areviewofmalaysianmedicinalplantswithpotential anti … · 2019. 7. 30. · susiendrini,3...

Review ArticleA Review of Malaysian Medicinal Plants with PotentialAnti-Inflammatory Activity

Fazleen Izzany Abu Bakar ,1,2 Mohd Fadzelly Abu Bakar ,1,2 Norazlin Abdullah ,1,2

Susi Endrini,3 and Asmah Rahmat1

1Faculty of Applied Sciences and Technology, Universiti Tun Hussein Onn Malaysia (UTHM), Hab Pendidikan Tinggi Pagoh,KM 1, Jalan Panchor, 84600 Muar, Johor, Malaysia2Centre of Research for Sustainable Uses of Natural Resources (CoR-SUNR), Universiti Tun Hussein Onn Malaysia (UTHM),Parit Raja, 86400 Batu Pahat, Johor, Malaysia3Faculty of Medicine, YARSI University, 10510 Jakarta, Indonesia

Correspondence should be addressed to Mohd Fadzelly Abu Bakar; [email protected]

Received 30 January 2018; Revised 25 April 2018; Accepted 20 May 2018; Published 9 July 2018

Academic Editor: Mohammad A. Rashid

Copyright © 2018 Fazleen Izzany Abu Bakar et al. +is is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work isproperly cited.

+is article aims to provide detailed information on Malaysian plants used for treating inflammation. An extensive search onelectronic databases including PubMed, Google Scholar, Scopus, and ScienceDirect and conference papers was done to findrelevant articles on anti-inflammatory activity of Malaysian medicinal plants. +e keyword search terms used were “in-flammation,” “Malaysia,” “medicinal plants,” “mechanisms,” “in vitro,” and “in vivo.” As a result, 96 articles on anti-inflammatoryactivity of Malaysianmedicinal plants were found and further reviewed. Forty-six (46) plants (in vitro) and 30 plants (in vivo) havebeen identified to possess anti-inflammatory activity where two plants, Melicope ptelefolia (Tenggek burung) and Portulacaoleracea (Gelang pasir), were reported to have the strongest anti-inflammatory activity of more than 90% at a concentration of250 µg/ml. It was showed that the activity was mainly due to the occurrence of diverse naturally occurring phytochemicals fromdiverse groups such as flavonoids, coumarins, alkaloids, steroids, benzophenone, triterpenoids, curcuminoids, and cinnamic acid.Hence, this current review is a detailed discussion on the potential of Malaysian medicinal plants as an anti-inflammatory agentfrom the previous studies. However, further investigation on the possible underlying mechanisms and isolation of activecompounds still remains to be investigated.

1. Introduction

A primary physiologic defence mechanism known as in-flammation helps to protect the body from noxious stimuli,resulting in the swelling or edema of tissues, pain, or even celldamage.+emain purpose of this mechanism is to repair andreturn the damaged tissue to the healthy state [1].+e increasein size of the vessels only occurs around the inflammatory loci(i.e., neutrophils, macrophages, and lymphocytes) during theearly stages of inflammation, but after 24 hours, many kindsof cells reach neutrophils, followed by macrophages within 48hours and lymphocytes after several days [1]. It is well knownthat the disruption of cells occurs during inflammationprocesses, leading to the release of arachidonic acid, andfurther undergoes two metabolic pathways known as the

cyclooxygenase (COX) and lipoxygenase (LOX) pathways.COX pathways consist of cyclooxygenase-1 (COX-1) andcyclooxygenase-2 (COX-2), while 5-lipoxygenase (5-LOX),12-lipoxygenase (12-LOX), and 15-lipoxygenase (15-LOX) arethe examples of the LOX pathway. +e products of the COXpathway are prostaglandins (mediators of acute inflamma-tion) and thromboxanes, while those of the LOX pathway areleukotrienes and hydroperoxy fatty acids [2, 3].

Clinically, the common signs of inflammation include pain,heat, redness, loss of function, and swelling on the affectedtissue [4]. Other signs include fever, leukocytosis, and sepsis.+ere are many causes of inflammation such as pathogens(e.g., bacteria, viruses, and fungi), external injuries, and effectsof chemicals or radiation. Inflammation can be classified intotwo categories: acute and chronic inflammation. Acute

HindawiAdvances in Pharmacological SciencesVolume 2018, Article ID 8603602, 13 pageshttps://doi.org/10.1155/2018/8603602

mailto:[email protected]://orcid.org/0000-0001-5366-0991http://orcid.org/0000-0002-3589-9533http://orcid.org/0000-0001-8828-8966https://doi.org/10.1155/2018/8603602

inflammation is considered as the first line of defence againstinjury. It occurs in a short period of time and is manifested bythe excretion of fluid and plasma proteins along with theemigration of leukocytes such as neutrophils. Meanwhile,chronic inflammation takes prolonged duration and is man-ifested by the action of lymphocytes andmacrophages, resultingin fibrosis and tissue necrosis. Inflammation is considered asone of the most common concern of diseases, ranging from theminor to a serious condition like cancer. Based on the recentadvancement in imaging technologies, the chronic vascularinflammation is not involved in atherosclerosis but also inarterial hypertension and metabolic syndrome [5].

