# A Review of Malaysian Medicinal Plants with Potential Anti-Inflammatory Activity

Authors: Fazleen Izzany Abu Bakar; Mohd Fadzelly Abu Bakar; Norazlin Abdullah; Susi Endrini; Asmah Rahmat
Journal: Advances in Pharmacological Sciences
 (2018)

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## Abstract

This article aims to provide detailed information on Malaysian plants used for treating inflammation. An extensive search on electronic databases including PubMed, Google Scholar, Scopus, and ScienceDirect and conference papers was done to find relevant articles on anti-inflammatory activity of Malaysian medicinal plants. The keyword search terms used were “inflammation,” “Malaysia,” “medicinal plants,” “mechanisms,” “in vitro,” and “in vivo.” As a result, 96 articles on anti-inflammatory activity of Malaysian medicinal plants were found and further reviewed. Forty-six (46) plants (in vitro) and 30 plants (in vivo) have been identified to possess anti-inflammatory activity where two plants, Melicope ptelefolia (Tenggek burung) and Portulaca oleracea (Gelang pasir), were reported to have the strongest anti-inflammatory activity of more than 90% at a concentration of 250 µg/ml. It was showed that the activity was mainly due to the occurrence of diverse naturally occurring phytochemicals from diverse 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 agent from the previous studies. However, further investigation on the possible underlying mechanisms and isolation of active compounds still remains to be investigated.


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## Body

## 1. Introduction

A primary physiologic defence mechanism known as inflammation helps to protect the body from noxious stimuli, resulting in the swelling or edema of tissues, pain, or even cell damage. The main purpose of this mechanism is to repair and return the damaged tissue to the healthy state [1]. The increase in size of the vessels only occurs around the inflammatory loci (i.e., neutrophils, macrophages, and lymphocytes) during the early stages of inflammation, but after 24 hours, many kinds of cells reach neutrophils, followed by macrophages within 48 hours and lymphocytes after several days [1]. It is well known that the disruption of cells occurs during inflammation processes, leading to the release of arachidonic acid, and further undergoes two metabolic pathways known as the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. COX pathways consist of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), while 5-lipoxygenase (5-LOX), 12-lipoxygenase (12-LOX), and 15-lipoxygenase (15-LOX) are the examples of the LOX pathway. The products of the COX pathway are prostaglandins (mediators of acute inflammation) and thromboxanes, while those of the LOX pathway are leukotrienes and hydroperoxy fatty acids [2, 3].Clinically, the common signs of inflammation include pain, heat, redness, loss of function, and swelling on the affected tissue [4]. Other signs include fever, leukocytosis, and sepsis. There are many causes of inflammation such as pathogens (e.g., bacteria, viruses, and fungi), external injuries, and effects of chemicals or radiation. Inflammation can be classified into two categories: acute and chronic inflammation. Acute inflammation is considered as the first line of defence against injury. It occurs in a short period of time and is manifested by the excretion of fluid and plasma proteins along with the emigration of leukocytes such as neutrophils. Meanwhile, chronic inflammation takes prolonged duration and is manifested by the action of lymphocytes and macrophages, resulting in fibrosis and tissue necrosis. Inflammation is considered as one of the most common concern of diseases, ranging from the minor to a serious condition like cancer. Based on the recent advancement in imaging technologies, the chronic vascular inflammation is not involved in atherosclerosis but also in arterial hypertension and metabolic syndrome [5].Currently, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin, diclofenac, and celecoxib are extensively used for the treatment of inflammation. These drugs exhibit their anti-inflammatory properties by inhibiting the COX-1 activity and thus preventing the synthesis of prostaglandins [4]. However, the major concern is that NSAIDs may cause various side effects such as gastrointestinal complications [6]. Considering this, the quests for the new drug with anti-inflammatory properties from the medicinal plants with free of or fewer side effects are greatly needed for the pharmaceutical industry [7, 8].Plant-based or herbal medicine has been used traditionally to treat pain, inflammation, and inflammatory-mediated pain [9]. Malaysia is among the world’s 12 megadiverse countries where endemism is highest. At least a quarter of our tree flora is not found elsewhere in the world, and many of our herbaceous flora and other groups of species are unique [10]. In Malaysia, about 2000 medicinal plant species are reported to possess health benefit properties [11]. Based on nutritional studies, these medicinal plants contain diverse nutritive values and possess potential bioactive compounds with the activity related to the various inflammation disorders including gout [12] or age-related diseases [13]. Hence, this current review aims to disseminate detailed information on the anti-inflammatory potential of Malaysian medicinal plants, focusing on the bioactive phytochemicals, and mechanisms of action against inflammation in both in vitro and in vivo studies.


