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Journal of Ethnopharmacology 320 (2024) 117439
A review of the traditional uses, phytochemistry, pharmacology, and
clinical evidence for the use of the genus Alchemilla (Rosaceae)
Katarzyna Jakimiuk
*
, Michał Tomczyk
Department of Pharmacognosy, Faculty of Pharmacy with the Division of Laboratory Medicine, Medical University of Bia
ł
ystok, Ul. Mickiewicza 2a, 15-230 Bia
ł
ystok,
Poland
A R T I C L E I N F O
Keywords:
Alchemilla
Rosaceae
Phytochemicals
Pharmacological profile
Clinical trials
A B S T R A C T
Ethnopharmacological relevance: The genus Alchemilla L. (lady’s mantle) comprises 1000 species, of which more
than 300 have been characterized from Europe. Notably, as folk medicines, Alchemilla species have long been
prescribed for the treatment of dysmenorrhea, pruritus vulvae, menopausal complaints, and related diseases in
women. This review summarizes the traditional uses, highlights promising plant species, and focuses on
phytochemical and biological studies to highlight future areas of research.
Aim of the review: This literature review aims to provide a comprehensive overview of Alchemilla species, covering
their botany, traditional uses, phytochemistry, and biological and pharmacological activities, and to summarize
the current research status to better understand the application value of Alchemilla plants in modern
phytotherapy.
Materials and methods: The search strategy utilized the major thematic platforms Reaxys, Web of Science, Google
Scholar, Scopus, ScienceDirect, PubMed, the USDA Plant Database and Kew Science (Royal Botanic Gardens) and
was performed with the term Alchemilla. These platforms were systematically searched for articles published
from 1960 to 2023.
Results and discussion: Alchemilla species, as members of the Rosaceae family, produce tannins, phenolic acids,
flavonoids, anthocyanins, coumarins, triterpenes and violet compounds. Effort has been made with this
comprehensive review of Alchemilla plants to highlight the recent developments and milestones achieved in
modern phytochemistry and phytotherapy, underlaying a broad spectrum of the activities of these plants, such as
antioxidant, anti-inflammatory, neuroprotective, antimicrobial, antiobesity, cardiovascular, anticancer, and
wound healing effects.
Conclusions: An increasing number of studies on the plants in the Alchemilla genus have provided data about the
main constituents and their importance in modern medicine. Both in vitro and in vivo studies have indicated that
Alchemilla plants possess an extensive spectrum of biological activities. Regardless of the remarkable medical
potential of Alchemilla extracts, clinical studies are limited and need to be performed to produce safer and less
expensive plant-based drugs.
1.
Introduction
Alchemilla (syn. Alchimilla Mill., lady’s mantle, bear’s foot (eng.),
Aslanpençesi (tr.), Aphanes L. (sp.), Lachemilla (Focke) Rydb., Zyg-
alchemilla Rydb. (N. Amer. Fl.), Percepier Moench (nom. illeg.) is a
genus of perennial or annual herbs or low shrubs in the family Rosaceae,
with the common name lady’s mantle (Graham, 1960; Royal Botanic
Gardens, ). These plants have traditionally been used as herbal infusions
to treat gynaecological diseases, including Alchemilla
xanthochlora
Rothm., or in Central Europe, called A. vulgaris. The data provided in
many papers clearly show that folk knowledge and the use of
plant-based medicines are still active. Several ethnobotanical reports on
A. vulgaris L. have pointed out its diverse biological properties against
problems such as dysmenorrhea, pruritus vulvae, menopausal com-
plaints, and related diseases in women (Jaradat and Zaid, 2019; Masullo
et al., 2015). To prepare a single part of the infusion, 2–4 g of the dried
herb is added to 150 mL of hot water and left for 10 min. The usual daily
dose of lady’s mantle herb is from 5 to 10 g. It is recommended to use 3
portions of the infusion during the day between meals (Czygan, 2004).
* Corresponding author. Department of Pharmacognosy, Faculty of Pharmacy with the Division of Laboratory Medicine, Medical University of Bialystok, ul.
Mickiewicza 2a, 15-230 Białystok, Poland.
E-mail addresses: katarzyna.jakimiuk@umb.edu.pl (K. Jakimiuk), michal.tomczyk@umb.edu.pl (M. Tomczyk).
https://doi.org/10.1016/j.jep.2023.117439
Received 27 June 2023; Received in revised form 24 October 2023; Accepted 14 November 2023
Available online 18 November 2023
0378-8741/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Contents lists available at ScienceDirect
Journal of Ethnopharmacology
journal
homepage:
www.elsevier.com/locate/jethpharm
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
2
The main galenic form of the drug prepared from Alchemilla is infusions;
however, to test their phytochemical profile and biological activity,
apart from water extracts, alcoholic or deep eutectic solvents have also
been used (Kova
ˇ
c et al., 2022). Several pharmacopoeias contain
monographs on Alchemilla species, e.g., Alchemillae herba (the flowering,
aerial parts of A. vulgaris) in the European Pharmacopoeia 10 (European
Pharmacopoeia, 2019) or Polish Pharmacopoeia XII (Farmakopea Pol-
ska, 2020). As members of the Rosaceae family, the main phytochemi-
cals in lady’s mantle species are tannins, flavonoids, and phenolic acids.
However, violet compounds, terpenes, and coumarins are also present in
smaller amounts (Kanak et al., 2022). Despite the fact that traditional
medicine is a powerful opportunity to exploit an unchanging knowledge,
the modern medicine demanding to follow restrictive guidelines to
preserve high quality of plant-based preparation. Therefore, using some
knowledge about rich chemical composition of Alchemilla plants, sup-
ported by many studies, puts them high among potential therapeutics in
the modern medicine. Following that, we presented research of extracts
obtained from Alchemilla which display a broad spectrum of pharma-
cological properties. Based on the knowledge of their phytochemical
composition, they have been studied as antioxidant, antimicrobial,
anticancer, anti-inflammatory, and neuroprotective agents in vitro
(Table 7) as well as therapeutics for obesity, convulsions, and endocrine
and female diseases in vivo (Table 8). Additionally, A. vulgaris glycerine
products were studied in clinical trials as drugs for the treatment of
common mouth ulcers (Shrivastava and John, 2006). Thus, this review
on the genus Alchemilla emphasizes the importance of plants as inex-
haustible sources of biologically active compounds, highlights the pos-
sibilities for conducting new scientific research and points to the gaps in
recent discoveries.
2.
Methodology/search strategy
A literature review was used in this study. The Science Direct/
ELSEVIER, Taylor & Francis Online, SCOPUS, PubMed/MEDLINE, Web
of Science (SCI-EXPANDED), Wiley Online Library, Google Scholar,
REAXYS, and EBSCO Discovery Service (EDS) databases were searched
for integrative manuscripts published between 1960 and May 2023.
Papers were included if they were published in English and used the
UV
IR
TLC
HP-TLC
HPLC
SFC
LC-MS
GC-MS
ABTS
EtOAc
MeOH
2-diphenyl-1-picrylhydrazyl
ethanol
FRAP
TEAC
TE
EAA
AA
MDA
SNP
ORAC
HORAC
TRAP
TBARS
LOX
TRL4
HRBC
MIC
Bs
Se
Ef
Sa
Kp
Pa
Ec
An
Ca
Sc
Pm
Bacillus subtilis
Staphylococcus epidermidis
Enterococcus faecalis
Staphylococcus aureus
Klebsiella pneumoniae
Pseudomonas aeruginosa
Escherichia coli
Aspergillus niger
Candida albicans
Saccharomyces cerevisiae
Proteus mirabilis
Sm Serratia marcescens
Aj Acinetobacter johnsonii
At Agrobacterium tumefaciens
Rs Rhizoctonia solani
Pi Penicillium italicum
Fo Fusarium oxysporum
Bc Branhamella catarrhalis
Tm Trichophyton mentagrophytes
Bm Bacillus mycoides
Ml Micrococcus lysodeikticus
St Salmonella typhimurium
Ac Azotobacter chroococcum
Tv Trichoderma viride
Tl Trichoderma longibrachiatum
Ab Aspergillus brasiliensis
Ga Glaucus atlanticus
Fo Fusarium oxysporum
Aa Alternaria alternata
Kr Kocuria rhizophila
St Salmonella typhimurium
Ea Enterobacter aerogenes
Sp Streptococcus pyogenes
Sd Shigella dysenteriae
St Salmonella typhi
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
3
following combinations of the above keywords: Alchemilla, Rosaceae,
phytochemistry, biological activity, flavonoid, tannin, phenolic com-
pounds, secondary metabolites, violet compounds, phenolic acids,
bioavailability, clinical trials, toxicology, traditional use, ethno-
pharmacology, extraction, isolation, in vivo, in vitro, in silico, genus dis-
tribution, and therapeutic agent. Search definitions were run in separate
or restricted combinations that accounted for the requirements or lim-
itations of the database used. A total of 169 publications were identified
for inclusion. The chemical compounds in Figs. 2–4 were drawn using
ChemSketch software. The all-plant names have been checked and
finally correspond to the latest revision in The Plant List (www.theplan
tlist.org).
3.
Botanical description and distribution
The genus Alchemilla is a group of perennial herbaceous plants that
are commonly known as lady’s mantle and comprise approximately
1000 species distributed across temperate regions of the Northern
Hemisphere, mainly in low temperate and subarctic regions of Europe
and Asia, although the native ranges of a few members of this genus are
in temperate to tropical mountains (Africa and the Americas) (see Fig. 1)
(Fro¨hner, 1995; Sepp and Paal, 1998; Shilpee et al., 2021; USDA, 2023).
The botanical identification and taxonomy of this genus are overly
complicated due to interspecific hybridization and facultative apomixis,
resulting in high morphological variability among the species. The genus
Alchemilla is divided into 18 sections, among which 5 are African
(Fro
¨
hner, 1995). Alchemilla plants are well represented in the moun-
tainous regions of Central and Southern Europe (Kurtto et al., 2007). In
this latter region, the number of species diminishes as one goes further
south, and the representatives of the genus are restricted to the more
humid zones in the mountains, especially to those communities
composed of elements with a boreal affinity. Alchemilla presents
apomictic species that are not easy to identify. These macro- and
micromorphological differences between taxa, due to apomixis, are
persistent, and very few are dependent on the environmental conditions
(Pihu et al., 2009).
Botanically, Alchemilla species share several characteristic features.
They typically have basal rosettes of leaves arising from a central crown.
Alchemilla plants typically grow in clumps and have a low, spreading
growth habit. They vary in size, with most species ranging from 15 to 60
cm (6–24 inches) in height. The leaves of Alchemilla plants are one of
their most distinctive features. They are palmate or lobed, resembling
the shape of a fan or the palm of a hand. The leaf margins may be
toothed or smooth. The leaves often have a slightly hairy or velvety
texture and are typically green, although some species exhibit variations
in coloration. Alchemilla plants produce small, inconspicuous flowers
that are arranged in loose clusters or panicles. The flowers are usually
yellowish-green, although they can also be white or reddish. The flowers
do not have petals but are composed of sepals, which are the leaf-like
structures surrounding the reproductive parts of the flower. The
flowers are borne in branched clusters called cymes or panicles. The
inflorescence arises from the leaf axils or terminal ends of the stems. The
clusters of flowers create a delicate and airy appearance. Alchemilla
plants reproduce both sexually, through seeds, and asexually, by form-
ing clumps through rhizomes or stolon. The flowers are pollinated by
insects, and after pollination, they develop small, dry fruits called
achenes. Alchemilla species are renowned for their ability to capture and
retain water droplets on the surface of their leaves. This phenomenon,
known as guttation, is facilitated by specialized hair-like structures
called trichomes. The water droplets on the leaves of Alchemilla plants
are said to resemble very small pearls, which enhances their aesthetic
appeal. Lady’s mantle plants are adaptable and can thrive in various soil
types, including moist, well-drained soils. They are commonly found in
meadows, woodlands, and alpine regions, often growing in clumps or as
groundcover. Some species of Alchemilla are also cultivated in gardens
for their ornamental value. These characteristics, along with their his-
torical uses and ornamental value, make Alchemilla plants a captivating
and popular choice among gardeners and plant enthusiasts.
4.
Traditional uses of
alchemilla
species
The use of plant extracts or plant-derived compounds to treat dis-
eases is a healing method that has stood the test of time. Currently, many
pharmacological classes of medicines, including prototypes of natural
products (e.g., atropine and morphine), were originally discovered
through explorations of traditional medicine and the sociocultural and
Fig. 1.
Distribution of native and introduced Alchemilla species.
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 1
4
Ethnopharmacological information of Alchemilla species (
A
– internal use;
B
– external use).
Alchemilla
species
Traditional medicine uses
ICPC-2 category
References
A. vulgaris
infusion against menstrual pain and headache
A
female
genital
(Ginko et al., 2023; Jaradat and Zaid,
2019)
weight loss, stomach and intestine pain and inflammation
A
metabolic and nutritional, digestive
Said et al. (2002)
wounds
B
, diarrhoea, menorrhagia
A
skin, digestive, female genital
Parthasarathy and Prince (2021)
eczema, skin rashes
B
skin
(Menkovi
´
c et al., 2011; Saad et al.,
2005)
weight loss
A
metabolic and nutritional
(Alachkar et al., 2011; Said et al., 2002,
2011s
antiseptic
B
skin
Kiselova et al. (2006)
astringent
B
skin
Trouillas et al. (2003)
diabetes
A
metabolic and nutritional
Swanston-Flatt et al. (1989)
A. pedata
common cold, thyroid, anaemia, depression or anxiety
A
digestive, respiratory, endocrine
Woldeamanuel et al. (2022)
A. mollis
women’s illness, asthma, cough, bronchitis, and liver inflammation
A
wounds, skin diseases
B
female genital, respiratory, skin
Parthasarathy and Prince (2021)
sore throat
A
, arrest haemorrhages
B
,
relieve nausea and vomiting
A
respiratory, general and unspecified,
digestive
Todorov et al. (2014)
A. monticola
wounds and burns
B
skin
Mladenova et al. (2021)
A. xanthochlora
ulcers
A
digestive
Herbrechter et al. (2020)
A. hirsutiflora
gynaecological
diseases
A
female genital
Kalankan et al. (2015)
A. hessii
wounds
B
skin
Kaval et al. (2014)
A. cryptantha
dysmenorrhea, lower
abdominal pains
A
A. alpina
stomach ache (intestinal
antalgic/anti-inflammatory), kidney stones (lithotriptic)
A
female
genital
Focho et al. (2009)
digestive, urological
Rigat et al. (2007)
religious beliefs of native peoples (Gilani and Atta-ur, 2005). A. vulgaris,
a well-known species from the genus Alchemilla, has been commonly
used in folk medicine to heal gynaecological disorders, such as menor-
rhagia, dysmenorrhea, or menstrual pain (Tadi
´
c et al., 2020). In the
ESCOP monograph, it is recommended that the aerial parts of the
A. vulgaris be used as agents for pruritus vulvae, uterine bleeding, and
menstrual pains (ESCOP, 2003). The ethnopharmacological applications
of other lady’s mantle species are outlined in Table 1. Most of the
modern indications fall into the International Classification of Primary
Care, 2nd edition (ICPC-2) disease categories of female genitalia
(A. vulgaris, A. mollis Rothm., A. hirsutiflora Rothm., and A. cryptantha
Steud. Ex A. Rich), skin (A. vulgaris, A. mollis, and A. hessii Rothm.) or
digestion (A. vulgaris, A. pedata Hochst. Ex A. Rich., A. mollis,
A. xanthochlora, and A. alpina L.).
5.
Towards a modern approach to traditional use
Phytomedicine traditions are a potent opportunity to take advantage
of unchanging knowledge. Ethnopharmacology is an evolutionary pro-
cess to discover plant-based drugs or new techniques for semi-synthetic
drugs. Often, the crucial role in this process plays the lack of scientific
data to support therapeutic uses. Although, results of the newest studies
of wound, gastrointestinal and gynaecological diseases healing, support
folkloric use of Alchemilla species. At this point, to evaluate wound
healing Tasi
´
c-Kostov and co-authors prepared a gel with A. vulgaris ex-
tracts and examined it topically on human skin sites pretreated with a
patch consisting of sodium lauryl sulfate (SLS). They also performed a
“scratch” test to explore the migration of fibroblasts and the extent of
wound closure (Tasi
´
c-Kostov et al., 2019). Likewise, lesion diameter
wound treatment for 7 consecutive days with fluid extract of A. vulgaris
led to a reduction of lesion diameter (Shrivastava et al., 2007).
Administration of the juice with A. vulgaris in rats with
indomethacin-induced gastric ulcers pro-inflammatory mediators, ul-
cers index and score have decreased (Karaoglan et al., 2020). As
mentioned in Table 1, A. mollis was used in female genitalia diseases.
Studies from 2019 showed that its extract decreased cystic formation
and reduced endometrioma (Bina et al., 2019). Furthermore, in vivo
experiments, lady’s mantle has confirmed the folk properties in meta-
bolic, nutritional, and digestive disorders (weight loss, stomach and
intestine pain, and inflammation). As mentioned above, there are
indisputable trends to involve ethnopharmacology in modern
phytotherapy.
6.
Phytochemical constituents
Alchemilla species, as members of the Rosaceae family, produce
tannins, phenolic acids, flavonoids, anthocyanins, coumarins, tri-
terpenes and volatile (essential oils) compounds. Notably, literature
surveys mainly show information concerning the total phenol, tannin,
steroid or saponin content rather than a detailed chemical composition
(Edrah, 2017).
