An Update on Phytochemicals and Pharmacological Activities of the Genus Persicaria and Polygonum

The discovery of new pharmaceutical identities, particularly anti-infective agents, represents an urgent need due to the increase in immunocompromised patients and the ineffectiveness/toxicity of the drugs currently used. The scientific community has recognized in the last decades the importance of the plant kingdom as a huge source of novel molecules which could act against different type of infections or illness. However, the great diversity of plant species makes it difficult to select them with probabilities of success, adding to the fact that existing information is difficult to find, it is atomized or disordered. Persicaria and Polygonum constitute two of the main representatives of the Polygonaceae family, which have been extensively used in traditional medicine worldwide. Important and structurally diverse bioactive compounds have been isolated from these genera of wild plants; among them, sesquiterpenes and flavonoids should be remarked. In this article, we firstly mention all the species reported with pharmacological use and their geographical distribution. Moreover, a number of tables which summarize an update detailing the type of natural product (extract or isolated compound), applied doses, displayed bioassays and the results obtained for the main bioactivities of these genera cited in the literature during the past 40 years. Antimicrobial, antioxidant, analgesic and anti-inflammatory, antinociceptive, anticancer, antiviral, antiparasitic, anti-diabetic, antipyretic, hepatoprotective, diuretic, gastroprotective and neuropharmacological activities were explored and reviewed in this work, concluding that both genera could be the source for upcoming molecules to treat different human diseases.


Introduction
Infectious diseases are caused by pathogenic microorganisms such as bacteria, viruses, parasites or fungi and can be transmitted, directly or indirectly, from one person to another. In the last decades, the rapid population growth, poverty, urban migration, international travels and environment changes have increased the exposure to several infectious agents [1]. According to the World Health Organization's estimations, infectious diseases constitute one-third of all deaths in the world. Despite the pharmaceutical efforts to design new antibiotics for the treatment of these diseases, the acquisition of microorganisms' resistance represents a worldwide concern, and this is attributed to the indiscriminate and improper use of current antimicrobial drugs [2]. For this reason, there is a need to search for alternative anti-infective substances, for example, antimicrobials of plant origin.
Plants have developed different active principles for defense towards the pathogens' attacks, called secondary metabolites. Phenolic compounds (e.g., coumarines and phy-toalexins), terpenoids (e.g., monoterpenes, saponins, steroids) and nitrogen compounds (e.g., alkaloids and lectins) are some secondary metabolites with biocidal capacity against human pathogens [3,4]. It has been estimated that 14-28% of higher plant species are used medicinally [5]. The use of antimicrobials of plant origin has many advantages [6]: they have no secondary effects, better patient tolerance, are less expensive, increase the bioavailability of free agents and demonstrate adequate therapeutic effect with relatively small doses.
The genus Polygonum comprises 250 species (20 represented in Argentina) of annual and perennial herbs distributed from the northern temperate to tropical and subtropical regions, preferably in low and humid areas, on the banks of streams and rivers. Nowadays, these species are classified into the Persicaria and Polygonum genera, according to botanical and phytochemical characteristics. Particularly, flavonoids and sesquiterpenes have played an important role in the systematics of Polygonum species as a chemotaxonomic marker and contributed to the regrouping of these species into Persicaria and Polygonum genera [7]. Species of Persicaria and Polygonum show different biological properties for, e.g., antiseptic, antibiotic [8], antinociceptive [9], antifungal [8,10,11], diuretic, antirheumatic, astringent [12,13] uses, and for the treatment of external infections such dermatoses, ulcers and sores [13,14].
The selection of the manuscripts for this review was based on the following inclusion criteria: articles published in English in the last three decades, with the keywords Persicaria, Polygonum and anti-infective in the title, abstract or full text. The authors firstly selected articles according to the title, then to the abstract and then through an analysis of the publication full text. The resulting articles were manually reviewed with the goal of identifying and excluding the works that did not fit the criteria described above. For scientific names of species, The Plant List updated database nomenclature was followed (www.theplantlist.org (accessed on 1 October 2021)).

Pharmacological Activities of Persicaria and Polygonum Products: Different Type of Extracts and Compounds Responsible for the Bioactivities
The following paragraphs will summarize, mainly in table format, the major biological activities depicted in the literature for these plant genera, not only for the different type of extracts generated from them but also for the pure compounds isolated. The parts of each species used to obtain the bioactive phytochemicals and a summary of the results, thrown by the displayed bioassays, will be also comment.

