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Leonurus cardiaca L. as a Source of Bioactive Compounds: An Update of the European Medicines Agency Assessment Report (2010)

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Leonurus cardiaca L. (motherwort) is a perennial herb, native to Asia and southeastern Europe, with widespread global occurrence in present days. The plant was historically used as cardiotonic and for treating gynaecological afflictions (such as amenorrhea, dysmenorrhea, menopausal anxiety, or postpartum depression). Although its use in oriental and occidental medicine is relatively well documented, the recent progress registered raises the need for an update of the Medicines Agency assessment report on Leonurus cardiaca L., herba (2010). The current study presents the progress made within the 2010-2018 timeframe regarding the potential applications and scientific evidences supporting the traditional use of motherwort, in the same time suggesting future research opportunities.
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Review Article
Leonurus cardiaca L. as a Source of Bioactive Compounds:
An Update of the European Medicines Agency Assessment
Report (2010)
Radu Claudiu Fierascu,1,2 Irina Fierascu ,1,2 Alina Ortan,1
Ioana Catalina Fierascu,3Valentina Anuta,3Bruno Stefan Velescu,3
Silviu Mirel Pituru,3and Cristina Elena Dinu-Pirvu1,3
1University of Agronomic Sciences and Veterinary Medicine of Bucharest, 59 M˘
ar˘
as
,ti Blvd., 011464, Bucharest, Romania
2National Institute for Research & Development in Chemistry and Petrochemistry – ICECHIM Bucharest, 202 Spl. Independentei,
060021, Bucharest, Romania
3University of Medicine and Pharmacy “Carol Davila”, 37 Dionisie Lupu Str., 030167, Bucharest, Romania
Correspondence should be addressed to Irina Fierascu; dumitriu.irina@yahoo.com
Received 25 February 2019; Revised 22 March 2019; Accepted 31 March 2019; Published 17 April 2019
Academic Editor: Francesca Mancianti
Copyright ©  Radu Claudiu Fierascu et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Leonurus cardiaca L. (motherwort) is a perennial herb, nativeto Asia and southeastern Europe, with widespread global occurrence
in present days. e plant was historically used as cardiotonic and for treating gynaecological aictions (such as amenorrhea,
dysmenorrhea, menopausal anxiety, or postpartum depression). Although its use in oriental and occidental medicine is relatively
well documented, the recent progress registered raises the need for an update of the Medicines Agency assessment report on
Leonurus cardiaca L., herba (). e current study presents the progress made within the - timeframe regarding the
potential applications and scientic evidences supporting the traditional use of motherwort, in the same time suggesting future
research opportunities.
1. Introduction
Leonurus cardiaca L. (common names – motherwort in Eng-
lish, Echte Herzgespann –Deutsch,agripaume –French,
etc) represents a perennial herb belonging to the Lamiaceae
family. e plants grow up to  m, with the hollow aerial
stalks growing from the rhizomes. e leaves are palmately
lobed, being covered with sti hairs. Flowers, grouped in
- clusters in the leaf ’s axils of the last - knots, are
pink and about  cm long []. e plant, original to Asia
and southeastern Europe is now world-spread, due to its
medicinal use [–]. e potential application in treating
several cardiac disorders, as well as female-specic aictions,
made L. cardiaca a very good candidate for development
of alternative treatments, in both traditional eastern and
modern medicine [, ]. Besides the traditional medical use,
motherwort is used in some cuisines as condiment in various
vegetable soup recipes, particularly the lentil or split peas
ones, or for avoring of beer and tea [], thus increasing the
potential intake of the medicinal plant by the general public.
e current review intends to present the main ndings
regarding the composition and main biological activities of
L. cardiaca, as emerging from the scientic studies pub-
lished within the - timeframe. e time period
was selected in order to complete the very comprehensive
Assessment report on Leonurus cardiaca L., herba” pub-
lished by the European Medicine Agency [] with the latest
ndings. e search methodology involved accessing and
evaluating the papers found in the PubMed, ScienceDirect,
Wiley Online Library, ACS Publications, and SpringerLink
databases (search term “Leonurus cardiaca”, ..). Aer
the removal of duplicate entries,  studies were taken
into consideration. Figure  describes the distribution of the
reviewed works by publication year and type of paper. Most of
the information presented in the present work was collected
from the “Article” type papers ( works).
Hindawi
BioMed Research International
Volume 2019, Article ID 4303215, 13 pages
https://doi.org/10.1155/2019/4303215
BioMed Research International
2010
0
5
10
15
20
25
30
35
40
45
2011 2012 2013 2014
Publication year
Reviewed works
Articles
Book chapters
Others (Review, Editorial, Meeting Abstract, Reference work)
2015 2016 2017 2018
F : Works published in the time period - including L. cardiaca.
2. Composition of L. cardiaca
e composition of L. cardiaca was previously presented
by the EMA report [], consisting of furanic diterpenes
(labdanes), alkaloids (of special interest being stachydrine),
sterols, iridoids, avonoids, ursolic acid, minerals, and others.