## 2. Methods

The bibliographic research was performed in the following databases: PubMed, Google Scholar, Scopus, and ScienceDirect, where these databases were searched for relevant studies which included at least one keyword from each of the following: (i) inflammation, (ii) Malaysia, (iii) medicinal plants, (iv) mechanisms, (v)in vitro, and (vi) in vivo. No limit was placed on the search time frame in order to retrieve all relevant papers, and the last search was performed on April 20, 2018. About 96 papers have been reviewed including journal articles and proceedings as well as the reference lists of articles for additional relevant studies.


## 3. Discussion

The World Health Organization (WHO) defines medicinal plants as plants which possess compounds that can be used for the therapeutic purposes as well as producing useful drugs from the metabolites. According to the WHO, medicinal plants are still being used by the people in developing countries to treat various diseases, and these products’ market continue to grow [14] which gives a good sign of economic importance of medicinal plants. Based on the previous report, 15% out of 300,000 plant species in the world have been studied for the pharmacological activity. Interestingly, about 25% of modern medicines have been developed from the natural resources such as medicinal plants [15]. Recently, the research on the medicinal plants for the health benefit purposes has increased worldwide and gained attention from all researchers all over the world including Malaysia. Malaysia is known as a country that is rich in the medicinal plant species. For instance, 1300 medicinal plant species and 7411 plant species have been recorded in Peninsular Malaysia and Sabah, respectively [16, 17].Inflammation is a response of tissue to cell injury due to pathogens, damaged tissues, or irritants which initiates the chemical signals to heal the afflicted tissue [18]. The leukocytes such as neutrophils, monocytes, and eosinophils are activated and migrated to the sites of damage. During the inflammatory processes, the excessive nitric oxide (NO) and prostaglandin E2 (PGE2) as well as proinflammatory cytokines (i.e., tumour necrosis factor-alpha (TNF-α) and interleukins) are secreted by the activated macrophages. The nitric oxide and prostaglandin productions from the inducible nitric oxide synthase (iNOS) and COX-2, respectively, are the proinflammatory mediators responsible for many inflammatory diseases [19, 20]. Inflammation can be classified into two types known as acute and chronic inflammation. The vascular response to inflammation in the early stage (acute inflammation) can be clearly seen at the affected tissue as it becomes reddened due to the increase of blood flow and swollen due to edema fluid. Three main processes that involve during the vascular response to acute inflammation are (1) changes in vessel caliber and blood flow, (2) the increase in vascular permeability, and (3) fluid exudate formation. It is important to understand that an uncontrolled inflammation may contribute to many chronic illnesses [21]. For instance, chronic inflammation may lead to infectious diseases and cancer [22], while the prolonged inflammation may cause abnormal gene expression, genomic instability, and neoplasia [23, 24]. Currently, NSAIDs exhibit great effects in inhibiting the activity of COX-1 and COX-2, but COX-1 inhibitors are reported to exert side effects such as gastrointestinal erosions and renal and hepatic insufficiency [25]. COX-2 (Vioxx) also has been reported to cause serious cardiovascular events [2]. To overcome this, many studies on anti-inflammatory drugs from natural resources have been conducted. Enzyme inhibitory assays (i.e., COX and LOX) have been extensively used to study the effectiveness of medicinal plants in treating the inflammation due to the presence of many phytochemicals, and they are being consumed as a food or food supplement for many years. The Malaysian medicinal plants that possess an anti-inflammatory activity are shown in Tables 1 and 2 for in vitro and in vivo studies, respectively.Table 1
The medicinal plants which are considered to possess anti-inflammatory activity based onin vitro studies.