Antimicrobial Activity
Many authors all over the world have investigated the ability of Persicaria and Polygonum species to treat human fungal and bacterial pathogens. Table 2 summarizes the plants which show antimicrobial capacities against different fungal and bacterial strains. Table 2. Antimicrobial activity of Persicaria and Polygonum species against human fungal and bacterial pathogens. Extracts, compounds, part of plant used, antimicrobial activity, standard drug and references are shown. Extracts: DCM (dichloromethane); EtOH (ethanol); MeOH (methanol); Chl (chloroform); Hex (hexane); EtOAc (ethyl acetate); But (butanol). Part used: L (leaves); F (flowers); R (roots); Sp (sprouts); S (seeds); St (stems); WP (whole plant); AP (aerial parts).   EtOH (75%) S. aureus, B. subtilis and P. aeruginosa MIC 5-10 mg/mL [183] From the analysis of Table 1, it could be stated that the three main bioassays displayed for detecting antimicrobial activities of different type of extracts of Polygonum or Persicaria species, as well as their bioactive compounds, include the percentage of microorganism growth inhibition, the determination of IC 50 or the Minimum Inhibitory Concentration of each tested sample (extract or isolated compound). The last one constitutes a standard method for detecting antimicrobial susceptibility, so that the results obtained from carrying out these bioassays should be more convincing. In this sense, P. acuminata, P. ferruginea, P. hydropiperoides, P. lapathifolia and P. arenastrum were tested only as antifungals against yeasts or filamentous fungi, resulting in P. acuminata and P. ferruginea being the most active ones (MICs between 3.9 and 125 µg/mL). Authors correlated these promising activities with the presence of the sesquiterpene polygodial in P. acuminata extracts [25] and the chalcones cardamonin and pashanone present in P. ferruginea extracts [8]. Moreover, P. chinensis, P. hydropiper, P. maculosa, P. punctata, P. senegalensis, P. aviculare and P. cognatum resulted in both antifungals and antibacterials, highlighting the MICs values obtained for isolated compounds confertifolin and drimenol from P. hydropiper essential oil and polygodial from its chloroformic extract (MICs between 0.39 and 125 µg/mL comparable with standard drugs) [71][72][73][74][75]. Finally, P. capitata, P. glabra, P. minor, P. tinctoria and P. perfoliatum were reported in the literature only as antibacterials, remarking the high activity against S. aureus, E. coli, K. pneumoniae and N. gonorrhoeae of flavonoid-enriched fractions of aqueous extracts of P. capitata (MICs comparables to ciprofloxacin) [48]. These results are promising but limited to the in vitro evaluation, and thus, more studies regarding solubilities, absorption, blood distribution, pharmacodynamics, pharmacokinetics and tissue toxicity should be performed before these extracts or compounds could become remedies.

P. amplexicaulis
Nine known compounds and a previously undetermined one (5, 6-dihydropyranobenzopyrone), amplexicine and gallic acid (isolated from EtOH extract) AP IC 50 values of 10.2 µmol/L (5, 6-dihydropyranobenzopyrone), 12.2 µmol/L (amplexicine) and 14.4 µmol/L (gallic acid). [30] Crude MeOH extract and their fractions (But, EtOH, EtOAc and aqueous) Sh, L, Rh All fractions and parts of plant displayed antioxidant activity (IC 50 between 1.03 and 58.2 µg/mL), but leaf crude MeOH and EtOAc fraction were the most effective for radical scavenging activity DPPH, with IC 50 = 1.03 and 3.1µg/mL, respectively.  MeOH extract L IC 50 from DPPH of 26 µg/mL, IC 50 from FRAP of 48 µg/mL and IC 50 from CCA of 770 µg/mL. Benzoic acid, phloroglucinol, phytol and linolenic acid were identified as possible compounds responsible for these bioactivities. [177] Crude extracts AP Good antioxidant scavenging effects on DPPH radical (7.71 µg/mL). Positive controls: BHA, L-ascorbic acid and quercetin (DPPH 2.59-2.61 µg/mL). [175] P. orientalis Taxifolin L, S Inhibitory effect on DPPH radical of 100% at a concentration of 7.5 µmol/L and the IC 50 value for taxifolin was 4.11 mmol/L. [125] From the analysis of this table, it could be remarked that gallic, chlorogenic and ellagic acids may be the responsible for the strong antioxidant activities showed by P. equisetiforme, P. lapathifolia, P. amplexicaulis, P. chinense var. chinense, P. chinense var. hispidum, P. bellardii, P. paleaceum and P. sagittata, which in many experiments resulted to be even more potent than the standard drugs. On the other hand, some specific compounds such as persilben, amplexicine, quercitrin and brevifolin carboxylic acids, vanicoside A and B and taxifolin, were associated to the antioxidant response during the different bioassays carried out with P. maculosa, P. amplexicaulis, P. chinense var. chinense, P. chinense var. hispidum, P. sagittata and P. orientalis, respectively. Conspicuously, a study performed with MeOH extract and zinc oxide nanoparticles (ZnO-NPs) of P. bistorta inhibited the ABTS radicals with an IC 50 value of 40 µg/mL, and it was observed that the activity was dose-dependent. Moreover, it is well known that phenolic compounds are widespread in the plant kingdom, acting as antioxidants offering plant protections, so the Persicaria and Polygonum genera are not exceptional.

Species
Extract/Isolated Compounds Part Used Summarized Bioactivity Ref.

