ReviewArticle Benefits of Hesperidin for Cutaneous Functionsdownloads.hindawi.com/journals/ecam/2019/2676307.pdf · 2019-07-30 · T : Continued. AnimalModels/Human Diseases/Cells

Review ArticleBenefits of Hesperidin for Cutaneous Functions

Mao-Qiang Man 12 Bin Yang 1 and Peter M Elias2

1Dermatology Hospital Southern Medical University Guangzhou 510091 China2Department of Dermatology University of California San Francisco and Veterans Affairs Medical CenterSan Francisco CA 94121 USA

Correspondence should be addressed to Mao-Qiang Man mqmanhotmailcom

Received 22 January 2019 Accepted 19 March 2019 Published 2 April 2019

Academic Editor Anderson Luiz-Ferreira

Copyright copy 2019 Mao-QiangMan et alThis is an open access article distributed under theCreativeCommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Hesperidin is a bioflavonoid with high concentration in citrus fruits In addition to its well-known benefits for cardiovascularfunction type II diabetes and anti-inflammation recent studies have demonstrated multiple benefits of hesperidin for cutaneousfunctions including wound healing UV protection anti-inflammation antimicrobial antiskin cancer and skin lightening Inaddition hesperidin enhances epidermal permeability barrier homeostasis in both normal young and aged skin The mechanismsby which hesperidin benefits cutaneous functions are attributable to its antioxidant properties inhibition of MAPK-dependentsignaling pathways and stimulation of epidermal proliferation differentiation and lipid production Because of its low cost wideavailability and superior safety hesperidin could prove useful for the management of a variety of cutaneous conditions

1 Introduction

In humans no organ has attracted as much attention as theskin does because of both cosmetic and medical concernsFor cosmetic concerns average daily costs of facial carefor an American woman can be as much as $800 [1] In2017 the sale value of skin care products exceeds $26 billionper year in China alone [2] Recent studies showed thattopical applications of certain skin care products exert avariety of benefits for both chronic and photoaged skinantimicrobials and anti-inflammation [3ndash7] Because use ofskin care products has become increasingly popular muchwork has been focused on the identification of ingredientswith multiple benefits on the skin in the development of skincare products

Because skin suffers from as many diseases as anyother organ in the body proper management of cutaneousconditions is of substantial importance Over a lifetimeeveryone will eventually suffer from some cutaneous prob-lems because the skin interfaces with the environmentmaking it more vulnerable to external physical chemicalandmicrobial stress In addition to their psychosocial impactand the quality of life for affected patients and their familiescertain chronic cutaneous disorders can also contribute tothe development of other systemic diseases For example

both psoriasis and eczematous dermatitis increase circulatinglevels of proinflammatory cytokines [8ndash10] which appear toplay a pathogenic role in the development of cardiovasculardiseases obesity type II diabetes andAlzheimerrsquos disease [11ndash14] Because of its vast size even subclinical inflammationin the skin can dramatically increase serum cytokine levelswhich could be linked to some of these age-associated disor-ders [12 15] Due to the complexity of cutaneous functionsand the potential risk of developing multiple disorders in theskin ingredients that exert multiple benefits to the skin aremuch desirable In search for these ingredients hesperidinwould appear to be a potential candidate Studies havedemonstrated that both topical and systemic administrationsof hesperidin can benefit a variety of cutaneous functions inboth normal and diseased skin In this review we compre-hensively summarize the benefits of hesperidin for cutaneousfunctions

2 Sources and Chemical Propertiesof Hesperidin

Hesperidin was first isolated from the inner portion oforange peels in 1828 Hesperidin together with other similarbioflavonoids was formerly called ldquovitamin Prdquo (reviewed

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2019 Article ID 2676307 19 pageshttpsdoiorg10115520192676307

2 Evidence-Based Complementary and Alternative Medicine

in [16]) Hesperidin is abundant in citrus fruits includinglemon orange lime and grapefruit The content of hes-peridin in citrus fruits varies greatly with species part ofthe fruit itself geographic sites of cultivation and processingprocedures (Table 1) [17ndash22] For example hesperidin contentin fresh Satsuma pulp is 73 mg per kilogram and 157 mgper kilogram in fresh peel [20] Generally hesperidin contentis higher in citrus peel than in the other parts of thecitrus fruits But lemon seeds contain more hesperidin thanpeel by methanol extraction [23] Hand-squeezed Floridaorange juice contains 335ndash351mg hesperidin per litter whileIsrael Ortanique citrus juice contains 273ndash287 mg per litter[24] Juice from pigmented citrus contains more hesperidinthan that from nonpigmented citrus [25] It is likely thatimmature citrus may contain more hesperidin than ripencitrus does [26] Pasteurization with heat did not decreasehesperidin content in citrus juice at least stored at 4∘C forup to 12 days Instead hesperidin content increases followingpasteurization of citrus juice at 90∘C for 20 seconds [27]Hesperidin content ranges from 555 to 761 mg per litterin single-strength juice and from 470 to 614 mg per litterin concentrated juice suggesting that processing procedureaffects hesperidin content in citrus juice [28] In additionto citrus fruits peppermint (Mentha x piperita L) alsocontains hesperidin whose content increases following UVBirradiation [29] Methanol extract of Porphyra dentata a rededible seaweed contains 5 hesperidin [30]

Hesperidin (357 trihydroxyflavanone 7-rhamnogluco-side C

28H34O15) is also named hesperetin 7-rutinoside or

7-O-glycoside hesperitin with a molecular weight of 61057The melting and boiling points of hesperidin are 250-255∘Cand 57616∘C respectively It is stable for at least for 2years if stored at -20∘C Although hesperidin alone barelydissolves in aqueous solution it dissolves well in bothpropylene glycol and poly(ethylene glycol)-400 [71] Reactionof hesperidin with chitooligosaccharide yields hesperidin-chitooligosaccharide complex which renders it water sol-uble and further exhibits superior antioxidant activity tohesperidin alone [72] Moreover mix of hesperidin andother flavonoids such as theaflavin-3 31015840-digallate can increasethe solubility of hesperidin in 10 dimethyl sulfoxide [73]Additionally alpha glucosyl hesperidin is also water solubleand therefore commonly used in both topical and systemicpreparations Pertinently the area under the curve for serumhesperidin in rats was over 3-fold higher following orallyadministrations of glucosyl hesperidin than hesperidin itself[74]

3 Safety

Hesperidin is generally safe for both topical and systemicadministrations Topical applications of 2 hesperidin for9 days caused no adverse cutaneous reactions in mice [32]Similarly intragastrically given Daflon-500 mg containing10 hesperidin at daily dose of 100 mg did not show signsor symptoms of side effects in rats [75] Likewise oraladministrations of diets containing either methyl hesperidin

or hesperidin did not show signs or symptoms of sideeffects in mice and rats either [76 77] Moreover no adverseevents were observed in mice followed daily intraperitonealinjections of phosphorylated hesperidin at dose of 20mgkgbody weight for over 4 weeks [78] Although one studyshowed that orally given Daflon-500 mg twice-daily for 60days caused minor temporal side effects such as headacheand faintness [79] other studies showed that oral Daflon-500mg is safe in humans [80 81]

4 Benefits of Hesperidin forCutaneous Functions

Nowadays the benefits of bioflavonoids including hes-peridin on human health have been well appreciated Alarge number of studies have demonstrated that systemicadministrations of hesperidin exhibit benefits for a vari-ety of diseases including cardiovascular diseases diabetesAlzheimerrsquos disease and cancer [82ndash88] Likewise the ben-efits of hesperidin on various cutaneous conditions have alsobeen well illustrated (Table 2)

41 Epidermal Permeability Barrier Function Epidermal per-meability barrier residing in the stratum corneum preventsmovement of agents andwater through the stratum corneumImportantly recent studies demonstrate that epidermal per-meability barrier plays crucial role in the pathogenesis of bothcutaneous and possibly systemic disorders [89ndash91] Thusskin care product makers have been striving to developproducts that can potently improve epidermal permeabilitybarrier function Because of the high incidence of adversecutaneous reactions to skin care products identification ofsafe and effective ingredients is becoming emergent [92 93]Our group has demonstrated that twice-daily applications of2 hesperidin to young mouse skin for 6 days acceleratedpermeability barrier recovery in a model of acute barrierdisruption although basal transepidermal water loss ratesstratum corneum hydration and skin surface pH remainedunchanged [31] Aged skin displays delayed permeabilitybarrier recovery and elevated skin surface pH [94 95] whichboth possibly contribute to the development of certain aging-associated disorders Regimens that can improve epidermalpermeability barrier function particularly at gene levels arelimited At least on study showed that topical applications of2 hesperidin twice-daily for 9 days markedly acceleratedpermeability barrier recovery along with significant reduc-tion in skin surface pH in aged mice [32] In addition to nor-mal skin topical hesperidin can also prevent abnormalitiesof epidermal permeability barrier induced by topical gluco-corticoid in mice For example repeated topical applicationsof glucocorticoids delayed barrier recovery But if hesperidinwas topically given following each glucocorticoid applicationto mice abnormalities in both permeability barrier recoveryand skin surface pH were normalized [33] No adversereactions were observed following topical applications ofhesperidin Taken together these studies demonstrate that

Evidence-Based Complementary and Alternative Medicine 3

Table1Hesperid

incontentincitrus

fruits

Species

GeographicS

iteof

Cultivatio

nEx

tractio

nSolvent

Peel(m

ggdried)

Ref

Cretic

ulateldquo

Erythrosardquo

Shim

enCou

ntyHun

anC

hina

Methano

l74236plusmn0845

[17]

Cretic

ulateldquo

Unshiurdquo

ChaheHub

eiC

hina

Methano

l60540plusmn0763

[17]

Cretic

ulateldquo

Unshiurdquo

Yang

shuo

Cou

ntyGuang

xiC

hina

Methano

l70232plusmn0487

[17]

Cretic

ulateldquo

Subcom

pressardquo

Yongqu

anZ

hejiang

China

Methano

l100525plusmn13

98[17]

Cretic

ulateldquo

Subcom

pressardquo

Huang

yan

Zhejiang

China

Methano

l62678plusmn0697

[17]

Cretic

ulateldquo

Chachirdquo

GujinJiang

menG

uangdo

ngC

hina

Methano

l62919plusmn0543

[17]

Cretic

ulateldquo

Chachirdquo

HuichengJiang

menG

uangdo

ngC

hina

Methano

l59012plusmn0787

[17]

Cretic

ulateldquo

Chachirdquo

LuokengJiang

menG

uangdo

ngC

hina

Methano

l74973plusmn0845

[17]

Cretic

ulateldquo

Chachirdquo

DazeJiang

menG

uangdo

ngC

hina

Methano

l54075plusmn0578

[17]

Cretic

ulateldquo

Chachirdquo

YamenJiang

menG

uangdo

ngC

hina

Methano

l88087plusmn10

62[17]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

Methano

l51921plusmn0768

[17]

Cretic

ulateldquo

Chachirdquo

Siqian

Town

Jiang

menG

uangdo

ngC

hina

Methano

l5013

7plusmn0301

[17]

Cretic

ulateldquo

Chachirdquo

GujingJiang

menG

uangdo

ngC

hina

50Metho

d37

[18]

Cretic

ulateldquo

Chachirdquo

Meijiang

Jiang

menG

uangdo

ngC

hina

50Metho

d42

[18]

Cretic

ulateldquo

Chachirdquo

WengyuanSh

aoguanG

uangdo

ngC

hina

50Metho

d79

[18]

Cretic

ulateldquo

Chachirdquo

Xiaogan

Jiang

menG

uangdo

ngC

hina

50Metho

d30

[18]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

50Metho

d53

[18]

Cretic

ulateldquo

Chachirdquo

Wengyuan

ShaoguanG

uangdo

ngC

hina

50Metho

d66

[18]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

50Metho

d46

[18]

CSinensis(linn

)Osbeck

North

ofIran

Petro

latum

etherfi

rstfollo

wed

bymethano

l

52-62

[19]

CSinensis

North

ofIran

52-61

[19]

Cretic

ulateB

lanco

North

ofIran

45-61

[19]

Cun

shiu

Marc

North

ofIran

13-58

[19]

Cun

shiu

Marc

Neretva

ValleyCr

oatia

12M

HCI

in80methano

lwater

042

[20]

Cretic

ulateB

lanco

Neretva

ValleyCr

oatia

047

[20]

lemon

juice

AdanaTu

rkey

lowast1136plusmn

110litte

r[21]

Pulpremoving

AdanaTu

rkey

lowast815plusmn127mglitter

[21]

Paste

urization

AdanaTu

rkey


[21]

lemon

Spain

lowast536plusmn234mgml

[22]

Grapefruit

Spain

lowast33plusmn3mgml

[22]

lowastCon

tent

injuice


Table2Be

nefitso

fhesperid

inon

cutaneou

sfun

ctions

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

EpidermalPerm

eabilityB

arrie

rFun

ction

Youn

gmice

Topicalapp

lications

of2

hesperidin

twice-daily

for6

days

uarrAc

uteb

arrie

rrecovery

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLamellarb

odysecretion

[31]

Agedmice

Topicalapp

lications

of2

hesperidin

twice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrDifferentiatio

nuarrLipidprod

uctio

nuarrNHE1

andsPLA

2expressio

nuarrLamellarb

odyform

ationandsecretion

[32]

Glucocorticoid-tre

ated

mice

One

hour

after

each

topicalapp

licationof

005

clobetasolpropion

ate2

hesperidin

was

applied

Treatm

entsweretwice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLipidprocessin

guarrAntioxidatio

nuarrLamellarb

odyform

ationandsecretion

uarr120573-glucocerebrosidasea

ctivity

[33]

Evidence-Based Complementary and Alternative Medicine 5Ta

ble2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Protectin

gUVIrr

adiatio

n

Keratin

ocytes

Keratin

ocytes

firsttre

ated

with

50120583M

hesperidin

for1

hrfollowed

byUVBirr

adiatio

n(30mJc

m2)

darrDNAdamage

darrlip

idperoxidatio

ndarrProteincarbon

ylation

darrAp

optotic

index

darrAb

sorb

UVB

darrRe

activ

eoxygenspecies

darrBc

l-2expressio

ndarrBA

Xexpressio

n

[34]

Keratin

ocytes

weretreated

with

hesperidin

(220120583gml)

for2

4hrfollowed

byUVA

irradiatio

n(10Jc

m2)Cells

wereincub

ated

with

hesperidin

fora

ddition

al6or

24hr

uarrCellviability

darrMDAcontent

darrTN

F-120572IL-1120573

andIL-6

mRN

ALevels

uarrSO

Dactiv

ity[35]

Keratin

ocytes

weretreated

with

hesperidin

(50100

20040

060

010

00mgL)

for2

4hrfollowed

byUVB

irradiatio

n(15mJc

m2)

darrCX

CR2expressio

nNot

determ

ined

[36]

Dermalfib

roblasts

Fibrob

lasts

irradiatedwith

UVA

atdo

se10Jc

m2and

treated

with

hesperetin

containing

extractatvarious

concentrationfor7

2hr

darrMatrix

metalloproteinase

expressio

ndarr120573-galactosid

ase

expressio

nuarrCollagenbiosynthesis

Not

determ

ined

[37]

Pretreated

fibroblastswith

3and30120583M

hesperetin

glucuron

idefollo

wed

byUVA

irradiatio

nat500kJmminus2darrNecrotic

celldeath

Not

determ

ined

[38]

Mice

Micetreated

topically

with

hesperidin

(3mgml)daily

for10days30min

after

each

applicationof

hesperidin

micew

ereirradiatedwith

180mJc

m2UVB

darrSkin

erythemaamp

edem

adarrEp

idermalproliferatio

ndarrLipidperoxidatio

ndarrInflammation

darrDNAdamage

uarrCa

talase

andsuperoxide

dism

utasea

ctivity

[39]

