4/9/2021 A Review of Oenanthe javanica (Blume) DC.

as Traditional Medicinal Plant and Its Therapeutic Potential

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Review Article | Open Access

Volume 2019 | Article ID 6495819 | https://doi.org/10.1155/2019/6495819

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A Review of Oenanthe javanica (Blume) DC. as Traditional

Medicinal Plant and Its Therapeutic Potential

Chuan-li Lu  1,2 and Xiu-fen Li3

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Academic Editor: José L. Rios

Published: 01 Apr 2019

Abstract
Oenanthe javanica, popularly known as water dropwort, has long been used in various ethnomedical systems

in Asia, especially in China, Korean, and Japan, for treating various chronic and acute hepatitis, jaundice,

alcohol hangovers, abdominal pain, and inflammatory conditions. The present review aims to provide a

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general report of the available literature on traditional uses, phytochemical, pharmacological, nutritional, and

toxicological data related to the O. javanica as a potential source of new compounds with biological

activities. Considering phytochemical studies, coumarins, flavonoids and flavonoid glycosides, organic acids,

and polyphenols were the main classes of compounds identified in the whole plant which were correlated
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with their biological activities such as hepatoprotective, anti-inflammatory, immune enhancement, ethanol

elimination, antioxidant, antiviral, neuroprotective, anti-cancer, anticoagulant, anti-fatigue, hypoglycemic,

cardiovascular protection, analgesic, and insecticidal activities.

1. Introduction
Before modern drugs began to take shape in the medical care industry, people were highly dependent on
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conventional or traditional medicine, which have been recognized by the World Health Organization as
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reliable medicinal sources for therapeutic activities [1, 2]. Medicinal plants, the “backbone”
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of traditional

medicine, are utilized today by more than 3.3 billion people in the less developed countries [3].

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4/9/2021 A Review of Oenanthe javanica (Blume) DC. as Traditional Medicinal Plant and Its Therapeutic Potential

Oenanthe javanica (Blume) DC. (Apiaceae), which is a small perennial herb, has been cultivated in tropical

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and temperate regions of Asia for thousands of years and has long been used as a folk remedy for alleviating

a wide spectrum of diseases. A variety of biological activities of O. javanica have been reported, including
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hepatoprotective [4, 5], anti-inflammatory [6, 7], immune enhancement [8], ethanol elimination [9],

antioxidant [10], and antiviral [11]. Phytochemical assessments have revealed that O. javanica contains

coumarins [12], flavonoids and flavonoid glycosides [13], and polyphenols [4]. In addition, toxicity studies

have demonstrated that O. javanica does not exhibit acute or genetic toxicity [14, 15]. However, oral

administration of dry O. javanica power could significantly increase the rate of mice sperm deformity and

even induce reduction of weight and food consumption at a high dose [15]. Moreover, total phenolics acid

extract from O. javanica at a high dose (equivalent to 20 times of recommended human clinical dose) showed

a reversible subchronic toxicology [16].

Thus, this review is aimed at elucidating the biological and pharmacological activities, as well as toxicology

of O. javanica.

2. Plant Description
Since O. javanica distributes and is cultivated in many areas of Asia and Australia, each group of local

people have a specific name for this plant as listed in Table 1 [10, 17–26]. In China, this plant is commonly

known as Shui qin, Shui qin cai, Shui ying, and so on [17, 18], while it is known as Seri in Japan [19–21].

The plant is called Minari [22], Selom [23–26], and Phak-chilom [10] in Korea, Malaysia, and Thailand,

respectively.

 
Table 1

Common names used for O. javanica in different countries.

This plant is a small perennial herb and grows up to 10-80 cm with fibrous roots that emerge from all nodes.

The stems are light green, terete, glabrous, vertically veined, and hollow, which are more or less erect, but

sometimes sprawl. Its basal petioles are 5-10 cm long. The leaves are aromatic and glabrous and have a

sheath covering the stem. The blade is oblong-ovate with 1-2 pinnate, while ultimate segments are 5–50 mm

long with 5–20 mm broad either ovate or rhombic-ovate shape, margins serrate. Cauline leaves gradually
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reduced upwards, smaller, becoming sessile on expanded sheaths. There are 5 white petals and 5 stamens for

its flowers, with umbels 3–5 cm across, peduncles 2–16 cm, bracts absent or occasionally 1 bract, and rays 6–

16(–30), 1–3 cm, subequal or unequal; bracteoles 2–8, linear, 2–4 cm, as long as pedicels; umbellules ca. 20-
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flowered; pedicels 1.5–4 mm. Calyx teeth ca. 0.5 mm. Its fruit is subglobose or ovoid, ca. 2.5 × 2 mm, while

dorsal and intermediate ribs are slightly corky-thickened [27, 28].