P. chinensis
MeOH extract AP At a concentration of 300 µg/mL, extract significantly inhibited regulation of nitric oxide (NO) at 72% in RAW264.7 cells and prostaglandin (PGE2) production was strongly suppressed up to 53%. These authors tested a murine HCl/EtOH-induced gastric ulcer model to evaluate the anti-inflammatory activity in vivo and found that the extract exhibited a significant anti-gastric activity, compared with the standard anti-ulcer ranitidine (40 mg/kg). [53] P. chinensis var. hispidum Aqueous extract AP Ellagic acid and quercitrin inhibited the development of xylene-induced ear edema, with significant inhibition at a dose of 400 mg/kg. [52] P. alpina MeOH extract Rh HRBC (Human Red Blood Cell) membrane stabilization method and percentage of inhibition protein denaturation method were used for tested in vitro anti-inflammatory activity of MeOH and aqueous extracts which showed a good anti-inflammatory ability, with a membrane stabilizing activity of 81.29% and an inhibition of protein denaturation of 72.70%, compared to the standard Indomethacin (95.56 and 88.26%, respectively). [27] P. hydropiper MeOH extract L Extract blocked the production of NO, PGE2 and tumour necrosis factor on RAW264.7 cells and peritoneal macrophages. [79] Aqueous extract Sta Extract attenuated the weight and length ratio of the colon, ameliorated the activity of MPO and the GSH content and regulated Cox-2, TNF-α and IL-1β levels in rats with TNBS-induced intestinal inflammation. [80] The compound showed the most potent analgesic activity at a dose of 40 mg/kg b.w. (body weight), with an inhibition of acetic-acid-induced writhing response of 48.9%, compared to 62.2% for standard aminopyrine. [191] P. lapathifolium var. diclofenac Na (inhibition of 86.85%). [126] EtOAc and ethyl ether extracts St, L All doses tested (3.75, 5 and 7.5 g/kg) of the two extracts showed anti-inflammatory and analgesic activity, significantly inhibiting ear edema and significantly decreasing writhing in mice. [127] P. stagnina Hex, EtOAc and MeOH extracts AP The most potent analgesic activity was observed with the EtOAc extract (writhing inhibition of 50.3% at a dose of 400 mg/kg b.w.), while Hex extract showed the highest levels of anti-inflammatory activity (carrageenan-induced edema inhibition of 60.1% at a dose of 200 mg/kg b.w.), a much better effect than that of the conventional anti-inflammatory agent phenylbutazone (maximum 38.3% after 4 h). [145] P. maritimum MeOH and DCM extracts L Extracts showed significant inhibition of NO production by LPS-stimulated RAW 264.7, at a concentration of 100 µg/mL. β-sitosterol, stigmasterol, 1-octacosanol and linolenic acid were identified as the possible compounds responsible for these bioactivities. [177] Acetone extract AP Extract showed a potent ability to reduce NO production on LPS-stimulated RAW 264.7 macrophages (IC 50 of 22.0 µg/mL). Positive control: L-NAME (IC 50 of 27.6 µg/mL). [176]

P. jucundum
EtOH extract AP Extract inhibited inflammatory reactions that cause instant irritation of the mouse ear, significantly inhibiting inflammatory mediators such as RAW264.7 cells (amurine macrophage cell line), production of NO, tumour necrosis factor TNF-α and IL-6 production in a dose-dependent manner. Flavonoids and sesquiterpene lactones may be responsible for the anti-inflammatory effect. [173] P. minor Aqueous and EtOH extracts AP At a dose of 30 µg/mL, EtOH extract inhibited the activities of lipoxygenase and cyclooxygenase-1, while the aqueous extract completely reduced paw edema induced by λ-carrageenan at doses of 100 or 300 mg/kg b.w. [115] P. punctata Decoction and EtOH-water extract WP Exhibited anti-inflammatory activity against the carrageenan-induced pedal edema/Gastric intubation in vivo. [140] P. tinctoria

Tryptanthrin (isolated from EtOH extract) L
Compound significantly inhibited the protein expression of iNOS and COX-2, suppressed the activation of p38 MAPK pathway and inhibited the TLR4 and MyD88 protein expression in LPS-stimulated BV2 microglial cells. [151] Polyphenolic fraction L Reduced NO synthesis in murine RAW264 macrophage cells stimulated with LPS, which showed a good analgesic activity. [148] Extracts St Exhibited protective effects of DNA damage against oxidative stress and anti-inflammatory effects by its capacity for NO suppression in LPS-induced RAW264.7 cells. [149] P. barbata Petroleum ether extract AP Inhibition of 39.3% paw edema after 2 h at a dose of 400 mg/kg b.w. (inhibitory ability slightly higher than that of the conventional anti-inflammatory agent phenylbutazone, 38.3% after 4 h). [35] P. vivipara 2-propanol extract Exhibited anti-inflammatory activity against LPS-induced inflammation in RAW264.7 macrophages (IC 50 = 270 µg/mL) by inhibiting NO, prostaglandin, interleukin and tumour necrosis factor (TNF)-α release at similar levels as positive control. [156] P. bistorta But extract Extract exhibited analgesic effect, as it could reduce the writhing times of the mice induced by acetic acid and raised the threshold of pain induced by hot and electric stimulation. [41]