Figure  presents the constituents of L. cardiaca and their
potential biomedical application, as presented by the pre-
literature sources.
e data briey presented in Figure  can be completed
with the ndings from the time period covered by the present
review.Ruschetal.[]identiedintheL. cardiaca extract the
presence of a chlorinated major iridoid glucoside (-chloro--
desoxy-harpagide), conrmed by ESI-MS and d/d H/C
NMR. Kuchta et al. [] quantied by RP-HPLC the presence
of ferulic acid, chlorogenic acid, caeic acid, cichoric acid,
rutoside, lavandulifolioside, verbascoside, and isoquercitrin
in L. cardiaca extract, as well as stachydrine in dierent parts
of L. cardiaca, included, for the rst time in literature, in the
fruits (.%) [, ].
e leaves essential oil was found to contain caryophyl-
lene, .%; 𝛼-humulene, .%; 𝛼-pinene, .%; 𝛽-pinene,
.%; linalool, .%; and limonene, .%, while the ursolic
acid present in the leaves was quantied to be .% (dry wt.)
[].
Using HPLC-MS, Zhogova et al. [] quantied sev-
eral active compounds in both medicinal plant raw mate-
rial and medicinal preparation (harpagide, ajugol, galirido-
side, harpagide acetate, ajugoside, galiridoside, chlorogenic
acid, lavandulifolioside, verbascoside, rutin, hyperoside, iso-
quercitrin, and apigenin--O-glucoside).
An optimized recipe for the extraction of polysaccharides
from motherwort leaves was presented by Tahmouzi and
Ghodsi [], obtaining a yield of . ±.% for .C
extraction temperature, . min. extraction time, and .
ratio of water to raw material. Although the presence of
leonurine in the L. cardiaca extracts is presented by some
authors, including the previously cited report [, ], others
support the contrary, not identifying the compound in the L.
cardiaca extract [].
3. Biological Activities of L. cardiaca
e main biological activities of L. cardiaca can be divided in
several main categories.
3.1. Cardiovascular Action. e application of L. cardiaca
in cardiovascular disorders represents one of the main
applications of motherwort products []. Ritter et al. []
evaluated the cardiac and electrophysiological eects of
several types of L. cardiaca extracts by epicardial potential
mapping and by evaluation of the eect on the cardiac ion
currents using dierent types of cell models. e obtained
results suggested that L. cardiaca extractactsasamixed
ICa.L- (L-type calcium current), IKr- (rapid delayed rectier
current) antagonist, and If(funny current, recorded in
sinoatrial node cells from guinea pigs) modulator, support-
ing its application as an antianginal and antiarrhythmic
agent.
e cardioprotective potential of ursolic acid (the natural
pentacyclic triterpenoid carboxylic acid commonly found
in dierent L. cardiaca formulations) was demonstrated by
Liobikas et al. []. eir study revealed that the ursolic acid
induced uncoupling of oxidative phosphorylation in the h eart
mitochondria without aecting State  respiration rate, in
thesametimesuppressingtheH
2O2production in isolated
mitochondria, in a dose-dependent manner. e uncoupling
of mitochondrial oxidation from phosphorylation, partial
inhibition of the mitochondrial respiratory chain, and a
reduction in the generation of free radicals in mitochondria
were also observed by Bernatoniene et al. [] in rat heart
mitochondria using L. cardiaca ethanol extracts.
BioMed Research International
OH
O
OOOO
O
O
O
O
O
O
O
O
Constituents
Furanic labdane diterpenes
leocardin leosibiricin
leonurine Glycosides
Application
Anti-inammatory
Antiatulent
Antispasmodic
Astringent
Birthing aid
Cardiac
Diaphoretic
Emmenagogue
Nervine
Analgesic
Stomachic
Tonic
Women’s complaints
Antibacterial
Antioxidant
Antiarrhythmic
Lavandulifolioside
reptosid
ajugol
Others
ursolic acid germacrene D chlorogenic acid
hispanolone
Alkaloids
O
OO
O
O
O
O
OO
O
O
O
O
O
O
O
O
H
H
O
OGlucose
O
O
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
HO
H
H
H
H
HO
HO
OH
OH
OH
OH
OH OH
OH
OH
OH
OH
OH
OH
OH
OH
N
N
+
-
O
OH
H
H
H
H
H
H
H
O
H
H
OO
O
O
#(3
#(3
#(3
#(3
#(3
3C
#(3
3C
3C
.(2
.(2
#/2H
stachydrine
Iridoids
-sitosterol
F : Composition and applications of L. cardiaca as emerging from pre- works (adapted from []).
e clinical trial conducted by Shikov et al. [] on
y patients treated with  mg L. cardiaca oil extract
per day for  days revealed signicant changes in systolic
blood pressure, diastolic blood pressure, heart rate, and
ECG for patients with stages  and  arterial hypertensions,
accompanied by an improvement of psychoemotional status
(anxiety, emotional liability, headache, and sleep disorders),
especially visible for stage  patients.
Stachydrine (alkaloid found in L. cardiaca)wasprovenby
Xie et al. [] to ameliorate homocysteine- (Hcy-) induced
endothelial dysfunction via nuclear factor erythroid –
related factor  (Nrf) dependent upregulation of guanosine
triphosphate cyclohydrolase I (GTPCH) and dihydrofolate
reductase (DHFR) enzymes and increase in bioavailabilities
of tetrahydrobiopterin (BH) and nitric oxide (NO), thus
protecting endothelial function.
e cardiotonic potential of L. cardiaca has been men-
tioned by Goetz [, ], Zaurov et al. [], Brenyo and Aktas
[], Kidd [], Jari´
c et al. [], Suroowan and Mahomoodally
[], Wang et al. [], Madridejos Mora [], Yarnell [],
Orhan et al. [], Dong et al. [], and Bianchi [].
