Phytochemistry and Evidence-Based Traditional Uses of the Genus Achillea L.: An Update (2011–2021)

: Knowledge within the ﬁeld of phytochemistry research has accelerated at a tremendous speed. The excess of literature reports featuring plants of high ethnopharmacological importance, in combination with our interest in the Asteraceae family and traditional medicine, led us to acknowledge the value of the Achillea L. genus. In a broad context, the various Achillea species are used around the globe for the prevention and treatment of different diseases, including gastrointestinal problems, haemorrhages, pneumonia, rheumatic pains, diuresis, inﬂammation, infections, and wounds, as well as menstrual and gynaecologic abnormalities. The present review aims to provide and summarize the recent literature (2011–2021) on the phytochemistry of the Achillea genus. In parallel, this study attempts to bridge the reports on the traditional uses with modern pharmacological data. Research articles that focused on secondary metabolites, traditional uses and pharmacological activities were collected from various scientiﬁc databases such as Pubmed, ScienceDirect, Reaxys and Google Scholar. This study revealed the presence of 141 phytochemicals, while 24 traditionally used Achillea spp. were discussed in comparison to current data with an experimental basis.


Introduction
The traditional knowledge of medicinal plants is a cornerstone on which medicine has been built since the beginning of mankind [1].By combining this traditional knowledge with new methods derived from modern science, the possibilities for drug development seem endless.Thus, the field of ethnopharmacology has expanded greatly, with a plethora of articles published each year.
The excess of literature reports featuring plants of high ethnopharmacological importance, in combination with our interest in the Asteraceae family and traditional medicine, led us to acknowledge the value of the Achillea L. genus.The genus Achillea (Asteraceae, Anthemideae) comprises over 130 perennial and flowering species, which are mainly distributed in the northern hemisphere with diversity centres in S.E.Europe and S.W. Asia [2,3].Remarkably, the genus is characterized by its ability to adapt in diverse ecological amplitudes and ranges in extreme environmental conditions, such as deserts to water-logged habitats and from seacoasts to the nival zone of high mountains or mild agricultural areas [4].The most obvious and outstanding characteristics of this genus are the numerous flowers, small and white, yellow, orange, pink or red.Specifically, the genus can be described as perennial herbs of 6-80 cm tall with alternate leaves and finely pinnatisect.The capitula in corymbs are heterogamous with seriate phyllaries.The achenes are strongly flattened and not ribbed and the fruits are shiny, with no pappus [5].The name of the genus derives from the Greek hero, Achilles.According to Greek mythology, this powerful warrior was tutored by the centaur Chiron in the arts of war, music, and medicine.During the Trojan War, Achilles used Achillea, whose virtues for blood control and wound healing were well-known, to treat his fellow soldier Telephos.Historically, the medicinal properties of these plants are described in the ancient medical texts of Dioscorides (1st c.A.D.) and Pliny the elder (1st c.A.D.) [6,7].
Several species of this genus are widely used in traditional medicines of different countries.In particular, A. millefolium aggr.(closely related species that are treated as a single species), known as common yarrow, is utilized in crude forms for various therapeutic purposes such as teas for digestive problems and respiratory infections or poultices powders for skin disorders, etc. [8].Nowadays, monographs by the WHO (World Health Organization; www.who.int(accessed on 1 September 2021)) [9] and EMA (European Medicines Agency; www.ema.europa.eu(accessed on 1 September 2021)) [10] also address the medicinal use of A. millefolium L. for loss of appetite, skin disorders and minor wounds, urinary tract, genital and gastrointestinal disorders.Plenty of research studies are conducted to determine the biological activities of this genus, focusing not only on crude forms and extracts but also on isolated specialized products extracted in solvents of different polarities.
Some of the reported and validated pharmacological activities (in vitro, in vivo, and clinical tests) of the Achillea species are antioxidant, anti-inflammatory, analgesic, antipyretic, antidiabetic, antibacterial, anthelmintic, antihypertensive.These important biological effects are directly correlated to plant-derived bio-active phytochemicals.Previous reports demonstrated the occurrence of various chemical constituents in Achillea species, with sesquiterpene lactones and flavonoids as the principal bioactive constituents.Moreover, triterpenes, sterols, coumarins and phenolic acids were also reported [11].Additionally, there are a lot of studies reporting the volatile constituents of the genus, which have been summarized in recent years [12,13].Essential oils, isolated from Achillea spp., as secondary metabolites involve complex mixtures that also contribute significantly to the observed biological activities against a variety of ailments, and especially intestinal disorders and inflammatory diseases [12,13].
A landmark study by Si et al. [11] was meticulously planned, including the structures and biological properties of known phytochemicals from Achillea spp., followed by the comprehensive summary of Saeidnia et al. [14] and other numerous reviews on this topic [12,13].Therefore, ten years after the last overviews by Si et al. [11] and Saeidnia et al. [14] (2006 and 2011, respectively), the present review aims to provide and summarize the existing knowledge on the genus Achillea, focusing on traditional uses, phytochemistry and pharmacological activities.In comparison with a similar study [12] in our review, we exhaustively summarized the non-volatile secondary metabolites of the last decade, identifying more than 141 chemical entities whose structures are depicted herein.Moreover, this overview gives an account of the ethnopharmacological relevance for the traditional uses of the genus supported by modern pharmacological research knowledge.Specifically, aspects of the folkloric uses of this genus are discussed in comparison to current data with an experimental basis.It is hoped that such work could encourage researchers to continue working on this outstanding genus, aiming to unveil the whole potential of its diverse phytochemical profile, with flavonoids and sesquiterpene lactones being lead compounds for future drug development, targeting serious human ailments.

