Journal of Ethnopharmacology 276 (2021) 114171

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Review

Phytochemical properties, biological activities and medicinal use of

Centaurium erythraea Rafn
Naoual El Menyiy a, Fatima-Ezzahrae Guaouguaou b, Aicha El Baaboua c, Nasreddine El Omari d,
Douae Taha e, Najoua Salhi f, Mohammad Ali Shariati g, Tarik Aanniz h, Taoufiq Benali i,
Gokhan Zengin j, Mohamed El-Shazly k, l, Imane Chamkhi m, n, Abdelhakim Bouyahya o, *
a
Laboratory of Natural Substances, Pharmacology, Environment, Modeling, Health and Quality of Life (SNAMOPEQ), Faculty of Sciences Dhar El Mahraz, Sidi
Mohamed Ben Abdellah University, Fez, Morocco
b
Mohammed V University in Rabat, LPCMIO, Materials Science Center (MSC), Ecole Normale Supérieure, Rabat, Morocco
c
Biology and Health Laboratory, Department of Biology, Faculty of Science, Abdelmalek-Essaadi University, Tetouan, Morocco
d
Laboratory of Histology, Embryology, and Cytogenetic, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco
e
Laboratoire de Spectroscopie, Modélisation Moléculaire, Matériaux, Nanomatériaux, Eau et Environnement, CERNE2D, Faculté des Sciences, Université Mohammed V,
Rabat, Morocco
f
Laboratory of Pharmacology and Toxicology, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco
g
Departement of Technology of Food Production, K.G. Razumoysky Moscow State University of Technologies and Management (the First Cossack University), 109004,
Moscow, Russian Federation
h
Environment and Health Team, Polydisciplinary Faculty of Safi, Cadi Ayyad University, Marrakech, Morocco
i
Medical Biotechnology Laboratory (MedBiotech), Rabat Medical & Pharmacy School, Mohammed V University in Rabat, 6203, Rabat, Morocco
j
Biochemistry and Physiology Laboratory, Department of Biology, Faculty of Science, Selcuk University, Campus, Konya, Turkey
k
Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566, Egypt
l
Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, 11835, Egypt
m
Laboratory of Plant-Microbe Interactions, AgroBioSciences, Mohammed VI Polytechnic University, Ben Guerir, Morocco
n
Centre GEOPAC, Laboratoire de Geobiodiversite et Patrimoine Naturel Université Mohammed V de, Institut Scientifique Rabat, Morocco
o
Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, And Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy,
Mohammed V University in Rabat, Morocco

A R T I C L E I N F O A B S T R A C T

Keywords: Ethnopharmacological relevance: Centaurium erythraea is an important medicinal plant in many countries, e.g.
Centaurium erythraea Morocco, Algeria, Italy, Spain, Portugal, and countries of Balkan Peninsula. It is used in folk medicine to treat
Terpenoids various illnesses. It is also used as an antiapoplectic, anticoagulant, anticholagogue, antipneumonic, hema­
Phenolic acids
tocathartic, and as a hypotensive agent.
Flavonoids
Aim of the review: In this review, previous reports on the taxonomy, botanical description, geographic distribu­
Antidiabetic effects
Pharmacological action tion, ethnomedicinal applications, phytochemistry, pharmacological properties, and toxicity of Centaurium
erythraea were critically summarized.
Materials and methods: Scientific search engines including PubMed, ScienceDirect, SpringerLink, Web of Science,
Scopus, Wiley Online, SciFinder, and Google Scholar were consulted to collect data on C. erythraea. The data
presented in this work summarized the main reports on C. erythraea phytochemical compounds, ethnomedicinal
uses, and pharmacological activities.
Results: C. erythraea is used in traditional medicine to treat various diseases such as diabetes, fever, rhinitis,
stomach ailments, urinary tract infections, dyspeptic complaints, loss of appetite, and hemorrhoids, and as
diuretic. The essential oils and extracts of C. erythraea exhibited numerous biological properties such as anti­
bacterial, antioxidant, antifungal, antileishmanial, anticancer, antidiabetic, anti-inflammatory, insecticidal,
diuretic, gastroprotective, hepatoprotective, dermatoprotective, neuroprotective, and inhibitory agent for larval

* Corresponding author.
E-mail addresses: Nawal.elmenyiy@usmba.ac.ma (N. El Menyiy), f.guaouguaou@gmail.com (F.-E. Guaouguaou), elbaabou.aicha@gmail.com (A. El Baaboua),
nasrelomari@gmail.com (N. El Omari), douae.taha02@gmail.com (D. Taha), salhi.najoua@yahoo.fr (N. Salhi), shariatymohammadali@gmail.com
(M.A. Shariati), tarik.aanniz@gmail.com (T. Aanniz), benali.taoufiq@gmail.com (T. Benali), biyologzengin@gmail.com (G. Zengin), mohamed.elshazly@pharma.
asu.edu.eg (M. El-Shazly), chamkhi.imane@gmail.com (I. Chamkhi), boyahyaa-90@hotmail.fr (A. Bouyahya).

https://doi.org/10.1016/j.jep.2021.114171
Received 13 September 2020; Received in revised form 1 April 2021; Accepted 24 April 2021
Available online 30 April 2021
0378-8741/© 2021 Elsevier B.V. All rights reserved.
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

development. Phytochemical characterization of C. erythraea revealed the presence of several classes of sec­
ondary metabolites such as xanthonoids, terpenoids, flavonoids, phenolic acids, and fatty acids.
Conclusions: Ethnomedicinal studies demonstrated the use of C. erythraea for the treatment of various disorders.
Pharmacological reports showed that C. erythraea especially its aerial parts and roots exhibited potent, and
beneficial activities. These findings confirmed the link between the traditional medicinal use and the results of
the scientific biological experiments. Considering these results, further investigation using diverse in vivo
pharmacological assays are strongly recommended to validate the results of its traditional use. Toxicological tests
and pharmacokinetic studies are also required to validate the safety and efficacy of C. erythraea and its bioactive
contents.

1. Introduction pharmacological effects no review was published to critically outline

Centaurium erythraea is an annual or biennial herbaceous plant
(20–60 cm in height). This species belongs to the family Gentianaceae
and the genus Centaurium comprises approximately 28 species.
C. erythraea is found in many countries among Morocco, Algeria, Italy,
Spain, Portugal, and countries of Balkan Peninsula.
This plant is an important element in traditional medicine because it
is used to treat numerous diseases such as fever (Benítez et al., 2010;
Mustafa et al., 2012a; Pieroni and Quave, 2005), dyspeptic complaints,
loss of appetite, and diabetes (Benali et al., 2017; Benkhnigue et al.,
2014; Idm’hand et al., 2020; Menković et al., 2011; Merzouki and
-derfoufi, 2000; Sefi et al., 2011), digestive disorders (Vinagre et al.,
2019), atopic dermatitis (Eraslan et al., 2020), cancer (Bouyahya et al.,
2018; Tuğlu et al., 2018), pneumonia (Agelet and Vallès, 2003), car­
diovascular problems (Chda et al., 2020; Zahrae Redouan et al., 2020),
asthma (Orch et al., 2020), gastric pain (Merzouki et al., 2000), kidney
diseases (El-Hilaly et al., 2003), and skin diseases (Bouyahya et al.,
2017a). Furthermore, it is used as an antiapoplectic and anticoagulant
(Agelet and Vallès, 2003). Ethno-pharmacological reports demonstrated
that C. erythraea is used against rhinitis, stomach ailments, urinary tract
infection, hemorrhoids, and as a diuretic, (Mustafa et al., 2012a; Vokou
et al., 1993). Phytochemical surveys showed that C. erythraea contains
numerous groups of bioactive substances including secoiridoids, xan­
thonoids, terpenoids, flavonoids, phenolic acids, and fatty acids (Aber­
ham et al., 2011; Bouyahya et al., 2019; Guedes et al., 2019;
Hatjimanoli, 1988; Jovanović et al., 2013; Kaouadji et al., 1986;
Mebavý, 1987; Mihaylova et al., 2019; Šiler et al., 2014; Stefkov et al.,
2014; Subotić et al., 2009; Trifunović-Momčilov et al., 2016). Pharma­
cological experiments revealed that essential oils from C. erythraea aerial
parts exhibited various biological effects including antibacterial (Bas­
sanetti et al., 2017; Bouyahya et al., 2017a, 2019; Božunović et al.,
2018; Kamatou et al., 2013; Kumarasamy et al., 2002, 2003; Šiler et al.,
2014), antioxidant (Bouyahya et al., 2017a, 2018, 2019; Božunović
et al., 2018; Kachmar et al., 2019; Merghem and Dahamna, 2020;
Mihaylova et al., 2019; Shahat et al., 2003; Valentão et al., 2001, 2003),
antifungal (Božunović et al., 2018; Kirbağ et al., 2009; Pereira et al.,
2011; Šiler et al., 2014), antileishmanial (Bouyahya et al., 2017b),
cytotoxic (Bouyahya et al., 2018; Tuğlu et al., 2018), antidiabetic (Sefi
et al., 2011; Mansar-Benhamza et al., 2013; Hamza et al, 2010, 2015;
Stefkov et al., 2014; Tahraoui et al., 2017; Bouyahya et al., 2019;
Đorđević et al, 2017, 2019, 2020), anti-inflammatory (Mascolo et al.,
1987; Berkan et al., 1991; Kachmar et al., 2019), insecticidal and
inhibitory of larval development (Pascual-Villalobos and Robledo, 1998;
Jbilou et al., 2008), spasmolytic action (Berridge, 2008; Chda et al.,
2016; Moradi et al., 2013; Ragy and Elbassuoni, 2012; Stefkov et al.,
2014; Toda et al., 1990; Zyromski et al., 2001), gastroprotective (Bafna
and Balaraman, 2004; El-Missiry et al., 2001; Hoppenkamps et al., 1984;
Szelenyi and Brune, 1988; Tanaka and Yuda, 1996; Tuluce et al., 2011;
Wallace et al., 1990), dermatoprotective (Karioti et al., 2007; Bouyahya
et al., 2019), hepatoprotective (Mroueh et al., 2004), neuroprotective
(Orhan et al., 2017; Guedes et al., 2019), analgesic, and antipyretic
activities (Berkan et al., 1991). Even though many studies highlighted
the richness of C. erythraea in secondary metabolites with a plethora of
these reports and suggest future potential applications of this plant. This
motivated us to write this review on C. erythraea in which we empha­
sized its taxonomy, botanical description, geographical distribution,
ethnomedicinal uses, phytochemical compounds, pharmacological
properties, and toxicity.
2. Research methodology
The collection of data concerning botanical description, taxonomy,
distribution, ethnobotany, phytochemistry, and pharmacology of Cen­
taurium erythraea was achieved using several scientific search engines
such as Google Scholar, Web of Science, Scopus, ScienceDirect,
SpringerLink, Wiley Online, SciFinder, and PubMed. Only scientific ar­
ticles are included, while Ph.D. and master thesis are excluded. The
articles used are published in English. The collected data were organized
and classified, analyzed, and summarized in this review according to
each field. For this bibliometric survey, different keywords related to
Centaurium erythraea Rafn were used including Centaurium erythraea,
Centaurium erythraea essential oils, Centaurium erythraea extracts, bio­
logical effects of Centaurium erythraea, the chemical composition of
C. erythraea, and genus Centaurium. Concerning phytochemistry data,
the IUPAC names of the identified chemical compounds were checked
using PubChem database. The chemical structures were drawn using
ChemDraw Pro 8.0 software.
3. Results and discussion
3.1. Botanical description
Centaurium erythraea Rafn is a herbaceous biennial/winter annual
species (2–50 cm in height) (Barešová, 1988; Van Rossum, 2009), with
straight stems, solitary or 2–5 from common base, 4-angled, in upper
part branched, the branches upright (Paniagua-Zambrana and Buss­
mann, 2020). Basal leaves are obovate or elliptic (10–50x8-20mm),
prominently three to sevenveined. Cauline leaves are shorter, narrow,
and acute, and flowers are sessile or subsessile (Barešová, 1988).
Moreover, it possesses the lateral flowers with 2 small linear-subulate
bracteoles inserted just below the calyx (Barešová, 1988). Teeth are
linear-subulate and shorter or rarely equal to the corolla tube. The
corolla is about 10 mm in length and up to 10 mm in diameter at the
flower throat. The corolla lobes are oval, obtuse, bright pink in color.
Capsule narrowly oblong, c.10 mm long with numerous brownish,
irregularly globose seeds (Paniagua-Zambrana and Bussmann, 2020).
The germination of C. erythraea fruits takes place in March. The flow­
ering stage lasts between June and August and the plant can reach the
stage of senescence in September (Paniagua-Zambrana and Bussmann,
2020).
3.2. Taxonomy, geographic distribution and ecological factors
Centaurium erythraea Rafn (Synonym: C. umbellatum Gilib., C. minus
Moench, Erythraea centaurium Pers., common centaury), is a member of
the family Gentianaceae (Melderis, 1972; Zeltner, 1970). This medicinal

2
N. El Menyiy et al.
plant, commonly known as “feverfoullie”, “centaury gentian” or “cen­
taury” (Kumarasamy et al., 2003), described by Dioscorides as early as
in the first century A. D. Comprehensive reports on the taxonomy of the
genus Centaurium were published inter alia by several researchers
(Zeltner, 1970; Melderis, 1972; Mansion, 2004, 2014; Mansion and
Struwe, 2004; Mansion et al., 2005). Centaurium erythraea is widespread
in most of Europe (Flora Europaea Online database, 2011), as far as
Afghanistan and limited to the south by North Africa (GRIN Online
Database, 2011). This glabrous plant from oceanic Europe and the
Mediterranean is also naturalised in America (Flora Celtica Online
database, 2001; Flora Europaea Online database, 2002; GRIN Online
Database, 2011). Formerly, the plants was mainly collected from local
wild populations all over Europe, nowadays, this plant is collected
mainly from wild populations of the Mediterranean region, principally
in Balkans, Algeria, and Morocco (Barešová, 1988). The most
C. erythraea populations in central Europe are declining due to over­
exploitation and deterioration of their natural habitats.
3.3. Ethnobotanical studies
Numerous ethnobotanical surveys pointed out the importance of
C. erythraea in traditional medicine. This species belongs to the family
Gentianaceae, one of the famous medicinal plant families frequently
reported and cited in ethnobotanical studies in Morocco. The medicinal
application depends on the used part of the plant. Regardless of the part
of the plant, it has been used in traditional medicine for almost the same
therapeutic purposes. The applications of C. erythraea in traditional
therapeutic systems are listed in Table 1. The main medicinal uses of the
plant in traditional Moroccan medicine systems include the treatment of
diabetes in different regions (Benali et al., 2017; Benkhnigue et al.,
2014; Hachi et al., 2016; Hachlafi et al., 2020; Idm’hand et al., 2020;
Jamila and Mostafa, 2014; Jouad et al., 2001; Labiad et al., 2020;
Merzouki et al., 2000, 2003; H Orch et al., 2015). Interestingly, the use
of this plant as an antidiabetic agent has been the most requested by
many populations. Effectively, the population of eastern Morocco uses
the whole plant as a decoction against diabetes (Jamila and Mostafa,
2014), the population of north-west Morocco (KsarLakbir) uses the
whole plant as an infusion (Merzouki et al., 2000), as well as the pop­
ulation of northern Morocco (Izarene region and Chefchaouen prov­
ince), and central Morocco (Al Haouz-Rhamna region). The population
of north-eastern of Morocco (Guercif Province) uses the aerial parts as an
infusion and/or maceration (Benali et al., 2017; Benkhnigue et al., 2014;
Merzouki et al., 2003; H. Orch et al., 2015). In the central Middle Atlas
region of Morocco, C. erythraea has also been used as a remedy for
diabetes by preparing the flowers of this plant as an infusion (Hachi
et al., 2016). Moreover, the population of the Fes - Boulemane region
uses the aerial part against the same disease (Jouad et al., 2001). The
leaves were prepared as an infusion and/or maceration in northern
Morocco (Labiad et al., 2020), as well as a decoction by the population
of central Morocco (region of Rabat-Salé-Kénitra) for the same thera­
peutic purposes (Hachlafi et al., 2020). Similarly, the aerial parts of
C. erythraea mixed with the flowers as an infusion and/or decoction have
been used as an antidiabetic remedy (Idm’hand et al., 2020). Other
ethnobotanical studies of this medicinal plant in the northeast region of
the Dahra mountains, Bissa region, Algeria, and Kabylia region included
the use of the leaves against diabetes (Meddour and Meddour-Sahar,
2015; Senouci et al., 2019). Likewise, the aerial parts of C. erythraea
have been traditionally used as an infusion in the northwest and
southwest of Algeria against diabetes (Rachid et al., 2012), as well as in
most provinces of Algeria (Hamza et al., 2019). It has also been noted
that the Portuguese (central Portugal, Santarém) use a decoction of the
C. erythraea aerial parts as an anti-diabetic agent (Gaspar et al., 2002).
On the other hand, C. erythraea has been used against various other
diseases. Indeed, the plant flowers are macerated and used in traditional
medicine against skin diseases by the local population of north-west
Morocco (Bouyahya et al., 2017a). The flowers are also used against
3
Journal of Ethnopharmacology 276 (2021) 114171
rhinitis and as a diuretic by the population of northern Morocco (Labiad
et al., 2020). C. erythraea is also used for digestive disorders (El-Hilaly
et al., 2003; Merzouki et al., 2000; Zahrae Redouan et al., 2020), feeding
problems (Jamila and Mostafa, 2014), kidney diseases (El-Hilaly et al.,
2003), for gastric pain, a bilious stimulant, helminthiasis (Merzouki
et al., 2000), and for cardiovascular diseases (Zahrae Redouan et al.,
2020). The aerial parts are prepared by the population of northern
Morocco (Izarene region) as an infusion and/or decoction for the
treatment of asthma (Zahrae Redouan et al., 2020).
The leaves mixed with the flowers are used by the population of the
Kabylie region of Algeria against fever, gastric disorders, and against
worms (Meddour and Meddour-Sahar, 2015). Tuttolomondo et al.
(2014) reported the ethnobotanical use of C. erythraea aerial part as a
decoction in Nebrodi regional park in north-eastern Sicily, Italy for the
treatment of fever. This anti-fever effect is also known in different re­
gions of Italy (Pieroni and Quave, 2005). The whole plant has been used
as a decoction by the population of southern Italy (Cilento National Park
and Vallo Di Diano, Campania) as an antipyretic (Di Novella et al.,
2013), the same effect was cited in another ethnobotanical study in
central Italy (Marche, Abruzzo, and Lazio) (Guarrera, 2005).
The aerial parts of C. erythraea showed multiple therapeutic activities
according to an ethnobotanical study in Spain (Region of Pallars, Pyr­
enees, Catalonia, Iberian Peninsula) (Agelet and Vallès, 2003) demon­
strating antiapoplectic, anticoagulant, anticholagogue, antipneumonic,
intestinal antiseptic, hematocathartic and hypotensive effects. More­
over, the aerial parts have been used as an infusion by the population of
the L’AltEmporda region of Catalonia, the Iberian Peninsula for the
treatment of influenza (Bonet et al., 1999).
The flowers of the plant have been used as a decoction by the pop­
ulation of southern Spain (western part of the province of Granada)
against fever (Benítez et al., 2010). The flower decoction has been also
used to treat the loss of appetite as mentioned in another ethnobotanical
study in the Navarra region of Spain (Calvo et al., 2013).
In Serra de Montejunto, Portugal, the infusion of C. erythraea aerial
parts has been used against digestive disorders and parasites (Vinagre
et al., 2019). Portuguese also use C. erythraea to treat the loss of appetite
(Gaspar et al., 2002; Vinagre et al., 2019).
In Greece (Epirus, Zagori), C. erythraea has been known for its effect
against hemorrhoids, wounds, as anthelmintic, diuretic, tonic, and
stimulant (Vokou et al., 1993). The aerial parts of C. erythraea are also
used in the high mountain region of Montenegro by local people to treat
dyspeptic complaints, loss of appetite, and diabetes (Menković et al.,
2011).
The population of the rural alpine communities in Kosovo uses the
decoction of C. erythraea aerial parts as anti-hemorrhoid, anti-diabetic,
lithontriptic, and against fever (Mustafa et al., 2012a). The aerial parts
extract with cold water is used to treat stomach ailments and urinary
tract infections (Mustafa et al., 2012a). The stem decoction exerts a
lithotriptic effect (Mustafa et al., 2012a).
Another ethnobotanical study in the Gollak region, Kosovo demon­
strated that the infusion of C. erythraea flowers is used to treat fever
(Mustafa et al., 2012b). In the northeast of Bosnia and Herzegovina
(Konjuh mountain), the flowers of C. erythraea has been known for its
sedative, blood purification, and appetite stimulant effects as well as
against gastrointestinal complaints and anemia (Saric-Kundalic et al.,
2010). In Eastern Serbia (Rtanj Mountain), Zlatković et al. (2014)
created a list of medicinal plants, collected by the local community,
including C. erythraea (whole plant) which was prepared as an infusion
for therapeutic purposes as a stimulant, antidiabetic, and antiflatulent
and also against digestive disorders. Similarly, the following year, Jarić
and colleagues analyzed data collected in another region in
south-eastern Serbia (Suva planina) with those from the Western Bal­
kans (Jarić et al., 2015). Indeed, the aerial parts of C. umbellatum Gilib
(Synonym: C. erythraea) have been used in the treatment of stomach
ulcers, diabetes, fever, laryngitis, intoxication, loss of appetite, and also
against cold (tea) and back pain (tincture based on komovica). Also, the
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 1
Ethnomedicinal uses of Centaurium erythraea.
Traditional use Study area Used part Mode of References
preparation