3.2. Anti-Inammatory, Antimicrobial Eect, and Applica-
tion in Female Disorders. e anti-inammatory poten-
tial of leonurine (considered by some authors a natural
component of L. cardiaca []) on E. coli-induced mas-
titis in mice []: their results suggested that leonurine
alleviates the histopathological changes, downregulates the
levels of proinammatory cytokines (TNF-𝛼and IL-),
upregulates the level of anti-inammatory cytokine IL-,
and inhibits the expression of nitric oxide synthase (iNOS)
and cyclooxygenase- (COX-). e suggested mechanism
involves the inhibition of expression of toll-like receptor
(TLR)andnuclearfactor-kappaB(NF-𝜅B) activation
and mitogen-activated protein kinases (p), extracellular
signal-regulated kinase (ERK), and Jun N-terminal kinase
(JNK) phosphorylation. e anti-inammatory potential of
leonurine was also demonstrated by Liu et al. [] in rat
animal models of acute gouty arthritis. e obtained results
support the use of leonurine as COX-, mPGES- (microso-
mal prostaglandin E synthase-), and -LOX (-lipoxygenase)
inhibitor, leading to antiarthritis eects. In the same time,
amelioration of monosodium urate crystal-induced inam-
mation was achieved by decreasing interleukin-𝛽(IL-𝛽)
and tumor necrosis factor-alpha (TNF-𝛼)production.
e immunomodulatory potential of acetone/water
extract of L. cardiaca at a 𝜇g/ml concentration was
assessed by Sadowska et al. [], revealing a signicant
reduction of the platelet aggregation in the presence of
arachidonic acid, an application that could be benecial in
preventing inammatory lesions. In the same time, the tested
extract did not exhibit proapoptotic activity.
e traditional use of L. cardiaca as an anti-inammatory
and antimicrobial agent was also supported by the results
presented by Flemmig et al. []. ey tested several extracts
and components of L. cardiaca for their ability to regenerate
the pseudo-halogenating activity of lactoperoxidase (LPO).
e results supported the use of components with a ,-
dihydroxyphenylic partial structure (such as caeic acid
derivatives or phenylethanoids) as ecient LPO activity
BioMed Research International
regenerators, as well as the use of L. cardiaca ethanol extract
for the same application. e same study also presents the
isolation of the compound caeoylmalic acid, which also
revealed moderate LPO activity-regenerating eects.
Micota et al. [] studied the antimicrobial potential of L.
cardiaca acetone-water extract and its component ursolic acid
by determining the minimal inhibitory concentration, as well
as the antiadhesive and antibiolm properties against Staphy-
lococcus aureus strain (potential etiological agent of infective
endocarditis). eir results (MIC =  mg/ml for extract and
. mg/ml for ursolic acid) showed weak biostatic activity
of L. cardiaca extract in comparison to ursolic acid, but both
preparations possessed antiadhesive potential. e S. aureus
biolm formation was slightly inhibited by the extract (%),
but strongly inhibited by ursolic acid (%) at concentrations
of / MIC.
e study of Samoilova et al. [] on the eect of
subinhibitory doses of plant extract (including L. cardiaca)on
Escherichia coli biolm formation revealed that motherwort
extract showed a synergistic eect with sublethal concen-
tration of streptomycin ( 𝜇g/ml), inhibiting the specic
biolm formation. As the study was focused on the capacity
of low concentration plant extracts and p olyphenols to induce
adaptive mechanisms in E. coli,itcannotbeconsideredatruly
antimicrobial study.
Micota et al. [] used subinhibitory doses of L. car-
diaca extract to establish its eects on the characteristics
of Staphylococcus aureus. e benecial eect of the extract
was observed, such as reduction in staphylococcal adher-
ence, aggregates formation, coagulase activity, protein A
expression, or alpha-toxin synthesis. However, some of their
ndings (e.g., enhancement of staphylococcal tolerance to
exogenous hydrogen peroxide aer preincubation with the
extract) led to the conclusion of a possible risk of adverse
eects.
Wu et al. [] presented the application of leonurine
for ameliorating the inammatory responses in endometritis
model in mice. e leonurine treatment suppressed the
TNF-𝛼and IL-𝛽mRNA levels in uterus tissues, inhibited
lipopolysaccharide-induced TLR expression, and reduced
the phosphorylated p and I𝜅B𝛼proteins.
e clinical trial conducted by Denham et al. [] docu-
mented the herbal prescribing in usual practice, covering a
total of  herbs on  prescriptions (the most encountered
being L. cardiaca - %) for treatment of symptoms associated
with the menopause on  subjects. L. cardiaca was mainly
prescribed to control hot ushes, as a gynecological tonic and
as a relaxant.
Inarandomizedstudyconductedonwomenunder-
going cesarean section, motherwort, in combination with
oxytocin, proved to be ecient for preventing postpartum
hemorrhage [].
Regarding the use of L. cardiaca in female disorders, the
plant is listed as a natural remedy for female reproductive
system (anxiolytic, antispasmodic, PMS, and menopausal
anxiety) [], as an emmenagogue, nervine, amenorrhea,
analgesic, and uterine astringents/vascular decongestants
and for treating adolescent dysmenorrhea [], for treating
menopausal anxiety, and as tranquilizer []. Lans et al.
[] present motherwort as a natural cure used in North
America from colonial times, due to its tonic, emmenagogue,
antispasmodic, and nervine properties, citing pre-
works.