Materials and Methods
A comprehensive search on the relevant literature of the last decade was conducted on the major scientific databases, including Pubmed, ScienceDirect, Reaxys and Google Scholar.The search terms "Achillea", "Achillea genus", "Achillea species", "Achillea medicinal uses", "Achillea pharmacological", "Achillea traditional uses", "Achillea compounds", "Achillea phytochemicals", "Achillea biological" and "Achillea bioassays", were used for data collection.We are also aware of the fact that these databases are updated routinely; thus, the data presented in Table 1a are indicative of the available information at the time this paper was prepared.Searches were also performed for other potential studies by manual screening references in the identified studies.A bibliometric method was applied using VOSviewer (version 1.6.15) in "Full Record and Cited References" for further analysis under the following parameters: co-authorship, co-occurrence, citation, bibliographic coupling and themes.The analysed articles were retrieved from the PubMed database.Map data visualizations were generated to build (a) a keyword map based on shared networks, (b) a term map from the titles and abstracts on shared networks, and (c) the co-authorship/co-occurrence authors network (see Supplementary Figures S1s, S2 and S3).The top 5 most cited authors, documents and keywords are provided in Table 1b.
For the selection of relevant publications, three major criteria were used in this review: A. Phytochemicals: For the chemical compounds, all the publications that could be accessed were included with any information on the isolation or/and identification methods, excluding articles solely on essential oil and volatile constituents.B. Ethnopharmacology: For the traditional uses all the publications that could be accessed were included with any information on local medicinal uses of the genus Achillea.C. Pharmacological activities: For this section, only the literature data which associate the traditional knowledge of the genus Achillea with the pharmacological activities were included.
Members of the genus Achillea are presented as individual species in this work and for the validation of their scientific names the International Plant Name Index (www.ipni.org (accessed on 1 September 2021)), the Plant list (www.theplantlist.org(accessed on 1 November 2021)) and/or the Euro+Med (www.emplantbase.org(1 September 2021)) databases were used.This helped to identify misspellings and the use of synonyms for different or related species.
Order of covered compounds: Due to the reticulate nature of biosynthetic pathways, there is no universal way to order natural products and compound categories.Thus, compounds covered in this review have been ordered as follows: flavonoids, phenolic acids, quinic acids, sesquiterpene lactones and other compounds.Compounds are catego-rized by species in Tables 2, 5 and 7, with the attempt of discrimination between publications describing metabolites by isolation or identification/screening (HPLC, LC-MS, etc.).The chemical structures of the bioactive compounds are shown in Tables 3, 4, 6 and 8-13.Finally, the traditional medicinal uses of Achillea species are reported in Table 14.

