral losses
chytokines
Metabolic Syndrome
Health Destroyer
A collection of metabolic risk factors that accelerate the
onset of diabetes, heart disease, stroke and certain
cancers.
Proinflammatory
Cytokines Released
Glucose Uptake
Decreases
Pancreas Increases
Insulin Production
Hyperinsulinemia
Triglycerides Released to
Blood Stream
Cardiovascular Disease
OXIDATIVE STRESS
ROS
NOS
Oxidative stress
1)Redox status
2) Depletion of antioxidants
FROM
EPIDEMIOLOGICAL STUDIES : antioxidant status (vit C, E)
scientific evidence
Clinical - prevention
- treatment
As - a primary cause
- a secondary complication in many disorders
- inflamatory bowel disease
- retinal ischemic
- CVD and restenosis
- AIDS
- adult respiratory distress syndrome
- stroke
- Parkinsons disease
- Al zheimers disease
Major natural
antioxidant enzyme/ substances (in
foods & beverage)
- vit E, A, C
- flavonoids
- polyphenols
- caretenoids
- lipoic acid
- coenzyme Q10
- carnitine
- other micro nutrients
Trauma/infection/burn
Immune system activation
Immuno
nutrition
Pro-inflammatory cytokines
oxidants
Pathogen
killing
Antioxidant
defence
Tissue
damage
Creation of a
hostile enviroment
Feedback
Systems
IL10, Heat
Shock proteins
T and B Cells
Glucose
Glutamine
Nutrient
Release from
Host tissues
Appetite loss
Sulphur
amino
acids
Glutathione
Synthesis
Antioxidant
defences
strenghened
Methionine
Homocysteine
Vit B6
Cysteine
Oxidants
Vit E
Reduced
Vit E
oxidised
Dehydro
ascorbic
acid
Ascorbic
acid
Glutathione
GSH
Glutathioner
eductase
Riboflavin
Glutathione
GSSG
Inflammatory stimuli
LPS, Oxidants, stress
Transciption
factors
AP1
Cell
Proliferation
NFKB
IL2
Acute
Phase
protein
GSH
synthesis
Adhesion
molecules
IL1,
IL6,
IL8,
TNF
HIV
replication
Antioxidants
Preventions of Oxidative
Damage towards Lipids
Proteins and DNA
Redox Signalling
Molecules
Scavenger receptor
expression
Inhibitory
Effect of
Vitamin E on
Platelet adhesion
And-aggregation
Cell receptors, cellular key enzymes, and transcription factors as molecular targets of oxidants
and antioxidants
Receptors
Phosphatase
Kinases
Transcription
Factors
Oxidants
Antioxidants
Gene Expression
Protein levels
Enzyme Activity
NUTRIGENOMIC
Pangan - GIZI
(anugerah)
KEBODOHAN
(logos)
BIOTEKNOLOGI
Rekayasa genetika
pangan
KEARIFAN
LOKAL
KESERAKAHA
N (eros)
Kanker
(Musibah)
GLOBALISASI
Perilaku
GAYA
HIDUP
Pola/kebiasaan
makan
Rokok, alkohol
Sedentary (obeis)
KANKER
LINGK
Pangan
- Genotoksik/ pro kanker
- Anti kanker
-
Olah
Simpan
BTP
Plastik
GLOBALISASI
- Kontaminan
- Pestisida
- Limbah
Fenotipe Sehat
Fenotipe Sakit
UJI
KLINIS
RISET
EPIDEMIK
Uji
Hewan
Fakta Epidemiologis
Kashmir : Ca. Oesofagus ~ pengolahan teh + garam
Skandinavia : Cancer lambung & colon ~ daging merah
Migran Jepang : kacang cycad
Mesir : Cancer hati ~ bijian disimpan
Kaukasus : Cancer payudara ~ lemak
Ceko-Polandia : Lemak >< kubis
China : teh hijau, bumbu/ rempah cara masak singkat
PANGAN KARCINOGENIC
Alamiah :
hidrazin
