Ethnobotanical, Phytochemical, Pharmacological, and Toxicological Aspects of Persicaria hydropiper (L.) Delarbre

Persicaria hydropiper (L.) Delarbre, belonging to Polygonaceae family, is a common weed found in most of the temperate countries including Bangladesh, China, Malaysia, and Japan. The plant is also referred to as “marsh pepper” or “smart weed.” It appears to be a useful herb with evidence-based medicinal properties. The present work addresses the botanical description, traditional uses, phytochemistry, pharmacology, and toxicology of P. hydropiper. All plant parts have been commonly used in the traditional systems of medicines. Flavonoids are the major group of phytochemical components followed by drimane-type sesquiterpenes and sesquiterpenoids, as well as phenylpropanoids. Different extracts and plant parts showed remarkable pharmacological activities including antioxidant, antibacterial, antifungal, antihelminth, antifeedant, cytotoxicity, anti-inflammatory, antinociceptive, oestrogenicity, antifertility, antiadipogenicity, and neuroprotection. Mutagenicity and acute and subchronic toxicities of the plant were also reported. P. hydropiper has tremendous medicinal properties that could further be investigated for the development of evidence-based herbal products.


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Evidence-Based Complementary and Alternative Medicine for a variety of traditional dishes [15][16][17]. The Japanese people use the young shoot as spice and garnish with raw fish such as "sashimi" for its pungent taste [18], while the water or ethanol leaf extract served as a food additive to preserve pickles, dressing, and cooked foods [19]. In Southeast Asia, the Chinese and Malays use the leaves in traditional laksa dishes [16].
Most importantly, P. hydropiper also has a wide range of traditional uses for medicinal purposes. In Europe, the plant has been used as diuretic and emmenagogue [20] and to regulate menstrual irregularities [21]. In addition, decoction of the whole plant, either alone or mixed with other medicinal plants, is also given for diarrhea, dyspepsia, itching skin, excessive menstrual bleeding, and hemorrhoids [22]. The leaves and seeds are used in a folk medicine against cancer [23]. The Romanian people in Oltenia utilized infusion of the aerial part as astringent and cicatrising, as well as for gastric, pulmonary problems, and uterine hemorrhages [24]. The use of bruised leaves and seeds as vesicants has also been reported [25].
In India, the Mishing women in Assam take the dried root powder of P. hydropiper for termination of pregnancy and it may lead to permanent sterility if taken continuously for more than a year [26,27]. Leaf 's juice is consumed for uterine disorders [28]. In Arunachal Pradesh, the whole plant extract and ground plant paste are used as fish poisons [28,29], whereas the leaf infusion is used to relieve colic pain [30]. The plant has also been utilized as natural dyes [31].
In Bangladesh, the Garo tribe uses the leaf juice for menstrual pain, the leaf paste to stop bleeding, and the whole plant as pesticide for stored grains [32]. Another tribe of Tripura uses the mixture of crushed P. hydropiper leaf with black pepper for headache [33]. In a district of Sylhet, the crushed plant helps to arrest hemorrhage and in Rema-Kalenga, the leaves are used for stomach pain [34]. The leaf juice has been given for treating many health problems like headache, pain, toothache, liver enlargement, gastric ulcer, dysentery, loss of appetite, and dysmenorrhea, while the roots are used as stimulant and their juice is applied to wounds, skin diseases, and painful carbuncles [35].
In Vietnam, the stems and leaves are taken for snake-bite and as diuretic and anthelmintic [12]. In China, the plant is consumed to prevent ovulation and cease pregnancy [36], while the root is used as stimulant, diuretic, carminative, tonic, and anthelmintic [37]. This plant has been found to be toxic to pigs and sheep [38].