Phytochemicals
Phytochemical investigations of the genus Achillea have revealed that many components are present in these plants, such as sesquiterpene lactones, mainly guaianolides and germacranolides, flavonoids, phenolic acids, coumarins, alkaloids, amino acids, fatty acids, alkanes, polyacetylenes, saponins, sterols, sugars, and essential oils [11,15].The genus is characterized by the ability to biosynthesize terpenoids, especially sesquiterpene lactones and essential oils, being all important chemotaxonomic markers of Achillea.From a phytochemical point of view, the following section summarizes the reported phytochemicals (excluding the reports on the essential oils) in Tables 2-13.

Polyphenols
Polyphenols are one of the largest and most widespread chemical groups of natural compounds.This category of specialised products is of great interest due to their common occurrence and their attractive biological properties.Polyphenols of the genus Achillea can be divided into two sub-groups according to their chemical structures, i.e., flavonoids  and phenolic acids , based on literature data from 2011 to 2021 (Tables 2-5).

Flavonoids
Flavonoids represent the largest group of polyphenolic compounds occurring in Achillea spp.and are in accordance with those of other taxa of the Asteraceae family.In general, the pattern of these flavonoids demonstrates a tendency for methylation at the C6 and C4 positions.Furthermore, their biological activities vary depending on the structure degree of hydroxylation, substitution, and conjugation.The first isolation of flavonoids, dating back to 1961, unveiled two flavonoids with antispasmodic activity, namely cynaroside and cosmoside from A. millefolium [52][53][54][55].
Flavones and 3-hydroxyflavones are well documented by numerous studies and consist of the most frequently isolated compounds along with sesquiterpene lactones.Among them, luteolin (19), apigenin (2) and quercetin (44), with their corresponding glycosides, seem to be principal compounds in a high number of Achillea species (Table 2).Impressively, the genus accumulates a wide variety of C-glycosylflavones bearing luteolin (19) and apigenin (2) skeletons.Likewise, an array of methylated flavonoids were also obtained both as aglycons and glycosides [11,14,56].All stated chemical categories are exhaustively discussed below.
Furthermore, several simple flavonols (3-hydroxyflavones), either possessing methoxy groups or rarely as glycosides, were surveyed in the genus.In this study, 27 flavonols were found in the Achillea species.Among them, quercetin (44) and rutin (58) were the most representative secondary metabolites.Precisely, the first one was reported in 16 species, while the latter was found in 18 species.Another example was kaempferol (37), which was encountered in six species.

Phenolic and Quinic Acids Derivatives
Regarding the phenolic profile of Achillea spp. reported in the updated literature (2011-2021), the genus is characterised by the occurrence of benzoic, caffeic, chlorogenic and caffeoylquinic acid derivatives (Tables 5 and 6).

Sesquiterpenes Lactones (SLs)
The Asteraceae family is characterized by an extraordinary range of structurally modified and highly substituted skeletons of SLs.Due to this structural diversity and their diverse array of biological activities, SLs from Achillea spp.are considered as one of the most interesting phytochemical groups among others of the genus.Although different types of SLs were reported, germacranolides, guaianolides and seco-guaianolides are the most representative classes.Previous studies highlighted the structural features of SLs in Achillea spp.In a review conducted by Si et al. [11], more than 100 compounds were described with guaianolides and germacranolides being the major constituents, by far.The study also reported other skeletal types, such as seco-guaianolides, 12,6α-eudesmanolides and other eudesmanolides.The literature data from the past decade include approximately 35 SLs divided mainly into three sub-groups according to their chemical natures, i.e., guaianolides, seco-guaianolides, germacranolides, which are discussed below (Tables 7-13).

Other Compounds
In addition to the principal components of the genus, such as the sesquiterpene lactones and the flavonoids, several phytochemical investigations have revealed the presence of other compounds.More specifically, some studies report the isolation of alkamides [68], lipid acids [27,40] and sterols [31].Saponins have been also isolated, for example from A. wilhelmsii [65].Interestingly, even from the well-investigated A. millefolium, two new compounds were recently isolated, one terpenoid and one lignan [69].These indicate that the phytochemical profile of the taxa could be subjected to variations; however, this biodiversity may explain the bioactivity of Achillea species.