Micew

eretreated

topically

1hesperidin

methyl

chalcone

before

andaft

eron

eirradiatio

nwith

414

mJc

m2UVB

darrCy

tokine

expressio


n

uarrNuclear

factor

erythroid2-relatedfactor

2uarrGlutathione

peroxidase-1glutathione

redu

ctaseamp

hemeo

xygenase-1

[40]

Hesperid

inmethylchalco

neatthed

oseo

f300

mgkg

was

intraperito

neallygiven1h

rbeforea

nd7hr

after

irradiatio

nwith

414

mJc

m2UVB

darrSkin

edem

aneutroph

ilrecruitm

entand

matrix

metalloproteinase-9

activ

ity

darrCy

tokine

expressio

ndarrMyeloperoxidase

activ

ity

darrLipidperoxidatio

n

uarrGlutathione

levelsandcatalase

activ

ity

[41]

Orally

administered

01m

Lof

water

containing

100

mgkg

body

weighth

esperid

indailyw

hilemicew

ere

irradiated3tim

esat48

hintervalsp

erweekfor12

weeksD

oeso

fUVBwereincreased

60mJc

m2per

expo

sure

atweek1to90

mJc

m2atweek7

darrTransepiderm

alwater

loss

darrmatrix

metalloproteinase-9

expressio

nampactiv

ity

darrCy

tokine

expressio

ndarrwrin

kleformation

darrEp

idermalproliferatio

n

darrPh

osph

orylationof

mito

genactiv

ated

proteinkinase

ampextracellularsignal-regulated

kinases

[42]

Sing

leUVBirr

adiatio

natdo

seof

180mJc

m2

darrCy

clobu

tane

pyrim

idine

dimers

uarrp53expressio

nNot

determ

ined

[43]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne

weeklater1hesperetin

was

topically

applieddaily

totheh

yperpigm

entedareas(2mgcm2)for

4successiv

eweeks

darrTransepiderm

alwater

loss

Not

determ

ined

[44]

Pigm

entatio

n

B16mou

semelanom

acells

Cellsincubatedwith

20120583gmLof

Citru

sextractso

r3-50120583M

ofhesperetin

for4

8hr

uarrMela

nincontent

uarrTy

rosin

asep

rotein

uarrTy

rosin

asea

ctivity

uarrMela

nogenesis

-rela

tedproteins

uarr120573-C

atenin

expressio

nuarrPh

osph

orylated

glycogen

synthase

kinase-3120573

[4546

]

Cellsincub

ated

with

hesperidin

(3225mgmL)

for3

days

Minim

uminhibitio

nof

melanogenesis

Not

determ

ined

[4748]

Cellsw

eretreated

with

hesperidin

(5010020040

060

01000mgL)

for2

4hrfollowed

byUVBirr

adiatio

n(15mJc

m2)

darrTy

rosin

asea

ctivity

darrMela

nincontent

Not

determ

ined

[36]

Cellsincubatedwith

5-20120583M

hesperidin

for3

days

uarrMela

nincontent

Not

determ

ined

[49]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

darrTy

rosin

ase-related

protein12

darrMela

nogenesis

-rela

tedproteins

uarrp-Erk12

uarrProteasomea

ctivity

[50]

Cellsincubatedwith

Citru

sextracts(125250and500

120583gmL)

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

ampactiv

ity

darrTy

rosin

ase-related

protein12

darrMicroph

thalmia-associatedtranscrip

tionfactor

(MITF)

proteins

[51]

Hum

anepidermal

melanocytes

Cellsincubatedwith

3-50120583M

ofhesperetin

for4

8hruarrMela

nincontent

uarrTy

rosin

asea

ctivity

Not

determ

ined

[46]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asea

ctivity

Not

determ

ined

[50]

Cellsincubatedwith

04m

gmlC

itrus

extractsfor3

daysdarrTy

rosin

asea

ctivity

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure

uarrCollagensynthesis

[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep

atientsreceivedDaflon

500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim

edarrHospitalizationdu

ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN

F-120572proteinampmRN

A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin

priortocarrageenanor

dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof

125120583lof1hesperidin

solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim

ethylbenz[a]anthraceneT

PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2


topical hesperidin improves epidermal permeability bar-rier function in both normal and glucocorticoid-disruptedskin

42 UV-Induced Cutaneous Damage Because the skin is theoutermost layer of the body it is more vulnerable to ultravio-let (UV) irradiation leading to the development of photoag-ing and other cutaneous disorders such as actinic keratosisand skin cancers [96 97] Thus protection against UVirradiation can prevent andor mitigate UV-induced cuta-neous damage Study showed that treatment of keratinocyteswith 50 120583M hesperidin could cause over 70 reduction inapoptotic index induced by UVB irradiation in comparisonto vehicle-treated keratinocytes [34] In addition to UVBhesperidin can also protect keratinocytes fromUVA-induceddamage Li et al [35] reported that treatment of keratinocyteswith hesperidin for 24 hr induced a dose-dependent increasein viability of UVA-irradiated keratinocytes Pretreatmentof keratinocytes with hesperidin at a dose of 220 120583gmlalso significantly reduced UVA-induced oxidative stress andexpression levels of proinflammatory cytokines These dataindicate that hesperidin protects keratinocytes from bothUVA- and UVB-induced damage

The wavelength of UVA is 320-400 nm which canpenetrate into the dermis leading to premature skin aging(photoaging) upon repeated exposure It appears that hes-peridin can also attenuate UVA-induced damage to fibrob-lasts Because hesperidin is hydrolyzed to hesperetin bythe gut microbiota and absorbed by passive transportin the large intestine [36] some studies use hesperetininstead of hesperidin Bae et al [37] reported that treat-ment of UVA-irradiated human fibroblasts with 01 Citrusunshiu peel extract containing hesperetin (metabolite ofhesperidin) decreased expression levels of 120573-galactosidasematrix metalloproteinase-1 and the number of senescentcells Moreover pretreatment of human fibroblasts withhesperetin glucuronides induced a 25 protection againstUV-A-induced necrotic cell death [38]

Hesperidin not only protects cells against UV-induceddamage in vitro but also protects the skin from UV-induced damage in vivo Pretreatment of mouse skin withtopical hesperidin could prevent UVB-induced elevationsin cutaneous cytokine expression and lipid peroxidationwhile increasing expression levels of antioxidant enzymessuch as glutathione peroxidase-1 glutathione reductase andheme oxygenase-1 in mouse skin following either singleor multiple UVB irradiation [39 40] In addition topicalapplications of hesperidin also markedly prevented UVBirradiation-induced erythema edema and epidermal pro-liferation [39] Moreover intraperitoneal administrations ofhesperidin methyl chalcone can prevent UVB irradiation-induced reductions in antioxidant capacity and elevationsin both cutaneous cytokine expression and myeloperoxidaseactivity [41] Lee et al [42] reported that daily drinkingwater containing hesperidin attenuated a number cutaneousabnormalities induced by repeated UVB irradiation includ-ing compromised epidermal permeability barrier promotedwrinkle formation increased cytokine expression and both

expression levels and activity of matrix metalloproteinase-9Furthermore pretreatment of mice with topical hesperidincould enhance repair of DNA damage induced by UVBirradiation [43] Finally topical hesperetin lowered transepi-dermal water loss by asymp50 in guinea pigs subjected torepeated UVB irradiation [44] Collectively either topicalor oral administrations of hesperidin can protect skin fromdamage induced by both UVA and UVB irradiation

43 Melanogenesis For beauty concern skin whitening isvery popular particularly in Asia Hesperidin has long beenused as a skin whitening agent although the results of itseffects on melanogenesis are controversy Study showed thattreatment of murine B16-F10 melanoma cells with 20 120583gmLcitrus extract (containing 3623 plusmn 167 120583gmL hesperetin)induced onefold increase in melanin content while hes-peridin alone also increased melanin content by over 20[45] Likewise 50120583M hesperetin increased melanin contentby over 80 in murine B16-F10 melanoma cells [46] Incontrast other studies demonstrated that hesperidin did notaffect melanin production in B16F10 murine melanoma cells[47ndash49] However most of other studies showed that bothcitrus extract and hesperidin inhibitedmelanogenesis in bothmurine B16-F10melanoma cells and humanmelanocytes [3644 50ndash53] For example treatments with 50120583M hesperidinfor 48-72 hr induced 60 reduction in melanin contentin murine B16-F10 melanoma cells and asymp30 reductionin human melanocytes [50] Topical applications of 02hesperidin to reconstructed human epidermis for 14 daysreduced pigment by asymp25 [49] In addition topical appli-cations of hesperetin a metabolite of hesperidin lightenedskin in UVB-induced hyperpigmentation [44] Thus topicalapplications of hesperidin and its metabolite can reduceepidermal pigmentation in both normal andUVB challengedskin

44 Cutaneous Wound Healing Cutaneous wounds are verycommon while management of cutaneous wounds is still achallenge particularly in certain conditions such as diabeticand venous wounds A number of studies have demonstratedthat hesperidin accelerated wound healing both in vitro andin vivo Wessels et al [54] reported that addition of a culturemedium containing 005 hesperidin for 24 hr acceleratedwound closure by 39 in comparison to vehicle controlin in vitro scratch models In diabetic rats wound almostcompletely healed (97) following orally given hesperidin(100 mgkg body weight) for 21 days while the wounddid not close at all in the vehicle-treated controls [55]In diabetic rats the benefits of oral hesperidin on woundhealing and other biomarkers including serum glucose andglycated hemoglobin were comparable to insulin treatments[56] Besides diabetic wound treatment of wound in venousinsufficient subjects is also troublesome Although woundhealing times were similar in patients treated with oraldiosminhesperidin (45050 mg) and with pycnogenol [57]more patientswere completely healed in diosminhesperidin-treated group than in placebo controls (32 versus 13)after 2-month treatment [58] Moreover either topical or


oral administrations of hesperidin shortened wound heal-ing time asymp3 days in 120574 ray-irradiated mice [59 60] Thesedata demonstrate that either topically or orally given hes-peridin can accelerate cutaneous healing under various con-ditions

45 Inflammation Benefits of flavonoids on both systemicand local inflammation have been demonstrated [98 99]Because nitric oxide is an inflammatory mediator it is oftenused as a biomarker to evaluate inflammatory response Invitro study demonstrated that treatment ofmouse RAW2647cells with lipopolysaccharide (LPS) for 24 hr induced over9-fold increase in nitrite levels But addition of hesperidin(250 120583gml) to culture medium lowered nitrite levels byasymp75 in LPS-treated cells [30] Yang et al [61] performeda similar study using hesperetin and its metabolites Theresults showed that stimulation of RAW 2647 cells withLPS markedly increased in both nitric oxide and induciblenitric oxide synthase mRNA levels which both significantlydecreased by coincubation of RAW 2647 cells with LPS and10 120583Mhesperetin metabolite Interestingly hesperetin only atlower dose (1120583M) lowered nitric oxide and inducible nitricoxide synthase mRNA levels but hesperetin at dose of 10 120583Mhad no effect

The skin serves as the first line of defense against to exter-nal stimuli Keratinocytes can produce and release proin-flammatory cytokines upon stimulation [90] Hesperidincan lower cytokine production in keratinocyte cultures Forinstance prior to challenge with H

2O2(100 120583M) treat-

ment of keratinocytes with hesperidin (20 120583gml) for 2hr could inhibit IL-8 and TNF120572 production by 96 and78 respectively [62] Expression levels of cyclooxygenase-2 (COX-2) protein and mRNA also significantly decreasedin keratinocytes cotreated with hesperidin versus treatedwith alone H

2O2 Evidence indicates that hesperidin can

inhibit bacterial pathogen-induced cytokine production tooIncubation of keratinocytes with both Propionibacteriumacnes and 5-5 120583gmL of hesperidin for 24 hr inhibitedIL-8 and TNF120572 production by 49 and 71 respectivelywhich were comparable to the levels inhibited by dexametha-sone treatment [63] Moreover pretreatment of hesperidinmethyl chalcone (02 mgml) also dramatically decreasedthe proportion of dilated vessels (48 inhibition) totalvessel area (72 inhibition) and IL-8 production (79inhibition) in human skin explants following stimulationwith substance P [64] Thirty minutes prior to subcuta-neous injection of carrageenan (1) subcutaneous injectionof hesperidin at doses of 50 and 100 mgkg reduced thepaw edema by 47 and 63 respectively within 5 hr [65]Hesperidin at dose of 100 mgkg also decreased dextran-induced edema by 33 The efficacy of hesperidin on edemawas comparable to that produced by oral indomethacin (10mgkg) However hesperidin did not prevent histamine-induced paw edema Pelzer et al [66] reported that intraperi-toneal injection of hesperidin could also inhibit carrageenan-induced paw edema by 36 to 40 within 7 hr One hourprior to edema induction with carrageenan on the paw

oral administration of hesperidin (40 mgkg body weight)could decrease the edema by 50 51 63 and 77 respectively while indomethacin (10mgkg) decreased theedema by 65 71 72 and 74 respectively after 1 2 3and 4 hours [67] These results indicate that hesperidin canprevent and treat cutaneous inflammation induced by variousagents

46 Cutaneous Cancers In addition to the preventive andtherapeutic benefits for other cancers [100 101] studiesshowed that hesperidin and its metabolite also benefit cuta-neous cancers Smina et al [68] showed that treatment ofA431 cells with hesperetin at as low as 10 120583M inducedDNA fragmentation along with significant increase in Baxan apoptotic protein expression while reducing expressionlevels of cyclin B1 D1 D3 and E1 proteins by over 1-foldA similar study also demonstrated that incubation of A431cells with 10 120583M hesperidin induced over 10-fold increase inapoptosis and DNA damage [69] In vivo study demonstratedthat hesperidin can prevent the development of skin tumorFor example daily subcutaneous injection of 125 120583l of 1hesperidin 1 week prior to induction of skin tumor bytopical 12-O-Tetradecanoylphorbol-13-acetate (TPA) resultedin reductions in tumor incidence by 50 and the numberof papillomas per mouse by 48 after 20 weeks of TPAapplications [70] Thus hesperidin could be an alternativeregimen for preventing and treating cutaneous cancers

47 Other Cutaneous Functions Evidence also indicates ben-efits of hesperidin on other cutaneous functions Orally givenhesperidin 30 min prior to irradiation with 120574 ray upregulatedexpression levels of mRNA for vascular endothelial growthfactor by over 25 folds [102] Hesperidin exhibited antimi-crobial activity including the common pathogens in thecutaneous infections such as Staphylococcus aureus Candidaalbicans Candida tropicalis and Streptococcus pyogenes withthe minimum inhibitory concentration of 825 for bothCandida albicans and Staphylococcus aureus [103ndash106] Aclinical trial on humans showed that orally given hesperidin(500mgdaily) for 28 daysmarkedly reduced facial roughnessand 33 reduction in beta-galactosidase a biomarker ofaging by 6 months [107]

5 Mechanisms

Although a line of evidence shows that hesperidin benefits anumber of cutaneous functions the underlying mechanismsby which hesperidin acts are unclear yet It appears thathesperidin and its metabolite act via a variety of mechanismsdepending on which function regulated by hesperidin

51 Improvements in Epidermal Permeability Barrier FunctionFormation of epidermal permeability barrier is highly reg-ulated by multiple keratinocyte functions including prolif-eration differentiation lipid production acidification andantimicrobial peptide expression [108] In young micetopical hesperidin mainly upregulated expression levels offilaggrin and stimulated keratinocyte proliferation [31] while


in aged mice topical hesperidin upregulated expressionlevels of a whole panel of mRNA associated with epi-dermal permeability barrier including sodiumhydrogenexchanger (NHE1) secretory phospholipase A2 (sPLA2)differentiation-related proteins (filaggrin involucrin andloricrin) lipid synthetic enzymes (fatty acid synthase 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase) and lipidtransport protein (ATP-binding cassette subfamily A mem-ber 12) [32] However in glucocorticoid-treated mouse epi-dermis topical hesperidin dramatically increased filaggrinprotein and glutathione reductase mRNA expression 120573-glucocerebrosidase activity and epidermal proliferation [33]Thus the underlying mechanisms by which topical hes-peridin improves epidermal permeability barrier functioncould be attributable to upregulation of these functionsdepending on the skin conditions

