The traditional herb Polygonum hydropiper from China: a comprehensive review on phytochemistry, pharmacological activities and applications

Abstract Context Polygonum hydropiper L. (Polygonaceae) (PH) is a traditional Chinese traditional medicine with a pungent flavor and mild drug properties. PH is mainly distributed in the channel tropism in the stomach and large intestine. PH has multiple uses and can be used to treat a variety of diseases for a long time. Objective This review summarizes the phytochemical and pharmacological activities, and applications of PH from 1980 to 2022. We also provide suggestions for promoting further research and developing additional applications of PH. Methods The data and information on PH from 1980 to 2022 reviewed in this article were obtained from scientific databases, including Science Direct, PubMed, Science Citation Index, SciFinder Scholar (SciFinder), Springer, American Chemical Society (ACS) Publications, and China National Knowledge Infrastructure (CNKI), etc. Some information was obtained from classic literature on traditional Chinese medicines. The search terms were Polygonum hydropiper, phytochemistry compositions of Polygonum hydropiper, pharmacological activities of Polygonum hydropiper, and applications of Polygonum hydropiper. Results The comprehensive analysis of the literature resulted in 324 compounds being isolated, identified, and reported from PH. Regarding traditional uses, the majority of phytochemical and pharmacological studies have indicated the diverse bioactivities of PH extracts, flavonoids, and volatile oil elements, including antibacterial, antifungal, insecticidal, antioxidant, and anti-inflammatory. Conclusions PH has a long history of diversified medicinal uses, some of which have been verified in modern pharmacological studies. Further detailed studies are required to establish scientific and reasonable quality evaluation standards and action mechanisms of active constituents from PH.


Introduction
The Polygonaceae family consists of 50 genera and 1120 species; of these, approximately 13 genera and 238 species are found in China. Polygonum is the major Polygonaceae genus for medicinal purposes, with approximately 300 species worldwide. In total, there are 131 species and 31 varieties of Polygonum in China; 72 species have medicinal value, are distributed in many provinces in northern and southern China, and are commonly found on roadsides or in watery wet places Wang 2008;Wang et al. 2012). ophthalmological diseases, and sebaceous cysts, etc. (Huang and Zhen 2013).
Previous studies in the 1990s found that PH has antimicrobial, insecticidal, antioxidant, antitumor, and other biological activities (Haraguchi et al. 1992(Haraguchi et al. , 1993(Haraguchi et al. , 1996Yagi et al. 1994). The active ingredients are flavonoids and volatile oils. In recent years, there have been many reports about the phytochemical composition and pharmacological activities of PH worldwide. Flavonoids have antimicrobial and anti-inflammatory effects, and volatile terpenoids have insecticidal activities, which can provide some references for the development of new drugs and new plant-based pesticides. Moreover, there is a certain development prospect in the fields of medicine, food, botanical pesticides, veterinary medicine, and food additives (Zeng et al. 2006;Huang and Zhen 2013). However, an overall review of these factors is lacking. In this review, the phytochemical constituents, pharmacological activities, and applications of PH have been summarized for the further detailed research, with the hope that PH can be fully and effectively developed and utilized.

Methods
This literature review of PH covers the reports from 1980 to 2022. The data and information were obtained from multiple scientific databases, including Science Direct, PubMed, Science Citation Index, Sci Finder, Springer, ACS Publications, Innojoy, Google Scholar, Baidu Scholar, and China National Knowledge Infrastructure (CNKI). Additional information was obtained from classic literature on traditional Chinese medicines, as well as PhD and MSc theses in the school library, and downloaded from CNKI, read manually and analyzed in groups. The search terms were Polygonum hydropiper, phytochemistry compositions of Polygonum hydropiper, pharmacological activities of Polygonum hydropiper, applications of Polygonum hydropiper and other related search terms. We excluded reports and articles that appeared in some news media or newspapers, as well as literature that was not published in formal professional magazines or periodicals.

Phytochemistry
To date, 324 compounds have been isolated and identified from PH, and researchers have adopted multiple separation techniques for the isolation and purification of chemical constituents from PH, including 40 flavonoids, 9 phenylpropanoids, 169 volatile oils, 75 terpenoids, 19 organic acids, 7 steroids, and 5 others. The percentages of chemical constituents are shown in Figure 1.