Diabetes Different Moroccan provinces Flowering tops and Infusion and Idm’hand et al. (2020)
aerial parts decoction
Diabetes Morocco (Central Middle Atlas region) Flowering top Infusion Hachi et al. (2016)
Diabetes North of Morocco (Izarene region) Aerial parts Infusion and Orch et al. (2015)
decoction
Diabetes Morocco (Al Haouz-Rhamna region) Aerial parts Infusion and Benkhnigue et al. (2014)
decoction
Diabetes Northcentral region of Morocco Aerial parts Not reported Jouad et al. (2001)
(Fez–Boulemane)
Diabetes North-West Morocco (Ksar Lakbir Aerial parts Infusion (Merzouki et al., 2000)
district)
Diabetes Morocco (Rabat-Sale-Kenitra region) Leaves Decoction Hachlafi et al. (2020)
Diabetes North-East of Morocco (Province of Aerial parts Infusion Benali et al. (2017)
Guercif)
Diabetes North of Morocco (Chefchaouen Aerial parts Infusion Merzouki et al. (2003)
province)
Diabetes Different Algeria provinces Aerial parts Not reported Hamza et al. (2019)
Diabetes Northwestern and South Western Algeria Aerial parts Infusion Rachid et al. (2012)
Diabetes Northeastern Dahra Mountains, Algeria Leaves Infusion Senouci et al. (2019)
(The Region of Bissa)
Diabetes Northern Morocco Leaves Infusion/ Labiad et al. (2020)
maceration
Diabetes Center of Portugal (Santarém) Aerial parts Decoction Gaspar et al. (2002)
Diabetes Oriental Morocco Whole plant Decoction Jamila and Mostafa
(2014)
Diabetes Algeria (Kabylia region) Leaves and flowers Not reported Meddour and
Meddour-Sahar (2015)
Diabetes Montenegro (Prokletije Mountains) Aerial parts Not reported Menković et al. (2011)
Fever and stomach pain Algeria (Kabylia region) Leaves and flowers Not reported Meddour and
Meddour-Sahar (2015)
Anti-fever Different Italian provinces Aerial parts Not reported Pieroni and Quave
(2005)
Anti-fever North-Eastern Sicily, Italy (Nebrodi Aerial part Decoction Tuttolomondo et al.
Regional Park) (2014)
Anti-fever Southern Spain (Western part of Granada Flowers Infusion Benítez et al. (2010)
province)
Anti-fever Rural alpine communities in Kosovo Aerial parts Decoction Mustafa et al. (2012a).
Anti-fever Kosovo (Gollak region) Flowers Infusion Mustafa et al. (2012b)
Antipyretic Southern Italy (National park of Cilento Whole plant Decoction Di Novella et al. (2013)
and Vallo Di Diano, Campania)
Antipyretic Central Italy (Marche, Abruzzo, and Leaves Infusion Guarrera (2005)
Latium)
As stomachic, digestive, and for helminthiasis North-West Morocco (Ksar Lakbir Aerial parts Decoction (Merzouki et al., 2000)
district)
Digestive Northern Morocco (Taounate province) Leaves and flowers Decoction El-Hilaly et al. (2003)
Digestive Northern Morocco (Talassemtane Not reported Not reported Zahrae Redouan et al.
National Park) (2020)
Digestive, antiflatulent, stimulant, gastritis Eastern Serbia (Rtanj Mountain) Whole plant Infusion Zlatković et al. (2014)
Stomach ulcers, diabetes, fever, laryngitis, intoxication, loss South-eastern Serbia (Suva planina) Aerial parts Not reported Jarić et al. (2015)
of appetite, and against cold and back pain
Digestive diseases, loss of appetite, liver diseases, and against Portugal (protected landscape of “Serra Aerial parts Infusion Vinagre et al. (2019)
parasites de Montejunto”)
Stomach disorders, and urinary system infections Rural alpine communities in Kosovo Aerial parts Extracted with Mustafa et al. (2012a).
cold water
Dyspeptic complaints and loss of appetite, Montenegro (Prokletije Mountains) Aerial parts Not reported Menković et al. (2011)
Liver, as an appetite stimulator Center of Portugal (Santarém) Aerial parts Decoction Gaspar et al. (2002)
Power problems (appetizer, tonic/weakness, restoration of Oriental Morocco Whole plant Decoction Jamila and Mostafa
vitality, obesity, weakness, and general tiredness) (2014)
Skin diseases North-West of Morocco Flowering tops Maceration (Bouyahya et al., 2017)
Skin diseases Northern Morocco (Talassemtane Not reported Not reported Zahrae Redouan et al.
National Park) (2020)
Cardiovascular Northern Morocco (Talassemtane Not reported Not reported Zahrae Redouan et al.
National Park) (2020)
Rhinitis Northern Morocco Flowers Infusion Labiad et al. (2020)
Asthma North of Morocco (Izarene region) Aerial parts Decoction/ Orch et al. (2020)
infusion
Antiapoplectic, anticoagulant, anticholagogue, Spain (Region of Pallars, Pyrenees, Aerial parts Not reported Agelet and Vallès (2003)
antipneumonic, intestinal antiseptic, hematocathartic, and Catalonia, Iberian Peninsula)
hypotensive
Against influenza Spain (Region of L’Alt Emporda Aerial parts Infusion Bonet et al. (1999)
Catalonia, Iberian Peninsula)
Against influenza Two southern Ecuadorian provinces, Stems and leaves Infusion Tene et al. (2007)
namely, Loja and Zamora-Chinchipe
(continued on next page)

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 1 (continued )
Traditional use Study area Used part Mode of References
preparation

Loss of appetite Spain (Navarra region) Flowers Not reported Calvo et al. (2013)
Eczema Different Turkey provinces Flowering buds Infusion Eraslan et al. (2020)
Liver diseases, anthelminthic, diuretic, for wounds, as tonic, Greece (Epirus, Zagori) Not reported Not reported Vokou et al. (1993)
and stimulant
Against hemorrhoids Rural alpine communities in Kosovo Aerial parts Decoction Mustafa et al. (2012a).
Against hemorrhoids Greece (Epirus, Zagori) Not reported Not reported Vokou et al. (1993)
Lithontriptic Rural alpine communities in Kosovo Stems Decoction Mustafa et al. (2012a).
Kidney problems Two southern Ecuadorian provinces, Stems and leaves Infusion Tene et al. (2007)
namely, Loja and Zamora-Chinchipe
Diuretic Northern Morocco Flowers Infusion Labiad et al. (2020)
Kidney diseases Northern Morocco (Taounate province) Leaves and flowers Decoction El-Hilaly et al. (2003)
Sedation, gastrointestinal ailments, anemia, blood North-East Bosnia and Herzegovina Flowers Powder Saric-Kundalic et al.
purification, and loss of appetite (Konjuh Mountain) (2010)
Internal infections Two southern Ecuadorian provinces, Stems and leaves Infusion Tene et al. (2007)
namely, Loja and Zamora-Chinchipe

flowers have been used in Turkey for the treatment of eczema (Eraslan
et al., 2020). Tene et al. (2007) have shown from an ethnobotanical
survey in two regions of southern Ecuador, namely Loja and
Zamora-Chinchipe, that the flowers and the stem infusions of
C. erythraea play a potential therapeutic role against internal infections,
purification of the blood, kidney problems, and in the treatment of
influenza.
3.4. Phytochemistry
Phytochemical work on C. erythraea has led to the identification of a
large set of different classes (terpenoids, flavonoids, phenolic acids, fatty
acids, and others) of chemical compounds summarized in Table 2. Some
of these compounds belong to secondary metabolites and subject to an
increasing number of biological and chemical studies due to their potent
therapeutic effects and their variant chemical structures.
3.4.1. Secoiridoids and xanthonoids
The main compounds isolated from C. erythraea were xanthonoids
and secoiridoids (Figs. 1 and 2). Secoiridoids, such as gentiopicrin and
sweroside, and several xanthonoids, such as di-hydroxy-
dimethoxyxanthone, were identified from the aqueous extract of the
aerial parts of C. erythraea from Portugal (Guedes et al., 2019). Indeed,
van der Sluis and Labadie were the first researchers to identify three
secoiridoids in the methanolic extract from the C. erythraea flowers,
notably sweroside, swertiamarin (the main compound), and gentiopi­
crin (van der Sluis and Labadie, 1981).
The work of Šiler et al. (2012) demonstrated that the methanol
extract of the aerial parts and roots of C. erythraea originating in Serbia
were rich in secoiridoid glycosides namely gentiopicrin, swertiamarin,
and sweroside. In another study, Šiler et al. (2014) identified the same
secoiridoid glycosides, and xanthonoids including eustomine, deme­
thyleustomine, decussatin, and methylbellidifoline in the same part and
type of C. erythraea extract with commercial mangiferin as an internal
standard. Staying in the same country (Serbia), researchers were able to
identify secoiridoids and xanthonoids from the methanol extract of the
aerial parts and roots of C. erythraea (Subotić et al., 2009; Trifuno­
vić-Momčilov et al., 2016).
The HPLC-DAD-ESI-MS analyses of lyophilized extract of C. erythraea
aerial parts grown in North Macedonia revealed the presence of four
different secoiridoids constituting 53% (swertiamarin, gentiopicrin,
sweroside, and centapicrin), and seven xanthonoids constituting 22%
(methoxyxanthone and its derivatives such as 1-hydroxy-3-methoxyxan­
thone-3 rhamnose, 1-hydroxy-3-methoxyxanthone, 3-hydroxy-3-
methoxyxanthone, 3-hydroxy-3-methoxyxanthone, and eustomin)
(Stefkov et al., 2014).
Phytochemical analysis of C. erythraea originating in Austria led to
the isolation of 25 xanthonoids and three secoiridoids in the methanolic
extract. 1,3,8-Trihydroxy-5,6-dimethoxyxanthone was identified for the
first time in this study (Aberham et al., 2011).
The plant tissue culture technique was implemented to improve the
yield of the active constituents. A 10-week micropropagated plant
growth of C. erythraea from Poland resulted in the accumulation of
secoiridoid glucosides (gentiopicrin, swertiamarin, and sweroside) up to
149 mg/g dry weight (Piatczak et al., 2005). Six methoxylated xantho­
noid (1,5-hydroxy-3-methoxyxanthone, 1-hydroxy-3,5,6-trimethoxyx­
anthone, 1-hydroxy-3,5,6,7-tetramethoxyxanthone, 1-hydroxy-3,5,6,7,
8-pentamethoxyxanthone, 1-hydroxy-3,7,8-trimethoxyxanthone and 1,
8 dihydroxy-3,5,6,7 tetramethoxyxanthone) were isolated and identi­
fied by spectroscopic analyses from the chloroform extract of the aerial
parts of C. erythraea grown in Portugal (Valentão et al., 2002). Three
xanthonoids (1,6-dihydroxy-3,5 dimethoxyxanthone, 3-hydroxy-1,5,
6-trimethoxyxanthone, and 1,3,5-trihydroxy-2 methoxyxanthone)
were isolated for the first time from the chloroform extract of the aerial
parts of C. erythraea from the same country (Valentão et al., 2000).
Two methoxylated xanthone derivatives, eustomine and demethy­
leustomine, were isolated from the ethanol extract of C. erythraea aerial
parts grown in Morocco (Schimmer and Mauthner, 1996). Three xan­
thonoids (1,2,3-trihydroxy-5-methoxyxanthone, 1-hydroxy-3,5,6,7,
8-penta-methoxyxanthone, 1,8-dihydroxy-2,3,4,6-tetramethoxyx­
anthone) were isolated from C. erythraea ethanol extract grown at the
time in Czechoslovakia (Mebavý, 1987). Phytochemical investigation of
the n-hexane extract from the roots of C. erythraea originating in Greece
led to the isolation of six xanthonoids including methylbellidifolin,
8-desmethyleustomin, l-hydroxy-3,5,6,7-tetramethoxyxanthone, l-hy­
droxy-3,5,6-trimethoxyxanthone, decussatin, and eustomin (Kaouadji
et al., 1986). The different results obtained between these several de­
terminations are certainly due the region studied and the plant part used
for extraction.
3.4.2. Terpenoids and fatty acids
The main terpenoids and fatty acids isolated from C. erythraea are
shown in Figs. 3 and 4. Our group (Bouyahya et al., 2019) investigated
the content of C. erythraea essential oil from Morocco where we recorded
that the main terpenoids isolated from this plant were carvacrol,
menthol, and tricosan (with respective percentages at different stages).
Phytochemical analysis of C. erythraea essential oil originating in
Serbia led to the identification of several dominant compounds namely
the neophytadiene isomer III (10.1%), carvacrol (7.9%), p-camphorene
(5.6%), hexadecanoic acid (4.9%), and thymol (4.2%) (Jovanović et al.,
2013). Another research team analyzed the essential oil of C. erythraea
from Croatia and showed that this oil contained a low content of
oxygenated monoterpenes (Jerković et al., 2012). Additionally, the
identified compounds were menthol (7.0%), linalool (3.0%), borneol
(1.4%), and menthone (2.5%). Borneol (1.4%) and camphor (1.5%)
were identified in C. erythraea oil collected from Croatia, while only

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Table 2
Chemical composition of C. erythraea extracts and essential oils.
Country Part Extracts/ Compounds Compounds References
Essential oils classes

Morocco Aerial Essential oil Terpenoids Menthol, carvacrol, and tricosane Bouyahya et al. (2019)
parts
Morocco Aerial Methanol Flavonoids - Quercetin-3-O-(rhamnoside)rutinoside-7-O-rhamnoside Chda et al. (2020)
parts extract - Kaempferol-3-O-(rhamnoside)rutinoside-7-O-rhamnoside
- Kaempferol-3-(caffeoyl, rhamnoside)rutinoside-7-hexoside
- Quercetin-3-(rhamnoside)rutinoside -7-(caffeoyl)rhamnoside
- Quercetin-3-O-rutinoside-7-O-rhamnoside
- Kaempferol-3-O-rutinoside-7-O-rhamnoside
- Kaempferol-3-(p-coumaroyl, rhamnoside)rutinoside-7-hexoside
- Quercetin-3-(rhamnoside)rutinoside-7-(caffeoyl)rhamnoside
- Quercetin-3-(rhamnoside)rutinoside-7-(p-coumaroyl)rhamnoside
- Kaempferol-3-(p-coumaroyl, rhamnoside)rutinoside-7-rhamnoside
- Isorhamnetin-3-(p-coumaroyl, rhamnoside)rutinoside-7-rhamnoside
- Kaempferol-3-(caffeoyl)rutinoside -7-rhamnoside
- Kaempferol-3-(p-coumaroyl)rutinoside-7-rhamnoside
Portugal Aerial Aqueous Secoiridoids Secologanoside, swertiamarin, gentiopicroside, and sweroside Guedes et al. (2019)
parts extract Xanthonoids Di-hydroxy-tetrame-toxy-O-pentosyl-hexosylxanthone, tri-hydroxy-monome-
toxyxanthone, di-hydroxy-dimetho-xyxanthone, di-hydroxy-tetrame-
thoxyxanthone, monohydroxy-trime-toxyxanthone, and tri-hydroxy-dimeto-
xyxanthone
Flavonoids Quercetin
Morocco Aerial Aqueous Flavonoids - Quercetin-3-O-(rhamnoside)rutinoside-7-O-rhamnoside Kachmar et al. (2019)
parts extract - Kaempferol-3-O-(rhamnoside)rutinoside-7-O-rhamnoside
- Kaempferol-3-(caffeoyl, rhamnosidcd)rutinoside-7-hexoside
- Quercetin-3-(rhamnoside)rutinoside-7-(p-coumaroyl) rhamnoside
- Quercetin-3-O-rutinoside -7-O-rhamnoside
- Quercetin-3-(rhamnoside)rutinoside-7-(caffeoyl)rhamnoside
- Kaempferol-3-O-rutinoside-7-O-rhamnoside
- Kaempferol-3-(p-coumaroyl, rhamnoside)rutinoside-7-hexoside
- Kaempferol-3-(p-coumaroyl, rhamnoside)rutinoside-7-rhamnoside
- Isorhamnetin-3-(p-coumaroyl, rhamnoside)rutinoside-7-rhamnoside
- Kaempferol-3-(p-coumaroyl, rhamnoside)rutinoside-7-rhamnoside
- Quercetin-3-(p-coumaroyl)rutinoside-7-rhamnoside
- Kaempferol-3-(p-coumaroyl)rutinoside-7-rhamnoside
- Kaempferol-3-O-(rhamnoside)rutinoside-7-O-hexoside
- Isorhamnetin-3-O-(rhamnoside)rutinoside-7-O-rhamnoside
- Kaempferol-3-O-(rhamnoside)rutinoside
Bulgaria Aerial Infusion extract Phenolic acids Ferulic acid, p-coumaric acid, sinapic acid, and rosmarinic acid Mihaylova et al. (2019)
parts Decoction Phenolic acids Gallic acid, chlorogenic acid, caffeic acid, ferulic acid, p-coumaric acid, and
extract rosmarinic acid,
Microwave Phenolic acids Chlorogenic acid, caffeic acid, p-coumaric acid, rosmarinic acid, and cinnamic
extract acid
Tincture Phenolic acids Proto-catechuic acid, chlorogenic acid, caffeic acid, p-coumaric acid, sinapic
extract acid rosmarinic acid, and cichoric acid
Serbia Aerial Methanol Secoiridoids – Trifunović-Momčilov
parts extract Xanthonoids – et al. (2016)
Romania Aerial Ethanol extract Total – Sandru et al. (2016)
parts polyphenols
Serbia Aerial Methanol Secoiridoids Gentiopicrin, swertiamarin, and sweroside Šiler et al. (2014)
parts extract Xanthonoids Eustomin, demethyleustomin, decussatin, and methylbellidifolin
North Aerial Methanol Secoiridoids Swertiamarin, gentiopicrin, sveroside, and centapicrin Stefkov et al. (2014)
Macedonia parts extract Flavonoids Quercetin-3-O-rhamnoside-7-glucosyl-(1–2)-rhamnoside, quercetin-3-O-
glucoside, kaempferol-3-O-glucoside, kaempferol-3-O-rhamnoside-7-glucosyl-
(1–2)-rhamnoside, quercetin3-O-rutinoside, kaempferol-3-O-glycosyl-(1–2)-
rhamnoside, and isovitexin
Xanthonoids 1-Hydroxy-3-methoxyxanthone-3 rhamnose, 1-hydroxy-3-methoxyxanthone,
3-hydroxy-1-methoxyxanthone, eustomin, 3-hydroxy-3-methoxyxanthone, and
3-hydroxy-3-methoxyxanthone
Serbia Aerial Essential oils Terpenoids Neophytadiene isomer III, carvacrol, p-camphorene, and thymol Jovanović et al. (2013)
parts Fatty acids Hexadecanoic acid
Carotenoids –
Croatia Aerial Essential oils Terpenoids Menthol, linalool, borneol, methone, β-thujone, borneol, camphor, thymol, Jerković et al. (2012)
parts carvacrol, γ-terpinene, p-cymene, neophytadiene, tricosane, caryophyllene
oxide, and δ-cadinene
Fatty acids Hexadecanoic acid, linoleic acid, and tetradecanoic acid
Serbia Aerial Methanol Secoiridoids Gentiopicrin, swertiamarin, and sweroside Šiler et al. (2012)
parts extract
Austria Aerial Methanol Iridoids Loganic acid Aberham et al. (2011)
parts extract Secoiridoids Gentiopicrin, swertiamarin, and sweroside
Xanthonoids 1,3,8-Trihydroxy-5,6-dimethoxyxanthone
Germany Aerial Methanol Terpenoids Lupane, oleanane, and ursane Jäger et al. (2009)
parts extract
Serbia Secoiridoids – Subotić et al. (2009)
(continued on next page)