3. Ethnomedicinal Uses of O. javanica

Generally, O. javanica is a valuable herbal plants consumed and used by East Asian countries for both food

and various medicinal purposes (Table 2) [4, 5, 11, 13, 17, 23, 29–41]. For example, the flower and stem (or

the aerial parts) of this plant are commonly used in China for the treatment of various types of chronic and
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acute hepatitis [11, 17, 29, 30]. It is also used in China for jaundice [13, 23, 35, 36], fever [4, 35, 37],
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hypertension [13, 32, 35–37], abdominal pain, and urinary difficulties [4, 35, 36,
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39, 40], as well as for
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eliminating pathogenic wind [17, 29]. Similarly, treatments for fever and hypertension are also common

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4/9/2021 A Review of Oenanthe javanica (Blume) DC. as Traditional Medicinal Plant and Its Therapeutic Potential

medicinal uses in Korea and Malaysia [23, 32–34]. In Korea, this plant is also used for treating alcohol

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hangovers and inflammatory conditions [11, 39, 41].
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Table 2

Ethnomedicinal uses of O. javanica in different countries.

Besides medicinal applications, O. javanica has also been widely consumed as a dietary product. The whole

plant or the aerial parts of O. javanica in Malaysia are a well-known vegetable and freshly consumed as the

main ingredient in local famous food “ulam,” which constitutes an important part of the food intake among

the local peoples especially the Malay and Indigenous communities [23–26], while, in Korea, this plant is

widely used in salad and soups [22]. In Japan, O. javanica named “seri” is one of the ingredients of the

symbolic dish, Nanakusa-no-sekku, consumed in the Japanese spring-time festival [19–21].

4. Phytochemistry of O. javanica/Chemical Components

4.1. Flavonoids and Flavonoid Glycosides

Flavonoids and flavonoid glycosides are abundant in O. javanica, and more than ten flavonols have been

isolated and identified from O. javanica thus far, including apigenin [3], isorhamnetin-3-O-β-D-

glucopyranoside [18], quercetin [37], isorhamnetin-3-O-galactoside [39], afzelin [41], persicarin,

isorhamnetin, hyperoside [56], luteolin [57], kaempferol, rutin, nictoflorin, and quercetin-3-L-rhamnoside [5

8, 59] (their structures are depicted in Figure 1). In general, all of the flavonoids and flavonoid glycosides

obtained from this plant have free phenolic hydroxyl groups in the 5, 7, and 4′-position. Most of them are

substituted in the 3 and 3′-position. For all flavonoid glycosides obtained from this plant, aglycons are

attached at 3-position.

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Figure 1

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Structures of flavonoids and flavonoid glycosides isolated from O. javanica.

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4.2. Coumarins

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Approximately nine coumarins have been identified from O. javanica, namely, xanthotoxin, bergapten,

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isopimpinellin [12], sioimperatorin, imperatorin, columbianadin, 5-hydroxy-8-methoxypsoralen, 6,7-

dihydroxycoumarin, and scopoletin [18] (the structures are presented in Figure 2). Most of these components

are the linear furanocoumarins, with the 5- and 8-positions being substituted by methoxyl and isoamylenoxyl

groups.

 
Figure 2

Structures of coumarins isolated from O. javanica.

4.3. Phenolic Constituents

Phenolics are also abundant in O. javanica, including neochlorogenic acid [4], chlorogenic acid [4, 5, 11, 60],

caffeic acid [4, 5, 48, 57, 60], gallic acid [4, 57], α-tocopherol [10, 61], lunularin, p-hydroxyphenylethanol

ferulate, 5-p-trans-coumaroylquinic acid [18], carvacrol, ferullic acid [57], and catechin [45] (the structures

are presented in Figure 3). For phenolic acids and ester identified from O. javanica, most of them are caffeic

acid derivatives. The content of total phenolic acids in O. javanica from Korean was 88.9 ± 0.46 mg GAE/g

[45] and in O. javanica from Guizhou Province of China was 131.5-173.2 mg/g [62]. In addition, O. javanica
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extract contains α-tocopherol (146.8 mg/kg) [61], gallic acid (0.9 ± 0.23 mg/g), catechin (1.2 ± 0.19 mg/g),

chlorogenic acid (227.1 ± 0.62 mg/g), and caffeic acid (4.0 ± 0.35 mg/g) [45].

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Figure 3

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Structures of phenolic constituents isolated from O. javanica.

4.4. Volatile Oils

The volatile constituents are extracted with steam distillation, vacuum simultaneous steam distillation and

solvent extraction, and solid-phase microextraction, and 59 chemical constituents have been identified with

gas chromatography-mass spectrometer and computer retrieval technique, including 28 hydrocarbons, 16

alcohols, 8 aldehydes, 4 esters, 2 ethers, and 1 ketone. Furthermore, by using the gas chromatography-

olfactometry, p-cymene has been identified as a character-impact aroma-active compound of O. javanica, and

α-terpinolene, α-terpinene, (E)-caryophyllene, and (Z,E)-α-farnesene also play significant roles in the aroma

of O. javanica [42]. Lee et al. identified 15 compounds representing 100% of volatile oil, mainly including β-

caryophyllene, δ-cadinene, β-bisabolene, α-terpinolene, γ-terpinene, and α-amorphene [44]. Zhang et al.

reported 16 volatile constituents consisting of 96.46% of oil, and the principal constituents were eudesma-

4(14),11-diene,2,3-dihydro-3-methyl-3-benzofuran-methanol, limonene, and allylphenoxyacetate [43]. The

identified volatile constituents from O. javanica are presented in Table 3.