Scientific name
Family
Local name
Part/solvent used
Types of assays
Anti-inflammatory activity (%)
IC50
Active compounds
References
Agelaea borneensis
Connaraceae
Akar rusa-rusa
Bark/methanol
LOX inhibition
71%–100% at 100μg/ml
NA
NA
[26]
Anacardium occidentale
Anacardiaceae
Pokok gajus
Leaves/methanol
NO inhibition
16.10% at 250μg/ml
NA
NA
[13]
Averrhoa bilimbi
Oxalidaceae
Belimbing buluh
Fruits/water
NO inhibition
22.30% at 250μg/ml
NA
NA
[13]
Barringtonia racemosa
Lecythidaceae
Putat kampung
Leaves/chloroform
Griess assay (NO inhibition)
57.7% at 100μg/ml
NA
NA
[27]
Leaves/ethanol
29.80% at 100μg/ml
Leaves/hexane
42.39% at 100μg/ml
Boesenbergia rotunda
Zingiberaceae
Temu kunci
Rhizomes/hexane
Griess assay (nitrite determination)
NA
36.68μM
Boesenbergin A
[28]
Boswellia serrata
Burseraceae
Salai guggul and kemenyan
Leaves/methanol
Human red blood cell method
80.00% at 2000μg/ml
NA
NA
[29]
Buchanania insignis
Anacardiaceae
Tais/mangga hutan
Bark/methanol
LOX inhibition
41%–70% at 100μg/ml
NA
NA
[26]
Canarium patentinervium
Burseraceae
Kedondong and kaju kedapak
Leaves and barks/hexane, chloroform, and ethanol
5-LOX inhibition
NA
1.76μM
Scopoletin
[30]
Carica papaya
Caricaceae
Betik
Leaves/methanol
Griess assay (NO inhibition)
72.63% at 100μg/ml
60.18μg/ml
NA
[31]
Chisocheton polyandrus
Meliaceae
Lisi-lisi
Bark/methanol
LOX inhibition
71%–100% at 100μg/ml
NA
NA
[26]
Leaves/hexane, dichloromethane, and methanol
Soybean LOX inhibition assay
NA
0.69μM and 1.11 μM
Dammara-20,24-dien-3-one and 24-hydroxydammara-20,25-dien-3-one
[32]
Citrullus lanatus
Cucurbitaceae
Tembikai
Fruit pulp/petroleum ether, chloroform, and 90% ethanol
COX-2 inhibitory activity
60–70% at 100μM
69μM
Cucurbitacin E
[33]
Griess assay (NO inhibition)
17.6μM
Cosmos caudatus
Asteraceae
Ulam raja
Leaves/methanol
NO inhibition
15.40% at 250μg/ml
NA
NA
[13]
Crinum asiaticum
Amaryllidaceae
Pokok bakung
Leaves/ethanol
NO inhibition
NA
58.5μg/ml
NA
[34]
Curcuma longa
Zingiberaceae
Kunyit
Rhizomes/hexane-ethyl acetate and methanol
COX-2 inhibitory activity
82.50% and 58.90% at 125μg/ml
NA
Monodemethoxycurcumin and bisdemethoxycurcumin
[35]
Curcuma mangga
Zingiberaceae
Temu mangga
Rhizomes/methanol
NO inhibition
19.20% at 250μg/ml
NA
NA
[13]
Cythostema excelsia
Annonaceae
Lianas
Leaves and stems/methanol
LOX inhibition
41%–70% at 100μg/ml
NA
NA
[26]
Desmos chinensis
Annonaceae
Kenanga hutan
Bark/methanol
LOX inhibition
41%–70% at 100μg/ml
NA
NA
[26]
Eurycoma longifolia
Simaroubaceae
Tongkat ali
Root/hydroalcoholics
Human red blood cell membrane stabilization method
70.97% at 1000μg/ml
NA
NA
[36]
Ficus deltoidea
Moraceae
Mas cotek
Leaves/methanol
LOX inhibition
10.35% at 100μg/ml
NA
NA
[37]
Garcinia cuspidata
Clusiaceae
Asam kandis
Bark/methanol
LOX inhibition
71%–100% at 100μg/ml
28.3μg/ml
NA
[26]
Garcinia subelliptica
Guttiferae
Pokok penanti
Seeds/chloroform
Chemical mediator released from mast cell and neutrophil inhibition
NA
15.6μM, 18.2 μM, and 20.0 μM
Garsubellin A and garcinielliptin oxide
[38]
Gynura pseudochina
Asteraceae
Pokok daun dewa
Leaves/ethyl acetate
IL-6/luciferase assay
NA
11.63μg/ml
NA
[39]
Jatropha curcas
Euphorbiaceae
Jarak pagar
Latex and leaves/aqueous methanol
NO inhibition
NA