Flavonoids
Flavonoid ingredients are the main active ingredients of PH. In addition, flavonoid glycosides, flavonol and its glycosides, flavone and its glycosides, chalcone, and dihydrochalcone are found in PH. The species, compounds, and molecular formulas of PH are shown in Table 1. The basic parent nuclei and structures of flavonoids 1 to 40 are shown in Figure 2.

Volatile oils
The volatile oils stored in PH are extremely complex, mainly sesquiterpenoids, and contain enol tautomerisms and sterols. Due to the volatility and instability of the volatile oils, different origins, different months, and different extraction methods can affect the volatile components of PH.
Eight volatile oil components were first separated and identified by the supercritical CO 2 technique and combined GC-MS coupling technique (Zhang and Zeng 2005). A total of 125 volatile oils from the aboveground parts of PH grown in May, August, and November in Guizhou in 2018 were obtained and identified by steam distillation and GC-MS coupling techniques; they had 15 similar components (Table 2) (Yu et al. 2018). Volatile oils of PH were first extracted by the methods of steam distillation and CO 2 supercritical extraction, and identified by the GC-MS coupling technique, which yielded 14 and 4 volatile oil-like components, respectively, including 2 similar compounds (Li 2007). Seventy-five volatile components from PH in Guizhou contained the same 5 compounds, and they were obtained and distinguished by solid phase extraction, steam distillation and GC-MS coupling techniques . Fifty-three volatile components of PH from Hunan were obtained by steam distillation combined with GC-MS (Yao et al. 1999). Six volatile components of PH were first found first from an ether extraction part of alcohol extraction by GC-MS (Zeng 2007). Altogether, 103 volatile components of PH were isolated and identified by steam distillation and GC-MS coupling techniques (Wu et al. 2007;Wang et al. 2017). The volatile oil compounds (from 50 to 218) of PH are shown in Table 2. The structures of phenylpropanoids 50 to 218 are shown in Figure 4.

Organic acids
Multiple compounds of the organic acid are found in PH, such as fatty acids, polyphenols and carboxylic acids. The fatty acidlike components are mostly unsaturated fatty acids. Sixteen constituents of organic acids were isolated and identified by GC-MS (Liu, Qin et al. 2009), and 3 organic acids were purified and isolated by column chromatography Xu et al. 2017). The compounds and molecular formulas from 309 to 327 are shown in Table 3. The structures from 294 to 312 are shown in Figure 6.  (Liu, Qin et al. 2009;Li et al. 2017;Wang et al. 2018). The structures from 313 to 319 are shown in Figure 7.

Others
Gallic acid (320), which is the tannin monomer, was isolated from PH extract with 75% ethanol (Huang et al. 2012). Ellagic acid (321), a tannin component, was obtained from PH ). An acidic polysaccharide named PFMP (322) was separated by DEAE column chromatography and authenticated to consist of D-mannose, L-rhamnose, D-glucuronic acid, D-galactose, D-glucose, and L-arabinose by HPLC (Zhu 2020). Pinosylvin (323) and 5,6-dehydrokawain (324) were isolated from chloroform extract (Xiao 2018). Rich metallic elements, such as Ca, Mg, Al, K, Fe, Mn, Ag, and Zn, and several harmful metals, such as Pb, As, Cu, Hg, and Cd, were discovered by microscopic with identification combined inductively coupled emission spectrometry (Wang et al. 2019). The contents of four heavy metals, Pb, Cd, As, and Hg, were detected by flame atomic absorption spectroscopy, and all met the Green Trade Standard (Lai et al. 2011). The structures of 320, 321, 323 and 324 are shown in Figure 8.

Antibacterial and antifungal effects
The extracts from different parts of PH have some antibacterial and antifungal effects, especially in vitro, showing more extensive antibacterial and antifungal effects. The components of PH, including volatiles, flavones and carboxylic acids, have good broad-spectrum inhibition of bacterial activity Li et al. 2017;Ma et al. 2017). The ethanol extract and acetone extract of PH have antifungal activity and may be used in the treatment of fungal infections, such as Trichospora photospora and Pestalotia funerea in poultry. In conclusion, the active ingredients of PH with antibacterial and antifungal activities may be flavonoids and volatile oils. The active fractions and antibacterial and antifungal species of PH with antibacterial and antifungal activities are shown in Table 4.

Antiviral effects
Both the ethyl acetate and n-butanol portions of PH have antiviral effects. The main active component with antiviral effects is flavonoids (Zhou et al. 2020;Lu et al. 2021). The antiviral species and mechanisms of PH are shown in Table 5.