3.3. Antioxidant Action. e antioxidant activity of L. car-
diaca products was evaluated using several methods. Sad-
owska et al. [] evaluated the antioxidant potential of L. car-
diaca extract by ABTS, DPPH, and ferric reducing antioxi-
dant power assay, obtaining values of the antioxidant capacity
in the range ±–± 𝜇MTrolox/g.Ebrahimzadeh
et al. [] evaluated the antioxidant potential of Iranian
native L. cardiaca extract obtained from dried aerial parts by
percolation using methanol, by comparison with Grammos-
ciadium platycarpum and Onosma demawendicum extracts.
e results obtained by DPPHassay (IC50 =±.
mg/ml), iron reducing assay (results superior to vitamin
Cintheconcentration range-𝜇g/ml), nitric oxide-
scavenging assay (IC50 = . ±. mg/ml), metal chelating
assay (IC50 =±𝜇g/ml), and scavenging of hydrogen
peroxide (IC50 =.±. 𝜇g/ml) were correlated with the
total phenol content (. ±. mg gallic acid equivalent/g of
extract). Ebrahimzadeh et al. [] evaluated the correlation
between the total phenolic compounds and total avonoids
content and the nitric oxide scavenging properties for 
Iranian medicinal plants. e authors found good correlation
between total phenolic content (. ±. mg gallic acid
equivalent/g of extract) for L. cardiaca aerial parts methanol
extract, total avonoids content (. ±. mg quercetin
equivalents/g of extract), and nitric oxide radical scavenging
activity (IC50 = . ±. mg/ml).
Armatu et al. [] evaluated the antioxidant potential of
several extracts obtained from Romanian Lamiaceae species
(including L. cardiaca methanol extract) using the DPPH
assay, phosphomolybdenum method, and chemilumines-
cence assay in relationship with HPTLC ngerprints and
total phenolic content. e results obtained by the three
antioxidant assays at  mg/ml concentration (DPPH–%,
total antioxidant capacity –approx.  mg ascorbic acid
equivalents/g and % antioxidant activity for the chemilu-
minescence activity) were correlated with the relatively low
total phenolics content (. mg gallic acid equivalents/g of
extract).
Jafari et al. [] evaluated the total phenolic content and
antioxidant capacity (DPPHassay) of dierent fractions of
Iranian L. cardiaca extract. e best results were obtained for
the : metanolic-aqueous fraction (total phenolic content
.±. gallic acid equivalents/g of fraction and IC50 =
. 𝜇g/ml – DPPHassay).
e inuence of drying method was studied by Yi and
Wetzstein [] using three drying methods (greenhouse
sun-drying, C oven-drying, and Coven-drying)on
% methanol and % ethanol extracts from the leaves of
cultivated L. cardiaca plants. e best results were obtained
for ethanol extracts of C oven-dried plants (total polyphe-
nolics – approx.  mg/g GAE, Trolox-equivalent antioxidant
capacity – approx.  mM/g TE).
Polysaccharides from L. cardiaca extract exhibited a very
good scavenging activity of hydroxyl radicals (IC50 =.
BioMed Research International
±. mg/mL), compared with vitamin C (IC50 =.±
. mg/mL) []. Wong et al. [] evaluated the antioxidant
potentialandphytochemicalcompositionofaqueousextracts
obtained from Malaysian plants. e extract showed a rela-
tively good antioxidant potential (>% DPPHscavenging
activity at  mg/ml, >% NO scavenging activity at 
mg/ml, and >% metal chelating activity at  mg/ml) for
a phytochemical composition of . ±. mg GAE/g dry
weight (total phenolics), .±.mgQE/gdw(total
avonoids), and . ±. mg CAE/g dw (hydroxycinnamic
acids). e study of Ji et al. [] on the antioxidant eect of
plants with therapeutic potential on gynecological diseases
revealed no signicant inuence on the lag phase duration
of copper-induced low-density lipoprotein cholesterol (LDL-
C) oxidation, the authors suggesting as main reason for the
lack of antioxidant activity the solvent used for extraction.
Ziyatdinova et al. [] proposed an alternative method for the
evaluation of the antioxidant activity (determined as DPPH
inhibition using dierential pulse voltammetry) and com-
pared the values obtained for several medicinal plants with
those obtained spectrophotometrically. e results showed
better antioxidant eect for the L. cardiaca infusion (±%,
determined by dierential pulse voltammetry, respectively,
±%, determined by spectrophotometry) compared with
the tincture (% ethanol, .±.%, determined by dif-
ferential pulse voltammetry, respectively, ±% determined
by spectrophotometry). Ziyatdinova et al. [] described
a chronocoulometric method for the evaluation of the
antioxidant potential of  commercial-available medicinal
plants tinctures (including L. cardiaca), also establishing a
correlation between the antioxidant potential and the total
phenolics content. e evaluation revealed a relatively low
antioxidant capacity for the L. cardiaca tincture (.±. mg
quercetin/mL).
e antioxidant potential of L. cardiaca extracts was also
briey presented in other works (for example, the works of
Sen and Chakraborty [] and Krishnaiah et al. []).