6.1.
Tannins and related compounds (see Fig. 2)
The abundance and widespread presence of tannins is a typical
feature of the Rosaceae family (Augustynowicz et al., 2021; Tomczyk
and Latt´e, 2009). Alchemilla species and the recent reports of their tannin
contents are summarized in Table 2. The largest number of this type of
phytoconstituent was found in A. persica Rothm. (14 compounds),
A. vulgaris and A. viridiflora Rothm. (both 11 compounds). Ellagic acid, a
dimeric hydrolysable molecule, is the product ellagitannin degradation
and seems to be the most abundant tannin among all described
Alchemilla species. Apart from ellagic acid, casuarictin has been reported
in the genus Alchemilla as well as its derivative pedunculagin, formed via
the loss of a gallate group. Several more phytochemical studies have
demonstrated the presence of the antitumor tannin agrimoniin (a
dimeric potentillin monomer linked via a dehydrogalloyl group) in
A. persica, A. xanthochlora, A. vulgaris, A. viridiflora and A. mollis
(Fedotcheva et al., 2021; Grochowski et al., 2017). Additionally, char-
acteristic constituents isolated from Alchemilla species are sanguiins
SH-6 and SH-10 as well as other hexahydrodiphenoyl (HHDP)
derivatives.
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
5
Table 2
Tannins and related compounds isolated from Alchemilla species.
Compounds
Alchemilla
species
References
ellagic acid
A. vulgaris
(Duckstein et al., 2012; Ibrahim et al., 2022; Ili
´
c-Stojanovi
´
c et al., 2018; Jela
´
ca et al., 2022; Møller et al., 2009; Neagu et al.,
2015; Yazici, 2021)
A. mollis
(Duckstein et al., 2012; Ibrahim et al., 2022; Ili
´
c-Stojanovi
´
c et al., 2018; Møller et al., 2009)
A. xanthochlora
Fraisse et al. (1999)
A. glabra
Krivoku
´
ca et al. (2015)
A. fissa
A. viridiflora
A. monticola
A. persica
Afshar et al. (2015)
pedunculagin
A. persica
(O
¨
z et al., 2016; O
¨
zbilgin et al., 2019)
A. vulgaris
Duckstein et al. (2012)
A. mollis
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
A. xanthochlora
Geiger et al. (1994)
pedunculagin isomers
A. persica
Afshar et al. (2015)
A. viridiflora
Radovi
´
c et al. (2022b)
laevigating F
A. xanthochlora
Geiger et al. (1994)
casuarictin
A. persica
(O
¨
z et al., 2016; O
¨
zbilgin et al., 2019)
vescalagin/castalagin
isomer
A.
mollis
Duckstein et al. (2012)
A.
vulgaris
A.
persicaria
(O
¨
z et al., 2016; O
¨
zbilgin et al., 2019)
sanguiin H-6 isomers
A. vulgaris
(Duckstein et al., 2012; Gesek et al., 2021)
A. mollis
sanguiin H-10 isomers
A. persicaria
(Afshar et al., 2015; O
¨
z et al., 2016; O
¨
zbilgin et al., 2019)
A. vulgaris
(Duckstein et al., 2012; Gesek et al., 2021)
A. mollis
A. viridiflora
Radovi
´
c et al. (2022b)
catechin
A. vulgaris
(El-Hadidy et al., 2018; Ibrahim et al., 2022; Juri
´
c et al., 2020; Møller et al., 2009; Valcheva-Kuzmanova et al., 2019; Yazici,
2021)
A. barbatiflora
Renda et al. (2018)
A. monticola
Mladenova et al. (2021)
A. mollis
(Karatoprak et al., 2017; Kurtul et al., 2022)
A. persica
(Afshar et al., 2015; Kurtul et al., 2022)
A. caucasia
Karaoglan et al. (2020)
A. glabra
Denev et al. (2014)
epicatechin
A. vulgaris
(Aug
ˇ
spole et al., 2018; El-Hadidy et al., 2018; Møller et al., 2009; Neagu et al., 2015; Valcheva-Kuzmanova et al., 2019)
A. mollis
Karatoprak et al. (2017)
A. persica
Afshar et al. (2015)
A. glabra
Denev et al. (2014)
procyanidin B1
A. persica
Afshar et al. (2015)
procyanidin B3
A. barbatiflora
Renda et al. (2018)
pentagalloylglucose
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
tellimagrandin I
tellimagrandin II
brevifolin
A. vulgaris
Jela
´
ca et al. (2022)
brevifolin carboxylic acid
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
A. vulgaris
Jela
´
ca et al. (2022)
methyl-gallate
A. mollis
Karatoprak et al. (2017)
A. persica
Afshar et al. (2015)
galloyl-HHDP hexose
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
A. persica
Afshar et al. (2015)
A. vulgaris
Jela
´
ca et al. (2022)
galloyl-bis-HHDP-glucose
A. viridiflora
Radovi
´
c et al. (2022b)
digalloyl-galloyl galloside
A. persica
Afshar et al. (2015)
agrimoniin
A. persica
(Afshar et al., 2015; O
¨
z et al., 2016; O
¨
zbilgin et al., 2019)
A. viridiflora
Radovi
´
c et al. (2022b)
A. vulgaris
(Duckstein et al., 2012; Ghedira et al., 2012; Grochowski et al., 2017; Jela
´
ca et al., 2022)
A. mollis
Duckstein et al. (2012)
A. xanthochlora
Geiger et al. (1994)
The condensed tannins of A. persica and A. barbatiflora Juz. Consist of
a (
-
)-epicatechin and (
+
)-catechin or two (
+
)-catechin units joined by a
bond between positions 4 and 8
′
, procyanidin B1 and procyanidin B3,
respectively. In addition to procyanidins, their precursors, including
catechin and epicatechin, were identified in several Alchemilla species.
Some typical tannin molecules are depicted in Fig. 2. Beyond isolation
and identification analyses, many authors have expressed the presence
of tannins as their total content. For example, Oktyabrsky et al. revealed
that the inflorescence of a. vulgaris does not contain tannins, while the
leaves hold 6.6 mg/g dw (Oktyabrsky et al., 2009). The high content of
tannins (4.6
±
0.3%) in the whole herb of A. vulgaris was also deter-
mined by Maier et al. (2017). Using spectrophotometric methods, the
total tannin contents in the aboveground parts of A. kiwuensis Engl.
(Ngoupaye et al., 2022), A. mollis, A. achtarowii Pawl., or
A. jumrukczalica Pawl. Were determined (Ilugin et al., 2016; Vitkova
et al., 2013).
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
6
Fig. 2.
Structures of tannins from Alchemilla species; A - catechin, B - brevifolin, C - tellimagrandin II, D - ellagic acid, E
-
procyanidin B1.
6.2.
Phenolic acids and related compounds
Phenolic acids, the most prominent group of polyphenols, possess a
phenolic moiety and a resonance-stabilized structure, resulting in the
allocation of hydrogen atoms (Kumar and Goel, 2019). Due to their
bioactive properties, phenolic acids from plant in the Rosaceae family
and Alchemilla genus have been extensively studied. Altogether, 29
phenolic acids (Table 3) have been structurally identified in Alchemilla
species. Many of these compounds (25) have been described from
A. vulgaris. Additionally, gallic acid, caffeic acid and chlorogenic acid
were detected in 4–6 varied species.
6.3.
Flavonoids, anthocyanins, and their derivatives (see Fig. 3)
Flavonoids are the group of natural compounds with the largest
number of structures altogether (61). Among them, 15 were identified as
aglycones, 35 as mono- or di-O-glycosides and 6 as mono- or di-C-
glycosides (Table 4). The most abundant O-glycosides contain quer-
cetin as the aglycone combined with a saccharide at the C-3 position in
the C-ring in the flavanol structure (e.g., hyperoside, guaijaverin, avi-
cularin, and isoquercitrin) (Jela
´
ca et al., 2022). On the other hand, the
flavones apigenin and luteolin remain as aglycones among C-glycosides
(vitexin, orientin) (Kaya et al., 2012a). In terms of the content of both
phenolic acids and flavonoids, A. vulgaris seems to be the most thor-
oughly studied species among the entire genus; 30 flavonoids have been
identified from this plant. Moreover, isoflavones, including genistein
and daidzein, were isolated from A. vulgaris, representing their first
instance of isolation from a species in this genus (Neagu et al., 2015).
Among all reported compounds, the most widespread are quercetin
3-O-galactoside (hyperoside) (Fig. 3), quercetin 3-O-glucoside (iso-
quercitrin) and quercetin 3-O-rutinoside (rutin), which have been
detected in 19, 18 and 17 species, respectively.
Aside from the flavonoids presented in Table 4, flavonoids are
typically found in only Southern European species, such as A. velebitica
Borb s ex Janch. (Juranovi
´
c Cindri
´
c et al., 2015). Although total
bioactive compound content assays provide limited insight into the
phytochemical composition, Smolyakova et al. attempted to develop
extraction techniques and standardization methods for generating an
extract using the aboveground parts of lady’s mantle using the percent
flavonoid content (Smolyakova et al., 2012). Among anthocyanins, only
cyanidin derivatives have been found in A. vulgaris (Valcheva-Kuzma-
nova et al., 2019).
6.4.
Essential oils and volatile compounds
As essential oils are isolated by distillation from flowers or leaves,
they contain a diversity of volatile molecules—phenol-derived aromatic
compounds, terpenes and terpenoids, and aliphatic components (Jaki-
miuk et al., 2022b). To date, the broad spectrum of these kinds of
compounds has been detected in only seven Alchemilla species:
A. phegophila Juz. (Dubel et al., 2022), A. alpina (Falchero et al., 2008),
A. xanthochlora (Falchero et al., 2009), A. persica (Afshar et al., 2015)
and A. vulgaris (Ahmed and Zhang, 2019) and А. labellate, A. subrenata
(not occur in “The Plant List”) (Dubel et al., 2022). All of the essential oil
compounds that have been detected in Alchemilla species are summa-
rized in Table 5.
6.5.
Other compounds (see Fig. 4)
In addition to the compounds mentioned above, Alchemilla species
contain fatty acids, sterols, coumarins, stilbenes and triterpenes (Fig. 4
and Table 6).
Olafsdottir et al. detected ursolic acid and its derivative oleanolic
acid in A. faero
¨
ensis Buser, A. alpina and A. vulgaris (Olafsdottir et al.,
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 3
7
Phenolic acids and related compounds isolated from Alchemilla species.
Compounds
Alchemilla
species
References
gallic acid
A. vulgaris
(Condrat et al., 2010; Duckstein et al., 2012; El-Hadidy et al., 2018; Ibrahim et al., 2022; Jela
´
ca et al., 2022; Neagu et al., 2015;
Yazici,
2021)
A.
mollis
(Duckstein et al., 2012; El-Hadidy et al., 2018; Ibrahim et al., 2022)
A.
jumrukczalica
Nikolova et al. (2011)
A.
acutiloba
Szewczyk et al. (2022)
A.
persica
Afshar et al. (2015)
A.
glabra
Denev et al. (2014)
gallic acid 4-glycoside
A. persica
Afshar et al. (2015)
gallic acid methoxy
glycoside
gallic acid-O-glycoside
benzoic acid
A. vulgaris
(Ahmed and Zhang, 2019; El-Hadidy et al., 2018; Nikolova et al., 2011)
A.
jumrukczalica
Nikolova et al. (2011)
p-hydroxybenzoic acid
A. vulgaris
(Juri
´
c et al., 2020; Nikolova et al., 2011; Yazici, 2021)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
m-hydroxybenzoic acid
A. vulgaris
Nikolova et al. (2011)
A. jumrukczalica
2,5-dihydroxybenzoic acid
A. vulgaris
Vlaisavljevi
´
c et al. (2019)
3,4-dihydroxybenzoic acid
A. vulgaris
Valcheva-Kuzmanova et al. (2019)
A. glabra
Denev et al. (2014)
salicylic acid
A. vulgaris
(El-Hadidy et al., 2018; Ibrahim et al., 2022; Nikolova et al., 2011)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
cinnamic acid
A. vulgaris
(El-Hadidy et al., 2018; Ibrahim et al., 2022)
A. jumrukczalica
Nikolova et al. (2011)
3,4,5-methoxy-cinnamic
acid
A. vulgaris
El-Hadidy et al. (2018)
chlorogenic acid
A. mollis
Duckstein et al. (2012)
A. vulgaris
(El-Hadidy et al., 2018; Jela
´
ca et al., 2022; Juri
´
c et al., 2020; Møller et al., 2009; Neagu et al., 2015; Valcheva-Kuzmanova
et al., 2019; Yazici, 2021)
A. persica
Afshar et al. (2015)
A. glabra
Denev et al. (2014)
neochlorogenic acid
A. vulgaris
Valcheva-Kuzmanova et al. (2019)
ferulic acid
A. vulgaris
(Juri
´
c et al., 2020; Tasi
´
c-Kostov et al., 2019)
A. acutiloba
Szewczyk et al. (2022)
iso-ferulic acid
A. vulgaris
El-Hadidy et al. (2018)
vanillic acid
A. monticola
Mladenova et al. (2021)
A. vulgaris
(El-Hadidy et al., 2018; Nikolova et al., 2011)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
protocatechuic
acid
A. vulgaris
(El-Hadidy et al., 2018; Ibrahim et al., 2022; Nikolova et al., 2011)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
caffeic acid
A. vulgaris
(El-Hadidy et al., 2018; Ibrahim et al., 2022; Jela
´
ca et al., 2022; Juri
´
c et al., 2020; Nikolova et al., 2011; Valcheva-Kuzmanova
et al., 2019)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
A. mollis
Karatoprak et al. (2017)
A. glabra
Denev et al. (2014)
syringic acid
A. vulgaris
(Ibrahim et al., 2022; Juri
´
c et al., 2020; Neagu et al., 2015; Renda et al., 2018)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
p-coumaric acid
A. vulgaris
(El-Hadidy et al., 2018; Jela
´
ca et al., 2022; Juri
´
c et al., 2020; Neagu et al., 2015; Nikolova et al., 2011)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
p-coumaroylquinic acid
A. vulgaris
Jela
´
ca et al. (2022)
sinapic acid
A. vulgaris
(Juri
´
c et al., 2020; Nikolova et al., 2011)
A. jumrukczalica
Nikolova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
β
-phenylpyruvic acid
A. jumrukczalica
Nikolova et al. (2011)
A. vulgaris
gentisic acid
A. jumrukczalica
Nikolova et al. (2011)
A. vulgaris
A. acutiloba
Szewczyk et al. (2022)
A. mollis
Karatoprak et al. (2017)
β
-resorcylic acid
A.
jumrukczalica
Nikolova et al. (2011)
A. vulgaris
mandelic acid
A. jumrukczalica
Nikolova et al. (2011)
A. vulgaris
3,4,5-trimethoxymandelic
acid
A. jumrukczalica
Nikolova et al. (2011)
A. vulgaris
rosmarinic acid
A. acutiloba
Szewczyk et al. (2022)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
8
Table 4
Flavonoids, anthocyanins and their derivatives isolated from Alchemilla species.