29.7 and 93.5μg/ml
NA
[40]
Kaempferia galanga
Zingiberaceae
Cekur
Rhizomes/petroleum ether, chloroform, methanol, and water
COX-2 inhibitory screening assay
57.82% at 200μg/ml
0.83μM
Ethyl-p-methoxycinnamate
[41]
Labisia pumila var. alata
Myrsinaceae
Kacip fatimah
Roots/methanol
Colorimetric nitric oxide assay (macrophage cell line)
75.68% at 100μg/ml
NA
NA
[42]
Leucas linifolia
Lamiaceae
Ketumbak
Whole plant/methanol
LOX inhibition
34% at 100μg/ml
NA
NA
[43]
Litsea garciae
Lauraceae
Engkala/pengalaban
Fruits/methanol
LOX assay
9.42% at 2 mg/ml
NA
NA
[44]
Hyaluronidase assay
27.70% at 5 mg/ml
Melicope ptelefolia
Rutaceae
Tenggek burung
Leaves/methanol
NO inhibition
95% at 250μg/ml
NA
p-O-geranylcoumaric acid, kokusaginine, and scoparone
[13, 45]
Soybean 15-LOX inhibition assay
72.3%
Moringa oleifera
Moringaceae
Kelur
Fruits/ethyl acetate
NO inhibition
NA
0.136μg/ml1.67 μM
(1) 4-[(20-O-Acetyl-α-L rhamnosyloxy)benzyl]isothiocyanate
[46]
2.66μM
(2) 4-[(30-O-Acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate
2.71μM
(3) 4-[(40-O-Acetyl-α-L-rhamnosyloxy)benzyl]isothiocyanate
Musa acuminata
Musaceae
Pisang abu nipah
Flowering stalk/methanol
Griess assay (NO inhibition)
71.06% at 100μg/ml
42.24μg/ml
NA
[31]
Ocimum basilicum
Lamiaceae
Daun selasih
Leaves/methanol
NO inhibition
30.00% at 250μg/ml
NA
NA
[13]
Ocimum canum
Lamiaceae
Kemangi putih
Whole plant/methanol
LOX inhibition
32% at 100μg/ml
NA
NA
[43]
Oenanthe javanica
Apiaceae
Selom
Whole plant/methanol
Griess assay (NO inhibition)
75.64% at 100μg/ml
54.12μg/ml
NA
[31]
Orthosiphon stamineus
Lamiaceae
Misai kucing
Leaves/petroleum ether, chloroform, and methanol
NO inhibition
NA
5.2μM (eupatorin)9.2 μM (sinensetin)
Eupatorin and sinensetin
[47]
Pandanus amaryllifolius
Pandanaceae
Pandan
Leaves/methanol
NO inhibition
34.10% at 250μg/ml
NA
NA
[13]
Persicaria tenella
Polygonaceae
Daun kesum
Leaves/methanol
NO inhibition
87.80% at 250μg/ml
8μg/ml
NA
[13]
Phaleria macrocarpa
Thymelaeaceae
Mahkota dewa
Mesocarp/methanol
NO inhibition
69.50% at 200μg/ml
NA
NA
[48]
Pericarp/methanol
63.40% at 200μg/ml
Seeds/methanol
38.10% at 200μg/ml
Piper sarmentosum
Piperaceae
Kaduk
Leaves/methanol
Griess assay (NO inhibition)
62.82% at 100μg/ml
60.24μg/ml
NA
[31]
Pithecellobium confertum
Fabaceae
Medang
Seeds/methanol
NO inhibition
23.50% at 250μg/ml
NA
NA
[13]
Portulaca oleracea
Portulacaceae
Gelang pasir
Leaves/methanol
NO inhibition
94.80% at 250μg/ml
44μg/ml
NA
[13]
Psophocarpus tetragonolobus
Fabaceae
Kacang botol
Pod/methanol
Griess assay (NO inhibition)
39.28% at 100μg/ml
>100μg/ml
NA
[31]
Sauropus androgynus
Phyllanthaceae
Cekur manis
Leaves/methanol
Griess assay (NO inhibition)
68.28% at 100μg/ml
58.34μg/ml
NA
[31]
Solanum nigrum
Solanaceae
Terung meranti
Leaves/methanol
NO inhibition
27.60% at 250μg/ml
NA
NA
[13]
Solanum torvum
Solanaceae
Terung belanda
Leaves and fruits/methanol
NO inhibition
25.20% at 250μg/ml
NA
NA
[13]
Thymus vulgaris
Lamiaceae
Taim
Whole plant/methanol
LOX inhibition
62% at 100μg/ml
NA
NA
[43]
Timonius flavescens
Rubiaceae
Batut
Leaves/methanol
LOX inhibition
71%–100% at 100μg/ml
8.9μg/ml
NA
[26]Table 2
The medicinal plants which are considered to possess anti-inflammatory activity based onin vivo studies.