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Table 2 (continued )
Country Part Extracts/ Compounds Compounds References
Essential oils classes

Aerial Methanol Xanthonoids –

parts extract
Lebanon Aerial n-hexane Terpenoids Sabinene, α-3-carene, α-terpinene, and γ-terpinene Loizzo et al. (2008)
parts extract Fatty acids Methyl palmitate, palmitic acid, methyl linoleate, and ethyl linoleate
Chloroform Terpenoids α-Pinene, sabinene, α-phellandrene, m-cymene, and γ-terpinene
extract Fatty acids 2-Heptadecanone, methyl palmitate, palmitic acid, ethyl palmitate, methyl
stearate, ethyl linoleate, ethyl oleate, and linolenic acid
Steroids Stigmast-5-en-3-ol, 3-keto-urs-12-ene, and stigmasta-3,5-dien-7-one
Poland Aerial Methanol Secoiridoids Gentiopicroside, swertiamarin, and sweroside Piatczak et al. (2005)
parts extract
Yugoslavia Aerial Methanol Secoiridoids Gentiopicrin, and swertiamarin Janković et al. (2002)
parts extract Xanthonoids Eustomin, and demethyleustomin
Portugal Aerial Chloroform Xanthonoids 3-hydroxy-1,5,6-tri-methoxy-xanthone, 1,3,5-tri- hydroxy-2- methoxy- Valentão et al. (2002)
parts extract xanthone, 1,5-di-hydroxy-3-methoxy-xanthone, 1,6-di-hydroxy-3,5-di-
methoxy-xanthone, 1-hydroxy-3,7,8-tri-methoxy-xanthone, 1-hydroxy-3,5,6-
tri-methoxy-xanthone, 1-hydroxy-3,5,6,7,8-penta-methoxy-xanthone, 1-hy­
droxy-3,5,6,7-tetra-methoxy-xanthone, and 1,8-di-hydroxy-3,5,6,7-tetra-
methoxy-xanthone
Portugal Aerial Chloroform Xanthonoids 1,6-dihydroxy-3,5-dimethoxyxanthone, 3-hydroxy-l,5,6-trimethoxyxanthone, Valentão et al. (2000)
parts extract and 1,3,5-trihydroxy-2-methoxyxanthone
Morocco Aerial Ethanol extract Xanthonoids Eustomin and demethyleustomin Schimmer and Mauthner
parts (1996)
Germany Aerial Methanol Xanthonoids 3,5,6,7,8-pentamethoxy-l-oprimeverosylxanthone, 1-hydroxy-3,5,6,7,8-pen­ Beerhues and Berger
parts extract tamethoxyxanthone, 1,8-dihydroxy-3,5,6,7-tetramethoxyxanthone, and 1,8- (1994)
dihydroxy-3,5-dimethoxyxanthone
France Aerial Methanol Phenolic acids Hydroxyterephthalic acid, and 2,5-dihydroxyterephthalic acid Hatjimanoli (1988)
parts extract
Aqueous Phenolic acids Hydroxyterephthalic acid, and 2,5-dihydroxyterephthalic
extract Acid
Czechoslovakia Aerial Ethanol extract Xanthonoids 1,2,3-trihydroxy-5-methoxyxanthone, 1-hydroxy-3,5,6,7,8-penta-methoxyxan­ Mebavý (1987)
parts thone, and 1,8-dihydroxy-2,3,4,6-tetramethoxyxanthone
Flavonoids Sakuranin
Phenolic acids Chlorogenic acid, ferulic acid, a derivative of cinnamic acid I, and derivative of
cinnamic acid II
Egypt Aerial Ethanol extract Alkaloids Gentianine Bishay et al. (1978)
parts
Serbia Roots Methanol Secoiridoids – Trifunović-Momčilov
extract Xanthonoids – et al. (2016)
Serbia Roots Methanol Secoiridoids Gentiopicrin, and swertiamarin, and sweroside Šiler et al. (2014)
extract Xanthonoids Eustomin, demethyleustomin, decussatin, and methylbellidifolin
Serbia Roots Methanol Secoiridoids Gentiopicrin, swertiamarin, and sweroside Šiler et al. (2012)
extract
Serbia Roots Methanol Secoiridoids – Subotić et al. (2009)
extract Xanthonoids –
Greece Roots n-Hexane Xanthonoids 1,8-dihydroxy-3,5-dimethoxyxanthone (methylbellidifolin), 1,8-dihydroxy- Kaouadji et al. (1986)
3,5,6,7-tetramethoxyxanthone (8-desmethyleustomin), l-hydroxy-3,5,6,7-
tetramethoxyxanthone, l-hydroxy-3,5,6-trimethoxyxanthone, l-hydroxy-3,7,8-
trimethoxyxanthone (decussatin), and l-hydroxy-3,5,6,7,8-
pentamethoxyxanthone (eustomin)
Portugal and Flowers Methanol Secoiridoids Gentiopicroside, swertiamarin, and sweroside van der Sluis and Labadie
Spain extract (1981)

traces of these compounds were reported in C. erythraea oil collected
from Serbia. Besides, methanol extract of C. erythraea collected from
Germany was found to be rich in lupane, oleanane, and ursane (Jäger
et al., 2009). These differences recorded between studies may be due to
extraction methodologies, detection devices, plant parts, growing con­
ditions, and geographic origin.
The main fatty acids isolated from C. erythraea are shown in Fig. 4.
The major compound identified in C. erythraea (essential oil) originating
in Serbia was hexadecanoic acid with a percentage of 4.9% (Jovanović
et al., 2013). However, palmitic and linoleic acids were the major fatty
acids identified from C. erythraea (essential oil fraction) from Croatia
(Jerković et al., 2012). Essential oil compounds are variable depending
on the origin of C. erythraea and the extract part. Indeed, it is known that
the synthesis and the secretion of volatile compounds is related to the
geographic location of the species and the plan part used for the
extraction.
3.4.3. Phenolic acids and flavonoids
Phenolic acids and flavonoids are phenolic molecules recognized by
their important biological effects. These molecules can be found in
plants as secondary metabolites. As other medicinal species C. erythraea
is rich in phenolic acids and flavonoids. Indeed, the main phenolic acids
and flavonoids identified from the aerial parts of C. erythraea extracts are
represented in Figs. 5 and 6. The total phenolic content of different
C. erythraea extracts from Bulgaria varied between 595.17 and 2208.6
μg/g. The lowest content was obtained with microwave extraction.
C. erythraea decoction gave 1009 μg/g in total phenols. The compounds
identified in all extracts were rosmarinic acid and p-coumaric acid
(Mihaylova et al., 2019). Chda et al. (2020) demonstrated that the
methanol extract from the aerial parts of C. erythraea from Morocco was
rich in flavonoids. The most abundant flavonoids were kaempfer­
ol-3-O-(p-coumaroyl, rhamnosyl) rutinoside-7-O-rhamnoside and quer­
cetin-3-O-(rhamnosyl) rutinoside-7-O-(p-coumaroyl) rutinoside, with a
percentage of 23.3% and 18.1%, respectively, of the total content of
phenolic compounds. Isorhamnetin-3-O-(p-coumaroyl, rhamnosyl)
rutinoside 7-O-rhamnoside was the only identified isorhamnetin deriv­
ative, representing 6.4% of the total content of phenolic compounds.
Phytochemical analysis of the aqueous extract from the aerial parts

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Fig. 1. Chemical structures of xanthonoids.

Fig. 2. Chemical structures of secoiridoids.

Fig. 3. Chemical structures of terpenoids.

of C. erythraea by HPLC DAD-ESI/MS indicated the presence of twenty- flowering tops comprised p-coumaroyl derivatives of quercetin-3-O-
two flavonoids glycosides, comprising derivatives of acylated quercetin, (rhamnosyl) rutinoside-7-O-rhamnoside and kaempferol-3-O-(p-cou­
kaempferol, and isorhamnetine. The aqueous extract of C. erythraea maroyl, rhamnosyl) rutinoside-7-O-rhamnoside (Kachmar et al., 2019).

8
N. El Menyiy et al.
Fig. 4. Chemical structures of fatty acids.
HPLC-DAD-ESI-MS analysis of the aerial parts of C. erythraea methanol
extract originating in North Macedonia revealed the presence of seven
flavonoids glycosides (quercetin, kaempferol, and their derivatives)
representing 25% of all compounds (Stefkov et al., 2014). The total
phenolic content of the aerial parts of C. erythraea ethanol extract from
Romania was 271.613 mg/L gallic acid equivalents (Sandru et al.,
2016). Hydroxyterephthalic and 2,5-dihydroxyterephthalic acids were
two phenolic acids identified in the aerial parts of C. erythraea methanol
and aqueous extracts from France (Hatjimanoli, 1988).
3.4.4. Other classes of chemical compounds
C. erythraea extracts were found to contain other bioactive com­
pounds belonging to steroids (Fig. 7), iridoids (Fig. 8), and alkaloids
(Fig. 9) (Loizzo et al., 2008; Aberham et al., 2011; Bishay et al., 1978).
3.5. Biological activities
In vitro and in vivo studies showed that C. erythraea extracts and some
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Journal of Ethnopharmacology 276 (2021) 114171
of their major compounds exhibited several biological activities
including antidiabetic, antioxidant, antimicrobial, anti-inflammatory,
spasmolytic, cytotoxic, and other biological effects.
3.5.1. Antibacterial activity
Numerous works showed the antibacterial efficacy of different
essential oils or extracts from different parts of C. erythraea (Kumar­
asamy et al., 2002; Šiler et al., 2014; Božunović et al., 2018; Bouyahya
et al., 2017, 2019). Table 3 summarizes all studies that evaluated the
antibacterial activity of C. erythraea including the part used, type of
extract, type of antibacterial assay, tested strains, and main results. A
literature survey showed that many researchers investigated the anti­
bacterial potential of C. erythraea against Gram-positive and
Gram-negative bacteria. Kumarasamy et al. (2002) evaluated the anti­
microbial activity of n-hexane, dichloromethane, and methanol extracts
from the seeds of C. erythraea using the broth dilution method against 11
species of Gram-positive and Gram-negative pathogens. They found that
Staphylococcus hominis 11320, Staphylococcus aureus 10788, and
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Fig. 5. Chemical structures of phenolic acids.

Fig. 6. Chemical structures of flavonoids.

Staphylococcus aureus 11940 were the most sensitive strains to the
methanol extracts with MIC values of 0.01, 0.10, and 1.00 mg/mL,
respectively. The n-hexane and dichloromethane extracts did not show
any antibacterial activity at the tested concentrations. However, Šiler
et al. (2014) tested the antibacterial activity of the methanol extracts of
C. erythraea aerial parts and roots using the microdilution method
against four Gram-negative, including Escherichia coli (ATCC 35210),
Pseudomonas aeruginosa (ATCC 27853), Salmonella typhimurium (ATCC
13311), Enterobacter cloacae (human isolate) and four Gram-positive
bacteria including Listeria monocytogenes (NCTC 7973), Bacillus cereus
(human isolate), Micrococcus flavus (ATCC 10240), and Staphylococcus
aureus (ATCC 6538). The extracts demonstrated antibacterial activity
with MIC values ranging from 0.10 to 0.25 mg/mL. The most sensitive
bacteria to the methanol extract of the aerial parts were B. cereus,
M. flavus, S. aureus, E. coli, P. aeruginosa, and S. typhimurium with a MIC
value of 0.10 mg/mL. E. coli was the most sensitive bacteria to the
methanol extract of the roots with a MIC of 0.10 mg/mL. Božunović
et al. (2018), determined the in vitro antibacterial activity of the

10
N. El Menyiy et al.
Fig. 7. Chemical structures of steroids.
Fig. 8. Chemical structure of loganic acid (iridoid).
methanol extract and hydrolyzed methanol extract of C. erythraea
against eight bacterial species using microdilution method. The bacteria
tested were four Gram-positive, namely Staphylococcus aureus (ATCC
6538), Bacillus cereus (clinical isolate), Listeria monocytogenes (NCTC
7973), and Micrococcus flavus (ATCC 10240), as well as four
Gram-negative bacteria including Pseudomonas aeruginosa (ATCC
27853), Escherichia coli (ATCC 35210), Salmonella typhimurium (ATCC
13311), and Enterobacter cloacae (human isolate). In this study, the
microdilution method demonstrated that the antibacterial activity of
C. erythraea non-hydrolyzed methanol extract with MICs ranged from
0.125 to 0.300 mg/mL and MBC varied from 0.250 to 0.450 mg/mL. For
the hydrolyzed methanol extract, MICs were in the range of 0.125 and
0.375 mg/mL and MBCs values ranged from 0.250 to 0.450 mg/mL.
C. erythraea methanol extract was more efficient against S. aureus,
L. monocytogenes, M. flavus and E. coli than the hydrolyzed methanol
extract. More interestingly, the non-hydrolyzed methanol extract
showed more potent antibacterial potential on S. aureus and
L. monocytogenes compared with the standard antibiotic streptomycin
used as the positive control. In contrast, the hydrolyzed methanol
extract showed lower antibacterial potential compared with the positive
control.
In a recent study, the in vitro antibacterial activity of the phenolic
extracts of C. erythraea (methanol, ethanol, n-hexane, and ethyl acetate)
against Staphylococcus aureus, Escherichia coli, Listeria monocytogenes,
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Journal of Ethnopharmacology 276 (2021) 114171
Fig. 9. Chemical structure of gentianine (alkaloid).
and Pseudomonas aeruginosa were determined using the well diffusion
and the microdilution assay methods (Bouyahya et al., 2017b). The re­
sults showed that the inhibitory activity of the methanol, n-hexane, and
ethyl acetate extracts exhibited a good antibacterial effect against all
tested strains. The diameter of the inhibitory zone ranged from 14 to 45
mm. The values of MIC and MBC ranged between 0.25 and 8.00 mg/mL.
Pseudomonas aeruginosa was the most resistant strain compared to all the
other bacteria tested, while Staphylococcus aureus was the most sensitive
toward the tested extracts. The n-hexane extract demonstrated the
highest antibacterial activity against all bacteria with the MIC and MBC
values ranging from 0.25 to 2 mg/mL and from 0.5 to 8 mg/mL,
respectively, but the methanol, ethanol, and ethyl acetate extracts did
not show any antibacterial activity. Pseudomonas aeruginosa was the
most resistant strains compared with all other tested bacteria, while
Staphylococcus aureus was the most sensitive toward the tested extracts
(Bouyahya et al., 2017b). In another study, our group reported the
antibacterial activity of the essential oils (EOs) of C. erythraea at three
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 3
Antibacterial effects of Centaurium erythraea.
Use part Extracts Used method Tested strains Key results References

Aerial parts Methanolic extract Microdilution method Bacillus cereus MIC = 0.10 mg/mL Šiler et al. (2014)
MBC = 0.25 mg/mL
Mariniluteicoccus flavus MIC = 0.10 mg/mL
MBC = 0.30 mg/mL
Staphylococcus aureus MIC = 0.10 mg/mL
MBC = 0.30 mg/mL
Listeria monocytogenes MIC = 0.20 mg/mL
MBC = 0.25 mg/mL
Escherichia coli MIC = 0.10 mg/mL
MBC = 0.20 mg/mL
Enterobacter cloacae MIC = 0.20 mg/mL
MBC = 0.30 mg/mL
Pseudomonas aeruginosa MIC = 0.10 mg/mL
MBC = 0.25 mg/mL
Salmonella typhimurium MIC = 0.10 mg/mL
MBC = 0.30 mg/mL
Roots Methanolic extract Microdilution method Bacillus cereus MIC = 0.20 mg/mL
MBC = 0.30 mg/mL
Mariniluteicoccus flavus MIC = 0.25 mg/mL
MBC = 0.40 mg/mL
Staphylococcus aureus MIC = 0.20 mg/mL
MBC = 0.40 mg/mL
Listeria monocytogenes MIC = 0.25 mg/mL
MBC = 0.40 mg/mL
Escherichia coli MIC = 0.10 mg/mL
MBC = 0.25 mg/mL
Enterobacter cloacae MIC = 0.20 mg/mL
MBC = 0.40 mg/mL
Pseudomonas aeruginosa MIC = 0.25 mg/mL
MBC = 0.30 mg/mL
Salmonella typhimurium MIC = 0.20 mg/mL
MBC = 0.30 mg/mL
Disk diffusion method Bacillus megaterium Ф = 13 mm Kirbağ et al. (2009)
Pseudomonas aeruginosa No inhibition zone
Escherichia coli No inhibition zone
Klebsiella pneumoniae Ф = 8 mm
Proteus vulgaris Ф = 7 mm
Staphylococcusaureus No inhibition zone
Leaves and Ethanol extract Agar diffusion test Streptococcus mutans Ф = 10.88 ± 4.54 mm Pereira et al. (2011)
stems Staphylococcusaureus Ф = 17.71 ± 4.50 mm
Actinobacillus Ф = 13.38 ± 3.95 mm
actinomycetemcomitans
n-Hexane extract Agar diffusion test Streptococcus mutans Ф = 9.87 ± 1.47 mm
Staphylococcusaureus Ф = 10.56 ± 0.89 mm
Actinobacillus Ф = 0.00 ± 0.00 mm
actinomycetemcomitans
Leaves and n-butanol extract Agar diffusion test Streptococcus mutans Ф = 10.09 ± 0.43 mm Pereira et al. (2011)
stems Staphylococcuaureus Ф = 9.78 ± 1.97 mm
Actinobacillus Ф = 8.97 ± 1.09 mm
actinomycetemcomitans
Microdilution test Streptococcus mutans MIC = 6.60 ± 1.30 mg/
mL
Staphylococcusaureus MIC = 16.00 ± 0.00
mg/mL
Actinobacillus MIC = 13.30 ± 2.60
actinomycetemcomitans mg/mL
Seeds n-Hexane, dichloromethane and MeOH Broth dilution method Staphylococcus aureus 10788 MIC = 0.10 mg/mL Kumarasamy et al.
extract Staphylococcus aureus 11940 MIC = 1.00 mg/mL (2002)
Staphylococcus epidermidis 8558 no inhibition
Staphylococcus hominis 11320 MIC = 0.01 mg/mL
Lactobacillus plantarum 6376 no inhibition
Bacillus cereus 9689 no inhibition
Proteus mirabilis 60 no inhibition
Escherichia coli 8110 no inhibition
Escherichia coli 4174 no inhibition
Pseudomonas aeruginosa 6750 no inhibition
Serratia marcescens 1377 no inhibition
Aerial parts Essential oil Disk diffusion method Escherichia coli Ф = 13 ± 0.577 mm Jerković et al. (2012)
Pseudomonas fluorescens Ф = 0 ± 0 mm
Salmonella enteritidis Ф = 13 ± 1 mm
Bacillus cereus Ф = 7 ± 0.693 mm
Listeria monocytogenes Ф = 0 ± 0 mm
Staphylococcus aureus Ф = 8 ± 0.289 mm
Ethanolic extract Disk diffusion method Escherichia coli Ф = 5.66 ± 1.12 mm Ivanišová et al. (2017)
(continued on next page)

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Table 3 (continued )
Use part Extracts Used method Tested strains Key results References