Compounds
Alchemilla
species
References
Flavonoids and flavonoid derivatives
Apigenin
A. vulgaris
Juri
´
c et al. (2020)
A. caucasia
Karaoglan et al. (2020)
apigenin 7-O-glucoside (cosmosiin)
A. vulgaris
Tasi
´
c-Kostov et al. (2019)
A. mollis
Karatoprak et al. (2017)
apigenin 8-C-glucoside (vitexin)
A. monticola
Mladenova et al. (2021)
A. stricta
Kaya et al. (2012b)
A. armeniaca
Kaya et al. (2012a)
A. erzincanensis
A. orduensis
A. ikizdereensis
(Kaya et al., 2012a; Türk et al., 2011)
apigenin 6-C-arabinose-8-C-glucoside
A. vulgaris
El-Hadidy et al. (2018)
apigenin 6-C-rhamnose-8-C-glucoside
apigenin 7-O-neohesperoside
Acacetin
aromadendrin glucoside derivative
A. persica
Afshar et al. (2015)
Luteolin
A. vulgaris
(Ibrahim et al., 2022; Neagu et al., 2015; Shrivastava and John, 2006)
A. mollis
Shrivastava and John (2006)
luteolin 7-O-glucoside (cynaroside)
A. vulgaris
(Jela
´
ca et al., 2022; Tasi
´
c-Kostov et al., 2019)
A. speciosa
Felser and Schimmer (1999)
A. mollis
Karatoprak et al. (2017)
luteolin 8-C-glucoside (orientin)
A. procerrima
Kaya et al. (2012b)
A. stricta
A. armeniaca
Kaya et al. (2012a)
A. cimilensis
A. orduensis
A. ikizdereensis
A. hirsutiflora
A. erythropoda
Türk et al. (2011)
A. ikizdereensis
luteolin 7-O-
β
-D-glucosyl-(2-O-
α
-L-rhamnoside)
(lonicerin, scolymoside)
A. speciosa
Felser and Schimmer (1999)
luteolin 6-C-arabinose-8-C-glucoside
A. vulgaris
El-Hadidy et al. (2018)
luteolin 6-C-glucose-8-C-arabinoside
Quercetin
A. vulgaris
(Mandrone et al., 2018; Neagu et al., 2015; Tasi
´
c-Kostov et al., 2019; Valcheva-Kuzmanova et al., 2019)
A. speciosa
Felser and Schimmer (1999)
A. monticola
Mladenova et al. (2021)
A. acutiloba
Szewczyk et al. (2022)
quercetin 3-O-glucuronide
A. vulgaris
(Duckstein et al., 2012; Mandrone et al., 2018)
A. mollis
Duckstein et al. (2012)
A. monticola
Mladenova et al. (2021)
A. xanthochlora
Lamaison et al. (1991)
A. caucasia
Karaoglan et al. (2020)
A. persica
Afshar et al. (2015)
quercetin 3-O-galactoside (hyperoside)
A. vulgaris
(Jela
´
ca et al., 2022; Tasi
´
c-Kostov et al., 2019)
A. barbatiflora
Renda et al. (2018)
A. procerrima
Kaya et al. (2012b)
A. hirtipedicellata
A. sericata
A. mollis
(Küpeli Akkol et al., 2015; Trendafilova et al., 2011)
A. acutiloba
Szewczyk et al. (2022)
A. speciosa
Felser and Schimmer (1999)
A. achtarowii
Trendafilova et al. (2012)
A. armeniaca
Kaya et al. (2012a)
A. cimilensis
A. orduensis
A. oriturcica
A. bursensis
A. hirsutiflora
A. ikizdereensis
(Kaya et al., 2012a; Türk et al., 2011)
A. erythropoda
Türk et al. (2011)
A. oriturcica
A. persica
Küpeli Akkol et al. (2015)
quercetin 3-O-rhamnoside (quercitrin)
A. orduensis
Kaya et al. (2012a)
A. hirsutiflora
quercetin 3-O-
α
-L-arabinoside (guaijaverin)
A. trabzonica
A. xanthochlora
Türk et al. (2011)
Fraisse et al. (2000)
A. barbatiflora
Renda et al. (2018)
A. pedata
Taddese et al. (2009)
A. achtarowii
Trendafilova et al. (2012)
quercetin 3-O-
α
-L-arabinoside (avicularine)
A. vulgaris
A. vulgaris
(D’Agostino et al., 1998; Jela
´
ca et al., 2022)
Jela
´
ca et al. (2022)
quercetin 3-O-
β
-D- sambubioside
A. speciosa
Felser and Schimmer (1999)
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 4
(continued )
9
Compounds
Alchemilla
species
References
quercetin 3-O-
β
-D-sambubioside-7-O-
β
-D-
glucoside
quercetin 3 -O-
β
-(2
′
-O-
α
-L-rhamnosyl)-glucoside
uronic acid
quercetin 3-O-glucoside (isoquercetin)
A. vulgaris
(D’Agostino et al., 1998; Jela
´
ca et al., 2022; Neagu et al., 2015; Tasi
´
c-Kostov et al., 2019;
Valcheva-Kuzmanova et al., 2019)
A. monticola
Mladenova et al. (2021)
A. speciosa
Felser and Schimmer (1999)
A. stricta
Kaya et al. (2012b)
A. hirtipedicellata
A. sericata
A. mollis
(Aslı et al., 2022; Küpeli Akkol et al., 2015; Trendafilova et al., 2011)
A. acutiloba
Szewczyk et al. (2022)
A. achtarowii
Trendafilova et al. (2012)
A. erzincanensis
Kaya et al. (2012a)
A. cimilensis
A. orduensis
A. bursensis
Kaya et al. (2012a)
A. oriturcica
(Kaya et al., 2012a; Türk et al., 2011)
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
A. erythropoda
Türk et al. (2011)
A. persica
Küpeli Akkol et al. (2015)
quercetin 3-O-arabinoside-7-O-glucoside
quercetin 3-O-
α
-L-arabinosyl-(1–6)-
β
-D-
A. vulgaris
Jela
´
ca et al. (2022)
glucoside (quercetin-3-O-vicianoside)
quercetin 3-O-(6-O-acetyl-
β
-D-glucoside
quercetin glucuronide methyl ether
A. vulgaris
Duckstein et al. (2012)
A. mollis
quercetin di-O-methyl ether
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
quercetin 3-(6
″
-ferulylglucoside)
quercetin 3-methyl ether-7-glucuronide
quercetin 3-O-rutinoside (rutin)
A. vulgaris
(Al-Osaj et al., 2016; D’Agostino et al., 1998; El-Hadidy et al., 2018; Ibrahim et al., 2022; Jela
´
ca et al., 2022;
Juri
´
c et al., 2020; Mandrone et al., 2018; Neagu et al., 2015; Tasi
´
c-Kostov et al., 2019;
Valcheva-Kuzmanova et al., 2019)
A. speciosa
Felser and Schimmer (1999)
A. monticola
Mladenova et al. (2021)
A. procerrima
Kaya et al. (2012b)
A. stricta
A. hirtipedicellata
A. sericata
A. acutiloba
Szewczyk et al. (2022)
A. cimilensis
Kaya et al. (2012a)
A. orduensis
A. bursensis
A. hirsutiflora
A. ikizdereensis
(Kaya et al., 2012a; Türk et al., 2011)
A. oriturcica
A. mollis
Karatoprak et al. (2017)
A. glabra
Denev et al. (2014)
quercetin 3-O-glucuronic acid (miquelianin)
A. speciosa
Felser and Schimmer (1999)
A. mollis
(Kurtul et al., 2022; Trendafilova et al., 2011)
A. barbatiflora
Renda et al. (2018)
A. coriacea
(Fraisse et al., 1999; Trendafilova et al., 2012)
A. filicauli
A. glabra
A. achtarowii
Trendafilova et al. (2012)
A. persica
Kurtul et al. (2022)
A. viridiflora
(Radovi
´
c et al., 2022b; Suru
ˇ
ci
´
c et al., 2022)
A. vulgaris
Jela
´
ca et al. (2022)
Kaempferol
A. vulgaris
(El-Hadidy et al., 2018; Filippova, 2017; I brahim et al., 2022; Juri
´
c et al., 2020; Neagu et al., 2015;
Tasi
´
c-Kostov et al., 2019; Vlaisavljevi
´
c et al., 2019)
A. monticola
Mladenova et al. (2021)
A. acutiloba
Szewczyk et al. (2022)
kaempferol 3-O-glucuronide
A. vulgaris
Duckstein et al. (2012)
A. mollis
A. speciosa
Felser and Schimmer (1999)
kaempferol 3-O-glucoside (astragalin)
A. vulgaris
(Jela
´
ca et al., 2022; Tasi
´
c-Kostov et al., 2019)
A. viridiflora
Radovi
´
c et al. (2022b)
A. achtarowii
Trendafilova et al. (2012)
A. speciosa
Felser and Schimmer (1999)
A. monticola
(Mladenova et al., 2021; Patel et al., 2022)
A. acutiloba
Szewczyk et al. (2022)
kaempferol 3-O-
β
-D-xyloside
A. barbatiflora
Renda et al. (2018)
A. vulgaris
Jela
´
ca et al. (2022)
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 4
(continued )
10
Compounds
Alchemilla
species
References
kaempferol 3-O-
β
-(2
′
-O-
α
-L-rhamnosyl)-
glucoside uronic acid
kaempferol 3-O-(6
″
-E-coumaroyl-
β
-D-glycoside)
(tiliroside)
A. speciosa
Felser and Schimmer (1999)
A. vulgaris
(D’Agostino et al., 1998; Jela
´
ca et al., 2022; Tasi
´
c-Kostov et al., 2019)
A. speciosa
Felser and Schimmer (1999)
A. barbatiflora
Renda et al. (2018)
A. mollis
Trendafilova et al. (2011)
A. acutiloba
Szewczyk et al. (2022)
A. achtarowii
Trendafilova et al. (2012)
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
kaempferol 3-O-rutinoside (nicotiflorin)
A. acutiloba
Szewczyk et al. (2022)
A. persica
Afshar et al. (2015)
A. vulgaris
Jela
´
ca et al. (2022)
kaempferol 3-O-(4
″
-E-p-coumaroyl)-
robinobioside (variabiloside G)
A. achtarowii
Trendafilova et al. (2012)
kaempferol 7-O-glucoside
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
kaempferol 7-O-glucuronide
kaempferol 3,7-O-dirhamnoside
A. vulgaris
El-Hadidy et al. (2018)
Morin
A. vulgaris
Tasi
´
c-Kostov et al. (2019)
Rhamnetin
A. vulgaris
El-Hadidy et al. (2018)
A. acutiloba
Szewczyk et al. (2022)
isorhamnetin
A. acutiloba
Szewczyk et al. (2022)
isorhamnetin-3-O-glucoside
A. acutiloba
Szewczyk et al. (2022)
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
isorhamnetin-3-O-rutinoside (narcissoside)
A. acutiloba
Szewczyk et al. (2022)
gosselin 7-O-
α
-rhamnoside (rhodiolgin)
A. mollis
Trendafilova et al. (2011)
gosselin-3-O-
β
-D-galactosyl-7-O-
α
-L-rhamnoside
sinocrassoside D
2
A. mollis
Trendafilova et al. (2011)
Naringin
A. vulgaris
Ibrahim et al. (2022)
Naringenin
A. acutiloba
Szewczyk et al. (2022)
naringenin 7-O-glucoside
Eriodictyol
Hesperetin
A. vulgaris
El-Hadidy et al. (2018)
Myricetin
A. vulgaris
Neagu et al. (2015)
myricetin 3-O-glucuronide
A. viridiflora
Suru
ˇ
ci
´
c et al. (2022)
chrysoeriol 7-O-glucuronide
A. vulgaris
Jela
´
ca et al. (2022)
Genistein
A. vulgaris
Neagu et al. (2015)
Dadzein
Anthocyanins and anthocyanins derivatives
cyanidin 3-galactoside
A. vulgaris
Valcheva-Kuzmanova et al. (2019)
cyanidin 3-glucoside
cyanidin 3-arabinoside
cyanidin 3-xyloside
Fig. 3.
Structures of flavonoids from Alchemilla species; A - apigenin, B - orientin, C – genistein, D - cosmosiin, E
-
hyperoside, F – naringenin 7-O-glucoside.
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
11
Table 5
Essential oils compounds detected in Alchemilla species.
Compound
Alchemilla
References
Table 5
(continued )
Compound
Alchemilla
species
References
species
phenylacetaldehyde
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
A. alpina
Falchero et al. (2008)
cis-linalool oxide
A. phegophila
Dubel et al. (2022)
A. alpina
Falchero et al. (2008)
trans-linalool oxide
A. phegophila
Dubel et al. (2022)
A. alpina
Falchero et al. (2008)
nonanal
A. phegophila
Dubel et al. (2022)
A. subrenata
linalool
A. phegophila
A. subrenata
β
-phenethyl alcohol
А. flabellata
2-ethylcaproic acid
А. flabellata
A. phegophila
A. subrenata
terpinene-4-ol
A. phegophila
A. alpina
Falchero et al. (2008)
p-cymene-8-ol
A. phegophila
Dubel et al. (2022)
α-
terpineol
А.
flabellata
A. phegophila
A. alpina
Falchero et al. (2008)
α
-terpinyl acetate
A. alpina
decanal
А. flabellata
Dubel et al. (2022)
A. phegophila
A. alpina
Falchero et al. (2008)
caprylic acid
А. flabellata
Dubel et al. (2022)
myrtenol
A. phegophila
A. persica
Afshar et al. (2015)
geraniol
A. phegophila
Dubel et al. (2022)
A. alpina
Falchero et al. (2008)
indole
A. subrenata
Dubel et al. (2022)
2-
methoxy-4-vinylphenol
А. flabellata
A.
phegophila
A.
subrenata
3-
methyl-butanal
A. alpina
Falchero et al. (2008)
3-methyl-2-butenol
2-
methylbutanal
pentanal
3-
penten-2-ol
hexanal
(E)-2-hexenal
hexanol
(Z)-3-hexenol
furfural
heptanol
A. alpina
Falchero et al. (2008)
nonanoic acid
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
A. alpina
Falchero et al. (2008)
γ
-
nonalactone
А. flabellata
Dubel et al. (2022)
eugenol
А. flabellata
A. persica
Afshar et al. (2015)
β
-ionone epoxide
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
β-
ionone
А. flabellata
A. phegophila
A. persica
Afshar et al. (2015)
β-
pinene
A. alpina
Falchero et al. (2008)
undecanal
A. alpina
undecanoic acid
А. flabellata
Dubel et al. (2022)
tetradecanal
А. flabellata
A. phegophila
A. subrenata
megastigmatrienon
A. subrenata
spatulenol
А. flabellata
caryophyllene oxide
A. phegophila
A. persica
Afshar et al. (2015)
lauric acid
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
benzophenone
А. flabellata
A. phegophila
A. subrenata
β-
eudesmol
А. flabellata
tridecanoic acid
А. flabellata
A. phegophila
A. subrenata
hexadecanal
А. flabellata
A. phegophila
A. subrenata
A. alpina
Falchero et al. (2008)
11-tetradecenoic acid
А. flabellata
Dubel et al. (2022)
13-tetradecenoic
A. phegophila
myristicin
A. alpina
Falchero et al. (2008)
myristic acid
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
hexahydropharnesyl acetone
А. flabellata
A. phegophila
A. subrenata
14-pentadecenoic
А. flabellata
pentadecanoic acid
А. flabellata
pentadecanal
A. alpina
Falchero et al. (2008)
A. phegophila
Dubel et al. (2022)
A. subrenata
methyl palmitate
A. subrenata
palmitoleic acid
А. flabellata
A. phegophila
A. subrenata
palmitic acid
А. flabellata
A. phegophila
A. subrenata
heptanoic acid
A. vulgaris
Ahmed and Zhang
A. phegophila
A. subrenata
A. alpina
Falchero et al. (2008)
vanillin
A. alpina
octanoic acid
hexanoic acid
hexadecenoic acid
(2019)
A. alpina
Falchero et al. (2008)
2-dodecenal
А. flabellata
Dubel et al. (2022)
A. phegophila
capric acid
А. flabellata
A. phegophila
A. subrenata
ethyl caprynate
A. phegophila
dodecanal
А. flabellata
A. alpina
Falchero et al. (2008)
tridecanal
A. alpina
2,3-dehydro-
α
-ionone
A. phegophila
Dubel et al. (2022)
β-
caryophyllene
А.
flabellata
A. persica
Afshar et al. (2015)
A. alpina
Falchero et al. (2008)
geranylacetone
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
β-
farnesene
A. subrenata
heptadecanoic acid
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
methyl linolenate
А. flabellata
A. subrenata
phytol
А. flabellata
A. phegophila
A. subrenata
A. persica
Afshar et al. (2015)
A. alpina
Falchero et al. (2008)
phytone
A. persica
Afshar et al. (2015)
linoleic acid
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
A. alpina
Falchero et al. (2008)
stearic acid
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
12
Table 5
(continued )
Compound
Alchemilla
species
References
2001). Other triterpenes that have been isolated from lady mantle spe-
cies are betulinic acid and arjungenin (Jela
ˇ
ca et al., 2022; Soko-
łowska-Wo´zniak and Krzaczek, 1993). A. sericata Rchb. Ex Buser and A.
A. vulgaris
Ahmed and Zhang
(2019)
tricosane
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
A. persica
Afshar et al. (2015)
tetracosane
A. phegophila
Dubel et al. (2022)
A. persica
Afshar et al. (2015)
pentacosane
А. flabellata
Dubel et al. (2022)
A. persica
Afshar et al. (2015)
heptacosane
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
A. persica
Afshar et al. (2015)
squalene
А. flabellata
Dubel et al. (2022)
A. phegophila
A. subrenata
nonacosane
A. phegophila
A. subrenata
docosane
A. persica
Afshar et al. (2015)
1,27-octacosadiene
A. phegophila
Dubel et al. (2022)
A. subrenata
triacontanol
А. flabellata
A. phegophila
A. subrenata
tritriacontanol
А. flabellata
A. phegophila
A. subrenata
camphor
A. vulgaris
Ahmed and Zhang
(2019)
octanal
A. alpina
Falchero et al. (2008)
vulgaris are sources of fatty acids, while sterols were found in A. caucasia
Buser and A. pastoralis Buser (Sezen Karaog
˘
lan and Yılmaz, 2018; Sha-
faghat et al., 2017). Furthermore, the benzopyrone derivatives esculetin
and aesculetin were identified in A. speciosa Buser and A. vulgaris,
respectively (Borges et al., 2005; Juri
´
c et al., 2020).
7.
Phytochemical standardization and quality control of the
extracts from
alchemilla
L
The quality of the herbal medicinal products, which are consumed by
humans is principal since they are used for the well-being of humankind.