Scientific name
Family
Local name
Part/solvent used
Dose of the extract
Experimental animals
Results
References
Achyranthes aspera
Amaranthaceae
Ara songsang
Root/ethyl alcohol
50, 100, and 200 mg/kg
Wistar rats
All the doses caused significant reduction in paw edema compared to control
[49]
Annona muricata
Annonaceae
Durian belanda
Leaves/aqueous ethanol
10–300 mg/kg
Sprague-Dawley rats
A significant decrease of the concentration of the proinflammatory cytokines TNF-α and IL-1β was observed
[50]
Ardisia crispa
Myrsinaceae
Mata pelandok
Root/ethanol
3, 10, 30, 100, and 300 mg/kg of body weight
Sprague-Dawley rats
A significant inhibition (93.34%) was observed in carrageenan-induced edema in rats at a dose of 300 mg/kg
[51]
Atylosia scarabaeoides
Fabaceae
Kara-kara/kacang kerara
Leaves/ethanol
150, 300, and 450 mg/kg
Swiss albino mice
The extract displayed significant inhibition of inflammation. Highest inhibition of paw edema (38.38%) at a dose of 450 mg/kg after 4 h of administration
[52]
Citrullus lanatus
Cucurbitaceae
Tembikai
Fruit pulp/petroleum ether, chloroform, and 90% ethanol
30 and 60 mg/kg of body weight
BALB/c mice
Cucurbitacin E inhibits inflammation significantly from the fourth hour and is able to revert paw edema through the COX-2 inhibition
[33]
Corchorus capsularis
Malvaceae
Kancing baju
Leaves/chloroform
20, 100, and 200 mg/kg
BALB/c mice and Sprague-Dawley rats
The extract caused significant reduction in the thickness of edematous paw for the first 6 h
[53]
Crinum asiaticum
Amaryllidaceae
Pokok bakung
Leaves/methanol
50 mg/kg of the extract
Mice
Inhibition of paw edema (94.8%)
[54]
Curcuma aeruginosa
Zingiberaceae
Temu hitam
Rhizomes/chloroform, methanol, and water
100, 200, 400, and 800 mg/kg
Swiss mice and Wistar rats
No significant suppression was observed after oral administration of all doses on carrageenan-induced paw edema
[55]
Curcuma longa
Zingiberaceae
Kunyit
Rhizomes/water
200 mg/kg of body weight
Wistar albino rats
The production of anti-inflammatory/proinflammatory cytokines is decreasing
[56]
Cyathula prostrata
Amaranthaceae
Ketumbar
Leaves/methanol
50,100, and 200 mg/kg
Wistar rats and Swiss albino mice
All extracts displayed a significant dose-dependent inhibition in the carrageenan-, arachidonic acid-, and xylene-induced tests
[57]
Dicranopteris linearis
Gleicheniaceae
Resam
Leaves/chloroform
10, 100, and 200 mg/kg
BALB/c mice and Sprague-Dawley rats
The extract produced significant anti-inflammatory activity that did not depend on the doses of the extract
[58]
Ficus deltoidea
Moraceae
Mas cotek
Whole plant/water
30, 100, and 300 mg/kg
Sprague-Dawley rats
The rats’ paw edema volume reduced significantly in a dose-dependent manner
[59]
Garcinia subelliptica
Guttiferae
Pokok penanti
Seeds/chloroform
3, 10, 30, 50, and 100µM
Sprague-Dawley rats
A potent inhibitory effect on fMLP/CB-induced superoxide anion generation was observed in the isolated compound garcinielliptin oxide
[38]
Justicia gendarussa
Acanthaceae
Daun rusa
Root/methanol
50 mg/kg of the extract
Wistar rats
80% and 93% edema inhibition at the third and fifth hours
[60]
Kaempferia galanga
Zingiberaceae
Cekur
Rhizomes/chloroform
2 g/kg of the extract
Male Sprague-Dawley rats
Highest edema inhibition (42.9%)
[41]
Manilkara zapota
Sapotaceae
Ciku
Leaves/ethyl acetate
300 mg/kg of body weight
Albino Wistar rats
Inhibition of paw edema (92.41%)
[61]
Mitragyna speciosa
Rubiaceae
Biak-biak and ketom
Leaves/methanol
50, 100, and 200 mg/kg
Sprague-Dawley rats
Both doses of 100 and 200 mg/kg showed a significant inhibition of the paw edema (63%)
[62]
Moringa oleifera
Moringaceae
Kelur
Leaves/water
10, 30, and 100 mg/kg
BALB/c mice and Sprague-Dawley rats
Highest edema inhibition (66.7%) at the second hour at 100 mg/kg of dose
[63]
Muntingia calabura
Muntingiaceae
Kerukup siam
Leaves/water
27 mg/kg, 135 mg/kg, and 270 mg/kg
