Available

online at www.sciencedirect.com

Journal of Nutritional Biochemistry 19 (2008) 643 654

R !" #$% &'RR N( ()*"&$

(he +ossi,le roles of foo-.-eri/e- ,ioacti/e +e+ti-es in re-ucin0 the ris1 of car-io/ascular -isease
2ati r-mann3 Belin-a #454 &heun03 6ennin0 $chr7-er
8e+artment of *harmaceutics3 &olle0e of *harmacy3 'ni/ersity of 9innesota3 9innea+olis3 9N 554553 '$: Recei/e- 2 )cto,er 200;< acce+te- 26 No/em,er 200;

:,stract !ascular -iseases such as atherosclerosis3 stro1e or myocar-ial infarction are a si0nificant +u,lic health +ro,lem =orl-=i-e4 :ttem+ts to +re/ent /ascular -iseases often im+ly mo-ifications an- im+ro/ement of causati/e ris1 factors such as hi0h ,loo- +ressure3 o,esity3 an unfa/ora,le +rofile of ,loo- li+i-s or insulin resistance4 "n a--ition to numerous +re/enti/e an- thera+eutic -ru0 re0imens3 there has ,een increase- focus on i-entifyin0 -ietary com+oun-s that may contri,ute to car-io/ascular health in recent years4 >oo-.-eri/e- ,ioacti/e +e+ti-es re+resent one such source of health.enhancin0 com+onents4 (hey can ,e release- -urin0 0astrointestinal -i0estion or foo+rocessin0 from a multitu-e of +lant an- animal +roteins3 es+ecially mil13 soy or fish +roteins4 Biolo0ically acti/e +e+ti-es are consi-ereto +romote -i/erse acti/ities3 inclu-in0 o+iate.li1e3 mineral ,in-in03 immunomo-ulatory3 antimicro,ial3 antio?i-ant3 antithrom,otic3 hy+ocholesterolemic an- antihy+ertensi/e actions4 By mo-ulatin0 an- im+ro/in0 +hysiolo0ical functions3 ,ioacti/e +e+ti-es may +ro/i-e ne= thera+eutic a++lications for the +re/ention or treatment of chronic -iseases4 :s com+onents of functional foo-s or nutraceuticals =ith certain health claims3 ,ioacti/e +e+ti-es are of commercial interest as =ell4 (he current re/ie= centers on ,ioacti/e +e+ti-es =ith +ro+erties rele/ant to car-io/ascular health4 @ 2008 lse/ier "nc4 :ll ri0hts reser/e-4
2ey=or-s% :ntihy+ertensi/e< :ntio?i-ant< :ntithrom,otic< Bioacti/e +e+ti-es< &ar-io/ascular -isease< 6y+ocholesterolemicAhy+otri0lyceri-emic

ri+enin0 anmil1 fermentation)4 (hey usually contain 220 amino aciresi-ues +er molecule3 ,ut in 14 "ntro-uction some cases may consist of Biolo0ically acti/e +e+ti-es are foo-.-eri/e- +e+ti-es that more than 20 amino aci-s4 -i0estion3 e?ert ,eyon- their nutritional /alue a +hysiolo0ical3>ollo=in0 hormone.li1e effect in humans4 (hey are foun- in mil13 e003 meat ,ioacti/e +e+ti-es can either an- fish of /arious 1in-s as =ell as in many +lants4 Bioacti/e ,e a,sor,e- throu0h the +e+ti-es are inacti/e =ithin the seBuence of their +arent +rotein intestine to enter the ,looan- can ,e release- ,y enCymatic hy-rolysis either -urin0circulation intact an- e?ert 0astrointestinal -i0estion or -urin0 foo- +rocessin0 (e4043 cheese systemic effects3 or +ro-uce local effects in the

0astrointestinal tract4 8e+en-in0 on the seBuence of amino aci-s3 these +e+ti-es can e?hi,it -i/erse acti/ities3
&orres+on-in0 author4 (el4% D1 612 625 5695< fa?% D1 612 624 66954 .mail a--ress% schro601Eumn4e-u (64 $chr7-er)4 0955.2863AF see front matter @ 2008 lse/ier "nc4 :ll ri0hts

reser/e-4 -oi% 1041016AG4Gnut,io4200;4114010

inclu-in0 o+iate.li1e3 mineral ,in-in03 immunomo-ulatory3 antimicro,ial3 antio?i-ant3 antithrom,otic3 hy+ocholestero.lemic3 anantihy+ertensi/e actions H1 4I4 9any of the 1no=n ,ioacti/e +e+ti-es are multifunctional an- can e?ert more than one of the effects mentione- H5;I4 Because of their health.enhancin0 +otential an- safety +rofiles they may ,e use- as com+onents in functional foo-s or nutraceuticals4 6o=e/er3 mil1 +roteins are currently the main source of se/eral ,iofunctional

+e+ti-es an- -aily inta1e of mil1 an- mil1 +ro-ucts has +ro/e- to ,e +hysiolo0ically im+ortant to ,oth neonates an- a-ults H810I4

(his re/ie= centers on ,ioacti/e +e+ti-es =ith +ro+er.ties rele/ant to car-io/ascular health inclu-in0 effects on ,loo+ressure3 o?i-ati/e stress3 hemostasis3 a++etite anli+i- meta,olism4 24 &ar-io/ascular -isease an- nutraceuticals
&ar-io/ascular -isease (&!8) is the sin0le lea-in0 cause of -eath for ,oth males an- females in the 'nite$tates

644

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

an- other technolo0ically a-/ance-functional foo-s or countries in the =orl-4 "n lesser. nutraceu.ticals3 are -e/elo+e- countries it 0enerally ran1s0enerally -efine- as amon0 the to+ fi/e causes of -eath4 (he+ro-ucts that ha/e ,een #orl- 6ealth )r0aniCation estimatessatisfactorily that ,y 20203 heart -isease an- stro1e -emonstrate- to ha/e =ill ha/e sur+asse- infectious -iseases +ositi/e effects on one to ,ecome the lea-in0 cause of -eath or more functions in the an- -isa,ility =orl-=i-e H11I4,o-y3 ,eyon- their &onseBuently3 there has ,een annutritional +ro+er.ties3 in increase- focus on im+ro/in0 -iet an- a =ay =hich is rele/ant lifestyle as a strate0y for &!8 ris1 to either an im+ro/ere-uction4 &urrent -ietary a-/ice tostate of health an- =ell. re-uce ris1 of &!8 inclu-es,ein0 an-Aor a re-uction su,stitutin0 saturatefat =ithof -isease ris14 (hey car,ohy-rate =ithout chan0in0 theshoul- remain as foo-s +rotein content4 "n the '$:3 the or ,e/era0es an- not in 8:$6.-iet (8ietary :++roaches to+harmaceutical forms $to+ 6y+ertension)3 =hich is rich in such as ta,lets or fruits3 /e0eta,les an- lo=.fat -airyca+sules4 :s +art of a +ro-ucts3 is recommen-e- to meet thisnormal -ietary re0imen o,Gecti/e4 (he 8:$6.-iet is ,ase- on athey must -emonstrate re-uce- inta1e of saturate- fat that is their effects in amounts re+lace- ,y car,ohy-rate4 $uch hi0h. that are reasona,ly car,ohy.-rate3 lo=.+rotein -iets aree?+ecteto ,e 1no=n to re-uce ,loo- +ressure an-consume- in the -iet4 lo=.-ensity li+o+rotein (J8J)(he +hysiolo0ically cholesterol H8312I3 ,ut also to re-uceacti/e com+onents of hi0h.-ensity li+o+rotein (68J)func.tional foo-s are cholesterol le/els an- to raise fastin0 either a--e- or enrichetri0lyceri-es H13314I4 Recent e/i-ence,y mo-ification of the manufacturin0 su00ests that an increase- consum+tionusual of +rotein3 +articularly +lant +rotein3+rocess4 &onseBuently3 may further lo=er the ris1 of increasin0 attention has hy+ertension an- &!8 H15316I4 (hefocuse- on i-entifyin0 com+oun-s3 )mni6eart ()+timal 9acro.Nutrient-ietary from +lants (i4e43 "nta1e to *re/ent 6eart 8isease) trial +hytochemicals) as =ell -emonstrate- that +artial su,stitution of as animals (i4e43 car,ohy-rate =ith +rotein sources lo= for in saturate- fat can lo=er ,loo-Coochemicals)3 +romotion of s+ecific +ressure3 im+ro/e li+i- le/els3 facilitate short.term =ei0ht loss an- re-uce the health ,enefits H20321I4 ris1 of &!8 H1;I4 (he mechanisms ,yBase- on o,ser/ations =hich +rotein coul- e?ert its ,eneficial ma-e in human stu-ies effects inclu-e an increase- inta1e ofo/er the last se/eral ,iolo0ically acti/e amino aci-s or years such as the alrea-y mentione- )mni6eart +e+ti-es H18319I4
trial3 ,ioacti/e +e+ti-es (hese an- other fin-in0s ha/e ha/e 0aine- scientific increase- the a=areness of the critical interest as constituents lin1 ,et=een -iet an- health4 9oreo/er3 of nutraceuticals for they ha/e le- to the -e/elo+ment of their +otential in -isease nutritionally enhance- foo- +ro-ucts +re/ention an- health -esi0ne- to suit s+ecific health concerns3 im+ro/ement4 +articu.larly =ith rele/ance to the mana0ement of lifestyle.relate- -iseases4

