A comprehensive review on phytochemical, pharmacological and therapeutic properties of Agrimonia eupatoria L

Introduction Compared to conventional drugs, medicinal plants usually have low toxicity. Furthermore, in spite of the availability of all kinds of medicines and all health facilities, due to the high costs of hospital care or because of cultural beliefs and historical customs in most of the undeveloped countries, people still trust herbal medicines and some of the herbs still have kept their popularities (1). Agrimonia eupatoria from the Rosaceae family, known as “Common Agrimony”, is an erect perennial plant (30– 60 cm in height). It is native to mainland Europe and found across Asia Minor and North Africa (2). It is traditionally used as an antiadhesive, antibacterial (3,4), antioxidant, astringent (5,6), anti-inflammatory (7-9), and hepatoprotective (10) agent. It is also used for bed-wetting (11), treatment of hemorrhagic colitis, liver and urinary diseases (6,12), cancer (13), acute diarrhea, diabetes mellitus, inflammation of oral and pharyngeal mucosa (14,15), and the hepatitis B virus (16). In this article we aimed to present a comprehensive review on phytochemical, pharmacological, and therapeutic properties of this plant. Botany Scientific Classification The scientific classification of A. eupatoria (Figure 1) is as follows: Super kingdom: Eukaryota Kingdom: Viridiplantae Phylum: Streptophyta Subphylum: Streptophytina Class: Magnoliopsida http://www.herbmedpharmacol.com doi: 10.34172/jhp.2021.02


Introduction
Compared to conventional drugs, medicinal plants usually have low toxicity. Furthermore, in spite of the availability of all kinds of medicines and all health facilities, due to the high costs of hospital care or because of cultural beliefs and historical customs in most of the undeveloped countries, people still trust herbal medicines and some of the herbs still have kept their popularities (1).
Agrimonia eupatoria from the Rosaceae family, known as "Common Agrimony", is an erect perennial plant (30-60 cm in height). It is native to mainland Europe and found across Asia Minor and North Africa (2).

Description
Agrimonia eupatoria is a plant with bear pinnate, toothed alternate, leaves with undersides like velvet and small pairs between larger pairs with erect, reddish and pubescent stems (50-150 cm high). It has basal leaves as a rosette, and on its long, slender spikes grow five small petals of bright yellow flowers. The fruits are small, cone-shaped, enclosed in a calyx-tube with bristle. The bristles with hook enable the dispersal of the seeds on animal fur. It also spreads vegetatively by stout, woody, deep-lying rhizomes (21).
Some insects associate only with this herb like an eriophyoid mite, Aculus castriferrei n. sp (22) and Stigmella aeneofasciella Larvae (23). This is why Agrimony is called "Shajarat ol barāghith" in Arabic, which means the tree of fleas in English.

Related species
Agrimonia pilosa and A. viscidula Bunge are used in China for comparable conditions (24). The German Commission E Pharmacopoeial Monograph enables the use of A. procera as a second precious source of Agrimoniae herba. Granica et al have shown, based on their collected data, that a legitimate source of plant materials for drug preparation is A. procera (Fragrant agrimony) (25).
Cultivation and habitat Agrimony is a native European herb mostly found in marshes, on wasteland, and wet meadows (1). It is one of the most common species of dry grasslands in the ex-arable land of the SE Czech Republic (26) and Slovak Republic (18). Thus, it has been found in the Hindu Kush Mountains of Pakistan (27), as well as Western Himalaya, and India (28). It is harvested during its flowering stage in summer (1). Agrimonia eupatoria does not reach the edge of its distribution. It displayed dynamic changes in leaf morphology in response to tree shade and in elongation of stems and inflorescences because of herbaceous shade. Because of A. eupatoria's high active plasticity, it can maintain constant shoot growth in a variety of light conditions (29). The normal distance in cultivation on seed yield is 4/m-2 (30). A. eupatoria best germination results obtained at 20°C at 12-hour daily photoperiod, 5.5 cm root cuttings develop stems and/or roots at 15°C and 25°C (31).

Ethnopharmacology
The plant has a "cool" and "drying" characteristics. All parts, mostly the aerial parts of the plant are used for various diseases (33).
History and folklore Agrimonia eupatoria was named by Mithridates Eupator, a king of Pontus, a famous plant collector and botanical text author in Greek. Thus, Pliny records, 'it has gotten credit and reputation by a king, as may appear by the name' . Many centuries later, Fuchs named it 'Hepatorium' , because of its protective effects on the liver. Until the 18 th century Agrimony was known in the Linnaean classification under the title 'Eupatorion' , so Dioscorides (IV 41) named it the same (21).