Currently, nonsteroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, aspirin, diclofenac, and celecoxib are ex-tensively used for the treatment of inflammation.+ese drugsexhibit their anti-inflammatory properties by inhibiting theCOX-1 activity and thus preventing the synthesis of pros-taglandins [4]. However, the major concern is that NSAIDsmay cause various side effects such as gastrointestinal com-plications [6]. Considering this, the quests for the new drugwith anti-inflammatory properties from the medicinal plantswith free of or fewer side effects are greatly needed for thepharmaceutical industry [7, 8].

Plant-based or herbal medicine has been used traditionallyto treat pain, inflammation, and inflammatory-mediated pain[9]. Malaysia is among the world’s 12 megadiverse countrieswhere endemism is highest. At least a quarter of our tree flora isnot found elsewhere in the world, and many of our herbaceousflora and other groups of species are unique [10]. In Malaysia,about 2000 medicinal plant species are reported to possesshealth benefit properties [11]. Based on nutritional studies,these medicinal plants contain diverse nutritive values andpossess potential bioactive compounds with the activity relatedto the various inflammation disorders including gout [12] orage-related diseases [13]. Hence, this current review aims todisseminate detailed information on the anti-inflammatorypotential of Malaysian medicinal plants, focusing on the bio-active phytochemicals, and mechanisms of action against in-flammation in both in vitro and in vivo studies.

2. Methods

+e bibliographic research was performed in the followingdatabases: PubMed, Google Scholar, Scopus, and Science-Direct, where these databases were searched for relevantstudies which included at least one keyword from each of thefollowing: (i) inflammation, (ii) Malaysia, (iii) medicinalplants, (iv) mechanisms, (v) in vitro, and (vi) in vivo. Nolimit was placed on the search time frame in order to retrieveall relevant papers, and the last search was performed onApril 20, 2018. About 96 papers have been reviewed in-cluding journal articles and proceedings as well as the ref-erence lists of articles for additional relevant studies.

3. Discussion

+e World Health Organization (WHO) defines medicinalplants as plants which possess compounds that can be used forthe therapeutic purposes as well as producing useful drugs

from the metabolites. According to the WHO, medicinalplants are still being used by the people in developingcountries to treat various diseases, and these products’ marketcontinue to grow [14] which gives a good sign of economicimportance of medicinal plants. Based on the previous report,15% out of 300,000 plant species in the world have beenstudied for the pharmacological activity. Interestingly, about25% of modern medicines have been developed from thenatural resources such as medicinal plants [15]. Recently, theresearch on the medicinal plants for the health benefit pur-poses has increased worldwide and gained attention from allresearchers all over the world including Malaysia. Malaysia isknown as a country that is rich in the medicinal plant species.For instance, 1300 medicinal plant species and 7411 plantspecies have been recorded in Peninsular Malaysia and Sabah,respectively [16, 17].

Inflammation is a response of tissue to cell injury due topathogens, damaged tissues, or irritants which initiates thechemical signals to heal the afflicted tissue [18]. +e leu-kocytes such as neutrophils, monocytes, and eosinophils areactivated and migrated to the sites of damage. During theinflammatory processes, the excessive nitric oxide (NO) andprostaglandin E2 (PGE2) as well as proinflammatory cyto-kines (i.e., tumour necrosis factor-alpha (TNF-α) and in-terleukins) are secreted by the activated macrophages. +enitric oxide and prostaglandin productions from the in-ducible nitric oxide synthase (iNOS) and COX-2, re-spectively, are the proinflammatory mediators responsiblefor many inflammatory diseases [19, 20]. Inflammation canbe classified into two types known as acute and chronicinflammation. +e vascular response to inflammation in theearly stage (acute inflammation) can be clearly seen at theaffected tissue as it becomes reddened due to the increase ofblood flow and swollen due to edema fluid. +ree mainprocesses that involve during the vascular response to acuteinflammation are (1) changes in vessel caliber and bloodflow, (2) the increase in vascular permeability, and (3) fluidexudate formation. It is important to understand that anuncontrolled inflammation may contribute to many chronicillnesses [21]. For instance, chronic inflammation may leadto infectious diseases and cancer [22], while the prolongedinflammation may cause abnormal gene expression, geno-mic instability, and neoplasia [23, 24]. Currently, NSAIDsexhibit great effects in inhibiting the activity of COX-1 andCOX-2, but COX-1 inhibitors are reported to exert sideeffects such as gastrointestinal erosions and renal and he-patic insufficiency [25]. COX-2 (Vioxx) also has been re-ported to cause serious cardiovascular events [2]. Toovercome this, many studies on anti-inflammatory drugsfrom natural resources have been conducted. Enzyme in-hibitory assays (i.e., COX and LOX) have been extensivelyused to study the effectiveness of medicinal plants in treatingthe inflammation due to the presence of many phyto-chemicals, and they are being consumed as a food or foodsupplement for many years. +e Malaysian medicinal plantsthat possess an anti-inflammatory activity are shown inTables 1 and 2 for in vitro and in vivo studies, respectively.

Based on the results obtained, many studies used the NOinhibition assay as a method to show the anti-inflammatory

2 Advances in Pharmacological Sciences

Tabl

e1:

+emedicinal

plants

which

areconsidered

topo

ssessanti-inflammatoryactiv

itybasedon

invitrostud

ies.