There are guidelines for the quality control and standardization of the
herbal medicines. Moreover, as in the recent times is a growing
requirement for traditional herbal-based products, there is a necessity to
provide their quality control (Balekundri and Mannur, 2020). The WHO
set guidelines about quality control methods for medicinal plant mate-
rials based on organoleptic properties, ash values, moisture content,
microbial contamination, and chromatographic and spectroscopic pa-
rameters (Kamble et al., 2018). The qualitative estimation of the herbal
products is carried out mostly by UV, IR and TLC techniques, while the
quantitative examination based on HP-TLC, HPLC, SFC, LC-MS or
GC-MS methods (Balekundri and Mannur, 2020). The qualitative and
quantitative evaluations are crucial to determine the authenticity of
specific species as well as identify the false one. For example, Karaoglan
and Yilmaz, contributed to the quality of the methanol extracts from
A. caucasica by GC-MS fingerprint implying content of the fourteen
1,3,3-trimethyl-2- oxabicyclo [2.2.2]
octane
1,2-dihydro-1,1,6-trimethyl-
naphthalene
germacrene
(E)-β-Damascenone
A. vulgaris
Ahmed and Zhang
(2019)
A. persica
Afshar et al. (2015)
phytocomponents (Karaoglan and Yilmaz, 2018). The aqueous ethanolic
extracts from leaves of A. hirtipedicellata, A. procerrima, A. sericata, and
A. stricta were standardized using TLC and HPLC techniques (Kaya et al.,
2012b). The most valuable from the pharmacological point of view
seems to be Alchemilla vulgaris. According to Polish Pharmacopoeia XII
1-octen-3-ol
A. alpina
Falchero et al. (2008)
myrcene
perilla alcohol
apiole
Alchemilla herbs should be standardized for tannins content (no less
than 6 %) in conversion to pyrogallol (dry substance) (Farmakopea
Polska, 2020). Furthermore, Kova
ˇ
c and co-workers perfected of deep
eutectic solvent extraction of A. vulgaris for gallic acid and total tannins
contents (Kovaˇc et al., 2022). Also, to investigate A. mollis and A. persica
chemical composition have been used HPLC analysis with some stan-
dards (hyperoside, isoquercitrin) (Küpeli Akkol et al., 2015).
Fig. 4.
Structures of other compounds found in Alchemilla species; A -
β
-sitosterol, B - stigmasterol, C - esculetin, D - ursolic acid, E
-
oleanolic acid, F - arjungenin.
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
13
Table 6
Other compounds found in Alchemilla species.
Compounds
Alchemilla
species
Fatty acids and related compounds
References
8.1.
In vitro assays
8.1.1.
Antioxidant activity
One of the best-shown assets of plant extracts with high phenols
content is their potential antioxidant activity. Excess free radicals can
9-hexadecenoic acid, methyl
ester
hexadecanoic acid, methyl ester
9-octadecenoic acid(z), methyl
ester
heptadecanoic acid, methyl
ester
1,2-benzenedicarboxylic acid,
butylmethyl ester
9,12-octadecadienoic acid (z, z)-
, methyl ester
octadecanoic acid, methyl ester
11-eicosenoic acid, methyl ester
docosanoic acid, methyl ester
bis (2-ethylhexyl) phthalate
A. sericata
Shafaghat et al. (2017)
cause oxidative stress in normal cells, leading to an increase in patho-
logical processes (Mainka et al., 2021). Due to the fact that preparations
from Alchemilla species contain a broad spectrum of polyphenols (fla-
vonoids, tannins, phenolic acids), a considerable number of studies have
reported that they can be used as antioxidants. Most references mention
an antiradical effect using DPPH and ABTS tests, chiefly extracts of
A. vulgaris, A. mollis, A. persica and A. alpina and their fractions (Table 7).
Additionally, a wide range of solvents for raw material extraction has
been used, e.g., ethanol (10%–96%) (Nedyalkov et al., 2015), methanol
(70%–100%) (Boroja et al., 2018), water (Karatoprak et al., 2018) and a
mixture of ethanol and glycerine (Dzabijeva et al., 2018). The efficacy of
individual extracts is given in Table 7, expressed as Trolox equivalents,
percent inhibition or IC
50
values. The most active extracts in the
DPPH
linoleic acid ethyl ester
A. vulgaris
Ahmed and Zhang (2019)
Sterols
β
-sitosterol
A. caucasia
Sezen Karaog
˘
lan and Yılmaz
(2018)
acetates
β
-sitosterol
A. pastoralis
Sokołowska-Wo
´
zniak and
test seem to be ethanolic extracts of the roots (495.38
±
19.32 mmol
TE/g dry mass) rather than the aerial parts (366.55
±
12.62 mmol TE/g
dry mass), which is presumably associated with the higher content of
tannins (Sapko et al., 2016). Moreover, Nedyalkov et al. using the ABTS
assay, indicated that a fresh extract is a better antiradical agent than the
stigmasterol
ergosterol
Coumarins
Krzaczek
(1993)
preparation after 20 days of storage (Nedyalkov et al., 2015). The
abovementioned methods of testing antiradical properties used spec-
esculetin
A. speciosa
(Borges et al., 2005; Schimmer
and Eschelbach, 1997)
aesculetin
A. vulgaris
Juri
´
c et al. (2020)
Stilbenes
resveratrol
A. vulgaris
El-Hadidy et al. (2018)
Triterpens
ursolic acid
A. faero
¨
ensis
Olafsdottir et al. (2001)
A. alpina
A. vulgaris
2
α
-hydroxyursolic acid
A. faero
¨
ensis
Olafsdottir et al. (2001)
A. alpina
A. vulgaris
trophotometric measurements; however, the ORAC assay measures a
fluorescence signal from a probe that is quenched in the presence of
reactive oxygen species (ROS). Extracts of A. glabra were found to have
an activity of 1337
±
68
μ
mol TE/g (Denev et al., 2014). Another
valuable mechanism involved in antioxidant pathways is the reducing
power of ions (Jakimiuk et al., 2022a). To this end, FRAP and CUPRAC
assays have been performed. In one of these studies, Vlaisavljevi
´
c et al.
evaluated reducing ion potential of 80% methanol (MeOH), 70%
ethanol (EtOH), ethyl acetate (EtOAc) and water extracts of A. vulgaris,
and their activity followed the order of EtOAc
>
80% MeOH
>
70% EtOH
2
α
,19
α
- dihydroxyursolic acid
(tormentic acid)
2
α
,3
α
,19
α
-trihydroxyurs-12-en-
28-oic acid (euscophic acid)
A. faero
¨
ensis
Olafsdottir et al. (2001)
A. alpina
A. vulgaris
A. faero
¨
ensis
Olafsdottir et al. (2001)
A. alpina
A. vulgaris
>
water (Vlaisavljevi
´
c et al., 2019). Although the determination of
β
-carotene-linolenic acid is a common method by which antioxidant
activity can be assessed, there are many difficulties when obtaining
reliable results (low reproducibility, problematic quantification, com-
plex preparation of reagents, temperature interference, and pH) (Prieto
oleanolic acid
A. faero
¨
ensis
Olafsdottir et al. (2001)
A. alpina
A. vulgaris
A. pastoralis
Sokołowska-Wo
´
zniak and
Krzaczek
(1993)
betulinic acid
A. pastoralis
Sokołowska-Wo
´
zniak and
Krzaczek (1993)
arjungenin
A. vulgaris
Jela
´
ca et al. (2022)
8.
Pharmacological profile
Lady’s mantle plants are perennials with a confirmed, diverse spec-
trum of biological activities. The pharmacological effects of Alchemilla
plants are similar to those of several other tannin- and flavonoid-
containing herbs of the Rosaceae family (van Wyk and Wink, 2017).
They possess a broad spectrum of pharmacological features, confirmed
in both in vitro and in vivo studies, such as antioxidant,
anti-inflammatory (Stephens et al., 2013), neuroprotective
(Vlaisavljevi
´
c et al., 2019), antimicrobial (Makau, 2013), antiobesity
(Mladenova et al., 2021), cardiovascular (Pawlaczyk-Graja et al., 2009),
anticancer (Trouillas et al., 2003) and wound healing (Tasi
´
c-Kostov
et al., 2019) activities. All of the pharmacological effects of Alchemilla
species are summarized in Tables 7 and 8.
et al., 2012). Notably, only one study mentioned this type of activity
from A. vulgaris extracts, pointing out their dose-dependent activity
(Tasi
´
c-Kostov et al., 2019). Additionally, the preliminary TLC-DPPH
screening method indicated the presence of antioxidant compounds in
n-hexane, chloroform, ethyl acetate, methanol, and water extracts
(Ondrejovi
ˇ
c et al., 2009). Said and co-workers tested antioxidant profile
of tablets that contained A. vulgaris extract by measuring the lipid per-
oxidation induced by incubating the rat liver homogenate with ferro-
sulfate. They found out that even an incredibly low dosage (10
μ
g/mL)
reduced MDA release to 0.53 nM/mg (from 0.89 nM/mg) (Said et al.,
2011). To analyse NO
•
scavenging activity of A. mollis, as well as
detected in this extract hyperoside and isoquercitrin, K562 cell line has
been used. At the dosage from 62.5 to 3000
μ
g/mL A. mollis methanolic
extracts exhibited dose dependent inhibition of nitrite levels (Aslı et al.,
2022). A broad discussion of the antioxidant potential of Alchemilla was
presented by Kanak et al. (2022).
8.1.2.
Anti-inflammatory activity
Inflammation plays a crucial role in the development of various
diseases, and since ancient times, inflammatory disorders have been
cured with plants or plant-based products (Mueller et al., 2010). Addi-
tionally, research on three Alchemilla species (A. vulgaris, A. persica, and
A. mollis) as anti-inflammatory agents has been performed (Table 7).
Kurtul et al. used the human red blood cell (HRBC) test, which utilizes
fresh human whole blood collected from healthy individuals who had
not taken any anti-inflammatory or steroidal drugs for 14 days before
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
14
the study. Sample activity was determined by measuring its stabilization
capacity against heat-induced hemolysis of the HRBC membrane. The
extracts (A. mollis and A. persica, 80% methanol) significantly protected
the HRBC membranes from hemolysis compared to the standard drug
acetylsalicylic acid. The A. mollis aerial part extract (IC
50
=
1.22
±
0.07
mg/mL) showed an elevated HRBC membrane stabilizing effect, while
A. persica root extract displayed the lowest activity (IC
50
=
1.82
±
0.14
mg/mL). Furthermore, after multistep separation process, the authors
isolated ellagic acid and miquelianin from A. mollis. They found out that
miquelianin possess similar activity to A. mollis (IC
50
=
1.23
±
0.02
mg/mL) extracts while ellagic acid is much more effective
anti-inflammatory agent (IC
50
=
0.57
±
0.01 mg/mL). Thus, these re-
sults can be attributed to the higher tannin content, especially ellagic
acid (Kurtul et al., 2022). The water and 70% ethanol extracts of
A. vulgaris were investigated as potential products involved in the in-
flammatory response. The loss of soybean 15-lipoxygenase activity in
the presence of the plant water extract was measured. The results are
expressed as the IC
50
value (0.52 mg/mL), which proves the high
inhibitory activity of the transformation of arachidonic acid metabolites
(Trouillas et al., 2003). Furthermore, a 70% ethanol A. vulgaris extract
decreased LPS-induced IL-8 release and inhibited stimulation of the
TLR2 and TLR4 signaling pathways. On the other hand, this extract was
not effective against NF-κB p65 translocation (Schink et al., 2018).
8.1.3.
Antimicrobial activity
The increasing number of drug-resistant pathogens creates an urgent
need to identify plant-derived therapeutics that can provide alternatives
to combat pathogenic bacteria (Vaou et al., 2021). An antimicrobial
review of the Alchemilla literature revealed a broad spectrum of research
activity in this field. Among 16 available publications, most found
antimicrobial potential using agar well diffusion or broth microdilution
methods (Table 7). A few investigations have compared many extracts
using methods that are directly comparable. For example, A. vulgaris
extracts (80% methanol, ethanol, and 50% ethanol/6% glycerine) in the
agar well diffusion assay displayed dose-dependent activity against
selected bacteria (Edrah, 2017; Ibrahim et al., 2022; Keskin et al., 2010;
Usta et al., 2014). Comparing the activities of the A. vulgaris methanolic
and the A. sericata hexane extracts, it was noticed that the inhibition
zones for Staphylococcus epidermidis (12 mm and 11.1 mm, respectively)
and Pseudomonas aeruginosa (11 mm and 10.1, respectively) were
similar, while the ethanol extract possesses weaker inhibitory activity (7
mm) than the hexane extract (12.2 mm) against Staphylococcus aureus.
(Ibrahim et al., 2022; Shafaghat et al., 2017). Quantitative analysis of
the components of A. vulgaris methanolic root extract showed high sal-
icylic and ellagic acids content, as well as quercetin and catechin con-
tents. Synergic action of detected compounds may have crucial role in
the antibacterial activity of the Alchemilla plants (Ibrahim et al., 2022).
On the other hand, A. mollis alcoholic and water extracts did not exhibit
activity against S. aureus (Usta et al., 2014). The effectiveness of me-
dicinal plant extracts to inhibit bacterial growth may also be expressed
as the minimum inhibitory concentration (MIC). To this end, A. mollis
and A. persica 80% methanol extracts were tested employing the
microdilution method against S. aureus, Enterococcus faecalis, Bacillus
subtilis, Escherichia coli and P. aeruginosa. The results showed that both
the aerial parts and roots of A. persica, tested with serial twofold di-
lutions ranging from 10 to 0.078 mg/mL, displayed activity superior to
that of A. mollis (Kurtul et al., 2022). Moreover, data obtained from
A. vulgaris analyses indicated only slight differences between the inhi-
bition of bacterial growth exhibited by its aboveground parts and root
methanolic extract (40 mg/mL) (Boroja et al., 2018). Said and co-
workers conducted a study to evaluate the efficacy of a topical cream
(HPC) consisting of water-ethanol extracts of the combination of Nigella
sativa, A. vulgaris and Conyza canadensis (1:0.6:0.6 w/w) in vitro. In this
study, the disc diffusion method with E. coli was used with HPC con-
centrations of 1, 2 and 5 mg/disc. The plant-based formulation showed
dose-dependent antibacterial activity, expressed as 60% inhibition, in
comparison to the reference antibiotic ampicillin at 5 mg/disc (Said
et al., 2022).
8.1.4.
Cardiovascular activity
Cardiovascular diseases involve the cardiovascular system, which
comprises the heart and veins, and are known as the most frequent
causes of death worldwide (Michel et al., 2020). Bearing in mind that
plants are widely used for the treatment of hypertension, Radovi
´
c et al.
hypothesized that methanol extracts of A. viridiflora may be angiotensin
I-converting enzyme (ACE) inhibitors. The enzymatic assay showed that
the inhibitory activity of A. viridiflora (IC
50
value) was 2.51
±
0.00
μ
g/mL. The authors pointing out that this activity is highly probable
connected with the tiliroside, tellimagrandin I, galloyl-HHDP and ellagic
acid pentose contents (Radovi
´
c et al., 2022). To investigate the vascular
effects of methanol extract and aqueous extract of A. vulgaris (0.01–10
mg/mL) isolated rat aorta has been used. Interestingly, methanol and
aqueous extracts of A. vulgaris displayed opposite vascular effects. After
administration of an aqueous extract the contraction of the rings has
been increased, while methanol extract caused their relaxation (Takir
et al., 2014).
8.1.5.
Neuroprotective activity
Herbrechter and coauthors investigated the effect of 158 herbal
remedies, including A. xanthochlora, on human TRPV1 and the two-pore
domain potassium channels KCNK2, KCNK3 and KCNK9. They proved
that the ethanol extract of the aerial parts of this plant is a positive
modulator of the TRPV1 channel. TRPV1 is a pain detector for noxious
heat and has been a target in the development of pain reducers (Her-
brechter et al., 2020).
8.1.6.
Anticancer activity
Numerous phytochemicals have been identified as potential candi-
dates that can block or slow the growth of cancer cells with a lack of side
effects (Iqbal et al., 2017). Previous studies have implied that herbs with
antioxidant and anti-inflammatory potential, especially phenolic-rich
plants, inhibit tumor promotion and cell proliferation (Huang et al.,
1994). On several occasions, the anticancer characteristics of Alchemilla
extracts have been investigated (Table 7). The abovementioned studies
mainly involve MTT and sulforhodamine B (SRB) assays. An SRB
colorimetric assay for cytotoxicity screening was used to investigate
A. mollis extracts against the breast cancer cell line MCF-7. Karatoprak
et al. claimed that the water and deionized water extracts of A. mollis
inhibit the viability of cells by 70% at 125
μ
g/mL and may contain
cytotoxic agents for medical use (Karatoprak et al., 2018). Notably, the
MTT assay is more commonly used to determine the viability of cancer
cells (Strawa et al., 2022). Using the MTT assay, Ibrahim and coworkers
revealed that the A. vulgaris 80% MeOH extract displays moderate
cytotoxic activity against MCF-7 (IC
50
=
92.25
μ
g/mL), PC-3 (IC
50
=
88.60
μ
g/mL) and Caco-2 (IC
50
=
110.51
μ
g/mL) cancer cell lines
(Ibrahim et al., 2022). Additionally, the hexane and chloroform frac-
tions of A. vulgaris in a polyherbal formula (PHF6) containing Cichorium
pumilum, Crataegus azarolus, Eruca sativa, Ferula hermonis, and Hypericum
triquetrifolium extracts were investigated against the MDA MB-231 and
MCF-7 cell lines. PHF6 decreases the viability of cancer cells, causes
significant LDH release and induces apoptosis in both MDA MB-231 and
MCF-7 cells (Al-Zharani and Abutaha, 2023). In addition, Vlaisavljevi
´
c
et al. studied the viability of A2780, HeLa, MCF-7, and PC-3 cells via CV
and MTT assays. According to the obtained results, the 70% ethyl ace-
tate fraction possessed the strongest toxicity to HeLa, MCF-7, and PC-3
cells, while the 80% methanol fraction had the strongest toxicity to
A2780 cells (Vlaisavljevi
´
c et al., 2019). Among 16 water plant extracts
investigated by Trouillas et al., A. vulgaris seems to be one of the most
potent anticancer extracts against the melanoma cell line B16. The
antiproliferative effect ranged from 15% to 60% at concentrations of
0.0125–0.1 mg/mL (Trouillas et al., 2003). In addition to A. vulgaris, the
A. mollis methanolic extract and A. smirnovii 96% ethanolic extract were
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
15
tested in MTT assays using the K562 and A549 cell lines, respectively.