52 Protection against UV Irradiation UV irradiation causesskin damage mainly in three aspects ie oxidative stressDNA fragmentation and inflammation Nuclear factor ery-throid 2-related factor 2 (Nrf2) is a mast regulator ofantioxidant system in the cells [109 110] Nrf2 deficiencyaccelerated UV irradiation-induced photoaging and inflam-mation [111 112] while activation Nrf2 can protect UVirradiation-induced apoptosis and inflammation [113 114]In addition to upregulation of Nrf2 expression in the senes-cent rat heart [115] methylhesperidin methylated derivativeof hesperidin enhanced translocation of Nrf2 from cyto-plasm to nuclear resulting in upregulation of antioxidant-related gene expression and reduction in reactive oxygenspecies consequently leading to protection of epidermalkeratinocytes against UVB-induced damage in keratinocytecultures [116] Hesperidin-induced reductions in DNA dam-age and cytokine expression appear to be due to decreasedoxidative stress in UV-irradiated keratinocytes [34 35]Moreover hesperidin inhibited UVB irradiation-inducedincrease in expression levels of phosphorylation of mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK) in mice [42] Hence UV protectionof hesperidin can be primarily due to upregulation of antiox-idant and downregulation of MAPKERK signaling pathway

53 Melanogenesis Skin pigmentation is determined byboth melanogenesis and melanosome transport Proteinsinvolved in melanogenesis include tyrosinase tyrosinase-related proteins (TRP) and microphthalmia-associated tran-scription factor (MITF) Upregulation of expression levelsof tyrosinase TRPs and MITF can increase melanin pro-duction [117 118] A number of studies demonstrated thathesperidin decreased expression levels and activity of tyrosi-nase TRPs and MITF in both B16 mouse melanoma cellsand human melanocytes [36 50ndash52] Moreover hesperidincould activate 120572 adrenergic receptor leading to inductionof aggregation of melanophores in B melanostictus sug-gesting that hesperidin-induced skin lightening is mediatedby adrenergic receptor [119] Another mechanism wherebyhesperidin lightens skin could be attributable to inhibition ofmelanosome transport in melanocytes instead of inhibition

ofmelanogenesis [49]Therefore hesperidin lightens skin viainhibition of bothmelanogenesis andmelanosome transport

54 Acceleration of Cutaneous Wound Healing Wound heal-ing is involved in cell proliferation and migration and vascu-lar formation Activation of tumor growth factor beta (TGF-120573) signaling and vascular endothelial growth factor (VEGF)expression are crucial for wound healing and restorationof epidermal permeability barrier function [120ndash123] Studyshowed that oral administration of hesperidin (50 mgkgbody weight) increased TGF-120573 and VEGF-c mRNA expres-sion by over 2-fold in a diabetic model of Sprague Dawleyrats [55] Additionally expression levels of mRNA for VEGFreceptors also increased following oral administrations ofhesperidin at a dose of 50 mgkg body weight [56] Oxidativestress can impede wound healing in both diabetic andnormal conditions while antioxidants can improve woundhealing [124ndash126] In diabetic rats orally given hesperidinsignificantly increased cutaneous SOD and GSH contentwhile reducingMDAcontent alongwith acceleration of cuta-neous wound healing indicating the antioxidant propertyof hesperidin contributes to its acceleration of cutaneoushealing [55 56]

Inflammatory response is required for wound healing inearly phase Topical applications of cytokines such as recom-binant human granulocyte-macrophage colony-stimulatingfactor accelerated cutaneous wound healing [127ndash129] How-ever excessive inflammation can delay wound healing andpotentially cause scar formation [130] Accordingly anti-inflammation could accelerate cutaneous wound healing [131132] Hesperidin decreased cytokine expression includingTNF120572 IL-6 and IL-8 in both rat skin and human ker-atinocyte cultures [56 62 63] Taken together hesperidin-induced acceleration of cutaneous wound healing can beattributable to upregulating expression of VEGF antioxidantenzymes and anti-inflammation

55 Attenuation of Inflammation Development of inflamma-tion is a complex process involving interactions of a numberof molecules in various signaling pathways including p38mitogen-activated protein kinase (MAPK) pathway [133]Inhibition of p38 MAPK signaling pathway can markedlylower expression of IL-1120573 and IL-6 IL-8 IL-18 and TNF120572 inboth macrophage culture and mice [134 135] Study showedthat prior to H

2O2stimulation treatment of keratinocytes

with hesperidin for 2 hr induced over 50 reduction inNF-120581B and phosphorylated p38 MAPK in comparison withthose without pretreatment with hesperidin [62] Likewisetreatment ofmouse RAW2647 cells with hesperetinmetabo-lite almost completely reversed lipopolysaccharide-inducedincrease in NF-120581B expression in addition to reductions inphosphorylated p38 MAPK and c-Jun N-terminal kinase12 [61] Thus hesperidin-induced inhibition of p38 MAPKsignaling pathway could contribute its attenuation of inflam-mation

56 Treatment of Cutaneous Cancers Although studies havedemonstrated that hesperidin and its metabolite exerted


anticancer property both in vitro an in vivo [68ndash70] theunderlying mechanisms are inconclusive Zhao et al [69]showed that treatment of A431 human skin carcinoma cellswith hesperidin (25120583M) for 72 hr induced over 1-fold increasein reactive oxygen species 40 reduction in intercellularATP content and 80 reduction in SOD content Using othercell lines it has been demonstrated hesperidin can induceendoplasmic reticulum stress and activate caspase-9 caspase-8 and caspase-3 activities [136ndash138] Moreover TGF120573-Smadsignaling pathway particularly Smad3 plays a key role inthe development of certain cancers [139 140] Previous studyrevealed that oral administrations of hesperidin (100 mgkgbody weight) for 18 weeks inhibited TGF120573-Smad3 signalingand prevented development of hepatic cancer [141] Further-more several studies have demonstrated that reduction inthe formation of micronucleus could contribute to the anti-cancer properties of hesperidin at least in models of somechemically induced cancers Hesperidin-induced protectionin 120574 ray-induced DNA damage could also be attributableto the reduction in the formation of micronucleus Addi-tionally hesperidin can increase apoptosis of cancer cells viaupregulation of peroxisome proliferator-activated receptor 120574expression

Signaling pathways involved in the action of anti-cancers induced by hesperidin include (a) inhibition ofJanus kinasesignal transducer and activator of transcription(JAKSTAT) pathway activation of which can enhance pro-liferation invasion and metastasis of cancer cells (b) inhi-bition of phosphatidylinositol-3-kinase (PI3K)Akt and themammalian target of rapamycin (mTOR) pathways whichalso play crucial role in proliferation survivability invasionand metastasis of cancer cells upon activation (c) activationof Notch pathway in which activation of Notch receptorsleads to translocation of Notch into nucleus and binding totarget genes resulting in increased apoptosis [142] Of courseother signaling pathways such as MAPK-ERKWingless andINT-1NF-120581B and cyclooxygenase-2 pathways have also beenproposed to be involved in hesperidin-induced preventionand inhibition of cancers [142] Therefore anticancer benefitof hesperidin is likely via multiple mechanisms includinginhibition of TGF120573-Smad3 PI3KAkt and JAKSTAT signal-ing pathways activation of Notch pathway reduction in ATPcontent and induction of apoptosis

57 Antioxidation Oxidative stress has been linked to thedevelopment of a variety of disorders [143 144] As men-tioned above Nrf2 is a key regulator of antioxidant system[109 110] In normal condition Nrf2 is present as Nrf2Keap1complex in the cytoplasm and degraded in proteasome Uponoxidative stress Nrf2 is separated from Keap1 and enters intonucleus whereNrf2 can bind to antioxidant response element(ARE) within gene promoter region leading activation ofgene transcription including reactive oxygen scavengingenzymes such as superoxide dismutase glutathione perox-idase glutathione reductase catalase and heme oxygenase1 [109 145] which all play crucial role in protecting cellsfrom oxidative stress Previous studies have shown thathesperidin and its metabolite hesperitin can increased Nrf2expression while stimulating degradation of Keap1 resulting

in an increase in nuclear translocation ofNrf2 andproductionof antioxidant enzymes along with reduction in oxidation[109 146ndash148] Thus antioxidant property of hesperidin alsolargely accounts for its benefits in the skin

In conclusions either topical or systemic administrationsof hesperidin appear to benefit multiple cutaneous functionsvia divergent mechanisms Taking citrus juice or otherhesperidin-containing products likely could benefit cuta-neous functions However proper clinical trials are requiredto validate the benefits of hesperidin for various cutaneousconditions

Abbreviations

VEGF Vascular endothelia growth factorSOD Superoxide dismutaseGSH Reduced glutathioneMDA MalondialdehydeTGF-120573 Transform growth factor 120573MAPK Mitogen-activated protein kinases

Conflicts of Interest

All authors declare no conflicts of interest

Authorsrsquo Contributions

Mao-QiangMan originated the concept and literature searchand wrote the draft Bin Yang and Peter M Elias criticallyreviewed the manuscript

Acknowledgments

This work was supported in part by the NIH grantAR061106 administered by the Northern California Insti-tute for Research and Education with resources from theResearch Service Department of Veterans Affairs

References

[1] S Johnson How much is your face worth American womenaverage at $8 per day 2018httpswwwhuffingtonpostcomentryhow-much-is-your-face-worth-american-women-average us58befa65e4b06660f479e594

[2] ldquoMarket status of skin care products in Chinardquohttpchina-trade-researchhktdccombusiness-newsarticle中国消费市场中国化妆品市场概况ccmsc11X0000001X002L09htm (obtained on December 9th 2018)

[3] M Milani and A Sparavigna ldquoAntiaging efficacy of melatonin-based day and night creams A randomized split-face assessor-blinded proof-of-concept trialrdquo Clinical Cosmetic and Investi-gational Dermatology vol 11 pp 51ndash57 2018

[4] S J Choi S Lee K Kim et al ldquoBiological effects of rutin on skinagingrdquo International Journal of Molecular Medicine vol 38 no1 pp 357ndash363 2016

[5] A Sethi T Kaur S K Malhotra and M L Gambhir ldquoMoistur-izers The slippery roadrdquo Indian Journal of Dermatology vol 61no 3 pp 279ndash287 2016


[6] M Liu X Li X-Y Chen F Xue and J Zheng ldquoTopical applica-tion of a linoleic acid-ceramide containing moisturizer exhibittherapeutic and preventive benefits for psoriasis vulgaris arandomized controlled trialrdquoDermatologicTherapy vol 28 no6 pp 373ndash382 2015

[7] M Zasada R Debowska M Pasikowska and E Budzisz ldquoTheassessment of the effect of a cosmetic product brightening theskin of people with discolorations of different etiologyrdquo Journalof Cosmetic Dermatology vol 15 no 4 pp 493ndash502 2016

[8] S M Solberg L F Sandvik M Eidsheim R Jonsson Y TBryceson and S Appel ldquoSerum cytokine measurements andbiological therapy of psoriasis - Prospects for personalizedtreatmentrdquo Scandinavian Journal of Immunology vol 88 Arti-cle ID e12725 2018

[9] P M Brunner M Suarez-Farinas H He et al ldquoThe atopic der-matitis blood signature is characterized by increases in inflam-matory and cardiovascular risk proteinsrdquo Scientific Reports vol7 no 1 Article ID 8707 2017

[10] E Vakirlis E Lazaridou T G Tzellos S Gerou D Chatzidim-itriou and D Ioannides ldquoInvestigation of cytokine levels andtheir association with SCORAD index in adults with acuteatopic dermatitisrdquo Journal of the European Academy of Derma-tology and Venereology vol 25 no 4 pp 409ndash416 2011

[11] C S Souza C C de Castro F R Carneiro et al ldquoMetabolicsyndrome and psoriatic arthritis among patients with psoriasisvulgaris Quality of life and prevalencerdquoThe Journal of Derma-tology vol 46 no 1 pp 3ndash10 2019

[12] C Franceschi and J Campisi ldquoChronic inflammation (inflam-maging) and its potential contribution to age-associated dis-easesrdquo The Journals of Gerontology Series A Biological Sciencesand Medical Sciences vol 69 supplement 1 pp s4ndashs9 2014

[13] A Mishra and R D Brinton ldquoInflammation bridging agemenopause and APOE1205764 genotype to alzheimerrsquos diseaserdquoFrontiers in Aging Neuroscience vol 10 p 312 2018

[14] M S Ellulu I Patimah H Khazarsquoai A Rahmat and Y AbedldquoObesity and inflammation the linking mechanism and thecomplicationsrdquo Archives of Medical Science vol 4 pp 851ndash8632017

[15] M Atienza J Ziontz and J L Cantero ldquoLow-grade inflam-mation in the relationship between sleep disruption dysfunc-tional adiposity and cognitive decline in agingrdquo Sleep MedicineReviews vol 42 pp 171ndash183 2018

[16] A Garg S Garg L J D Zaneveld and A K Singla ldquoChemistryand pharmacology of the Citrus bioflavonoid hesperidinrdquoPhytotherapy Research vol 15 no 8 pp 655ndash669 2001

[17] E-H Liu P Zhao L Duan et al ldquoSimultaneous determinationof six bioactive flavonoids in Citri Reticulatae Pericarpium byrapid resolution liquid chromatography coupled with triplequadrupole electrospray tandem mass spectrometryrdquo FoodChemistry vol 141 no 4 pp 3977ndash3983 2013

[18] X Ye F Song G Fan and F Wu ldquoSimultaneous deter-mination of 11 constituents in Citrus reticulate rsquoChachirsquo byhigh performance liquid chromatographyrdquo Chinese Journal ofChromatography vol 33 no 4 pp 423ndash427 2015

[19] R Omidbaigi and N M Faghih ldquoQuantitative distributionof hesperidin in Citrus species during fruit maturation andoptimal harvest timerdquo Natural Product Radiance vol 4 pp 12ndash15 2004

[20] B Levaj D-U Verica D B Kovacevic and N KrasnicildquoDetermination of flavonoids in pulp and peel of mandarinfruitsrdquo Agriculturae Conspectus Scientificus vol 74 no 3 pp221ndash225 2009

[21] E Agcam A Akyıldız and G A Evrendilek ldquoComparisonof phenolic compounds of orange juice processed by pulsedelectric fields (PEF) and conventional thermal pasteurisationrdquoFood Chemistry vol 143 pp 354ndash361 2014

[22] B Abad-Garcıa L A Berrueta S Garmon-Lobato A UrkaregiB Gallo and F Vicente ldquoChemometric characterization offruit juices from spanish cultivars according to their phenoliccompound contents I Citrus fruitsrdquo Journal of Agricultural andFood Chemistry vol 60 no 14 pp 3635ndash3644 2012

[23] A Bocco M-E Cuvelier H Richard and C Berset ldquoAntioxi-dant activity and phenolic composition of citrus peel and seedextractsrdquo Journal of Agricultural and Food Chemistry vol 46no 6 pp 2123ndash2129 1998

[24] P Mouly E M Gaydou and A Auffray ldquoSimultaneous sepa-ration of flavanone glycosides and polymethoxylated flavonesin citrus juices using liquid chromatographyrdquo Journal of Chro-matography A vol 800 no 2 pp 171ndash179 1998

[25] A R Proteggente A Saija A De Pasquale and C A Rice-Evans ldquoThe compositional characterisation and antioxidantactivity of fresh juices from sicilian sweet orange (Citrussinensis L Osbeck) varietiesrdquo Free Radical Research vol 37 no6 pp 681ndash687 2003

