cocoa health benefi

Copy

CURRENTOPINION Health benefits of cocoa

ionery, contrary to its medicinal use in the past.ival of talks about cocoas health beneficial effects.cently. This review discusses the recent progresses ones,un

, thts ruptiesin Evel

oa,inju

Keywordscocoa fl

INTRODUCTION

Cocoa and cocoa-baseare one of the major nnoids because of its hepicatechin, catechinand the procyanidinsresearch has become thThe cardiovascular effbeen investigated andeven found to be cost-dearth of studies dealinsuch as immune moinflammatory, neuropobesity, and so on. Tbring into the limelighknown effects and sudence of the effectssystems other than ca

EFFECTS OF CHOCOLATE ONSYSTEThe cocoa/chocolate influences muthe im

Correspondence to Dr Rabia Latif, MBBS, MPhil, PhD, Department of

1363-19

REVIEWmune system. The recent advances in this DOI:10.1097/MCO.0b013e328365a235

50 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-clinicalnutrition.comright Lippincott Williamltiple aspects of Curr Opin Clin Nutr Metab Care 2013, 16:669674

M @gmail.com, [email protected], College of Medicine, University of Dammam, Dammam,Kingdom of Saudi Arabia. Tel: +966 596 212 648; e-mail: dr.rabialatifavonoids, cognition, immune system, inflammation, insulin resistance, obesity, oxidative stress

d products such as chocolateatural sources of dietary flavo-igh content of polyphenols,

primarily and their oligomers,. Over the last decade, cocoae center of growing attention.ects of chocolate/cocoa havereviewed thoroughly [1

&

], andeffective [2

&

]; however, there isg with other beneficial effects

dulation, antioxidative, anti-rotective, insulin resistance,he aim of this review is tot these unvisited, not too well

mmarize the most recent evi-of chocolate/cocoa on bodyrdiovascular.

context are the effect of cocoa/chocolate on allergyand intestinal immune system.

ALLERGY

Allergy is characterized by dysregulated immuneresponse in atopic individuals. Various nutritionalinterventions against allergic diseases have beeninvestigated recently, coca being one of theseemerging nutraceuticals [3]. In a recent experimen-tal study of rat allergic model, cocoa diet causedconsiderably lower concentrations of total serumimmunoglobulin E (IgE), decreased tumor necrosisfactor, and interleukin (IL)-10, signifying a possible

Department of Physiology, College of Medicine, University of Dammam,Dammam, Kingdom of Saudi Arabiahyperglycemia, and insulin resistance.Purpose of reviewIn modern society, cocoa is being eaten as a confectHowever, since the last decade, there has been a revDevelopment has been made at the molecular level repotential health benefits of cocoa and/or its derivativlittle attention so far, such as the role of cocoa in immoxidative stress, obesity, and diabetes control.

Recent findingsThanks to the advancement in analytical technologiesproperly mapped providing essential information on imitochondrial biogenesis. It increases muscle glucosemuscles membrane. Because of its antioxidant propercognition and positive mood. It lowers immunoglobulimmune response and bacterial growth at intestinal lefactor-kB.

SummaryKeeping in view the pleiotropic health benefits of cocprevention/treatment of allergies, cancers, oxidativeRabia Latifs & Wilkins. Unauthorizeit may have the potential to be used for theries, inflammatory conditions, anxiety,with a focus on the areas that have been paide regulation, inflammation, neuroprotection,

e cocoas metabolic pathways have now beenoles. Cocoa helps in weight loss by improvingtake by inserting glucose transporter 4 in skeletal, cocoa offers neuron protection and enhancesrelease in allergic responses. It can affect the

s. It reduces inflammation by inhibiting nucleard reproduction of this article is prohibited.

Copyrigh

role fordisorders [4

INTESMICRO

In theToll-likintestin

(1) IL-6, a cytokine essential for the conversion ofB c

(2) chereqint

(3) gening

Cointact athe colmicrobintestin[7

&

]. Itpatternand IgnificanClostrid[8].