The methanol extract of A. mollis decreased cell viability at a concen-
tration of
>
0.02 mg/mL, while the A. smirnovi ethanol extract exhibited
a strong cytotoxic effect at the lowest concentration used, 0.125 mg
DW/mL (Aslı et al., 2022; Ginovyan et al., 2022). Immunocytochemical
staining via the caspase-3 method was used to determine the apoptotic
effect in HeLa cells using A. erythropoda, A. ikizdereensis, A. oriturcica,
and A. trabzonica extracts. The lowest apoptotic activity at the highest
tested concentration (200
μ
g/mL) was found with A. oriturcica (14%),
while the strongest effect was found with A. trabzonica (24%) (Türk
et al., 2011).
8.1.7.
Anti-overweight activity
Because obesity has become a civilization disease, Mladenova and
coworkers attempted to translate traditional knowledge into modern
therapeutic applications (Table 7). Therefore, they hypothesized that
the A. monticola water-methanol extract had anti-adipogenic potential.
The results of the in vitro analysis showed that the expression of the
adipogenic genes CCAAT/enhancer-binding protein alpha (CEBPA) and
PPARG was downregulated upon treatment with the plant product.
Furthermore, the obtained nuclear magnetic resonance (NMR) based
metabolomics data showed that the most abundant signals corresponded
to kaempferol 3-O-glucoside and quercetin 3-O-rhamnoside, implying
their responsibility for pharmacological activity of prepared extracts
(Mladenova et al., 2021).
8.1.8.
Enzyme inhibitory activity
Enzyme inhibitory factors seem to be attractive because of their
application in curing various diseases. The secondary metabolites of
plants may be enzyme inhibitors that block their activity and can destroy
a pathogen or restore metabolic imbalances (Omar et al., 2023). For
example, the 80% methanol, 70% ethanol, 70% ethyl acetate and water
extracts of A. vulgaris were studied as potential amylase, acetylcholin-
esterase and butyrylcholinesterase inhibitors (Table 7). Based on the
obtained results, the 70% ethanol extract possessed the highest
anti-acetylcholinesterase potential (5.14 mg GALE per g of extract), and
the 80% methanol extract maintained the most potent butyr-
ylcholinesterase inhibition (9.59 mg GALE per g of extract), while the
extracts that acted as amylase inhibitors ranged from highest to lowest
activity as follows: water
>
70% ethanol
>
80% methanol
>
ethyl ace-
tate. The extracts with the highest content of gallic acid, caffeic acid,
catechin and quercetin also display the highest activity
(Vlaisavljevi
´
c
et al., 2019). Additionally, lady mantle herbs may be attractive targets
for cosmeceutical research due to their inhibition of tyrosinase activity.
The available research points out the strong activity of the 70% ethanol
extract of A. vulgaris with 71.55
±
4.39% inhibition of tyrosinase at 3
mg/mL (Neagu et al., 2015). The bioassay-guided fractionation of the
water-methanolic extract of A. vulgaris led to the identification and
isolation of flavonoids with collagenase inhibitory activity (Mandrone
et al., 2018).
8.1.9.
Wound healing activity
Ethnopharmacological studies have suggested that A. vulgaris,
A. mollis and A. hessii possess wound healing properties (Kaval et al.,
2014; Parthasarathy and Prince, 2021). Additionally, lady’s mantle
species exhibit a broad spectrum of antiradical characteristics, and it has
been proven that wound-healing properties and antioxidant activity
coexist in many plant species (Süntar et al., 2012). Thus, Tasi
´
c-Kostov
and coworkers performed a scratch test, which revealed the wound
healing effects of the 70% ethanol, 80% propylene glycol and water
extracts of A. vulgaris. The most beneficial effect on wound healing was
observed with hydrogels of the propylene glycol extract at 250
μ
g/mL.
Likewise, the ethanolic extract (at 50
μ
g/mL) displayed activity on
fibroblast migration and the extent of wound closure (Tasi
´
c-Kostov
et al., 2019). On the other hand, Shrivastava et al. demonstrated wound
healing activity of the 1% A. vulgaris hydroglycerinated fluid extract
using the Chang liver and Madin–Darby bovine kidney (MDBK)
epithelial cell lines and myofibroblasts, attaining 21.3%, 10.6% and
15.5% increases in the cell numbers, respectively (Shrivastava et al.,
2007).
8.2.
In vivo assays
An in-depth overview of the literature concerning the in vivo activity
of Alchemilla plants includes to 22 different studies, describing anti-
convulsant, hormone regulation, anti-overweight, neuroprotective,
antitoxic, hepatoprotective, gastroprotective, wound healing, antiaging,
anti-inflammatory, cardiovascular activities as well as healing activity in
female diseases (Table 8).
8.2.1.
Anticonvulsant activity
According to a Ngoupaye study from 2022, scientists reported the
anticonvulsant effect of the A. kiwuensis water extract. In this study,
acute epileptic seizures were provoked in mice aged 2.5–3 months with
pentylenetetrazole (PTZ), picrotoxin (PIC) and strychnine (STR). For
this test, animals of both sexes were randomly distributed into 5 groups,
where group 1 received distilled water, group 2 received clonazepam (as
a positive control) and groups 3, 4, and 5 received 20.63 mg/kg, 41.25
mg/kg, and 82.5 mg/kg plant extract, respectively. One hour after the
oral administration of various therapeutics, clonic seizures were
induced. Factors estimated in this investigation were protection against
seizures and seizure onset time. Mice that did not convulse after 10 or
15 min of observation were classified as protected. The results showed
that after PTZ-induced seizures, mice were protected by administrating
82.5 and 41.25 mg/kg A. kiwuensis with efficacies of 71% and 86%,
respectively. The plant extract protected against seizures at a dose of
82.5 mg/kg and had 57.17% activity after PIC-induced convulsions. On
the other hand, the plant extract did not have an effect on STR-induced
seizures, including death. Furthermore, A. kiwuensis extract at a dose of
5000 mg/kg was declared nontoxic (Ngoupaye et al., 2022).
8.2.2.
Hormone regulation activity
In another study, scientists surveyed the effects of polyphenol com-
pounds from a. vulgaris on the morpho-functional state of the thyroid
gland in rats exposed to low temperatures. Two weeks of treatment with
water herb extract (10 mg/kg/day) resulted reduced T4 levels in the
blood and an increased deiodination ratio. Additionally, the contents of
thyroid hormones and thyroglobulin in the thyroid gland (TG) increased
compared to the baseline values (Borodin et al., 1999).
8.2.3.
Anti-overweight activity
A formulation containing 60 mg of A. vulgaris leaves, 50 mg of Olea
europaea leaves, 20 mg of Mentha longifolia leaves, 25 mg of Cuminum
cyminum seeds, 7 mg of vitamin C and 148 mg of tricalcium phosphate
was used as slimming pills (“Weightlevel”) in chickens and rats. The
antiobesity properties of weight level studies in chickens pointed out
that the group fed normal food enriched with 3% product extract weekly
displayed reduced weight (to 815
±
10 g) in the 4th week, where the
baseline body weight of the chickens was 1000
±
15 g. Notably, safety
analysis, defined by the LD
50
, in rats indicated toxicity at a high con-
centration of approximately 5 g/kg (Said et al., 2011).
8.2.4.
Healing activity in female diseases
Following ethnopharmacological reports on A. mollis and A. persica
used for women’s illnesses, Küpeli Akkol and coworkers evaluated the
treatment potential of 80% methanol extracts of both A. mollis and
A. persica in experimentally induced endometriosis in rats. In this study,
six-week-old female rats were surgically auto transplanted with endo-
metrial tissue into the abdominal wall. For this test, animals were
randomly divided into groups, one of which was the control group, the
second group took a reference drug (20 mg of Receptal®), and 100 mg/
kg extract doses were administered to the study groups. After the end of
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
16
Table 7
Bioactivities of Alchemilla species reported in vitro experimental models.
Activity
Tested material
Experimental model
Concentration used
Efficacy
References
Antioxidant
A. mollis
10–90%
ABTS
test
not given
96.61
±
1.54 to 308.44
±
6.74
mmol TE/dm
3
(for fresh extracts)
Nedyalkov et al.
(2015)
EtOH
extracts
and 27.10
±
0.22 to 212.40
±
2.24 mmol TE/dm
3
after 20 days
of storage
A. mollis
ABTS
test
not given
IC
50
=
7.8
μ
g/mL
Hwang et al.
50% EtOH extract
(2018)
A. vulgaris
ABTS
test
not given
4.79
±
0.14 mM TEAC
Kiselova et al.
H
2
O extract
(2006)
A. vulgaris MeOH
ABTS
test
not given
IC
50
(
μ
g/mL):
Boroja et al.
extracts
Aerial parts: 14.80
±
2.15
(2018)
Roots: 32.49
±
1.95
A. vulgaris 80% MeOH
ABTS
test
not given
MeOH: 143.55
±
3.65
Vlaisavljevi
´
c
70% EtOH 70% EtOAc,
EtOH: 119.62
±
3.20
et al. (2019)
H
2
O extracts
EtOAc: 174.05
±
0.90
H
2
O: 37.50
±
0.39 mg TE per g
extract
A. vulgaris
ABTS
test
plant material–solvent ratio of
roots: 495.38
±
19.32
Sapko et al.
70% EtOH extract
1/50 (g/v)
aerial parts: 366.55
±
12.62
(2016)
mmol TE/g of dry mass
DPPH
test
plant material–solvent ratio of
roots: 1535.5
±
72.15
Sapko et al.
1/50 (m/v)
aerial parts: 841.84
±
36.41
(2016)
mmol TE/g of dry mass
A. alpina
DPPH
test
1.25, 2.5, 5, 10 mg/mL
Percent of inhibition (%):
(I
˙
nci et al.,
96% MeOH, EtOH and
1.25 mg/mL - 45.4
±
0.440
2021)
ChCl
3
extracts
2.5 mg/mL - 67.8
±
0.978
5 mg/mL - 84.8
±
1.348
10 mg/mL - 94.4
±
1.301
A. mollis
DPPH
test
not given
IC
50
=
42.4
μ
g/mL
Hwang et al.
50% EtOH extract
(2018)
A. sericata hexane
DPPH
test
not given
IC
50
=
185
μ
g/mL
Shafaghat et al.
extract
(2017)
A. smirnovii 96% EtOH
DPPH
test
not given
dose-dependent antiradical
Ginovyan et al.
extract
activity
(2022)
A. mollis
DPPH
test
not given
IC
50
(
μ
g/mL):
Trendafilova
MeOH, EtOAc, ChCl
3
CHCl
3
>
200
et al. (2011)
extracts
EtOAc - 9.8
±
1.8
MeOH - 31.7
±
4.9
A. mollis
10–90%
DPPH
test
not given
76.17
±
1.53 to 247.58
±
2.26
mmol TE/dm
3
(for fresh extracts)
Nedyalkov et al.
(2015)
EtOH
extracts
and 21.50
±
0.10 to 97.53
±
0.59 mmol TE/dm
3
after 20 days
of storage
A. vulgaris
DPPH
test
H
2
O: 10–160
μ
g/mL, 70%
IC
50
(
μ
g/mL):
Tasi
´
c-
Kostov
70% EtOH (AE), 80%
EtOH: 0.1–80
μ
g/mL, 80%
AE: 0.11
±
0.07
et al. (2019)
propylene (AP) glycol,
propylene glycol: 0.5–20
μ
L/
AW: 27.22
±
1.14
H
2
O extracts (AW)
mL
AP: 2.88
±
0.21
A. vulgaris MeOH
DPPH
test
serial dilutions: started from
IC
50
(
μ
g/mL):
Boroja et al.
extracts
0.25 mg/mL
Aerial parts: 5.96
±
0.21
(2018)
Roots: 11.86
±
0.56
A. vulgaris
DPPH
test
not given
18.02
±
0.02
μ
g/gsr trolox
Jela
´
ca et al.
EtOH
extract
(2022)
A. persica
DPPH
test
1 to 0.015 mg/mL
root: IC
50
=
0.055 M
Ergene et al.
MeOH:H
2
O (8:2) extract
aerial parts: IC
50
=
0.151 M
(2010)
A. vulgaris
DPPH
test
not given
TLC: white colored bands on
Simion et al.
purple background
(2018)
A. vulgaris
DPPH
test
not given
IC
50
=
0.09 mg/mL
Trouillas et al.
H
2
O extract
(2003)
A. vulgaris
0.02 g/mL
no clear data
Dimin¸
ˇ
s et al.
H
2
O extract
(2013)
A. vulgaris 50% EtOH/
DPPH
test
plant material–solvent ratio of
IC
50
=
0.2 mg/mL
Dzabijeva et al.
6% glycerin solution
1/10 (m/v)
(2018)
A. vulgaris hexane and
DPPH
test
1 mg/mL of polyherbal
hexane: 35.1%
±
0.01
Al-Zharani and
ChCl
3
extracts
formula (PHF6): A. vulgaris, C.
ChCl
3
: 36.9%
±
0.006
Abutaha
(2023)
pumilum, C. azarolus, E. sativa,
F. hermonis, and H.
triquetrifolium
A. vulgaris
DPPH
test
20–100
μ
g/mL
IC
50
: 66.71% (EtOAc) and
Shilpee et al.
EtOAc and MeOH
23.47% (MeOH)
(2021)
extracts
A. vulgaris
DPPH
test
not given
EtOH extracts: 87.95% (at 3 mg/
(Neagu et al.,
10% mass H
2
O and 10%
mL) and 80.71% ( at 1.5 mg/mL)
2015)
mass 70% EtOH extracts
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 7
(continued )
17
Activity
Tested material
Experimental model
Concentration used
Efficacy
References
A. jvuumlgraurkisczalica,
DPPH
test
not given
IC
50
: 19.692
μ
g/mL
Nikolova et al.
80% MeOH extract
(2011)
A. mollis H
2
O (WE),
DPPH
test
not given
IC
50
(mg/mL):
Karatoprak
deodorized H
2
O (DWE),
WE: 0.264
±
0.028
et al. (2018)
50 % MeOH (ME)
DWE: 0.146
±
0.015
extracts
ME: 0.161
±
0.018
A. vulgaris 80% MeOH
DPPH
test
not given
MeOH: 153.30
±
0.013
Vlaisavljevi
´
c
70% EtOH 70% EtOAc,
EtOH: 95.99
±
0.005
et al. (2019)
H
2
O extracts
EtOAc: 502.56
±
0.01
H
2
O: 89.25
±
0.02 mg TE per g
extract
CUPRAC
test
not given
MeOH: 216.14
±
6.86
Vlaisavljevi
´
c
EtOH: 203.53
±
9.29
et al. (2019)
EtOAc: 283.16
±
12.36
H
2
O: 78.56
±
0.26 mg TE per g
extract
A. mollis
10–90%
CUPRAC
test
not given
125.10
±
0.48 to 363.79
±
0.74
mmol TE/dm
3
(for fresh extracts)
Nedyalkov et al.
(2015)
EtOH
extracts
and from 79.72
±
1.12 to 226.52
±
1.22 mmol TE/dm
3
after 20
days of storage
A. mollis
10–90%
FRAP
test
not given
214.16
±
1.58 to 382.78
±
1.16
mmol TE/dm
3
(for fresh extracts)
Nedyalkov et al.
(2015)
EtOH
extracts
and 67.91
±
0.31 to 275.55
±
0.96 mmol TE/dm
3
after 20 days
of storage
A. vulgaris
FRAP
test
not given
H
2
O extract: above 1.5
Neagu et al.
10% mass H
2
O and 10%
EtOH extract: above 1.7
(2015)
mass 70% EtOH extracts
A. vulgaris MeOH
FRAP
test
not given
Aerial parts: 632.99
±
10.26
Boroja et al.
extracts
Roots: 607.52
±
10.01 mg
(2018)
Trolox/g of extract
A. vulgaris
FRAP
test
plant material–solvent ratio of
roots: 988.92
±
49.76
Sapko et al.
70% EtOH extract
1/50 (g/v)
aerial parts: 963.17
±
43.00
mmol Fe
2
+
/g of dry mass
(2016)
A. vulgaris 80% MeOH
FRAP
test
not given
MeOH: 7899.45
±
0.49
Vlaisavljevi
´
c
70% EtOH 70% EtOAc,
EtOH: 6405.75
±
0.08
et al. (2019)
H
2
O extracts
EtOAc: 8745.31
±
0.04
H
2
O: 3240.09
±
0.08 mg EAA per
g of extract
metal chelating
not given
MeOH: 42.58
±
0.26
Vlaisavljevi
´
c
EtOH: 42.32
±
0.05
et al. (2019)
EtOAc: 37.96
±
1.29
H
2
O: 39.23
±
0.32 mg EDTAE per
g extract
A. vulgaris 80% MeOH
phosphomolybdenum assay
not given
MeOH: 1.77
±
0.01
Vlaisavljevi
´
c
70% EtOH 70% EtOAc,
EtOH: 1.57
±
0.02
et al. (2019)
H
2
O extracts
EtOAc: 2.22
±
0.07
H
2
O: 0.53
±
0.03 mg TE per g
extract
A. vulgaris MeOH
phosphomolybdenum assay
not given
Aerial parts: 265.62
±
12.10
Boroja et al.
extracts
Roots: 316.47
±
18.71 mg AA/g
(2018)
of extract
A. vulgaris
fenton reaction
10 mM
IC
50
=
0.18 mg/mL
Trouillas et al.