$uch

foo-s3

terme-

34 :ntihy+ertensi/e (:& inhi,itory) +e+ti-es le/ate,loo+ressure is one of the maGor in-e+en-ent ris1 factors for &!8 H22323I4 :n0iotensin ". con/ertin0 enCyme (:& ) +lays a crucial role in the re0ulation of ,loo- +ressure as it +romotes the con/ersion of an0iotensin " to the +otent /asoconstrictor an0iotensin "" as =ell as inacti/ates the /aso-ilator ,ra-y1inin ( >i04 1)4 By inhi,it.in0 these +rocesses3 synthetic :& inhi,itors ha/e lon0 ,een useas antihy+ertensi/e a0ents4 "n recent years3 some foo- +roteins ha/e ,een i-entifie- as sources of :& inhi,itory +e+ti-es anare currently the ,est 1no=n class of ,ioacti/e +e+ti-es H24I4 (hese nutritional +e+ti-es ha/e recei/econsi-era,le attention for their effecti/eness in ,oth the +re/ention an- the treatment of hy+ertension4 (he main sources of :& inhi,itory +e+ti-es are -airy +ro-ucts an- fish3 ,ut they are also -eri/e- from +lant (e4043 soy3 =heat)3 meat an- e004 *otent :& inhi,itory +e+ti-es from caseins an- =hey +roteins are termecaso1inins anlacto1inins3 res+ecti/ely H2324 26I4 Numerous stu-ies in s+ontaneously

hy+ertensi/e rats ($6R) as =ell as in hy+ertensi/e human /olunteers ha/e ,een +erforme- to -etermine the antihy+ertensi/e effects of foo-. -eri/e- :& inhi,itors4 (hese in /i/o stu-ies ha/e -emonstrate- that se/eral :& inhi,itory +e+ti-es si0nifi.cantly re-uce ,loo- +ressure3 either after intra/enous or oral a-ministration4 :& inhi,itory +e+ti-es =ith -ocumente- in /i/o antihy+ertensi/e effects are liste- in (a,le 14 :n im+ortant o,ser/ation from these trials is that the +e+ti-es ,ein0 stu-ie- ha/e little or no effect on ,loo- +ressure of normotensi/e su,Gects su00estin0 that they e?ert no acute hy+otensi/e effect4 (herefore3 :& inhi,itory +e+ti-es coul- ,e a++lie- as initial treatment in mil-ly hy+ertensi/e in-i/i-uals or as su++lemental treatment4 (hey =oulalso re+resent a lo=.cost alternati/e treatment for hy+ertension4 :nother a-/anta0e is that these +e+ti-es ha/e not ,een associate- =ith the harmful si-e effects re+orte- for synthetic :& inhi,itors such as -ry cou0h3 s1in rashes an- an0ioe-ema3 +ro,a,ly -ue to the lo=er :& inhi,itory acti/ity -etermine- in /itro H24338I4

>i04 14 (he renin an0iotensi n system4

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654 (a,le 1 ?am+les of :& inhi,itory +e+ti-es =ith in /i/o antihy+ertensi/e effects )ri0in $eBuenceAname "&50 (molAJ) $u,Gects

645

Reference H2;328 I

9il1 (.casein)

!** "**

940 540

$6R3 humans

9il1 (.lacto0lo,ulin)

"*: (.lactosin :)
:J*9 (.lactosin B)

14140 92840

$6R

H29330 I

>ish (sar-ine muscle) >ish (,onito muscle) 9eat (chic1en muscle)

!5 J2*N9 J2* J2* "2# J:* 9N**2 (myo+enta+e+ti-e :) "((N* (myo+enta+e+ti-e B) J# N#K*J! ":*

2640 244 0432 0432 0421 345 94545 54940 648 21 24;

$6R3 humans $6R $6R

H31332 I H33I H34I

9eat (+orcine muscle) 00 (o/al,umin) $oy (0lycinin) #heat (0lia-in)

$6R $6R $6R $6R

H35I H34I H36I H3;I

effects3 althou0h the +otency of the +e+ti-es -ecreases as (he +otency of an :& inhi,itor is usually the chain len0th e?+resse- as an "&50 /alue3 =hich is the inhi,itor H45I4 concentration lea-in0 to 50L inhi,ition of :& increases acti/ity4 (he maGority of mil1 +rotein.-eri/e- 6o=e/er3 ,in-in0 to :& inhi,itors ha/e mo-erate inhi,itory:& a++ears to ,e stron0ly influence+otencies3 usually =ithin an "& 50 ran0e of 100 ,y the &.terminal 500 molAJ H39I4 8ue to the incom+lete an- seBuence of the often un1no=n ,ioa/aila,ility of the :& +e+ti-es4 "t has ,een inhi,itory +e+ti-es follo=in0 oral+ostulatethat a-ministration3 it is -ifficult an- unrelia,le to +roline3 lysine or +re-ict the in /i/o antihy+ertensi/e effect ,ase- ar0inine is +referreon measure- inhi,itory acti/ity in /itro4 "n or-er as &.terminal resi-ue to +ro-uce antihy+ertensi/e effects in /i/o the an- thus contri,utes +e+ti-es ha/e to ,e a,sor,e- intact throu0h the to the :& intestine an- reach the car-io/ascular system ininhi,itory +otency an acti/e form4 "n this re0ar-3 s+ecific structuralH4I4 >urthermore3 +ro+erties +lay an im+ortant role4 9ost of the stu-ies in $6R :& inhi,itory +e+ti-es are short +e+ti-es =ithre/ealethat only t=o to nine amino aci-s4 "t has ,een -i+e+ti-es =ith a &. -emonstrate- that -i. or tri+e+ti-es3 es+eciallyterminal tyrosine those =ith &.terminal +roline or hy-ro?y+roline resi-ue +ro-uce- a resi-ues3 are 0enerally resistant to -e0ra-a.tion slo= ,ut +rolon0e,y -i0esti/e enCymes H40341I4 "n a--ition3 short-ecrease in systolic +ressure +e+ti-es consistin0 of t=o or three amino aci-s ,looto are a,sor,e- more ra+i-ly than free amino aci-s com+are=ith H42343I4 (he :& inhi,itory tri+e+ti-es "** an- -i+e+ti-es !**3 for e?am+le3 =ere -etecte- in the aorta of+henylalanine at the "n $6R3 follo=in0 oral a-ministration of fermente-&.terminal4 contrast3 -i+e+ti-es mil1 H44I4 Jar0er +e+ti-es (1051 amino aci-s) &.terminal +resent in the -iet can also ,e a,sor,e- intact =ith +henylalanine throu0h the intestine an- +ro-uce ,iolo0ical

cause- a more ra+ire-uction an- a shorter -uration of action H46I4 (a,le 2 +resents e?am+les of structural +ro+erties of selecte,iofunctional +e+ti-es4

44 :ntio?i-ant "n /i/o com+arati/e stu-ies =ith ca+to+ril3 a+e+ti-es

clinically use- :& inhi,itor3 ha/e sho=n that stress3 :& inhi,itory +e+ti-es =ith antihy+ertensi/e )?i-ant the increaseeffect e?hi,it hi0her in /i/o acti/ity than =oulof ,e e?+ecte- from their in /itro acti/ity4 (he +ro-uction reacti/e o?y0en e?act mechanisms un-erlyin0 this o,ser/ation ha/e not yet ,een i-entifie-4 >uGita an- s+ecies (R)$) in com,ination =ith 5oshi1a=a H33I su00este- that ,ioacti/e outstri++in0 +e+ti-es ha/e hi0her tissue affinities an- are en-o0enous su,Gect to a slo=er elimination than ca+to+ril4 antio?i-ant -efense 6o=e/er3 these +e+ti-es may influence is ,loo- +ressure ,y mechanisms other than the mechanisms3 another si0nificant esta,lishe- :& inhi,ition4 (he release of /aso-ilatory su,stances li1e +rosta0lan-in "2causati/e factor for the initiation or H59I3 N) H60I or &) H61I coul- also of contri,ute to the ,loo- +ressure.lo=erin0+ro0ression /ascular effects of /arious :& inhi,itory +e+.ti-es4se/eral Recently3 Nurminen et al4 H62I re+orte- that-iseases4 R)$ can e?tensi/e the antihy+ertensi/e effect of .lactor+hin3 acause +e+ti-e =ith o+iate.li1e an- :& inhi,itory-ama0e to ,iolo0ical +ro+erties3 =as me-iate- throu0h themacromolecules li1e /aso-ilatory action of ,in-in0 to o+ioi- 8N:3 +roteins an-

increaseathero0enicity of o?i-iCeJ8J H65366I4 (herefore3 +rolon0e+ro-uction of R)$ is thou0ht to contri,ute to the -e/elo+ment of se/ere tissue inGury H6;I4 8ietary consum+tion of antio?i-ants a++ears to +ro/i-e further ,enefits to the en-o0enous antio?i-ant -efense strate0ies in the fi0ht a0ainst o?i-ati/e stress H68;0I4 "n a--ition to the =ell. 1no=n -ietary antio?i-ants li1e /itamin &3 /itamin 3 +oly+henols ancarotenoi-s3 other -ietary

rece+tors4 >urthermore3 inhi,ition of chymase ,y :& inhi,itory +e+ti-es has ,eenli+i-s su00este- to +ro/i-e an a--itional$+ecifically3 o?i-ati/e antihy+ertensi/e effect as =ell H63I4

