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Effect of novel plant antioxidant

Effect of novel plant antioxidant


from
from
Aronia melanocarpa
Aronia melanocarpa
on
on
cardiovascular risk factors in
cardiovascular risk factors in
patients after MI
patients after MI
Marek A. Naruszewicz
Marek A. Naruszewicz
Medical University of Warsaw
Medical University of Warsaw

Proposed mechanism by which
Proposed mechanism by which
flavonoids
flavonoids
may reduce risk for
may reduce risk for
cardiovascular diseases
cardiovascular diseases

Oxidative stress
Oxidative stress

Scavene reactive oxyen and nitroen species


Scavene reactive oxyen and nitroen species

!"elate redox#active transition metal ions


!"elate redox#active transition metal ions

Spare and interact wit" ot"er antioxidants


Spare and interact wit" ot"er antioxidants

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


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

In"i$ition of pro#oxidant enzymes


In"i$ition of pro#oxidant enzymes

Induction of antioxidant enzymes


Induction of antioxidant enzymes

Proposed mechanism by which
Proposed mechanism by which
flavonoids
flavonoids
may reduce risk for
may reduce risk for
cardiovascular diseases
cardiovascular diseases

Growth of atherosclerotic plaque


Growth of atherosclerotic plaque

%educe ad"esion molecule expression


%educe ad"esion molecule expression

Anti#inflammatory
Anti#inflammatory

%educe t"e capacity of macrop"aes to


%educe t"e capacity of macrop"aes to
oxidatively modif
oxidatively modif
ied
ied
&'&
&'&

Proposed mechanism by which
Proposed mechanism by which
flavonoids
flavonoids
may reduce risk for
may reduce risk for
cardiovascular diseases
cardiovascular diseases

(latelet function and "aemostasis


(latelet function and "aemostasis

In"i$it platelet areation


In"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
relaxation
relaxation

The role of CD36 and LOX-1 receptors
The role of CD36 and LOX-1 receptors
in foam cell development
in foam cell development
Endothelial cells Endothelial cells
LDL LDL
OX-LDL OX-LDL
CD36 CD36
NO NO
H H
2 2
O O
MPO MPO
Macrophage Macrophage
IL-6, MCP- IL-6, MCP-
PP!" PP!"

#ranscription #ranscription
Cholesterol esters Cholesterol esters
OX-LDL OX-LDL
LDL LDL
s-IC!M s-IC!M
s-$C!M s-$C!M
LOX- LOX-
LOX- LOX-


Aronia )erries
Aronia )erries

Aronia *("otinia melanocaarpa+ also known as Aronia melanocarpa and Aronia *("otinia melanocaarpa+ also known as Aronia melanocarpa and
Aronia nira,+ is a native American $us" t"at "as $een successfully Aronia nira,+ is a native American $us" t"at "as $een successfully
exported 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 are melanocarpa, "as at least two cousins wort" mentionin. 0"ese are
("otinia flori$unda+ also known as Aronia ("otinia flori$unda+ also known as Aronia a atropurpurea+ t"e .purple tropurpurea+ t"e .purple
c"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 from 1eoria into !anada+ and all areas in $etween. 0"e latter ranes from
0exas#2kla"oma eastward t"rou" 0ennessee to t"e Atlantic and from 0exas#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"y 3lorida nort"ward into !anada. 0"e Aronia $erry "as all of t"e "ealt"y
attri$utes of t"e cran$erry+ $ut also contains five to ten times t"e attri$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.

Antioxidant activity *2%A!,+ Ant"ocyanin
Antioxidant 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 $hokeberry
4.56 7.85 9:.; &inon$erry
9.;5 7.96 ;:.5 !ran$erry
8.;6 ;.67 6:.< )lue$erry
0otal p"enolic
*m=,
Ant"ocyanin
*m=,
2%A!
*>mol of 0E=,
species

Effect of
Effect of
A. melanocarpa
A. melanocarpa
extract on superoxide
extract on superoxide
production $y "uman arterial wall cells from patients
production $y "uman arterial wall cells from patients
wit" cardiovascular risk factors
wit" cardiovascular risk factors
NA'(? oxidase activity NA'(? oxidase activity %2S eneration %2S eneration

kontrola 0,1 1 5 10 100 kontrola 0,1 1 5 10 100
0 0
00 00
!0 !0
0 0
1"00 1"00
160 160
0 0
"000 "000
"00 "00
"!00 "!00
# #