H
2
O extract
(2003)
A. vulgaris
superoxide radical scavenging test
not given
IC
50
=
0.95 mg/mL
Trouillas et al.
H
2
O extract
(2003)
A. vulgaris
rat liver homogenates
tablet contained 60 mg A.
10
μ
g/mL of product reduces
Said et al.
vulgaris L., 50 mg O. europaea
MDA release from 0.89
±
0.05 to
(2011)
L., 20 mg M. longiforia L., 25
0.53
±
0.03 nM/mg protein, at
mg C. cyminum L., 7 mg
50
μ
g/mL to 0.28
±
0.03 nM/mg
vitamin C and 148 mg
protein
tricalcium phosphate
A. mollis
SNP induced NO
•
production
62.5, 125, 250, 500, 1000,
significant dose dependent
Aslı et al. (2022)
MeOH
extract
3000
μ
g/mL
inhibition of nitrite levels
A. glabra
ORAC
assay
not given
1337
±
68
μ
mol TE/g
Denev et al.
HORAC
assay
1999
±
70
μ
mol TE/g
(2014)
TRAP assay
1815
±
38
μ
mol GAE/g
A. persica
TBARS
assay
not given
MDA level (nmol/mL): aerial
Ergene et al.
MeOH: H
2
O (8:2)
parts: 5.9, roots: 19.08
(2010)
extract
A. vulgaris
β
-carotene–linoleic acid assay
12.5–200
μ
g/mL
Dose dependent activity:
Tasi
´
c-
Kostov
70% EtOH, 80%
70 % EtOH: 60.20
±
1.74–69.86
et al. (2019)
propylene glycol, H
2
O
±
0.67 %
extracts
H
2
O: 68.08
±
0.44–78.95
±
1.13
%
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 7
(continued )
18
Activity
Tested material
Experimental model
Concentration used
Efficacy
References
80% propylene glycol: 65.33
±
0.29–79.57
±
0.96 %
Neuroprotective
A. xanthochlora
Xenopus laevis oocytes, TASK-1 and
0.2 g/mL
positive modulators of the
Herbrechter
EtOH
extract
TASK-3 channels
channels
et al. (2020)
Anti-
inflammatory
A. vulgaris
H
2
O extract
A. vulgaris
15-LOX
THP-1 m onocytes and HeLa-TLR4
2, 1.25, 0.625 and 0.1 mg/mL
0.2 g/mL
IC
50
=
0.52 mg/mL
decrease of LPS-induced IL-8
Trouillas et al.
(2003)
Schink et al.
70% EtOH extract
transfected reporter cells
release, inhibitory effects on
(2018)
stimulated signaling pathways of
both TLR2 and TLR4, no effect on
NF-κB p65 translocation
A. mollis
MeOH: H2O (8:2)
HRBC
test
Stock solution: 20 mg of
extract/acetylsalicylic
acid
IC
50
(mg/mL):
Aerial parts: 1.22
±
0.07; Roots:
Kurtul et al.
(2022)
extracts
with 1 mL of their solvents
1.34
±
0.08.
A. persica
MeOH: H2O (8:2)
IC
50
(mg/mL):
Aerial parts: 1.52
±
0.09; Roots:
extracts
1.82
±
0.14.
Cardiovascular
HPC (N.sativa, A.
blood vessels from Sprague–Dawley
10 mg/mL
vasoconstriction effect on
Said et al.
vulgaris, C. canadensis,
male rats
intestinal vein rings (40%
(2022)
1:0.6:0.6
w/w)
increase compared to
phenylephrine)
A. vulgaris
isolated rat aorta
0.01–10 mg/mL
ME: concentration-dependent
Takir et al.
MeOH (ME) and H
2
O
(AE) extracts
relaxations in rat aortic rings;
AE: increased contractions in
(2014)
aortic rings.
10 mg/mL, 20 min
ME: reduced the maximal
contractility to NA and K
+
;
AE: increase contractions induced
by NA and K
+
A. viridiflora
MeOH
extract
angiotensin I-converting Enzyme
(ACE) Inhibitory Activity
0.0016–5.00 mg/mL
IC
50
=
2.51
±
0.00
μ
g/mL
Radovi
´
c et al.
(2022)
Antimicrobal
A. vulgaris
vaccinia and ectromelia viruses
12.5–200
μ
g/mL
neutralization index for: vaccinia
Filippova
EtOAc and EtOH
– 4.0 l g
(2017)
extracts
ectromelia - 3.5 l g
A. glabra, A. fissa, A.
Helicobacter pylori
not given
ranges of concentrations 4
μ
g/mL
Krivoku
´
ca et al.
viridiflora, A. monticol
for MeOH extracts of A. viridiflora,
(2015)
MeOH, CH
2
Cl
2
, C
6
H
6
extracts
A. glabra, A. monticola, and 256
μ
g/mL for C
6
H
6
extracts of
A. viridiflora, A. glabra, A. fissa.
The best overall activity possesses
A. monticola extracts
A. sericata hexane
agar diffusion test with: B. subtilis (Bs),
30
μ
L of the hexane extracts
Zone of inhibition (mm):
Shafaghat et al.
extract
S. epidermidis (Se), E. faecalis (Ef),
Bs: 12.9
±
0.15; Se: 11.1
±
0.11;
(2017)
S. aureus (Sa), K. p neumoniae (Kp),
Ef: NA; Sa: 12.2
±
0.14; Kp: 9.2
±
P. aeruginosa (Pa), E. coli (Ec), A. niger
0.21; Pa: 10.1
±
0.12; Ec: NA; An:
(An) C. albicans (Ca), S. cerevisiae (Sc)
10.7
±
0.21; Ca: 8.9
±
0.14;
Sc:10.1
±
0.11
A. vulgaris
microdilution method with: S. aureus
0.015–2 mg/mL
MIC, mg/mL: Sa
>
2; Pm
=
1; Ec
(Đukanovi
´
c
H
2
O: EtOH extracts
A. vulgaris MeOH: H
2
O
(8:2, v/v) extracts
(Sa), E. coli (Ec), P. mirabilis (Pm)
agar diffusion test with: S. marcescens
(Sm), A. johnsonii (Aj), A. tumefaciens
15.6–1000
μ
g/mL
= 1.
Inhibition zone (mm):
Sm: 6–10; Aj: 6–12.33; At: 6–11;
et al., 2021)
Ibrahim et al.
(2022)
(At), R. solani (Rs), P. italicum (Pi),
Rs: 7–8.23; Pi: 6.97–8.30; Fo:
F. oxysporium (Fo)
4.90–6.17;
Growth Inhibition (%):
Sm: 0 –83.33; Aj: 0–105.56; At:
0–83.33; Rs: 8.52–22.22; Pi:
7.97–22.59; Fo: 31.48–45.56;
A. vulgaris
disc diffusion method with: S. aureus
10 mg/mL,
Inhibition zone (mm): Ec: 10, Kp:
Edrah
(2017)
EtOH
extract
(Sa), S. epidermidis (Se), E. coli (Ec),
50
μ
L/disc
9, Pa: 11, Sa: 7, Se: 12, Ca: 15
K. pneumoniae (Kp), P. aeruginosa (Pa),
C. albicans (Ca)
A. mollis H
2
O (WE),
deodorized H
2
O (DWE),
50 % MeOH (ME)
agar dilution method with: S. aureus
(Sa), E. faecalis (Ef), E. coli (Ec),
P. aeruginosa (Pa), C. albicans (Ca),
0.1–10.0 mg/mL
MIC
(mg/mL):
Sa: 0.5 for WE, DWE, ME; Ec: 5.0
for WE, DWE; Pa: 2.0 for WE,
Karatoprak
et al. (2018)
extracts
K. pneumoniae (Kp)
DWE, ME
Ef: 5.0 for ME, 7.5 for DWE, WE;
Kp: .0 for ME, 7.5 for DWE, WE;
Ca: no activity
A. mollis
microdilution methods with: S. aureus
Serial two-fold dilutions
Aerial parts: (MIC, mg/mL): Sa
=
Kurtul et al.
MeOH: H2O (8:2)
(Sa), E. faecalis (Ef), B. subtilis (Bs),
ranging from 10 to 0.078 mg/
5; Ef
=
5; Pa
=
10; Roots: (MIC,
(2022)
extracts
E. coli (Ec), P. aeruginosa (Pa),
mL
mg/mL): Sa
=
5; Bs
=
10; Pa
=
10;
A. persica
C. albicans (Ca)
MIC (mg/mL): aerial parts: Sa
=
MeOH: H2O (8:2)
5; Ef
=
5; Pa
=
5; Ca
=
10; roots:
extracts
Sa = 5; Ef = 10; Bs = 2.5; Pa = 10;
Ca
=
10
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 7
(continued )
19
Activity
Tested material
Experimental model
Concentration used
Efficacy
References
A. rizeensis CHCl
3
and
H
2
O extracts
agar well diffusion and broth
microdilution methods with: E. coli
(Ec), B. catarrhalis (Bc), S. aureus (Sa),
not given
MIC (mg/mL): Bc
>
1000; Sa
=
0.312; Hp
>
1000; Tr
=
0.625
Buruk et al.
(2006)
B. subtilis (Bs), H. pylori (Hp),
C. albicans (Ca) T. rubrum (Tr)
A. pedata
agar well diffusion with: E. coli (Ec),
25 and 5 mg/mL
MIC (mg/mL): Ec
=
0.125; Sa
=
Taddese et al.
S. aureus (Sa), C. albicans (Ca)
0.125; Ca
=
10; Tm
=
10.
(2009)
T. mentagrophytes (Tm)
A. vulgaris MeOH
microdilution method with:
40 mg/mL
MIC (mg/mL): aerial parts: Ml
=
Boroja et al.
extracts
M. lysodeikticus (Ml), S. typhimurium
0.156; St
=
0.625; Bs
=
2.5; Ef
=
(2018)
(St), B. subtilis (Bs), E. faecalis (Ef),
0.625; Ec
=
1.25; Kp
=
5; Pa
=
E. coli (Ec), K. pneumoniae (Kp),
2.5; Bm
=
0.625; Ac
=
5; Pf, Fs
=
P. aeruginosa (Pa), B. mycoides (Bm),
10; Pc, Ab, Aa
=
20; Ag
=
5; Ds
=
A. chroococcum (Ac), P. fastigiate (Pf),
2.5; Tv, Tl, Ca
>
20.
P. canescens (Pc), T. viride (Tv),
roots: Ml
=
0.156; St
=
0.625; Bs
T. longibrachiatum (Tl), A. brasiliensis
=
1.25; Ef
=
0.156; Ec
=
1.25; Kp
(Ab), A. glaucus (Ag), F. oxysporum
=
10; Pa
=
5; Bm
=
0.156; Ac
=
(Fo), A. alternata (Aa), D. stemonitis
2.5; Pf, Pc, Tv, Tl, Fo
=
20; Ag
=
(Ds), C. albicans (Ca)
10; Ds
=
5; Ab, Aa, Ca
>
20.
A. vulgaris
well diffusion with: S. aureus (Sa),
4 mg/well
Inhibition zone (mm):
Keskin et al.
EtOH
extract
E. coli (Ec), K. rhizophila (Kr), B. cereus
Sa: 12, Kr: 14, Pv: 10, Ef: 12, Ca:
(2010)
(Bc), B. subtilis (Bs), S. typhimurium
10, Ec, Bc, Bs, St, Ec, Ea: equal to
(St), P. vulgaris (Pv), E. faecalis (Ef),
negative control inhibitions or
E. aerogenes (Ea), C. albicans (Ca)
under recorded
A. mollis
well diffusion with: S. aureus (Sa),
stock: 100 mg/mL
Inhibition zone (mm):
Usta et al.
EtOH, MeOH, H
2
O
extracts
S. epidermidis (Se), S. pyogenes (Sp),
P. aeruginosa (Pa), K. pneumonia (Kp),
Sa, Sp, Kp: not active; Se: MeOH
10.00; Pa: EtOH 22.67, MeOH
(2014)
E. coli (Ec)
22.67; Ec: H
2
O 9.33, EtOH 15.33,
MeOH
9.33.
A. vulgaris
well diffusion with: S. epidermis (Se),
plant material–solvent ratio of
Inhibition zone (mm):
Dzabijeva et al.
50% EtOH/6% glycerin
P. acnes (Pa), P. granulosum (Pg)
1/10 (m/v)
Se:
0,
(2018)
solution
Pa: 10, Pg: 13.
A. diademata MeOH:
disk diffusion method with: E. coli,
10 and 20
μ
L extract per disk
10
μ
L: 22.2 %
Barbour et al.
H
2
O (v/v): 1:0, 1:1, 1:2,
1:3, 1:4, 1:5, 1:6
Proteus sp., P. aeruginosa, S.
dysenteriae, S. enteritidis, S. typhi, S.
20
μ
L: 55.5 %
(2004)
aureus, S. faecalis, C. albicans
HPC cream (N. sativa,
disk diffusion method with E. coli
1, 2 and 5 mg/disc
dose-dependent antibacterial
Said et al.
A. vulgaris,
activity (60% inhibition
(2022)
C. canadensis, 1:0.6:0.6
compared to ampicillin at 5 mg/
w/w)
disc)
Anticancer
A. erythropoda A.
MTT test using HeLa cells,
0–200
μ
g/mL
150–200
μ
g/mL caused the
Türk et al.
ikizdereensis
immunocytochemical staining of
increase of necrotic effect, lowest
(2011)
A. oriturcica A.
caspase-3
apoptotic effect was found in
trabzonica
A. oriturcica (14%) and the
highest apoptotic effect found in
A. trabzonica was (24%)
A. vulgaris
B16 melanoma cell line, after 2 days of
0.0125, 0.025, 0.05 and 0.1
~15%, 25%, 35%, 60%
Trouillas et al.
H
2
O extract
A. vulgaris MeOH: H
2
O
(8:2, v/v) extracts
growth
MTT test using MCF-7, PC-3,
Caco-2 cells
mg/mL
not given
antiproliferative effect
IC
50
(
μ
g/mL):
MCF-7: 92.25,
(2003)
Ibrahim et al.
(2022)
PC-3: 88.60,
Caco-2: 110.51
A. mollis
MTT test using K562 cells
not given
cell viability decreased at
Aslı et al. (2022)
MeOH
extract
A. mollis
SRB test using MCF7 cells
62.5–1000
μ
g/mL
concentrations
>
0.02 mg/mL
IC
50
(
μ
g/mL):
(I
˙
lgün et al.,
MeOH, DDW and H
2
O
extracts
H
2
O: 59.34
±
3.41, DDW:87.37
±
25.15 MeOH: 68.18
±
6.12
2017)
A. vulgaris extracts
MTT test using B16 and B16F10 cells
not given
dose-dependent decrease of cell
Jela
ˇ
ca et al.
viability after 72 h- treatment
(2021)
A. vulgaris
breast cancer cells 4T1
not given
decreased viability of cancer cells
Jela
ˇ
ca et al.