Scientific

name

Family

Localn

ame

Part/solvent

used

Typesof

assays

Anti-

inflammatory

activ

ity(%

)IC

50Activecompo

unds

References

Agelaea

borneensis

Con

naraceae

Akarrusa-rusa

Bark/m

ethano

lLO

Xinhibitio

n71%–1

00%

at100μg/m

lNA

NA

[26]

Ana

cardium

occidentale

Anacardiaceae

Poko

kgajus

Leaves/m

ethano

lNO

inhibitio

n16.10%

at250μg/m

lNA

NA

[13]

Averrhoa

bilim

biOxalid

aceae

Belim

bing

buluh

Fruits/w

ater

NO

inhibitio

n22.30%

at250μg/m

lNA

NA

[13]

Barrington

iaracemosa

Lecythidaceae

Putatk

ampu

ng

Leaves/chloroform

Griessassay(N

Oinhibitio

n)

57.7%

at100μg/m

l

NA

NA

[27]

Leaves/ethanol

29.80%

at100μg/m

l

Leaves/hexane

42.39%

at100μg/m

lBo

esenbergia

rotund

aZing

iberaceae

Temuku

nci

Rhizom

es/hexane

Griessassay(nitrite

determ

ination)

NA

36.68μM

Boesenbergin

A[28]

Bosw

ellia

serrata

Burseraceae

Salaig

uggula

ndkemenyan

Leaves/m

ethano

lHum

anredbloo

dcell

metho

d80.00%

at2000

μg/m

lNA

NA

[29]

Buchan

ania

insig

nis

Anacardiaceae

Tais/manggahu

tan

Bark/m

ethano

lLO

Xinhibitio

n41%–7

0%at

100μg/m

lNA

NA

[26]

Cana

rium

patentinervium

Burseraceae

Kedon

dong

and

kaju

kedapak

Leaves

andbarks/hexane,

chloroform

,and

ethano

l5-LO

Xinhibitio

nNA

1.76

μMScop

oletin

[30]

Caric

apapaya

Caricaceae

Betik

Leaves/m

ethano

lGriessassay(N

Oinhibitio

n)72.63%

at100μg/m

l60.18μg/m

lNA

[31]

Chiso

cheton

polyan

drus

Meliaceae

Lisi-lisi

Bark/m

ethano

lLO

Xinhibitio

n71%–1

00%

at100μg/m

lNA

NA

[26]

Leaves/hexane,

dichloromethane,and

methano

l

SoybeanLO

Xinhibitio

nassay

NA

0.69

μMand

1.11

μM

Dam

mara-20,24-dien-3-

oneand24-

hydroxydam

mara-20,25-

dien-3-one

[32]

Citrullus

lana

tus

Cucurbitaceae

Tembikai

Fruitp

ulp/petroleum

ether,chloroform

,and

90%

ethano

l

COX-2

inhibitory

activ

ity60–7

0%at

100μM

69μM

CucurbitacinE

[33]

Griessassay(N

Oinhibitio

n)17.6μM

Cosm

oscaud

atus

Asteraceae

Ulam

raja

Leaves/m

ethano

lNO

inhibitio

n15.40%

at250μg/m

lNA

NA

[13]

Crinum

asiaticum

Amaryllid

aceae

Poko

kbaku

ngLeaves/ethanol

NO

inhibitio

nNA

58.5μg/m

lNA

[34]

Curcum

alonga

Zing

iberaceae

Kun

yit

Rhizom

es/hexane-ethyl

acetateandmethano

lCOX-2

inhibitory

activ

ity82.50%

and

58.90%

at125μg/m

lNA

Mon

odem

etho

xycurcum

inand

bisdem

etho

xycurcum

in[35]

Curcum

aman

gga

Zing

iberaceae

Temumangga

Rhizom

es/m

ethano

lNO

inhibitio

n19.20%

at250μg/m

lNA

NA

[13]

Advances in Pharmacological Sciences 3

Tabl

e1:

Con

tinued.

Scientific

name

Family

Localn

ame

Part/solvent

used

Typesof

assays

Anti-

inflammatory

activ

ity(%

)IC

50Activecompo

unds

References

Cythostema

excelsia

Ann

onaceae

Lianas

Leaves

and

stem

s/methano

lLO

Xinhibitio

n41%–7

0%at

100μg/m

lNA

NA

[26]

Desmos

chinensis

Ann

onaceae

Kenanga

hutan

Bark/m

ethano

lLO

Xinhibitio

n41%–7

0%at

100μg/m

lNA

NA

[26]

Eurycoma

longifo

liaSimarou

baceae

Tong

kata

liRo

ot/hydroalcoho

lics

Hum

anredbloo

dcell

mem

branestabilizatio

nmetho

d

70.97%

at1000

μg/m

lNA

NA

[36]

Ficusdelto

idea

Moraceae

Mas

cotek

Leaves/m

ethano

lLO

Xinhibitio

n10.35%

at100μg/m

lNA

NA

[37]

Garcinia

cuspidata

Clusia

ceae

Asam

kand

isBa

rk/m

ethano

lLO

Xinhibitio

n71%–1

00%

at100μg/m

l28.3μg/m

lNA

[26]

Garcinia

subelliptica

Guttiferae

Poko

kpenanti

Seeds/chloroform

Chemical

mediator

released

from

mastc

ell

andneutroph

ilinhibitio

nNA

15.6μM

,18.2μM

,and

20.0μM

GarsubellinA

and

garcinielliptin

oxide

[38]