P. paleaceum Extracts
Extracts reduced malondialdehyde (MDA) content in inflamed paws, inhibited NO synthase and β-NAG activities and significantly reduced the content of NO, IL-1β and TNFα in exudates.
[ From the analyses in Table 4, it could be observed that unlike the bioactivities described in the previous tables, for the evaluation of analgesic and anti-inflammatory effects, the whole extract of each species was evaluated more than the isolated compounds. Oppositely, more in vivo studies were informed for these bioactivities. The MeOH extract of P. chinensis exhibited anti-gastric activity compared with the standard ranitidine, but this effect was not correlated with the presence of any compound. The same fact occurred with the MeOH extract of P. alpina, which showed anti-inflammatory abilities compared to the standard Indomethacin, and with the MeOH extract of P. lapathifolium var. lanatum, which offered analgesic activity at the same level of the standard aminopyrine. These results could be explained by the synergistic effects of the compounds present in the MeOH extracts instead of the specific action of any compound present in them. On the other hand, α-Santalone (isolated from the MeOH extract of P. pubescens) demonstrated to be the responsible for the potent analgesic activity of the extract, while flavonoids and sesquiterpene lactones may be responsible for the anti-inflammatory effect of P. jucundum. Finally, quercetin-3-O-β-Dglucuronide isolated from P. perfoliatum suppressed ear edema and peritoneal permeability in mice showing higher inhibition percentage respect to aspirin.

Antinociceptive Activity
Antinociceptive activities of the n-Hex, EtOAc and MeOH extracts from P. hydropiper were tested by acetic-acid-induced writhing method in Swiss albino mice of either sex [81]. Ethyl acetate extract showed a moderate dose-dependent effect, with writhing inhibition of 54.95% at a dose of 500 mg/kg compared with the standard aminopyrine (inhibition of 73.62% at dose of 50 mg/kg). Additionally, Oany et al. [82] reported that crude EtOH extract of P. hydropiper leaves exhibited a good antinociceptive activity compared to the standard drug aspirin, displaying a reduction in the abdominal writhing's number of 41.02% and 69.23%, respectively, at a dose of 400 mg/kg b.w. Petroleum ether and chloroform (Chl) extracts of P. barbata showed antinociceptive properties, with an inhibition of writhing response of 46.8% and 44.8%, respectively (at a dose of 400 mg/kg b.w.), compared to 62.2% for the positive control aminopyrine [35]. The authors concluded that the compounds responsible for this activity were of apolar nature, possibly sterols or terpenoids. With respect to P. acuminata, the EtOH extracts of the leaves and stems exhibited antinociceptive activities with a percentage of writhing inhibition of 53.57% and 50%, respectively, at a dose of 500 mg/kg, similar values compared to the standard diclofenac (57.7% at a dose of 25 mg/kg) [9]. The antinociceptive activity of the crude MeOH extract of P. verticillatum rhizomes was tested by Khan et al. [193]. They found that at dose-dependency and through an opioid system, the extract could significantly reduce (72%) the number of writhes induced by acetic acid. The extract contained a high content of saponins and alkaloids.

Species
Extract/Isolated Compounds Part Use Cell Line Summarized Bioactivity Ref.  Aqueous extract WP Hep3B

P. amphibia
Inhibited autophagosome and proteasome activity, resulting in restriction of cell motility and apoptosis induction in Hep3B cells. [43] Zinc oxide nanoparticles (ZnO-NPs) (synthesized using P. bistorta extract) R MCF-7 Effective dose-dependent activity, with a percentage of cells viability < 10% (at a concentration of 125 µg/mL). [40] n-Hex and Chl fractions and its sub-  Dose-dependent effects, with a percentage of apoptotic cells > 70% (at a dose of 1 µM) and a percentage of necrotic cells > 80% (at a dose of 10 µM). [100]

Species
Extract/Isolated Compounds Part Use Pathogen Summarized Bioactivity Ref.

P. muricatum EtOH extract L Earthworms
At a concentration of 100 mg/mL, the paralysis and death times were 35 and 43 min, respectively. Standard drug: Albendazole (paralysis and death time = 20 and 30 min, respectively). Phytochemical analysis identified various constituents such as alkaloids, carbohydrates, glycosides, phytosterols, phenolic compounds, tannins, saponins, proteins and amino acids. [179] P. viscosum MeOH extract [194] Few antiparasitic studies have been conducted using these two plant genera, and most of them were carried out with extracts. It could be remarked the anti-trypanocide activities of two chalcones obtained from P. decipiens, which showed IC 50 values compared to the standard drugs diminazene and pentamidine against T. brucei and T. congolense. In addition, saponins from the butanolic extract of P. hydropiper displayed anti-leishmanial actions similar to the standard drug piperazine citrate.