Thelatory(T lymin tum

immunity in autoimmune diseases and allografttransplantation) percentage [9]. This immunemodulation may be important in cancers, inflam-

onim

DA

e iay hao

momes involved in intestinal protection [10

&

].evvostigvoitis [11

&

,12]. Cocoa supplementation resultedcreieseasag

tatand ov

mse

of tproinxi

intestin2-

lat

KEY POINTS

Cocoa reduces body weight by increasingmitocmusc

Cocohype(GLU

CocototalIL-10the tr

Cocoand

Coconucle

The cimpoor fo

Functional foods and dietary supplements

670ells to IgA-secreting cells;mokine ligands and its chemokine receptors,

roidreguTINAL IMMUNE SYSTEM ANDBIOTA

gut immune system, chocolate/cocoa alterse receptors expression and downregulatesal IgA by decreasing:

systeexpooneKetoandantiot

uireestines acell

coand

on. Liotaal lresuandA-cot deium

cocT cephoors

ww&

]. Chenmencocoa flavonoids in the treatment of allergic

specdecrcocood a

arthrin in

in cancers, inflammation, diseases like celiacllergies, and autoimmune pathogenesis.matiauto

OXI

ThercocostudcocofrombyenzyHowin viinvein vi

hondrial biogenesis, capillarity, andular performance.

a protects against insulin resistance andrglycemia by inserting glucose transporter 4T4) in skeletal muscle membranes.

a causes considerably lower concentrations ofserum IgE, decreased tumor necrosis factor, and, signifying a possible role for cocoa flavonoids ineatment of allergic disorders.

a has a positive effect on mood, neural efficiency,may enhance cognition.

a reduces inflammatory potential by inhibitingar factor-kB (NF-kB).

ocoa-induced immune modulation may bertant Lippincott Williams & Wilkins. Unauthorized

d for promoting cell recruitment inal lamina propria; andssociated with gut homing of IgA-secret-s [5

&

].

procyanidins and fiber reach the colonact as a bacterial growth substrate insideong-term cocoa intake can even modifycomposition and immune response atevel [6], excellently reviewed recentlylts in a differential Toll-like receptorsa decrease in the intestinal IgA secretionating bacteria associated with a sig-

crease in the proportion of Bacteroides,, and Staphylococcus genera in the feces

oa intake also reduces helper and regu-lls and increases natural killer T cellcytes that promote cellular immunityand infections, and suppresses cellular

tion. Tuse ofintestin

NEUR

The nerecentl

MOOD

The linvasculavasculaperformto signcogniti[16]. Chocolate also reduces symptoms of anxietyand depRecent

w.co-clinicalnutrition.comreproduction of this article is prohibited.

ression in patients with chronic fatigue [17].ly, direct effects of high and low cocoa

Volume 16 Number 6 November 2013ased splenic catalase and less reactive oxygen(ROS) synthesis by macrophages [11

&

]. Thised synthesis of ROS is most likely due toflavonoids free radical quenching activity.et al. [13

&&

] suggested that catechin supple-ion significantly inhibited oxidative damageerturned the impairment of the antioxidantin the intestinal mucosa of Ketoprofen-

d rats. Cheng et al. showed that catechin,he constituents of cocoa, effectively preventsfen-induced intestinal epithelial cell injury

duces expression of heme oxygenase-1 (andant enzyme associated with protection ofes) via modulation of nuclear factor eryth-

related factor 2 (a transcription factor thates antioxidant enzymes) protein transloca-hese findings strongly support the potentialcocoa as a dietary preventive agent againstal injuries induced by oxidative stress.

OPROTECTIVE EFFECTS

uroprotective effects of cocoa have beeny reviewed by Nehlig [14

&

].

k between cocoa consumption and cardio-r health is well documented. Good cardio-r health is related to better cognitiveance [15]. Cocoa flavonols have been shown

ificantly reduce mental fatigue and improveve thinking during sustained mental efforter, the antioxidant efficacy of flavonoidsis less recognized. Two recent studies haveated the effects of cocoa supplementation

in rat models of adjuvant and autoimmune, diseases like celiac or food allergies, andmune pathogenesis.

TIVE STRESS

s a strong evidence for antioxidant effects ofin a variety of in-vitro studies. Recently, aas revealed that procyanidin flavonoids fromhave the potential to protect colonic cellsxidative stress and chemical-induced injurydulating major antioxidant/detoxificant

Copyr ize

polyphenols on cognitive performance and mood inhealthy individuals have been revealed through adouble-blind, placebo-controlled study using highlyvalidated,[18

&&

]. Cocotentednessprobably byreceptors [metabolisma calmingformancontrary to Scholey et al. [16]. Pase et al. [18 ]suggestmay oncalm fenhancparticiplevel wcognitipants w[19].