 
Table 3

Volatile compounds identified from O. javanica.

4.5. Other Ingredients

Other compounds, not list above, have been isolated from O. javanica including butanedioic acid [4], β-

sitosterol [18], and falcarindiol [21]. Their structures are shown in Figure 4.

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Structures of other ingredients isolated from O. javanica.

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5. Nutrient Constituent of O. javanica
The fresh O. javanica plant has wide variety nutrients such as carbohydrates, proteins, vitamins, and fat, as

well as mineral micronutrients, as shown in Table 4 [10, 45–47]. O. javanica has high iron content, followed

by kalium, calcium, natrium, and magnesium, which are useful for patients with mineral deficiencies

problems. The plant has moisture content of up to 88% [10] and a total ashes value of 8.9% [45] suitable for

body hydration.

 
Table 4

Nutritional composition of O. javanica.

6. Pharmacological Activities

6.1. Hepatoprotective Effect

Although O. javanica has been traditionally used as a Dai ethnic medicine for various liver diseases, the

scientific evidence that justifies its usage has only recently been reported (summarized in Table 5). The

significantly hepatoprotective effect of O. javanica extracts has been demonstrated on both cell lines and

animal models.

 
Table 5

Summary of hepatoprotective activities of different parts, extracts, and active compounds of O. javanica.

Treatment with boiling water extract of O. javanica (at dose equivalent to 12 g fresh material/kg) showed a Cookies Settings
significantly suppression effect on the elevation of serum bilirubin level and the degeneration and necrosis of

hepatic cells in α-naphthylisocyanate-stimulated Wistar rats, but no effect on serum alanine aminotransferase

(ALT) level [49]. In addition, the hepatoprotective effects of total phenolics from O. javanica have been
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reported on different liver injury models, including -galactosamine- and carbon tetrachloride (CCl )-
4

induced acute liver injury in mice [4, 50, 51], CCl -induced chronic hepatic fibrosis in rats [51], a-
4

naphthylisothiocyanate-induced liver jaundice in rats [52], and high-sugar high fat-induced non-alcoholic

fatty liver in rats [53].

Moreover, fermented O. javanica extracts, in which caffeic acid and chlorogenic acid were the major

constituents, have been reported to dose-dependently inhibit tert-butylhydroperoxide-induced HepG2 cells

death and lactate dehydrogenase leakage, as well as prevent the increase of hepatic enzyme markers ALT,
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aspartate aminotransferase (AST), and gene expressions of cytochrome P450 enzyme (CYP)2E1, CYP4A2
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and PPARγ in CCl -induced hepatic damage in rats [5], while other studies demonstrated
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that pretreatment

by ethanol extract of O. javanica (500 μg/ml) or its active component (caffeic acid, 250 mM) could

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significantly reduce hydrogen peroxide (H O )-induced cellular toxicity in human liver hepatocellular
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carcinoma HepG2 cell line [48] and counteract the oxidative stresses through increasing the expressions of

endogenous enzymatic antioxidants such as superoxide dismutase (SOD),

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glutathione peroxidase (GPx) in the liver cells of rat [32].

A recent study indicated that persicarin isolated from O. javanica could effectively prevent diabetes-induced

liver damage by attenuating oxidative stress and inflammation response under hyperglycemic conditions [41].

Another study in a different experimental model of liver disease, nonalcoholic fatty liver disease (NAFLD),

revealed that both boiling water extract and n-butanol extracts of O. javanica pretreatment effectively lowered

plasma triglyceride and glucose levels [54]. In addition, the underlying mechanism of hepatoprotective

effects of O. javanica was demonstrated to be attributed to the improvement of antioxidant capacity and the

inhibition of hepatic stellate cell activation and hepatic malondialdehyde production, and consequent

attenuation of inflammatory responses and chemical-induced liver injury [55].