Leaves and Salmonella enteric Ф = 4.66 ± 0.44 mm

flowers Pseudomonas aeruginosa Ф = 4.66 ± 0.18 mm
Bacillus thuringiensis Ф = 6.00 ± 0.33 mm
Staphylococcus aureus Ф = 9.00 ± 1.18 mm
Aerial parts Methanolic extract Microdilution method Staphylococcusaureus MIC = 0.187 mg/mL Božunović et al. (2018)
MBC = 0.250 mg/mL
Bacillus cereus MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Listeriamonocytogenes MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Mariniluteicoccus flavus MIC = 0.250 mg/mL
MBC = 0.450 mg/mL
Pseudomonas aeruginosa MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Escherichia coli MIC = 0.300 mg/mL
MBC = 0.350 mg/mL
Salmonella typhimurium MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Enterobacter cloacae MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Aerial parts Hydrolyzed methanol extract Microdilution method Staphylococcusaureus MIC = 0.250 mg/mL Božunović et al. (2018)
MBC = 0.300 mg/mL
Bacillus cereus MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Listeria monocytogenes MIC = 0.187 mg/mL
MBC = 0.250 mg/mL
Mariniluteicoccus flavus MIC = 0.375 mg/mL
MBC = 0.450 mg/mL
Pseudomonas aeruginosa MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Escherichia coli MIC = 0.375 mg/mL
MBC = 0.450 mg/mL
Salmonella typhimurium MIC = 0.125 mg/mL
MBC = 0.300 mg/mL
Enterobacter cloacae MIC = 0.125 mg/mL
MBC = 0.250 mg/mL
Essential oil (vegetative stage) Agar-well diffusion Staphylococcus aureus 994 Ф = 34 ± 0.5 mm Bouyahya et al. (2019)
assays MIC = 0.25 (v/v)
Broth microdilution MBC = 0.5 (v/v)
assay Pseudomonas aeruginosa Ф = 13 ± 1.33 mm
MIC = 1 (v/v)
MBC < 2 (v/v)
Listeria monocytogenes Ф = 31 ± 0.66 mm
MIC = 0.25 (v/v)
MBC = 0.5 (v/v)
Bacillus subtilis 6633 Ф = 24 ± 0.5 mm
MIC = 0.5 (v/v)
MBC = 1 (v/v)
Proteus mirabilis Ф = 21 ± 1.5 mm
MIC = 0.25 (v/v)
MBC = 0.5 (v/v)
Escherichia coli K12 Ф = 14 ± 1.5 mm
MIC = 1 (v/v)
MBC < 2 (v/v)
Essential oil (flowering stage) Agar-well diffusion Staphylococcus aureus 994 Ф = 28 ± 1.5 mm Bouyahya et al. (2019)
assays MIC = 0.25 (v/v)
Broth microdilution MBC = 1 (v/v)
assay Pseudomonas aeruginosa Ф = 11 ± 0.5 mm
MIC = 2 (v/v)
MBC < 2 (v/v)
Listeria monocytogenes Ф = 26 ± 2.5 mm
MIC = 0.25 (v/v)
MBC = 1 (v/v)
Bacillus subtilis 6633 Ф = 23 ± 1.5 mm
MIC = 1 (v/v)
MBC = 2 (v/v)
Proteus mirabilis Ф = 19 ± 0.33 mm
MIC = 0.5 (v/v)
MBC = 1 (v/v)
Escherichia coli K12 Ф = NA
MIC = 1 (v/v)
MBC = 1 (v/v)
Essential oil (post-flowering stage) Agar-well diffusion Staphylococcus aureus 994 Ф = 33 ± 1.5 mm Bouyahya et al. (2019)
assays MIC = 0.125 (v/v)
Broth microdilution MBC = 0.125 (v/v)
assay Pseudomonas aeruginosa
(continued on next page)

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 3 (continued )
Use part Extracts Used method Tested strains Key results References

Ethanolic extract
Methanolic extract
n-Hexane extract
Ethyl acetate extract
Listeria monocytogenes
Bacillus subtilis 6633
Proteus mirabilis
Escherichia coli K12
Agar-well diffusion Escherichia coli K12
assay Staphylococcus aureus
Listeria monocytogenes
Pseudomonas aeruginosa
Agar-well diffusion Escherichia coli K12
assay
Broth micro-dilution
assay Staphylococcus aureus
Listeria monocytogenes
Pseudomonas aeruginosa
Agar-well diffusion Escherichia coli K12
assay
Broth micro-dilution
assay Staphylococcus aureus
Listeria monocytogenes
Pseudomonas aeruginosa
Agar-well diffusion Escherichia coli K12
assay
Broth micro-dilution
assay Staphylococcus aureus
Listeria monocytogenes
Pseudomonas aeruginosa
Ф = 15 ± 1.5 mm
MIC = 1 (v/v)
MBC = 1 (v/v)
Ф = 30 ± 2.33 mm
MIC = 0.25 (v/v)
MBC = 0.25 (v/v)
Ф = 27 ± 0.66 mm
MIC = 0.25 (v/v)
MBC = 0.5 (v/v)
Ф = 24 ± 2.0 mm
MIC = 0.25 (v/v)
MBC = 0.25 (v/v)
Ф = 25 ± 2.66 mm
MIC = 1 (v/v)
MBC = 2 (v/v)
Ф = 19.00 ± 2.34 mm Bouyahya et al.
Ф = 24.00 ± 0.50 mm (2017b)
Ф = 19.00 ± 0.20 mm
Ф = 36.00 ± 1.70 mm
Ф = 27.00 ± 1.23 mm
MIC > 8 mg/mL
MBC > 8 mg/mL
Ф = 15.00 ± 2.30 mm
MIC = 0.25 mg/mL
MBC = 1 mg/mL
Ф = NA
MIC = 4 mg/mL
MBC = 4 mg/mL
Ф = 34.00 ± 1.10 mm
MIC = 2 mg/mL
MBC = 8 mg/mL
Ф = 29.00 ± 1.86 mm
MIC = 8 mg/mL
MBC > 8 mg/mL
Ф = 14.00 ± 0.11 mm
MIC = 0.5 mg/mL
MBC = 1 mg/mL
Ф = 18.00 ± 0.10 mm
MIC = 2 mg/mL
MBC = 4 mg/mL
Ф = 43.00 ± 1.50 mm
MIC = 0.5 mg/mL
MBC = 2 mg/mL
Ф = 32.00 ± 2.42 mm Bouyahya et al.
MIC > 8 mg/mL (2017b)
MBC > 8 mg/mL
Ф = 24.00 ± 1.60 mm
MIC = 0.5 mg/mL
MBC = 0.5 mg/mL
Ф = 17.00 ± 1.00 mm
MIC = 4 mg/mL
MBC = 4 mg/mL
Ф = 34.00 ± 2.30 mm
MIC = 1 mg/mL
MBC > 8 mg/mL

developmental stages, by determining diameters of inhibition, MIC, and
MBC (Bouyahya et al., 2019). The essential oils showed important
antibacterial inhibitory activity at three seasonal stages especially
against Staphylococcus aureus (28–34 mm) and Listeria monocytogenes
(26–31 mm). Moreover, Centauruim erythraea essential oils (CEEO) at
the post-flowering stage was the most active essential oils against the
tested strains and showed bactericidal effects especially against S. aureus
(MIC = MBC = 0.125% (v/v)), L. monocytogenes (MIC = MBC = 0.125%
(v/v)), and Proteus mirabilis (MIC = MBC = 0.125% (v/v)). MIC was
equal to MBC against S. aureus indicating a bactericidal action at MIC
values. Also, Gram-positive bacteria were more sensitive to the essential
oils than Gram-negative strains (Bouyahya et al., 2019).
Further studies on the in vitro antibacterial activity involving the
determination of the inhibition zone diameter (expressed in mm), MICs,
and MBCs against a wide range of Gram-positive and Gram-negative
bacterial isolates for different EOs and extracts of C. erythraea. are
presented in Table 3. The difference between several study could be
justified by the difference in the chemical compounds containing in
different extracts. Indeed, the used sovent, the plant part and the origin
of species influence importantly the diversity and the amount of
bioactive compounds and therefore can modify the antibacterial
activity.
The antibacterial activity of medicinal plant extracts and EOs was
linked to the presence of secondary metabolites, which were able to
inhibit the growth of bacteria strains. The main compounds of essential
oils of C. erythraea such as carvacrol and menthol are known for their
antimicrobial activity (Bassanetti et al., 2017; Kamatou et al., 2013).
Trombetta et al. (2005) suggested that the antimicrobial activity of (+)
menthol may result, at least partially, from a perturbation of the lipid
fraction of the microorganism plasma membrane, resulting in the
alteration of membrane permeability and the leakage of intracellular
materials. The antibacterial effect of carvacrol against E. coli was

14
N. El Menyiy et al.
attributed to their ability to permeabilize and depolarize the cyto­
plasmic membrane (Xu et al., 2008). Also, carvacrol disrupted the bac­
terial cell membrane by increasing its permeability, decreasing
membrane integrity, inhibiting the quorum sensing system, and
inducing interference with signaling pathways (Bouyahya et al, 2017b,
2019, 2017b; Ultee et al., 1999).
3.5.2. Antifungal activity
The antifungal activity of C. erythraea extracts and essential oil
against many fungal species was reported in several works (Božunović
et al., 2018; Kirbağ et al., 2009; Pereira et al., 2011; Šiler et al., 2014)
(Table 4). The methanolic extract prepared from the aerial parts of
C. erythraea was evaluated against eight fungal species using micro­
dilution method (Šiler et al., 2014). The results showed that the used
extract exhibited a strong activity against Penicillium funiculosum (MIC
= 0.20 mg/mL and MFC = 0.40 mg/mL), Penicillium ochrochloron (MIC
= 0.20 mg/mL and MFC = 0.40 mg/mL), Trichoderma viride (MIC =
0.30 mg/mL and MFC = 0.40 mg/mL), Aspergillus fumigatus (MIC = 0.20
mg/mL and MFC = 0.40 mg/mL), Aspergillus niger (MIC = 0.20 mg/mL
and MFC = 0.40 mg/mL), Aspergillus flavus (MIC = 0.20 mg/mL and
MFC = 0.40 mg/mL), Aspergillus versicolor (MIC = 0.10 mg/mL and MFC
= 0.40 mg/mL) and Candida albicans (MIC = 0.10 mg/ml and MFC =
0.40 mg/mL) (Šiler et al., 2014). Moreover, the methanolic extract of
C. erythraea roots inhibited the growth of Penicillium funiculosum (MIC =
0.10 mg/mL and MFC = 0.40 mg/mL), Penicillium ochrochloron (MIC =
0.20 mg/mL and MFC = 0.50 mg/mL), Trichoderma viride (MIC = 0.25
mg/mL and MFC = 0.60 mg/mL), Aspergillus fumigatus (MIC = 0.20
mg/mL and MFC = 0.50 mg/mL), Aspergillus niger (MIC = 0.20 mg/mL
and MFC = 0.60 mg/mL), Aspergillus flavus (MIC = 0.30 mg/mL and
MFC = 0.60 mg/mL), Aspergillus versicolor (MIC = 0.10 mg/mL and MFC
= 0.40 mg/mL), and Candida albicans (MIC = 0.10 mg/mL and MFC =
0.40 mg/mL) (Šiler et al., 2014). Pereira et al. (2011) using the agar
diffusion test reported that the ethanol extract (90%) prepared from
C. erythraea leaves and stem inhibited the growth of Candia albicans,
followed by the n-hexane (70%) and n-butanal (70%) fractions. The
diameter of inhibition zone was Ф = 16.00 ± 2.54 mm for the ethanolic
extract, Ф = 12.33 ± 1.03 mm for the n-hexane extract, and Ф = 10.81 ±
1.03 mm for the n-butanol extract. Microdilution method was also used
to show that C. erythraea leaves and stems extracts inhibited the growth
of Candida albicans (MIC = 10.50 ± 0.50 mg/mL) (Pereira et al., 2011).
In another survey, the antifungal activity of the methanolic extract
(ME) and hydrolyzed methanol extract (HME) of C. erythraea seeds was
studied using microdilution method against eight fungal species
(Božunović et al., 2018). Both extracts showed strong activities, similar
or even more potent, in some cases, than those of the commercial fun­
gicides (e.g. ketoconazole and bifonazole). The minimal fungicidal
concentration (MFC) ranged from 0.250 to 0.400 mg/mL with no dif­
ference between HME and ME, except in the case of Aspergillus ochraceus
where ME was more effective (MIC = 0.125 mg/mL and MFC = 0.250
mg/mL) than HME (MIC = 0.300 mg/mL and MFC = 0.400 mg/mL).
The extracts were effective against Aspergillus fumigatus (MIC = 0.125
mg/mL and MFC = 0.250 mg/mL), Aspergillus versicolor (MIC = 0.125
mg/mL and MFC = 0.250 mg/mL), Aspergillus niger (MIC = 0.250
mg/mL and MFC = 0.300 mg/mL), Trichoderma viride (MIC = 0.125
mg/mL and MFC = 0.250 mg/mL), Penicillium funiculosum (MIC = 0.062
mg/mL and MFC = 0.250 mg/mL), Penicillium ochrochloron (MIC =
0.062 mg/mL and MFC = 0.250 mg/mL) and Penicillium verrucosum
(MIC = 0.062 mg/mL and MFC = 0.250 mg/mL). The antifungal activity
could be due to secoiridoid glycosides (monoterpenes) and phenolics,
including flavonoids and xanthonoids (Šiler et al., 2014). Many studies
highlighted the antimicrobial activity of some iridoid glycosides, but
only in the presence of plant-derived β-glucosidases, suggesting that the
effects on microorganisms were restricted to the aglycone form (Marak
et al., 2002). The antifungal effect could be also ascribed to the presence
of the aglycone of gentiopicrin and its metabolized product (Božunović
et al., 2018).
15
Journal of Ethnopharmacology 276 (2021) 114171
3.5.3. Antioxidant activity
Different studies indicated the antioxidant activity of the essential oil
and extracts from different parts of C. erythraea using well-known assays
such as DPPH, FRAP, β-carotene, ABTS, CUPRAC, TBARS, NO, and TAC
methods (Bouyahya et al., 2017, 2018, 2019; Božunović et al., 2018;
Kachmar et al., 2019; Merghem and Dahamna, 2020; Mihaylova et al.,
2019; Valentão et al., 2001, 2003; Shahat et al., 2003) (Table 5). The
methanol, ethanol, n-hexane, and ethyl acetate extracts of C. erythraea
were tested by our group for their in vitro antioxidant activity using
DPPH assay (Bouyahya et al., 2017b). The n-hexane extract demon­
strated a significant ability (p < 0.05) to reduce the radical DPPH (IC50
= 49.54 ± 2.43 μg/mL) followed by methanol (IC50 = 58.34 ± 2.86
μg/mL), ethyl acetate (IC50 = 376.08 ± 3.18 μg/mL), and ethanol (IC50
= 382.25 ± 5.59 μg/mL) extracts. The IC50 of the n-hexane extract was
comparable to the standard antioxidants namely ascorbic acid (IC50 =
27.20 ± 0.17 μg/mL) and Trolox (IC50 = 43.72 ± 0.31 μg/mL). In 2018,
we also evaluated the antioxidant effect of the methanol, ethanol, and
n-hexane extracts of C. erythraea aerial parts using ABTS and FRAP
methods (Bouyahya et al., 2018). The results showed that a high ferric
reductive capacity was obtained by the n-hexane extract (IC50 = 17.43
± 0.07 μg/mL) and was significantly comparable (p ˃ 0.05) to the
standard antioxidants; Trolox (IC50 = 85.45 ± 1.36 μg/mL) and ascorbic
acid (IC50 = 47.63 ± 0.58 μg/mL), followed by methanol and ethanol
extract with IC50 values of 27.28 ± 0.74 and 98.63 ± 2.82 μg/mL,
respectively. In the ABTS test, the n-hexane extract of C. erythraea
showed potent antioxidant activity (32.07 ± 0.53 μg/mL), compared
with the reference antioxidants Trolox (IC50 = 37.82 ± 2.75 μg/mL) and
ascorbic acid (IC50 = 19.62 ± 0.87 μg/mL) (p < 0.05), which showed
IC50 values of 37.82 ± 2.75 and 19.62 ± 0.87 μg/mL, respectively. The
methanolic extract of C. erythraea showed potent antioxidant capacity to
scavenge the ABTS radical with an IC50 value of 27.28 ± 0.74 μg/mL,
while the ethanol extract showed IC50 value of 232.75 ± 8.63 μg/mL. In
another study, our group tested the antioxidant effect of the essential
oils of the flowering tops of C. erythraea at three developmental stages
(vegetative, flowering, and post-flowering) using DPPH, FRAP, and
ABTS assays (Bouyahya et al., 2019). According to our results,
C. erythraea essential oils at the three phenological stages showed
important antioxidant capacity. Interestingly, the essential oil at the
flowering stage was the most active with IC50 values of 47.18 ± 3.62,
53.25 ± 2.19, 65.34 ± 3.71 μg/mL determined by DPPH, FRAP, and
ABTS assays, respectively. Additionally, among the methods used, the
DPPH assay showed the highest sensitivity and the lowest IC50.
Using the DPPH, FRAP, and ABTS assays, Božunović et al. (2018)
reported the antioxidant activity of the methanol extract and hydrolyzed
methanol extract of C. erythraea. In FRAP assay, the results demon­
strated that both extracts exhibited a good antioxidant activity with
FRAP capacity values of 127.087 and 134.688 gallic acid equivalent
reducing activity (mmol GAE) per 100 mg− 1 of dry extract (DE),
respectively. In ABTS assay, the hydrolyzed methanol extract showed an
interesting power to reduce ABTS (115.665 mmol GAE 100 mg− 1 DE)
compared to the methanol extract (94.783 mmol GAE 100 mg− 1 DE). In
DPPH assay, both extracts demonstrated potent antioxidant effect with a
radical scavenging activity of 59.432 mmol GAE 100 mg− 1 DE and
46.812 mmol GAE 100 mg− 1 DE, for the hydrolyzed methanol extract
and non-hydrolyzed methanol extract, respectively.
In another investigation, the aqueous extract from the aerial parts of
C. erythraea exhibited potent anti-DPPH activity with an IC50 value of
14.27 ± 0.92 and IC50 = 251.29 ± 44.16 μg extract/mL, for superoxide
anion radical and NO methods, respectively (Kachmar et al., 2019).
Moreover, Merghem and Dahamna (2020) demonstrated that the stems
aqueous and methanol extracts possessed antioxidant activity using the
DPPH, β-carotene, and reducing power assays. The results of the DPPH
test showed a powerful antioxidant activity with a very similar IC50
values for the methanolic (IC50 = 0.232 ± 0.002 mg/mL) and aqueous
(0.208 ± 0.002 mg/mL) extracts. The inhibitory activity of both extracts
in the β-carotene/linoleic acid assay was (86.781 ± 0.17%) for the
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 4
Antifungal activity of Centaurium erythraea.
Use part Extracts Used method Tested strains Key results References