H64I4 the

mo-ification of J8J results in the

646

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

(a,le 2 $tructural +ro+erties of selecte- ,iofunctional +e+ti-es :cti/ity $tructural elements Remar1s Refere nce H40341 I H4I H46I

:& inhi,itory

*ro or hy-ro?y.*ro as &.terminus *ro3 Jys or :r0 as &.terminus (yr or *he as &.terminus

'sually resistant to -e0ra-ation ,y -i0esti/e enCymes *referre- &.terminal resi-ues =ith contri,ution to the :& inhi,itory +otency 8i+e+ti-es =ith a &.terminal (yr +ro-ucea hi0her antihy+ertensi/e effect com+areto -i+e+ti-es =ith &.terminal *he

:ntio?i-ant

6i0h amounts of 6is anhy-ro+ho,ic amino aci-s *e+ti-es =ith a *ro.6is.6is seBuence

&ontri,ution to the antio?i-ant +otency *e+ti-es =ith a *ro.6is.6is seBuence sho=e- the 0reatest antio?i-ant acti/ity amon0 all teste- +e+ti-es "m+ortant for the antithrom,otic acti/ity *ositi/e correlation =ith antithrom,otic acti/ity >a/ors a hy+ocholesterolemic effect

H4;348 I H49I

:ntithrom,otic

"le 3 Jys an- :s+ resi-ues of caso+latelin $u0ar content

108

112

115

H50I H51I H52 54I H55356 I H5;I H58I

6y+ocholesterolemic

Jo= ratios of methionine0lycine an- lysinear0inine in the -ietary +rotein 6i0h amounts of hy-ro+ho,ic amino aci-s

6y-ro+ho,ic +e+ti-es can ,in- ,ile aci-s an- there,y enhance the fecal steroi- e?cretion *e+ti-e len0th influences &&2.releasin0 acti/ity (-ifferent amon0 each -ietary +rotein) Necessary con-ition for &&2 release throu0h -irect ,in-in0 to intestinal cells

:ntio,esity

*e+ti-e len0th 9ulti+le :r0 resi-ues

*re/iously3 our la,oratory has sho=n that the com+oun-s ha/e 0enerate- +articular interest as -efenses a0ainst ,iofunctional -i+e+ti-e 953 o?i-ati/e -ama0e4 Recent stu-ies ha/e sho=n that +e+ti-es =ith -eri/e- from sar-ine muscle3 antio?i-ant +ro+erties can ,e release- from foo- sources such as stimulates e?+ression of the mil1 casein H;1I3 =hey +rotein H;2I3 e00 H;33;4I an- soyantio?i-ant -efense +roteins +rotein H;5I4 (a,le 3 lists some e?am+les of ,ioacti/e +e+ti-es heme o?y0enase.1 (6).1) -eri/e- from -ifferent +rotein sources4 an- ferritin in en-othelial $ome +e+ti-es -eri/e- from hy-rolyCe- foo- +roteins e?ert cells (>i04 2)4 (hese antio?i-ant acti/ities a0ainst enCymatic (li+o?y0en.ase.me-iate-)0enomic actions of 95 ha/e an- nonenCymatic +ero?i-ation of li+i-s an- essential fatty aci-s ,een associate- =ith a H493;6;8I4 (he e?act mechanisms ,ehin- these effects are notsustaine- cellular +rotection fully un-erstoo-4 (he antio?i-ant +ro+erties of these +e+ti-es from o?i-ati/e stress H61I4 ha/e ,een su00este- to ,e -ue to metal ion chelation3 free ra-ical (he antio?i-ant acti/ity of sca/en0in0 an- sin0ulet o?y0en Buenchin0 H2I4 6o=e/er3=hey.-eri/e- +e+ti-es anthrou0h the in/esti0ation of synthetic histi-ine.containin0 =hey itself has ,een lin1e+e+ti-es3 &hen et al4 H4;I -emonstrate- that none of these=ith the +resence of +ro+erties can ,e correlate- solely =ith the antio?i-ant acti/ity of cysteine.rich +roteins =hich the teste- +e+ti-es4 (herefore3 o/erall antio?.i-ant action is most +romote the synthesis of li1ely attri,ute- to the coo+erati/e effects of the mechanisms 0lutathione3 a +otent intracellular antio?i-ant mentione- H4;I4 :nother +lausi,le mo-e of action may ,e the in-uction of 0enes =hich +rotect cells from -ama0e ,y R)$4 H39I4 "n a stu-y ,y Ri/al et

al4 H85I3 caseins an-

casein.-eri/e- +e+ti-es =ere foun- to inhi,it li+o?y0enase3 an to increase- accessi,ility to enCyme =hich catalyCes the +ero?i-ation of unsaturate- fatty hy-ro+ho,ic tar0ets (e4043 aci-s such as linoleic aci-4 li+o+hilic fatty aci-s) H4;I4
(he antio?i-ant acti/ity has ,een attri,ute- to certain amino >urthermore3 there is some aci- seBuences H;1I4 6i0h amounts of histi-ine an- some e/i-ence that the antio?i-ant hy-ro+ho,ic amino aci-s are relate- to the antio?.i-ant +otency effect of certain amino aci-s H48I4 (he acti/ity of histi-ine.containin0 +e+ti-es is thou0ht to ,e is 0reater =hen they are connecte- to hy-ro0en.-onatin0 a,ility3 li+i- +ero?yra-icalincor+orate- in -i+e+ti-es tra++in03 an-Aor the metal ion chelatin0 a,ility of the imi-aCole H8;388I4 >or e?am+le3 the 0rou+ H86I4 (he a--ition of a leucine or +roline resi-ue to the N. constituent amino aci-s of histi-ine containin0 terminus of a histi-inehisti-ine -i+e+ti-e =oul- enhance the -i+e+.ti-e carnosine anantio?i-ant acti/ity4 :ccor-in0 to &hen et al4 H49I3 +e+ti-es =ith relate- a0ents are far less a *ro.6is.6is seBuence sho=e- the 0reatest antio?i-ant acti/ity effecti/e antio?i-ants than amon0 all teste- +e+ti-es an- ha- syner0istic effects =ith non+e+ti-ic antio?i-ants4 (he hy-ro+ho,icity of the +e+ti-e also their +arent +roteins H89I4 :s a++ears to ,e an im+ortant factor for its antio?i-ant acti/ity -ue another e?am+le3 mil1 casein

has ,een re+orte- to inhi,it the li+o?y0enase.me-iateli+i- auto?i-ation3 =hereas the free amino aci-s coulnot su,stitute for casein as the antio?i-ant H90I4 (he results su00est a crucial role of the +e+ti-e ,on- an-Aor s+ecific structural features of the +e+ti-es re0ar-in0 antio?i-ant +otency4 "n contrast3 recent results on the antio?i-ant effect of =hey +rotein hy-rolysates in-icate-

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

64;

54 :ntithrom,otic +e+ti-es :nother com+lication relateto &!8 is the inclination to -e/elo+ throm,osis -ue to a,normalities in coa0ulation4 "ncreaseoccurrence of throm,osis has ,een lin1e- to +latelet hy+erreacti/ity3 hi0h le/els of hemostatic +roteins (e4043 fi,rino0en)3 -efecti/e fi,rinolysis an- hy+er/iscosity of the ,loo- H91392I4 6ence3 antithrom,otic -ru0s are commonly use- to re-uce >i04 24 (he heme o?y0enase (6)) enCyme reaction% 6).1 is an +latelet a00re0ation an- enhance in-uci,le enCyme that catalyCes the -e0ra-ation of the to?ic heme fi,rinolysis4 moiety4 (his +rocess lea-s to 0eneration of car,on mono?i-e "n-ee-3 it has ,een +ro/e(&))3 free iron an- ,ili/er-in< the latter is su,seBuently con/erte- that there is a si0nificant amount molecular similarities to ,iliru,in ,y ,ili/er-in re-uctase (B!R) H;9380I4 &) an-of ,et=een the mechanisms ,iliru,in ha/e ,een causally lin1e- to a hi0her resistance a0ainst in/ol/ein mil1 clottin03 car-io/ascular -isease H8183I4 >urthermore3 the 6).1.-efine- ,y the interaction of . casein =ith chymosin3 an- ,loo-e+en-ent release of free iron -urin0 heme cata,olism results in clottin03 -efine,y the the u+.re0ulation of ferritin +rotein e?+ression H84I4 "n-uction ofinteraction of fi,rino0en =ith 6).1 an- ferritin is consi-ere- to ,e an a-a+ti/e an- ,eneficial throm,in H93I4 (o -ate3 foo-. -eri/e+e+ti-es =ith res+onse to o?i-ati/e stress in a =i-e /ariety of cells4