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kontrola 0,1 1 5 10 100 kontrola 0,1 1 5 10 100
0 0
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concentration of concentration of A. melanocarpa A. melanocarpa
pol,phenols e-tract & pol,phenols e-tract & *)ml+ *)ml+

concetration of concetration of A. melanocarpa A. melanocarpa
pol,phenols e-tract & pol,phenols e-tract &. .*)ml+ *)ml+
'ata are s"own as means @=#SEM+ A # pB7+75 vs. native usin appropriate tests dependin on data distri$ution

Effect of
Effect of
A. melanocarpa
A. melanocarpa
extract
extract
on
on

vasoconstruction
vasoconstruction

7 7
;7 ;7
67 67
97 97
87 87
57 57
47 47
C7 C7
:7 :7
7 7 7+77; 7+77; 7+; 7+; 5 5 ;77 ;77
st%&enie polifenoli ekstraktu st%&enie polifenoli ekstraktu '. melanocarpa '. melanocarpa
( () )*+ml, *+ml,
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?SD ?SD
Increasin concentration of Increasin concentration of
A. melanocarpa extract A. melanocarpa extract
Increasin concentration of Increasin concentration of
A. melanocarpa A. melanocarpa extract extract

!orrelation $etween endot"elium function and
!orrelation $etween endot"elium function and
vasorelaxat
vasorelaxat
ion
ion
activity of
activity of
A. melanocarpa
A. melanocarpa
extract
extract
% % % % 2% 2% 3% 3% &% &% '% '%
/Ch maks% &0+ /Ch maks% &0+
% %
2% 2%
&% &%
6% 6%
(% (%
%% %%
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M
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ec"anism of vasorelaxtion activity of
ec"anism of vasorelaxtion activity of
A.
A.
melanocarpa
melanocarpa
polyp"enols
polyp"enols



%ole of eN2S
%ole of eN2S


*incu$ation wit" &#NAME,
*incu$ation wit" &#NAME,
Endot"elium function
Endot"elium function
concentration of concentration of A. melanocarpa A. melanocarpa
polyp"enols extract polyp"enols extract * *> >=ml, =ml,
7 7
67 67
87 87
47 47
:7 :7
7 7 7+77; 7+; 5 ;77 7+77; 7+; 5 ;77
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incu$ation wit" &#NAME and polyp"enols incu$ation wit" &#NAME and polyp"enols
incu$ation wit" &#NAME *;77 incu$ation wit" &#NAME *;77 > >M, M,
A A
A A
A A
7 7
67 67
87 87
47 47
:7 :7
7 7 7+77; 7+; 5 ;77 7+77; 7+; 5 ;77
concentration of concentration of A. melanocarpa A. melanocarpa
polyp"enols extract *>=ml, polyp"enols extract *>=ml,







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endot"elial cells endot"elial cells
wit"out wit"out
endot"elial cells endot"elial cells
A A

A A
A A
A A

Superoxide production in platelets and
Superoxide production in platelets and
effect of
effect of
A. melanocarpa
A. melanocarpa
polyp"enols
polyp"enols
(roduction of 2
(roduction of 2
6 6
#. #.
in platelets
in platelets
# correlation wit" risk factors correlation wit" risk factors
control risk factors control risk factors
7 7
57 57
;77 ;77
;57 ;57
677 677
657 657
977 977
957 957
877 877




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Superoxide production in platelets and effect
Superoxide production in platelets and effect
of
of
A. melanocarpa
A. melanocarpa
polyp"enols
polyp"enols
Risk factors
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Effect of increasin
Effect of increasin
A. melanocarpa
A. melanocarpa