Sprague-Dawley rats
The extract was found to exhibit a concentration-independent anti-inflammatory activity
[64]
Orthosiphon stamineus
Lamiaceae
Misai kucing
Leaves/methanol : water
125, 250, 500, and 1000 mg/kg
Charles River mice and Sprague-Dawley rats
Increase in edema inhibition (26.79%)
[65]
Peperomia pellucida
Piperaceae
Ketumpangan air
Whole plant/petroleum ether
1000 mg/kg
Sprague-Dawley rats
The extract showed significant inhibition in magnitude of swelling after 4 h of administration
[66]
Phyllanthus acidus
Phyllanthaceae
Cermai
Leaves/methanol, ethyl acetate, and petroleum ether
250 and 500 mg/kg
Wistar rats and albino mice
All the extracts showed reduction in carrageenan-induced paw edema with highest inhibition (90.91%) in the methanol extract
[67]
Physalis minima
Solanaceae
Pokok letup-letup
Whole plant/methanol and chloroform fraction
200 and 400 mg/kg
NMRI mice and Wistar rats
Crude extract and chloroform fraction showed highest inhibition of paw edema at 66% and 68% at 400 mg/kg, respectively
[68]
Piper sarmentosum
Piperaceae
Kaduk
Leaves/water
30–300 mg/kg of the extract
Sprague-Dawley rats and male BALB/c mice
All doses exerted anti-inflammatory activity in a dose-dependent manner
[69]
Polygonum minus
Polygonaceae
Kesum
Aerial parts/water
100 mg/kg and 300 mg/kg
Wistar albino rats
The extracts significantly reduced the paw edema volume in the rats after 4 h
[70]
Sandoricum koetjape
Meliaceae
Sentul
Stems/methanol
5 mg/ear
BALB/c mice
A significant inhibition (94%) in TPA-induced edema was observed in the isolated compound 3-oxo-12-oleanen-29-oic acid
[71]
Solanum nigrum
Solanaceae
Terung meranti
Leaves/water
10, 50, and 100% of concentration
BALB/c mice and Sprague-Dawley rats
Extracts produce apparently two-phase anti-inflammatory activity: the first phase between 1 and 2 h and the second phase between 5 and 7 h after carrageenan administration
[72]
Stachytarpheta jamaicensis
Verbenaceae
Selasih dandi
Leaves/ethanol
50, 100, and 150 mg/kg
BALB/c albino strain mice and Sprague-Dawley rats
A significant dose-dependent anti-inflammatory activity was observed 30 min after the administration of the extract at all doses
[73]
Vitex negundo
Lamiaceae
Legundi
Leaves/ethanol
2 mg/ear
Mice
The extract showed an inhibitory activity of 54.1%
[74]
Zingiber zerumbet
Zingiberaceae
Lempoyang
Rhizomes/methanol
25, 50, and 100 mg/kg
BALB/c mice
A significant antiedema activity was observed at all doses in a dose-dependent manner (i.e., 50 and 100 mg/kg doses of the extract exhibited activity at 90 min after administration, while 25 mg/kg exhibited at 150 min)
[75]
5, 10, 50, and 100 mg/kg
ICR mice
The isolated compound (zerumbone) significantly showed dose-dependent inhibition of paw edema induced by carrageenan at all doses (5, 10, 50, and 100 mg/kg) in mice with percentage of inhibition of 33.3, 66.7, 83.3, and 83.3%, respectively
[76]Based on the results obtained, many studies used the NO inhibition assay as a method to show the anti-inflammatory activity of the plants. Many diseases such as rheumatoid arthritis, diabetes, and hypertension have been reported to be occurred due to the excessive production of NO [77]. NO is synthesized by inducible NO synthase which has three isomers: (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 transducer and activator of transcription (STAT) regulate the inducible enzyme (i.e., iNOS), which then make this enzyme to be expressed in some tissues [79]. Apart from the nitric oxide inhibition assay, some studies used the LOX assay in order to evaluate the anti-inflammatory of the plants. In this mechanism, arachidonic acid is metabolized by 5-LOX to various forms of inflammatory leukotrienes such as leukotriene (LT) A4, LTB4, LTC4, LTD4, and LTE4 [80], where LTB4 (one of the mediators of inflammation) is reported to be the most crucial in the inflammatory