(his un-eca+e+ti-e inhi,its ,oth the a00re0ation of :8*.acti/ate+latelets as =ell as the ,in-in0 of human fi,rino0en .chain to its rece+tor re0ion on the +latelet surface4 $maller fra0ments of this +e+ti-e3 1no=n as caso+latelins3 can also affect +latelet function althou0h they ha/e much lo=er

inhi,itory acti/ity than the com+lete fra0ment H95I4 (hree amino aci- resi-ues 108 112 115 ("le 3 Jys 3 :s+ ) of the aforementione- un-eca+e+ti-e seem to ,e im+ortant for the antithrom,otic effect3 ,ecause they are homolo0ous in +ositions to the .chain seBuence of human fi,rino0en4 (herefore3 antithrom,otic acti/ity is influence- ,y the com+etition for +latelet rece+tors ,et=een caso+latelin an- the .chain of human fi,rino0en H50I4 >urthermore3 a correlation ,et=een su0ar le/el an- antithrom,otic acti/ity has ,een su00este- since the human .caseino0lycomacro.+e+ti-e3 =hich is richer in su0ars than that in ,o/ine3 is re+orte-ly more +otent H51I4 "t is thou0ht that mil1 +rotein.-eri/e- antithrom,otic +e+ti-es are a,sor,e- intact into the ,loo-stream4 6uman an,o/ine . caseino0lycomacro+e+ti-es3 t=o antithrom,o.tic +e+ti-es -eri/efrom the corres+on-in0 . caseins3 ha/e ,een -etecte- at +hysiolo0ically acti/e concentrations in the +lasma of ne=,orn chil-ren follo=in0 in0estion of ,reast mil1 or co= mil1.,aseformula3 res+ecti/ely H51I4
>urthermore3 a +e+ti-e -eri/efrom human lactoferrin3 2R8$3 =hich hol-s structural similarities to fi,rino0en .chain3 has ,een sho=n to inhi,it +latelet a00re0ation ,ut to a lesser e?tent than the fi,rino0en analo0ue3 RK8$ H9639;I4 "t is li1ely that 2R8$ an- RK8$ ha/e -ifferent mechanisms of action an-Aor their ,in-in0 sites are -ifferent anseBuence s+ecific4 "nhi,ition of +latelet a00re0ation ,y 2R8$ has ,een associate- =ith an inhi,ition of the release of the -ense 0ranule +rotein serotonin3 =hereas RK8$ -i- not e?hi,it a similar inhi,ition H98I4

antithrom,otic +ro+erties are mainly the result of enCymatic hy-rolysis of ,o/ine .casein4 that the +e+ti-e lin1a0e or structural +e+ti-e Recently3 antithrom,otic conformation can also attenuate the antio?i-ant +e+ti-es ha/e ,een isolate- from human an- shee+ .casein as acti/ity of the constituent amino aci-s H;2I4 (hus3=ell H51394I4 +e+ti-e conformation can lea- to ,oth syner0istic (he main antithrom,otic 9:"**22NM823 an- anta0onistic effects in re0ar- to the antio?i-ant +e+ti-e isolate- from the solu,le &. terminal fra0ment acti/ity of free amino aci-s4 >urther research comacro+e+ti-e) of(caseino0ly. ,o/ine . e?aminin0 the structureacti/ity relation.shi+ incasein3 corres+on-s to the resi-ues 106 to 116 of .casein +e+ti-es is nee-e-4 an- is terme- caso+latelin4

"n /i/o antithrom,otic acti/ities ha/e ,een sho=n for the .casein.-eri/e-

un-eca+e+ti-e H99I as =ell as for the lactoferrin. RK8$ +ossi,ly -ue to their -eri/e- tetra+e+ti-e H98I4 "n a--ition3 no -etecta,le -ifferent mo-es of action H100I4 to?ic effect has ,een re+orte-4 6ence3 case. ino0lycomacro+e+ti-e coul- +otentially ,e use- to64 6y+ocholesterolemic treat or +re/ent throm,osis4 "n contrast3 the RK8$ an- hy+otri0lyceri-emic seBuence has ,een foun- to in-uce -etachment of+e+ti-es en-othelial cells in /itro an- therefore serious concerns e?ist re0ar-in0 the to?icity of this seBuence :n unfa/ora,le +rofile of in /i/o4 (he relate- +e+ti-e 2R8$ -oes not a++ear ,loo- li+i-s is another im+ortant to ha/e the same +otential -etrimental effects as

ris1 factor for the 0enesis of /arious &!8s4 9any stu-ies ha/e foun- a +ositi/e correlation ,et=een hy+ercholesterolemia an-Aor hy+ertri0lyceri-emia anthe li1elihoo- for -e/elo+in0 &!8 H9231013102I4 Not sur+ris. in0ly3 treatment for hy+erli+i-emia.accelerate-iseases

648

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

often inclu-es the im+ro/ement of ,een sho=n that soy serum li+i- -istri,ution throu0h -iet +rotein hy-ro.lysates mo-ifications4 re-uce total cholesterol "t is 0enerally 1no=n that se/eral le/els more effecti/ely -ietary +roteins can im+ro/e ,loo-than intact soy +rotein li+i+rofiles4 (o -ate3H1043112I4 $e/eral more hy+ocholesterolemic +ro+erties ha/ere+orts in-icate that ,een re+orte- for soy H1033104I3 =heyhy-ro+ho,ic +e+ti-es H1053106I an- fish +rotein H52I3-eri/e- from soy +rotein ca+a,le of alterin0 the +lasma +rofilecan ,in- ,ile aci-s from athero0enic to car-io+rotecti/e4there,y enhancin0 fecal "n contrast3 ,o/ine casein ten-s tosteroi- e?cretion =hich cause s+ecies.-e+en-entmay contri,ute to the hy+ercholesterolemia an- atheromatoushy+ocholesterolemic +laBues in animal stu-ies H10;3108I4acti/ity H55356I4 (he e?act mechanisms res+onsi,le for Recently3 J*5*R3 a the hy+ocholesterolemic effects ha/e+e+ti-e -eri/e- from not ,een fully i-entifie-3 ,ut e/i-encesoy 0lycinin3 =as founsu00ests that the s+ecific amino aci- to +ro-uce serum com+osi.tion of -ietary +roteinscholesterol.lo=erin0 +ro,a,ly influences the effect of the effects in mice follo=in0 +rotein source on +lasma cholesterol oral a-ministration le/els4 "t has ,een re+orte- that -ietaryH113I4 J*5*R is +roteins =ith lo= ratios of methionine structurally homolo0ous 0lycine an- lysinear0inine3 such asto enterostatin soy an- fish +rotein3 fa/or a (!*8*R)3 an hy+ocholesterolemic effect H5254I4 "nen-o0enous +e+ti-e contrast3 ,o/ine casein ten-s to ele/ate e?hi,itin0 cholesterol le/els +ro,a,ly -ue to itshy+ocholesterolemic hi0h ratios of methionine.0lycine an- an- anorectic effects H114I4 :nother 0lycinin. lysine.ar0inine H10;I4