Antifeedant and insecticide effects
Because PH has strong antifeedant and insecticidal effects, it could be used in the development of novel pesticides and insecticides in the future. The active constituents of PH with antifeedant and insecticidal effects may be terpenoids. The active ingredients of PH with antifeedant or insecticidal and insect categories are shown in Table 6.

Antioxidant activity
The flavonoids from PH have good antioxidant activity, and the antioxidant activity of PH is different because of its different structure. Flavonoids with more enol structures have stronger antioxidant capacity, and quercetin has stronger antioxidant activity than vitamin C Ma et al. 2017). The alcohol extracts from different parts of PH have the ability to scavenge DPPH in the order of caffeic acid > rutin > PH flowers > PH leaves > PH stems > PH roots and the ability to scavenge OHin the order of PH leaves > PH stems of > PH roots > PH flowers > caffeic acid > rutin (Yang et al. 2014). Muhammad et al. (2014) found that n-hexane, chloroform, ethyl acetate, n-butanol, water and saponins of PH all had certain antioxidant activities, which were all concentration-dependent on DPPH and could inhibit the activity of acetylcholinesterase. The hexane, chloroform, ethyl acetate, and water fractions of PH had inhibitory activity on butyrylcholinesterase. Yagi et al. (1994) determined the antioxidant activity of flavonoids in PH by the ferric thiocyanate method and discovered that PH had a high eradication rate of superoxide ions in a dose-dependent manner. It was speculated that flavonoids might play a role in scavenging superoxide anions by inhibiting xanthine and xanthine oxidase, thus having antioxidant activity. Sharif et al. (2013) discovered that methanol, ethanol, chloroform, petroleum ether and n-hexane fractions of PH all had antioxidant activity, and methanol, ethanol, and petroleum ether had the strongest activity. Overall, PH has good antioxidant activity and can become a natural antioxidant, probably because it contains a large number of flavonoids, terpenoids, and tannins.

Anti-inflammatory effects
Both the aqueous and alcoholic extracts of PH herbs have certain anti-inflammatory effects. Their active ingredients and their antiinflammatory effects, inflammation categories, inflammatory modeling methods and anti-inflammatory mechanisms or pathways are shown in Table 7.
Impact on the immune system PH can inhibit Escherichia coli diarrhea and hepatitis B virus to some extent and can resist immunosuppression caused by cyclophosphamide in mice, which proves that it has a certain immunomodulatory effect. The active components of PH with immunomodulatory effects, the impacts on the immune system and the mechanisms of action are shown in Table 8.    No.

Compound
Ref. No.
128 2,4,6 tripropyl-1,3,5-trioxane 205 9,12-octadecadienoic acid methyl ester Yao et al. 1999 Protection of the gastrointestinal tract PH aqueous extract has a good therapeutic effect on E. coli diarrhea , and acute gastric mucosal injury of rats caused by ethanol (Ren et al. 2018). The mechanism of treatment of E. coli diarrhea may be related to reducing the release of inflammatory factors in intestinal tissues, improving the intestinal mucosal barrier and intervening with TGF-b/Smad signal transduction. The mechanism of treating acute gastric mucosal injury induced by ethanol may be related to increasing the content of Nrf 2 and the activity of SOD in gastric mucosal tissues .

Others
In addition, PH has analgesic ( . PH also has a therapeutic effect on the reproductive system and influences the expression of insulin-like growth factor in the uterus of early pregnancy rats (Goswami et al. 2014). The volatile composition of PH, b-sitosterol, can improve memory deficits and disorders such as Alzheimer's disease, and is mainly manifested in the aspects of anticholinesterase, improvement of working memory, spontaneous alternating behavior, motor coordination, etc. of transgenic animals (Ayaz et al. 2015, Ayaz, Junaid, Ullah, Subhan, et al. 2017. PH water extracts alleviate hepatic and duodenal injury induced by enteropathogenic E. coli. The mechanism of E. coli infection is that PH inhibits the secretion and expression of inflammatory cytokines and regulates the expression level of CYPs (Huang et al. 2022).