[26] D Barreca E Bellocco C Caristi U G O Leuzzi and GGattuso ldquoFlavonoid composition and antioxidant activity ofjuices from chinotto (Citrus x myrtifolia Raf) fruits at differentripening stagesrdquo Journal of Agricultural and FoodChemistry vol58 no 5 pp 3031ndash3036 2010

[27] F Ucan E Agcam and A Akyildiz ldquoBioactive compounds andquality parameters of natural cloudy lemon juicesrdquo Journal ofFood Science and Technology vol 53 no 3 pp 1465ndash1474 2016

[28] U Leuzzi C Caristi V Panzera and G Licandro ldquoFlavonoidsin pigmented orange juice and second-pressure extractsrdquo Jour-nal of Agricultural and Food Chemistry vol 48 no 11 pp 5501ndash5506 2000

[29] Y Dolzhenko C M Bertea A Occhipinti S Bossi and ME Maffei ldquoUV-B modulates the interplay between terpenoidsand flavonoids in peppermint (Menthatimespiperita L)rdquo Journal ofPhotochemistry and Photobiology B Biology vol 100 no 2 pp67ndash75 2010

[30] K Kazłowska T Hsu C-C Hou W-C Yang and G-J TsaildquoAnti-inflammatory properties of phenolic compounds andcrude extract from Porphyra dentatardquo Journal of Ethnopharma-cology vol 128 no 1 pp 123ndash130 2010

[31] M Hou M Man W Man et al ldquoTopical hesperidin improvesepidermal permeability barrier function and epidermal differ-entiation in normal murine skinrdquo Experimental Dermatologyvol 21 no 5 pp 337ndash340 2012

[32] G Man T M Mauro Y Zhai et al ldquoTopical hesperidinenhances epidermal function in an agedmurinemodelrdquo Journalof Investigative Dermatology vol 135 no 4 pp 1184ndash1187 2015

[33] G Man T M Mauro P L Kim et al ldquoTopical hesperidinprevents glucocorticoid-induced abnormalities in epidermalbarrier function in murine skinrdquo Experimental Dermatologyvol 23 no 9 pp 645ndash651 2014

[34] S R Hewage M J Piao K A Kang et al ldquoHesperidin atten-uates ultraviolet b-induced apoptosis by mitigating oxidativestress in human keratinocytesrdquo Biomolecules amp Therapeuticsvol 24 no 3 pp 312ndash319 2016

[35] M Li X-F Lin J Lu B-R Zhou and D Luo ldquoHesperidinameliorates UV radiation-induced skin damage by abrogationof oxidative stress and inflammatory in HaCaT cellsrdquo Journal of


Photochemistry and Photobiology B Biology vol 165 pp 240ndash245 2016

[36] R Z Zhang W Y Zhu F Xie X S Ge and H L JinldquoEffect of hesperidin on B16 and HaCaT cell lines irradiated bynarrowband-UVB lightrdquo Journal of Clinical Dermatology vol37 pp 146ndash149 2008

[37] J T Bae H J Ko G B Kim H B Pyo and G S LeeldquoProtective effects of fermented citrus unshiu peel extractagainst ultraviolet-a-induced photoageing in human dermalfibrobolastsrdquo Phytotherapy Research vol 26 no 12 pp 1851ndash1856 2012

[38] A R Proteggente S Basu-Modak G Kuhnle et al ldquoHesperetinglucuronide a photoprotective agent arising from flavonoidmetabolism in human skin fibroblastsrdquo Photochemistry andPhotobiology vol 78 no 3 pp 256ndash261 2003

[39] A Petrova L M Davids F Rautenbach and J L MarnewickldquoPhotoprotection by honeybush extracts hesperidin andmangiferin against UVB-induced skin damage in SKH-1 micerdquoJournal of Photochemistry and Photobiology B Biology vol 103no 2 pp 126ndash139 2011

[40] R M Martinez F A Pinho-Ribeiro V S Steffen et al ldquoTopicalformulation containing hesperidin methyl chalcone inhibitsskin oxidative stress and inflammation induced by ultravioletB irradiationrdquo Photochemical amp Photobiological Sciences vol 15no 4 pp 554ndash563 2016

[41] R M Martinez F A Pinho-Ribeiro V S Steffen et al ldquoHes-peridinmethyl chalcone inhibits oxidative stress and inflamma-tion in a mouse model of ultraviolet B irradiation-induced skindamagerdquo Journal of Photochemistry and Photobiology B Biologyvol 148 pp 145ndash153 2015

[42] H J Lee A-R Im S-M Kim H-S Kang J D Lee and SChae ldquoThe flavonoid hesperidin exerts anti-photoaging effectby downregulating matrix metalloproteinase (MMP)-9 expres-sion via mitogen activated protein kinase (MAPK)-dependentsignaling pathwaysrdquo BMC Complementary and AlternativeMedicine vol 18 no 1 article no 39 2018

[43] S Jin B Zhou and D Luo ldquoHesperidin promotes cyclobutanepyrimidine dimer repair inUVB-exposedmice epidermisrdquo IrishJournal of Medical Science vol 180 no 3 pp 709ndash714 2011

[44] Y-H Tsai K-F Lee Y-B Huang C-T Huang and P-C WuldquoIn vitro permeation and in vivo whitening effect of topical hes-peretin microemulsion delivery systemrdquo International Journalof Pharmaceutics vol 388 no 1-2 pp 257ndash262 2010

[45] Y-C Huang K-C Liu and Y-L Chiou ldquoMelanogenesisof murine melanoma cells induced by hesperetin a Citrushydrolysate-derived flavonoidrdquo Food and Chemical Toxicologyvol 50 no 3-4 pp 653ndash659 2012

[46] I Usach R Talens-Visconti L Magraner-Pardo and J-EPeris ldquoHesperetin induces melanin production in adult humanepidermal melanocytesrdquo Food and Chemical Toxicology vol 80pp 80ndash84 2015

[47] C Zhang Y Lu L Tao X Tao X Su and D Wei ldquoTyrosinaseinhibitory effects and inhibition mechanisms of nobiletin andhesperidin from citrus peel crude extractsrdquo Journal of EnzymeInhibition and Medicinal Chemistry vol 22 no 1 pp 91ndash982007


[49] B Kim J-Y Lee H-Y Lee et al ldquoHesperidin suppressesmelanosome transport by blocking the interaction of rab27a-melanophilinrdquo Biomolecules amp Therapeutics vol 21 no 5 pp343ndash348 2013

[50] H J Lee W J Lee S E Chang and G-Y Lee ldquoHesperidin apopular antioxidant inhibitsmelanogenesis via Erk12mediatedMITF degradationrdquo International Journal of Molecular Sciencesvol 16 no 8 pp 18384ndash18395 2015

[51] S S Kim M-J Kim Y H Choi et al ldquoDown-regulation oftyrosinase TRP-1 TRP-2 andMITF expressions by citrus press-cakes in murine B16 F10 melanomardquo Asian Pacific Journal ofTropical Biomedicine vol 3 no 8 pp 617ndash622 2013

[52] S Kiefer M Weibel J Smits M Juch J Tiedke and NHerbst ldquoCitrus flavonoids with skin lightening effects ndash safetyand efficacy studiesrdquo International Journal of Applied SciencesSOFW vol 136 pp 46ndash54 2010

[53] S-N Lou M-W Yu and C-T Ho ldquoTyrosinase inhibitorycomponents of immature calamondin peelrdquo Food Chemistryvol 135 no 3 pp 1091ndash1096 2012

[54] QWessels E Pretorius CM Smith andHNel ldquoThe potentialof a niacinamide dominated cosmeceutical formulation onfibroblast activity and wound healing in vitrordquo InternationalWound Journal vol 11 no 2 pp 152ndash158 2014

[55] W Li A D Kandhare A A Mukherjee and S L BodhankarldquoHesperidin a plant flavonoid accelerated the cutaneouswoundhealing in streptozotocin-induced diabetic rats Role of TGF-BSMADS and ANG-1TIE-2 signaling pathwaysrdquo EXCLI Jour-nal vol 17 pp 399ndash419 2018

[56] L Wang T He A Fu et al ldquoHesperidin enhances angiogenesisvia modulating expression of growth and inflammatory factorin diabetic foot ulcer in ratsrdquo European Journal of Inflammationvol 16 2018

[57] R R Toledo M E R D C Santos and T B Schnaider ldquoEffectof Pycnogenol on the Healing of Venous Ulcersrdquo Annals ofVascular Surgery vol 38 pp 212ndash219 2017

[58] J J GuilhouODereure LMarzin et al ldquoEfficacy ofDaflon 500mg in venous leg ulcer healing A double-blind randomizedcontrolled versus placebo trial in 107 patientsrdquo Angiology vol48 no 1 pp 77ndash85 1997

[59] G C Jagetia and K V N M Rao ldquoHesperidin treatment abatesradiation-induced delay in healing of deep cutaneous excisionwound of mice hemi-body exposed to different doses of 120574-radiationrdquo Clinical Dermatology Dermatitis vol 1 p 104 2018

[60] G C Jagetia and K V N M Rao ldquoTopical application ofhesperidin a citrus bioflavanone accelerates healing of fullthickness dermal excision wounds in mice exposed to 6 Gy ofwhole body 120574-radiationrdquo Transcriptomics vol 3 no 111 2015

[61] H-L Yang S-C Chen K J Senthil Kumar et al ldquoAntioxi-dant and anti-inflammatory potential of hesperetin metabolitesobtained from hesperetin-administered rat serum An ex vivoapproachrdquo Journal of Agricultural and Food Chemistry vol 60no 1 pp 522ndash532 2012

[62] P-D Moon and H-M Kim ldquoAntiinflammatory effects of tra-ditional Korean medicine JinPi-tang and its active ingredienthesperidin in HaCaT cellsrdquo Phytotherapy Research vol 26 no5 pp 657ndash662 2012

[63] S Fu C Sun X Tao and Y Ren ldquoAnti-inammatory effectsof active constituents extracted from Chinese medicinal herbsagainst Propionibacterium acnesrdquo Natural Product Research(Formerly Natural Product Letters) vol 26 no 18 pp 1746ndash17492012


[64] H Hernandez-Pigeon L Garidou M Galliano et al ldquoEffectsof dextran sulfate 4-t-butylcyclohexanol pongamia oil andhesperidin methyl chalcone on inflammatory and vascularresponses implicated in rosaceardquo Clinical Cosmetic and Inves-tigational Dermatology vol 11 pp 421ndash429 2018

[65] J A Emim A B Oliveira and A J Lapa ldquoPharmacolog-ical evaluation of the anti-inflammatory activity of a citrusbioflavonoid hesperidin and the isoflavonoids duartin andclaussequinone in rats and micerdquo Journal of Pharmacy andPharmacology vol 46 no 2 pp 118ndash122 1994

[66] L E Pelzer T Guardia A O Juarez and E Guerreiro ldquoAcuteand chronic antiinflammatory effects of plant flavonoidsrdquo Far-maco vol 53 no 6 pp 421ndash424 1998

[67] W M Kaidama and R N Gacche ldquoAnti-inflammatory prop-erties of hesperidin in guinea pigsrdquo International Journal ofPharmacy and Pharmaceutical Research vol 6 pp 206ndash2172016

[68] T P Smina A Mohan K A Ayyappa S Sethuraman and UM Krishnan ldquoHesperetin exerts apoptotic effect on A431 skincarcinoma cells by regulating mitogen activated protein kinasesand cyclinsrdquo Cellular and Molecular Biology vol 61 no 6 pp92ndash99 2015

[69] W Zhao Y Chen and X Zhang ldquoHesperidin-triggerednecrosis-like cell death in skin cancer cell line A431 mightbe prompted by ROS mediated alterations in mitochondrialmembrane potentialrdquo International Journal of Clinical andExperimental Medicine vol 11 pp 1948ndash1954 2018

[70] B Berkarda H Koyuncu G Soybir and F Baykut ldquoInhibitoryeffect of Hesperidin on tumour initiation and promotion inmouse skinrdquo Research in Experimental Medicine vol 198 no2 pp 93ndash99 1998

[71] M K Anwer R Al-Shdefat S Jamil P Alam M S Abdel-Kader and F Shakeel ldquoSolubility of bioactive compound hes-peridin in six pure solvents at (29815 to 33315) Krdquo Journal ofChemical amp Engineering Data vol 59 no 6 pp 2065ndash20692014

[72] R Cao Y Zhao Z Zhou and X Zhao ldquoEnhancement ofthe water solubility and antioxidant activity of hesperidinby chitooligosacchariderdquo Journal of the Science of Food andAgriculture vol 98 no 6 pp 2422ndash2427 2018

[73] R Xu Y Cong M Zheng G Chen J Chen and H ZhaoldquoSolubility and modeling of hesperidin in cosolvent mixturesof ethanol isopropanol propylene glycol and n -propanol +waterrdquo Journal of Chemical amp Engineering Data vol 63 no 3pp 764ndash770 2018

[74] M Yamada F Tanabe N Arai et al ldquoBioavailability of glucosylhesperidin in ratsrdquo Bioscience Biotechnology and Biochemistryvol 70 no 6 pp 1386ndash1394 2006

[75] M Damon O Flandre F Michel L Perdrix C Labrid and ACrastes de Paulet ldquoEffect of chronic treatment with a purifiedflavonoid fraction on inflammatory granuloma in the rat Studyof prostaglandin E

2and F

2120572 and thromboxane B

2release and

histological changesrdquo Drug Research vol 37 no 10 pp 1149ndash1153 1987

[76] K Mayumi T Seiko S Masa-Aki H Masao F Shoji and INobuyuki ldquoSubchronic toxicity study of methyl hesperidin inmicerdquo Toxicology Letters vol 69 no 1 pp 37ndash44 1993

[77] K Kawaguchi T Mizuno K Aida and K Uchino ldquoHesperidinas an inhibitor of lipases from porcine pancreas and pseu-domonasrdquo Bioscience Biotechnology and Biochemistry vol 61no 1 pp 102ndash104 1997

[78] B F Sieve ldquoA new antifertility factor (a preliminary report)rdquoScience vol 116 no 3015 pp 373ndash385 1952

[79] S S Shoab J B Porter J H Scurr and P D Coleridge-SmithldquoEffect of oral micronized purified flavonoid fraction treatmenton leukocyte adhesion molecule expression in patients withchronic venous disease A pilot studyrdquo Journal of VascularSurgery vol 31 no 3 pp 456ndash461 2000

[80] M Cospite ldquoDouble-blind placebo-controlled evaluation ofclinical activity and safety of Daflon 500 mg in the treatmentof acute hemorrhoidsrdquo Angiology vol 45 no 6 pp 566ndash5731994

[81] E Rabe G B Agus and K Roztocil ldquoAnalysis of the effectsof micronized purified flavonoid fraction versus placebo onsymptoms and quality of life in patients suffering from chronicvenous disease From a prospective randomized trialrdquo Interna-tional Angiology vol 34 no 5 pp 428ndash436 2015

[82] N Sugasawa A Katagi H Kurobe et al ldquoInhibition ofatherosclerotic plaque development by oral administrationof 120572-glucosyl hesperidin and water-dispersible hesperetin inapolipoprotein E knockout micerdquo Journal of the AmericanCollege of Nutrition pp 1ndash8 2018

[83] C Morand C Dubray D Milenkovic et al ldquoHesperidincontributes to the vascular protective effects of orange juice arandomized crossover study in healthy volunteersrdquo AmericanJournal of Clinical Nutrition vol 93 no 1 pp 73ndash80 2011

[84] M Xue M O Weickert S Qureshi et al ldquoImproved glycemiccontrol and vascular function in overweight and obese subjectsby glyoxalase 1 inducer formulationrdquoDiabetes vol 65 no 8 pp2282ndash2294 2016

[85] F Homayouni F Haidari M Hedayati M Zakerkish and KAhmadi ldquoHesperidin supplementation alleviates oxidative dnadamage and lipid peroxidation in type 2 diabetes a randomizeddouble-blind placebo-controlled clinical trialrdquo PhytotherapyResearch vol 31 no 10 pp 1539ndash1545 2017