The hepatoprotective activity of O. javanica extract was also caused by selective inhibition activity of

cytochrome P and consequently affected various xenobiotic metabolism. Investigation in HepG2 also
450

revealed that the root extract of O. javanica could significantly elevate the mRNA expressions (by 68% and

102%, respectively) and protein levels (by 112 and 157%, respectively) of CYP1A1 and CYP1A2 and these

effects were much more pronounced than those of leaf and stem extracts [12]. Of note, this study provides

additional evidence that the levels of major coumarin derivatives determined by GC–MS, including

xanthotoxin, bergapten, and isopimpinellin, were significantly higher in root extract than in leaf or stem

extracts, which might be responsible for those effects, suggesting dietary exposure to O. javanica may

modulate phase I enzymes and thereby affect various xenobiotic metabolism [12]. Specifically, hyperoside

(quercetin-3-O-galactoside), a flavonoid isolated from O. javanica, was reported to selectively inhibit the

cytochrome P isoform and strongly decreased CYP2D6 activity at dose-, but not time-dependent manner
450

in human liver microsomes (HLMs). In this case, hyperoside strongly inhibits CYP2D6-catalyzed

dextromethorphan O-demethylation, with IC values of 1.2 and 0.81 μM after 0 and 15 min of
50

preincubation and a Ki value of 2.01 μM in HLMs, respectively. Moreover, hyperoside decreased CYP2D6-

catalyzed dextromethorphan O-demethylation activity of human recombinant cDNA-expressed CYP2D6,

with an IC value of 3.87 μM using a cocktail probe assay. However, no inhibition of other CYPs by
50

hyperoside was observed. These results suggest that hyperoside isolated from O. javanica might cause herb-

drug interactions when coadministered with CYP2D6 substrates [22].

6.2. Anti-Inflammatory Effect

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It has been reported that O. javanica extracts possessed significant anti-inflammatory activities, while

isorhamnetin, hyperoside, and persicarin were revealed as its main active components for anti-inflammatory

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The extract of O. javanica showed a significant inhibitory effect on nitric oxide production (IC < 61 μg/ml)
50

in interferon gamma/lipopolysaccharide stimulated RAW264.7 cells assay, without cytotoxicity [23], as well

as an attenuate effect in phorbol 12-myristate 13-acetate-treated THP-1 or bone marrow derived

macrophages cells on secretion of interleukin-1β and formation of Asc pyroptosome resulting from NOD-

like receptor (NLR)P3, NLRC4 and absent in melanoma 2 (AIM2) inflammasome activation without

interruption of cytokine transcription [6]. In addition, its main component, isorhamnetin, a 3′-O-methylated

flavonoid, exhibited a selectively inhibitory effect on NLRP3 and AIM2 inflammasome activation and

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expression of proinflammatory cytokine, while hyperoside, another component of O. javanica, selectively

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Furthermore, the anti-inflammatory effect of isorhamnetin in lipopolysaccharide-activated RAW264.7 cells

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was confirmed to be partly mediated by inhibiting the mitogen activated protein kinase (MAPK)-nuclear

factor-kappa B (NF-κB) signaling pathway [7]. The in vivo anti-inflammatory activity of isorhamnetin was
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also confirmed in carrageenan-induced rats, which showed that oral administration of isorhamnetin (10 or 30

mg/kg) could markedly inhibit carrageenan-induced paw swelling, inflammatory cell infiltration, and

proinflammatory gene expression in rats [7]. Moreover, the anti-inflammatory activities of isorhamnetin-3-O-

galactoside and persicarin isolated from the aerial parts of O. javanica were demonstrated on high mobility

group box 1 (HMGB1)-mediated inflammatory response, and the results showed that both of them could

inhibit the releasing of HMGB1 and HMBG1-dependent inflammatory responses in human endothelial cells,

as well as HMBG1-mediated hyperpermeability and leukocyte migration in mice [63, 64].

6.3. Enhancing Immunity

The effects of O. javanica extract on immune function/regulation were evaluated in normal and

hydrocortisone-induced immunodepressed mice [8, 65].

Total flavone from O. javanica has been demonstrated to possess an upregulatory effect on cell immunity,

humoral immunity, and nonspecific immunity in hydrocortisone-induced immunodepressed mice model, as it

could obviously increase the carbon clearance index, the serum hemolysin content, and spleen and thymus

index and enhance delayed-type hypersensitivity [8]. In line with these findings, the enhancement effect of

total phenolics acid extract of O. javanica on immune function was also demonstrated on normal mice, by

markedly increasing the content of serum hemolysin and interleukin-2, promoting proliferative response of

splenic T-lymphocyte induced by concanavalin A, and improving the clearance rate of charcoal particles in

peripheral blood in mice [65].

6.4. Ethanol Elimination/Alcohol Detoxication

Alcohol abuse, especially excess alcohol consumption or alcohol hangovers, is related to impaired liver

function. According to surveys, prolonged use is related to increase the risk of liver disease, such as cirrhosis

and liver failure.

