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

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 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 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.


Introduction
Before modern drugs began to take shape in the medical care industry, people were highly dependent on conventional or traditional medicine, which have been recognized by the World Health Organization as reliable medicinal sources for therapeutic activities [1,2]. Medicinal plants, the "backbone" of traditional medicine, are utilized today by more than 3.3 billion people in the less developed countries [3].
Oenanthe javanica (Blume) DC. (Apiaceae), which is a small perennial herb, has been cultivated in tropical 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 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.

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][46][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.

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.
Treatment with boiling water extract of O. javanica (at dose equivalent to 12 g fresh material/kg) showed a significantly suppression effect on the elevation of serum bilirubin level and the degeneration and necrosis of hepatic cells in -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 reported on different liver injury models, including -galactosamine-and carbon tetrachloride (CCl 4 )-induced acute liver injury in mice [4,50,51], CCl 4 -induced chronic hepatic fibrosis in rats [51], anaphthylisothiocyanate-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, aspartate aminotransferase (AST), and gene expressions of cytochrome P450 enzyme (CYP)2E1, CYP4A2 and PPAR in CCl 4 -induced hepatic damage in rats [5], while other studies demonstrated that pretreatment by ethanol extract of O. javanica (500 g/ml) or its active component (caffeic acid, 250 mM) could significantly reduce hydrogen peroxide (H 2 O 2 )-induced cellular toxicity in human liver hepatocellular carcinoma HepG2 cell line [48] and counteract the oxidative stresses through increasing the expressions of the endogenous enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the liver cells of rat [32].
The hepatoprotective activity of O. javanica extract was also caused by selective inhibition activity of cytochrome P 450 and consequently affected various xenobiotic metabolism. Investigation in HepG2 also 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 450 isoform and strongly decreased CYP2D6 activity at dose-, but not time-dependent manner in human liver microsomes (HLMs). In this case, hyperoside strongly inhibits CYP2D6catalyzed dextromethorphan O-demethylation, with IC 50 values of 1.2 and 0.81 M after 0 and 15 min of preincubation and a Ki value of 2.01 M in HLMs, respectively. Moreover, hyperoside decreased CYP2D6-catalyzed dextromethorphan O-demethylation activity of human recombinant cDNAexpressed CYP2D6, with an IC 50 value of 3.87 M using a cocktail probe assay. However, no inhibition of other CYPs by hyperoside was observed. These results suggest that hyperoside isolated from O. javanica might cause herb-drug interactions when coadministered with CYP2D6 substrates [22].

Anti-Inflammatory Effect.
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 antiinflammatory effect.
The extract of O. javanica showed a significant inhibitory effect on nitric oxide production (IC 50 < 61 g/ml) 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-1 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 expression of proinflammatory cytokine, while hyperoside, another component of O. javanica, selectively interrupted NLRC4 and AIM2 inflammasome activation but did not alter cytokine expression. In addition, both of them showed an obvious suppression effect on caspase-1 secretion [6].
Furthermore, the anti-inflammatory effect of isorhamnetin in lipopolysaccharide-activated RAW264.7 cells was confirmed to be partly mediated by inhibiting the mitogen activated protein kinase (MAPK)-nuclear factor-kappa B (NF-B) signaling pathway [7]. The in vivo anti-inflammatory  activity of isorhamnetin was also confirmed in carrageenaninduced 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-    Total flavone from O. javanica has been demonstrated to possess an upregulatory effect on cell immunity, humoral immunity, and nonspecific immunity in hydrocortisoneinduced immunodepressed mice model, as it could obviously increase the carbon clearance index, the serum hemolysin 10 Evidence-Based Complementary and Alternative Medicine Boiling water extract of O. javanica (equivalent to 12 g fresh material/kg)

ANIT-induced hepatitis in Wistar rats
significantly decreasing the elevated serum bilirubin level and alleviated the condition of the degeneration and necrosis of hepatic cells. [49] Total phenolic acid (OJTPA, 500, 250, and 125 mg/kg)

D -gala-induced liver injury in mice
Inhibiting MDA concentration and raised SOD activity, as well as alleviated the damaged condition of livers in D -gala-induced mice. [50] Total phenolic acid (OJTPA, 500, 250, and 125 mg/kg) CCl 4 -induced liver damage in mice Significantly inhibiting the increasing serum ALT and AST levels. [51] Total phenolic acid (OJTPA, 300, 150, and 75 mg/kg)
Evidence-Based Complementary and Alternative Medicine 11 content, and spleen and thymus index and enhance delayedtype 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].

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 ethanoltreated 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 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 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].  [25]. In addition, the 95% ethanol extract of the dried leaves exhibited a radical scavenging for DPPH and inhibitory effect on SOD activity, with the inhibition rates of 56.87 ± 1.43% and 73.51 ± 0.54% at concentration of 10 mg/ml, respectively. However, 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 IC 50 value was 87.42 ± 0.64 g/ml [23] 50 ) and maximum nontoxic concentration (TC 0 ) was 2.28 g/L and 1.00 g/L, respectively. The maximum 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 CCC 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 10day 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 g/ml and half value of effective concentration (EC 50 ) was 1120.8 g/ml, which was much less than its TC 50 (10000 g/ml), indicating O. 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 g/ml) in vitro and 73.3% (at dose of 8 g/kg) in vivo, indicating strong inhibition effect of O. javanica on DHBV-NDA polymerase. In addition, IC 50 (407 g/ml) was far less than TC 50 (>10000 g/ml) on liver cell [70].
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 50 of the extract was 2284.73 ± 127.35 g/ml, and the TC 0 was 1000 g/ml. After 6 and 9 days' treatment, the extract significantly inhibited the secretion of HBsAg and HBeAg in HepG2.2.15 cell line at doses of 1000 and 500 g/ml [71]. 6.7. Neuroprotective Activity. The neuroprotective activities of O. javanica extracts have been uncovered by several studies, which showed that the extracts could improve cell proliferation and neuroblast differentiation, protect neurons from ischemic damage, and maintain antioxidants immunoreactivities [34,38,40,72]. The ethanol extract of O. 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 [38].

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 antimetastatic effect, which may correlate with its inhibition of reactive oxygen species-mediated hypoxia inducible factor-1 (HIF-1 ) accumulation [74]. It could significantly inhibit cobalt chloride (CoCl 2 )-or hypoxia-induced HIF-1 accumulation in human cancer cells (HCT116 and HT29 cell lines), as well as suppress CoCl 2 -induced activity of hypoxia response element reporter gene and HIF-1 -dependent 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 2 O 2 -induced HIF-1 accumulation was also observed in HEK293 cells.
6.9. Anticoagulant/Antithrombotic Activities. 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-1/tissue-type plasminogen activator. The anticoagulant and profibrinolytic effects showed that persicarin > isorhamnetin, hyperoside > isorhamnetin-3-O-galactoside, which suggest that the sulfonate group of persicarin or the methoxy group of isorhamnetin-3-O-galactoside positively regulates its anticoagulatory function.
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]. which indicated that 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, 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].
6.13. Antinociceptive/Analgesic Effect. The antinociceptive active of O. javanica methanol extract (at 200 mg/kg) was tested in the acetic acid-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. 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].

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 g/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].
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 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 antiinflammatory treatment.

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 although scientific studies of bioactivities of O. javanica might justify some of its ethnomedicinal claims, the data are insufficient and, to some extent, preliminary. In the future, further systemic studies in humans are necessary. Furthermore, a subchronic toxicology of O. javanica at high dose (equivalent to 20 times the recommended human clinical dose) was observed in rats, but the potential toxic component and its possible 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.