polyp"enols concentrations on platelet
polyp"enols concentrations on platelet
areation
areation
Control Control
"is- .actors "is- .actors
% % 2% 2% &% &% 6% 6% (% (% %% %% 2% 2% &% &% 6% 6% (% (% 2%% 2%% 22% 22%
aggregation aggregation /"01 /"01
thro23in ind4ced thro23in ind4ced /2%2052l1 /2%2052l1
CON#"OL CON#"OL
3 3
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2% 2%
3% 3%
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%% %%
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aggregation aggregation /"01 /"01
thro23in ind4ced thro23in ind4ced /2%2052l1 /2%2052l1
CON#"OL CON#"OL
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0"e effect of increasin concentrations of
0"e effect of increasin concentrations of
Aronia
Aronia
flavonoids from c"oke$erry on
flavonoids from c"oke$erry on
eN2S expression in ?UDE! cells
eN2S 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
-
O
S
+
%
.
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S
+
%
.
/ /
+
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+
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0"e effect of increasin concentrations of
0"e effect of increasin concentrations of
Aronia
Aronia
flavonoids from c"oke$erry on
flavonoids from c"oke$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
0
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+
%
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+
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(roductH A
(roductH A
ronia fruits extract =A%2N2G=
ronia fruits extract =A%2N2G=

Scientific nameH Aronia meelanocarpa
Scientific 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 ,6
Antio*i"ant acti+it#
' , -rolo*/g "rie" .eight)
/PP! ra"icals


%%5.8
A0-1 ra"icals %(9.%



/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 *;;women
parallel trial. 3orty four patients *;;women
and 99men+ mean ae 44years, w"o survived
and 99men+ mean ae 44years, w"o survived
myocardial infarction and "ave received statin
myocardial infarction and "ave received statin
t"erapy for at least 4mont"s *:7I dose of
t"erapy for at least 4mont"s *:7I dose of
87m=day simvastatin, were included in t"e
87m=day simvastatin, were included in t"e
study. 0"e su$Jects were randomised to receive
study. 0"e su$Jects were randomised to receive
eit"er 9 x :5m=day of c"oke$erry flavonoid
eit"er 9 x :5m=day of c"oke$erry flavonoid
extract or place$o for a period of 4weeks.
extract or place$o for a period of 4weeks.

$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
12rren* s"o(ers
(.)
1, 19
&edica*ion
S*a*ins (.) 1++.+ 1++.+
si"vas*a*in ,+ "g 81 86
a*orvas*a*in 2+
"g
19 1,
As0irin (.) 81 73
A13 in4ibi*ors (.) 5, 5+



Effect of
Effect of
Aronia flavonoids
Aronia flavonoids
or place$o on
or place$o on
lipids+ lipoproteins and "omocysteine levels in
lipids+ lipoproteins and "omocysteine levels in
patients wit" a "istory of MI
patients wit" a "istory of MI
An*4oc)anins (n=22) Placebo (n=22)
before af*er before af*er A567A
89 :"g$dl; 162.7 66.2 152.7 55.5 131.8
33.3
127.2 36.5 ns
14ol :"g$dl; 198.+ 25.6 199.8 28.2 2+2.2
,3.8
196.+ ,2.6 ns
<-< :"g$dl; 117.3 25.9 116.9 27.9 116.8
33.9
11+.+ 32., ns
/-< :"g$dl; ,2.2 9.56 ,3., 9.7 ,5.6 9.2 ,6., 9.57 ns
<0(a) :"g$dl; 27.3 33.6 28.2 37.+ 25.2 36., 25.3 36.3 ns
/o"oc)s*eine
:="ol$l;
17.2 7.3 17.1 8.2 16.+ 7.+ 16.2 5.9 ns


0"e effect of
0"e effect of
Aronia
Aronia
flavonoids on
flavonoids on
plasma
plasma
total
total
36#isoprostanes level
36#isoprostanes level
200
300
400
200
600
3efore after
Aronia
Place3o
4g/ml5
67002 67002

388 388

0"e effect of
0"e effect of
Aronia
Aronia
flavonoids on
flavonoids on
plasma 2G#&'& level
plasma 2G#&'& level
0
20
40
60
80
100
120
3efore after
Aronia
Place3o
670001 670001
49/l5

2:8 2:8

0"e effect of Aronia flavonoids on
0"e effect of Aronia flavonoids on
systolic $lood pressure
systolic $lood pressure
118
120
122
124
126
128
130
132
134
136
3efore after
Aronia
Place3o
670001 670001
4mm!g5