A hot-water extract of O. javanica injection exhibited a rapidly reducing effect on the plasma ethanol level in

ethanol-treated New Zealand white rabbit. In addition, oral administration of O. javanica extract and its n-

butanol fraction could eliminate up to 44% and 70% of the plasma ethanol, respectively (compared to orally

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ethanol-treated mice). Specifically, the n-butanol fraction exhibited the strongest activity in eliminating

plasma alcohol. These data indicated that O. javanica extract is effective in overcoming alcohol intoxication

by accelerating ethanol metabolism [9]. Moreover, the methanol extract of O. javanica and persicarin isolated

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from the aerial parts of the plant possessed a dose-dependent stimulatory effect on alcohol-metabolizing

enzymes, including alcohol dehydrogenase, aldehyde dehydrogenase, and the microsomal ethanol-oxidizing

system in ethanol-treated rats [56].

6.5. Antioxidant Activity

The antioxidant activity of O. javanica have been evaluated using several types of assays, such as scavenging

2,2-diphenylpicrylhydrazyl (DPPH) radical, oxygen radical absorbance capacity (ORAC), ferric reducing

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antioxidant power (FRAP), and Xanthine oxidase assays. The antioxidant activity of O. javanica methanol

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extract was firstly revealed by Huda-Faujan et al. using FRAP tests [25]. In addition, the 95% ethanol extract

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of the dried leaves exhibited a radical scavenging for DPPH and inhibitory effect on 
SOD activity, with the 
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inhibition rates of 56.87 ± 1.43% and 73.51 ± 0.54% at concentration of 10 mg/ml, respectively. However,

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there was no significant correlation between antioxidant activities and its phenolic contents [66]. Similarly,

the antioxidant properties of methanol extract from O. javanica performed by using DPPH assay showed that
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was 87.42 ± 0.64 μg/ml [23]. Recently, Kongkachuichai et al. showed that hydrophilic ORAC and

FRAP activities of O. javanica were about 9000 and 2000 μmol Trolox equivalent /100 g fresh weight [10].

To date, studies dealing with the antioxidant activity of O. javanica related to phenolics are not conclusive.

6.6. Antiviral Effect

The anti-hepatitis B virus (HBV) effects of O. javanica were conducted in human hepatoma (HepG2.2.15

cells) culture system and HBV-infected duck models. Total phenolics, flavones, and ethyl acetate extracts

from O. javanica have been revealed to possess significant anti-HBV activities. Flavones extract from O.

javanica showed a significant inhibitory effect on HBsAg and HBeAg secretion in HepG2.2.15 cells within

nontoxic concentrations, and on duck hepatitis B virus (DHBV)-DNA levels in HBV-infected duck model

with concentrations of 0.50 and 1.00 g/kg. Results indicated that the half value of toxic concentration (TC )
50

and maximum nontoxic concentration (TC ) was 2.28 g/L and 1.00 g/L, respectively. The maximum
0

inhibition peak of viremia was at dose of 1.00 g/kg and reached 54.3% on day 5 and 64.5% on day10,

respectively [13].

Total phenolic acid from O. javanica (OJTP) also showed a strong inhibition effect on HBV-DNA (inhibition

rate: 62.3%, 47.7%) and DNA (inhibition rate: 62.7%, 61.3%) expressions at 250 and 500 mg/L at day 8,

respectively, in HepG2.2.15 cells. Besides, this inhibition rate remained high after 3 days of O. javanica

treatment [67]. In addition, OJTP exhibited dose-dependent suppression activities against the production of

the HBeAg and HBsAg in HepG2.2.15 cells line [11, 67], and DHBV-DNA replication in ducks [11]. The

maximum inhibition peak of viremia was at dose of 0.20 g/kg and reached 64.10% on day 5 and 66.48% on

day 10, respectively. Histopathological evaluation of the liver revealed significant improvement by OJTP. No

matter whether 5-day or 10-day administration, or 3 days after 10-day administration, the groups treated with

OJTP (500, 250, 125 mg/kg/d) had significantly inhibitory action on DHBV-DNA induced hepatitis model in

Peking ducks. Histopathological evidences from the results showed that OJTP treated hepatic lobules were

regular, and the denaturation, dropsy, and necrosis of cells were trivial. Meanwhile the hepatic cells are

confused and disorderly, oxyphilous denaturation, and dropsy and necrosis is obviously surrounding hepatic

lobules. These data indicated that OJTP has significantly inhibitory effects on DHBV-DNA and can protect

duck livers from damage in virus hepatitis [68]. Similar results were reported by Huang et al. [69, 70]. In

DHBV infected duck primary hepatocytes culture, water extract of O. javanica was shown to potentially

inhibit DHBV-DNA levels with the inhibition rate of 64% at 2500 μg/ml Cookies Settings
and half value of effective

concentration (EC ) was 1120.8 μg/ml, which was much less than its TC (10000 μg/ml), indicating O.
50 50

javanica is a hopeful drug for controlling DHBV [69]. The mean inhibition rate of O. javanica on DHBV-

NDA polymerase was 75.5% (at dose of 10000 μg/ml) in vitro and 73.3% (at dose of 8 g/kg) in vivo, Accept All Cookies
indicating strong inhibition effect of O. javanica on DHBV-NDA polymerase. In addition, IC (407 μg/ml)
50

was far less than TC (>10000 μg/ml) on liver cell [70].

