Naruszewicz2008

8/11/2019 Naruszewicz2008

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Effect of novel plant antioxidantEffect of novel plant antioxidant

fromfromAronia melanocarpaAronia melanocarpaononcardiovascular risk factors incardiovascular risk factors in

patients after MIpatients after MIMarek A. NaruszewiczMarek A. Naruszewicz

Medical University of WarsawMedical University of Warsaw


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Proposed mechanism by whichProposed mechanism by which

flavonoidsflavonoidsmay reduce risk formay reduce risk for

cardiovascular diseasescardiovascular diseases Oxidative stressOxidative stress

Scavene reactive oxyen and nitroen speciesScavene reactive oxyen and nitroen species

!"elate redox#active transition metal ions!"elate redox#active transition metal ions Spare and interact wit" ot"er antioxidantsSpare and interact wit" ot"er antioxidants

In"i$ition of t"e redox#sensitive transcriptionIn"i$ition of t"e redox#sensitive transcription

factorsfactors In"i$ition of pro#oxidant enzymesIn"i$ition of pro#oxidant enzymes

Induction of antioxidant enzymesInduction of antioxidant enzymes


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cardiovascular diseasescardiovascular diseases

Growth of atherosclerotic plaqueGrowth of atherosclerotic plaque

%educe ad"esion molecule expression%educe ad"esion molecule expressionAnti#inflammatoryAnti#inflammatory

%educe t"e capacity of macrop"aes to%educe t"e capacity of macrop"aes to

oxidatively modifoxidatively modifiedied&'&&'&


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cardiovascular diseasescardiovascular diseases (latelet function and "aemostasis(latelet function and "aemostasis

In"i$it platelet areationIn"i$it platelet areation

)lood pressure and vascular reactivity)lood pressure and vascular reactivity (romote nitric oxide#induced endot"elial(romote nitric oxide#induced endot"elial

relaxationrelaxation


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The role of CD36 and LOX-1 receptorsThe role of CD36 and LOX-1 receptors

in foam cell developmentin foam cell development

Endothelial cellsEndothelial cellsLDLLDL

OX-LDLOX-LDLCD36CD36

NONO

HH

22OO

MPOMPO

MacrophageMacrophage

IL-6, MCP-IL-6, MCP-

PP!"PP!"

#ranscription#ranscription

Cholesterol estersCholesterol esters

OX-LDLOX-LDL

LDLLDL

s-IC!Ms-IC!M

s-$C!Ms-$C!M

LOX-LOX-

LOX-LOX-


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Aronia )erriesAronia )erries Aronia *("otinia melanocaarpa+ also known as Aronia melanocarpa andAronia *("otinia melanocaarpa+ also known as Aronia melanocarpa and

Aronia nira,+ is a native American $us" t"at "as $een successfullyAronia nira,+ is a native American $us" t"at "as $een successfullyexported to Eastern Europe and is commercially rown in 'enmark+exported to Eastern Europe and is commercially rown in 'enmark+

(oland+ %ussia and elsew"ere.(oland+ %ussia and elsew"ere.

-nown commonly as c"oke$erry/ or $lak c"oke$erry/+ *("otinia-nown commonly as c"oke$erry/ or $lak c"oke$erry/+ *("otinia

melanocarpa, "as at least two cousins wort" mentionin. 0"ese aremelanocarpa, "as at least two cousins wort" mentionin. 0"ese are

("otinia flori$unda+ also known as Aronia("otinia flori$unda+ also known as Aronia aatropurpurea+ t"e purpletropurpurea+ t"e purplec"oke$erry/+ and ("otinia pyrofilia+ also known as Aronia ar$utifolia+c"oke$erry/+ and ("otinia pyrofilia+ also known as Aronia ar$utifolia+

t"e red c"oke$erry/. 0"e former ranes from Mississippi to Wisconsin+t"e red c"oke$erry/. 0"e former ranes from Mississippi to Wisconsin+

1eoria into !anada+ and all areas in $etween. 0"e latter ranes from1eoria into !anada+ and all areas in $etween. 0"e latter ranes from