Anti-Diabetic Activity
The anti-diabetic ability of EtOH extract from P. aviculare leaves was tested by Cai et al. [163]. The results showed that the extract is a potent inhibitor of α-glucosidase levels, higher than the standard drug acarbose, with IC 50 values of 21.42 and 176.79 µg/mL, respectively. Additionally, the compounds myricitrin, quercetin, polydatin and isoquercitrin (present in the phenolic portion of P. aviculare extracts) were primarily responsible for this activity, with IC 50 values of 8.65, 15.17, 35.15 and 148 µg/mL, respectively [163]. Ethanol extract of P. pulchra leaves showed a good α-glucosidase (involved in Type 2 diabetes mellitus) inhibition with IC 50 value of 22.67 mg/mL, respect to the positive control acarbose (7.77 g/mL) [134]. In addition, Oany et al. [82] tested antihyperglycemic activity of crude EtOH extracts from leaves and stems of P. hydropiper and found that for all the doses tested (50, 100, 200 and 400 mg/kg b.w.), leaves's extract showed higher effectiveness than standard glibenclamide, diminishing blood glucose levels between 48.8 and 58.2% for the extract and 42.1% for glibenclamide (at dose 10 mg/kg b.w.). Furthermore, the extracts of the leaves and stems (principally n-Hex, Chl and MeOH extracts) displayed α-amylase inhibitory activities, with IC 50 values between 1.03 and 3.517 mg/mL [75]. This enzyme can increase the blood sugar level, as hydrolyses (1,4)-α-D-glycosidic linkages in polysaccharides contain three or more (1,4)-α-linked D-glucose units. Another study demonstrated that the EtOH extract of P. cognatum strongly inhibited α-amylase activity (86.6%) and moderately inhibited α-glucosidase activity (41.05%) with respect to the standard acarbose (58.4% and 57.56%, respectively) [169].
Kubinova et al. [97] tested the anti-diabetic activity of isolated compounds from the MeOH extract of P. lapathifolia aerial parts by the inhibition of AChE, BuChE and α/βglucosidase. At a dose of 100 µM, kaempferol showed the highest inhibition of AChE (60.4%) and BuChE (74.5%), compared to the standard galantamine (95.7 and 47.9%, respectively), while gallic acid was only effective on AChE (inhibition of 51.2%). With respect to the α-glucosidase inhibitory assay, all isolated flavonoids showed potent enzyme inhibitory activity (72.6-97.2%) and eightfold higher activity than standard acarbose (11.4%), while for the β-glucosidase inhibitory assay, only quercitrin and isoquercitrin inhibited the enzyme with higher efficacy than the standard quercetin (23.6, 23.4 and 16.7%, respectively). Rodrigues et al. [177] tested the anti-diabetic ability of the leaf and root extracts of P. maritimun on α-amylase, baker's yeast (α-glucosidase) and rat's α-glucosidases. Both the MeOH and DCM extracts showed IC 50 values lower than the positive control (acarbose) on α-glucosidase, but the MeOH extract had the highest capacity to inhibit the baker's yeast α-glucosidase, with an IC 50 value significantly lower than that of acarbose (IC 50 value of 19 and 29 µg/mL for roots and leaves; 3144 µg/mL for acarbose).
The anti-hyperglycaemic effect of aqueous extract of P. orientalis flowers was tested on streptozotocin (STZ)-induced diabetic mice [130]. At a dose of 200 mg/kg, it was observed the most potent results: the extract significantly decreased blood glucose levels (144 mg/mL, 21 days) and serum cholesterol (53.2 mg/dL) compared to the control (210.06 and 82.4 mg/dL, respectively) and increased glycogen content in liver (30.7 mg/g for treatment and 11.86 mg/g for diabetic control). The hydroalcoholic (50%) extract of P. senegalensis leaves exhibited a potent anti-diabetic activity, inhibiting 100% of the α-glucosidase activity at a concentration of 10 ug/mL [144].

Antipyretic Activity
The antipyretic activity of the aqueous root extract of P. bistorta was studied in albino rats with Brewer's-yeast-induced fever [45]. At a concentration of 100 mg/kg and after 4 h of treatment, the extract exhibited similar pyrexia activities to that of the standard drug acetaminophen, with a decrease in the rectal temperature of 0.8 • C. Another study revealed that the MeOH root extract of P. glabra exhibited a significant dose-dependent antipyretic activity on albino rats submitted to the Brewer's-yeast-induced hyperpyrexia method [68]. Alkaloids, flavonoids and phenolic compounds could be responsible for this activity. Finally, Akhter et al. [89] tested the antipyretic activity of MeOH, EtOH, Chl, petroleum ether and n-Hex extracts of P. hydropiper leaves on Albino Swiss mice of both sexes. At doses of 200 and 400 mg/kg b.w., the MeOH, EtOH and Chl extracts showed a good activity compared to the standard drug paracetamol (50 mg/kg b.w.) by reducing temperature up to 4-7%, approximately.