[86] A Justin Thenmozhi T R William Raja T ManivasagamU Janakiraman and M M Essa ldquoHesperidin amelioratescognitive dysfunction oxidative stress and apoptosis againstaluminium chloride induced rat model of Alzheimerrsquos diseaserdquoNutritional Neuroscience vol 20 no 6 pp 360ndash368 2016

[87] A J Thenmozhi T R W Raja U Janakiraman and TManivasagam ldquoNeuroprotective effect of hesperidin on alu-minium chloride induced alzheimerrsquos disease in wistar ratsrdquoNeurochemical Research vol 40 no 4 pp 767ndash776 2015

[88] A Ahmadi andA Shadboorestan ldquoOxidative stress and cancerthe role of hesperidin a citrus natural bioflavonoid as a cancerchemoprotective agentrdquoNutrition and Cancer vol 68 no 1 pp29ndash39 2016

[89] P M Elias ldquoPrimary role of barrier dysfunction in the patho-genesis of atopic dermatitisrdquo Experimental Dermatology vol 27no 8 pp 847ndash851 2018

[90] LHu TMMauro E Dang et al ldquoEpidermal dysfunction leadsto an age-associated increase in levels of serum inflammatorycytokinesrdquo Journal of Investigative Dermatology vol 137 no 6pp 1277ndash1285 2017

[91] M Man L Ye L Hu S Jeong P M Elias and C Lv ldquoImprove-ments in epidermal function prevent relapse of psoriasis a self-controlled studyrdquo Clinical and Experimental Dermatology 2019

[92] L Huang Y Zhong D Liu et al ldquoAdverse cutaneous reactionsto skin care products on the face varywith age but not with sexrdquoContact Dermatitis vol 79 no 6 pp 365ndash369 2018

[93] M Kwa L J Welty and S Xu ldquoAdverse events reported to theUS food and drug administration for cosmetics and personal


care productsrdquo JAMA InternalMedicine vol 177 no 8 pp 1202ndash1204 2017

[94] P M Elias and R Ghadially ldquoThe aged epidermal permeabilitybarrier Basis for functional abnormalitiesrdquo Clinics in GeriatricMedicine vol 18 no 1 pp 103ndash120 2002

[95] M Q Man S J Xin S P Song et al ldquoVariation of skin surfacepH sebum content and stratum corneum hydration with ageand gender in a large chinese populationrdquo Skin Pharmacologyand Physiology vol 22 no 4 pp 190ndash199 2009

[96] J DrsquoOrazio S Jarrett A Amaro-Ortiz and T Scott ldquoUVradiation and the skinrdquo International Journal of MolecularSciences vol 14 no 6 pp 12222ndash12248 2013

[97] A Amaro-Ortiz B Yan and J A DrsquoOrazio ldquoUltravioletradiation aging and the skin Prevention of damage by topicalcAMP manipulationrdquo Molecules vol 19 no 5 pp 6202ndash62192014

[98] I Peluso C Miglio G Morabito F Ioannone and M SerafinildquoFlavonoids and immune function in human a systematicreviewrdquo Critical Reviews in Food Science and Nutrition vol 55no 3 pp 383ndash395 2015

[99] K Kawaguchi H Maruyama T Kometani and Y KumazawaldquoSuppression of collagen-induced arthritis by oral administra-tion of the Citrus flavonoid hesperidinrdquo Planta Medica vol 72no 5 pp 477ndash479 2006

[100] T Tanaka T Tanaka M Tanaka and T Kuno ldquoCancer chemo-prevention by citrus pulp and juices containing high amountsof 120573-cryptoxanthin and hesperidinrdquo Journal of Biomedicine andBiotechnology vol 2012 Article ID 516981 2012

[101] H A Al-Ashaal and S T El-Sheltawy ldquoAntioxidant capacityof hesperidin from Citrus peel using electron spin resonanceand cytotoxic activity against human carcinoma cell linesrdquoPharmaceutical Biology vol 49 no 3 pp 276ndash282 2011

[102] G Haddadi A Abbaszadeh M Mosleh-Shirazi M OkhovatA Salajeghe and Z Ghorbani ldquoEvaluation of the effect ofhesperidin on vascular endothelial growth factor gene expres-sion in rat skin animal models following cobalt-60 gammairradiationrdquo Journal of Cancer Research and Therapeutics vol14 no 7 pp 1098ndash1104 2018

[103] C K Karayıldırım ldquoCharacterization and in vitro evolution ofantibacterial efficacy of novel hesperidin microemulsionrdquo CelalBayar Universitesi Fen Bilimleri Dergisi vol 13 pp 943ndash9472017

[104] A Corciova C Ciobanu A Poiata et al ldquoInclusion complexesof hesperidin with hydroxypropyl-120573-cyclodextrin Physico-chemical characterization and biological assessmentrdquo DigestJournal of Nanomaterials and Biostructures vol 9 no 4 pp1623ndash1637 2014

[105] Z Cvetnic and S Vladimir-Knezevic ldquoAntimicrobial activity ofgrapefruit seed andpulp ethanolic extractrdquoActa Pharmaceuticavol 54 no 3 pp 243ndash250 2004

[106] S A Nagem T K Mohammud S K Zair and E H AbassldquoRecovery of pure Hesperidin from Iraqi Sweet Oranges Peeland study the effect in some bacteriardquo Baghdad Science Journalvol 11 pp 455ndash460 2014

[107] A Gueniche D Philippe E Buyukpamukcu et al ldquoThenatural flavonoid hesperidin improves skin aging surfaceparameters following oral intakerdquo Research Gate 2012httpswwwresearchgatenetpublication327832482THE NATURAL FLAVONOID HESPERIDIN IMPROVESSKIN AGING SURFACE PARAMETERS FOLLOWINGORAL INTAKE

[108] K R Feingold and P M Elias ldquoRole of lipids in the forma-tion and maintenance of the cutaneous permeability barrierrdquoBiochimica et Biophysica Acta (BBA) - Molecular and CellBiology of Lipids vol 1841 no 3 pp 280ndash294 2014

[109] T Nguyen P Nioi and C B Pickett ldquoThe Nrf2-antioxidantresponse element signaling pathway and its activation byoxidative stressrdquo The Journal of Biological Chemistry vol 284no 20 pp 13291ndash13295 2009

[110] H Ikehata and M Yamamoto ldquoRoles of the KEAP1-NRF2 sys-tem in mammalian skin exposed to UV radiationrdquo Toxicologyand Applied Pharmacology vol 360 pp 69ndash77 2018

[111] A Hirota Y Kawachi M Yamamoto T Koga K Hamada andF Otsuka ldquoAcceleration of UVB-induced photoageing in nrf2gene-deficient micerdquo Experimental Dermatology vol 20 no 8pp 664ndash668 2011

[112] C L L Saw A Y Yang M-T Huang et al ldquoNrf2 nullenhances UVB-induced skin inflammation and extracellularmatrix damagesrdquo Cell amp Bioscience vol 4 no 1 article 39 2014

[113] A Hirota Y Kawachi K Itoh et al ldquoUltraviolet A irradiationinduces NF-E2-related factor 2 activation in dermal fibroblastsprotective role in UVA-induced apoptosisrdquo Journal of Investiga-tive Dermatology vol 124 no 4 pp 825ndash832 2005

[114] C L Saw M-T Huang Y Liu T O Khor A H Conneyand A-N Kong ldquoImpact of Nrf2 on UVB-induced skininflammationphotoprotection and photoprotective effect ofsulforaphanerdquoMolecular Carcinogenesis vol 50 no 6 pp 479ndash486 2011

[115] J Elavarasan P Velusamy T Ganesan S K RamakrishnanD Rajasekaran and K Periandavan ldquoHesperidin-mediatedexpression of Nrf2 and upregulation of antioxidant status insenescent rat heartrdquo Journal of Pharmacy and Pharmacologyvol 64 no 10 pp 1472ndash1482 2012

[116] T Kuwano M Watanabe D Kagawa and T MuraseldquoHydrolyzed methylhesperidin induces antioxidant enzymeexpression via the nrf2-are pathway in normal human epider-mal keratinocytesrdquo Journal of Agricultural and Food Chemistryvol 63 no 36 pp 7937ndash7944 2015

[117] I F D S Videira D F Lima Moura and S B L MVasconcelos Magina ldquoMechanisms regulating melanogenesisrdquoAnais Brasileiros de Dermatologia vol 88 no 1 pp 76ndash83 2013

[118] H Y Park M Kosmadaki M Yaar and B A Gilchrest ldquoCellu-lar mechanisms regulating humanmelanogenesisrdquoCellular andMolecular Life Sciences vol 66 no 9 pp 1493ndash1506 2009

[119] J M Galgut and S A Ali ldquoHesperidin induced melanophoreaggregatory responses in tadpole of bufo melanostictus via a-adrenoceptorsrdquo Pharmacologia vol 3 no 10 pp 519ndash524 2012

[120] K W Finnson S McLean G M Di Guglielmo and A PhilipldquoDynamics of transforming growth factor beta signaling inwound healing and scarringrdquo Advances in Wound Care vol 2no 5 pp 195ndash214 2013

[121] K E Johnson and T A Wilgus ldquoVascular endothelial growthfactor and angiogenesis in the regulation of cutaneous woundrepairrdquo Advances in Wound Care vol 3 no 10 pp 647ndash6612014

[122] T AWilgus AMMatthies K A Radek et al ldquoNovel functionfor vascular endothelial growth factor receptor-1 on epidermalkeratinocytesrdquo The American Journal of Pathology vol 167 no5 pp 1257ndash1266 2005

[123] P M Elias J Arbiser B E Brown et al ldquoEpidermal vas-cular endothelial growth factor production is required forpermeability barrier homeostasis dermal angiogenesis and the


development of epidermal hyperplasia Implications for thepathogenesis of psoriasisrdquo The American Journal of Pathologyvol 173 no 3 pp 689ndash699 2008

[124] D Kido K Mizutani K Takeda et al ldquoImpact of diabetes ongingival wound healing via oxidative stressrdquo PLoS ONE vol 12Article ID e0189601 2017

[125] M Schafer and S Werner ldquoOxidative stress in normal andimpaired wound repairrdquo Pharmacological Research vol 58 no2 pp 165ndash171 2008

[126] R M El-Ferjani M Ahmad S M Dhiyaaldeen et al ldquoIn vivoassessment of antioxidant and wound healing improvement ofa new schiff base derived Co (ii) complex in ratsrdquo ScientificReports vol 6 Article ID 38748 2016

[127] L Bianchi A Ginebri J H Hagman F Francesconi I Car-boni and S Chimenti ldquoLocal treatment of chronic cutaneousleg ulcers with recombinant human granulocyte-macrophagecolony-stimulating factorrdquo Journal of the European Academy ofDermatology and Venereology vol 16 no 6 pp 595ndash598 2002

[128] K Remes and T Ronnemaa ldquoHealing of chronic leg ulcersin diabetic necrobiosis lipoidica with local granulocyte-macrophage colony-stimulating factor treatmentrdquo Journal ofDiabetes and its Complications vol 13 no 2 pp 115ndash118 1999

[129] E Jaschke A Zabernigg and C Gattringer ldquoRecombi-nant human granulocyte-macrophage colony-stimulating fac-tor applied locally in low doses enhances healing and preventsrecurrence of chronic venous ulcersrdquo International Journal ofDermatology vol 38 no 5 pp 380ndash386 1999

[130] R G Rosique M J Rosique and J A Farina Junior ldquoCurbinginflammation in skin wound healing a reviewrdquo InternationalJournal of Inflammation vol 2015 Article ID 316235 9 pages2015

[131] M Streit Z Beleznay and L R Braathen ldquoTopical applicationof the tumour necrosis factor-120572 antibody infliximab improveshealing of chronic woundsrdquo International Wound Journal vol3 no 3 pp 171ndash191 2006

[132] V-L Nguyen C-T Truong B C Q Nguyen et al ldquoAnti-inflammatory and wound healing activities of calophyllolideisolated from Calophyllum inophyllum Linnrdquo PLoS ONE vol12 no 10 Article ID e0185674 2017

[133] T Zarubin and J Han ldquoActivation and signaling of the p38MAPkinase pathwayrdquo Cell Research vol 15 no 1 pp 11ndash18 2005

[134] J Westra B Doornbos-van der Meer P de Boer M A vanLeeuwen M H van Rijswijk and P C Limburg ldquoStronginhibition of TNF-alpha production and inhibition of IL-8 andCOX-2 mRNA expression in monocyte-derived macrophagesby RWJ 67657 a p38 mitogen-activated protein kinase (MAPK)inhibitorrdquo Arthritis Research ampTherapy vol 6 no 4 pp R384ndashR392 2004

[135] W Song L Wei Y Du Y Wang and S Jiang ldquoProtectiveeffect of ginsenoside metabolite compound K againstdiabetic nephropathy by inhibiting NLRP3 inflammasomeactivation and NF-120581Bp38 signaling pathway in high-fatdietstreptozotocin-induced diabetic micerdquo InternationalImmunopharmacology vol 63 pp 227ndash238 2018

[136] YWang H Yu J Zhang J Gao X Ge andG Lou ldquoHesperidininhibits HeLa cell proliferation through apoptosis mediated byendoplasmic reticulum stress pathways and cell cycle arrestrdquoBMC Cancer vol 15 no 1 article no 682 2015

[137] J Zhao Y Li J Gao and Y De ldquoHesperidin inhibits ovariancancer cell viability through endoplasmic reticulum stresssignaling pathwaysrdquo Oncology Letters vol 14 no 5 pp 5569ndash5574 2017

[138] R Banjerdpongchai B Wudtiwai P Khaw-on W RachakhomN Duangnil and P Kongtawelert ldquoHesperidin from Citrusseed induces human hepatocellular carcinoma HepG2 cellapoptosis via bothmitochondrial and death receptor pathwaysrdquoTumor Biology vol 37 no 1 pp 227ndash237 2016

[139] V Syed ldquoTGF-120573 signaling in cancerrdquo Journal of Cellular Bio-chemistry vol 117 no 6 pp 1279ndash1287 2016

[140] M Petersen E Pardali G Van Der Horst et al ldquoSmad2 andSmad3 have opposing roles in breast cancer bone metastasis bydifferentially affecting tumor angiogenesisrdquo Oncogene vol 29no 9 pp 1351ndash1361 2010

[141] AMMahmoud HMMohammed S M Khadrawy and S RGalaly ldquoHesperidin protects against chemically induced hep-atocarcinogenesis via modulation of Nrf2AREHO-1 PPAR120574and TGF-1205731Smad3 signaling and amelioration of oxidativestress and inflammationrdquo Chemico-Biological Interactions vol277 pp 146ndash158 2017

[142] I Liguori G Russo F Curcio et al ldquoOxidative stress agingand diseasesrdquo Clinical Interventions in Aging vol 13 pp 757ndash772 2018

[143] D Giustarini I Dalle-Donne D Tsikas and R Rossi ldquoOxida-tive stress and human diseases origin link measurementmechanisms and biomarkersrdquo Critical Reviews in ClinicalLaboratory Sciences vol 46 no 5-6 pp 241ndash281 2009

[144] F Ahmadinejad S GMoslashllerMHashemzadeh-Chaleshtori GBidkhori and M-S Jami ldquoMolecular mechanisms behind freeradical scavengers function against oxidative stressrdquo Antioxi-dants vol 6 no 3 p E51 2017

[145] C Zhu Y Dong H Liu H Ren and Z Cui ldquoHesperetinprotects against H2O2-triggered oxidative damage via upregu-lation of theKeap1-Nrf2HO-1 signal pathway inARPE-19 cellsrdquoBiomedicine amp Pharmacotherapy vol 88 pp 124ndash133 2017