Aerial parts Methanolic extract
Roots Methanolic extract
Leaves and stems Ethanolic extract
n-Hexane extract
n-Butanol extract
Aerial parts Methanolic extract
Aerial parts Hydrolyzed methanol extract
Microdilution method Penicillium funiculosum MIC = 0.20 mg/mL Šiler et al. (2014)
MFC = 0.40 mg/mL
Penicillium ochrochloron MIC = 0.20 mg/mL
MFC = 0.40 mg/mL
Trichoderma viride MIC = 0.30 mg/mL
MFC = 0.40 mg/mL
Aspergillus fumigatus MIC = 0.20 mg/mL
MFC = 0.40 mg/mL
Aspergillusniger MIC = 0.20 mg/mL
MFC = 0.40 mg/mL
Aspergillusflavus MIC = 0.20 mg/mL
MFC = 0.40 mg/mL
Aspergillus versicolor MIC = 0.10 mg/mL
MFC = 0.40 mg/mL
Candida albicans MIC = 0.10 mg/mL
MFC = 0.40 mg/mL
Microdilution method Penicillium funiculosum MIC = 0.10 mg/mL
MFC = 0.40 mg/mL
Penicillium ochrochloron MIC = 0.20 mg/mL
MFC = 0.50 mg/mL
Trichoderma viride MIC = 0.25 mg/mL
MFC = 0.60 mg/mL
Aspergillus fumigatus MIC = 0.20 mg/mL
MFC = 0.50 mg/mL
Aspergillusniger MIC = 0.20 mg/mL
MFC = 0.60 mg/mL
Aspergillusflavus MIC = 0.30 mg/mL
MFC = 0.60 mg/mL
Aspergillus versicolor MIC = 0.10 mg/mL
MFC = 0.40 mg/mL
Candida albicans MIC = 0.10 mg/mL
MFC = 0.40 mg/mL
Disk diffusion method Candida albicans Ф = No inhibition zone Kirbağ et al. (2009)
Candida glabrata Ф = No inhibition zone
Candida tropicalis Ф = No inhibition zone
Agar diffusion test Candida albicans Ф = 16.00 ± 2.54 mm Pereira et al. (2011)
Agar diffusion test Candida albicans Ф = 12.33 ± 1.03 mm
Agar diffusion test Candida albicans Ф = 10.81 ± 1.03 mm
Micro-dilution method Candida albicans MIC = 10.50 ± 0.50 mg/mL
Micro-dilution method Aspergillus fumigatus MIC = 0.125 mg/mL Božunović et al. (2018)
MFC = 0.250 mg/mL
Aspergillus versicolor MIC = 0.125 mg/mL
MFC = 0.250 mg/mL
Aspergillus ochraceus MIC = 0.125 mg/mL
MFC = 0.250 mg/mL
Aspergillus niger MIC = 0.250 mg/mL
MFC = 0.300 mg/mL
Trichoderma viride MIC = 0.125 mg/mL
MFC = 0.250 mg/mL
Penicillium funiculosum MIC = 0.062 mg/mL
MFC = 0.250 mg/mL
Penicillium ochrochloron MIC = 0.062 mg/mL
MFC = 0.250 mg/mL
Penicillium verrucosum MIC = 0.062 mg/mL
MFC = 0.250 mg/mL
Micro-dilution method Aspergillus fumigatus MIC = 0.125 mg/mL
MFC = 0.250 mg/mL
Aspergillus versicolor MIC = 0.125 mg/mL
MFC = 0.250 mg/mL
Aspergillus ochraceus MIC = 0.300 mg/mL
MFC = 0.400 mg/mL
Aspergillus niger MIC = 0.250 mg/mL
MFC = 0.300 mg/mL
Trichoderma viride MIC = 0.125 mg/mL
MFC = 0.250 mg/mL
Penicillium funiculosum MIC = 0.062 mg/mL
MFC = 0.250 mg/mL
Penicillium ochrochloron MIC = 0.062 mg/mL
MFC = 0.250 mg/mL
Penicillium verrucosum MIC = 0.062 mg/mL
MFC = 0.250 mg/mL

16
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 5
Antioxidant activity of Centaurium erythraea.
Use part Extracts Used methods Key results References

Ethanolic extract DPPH IC50 = 382.25 ± 5.59 μg/mL Bouyahya et al. (2017b)
Methanolic extract DPPH IC50 = 58.34 ± 2.86 μg/mL
n-Hexane extract DPPH IC50 = 376.08 ± 3.18 μg/mL
Ethyl acetate: extract DPPH IC50 = 49.54 ± 2.43 μg/mL
Aerial part Methanolic extract ABTS IC50 = 27.28 ± 0.74 μg/mL Bouyahya et al. (2018)
Reducing power assay IC50 = 27.28 ± 0.74 μg/mL
Ethanolic extract ABTS IC50 = 232.75 ± 8.63 μg/mL
Reducing power assay IC50 = 98.63 ± 2.82 μg/mL
n-Hexane extract ABTS IC50 = 32.07 ± 0.53 μg/mL
Reducing power assay IC50 = 17.43 ± 0.07 μg/mL
Essential oil (vegetative stage) DPPH IC50 = 61.53 ± 2.08 μg/mL Bouyahya et al. (2019)
FRAP IC50 = 73.42 ± 5.83 μg/mL
ABTS IC50 = 134.81 ± 4.73 μg/mL
Essential oil (flowering stage) DPPH IC50 = 47.18 ± 3.62 μg/mL
FRAP IC50 = 53.25 ± 2.19 μg/mL
ABTS IC50 = 65.34 ± 3.71 μg/mL
Essential oil (post-flowering DPPH IC50 = 69.25 ± 4.31 μg/mL
stage) FRAP IC50 = 82.06 ± 6.57 μg/mL
ABTS IC50 = 101.62 ± 6.74 μg/mL
Aerial parts Methanol extract ABTS Radical scavenging activity = 94.783 mmol GAE 100 Božunović et al. (2018)
mg− 1 DE
DPPH Radical scavenging activity = 46.812 mmol GAE 100
mg− 1 DE
FRAP FRAP capacity = 127.087 mmol GAE 100 mg− 1 DE
Hydrolyzed methanol extract ABTS Radical scavenging activity = 115.665 mmol GAE 100
mg-1 DE
DPPH Radical scavenging activity = 59.432 mmol GAE 100
mg− 1 DE
FRAP FRAP capacity = 134.688 mmol GAE 100 mg-1 DE
Leaves Decoction DPPH Percent activity = 25.25 ± 0.72% Guedes et al. (2019)
TBARS Percent activity = 32.23 ± 0.93%
NO IC50 = 774.9 ± 13.8 μg/mL
Decoction mucilage free DPPH Percent activity = 21.95 ± 0.46%
TBARS no activity
NO no activity
Xanthonoids fraction DPPH Percent activity = 17.63 ± 0.41%
TBARS no activity
NO no activity
Leaves with Ethanolic extract ABTS Antioxidant capacity = 35.74 ± 3.49 mg TEAC/g Ivanišová et al. (2017)
flowers Reducing power Antioxidant capacity = 161.48 ± 2.12 mg TEAC/g
Aerial parts Aqueous extract superoxide anion radical IC50 = 14.27 ± 0.92 μg extract/mL Kachmar et al. (2019)
NO IC50 = 251.29 ± 44.16 μg extract/mL
Seeds n-Hexane extract DPPH RC50 = 2.00 mg/mL Kumarasamy et al. (2007)
Dichloromethane extract DPPH no activity
Methanolic extract DPPH RC50 = 1.00 mg/mL
Aqueous extract DPPH IC50 = 0.208 ± 0.002 mg/mL Merghem and Dahamna
β-Carotene Percent activity = 77.816 ± 0.69% (2020)
Reducing power IC50 = 1.31 ± 0.047 mg/mL
Methanolic extract DPPH IC50 = 0.232 ± 0.002 mg/mL
β-Carotene Percent activity = 86.781 ± 0.17%
Reducing power IC50 = 0.35 ± 0.066 mg/mL
Stems Aqueous extract (infusion) ABTS TEAC value = 33.2 ± 0.1 μmol TE/g DW Mihaylova et al. (2019)
DPPH TEAC value = 22.0 ± 0.05 μmol TE/g DW
FRAP TEAC value = 44.7 ± 0.7 μmol TE/g DW
CUPRAC assay TEAC value = 65.7 ± 1.0 μmol TE/g DW
Aqueous extract (decoction) ABTS TEAC value = 88.3 ± 1.5 μmol TE/g DW
DPPH TEAC value = 41.3 ± 0.6 μmol TE/g DW
FRAP TEAC value = 70.1 ± 0.3 μmol TE/g DW
CUPRAC assay TEAC value = 94.7 ± 0.3 μmol TE/g DW
Microwave-assisted extract ABTS TEAC value = 33.9 ± 0.2 μmol TE/g DW
DPPH TEAC value = 32.2 ± 0.1 μmol TE/g DW
FRAP TEAC value = 33.7 ± 0.3 μmol TE/g DW
CUPRAC assay TEAC value = 33.7 ± 0.3 μmol TE/g DW
Ethanol (tincture) ABTS TEAC value = 72.5 ± 1.8 μmol TE/g DW
DPPH TEAC value = 48.6 ± 0.4 μmol TE/g DW
FRAP TEAC value = 79.3 ± 1.8 μmol TE/g DW
CUPRAC assay TEAC value = 96.0 ± 1.0 μmol TE/g DW
Aerial part Ethanolic extract DPPH Percent activity = 6.02 ± 0.18% Orhan et al. (2017)
DMPD no activity
NO Percent activity = 19.76 ± 0.85%
Methanolic extract DPPH Percent activity = 11.96 ± 3.03%
DMPD no activity
NO Percent activity = 24.75 ± 2.24%
Aerial parts Methanolic extract ABTS Šiler et al. (2014)
(continued on next page)

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 5 (continued )
Use part Extracts Used methods Key results References

Free radical scavenging activity = 43.446 mmol GAE 100

mg-1 DW
DPPH Free radical scavenging activity = 124.039 mmol GAE
100 mg-1 DW
FRAP
antioxidant
power =
11.533 mmol
GAE 100 mg-1
DW
Flowering tops Lyophilized infusion Hydroxyl radical assay IC50 = 44.4 μg/mL Valentão et al. (2003)
Hypochlorous acid scavenging IC25 = 933 μg/mL
assay
Aerial part Aqueous extract (cold DPPH Free radical scavenging activity = 8.92 ± 0.82 mmol TE Gonçalves et al. (2013)
infusion) gdw-1
TBARS Significantly reduced the amount of Fe2+ induced lipid
peroxidation
Reducing activity Activity increasing in a dose-dependent manner
Chelating activity Percent activity = 61.32 ± 0.66% at 0.4 mg/mL
Hydroxyl radical scavenging Percent activity = 37.16 ± 4.46% at 1.6 mg/mL
activity
Aqueous extract (Hot infusion) DPPH Free radical scavenging activity = 14.10 ± 0.58 mmol TE
gdw− 1
TBARS Significantly reduced the amount of Fe2+ induced lipid
peroxidation
Reducing activity Activity increasing in a dose-dependent manner
Chelating activity Percent activity = 67.39 ± 0.86% at 0.4 mg/mL
Hydroxyl radical scavenging Percent activity = 54.60 ± 4.71% at 1.6 mg/mL
activity
Flowering tops Lyophilized infusion Superoxide Radical Scavenging IC50 = 22.8 μg/mL Valentão et al. (2001)
Xanthine Oxidase Inhibitory IC50 = 73.2 μg/mL
Activity
Acetylated flavonol glycosides DPPH Higher scavenging activities IC50 ( Shahat et al. (2003)
13.9 ± 0.3–25.8 ± 0.2 μM)

methanolic extract and (77.816 ± 0.69%) for the aqueous extract. The
methanol extract showed more potent reducing power (IC50 = 0.35 ±
0.066 mg/mL) compared with the aqueous extract (IC50 = 1.31 ± 0.047
mg/mL).
Mihaylova et al. (2019) evaluated the in vitro antioxidant activity of
the aqueous extracts prepared by infusion, decoction, and microwave
extraction using four common procedures including DPPH and ABTS
antiradical activities; FRAP and CUPRAC methods. The authors also
evaluated the antioxidant activity of 70% ethanol (v/v, tincture). Ac­
cording to the results, the different extracts showed an important ac­
tivity in the different assays. But the highest results were obtained with
the decoction and tincture. In ABTS assay, the highest result was
established by the aqueous decoction (88.3 ± 1.5 μmol TE/g DW) fol­
lowed by the tincture (72.5 ± 1.8 μmol TE/g DW). The other three assays
(DPPH, FRAP, and CUPRAC) indicated that the tincture exhibited the
most potent antioxidant activity with TEAC value of 48.6 ± 0.4 μmol
TE/g DW, 79.3 ± 1.8 μmol TE/g DW and 96.0 ± 1.0 μmol TE/g DW,
respectively.
C. erythraea lyophilized infusions exhibited potent antioxidant
properties. The IC50 values were 22.8, 44.4, and 73.2 μg/mL in hydroxyl
radical, superoxide radical scavenging, and xanthine oxidase inhibitory
assays, respectively. The antioxidant activity of C. erythraea lyophilized
infusions is achieved also by the scavenging ability observed against
hypochlorous acid with an IC25 value of 933 μg/mL (Valentão et al.,
2001, 2003). Acetylated flavonol glycosides extracted from C. erythraea
exhibited an interesting anti-DPPH power with IC50 values ranged be­
tween 13.9 ± 0.3 and 25.8 ± 0.2 μM (Shahat et al., 2003). Šiler and
co-workers also investigated, in the aforementioned study, the antioxi­
dant capacity of the aerial parts and the roots of this plant using the
ABTS, DPPH and FRAP assays (Šiler et al., 2014). Consequently, the
results of these assays showed that the methanol extracts from the aerial
parts had higher effects (up to 13 times) than those from the roots. Be­
sides, these findings obtained by the different methods had a strong and
significant correlation proved by the analysis of linear regression and
correlation.
3.5.4. Antidiabetic activity
Numerous studies reported the in vitro and in vivo antidiabetic effect
of the extracts and essential oil obtained from different parts of
C. erythraea (Bouyahya et al., 2019; Đorđević et al, 2017, 2019, 2020;
Hamza et al, 2010, 2015; Mansar-Benhamza et al., 2013; Sefi et al.,
2011; Stefkov et al., 2014; Tahraoui et al., 2017) (Tables 6 and 7). Loizzo
et al. (2008), demonstrated the inhibitory effect of chloroform extract on
α-glycosidase and α-amylase with IC50 values of 74.9 and 64.9 μg/mL,
respectively. Moreover, our group studied the in vitro antidiabetic effect
of the essential oils of the flowering tops of C. erythraea at three
phenological stages (vegetative, flowering, and post-flowering stages)
using α-amylase and α-glucosidase enzymes inhibition assays (Bouyahya
et al., 2019). The results showed that EOs exhibited an
anti-hyperglycemic activity by inhibiting α-glycosidase and α-amylase
and the results were comparable to the standard drug (acarbose). This
inhibition was more potent with essential oils extracted at the vegetative
stage than at the flowering and post-flowering stages. In STZ-induced
diabetic rats, the oral administration of C. erythraea extract signifi­
cantly decreased blood glucose and glycated hemoglobin concentra­
tions, elevated serum insulin in the pre-treated and post-treated groups,
and improved lipid profile. Also, the treatment with the C. erythraea
methanol extract significantly reduced lipid peroxidation in both
post-treated and pre-treated animals and ameliorated oxidative damage
and protected RBC proteins from hyperglycemia-induced damage by
suppressing non-enzymatic glycation and enzymatic glycosylation pro­
cesses (Đorđević et al., 2017). Sefi and collaborators evaluated the hy­
poglycemic and antioxidant activities of the C. erythraea leaves
lyophilized aqueous extract in streptozotocin-induced diabetic rats. The
use of 200 mg/kg BW/day, i.p. for 30 days significantly decreased blood
glucose and MDA levels, elevated the activities of both enzymatic, and

18
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Table 6
In vivo antidiabetic effects of Centaurium erythraea.
Part Extract tested Dose Model Key results References
used

Aerial Aqueous 1.32 mg/kg body Normoglycemic rats and rats Significant reduction in blood glucose levels Mansar-Benhamza
parts extract weight subjected to oral glucose tolerance et al. (2013)
test overload OGTT
Butanoic 0.03 mg/kg body Normoglycemic rats and rats Significant reduction in blood glucose levels
extract weight subjected to oral glucose tolerance
test overload OGTT
Aqueous 250 mg/kg body Rodent model of metabolic Reduced plasma glucose, insulin, TC and LDL-cholesterol Tahraoui et al. (2017)
extracts weight syndrome (MetS). Decreased HOMA-IR and atherosclerotic index
Aerial Methanolic 100 mg/kg body Streptozotocin (STZ) induced Increased serum insulin level Đorđević et al. (2017)
parts extract weight diabetic rat Reduced blood glucose
Glycated hemoglobin concentration
Improved lipid profile
Aerial Methanolic 100 mg/kg body Streptozotocin (STZ)-treated Ameliorated the insulin level and glycemic control in STZ- Đorđević et al. (2019)
parts extract weight diabetic rats induced diabetic rat
Reduced the disturbance of islet morphology and islet cell
contents
Protective effect on the levels of insulin, GLUT-2 and p-Akt
in diabetic islets
Improved the disturbance of the transcriptional regulation
of CAT, MnSOD, CuZnSOD, GPx, and GR enzymes in beta-
cells induced by oxidative stress
Aerial Hydro- 2000 mg/kg body Type 2 diabetes induced by high-fat Significant reduction in mean fasting blood glucose, Hamza et al. (2010)
parts alcoholic weight diet in the C57BL/6J mouse triglyceride concentrations, and serum insulin levels
extract Reduced insulin resistance
Aerial Hydro- 2000 mg/kg Type 2 diabetes induced by high-fat Reduced the development of liver steatosis by 70% Hamza et al. (2015)
parts alcoholic bodyweight diet in C57BL/6J mice Despite the continued intake of the high-fat diet
extract Histological examination of mice Reduced the severity of hepatic macrovesicular steatosis
liver and triglyceride accumulation
Reduced hypertriglyceridemia and glycemia
Improved insulin sensitivity (reduced HOMA-IR)
Leaves Lyophilized 200 mg/kg body Streptozotocin-induced diabetes Significant reduction in blood glucose and MDA levels in Sefi et al. (2011)
extract weight rats. STZ treated rats
Significant increase in the activities of both enzymatic and
non-enzymatic antioxidants
Aerial Methanol 125, 250 and 500 Normal and streptozotocin (STZ) Reduction of the produced hyperglycemia Stefkov et al. (2014)
parts extract mg/kg body weight hyperglycemic Wistar rats Significant impact on the hepatic carbohydrate metabolism
Decreased HbA1c in CE-treated group
Decreased total cholesterol, triglycerides, HDL, and LDL
level in normal and STZ-hyperglycemic rats

non-enzymatic antioxidants compared with diabetic rats (Sefi et al.,
2011). Using the same experimental model, Stefkov et al. (2014) showed
that the methanolic extract of C. erythraea aerial parts administrated at
three increasing doses (125, 250, and 500 mg/kg body weight) had a
significant impact on the hepatic carbohydrate metabolism by
enhancing the direct synthesis of glycogen, normalizing phosphorylase
activity and reducing the activity of glucose-6-phosphatase that caused a
decrease in the production of blood glucose level. It also induced an
antilipidemic effect by reducing total cholesterol, triglycerides, HDL,
and LDL level in the blood of normal and diabetic rats. This activity was
attributed to secoiridoids, xanthonoids, and flavonoids that were iden­
tified in this plant (Stefkov et al., 2014). C. erythraea extract had also a
significant effect on β-cells. This effect was reported by Đorđević et al.
(2019) who analyzed the protective effects of the methanolic extract
from the aerial parts of C. erythraea on the RIN-5F β-cell line exposed to
the diabetogenic agent streptozotocin. The study showed that the
methanolic extract of C. erythraea aerial parts promoted the proliferative
and pro-survival pathways in β-cells and improved their structural and
functional properties by influencing the endogenous antioxidant
mechanisms. The methanolic extract of C. erythraea ameliorated the
disturbance of redox homeostasis in β-cells, suppressed DNA damage
and lipid peroxidation, promoted cell viability, and insulin expres­
sion/secretion in H2O2-treated β-cells. The methanol extract of the aerial
part of C. erythraea also adjusted the disturbed CAT, GPx, GR, MnSOD,
and CuZnSOD activities, as well as mRNA and protein levels of GPx,
MnSOD, and CAT induced by H2O2 and SNP in RIN-5F cells (Đorđević
et al., 2020). The hypoglycemic effect of the hydro-alcoholic extract of
C. erythraea at a dose of 2 g/kg/body weight was tested in vivo using
models of type 2 diabetes-induced with a standardized high-fat diet
(HFD) in C57BL/6J mice (Hamza et al., 2010, 2015). The study showed
that the oral administration of hydro-alcoholic extract of C. erythraea
aerial parts significantly inhibited the increased blood glucose, triglyc­
eride, serum insulin, and insulin resistance (Hamza et al., 2010).
C. erythraea treatment also decreased the development of liver steatosis
by 70%, despite the continued intake of the high-fat diet. It also reduced
the severity of hepatic macrovesicular steatosis and triglyceride accu­
mulation, suppressed hypertriglyceridemia, hyperglycemia, and
improved insulin sensitivity (Hamza et al., 2015).
3.5.5. Anti-inflammatory activitiy
Several studies evaluated the anti-inflammatory effect of C. erythraea
extracts (Berkan et al., 1991; Kachmar et al., 2019; Mascolo et al., 1987).
Table 8 summarizes all studies that evaluated the anti-inflammatory
activity of C. erythraea including the part used, type of extract, experi­
mental approach, and main results. The anti-inflammatory effect was
carried out in vivo using three models (carrageenan-induced paw edema,
air-pouch granuloma bioassay, and polyarthritis induced by the intra­
dermal injection of Freund’s adjuvant). In carrageenan-induced paw
edema in rats, the oral administration of the ethanolic extract (100
mg/kg) of the flowering tops inhibited edema up to 19% (Mascolo et al.,
1987). However, Berkan and colleagues studied the antiinflammatory
activity of this herb using air-pouch granuloma bioassay (air injected s.c.
into the shaved dorsal surface of animals forming a pocket) and
adjuvant-induced polyarthritis. They showed that 10% aqueous extract
cream at 200 mg/day significantly decreased exudate formation. 2.5%
and 5% C erythraea extract creams inhibited the exudate formation by