Hepatoprotective Activity
El-Toumy et al. [172] tested the hepatoprotective activity of the MeOH extract of P. equisetiforme's aerial parts on CCl 4 -induced hepatic illness in Sprague-Dawley rats by measuring the levels of serum marker enzyme activities (alanine amino transferase-ALT and aspartate amino transferase-AST) and the oxidative stress mediator levels (NO, malondialdehyde-MDA, glutathione-GSH, glutathione peroxidase-GPx and superoxide dismutase-SOD). The results showed that when the rats were pre-treated with the extract, they exhibited normal levels of ALT and AST (64.86 and 45.16 IU/mL, respectively, at an extract dose of 200 mg/kg) compared to the control (64.86 and 44.22 IU/mL). The GSH, GPx and SOD levels decreased, while the NO and MDA levels increased in comparison to the control. On the other hand, Christapher et al. [119] assessed the hepatotoxicity ability of the MeOH extract obtained from the leaves of P. minor on CCl 4 and paracetamol-induced hepatotoxicity in Sprague-Dawley rats. They found that this extract significantly decreased the levels of AST, ALT, ALP and TB in both models compared to the CCl 4 and paracetamol controls. At dose-dependency, the MeOH extract of P. glabra roots reduced the marker levels of hepatic injury such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALKP) and total bilirubin in CCl 4 and paracetamol-induced rats [120].
The anti-fibrotic effects of the aqueous and organic extracts of P. plebeium (whole plant) on inflammatory liver disease in CCl 4 -induced rats were tested, and the authors found that the extracts reduced the ALT, AST and gamma-glutamyl transpeptidase (γGT) levels in CCl 4 -induced rats and restored the CCl 4 -induced tissue fibrosis [190]. In addition, the aqueous extract from the roots of P. bistorta exhibited significant hepatoprotective effect in rats with CCl 4 -induced liver damage: the CCl 4 administration on hepatic cells showed hydronic degeneration, swelling, congestion in portal vessels and sinusoids and optically empty cytoplasmic areas and increased the AST, ALT and total bilirubin levels in rats (173 and 223 IU/L and 1.15 mg/dL, repsectively) compared to the control (67.7 and 48.2 IU/L and 0.53 mg/dL, respectively). However, the cells recoupment when they were treated with aqueous roots extract of P. bistorta at a concentration of 100 mg/kg (levels of AST, ALT and total bilirubin decreased at 88.5 and 98.3 IU/L and 0.75 mg/dL, respectively) [46].
The hepatoprotective effects of the MeOH, EtOH and aqueous extracts of P. amplexicaulis rhizomes on albino mice were tested [34]. After the administration of CCl 4 to the mice's, ALT, AST, ALP and plasma bilirubin levels increased, and body weight decreased compared to the control; these levels were recouped when administrated aqueous, MeOH and EtOH extracts at a dose of 200 mg/kg. ALT, AST, ALP and plasma bilirubin decreased and body weight increased by 16.3, 12.96 and 8.08%, respectively, compared to the control silymarin (10.88% at a dose of 100 mg/kg). Furthermore, the EtOH fruit extract of P. orientalis exhibited significant hepatoprotective effects against CCl 4 -induced acute liver injury (ALI) in rats [131]. At doses of 0.5 and 1 g/kg of extract, the levels of AST, ALT, ALP, NO, tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) decreased, while the levels of SOD, GPx and GRd increased. Protocatechuic acid, taxifolin, and quercetin identified by HPLC in the extracts, might be mainly responsible for these effects. In addition, Fan et al. [132] tested the potential inhibitory ability of OATP1B1 (anion transporting polypeptide 1B1, associated with drug-induced liver injury) of flavonoids isolated from P. orientalis. The results demonstrated that the compounds isoorientin and orientin showed weak inhibitory effects on OATP1B1-mediated fluvastatin consumption in OATP1B1-HEK293 cells (27.72 and 23.3%, respectively). Nguyen et al. [135] reported that the EtOAc extract from the aerial parts of P. pulchra and its subfractions exhibited a potent hepatoprotective activity in CCl 4 -induced rats since it reduced ALT activity between 50 and 68%. Finally, Xu et al. [189] reported that the total flavonoids isolated from P. perfoliatum exhibited potential hepatoprotective effect in CCl 4 -exposed mice, decreasing liver functional enzymes (ALT and AST), TNF-α, interleukin 6 and heat shock protein 90 (Hsp90) and increasing intrasplenic integrin β1, 5 -nucleotidase and antigen KI-67 cells at doses of 60 and 120 mg/kg/day.
3.11. Neuropharmacological Activity 3.11.1. Anti-Alzheimer's The potential of β-sitosterol isolated from P. hydropiper for the management of Alzheimer's disease was tested [90]. Authors observed a significant decline in free radical's load in the brain tissues of the β-sitosterol-treated animals, with IC 50 values of 140, 120, and 280 µg/mL from DPPH, ABTS and H 2 O 2 assays, respectively. In addition, they performed memory assessment and coordination tasks (SWM, Y-maze and balance beam tests) and found that β-sitosteroltreated animals had gradual improvement in working memory and in motor coordination [90]. Previously, Ayaz et al. [78] reported that essential oil from the leaves and flowers of this plant demonstrated a significantly acetylcholinesterase (AChE) inhibitory ability (inhibition of 87 and 79.66%; IC 50 = 120 and 220 µg/mL, respectively) and a butyrylcholinesterase (BChE) inhibition of 82.66 and 77.5%; IC 50 of 225 µg/mL, respectively. Caryophyllene oxide and decahydronaphthalene were identified as the major components of the leaves' and flower's essential oils, respectively. Ahmad et al. [113] tested the AChE inhibition ability of different extracts (MeOH, EtOH, aqueous, DCM and n-Hex) and the essential oil of the leaves, stem and root of P. minor. Aqueous and MeOH leaf extracts showed the higher AChE inhibitory activity, with IC 50 values of 234 and 342.77 µg/mL, respectively; root extracts had the lowest AChE inhibitory activity (IC 50 > 1000 µg/mL). The presence of terpenoids could explain AChE activity of MeOH and aqueous extracts, as it can readily cross the blood-brain barrier by its small size and lipophilicity [113]. In addition, a study revealed that the aqueous extract of this plant could reverse scopolamine-induced memory deficits in a Barnes maze model (at a dose of 100 mg/kg) and could inhibit AChE activity by 68% with an IC 50 of 0.04 mg/mL [121]. Regarding P. glabra, the MeOH and EtOH extracts of its aerial parts exhibited neuroprotective activity against AlCl 3induced (aluminium chloride) toxicity in rats, improving learning and memory and decreasing AChE levels at similar values of the standard rivastigmine at a concentration of 400 mg/kg [69]. Another study stated that the MeOH extracts from roots and aerial parts of P. maritimum could be a good alternative for the treatment of neurodegenerative disorders such as Alzheimer's disease due to the ability for the inhibition of AChE and tyrosinase (TYRO), with IC 50 values of 0.17 and 0.27 mg/mL for AChE and 0.59 and 0.6 mg/mL for TYRO [178].