Gynura

pseudochina

Asteraceae

Poko

kdaun

dewa

Leaves/ethyl

acetate

IL-6/lu

ciferase

assay

NA

11.63μg/m

lNA

[39]

Jatropha

curcas

Euph

orbiaceae

Jarakpagar

Latexandleaves/aqu

eous

methano

lNO

inhibitio

nNA

29.7

and

93.5μg/m

lNA

[40]

Kaempferia

galanga

Zing

iberaceae

Cekur

Rhizom

es/petroleum

ether,chloroform

,methano

l,andwater

COX-2

inhibitory

screeningassay

57.82%

at200μg/m

l0.83

μMEthyl-p

-metho

xycinn

amate

[41]

Labisia

pumila

var.alata

Myrsin

aceae

Kacip

fatim

ahRo

ots/methano

lColorim

etricnitric

oxide

assay(m

acroph

agecell

line)

75.68%

at100μg/m

lNA

NA

[42]

Leucas

linifo

liaLamiaceae

Ketum

bak

Who

leplant/m

ethano

lLO

Xinhibitio

n34%

at100μg/m

lNA

NA

[43]

Litsea

garciae

Lauraceae

Engkala/peng

alaban

Fruits/m

ethano

lLO

Xassay

9.42%

at2mg/ml

NA

NA

[44]

Hyaluronidase

assay

27.70%

at5mg/ml

Melicope

ptelefolia

Rutaceae

Teng

gekbu

rung

Leaves/m

ethano

lNO

inhibitio

n95%

at250μg/m

lNA

p-O-geranylcoum

aric

acid,

koku

saginine,and

scop

aron

e[13,

45]

Soybean15-LOX

inhibitio

nassay

72.3%

Moringa

oleifera

Moringaceae

Kelur

Fruits/ethyl

acetate

NO

inhibitio

nNA

0.136μg/m

l1.67

μM

(1)4-[(20-O

-Acetyl-α

-Lrham

nosyloxy)benzyl]

isothiocyanate

[46]

2.66

μM(2)4-[(30-O

-Acetyl-α

-L-

rham

nosyloxy)benzyl]

isothiocyanate

2.71

μM(3)4-[(40-O

-Acetyl-α

-L-

rham

nosyloxy)benzyl]

isothiocyanate


Tabl

e1:

Con

tinued.

Scientific

name

Family

Localn

ame

Part/solvent

used

Typesof

assays

Anti-

inflammatory

activ

ity(%

)IC

50Activecompo

unds

References

Musa

acum

inata

Musaceae

Pisang

abunipah

Flow

ering

stalk/methano

lGriessassay(N

Oinhibitio

n)71.06%

at100μg/m

l42.24μg/m

lNA

[31]

Ocimum

basilicum

Lamiaceae

Daunselasih

Leaves/m

ethano

lNO

inhibitio

n30.00%

at250μg/m

lNA

NA

[13]

Ocimum

canu

mLamiaceae

Kem

angi

putih

Who

leplant/m

ethano

lLO

Xinhibitio

n32%

at100μg/m

lNA

NA

[43]

Oenan

the

javanica

Apiaceae

Selom

Who

leplant/m

ethano

lGriessassay(N

Oinhibitio

n)75.64%

at100μg/m

l54.12μg/m

lNA

[31]

Orthosip

hon

stam

ineus

Lamiaceae

Misa

ikucing

Leaves/petroleum

ether,

chloroform

,and

methano

lNO

inhibitio

nNA

5.2μM

(eup

atorin)

9.2μM

(sinensetin

)

Eupatorinandsin

ensetin

[47]

Pand

anus

amaryllifolius

Pand

anaceae

Pand

anLeaves/m

ethano

lNO

inhibitio

n34.10%

at250μg/m

lNA

NA

[13]

Persicaria

tenella

Polygonaceae

Daunkesum

Leaves/m

ethano

lNO

inhibitio

n87.80%

at250μg/m

l8μg/m

lNA

[13]

Phaleria

macrocarpa

+ym

elaeaceae

Mahko

tadewa

Mesocarp/methano

l

NO

inhibitio

n

69.50%

at200μg/m

l

NA

NA

[48]

Pericarp/m

ethano

l63.40%

at200μg/m

l

Seeds/methano

l38.10%

at200μg/m

lPiper

sarm

entosum

Piperaceae

Kaduk

Leaves/m

ethano

lGriessassay(N

Oinhibitio

n)62.82%

at100μg/m

l60.24μg/m

lNA

[31]

Pithecellobium

confertum

Fabaceae

Medang

Seeds/methano

lNO

inhibitio

n23.50%

at250μg/m

lNA

NA

[13]

Portulaca

oleracea

Portulacaceae

Gelangpasir

Leaves/m

ethano

lNO

inhibitio

n94.80%

at250μg/m

l44

μg/m

lNA

[13]

Psophocarpus

tetragon

olobus

Fabaceae

Kacangbo

tol

Pod/methano

lGriessassay(N

Oinhibitio

n)39.28%

at100μg/m

l>1

00μg/m

lNA

[31]

Sauropus

androgynus

Phyllanthaceae

Cekur

manis

Leaves/m

ethano

lGriessassay(N

Oinhibitio

n)68.28%

at100μg/m

l58.34μg/m

lNA

[31]