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 7 Table 8
In vitro antidiabetic effects of Centaurium erythraea. Anti-inflammatory effects of Centaurium erythraea.
Part Extract tested Model Keys results References Part used Extracts Experimental Key results Ref
used approach

Essential oils α-Amylase assay IC50 = 31.91 ± Bouyahya Flowering Ethanolic Carrageenan- Inhibition = 19% Mascolo
(vegetative 0.336 μg/mL et al. tops extract induced edema et al.
stage) α-Glucosidase IC50 = 56.77 ± (2019) (1987)
assay 1.02 μg/mL Leaves Aqueous Lipoxygenase Inhibit in a dose- Kachmar
Essential oils α-Amylase assay IC50 = 168.62 ± extract (LOX) inhibition dependent pattern et al.
(flowering 0.636 μg/mL assay IC25 = 78.71 ± (2019)
stage) α-Glucosidase IC50 = 87.18 ± 2.83 μg extract/mL
assay 0.422 μg/mL RAW 264.7 Not affect the
Essential oils α-Amylase assay IC50 = 94.99 ± macrophage cell mitochondrial
(post- 1.263 μg/mL line activity
flowering α-Glucosidase IC50 = 71.83 ± LPS-stimulated Reduction on NO
stage) assay 0.72 μg/mL RAW 264.7 levels of 20% at a
Aerial Methanol Rin-5F (ATCC- Increases cell- Đorđević macrophages concentration of
parts extract CRL-2058) cells viability and et al. 1.0 mg/mL
Comet assay insulin expression/ (2020) Aqueous Air-pouch Significant Berkan
Lipid secretion in H2O2- extract granuloma decrease in et al.
peroxidation and SNP-treated bioassay exudate formation (1991)
assay β-cells at a dose of 10%
Antioxidant Improved β-cell Inhibited the
enzyme activity response to H2O2- exudates
assays and SNP-mediated formation by 19%
redox challenge and 42% at 2.5%
Modulates the and 5% extract
expression of creams
antioxidant respectively
enzymes in H2O2- Polyarthritis, Reducing the
and SNP treated induced by the edematous phase
β-cells intradermal of the polyarthritis
Aerial Chloroform α-Amylase assay IC50 = 64.9 μg/mL Loizzo et al. injection of at doses of 10–500
parts extract α-Glucosidase IC50 = 74.9 μg/mL (2008) Freund’s mg/day
assay adjuvant
Aerial Methanol α-Amylase assay no inhibition Loizzo et al.
parts extract α-Glucosidase no inhibition (2008)
assay respectively (Tuğlu et al., 2018).
n-Hexane α-Amylase assay no inhibition
extract α-Glucosidase no inhibition
assay
3.5.7. Diuretic activity
The diuretic effect of C. erythraea extract was evaluated using adult
normotensive male Wistar rats weighing 280–300 g. The effect was
19% and 42%, respectively. This extract inhibited and reduced the evaluated on the urinary volume (UV) and the excretion of sodium,
edematous phase of polyarthritis at doses of 10–500 mg/day (Berkan potassium, and chloride by the oral administration (daily for 1 week) of
et al., 1991). Recently, Kachmar et al. (2019) evaluated the in vitro the aqueous extract of C. erythraea whole plant (dose of 10 mL/kg of 8%
anti-inflammatory effect C. erythraea aqueous extract was assessed by or 16% extract in distilled water) (Haloui et al., 2000). The concentra­
spectrophotometric microassays in non-cellular and cellular systems tion of electrolytes and urea in plasma and creatinine clearance were
(RAW 267.4 macrophage cell line). The results revealed that the also determined in the same study (Table 10). The results showed that
aqueous leaf extract inhibited 5-lipoxygenase in a dose-dependent the aqueous extract of C. erythraea whole plant significantly enhanced
pattern with an IC25 value of 78.71 ± 2.83 μg/mL and did not affect diuresis in rats from the fifth day of treatment. Interestingly, C. erythraea
the mitochondrial activity at the tested concentrations. The extract at aqueous extract showed a diuretic effect with the most effective dose
the highest tested concentration (1 mg/mL) caused a reduction in NO (8%) for water and electrolyte excretion, suggesting that the diuretic
levels (Kachmar et al., 2019). effect was none dose-dependent. The extract exhibited a significant in­
crease in urinary excretion of sodium, chloride, and potassium. It also
3.5.6. Cytotoxic activity led to a significant decrease in creatinine clearance after treatment with
The cytotoxic activity of the extracts of C. erythraea aerial parts was 8% of C. erythraea. No change in the concentration of sodium, potas­
reported in several studies (Bouyahya et al., 2018; Tuğlu et al., 2018) sium, and chloride in plasma was noticed. The diuretic activity was
(Table 9). Our group evaluated the cytotoxic activity of organic extracts attributed to several active principles such as flavonoids, saponins, or
of C. erythraea aerial parts (methanolic, ethanolic, and n-hexane ex­ organic acids present in the extract. The aqueous extract were found to
tracts) on three cancer cell lines (L20B, RD, and Vero) using MTT assay. act as a diuretic agent that acts directly or indirectly on glomerular
The pharmacological selectivity index (PSI) was calculated using PBMC filtration rate mediated by tubuloglomerular feedback. The delayed
as the normal cell line. C. erythraea extracts inhibited the proliferation of response of the observed natriuresis supported the hypothesis of an in­
L20B, RD, and Vero with IC50 values of 219.83 ± 3.25, 218.47 ± 3.91, direct effect of the extract on the glomerular filtration rate (Haloui et al.,
and 248.52 ± 2.73 μg/mL, respectively for the methanolic extract, while 2000).
the other extracts inhibited both cell line with IC50 value ˃ 250 μg/mL
(Bouyahya et al., 2018). In another study, n-Hexane extract of C. 3.5.8. Spasmolytic activity
erythraea (aerial part) was investigated for their cytotoxic effect on Chda et al. (2016) reported that the aqueous extract of C. erythraea
MCF-7, MB-MDA-231, 67NR, and 4T1 breast carcinoma cell lines, NB2a aerial parts exhibited a spasmolytic effect (Table 10). Spasm was
neuroblastoma cell line, and L929 fibroblast cell line. C. erythraea induced by tyrode solution containing high KCl (60 mM) or with
exhibited a potent antiproliferative effect against human cancer cell acetylcholine (ACh, 10-5 M) and the spasmolytic effect of C. erythraea
lines with IC50 values of 7.5, 8.00, 6.00, 5.75, 7.55, and 8.25 μg/mL, was evaluated on rabbit jejunum through calcium channel blockade and

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 9 candidates for mediating nonadrenergic-noncholinergic smooth muscle

Cytotoxic effects of C. erythraea. relaxation through the gastrointestinal tract (Ragy and Elbassuoni,
Part Extracts Cell lines Key Ref 2012; Toda et al., 1990; Zyromski et al., 2001) via an increase of cellular
used results concentration of cGMP (Moradi et al., 2013; Takeuch et al., 2001) which
Aerial Methanolic Human embryonal IC50 = Bouyahya activates in turn a protein kinase G (Takeuch et al., 2001). The smooth
parts extract rhabdomyosarcoma 218.47 ± et al. muscle motility can possibly be inhibited due to the presence of gen­
cancerous cell lines (ATCC 3.91 μg/ (2018) tiopicrin, xanthone, and flavonoids (Capasso et al., 2009; Rojas et al.,
N◦ CCL-136) mL 2000). The spasmolytic effect of the aqueous extract of C. erythraea
Rat embryonal IC50 =
rhabdomyosarcoma 219.83 ±
aerial parts may be ascribed at least to these compounds. However, an
cancerous cell lines (3T6 3.25 μg/ additional investigation is necessary to determine the main bioactive
Swiss albino, ATCC CCL96) mL compound(s) responsible for the spasmolytic effect.
Monkey kidney cancerous IC50 =
cell lines (ATCC N◦ CCL-81) 248.52 ±
3.5.9. Gastroprotective activity
2.73 μg/
mL The gastroprotective activity of the aqueous ethanolic extract pre­
Ethanolic Human embryonal IC50 ˃ pared from C. erythraea aerial parts was carried out by the evaluation of
extract rhabdomyosarcoma 250 μg/ aspirin-induced gastric damage in Sprague-Dawley male albino rats. The
cancerous cell lines (ATCC mL ulcer index, oxidant levels (free radicals generated by ROS and NOS),
N◦ CCL-136)
Rat embryonal IC50 ˃
and antioxidant levels (antioxidant enzymes activity) were measured
rhabdomyosarcoma 250 μg/ (Tuluce et al., 2011) (Table 10). The extract significantly reduced the
cancerous cell lines (3T6S mL percentage of lesion area (77%) to the total gastric surface area (ulcer
Swiss albino, ATCC CCL96) index). The myeloperoxidase (MPO) (an essential marker for normal
Monkey kidney cancerous IC50 ˃
neutrophil function) and lipid peroxidation (LPO) activities were also
cell lines (ATCC N◦ CCL-81) 250 μg/
mL significantly reduced while glutathione (GSH) and vitamin A levels were
n-Hexane Human embryonal IC50 ˃ significantly enhanced (Tuluce et al., 2011). It is a well-known phe­
extract rhabdomyosarcoma 250 μg/ nomenon that ulceration causes the accumulation of oxygen free radi­
cancerous cell lines (ATCC mL cals resulting in pathophysiological changes in gastric ulceration
N◦ CCL-136)
(Szelenyi and Brune, 1988; Wallace et al., 1990). The treatment with
Rat embryonal IC50 =
rhabdomyosarcoma 210.67 ± potent scavengers of free radicals such as superoxide dismutase (SOD) or
cancerous cell lines (3T6S 4.48 μg/ catalase (CAT), by subcutaneous injection, caused mucosal protection
Swiss albino, ATCC CCL96) mL and significantly reduced the severity of the lesions (Yoshikawa et al.,
Monkey kidney cancerous IC50 ˃
1993). The significant reduction in MPO activity and LPO resulted in the
cell lines (ATCC N◦ CCL-81) 250 μg/
mL attenuation of the mucosal damage by activated neutrophils (Tuluce
MCF-7 breast carcinoma IC50 = Tuğlu et al. et al., 2011). These results suggested that the used extract protected
cell lines 7.5 μg/ (2018) gastric mucosa against aspirin-induced damage due to its antioxidant
mL activity (Tuluce et al., 2011). The suppression of CAT by aspirin resulted
MB-MDA-231 breast IC50 =
in the accumulation of H2O2 with the subsequent oxidation of the lipids.
carcinoma cell lines 8.00 μg/
mL Thus, the inhibition of CAT was relatively responsible for the oxidative
67NR breast carcinoma cell IC50 = tissue damage of gastric mucosa in aspirin-treated rats (Tuluce et al.,
lines 6.00 μg/ 2011). GSH is a known endogenous antioxidant that protects the gastric
mL
mucosa. It is an important mediator for the maintenance of mucosal
4T1 breast carcinoma cell IC50 =
lines 5.75 μg/
integrity, and its depletion in the gastric mucosa induces macroscopic
mL mucosal ulceration (Hoppenkamps et al., 1984; Tanaka and Yuda,
NB2 neuroblastoma cell IC50 = 1996). It was shown that the administration of NSAIDs and ethanol
line 7.55 μg/ decreased the levels of GSH in gastric tissues (Bafna and Balaraman,
mL
2004; El-Missiry et al., 2001). The restoration of GSH levels provides
L929 fibroblast cell line IC50 =
8.25 μgr/ evidence for the involvement of GSH in the antiulcer activity. The
mL reduction in the levels of –SH compounds especially GSH results in
enhanced LPO and protein oxidation. Blocking oxidative damage
through LPO and protein oxidation, SC could help to prevent the loss of
by the activation of the NO/cGMP pathway (Chda et al., 2016). The used membrane permeability, and dysfunction of cellular proteins, leading to
extract significantly reduced the jejunum’s spontaneous contractions as the survival of the functionally active cells (Tuluce et al., 2011).
well as those induced by a high potassium concentration during calcium
supplementation, inhibited the recovery of spontaneous contraction, 3.5.10. Neuroprotective activity
and shifted to the right the concentration responses curve of high po­ The inhibition of acetylcholinesterase (AChE), butyrylcholinesterase
tassium concentration (spasmogens) induced jejunum contraction (BChE), and tyrosinases (TYR) is related to Alzheimer’s and Parkinson’s
similarly to the effect produced by verapamil, a known calcium channel diseases. This inhibition was used to assess the neurobiological activity
blocker (Chda et al., 2016). The pretreatment with L-NAME or ODQ of both ethanol and methanol extracts of C. erythraea aerial parts. The
significantly reduced the antispasmodic effect demonstrating the extracts were subjected to the microtiter enzyme inhibition assays (in
involvement of the NO pathway in this effect. This suggested that the vitro) at 100 μg/mL (Table 10). The ethanolic extract exhibited the
aqueous extract contained spasmolytic constituents mediating their ef­ highest inhibition against AChE (51.33 ± 3.35%). Regarding the
fect at least through Ca+ 2 influx blockade and NO-cGMP pathway acti­ methanolic extract, it showed 10.42 ± 1.43% against BChE, 4.38 ±
vation. The authors suggested that the spasmolytic action involved the 0.68% against TYR activity, and ineffective against AChE (Orhan et al.,
inhibition of extracellular calcium influx through blockade of VDCCs, 2017). In another in vitro study, the decoction, decoction mucilage free
since substances that inhibit KCl induce contraction of the smooth and xanthonoids fraction prepared from C. erythraea leaves inhibited
muscle are referred to as voltage-dependent calcium channel blockers AChE by 56.43 ± 0.84% at 500 μg/mL, 47.09 ± 0.95% at 500 μg/mL,
(Berridge, 2008). NO is considered as one of the most promising and 47.09 ± 0.95% at 500 μg/mL, respectively (Guedes et al., 2019). In

21
N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 10
Other activities of Centaurium erythraea.
Activities Use part Extract Experimental approach Key results References

Analgesic activity Aqueous extract Injection of 3% acetic acid at the dose level of The extract did not show any analgesic Berkan et al. (1991)
300 mg/kg (10 mL/kg) activity in mice in both methods tested
Hotplate method (53.5 ◦ C) in any of the doses administered
Extract at concentration of 1, 5, 10, 50, and
100 mg
Antipyretic activity Aqueous extract Yeast-induced hyperthermia Reduced yeast-induced hyperthermia
2,4-Dinitrophenol (DNP) induced at the dose of 100 mg
hyperthermia d-Amphetamine sulphate (10 Decreased high temperature
mg/kg) induced hyperthermia
Antileishmanial activity Methanolic Leishmania infantum (MHOM/MA/1998/ IC50 = 124.82 ± 1.75 μg/mL Bouyahya et al.
extract LVTA), (2017b)
Leishmania tropica (MHOM/MA/2010/ IC50 = 247.24 ± 2.59 μg/mL
LCTIOK-4)
Leishmania major (MHOM/MA/2009/LCER19- IC50 = 126.16 ± 3.29 μg/mL
09)
Ethanolic Leishmania infantum (MHOM/MA/1998/ IC50 = 373.18 ± 2.23 μg/mL
extract LVTA),
Leishmania tropica (MHOM/MA/2010/ IC50 > 500 μg/mL
LCTIOK-4)
Leishmania major (MHOM/MA/2009/LCER19- IC50 > 500 μg/mL
09)
n-Hexane Leishmania infantum (MHOM/MA/1998/ IC50 = 125.04 ± 1.9 3 μg/mL
extract LVTA),
Leishmania tropica (MHOM/MA/2010/ IC50 = 37.20 ± 1.62 μg/mL
LCTIOK-4)
Leishmania major (MHOM/MA/2009/LCER19- IC50 = 64.52 ± 2.20 μg/mL
09)
Ethyl acetate Leishmania infantum (MHOM/MA/1998/ IC50 = 143.20 ± 3.82 μg/mL
extract LVTA),
Leishmania tropica (MHOM/MA/2010/ IC50 > 500 μg/mL
LCTIOK-4)
Leishmania major (MHOM/MA/2009/LCER19- IC50 = 128.30 ± 2.35 μg/mL
09)
Diuretic effect Whole Aqueous extract Adult normotensive male Wistar rats Diuretic effect of the aqueous extract of Haloui et al. (2000)
plant Determine the effect on urinary volume (UV) C. erythraea L
and the excretion of sodium (UNaV), potassium Significantly enhanced diuresis in rats
(UKV), and chloride (UClV) oral Significantly increased urinary
administration of the extract at the dose of 10 excretion of sodium, chloride, and
mL/kg of 8 or 16% potassium
Significant decrease in creatinine
clearance
No change in the concentration of
sodium, potassium, and chloride in
plasma
Spasmolytic action Aerial Aqueous extract Rabbit Jejunum is through Calcium Channel Significantly reduced the jejunum’s Chda et al. (2016)
parts Blockade and NO Release spontaneous contractions
Spasm was induced by Tyrode containing high Significantly inhibited the recovery of
KCl (60 mM) or with acetylcholine (ACh, 10-5 spontaneous contraction
M) Shifted to the right the concentration
responses curve of high K+ induced
jejunum contraction
Gastroprotective effect Aerial Aqueous Aspirin-induced gastric damage in rats Reduced the lesion area to total gastric Tuluce et al. (2011)
parts ethanolic measured the ulcer index, oxidant, and surface area (ulcer index) was
extract antioxidant levels significantly (77%), a significant
reduction in MPO activity and LPO,
increased GSH and vitamin A levels
Neurobiological effect Aerial Ethanolic Inhibition of acetylcholinesterase (AChE) Inhibitory effect = 51.33 ± 3.35% Orhan et al. (2017)
part extract Butyrylcholinesterase (BChE) Inhibitory effect = 15.21 ± 1.32%
Tyrosinase (TYR) Inhibitory effect = 8.00 ± 1.65%
Methanolic Inhibition of acetylcholinesterase (AChE) No inhibition
extract Butyrylcholinesterase (BChE) Inhibitory effect = 10.42 ± 1.43%
Tyrosinase (TYR) Inhibitory effect = 4.38 ± 0.68%
Leaves Decoction Inhibition of acetylcholinesterase (AChE) Inhibitory effect = 56.43 ± 0.84% at Guedes et al. (2019)
500 μg/mL
Decoction Inhibition of acetylcholinesterase (AChE) Inhibitory effect = 47.09 ± 0.95% at
mucilage free 500 μg/mL
Xanthonoids Inhibition of acetylcholinesterase (AChE) Inhibitory effect = 47.09 ± 0.95% at
fraction 500 μg/mL
Hepatoprotective activity Aerial Methanol Acetaminophen-induced Hepatotoxicity in Significantly reduced the elevated Mroueh et al. (2004)
parts extract Rats levels of three enzymes to 10.4% for
SGOT, 31.9% for SGPT, and 22.9% for
LDH.
Dermatoprotective activity Tyrosinase inhibitory assay IC50 = 103.592 ± 0.0 μg/mL Bouyahya et al.
(2019)
(continued on next page)

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N. El Menyiy et al. Journal of Ethnopharmacology 276 (2021) 114171

Table 10 (continued )
Activities Use part Extract Experimental approach Key results References

