lecture 27: polyphenols

Question 1

polyphenols

Answer 1

plant secondary metabolites

Question 2

flavonoids

Answer 2

plant polyphenols with a basic chemical structure of 15C

Question 3

flavanols

Answer 3

sub-family of polyphenols
catechin, epicatechin

most abundant is (-)-epicatechin

Question 4

procyanidins

Answer 4

polymers/oligomers of flavanols
not degraded through gastric transit, found in intestine

conc in GI tract can be maintained or increased when consumed on a daily basis

local effects at GI tract

can prevent DCA-induced CRC, inhibit oxidant production and Ca2+ increases

Question 5

catechin, epicatechin absorption and metabolism

Answer 5

absorption and metabolism influenced by stereochemical configuration

(-)-epicatechin best absorbed

after absorption, transformed into several methylated, sulfated, etc metabolites

Question 6

how to flavanols and procyanidins prevent cholesterol and TAG absorption?

Answer 6

tea polyphenols inhibit pancreatic lipase activity

Question 7

polyphenol inhibition of fat absorption

Answer 7

flavanols and procyanidins in tea inhibit TG absorption
tea polyphenols inhibit activity of pancreatic lipase (TG to FA)

Question 8

NOX (NADPH Oxidase)

Answer 8

oxidizes NADPH and forms O2-
O2- and NO can form peroxynitrite, potent oxidant

Question 9

polyphenol regulation of BP

Answer 9

OVERALL: flavanols improve NO bioavailability > decrease BP
epicatechin decrease NOX or increase eNOS

Question 10

polyphenols and antioxidant effects

Answer 10

decreased oxidative stress, action of flavanols and procyanidins on cellular components > decreased level of tissue oxidants

Question 11

if the concentration of flavonoids do not reach concentrations within the body to be effective metal chelators or free radical scavengers, how can they have antioxidant actions?

Answer 11

they must be effective modulators of specific protein targets

ex. flavanols inhibit NOX

Question 12

2 measures of oxidative stress

Answer 12

GSH and MDA

Question 13

glutathione (GSH)

Answer 13

antioxidant, preventing damage caused by ROS by serving as electron donor > dimeric form GSSG
ratio of GSH:GSSG is indicator of oxidative stress

Question 14

malondialdehyde (MDA)

Answer 14

results from lipid perodixation of PUFAs

Question 15

suggested effects of epicatechin

Answer 15

1) increase in eNOS activity
eNOS activation via PI3K/AKT or Ca2+/calmodulin pathway

2) diminished NOX activity

both increase NO bioavailability!

Question 16

DCA (deoxycholic acid)

Answer 16

secondary bile acid for emulsification of fats
increase ROS production > oxidative stress

affects local conc of cholesterol and alters membrane lipid rafts

Question 17

lipid rafts

Answer 17

specialized areas of the plasma membrane characterized by high content of cholesterol

Question 18

MAPK/ERK Pathway

Answer 18

ligand binds to EGFR > phosphorylation cascade to activate ERK1/2, which activates transcription factors like NF-kB > activate TNFa

overactivation > tumor growth

Question 19

protein kinase C (PKC)

Answer 19

can be activated by DAG or Ca2+

overactivation > tumor growth

Question 20

NF-kB

Answer 20

transcription factor involved in inflammatory response

maintained in inhibited state by IkBa, activated/released upon phosphorylation of IkBa, NFkB enters nucleus

Question 21

TNFa

Answer 21

cell signaling protein (cytokine) involved in inflammation

triggers adipocyte activation of ERK1/2, JNK, p38, AP-1, NFkB

Question 22

AP-1

Answer 22

transcription factor, downstream target of ERK 1/2 and p38
activated by DCA

Question 23

procyanidins and DCA

Answer 23

blocks ERK 1/2, p38, Akt, AP1, NF-kB activation

Question 24

procyanidins and cholesterol

Answer 24

prevents redistribution/depletion of cholesterol from membrane (alter of lipid rafts)

Question 25

ER stress

Answer 25

oversupply of nutrients available, accumulation of misfolded proteins in ER > activate unfolded protein response (UPR) linked with oxidative stress > insulin resistance

Question 26

main source of superoxide and hydrogen peroxide

Answer 26

NOX enzymes high fructose/fat diet > increased expression of NOX

Question 27

UPR (unfolded protein response)

Answer 27

JNK and IKK activated, triggered by inflammation IKK activates NFkB

Question 28

adiposity promotes...

Answer 28

secretion of proinflammatory cytokines such as TNFa > insulin resistance

Question 29

binding of TNFa to its receptor

Answer 29

causes activation of NADPH oxidase > increase in oxidant production

Question 30

PTP1B

Answer 30

negative regulator of the insulin signaling pathway can dephosphorylate activated insulin receptor kinase

Question 31

PTP1B pathway

Answer 31

1) binding of insulin to receptor 2) phosphorylation of tyrosine residues in receptor 3) receptor generates binding sites for insulin receptor substrate 4) PTP1B inactivates the insulin receptor and substrate by dephosphorylation 5) diminished GLUT4 translocation > glucose in bloodstream NFkB > increased PTP1B > inactivates insulin receptor > diminished GLUT4 translocation

Question 32

PPAR(y)

Answer 32

increases insulin sensitivity downregulated by TNFa - this decreases insulin sensitivity

Question 33

NOX and insulin resistance

Answer 33

NOX inhibitor improves insulin sensitivity, epicatechin

Question 34

When considering the biological actions of polyphenols that are absorbed, what are two factors that should be considered?

Answer 34

1) Bioavailability: amount absorbed, structural modification into metabolites after absorption 2) Concentration at target tissue

Question 35

How does epicatechin increase nitric oxide bioavailability? What impact does this have on blood pressure?

Answer 35

inhibits NOX and enhances eNOS, increasing NO bioavailability > vasodilation

Question 36

Epicatechin and procyanidins are both capable of preventing the activation of NF-kB. However, their mechanism of action appears to be different. Explain how both forms of polyphenols accomplish this.

Answer 36

1) Epicatechin monomer, can be absorbed Inhibit NOX, activate eNOS > inhibit NF-kB inhibits the degradation of IkBa, which maintains NF-kB in the inhibited state 2) Procyanidins cannot be absorbed → acting on the GI tract prevents lipid rafts disruption and cholesterol redistribution block Akt and p38 activation - upstream to NF-kB activation

Question 37

We discussed epicatechin as a food molecule that can aid in increasing insulin sensitivity. How do high amounts of dietary sugar decrease insulin sensitivity? How is NADPH oxidase involved?

Answer 37

High dietary sugar > ER stress > oxidative stress > increase NOX > ROS, NF-kB, PTP1B GLUT 4 translocation blocked > lack of glucose absorption Promoting expression of TNFa, activate NFkB

Question 38

superoxide and peroxynitrite

Answer 38

NO can react with superoxide (O2-) to form peroxynitrite superoxide production by NOX therefore, NOX inhibition increases NO bioavailability