[146] H Ren J Hao T Liu et al ldquoHesperetin suppresses inflam-matory responses in lipopolysaccharide-induced RAW 2647cells via the inhibition of NF-120581B and activation of Nrf2HO-1pathwaysrdquo Inflammation vol 39 no 3 pp 964ndash973 2016

[147] B Hemanth Kumar B Dinesh Kumar and P V DiwanldquoHesperidin a citrus flavonoid protects against l-methionine-induced hyperhomocysteinemia by abrogation of oxidativestress endothelial dysfunction and neurotoxicity in wistar ratsrdquoPharmaceutical Biology vol 55 no 1 pp 146ndash155 2017

[148] M S Aly S R Galaly N Moustafa H M Mohammed SM Khadrawy and A M Mahmoud ldquoHesperidin protectsagainst diethylnitrosaminecarbon tetrachloride-induced renalrepercussions via up-regulation of Nrf2HO-1 signaling andattenuation of oxidative stressrdquo Journal of Applied Pharmaceu-tical Science vol 7 no 11 pp 7ndash14 2017

Stem Cells International

Hindawiwwwhindawicom Volume 2018


MEDIATORSINFLAMMATION

of

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

The Scientific World Journal

Volume 2018

Immunology ResearchHindawiwwwhindawicom Volume 2018

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine


Behavioural Neurology

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


in [16]) Hesperidin is abundant in citrus fruits includinglemon orange lime and grapefruit The content of hes-peridin in citrus fruits varies greatly with species part ofthe fruit itself geographic sites of cultivation and processingprocedures (Table 1) [17ndash22] For example hesperidin contentin fresh Satsuma pulp is 73 mg per kilogram and 157 mgper kilogram in fresh peel [20] Generally hesperidin contentis higher in citrus peel than in the other parts of thecitrus fruits But lemon seeds contain more hesperidin thanpeel by methanol extraction [23] Hand-squeezed Floridaorange juice contains 335ndash351mg hesperidin per litter whileIsrael Ortanique citrus juice contains 273ndash287 mg per litter[24] Juice from pigmented citrus contains more hesperidinthan that from nonpigmented citrus [25] It is likely thatimmature citrus may contain more hesperidin than ripencitrus does [26] Pasteurization with heat did not decreasehesperidin content in citrus juice at least stored at 4∘C forup to 12 days Instead hesperidin content increases followingpasteurization of citrus juice at 90∘C for 20 seconds [27]Hesperidin content ranges from 555 to 761 mg per litterin single-strength juice and from 470 to 614 mg per litterin concentrated juice suggesting that processing procedureaffects hesperidin content in citrus juice [28] In additionto citrus fruits peppermint (Mentha x piperita L) alsocontains hesperidin whose content increases following UVBirradiation [29] Methanol extract of Porphyra dentata a rededible seaweed contains 5 hesperidin [30]

Hesperidin (357 trihydroxyflavanone 7-rhamnogluco-side C

28H34O15) is also named hesperetin 7-rutinoside or

7-O-glycoside hesperitin with a molecular weight of 61057The melting and boiling points of hesperidin are 250-255∘Cand 57616∘C respectively It is stable for at least for 2years if stored at -20∘C Although hesperidin alone barelydissolves in aqueous solution it dissolves well in bothpropylene glycol and poly(ethylene glycol)-400 [71] Reactionof hesperidin with chitooligosaccharide yields hesperidin-chitooligosaccharide complex which renders it water sol-uble and further exhibits superior antioxidant activity tohesperidin alone [72] Moreover mix of hesperidin andother flavonoids such as theaflavin-3 31015840-digallate can increasethe solubility of hesperidin in 10 dimethyl sulfoxide [73]Additionally alpha glucosyl hesperidin is also water solubleand therefore commonly used in both topical and systemicpreparations Pertinently the area under the curve for serumhesperidin in rats was over 3-fold higher following orallyadministrations of glucosyl hesperidin than hesperidin itself[74]

3 Safety

Hesperidin is generally safe for both topical and systemicadministrations Topical applications of 2 hesperidin for9 days caused no adverse cutaneous reactions in mice [32]Similarly intragastrically given Daflon-500 mg containing10 hesperidin at daily dose of 100 mg did not show signsor symptoms of side effects in rats [75] Likewise oraladministrations of diets containing either methyl hesperidin

or hesperidin did not show signs or symptoms of sideeffects in mice and rats either [76 77] Moreover no adverseevents were observed in mice followed daily intraperitonealinjections of phosphorylated hesperidin at dose of 20mgkgbody weight for over 4 weeks [78] Although one studyshowed that orally given Daflon-500 mg twice-daily for 60days caused minor temporal side effects such as headacheand faintness [79] other studies showed that oral Daflon-500mg is safe in humans [80 81]

4 Benefits of Hesperidin forCutaneous Functions

Nowadays the benefits of bioflavonoids including hes-peridin on human health have been well appreciated Alarge number of studies have demonstrated that systemicadministrations of hesperidin exhibit benefits for a vari-ety of diseases including cardiovascular diseases diabetesAlzheimerrsquos disease and cancer [82ndash88] Likewise the ben-efits of hesperidin on various cutaneous conditions have alsobeen well illustrated (Table 2)

41 Epidermal Permeability Barrier Function Epidermal per-meability barrier residing in the stratum corneum preventsmovement of agents andwater through the stratum corneumImportantly recent studies demonstrate that epidermal per-meability barrier plays crucial role in the pathogenesis of bothcutaneous and possibly systemic disorders [89ndash91] Thusskin care product makers have been striving to developproducts that can potently improve epidermal permeabilitybarrier function Because of the high incidence of adversecutaneous reactions to skin care products identification ofsafe and effective ingredients is becoming emergent [92 93]Our group has demonstrated that twice-daily applications of2 hesperidin to young mouse skin for 6 days acceleratedpermeability barrier recovery in a model of acute barrierdisruption although basal transepidermal water loss ratesstratum corneum hydration and skin surface pH remainedunchanged [31] Aged skin displays delayed permeabilitybarrier recovery and elevated skin surface pH [94 95] whichboth possibly contribute to the development of certain aging-associated disorders Regimens that can improve epidermalpermeability barrier function particularly at gene levels arelimited At least on study showed that topical applications of2 hesperidin twice-daily for 9 days markedly acceleratedpermeability barrier recovery along with significant reduc-tion in skin surface pH in aged mice [32] In addition to nor-mal skin topical hesperidin can also prevent abnormalitiesof epidermal permeability barrier induced by topical gluco-corticoid in mice For example repeated topical applicationsof glucocorticoids delayed barrier recovery But if hesperidinwas topically given following each glucocorticoid applicationto mice abnormalities in both permeability barrier recoveryand skin surface pH were normalized [33] No adversereactions were observed following topical applications ofhesperidin Taken together these studies demonstrate that


Table1Hesperid

incontentincitrus

fruits

Species

GeographicS

iteof

Cultivatio

nEx

tractio

nSolvent

Peel(m

ggdried)

Ref

Cretic

ulateldquo

Erythrosardquo

Shim

enCou

ntyHun

anC

hina

Methano

l74236plusmn0845

[17]

Cretic

ulateldquo

Unshiurdquo

ChaheHub

eiC

hina

Methano

l60540plusmn0763

[17]

Cretic

ulateldquo

Unshiurdquo

Yang

shuo

Cou

ntyGuang

xiC

hina

Methano

l70232plusmn0487

[17]

Cretic

ulateldquo

Subcom

pressardquo

Yongqu

anZ

hejiang

China

Methano

l100525plusmn13

98[17]

Cretic

ulateldquo

Subcom

pressardquo

Huang

yan

Zhejiang

China

Methano

l62678plusmn0697

[17]

Cretic

ulateldquo

Chachirdquo

GujinJiang

menG

uangdo

ngC

hina

Methano

l62919plusmn0543

[17]

Cretic

ulateldquo

Chachirdquo

HuichengJiang

menG

uangdo

ngC

hina

Methano

l59012plusmn0787

[17]

Cretic

ulateldquo

Chachirdquo

LuokengJiang

menG

uangdo

ngC

hina

Methano

l74973plusmn0845

[17]

Cretic

ulateldquo

Chachirdquo

DazeJiang

menG

uangdo

ngC

hina

Methano

l54075plusmn0578

[17]

Cretic

ulateldquo

Chachirdquo

YamenJiang

menG

uangdo

ngC

hina

Methano

l88087plusmn10

62[17]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

Methano

l51921plusmn0768

[17]

Cretic

ulateldquo

Chachirdquo

Siqian

Town

Jiang

menG

uangdo

ngC

hina

Methano

l5013

7plusmn0301

[17]

Cretic

ulateldquo

Chachirdquo

GujingJiang

menG

uangdo

ngC

hina

50Metho

d37

[18]

Cretic

ulateldquo

Chachirdquo

Meijiang

Jiang

menG

uangdo

ngC

hina

50Metho

d42

[18]

Cretic

ulateldquo

Chachirdquo

WengyuanSh

aoguanG

uangdo

ngC

hina

50Metho

d79

[18]

Cretic

ulateldquo

Chachirdquo

Xiaogan

Jiang

menG

uangdo

ngC

hina

50Metho

d30

[18]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

50Metho

d53

[18]

Cretic

ulateldquo

Chachirdquo

Wengyuan

ShaoguanG

uangdo

ngC

hina

50Metho

d66

[18]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

50Metho

d46

[18]

CSinensis(linn

)Osbeck

North

ofIran

Petro

latum

etherfi

rstfollo

wed

bymethano

l

52-62

[19]

CSinensis

North

ofIran

52-61

[19]

Cretic

ulateB

lanco

North

ofIran

45-61

[19]

Cun

shiu

Marc

North

ofIran

13-58

[19]

Cun

shiu

Marc

Neretva

ValleyCr

oatia

12M

HCI

in80methano

lwater

042

[20]

Cretic

ulateB

lanco

Neretva

ValleyCr

oatia

047

[20]

lemon

juice

AdanaTu

rkey

lowast1136plusmn

110litte

r[21]

Pulpremoving

AdanaTu

rkey


[21]

Paste

urization

AdanaTu

rkey


[21]

lemon

Spain


[22]

Grapefruit

Spain

lowast33plusmn3mgml

[22]

lowastCon

tent

injuice


Table2Be

nefitso

fhesperid

inon

cutaneou

sfun

ctions

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

EpidermalPerm

eabilityB

arrie

rFun

ction

Youn

gmice

Topicalapp

lications

of2

hesperidin

twice-daily

for6

days

uarrAc

uteb

arrie

rrecovery

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLamellarb

odysecretion

[31]

Agedmice

Topicalapp

lications

of2

hesperidin

twice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrDifferentiatio

nuarrLipidprod

uctio

nuarrNHE1

andsPLA

2expressio

nuarrLamellarb

odyform

ationandsecretion

[32]

Glucocorticoid-tre

ated

mice

One

hour

after

each

topicalapp

licationof

005

clobetasolpropion

ate2

hesperidin

was

applied

Treatm

entsweretwice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLipidprocessin

guarrAntioxidatio

nuarrLamellarb

odyform

ationandsecretion


ctivity

[33]


ble2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Protectin

gUVIrr

adiatio

n

Keratin

ocytes

Keratin

ocytes

firsttre

ated

with

50120583M

hesperidin

for1

hrfollowed

byUVBirr

adiatio

n(30mJc

m2)

darrDNAdamage

darrlip

idperoxidatio

ndarrProteincarbon

ylation

darrAp

optotic

index

darrAb

sorb

UVB

darrRe

activ

eoxygenspecies

darrBc

l-2expressio

ndarrBA

Xexpressio

n

[34]

Keratin

ocytes

weretreated

with

hesperidin

(220120583gml)

for2

4hrfollowed

byUVA

irradiatio

n(10Jc

m2)Cells

wereincub

ated

with

hesperidin

fora

ddition

al6or

24hr

uarrCellviability

darrMDAcontent

darrTN

F-120572IL-1120573

andIL-6

mRN

ALevels

uarrSO

Dactiv

ity[35]

Keratin

ocytes

weretreated

with

hesperidin

(50100

20040

060

010

00mgL)

for2

4hrfollowed

byUVB

irradiatio

n(15mJc

m2)

darrCX

CR2expressio

nNot

determ

ined

[36]

Dermalfib

roblasts

Fibrob

lasts

irradiatedwith

UVA

atdo

se10Jc

m2and

treated

with

hesperetin

containing

extractatvarious

concentrationfor7

2hr

darrMatrix

metalloproteinase

expressio


ase

expressio


Not

determ

ined

[37]

Pretreated

fibroblastswith

3and30120583M

hesperetin

glucuron

idefollo

wed

byUVA

irradiatio


celldeath

Not

determ

ined

[38]

Mice

Micetreated

topically

with

hesperidin

(3mgml)daily

for10days30min

after

each

applicationof

hesperidin

micew

ereirradiatedwith

180mJc

m2UVB

darrSkin

erythemaamp

edem

adarrEp

idermalproliferatio


ndarrInflammation

darrDNAdamage

uarrCa

talase

andsuperoxide

dism

utasea

ctivity

[39]

Micew

eretreated

topically

1hesperidin

methyl

chalcone

before

andaft

eron

eirradiatio

nwith

414

mJc

m2UVB

darrCy

tokine

expressio


n

uarrNuclear

factor


2uarrGlutathione


redu

ctaseamp

hemeo

xygenase-1

[40]

Hesperid

inmethylchalco

neatthed

oseo

f300

mgkg

was

intraperito

neallygiven1h

rbeforea

nd7hr

after

irradiatio

nwith

414

mJc

m2UVB

darrSkin

edem

aneutroph

ilrecruitm

entand

matrix

metalloproteinase-9

activ

ity

darrCy

tokine

expressio


activ

ity


n

uarrGlutathione

levelsandcatalase

activ

ity

[41]

Orally

administered

01m

Lof

water

containing

100

mgkg

body

weighth

esperid

indailyw

hilemicew

ere

irradiated3tim

esat48

hintervalsp

erweekfor12

weeksD

oeso

fUVBwereincreased

60mJc

m2per

expo

sure

atweek1to90

mJc

m2atweek7

darrTransepiderm

alwater

loss

darrmatrix

metalloproteinase-9

expressio

nampactiv

ity

darrCy

tokine

expressio

ndarrwrin

kleformation

darrEp

idermalproliferatio

n

darrPh

osph

orylationof

mito

genactiv

ated

proteinkinase


kinases

[42]

Sing

leUVBirr

adiatio

natdo

seof

180mJc

m2

darrCy

clobu

tane

pyrim

idine

dimers

uarrp53expressio

nNot

determ

ined

[43]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrTransepiderm

alwater

loss

Not

determ

ined

[44]

Pigm

entatio

n

B16mou

semelanom

acells

Cellsincubatedwith

20120583gmLof

Citru

sextractso

r3-50120583M

ofhesperetin

for4

8hr

uarrMela

nincontent

uarrTy

rosin

asep

rotein

uarrTy

rosin

asea

ctivity

uarrMela

nogenesis

-rela

tedproteins

uarr120573-C

atenin

expressio

nuarrPh

osph

orylated

glycogen

synthase

kinase-3120573

[4546

]

Cellsincub

ated

with

hesperidin

(3225mgmL)

for3

days

Minim

uminhibitio

nof

melanogenesis

Not

determ

ined

[4748]

Cellsw

eretreated

with

hesperidin

(5010020040

060

01000mgL)

for2

4hrfollowed

byUVBirr

adiatio

n(15mJc

m2)

darrTy

rosin

asea

ctivity

darrMela

nincontent

Not

determ

ined

[36]

Cellsincubatedwith

5-20120583M

hesperidin

for3

days

uarrMela

nincontent

Not

determ

ined

[49]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

darrTy

rosin

ase-related

protein12

darrMela

nogenesis

-rela

tedproteins

uarrp-Erk12

uarrProteasomea

ctivity

[50]