50

The inhibition effect of ethyl acetate extract of O. javanica on HBsAg and HBeAg and its toxicity was

demonstrated in the HBV transfected HepG2.2.15 cells. The results showed that the TC of the extract was
50

2284.73 ± 127.35 μg/ml, and the TC was 1000 μg/ml. After 6 and 9 days’ treatment, the extract significantly
0

inhibited the secretion of HBsAg and HBeAg in HepG2.2.15 cell line at doses of 1000 and 500 μg/ml [71].

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6.7. Neuroprotective Activity

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The neuroprotective activities of O. javanica extracts have been uncovered by several studies, which showed

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the extracts could improve cell proliferation and neuroblast differentiation,

ischemic damage, and maintain antioxidants immunoreactivities [34, 38, 40, 72]. The ethanol extract of O.
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protect neurons from

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javanica showed an ameliorating effect on cell proliferation and neuroblast differentiation by increasing

brain-derived neurotrophic factor immunoreactivity in the dentate gyrus of adolescent rat [40]. Park et al.

revealed that treatment with O. javanica extract (at a dose of 200 mg/kg) exhibited a protective effect on the

hippocampal cornus ammonis 1 pyramidal neurons against cresyl violet induced ischemic damage, and this

protective effect is closely associated with increasing or maintaining intracellular antioxidant enzymes such

as glutathione peroxidase [34]. The F-box-protein 7 (FBXO7) mutations were found in typical and young

onset Parkinson’s disease, which plays an important role in the development of dopaminergic neurons.

Increased stability and overexpression of FBXO7 may be beneficial to Parkinson’s disease. Chen et al.

demonstrated that 95% ethanol extract of O. javanica could, through enhancing FBXO7 and decreasing

tumor necrosis factor receptor-associated factor 2 expression, improve cell viability of both 1-methyl-4-
+
phenylpyridinium ion (MPP )-treated human embryonic kidney-293 (HEK-293) and SH-SY5Y cells,
+
increase proteasome activity in MPP -treated HEK-293 cells, and restore mitochondrial membrane potential
+
in MPP -treated SH-SY5Y cells. Thus, ethanol extract of O. javanica could be developed as a potential

treatment of Parkinson’s disease [72]. In addition, Ma et al. documented that persicarin, isolated from n-

butanol fraction of O. javanica, possessed an obvious neuroprotective activity in glutamate-injured rat

cortical cells by reducing calcium influx, inhibiting the subsequent overproduction of nitric oxide and

intracellular peroxide, restoring the reduced activities of glutathione reductase and glutathione peroxidase [3

8].

6.8. Anti-Cancer Activity

It was demonstrated that the total phenolics acid extract from O. javanica possessed an inhibitory effect on

HepG2.2.15 cell proliferation, which could reduce cell growth at S phase [73]. In addition, an in vitro

migration and invasion assay showed that isorhamnetin, a flavonoid isolated from O. javanica, possessed an

anti-metastatic effect, which may correlate with its inhibition of reactive oxygen species-mediated hypoxia

inducible factor-1α (HIF-1α) accumulation [74]. It could significantly inhibit cobalt chloride (CoCl )- or
2

hypoxia-induced HIF-1α accumulation in human cancer cells (HCT116 and HT29 cell lines), as well as

suppress CoCl -induced activity of hypoxia response element reporter gene and HIF-1α-dependent
2

transcription of gene such as glucose transporter 1, lactate dehydrogenase A, carbonic anhydrase-IX, and

pyruvate dehydrogenase kinase 1. And the inhibitory effect of isorhamnetin on H O -induced HIF-1α
2 2

accumulation was also observed in HEK293 cells.

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6.9. Anticoagulant/Antithrombotic Activities

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Persicarin, isorhamnetin, hyperoside, and isorhamnetin-3-O-galactoside, which were isolated from O.

javanica, were demonstrated to possess significantly antithrombotic activities [39, 75]. All of them could

significantly prolong activated partial thromboplastin time and prothrombin time and inhibit both the

activities and generations of thrombin and factor X in human umbilical vein endothelial cells (HUVECs). In

accordance with these anticoagulant activities, these four compounds also exhibited inhibitory effect on

tumor necrosis factor-alpha-induced plasminogen activator inhibitor type 1 (PAI-1) production. Moreover,

persicarin and isorhamnetin showed a prolonged effect on bleeding time in vivo, while treatment with

isorhamnetin-3-O-galactoside or persicarin resulted in a significant reduction effect on the ratio of PAI-

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1/tissue-type plasminogen activator. The anticoagulant and profibrinolytic effects showed that persicarin >
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isorhamnetin, hyperoside > isorhamnetin-3-O-galactoside, which suggest that
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persicarin or the methoxy group of isorhamnetin-3-O-galactoside positively regulates its anticoagulatory