Pharmacological Properties
Several reports on pharmacological properties of P. hydropiper are available to support the ethnomedicinal uses of the plant including antioxidant, antibacterial, antifungal, antihelminth, antifeedant, cytotoxicity, anti-inflammatory, antinociceptive, oestrogenicity, anti-fertility, anti-adipogenicity, anticholinesterase, and neuroprotection. Toxicological effects of P. hydropiper are also described.
An in vivo study performed by Raihan et al. [65] showed that the methanol (99%) extract of P. hydropiper aerial part had antiproliferative activity against Ehrlich Ascites Carcinoma (EAC) cells inoculated intraperitoneally (i.p.) in Swiss-Webster albino male mice. The extract at a dose of 50 mg/kg/day (i.p.) significantly ( < 0.001) inhibited (84.54%) EAC cell growth, decreased tumor weight to 7.85 g, and improved mean survival time (68.0% increase of life span) of EAC bearing mice, as compared to the positive standard, bleomycin (0.3 mg/kg, i.p.) with values of 98.55%, 7.05 g, and 94.66%, respectively.
Furuta et al. [51] demonstrated the anti-inflammatory property of polygonolide isolated from methanol extract of P. hydropiper root by inhibiting reversed passive Arthus reaction. A dose of 100 mg/kg polygonolide administered orally 1 hour before induction of inflammation on the rat skin was able to inhibit 39.2% ( < 0.05) of the acute inflammation.
Mendes et al. [77] isolated polygodial from the barks of D. winteri and found that it (0.1 to 10 mg/kg, administered by intraperitoneal injection) was able to inhibit mice abdominal contractions induced by acetic acid (ID 50 0.8 mg/kg), zymosan (ID 50 2.1 mg/kg,) and kaolin (ID 50 2.6 mg/kg). Polygodial also demonstrated distinct systemic, spinal, and supraspinal antinociceptive effect on mice, mainly preventing the formalin-and capsaicin-induced neurogenic pain, via several mechanisms including binding to the k and d subtypes of opioid receptors, activation of pertussis toxin-sensitive Gi/Go-protein, binding to 1 -adrenoceptors and serotoninergic system [78]. Neurogenic antinociceptive and thermal antihyperalgesic effects were observed in neonatal treatment of rats [79].

4.9.
Oestrogenic and Antifertility Activity. Garg et al. [80] first reported the antifertility activity of ethanol extract of P. hydropiper root on female albino rats. Recently, the methanol root extract administered orally to ovary-intact and ovariectomized adult albino rats at a dose of 1000 mg/kg body weight/day for three consecutive oestrous cycles (12 days) was found to induce endometrial proliferation and follicular growth that was evidenced by the regulation of endometrial protein expression, suggesting its oestrogenic property comparable to estradiol-17 [26,81]. Further investigations have demonstrated that the steroid-containing fraction of P. hydropiper methanol root extract, administered subcutaneously at a dose of 5 mg/kg/day, stimulated proliferation of uterine epithelium of ovariectomized adult albino rats [27]. The fraction also stimulated expression of various uterine proteins in ovary intact (molecular weight ≈150000, ≈90000, ≈82000, ≈56000, ≈43000, and ≈38000) and ovariectomized (≈38000) rats but reduced expression of proteins (≈65000 and ≈38000) in pregnant rats of 5-6 days after implantation [82]. The latter was indicated by the suppressed expression of estrogen-sensitive transforming growth factor-I in the primary decidual zone of the implantation sites during day 6 of gestation, suggesting the antifertility activity [83].

Antiadipogenic Activity.
Methanol extract of P. hydropiper whole plant (1 g/mL) and its flavonol components, isoquercitrin (50 M) and isorhamnetin (50 M), were shown to activate the Wnt/ -catenin signaling in HEK 293 cells containing pTOPFlash reporter gene, increase nuclear localization of -catenin in 3T3-L1 adipocyte cells, and inhibit adipocyte differentiation, suggesting its potential application as antiobesity agents and for associated disorders [84].