H1103111I4 "t has also

)f the limite- num,er of +e+ti-es -eri/e- +e+ti-e =ith re+orte- to ha/e hy+ocholesterolemiccholesterol.lo=erin0 effects3 -ietary soy +rotein has recei/e- acti/ity is ":!*K !: "n /itro the most attention4 *u,lishe- -ata offer aH115I4 measurements ha/e ran0e of +ossi,le mechanism of action in soy +roteinNs a,ility to re-uce total sho=n that ,oth J*5R* ":!*K !: +lasma cholesterol inclu-in0 in-uction ofanJ8J rece+tor e?+ression3 increase of ,ile inhi,ite- 3.hy-ro?y.3. coen. aci- synthesis an- e?cretion as =ell asmethyl0lutaryl : re-uctase -ecrease in steroi- a,sor+tion from the Cyme intestine4 "n a--ition3 chan0es in the (69KR) =hich is a en-ocrine status such as alteration in the 1no=n 1ey enCyme in insulin0luca0on ratio an- in thyroi-cholesterol ,iosynthesis4 hormone concen.trations ha/e also ,een "n/esti0ations on the structure acti/ity re+orte- H109I4 :lthou0h these effects relationshi+ re/ealeha/e not ,een attri,ute- to s+ecific soy that the hy-ro+ho,ic constituents3 se/eral stu-ies su00est that re0ion of ,oth +e+ti-es +e+ti-es -eri/e- from soy +rotein may ,e is a reBuire- structural the ,ioacti/e com+onents4 #hen amino element for their aci- mi?tures mimic1in0 soy +rotein ,iolo0ical acti/ity4 (he =ere fe- to rats or ra,,its3 the resultin0 ma?imum len0th of the ,loocholesterol le/els =ere hy-ro+ho,ic si0nificantly lo=ere- ,ut not as lo= as those that =ere fe- =ith the intact +rotein

seBuence =as state- to ,e four amino aci-s4 9oreo/er3 the +roline resi-ue seems to ,e a 1ey com+onent an- can ,e locate- at ,oth the &.terminus an- in any other +osition of the amino aci- seBuence e?ce+t the N.terminus H116I4 $e/eral +e+ti-e fra0ments o,tainefrom the su,units of . con0lycinin are consi-ere- to +ossess hy+ocholesterole.mic acti/ity4 (he re0ulation of cholesterol homeostasis has ,een +ro+ose- to ,e -ue to the acti/ation of J8J rece+tors an- J8J -e0ra-ation in li/er cells at least in /itro4 *reliminary -ata e/i-ently su00est a +ositi/e mo-ulation of J8J rece+tor in-uce,y a s+ecific seBuence corres+on-.in0 to the +ositions 12;150 of .con0lycinin H11;I4 8uranti et al4 H118I re+orte- a mar1e- u+. re0ulation of li/er . /ery lo=.-ensity li+o+rotein (!J8J) rece+tors ana si0nificant -ecrease in +lasma tri0lyceri-es in hy+ercholesterolemic rats after oral treatment =ith the .su,unit of .con0lycinin4 (hey hy+othesiCethat +e+ti-es arisin0 from -i0estion elicit the ,iolo0ical effect H118I4
:s for the o,ser/ehy+otri0lyceri-emic acti/ity3 there is some e/i-ence that -ietary +rotein may affect li+o0enesis in the li/er4 "ritani et al4 H119I ha/e sho=n that oral a-ministration of soy +rotein to rats re-ucethe concentra.tions of tri0lyceri-es in +lasma an- more +rominently in li/er4 (hese effects =ere associate=ith si0nificant re-uc.tions in the acti/ities of he+atic li+o0enic enCymes in-icatin0 that soy +rotein re-uces li/er tri0lyceri-es or fat in +art ,y inhi,itin0 he+atic fatty aci-

synthesis H119I4 >urthermore3 -ietary soyintestinal fat a,sor+tion +rotein a++eare- to cause a stimulation of as =ell as an enhanceli+olysis of tri0lyceri-es li+olysis an- fatty aci- utiliCation H120I4 H122I4 (he "n mice3 9oriyama et al4 H121Ihy+otri0lyceri-emic -emonstrate- that .con0lycinin re-uce-effect of hy-rolyCeserum tri0lyceri-e le/els ,y the0lo,in has also ,een acceleration of .o?i-ation3 su++ression-emonstrate- in humans of fatty aci- synthesis an- increase- fecal H123I4 e?cretion of tri0lyceri-es4 (hey Numerous stu-ies conclu-e- that some s+ecific .ha/e sho=n that mil1 con0lycinin +e+ti-es mi0ht ,e=hey +rotein3 in contrast res+onsi,le for these multi+le e/entsto mil1 casein3 -ecreases H121I4 Remar1a,le hy+otri0lyceri-emicserum cholesterol acti/ities in -ifferent animal s+ecies =eresimilar to soy +rotein (his also achie/e- ,y the a-ministration ofH10631243125I4 hy-rolyCe- 0lo,in4 !!5*3 !5* an- !(Jeffect =as more mar1e=ere i-entifie- as the effecti/e =ith the =hey +e+ti-e constituent +e+ti-es4 (hefraction than =ith the hy+otri0lyceri-emic effect of theseintact =hey +rotein +e+ti-es =as associate- =ith -ecrease- H124I4 Na0ao1a et al4 H126I i-entifie- "": 2

as the hy+ocholesterolemic +e+ti-e -eri/e- from ,o/ine mil1 . lacto0lo,ulin4 "n animal stu-ies3 "": 23 =hich is also terme- lactostatin3 e?hi,itea 0reater hy+ocholesterolemic effect than .sitosterol4 >ollo=in0 oral a-ministration to rats3 total serum cholesterol le/els =ere si0nificantly lo=er3 =hereas 68J concentration anathero0enic in-e? (68J cholesterolA total cholesterol) =ere si0nificantly hi0her than in the 0rou+ fe- =ith . sitosterol4 (hese effects ha/e ,een s+eculate- to

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

649

such as soy is effecti/e ,e at least in +art -ue to a -ecrease of in re-ucin0 ,o-y micellar solu,ility of cholesterol =hich =ei0ht anin lea-s to lo=er intestinal cholesterol im+ro/in0
a,sor+tion H126I4 Recent -ata ha/e sho=n that lactostatin is ca+a,le of in-ucin0 the 0ene transcri+tion of human(a,le 3 cholesterol ;.hy-ro?ylase (&5*;:1)3 a ?am+les of ,ioacti/e cholesterol.meta.,oliCin0 enCyme3+e+ti-es -eri/e- from fooresultin0 in hy+ocholesterolemic effects4 (his ne= site of action in/ol/es &a an9:*2.-e+en-ent si0nalin0 +ath=ays4 >urther results im+ly that the &.terminal si-e of lactostatin3 es+ecially the 0lutamyllysine seBuence3 is crucial for the in-uction of human &5*;:1 transcri+tion4 6o=e/er3 an amino acimi?ture constituently eBui/alent to lactostatin faile- to in-uce the &5*;:1 0ene H12;I4

car-io/ascular ris1 factors4 "n contrast3 the re0ular inta1e of +rotein sources rich in saturatefat an- cholesterol such as re- meat an- e00s may increase the ris1 of &!8 H1313133I4 Ne/ertheless3 relia,le information on the lon0. term effects of hi0h. +rotein -iets on o/erall health is not yet a/aila,le4 "n0estion of soy3 casein an- =hey +rotein has all ,een sho=n to holantio,esity or anorectic +ro+erties =ith the effect of soy +rotein in re-ucin0 ,o-y =ei0ht more su+erior than that of casein an- =hey +rotein H134136I4 (he mechanisms ,y =hich +roteins e?ert anorectic actions are still unclear4 $e/eral stu-ies s+eculate that +e+ti-es releasefrom -ietary +roteins -urin0 -i0estion can initiate se/eral satiety si0nals from the 0ut anthus +re/ent further foointa1e4 Because these +e+ti-es act at the intestinal site they -o not nee- to ,e a,sor,einto the systemic circulation4 *u+o/ac an:n-erson H13;I conclu-e that the in-uction of satiety ,y +e+ti-es -eri/e- from soy an- casein +rotein is me-iate,y in-e+en-ent acti/ation of ,oth o+ioi- ancholecysto1inin (&&2). : rece+tors4 (he +i/otal role of o+ioi- an- &&2. : rece+tors in the re0ulation of foo- inta1e is =ell reco0niCe-4 *e+ti-es =ith o+ioi-.

;4 :ntio,esity +e+ti-es
"n many in-ustrial countries o,esity is a serious health issue that has ,een associate- =ith hi0her inci-ence of &!8 anrelate-isor-ers H128I4 6y+erinsulinemia3 insulin resistance ana,normalities in li+i- meta,olism ha/e all ,een lin1e- to o,esity4 Ji+o+rotein +rofile o,taine- in o,ese su,Gects re/eale- a +attern of hi0her le/els of tri0lyceri-es3 ele/ate- J8J.cholesterol an- lo= 68J.cholesterol4 Restric.tion of caloric inta1e an- increasin0 +hysical e?ercise are recommen-e- for the treatment of a-i+osity4 Both =ei0ht loss an- e?ercise can also im+ro/e insulin resistance an- associate- -ysli+i-emia H1293130I4

"t is 0enerally acce+te- that +rotein is the most satiatin0 macronutrient H1313132I4 Besi-es in-ucin0 the feelin0 of satiety3 a hi0h.+rotein -iet +romotes thermo0enesis lea-in0 to a faster rate of caloric meta,olism4 8iets rich in +rotein are 1no=n to su++ress foointa1e an- facilitate short.term =ei0ht loss e/en more effecti/ely than hi0h. car,ohy-rate -iets an- thus can ,e usein the mana0ement of o,esity4 6o=e/er3 some e/i-ence su00ests that -ifferent sources of -ietary +rotein in lo=.calorie -iets +ro-uce /aryin0 effects on meta,olism an- therefore stron0ly influence =ei0ht loss4 >or e?am+le3 the in0estion of +lant +rotein

li1e acti/ities affect foo- inta1e ,y the +rotein in-icatin0 that -elay of 0astric em+tyin0 an- intestinalhy-rolysis of soy +rotein transit H4I4 &22 is an im+ortant is im+ortant in its effect +hysiolo0ic en-ocrine factor thatof =ei0ht re-uction re0ulates a++etite an- 0astric em+tyin04 H1353140I4 >urthermore3 (he stimulation of &&2 releaseamino aci- mi?tures contri,utes to a++etite su++ression in thesimulatin0 soy ancentral ner/ous system as =ell as in the casein +rotein =ere not effecti/e in releasin0 +eri+hery H1383139I4 &&2 from mucosal cells "n re0ar- to soy +rotein3 it has ,een H5;31413142I4 (hese sho=n that the -ecline in ,o-y fat anresults in-icate that foo- inta1e =as more si0nificant =ith the +e+ti-es release- from soy +e+ti-e fraction than =ith the intact

-ietary contri,ute initiation

+roteins to the of satiety

si0nals4 Nishi et al4 H5;I hy+othesiCe that the +e+ti-e len0th mi0ht ,e an im+ortant factor in &&2.releasin0 acti/ity4 (he o+timal +e+ti-e siCe seems to ,e -ifferent amon0 each -ietary +rotein4 #ell.