EtOH
extract
and apoptosis detection
(2022)
A. vulgaris hexane and
MTT and LDH assays using MDA MB-
0–250
μ
g/mL of polyherbal
MTT - hexane: 48.7
μ
g/mL
Al-Zharani and
ChCl
3
extracts
231 and MCF-7 cells, apoptosis assays
formula (PHF6): A. vulgaris, C.
pumilum,
C. azarolus, E. sativa, F.
(MCF7), 82.8
μ
g/mL (MDA-MB-
231) and ChCl
3
: 44.4
μ
g/mL
(MCF7 and MDA-MB-231),
Abutaha
(2023)
hermonis, H. triquetrifolium
hexane and ChCl
3
extracts caused
a significant LDH release at 250
and 125
μ
g/mL, extract induced
apoptosis in MCF7 and MDA-MB-
231
A. vulgaris
80% MeOH 70% EtOH
MTT assay u sing A2780, HeLa, MCF7,
PC-3 cells
not given
IC
50
(
μ
g/mL):
A2780: MeOH 27.9
±
1.9, HeLa:
Vlaisavljevi
´
c
et al. (2019)
70% EtOAc, H
2
O
extracts
EtOAc 46.4
±
5.1, MCF7: EtOAc
31.3
±
1.5,
PC-3: EtOAc 18.7
±
0.9
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
Table 7
(continued )
20
Activity
Tested material
Experimental model
Concentration used
Efficacy
References
CV assay using A2780, HeLa, MCF7,
PC-3 cells
not given
IC
50
(
μ
g/mL):
A2780: MeOH 38.3
±
1.1, HeLa:
Vlaisavljevi
´
c
et al. (2019)
EtOAc 53.8
±
3.9, MCF7: EtOAc
37.5
±
5,
PC-3: EtOAc 31.7
±
0.3
A. smirnovii 96% EtOH
MTT assay using HeLa and A549 cells
0.5, 0.25, and 0.125 mg DW/
strong cytotoxicity at the lowest
Ginovyan et al.
extract
mL
tested concentration 0.125 mg
(2022)
DW/mL
A. mollis H
2
O (WE),
deodorized H
2
O (DWE),
50% MeOH (ME)
SRB viability assay on MCF7 cells
15.625, 31.25, 62.5, 125, 250,
500, 1000
μ
g/mL
WE and DWE inhibited the
viability cells by 70% at a 125
μ
g/
mL
Karatoprak
et al. (2018)
extracts
Anti-
A. monticola
human adipocytes
5, 10 and 25
μ
g/mL
downregulated genes: CCAAT/
(Mladenova
Overweight
50% MeOH extract
enhancer-binding protein alpha
et al., 2021;
(CEBPA) and PPARG, inhibitory
Patel et al.,
effect on protein kinase B (AKT),
2022)
PI3K and PPARγ in dose-
dependent manner
Enzymes
A. vulgaris 80% MeOH
amylase
inhibition
not given
MeOH: 0.34
±
0.04
Vlaisavljevi
´
c
inhibition
70% EtOH 70% EtOAc,
EtOH: 0.32
±
0.03
et al. (2019)
H
2
O extracts
EtOAc: 0.41
±
0.03
H
2
O: 0.22
±
0.03 mmol ACAE per
g extract
A. vulgaris
10% mass H
2
O and 10%
mass 70% EtOH extracts
tyrosinase
inhibition
3, 1.5, 0.75 mg/mL
H
2
O (%): 60.00
±
2.78 (3 mg/
mL), 53.21
±
6.78 (1.5 mg/mL),
39.21
±
5.29 (0.75 mg/mL);
Neagu et al.
(2015)
EtOH (%): 71.55
±
4.39 (3 mg/
mL), 59.12
±
2.51 (1.5 mg/mL),
45.12
±
4.26 (0.75 mg/mL).
A. vulgaris 80% MeOH
acetylcholinesterase
inhibition
not given
MeOH: 5.17
±
0.02
Vlaisavljevi
´
c
70% EtOH 70% EtOAc,
EtOH: 5.14
±
0.01
et al. (2019)
H
2
O extracts
EtOAc: 5.21
±
0.05
H
2
O: 5.17
±
0.02 mg GALAE per
g extract
A. vulgaris
10% mass H
2
O and 10%
mass 70% EtOH extracts
100
μ
L of sample solution at 3,
1.5, 0.75 mg/mL
H
2
O (%): 84.56
±
5.64 (3 mg/
mL), 71.36
±
3.54 (1.5 mg/mL),
50.76
±
5.78 (0.75 mg/mL);
Neagu et al.
(2015)
EtOH (%): 96.50
±
4.93 (3 mg/
mL), 78.56
±
2.45 (1.5 mg/mL),
56.83
±
3.25 (0.75 mg/mL).
A. vulgaris 80% MeOH
butyrylcholinesterase
inhibition
not given
MeOH: 9.59
±
0.14
Vlaisavljevi
´
c
70% EtOH 70% EtOAc,
EtOH: 9.71
±
0.09
et al. (2019)
H
2
O extracts
EtOAc: 9.61
±
0.02
H
2
O: 10.19
±
0.16 mg GALAE per
g extract
Wound healing
A. vulgaris
70% EtOH, 80%
“scratch” test
50
μ
g/mL for AW (H
2
O) and AE
(70% EtOH); 250
μ
g/Ml for AP
Effect of AE and AP extracts on
migration of fibroblasts, extent of
Tasi
´
c-
Kostov
et al. (2019)
propylene glycol, H
2
O
extracts
(80% propylene glycol)
wound closure, wound healing
process were the most
pronounced.
A. vulgaris
MDBK epithelial cells
1 % of extract
increase in cells number 21.3
±
Shrivastava
hydroglycerinated fluid
2.1%
et al. (2007)
extract
primary smooth muscle cell
increase in cells number 15.5
±
myofibroblast cultures
2.2%
Chang liver cells
increase in cells number 10.6
±
0.6%
a
MeOH -methanol; EtOH – ethanol; EtOAc - ethyl acetate.
treatment, endometriotic foci areas and intraabdominal adhesions were
estimated and compared with the former findings. The results indicated
that the aerial parts of A. mollis and A. persica caused cystic formation
and that TNF-
α
, VEGF and IL-6 levels decreased. The root extracts did
not display any difference between pre- and posttreatment (Küpeli
Akkol et al., 2015).
8.2.5.
Neuroprotective activity
To study the neuroprotective effect of A. vulgaris, the plant water
infusion was administered to animals at doses of 5 or 25 mL/kg daily for
5 days. The positive control was piracetam (400 mg/kg Nootropil®). At
a concentration of 5 mg/mL, the hypoxia latent time remained 29.6 min,
while at 25 mg/mL, the hypoxia latent time was 32.5 min. Adminis-
tration of the infusion also affected the latent time for entry into the dark
arm during reflex training, which was 15.7 min and 28.0 min at 5 and
25 mL/kg, respectively. On the other hand, neither studied dose
significantly influenced the latent survival time of mice under hermetic
chamber conditions (Shilova et al., 2020).
8.2.6.
Antitoxic activity
To evaluate a protective effect of methanolic extracts of aerial parts
(AVA) and roots (AVR) of A. vulgaris against cisplatin-induced toxico-
logical alterations in rats Juri
´
c and coworkers treated them with extracts
for 10 days (at three different dosages: 50, 100, 200 mg/kg). According
to their results treatments with both AVA and AVR decreased levels of
serum parameters of liver (TB, TP, ALT, ALP, GGT) and kidneys (UR,
CRE, UA) impaling that these extracts may be used in preventing
cisplatin-induced toxicity during chemotherapy (Juri
´
c et al., 2020).
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
21
Table 8
Bioactivities of Alchemilla species reported in vivo experimental models.
Activity
Tested material
Experimental
model
Concentration
Efficacy
References
Anticonvulsant
A. kiwuensis
mice
20.63 mg/kg, 41.25 mg/kg and
PTZ-induced seizure: protected mice
Ngoupaye et al. (2022)
H
2
O extract
82.5 mg/kg
against seizures at 82.5 and 41.25 mg/kg
with 71% and 86%, respectively; PTZ-
induced seizure onset time: increased at
the 82.5 and 41.25 mg/kg; PIC-induced
seizures: protected against seizures at
82.5 mg/kg with 57.17%; PIC-induced
seizure onset time: increase in a dose
dependent manner; STR-induced
seizures: had no effect seizure and death
Hormone
A. vulgaris
rats
10 mg/kg/day
lowered the blood level of T
4
, increased
Borodin et al. (1999)
regulation
H
2
O extract
the deiodination ratio, activate
proliferative processes in the
interfollicular islets, content of thyroid
hormones and thyroglobulin in the TG
increased compared to the baseline
values
Anti-overweight
A. vulgaris
chickens
tablet contained 60 mg A.
administration the product during 4
Said et al. (2011)
vulgaris, 50 mg O. europaea, 20
weeks of study reduces body weight in
mg M. longiforia, 25 mg C.
the study group
rats
cyminum, 7 mg vitamin C and
weigh level extr acts stimulate IBAT
148 mg tricalcium phosphate
respiration rate, in a dose-dependent
manner up to
>
3-fold higher than basal
MO2
values.
Female diseases
A. mollis
A. persica
rats
100 mg/kg doses in 0.5% CMC
suspension in d istilled water
A. mollis: the cystic formation decreased
from 101.35 to 11.87 mm
3
, TNF-
α
, VEGF
(Bina et al., 2019; Küpeli
Akkol et al., 2015)
MeOH: H
2
O (8:2)
and IL-6;
extracts
A. persica: reduction in the
endometrioma
Neuroprotective
A. vulgaris
mice
5 and 25 mL/kg daily for 5 days
hypoxia latent time: 5 mL/kg - 29.6
±
Shilova et al. (2020)
H
2
O extract
2.5 min, 25 mL/kg - 32.5
±
2.9 min;
latent time for entry into dark arm during
reflex training: 5 mL/kg - 15.7
±
1.6 min,
25 mL/kg - 28.0
±
2.9 min
Antitoxic
A. vulgaris
rats
extracts: 50, 100, and 200 mg/
decreased levels of serum parameters of
Juri
´
c et al. (2020)
MeOH
extract
kg for 10 days
liver, kidneys and testicles injury, tissue’s
morphology and p arameters of oxidative
stress
Antidiabetic
A. mollis
alloxan-induced
100 mg/kg and 200 mg/kg
none of the extracts induced significant
(Ozbek et al., 2017;
MeOH: H
2
O (8:2, v/v)
rats
reduction on levels of blood sugar
Parthasarathy and Prince,
extract
2021)
A. persica
alloxan-induced
100 mg/kg and 200 mg/kg
none of the extracts exhibited a
O
¨
zbilgin et al. (2019)
MeOH: H
2
O (8:2, v/v)
diabetic mice
significant lowering effect on blood
extract
glucose levels
A. viridiflora
streptozotocin-
50, 100 and 200 mg/kg, p.o
200 mg/kg: decreased blood glucose
Radovi
´
c et al. (2022)
MeOH
extract
induced diabetic
level after 10 (32.2%) and 20 days
rats
(38.3%); 50 mg/kg had no statistically
significant effect
Hepatoprotective
A. mollis
CCl
4
- induced
100 mg/kg, 200 mg/kg
ALT levels were lowered, significant
Ozbek et al. (2017)
MeOH: H
2
O (8:2, v/v)
toxity
rats
differences in AST levels were not found
extract
A. vulgaris
rats
50, 100 ppm of EtOH and 50,
decrease in liver enzymes (AST, ALT,
El-Hadidy et al. (2018)
80% EtOH and H
2
O
100 ppm of H
2
O
ALP) after administration 100 ppm of
extract
EtOH extract
Gastroprotective
A. caucasica
IND-induced ulcer
50, 100, and 200 mg/kg
200 mg/kg dose was the most effective,
Karaoglan et al. (2020)
MeOH
extract
in rats
all doses reduced MDA level and
enhanced SOD activity and GSH level
juice: 20 g of the
IND-induced
10 mL/kg was administered for
ulcer score: 1.40
±
0.54
Valcheva-
Kuzmanova
A. vulgaris with 1 kg A.
gastric ulcers in
10 days
ulcer index: 1.40
et al. (2019)
melanocarpa fruit
rats
percentage of protection: 68.25%
TBARS: above 5 nmol/g
Wound healing
A. mollis, A.persica
male Swiss albino
not given
PGE
2
: approx. 1500 pg/g
tensile strength values on the incision
O
¨
z et al. (2016)
MeOH: H2O (8:2, v/v)
mice and Sprague-
wound model: 39.3% (A. mollis), 33.3%
extracts
Dawley
rats
(A.persica), contraction values: 51.4%
(A. mollis), 43.5% (A.persica)
Gels with A. vulgaris
human skin sites
1/200 for all examined gels
satisfying barrier repairment potential of
Tasi
´
c-Kostov et al. (2019)
70 % EtOH (GAE), 80%
pretreated with
investigated samples after 3 (GAE and
propylene glycol (GAP),
patch with SLS
GAW gels) and 7 (GAP gel) days of
H
2
O (GAW) extracts
treatment compared to basal parameters
A. vulgaris (20%),
7-week-old male
0.1 g of ointment containing
herbal mixture promoted re-
Choi et al. (2018)
M. tenuiflora (20%)
BALB/c
mice
herbal mixture every 12 h for 12
epithelialization, collagen synthesis, and
extracts, glycerol (42%),
days
regeneration of skin appendages
(continued on next page)
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
22
Table 8
(continued )
Activity
Tested material
Experimental
model
Concentration
Efficacy
References
honey (10%), xanthan
gum (8%)
A. vulgaris glycerinated
rats
3% in glycerin, once a day for 7
Lesion diameter (mm):
Shrivastava et al. (2007)
fluid extract
consecutive days
Day 1: 8.0
±
0.1
Day 7: 0.1
±
0.1
Anti-
A. mollis, A. persica
mice and rats
0.2 mL/20 g
at 200 mg/kg dose 30.6% (A. mollis) and
O
¨
z et al. (2016)
inflammatory
MeOH: H
2
O (8:2, v/v)
26.6% (A. persica) anti-inflammatory
extract
activity
Cardiovascular
A. vulgaris
rats
10 mg/mL
E
max
: mN/mm
Takir et al. (2015)
MeOH and H
2
O extracts
PGF
2α
: MeOH: 1.39
±
0.43;
H
2
O: 1.67
±
0.41
K
+
: MeOH: 1.14
±
0.13;
H
2
O: 2.05
±
0.11
300 mg/kg/day for 5 weeks
Blood pressure (mm/Hg) at 5th week:
MeOH: 119.60
±
2.50;
H
2
O: 138.50
±
2.14
A. vulgaris extract
rats
300 mg/kg for 10 days
lysophospholipids decrease, increased
Plotnikov et al. (2006)
lipid content and normalizes
phospholipid composition of erythrocyte
membra- nes, improvement of
erythrocyte deformability
Anti-photoaging
A. mollis
mice
exposure on UV
+
diet
prevention of wrinkle formation, skin
Hwang et al. (2018)
50% EtOH extract
containing 0.1% or 1 % of
thickening, water loss, and erythema
extract
8.2.7.
Antidiabetic activity
Diabetes mellitus is a metabolic disorder affecting nearly 10% of the
population worldwide, and is incidence is increasing daily. The use of
drugs of natural origin allows for a delay in the progression of this dis-
ease or a reduction in the dose of antidiabetic drugs needed (Ahad
Hussain et al., 2014; Sabu and Kuttan, 2002). A. viridiflora methanol
extracts possess moderate antidiabetic activity. When given per os, 200
mg/kg A. viridiflora extract decreased the blood glucose levels of
streptozotocin-induced diabetic rats after 10 and 20 days by 32.2% and
38.3%, respectively (Radovi
´
c et al., 2022). On the other hand, Ozbek
and co-authors evaluated the antidiabetic activity of the aerial parts and
roots methanolic-water extracts of A. mollis on alloxan-induced diabetic
rats. They proved that the intake of extracts at doses of 100 mg/kg and
200 mg/kg did not induce a significant reduction in blood sugar levels
(Ozbek et al., 2017). Similar conclusions were presented by
Swanston-Flatt et al., in 1989. After 12 days of administration of
A. vulgaris infusion to streptozotocin-induced diabetic mice, no signifi-
cant changes in plasma glucose or insulin concentrations were observed
(Swanston-Flatt et al., 1989). In another study, alloxan-induced diabetic
mice treated with 100 and 200 mg/kg 80% methanol extract of the
aerial parts and roots of A. persica did not exhibit a significant blood
glucose level lowering effect (Ozbek et al., 2017). Because the data
presented in these publications indicate that preparations from
Alchemilla plants have low antidiabetic activity, it seems unreasonable
to examine them as future antidiabetic drugs of natural origin.
8.2.8.
Hepatoprotective activity
To characterize the hepatoprotective activity of aerial parts and roots
of A. mollis, Ozbek and coworkers used rats with CCl
4
-induced toxicity.
After 2 days of intraperitoneal administration of CCl
4
(0.8 mL/kg), two
groups received 100 mg/kg aerial parts or roots 80% methanol extract of
A. mollis and two other treatment groups received 200 mg/kg the same
samples once a day. The study was conducted for 7 days. The downside
of the experiment was the lack of a positive control. However, the results
of this test showed that extracts of both aerial parts and roots of A. mollis
lowered alanine transaminase (ALT) levels, although aspartate trans-
aminase (AST) levels were not significantly different between the
treatment groups and the CCl
4
group. Furthermore, histopathological
examinations displayed prominent recovery after the administration of
all dosages except 100 mg/kg A. mollis aerial part extract (Ozbek et al.,
2017). Similar experiments were conducted by El-Hadidy et al. using
80% ethanolic and aqueous A. vulgaris extracts (50 or 100 ppm), as well
as its dried leaves (1% and 2%). In this study, AST, ALT, and alkaline
phosphatase (ALP) levels were evaluated in rats induced by CCl
4
. Sig-
nificant reductions in AST, ALT, ALP, and bilirubin levels were seen after
A. vulgaris treatment in all groups except for the 50-ppm water extract
group. No changes were observed in albumin levels compared to the
normal group (El-Hadidy et al., 2018).
8.2.9.
Gastroprotective activity
Efforts have been made to examine the gastroprotective activity of
A. caucasica extract at doses of 50, 100, and 200 mg/kg against
indomethacin-induced ulcers in rats. Rats were divided into 6 groups:
group 1 contained healthy animals, group 2 received 25 mg of indo-
methacin (IND), group 3 received 25 mg of IND and 40 mg of famotidine
as a positive control, and groups 4, 5 and 6 received 25 mg of IND with
50 mg/kg extract, 25 mg of IND with 100 mg/kg extract and 25 mg of
IND with 200 mg/kg extract, respectively. After biochemical estimation,
the 200 mg/kg dose was determined to be the most effective and similar
to the healthy group. Nevertheless, A. caucasica reduced the malon-
dialdehyde (MDA) level, increased the glutathione (GSH) level, and
enhanced superoxide dismutase (SOD) activity, proving its gastro-
protective activity (Karaoglan et al., 2020). Another study aimed to
investigate the effect of the juice produced from 1 kg of Aronia mela-
nocarpa fruits and 20 g of A. vulgaris herbs. Over a period of 10 days, the
treatment group was pretreated with the juice at a dose of 10 mL/kg. On
the 10th day, 1 h after pretreatment, 30 mg/kg IND was subcutaneously
injected into rats, and after 4 h, gastric ulcer formation was evaluated.