response [81]. To support this, it is reported that patients with rheumatoid arthritis and inflammatory bowel disease possess high levels of LTB4 [82, 83]. In addition, LTs are reported to be linked with few diseases such as bronchial asthma and skin inflammatory disorders [84]. In 2011, Kwon et al. [85] demonstrated that esculetin, one of the examples of coumarins, exhibited anti-inflammatory activity in vivo against animal models of skin inflammation. In the LOX assay, any LOX inhibitors will reduce Fe3+ to Fe2+, providing a rapid colorimetric assay [26]. Another common assay in determining the anti-inflammatory activity is COX. Two isoforms of COX, COX-1 (mainly involved in physiological functions and constitutively expressed) and COX-2 (involved in inflammation and induced in the inflamed tissue), are the enzymes responsible for the synthesis of prostaglandins [86]. Besides, the COX-2 gene is also a gene for iNOS induced during inflammation and cell growth [87]. The Griess assay is another assay commonly used in the murine macrophage cell line (RAW 264.7) as a culture medium in the cell-based study in order to determine the concentration of nitrite (NO2−), the stable metabolite of NO.Based on Table1 (in vitro study), 46 plants have been identified and studied for the anti-inflammatory activity from the previous studies. As a result, only two plants have been reported to exhibit more than 90% of anti-inflammatory activity using the nitric oxide inhibition assay, which were Melicope ptelefolia (Tenggek burung) and Portulaca 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 exerted anti-inflammatory activity between 70% and 80% at 100 µg/ml to 2000 µg/ml which can be considered to be higher such as Jatropha curcas (Jarak pagar), Curcuma longa (Kunyit), Boswellia serrata (Kemenyan), Labisia pumila (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]. The 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%), Thymus vulgaris (62.00%), Barringtonia racemosa (57.70%), and Kaempferia galanga (57.82%) at 100 µg/ml to 2000 µg/ml [27, 31, 41, 43, 48]. In addition, plants from the Zingiberaceae, Lamiaceae, Annonaceae, and Fabaceae families have been studied extensively for the anti-inflammatory activity. Among these families, the active compound of Curcuma longa from the Zingiberaceae family, monodemethoxycurcumin, had the highest activity with 82.50% at 125 µg/ml [35]. Of the other study, Kaempferia galanga from the Zingiberaceae family exhibited moderate activity with 57.82% at 200 µg/ml where the isolated compound, ethyl-p-methoxycinnamate, was found to have anti-inflammatory activity via inhibiting the actions of COX-1 and COX-2 [41]. In the Lamiaceae family, Thymus vulgaris showed the highest percentage of anti-inflammatory activity compared to other plants with 62% at 100 µg/ml [43], with the total phenolic 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 leaves ofMelicope ptelefolia (Tenggek burung) varied between two previous studies due to the different types of assays used by both studies: nitric oxide inhibition and soybean 15-lipoxygenase 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 Litsea garciae fruits showed 9.42% (lipoxygenase assay) and 27.70% (hyaluronidase assay) [44]. Based on these results, it can be concluded that different assays used might produce different results. For the COX inhibition assay, all the curcumins isolated from Curcuma longa rhizomes (i.e., curcumin I, curcumin II (monodemethoxycurcumin), and curcumin III (bisdemethoxycurcumin)) displayed greater inhibition of COX-2 compared to COX-1 at the same test concentration [35]. For the Griess assay, all the species tested such as the leaves of Carica papaya, Sauropus androgynus, and Piper sarmentosum, the flowering stalk of Musa acuminata, and the whole plant of Oenanthe javanica displayed significant NO inhibitory