Anti-Depressant and Sedative
The anti-depressant activity of the aqueous extract of P. glabra was tested by Nizar et al. [70]. The results showed that the extract, in a dose-dependent manner (50, 100 and 200 mg/kg), induced a significant decrease in the immobility time of mice during behavioural despair test (BDT) and tail suspension test (TST) and increased the hyperactivity scores in an L-dopainduced hyperactivity test, with similar values to the reference Imipramine (15 mg/kg). The depressant activity of four sesquiterpenes (viscosumic acid, viscozulenic acid, viscoazucine and viscoazulone) and the flavonoid glycoside quercetin-3-O-(6-feruloyl)-β-D-galactopyranoside isolated from the aerial parts of P. viscosum was tested by open-field test [196]. P. hydropiper showed anti-depressant and sedative activity: Sharif et al. [91] tested the antidepressant activity of the MeOH, EtOH and Chl leaf extracts by open field test and swimming test (mice were forced to swim and scored immobility). At a dose of 150 mg/kg, the Chl and EtOH extracts significantly decreased movements and exerted immobile phase in mice similar to the standard Imipramine (10 mg/kg). Devarajan et al. [92] examined the depressor effect of extracts of P. hydropiper leaves in salt-induced hypertension in mice and found that both could reduce blood pressure and heart rate in a dose-dependent manner. Shahed-Al-Mahmud and Lima [93] revealed that the MeOH leaf extract presented a good sedative and anxiolytic activity (at a concentration between 50 and 500 mg/kg) compared to a positive control of diazepam (1 mg/kg) using different test types such as open field test and thiopental sodium-induced sleeping time test in mice (for sedative activity) and elevated-plus maze and light-dark box (for anxiolytic activity). Finally, the ion channel-blocking activity K + of G protein-activated inwardly (responsible for maintaining the resting membrane potential and cell excitability) of different extracts of P. maculosa were tested through the automated patch-clamp method [109]. They found that Chl extract and its HPLC eluate fractions, at a concentration of 0.1 mg/mL, showed a potent K + channel-inhibitory activity compared to the reference compound Propafenone (between 62 and 76% and 71 and 81%, respectively).

Neuroprotective Activity
Won and Ma [164] tested the neuroprotective activity of the aqueous-MeOH extract of P. aviculare by glutamate-induced neurotoxicity assay in primary cultures of rat cortical cells assay. The results showed that at a concentration of 100 µg/mL, a good neuroprotective potency of 50.1% compared to the standards CNQX (59.2%) and MK-801 (70.8%) was observed. Additionally, the juglandin extracted from crude P. aviculare exhibited a good neuroprotective activity in mice with LPS-induced Parkinson's disease, attenuating memory impairments, promoting the expression of synaptic markers (SYP, PSD-95 and SNAP-25), decreasing production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-18 and COX-2) and blocking TLR4/NF-κB pathway [165]. In addition, the extract of P. aviculare was tested for its neuro-inflammatory properties, and it was found that the extract could decrease lethargy-like behaviour and the compounds corticosterone, serotonin, and catecholamines (fatigue-related) in the brain and inhibited the production protein TNFα (tumour necrosis factor) [166]. Finally, the neuroprotector effect of orientin (pyrone glucoside extracted from P. orientalis) was tested in pheochromocytoma cell line (PC12) stimulated by H 2 O 2 in mice [133]. The results demonstrated that orientin was not toxic for PC12 cells and could reduce the H 2 O 2 -induced viability of PC12 cells at higher concentrations than 40 µg/mL. Moreover, orientin decreased H 2 O 2 -induced phosphorylation of signaling proteins (MAPKs, AKT and Src) and inhibited ROS (causing neurodegenerative diseases) accumulation in cells [133].

Diuretic Activity
In a Lipschitz test, the petroleum ether, Chl and EtOAc extracts of P. barbata's aerial parts exhibited dose-dependent diuretic activity, but EtOAc extract (at a dose of 400 mg/kg) showed the most significant effect after 2 h of administration (diuretic activity = 1.77) compared to the standard Furosemide (diuretic activity = 1.72) [35]. In addition, the EtOAc extract of P. lapathifolium var. lanatum demonstrated a moderate to good diuretic activity, with values of 1.422 and 1.87 at doses of 150 mg/kg and 300 mg/kg b.w., respectively [98]. Finally, the diuretic activity of α-Santhalone isolated from P. pubescens aerial parts was tested by the Lipschitz methods, and it was found that at a concentration of 40 mg/kg, this compound presented a good activity after the first hour of administration (diuretic activity = 1.24) compared to the standard Furosemide 3 mg/kg (diuretic activity = 1.81) [191].