Traditional applications
Many ancient medical books in China described the traditional effects of PH. As recorded in Mingyi Bielu: 'Polygonum leaves, the meridian tropism is tongue, could remove the small and large intestinal evil, also benefit in the intelligence.' As recorded in Tang Materia Medica: 'PH main treatment snake bite, mashed to apply; juice to take, treatment of snake venom caused by abdominal stuffiness; soak feet in water decocted solution of PH, followed by massage, remove beriberi swelling.' As recorded in Bencao Shiyi: 'PH, the main treatment of periumbilical and hypochondriac firmness and pain, takes 60 g daily after boiling; PH treats cholera with muscular spasm and to massage feet with hot water decoction; the leaves are crushed and applied to treating the huci nevus; the leaves are also used for treating the head sores in children.' As recorded in Lingnan Caiyaolu: 'PH can be applied to the injury site, can be used to clean the surface of naevus scabies, and also can itch and swell.' (Zhang 2004).

Modern applications
PH can be used for preventing and treating enteritis in black carp and grass carp in the high temperature season (July to September every year). The feed method comprises chopped herb PH hay or fresh herb PH decocted with an appropriate amount of water, mixing that filtrate with bait, and continuously feeding for 3-6 days (250 g hay or 1.5 kg fresh herb PH per   50 kg) (Wang et al. 2021). Planting PH on the mud bank of eel ponds can prevent red-skin disease for a long time (Liu 2020). Cleaning and mashing fresh stems and leaves of PH, adding water to soak for 24 h, filtering to remove residues, diluting with water and spraying a solution that is five times that of the original on leaf surfaces helps to prevent and control plant hoppers, aphids, rice leafhoppers, tea caterpillars, etc. The fresh stems and leaves of PH can be washed, dried, powdered and sprinkled to prevent and control cutworms and grubs (Ao 2019;Zhou and Du 2019). Intramuscular injection of the PH liquid can be used for treating porcine epidemic diarrhea (Ren 2017). After drying, PH is crushed and mixed into grain at a ratio of 1:1000, which can keep the grain free of insects for a year. The mung bean weevil can be controlled by putting PH into mung beans at a ratio of 9:1000 (Peng 2016). Feeding dried or fresh PH to fish can prevent and cure rotten gill disease (Wang 2016). PH has been boiled in water and mixed with chopped tender grass or bait to treat fish enteritis . PH has also been ground into powder, mixed with bait and fed to cure fish enteritis, rotten gill and red-skin disease (Liu 2017). The stem or whole plant of fresh herba PH can be mashed into mud and applied to the affected part to treat livestock pellagra (Zhang 2014). Clinically, PH and Gardenia jasminoides Ellis (Rubiaceae) can treat ovarian cysts (Li and Gu 2018).
There are few studies on the toxicology of PH. At present, only Zhang et al. (2022) and Zhu et al. (2020) found that the flavonoid extract of PH at 5 g/(kgÁBW) and below had no acute toxic effects or side effects in mice, has no subchronic toxic effects after long-term continuous medication, and has good safety.

Prospects
Since PH contains many active ingredients, each with different medicinal effects, it also has more prospects for development and application. The polysaccharide isolated from PH can be used as an immunomodulator in health food. PH can be made into new anti-trypanosomal drugs due to its anti-trypanosomal activity. In places where mosquitoes are very likely to breed, such as cesspools and gutters, a certain amount of volatile oil extract of PH can be added as an insecticide and mite killer. In addition, PH can be made into plant pesticides, antibacterial agents, and natural antioxidants.