Solanu

mnigrum

Solanaceae

Terung

meranti

Leaves/m

ethano

lNO

inhibitio

n27.60%

at250μg/m

lNA

NA

[13]

Solanu

mtorvum

Solanaceae

Terung

beland

aLeaves

and

fruits/m

ethano

lNO

inhibitio

n25.20%

at250μg/m

lNA

NA

[13]

=ym

usvulgaris

Lamiaceae

Taim

Who

leplant/m

ethano

lLO

Xinhibitio

n62%

at100μg/m

lNA

NA

[43]

Timon

ius

flavescens

Rubiaceae

Batut

Leaves/m

ethano

lLO

Xinhibitio

n71%–1

00%

at100μg/m

l8.9μg/m

lNA

[26]


Tabl

e2:

+emedicinal

plants

which

areconsidered

topo

ssessanti-inflammatoryactiv

itybasedon

invivo

stud

ies.

Scientificname

Family

Localn

ame

Part/solvent

used

Doseof

theextract

Experimentala

nimals

Results

References

Achyran

thes

aspera

Amaranthaceae

Ara

song

sang

Root/ethyl

alcoho

l50,1

00,and

200mg/kg

Wistar

rats

Allthedo

sescaused

significant

redu

ctionin

paw

edem

acomparedto

control

[49]

Ann

ona

muricata

Ann

onaceae

Durian

beland

aLeaves/aqu

eous

ethano

l10–3

00mg/kg

Sprague-Daw

leyrats

Asig

nificantd

ecreaseof

the

concentrationof

the

proinfl

ammatorycytokines

TNF-αandIL-1βwas

observed

[50]

Ardisiacrisp

aMyrsin

aceae

Matapeland

okRo

ot/ethanol

3,10,3

0,100,

and

300mg/kg

ofbo

dyweigh

tSprague-Daw

leyrats

Asig

nificantinh

ibition

(93.34%)

was

observed

incarrageenan-

indu

cededem

ain

ratsat

ado

seof

300mg/kg

[51]

Atylosia

scarabaeoides

Fabaceae

Kara-

kara/kacang

kerara

Leaves/ethanol

150,

300,

and450mg/kg

Swiss

albino

mice

+eextractd

isplayedsig

nificant

inhibitio

nof

inflammation.

Highestinhibitio

nof

pawedem

a(38.38%)at

ado

seof

450mg/kg

after4hof

administratio

n

[52]

Citrullus

lana

tus

Cucurbitaceae

Tembikai

Fruitpu

lp/petroleum

ether,

chloroform

,and

90%ethano

l30

and60

mg/kg

ofbo

dyweigh

tBA

LB/c

mice

CucurbitacinEinhibits

inflammationsig

nificantly

from

thefourth

hour

andisable

torevert

paw

edem

athroughthe

COX-2

inhibitio

n

[33]

Corchorus

capsularis

Malvaceae

Kancing

baju

Leaves/chloroform

20,1

00,and

200mg/kg

BALB

/cmiceandSprague-

Daw

leyrats

+eextractc

ausedsig

nificant

redu

ctionin

thethickn

essof

edem

atou

spaw

forthefirst

6h

[53]

Crinum

asiaticum

Amaryllid

aceae

Poko

kbaku

ngLeaves/m

ethano

l50

mg/kg

oftheextract

Mice

Inhibitio

nof

pawedem

a(94.8%)

[54]

Curcum

aaerugino

saZing

iberaceae

Temuhitam

Rhizom

es/chloroform,

methano

l,andwater

100,

200,

400,

and

800mg/kg

Swiss

miceandWistar

rats

Nosig

nificants

uppressio

nwas

observed

afteroral

administratio

nof

alld

oses

oncarrageenan-indu

cedpaw

edem

a

[55]

Curcum

alonga

Zing

iberaceae

Kun

yit

Rhizom

es/w

ater

200mg/kg

ofbo

dyweigh

tWistar

albino

rats

+eprod

uctio

nof

anti-

inflammatory/proinfl

ammatory

cytokinesisdecreasin

g[56]

Cyathu

laprostrata

Amaranthaceae

Ketum

bar

Leaves/m

ethano

l50,100,and

200mg/kg

Wistar

rats

andSw

issalbino

mice

Allextracts

displayed

asig

nificantdo

se-dependent

inhibitio

nin

thecarrageenan-,

arachido

nicacid-,andxylene-

indu

cedtests

[57]

Dicrano

pteris

linearis

Gleicheniaceae

Resam

Leaves/chloroform

10,1

00,and

200mg/kg

BALB

/cmiceandSprague-

Daw

leyrats

+eextractp

rodu

cedsig

nificant

anti-inflammatoryactiv

itythat

didno

tdependon

thedo

sesof

theextract

[58]


Tabl

e2:

Con

tinued.