Traditional uses
Agrimonia eupatoria was worshiped in the Kysuce region (18). Since then, people have found various methods for using Agrimony for almost all parts of the body illnesses as shown in Table 3. A. eupatoria has been used since Saxon times. It was the primary ingredient of a battlefield cure for bullet wounds called "Arquebusade water" in the 15 th century. Agrimony healing power is now credited with the herb's high silica content (33). A. eupatoria, known as Ghafath in Iranian traditional medicine (ITM), has been repeatedly used for liver strengthen and it was well documented as an outstanding liver tonic. It is very useful and extensively recommended in Iranian medical literature (34), and used mainly to treat liver disorders (35). It is one of the most important ingredients of ITM tablets like "Qurse Rewand" which means "Rhubarb tablet" in Iranian dialect. Its effects on rats have been recently documented as significant hepatocurative agent and showed signs of recovery and regeneration in damaged liver cells (36).
Arial parts/leaves applications of A. eupatoria are given in Table 3 (33). It has been reported that giving Tisane (cold) to lambs has an antidiarrhoeal effect and Tisane (hot) has laxative effects in lambs (38).

Recommendations on safety
It should be used with caution when there is a constipation (21,33). Side effects of nausea and constipation with excessive doses are likely (21).

Phytochemistry
The Agrimony plant contains tannins, volatile oil and coumarins (1), gum, a phytosterol (24), polysaccharides, and flavonoids such as luteolin. From its dried aerial parts, the polyphenolic-polysaccharide complex was isolated with 55 × 10 3 g/mol molecular weight. It consisted mainly of pectin-like polysaccharides and polyphenolic moieties, composed of lignin-related units, with the dominance of dimethoxy phenyl structures. Agrimonia complex specific carbohydrate composition rich in highly esterified galacturonic acid, constituting thus highly methylated pectin network in which, besides arabinogalactan type II, the highly esterified homogalacturonan and rhamnogalacturonan type I are present, while some units being partially methylated (39). Investigated samples have been shown to contain about 8.2-10.9 mg/g of various flavonoids, 6.3-10.9 mg/g of various tannins (mostly agrimoniin, 2.6-5.4 mg/g), and 0.6-0.9 mg/g of phenolic acids (40). The value of flavonoids determined in the leaves of agrimony (Agrimonia eupatoria) was 1.05 RU (41). Total phenolic compounds of more than 19.61 mg galic acid equivalent (GAE)/g to 220.31 mg GA (gallic acid)/g, flavonoids of 20.58 mg RU (rutin)/g to 97.06 mg RU/g, total tannins of 3.06 mg GA/g to 207.27 mg GA/g, and pro-anthocyanidins of 4.15 CChE (Cyanidin chloride equivalent)/g to 103.72 CChE/g have been identified (42), claiming that phenol compounds were the major group of constituents of this plant (40).
The primary metabolites From the primary metabolites, the amino acid composition has been determined. Seventeen amino acids and their respective amounts were identified in A. eupatoria, which is shown in Table 4 (43).
The second metabolites Sixty-eight out of 87 separated constituents of the volatile oil were quantified, which were more than 87.03% of the total contents. Isolated compounds from the leaf and root of A. eupatoria are shown in Table 5, isolated compounds from the leaf of A. eupatoria are shown in Table 6 (44), and the phenolic and flavonoid compounds isolated from free or glycosides of the leaf of A. eupatoria are shown in Table 7.
Antioxidant potential and scavenging activity Agrimony's anti-inflammatory ability may be clarified by its antioxidant activity. The plant has polyphenolic compounds capable of activating endogenous antioxidant defense mechanisms (51). The tests done on A. eupatoria extract and its polyphenol-enriched fractions against reactive species are shown in Table 8.     23 25  Hypochlorous acid (Elastase (E) + α 1 -antitrypsin (α 1 ) + Hypochlorous acid (HOCl)) and inhibition of Elastase Extract abolished elastase activity; affected the α 1 -antitrypsin activity, but promoted some inhibition of Elastase activity.

Pharmacological activities
Agrimonia eupatoria's physio-pharmacological activities are shown in Table 10.