Gastroprotective Activity
The anti-ulcer activity of the alcoholic and aqueous extracts of P. barbata were tested by Pylorus ligation models and ethanol-induced gastric mucosal injury in rats [38]. They found that both extracts, in a dose-dependent manner, could significantly reduce the number and index of ulcers and total acidity, as well as increasing the pH index. The compounds present in both extracts such as saponins, sterols, glycosides and alkaloids could explain this activity [38]. In addition, the aqueous extract from the leaves of P. chinensis showed a gastroprotective effect against ethanol-induced gastric mucosal injuries in Sprague-Dawley rats, as it reduced gastric lesions and malondialdehyde levels (MDA) and increased superoxide dismutase level (SOD) [57]. The anti-ulcer activity of the aqueous extract from the leaves of P. minor against ethanol-induced gastric ulcers in rats was tested [122]. The extract showed a significant antiulcer activity compared to the standard omeprazole (20 mL/kg): at dose-dependentcy (250 and 500 mL/kg), the extract increased pH and gastric mucous, suppressed areas of gastric ulcer formation (35.33-188.17 mm) and inhibited 78.25-95.92% of the gastric ulcer. In addition, Qader et al. [123] obtained five fractions (hexane:ethyl acetate 1:1 v/v (F1), ethyl acetate:methanol 1:1 v/v (F2), methanol:acetonitrile 1:1 v/v (F3), acetonitrile:distilled water 1:1 v/v (F4) and distilled water 1:1 v/v (F5)) from the EtOH extract of the leaves of P. minor and tested its gastroprotective activity using the ethanol induction method in rats. All the fractions exhibited gastroprotective activity, but F2 showed the best result at a dose-dependency (very similar to Omeprazole values), inhibiting 90% of ulcer lesions and increasing mucus content (120 mg/g), SOD, hexosamine and PGE2 synthesis levels in the stomach wall mucosa.
The gastroprotective effect of the hydro-alcoholic root extract of P. bistorta was tested by indomethacin-induced gastric ulcer in rats [47]. At a dose-dependency (500 and 1000 mg/kg), this extract significantly increased mucus, SOD and catalase levels and decreased the ulcer index and thiobarbituric acid (TBARS), with similar values shown by the standard drug ranitidine (20 mg/kg), compared to the ulcer control group. Ayaz et al. [74] tested the gastroprotective ability of the crude MeOH extract from P. hydropiper and its fractions by aspirin-induced ulcerogenesis in rats. At a dose dependency (100,200 and 400 mg/kg), the extract exhibited a good gastroprotective activity compared to the standard ranitidine (50 mg/kg), as it could decrease gastric juice volume, free acidity, total acidity and pepsin levels, as well as increased gastric juice pH levels. Additionally, the essential oil obtained from the leaves and saponins (fractions) showed the highest urease inhibition (> 70%, IC 50 = 90 and 98 µg/mL, respectively) compared to the control drug thiourea (urease inhibition > 80% and IC 50 = 80 µg/mL) [74].

Other Activities
The acetone extract from the aerial parts of P. maritimum is considered an interesting anti-melanogenic agent, as it was demonstrated to inhibit tyrosinase and melanin production in B16 4A5 melanoma cells, with IC 50 values of 64.1 and 77.7 µg/mL, respectively [176]. Myricitrin, catechin and monogalloyl-hexose isolates could be responsible for this activity. Another study conducted by George et al. [124] explored the immunomodulatory properties of aqueous extract of P. minor, and they showed that this extract displayed significant phagocytic index (K) at doses of 200 and 400 mg/kg b.w. (K = 0.045 and 0.062, respectively) compared with the standard levamisole (K = 0.060). Finally, Kimura et al. [155] tested the inhibitory activity of flavonol O-glycosides isolated from 80% MeOH extracts of P. tinctorea leaves against HMG-CoA reductase. The fraction eluted with 100% MeOH showed the most potent inhibitory activity (56.7%), while five compounds isolated from this fraction were effective dose-dependently, inhibiting HMG-CoA reductase activity by 50 to 67.6%.

Conclusions
This Polygonum and Persicaria genera revision revealed the great variety of chemical constituents present in these plants, highlighting the bioactive groups of sesquiterpenes, flavonoids and phenolic acids. Methanolic, ethanolic, hexanic, ethyl acetate and water extracts and their fractions and chemical phytoconstituents have demonstrated different pharmacological activities such as antifungal, antibacterial, antioxidant, anti-inflammatory, anticancer and neuropharmacological activities in many publications, which were updated and revised here. These findings revealed that the species of the Persicaria and Polygonum genera could be property developed as good candidates for clinical assays in the future, allowing for the expansion of knowledge for the treatment of new diseases. P. glabra, P. hydropiper, P. minor, P. lapathifolia and P. chinensis were the species that showed the highest number of medicinal properties. Native species of Asia and Europe are ones with the largest number of studies in the world, followed by African species. However, American species are poorly studied or do not present any study (e.g., P. ferruginea, P. hydropiperoides, P. punctata and P. paraguayense), which invites the investigation of these species in the future.
The wide range of pharmacological properties of Polygonum and Persicaria species may offer a new therapeutic promise to cure different diseases and health complications. So, an accelerated progress should be made through experimental research including robust clinical trials, in order to generate natural medicines that allow to counter the negative effects on human health.