Cellsincubatedwith

Citru


120583gmL)

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

ampactiv

ity

darrTy

rosin

ase-related

protein12

darrMicroph


tionfactor

(MITF)

proteins

[51]

Hum

anepidermal

melanocytes

Cellsincubatedwith

3-50120583M

ofhesperetin

for4

8hruarrMela

nincontent

uarrTy

rosin

asea

ctivity

Not

determ

ined

[46]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asea

ctivity

Not

determ

ined

[50]

Cellsincubatedwith

04m

gmlC

itrus

extractsfor3

daysdarrTy

rosin

asea

ctivity

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table1Hesperid

incontentincitrus

fruits

Species

GeographicS

iteof

Cultivatio

nEx

tractio

nSolvent

Peel(m

ggdried)

Ref

Cretic

ulateldquo

Erythrosardquo

Shim

enCou

ntyHun

anC

hina

Methano

l74236plusmn0845

[17]

Cretic

ulateldquo

Unshiurdquo

ChaheHub

eiC

hina

Methano

l60540plusmn0763

[17]

Cretic

ulateldquo

Unshiurdquo

Yang

shuo

Cou

ntyGuang

xiC

hina

Methano

l70232plusmn0487

[17]

Cretic

ulateldquo

Subcom

pressardquo

Yongqu

anZ

hejiang

China

Methano

l100525plusmn13

98[17]

Cretic

ulateldquo

Subcom

pressardquo

Huang

yan

Zhejiang

China

Methano

l62678plusmn0697

[17]

Cretic

ulateldquo

Chachirdquo

GujinJiang

menG

uangdo

ngC

hina

Methano

l62919plusmn0543

[17]

Cretic

ulateldquo

Chachirdquo

HuichengJiang

menG

uangdo

ngC

hina

Methano

l59012plusmn0787

[17]

Cretic

ulateldquo

Chachirdquo

LuokengJiang

menG

uangdo

ngC

hina

Methano

l74973plusmn0845

[17]

Cretic

ulateldquo

Chachirdquo

DazeJiang

menG

uangdo

ngC

hina

Methano

l54075plusmn0578

[17]

Cretic

ulateldquo

Chachirdquo

YamenJiang

menG

uangdo

ngC

hina

Methano

l88087plusmn10

62[17]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

Methano

l51921plusmn0768

[17]

Cretic

ulateldquo

Chachirdquo

Siqian

Town

Jiang

menG

uangdo

ngC

hina

Methano

l5013

7plusmn0301

[17]

Cretic

ulateldquo

Chachirdquo

GujingJiang

menG

uangdo

ngC

hina

50Metho

d37

[18]

Cretic

ulateldquo

Chachirdquo

Meijiang

Jiang

menG

uangdo

ngC

hina

50Metho

d42

[18]

Cretic

ulateldquo

Chachirdquo

WengyuanSh

aoguanG

uangdo

ngC

hina

50Metho

d79

[18]

Cretic

ulateldquo

Chachirdquo

Xiaogan

Jiang

menG

uangdo

ngC

hina

50Metho

d30

[18]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

50Metho

d53

[18]

Cretic

ulateldquo

Chachirdquo

Wengyuan

ShaoguanG

uangdo

ngC

hina

50Metho

d66

[18]

Cretic

ulateldquo

Chachirdquo

Shuang

shuiJiang

menG

uangdo

ngC

hina

50Metho

d46

[18]

CSinensis(linn

)Osbeck

North

ofIran

Petro

latum

etherfi

rstfollo

wed

bymethano

l

52-62

[19]

CSinensis

North

ofIran

52-61

[19]

Cretic

ulateB

lanco

North

ofIran

45-61

[19]

Cun

shiu

Marc

North

ofIran

13-58

[19]

Cun

shiu

Marc

Neretva

ValleyCr

oatia

12M

HCI

in80methano

lwater

042

[20]

Cretic

ulateB

lanco

Neretva

ValleyCr

oatia

047

[20]

lemon

juice

AdanaTu

rkey

lowast1136plusmn

110litte

r[21]

Pulpremoving

AdanaTu

rkey


[21]

Paste

urization

AdanaTu

rkey


[21]

lemon

Spain


[22]

Grapefruit

Spain

lowast33plusmn3mgml

[22]

lowastCon

tent

injuice


Table2Be

nefitso

fhesperid

inon

cutaneou

sfun

ctions

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

EpidermalPerm

eabilityB

arrie

rFun

ction

Youn

gmice

Topicalapp

lications

of2

hesperidin

twice-daily

for6

days

uarrAc

uteb

arrie

rrecovery

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLamellarb

odysecretion

[31]

Agedmice

Topicalapp

lications

of2

hesperidin

twice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrDifferentiatio

nuarrLipidprod

uctio

nuarrNHE1

andsPLA

2expressio

nuarrLamellarb

odyform

ationandsecretion

[32]

Glucocorticoid-tre

ated

mice

One

hour

after

each

topicalapp

licationof

005

clobetasolpropion

ate2

hesperidin

was

applied

Treatm

entsweretwice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLipidprocessin

guarrAntioxidatio

nuarrLamellarb

odyform

ationandsecretion


ctivity

[33]


ble2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Protectin

gUVIrr

adiatio

n

Keratin

ocytes

Keratin

ocytes

firsttre

ated

with

50120583M

hesperidin

for1

hrfollowed

byUVBirr

adiatio

n(30mJc

m2)

darrDNAdamage

darrlip

idperoxidatio

ndarrProteincarbon

ylation

darrAp

optotic

index

darrAb

sorb

UVB

darrRe

activ

eoxygenspecies

darrBc

l-2expressio

ndarrBA

Xexpressio

n

[34]

Keratin

ocytes

weretreated

with

hesperidin

(220120583gml)

for2

4hrfollowed

byUVA

irradiatio

n(10Jc

m2)Cells

wereincub

ated

with

hesperidin

fora

ddition

al6or

24hr

uarrCellviability

darrMDAcontent

darrTN

F-120572IL-1120573

andIL-6

mRN

ALevels

uarrSO

Dactiv

ity[35]

Keratin

ocytes

weretreated

with

hesperidin

(50100

20040

060

010

00mgL)

for2

4hrfollowed

byUVB

irradiatio

n(15mJc

m2)

darrCX

CR2expressio

nNot

determ

ined

[36]

Dermalfib

roblasts

Fibrob

lasts

irradiatedwith

UVA

atdo

se10Jc

m2and

treated

with

hesperetin

containing

extractatvarious

concentrationfor7

2hr

darrMatrix

metalloproteinase

expressio


ase

expressio


Not

determ

ined

[37]

Pretreated

fibroblastswith

3and30120583M

hesperetin

glucuron

idefollo

wed

byUVA

irradiatio


celldeath

Not

determ

ined

[38]

Mice

Micetreated

topically

with

hesperidin

(3mgml)daily

for10days30min

after

each

applicationof

hesperidin

micew

ereirradiatedwith

180mJc

m2UVB

darrSkin

erythemaamp

edem

adarrEp

idermalproliferatio


ndarrInflammation

darrDNAdamage

uarrCa

talase

andsuperoxide

dism

utasea

ctivity

[39]

Micew

eretreated

topically

1hesperidin

methyl

chalcone

before

andaft

eron

eirradiatio

nwith

414

mJc

m2UVB

darrCy

tokine

expressio


n

uarrNuclear

factor


2uarrGlutathione


redu

ctaseamp

hemeo

xygenase-1

[40]

Hesperid

inmethylchalco

neatthed

oseo

f300

mgkg

was

intraperito

neallygiven1h

rbeforea

nd7hr

after

irradiatio

nwith

414

mJc

m2UVB

darrSkin

edem

aneutroph

ilrecruitm

entand

matrix

metalloproteinase-9

activ

ity

darrCy

tokine

expressio


activ

ity


n

uarrGlutathione

levelsandcatalase

activ

ity

[41]

Orally

administered

01m

Lof

water

containing

100

mgkg

body

weighth

esperid

indailyw

hilemicew

ere

irradiated3tim

esat48

hintervalsp

erweekfor12

weeksD

oeso

fUVBwereincreased

60mJc

m2per

expo

sure

atweek1to90

mJc

m2atweek7

darrTransepiderm

alwater

loss

darrmatrix

metalloproteinase-9

expressio

nampactiv

ity

darrCy

tokine

expressio

ndarrwrin

kleformation

darrEp

idermalproliferatio

n

darrPh

osph

orylationof

mito

genactiv

ated

proteinkinase


kinases

[42]

Sing

leUVBirr

adiatio

natdo

seof

180mJc

m2

darrCy

clobu

tane

pyrim

idine

dimers

uarrp53expressio

nNot

determ

ined

[43]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrTransepiderm

alwater

loss

Not

determ

ined

[44]

Pigm

entatio

n

B16mou

semelanom

acells

Cellsincubatedwith

20120583gmLof

Citru

sextractso

r3-50120583M

ofhesperetin

for4

8hr

uarrMela

nincontent

uarrTy

rosin

asep

rotein

uarrTy

rosin

asea

ctivity

uarrMela

nogenesis

-rela

tedproteins

uarr120573-C

atenin

expressio

nuarrPh

osph

orylated

glycogen

synthase

kinase-3120573

[4546

]

Cellsincub

ated

with

hesperidin

(3225mgmL)

for3

days

Minim

uminhibitio

nof

melanogenesis

Not

determ

ined

[4748]

Cellsw

eretreated

with

hesperidin

(5010020040

060

01000mgL)

for2

4hrfollowed

byUVBirr

adiatio

n(15mJc

m2)

darrTy

rosin

asea

ctivity

darrMela

nincontent

Not

determ

ined

[36]

Cellsincubatedwith

5-20120583M

hesperidin

for3

days

uarrMela

nincontent

Not

determ

ined

[49]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

darrTy

rosin

ase-related

protein12

darrMela

nogenesis

-rela

tedproteins

uarrp-Erk12

uarrProteasomea

ctivity

[50]

Cellsincubatedwith

Citru


120583gmL)

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

ampactiv

ity

darrTy

rosin

ase-related

protein12

darrMicroph


tionfactor

(MITF)

proteins

[51]

Hum

anepidermal

melanocytes

Cellsincubatedwith

3-50120583M

ofhesperetin

for4

8hruarrMela

nincontent

uarrTy

rosin

asea

ctivity

Not

determ

ined

[46]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asea

ctivity

Not

determ

ined

[50]

Cellsincubatedwith

04m

gmlC

itrus

extractsfor3

daysdarrTy

rosin

asea

ctivity

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Be

nefitso

fhesperid

inon

cutaneou

sfun

ctions

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

EpidermalPerm

eabilityB

arrie

rFun

ction

Youn

gmice

Topicalapp

lications

of2

hesperidin

twice-daily

for6

days

uarrAc

uteb

arrie

rrecovery

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLamellarb

odysecretion

[31]

Agedmice

Topicalapp

lications

of2

hesperidin

twice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrDifferentiatio

nuarrLipidprod

uctio

nuarrNHE1

andsPLA

2expressio

nuarrLamellarb

odyform

ationandsecretion

[32]

Glucocorticoid-tre

ated

mice

One

hour

after

each

topicalapp

licationof

005

clobetasolpropion

ate2

hesperidin

was

applied

Treatm

entsweretwice-daily

for9

days

uarrAc

uteb

arrie

rrecovery

darrSkin

surfa

cepH

uarrProliferatio

nuarrFilaggrin

expressio

nuarrLipidprocessin

guarrAntioxidatio

nuarrLamellarb

odyform

ationandsecretion


ctivity

[33]


ble2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Protectin

gUVIrr

adiatio

n

Keratin

ocytes

Keratin

ocytes

firsttre

ated

with

50120583M

hesperidin

for1

hrfollowed

byUVBirr

adiatio

n(30mJc

m2)

darrDNAdamage

darrlip

idperoxidatio

ndarrProteincarbon

ylation

darrAp

optotic

index

darrAb

sorb

UVB

darrRe

activ

eoxygenspecies

darrBc

l-2expressio

ndarrBA

Xexpressio

n

[34]

Keratin

ocytes

weretreated

with

hesperidin

(220120583gml)

for2

4hrfollowed

byUVA

irradiatio

n(10Jc

m2)Cells

wereincub

ated

with

hesperidin

fora

ddition

al6or

24hr

uarrCellviability

darrMDAcontent

darrTN

F-120572IL-1120573

andIL-6

mRN

ALevels

uarrSO

Dactiv

ity[35]

Keratin

ocytes

weretreated

with

hesperidin

(50100

20040

060

010

00mgL)

for2

4hrfollowed

byUVB

irradiatio

n(15mJc

m2)

darrCX

CR2expressio

nNot

determ

ined

[36]

Dermalfib

roblasts

Fibrob

lasts

irradiatedwith

UVA

atdo

se10Jc

m2and

treated

with

hesperetin

containing

extractatvarious

concentrationfor7

2hr

darrMatrix

metalloproteinase

expressio


ase

expressio


Not

determ

ined

[37]

Pretreated

fibroblastswith

3and30120583M

hesperetin

glucuron

idefollo

wed

byUVA

irradiatio


celldeath

Not

determ

ined

[38]

Mice

Micetreated

topically

with

hesperidin

(3mgml)daily

for10days30min

after

each

applicationof

hesperidin

micew

ereirradiatedwith

180mJc

m2UVB

darrSkin

erythemaamp

edem

adarrEp

idermalproliferatio


ndarrInflammation

darrDNAdamage

uarrCa

talase

andsuperoxide

dism

utasea

ctivity

[39]

Micew

eretreated

topically

1hesperidin

methyl

chalcone

before

andaft

eron

eirradiatio

nwith

414

mJc

m2UVB

darrCy

tokine

expressio


n

uarrNuclear

factor


2uarrGlutathione


redu

ctaseamp

hemeo

xygenase-1

[40]

Hesperid

inmethylchalco

neatthed

oseo

f300

mgkg

was

intraperito

neallygiven1h

rbeforea

nd7hr

after

irradiatio

nwith

414

mJc

m2UVB

darrSkin

edem

aneutroph

ilrecruitm

entand

matrix

metalloproteinase-9

activ

ity

darrCy

tokine

expressio


activ

ity


n

uarrGlutathione

levelsandcatalase

activ

ity

[41]

Orally

administered

01m

Lof

water

containing

100

mgkg

body

weighth

esperid

indailyw

hilemicew

ere

irradiated3tim

esat48

hintervalsp

erweekfor12

weeksD

oeso

fUVBwereincreased

60mJc

m2per

expo

sure

atweek1to90

mJc

m2atweek7

darrTransepiderm

alwater

loss

darrmatrix

metalloproteinase-9

expressio

nampactiv

ity

darrCy

tokine

expressio

ndarrwrin

kleformation

darrEp

idermalproliferatio

n

darrPh

osph

orylationof

mito

genactiv

ated

proteinkinase


kinases

[42]

Sing

leUVBirr

adiatio

natdo

seof

180mJc

m2

darrCy

clobu

tane

pyrim

idine

dimers

uarrp53expressio

nNot

determ

ined

[43]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrTransepiderm

alwater

loss

Not

determ

ined

[44]

Pigm

entatio

n

B16mou

semelanom

acells

Cellsincubatedwith

20120583gmLof

Citru

sextractso

r3-50120583M

ofhesperetin

for4

8hr

uarrMela

nincontent

uarrTy

rosin

asep

rotein

uarrTy

rosin

asea

ctivity

uarrMela

nogenesis

-rela

tedproteins

uarr120573-C

atenin

expressio

nuarrPh

osph

orylated

glycogen

synthase

kinase-3120573

[4546

]

Cellsincub

ated

with

hesperidin

(3225mgmL)

for3

days

Minim

uminhibitio

nof

melanogenesis

Not

determ

ined

[4748]

Cellsw

eretreated

with

hesperidin

(5010020040

060

01000mgL)

for2

4hrfollowed

byUVBirr

adiatio

n(15mJc

m2)

darrTy

rosin

asea

ctivity

darrMela

nincontent

Not

determ

ined

[36]