Neuroprotective Activity.
Persicarin was discovered as a component of the P. hydropiper methanol leaf extract [45]. As a matter of fact, Ma et al. [85] reported that persicarin isolated from the stems and leaves of Oenanthe javanica demonstrated significant neuroprotective activity (40.8-74.5% protection at 10.0 M, < 0.001) in glutamate-induced neurotoxicity of rat cortical cells by inhibition of intracellular calcium influx, intracellular nitric oxide production, and cellular peroxide formation, as well as by increasing the antioxidant activities of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Depending on the amount of persicarin in P. hydropiper, its extract could potentially possess neuroprotective activity.

Toxicology
Kuroiwa et al. [86] stated that the P. hydropiper ethanol leaf fraction containing 7.0% polygodial gave positive mutagenicity in two tests, that is, the Ames test using Salmonella 8 Evidence-Based Complementary and Alternative Medicine typhimurium TA 100 and TA 98 and the chromosomal aberrations using Chinese hamster-derived CHL/IU cells, but it was negative for micronuclei in mouse bone marrow cells. It was also previously reported that polygodial was negatively mutagenic in the Ames test using TA 100, TA 98, and TA 2637 strains of S. typhimurium [71] and in the mammalian cell V79/HGPRT assay [87].
Acute toxicity in Swiss-Webster albino male mice was conducted by Raihan et al. [65], in which methanol (99%) extract of P. hydropiper aerial part (20-600 mg/kg) was injected intraperitoneally. After 24 hours, no mortality was observed up to 400 mg/kg, but 100% mice died at 600 mg/kg, suggesting the LD 50 of the extract to be 500 mg/kg (i.p.).
Kuroiwa et al. [86] also investigated the subchronic toxicity of WPE in male and female F344/DuCrj rats given ad libitum for 13 weeks. The no observed-adverse effect was found with 1000 ppm ethanol leaf fraction containing 7.0% polygodial (57.4 and 62.9 mg/kg/day for males and females, resp.), whereby there were no obvious clinical signs and no significant changes in food consumption, hematology and serum biochemistry, body and organ weights, and histopathology of organs of the tested rats.
The aerial parts cause blister of the skin upon repeated handling that could be due to the skin irritant polygodial [49,88]. Polygodial isolated from the bark of D. winteri was found to increase extracellular glutamate concentrations via concurrently inhibiting glutamate uptake by rat astrocytes and slices of cortex, striatum, and hippocampus and increasing glutamate release by synaptosomes, suggesting possible neurotoxic effect of polygodial [89].

Conclusions
The numerous ethnobotanical uses of P. hydropiper had drawn the attention of the scientists to investigate its traditional claims. The above discussion clearly gives us a perception on the scientific evidence of different pharmacological properties of this species which supports a number of its traditional uses such as antibacterial, antifungal, antihelminth, antifeedant, anticancer, anti-inflammatory, antinociceptive, oestrogenicity and antifertility uses. The antiallergic, antiadipogenic, and neuroprotective properties of the plant provided new knowledge on the extension of its uses. The plant contained several remarkable pharmacologically active compounds; for example, polygodial was found to have antibacterial, antifungal, antifeedant, antiinflammatory, antinociceptive, and antiallergic properties; polygonolide had anti-inflammatory activity. Warburganal acted as antifeedant; confertifolin had antibacterial and antifungal activities; persicarin demonstrated neuroprotective activity; isoquercitrin, quercetin, quercetin-3-O-rhamnoside, 7,4 -dimethylquercetin, galloyl quercitrin, isorhamnetin-3,7-disulphate, 3,5-dihydroxy-4-methoxybenzoic acid, hydropiperoside B, and vanicoside A showed antioxidant properties, while isoquercitrin and isorhamnetin were antiadipogenic. Oral consumption of ethanol leaf fraction containing 7% polygodial was found to be safe in vivo. Thus, this plant serves as a promising candidate as a multipurpose herbal medicinal agent owing to its economical viability and being a reservoir of many significant medicinal properties in treating diseases and ailments related to microbial infections, inflammation, pain, allergy, uterine disorders, fertility, obesity, and improvement of memory.