3.4. Other Applications. Motherwort was historically used
for the treatment of several nervous aictions, such as
depression, anxiety, or stress []. Romm [] classied L.
cardiaca as a natural remedy for the treatment of several aic-
tions, including postpartum depression, while the traditional
internal use of motherwort for the treatment of epilepsy was
documented by Adams et al. []. e potential towards the
treatment of anxiety and depressive disorders was evaluated
by Rauwald et al. [, ], by studying the eect of L. cardiaca
extract and constituents (isoleosibirin, R-chloro--desoxy-
harpagide, lavandulifolioside, stachydrine, and leonurine) on
the neuronal receptor gamma-aminobutyric acid (GABA).
e extract inhibited the concentration-dependent binding
of [()H]-SR to the GABA site of the GABA type
A receptor with a binding anity (IC50)of𝜇g/ml, sug-
gesting a potential neurological mechanism of action of
L. cardiaca, based on interaction to the GABA site of the
GABA type A receptor. e individual components tested
(except leonurine – IC50 -𝜇g/ml) did not exhibit signicant
activity. Commercially available leonurine was demonstrated
by Xu et al. [] to ameliorate LPS-induced acute kidney
injury in mice. e nephroprotective eect was expressed,
aer  days of treatment, by the values of reactive oxygen
species (ROS), malonyldialdehyde (MDA), and reduced glu-
tathione (GSH) which were reduced to near control levels,
while the lipopolysaccharide-induced tubular damage was
signicantly ameliorated, decreased renal injury biomarker
(KMI-), and inhibited the nuclear transfer of NF-𝜅Bp.
A similar nephroprotective eect was registered by Cheng
et al. [] in mouse unilateral urethral obstruction, by sup-
pressing ROS-mediated TGF-𝛽/Smad-induced tubulointer-
stitial brosis and inhibiting NF-𝜅B-mediated inammatory
response. Leonurine was also found to ameliorate cognitive
disfunction in rats’ model []. At a  concentration,
it was found to decrease the oxygen-glucose deprivation-
(OGD-) induced brain cell death to approx. % (fold of
control group), an approx. % reduction, compared with
the OGD group. Also, leonurine was found to alleviate
the impaired spatial learning and memory, as demonstrated
through Morris water maze test. Leonurine also decreased the
concentrations of glutamate and hydrogen peroxide in hip-
pocampus, ameliorated the impaired long-term depression
in hippocampus, improved cognitive function by modulating
the N-methyl-D-aspartate receptors-associated proteins, and
protected rats from bilateral carotid artery occlusion-induced
damage by inhibiting autophagy. e results suggested
leonurine as a potential drug candidate for chronic cerebral
hypoperfusion.
Ethanolic extract obtained from aerial parts of L. cardiaca
was evaluated by Rezaee-Asl et al. [] as a potential analgesic,
using formalin, tail ick, and hot plate tests in mice. e
results of the study proved that at  mg/kg the extract
was able to reduce the formalin-induced pain in the early
phase, increase the antinociceptive activity, and signicantly
inuence the reaction time of the animals to the hot plates,
supporting the analgesic properties of the extract, action
mediated through peripheral, and central inhibitory mech-
anisms.
e antiviral potential of L. cardiaca was reviewed by
Todorov et al. []. Dierent components of the extract were
found to be active against several types of viruses (ursolic
acid - HCV, HPV-; quearcetin - HSV-, poliovirus , RSV;
hyperoside – DHBV; apigenin – HSV-; rutin – HIV-), while
the chloroform and methanol extracts were presented to
possess antiherpes activity against HSV- and .
Onumah [] presents L. cardiaca as a potential adjuvant
in treating overactive thyroid, due to its action against
symptoms associated with hyperthyroidism (palpitations and
anxiety). Inhibition of the thyroid-stimulating hormone and
the reduction of excess production of thyroid hormones
were also presented by Shokri et al. [], the property being
assigned to its content in rosmarinic acid.
Unlike many other plant species, the evaluated liter-
ature data (even outside the time period covered by the
present review) presents no research regarding the phytosyn-
thesis of metallic nanoparticles using L. cardiaca extracts,
although the procedure was presented for L. japonicus
[].
Table  summarizes the main biological activities pre-
sented.
BioMed Research International
T : Biological activities of L. cardiaca (-).
Origin Part of plant/product Typ e of
paper Activity Tests performed
Components
responsible for
activity
Ref.
-AerialpartsReview
Against uterine
infection or other
gynecological
diseases,
tachyarrhythmia and
other cardiac
disorders
--[]
- Aerial parts Review Antioxidant -
Rutin and derivatives
of hydroxycinnamic
acid
[]
Commercially
available,
Germany
Aerial parts extract
(aqueous Soxhlet) and
rened extracts:
dichloromethane, %
hydroethanolic
Research Antianginal and
antiarrhythmic
Epicardial potential
mapping, eect on the
cardiac ion currents
phenolic constituents []
Commercially
available Ursolic acid Research Cardioprotective
Evaluation of
mitochondrial
respiratory rates,
mitochondrial H2O2
generation, H2O2
antioxidant activity
-[]
Wild-growing,
Lithuania % ethanol extract Research Cardioprotective
Measurement of the
mitochondrial
respiration rate and
mitochondrial H2O2
generation
Chlorogenic acid and
avonoids orientin,
quercetin, hyperoside,
and rutin
[]
- Soybean oil extract Clinical
trial
Treatment of arterial
hypertension
accompanied by
anxiety and sleep
disorders
dynamics of
psychoneurological
symptoms; state –
activity – mood, the
Clinical Global
Impression scale, systolic
blood pressure, diastolic
blood pressure, heart
rate and ECG
Iridoids []
Commercially
available Stachydrine Research endothelial function
protection
Determination of cell
viability, Nitric oxide
assay, Measurement of
BH, Measurement of
cGMP levels in rat
arterial rings.