0exas#2kla"oma eastward t"rou" 0ennessee to t"e Atlantic and from0exas#2kla"oma eastward t"rou" 0ennessee to t"e Atlantic and from

3lorida nort"ward into !anada. 0"e Aronia $erry "as all of t"e "ealt"y3lorida nort"ward into !anada. 0"e Aronia $erry "as all of t"e "ealt"yattri$utes of t"e cran$erry+ $ut also contains five to ten times t"eattri$utes of t"e cran$erry+ $ut also contains five to ten times t"e

amount of ant"ocyanins and polyp"enols of a cran$erry.amount of ant"ocyanins and polyp"enols of a cran$erry.


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Antioxidant activity *2%A!,+ Ant"ocyaninAntioxidant activity *2%A!,+ Ant"ocyanin!ontent and ("enolic !ontent in 3ruit of!ontent and ("enolic !ontent in 3ruit of

)lue$erry+ !ran$erry+ &inon$erry and)lue$erry+ !ran$erry+ &inon$erry and!"oke$erry!"oke$erry

W. Zheng, S.Y. Wang Oxygen radical absorbing capacity of phenolics in blueberries, cranberries,

chokeberries and lingonberries, J.gric.!ood "he#. $%, &'(()* $(%+$(

25.56.2!"6#.2$hokeberry

4.567.859:.;&inon$erry

9.;57.96;:.5!ran$erry

8.;6;.676:.mol of 0E=,

species


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Effect ofEffect ofA. melanocarpaA. melanocarpaextract on superoxideextract on superoxide

production $y "uman arterial wall cells from patientsproduction $y "uman arterial wall cells from patients

wit" cardiovascular risk factorswit" cardiovascular risk factors

NA'(? oxidase activityNA'(? oxidase activity%2S eneration%2S eneration

kontrola 0,1 1 5 10 100kontrola 0,1 1 5 10 10000

0000

!0!0

00

1"001"00

160160

00

"000"000

"00"00

"!00"!00

##

##

## ##prod$ctionofO

prod$ctionofO""-%-%

&'L()sek)m*+

&'L()sek)m*+

kontrola 0,1 1 5 10 100kontrola 0,1 1 5 10 10000

55

1010

1515

"0"0

"5"5

3030

3535

00

####

##

##prod$ctionof

O

prod$ctionof

O""-%-%

&'L()sec)m*+

&'L()sec)m*+

concentration ofconcentration ofA. melanocarpaA. melanocarpa

polphenols etract &polphenols etract &*)ml+*)ml+concetration ofconcetration ofA. melanocarpaA. melanocarpa

polphenols etract &polphenols etract &..*)ml+*)ml+

'ata are s"own as means @=#SEM+ # pB7+75 vs. native usin appropriate tests dependin on data distri$ution


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Effect ofEffect ofA. melanocarpaA. melanocarpa extractextractononvasoconstructionvasoconstruction

77

;7;7

6767

9797

8787

5757

4747

C7C7

:7:7

77 7+77;7+77; 7+;7+; 55 ;77;77

st%&enie polifenoli ekstraktust%&enie polifenoli ekstraktu'. melanocarpa'. melanocarpa(())*+ml,*+ml,

ro-ku

rc-

ro-ku

rc-

(.pr-ykurc-

uwst%pne*o,

(.pr-ykurc-uwst%pne*o,

IMAIMA

?SD?SD

Increasin concentration ofIncreasin concentration of

A. melanocarpa extractA. melanocarpa extractIncreasin concentration ofIncreasin concentration of

A. melanocarpaA. melanocarpa extractextract


11/41

!orrelation $etween endot"elium function and!orrelation $etween endot"elium function and

vasorelaxatvasorelaxationionactivity ofactivity ofA. melanocarpaA. melanocarpaextractextract

%% %% 2%2% 3%3% &%&% '%'%

/Ch maks% &+/Ch maks% &+

%%

2%2%

&%&%

6%6%

(%(%

%%%%

i*hest

i*hest

relaationafterad

ministration

relaationafteradministration

ofofA.me

lanocarpa

A.me

lanocarpapolphenolsetract2

polphenolsetract2

")%*6', p)%*%%+ n)2'")%*6', p)%*%%+ n)2'