:cti/ity :ntio?i-ant

)ri0in >ish (sar-ine muscle)

$oy (.con0lycinin)

$eBuenceAname 95 JJ*66 5>5* J 96"RJ3 5! 5: R5*"J J3 #5$J:9::$8"

Refere nce H61I H;5I H;1I H;2I H;3I H95I H9639; I H113I H115I H11;I H126I H122I H58I H14331 44I

9il1 (casein)
9il1 (.lacto0lo,ulin)

00 (e00 =hite) :ntithrom,otic

9il1 (.casein)

9:"**22NM82 (caso+latelin) an- smaller fra0ments

9il1 (lactoferrin) 6y+ocholesterolemic $oy (0lycinin) $oy (0lycinin)

$oy (.con0lycinin) 9il1 (.lacto0lo,ulin)

2R8$ J*5*R ":!*K !: $e/eral +e+ti-e fra0ments (e4043 seBuence corres+on-in0 to the resi-ues 12;150) "": 2 (lactostatin) !!5*3 !5*3 !(J !R"RJJMR>N2R$ &aseino0lycomacro+e+ti-e

6y+otri0lyceri-emic :ntio,ese

Bloo- (0lo,in)
$oy (.con0lycinin)

9il1 (.casein)

650

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

-i0este- soy +rotein for instance isrelease- from -i0estemore effecti/e than less.-i0este- one+rotein a++ear to on &&2 li,eration4 "n contrast3 lar0er +ro/i-e this satiety +e+ti-es of casein hy-rolysate seem tosi0nal3 ,ecause neither ,e in/ol/e- in the -irect stimulation ofintact +roteins nor free &&2 release H5;I4 amino aci- mi?tures
Nishi et al4 H58I i-entifie- the +e+ti-estimulate- the release of !R"RJJMR>N2R$ corres+on-in0 to theKJ*.1 H151I4 resi-ues 5163 of .con0lycinin as the ,ioacti/e a++etite su++ressant in soy +rotein4 (his +e+ti-e interacts -irectly =ith the intestinal mucosal cells to stimulate &&2 release4 >urther in/esti0ations on the ,in-in0 acti/ities of se/eral synthetic mo-el +e+ti-es in-icate that multi+le ar0inine resi-ues are a necessary con-ition for &&2 release throu0h -irect ,in-in0 to ,rush ,or-er mem,rane H58I4

H1493150I4

*e+ti-es

$e/eral stu-ies ha/e sho=n that satiety associate- =ith casein in0estion in/ol/es ,oth o+ioi- an- &&2 re0ulation H13;3142I4 *roteolysis of mil1 casein releases ,ioacti/e +e+ti-es rele/ant to hun0er re0ulation inclu-in0 casomor.+hins ancaseino0lycomacro+e+ti-e4 &asomor+hins are +e+ti-es =ith o+ioi-.li1e acti/ities that are 1no=n to interact =ith 0astric o+ioi- rece+tors to slo= 0astrointestinal motility an+re/ent further foo- inta1e H145I4 "n a--ition3 they influence a++etite re0ulation ,y mo-ifyin0 the +ost+ran-ial le/els of meta,olic hormones in/ol/e- in satiety H146I4 *e+ti-es =ith o+ioi- acti/ity ha/e ,een re/ie=ee?tensi/ely else=here H39314;I4 &aseino0lycoma.cro+e+ti-e3 a 64.amino aci- fra0ment from the &. terminal en- of ,o/ine casein3 has ,een sho=n to e?ert &&2.releasin0 acti/ity /ia -irect reaction =ith the small intestine an- therefore act as an a++etite su++ressant H1433144I4 "n a--ition3 caseino0lycomacro+e+ti-e has also ,een foun- to control foointa1e in animals at least in +art throu0h o+ioi- acti/ity H148I4
*rotein.in-uce- satiety may also ,e me-iate- throu0h the 0luca0on.li1e +e+ti-e.1 (KJ*.1) si0nalin0 +ath=ay4 "n rats as =ell as in humans it has ,een -emonstrate- that acti/ation of KJ*.1 rece+tor is in/ol/e- in casein. an- =hey. in-uce- su++ression of foo- inta1e

:,o/e an- ,eyonthe stimulation of satiety throu0h ,ioacti/e +e+ti-es3 li+i-.lo=erin0 effects as =ell as increas.in0 meta,olic rate are also ,eneficial in fi0htin0 o,esity4 :nother +ossi,le mo-e of action is the mo-ulation of a-i+ose 0enes that contri,ute to the homeostasis of meta,olism an/ascular functions4 "n the case of soy +rotein3 Na0asa=a et al4 H152I ha/e sho=n that it raises a-i+onectin mRN: e?+ression in mice4 :-i+onectin is an a-i+ose.s+ecific +lasma +rotein +ossessin0 antiathero0enic ananti.insulin.resistance +ro+erties H152I4 $oy +rotein may also re-uce a-i+osity ,y mo-ulatin0 the e?+ression of nuclear transcri+tion factors3 s+ecifically the +ero?isome +roliferator.acti/aterece+tors (**:Rs) ansterol re0ula.tory element ,in-in0 +roteins ($R B*s) that are +rinci+al re0ulators of fatty acimeta,olism ancholesterol home. ostasis H12131533154I4 >urther e/i-ence su00ests that the in0estion of soy an=hey +rotein im+ro/es insulin resistance =hich is a hallmar1 of o,esity H1363154I4 "t remains to ,e -etermine=hether s+ecific ,ioacti/e +e+ti-es are

res+onsi,le for the a,o/ementione-an- enhance- throm,osis effects4 ( (a,le 3)4 $ince &!8 is
a si0nificant +u,lic health 84 &onclusion +ro,lem =orl-=i-e3 ,iolo0ically acti/e Bioacti/e +e+ti-es ha/e ,een sho=n to +e+ti-es may ,e of /ital +ossess +ro+erties that may ,einterest in maintainin0 a a-/anta0eous to car-io/ascular health4 healthy +o+ulation4 :s (hese effects inclu-e the lo=erin0 of ,loo- +art of a foo- +ro-uct or +ressure an- li+i- le/els as =ell as re-ucin0 as a nutraceutical they free ra-ical formation4 /i-ence for ha/e a chronic rather than ,eneficial effects of ,ioacti/e +e+ti-es has an acute effect on health4 also ,een raise- un-er con-itions of o,esity Numerous +ro-ucts that contain ,ioacti/e +e+ti-es
(a,le 4 ?am+les of

are alrea-y on the mar1et ( (a,le 4)4 'ntil no=3 ho=e/er3 most of the claime+hysiolo0ical effects of ,ioacti/e +e+ti-es ha/e ,een o,ser/e- in /itro or in animal mo-el systems4 6uman clinical stu-ies are limite- or none?istent an- the o+timal +lasma le/els of ,ioacti/e +e+ti-es ha/e not ,een

commercially carryin0 ,ioacti/e +e+ti-es (mo-ifiea/aila,le from 6artmann an- 9eisel H1I) functional foo-s

24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654 +ostmeno+ausal =omen4 :m J &lin -etermine-4 (herefore3 further research Nutr 199;<65% 102; is nee-e- in or-er to clarify the 334

651 -isease4 *roc Nutr $oc 2003<62%495 5044

rele/ance an- +otential thera+eutic role of ,ioacti/e +e+ti-es in humans4 References

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6artmann R3 9eisel 64 >oo-.-eri/e+e+ti-es =ith ,iolo0ical acti/ity% from research to foo- a++lications4 &urr )+in Biotechnol 200;<18%16394 2itts 883 #eiler 24 Bioacti/e +roteins an- +e+ti-es from foo- sources4 :++lications of ,io+rocesses use- in isolation an- reco/ery4 &urr *harm 8es 2003<9%1309234 2o/acs.Nolan J3 *hilli+s 93 9ine 54 :-/ances in the /alue of e00s an- e00 com+onents for human health4 J :0ric >oo- &hem 2005<53% 8421314 9eisel 64 Biochemical +ro+erties of re0ulatory +e+ti-es -eri/e- from mil1 +roteins4 Bio+olymers 199;<43%119284
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6asler &94 (he chan0in0 face of functional foo-s4 J :m &oll Nutr 2000<19%499$506$4