Measurement of
vasorelaxation,
Quantitative reverse
transcriptase-PCR
(qRT-PCR), Western
blotting
-[]
- Extract Review Sedative, cardiotonic - []
- Aerial parts extract Review
cardiotonic
bradycardic agent,
hypotensive
--[]
- Aerial parts tincture Review
Sedative,
decreases arterial
pressure and
strengthens the
contraction of uterus
muscles
--[]
BioMed Research International
T  : C o n t i n u ed.
Origin Part of plant/product Typ e of
paper Activity Tests performed
Components
responsible for
activity
Ref.
-StachydrineReview
Protective eect in
experimental
myocardial ischemia
reperfusion
injury
--[]
--Review
Sedative,
antispasmodic,
electrophysiologic
[]
- Lavandulifolioside Review chronotropic eects - - []
- - Review Cardiovascular - - []
- Aerial parts, tea Review
Strengthening the
heart, arrhythmia,
antihypertensive
--[]
--Review
Cardiac arrhythmias,
tachycardia, heart
palpitations
-phenylpropanoid
glycosides []
-AerialpartsReview
Cardioprotective,
antioxidant --[]
--Review
relief of nervous
tension symptoms,
treatment of
arrhythmias
--[]
--Review
maintenance of
normal cardiac
rhythm
--[]
--ReviewCardiotonic--[]
--ReviewSedative,vasodilator--[]
Commercially
available Leonurine Research Anti-Inammatory
Histopathological
analysis, Cytokines
Analysis, Quantitative
Real-Time Polymerase
Chain Reaction, Western
Blot Analysis
-[]
Commercially
available Leonurine Research Agent for gouty
arthritis treatment
Histological
examination, Lentiviral
transduction, Western
blot analysis, Cytokine
measurement
-[]
Commercially
available, Poland
Acetone-water (:,
v/v) extract Research Immunomodulatory,
antioxidant
NO production in
Human umbilical vein
endothelial cells, platelet
aggregation, ABTS,
DPPHand FRAP assay
- []
Commercially
available,
Germany
Ethanol extract (%),
Soxhlet extraction,
Methanol extract, other
phases
Research
Anti-inammatory
and antimicrobial
Eect of extracts and
single components on
lactoperoxidase activity
Phenolic components
with
,-dihydroxyphenyl
partial
structure
[]
Commercially
available, Poland
Leaves acetone-water
(:, v/v) extract Research Antimicrobial
Evaluation of
antimicrobial,
anti-adhesive and
anti-biolm properties
against S. aureus
Iridoid glycosides, di-
and triterpenoids,
avonoids, tannins
and volatile oils
[]
BioMed Research International
T  : C o n t i n u ed.
Origin Part of plant/product Typ e of
paper Activity Tests performed
Components
responsible for
activity
Ref.
Commercially
available, Russia Aerial parts water extract Research Anti-biolm
formation Biolm formation assay - []
Commercially
available, Poland
Aerial parts
polyphenol-enriched
extract
Research
Eect of
sub-inhibitory
concentration
extracts on S. aureus
S. aureus survival,
staphylococcal tolerance
to oxidative stress, S.
aureus 𝛼-toxin (Hla)
release and protein A
(SpA) expression,
Staphylococcal
aggregation in human
plasma, Fibrinogen
polymerization and S.
aureusadhesion to brin
-[]
Commercially
available Leonurine Research Anti-inammatory
Histopathological
analysis, Cell viability
assay, Analysis of
cytokines, qRT-PCR
analysis,
immunoblotting
analysis,
-[]
- Aerial parts, tea Clinical
trial
To control h o t  u s h e s ,
gynaecological tonic,
relaxant
--[]
- Motherwort injection Trial
Preventing
postpartum
hemorrhage
Mean blood loss,
postpartum hemorrhage,
mean systolic blood
pressure, diastolic BP,
heart rate, respiratory
rate, hemoglobin and
platelet count, incidence
of postpartum
hemorrhage, safety
assessment
-[]
-AerialpartsReview
Anxiolytic,
antispasmodic, PMS,
and menopausal
anxiety
--[]
Aerial parts, tea,
tincture, infusion Review
Antispasmodic,
anti-inammatory
anxiolytic, uterine
tonic,
--[]
-Aerial parts, tincture,
tea, infusion Review
Menopausal anxiety,
insomnia, palpitations
hyperthyroidism,
--[]
-Aerial parts, infusion,
decoction Review
Tonic, Amenorrhoea,
suppressed lochia,
dysmenorrhoea,
antispasmodic,
nervine,
emmenagogue
--[]
Wild-growing,
Iran
Aerial parts, methanol
extract Research Antioxidant, radical
scavenging
DPPH
radical-scavenging
activity, reducing power,
nitric oxide-scavenging
activity, Metal chelating
activity, ferric
thiocyanate assay,
Scavenging of hydrogen
peroxide
Phenolic compounds []
BioMed Research International
T  : C o n t i n u ed.
Origin Part of plant/product Typ e of
paper Activity Tests performed
Components
responsible for
activity
Ref.