COGN

A noteMedicinlationand the23 cou

Inpotentimemorsome sthat coefficienenhanccular futhe bra

ALZHE

Alzheimcharactof amyshownof Alzhthroug[20

&&

] t

(1) Pyrtoofofredglyneuin

(2) Proteosome, a large protein complex that main-tains protein homeostasis and inhibits Abpeptide aggregation.

itn

hagie

properly mapped providing essential infor-onffe

Alzheimedne

otbedthoun,beF-bestra

OK

ceeeed

edm

neerolate consumption was assessed using a food-en

tifiwas fou

olhoonea

fedid

pasb

dery

A

aflammes

Health benefits of cocoa Latif

1363-195ight Lippincott Williams & Wilkins. Unauthor

IMERS DISEASE

ers disease is a neurodegenerative disordererized pathologically by plaques made uploid beta peptide (Ab). Cocoa has beento reduce Ab toxicity in an animal modeleimers disease by inhibiting oligomerizationh its antioxidant activity and upregulatinghe following pathways:

uvate pathway in which pyruvate changesacetyl CoA, a key substance for the synthesis

ATP and acetylcholine. Downregulationpyruvate pathway is associated with theuction of acetylcholine, ATP production,colysis, mitochondrial dysfunction, andronal death the features that are all present

Alzheimers disease [23,24].

chocto tLarssthe stifiedshowindivcomanismationinclumato

INFL

Cocoof inphag

0 2013 Wolters Kluwer Health | Lippincott Williams & WilkinsITION

recently published in New England Journal ofe reported a close, significant linear corre-between chocolate consumption per capita

number of Nobel laureates per in a total ofntries [21

&&

].another study, steady state visually evokedals measured in response to a spatial workingy task in cocoa supplemented group exhibitedignificant potential differences, suggestingcoa supplementation may improve neuralcy [22

&

]. The underlying mechanism ofed neural efficiency might be improved vas-nction and/or antioxidant processes within

in associated with cocoa intake.

BDNsugga the

STR

A rebetwin Swtigatbothplanlongchocfrequidened that improved cognition following cocoaly arise under situations of high stress and

eelings perhaps may not lead to cognitiveement. Another hypothesis was that theantswere highly educated (average educationas 16 years) and there was little scope forve enhancement as compared with partici-ho have suboptimal cognitive performance

tigatgersneuron Atreatfornervnitioalsoce wcomputerized cognitive test batterya improved self-rated calmness and con-following 30 days of treatment, mostknown actions of polyphenols on GABA

19] and by upregulating tryptophanleading to the production of serotonin:

neurotransmitter [20&&

]. Cognitive per-as not altered significantly, a finding

&&

(3) Ci

Tnolobeenmatithe ed reproduction of this article is prohibited.www.co-clinicalnutrition.com 671[12

atory mediators from peritoneal macro-], in line with the previous studiescy questionnaire and stroke cases wereed through a hospital discharge registry. Itnd that men, who ate the largest amount of

ate, had a 17% lower risk of stroke comparedse who did not consume any chocolate.et al. also conducted a meta-analysis using

rch terms chocolate and stroke and iden-ive studies. The analysis of these studiesan overall 19% decreased risk of stroke for

uals with highest chocolate consumptionred to nonchocolate consumers. The mech-responsible for this observed inverse associ-etween chocolate intake and stroke risk may

antioxidant, antiplatelet, and anti-inflam-effects of chocolate flavonoids.

MMATION

supplementation results in less secretionon its roles in Alzheimers disease. Recently,ct of cocoa polyphenolic extract on a humaners disease in-vitro model has been inves-

, which revealed that cocoa polyphenols trig-uroprotection by activating brain-derived

rophic factor (BDNF) survival pathway, bothplaque-treated cells and on Ab oligomers-cells [25

&&

]. BDNF is a neurotrophin requirede development and maintenance of thes system. It plays an important role in cog-learning, and memory formation and hasen implicated in Alzheimers disease [26].oosting neuroprotective effects in vitrothat the cocoa or its derivatives may have

peutic potential for Alzheimers disease.