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6.10. Anti-Fatigue Effect

The anti-fatigue effect of O. javanica was studied in a wheel apparatus-induced fatigue mice model, and

results indicated that oral administration of extract from O. javanica (125, 250 and 500 mg/kg per day) for 4

weeks could significantly prolong the exhausted running time, reduce serum levels of lactic acid,

malondialdehyde, and urea nitrogen, increase the activities of serum lactate dehydrogenase and superoxide

dismutase, and elevate glycogen reserves and hemoglobin concentration in whole blood [76]. And a further

study demonstrated that treatment with extract from O. javanica for 10 days could obviously upregulate the

decreases in locomotor activity, function of the axis of hypothalamic-pituitary-adrenal and gonadal axis, and

situation of peripheral fatigue and downregulate the elevated levels of central neurotransmitters and radical

toward normal values in forcing swimming-induced chronic fatigue syndrome mice model [77]. In addition,

Su et al. further demonstrated that treatment with extract from O. javanica significantly improved

hydrocortisone-induced decrease in locomotor activity, cyclic adenosine monophosphate (cAMP), ratio of

cAMP/cGMP (cyclic guanosine monophosphate), total testosterone level, and increased of malondialdehyde

(MDA) and SOD activity [78].

6.11. Hypoglycemic Effect

Oral administration of water extract of O. javanica (10 and 20 g/kg per day) for 2 days significantly lowered

the blood glucose levels in normal mice and alloxan-induced hyperglycemic mice, but did not affect mice

hyperglycemia induced by adrenaline [79]. In addition, a further study showed that pretreatment with water

extract of O. javanica (50, 100, and 200 g/kg) could significantly suppress the blood glucose level and

improve the decreased content of insulin in streptozotocin (STZ)-induced mice, and these effects may be due

to its alleviation of the condition of the degeneration and necrosis of islet cells induced by STZ [80].

Furthermore, 95% ethanol extract of O. javanica (400 and 800 mg/kg) was also revealed to possess a

moderate hypoglycemic activity in STZ-induced diabetic mice model, which could decrease the blood

glucose level from 27.6 mM to 20.8 mM and 17.7 mM, respectively [62].

6.12. Cardiovascular Protection

The antiarrhythmic effect of O. javanica was demonstrated in aconitine-induced rats, which indicated thatCookies Settings
intravenous administration of O. javanica injection (1.5 g/kg) could significantly increase the threshold levels

of ventricular premature, ventricular tachycardia, ventricular fibrillation, and cardiac arrest (respectively,

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27%, 22%, 32%, and 19% higher than aconitine along-treated rats) and also make rats arrhythmia induced by

barium chloride conversed to sinusrhythm within 6.29 min and keep sinusrhythm for another more 12.73

min, as well as decrease the rate of calcium chloride-induced rat ventricular fibrillation and death by 25%

and 50%, respectively [81].

Moreover, persicarin and isorhamnetin-3-O-galactoside isolated from O. javanica were revealed to possess

potential therapeutic for treatment of severe vascular inflammatory diseases, which could both, through

reducing phorbol 12-myristate 13-acetate-stimulated phosphorylation of p38 MAPK, extracellular regulated

kinases 1/2, and c-jun N-terminal kinase, suppress the expression of tumor necrosis factor-α and then inhibit

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the phorbol-12-myristate-13-acetate, cecal ligation, or puncture-induced endothelial protein C receptor [36].

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6.13. Antinociceptive/Analgesic and Alternative Medicine  
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4/9/2021 A Review of Oenanthe javanica (Blume) DC. as Traditional Medicinal Plant and Its Therapeutic Potential

The antinociceptive active of O. javanica methanol extract (at 200 mg/kg) was tested in the acetic acid-

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induced abdominal writhing response in mice, which indicated that O. javanica extract could reduce about

30% of abdominal constriction, while positive control-aspirin could inhibit about 62% of writing inhibition.
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Furthermore, the underlying mechanism of antinociceptive effect of O. javanica extract was demonstrated to

be mediated by the suppression of nitric oxide production and reducing the sensitization of the peritoneal

nociceptor in mice [23].

6.14. Insecticidal Effect

Huo et al. pointed out that O. javanica extract possesses a marked effect to kill the tetranychina harti (Ewing),

which supported its usage as a new plant candidate for acaricide [82].

7. Toxicological Studies and Adverse Reaction

O. javanica was documented to be a nontoxic level species by acute toxicity tests, because the maximum

tolerated dose of it was higher than 15 g/kg for mice [14, 15, 83]. In an acute toxicity study, a single oral

administration of fresh O. javanica (15 g/kg) did not cause young mice mortality or inductive changes in the

ALT, blood glucose, total protein, albumin, urea, and creatinine levels, and no signs of abnormal behavioral

changes or toxicity on organs including liver and kidney were observed after 14 days of treatment [14].