Toxicity
The safety and efficacy of A. eupatoria have been confirmed during a very long period of its traditional application. Recent studies have shown that A. eupatoria aqueous extract (AEE) consumption by subjects was safe and generally well-tolerated without severe adverse events (65). Agrimony is an herbal medicine, which its safety is comparable with coffee (37). But, since Agrimony is an indication of geogenic contamination of flysch soils, elements like Ni, Co, Mn, Cu, Cr, V, and Mo typically concentrate in the roots and shoots of the plant. So, high uptake of these elements by Agrimony growing on similar soils is possible (69).

Conclusion
This review presents A. eupatoria description, history, and advances in phytochemistry and other aspects. Pharmacological studies carried out on its extracts and traditional uses revealed that it could be an important source for new drugs.

Conflict of interests
There is no conflict of interest

Ethical considerations
Ethical issues including text plagiarism, misconduct, manipulation or appropriation, data fabrication, The A. eupatoria complex prevents the development of plasma clots, primarily in the intrinsic blood coagulation cascade pathway. It is primarily an indirect inhibitor of thrombin, mediated by antithrombin or by heparin cofactor II (39).

Anti-diabetic
Aqueous extract Into the diet (62.5 g/kg) and drinking water ( In the avoidance and/or adjuvant treatment of developing cardiovascular problems linked to DM and sicknesses related to oxidative stress, A. eupatoria extract suggests its higher clinical potential (58).

Treatments for diabetes mellitus Dried leaves
Supplied in the diet (6.25% by weight) or as decoctions or infusions (1 g/400 mL) in place of drinking water/ Streptozotocin (200 mg/kg i.p.) for 12 days Mice Treatment with agrimony reduced the level of hyperglycemia during the development of streptozotocin diabetes but did not reduce the rate of body weight loss. Certain traditional plant treatment for diabetes, namely Agrimony (14).

Anti-inflammatory Activity
Hydro-alcoholic extract and a polyphenol-enriched fraction Against the reactive species/ 96-well microplate-based broth dilution assay Agrimonia eupatoria anti-inflammatory activity mechanism could be its significant scavenging capacity of reactive species by its polyphenols (8).

BV2 microglial cells
Agrimoniae herba suppressed lipopolysaccharideinduced nitric oxide production in BV2 microglial cells and lipopolysaccharide-induced production of proinflammatory cytokines such as interleukin 1 beta, tumor necrosis factor, and interleukin 6 in a dose-dependent manner had no cytotoxicity and inhibited the expression of inducible nitric oxide synthase. It may be used as a form of pharmaceutical acupuncture therapy in the treatment of brain inflammation (9).

Tea
One-month Healthy humans Has potential in improving markers of lipid metabolism and inflammation (7). In the pin-prick test and plantar test, A. eupatoria extract displayed an antinociceptive property with a lower withdrawal time and a higher withdrawal threshold in the paw-withdrawal threshold test as compared to control animals. In the case of cold-allodynia, increased pawwithdrawal duration in the chemical test, and showed superior activity to gabapentin. A. eupatoria extract found to possess therapeutic potential for the treatment of neuropathic pain (61). It has a potential to increase the antioxidant status (63). The extract prepared at 60 ºC has the greatest effect. The inhibitory activity was the highest at mid-July. Agrimonia genus plants contain potential antiviral activity against HBV (16).

Enzymatic and nonenzymatic antioxidants
Extracts extract from the crop tops Administered in the water at a final concentration of 0.1% after 42 days of feeding the level of reduced glutathione was measured in the plasma and in liver, heart, and kidney mitochondria 120 one-day-old broilers COBB500 The activity of superoxide dismutase had a significant decrease. The application of agrimony extract appears to be suitable for the antioxidant effect against peroxidation of gamma-linolenic acid (63). Led to a decrease in catalase activity produced a decrease in SOD activity. In general, agrimony appeared to be a promising extract, in protection; and was even slightly toxic (53).
Aqueous extract (160 mg/d)/ two capsules twice a day for 8 weeks Subjects aged between 20 and 70 years who were diagnosed with mild to moderately elevated ALT levels (between 45 and 135 IU/L).
A significant reduction in elevated alanine transaminase (ALT) and serum triglyceride (TG) was observed (65). New Zealand white rabbits ANBP plays dual roles, promoting wound healing and alleviating scar formation (68).