Ethnopharmacological Relevance: Traditional Uses of the Genus Achillea and Established Biological Effects
The genus Achillea encompasses a significant number of medicinal plants globally.It is nevertheless noteworthy that traditional practices are diverse with regional and cultural differences and similarities.In a broad context, the various Achillea species are used for the prevention and treatment of different diseases, mainly in the form of infusions and decoctions (herb, flowers and leaves) for spasmodic gastrointestinal and hepato-biliary disorders, haemorrhages, pneumonia, rheumatic pain, wound healing, as diuretic, antiinflammatory and antipyretic agents, and to treat menstrual and gynaecologic abnormalities.Due to these activities, various thematic names have been given to the genus such as: bloodwood, staunchweed, militaryherb, etc. [15].
The following section summarizes the reported ethnopharmacological uses of 24 Achillea species, with the aim to bridge these features with current studies and in fact to provide some form of conclusive evidence and discuss the associated biological and pharmaceutical properties.Moreover, details on the uses of these species and the associated references are indicated in Table 14 [7,8,[18][19][20]28,30,31,35,36,44,49,50,56,57,60,67,.
The aerial parts of A. aleppica are used in Turkey under the name "Civanperçemi" in decoctions due to their diuretic, carminative, emmenagogue, antiasthmatic, cardiotonic, stomachic, and tonic effects, as well as for colds, nephralgia, gynaecologic ailments and wound healing [70,71].Concerning its biological activity, the methanol extract of A. aleppica subsp.zederbaueri was tested on cell viability and proliferation of the MCF7 (breast cancer cell line) by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.Since at concentrations of 100 and 250 µg/mL it effectively inhibited the cell proliferation, it could be considered as a herbal-based anti-cancerous agent.Another study investigated the protective ability of the ethanol extracts of A. aleppica subsp.aleppica and A. aleppica subsp.zederbaueri against the lipid peroxidation, protein oxidation and DNA damage induced by the Fenton system.This study revealed the antioxidant properties of the extract, which could contribute to the prevention of ROS to related chronic inflammatory diseases, such as cardiovascular diseases and cancer [92].Moreover, Bariş et al. [93] determined noticeable antimicrobial activity and confirmed the strong antioxidant activities of the above-mentioned extracts.
A. alpina is widely distributed in Asia and North America.It was recorded in Korea as a folk medicine for stomach disorders [18], while it was reported in the Pharmacopoeia of the People's Republic of China as having many properties, such as detox, dampness-clearing, bloodstream promotion, and analgesic activities [57].Another report suggests its use as a traditional herbal medicine for the treatment of acute inflammation and as healthpromoting agent (teas and spice) [15].Pharmacological studies showed that it possesses anti-inflammatory, antipyretic, and sedative properties [15].According to Lee et al. [18], two compounds isolated from this plant were highly active, and methyl 3,5-dicaffeoylquinic acid (78) in particular showed strong antioxidant activities, while isovitexin (11) showed antimelanogenic activity that was associated with the downregulation of intracellular tyrosinase activity, indicating that such compounds could act as antihyperpigmentation agents for skincare products.Moreover, a pair of natural caffeoylquinic acid derivatives (isochlorogenic acids A (86) and B (87) isolated from the plant showed an inhibitory activity (with antagonistic effects) on the transient receptor potential vanilloid 3 (TRPV3) channel by using a calcium fluorescent assay.This channel is associated with numerous human skin diseases including skin inflammation, cutaneous pain, chronic itch, atopic dermatitis, and Olmsted syndrome [57,94].
In Mongolia, A. asiatica has been traditionally used for its intestinal and stomach antiinflammatory effects, for persistent fever, ulcers, wounds, and rheumatism [20].Recently, the ethanol extract of this plant was tested on cutaneous wound healing in vivo (rats), and the study showed the beneficial effect of the extract in wounded skin, by supporting the keratinocyte development [20].