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

0"e effect of Aronia flavonoids on
0"e effect of Aronia flavonoids on
diastolic $lood pressure
diastolic $lood pressure
<4
<6
<8
80
82
84
86
88
3efore after
Aronia
Place3o
4mm!g5
670000 670000

* ; <72 mm!g * ; <72 mm!g



0"e effect of Aronia flavonoids or
0"e effect of Aronia flavonoids or
place$o on plasma A!E activity
place$o on plasma A!E activity
12
22
32
42
22
62
<2
82
3efore after
12
22
32
42
22
62
<2
82
3efore after
49/l5 49/l5 49/l5 49/l5
AR%=>A AR%=>A
P?AC@0% P?AC@0%

0"e effect of Aronia flavonoids on
0"e effect of Aronia flavonoids on
plasma I&#4 level
plasma I&#4 level
4
4,2
2
2,2
6
6,2
3efore after
Aronia
Place3o
4g/ml5
67003 67003

308 308

3
3,2
3,4
3,6
3,8
4
4,2
4,4
4,6
4,8
2
3efore after
Aronia
Place3o
0"e effect of
0"e effect of
Aronia
Aronia
flavonoids on
flavonoids on
plasma "s#!%( level
plasma "s#!%( level
67001 67001
4mg/l5

238 238

0"e effect of Aronia flavonoids on
0"e effect of Aronia flavonoids on
plasma adiponectin level
plasma adiponectin level
3,6
3,8
4
4,2
4,4
4,6
4,8
2
3efore after
Aronia
Place3o
4g/ml5
6703 6703

23768 23768

0"e effect of Aronia flavonoids on
0"e effect of Aronia flavonoids on
plasma M!(#; level
plasma M!(#; level
220
240
260
280
300
320
340
3efore after
Aronia
Place3o
4g/ml5
67001 67001

2:8 2:8

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

%eulation of E(!s followin t"e natural "istory of
%eulation of E(!s followin t"e natural "istory of
at"erosclerosis
at"erosclerosis
1. (. 3adini et al.+ At"erosclerosis ;<8 *677C, 84#58. 1. (. 3adini et al.+ At"erosclerosis ;<8 *677C, 84#58.

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

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


E(!s are a circulatin $one marrow#derived cell
population t"at express surface !'98+ !';99 and
population 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"elial


E(!s are incorporated into t"e sites of endot"elial
denudation and provide an endoenous repair
denudation 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 accelerate


E(!s from su$Ject wit" !D' s"owed in vitro accelerate
senescence and reduction in telomerase activity. 0"is
senescence and reduction in telomerase activity. 0"is
effect was partially t"rou" increase of oxidative stress
effect was partially t"rou" increase of oxidative stress
and in"i$itin eN2S.
and in"i$itin eN2S.

Effect of
Effect of
Aronia melanocarpa
Aronia melanocarpa
polyp"enols on
polyp"enols on
telomerase activity in E(!
telomerase activity in E(!

%
2%
&%
6%
(%
%%
8 o7LDL o7LDL9'%2g!rono7

Effect of c"oke$erry extract on
Effect of c"oke$erry extract on
telomerase activity in vivo in patients
telomerase activity in vivo in patients
wit" !D'
wit" !D'
4lace9o
4lace9o
Choke9err,
Choke9err,
%:
'%:
%%:
'%:
2%%:
2'%:
3%%:
;e.ore treat2ent !.ter treat2ent

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

!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&'&

!onclusions
!onclusions

0"ese results confirm t"e potential


0"ese results confirm t"e potential
usefulness if natural antioxidants in t"e
usefulness 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 for
restricted rants from (olis" Society for
At"rosclerosis %esearc" and from
At"rosclerosis %esearc" and from
Arop"arm
Arop"arm

$onclusion
$onclusion

In view of t"e fact t"at c"oke$erry flavonoids


In view of t"e fact t"at c"oke$erry flavonoids
reduce t"e severity of inflammation+ reardless
reduce t"e severity of inflammation+ reardless
of statins+ t"ey can $e used clinically for
of statins+ t"ey can $e used clinically for
secondary prevention of isc"aemic "eart
secondary 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 for
restricted rants from (olis" Society for
At"rosclerosis %esearc" and from Arop"arm
At"rosclerosis %esearc" and from Arop"arm