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MMec"anism of vasorelaxtion activity ofec"anism of vasorelaxtion activity of

A.A.melanocarpamelanocarpa polyp"enolspolyp"enols

%ole of eN2S%ole of eN2S

*incu$ation wit" NAME,*incu$ation wit" NAME,Endot"elium functionEndot"elium function

concentration ofconcentration ofA. melanocarpaA. melanocarpapolyp"enols extractpolyp"enols extract**>>=ml,=ml,

77

6767

8787

4747

:7:7

77 7+77; 7+; 5 ;777+77; 7+; 5 ;77

relaxation

relaxation

incu$ation wit" NAME and polyp"enolsincu$ation wit" NAME and polyp"enols

incu$ation wit" NAME *;77incu$ation wit" NAME *;77 >>M,M,

77

6767

8787

4747

:7:7

77 7+77; 7+; 5 ;777+77; 7+; 5 ;77

concentration ofconcentration ofA. melanocarpaA. melanocarpa

polyp"enols extract *>=ml,polyp"enols extract *>=ml,

relaxa

tion

relaxa

tion

endot"elial cellsendot"elial cells

wit"outwit"out

endot"elial cellsendot"elial cells


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Superoxide production in platelets and effectSuperoxide production in platelets and effect

ofofA. melanocarpaA. melanocarpa polyp"enolspolyp"enols

Risk factors

0

50

100

150

"00

"50

kontro

la

0,01

0,03

0,1 1 3 1

0"0

30

1

00

A. melanocarpapolphenols conc% &.*)ml+

4la

telets$peroide

prod$ction

"-%

&'L()sek)105

ptek+

-ontrola 3 % 3% %%

st67enie polifenoli

ekstrakt$ A. melanocarpa &$*)ml+

%

'

%

'

2%

2'

3%

3'

&%

prod$kc8aO

"-%

&'L()sek)10

5p,tek+ Control


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Effect of increasinEffect of increasinA. melanocarpaA. melanocarpapolyp"enols concentrations on plateletpolyp"enols concentrations on platelet

areationareation

ControlControl "is .actors"is .actors

%% 2%2% &%&% 6%6% (%(% %%%% 2%2% &%&% 6%6% (%(% 2%%2%% 22%22%

aggregationaggregation/"01/"01

throin ind4cedthroin ind4ced/2%05l1/2%05l1

CON#"OLCON#"OL

33

''

%%

2%2%

3%3%

'%'%

%%%%

A.melanocarpa

A.melanocarpapol6ph

enols

pol6ph

enols

e7tractconc*

e7tractconc*

/4g52l1

/4g52l1

%% 2%2% &%&% 6%6% (%(% %%%% 2%2% &%&% 6%6% (%(% 2%%2%% 22%22%

aggregationaggregation/"01/"01

throin ind4cedthroin ind4ced/2%05l1/2%05l1

CON#"OLCON#"OL

''

%%

''

2%2%

3%3%

%%%%

A.melanocarpa

A.melanocarpapol6phenols

pol6phenols

e7tractconc

e7tractconc..

/4g52l1

/4g

52l1


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0"e effect of increasin concentrations of0"e effect of increasin concentrations of

AroniaAronia flavonoids from c"oke$erry onflavonoids from c"oke$erry on

eN2S expression in ?UDE! cellseN2S expression in ?UDE! cells

0

0,2

0,4

0,6

0,8

1

control 0,1 ug/ml 1 ug/ml

3 hours

24 hours

e-

OS+%.

e-OS+%.//+actin

+actin


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0"e effect of increasin concentrations of0"e effect of increasin concentrations of

AroniaAronia flavonoids from c"oke$erry onflavonoids from c"oke$erry on

&2G#; expression in ?UDE! cells&2G#; expression in ?UDE! cells

0

0,1

0,2

0,3

0,4

control 0,1 ug/ml 1 ug/ml

3 hours

24 hours

0O1+%.