Scientificname

Family

Localn

ame

Part/solvent

used

Doseof

theextract

Experimentala

nimals

Results

References

Ficusdelto

idea

Moraceae

Mas

cotek

Who

leplant/w

ater

30,1

00,and

300mg/kg

Sprague-Daw

leyrats

+erats’p

awedem

avolume

redu

cedsig

nificantly

inado

se-

depend

entmanner

[59]

Garcinia

subelliptica

Guttiferae

Poko

kpenanti

Seeds/chloroform

3,10,30,50,and

100µM

Sprague-Daw

leyrats

Apo

tent

inhibitory

effecto

nfM

LP/CB-indu

cedsuperoxide

aniongeneratio

nwas

observed

intheiso

latedcompo

und

garcinielliptin

oxide

[38]

Justicia

gend

arussa

Acanthaceae

Daunrusa

Root/m

ethano

l50

mg/kg

oftheextract

Wistar

rats

80%

and93%

edem

ainhibitio

nat

thethirdandfifth

hours

[60]

Kaempferia

galanga

Zing

iberaceae

Cekur

Rhizom

es/chloroform

2g/kg

oftheextract

MaleSprague-Daw

leyrats

Highest

edem

ainhibitio

n(42.9%

)[41]

Man

ilkara

zapota

Sapo

taceae

Ciku

Leaves/ethyl

acetate

300mg/kg

ofbo

dyweigh

tAlbinoWistar

rats

Inhibitio

nof

paw

edem

a(92.41%)

[61]

Mitragyna

speciosa

Rubiaceae

Biak-biakand

ketom

Leaves/m

ethano

l50,1

00,and

200mg/kg

Sprague-Daw

leyrats

Both

doseso

f100

and200mg/kg

show

edasig

nificantinh

ibition

ofthepaw

edem

a(63%

)[62]

Moringa

oleifera

Moringaceae

Kelur

Leaves/w

ater

10,3

0,and100mg/kg

BALB

/cmiceandSprague-

Daw

leyrats

Highest

edem

ainhibitio

n(66.7%

)at

thesecond

hour

at100mg/kg

ofdo

se[63]

Mun

tingia

calabu

raMun

tingiaceae

Keruk

upsia

mLeaves/w

ater

27mg/kg,1

35mg/kg,

and270mg/kg

Sprague-Daw

leyrats

+eextractw

asfoun

dto

exhibit

aconcentration-independ

ent


ity[64]

Orthosip

hon

stam

ineus

Lamiaceae

Misa

ikucing

Leaves/m

ethano

l:water

125,

250,

500,

and

1000

mg/kg

Charle

sRivermiceand

Sprague-Daw

leyrats

Increase

inedem

ainhibitio

n(26.79%)

[65]

Peperomia

pellu

cida

Piperaceae

Ketum

pang

anair

Who

leplant/p

etroleum

ether

1000

mg/kg

Sprague-Daw

leyrats

+eextracts

howed

significant

inhibitio

nin

magnitude

ofsw

ellin

gafter4hof

administratio

n

[66]

Phyllanthu

sacidus

Phyllanthaceae

Cermai

Leaves/m

ethano

l,ethyl

acetate,andpetroleum

ether

250and500mg/kg

Wistar

rats

andalbino

mice

Alltheextracts

show

edredu

ctionin

carrageenan-

indu

cedpawedem

awith

high

est

inhibitio

n(90.91%)in

the

methano

lextract

[67]

Physalis

minim

aSolanaceae

Poko

kletup-

letup

Who

leplant/m

ethano

land

chloroform

fractio

n200and400mg/kg

NMRI

miceandWistar

rats

Crude

extracta

ndchloroform

fractio

nshow

edhigh

est

inhibitio

nof

pawedem

aat

66%

and68%

at400mg/kg,

respectiv

ely

[68]

Piper

sarm

entosum

Piperaceae

Kaduk

Leaves/w

ater

30–3

00mg/kg

ofthe

extract

Sprague-Daw

leyrats

and

maleBA

LB/c

mice

Alldo

sesexertedanti-

inflammatoryactiv

ityin

ado

se-

depend

entmanner

[69]


Tabl

e2:

Con

tinued.

Scientificname

Family

Localn

ame

Part/solvent

used

Doseof

theextract

Experimentala

nimals

Results

References

Polygonu

mminus

Polygonaceae

Kesum

Aerialp

arts/w

ater

100mg/kg

and

300mg/kg

Wistar

albino

rats

+eextracts

significantly

redu

cedthepaw

edem

avolume

intherats

after4h

[70]

Sand

oricum

koetjape

Meliaceae

Sentul

Stem

s/methano

l5mg/ear

BALB

/cmice

Asig

nificantinh

ibition

(94%

)in

TPA-in

ducededem

awas

observed

intheiso

lated

compo

und3-oxo-12-oleanen-

29-oic

acid

[71]

Solanu

mnigrum

Solanaceae

Terung

meranti

Leaves/w

ater

10,5

0,and100%

ofconcentration

BALB

/cmiceandSprague-

Daw

leyrats

Extracts

prod

uceapparently

two-ph

aseanti-inflammatory

activ

ity:the

firstph

aseb

etween1

and2handthesecond

phase

between5and7hafter

carrageenanadministratio

n

[72]

Stachytarpheta

jamaicensis

Verbenaceae

Selasih

dand

iLeaves/ethanol

50,1

00,and

150mg/kg

BALB

/calbino

strain

mice

andSprague-Daw

leyrats

Asig

nificantdo

se-dependent


itywas

observed

30min

afterthe

administratio

nof

theextracta

talld

oses

[73]

Vitexnegund

oLamiaceae

Legund

iLeaves/ethanol

2mg/ear

Mice

+ee

xtractshow

edan

inhibitory

activ

ityof

54.1%

[74]