Wild-growing,
Iran
Aerial parts, methanol
and water extracts Research Antioxidant Nitric oxide radical
scavenging activity
Phenolic compounds,
avonoids []
Cultivated,
Romania
Aerial parts, methanol
extract Research Antioxidant, free
scavenging potential
phosphomolybdenum
reduction assay, DPPH
assay,
Chemiluminescence
assay
Polyphenolics []
Cultivated, Iran Aerial parts, extracts and
fractions Research Antioxidant DPPHassay Phenolic compounds []
Cultivated,
Greece
Leaves, % methanol or
% ethanol Research Antioxidant ABTSassay Phenolic compounds []
Wild-growing,
Iran
Leaves, polysaccharides
extract Research Antioxidant,
antimicrobial
Hydroxyl radical
scavenging capacity,
DPPHassay,
antimicrobial eect
evaluated by the lter
disk diusion plate
method against bacteria,
yeast and fungi
Polysaccharides []
Wild-growing,
Malaysia
Aerial parts, water
extract Research Antioxidant,
antidiabetic
DPPHassay, nitric
oxide radical scavenging
assay, metal chelating
activity,
Alpha-glucosidase
inhibition assay
Phenolic compounds []
Commercially
available, China
Aerial parts, aqueous
extract Research Antioxidant LDLc oxidation delay - []
Commercially
available, Russia
Commercial tinctures
and infusions Research Antioxidant
DPPHassay,
voltammetry and
spectrophotometric
-[]
Commercially
available, Russia Commercial tinctures Research Antioxidant Chronocoulometry
Lavandulifolioside,
phenolic acids, caeic
acid -rutinoside,
tannins
[]
--ReviewAntioxidant--[]
- Methanol extract Review Antioxidant DPPHassay Flavonoid and
phenolic glycosides []
- Aerial part, tincture, tea Review Nervine relaxant,
anxiolytic, --[]
- - Review Epilepsy treatment - - []
Commercially
available,
Germany
Aerial parts, %
ethanol extract,
Stachydrine, Leonurine,
Lavandulifolioside,
Isoleosibirin, R-chloro-
-desoxy-harpagide
Research
Treatment of anxiety,
depression,
nervousness, sedative
In vitro GABA receptor
binding assays, -[,]
Commercially
available Leonurine Research Nephroprotective
Measurement of TNF-𝛼,
IL-, IL-, IL-,
Measurement of serum
creatinine and blood
urea nitrogen, Assay of
GSH, Assay of ROS,
Assay of MDA level,
Western blot analyses,
Protein assay,
Histological assay
-[]
 BioMed Research International
T  : C o n t i n u ed.
Origin Part of plant/product Typ e of
paper Activity Tests performed
Components
responsible for
activity
Ref.
Commercially
available Leonurine Research Nephroprotective
Measurement of TGF-𝛽,
TNF-𝛼,IL-andIL-𝛽
level, ROS assay, Assay
of MDA level, Assay of
GSH level, Western blot
analyses, Protein assay,
Histological assay
-[]
Commercially
available Leonurine Research Neuroprotective
Evaluation of spatial
learning and memory
performances of rats,
levels of glutamate and
H2O2of hippocampus,
Western blot assay
-[]
-Aerial parts, ethanolic
extract Research Analgesic Nociceptive Behavioral
Tests -[]
-Aerial parts, dierent
types of extracts Review Antiviral -
ursolic acid,
quercetin, hyperoside,
apigenin--
glucoside, rutin
[]
--Review
Treatment of
hyperthyroidism,
palpitations, anxiety
--[]
--Review
Treatment of
hyperthyroidism -Rosmarinicacid[]
4. Dosage and Toxicology
As previously has been presented, L. cardiaca preparations are
currently used in the treatment of several conditions. Relative
to commercial products, the EMA report cited [] presents
them to be safe, suggesting a duration of use limited to four
weeks. e report also presents the adverse eects of an intake
of . grams of a powdered extract per day (diarrhea, uterine
bleeding, and stomach irritation). L. cardiaca is listed as a
“herb to avoid during pregnancy” [, ], mainly due to its
emmenagogue and uterine stimulation properties. Kaye et
al. [] listed L. cardiaca as a “herbal drug associated with
bleeding abnormalities”, an aspect to be considered by the
anesthesia practitioner.
Anad´
on et al. [] presented the reduction of platelet
aggregation and brinogen levels upon intravenous adminis-
tration of motherwort. L. cardiaca also potentiates antithrom-
botic and antiplatelet eects, increasing the risk of bleed-
ing. When administered concomitant with benzodiazepines,
motherwort can also have a synergistic sedative eect result-
ing in coma [].
L. cardiaca was also presented to potentialize the eect of
warfarin, by inhibiting platelet aggregation [].
Related to individual compounds, data are scarce and
mainly outside the current review time period: Milkowska-
Leyck et al. presented moderate toxicity of lavandulifo-
lioside (LD50 approx.  mg/kg) and n-butanol extract
(LD50 approx.  mg/kg) for intravenous administration,
while for oral administration, the toxicity was much lower
(LD50 > mg/kg) []; Mitchell and Rook [] present
the potential of L. cardiaca leaves to cause photosensitization
and dermatitis; herbal intravenous injection has a LD50 of
- mg/kg (mice), while the intravenous LD50 of the total
alkaloids of the herb was approx.  mg/kg, while the
minimal lethal dose of leonurine in frogs (subcutaneous
administration) was - mg/kg []. Due to the lack
in scientic evidences, most of the sources presenting tra-
ditional use of motherwort suggest the strict following of
relevant directions on products containing L. cardiaca and
the requesting supplemental information from pharmacists,
physician, or other healthcare professionals before use [].
Some chemical components from L. cardiaca aerial parts
(pyrrolidine alkaloids, such as stachydrine, cyclic peptide,
such as cycloleonurinine or labdane diterpenes, such as
leosibiricin) are considered “chemicals of concern” for human
health when used in food and food supplements [].