0O1+%.//+actin

+actin


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(roductH A(roductH Aronia fruits extract =A%2N2G=ronia fruits extract =A%2N2G=Scientific nameH Aronia meelanocarpaScientific nameH Aronia meelanocarpa

*c"oke$erry,*c"oke$erry,

Parameter Result

Aearance 2o3der

Colour 4ed+bro3n

!umi"it# #ax 56

Anthoc#anins

C#$3$%$&a

'(+'$6

Polimeric roc#ani"ins

'()'$) eicatechin

7$$6

Phenolic aci"s ,6Antio*i"ant acti+it#

' -rolo*/g "rie" .eight)

PP! ra"icals %%5.8

A- ra"icals %(9.%


19/41


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/ethods/ethods

0"is was a dou$le $lind+ place$o controlled+

0"is was a dou$le $lind+ place$o controlled+ parallel trial. 3orty four patients *;; womenparallel trial. 3orty four patients *;; women

and 99 men+ mean ae 44 years, w"o survivedand 99 men+ mean ae 44 years, w"o survived

myocardial infarction and "ave received statinmyocardial infarction and "ave received statint"erapy for at least 4 mont"s *:7 dose oft"erapy for at least 4 mont"s *:7 dose of

87 m=day simvastatin, were included in t"e87 m=day simvastatin, were included in t"e

study. 0"e su$Jects were randomised to receivestudy. 0"e su$Jects were randomised to receive

eit"er 9 x :5 m=day of c"oke$erry flavonoideit"er 9 x :5 m=day of c"oke$erry flavonoidextract or place$o for a period of 4 weeks.extract or place$o for a period of 4 weeks.


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$linical and 0emo*raphic$linical and 0emo*raphic

$haracteristics of /1 Patients$haracteristics of /1 Patients Aronia flavonoids (n=22) Placebo (n=22)

Age 65.87 8.3 66.1 7.9

Se (!o"en# "en) 6$16 5$17

%&' (g$"2) 26.5 3.5 26.9 2.5

&' (ears af*er) 5.2 2.+ 5., 2.1

-iabe*es () 19 23

/0er*ension () 32 36

rren* s"oers

()

1, 19

&edica*ion

S*a*ins () 1++.+ 1++.+

si"vas*a*in ,+ "g 81 86

a*orvas*a*in 2+ 19 1,

As0irin () 81 73

A in4ibi*ors () 5, 5+


22/41

" ff f i fl id


23/41

0"e effect of0"e effect ofAroniaAronia flavonoids onflavonoids on

plasmaplasma totaltotal 36#isoprostanes level36#isoprostanes level

200

300

400

00

600

efore after

Aronia

Placeo

4g/ml5

700700

3838

ff f0" ff f A i ffl id


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plasma 2G#&'& levelplasma 2G#&'& level

0

20

40

60

80

100

120

efore after

Aronia

Placeo7000170001

49/l5

2:2:

0" ff f A i fl id


25/41

0"e effect of Aronia flavonoids on0"e effect of Aronia flavonoids on

systolic $lood pressuresystolic $lood pressure

118

120

122

124

126

128

130

132

134

136

efore after

Aronia

Placeo

7000170001

4mm!g5

* ; 11 mm!g* ; 11 mm!g

" ff f i fl id0" ff t f A i fl id


26/41


diastolic $lood pressurediastolic $lood pressure


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0"e effect of Aronia flavonoids or0"e effect of Aronia flavonoids or

place$o on plasma A!E activityplace$o on plasma A!E activity

1

2

3

4

6

A P?AC@%P?AC@%

0" ff t f A i fl id0" ff t f A i fl id


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plasma I levelplasma I level

4

4,

,

6

6,

efore after

Aronia

Placeo

4g/ml5

70037003

3030

0" ff t f0" ff t f A iA i fl idfl id


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3

3,2

3,4

3,6

3,8

4

4,24,4

4,6

4,8

efore after

Aronia

Placeo


plasma "s#!%( levelplasma "s#!%( level

70017001

4mg/l5

2323



30/41


plasma adiponectin levelplasma adiponectin level

3,6

3,8

4

4,2

4,4

4,6

4,8

efore after

Aronia

Placeo

4g/ml5

703703

23762376



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plasma M!(#; levelplasma M!(#; level