Essential oil
(vegetative
stage)
Essential oil Tyrosinase inhibitory assay IC50 = 41.863 ± 0.031 μg/mL
(flowering Essential oil (post-flowering stage) Tyrosinase inhibitory assay
IC50 = 49.183 ± 0.298 μg/ stage)
mL
Acute toxicity Whole Lyophilized Oral single administration of extract at doses NOAEL = 6 g/kg Tahraoui et al. (2010)
plant extract 1–15 g/kg given by gavage, and single LOAEL = 8 g/kg
intraperitoneal (i.p.) doses of 1–14 g/kg t to LD50 = 12.13 g/kg
adult IOPS OFA mice
Determination of mortality in 14 days
Sub-chronic toxicity Whole Lyophilized Oral administration of the extract at doses of Did not cause any change in
plant extract 100, 600, and 1200 mg/kg daily for 90 days to hematological and biochemical
Wistar rats parameters
A small reduction of mean corpuscular
volume
A decrease in serum glucose and
triglyceride levels at the higher doses
CE-extract is relatively non-toxic
Vascular effects through Aerial Methanolic Isolated mesenteric vascular bed (MVB) from Induce endothelium-dependent Chda et al. (2020)
endothelium- and parts fraction Wistar rats cardiac fibroblasts proliferation vasodilation
fibroblast-dependent NO determination Prevent fibroblast proliferation
pathways Fibroblast culture and MTT cell viability assay induced by angiotensin II
Insecticidal activity Aerial n-Hexane Larvae and pupae of Tribolium castaneum FI larvae = Inactive Pascual-Villalobos
parts Insect growth and/or feeding inhibition (FI) CT pupae = Inactive and Robledo (1998)
Contact toxicity (CT) TA pupae = Inactive
Topical applications (TA) TA larvae = activity in 0–39% of insects
Repellency bioassay (R) R larvae = activity in 0–39% of insects
Acetone Larvae and pupae of Tribolium castaneum Mortality of larvae = 80%
Insect growth and/or feeding inhibition (FI) FI larvae = activity in 0–39% of insects
Contact toxicity (CT) CT pupae = Inactive
Topical applications (TA) TA larvae = activity in 40–69% of
Repellency bioassay (R) insects
R larvae = activity in 0–39% of insects
Methanol Larvae and pupae of Tribolium castaneum FI larvae = activity in 0–39% of insects
Insect growth and/or feeding inhibition (FI) CT pupae = Inactive
Contact toxicity (CT) TA pupae = Inactive
Topical applications (TA) TA larvae = Inactive
Repellency bioassay (R) R larvae = non-tested bioassay
Larval development effect Stems Methanol Insect = Tribolium castaneum Inhibited growth of larvae. Jbilou et al. (2008)
and extract Bioassays = Extracts mixed with 4 g of the diet Mortality = 63% 10 days after
leaves at a concentration of 10% treatment

silico molecular docking approach indicated that a large number of
xanthonoids are promising AChE inhibitors identified in C. erythraea
(Guedes et al., 2019). No correlation was observed between the amount
of the total phenols present in the fractions and the enzyme inhibitory
activity (r2 = 0.0256), which was expected since many factors influence
the inhibition constant of AChE and most of them are not related to the
number of phenolic groups in the extract (Guedes et al., 2019).
3.5.11. Dermatoprotective activity
Enzymatic browning of human skin involves the formation of
melanin which goes through many stages involving several enzymes
(Karioti et al., 2007). Among these enzymes, tyrosinase is involved in the
first two stages and its inhibition represents a therapeutic avenue for the
development of skin-protective drugs. The inhibition of tyrosinase ac­
tivity is an important strategy for skin protection. The dermatopro­
tective activity of C. erythraea aerial parts in either vegetative, flowering
or post-flowering stage was evaluated using tyrosinase inhibitory assay
by our group (Table 10). The essential oil of flowering stage exhibited
the highest inhibitory effect of tyrosinase with an IC50 value of 41.83 ±
0.031 μg/mL, which was six times more active than quercetin used as
the standard. The essential oils obtained at the post-flowering and
vegetative stages showed important inhibition of tyrosinase with IC50
values of 49.183 ± 0.298 μg/mL and 103.592 μg/mL, respectively
(Bouyahya et al., 2019).
3.5.12. Vascular effects through endothelium- and fibroblast-dependent
pathways
The methanolic fraction of C. erythraea aerial parts induced
endothelium-dependent vasodilation and prevented fibroblast prolifer­
ation induced by angiotensin II (Chda et al., 2020). The effect on the
cardiovascular system was carried out using isolated mesenteric
vascular bed (MVB) from Wistar rats, NO determination, fibroblast
culture, and MTT cell viability assays (Chda et al., 2020) (Table 10). The
reduction of the perfusion pressure caused by the methanolic fraction
was endothelium-dependent and occurred in parallel with an increase in
NO release. These effects were inhibited by muscarinic receptor antag­
onists, by L-NAME (a NO synthase inhibitor), and by ODQ (a soluble
guanylate cyclase inhibitor). Endothelial control of vascular tone
involved NO, and a probable contribution of an endothelium-derived
hyperpolarizing factor in the vasorelaxation caused by the C. erythraea
extract. The methanol extract stimulated NO formation and the vaso­
relaxation through the activation of the NO-cGMP pathway, as it was
inhibited by L-NAME, an inhibitor of NO synthase, and by ODQ, an in­
hibitor of guanylate cyclase (Chda et al., 2020). The relaxation seemed
to be mediated, at least in part, by increasing K+ efflux through KATP
and KCa channels, according to the inhibition of this effect caused by
glibenclamide (a KATP channel inhibitor) and tetraethylammonium (a
KCa channel inhibitor) (Chda et al., 2020). The vasorelaxation may
involve the activation of muscarinic receptors, which is one of the first
and best-known mechanisms to induce the release of
endothelium-derived relaxing factors since it was blocked by different