Cellsincubatedwith

5-20120583M

hesperidin

for3

days

uarrMela

nincontent

Not

determ

ined

[49]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

darrTy

rosin

ase-related

protein12

darrMela

nogenesis

-rela

tedproteins

uarrp-Erk12

uarrProteasomea

ctivity

[50]

Cellsincubatedwith

Citru


120583gmL)

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

ampactiv

ity

darrTy

rosin

ase-related

protein12

darrMicroph


tionfactor

(MITF)

proteins

[51]

Hum

anepidermal

melanocytes

Cellsincubatedwith

3-50120583M

ofhesperetin

for4

8hruarrMela

nincontent

uarrTy

rosin

asea

ctivity

Not

determ

ined

[46]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asea

ctivity

Not

determ

ined

[50]

Cellsincubatedwith

04m

gmlC

itrus

extractsfor3

daysdarrTy

rosin

asea

ctivity

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















ble2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Protectin

gUVIrr

adiatio

n

Keratin

ocytes

Keratin

ocytes

firsttre

ated

with

50120583M

hesperidin

for1

hrfollowed

byUVBirr

adiatio

n(30mJc

m2)

darrDNAdamage

darrlip

idperoxidatio

ndarrProteincarbon

ylation

darrAp

optotic

index

darrAb

sorb

UVB

darrRe

activ

eoxygenspecies

darrBc

l-2expressio

ndarrBA

Xexpressio

n

[34]

Keratin

ocytes

weretreated

with

hesperidin

(220120583gml)

for2

4hrfollowed

byUVA

irradiatio

n(10Jc

m2)Cells

wereincub

ated

with

hesperidin

fora

ddition

al6or

24hr

uarrCellviability

darrMDAcontent

darrTN

F-120572IL-1120573

andIL-6

mRN

ALevels

uarrSO

Dactiv

ity[35]

Keratin

ocytes

weretreated

with

hesperidin

(50100

20040

060

010

00mgL)

for2

4hrfollowed

byUVB

irradiatio

n(15mJc

m2)

darrCX

CR2expressio

nNot

determ

ined

[36]

Dermalfib

roblasts

Fibrob

lasts

irradiatedwith

UVA

atdo

se10Jc

m2and

treated

with

hesperetin

containing

extractatvarious

concentrationfor7

2hr

darrMatrix

metalloproteinase

expressio


ase

expressio


Not

determ

ined

[37]

Pretreated

fibroblastswith

3and30120583M

hesperetin

glucuron

idefollo

wed

byUVA

irradiatio


celldeath

Not

determ

ined

[38]

Mice

Micetreated

topically

with

hesperidin

(3mgml)daily

for10days30min

after

each

applicationof

hesperidin

micew

ereirradiatedwith

180mJc

m2UVB

darrSkin

erythemaamp

edem

adarrEp

idermalproliferatio


ndarrInflammation

darrDNAdamage

uarrCa

talase

andsuperoxide

dism

utasea

ctivity

[39]

Micew

eretreated

topically

1hesperidin

methyl

chalcone

before

andaft

eron

eirradiatio

nwith

414

mJc

m2UVB

darrCy

tokine

expressio


n

uarrNuclear

factor


2uarrGlutathione


redu

ctaseamp

hemeo

xygenase-1

[40]

Hesperid

inmethylchalco

neatthed

oseo

f300

mgkg

was

intraperito

neallygiven1h

rbeforea

nd7hr

after

irradiatio

nwith

414

mJc

m2UVB

darrSkin

edem

aneutroph

ilrecruitm

entand

matrix

metalloproteinase-9

activ

ity

darrCy

tokine

expressio


activ

ity


n

uarrGlutathione

levelsandcatalase

activ

ity

[41]

Orally

administered

01m

Lof

water

containing

100

mgkg

body

weighth

esperid

indailyw

hilemicew

ere

irradiated3tim

esat48

hintervalsp

erweekfor12

weeksD

oeso

fUVBwereincreased

60mJc

m2per

expo

sure

atweek1to90

mJc

m2atweek7

darrTransepiderm

alwater

loss

darrmatrix

metalloproteinase-9

expressio

nampactiv

ity

darrCy

tokine

expressio

ndarrwrin

kleformation

darrEp

idermalproliferatio

n

darrPh

osph

orylationof

mito

genactiv

ated

proteinkinase


kinases

[42]

Sing

leUVBirr

adiatio

natdo

seof

180mJc

m2

darrCy

clobu

tane

pyrim

idine

dimers

uarrp53expressio

nNot

determ

ined

[43]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrTransepiderm

alwater

loss

Not

determ

ined

[44]

Pigm

entatio

n

B16mou

semelanom

acells

Cellsincubatedwith

20120583gmLof

Citru

sextractso

r3-50120583M

ofhesperetin

for4

8hr

uarrMela

nincontent

uarrTy

rosin

asep

rotein

uarrTy

rosin

asea

ctivity

uarrMela

nogenesis

-rela

tedproteins

uarr120573-C

atenin

expressio

nuarrPh

osph

orylated

glycogen

synthase

kinase-3120573

[4546

]

Cellsincub

ated

with

hesperidin

(3225mgmL)

for3

days

Minim

uminhibitio

nof

melanogenesis

Not

determ

ined

[4748]

Cellsw

eretreated

with

hesperidin

(5010020040

060

01000mgL)

for2

4hrfollowed

byUVBirr

adiatio

n(15mJc

m2)

darrTy

rosin

asea

ctivity

darrMela

nincontent

Not

determ

ined

[36]

Cellsincubatedwith

5-20120583M

hesperidin

for3

days

uarrMela

nincontent

Not

determ

ined

[49]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

darrTy

rosin

ase-related

protein12

darrMela

nogenesis

-rela

tedproteins

uarrp-Erk12

uarrProteasomea

ctivity

[50]

Cellsincubatedwith

Citru


120583gmL)

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

ampactiv

ity

darrTy

rosin

ase-related

protein12

darrMicroph


tionfactor

(MITF)

proteins

[51]

Hum

anepidermal

melanocytes

Cellsincubatedwith

3-50120583M

ofhesperetin

for4

8hruarrMela

nincontent

uarrTy

rosin

asea

ctivity

Not

determ

ined

[46]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asea

ctivity

Not

determ

ined

[50]

Cellsincubatedwith

04m

gmlC

itrus

extractsfor3

daysdarrTy

rosin

asea

ctivity

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrTransepiderm

alwater

loss

Not

determ

ined

[44]

Pigm

entatio

n

B16mou

semelanom

acells

Cellsincubatedwith

20120583gmLof

Citru

sextractso

r3-50120583M

ofhesperetin

for4

8hr

uarrMela

nincontent

uarrTy

rosin

asep

rotein

uarrTy

rosin

asea

ctivity

uarrMela

nogenesis

-rela

tedproteins

uarr120573-C

atenin

expressio

nuarrPh

osph

orylated

glycogen

synthase

kinase-3120573

[4546

]

Cellsincub

ated

with

hesperidin

(3225mgmL)

for3

days

Minim

uminhibitio

nof

melanogenesis

Not

determ

ined

[4748]

Cellsw

eretreated

with

hesperidin

(5010020040

060

01000mgL)

for2

4hrfollowed

byUVBirr

adiatio

n(15mJc

m2)

darrTy

rosin

asea

ctivity

darrMela

nincontent

Not

determ

ined

[36]

Cellsincubatedwith

5-20120583M

hesperidin

for3

days

uarrMela

nincontent

Not

determ

ined

[49]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

darrTy

rosin

ase-related

protein12

darrMela

nogenesis

-rela

tedproteins

uarrp-Erk12

uarrProteasomea

ctivity

[50]

Cellsincubatedwith

Citru


120583gmL)

for3

days

darrMela

nincontent

darrTy

rosin

asep

rotein

ampactiv

ity

darrTy

rosin

ase-related

protein12

darrMicroph


tionfactor

(MITF)

proteins

[51]

Hum

anepidermal

melanocytes

Cellsincubatedwith

3-50120583M

ofhesperetin

for4

8hruarrMela

nincontent

uarrTy

rosin

asea

ctivity

Not

determ

ined

[46]

Cellsincubatedwith

50120583M

hesperidin

for3

days

darrMela

nincontent

darrTy

rosin

asea

ctivity

Not

determ

ined

[50]

Cellsincubatedwith

04m

gmlC

itrus

extractsfor3

daysdarrTy

rosin

asea

ctivity

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Enzymaticassayof

mushroo

mtyrosin

ase

darrTy

rosin

asea

ctivity

Not

determ

ined

[49]

1mgmlofC

itrus

extracts

indu

cedover

40

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[52]

175mgmlofcalam

ondin

peelextractcon

taining

hesperidinind

uced

90

inhibitio

nof

tyrosin

ase

activ

ity

Not

determ

ined

[53]

Guineap

igs

Thed

orsalskinwas

expo

sedto

UVB3tim

esaw

eek

(every

otherd

ay)for

2consecutivew

eeksTh

etotal

energy

dose

ofUVBwas

1Jcm2pere

xposureOne


was

topically

applieddaily

totheh

yperpigm


4successiv

eweeks

darrPigm

entatio

nNot

determ

ined

[44]

Reconstructedhu

man

epidermis

Thee

piderm

iswas

treated

topically

with

02

hesperidin

for14days

darrPigm

entatio

nNot

determ

ined

[49]

Hum

ans

Topicalapp

lications

ofcream

containing

04mgml

Citru

sextractsfor

56days

gt8

increase

inskin

brightening

Not

determ

ined

[52]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

CutaneousW

ound

Healin

g

Dermalfib

roblast

Fibrob

lasts

wereincub

ated

with

mixture

containing

0sdot05

mgmlh

esperid

infor2

4or

96hr

uarrWou

ndclo

sure


[54]

Diabetic

rats

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(25-100

mgkg

body

weight)for2

1days

darrWou

ndclo

sure

uarrVEG

F-cAng

-1Tie-2T

GF-120573andSm

ad-23

mRN

Aexpressio

nuarrSO

DandGSH

levels

darrMDAandNOlevels

[55]

Afte

rwou

ndratsw

ereg

iven

oralhesperidin

(10-80

mgkg

body

weight)for2

0days

uarrWou

ndclo

sure

uarrVEG

FR1and

VEG

FR2levels

darrTN

F120572IL-6

uarrSO

DandGSH

levels

darrMDAlevels

[56]

Hum

answ

ithveno

usulcers

Fifte

enpatie

ntsw

eretreated

orallywith

diosminhesperid

in(45050mgtwiced

aily)for

90daysA

nother

15patie

ntstreated

with

pycnogenol(50

mgorally

3tim

esdaily)servedas

controls

Nodifferences

inwou

ndhealingtim

ebetweentwo

grou

psNot

determ

ined

[57]

Fifty

-threep


500mgand52

received

placebofor2

mon

ths

darrWou

ndhealingtim


ratio

nNot

determ

ined

[58]

120574irr

adiatedmice

Micew

ereg

iven

oralhesperidin

(100mgkg

body

weight)on

ce1h

rbefore120574

irradiatio

nWou

ndwas

madep

riortoirr

adiatio

n

uarrWou

ndcontraction

darrWou

ndhealingtim

e

uarrNO

uarrDNAsynthesis

uarrCollagen

uarrHexosam

ine

uarrDensitieso

fboldvessels

andfib

roblasts

[59]

Miceg

iven

125or

10of

hesperidin

ointment

topically

coverin

gthew

holeexcisio

nwou

ndstwice

daily

after

expo

sure

to6GyI3-radiatio

nun

tilcomplete

healingof

wou

nds

uarrWou

ndcontraction

darrWou

ndhealingtim

eAnti-o

xidativ

estre

ss[60]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Inflammation

Mou

seRA

W2647celllin

eIncubatedwith

hesperidin

(5-250120583gml)

darrLipo

polysaccharid

e-indu

cednitricoxide

prod

uctio

nNot

determ

ined

[30]

Incubatedwith

hesperidin

orhesperetin

(40-100120583M)

for3

0minfollowed

bystim

ulationwith

1120583gmLof

Lipo

polysaccharid

e

darrAntioxidativ

estre

ss

darrPG

E2

darrCO

X-2expressio

ndarrNitricoxidep

rodu

ction

darrNF-120581Bactiv

ation

darrJN

K12

andp38ph

osph

orylation

darrI120581B120572

darriN

OSmRN

A

darrAntioxidativ

estre

ss

[61]

Keratin

ocytes

Keratin

ocytes

treated

with

HES

(20120583gmL)

for2

hr

follo

wed

byincubatio

nwith

H2O2for4

8hr

darrIL-8

proteinampmRN

A

darrTN


A

darrCO

X-2expressio

n

darrNF-120581Bactiv

ation

phosph

orylated

I120581B120572

and

phosph

orylated

p38MAPK

[62]

Cellswereincub

ated

with

both

heat-killed

Prop

ionibacterium

acnesa

nd5-50120583gmLof

hesperidin

for2

4hr

darrIL-8

proteinampmRN

A

darrTN


A

Not

determ

ined

[63]

Hum

anskin

explants

Hum

anskin

explantswerep

re-in

cubatedwith

hesperidin

methylchalco

ne(02mgml)andthen

stim

ulated

with

SPfor2

4ho

urs

darrProp

ortio

nof

dilated

vessels

darrTo

talvesselarea

darrIL-8

prod

uctio

n

Not

determ

ined

[64]

Rats

Thirtymin


dextraninjection

hesperidin

(50or

100mgkg

body

weight)was

subcutaneous

injected

darrEd

ema

Not

determ

ined

[65]

Mice

Intraperito

nealinjectionof

hesperidin

(75mgkg)

follo

wingby

subcutaneous

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[66]

Guineap

igs

Hesperid

in(40m

gkg)w

asorallygiven1h

rprio

rto

injectionof

carrageenan

darrEd

ema

Not

determ

ined

[67]


Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

1weekpriortotumor

indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

Dsup

eroxided

ismutaseGSH

reduced

glutathion

eNOn

itricoxide(

NO)PG

E2prosta

glandinE2

VEG

Fvascular

endo

thelialgrow

thfactorM

POm

yeloperoxidaseM

DAm

alon

dialdehydeC

OX2

cyclo

oxygenase-2CO

X-2SP

substa

nceP

DMBA

712

-dim


PA12-O-te

tradecanoyl-13

-phorbolacetateRO

Sreactiv

eoxygenspeciesER

Kextracellular

signal-regulated

kinaseJNK

c-Jun

NH2-term

inalkinaseC

DK2

cyclin

-dependent

kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table2Con

tinued

AnimalMod

elsHum

anDise

asesC

ells

Treatm

ent

Benefits

Mechanism

sRe

f

Skin

Cancers

A431h

uman

skin

carcinom

acells

Incubatio

nof

cells

with

hesperetin

(10100500120583M)for

24hr

uarrDNAfragmentatio

nuarrAp

optotic

proteins

(p21

andBa

x)

darrlevelsof

cyclinA2B1D

1D3andE1

uarrER

KJN

Kp38RO

S[68]

Cellstreated

with

hesperidin

(1025

and50120583M)for

vario

ustim

es

darrCellviability

darrLevelsof

cyclinDC

DK2

andthym

idylates

ynthase

uarrAp

optosis

uarrRO

SdarrAT

Pcontent

[69]

Mice

Subcutaneous

injectionof


solutio

ndaily

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indu

ction

darrIncidenceo

ftum

orand

numbero

ftum

orper

mou

seNot

determ

ined

[70]

NoteSO

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nceP

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NH2-term

inalkinaseC

DK2

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kinase

2













2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of































2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























2O2(100 120583M) treat-







5 Mechanisms




















Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




































Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of

























Abbreviations






Acknowledgments


References
















































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of





























































































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






























































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
































2and F


2release and



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of


















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of


















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















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