220

240

260

280

300

320

340

efore after

Aronia

Placeo

4g/ml5

70017001

2:2:


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%ole of E(! in reendot"elisation and neovascularisation%ole of E(! in reendot"elisation and neovascularisation


33/41

%eulation of E(!s followin t"e natural "istory of%eulation of E(!s followin t"e natural "istory of

at"erosclerosisat"erosclerosis

1. (. 3adini et al.+ At"erosclerosis ;


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Endot"elial proenitor cells and at"erosclerosisEndot"elial proenitor cells and at"erosclerosis

E(!s are a circulatin $one marrow#derived cellE(!s are a circulatin $one marrow#derived cell

population t"at express surface !'98+ !';99 andpopulation t"at express surface !'98+ !';99 and

vascular endot"elial rowt" factor receptor 6 *DE13%#6,.vascular endot"elial rowt" factor receptor 6 *DE13%#6,.

E(!s are incorporated into t"e sites of endot"elialE(!s are incorporated into t"e sites of endot"elial

denudation and provide an endoenous repairdenudation and provide an endoenous repair

mec"anism to endot"elial inJury.mec"anism to endot"elial inJury. E(!s from su$Ject wit" !D' s"owed in vitro accelerateE(!s from su$Ject wit" !D' s"owed in vitro accelerate

senescence and reduction in telomerase activity. 0"issenescence and reduction in telomerase activity. 0"is

effect was partially t"rou" increase of oxidative stresseffect was partially t"rou" increase of oxidative stress

and in"i$itin eN2S.and in"i$itin eN2S.


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ff f " k $Eff f " k $


36/41

Effect of c"oke$erry extract onEffect of c"oke$erry extract on

telomerase activity in vivo in patientstelomerase activity in vivo in patients

wit" !D'wit" !D'

4lace9o4lace9o

Choke9err,

Choke9err,

%:

'%:

%%:

'%:

2%%:

2'%:

3%%:

;e.ore treatent !.ter treatent

!ells incu$ated wit" 57u of Aronia extract!ells incu$ated wit" 57u of Aronia extract


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!ells incu$ated wit" 57u of Aronia extract!ells incu$ated wit" 57u of Aronia extract

! ll i $ t d it" &'&! ll i $ t d it" &'&


38/41

!ells incu$ated wit" ox&'&!ells incu$ated wit" ox&'&

!ells incu$ated wit" Aronia extract and ox&'&!ells incu$ated wit" Aronia extract and ox&'&


39/41

!ells incu$ated wit" Aronia extract and ox&'&!ells incu$ated wit" Aronia extract and ox&'&


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!onclusions!onclusions

0"ese results confirm t"e potential0"ese results confirm t"e potential

usefulness if natural antioxidants in t"eusefulness if natural antioxidants in t"e

treatment of at"erosclerosis+ also t"rou"treatment of at"erosclerosis+ also t"rou"t"eir effect on E(! senescence in"i$ition.t"eir effect on E(! senescence in"i$ition.

3undin. 0"is work was supported $y non#3undin. 0"is work was supported $y non#

restricted rants from (olis" Society forrestricted rants from (olis" Society forAt"rosclerosis %esearc" and fromAt"rosclerosis %esearc" and from

Arop"armArop"arm


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$onclusion$onclusion

In view of t"e fact t"at c"oke$erry flavonoidsIn view of t"e fact t"at c"oke$erry flavonoidsreduce t"e severity of inflammation+ reardlessreduce t"e severity of inflammation+ reardless

of statins+ t"ey can $e used clinically forof statins+ t"ey can $e used clinically for

secondary prevention of isc"aemic "eartsecondary prevention of isc"aemic "eart

disease.disease.

3undin. 0"is work was supported $y non#3undin. 0"is work was supported $y non#

restricted rants from (olis" Society forrestricted rants from (olis" Society for

At"rosclerosis %esearc" and from Arop"armAt"rosclerosis %esearc" and from Arop"arm

Documents

Naruszewicz2008