Conclusions
As a traditional herbal medicine with a long history, PH can be used in a single or compound prescription. Because of its multiple effects and medicinal history, many researchers have a keen interest in PH. This review comprehensively summarizes the phytochemical constituents, pharmacological activities, and applications of PH, which could offer ideas and foundations for the further studies.
To date, a total of 324 compounds have been isolated and identified from PH, mainly flavonoids, phenylpropanoids, volatile oils, terpenoids and organic acids. Among them, flavonoids and volatile oil components have certain antibacterial and antiviral effects, but the active ingredients and pharmacodynamic substance basis have not been reported. The volatile oil component 'eugenol' was found to be a pesticide, and the insecticidal mechanism was that eugenol significantly inhibited the activities of acetylcholinesterase and glutathione-S-transferase (Zeng 2007). The second volatile oil component 'confertifolin' was considered for use in the control of human vector mosquitoes, but the mechanism is unclear (Maheswaran and Ignacimuthu 2013). Confertifolin is very promising for formulating a potent and affordable natural product to control dreadful disease transmission and nuisance-creating human vector mosquitoes. The other active insecticidal components were crude extracts. In general, the study of PH remains inadequate. Quercetin is an anti-inflammatory active ingredient, and its mechanism is that it inhibits the Src/Syk/NF-jB and IRAK/AP-1/CREB signaling pathways. It has been suggested that quercetin should be developed as a novel anti-inflammatory remedy . In particular, there is a lack of toxicity research. To date, only a few studies have reported that the flavonoids of PH have no acute toxicity and are nontoxic after long-term use. However, there is a lack of reports of other active components, especially volatile oil and terpenoid components. When used as pesticides, there is also a lack of reports on the optimal concentration and dose of pesticides for various pests and whether there is harm to the human body when used as pesticides. In ancient China, people often burned PH at night to repel mosquitoes and insects, and this practice could match the insecticidal effect in modern pharmacological research. The polygodial contained in PH is a volatile terpenoid, has good antifeedant activity to insects, and has antioxidation, good stability to air and light, and a half-life of more than one month. It is less stable to heat but has a half-life of more than 15 days, which is different from other herbs (Zhang 2004). While the current study only reported that the active ingredients of PH with insecticidal effects are volatile oils and some crude extracts, the active compounds have not been determined. High-temperature burning has a pungent odor, and whether the insecticidal mechanism is related to the pungent odor is unknown, so the subsequent research should involve more in-depth screening of the active substances with insecticidal effects, which can be developed into pesticides and insecticides of plant origin. The levels of TNF-a in serum, intestinal tissue and liver tissue were significantly decreased in all FEA dosage groups, and the mRNA expressions of TNF-a, IFN-c and IL-2 in lung were significantly decreased in all FEA dosage groups. Gu, Tao, Wu, et al. 2018 n-butanol part of flavone (FNB) (50, 100, 200 mg/kg) were administered orally for 3 consecutive days to mice before modeling.

Endotoxemia relieve
Mice were injected intra-peritoneally with 17 mg/kg 0.2mL. FNB can reduce the release of pro-inflammatory factors TNF-a, IL-1b, IL-6 and IL-8 induced by LPS stimulation, and reduce the expression level of TNF-a, IFN-a, IFN-c and IL-2mRNA in lung by enhancing the activity of antioxidant defense enzyme system in mouse liver. Gu, Tao, Yang, et al. 2018 As a common traditional herbal medicine, PH is often grown in ditches and depressions, probably because of its ability to resist the growth of weeds. Currently, with the continuous modernization, an increasing number of skyscrapers are rising from the ground, and the germplasm resources of PH are gradually decreasing. We must pay attention to the conservation of this natural medicinal resource. Since PH grows in gullies and depressions, such places are hotbeds of bacteria and many kinds of microorganisms; however, PH resists the growth of miscellaneous bacteria, probably because it has some important endophytic bacteria of its own. However, no research has been done on this topic yet, which could be another new research direction.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article. Table 8. Active components with immunomodulatory effects, dosage, mode of administration, modeling methods, the impact on the immune system and the mechanisms of action.
Active components, dosage, and mode of administration Modeling methods Impacts Mechanisms Ref.
water extract (5 and 10 g/kg) were orally administered to mice twice daily for 2 consecutive days prior to modeling.
Mice were intraperitoneally injected with E. coli suspension 10 mg/kg once on the first day, the third day and the seventh day respectively.
Protective effect against E. coli-induced diarrhea.
Under the condition of E. coli infection, the expression of CYPs mRNA and protein in the duodenum and liver of mice is generally reduced, and PH has obvious regulation effect on CYPs.
Has certain cellular immunity function and anti-hepatitis B virus function in vitro, and has a dose-effect relationship.
The 70% ethanol extract of PH could inhibit the secretion of HBsAg and HBeAg by HepG cells in a dose-dependent manner. Li et al. 2014 n-butanol part of flavone (FNB) (25, 50, 100, 150 mg/kg) were administered orally for 7 consecutive days to mice while modeling.
The immunosuppression model was established by interaperitonel injection of 30 mg/kg cyclophosphamide (CTX) for 7 days.
Enhances immunologic function in mice and counteracts CTX-induced immunosuppression in mice.
FNB can alleviate the impacts of immunosuppression by adjusting the level of NO and activities of MPO and NOS. Xie et al. 2021 Polysaccharides (100, 200 and 400 mg/mL) were administered orally for 10 consecutive days to mice while modeling.
Has certain immunoregulatory activity.
Polysaccharides promotes macrophage proliferation and phagocytosis in vitro, and protected mice from immunosuppression induced by cyclophosphamide in vivo.