Another study reported the uses of A. bibersteinii, found in Turkey, as a diuretic for wound healing and for the treatment of gastrointestinal disorders, including abdominal pains and haemorrhoids [70].Moreover, in Iran, A. biebersteinii (local name: ormaderen) has been used for colds, nephralgia, gynaecologic conditions, such as women' sterility and as emmenagogue or for jaundice, and as astringent for skin conditions, such as oedema and erythema [76,77].The antioxidant, antimicrobial and enzyme inhibitory abilities of this plant along with two other Achillea spp.(A.millefolium, A. teretifolia) were assessed for different extracts.In the Ferric Reducing Antioxidant Power (FRAP) assay, the best result was obtained from the A. biebersteinii MeOH extract (196.12 mgTE/g extract), whilst in the Cupric-Reducing Antioxidant Capacity (CUPRAC) assay, the most potent reducing capacity was obtained for the A. millefolium MeOH extract (255.66 mgTE/g extract).The MeOH and H 2 O extracts had stronger antioxidant effects.Apparently, the EtOAc extract of A. teretifolia was more effective, followed by the EtOAc extract of A. millefolium and A. biebersteinii, on the assessed cholinesterases, while the highest tyrosinase inhibitory effect was detected for MeOH extract (34.24 mg KAE/g).Moreover, the EtOAc and MeOH extracts exhibited remarkable antibacterial (MICs 0.015-0.60mg/mL, MBCs 0.025-0.8mg/mL) and antifungal (0.015-0.4 mg/mL, MBCs 0.025-0.8mg/mL) potential [96].In accordance with the previous results, another study revealed the antioxidant and antimicrobial properties of A. biebersteinii extracts.Concerning the wound-healing property of this plant, in vivo studies gave an account by testing different extracts on mice and rats, suggesting that the n-hexane extract possesses higher activity [97].Of note, rupicolin A (98) and rupicolin B (99) isolated from this plant, showed to have promising anti-inflammatory effects (76% and 80% inhibitions, respectively) by inhibiting the lipopolysaccharide-induced NO production in RAW264.7 macrophage cells [59].To provide more evidence in accordance with the traditional application of A. biebersteinii, the analgesic, antidepressant and anxiolytic activities of this plant were studied in vivo, showing that the methanol extract exerted analgesic and anxiolytic, but not antidepressant activities [98].
In Turkey, the leaves of A. cappadocica under the local name of "Buyucan" were used externally as a powder, or internally as a decoction/infusion for its astringent, emmena-gogue, stomachic effects and to treat oedema [71].The antioxidant, anticholinesterase, and antimicrobial activities of different extracts were tested, indicating that the methanol and water extracts had higher cation radical scavenging activity than that of α-tocopherol and BHT at 100 µg/mL in (2,2 -azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method.The acetone extract showed 70.62% inhibitory activity against butyrylcholinesterase at 200 µg/mL, while the acetone and methanol extracts exhibited moderate antimicrobial activity [99].
A. coarctata is locally used in the area of Kozani, central Greece, as a traditional remedy for gastrointestinal ailments and hypertension, due to its diuretic effects [7].Moreover, this plant was also reported from the neighbouring country, Turkey, where it has been used under the common name "Civanperçemi" for its diuretic, carminative, and menstrual effects in the form of decoction (aerial parts) [71].Recently, extracts and isolated compounds from this plant showed some significant cytotoxic effects in vitro against the human cancer cell lines MCF-7 and HeLa [7].
For A. collina, found in Bosnia and Herzegovina, contradictory uses have been reported, i.e., for bedwetting by children and to increased diuresis and excretion of urinary stones.Moreover, it has been used for blood purification, skin conditions such as injuries, rashes and psoriasis, purulent ulcers, liver ailments, regulation of menstruation, bronchitis, asthma and throat ache [72,73].Infusions from this plant showed good antioxidant and cytoprotective properties in vitro [100], as well as potent analgesic activity in vivo [101].
A. cretica is among the several Achillea species that are used traditionally for the treatment of gynaecological disorders and pathological symptoms analogous to endometriosis according to Persian (Iranian) traditional medicine, as well as for its wound-healing properties and to treat urogenital and respiratory disorders [28].With the aim to investigate the traditional use of this plant, Bina et al. [28] reported that the plant's extract could be used for the management of endometriosis in vivo by modulating inflammatory cytokines.
Nowadays, A. clavennae is used in Croatian folk medicine to relieve ailments such as abdominal pain, common cold, influenza, and respiratory disorders.However, it was described earlier at the beginning of the 17th century as a healing plant with cholagogue, stomachic, and anthelmintic properties [77].Isolated compounds from the plant were tested for their antiproliferative action with regard to HeLa, K562 and Fem-X human cancer cell lines.The most active compound was centaureidin (49) followed by 9α-acetoxyartecanin and apressin (106), with significant cytotoxic effects exerted on all tested lines, while inducumenone exhibited moderate activity [77].In another in vitro study, four extracts of Achillea species were tested, and A. clavennae in particular showed sufficient evidence for its ethnopharmacological use, possessing a broad spectrum of antimicrobial activities against many tested strains [102].