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Rats4 J >oo- $ci 2006<;1% &164;34

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Na1amura 53 5amamoto N3 $a1ai 23 (a1ano (4 :ntihy+ertensi/e effect of sour mil1 an- +e+ti-es isolate- from it that are inhi,itors to an0iotensin "Qcon/ertin0 H35I Na1ashima 53 enCyme4 J 8airy $ci 1995<;8%1253;4 :rihara 23 $asa1i :3 H28I $e++o J3 Jauhiainen (3 *oussa (3 9io 63 "shi1a=a $3 2or+ela R4 : fermente- mil1 hi0h in "toh 94 ,ioacti/e +e+ti-es has a ,loo:ntihy+ertensi/e +ressureQlo=erin0 effect in hy+ertensi/e :cti/ities of *e+ti-es su,Gects4 :m J &lin Nutr 2003<;;%326304 8eri/e- from *orcine H29I :,u,a1ar :3 $aito (3 2itaCa=a 63 $1eletal 9uscle 9yosin in 2a=ai 53 "toh (4 $tructural analysis of ne= $+ontaneously antihy+ertensi/e +e+ti-es -eri/e- from cheese 6y+ertensi/e Rats4 =hey +rotein ,y +roteinase 2 -i0estion4 J J >oo$ci 8airy $ci 1998<81%313184 2002<6;%434;4 H30I 9ura1ami 93 (onouchi 63 (a1ahashiH36I 2o-era (3 Nio N4 R3 2itaCa=a 63 2a=ai 53 Ne0ishi 63 et al4 "-entification of an $tructural analysis of a ne= :n0iotensin antiQhy+ertensi/e +e+ti-e (,etaQlactosin B) "Qcon/ertin0 nCyme isolate- from a commercial =hey +ro-uct4 J "nhi,itory *e+ti-es 8airy $ci 2004<8;%196;;44 from *rotein

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8rouet J3 Bal -it $ollier &3 &isse 93 *i0nau- K3 9aCoyer 3 >iat :93 et al4 (he antithrom,otic effect of 2R8$3 a lactotransferrin +e+ti-e3 com+are- =ith RK8$4 Nou/ Re/ >r 6ematol 1990<32%59624

$u0ano 93 Koto $3 5ama-a 53 5oshi-a 23 6ashimoto 53 9atsuo (3 et al4 &holesterol.lo=erin0 acti/ity of /arious un-i0este- fractions of soy,ean +rotein in rats4 J Nutr 1990<120%9;;854 Phan0 O3 Beynen :&4 Jo=erin0 effect of -ietary mil1.=hey +rotein / casein on +lasma anli/er cholesterol concentrations in rats4 Br J Nutr 1993<;0%139464

H105I

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9au,ois JJ3 Jeonil J3 (rou/e R3 Bouhalla, $4 9il1 +e+ti-es =ith +hysiolo0ical acti/ities% """ *e+ti-es =ith a car-io/ascular effect% antithrom,otic an- antihy+ertensi/e acti/ity4 Jait 1991<;1%249554

Bertina R94 9olecular ris1 factorsH100I Rutherfur2J3 for throm,osis4 (hrom, 6aemost Kill 6$4 *e+ti-es 1999<82%60194 affectin0 coa0ulation4

Br J Nutr Krun-y $93 Bala-y KJ3 &riBui 963 2000<84($u++l >letcher K3 Kreenlan- *3 6iratC1a J>3 et 1)%$99$1024 al4 *rimary +re/ention of coronary heart -isease% 0ui-ance from >ramin0ham% aH101I 6o1anson J 3 statement for healthcare +rofessionals :ustin 9:4 *lasma from the :6: (as1 >orce on Ris1 tri0lyceri-e le/el is a Re-uction :merican 6eart :ssociation4 ris1 factor for &irculation 1998<9;%18;68;4 car-io/ascular -isease in-e+en-ent of hi0h. H93I Jolles *4 $tructural as+ects of the mil1 -ensity li+o+rotein clottin0 +rocess &om+arati/e features =ith cholesterol le/el% a the ,loo- clottin0 +rocess4 9ol &ell meta.analysis of Biochem 19;5<;% ;3854 +o+ulation.,aseH94I Mian P53 Jolles *3 9i0liore.$amour +ros+ecti/e stu-ies4 J 83 $choent0en >3 >iat :94 $hee+ 1a++a. &ar-io/asc Ris1 casein +e+ti-es inhi,it +latelet 1996<3%21394 a00re0ation4 Biochim Bio+hys :cta H102I 9artin 9J3 1995<1244%411;4 6ulley $B3 Bro=ner H95I Jolles *3 Je/y.(ole-ano $3 >iat :93 #$3 2uller J63 $oria &3 Killessen 83 (homai-is :3 et al4 #ent=orth 84 $erum cholesterol3 ,loo:nalo0y ,et=een fi,rino0en an- casein +ressure3 anffect of an un-eca+e+ti-e isolate- from mortality% im+lications 1a++a.casein on +latelet function4 ur J from a cohort of Biochem 1986<158%3;9824 3613662 men4 Jancet H96I Raha $3 8osBuet &3 :,0rall J>3 Jolles 1986<2%93364 *3 >iat :93 &aen J*4 2R8$ a tetra+e+ti-e -eri/e- from lactotransferrin.H103I 6ori K3 #an0 9>3 &han 5&3 inhi,its ,in-in0 of monoclonal anti,o-y 2omatsu (3 #on0 53 a0ainst 0lyco+rotein "","""a on :8*. &hen (63 et al4 $oy stimu.late- +latelets an- me0a1aryocytes4 +rotein hy-rolyCate Bloo- 1988<;2%1;284 =ith ,ounH9;I 9aCoyer 3 Je/y.(ole-ano $3 Ren-u

H106I

Na0ao1a $3 2anamaru 53 2oGima (3 2u=ata (4 &om+arati/e stu-ies on the serum cholesterol lo=erin0 action of =hey +rotein an- soy,ean +rotein in rats4 Biosci Biotechnol Biochem 1992<56%148454

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&arroll 223 6amilton R9K4 ffects of -ietary +rotein an- car,ohy-rate on +lasma cholesterol le/els in relation to athero.sclerosis4 J >oo- $ci 19;5<40%18 234

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!an -er 9eer R3 8e !ries 6(3 !an (intelen K4 (he +hos+horylation state of H11;I Jo/ati 9R3 casein an- the s+ecies.-e+en-ency of its 9anConi &3 KianaCCa hy+ercholester.olaemic effect4 Br J Nutr 3 :rnol-i :3 1988<59%46;;34 2uro=s1a 3 &arroll *otter $94 )/er/ie= of +ro+osemechanisms for the hy+ocholes.terolemic effect of soy4 J Nutr 1995<125%606$11$4 223 et al4 $oy +rotein +e+ti-es re0ulate cholesterol homeostasis in 6e+ K2 cells4 J Nutr 2000<130%254394

*a1 !!3 2oo 93 Jee N3 2im 9$3 2=on 854 $tructure acti/ity relationshi+s of the +e+ti-e "le.:la. !al.*ro anits -eri/ati/es re/ealeusin0 the semi. em+irical :91 metho-4 &hem Nat &om+- 2005<41%454 604

2ishimoto 23 Na0ai 23 'ra-e R3 )0a=a (3 'tsumi $3 et al4 $oy,ean ,eta.con0lycinin -iet su++resses serum tri0lyceri-e le/els in normal an- 0enetically o,ese mice ,y in-uction of ,eta.o?i-ation3 -o=nre0ulation of fatty acisynthase3 aninhi,ition of tri0lyceri-e a,sor+tion4 Biosci Biotechnol Biochem 2004<68%35294

H122I

Na0ata 53 "shi=a1i N3 $u0ano 94 $tu-ies on the mechanism of antihy+ercholesterolemic action of soy +rotein an- soy +rotein.ty+e amino aci- H118I 8uranti 93 Jo/ati 9R3 8ani !3 Bar,iroli mi?tures in relation to the casein :3 $carafoni :3 counter+arts in rats4 J Nutr &asti0lioni $3 et al4 1982<112%1614254 (he al+ha su,unit H111I 6uff 9#3 &arroll 224 ffects of from soy,ean ;$ -ietary +roteins an- amino aci- mi?tures 0lo,ulin lo=ers on +lasma cholesterol le/els in ra,,its4 J +lasma li+i-s anNutr 1980<110% 16;6854 u+re0ulates li/er ,eta. !J8J rece+tors in H112I #an0 9>3 5amamoto $3 &hun0 693 rats fea &hun0 $53 9iyatani $3 9ori 93 et al4 hy+ercholesterolemic :ntihy+ercholesterolemic effect of -iet4 J Nutr un-i0este- fraction of soy,ean +rotein in 2004<134%133494 youn0 female /olunteers4 J Nutr $ci !itaminol ((o1yo) 1995<41%18;954