According to the scores obtained, pretreating rats with the juice caused a
reduction in the rawness of IND-induced gastric lesions (ulcer score and
index) and antagonized the impact of IND on apoptosis and lipid per-
oxidation processes (TBARS above 5 nmol/g) (Valcheva-Kuzmanova
et al., 2019).
8.2.10.
Wound healing activity
Within in vitro scratch assays, Tasi
´
c-Kostov et al. studied wound
healing with A. vulgaris extract gels on human skin irritated with a so-
dium lauryl sulfate (SLS) patch, which exerted a significant effect on
trans epidermal water loss (TEWL). The change seemed to be reversible
after 3 days of curing with gels containing water and the ethanol
A. vulgaris extract and after 7 days of treatment with the gels with the
80% propylene glycol plant extract. Based on the results, the authors
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
23
suggested that topical use of gels with lady mantle extracts provokes
epithelial cell proliferation, inducing wound healing (Tasi´c-Kostov et al.,
2019). Herbal extracts with wound healing properties for topical
application are traditionally incorporated into ointments that consist of
waxes, Vaseline, or lanolin (Eastman et al., 2014). In one study, 0.1 g of
ointment composed of A. vulgaris (20%) and Mimosa tenuiflora (20%)
extracts, glycerol (42%), honey (10%) and xanthan gum (8%) were
studied on 7-week-old mice with a 1 cm incisional wound. The topical
application of the herbal ointment as well as the fusidic acid ointment
was repeated every 12 h. After 12 days, treatment with the herbal
mixture resulted in reepithelialization, an increase in collagen synthesis,
and the regeneration of skin appendages (Choi et al., 2018). Addition-
ally, aqueous-methanol extracts of both A. mollis and A. persica incor-
porated into an ointment were estimated for their wound healing
potential. The herbal ointments, reference drug and ointment base were
topically applied to the dorsal wounds of each group of mice once daily
for 9 days. According to the obtained results, the tensile strength values
of the incision wound model were 39.3% and 33.3% for A. mollis and
A. persica, respectively. The contraction values reached 51.4% (A. mollis)
and 43.5% (A. persica) (O
¨
z et al., 2016).
8.2.11.
Anti-photoaging activity
In addition to the wound healing properties of A. mollis extracts or
their preparations, the ethanol-water extract of A. mollis has been tested
for its antiphotoaging activity. In this study, sixteen hairless mice were
UVB-irradiated with sunlamps. The exposure during the first week was
100 mJ/cm
2
seven times per week and 200 mJ/cm
2
twice a week for the
following nine weeks. One of the experimental groups of mice was fed a
diet containing 0.1% A. mollis extract, while the second group was fed a
diet containing 1% extract. It was found that in the treated groups, the
mouse skins appeared to be smoother and thinner than those in the
control group, and the effect was dose dependent. Furthermore, the
density of the collagen fibers treated with A. mollis extract was signifi-
cantly higher (Hwang et al., 2018).
8.2.12.
Anti-inflammatory activity
Anti-inflammatory activity of the 80% methanolic extracts from the
aerial parts of A. mollis and A. persica was studied using acetic acid-
induced increase in capillary permeability. It was found that extracts
from both plants possess anti-inflammatory activity at dose 200 mg/kg.
A. mollis exhibited activity with the values of 30.6% and A. presica of
26.6%.
8.2.13.
Cardiovascular activity
To investigate the blood pressure-lowering properties of A. vulgaris
methanol and water extracts, Takir and co-authors fed rats with a dose of
300 mg/kg/day of each of the extracts for 5 weeks. At the end of the
curation, blood pressure was measured. After administration of the
methanol extract, the blood pressure reached 119.60 mmHg, and the
blood pressure was 138.50 mmHg after water extract treatment,
compared to that in the control group (156.50 mmHg). In addition, both
extracts produced relaxations in PGF
2α
(MeOH: 1.39 and H
2
O: 1.67),
while the opposite vascular influence was noticed when the extracts
were applied in K
+
precontracted arteries (Takir et al., 2015). Plotnikov
et al. showed that treating rats for 10 days with 300 mg/kg extract
increased the lipid content and normalized the phospholipid composi-
tion of erythrocyte membranes, which favors decreases in the levels of
irreversibly modified erythrocytes and an improvement in erythrocyte
deformability (Plotnikov et al., 2006).
Place Table 8 here
8.3.
In silico assays
Recent developments in computational (in silico) approaches have
provided essential information on natural compounds and methods to
examine their pharmacological profiles. It is a tool that allows the
prediction of potential biological activity and supplies a better indica-
tion of how the structure of a plant-based compound can influence its
targets (Fang et al., 2017).
8.3.1.
Antiviruses activity
Suru
ˇ
ci
´
c et al. supplied information about the inhibitory effects of
A. viridiflora polyphenols on SARS-CoV-2 internalization in silico. Ac-
cording to their results, ellagitannins most likely blocked S-glycoprotein
interactions with ACE2, whereas the NRP1 receptor interacted with
flavonoid compounds (Suru
ˇ
ci
´
c et al., 2022).
8.3.2.
Cardiovascular activity
Also, Radovi
´
c and co-workers performed the molecular docking
simulation study of ACE inhibitory activity of compounds isolated from
methanolic extract of A. viridiflora. Among them tiliroside, tell-
imagrandin I, ellagic acid pentose and galloyl-HHDP-glucose showed
high affinity for ACE binding site (Radovi
´
c et al., 2022).
8.3.3.
Anti-overweight activity
To evaluate mechanism of action of kaempferol 3-O-glucoside and
quercetin 3-O-rhamnoside detected in the A. monticola docking runs
were performed using C/EBP
α
, PPARγ, AKT and PI3K proteins. The
strong binding free energies suggested a potential envolve of PI3K and
PPARγ proteins in the mechanism of action of these compounds in the
adipocytes (Mladenova et al., 2021).
8.4.
Clinical trials
Besides in vitro and in vivo studies there are some reports of the use of
the A. vulgaris herb for traditional therapeutic indications as a raw ma-
terial in certain clinical trials.
A clinical trial was conducted on 341 girls aged 11–17 suffering from
menstrual disorders. The patients selected for the study were orally
administered 50–60 drops of a liquid A. vulgaris extract containing 5.8%
tannin compounds and 2.2% flavonoid glycosides three to five times a
day. It was observed that as a result of treatment, menstrual bleeding
lasted no longer than three to five days. The extract also reduced the
intensity of menstrual bleeding when administered prophylactically for
a period of 10–15 days before menstruation. During the studies, no
adverse effects were observed, and the extract was considered safe for
use (Bradley, 2006).
The purpose of another clinical study using lady’s mantle was to
evaluate the efficacy of a 3% glycerine preparation containing an
A. vulgaris extract in the treatment of aphthous ulcers, one of the most
common types of recurrent ulcers in the oral mucosa. An open-label
study was conducted with 48 patients aged 4–44 years, excluding pa-
tients with herpes ulcers. The trial tried to determine the healing
properties and patient tolerance to the recommended preparation. The
preparation was applied topically three times a day. The results showed
that the preparation relieved discomfort and caused complete recovery
in most patients within two days and in 75% of patients within three
days, which was a significantly better result than the number of un-
treated patients with complete recovery (10.4% and 33.3%, respec-
tively) and those treated conventionally (15% and 40%, respectively).
The preparation used was well tolerated by patients, which suggests that
the tested agent containing A. vulgaris extract is safe and highly effica-
cious in the treatment of aphthous oral ulcers (Shrivastava and John,
2006).
In another study, the authors’ aim was to investigate the effects of
spraying a glycerine extract of A. vulgaris into the oropharynx to prevent
sore throat resulting from intubation following general anesthesia. The
study included 94 patients (aged
≥
18 years) who qualified for thoracic
surgery using a double-lumen tube. Prior to intubation, 0.2 mg/kg
dexamethasone was administered to all patients intravenously, and 2 mL
of saline was sprayed into the oropharyngeal cavity (n
=
45), or 0.04
mL/kg saline was administered intravenously, and 1 g of Neo Mucosal
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
24
Activator mixed with 1 mL of normal saline was sprayed into the
oropharyngeal cavity (n
=
43). The study was performed in a double-
blind, prospectively randomized manner. Postoperative sore throat
and hoarseness were recorded for each patient using a numerical rating
scale and a 4-point scale to detect changes in voice quality after tracheal
extubation at 1, 6 and 24 h. The incidence of sore throat 24 h after
surgery was assessed first. Secondary endpoints were the incidence and
severity of sore throat and hoarseness. There were no significant dif-
ferences between groups in the incidence of sore throat 24 h after sur-
gery (57.8% vs. 46.5%; p
=
0.290) or in the incidence and severity of
sore throat and hoarseness 1, 6 and 24 h after surgery. In conclusion, it
was determined that the application of A. vulgaris extract to the
oropharyngeal mucosa had no significant effects on preventing
intubation-induced sore throat or hoarseness compared with intrave-
nous injection of low-dose dexamethasone as a positive control. It is thus
justified to conduct further research on the method of application and
selection of the best dose of the extract by comparisons with placebo and
other drugs, as well as a more thorough verification of the preventive
effect of the tested formulation with A. vulgaris extract. Unfortunately,
this study had many limitations. First, it did not include a control group
of patients who did not receive prophylactic analgesics, which prevents
determination of the extent to which the A. vulgaris preparation reduced
the incidence of sore throat. In the study, the authors also did not
describe how the pharmaceutical formulation was prepared, and there
was no information on the full phytochemical standardization of the
extract necessary to describe its main active ingredients (Chung et al.,
2021).
One of the most common diseases of the digestive tract is hemor-
rhoids. Numerous conventional therapeutic methods for hemorrhoids
are very often associated with serious complications. Currently, the
search for traditional medicines, including those based on plant in-
gredients, is underway. For this purpose, a randomized, double-blind
clinical trial was conducted to determine the efficacy and safety of a
topical cream containing three plant extracts, including A. vulgaris
extract (0.3 g/50 mL). This study, with 77 patients enrolled, was
intended to determine the efficacy and safety of the formulation created
to treat hemorrhoids. This clinical trial included patients suffering from
symptomatic hemorrhoids at various stages of disease progression. The
preparations were applied twice a day for six days. Each patient atten-
ded five visits and a follow-up visit: baseline, at days 2, 4, 6, and at the
follow-up endpoint of 30 days. The results indicated that patients
showed significant clinical improvement in all parameters of disease
severity compared to those in the placebo group (Said et al., 2022).
The purpose of another clinical study using the aerial parts of
A. vulgaris was to evaluate the effects of plant extracts rich in tannins
(procyanidins) on the growth of fibroblasts and epithelial cells in an in
vitro model and then to assess their efficacy in healing deep wounds. As
noted, the growth of epithelial cells and fibroblasts applies to all types of
deep wounds; however, a limitation of the study was that the origin of
the wounds was not accounted for. The study included 93 adult patients
who were randomly divided into two groups. Forty-one patients were
randomized to the placebo group (AS-22) and 52 to the active treatment
group (AS-21) over a period of six weeks. A statistically significant dif-
ference was observed between the placebo and AS-21 group regarding
reductions in wound area (33.37% vs. 97.87%) and wound volume
(29.45% vs. 94.17%) after six weeks of treatment. During the study,
significant decreases in average wound moisture and pain sensation
were also observed. The results of this study also showed that the
healing time was significantly shorter in the group of patients treated
with the formulated topical product containing 1.5% dry procyanidin
extract of M. tenuiflora (13.5% polyphenols) and 1.5% dry extract of
A. vulgaris (12% polyphenols) compared to the placebo group. In addi-
tion, 64% glycerol and 33% honey were present in the product formu-
lation. The results of this study indicate that the fraction of procyanidins
from A. vulgaris and M. tenuiflora neutralized excess metalloproteinases
in the deep wound, thus stopping the degradation of the intercellular
matrix and creating a favorable environment for the growth of fibro-
blasts found deep in the wound and epithelial cells. It was also observed
that gradual decreases in wound depth due to fibroblast cell prolifera-
tion and wound surface area due to epithelial cell growth accelerated the
healing process (Shrivastava, 2011).
Another study prepared a blend of extracts from four plants used in
traditional Arabic and Islamic medicine as well as in European herbal-
ism and evaluated its safety and efficacy in weight loss. The study used
plant raw materials, including the leaves of A. vulgaris, O. europaea and
M. longifolia and the seeds of C. cyminum. In the first stage of the study,
no signs of toxicity were observed when cultured human fibroblasts
were treated with a mixture of the raw materials, as shown by the release
of lactate dehydrogenase. These results were confirmed in experimental
studies in rats, in which an LD
50
of 15.3 g/kg was determined. The
antioxidant properties at exceptionally low concentrations (10
μ
g/mL),
as determined by the lipid peroxidation method, were also evaluated.
Studies conducted on chickens given this mixture weekly for four weeks
showed that the animals had progressive and significant weight loss
compared with the chickens in the control group. The promising results
from preclinical studies became the basis for a clinical trial including 80
volunteers with a body mass index (BMI) of 30.67
±
2.14 kg/m
2
. All 80
subjects were asked to continue their usual diet, eating only three main
meals a day, and take one tablet of a product containing a mixture of raw
materials, including the leaves of A. vulgaris, exactly 30 min before each
meal. Fourteen patients were excluded due to noncompliance with the
protocol, and the remaining 66 patients were evaluated for treatment
efficacy and weight level tolerance every month for three months. The
ingested herbal product was well tolerated by all subjects, and no side
effects were reported. Progressive and significant weight loss was
observed in these participants throughout the study period. Greater
weight loss was seen in those with a BMI of 25–30 kg/m
2
(overweight)
compared to those with a BMI
>
30 kg m
2
(obese). The BMIs decreased
after three months from 28.5
±
1.2 and 32.1
±
1.8 kg/m
2
to 24.5
±
1.4
and 27.5
±
2.2 kg/m
2
in the overweight and obese groups, respectively
(Said et al., 2011).
9.
Toxicity
A. vulgaris is regarded as safe by the German Commission even at
large doses without known adverse effects (Said et al., 2011). For
example, in studies involving the administration of an extract of
A. vulgaris to teenage female patients at regular intervals over 6 years, no
significant changes in the monitored biochemical parameters were
found (Miętkiewska et al., 2018). Countless numbers of A. vulgaris ex-
tracts were tested for their toxic effects to normal cells using MTT or SRB
tests. Tasi
´
c-Kostov et al. used a fibroblast cell line and administered
different concentrations of different A. vulgaris extracts that were proven
in a viability assay (MTT) to be noncytotoxic: 50
μ
g/mL water and 70%
ethanolic extracts and 250
μ
g/mL 80% propylene glycol extract
(Tasi´c-Kostov et al., 2019). Additionally, to prove the safety of this plant,
the Ames test was performed using Salmonella typhimurium strains TA 98
and TA 100. This research proved that the commercial 70% ethanol
tincture of Alchemillae herba is not mutagenic (Schimmer et al., 1993,
1994). Moreover, it was found that the contents of tannins in the extracts
did not correlate with the antimutagenic properties; however,
tannin-free fractions did not inhibit the mutagenic activity. On this
basis, it was assumed that the tannin fraction is involved in the anti-
mutagenic extracts tested (Schimmer and Lindenbaum, 1995).
10.
Conclusions
A comprehensive review was conducted to gather information about
the traditional uses, botany, phytochemistry, pharmacology, and toxi-
cology of Alchemilla plants. A continually increasing number of com-
pounds isolated and identified from species in the Alchemilla genus have
provided substantial information about the main constituents
K. Jakimiuk and M. Tomczyk
Journal of Ethnopharmacology 320 (2024) 117439
25
underlying their usefulness in modern medicine. Although remarkable
progress has been made toward their development in science and
medicine, many people worldwide do not have access to present day
healthcare. Thus, we noticed a need for extensive scientific in-
vestigations aiming to rationalize the ethnopharmacological application
of bear’s foot plants in the treatment of many disorders, such as wounds,
gynecological, gastric, and cardiovascular diseases, as well as chronic
inflammation or infection. Both in vitro and in vivo study results have
indicated that Alchemilla species have a broad spectrum of biological
activities and could be considered useful in phytotherapy and the pro-
duction of safer and less expensive plant-based drugs. Although
A. vulgaris is a safe herb, the pharmacokinetics and pharmacodynamics
of the individual compounds, as well as estimations of their interactions
with dietary molecules and the most common drugs, need to be deter-
mined. Additionally, clinical study data are extremely limited. In sum-
mary, Alchemilla species, especially A. vulgaris, can open doors in the
development of many substantial remedies with various applications to
resolve several health aliments.
Funding
The study was funded by the project No. B.SUB.23.390 from the
Medical University of Bialystok (Poland).
CRediT authorship contribution statement
Katarzyna Jakimiuk:
Conceptualization, Data curation, Investiga-
tion, Writing – original draft, Writing – review & editing, Project
administration.
Micha
ł
Tomczyk:
Data curation, Writing – original
draft, Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data was used for the research described in the article.
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