Zingiber

zerumbet

Zing

iberaceae

Lempo

yang

Rhizom

es/m

ethano

l

25,5

0,and100mg/kg

BALB

/cmice

Asig

nificantantiedemaactiv

itywas

observed

atalld

oses

inado

se-dependent

manner(i.e.,

50and100mg/kg

dosesof

the

extracte

xhibitedactiv

ityat

90min

afteradministratio

n,while

25mg/kg

exhibitedat

150min)

[75]

5,10,5

0,and100mg/kg

ICRmice

+eiso

latedcompo

und

(zerum

bone)sig

nificantly

show

eddo

se-dependent

inhibitio

nof

paw

edem

aindu

cedby

carrageenanat

all

doses(5,10,50,and

100mg/kg)

inmicewith

percentage

ofinhibitio

nof

33.3,66.7,83.3,and

83.3%,respectively

[76]


activity of the plants. Many diseases such as rheumatoidarthritis, diabetes, and hypertension have been reported tobe occurred due to the excessive production of NO [77]. NOis synthesized by inducible NO synthase which has threeisomers: (i) neuronal nitric oxide synthase (nNOS), (ii)endothelial nitric oxide synthase (eNOS), and (iii) iNOS[78]. For instance, signaling molecules such as mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B(NF-κB), activator protein-1 (AP-1), and signal transducerand activator of transcription (STAT) regulate the inducibleenzyme (i.e., iNOS), which then make this enzyme to beexpressed in some tissues [79]. Apart from the nitric oxideinhibition assay, some studies used the LOX assay in order toevaluate the anti-inflammatory of the plants. In thismechanism, arachidonic acid is metabolized by 5-LOX tovarious forms of inflammatory leukotrienes such as leu-kotriene (LT) A4, LTB4, LTC4, LTD4, and LTE4 [80], whereLTB4 (one of the mediators of inflammation) is reported tobe the most crucial in the inflammatory response [81]. Tosupport this, it is reported that patients with rheumatoidarthritis and inflammatory bowel disease possess high levelsof LTB4 [82, 83]. In addition, LTs are reported to be linkedwith few diseases such as bronchial asthma and skin in-flammatory disorders [84]. In 2011, Kwon et al. [85]demonstrated that esculetin, one of the examples of cou-marins, exhibited anti-inflammatory activity in vivo againstanimal models of skin inflammation. In the LOX assay, anyLOX inhibitors will reduce Fe3+ to Fe2+, providing a rapidcolorimetric assay [26]. Another common assay in de-termining the anti-inflammatory activity is COX. Twoisoforms of COX, COX-1 (mainly involved in physiologicalfunctions and constitutively expressed) and COX-2 (in-volved in inflammation and induced in the inflamed tissue),are the enzymes responsible for the synthesis of prosta-glandins [86]. Besides, the COX-2 gene is also a gene foriNOS induced during inflammation and cell growth [87].+e Griess assay is another assay commonly used in themurine macrophage cell line (RAW 264.7) as a culturemedium in the cell-based study in order to determine theconcentration of nitrite (NO2−), the stable metabolite of NO.

Based on Table 1 (in vitro study), 46 plants have beenidentified and studied for the anti-inflammatory activityfrom the previous studies. As a result, only two plants havebeen reported to exhibit more than 90% of anti-inflammatory activity using the nitric oxide inhibition as-say, which were Melicope ptelefolia (Tenggek burung) andPortulaca oleracea (Gelang pasir) with the values of 95.00%and 94.80% at 250 µg/ml, respectively [13]. Besides that,many previous studies had reported the plants which exertedanti-inflammatory activity between 70% and 80% at100 µg/ml to 2000 µg/ml which can be considered to behigher such as Jatropha curcas (Jarak pagar), Curcumalonga (Kunyit), Boswellia serrata (Kemenyan), Labisiapumila (Kacip fatimah), Oenanthe javanica (Selom),Carica papaya (Betik), and Eurycoma longifolia (Tongkat ali)with the values of 86.00%, 82.50%, 80.00%, 75.68%, 75.64%,72.63%, and 70.97%, respectively [29, 31, 35, 36, 40, 42].+e moderate result of anti-inflammatory activity(50%–60%) also had been showed by several plants such as

Phaleria macrocarpa (69.50%), Sauropus androgynus(68.28%), Piper sarmentosum (62.82%), =ymus vulgaris(62.00%), Barringtonia racemosa (57.70%), and Kaempferiagalanga (57.82%) at 100 µg/ml to 2000 µg/ml[27, 31, 41, 43, 48]. In addition, plants from the Zingiber-aceae, Lamiaceae, Annonaceae, and Fabaceae families havebeen studied extensively for the anti-inflammatory activity.Among these families, the active compound of Curcumalonga from the Zingiberaceae family, mono-demethoxycurcumin, had the highest activity with 82.50% at125 µg/ml [35]. Of the other study, Kaempferia galanga fromthe Zingiberaceae family exhibited moderate activity with57.82% at 200 µg/ml where the isolated compound, ethyl-p-methoxycinnamate, was found to have anti-inflammatoryactivity via inhibiting the actions of COX-1 and COX-2[41]. In the Lamiaceae family, =ymus vulgaris showed thehighest percentage of anti-inflammatory activity compared toother plants with 62% at 100 µg/ml [43], with the totalphenolic content of 350 µg GAE/ml.