E

nt study has examined the associationn chocolate consumption and risk of strokeish men [27

&

]. Previous studies have inves-this association, either in women only or inen and women [28,29]. Larsson et al. [27

&

]d a large-scale (37 103 participants) andduration (over 10 years) study in whichric acid cycle pathway that is downregulatedAlzheimers disease.

nks to the advancement in analytical tech-s, the cocoas metabolic pathways have now

Copyrigh d

documenting anti-inflammatory effects of cocoa inhealthy animals [30]. However, it [12] was unique inthe sense that it showed anti-inflammatory effectsof orally taken cocoa in a pathological state.The suggested mechanism behind cocoa-inducedreduced inflammatory potential is inhibition ofNF-kB [31

&

], which is a transcriptional modulatorof genes involved in inflammation. NF-kB plays apivotal role in the development of inflammatorydiseases and regarded as a key therapeutic target atthe moment [32]. It is present in the cell cytoplasmas an inactive form. Upon activation, it migrates tothe nucleus to modulate the transcription of theinflammatory cytokines such as tumor necrosisfactor-a (TNF-a) and adhesion molecules. Cocoaflavonoids have been shown to prevent coloninflammation in a rat model of colon cancer andin TNF-a-stimulated Caco-2 cells (a well establishedin-vitro model of human intestines), by decreasingthe nuclear levels of NF-kB and the expression ofproinflammatory enzymes such as cyclo-oxygenase-2 and inducible nitric oxide [33

&

]. Rodrguez-Ramiroet al. [10

&

,33&

] elucidated the mechanisms involvedat molecular level that turned out to be inhibition of

NF-kB translocation and c-Jun N-terminal kinases(JNK) phosphorylation. Hence, cocoa could be effec-tive in the dietary prevention of intestinal inflam-mation and related cancer development.

OBESITY, HYPERGLYCEMIA, AND INSULINRESISTANCE

Hyperglycemia and obesity are closely related toinsulin resistance and type-2 diabetes mellitus.Chocolate products are often high in sugar andfat, leading to the assumption that eating chocolateenhances BMI. However, a recent study has refutedthis belief by showing that frequency of chocolateconsumption is significantly related to lower BMIafter adjusting for age and sex [34

&&

]. This study doesnot preclude the likelihood of some chocolate pro-ducts or chocolate consumption profiles doing so.Certainly this correlation does not establish causa-tion. However, compatible experimental findings inanimal studies suggest the association could becausal [35,36] and cocoa may reduce body weightwithout changing calories or exercise by increasingmitochondrial biogenesis, capillarity, and muscular

Plasma adiponectin

Cocoa

Inhibition of lipases

B

G

FIGURE improtein k in; PGC-1a, proliferator-activated receptor ccoactiva


672t Lippincott Williams & Wilkins. Unauthorize

Absorption of dietary fat

Fecal lipid output

Body weight

Mitochondrial biogenesis

UCP and PGC-1

1. Proposed mechanism of cocoa-induced weight loss andinase a; GLUT4, glucose transporter 4; UCP, uncoupling protetor-1a.

www.co-clinicalnutrition.comreproduction of this article is prohibited.Volume 16 Number 6 November 2013Fatty acid oxidation

Lipogenesis

GLUT4

AMP-K

lood glucose Serum lipids

lucose uptake

Insulin sensitivity

proved insulin sensitivity. AMP-Ka, AMP activated

Copyr ize

performance. Underlying mechanism behindcocoa-induced increased mitochondrial biogenesisis high plasma adiponectin levels that then causeactivatin skelAMPKametabolism by translocating GLUT4 to the plasmamembrtissue;resistanthe expof protinner mand enreceptomuscleobesitythermoprevening fatmuscle

Coinhibiting the activity of pancreatic lipase andsecreted phospholipase A2 [39] leading to areductian incmechanobesitybeen su

Minobesityspecificinhibitby decdirect b

CONC

Chocohave ato or bdiseasetion/auhypergHowevstudieshumanthe heacient.beneficthat wresults

Ackno

None.

Conflicts of interest

There are no conflicts of interest.

ERD

Papers ofbeen highl

speout

opeolsndomviewor cmerss ok ofodeltudye ps thelliomidenalleril-Gcoa:60udyhav

5.&

Perez-down-

12;tudyal Igyek13; rez-munudyity ars.assoecal7:1morich12;drgnsloAPKutr

udyt comajmotenus 2udyantmovon7:5henguced inudyt gashliggnitvieweciacarscu 436.holsultsstaithyaocondro

Health benefits of cocoa Latif

1363-195ight Lippincott Williams & Wilkins. Unauthor

on in rate of body weight gain along withrease in fecal lipid output [40

&

]. Suggestedism of the role of cocoa in preventing

, hyperglycemia, and insulin resistance hasmmarized in Fig. 1.et al. [41

&

] suggested that cocoa can avertby targeting insulin receptors in a tissue-manner. Min et al. [41

&

] showed that cocoas early stage of adipogenesis in preadipocytesreasing insulin receptor kinase activity viainding.