A. falcata is a well-known medicinal plant for local people in Jordan, with beneficial effects on internal haemorrhages, uterine haemorrhoids, stomach ailments, gastritis, and bladder stones [56,78].An antimicrobial investigation of A. falcata indicated that extracts possess low antibacterial activity in comparison with other Achillea species [103].Though, another study reported that the hydro-alcoholic extract had bactericidal activity against Streptococcus pneumoniae, Bacillus cereus and Klebsiella pneumoniae rather than a bacteriostatic effect.Another study showed no significant activity against Gram-negative bacteria and Candida albicans [104].
A. filipendulina, found in Israel, is one of the 15 plant species that are used to treat hypoglycaemia [56].It is native to central and southwestern Asia, commonly called ''Fernleaf Yarrow" or "Bumadaran Zard" or "Sari Chichak" by locals and is used to treat various conditions.More precisely, decoctions of this plant were used to treat arthritis, cardiovascular diseases, congestions, gastrointestinal disorders, gout, and malaria, and as a diuretic, anthelmintic, and purgative agent [79].Antioxidant and antimicrobial effects have been reported for this plant [22,105].
A. fragrantissima, found in Israel, is another species used to treat hypoglycaemia [56].In addition, the plant was used by Bedouin communities in Egypt in various conditions, including gastrointestinal disturbances, eye infections, and smallpox [30].In Egypt, there are several reports on the declared folk and traditional uses of this species to treat fever caused by viral infection, as well as in chronic diseases, such as arthritis and diabetes [80].Moreover, in the folk medicine of the Middle East, this plant is reputed for its antidiabetic properties [31], and more specifically, in the Arabia region, A. fragrantissima is used for the treatment of respiratory diseases and gastrointestinal disturbances [81].Additionally, cirsiliol (22) isolated from A. fragrantissima caused the relaxation of contracted rats' proximal aortas, tracheas, urinary bladders, and uteruses [106].Furthermore, the ethanolic extract of the plant was tested for its anti-inflammatory effects on lipopolysaccharide-activated primary cultures of brain microglial cells, suggesting that phytochemicals from this extract could be beneficial in preventing/treating neurodegenerative diseases [81].Moreover, the non-polar and polar extracts possessed anti-inflammatory and analgesic properties comparable to indomethacin and acetylsalicylic acid, respectively, while the extracts attenuated the macroscopic colonic damage induced by acetic acid in rats.Notably, no signs of toxicity were reported in this study [106].Furthermore, the antioxidant and antimicrobial effects of this plant were confirmed by different pharmacological studies [104].
A. lanulosa has been used in preparations of folk medicines, either internally as a decoction or infusion, or externally as a lotion or ointment, to treat many ailments, such as for wound healing and as a dermatological aid for sprains and swollen tissues, common colds, head-and earache, indigestion problems, and haemorrhoids, as well as a laxative agent, etc. [56].No recent in vitro or in vivo studies could be obtained regarding A. lanulosa.
A. ligustica, found in the Mediterranean region has been used as folk remedy for the treatment of gastrointestinal disorders [82].In Italy, the species A. ligustica was used as an anthelmintic agent and for the treatment of chronic diseases such as rheumatism and skin disorders or inflammation.Focusing on Sicilia and Sardinia, the fresh leaves of this plant were used as an antimicrobial and haemostatic agent topically applied or per os (swallowed as pellets) against stomach-ache [35,83,89].Strong antioxidant and anti-inflammatory activities [107,108], as well as weak antidiabetic effects [109], have been reported for this plant.