2a0a=a 23 9atsuta1a 63 >u1uhama &3 #atana,e 53 >uGino 64 Klo,in -i0est3 aci-ic +rotease hy-rolysate3 inhi,its -ietary hy+er. tri0lyceri-emia an!al.!al.(yr.*ro3 one of its constituents3 +ossesses most su+erior effect4 Jife $ci 1996<58%1;45554 2a0a=a 23 9atsuta1a 63 >u1uhama &3 >uGino 63 )1u-a 64 $u++ressi/e effect of 0lo,in -i0est on +ost+ran-ial hy+erli+i-emia in male /olunteers4 J Nutr 1998<128%56604 Na0ao1a $4 $tu-ies on re0ulation of cholesterol meta,olism in-uce,y -ietary fooconstituents or ?eno,iotics4 J J+n $oc Nutr >oo$ci 1996<49%303134 Na0ao1a $3 2anamaru 53 2uCuya 54 ffect of =hey +rotein an- casein on the +lasma an- li/er li+i- in rats4 :0ric Biol &hem 1991<55% 81384

H123I

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5oshi1a=a 93 >uGita 63 9ato,a N3 (a1ena1a 53 5amamoto (3 5amauchi R3 et al4 Bioacti/e +e+ti-es -eri/e- from foo+roteins +re/entin0 lifestyle.relate-iseases4 Biofactors 2000<12%14364

H114I

(a1ena1a 53 'tsumi $3 5oshi1a=a 94 "ntro-uction of enterostatin (!*8*R) ana relate- seBuence into soy,eanH120I "ritani N3 6osomi 63 >u1u-a 63 (a-a 23 +ro0lycinin :1aB1, su,unit ,y site. "1e-a 64 $oy,ean -irecte- muta0enesis4 Biosci Biotechnol +rotein su++resses Biochem 2000<64%2;3134 he+atic li+o0enic H115I *a1 !!3 2oo 9$3 2asymo/a (83 enCyme 0ene 2=on 854 "solation an- i-entification of e?+ression in #istar +e+ti-es from soy 11$.0lo,ulin =ith fatty rats4 J Nutr hy+ocholester.olemic acti/ity4 &hem Nat 1996<126%38084 &om+- 2005<41%;1044

"ritani N3 Na0ashima 23 >u1u-a 63 2atsura-a :3 (ana1a (4 ffects of -ietary +roteins on li+o0enic enCymes in rat li/er4 J Nutr 1986<116% 190;4

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24 r-mann et al4 A Journal of Nutritional Biochemistry 19 (2008) 643654

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Na0ao1a $3 >utamura 53 9i=a 23 :=ano (3 5amauchi 23 2anamaru 53 et al4 "-entification of no/el hy+ocholesterolemic +e+ti-es -eri/e- from ,o/ine mil1 ,eta.lacto0lo,ulin4 Biochem Bio+hys Res &ommun 2001<281%11;4

H141I

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9ori1a=a 23 2on-o "3 2anamaru 53 Na0ao1a $4 : no/el re0ulatory +ath=ay for cholesterol -e0ra-ation /ia H142I >roetschel 9:3 :Cain 9J3 lactostatin4 Biochem Bio+hys Res &ommun 200;<352%69; -=ar-s KJ3 Bar, &R3 :mos 6 4 ;024 )+ioiancholecysto1inin anta0onists alle/iate 0astric H128I 6u,ert 6B3 >einlei, 93 9cNamara *93 &astelli #*4 inhi,ition of foo- inta1e ,y ),esity as an in-e+en-ent ris1 factor for car-io/ascular +remeal loa-s of casein in meal. -isease% a 26.year follo=.u+ of +artici+ants in the fe- rats4 J Nutr 2001<131% 32;064 >ramin0ham 6eart $tu-y4 &irculation 1983< 6;%968;;4

Nishi (3 6ara 63 2asai (4 Kuani-inate- casein hy-rolysate stimulates +ancreatic secreta0o0ue release ,y -irect action to the intestine in rats4 *roc $oc ?+ Biol 9e- 1998<218%35; 644

incretin hormone 0luca0on.li1e +e+ti-e 1 an- the transcri+tion of the +ro0luca0on 0ene4 8ia,etes 1998<4;%1038454

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6o=ar- B!4 "nsulin resistance an- li+i- meta,olism4 :m J &ar-iol 1999<84%28J32J4 2rauss R93 #inston 93 >letcher RN3 Krun-y $94 ),esity% im+act of car-io/ascular -isease4 &irculation 1998<98%14;264

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*e-ersen NJ3 Na0ain.8omaine &3 9ahe $3 &hariot J3 RoCe &3 (ome 84 &aseinomacro+e+ti-e s+ecifically stimulates e?ocrine +ancreatic secretion in the anesthetiCe- rat4 *e+ti-es 2000<21%152;354

!elasBueC 9(3 Bhathena $J4 Role of -ietary soy +rotein in o,esity4 "nt J 9e- $ci 200;<4%;2 824 :scencio &3 (orres N3 "soar-Q:costa >3 KomeCQ*ereC >J3 6ernan.-eCQ*an-o R3 (o/ar :R4 $oy +rotein affects serum insulin an- he+atic $R B*Q1 mRN: an- re-uces fatty li/er in rats4 J Nutr 2004< 134%52294

:n-erson K63 9oore $ 4 8ietary +roteins in the H144I Beucher $3 Je/eneC >3 5/on re0ulation of foo- inta1e an- ,o-y =ei0ht in humans4 J 93 &orrin0 (4 ffects of 0astric Nutr 2004<134%9;4$9$4 -i0esti/e +ro-ucts from casein on Johnstone :93 $tu,,s RJ3 6ar,ron &K4 ffect of o/erfee-in0 macronutrients on -ay.to.-ay foo- inta1e in man4 ur J &lin Nutr 1996<50%418304 &&2 release ,y intestinal cells in rat4 J Nutr Biochem 1994<5%5;8 844

6u >B4 *rotein3 ,o-y =ei0ht3 an- car-io/ascular H145I 8aniel 63 !oh=in1el 93 Rehner K4 ffect of casein anhealth4 :m J &lin Nutr 2005<82%242$;$4 ,eta.casomor+hins on H134I :oyama (3 >u1ui 23 Na1amori (3 6ashimoto 53 0astrointestinal motility in rats4 J 5amamoto (3 (a1amatsu 23 et al4 ffect of soy an- mil1 Nutr 1990<120% 252;4 =hey +rotein isolates an- their hy-rolysates on =ei0ht H146I $chus-Ciarra !3 $chic1 :3 -e re-uction in 0enetically o,ese mice4 Biosci Biotechnol la >uente :3 $+echt J3 2lier 93 Biochem 2000<64%25946004 Brantl !3 et al4 ffect of ,eta. H135I :oyama (3 >u1ui 23 (a1amatsu 23 6ashimoto 53 casomor+hins an- analo0s on 5amamoto (4 $oy +rotein isolate an- its hy-rolysate re-uce insulin release in -o0s4 ,o-y fat of -ietary o,ese rats an- 0enetically o,ese mice n-ocrinolo0y 1983<112%88594
(yello= 22)4 Nutrition 2000<16%349544

H136I

Belo,raG-ic 8*3 9c"ntosh K63 )=ens J:4 : hi0h. =hey.+rotein -iet re-uces ,o-y =ei0ht 0ain an- alters insulin sensiti/ity relati/e to re- meat in #istar rats4 J Nutr 2004<134%145484 *u+o/ac J3 :n-erson K64 8ietary +e+ti-es in-uce satiety /ia cholecysto1inin.: an- +eri+heral o+ioirece+tors in rats4 J Nutr 2002<132%2;;5804

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Baile &:3 9cJau0hlin &J3 8ella.>era 9:4 Role of cholecysto1inin an- o+ioi- +e+ti-es in control of fooH149I :CiC :3 :n-erson K64 inta1e4 *hysiol Re/ 1986<66% 1;22344 ?en-in.43 a KJ*.1 rece+tor H139I Rei-el,er0er R84 &holecysto1inin an- control of fooa0onist3 interacts =ith +roteins inta1e4 J Nutr 1994<124%132;$33$4 an- their +ro-ucts of -i0estion to su++ress foo- inta1e in rats4 J H140I Nishi (3 6ara 63 (omita >4 $oy,ean ,eta.con0lycinin Nutr 2003<133%2326304 +e+tone su++resses foo- inta1e an- 0astric em+tyin0 ,y increasin0 +lasma cholecysto1inin le/els in rats4 J Nutr H150I 6all #J3 9ill=ar- 8J3 Jon0 2003<133%352;4

$J3 9or0an J94 &asein an- =hey e?ert -ifferent effects on +lasma amino aci- +rofiles3 0astrointestinal hormone secretion an- a++etite4 Br J Nutr 2003<89%239484

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