LUSION

late/cocoa therapy or its derivatives couldrole in the prevention of, or offer a substitutee used to complement drug therapy for

s such as inflammation, immune dysregula-toimmune pathogenesis, allergies, anxiety,lycemia, obesity, and insulin resistance.er, this needs extensive interventionalevaluating the effects of cocoa products inpopulations as clinical evidence supportinglth benefits of cocoa in humans is insuffi-Most reports documenting chocolatesial effects are coming from animal researcharrants extreme care in extrapolating theto human populations.

wledgements

20First sintestin6. Ha

207.&

Peim

This stimmundisorde8. M

fa52

9. Raen20

10.&

RotraMJ N

This stproteculating11.&

RaatRe

First stantioxid12. Ra

fla10

13.&&

Cindan

First stagains14.&

Neco

This rewith sp15. De

va16. Sc

resu

17. Sachsy

0 2013 Wolters Kluwer Health | Lippincott Williams & Wilkinsane in skeletal muscle and brown adiposethus, preventing hyperglycemia and insulince. The activation of AMPKa also promotesression of uncoupling protein (UCP); a familyon transporters located in the mitochondrialembrane and causes increased thermogenesisergy expenditure and proliferator-activatedr c coactivator-1a (PGC-1a) in skeletal, adipose tissue and liver, thus preventing

by increasing energy expenditure and/orgenesis. Activation of AMPKa also helps tot obesity by inhibiting lipogenesis, stimulat-ty acid oxidation in the liver and skeletals [38].coa also inhibits dietary fat absorption by

& of&& of

1.&

Ho3-ra

This reon maj2.&

Zonerism

First seffectivand ha3. Ka

evof

4.&

Abco65

First ststudiesion of AMP-activated protein kinase (AMPKa)etal muscle, liver, and adipose tissue [37

&

].regulates intracellular glucose and lipid

REFREAd reproduction of this article is prohibited.www.co-clinicalnutrition.com 673ey AB, French SJ, Morris PJ, et al. Consumption of cocoa flavonolsin acute improvements in mood and cognitive performance during

ned mental effort. J Psychopharmacol 2010; 24:15051514.palan T, Beckett S, Rigby AS, et al. High cocoa polyphenol richlate may reduce the burden of the symptoms in chronic fatigueme. Nutr J 2010; 9:55.li C. Cerebrovascular disease: assessinglar disease. Nat Rev Cardiol 2012; 9:435ENCES AND RECOMMENDEDINGparticular interest, published within the annual period of review, haveighted as:cial intereststanding interest

r L, Kay C, Abdelhamid A, et al. Effects of chocolate, cocoa, and flavan-on cardiovascular health: a systematic review and meta-analysis ofized trials. Am J Clin Nutr 2012; 95:740751.systematically reviews the effects of chocolate, cocoa, and flavan-3-olsardiovascular disease risk factors.E, Owen A, Magliano DJ, et al. The effectiveness and cost effective-f dark chocolate consumption as prevention therapy in people at highcardiovascular disease: best case scenario analysis using a Markov. BMJ 2012; 344:e3657.to show that cocoa consumption could be an effective and cost

rimary prevention strategy for those with cardiovascular risk factorspotential to prevent adverse cardiovascular events over the long term.ki M, Antoine JM, Herz U, et al. Guidance for substantiating thece for beneficial effects of probiotics: prevention and managementrgic diseases by probiotic. J Nutr 2010; 140:S713S721.il M, Massot-Cladera M, Perez-Cano FJ, et al. A diet enriched withprevents IgE synthesis in a rat allergy model. Pharmacol Res 2012;3608.to show antiallergic effects of cocoa in rat allergic model. Previouse reported the effects of cocoa on immune status of healthy rats.Berezoa T, Franterm A, Castellote C, et al. Mechanisms involved inregulation of intestinal IgA in rats by high cocoa intake. J Nutr Biochem23:838844.to reveal the mechanism behind cocoa-induced downregulation ofA in rats.N. Chocolate, gut microbiota, and human health. Front Pharmacol4:11.Cano FJ, Massot-Cladera M, Franch A, et al. The effects of cocoa on thee system. Front Pharmacol 2013; 4:71.reviews the influence of cocoa or its flavonoids on innate and acquirednd suggests that cocoa diet may be beneficial in certain immune

t-Cladera M, Berezo TP, Franch A, et al.Cocoa modulatory effect on ratmicrobiota and colonic crosstalk. Arch Biochem Biophys 2012;