Furthermore, in Ames assay (8-5000 μg/vessel) and mouse bone marrow cell micronucleus test (2.50-10.00

g/kg), O. javanica showed no obvious genetic toxicity [15]. But an increasing effect on the rate of sperm

deformity was observed in mice by oral administration of dry O. javanica power for 5 days (2.50, 5.00, and

10.00 g/kg, 1 g dry power equivalent to 13 g fresh material). Moreover, a subacute toxicity, including weight

loss and reduction in food consumption, was also observed in mice by oral administration of dry O. javanica

power for 30 days (5.00 g/kg/day) [15]. For subchronic toxicity assay, total phenolics acid extract from O.

javanica at doses of 1500 and 750 mg/kg (26 weeks) showed no significant effect on rats body weight, food

intake, behaviors, blood routine examination (counts of red blood cells, white blood cells, and platelets;

percentages of neutrophils, lymphocytes, monocytes, and hemoglobin; and prothrombin time), serum

biomarkers (AST, ALT, ALP, total bilirubin, urea nitrogen, Crea, total protein, albumin, total cholesterol, and

blood glucose), or organs [heart, liver, spleen, lung, kidney, adrenal, testis (for male rat), ovary (for female

rat), and brain]. However, at the dose of 3000 mg/kg, it showed a decreasing effect on weight gain and

lymphocyte number, and an increasing effect on neutrophil, but no effect on other tested items. Furthermore,

within a 4-week recovery period, the induced toxicity was basically recovered [16].

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In addition, a rare case of irritant contact dermatitis owing to O. javanica was reported by Xia and Li [84], in

which a 23-year-old male patient had edematous erythema and bullae appeared on his shoulder, back, and

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knees where fresh crush of O. javanica was applied. There was also burning-like epidermal exfoliation on the

lesions. The patient felt strong burning pain but no itching and was cured by 7-day anti-inflammatory

treatment.

8. Conclusions
The present review collectively discussed the ethnomedicinal uses of O. javanica and the available scientific

reports on its phytochemistry, pharmacological activities, and toxicology. It is worth mentioning that

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although scientific studies of bioactivities of O. javanica might justify some of its ethnomedicinal claims, the

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data are insufficient and, device to enhance
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extent, preliminary. analyze
In the sitefurther systemic studies in humans
future, are
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necessary. Furthermore,Complementary
efforts.
toxicologyand of Alternative Medicine
O. javanica at high dose (equivalent to 20 times
 the

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4/9/2021 A Review of Oenanthe javanica (Blume) DC. as Traditional Medicinal Plant and Its Therapeutic Potential

recommended human clinical dose) was observed in rats, but the potential toxic component and its possible

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mechanism have not been revealed. It would also be beneficial for in vivo and clinical studies to evaluate the

toxicity effects on the target organ.

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Abbreviations
AIM2: Absent in melanoma 2

ALP: Alkaline phosphatase

ALT: Alanine aminotransferase

AST: Aspartate aminotransferase

cAMP: Cyclic adenosine monophosphate

cGMP: Cyclic guanosine monophosphate

CAT: Catalase

CC : Carbon tetrachloride

CoC : Cobalt chloride

CYPs: Cytochrome P450 enzymes

DHBV: Duck hepatitis B virus

DPPH: 2,2-Diphenylpicrylhydrazyl radical

E : Half value of effective concentration

EEOJ: Ethanol extracts of O. javanica

FBXO7: F-box-protein 7

FRAP: Ferric reducing antioxidant power

GPx: Glutathione peroxidase

: Hydrogen peroxide

HBeAg: Hepatitis B e antigen

HBsAg: Hepatitis B surface antigen

HBV: Hepatitis B virus

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HIF-1α: Hypoxia-induced hypoxia inducible factor-1α

HLMs: Human liver microsomes

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HMGB1: High mobility group box 1

HUVECs: Human umbilical vein endothelial cells

I : Half maximal inhibitory concentration

MAPK: Mitogen activated protein kinase

NF-κB: Nuclear factor-kappa B

MDA: Malondialdehyde

MP By clicking
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1-Methyl-4-phenylpyridinium agree to the storing of
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HEK-293: Human embryonic kidney-293 cell (ATCC No. CRL-1573)
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NALFD: Nonalcoholic fatty liver disease

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NOD-like receptors PDF

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OJTP: Total phenolic acid from O. javanica

ORAC: Oxygen radical absorbance capacity

PAI-1: Plasminogen activator inhibitor type 1

SOD: Superoxide dismutase

STZ: Streptozotocin

T : Half value of toxic concentration.

Conflicts of Interest
The authors confirm that this article’s content has no conflicts of interest.

Acknowledgments
This work was financed by the National Natural Science Foundation of China (No. 81602991), GDAS’

Project of Science and Technology Development (No. 2019GDASYL-0103039), and “Light of West China”

Program of Chinese Academy of Sciences.

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