safrole
estragole
psoralen
Geno Toksik
Buatan/ perilaku
manusia
:
prose Simpan
: Aflatoksin, Patulin, Citrinin
s
Asupan :
PAH
HAA
NOC
sacharin
karamel
furyl furamid
pewarna azo
nitrat (III, V)
Reparasi
SEL
Respons
Radang
Metabolisme
Karsinogen
KOMPONEN
BIOAKTIF
PANGAN
Siklus SEL
Kematian Sel
Terprogram
Regulasi
Hormonal
Diferensiasi
Cegah terjadi
Hambat perjalanan keganasan
Halangi kekambuhan
Gambar : Modulasi Komponen pangan pd Sel Kanker
nutrigenomi
k
era post
genomik
Lokasi sel
target
Biomarker
Tahapan
Spesifik
Efek spesifik
Dapat dipantau
dipantau
Dapat
adanya perubahan
perubahan
adanya
risiko terhadap
terhadap respon
respon
risiko
intervensi gizi
gizi
intervensi
MEKANISME MOLEKULER
DIET ANTI KANKER
Aktivasi antioksidan
Replikasi tak
terbatas
Invasi metatase
Katekin
EGCG the hijau + hitam
Regulasi pembelahan
sel
genistein (isoflavon),
fitoestrogen kedele
Apoptosis
Angiogenesis
ANTI Oksidan
Et, Vitamin C
Caroten
Se
EGCG
Quercetin
Genestein
Taxifolin
ANTI Radang
Detoksifikasi
Enzim xenobiotik : Glukosinolat brocoli
Regulasi
Epigenik : - Folat
- Vit B, 12, B2, B6, methionin
- Zn, Se
- Retinoid acid
KHEMOPREVENSI KANKER
Carotenoid :
Fenolic :
Fenolic acid
Flavonoids
Stilbene
Tannin
Coumarin
Organosulfur :
- Flavonols (Quercetin)
- Flavones (Apigenin)
- Flavanols (Catechin)
- Flavanone (Naringetin)
- Anthocyanidine (Cyanidin)
- Isoflavonoid (Genistein)
Isotiosionat
Indole
sulfur CLA
: sulfida
Alyl
Makronutriet : omega 3,
spingolipid,
Serat
PREVENSI (Lain)
Intensif penggunaan fitokimia
buah
sayuran
biji utuh
serat
produk (ikan, kedele)
susu rendah lemak
Target Molekuler
Khemoprev. Diit
As. Empedu
Kalsium
Sitokrom P450s
-PE ITC
-Indol -3- carbinol
-Isoflavon
Karsinogen
Hambat aktivasi karsiongen
- PG Synthase
Hydroperoksidase
Curcumin
Slipoxygenase
- As. empedu
-Urosdial
Dexoksifikasi karsinogen
GSH/ GST
NAC bisulfida
Sitokran P450s
Katekin
Modulasi hormon
- Reseptor estroge
-Isoflavon
Aktivitas fc tumbuh
- Steroid 5 reductose
-Katekin
- IGF.1
-Isoflavon,,Likopen
- AP-1
-Retinoid
- PPARs
FP transferase
Limonen, DHEA
ODC induksi
TGF-
Selenium katekin
Reduksi inflamasi
NF.KB
Connexin 43
Lycopene retinoids
Induksi Apoptosis
- TGF
- Rosfarelisasi
- Arachidonic Acid
-Retinoic acid
- Caspase
-Retinoids
Induksi senesens
Telomerase
Vit D retinoids
Hambat angiogenesis
FGF receptor
Isoflavon restinoid
Tyronin kinase
Tranmodulin
Asam folat
Collagenase IV
Proteese inhibisi
G.6.P dehydrogenase
DHEA
MEMERANGI KANKER
Piramida Pedoman Makan
AICR
tinggi asupan
- buah-sayur
- karbohidart komplek
- serat
Lemak
- n-3
- FA
Tenets of Nutrigenomics
1.Improper diets are risk factors for disease
2.Dietary chemicals alter gene expression and/or
genome structure
3.Influence of diet on health depends upon an
individuals genetic make up
4.Genes regulated by diet play a role in chronic
diseases
5.Personalized nutrition diets based upon
genotype, nutritional requirements and status
prevents and mitigates chronic disease