5. Conclusions
e use of motherwort (Leonurus cardiaca L.) has been
documented since ancient times, especially as a cardiotonic
and for the treatment of gynecological conditions. e com-
position (dominated by furanic diterpenes, alkaloids, sterols,
andiridoids)wasprovedtopresentacomplexbiological
activity, with cardioprotective, antioxidant, antimicrobial,
anti-inammatory, analgesic, nephroprotective, and antiviral
properties, among others.
e current study aimed to present the progress made
in the study of motherwort from the date of the European
Medicine Agency “Assessment report on Leonurus cardiaca
BioMed Research International 
L., herba”. According to our ndings, most of the literature
data focuses on cardioprotective and antioxidant potential of
L. cardiaca, although the data also suggest the exploration of
new applications. is, in turn, would be a promising research
area for future studies. Future research should also be focused
on a denitive conclusion regarding the composition of
motherwort (especially the presence of leonurine), as well as
the opening of new research directions, such as the use of L.
cardiaca extracts in nanotechnology (for the phytosynthesis
of nanoparticles).
Conflicts of Interest
e authors declare no conicts of interest.
Authors’ Contributions
All authors contributed equally to data collection and analy-
sis, and manuscript design. Irina Fierascu and Radu Claudiu
Fierascu prepared and revised the manuscript.
Acknowledgments
e authors gratefully acknowledge the support obtained
through the project SusMAPWaste, SMIS , Contract
No. /.., from the Operational Program Compet-
itiveness -, project conanced from the European
Regional Development Fund.
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... The literature provides significant scientific data on the study of the chemical composition of motherwort herb (Leonurus cardiaca L.) [1,13,14], root/rhizome of valerian (Valeriana officinalis L.) [2], fruit, leaves with flowers of hawthorn (Crataegus genus) [3]. For example, the structures of about 300 substances have been isolated and determined from the motherwort (Leonurus genus) [13,14]. ...
... The literature provides significant scientific data on the study of the chemical composition of motherwort herb (Leonurus cardiaca L.) [1,13,14], root/rhizome of valerian (Valeriana officinalis L.) [2], fruit, leaves with flowers of hawthorn (Crataegus genus) [3]. For example, the structures of about 300 substances have been isolated and determined from the motherwort (Leonurus genus) [13,14]. They are represented by alkaloids, monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, iridoids, flavonoids, phenylpropanoids, steroids, cyclic peptides, etc. ...
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Objective: To substantiate the possibility of using polarimetry to control the quality of tinctures as an additional pharmacopoeial method. Methods: The polarimetric method (POL-1/2, Atago, Japan, the measurement accuracy of±0.002 °) was used to measure the optical activity (α °) of motherwort, valerian and hawthorn tinctures. The dynamic light scattering method (DLS; Zetasizer Nano ZS, Malvern, UK) was used to assess the stability of alcoholic and aqueous dilutions of tinctures according to the intensity of dynamic light scattering dependent on the size (d, nm) of the dispersed phase particles and the values of the electrokinetic potential (ξ, mV). Results: For the first time in this investigation, the polarimetry approach was proposed to evaluate the cardiotonic and hypotensive tinctures' quality and for their identification. Valerian tincture, dilution 1:40,-0.10°<α°<-0.89°; motherwort, tincture-dilution 1:10,-0.10°<α°<-2.21°; hawthorn, tincture without dilution,-0.76°<α°<-1.55°-these are the acceptable ranges of optical activity (α°) of their alcohol dilutions. Beyond these intervals, the use of the polarimetric approach is impossible. Values of optical activity below 0.1 correspond to too low a content of optically active components. Tinctures with optical activity above the upper value of the interval were unstable dispersed systems with low values of the electrokinetic potential (|ξ|≪25mV) and micron particle sizes. Reference tinctures were made from raw materials (Leonurus cardiaca L.) to verify the results. The quality parameters: optical activity (α°), spectra of dynamic light scattering by intensity, volume, and number ("I-d"; "V-d"; "N-d"), electrokinetic potential (ξ) values, and photon pulse count per second (Count Rate, kcps) corresponded to the results obtained for pharmaceutical dosage forms. Conclusion: The permissible intervals of optical activity (α°) of their ethanol dilutions, as well as their relationships with the particle size of the dispersed phase and the values of the electrokinetic potential, were established for the first time to evaluate the quality of tinctures. The obtained results show that polarimetry can be recommended as an additional pharmacopoeial quality control method for tinctures.
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Book
This book is a detailed guide to a new integrative approach to the prevention and treatment of various cardiac disorders and risk factors, including coronary artery disease, congestive heart failure, arrhythmias, dyslipidemia, and hypertension. This approach combines various strategies, including metabolic cardiology, low-dose medicine, exercise programs, stress management programs, evaluation for inherited risk factors, and various other healing modalities. Metabolic cardiology focuses on the prevention, management, and treatment of cardiovascular disease at the cellular level through biochemical interventions with nutritional supplements that can promote energy production in the heart. Low-dose medicine, on the other hand, interprets pathological phenomena as an imbalance in intercellular signaling that may be corrected through the administration of low physiological doses of messenger molecules. Therapies outside of mainstream medicine may also be deployed in integrative cardiology, for example acupuncture, herbal medicine, and homeopathy. Integrative Cardiology will be of interest to all practitioners wishing to learn about an approach that incorporates the incredible advances in medication and technology with a focus on nutrition, lifestyle, and mind–body influences.