In this study, it was found that the results of anti-inflammatory activity of the methanolic extract of the leavesof Melicope ptelefolia (Tenggek burung) varied between twoprevious studies due to the different types of assays used byboth studies: nitric oxide inhibition and soybean 15-lip-oxygenase inhibition assays with the values of 95% and 72.3%,respectively [13, 45]. Another study also reported that the anti-inflammatory activity of the methanolic extract of Litseagarciae fruits showed 9.42% (lipoxygenase assay) and 27.70%(hyaluronidase assay) [44]. Based on these results, it can beconcluded that different assays used might produce differentresults. For the COX inhibition assay, all the curcumins isolatedfrom Curcuma longa rhizomes (i.e., curcumin I, curcumin II(monodemethoxycurcumin), and curcumin III (bisdeme-thoxycurcumin)) displayed greater inhibition of COX-2compared to COX-1 at the same test concentration [35].For the Griess assay, all the species tested such as the leaves ofCarica papaya, Sauropus androgynus, and Piper sarmentosum,the flowering stalk ofMusa acuminata, and the whole plant ofOenanthe javanica displayed significant NO inhibitory activityin a concentration-dependent manner against IFN-c/LPS-treated macrophages [31].

For the in vivo study (Table 2), 30 plants have beenidentified in this study for the anti-inflammatory activity.Many of the studies from the previous years used thecarrageenan-induced rat paw edema method (a reliableinflammation model) as this carrageenan has been found tobe more trenchant in producing the edema compared toformalin [88]. It is also one of the conventional methodsused to evaluate the anti-inflammatory effect of drugs ormedicinal plants at the acute stage [89] and involves a bi-phasic event. Normally, the release of histamine and sero-tonin happens in the early phase (1-2 h), while the secondphase (3–5 h) involves the release of prostaglandins andkinins [90, 91]. For the edema formation, the rat paw isinjected with carrageenan. +is method is also a COX-dependent reaction with the control of arachidonate COX[92]. +e ability of the plant extracts to lessen the thicknessof the rats’ paw edema indicates the ability of these plantextracts to exert the anti-inflammatory properties. Based on


Table 2, the highest dose of the extract used was 1000mg/kgof body weight, while the lowest one was 3mg/kg of bodyweight. Most of the previous studies reported that the extractwas able to inhibit paw edema induced by carrageenan. Forinstance, a significant highest paw edema inhibition(93.34%) was observed in rats at a dose of 300mg/kg of theArdisia crispa (Mata pelandok) root extract [51]. Anotherstudy also showed that a significant highest inhibition wasobserved in two isolated compounds from Sandoricumkoetjape stems, 3-oxo-12-oleanen-29-oic acid and katonicacid with 94% and 81%, respectively, where 3-oxo-olean-12-en-29-oic acid had the percentage inhibition almost similarto the reference drug, indomethacin (97%) [71].

Based on the results obtained, few studies isolated thebioactive compounds to be further analyzed for the anti-inflammatory activity such as flavonoids (boesenbergin A,eupatorin, and sinensetin), coumarins (scopoletin andscoparone), triterpenoids (dammara-20,24-dien-3-one and24-hydroxydammara-20,25-dien-3-one), steroids (cucurbitacinE), curcuminoids (monodemethoxycurcumin and bisdeme-thoxycurcumin), benzophenones (garsubellin A and garci-nielliptin oxide), cinnamic acid (ethyl-p-methoxycinnamate),alkaloids (kokusaginine), benzene (p-O-geranylcoumaric acid),4-[(20-O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate,4-[(30-O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate,and 4-[(40-O-acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate[28, 30, 32, 33, 35, 38, 41, 45–47]. Interestingly, some ofthem exerted significant inhibition on inflammation. In 2000,Abad et al. [93] evaluated the common anti-inflammatory drugnaproxene isolated from Musa acuminate (pisang abu nipah)which exhibited good inhibition in COX-1 and COX-2 ac-tivities. Besides, in Carica papaya leaves, coumarin was isolatedand exerted anti-inflammatory activity by suppressing thecytokine TNF-α production [94, 95]. A compound known asdammara-20,24-dien-3-one was isolated from Chisochetonpolyandrus and displayed good inhibition of both human5-LOX and COX-2 [32]. Flavonoids have been confirmed by invitro studies to be able to suppress iNOS expression and toprevent nitric oxide production, depending on their structureor subclass of flavonoids for the strength level [96].

4. Conclusion

In overall, this review clearly demonstrates the potential ofMalaysianmedicinal plants as anti-inflammatory agents inwhichMelicope ptelefolia (Tenggek burung) and Portulaca oleracea(Gelang pasir) were found to exhibit potent anti-inflammatoryactivity in vitro. Pharmacological studies revealed that chemicaldiverse groups of naturally occurring substances derived from theplants show promising anti-inflammatory activity. +erefore,this review suggests further research needs to be carried out onthe bioactive compounds present in the particular plants whichhave a potential to treat an inflammation and the possible un-derlying mechanisms of inflammation.

Conflicts of Interest

+e authors do not have any conflicts of interest regardingthe content of the present work.

Acknowledgments

+is research was financially supported by Universiti TunHussein Onn Malaysia (UTHM) (Vot No. U758, U673, andU908).

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