Regarding A. magnifica, an endemic plant of Turkey known as the "karcivanı", its dried flowering parts are mixed with honey and used to treat stomach ailments [35,36,89].Taskin et al. [37] investigated the antioxidant, antiurease, anticholinesterase, and antiproliferative activities of different A. magnifica extracts.This study revealed that the chloroform crude extract or prepared with chitosan nanoparticles, as well as the isolated compounds (elenolic acid, luteolin (3), and eupatilin (23a)), showed strong antioxidant and cytotoxic activities.In fact, chitosan nanoparticles not only showed a strong and selective cytotoxic activity in breast cancer cells, but also did not have toxic effects in normal cells, suggesting that it might be suitable for preclinical and clinical studies in cancer treatment.Moreover, the ethanol extract has strong antiurease and anticholinesterase potential [37].
Another species from Italy, A. moschata, is also used in traditional medicine both in human and veterinary health-related problems.It is administered as an infusion against dyspepsia, abdominal bloating, flatulence, and gastric pains and, in general, to benefit the digestive system, as well as for colds, coughs, dysmenorrhea, earache, fever, gout, headache, hypertension, insomnia, menopausal disorders, neuralgia, oliguria, skin inflammations, urinary tract inflammations and vaginitis [43].Moreover, it is traditionally used against bacterial infections, and some in vitro studies demonstrated sufficient evidence for this ethnopharmacological indication.In fact, extracts from the aerial parts were found to possess a broad spectrum of antimicrobial activity against both Gram-positive and Gram-negative bacteria, showing that the less polar extracts possess greater efficacy than the methanolic extracts.Apparently, the methanolic extract was significantly effective against synthetic radicals (ABTS + and DPPH) [43,44].
Among the various species of the genus Achillea, A. millefolium stands out and is extensively used throughout the world.It is worth mentioning that the name millefolium reflects to 1000 leaves showing its folios branches.Documented by many sur-veys in the literature, yarrow has been extensively used against inflammatory disorders and wound healing [20,110], or for spasmodic gastrointestinal disorders and appetiteenhancing drugs due to its bitter taste, or for hepato-biliary complaints, as well as for many gynaecological abnormalities, including the regulation of the menstrual cycle, its emmenagogue properties or pathological symptoms similar to endometriosis in traditional medicine.The aerial parts of the plant are generally applied as aqueous or alcoholic extracts [111,112].Herba millefolii is an official traditional herbal medicinal product used for the temporary loss of appetite, the symptomatic treatment of mild, spasmodic gastrointestinal complaints, including bloating and flatulence, the symptomatic treatment of minor spasms associated with menstrual periods and for the treatment of small superficial wounds [10].Around the world, such as in Middle Europe (e.g., Germany, Italy, Hungary), A. millefolium is listed among the most commonly used medicinal plants.Its use against bleeding, stomach complaints, and menstrual spasm, both as an infusion or externally as a poultice, suggests its medicinal importance.Moreover, in Serbia, it is most frequently used for gastrointestinal ailments such as infusion.Another study reported its use to treat various complaints including gastrointestinal, urinary, respiratory, and dermatological disorders [84].Moreover, in Russian Pharmacopeia, A. millefolium has been recorded as a haemostatic and anti-inflammatory agent [85].In traditional Persian medicine, it has been claimed to have anti-inflammatory and emmenagogue properties and is used for the regulation of the menstrual cycle and treatment of gynaecological disorders, including endometriosis, as well as for the treatment of urogenital and respiratory disorders and as a wound-healing agent [28].Moreover, in West Azerbaijan, the infusion of dried flowers is considered suitable for the treatment of haemorrhoids, dyspepsia, dysmenorrhoea and gastritis [86].Similarly, in West Himalaya, India, aerial parts are used for gastric problems and fever [86].Once more, in Unani medicine of India, A. millefolium is used due to its anti-inflammatory, emmenagogue, antipyretic, diuretic, and analgesic properties [88].Its medical activities are also involved in many traditional practices in Turkey, mainly applied for the treatment of wounds, cold, influenza and for stomach or urinary problems, as antiseptic or antitussive agents, for abdominal pain, etc. [56,71].
It is worth mentioning that veterinary use of the Achillea spp. is rarely recorded.However, in Iran, A. nobilis was used against animal parasites, skin wounds and infections [90].Taskin et al. [45] investigated the antioxidant, antiurease and antimicrobial activities of different extracts from A. nobilis subsp.neilreichii.This study revealed that some of the extracts possess significant antimicrobial and antioxidant activities.