05112.s-Romero S, Perez-Cano FJ, Castellote C, et al. Effect of cocoa-ed diets on lymphocytes involved in adjuvant arthritis in rats. Br J Nutr107:378387.uez-Ramiro I, Ramos S, Bravo L, et al. Procyanidin B2 induces Nrf2cation and glutathione S-transferase P1 expression via ERKs and p38-pathways and protect human colonic cells against oxidative stress. Eur2012; 51:881892.shows that Procyanidin flavonoids from cocoa have the potential tolonic cells from oxidative stress and chemical-induced injury by mod-or antioxidant/detoxificant enzymes involved in intestinal protection.s-Romeroa S, Perez-Cano FJ, Ramiro-Puiga E, et al. Cocoa intakeates oxidative stress associated with rat adjuvant arthritis. Pharmacol012; 66:207212.to investigate the effects of cocoa supplementation on oxidant andstatus of rats with adjuvant arthritis.s-Romero S, Perez-Cano FJ, Perez-Berezo T, et al. Effect of a cocoaoid-enriched diet on experimental autoimmune arthritis. Br J Nutr 2012;23532.YT, Wu CH, Ho CY, Yen GC. Catechin protects against ketoprofen-d oxidative damage of the gastric mucosa by up-regulating Nrf2 in vitrovivo. J Nutr Biochem 2013; 24:475483.to support the potential use of cocoa as a dietary preventive agenttric/intestinal injuries induced by oxidative stress or NSAIDs.A. The neuroprotective effects of cocoa flavonol and its influence onive performance. Br J Clin Pharmacol 2012; 75:716727.focuses on the potential neuroprotective effects of cocoa flavonoidsl emphasis on brain activity, mood, and cognition.

the brain as an end-organ of

Copyrigh d

18.&&

Pase MP, Scholey AB, Pipingas A, et al.Cocoa polyphenols enhance positivemood states but not cognitive performance: a randomized, placebo-controlledtrial. J Psychopharmacol 2013; 27:451.

First randomized, controlled trial to verify the effects of cocoa polyphenols onpositive mood states in a nonclinical sample comprising healthy participants.19. Vignes M, Maurice T, Lante F, et al. Anxiolytic properties of green tea

polyphenol ()-epigallocatechin gallate (EGCG). Brain Res 2006; 1110:102115.

20.&&

Martorell P, Bataller E, Llopis S, et al. A cocoa peptide protects Caenorhab-ditis elegans from oxidative stress and b-amyloid peptide toxicity. PLoS ONE2013; 8:e63283.

In this study, a new bioactive peptide obtained from cocoa capable of reducingamyloid-b peptide toxicity in an animal model of Alzheimers disease was dis-covered.21.&&

Messerli FH. Chocolate consumption cognitive function and Nobel laureates.N Engl J Med 2012; 367:15621564.

First study to show significant linear correlation between chocolate consumptionper capita and the number of Nobel laureates in various countries.22.&

Camfield DA, Scholey A, Pipingas A, et al. Steady state visually evokedpotential (SSVEP) topography changes associated with cocoa flavanol con-sumption. Physiol Behav 2012; 105:948957.

It is a randomized, double-blind, placebo-controlled trial that shows increasedneural efficiency in spatial working memory function with chronic cocoa flavanolconsumption.23. Phelps ME, Barrio JR. Correlation of brain amyloid with aerobic glycolysis: a

question of assumptions? Proc Natl Acad Sci USA 2010; 107:1745917460.

24. Chou JL, Shenoy DV, Thomas N, et al. Early dysregulation of the mitochondrialproteome in a mouse model of Alzheimers disease. J Proteomics 2011;74:466479.

25.&&

Cimini A, Gentile R, DAngelo B, et al. Cocoa powder triggers neuro-protective and preventive effects in a human Alzheimers disease modelby modulating BDNF signaling pathway. J Cell Biochem 2013; 114:22092220.