activity in a concentration-dependent manner against IFN-γ/LPS-treated macrophages [31].For thein vivo study (Table 2), 30 plants have been identified in this study for the anti-inflammatory activity. Many of the studies from the previous years used the carrageenan-induced rat paw edema method (a reliable inflammation model) as this carrageenan has been found to be more trenchant in producing the edema compared to formalin [88]. It is also one of the conventional methods used to evaluate the anti-inflammatory effect of drugs or medicinal plants at the acute stage [89] and involves a biphasic event. Normally, the release of histamine and serotonin happens in the early phase (1-2 h), while the second phase (3–5 h) involves the release of prostaglandins and kinins [90, 91]. For the edema formation, the rat paw is injected with carrageenan. This method is also a COX-dependent reaction with the control of arachidonate COX [92]. The ability of the plant extracts to lessen the thickness of the rats’ paw edema indicates the ability of these plant extracts to exert the anti-inflammatory properties. Based on Table 2, the highest dose of the extract used was 1000 mg/kg of body weight, while the lowest one was 3 mg/kg of body weight. Most of the previous studies reported that the extract was able to inhibit paw edema induced by carrageenan. For instance, a significant highest paw edema inhibition (93.34%) was observed in rats at a dose of 300 mg/kg of the Ardisia crispa (Mata pelandok) root extract [51]. Another study also showed that a significant highest inhibition was observed in two isolated compounds from Sandoricum koetjape stems, 3-oxo-12-oleanen-29-oic acid and katonic acid with 94% and 81%, respectively, where 3-oxo-olean-12-en-29-oic acid had the percentage inhibition almost similar to the reference drug, indomethacin (97%) [71].Based on the results obtained, few studies isolated the bioactive compounds to be further analyzed for the anti-inflammatory activity such as flavonoids (boesenbergin A, eupatorin, and sinensetin), coumarins (scopoletin and scoparone), triterpenoids (dammara-20,24-dien-3-one and 24-hydroxydammara-20,25-dien-3-one), steroids (cucurbitacin E), curcuminoids (monodemethoxycurcumin and bisdemethoxycurcumin), benzophenones (garsubellin A and garcinielliptin 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 of them exerted significant inhibition on inflammation. In 2000, Abad et al. [93] evaluated the common anti-inflammatory drug naproxene isolated from Musa acuminate (pisang abu nipah) which exhibited good inhibition in COX-1 and COX-2 activities. Besides, in Carica papaya leaves, coumarin was isolated and exerted anti-inflammatory activity by suppressing the cytokine TNF-α production [94, 95]. A compound known as dammara-20,24-dien-3-one was isolated from Chisocheton polyandrus and displayed good inhibition of both human 5-LOX and COX-2 [32]. Flavonoids have been confirmed by in vitro studies to be able to suppress iNOS expression and to prevent nitric oxide production, depending on their structure or subclass of flavonoids for the strength level [96].


## 4. Conclusion

In overall, this review clearly demonstrates the potential of Malaysian medicinal plants as anti-inflammatory agents in whichMelicope ptelefolia (Tenggek burung) and Portulaca oleracea (Gelang pasir) were found to exhibit potent anti-inflammatory activity in vitro. Pharmacological studies revealed that chemical diverse groups of naturally occurring substances derived from the plants show promising anti-inflammatory activity. Therefore, this review suggests further research needs to be carried out on the bioactive compounds present in the particular plants which have a potential to treat an inflammation and the possible underlying mechanisms of inflammation.



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