A. santolina, in Iraq, is used to treat hypoglycaemia [56], while in Jordan, the traditional medical usage of this plant is based on its carminative, antispasmodic, depurative properties, as well as for its effects on stomach-aches and diabetes.The hypoglycaemic effects of the plant have been examined both in vitro and in vivo.The study of Kasabri et al. [113] showed that A. santolina lacked any favourable in vitro anti-α-amylase and anti-α-glucosidase effects, while Yazdanparast et al. [114] showed that it has a high hypoglycaemic activity against pancreatic damage in streptozotocin (STZ)-treated diabetic rats, which could be attributed to its antioxidative potential.
Once again in Turkey, a member of the Achillea genus, namely A. setacea (local name: Õrtkesan), was used traditionally as an emmenagogue and stomachic [71].Rupicolin B (99) and 11,13-dehydrodeacetylmatricarin isolated from this plant showed antiphlogistic/antiinflammatory effects in the croton oil ear test [115].
A. tenuifolia (local name: Çoban kirpi gi) has been used internally as a decoction for the treatment of hypercholesterolemia, diabetes, asthma, bronchitis and cough [71].A recent study by Bagheri et al. investigated the hydro-alcoholic extract of this plant on anxiety-like behaviour and reproductive parameters in a rat model of chronic restraint stress [116].
Furthermore, A. vermicularis, known by the local name of "Civanperçemi", is used in a form of decoction for its stomachic problems [71].Other reports, especially in Iranian traditional medicine, suggest its antitumour effect.Based on this, the apoptosis induction ability was evaluated through the activation of caspase 3 in intact MCF-7 cells, suggesting that the extract demonstrated signs of caspase 3 activations [117].More recently, studies reported its antioxidant, anti-inflammatory and antiurease potential [49].
A. wilhelmsii has been used traditionally used for the treatment of gastrointestinal and pulmonary complaints in Italy and Turkey [91].The capitula of this plant were traditionally used as a diuretic, for abdominal pain, as stomachic, emmenagogues and to treat women's sterility, while the aerial parts were used as antihaemorrhoidal agents [71].Lastly, in Iran (local name "boomaderun"), it was used for body-and stomach-ache, blood coagulation, diabetes, hypertension, kidney stones and constipation [50,71].Several studies report the antioxidant [118], as well as the antimicrobial effects of this plant [118,119].Niazmand et al. [120] investigated the traditionally reported gastrointestinal effects on rats' gastric acid output in basal, vagotomized, and vagal-stimulated conditions, suggesting that the A. wilhelmsii extract exhibits an inhibitory effect on the acid output in basal conditions.Moreover, another work reports that the extracts of A. wilhelmsii act as calcium antagonists and the intestinal relaxation effect of this plant supports its traditional use as an antispasmodic [121].Regarding the traditional uses for pain relief, a recent study reports the antinociceptive activity of the plant by using the hot-plate test in BALB/c mice [122].
Natural products and traditional medicines are of great importance, attracting the attention of the scientific community, and affording a plethora of bibliographic data.Though, valuable information is missing not only for the reliability of these ethnopharmacological reports but also in many cases where the mechanisms of action from validated traditional uses are not currently understood.Taking into consideration the above section on the ethnopharmacological relevance of the traditional uses of 24 Achillea spp. in combination with modern results for their biological activities, we can conclude that up to now mainly in vitro and in vivo experiments have been conducted, but clinical trials are limited.
The utilization of extracts or/and isolates from Achillea plants seems to have potential as antioxidant, antimicrobial, anti-inflammatory, cytotoxic agents, as well as for wound healing and the treatment of other skin-related ailments, endometriosis, neurodegenerative diseases, diabetes, and pain, while no significant toxicity was observed.

Species
Traditional Uses Ref.

Table 1 .
(a) Bibliometric results of keyword/phrase search for genus Achillea.(b) Bibliometric results of the top 5: co-occurring authors, cited documents and keywords.
# Structures are not provided.* Compounds were detected by HPLC, LC/MS, etc.The rest of the compounds were isolated.

Table 3 .
Chemical structures of the flavone derivatives from Achillea spp.

Table 8 .
Chemical structures of Guaianolides from Achillea spp.Part I.

Table 9 .
Chemical structures of Guaianolides from Achillea spp.Part II.

Table 12 .
Chemical structures of germacranolides from Achillea spp.

Table 14 .
Traditional medicinal uses of Achillea spp.