First study to jump to cellular level in in-vitro human model of Alzheimers diseaseand established how cocoa work to protect the brain on a cellular level.26. Schindowski K, Belarbi K, Buee L. Neurotrophic factors in Alzheimers

disease: role of axonal transport. Genes Brain Behav 2008; 7:4356.27.&

Larsson SC, Virtamo J, Wolk A. Chocolate consumption and risk of stroke: aprospective cohort of men and meta-analysis. Neurology 2013; 80:11731174.

First studystroke in monly or in m28. Buijss

bloodJ 2010

29. Larsson SC, Virtamo J, Wolk A. Chocolate consumption and risk of stroke inwomen. J Am Coll Cardiol 2011; 58:18281829.

30. Castell M, Franch A, Ramos-Romero S, et al. Effect of a diet rich in cocoaflavonoids on experimental acute inflammation. In: Keller RB, editor. Flavo-noids; biosynthesis, biological effects and dietary sources, 1st ed. Haup-pauge: Nova Science Publishers, Inc.; 2009. pp. 213229.

31.&

Vazquez-Agell M, Urpi-Sarda M, Sacanella E, et al. Cocoa consumptionreduces NF-kB activation in peripheral blood mononuclear cells in humans.Nutr Metab Cardiovasc Dis 2013; 23:257263.

First in-vivo study to show inhibition of NF-kB caused by a single dose of cocoa inhealthy participants.32. Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcrip-

tion factors in the immune system. Annu Rev Immunol 2009; 27:693733.33.&

Rodrguez-Ramiro I, Ramos S, Lopez-Oliva E, et al. Cocoa polyphenolsprevent inflammation in the colon of azoxymethane-treated rats and inTNF-a-stimulated Caco-2 cells. Br J Nutr 2013; 110:206215.

First study to elucidate the molecular mechanism involved in cocoa-inducedrepression of intestinal inflammation in a rat model of colon carcinogenesis.34.&&

Golomb BA, Koperski S, White HL. Association between more frequentchocolate consumption and lower body mass index. Arch Intern Med 2012;172:519521.

This study shows that the frequency of chocolate consumption is significantlyrelated to lower BMI after adjusting for age and sex.35. Villarreal F (2010). Chocolate: an exercise mimetic? Southwest Chapter

American College of Sports Medicine Annual Meeting. San Diego, CA.36. Nogueira L, Ramirez-Sanchez I, Perkins GA, et al. ()-Epicatechin enhances

fatigue resistance and oxidative capacity in mouse muscle. J Physiol 2011;589:46154631.

37.&

Yamashitaa Y, Okabe M, Natsume M, Ashida H. Prevention mechanisms ofglucose intolerance and obesity by cacao liquor procyanidin extract in high-fatdiet-fed C57BL/6 mice. Arch Biochem Biophys 2012; 527:95104.

First study to reveal downstream signaling pathways at molecular level behindcocoa-induced amelioration of hyperglycemia, obesity, and insulin resistance.38. Viollet B, Foretz M, Guigas B, et al. Activation of AMP-activated protein kinase

in the liver: a new strategy for the management of metabolic hepatic disorders.J Physiol 2006; 574:4153.

39. Gu Y, HurstWJ, Stuart DA, Lambert JD. Inhibition of key digestive enzymes bycocoa extracts and procyanidins. J Agric Food Chem 2011; 59:53055311.

40.&

Gu Y, Yu S, Lambert JD. Dietary cocoa ameliorates obesity-related inflamma-tion in high fat-fed mice. Eur J Nutr 2013. [Epub ahead of print]udy investigated the effects of cocoa supplementation on obesity-relatedation, insulin resistance, and fatty liver disease.in SYro a:58udyocy


674t Lippincott Williams & Wilkins. Unauthorize

en. Previous studies have investigated this association; either in womenen and women both.e B, Weikert C, Drogan D, et al. Chocolate consumption in relation topressure and risk of cardiovascular disease in German adults. Eur Heart; 31:16161623.

41.&

Mvit37

This stpreadip

www.co-clinicalnutrition.comreproduction of this article is prohibited.

, Yang H, Seo SG, et al.Cocoa polyphenols suppress adipogenesis innd obesity in vivo by targeting insulin receptor. Int J Obes 2013;4592. [Epub ahead of print].gives evidence that cocoa inhibits early stage of adipogenesis intes by reducing insulin receptor kinase activity via direct binding.

Volume 16 Number 6 November 2013to report the association between chocolate consumption and risk ofThis stinflamm

cocoa health benefi

Documents