23
N. El Menyiy et al.
muscarinic receptor antagonists (Furchgott, 1984). The methanolic
extract inhibited fibroblast proliferation induced by angiotensin II,
mimicking what would be expected from blockade of angiotensin II ef­
fects. It was suggested that C. erythraea contains compounds that may
inhibit wall remodeling of the cardiovascular system (Chda et al., 2020).
Quercetin and isorhamnetin are known compounds to reduce oxidative
stress and improve NO bioavailability leading to the attenuation of
endothelial dysfunction. Kaempferol is known to possess a relaxative
effect on agonist-induced vascular contraction regardless of endothelial
function that could be responsible for the observed activity (Chda et al.,
2020; Mahobiya et al., 2018; Xiao et al., 2009). Also, hydroxycinnamic
acids, such as p-coumaric and caffeic acids, were known to exhibit
vasorelaxant and antioxidant effects (Mudnic et al., 2010; Teixeira et al.,
2013).
3.5.13. Antileishmanial activity
The antileishmanial activity of the methanolic, ethanolic, n-hexane
and ethyl acetate extracts of C. erythraea was evaluated against Leish­
mania infantum (MHOM/MA/1998/LVTA), Leishmania tropica (MHOM/
MA/2010/LCTIOK-4), and Leishmania major (MHOM/MA/2009/
LCER19-09) by our group (Bouyahya et al., 2017b) (Table 10). The
n-hexane extract was the most active one by inhibiting the growth of
L. infantum (IC50 = 125.04 ± 1.9 3 μg/mL), L. tropica (IC50 = 37.20 ±
1.62 μg/mL) and L. major (IC50 = 64.52 ± 2.20 μg/mL). The methanolic
extract was highly efficient against L. infantum (IC50 = 124.82 ± 1.75
μg/mL) and L. major (IC50 = 126.16 ± 3.29 μg/mL), but showed a
moderate efficacy against L. tropica (IC50 = 247.24 ± 2.59 μg/mL). The
ethanolic and ethyl acetate extracts showed moderate to low activities.
The former moderately inhibited the growth of L. infantum (IC50 =
373.18 ± 2.23 μg/mL) and weakly inhibited growth of L. tropica (IC50 >
500 μg/mL) and L. major (IC50 > 500 μg/mL) while the latter moderately
inhibited the growth of L. infantum (IC50 = 143.20 ± 3.82 μg/mL),
L. major (IC50 = 128.30 ± 2.35 μg/mL) and weakly inhibited the growth
of L. tropica (IC50 > 500 μg/mL) (Bouyahya et al., 2017b). The differ­
ential antileishmanial effects of these extracts were not only related to
their chemical composition but also the nature of the Leishmania species
(Bouyahya et al., 2017b). The mechanism of action was suggested to be
dependent on the specific cellular targets that disrupt the cell membrane
and induce cell lysis. The interaction with the mitochondrial membrane
could also be considered as another targeting pathway inducing the
death of parasites by apoptosis (Bouyahya et al., 2017b). These actions
could be due to the total flavonoid contents, which showed a direct
correlation with antileishmanial capacity especially against L. major and
L. infantum (Bouyahya et al., 2017b).
3.5.14. Insecticidal and larval development activity
n-Hexane, acetone and methanol extracts of C. erythraea aerial parts
showed good insecticidal activity against larvae and pupae of Tribolium
castaneum, using growth and/or feeding inhibition, contact toxicity,
topical applications, and repellency bioassay (Pascual-Villalobos and
Robledo, 1998) (Table 10).
The n-hexane extract showed 0–39% of mortality in larvae after
topical application at a concentration of 3 μg/insect. No activity was
reported on larvae growth and/or feeding inhibition, pupae contact
toxicity, and topical applications (Pascual-Villalobos and Robledo,
1998). Acetone extract exhibited mortality of 80% in larvae, 0–39% of
growth and/or feeding inhibition, and repellency bioassay of larvae
while it showed 40–69% of activity in larvae topical applications. The
n-hexane extract of C. erythraea aerial parts showed no activity in con­
tact toxicity of pupae (Pascual-Villalobos and Robledo, 1998). The
methanol extract showed 0–39% in larvae growth and/or feeding inhi­
bition and no activity in pupae contact toxicity, topical applications, and
larvae topical applications (Pascual-Villalobos and Robledo, 1998).
Methanol extract of C. erythraea stems and leaves inhibited the
growth of Tribolium castaneum larvae vitellogenesis and egg production,
oviposition, or killed the larvae hatching from eggs laid in the culture
24
Journal of Ethnopharmacology 276 (2021) 114171
medium (Jbilou et al., 2008). The extracts were mixed with 4 g of the
diet at a concentration of 10% and the mortality was around 63% after
10 days of treatment. The emergence rate was also reduced by 66% and
F1 progeny production was inhibited (Jbilou et al., 2008).
3.5.15. Other activities
Berkan et al. (1991) reported that the aqueous extract of C. erythraea
exhibited no analgesic activity in any of the doses administered using
both injections of 3% acetic acid at the dose level of 300 mg/kg (10
mL/kg) and hotplate (53.5 ◦ C) methods (Table 10). The aqueous extract
of C. erythraea reduced yeast-induced hyperthermia at a dose of 100 mg.
This effect was lasting and was observed in hourly repeated measure­
ments up to the fourth hour (Berkan et al., 1991) (Table 10). Moreover,
Mroueh et al. (2004) reported that the methanolic extract from the
aerial parts (pretreatment at a dose of 300 mg/kg for 6 days), showed
good hepatoprotective activity against acetaminophen-induced liver
toxicity in rats. The extract significantly reduced the elevated levels of
three enzymes to 10.4% for serum glutamate oxaloacetate transaminase
(SGOT), 31.9% for serum glutamate pyruvate transaminase (SGPT), and
22.9% for lactate dehydrogenase (LDH) (Mroueh et al., 2004).
3.6. Toxicology investigation
The study of acute toxicity of the lyophilized aqueous extract of the
whole plant was carried out using oral single administration of the
extract at doses 1–15 g/kg given by gavage, and single intraperitoneal (i.
p.) doses of 1–14 g/kg to adult IOPS OFA mice (Tahraoui et al., 2010)
(Table 10). General behavioral adverse effects, mortality, and latency of
mortality were determined up to 14 days. The obtained results showed
that the extract was non-toxic via the oral route in mice and rats at least
up to the maximum doses. No deaths or any signs of toxicity were
observed after the oral administration of single doses of the aqueous
extract of C. erythraea whole plant at any dose level up to the highest
dose tested (15 g/kg) which was the no-observed-adverse-effect level
(NOAEL). However, the mortality rate as well as the acute toxicity of the
i.p. the administered lyophilized extract increased progressively with
the increasing dose. The NOAEL for the i.p. the dose was 6 g/kg while
the lowest-observed-adverse-effect level (LOAEL) was 8 g/kg. The
calculated acute toxicity (LD50) of i.p. administered CE-extract in mice
was 12.13 g/kg (Tahraoui et al., 2010). Except for the small decrease in
MCV, there were no significant alterations in the hematological pa­
rameters of rats as well as in the biochemical parameters, except for a
decrease in blood glucose and triglycerides at the higher doses. The
indicators of liver and kidney function remained also unaffected (Tah­
raoui et al., 2010). The lack of adverse effects after oral administration
of the aqueous extract may be ascribed to low bioavailability of the toxic
component(s) as a result of poor absorption from the gastrointestinal
tract or due to high first-pass effect and rapid metabolism to non-toxic
metabolites (Tahraoui et al., 2010).
On the other hand, the sub-chronic toxicity of the lyophilized extract
from the whole plant was studied using the oral administration of the
extract at doses of 100, 600, and 1200 mg/kg daily for 90 days to Wistar
rats. The extract did not cause any changes in hematological and
biochemical parameters. A small reduction of mean corpuscular volume,
a decrease in serum glucose and triglyceride levels at the higher doses,
and CE-extract was relatively non-toxic as reported by (Tahraoui et al.,
2010) (Table 10).
4. Conclusions
In this review, we reported the ethnobotanical use, phytochemistry,
pharmacology and toxicological investigations of C. erythraea. This
plant, widely answered in several countries of the world, is used by
different populations for the treatment of certain diseases. The results of
the ethnobotanical surveys discussed showed a variability of uses which
depends both on the part used, the disease treated, and the mode of use
N. El Menyiy et al.
but also it depends on the region in which the plant is used.
It was noticed that C. erythraea is used in different countries to fight
against several diseases in particularly diabetes and infectious diseases.
Traditional uses of C. erythraea showed some variability between
countries and the used parts which explain that this medicine is influ­
enced by local population. However, the variation of positive results in
different area can be attributed to the bioactive molecules expressed by
C. erythraea depending on different regions.
Phytochemical investigation showed that C. erythraea contain
chemical compounds belonging to several chemical classes such as ter­
penoids, flavonoids and phenolic acids.
C. erythraea traditional uses were scientifically confirmed by phar­
macological assays, which linked the ethnopharmacological uses to the
biological activities and secondary metabolite content. Furthermore, in
vitro and in vivo pharmacological investigations of C. erythraea essential
oils and extracts reported several effects such as antibacterial, anti­
fungal, antioxidant, antidiabetic, antiinflammatory, cytotoxic, diuretic,
spasmolytic, gastroprotective, neuroprotective, dermatoprotective,
antileishmanial, insecticidal and larval development, and vascular
activities.
Essential oils of C. erythraea showed an antimicrobial effect against
several Gram- and Gram + bacteria, and several fungi. It seems impor­
tant to thoroughly investigate the antibacterial and antifungal effects of
these EOs and their bioactive compounds against multiresistant bacteria
and fungal strains in order to understand the mechanism of action in
both in vitro and in vivo in experimentally infected animals.
The antioxidant effect of C. erythraea extracts and EOs is due, in
particular, to the presence of bioactive compounds, mainly phenolic
substances. Moreover, this species revealed an important pharmaco­
logical effects against some oxidative stress related diseases including
diabetic, inflammation and cancer. However, almost of these properties
were carried out only for plant extracts. Moreover, pharmacodynamic
action of studied activities was not determined. Therefore, further mo­
lecular investigations for determining the pharmacodynamic action and
pharmacokinetic studies for assuring the bioavailability of these bioac­
tive molecules are required.
Toxicological evidences in animal models did not reveal significant
toxicity. However, clinical trials were not conducted and there is an
urgent need to perform such trials in order to validate the safety of
C. erythraea. Moreover, its main compounds should also be tested for
their toxicity in order to complete the toxicity profil.
Authors’ contributions
Abdelhakim Bouyahya conceived the idea, provided guidance,
reviewed the article, wrote a part of the manuscript and structured the
article as per the journal guidelines. Naoual El Menyiy collected the
data, wrote a part of the manuscript, and cited the references as per the
journal guidelines, and reviewed the final version of the article. Fatima
Ezzahrae Guaouguaou drew the chemical structures using ChemDraw
Pro software. Tarik Aanniz, Taoufiq Ben, Nasreddine El Omari, Aicha
Elaaboua, Taoufiq Benali, Tarik Aanniz, and Douae Taha wrote a part of
the manuscript and reviewed the final version. Gokhan Zengin,
Mohammad Ali Shariati, and mohamed elshazly reviewed and corrected
the manuscript.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
There was no conflict of interest between authors.
25
Journal of Ethnopharmacology 276 (2021) 114171
Acknowledgments
Not applicable.
References
Aberham, A., Pieri, V., Croom, E.M., Ellmerer, E., Stuppner, H., 2011. Analysis of
iridoids, secoiridoids and xanthones in Centaurium erythraea, Frasera caroliniensis
and Gentiana lutea using LC–MS and RP-HPLC. J. Pharmaceut. Biomed. Anal. 54,
517–525. https://doi.org/10.1016/j.jpba.2010.09.030.
Agelet, A., Vallès, J., 2003. Studies on pharmaceutical ethnobotany in the region of
Pallars (Pyrenees, Catalonia, Iberian Peninsula). Part II. New or very rare uses of
previously known medicinal plants. J. Ethnopharmacol. 84, 211–227. https://doi.
org/10.1016/S0378-8741(02)00319-7.
Bafna, P.A., Balaraman, R., 2004. Anti-ulcer and antioxidant activity of DHC-1, a herbal
formulation. J. Ethnopharmacol. 90, 123–127. https://doi.org/10.1016/j.
jep.2003.09.036.
Barešová, H., 1988. Centaurium erythraea Rafn: micropropagation and the production of
secoiridoid glucosides, in: Bajaj, Y.P.S. (Ed.), Medicinal and Aromatic Plants I,
Biotechnology in Agriculture and Forestry. Springer, Berlin, Heidelberg, pp.
350–366. https://doi.org/10.1007/978-3-642-73026-9_19.
Bassanetti, I., Carcelli, M., Buschini, A., Montalbano, S., Leonardi, G., Pelagatti, P.,
Tosi, G., Massi, P., Fiorentini, L., Rogolino, D., 2017. Investigation of antibacterial
activity of new classes of essential oils derivatives. Food Contr. 73, 606–612. https://
doi.org/10.1016/j.foodcont.2016.09.010.
Beerhues, L., Berger, U., 1994. Xanthones in cell suspension cultures of two Centaurium
species. Phytochemistry 35, 1227–1231. https://doi.org/10.1016/S0031-9422(00)
94825-8.
Benali, T., Khabbach, A., Ennabili, A., Hammani, K., 2017. Ethnopharmacological
prospecting of medicinal plants from the Province of Guercif (NE of Morocco).
J. Biol. 14, 15.
Benítez, G., González-Tejero, M.R., Molero-Mesa, J., 2010. Pharmaceutical ethnobotany
in the western part of Granada province (southern Spain): ethnopharmacological
synthesis. J. Ethnopharmacol. 129, 87–105. https://doi.org/10.1016/j.
jep.2010.02.016.
Benkhnigue, O., Akka, F.B., Salhi, S., Fadli, M., Zidane, L., 2014. Catalogue des plantes
médicinales utilisées dans le traitement du diabète dans la région d’Al Haouz-
Rhamna (Maroc). J Anim Plant Sci 30.
Berkan, T., Üstünes, L., Lermioglu, F., Özer, A., 1991. Antiinflammatory, analgesic, and
antipyretic effects of an aqueous extract of erythraea centaurium. Planta Med. 57,
34–37. https://doi.org/10.1055/s-2006-960011.
Berridge, M.J., 2008. Smooth muscle cell calcium activation mechanisms. J. Physiol.
(Lond.) 586, 5047–5061. https://doi.org/10.1113/jphysiol.2008.160440.
Bishay, D., Shelver, W., Khalil, S., 1978. Alkaloids of erythraea Centaurium pers.
Growing in Egypt. Planta Med. 33, 422–423. https://doi.org/10.1055/s-0028-
1097408.
Bonet, M.À., Parada, M., Selga, A., Vallès, J., 1999. Studies on pharmaceutical
ethnobotany in the regions of L’alt empordà and les guilleries (Catalonia, iberian
Peninsula). J. Ethnopharmacol. 68, 145–168. https://doi.org/10.1016/S0378-8741
(99)00083-5.
Bouyahya, A., Abrini, J., EtTouys, A., Bakri, Y., Dakka, N., 2017a. Indigenous knowledge
of the use of medicinal plants in the North-West of Morocco and their biological
activities. European Journal of Integrative Medicine 13, 9–25. https://doi.org/
10.1016/j.eujim.2017.06.004.
Bouyahya, A., Bakri, Y., Belmehdi, O., Et-Touys, A., Abrini, J., Dakka, N., 2017b.
Phenolic extracts of Centaurium erythraea with novel antiradical, antibacterial and
antileishmanial activities. Asian Pac J Trop Dis 7 (7), 433–439.
Bouyahya, A., Bakri, Y., Et-Touys, A., Assemian, I.C.C., Abrini, J., Dakka, N., 2018. In
vitro antiproliferative activity of selected medicinal plants from the North-West of
Morocco on several cancer cell lines. European Journal of Integrative Medicine 18,
23–29. https://doi.org/10.1016/j.eujim.2018.01.001.
Bouyahya, A., Belmehdi, O., El Jemli, M., Marmouzi, I., Bourais, I., Abrini, J., Faouzi, M.
E.A., Dakka, N., Bakri, Y., 2019. Chemical variability of Centaurium erythraea
essential oils at three developmental stages and investigation of their in vitro
antioxidant, antidiabetic, dermatoprotective and antibacterial activities. Ind. Crop.
Prod. 132, 111–117. https://doi.org/10.1016/j.indcrop.2019.01.042.
Božunović, J., Živković, S., Gašić, U., Glamočlija, J., Ćirić, A., Matekalo, D., Šiler, B.,
Soković, M., Tešić, Ž., Mišić, D., 2018. In vitro and in vivo transformations of
Centaurium erythraea secoiridoid glucosides alternate their antioxidant and
antimicrobial capacity. Ind. Crop. Prod. 111, 705–721. https://doi.org/10.1016/j.
indcrop.2017.11.040.
Calvo, M.I., Akerreta, S., Cavero, R.Y., 2013. The pharmacological validation of
medicinal plants used for digestive problems in Navarra, Spain. European Journal of
Integrative Medicine 5, 537–546. https://doi.org/10.1016/j.eujim.2013.07.002.
Capasso, R., Aviello, G., Romano, B., Atorino, G., Pagano, E., Borrelli, F., 2009. Inhibitory
effect of quercetin on rat trachea contractility in vitro. J. Pharm. Pharmacol. 61,
115–119. https://doi.org/10.1211/jpp/61.01.0016.
Chda, A., Kabbaoui, M., Chokri, A., Abida, K., Tazi, A., Cheikh, R., 2016. Spasmolytic
action of Centaurium erythraea on rabbit jejunum is through calcium channel
blockade and NO release. EJMP 11, 1–13. https://doi.org/10.9734/EJMP/2016/
20374.
Chda, A., El Kabbaoui, M., Fresco, P., Silva, D., Gonçalves, J., Oliveira, A.P., Andrade, P.
B., Valentão, P., Tazi, A., El Abida, K., Bencheikh, R., 2020. Centaurium erythraea
N. El Menyiy et al.
extracts exert vascular effects through endothelium- and fibroblast-dependent
pathways. Planta Med. 86, 121–131. https://doi.org/10.1055/a-1023-8918.
Di Novella, R., Di Novella, N., De Martino, L., Mancini, E., De Feo, V., 2013. Traditional
plant use in the national park of cilento and Vallo di Diano, Campania, southern,
Italy. J. Ethnopharmacol. 145, 328–342. https://doi.org/10.1016/j.
jep.2012.10.065.
El-Hilaly, J., Hmammouchi, M., Lyoussi, B., 2003. Ethnobotanical studies and economic
evaluation of medicinal plants in Taounate province (Northern Morocco).
J. Ethnopharmacol. 86, 149–158. https://doi.org/10.1016/S0378-8741(03)00012-
6.
El-Missiry, M.A., El-Sayed, I.H., Othman, A.I., 2001. Protection by metal complexes with
SOD-mimetic activity against oxidative gastric injury induced by indometacin and
ethanol in rats. Ann. Clin. Biochem. 38, 694–700. https://doi.org/10.1258/
0004563011900911.
Eraslan, Z.B., Genç, G.E., Kültür, Ş., 2020. Medicinal plants traditionally used to treat
skin diseases in Turkey – eczema, psoriasis, vitiligo. TÜRKİYE’DE HALK ARASINDA
CİLT HASTALIKLARININ TEDAVİSİNDE KULLANILAN TIBBİ BİTKİLER – EGZAMA,
SEDEF HASTALIĞI, VİTİLİGO 44, 137–166. https://doi.org/10.33483/
jfpau.586114.
Flora Celtica Online Database, 2001. Royal Botanic Garden Edinburgh.
Flora Europaea Online Database, 2002. Royal Botanic Garden Edinburgh.
Flora Europaea Online Database, 2011. Royal Botanical Garden Edinburgh, Edinburgh.
Furchgott, R.F., 1984. The role of endothelium in the responses of vascular smooth
muscle to drugs. Annu. Rev. Pharmacol. Toxicol. 24, 175–197. https://doi.org/
10.1146/annurev.pa.24.040184.001135.
Gaspar, N., Godinho, J., Vasconcelos, T., Caldas, D., Mendes, P., Barros, O., 2002.
Ethnobotany in the center of Portugal (Santarém), in: Rauter, A.P., Palma, F.B.,
Justino, J., Araújo, M.E., dos Santos, S.P. (Eds.), Natural Products in the New
Millennium: Prospects and Industrial Application, Proceedings of the Phytochemical
Society of Europe. Springer Netherlands, Dordrecht, pp. 271–284. https://doi.org
/10.1007/978-94-015-9876-7_29.
Gonçalves, S., Gomes, D., Costa, P., Romano, A., 2013. The phenolic content and
antioxidant activity of infusions from Mediterranean medicinal plants. Ind. Crop.
Prod. 43, 465–471. https://doi.org/10.1016/j.indcrop.2012.07.066.
GRIN Online Database, 2011.
Guarrera, P.M., 2005. Traditional phytotherapy in Central Italy (marche, Abruzzo, and
latium). Fitoterapia 76, 1–25. https://doi.org/10.1016/j.fitote.2004.09.006.
Guedes, L., Reis, P.B.P.S., Machuqueiro, M., Ressaissi, A., Pacheco, R., Serralheiro, M.L.,
2019. Bioactivities of Centaurium erythraea (Gentianaceae) decoctions: antioxidant
activity, enzyme inhibition and docking studies. Molecules 24, 3795. https://doi.
org/10.3390/molecules24203795.
Hachi, M., Benkhnigue, O., Hachi, T., El Bouhaddioui, M., Bouabadi, I., Rochdi, A., 2016.
Contribution to the ethnobotanical study of antidiabetic medicinal plants of the
Central Middle Atlas region (Morocco). Lazaroa 37, 135–144.
Hachlafi, N.E., Chebat, A., Bencheikh, R.S., Fikri-Benbrahim, K., 2020.
Ethnopharmacological study of medicinal plants used for chronic diseases treatment
in Rabat-Sale-Kenitra region (Morocco). Ethnobot. Res. Appl. 20, 1–23.
Haloui, M., Louedec, L., Michel, J.-B., Lyoussi, B., 2000. Experimental diuretic effects of
Rosmarinus officinalis and Centaurium erythraea. J. Ethnopharmacol. 71, 465–472.
https://doi.org/10.1016/S0378-8741(00)00184-7.
Hamza, N., Berke, B., Cheze, C., Agli, A.-N., Robinson, P., Gin, H., Moore, N., 2010.
Prevention of type 2 diabetes induced by high fat diet in the C57BL/6J mouse by two
medicinal plants used in traditional treatment of diabetes in the east of Algeria.
J. Ethnopharmacol. 128, 513–518. https://doi.org/10.1016/j.jep.2010.01.004.
Hamza, N., Berke, B., Cheze, C., Marais, S., Lorrain, S., Abdouelfath, A., Lassalle, R.,
Carles, D., Gin, H., Moore, N., 2015. Effect of Centaurium erythraea Rafn, Artemisia
herba-alba Asso and Trigonella foenum-graecum L. on liver fat accumulation in
C57BL/6J mice with high-fat diet-induced type 2 diabetes. J. Ethnopharmacol. 171,
4–11. https://doi.org/10.1016/j.jep.2015.05.027.
Hamza, N., Berke, B., Umar, A., Cheze, C., Gin, H., Moore, N., 2019. A review of Algerian
medicinal plants used in the treatment of diabetes. J. Ethnopharmacol. 238, 111841.
https://doi.org/10.1016/j.jep.2019.111841.
Hatjimanoli, M., 1988. MONOHYDROXY-A N D 2,’j-DIHYDROXY
TEREPHTHALICACIDS, TWO UNUSUAL PHENOLICS ISOLATED FROM
CENTAURZUM ERYTHRAEA AND IDENTIFIED IN OTHER GENTIANACEAE
MEMBERS. J. Nat. Prod. 51, 4.
Hoppenkamps, R., Thies, E., Younes, M., Siegers, C.-P., 1984. Glutathione and GSH-
dependent enzymes in the human gastric mucosa. Klin. Wochenschr. 62, 183–186.
https://doi.org/10.1007/BF01731642.
Idm’hand, E., Msanda, F., Cherifi, K., 2020. Ethnopharmacological review of medicinal
plants used to manage diabetes in Morocco. Clin Phytosci 6, 18. https://doi.org/
10.1186/s40816-020-00166-z.
Ivanišová, E., Krajčovič, T., Tokár, M., Kántor, A., Kačániová, M., 2017. Potential of wild
plants as a source of bioactive compounds. Scientific Papers 6.
Jäger, S., Trojan, H., Kopp, T., Laszczyk, M., Scheffler, A., 2009. Pentacyclic triterpene
distribution in various plants – rich sources for a new group of multi-potent plant
extracts. Molecules 14, 2016–2031. https://doi.org/10.3390/molecules14062016.
Jamila, F., Mostafa, E., 2014. Ethnobotanical survey of medicinal plants used by people
in Oriental Morocco to manage various ailments. J. Ethnopharmacol. 154, 76–87.
https://doi.org/10.1016/j.jep.2014.03.016.
Janković, T., Krstić, D., Savikin-Fodulović, K., Menković, N., Grubisić, D., 2002.
Xanthones and secoiridoids from hairy root cultures of Centaurium erythraea and C.
pulchellum. Planta Med. 68, 944–946. https://doi.org/10.1055/s-2002-34927.
Jarić, S., Mačukanović-Jocić, M., Djurdjević, L., Mitrović, M., Kostić, O., Karadžić, B.,
Pavlović, P., 2015. An ethnobotanical survey of traditionally used plants on Suva
planina mountain (south-eastern Serbia). J. Ethnopharmacol. 175, 93–108.
26
Journal of Ethnopharmacology 276 (2021) 114171
Jbilou, R., Amri, H., Bouayad, N., Ghailani, N., Ennabili, A., Sayah, F., 2008. Insecticidal
effects of extracts of seven plant species on larval development, α-amylase activity
and offspring production of Tribolium castaneum (Herbst) (Insecta: Coleoptera:
tenebrionidae). Bioresour. Technol. 99, 959–964. https://doi.org/10.1016/j.
biortech.2007.03.017.
Jerković, I., Gašo-Sokač, D., Pavlović, H., Marijanović, Z., Gugić, M., Petrović, I.,
Kovač, S., 2012. Volatile organic compounds from Centaurium erythraea Rafn
(Croatia) and the antimicrobial potential of its essential oil. Molecules 17,
2058–2072. https://doi.org/10.3390/molecules17022058.
Jouad, H., Haloui, M., Rhiouani, H., El Hilaly, J., Eddouks, M., 2001. Ethnobotanical
survey of medicinal plants used for the treatment of diabetes, cardiac and renal
diseases in the North centre region of Morocco (Fez–Boulemane).
J. Ethnopharmacol. 77, 175–182. https://doi.org/10.1016/S0378-8741(01)00289-
6.
Jovanović, O., Radulović, N., Stojanović, G., Palić, R., Zlatković, B., Gudžić, B., 2013.
Chemical composition of the essential oil of Centaurium erythraea Rafn
(Gentianaceae) from Serbia. J. Essent. Oil Res. 21, 317–322. https://doi.org/
10.1080/10412905.2009.9700181.
Kachmar, M.R., Oliveira, A.P., Valentão, P., Gil-Izquierdo, A., Domínguez-Perles, R.,
Ouahbi, A., Badaoui, K.E., Andrade, P.B., Ferreres, F., 2019. HPLC-DAD-ESI/MSn
phenolic profile and in vitro biological potential of Centaurium erythraea Rafn
aqueous extract. Food Chem. 278, 424–433. https://doi.org/10.1016/j.
foodchem.2018.11.082.
Kamatou, G.P.P., Vermaak, I., Viljoen, A.M., Lawrence, B.M., 2013. Menthol: a simple
monoterpene with remarkable biological properties. Phytochemistry 96, 15–25.
https://doi.org/10.1016/j.phytochem.2013.08.005.
Kaouadji, M., Vaillant, I., Mariotte, A.-M., 1986. Polyoxygenated xanthones from
Centaurium erythraea roots [WWW Document]. https://doi.org/10.1021/np
50044a037.
Karioti, A., Protopappa, A., Megoulas, N., Skaltsa, H., 2007. Identification of tyrosinase
inhibitors from Marrubium velutinum and Marrubium cylleneum. Bioorg. Med.
Chem. 15, 2708–2714. https://doi.org/10.1016/j.bmc.2007.01.035.
Kirbağ, S., Zengin, F., Kursat, M., 2009. Antimicrobial activities of extracts of some
plants. Pakistan J. Bot. 41, 2067–2070.
Kumarasamy, Y., Cox, P.J., Jaspars, M., Nahar, L., Sarker, S.D., 2002. Screening seeds of
Scottish plants for antibacterial activity. J. Ethnopharmacol. 83, 73–77. https://doi.
org/10.1016/S0378-8741(02)00214-3.
Kumarasamy, Y., Byres, M., Cox, P.J., Jaspars, M., Nahar, L., Sarker, S.D., 2007.
Screening seeds of some Scottish plants for free radical scavenging activity.
Phytother Res. 21, 615–621. https://doi.org/10.1002/ptr.2129.
Labiad, H., Et-tahir, A., Ghanmi, M., Satrani, B., Aljaiyash, A., Chaouch, A., Fadli, M.,
2020. Ethnopharmacological survey of aromatic and medicinal plants of the
pharmacopoeia of northern Morocco. Ethnobot. Res. Appl. 19, 1–16.
Loizzo, M.R., Saab, A.M., Tundis, R., Menichini, Federica, Bonesi, M., Piccolo, V.,
Statti, G.A., de Cindio, B., Houghton, P.J., Menichini, Francesco, 2008. In vitro
inhibitory activities of plants used in Lebanon traditional medicine against
angiotensin converting enzyme (ACE) and digestive enzymes related to diabetes.
J. Ethnopharmacol. 119, 109–116. https://doi.org/10.1016/j.jep.2008.06.003.
Mahobiya, A., Singh, T.U., Rungsung, S., Kumar, T., Chandrasekaran, G., Parida, S.,
Kumar, D., 2018. Kaempferol-induces vasorelaxation via endothelium-independent
pathways in rat isolated pulmonary artery. Pharmacol. Rep. 70, 863–874. https://
doi.org/10.1016/j.pharep.2018.03.006.
Mansar-Benhamza, L., Djerrou, Z., Pacha, Y.H., 2013. Evaluation of anti-hyperglycemic
activity and side effects of Erythraea centaurium (L.) Pers. in rats. Afr. J. Biotechnol.
12 https://doi.org/10.4314/ajb.v12i50.
Mansion, G., 2004. A new classification of the polyphyletic genus Centaurium hill
(chironiinae, Gentianaceae): description of the new world endemic zeltnera, and
reinstatement of gyrandra griseb. And schenkia griseb. Taxon 53 (3), 719–740.
Mansion, G., 2014. Twenty-first century centauries: an updated review on Centaurium
hill and allies (Gentianaceae). In The Gentianaceae-Volume 1: Characterization and
Ecology (pp. 231-250). Springer, Berlin, Heidelberg.
Mansion, G., Struwe, L., 2004. Generic delimitation and phylogenetic relationships
within the subtribe Chironiinae (Chironieae: Gentianaceae), with special reference
to Centaurium: evidence from nrDNA and cpDNA sequences. Mol. Phylogenet. Evol.
32 (3), 951–977.
Mansion, G., Zeltner, L., Bretagnolle, F., 2005. Phylogenetic patterns and polyploid
evolution within the Mediterranean genus Centaurium (Gentianaceae-Chironieae).
Taxon 54 (4), 931–950.
Mascolo, N., Autore, G., Capasso, F., Menghini, A., Fasulo, M.P., 1987. Biological
screening of Italian medicinal plants for anti-inflammatory activity. Phytother Res.
1, 28–31. https://doi.org/10.1002/ptr.2650010107.
Mebavý, L., 1987. Phenolic substances in tissue cultures of Centaurium erythraea. Biol.
Plant. (Prague) 29, 81–87. https://doi.org/10.1007/BF02878153.
Meddour, R., Meddour-Sahar, O., 2015. Medicinal plants and their traditional uses in
Kabylia (Tizi Ouzou, Algeria). Arabian Journal of Medicinal and Aromatic Plants 1,
16.
Melderis, A., 1972. Centaurium hill. In: Tutin ro, Heywood VH, Burges NA, Moore DM,
Valentine DH, Walters SM, Webb DA.
Menković, N., Šavikin, K., Tasić, S., Zdunić, G., Stešević, D., Milosavljević, S., Vincek, D.,
2011. Ethnobotanical study on traditional uses of wild medicinal plants in Prokletije
Mountains (Montenegro). J. Ethnopharmacol. 133, 97–107. https://doi.org/
10.1016/j.jep.2010.09.008.
Merghem, M., Dahamna, S., 2020. Antioxidant activity of Centaurium erythraea extracts.
J. Drug Deliv. Therapeut. 10 (2), 171–174.
N. El Menyiy et al.
Merzouki, A., Ed-derfoufi, F., Molero Mesa, J., 2000. Contribution to the knowledge of
Rifian traditional medicine. II: folk medicine in Ksar Lakbir district (NW Morocco).
Fitoterapia 71, 278–307. https://doi.org/10.1016/S0367-326X(00)00139-8.
Merzouki, A., Ed-Derfoufi, F., Molero Mesa, J., 2003. Contribución al conocimiento de la
medicina rifeña tradicional III: fitoterapia de la diabetes en la provincia de
Chefchaouen (norte de Marruecos). Contribution to the Knowledge of Rifian
traditional medicine III: phytotherapy of diabetes in Chefchaouen province (North of
Morocco) 44, 59–67.
Mihaylova, D., Vrancheva, R., Popova, A., 2019. Phytochemical profile and in vitro
antioxidant activity of Centaurium erythraea Rafn. Bulgarian Chemical
Communications 51 6.
Moradi, M.-T., Rafieian-Koupaei, M., Imani-Rastabi, R., Nasiri, J., Shahrani, M.,
Rabiei, Z., Alibabaei, Z., 2013. Antispasmodic effects of yarrow (Achillea millefolium
L.) extract in the isolated ileum of rat. Afr. J. Tradit., Complementary Altern. Med.
10, 499–503. https://doi.org/10.4314/ajtcam.v10i6.19.
Mroueh, M., Saab, Y., Rizkallah, R., 2004. Hepatoprotective activity ofCentaurium
erythraea on acetaminophen-induced hepatotoxicity in rats. Phytother Res. 18,
431–433. https://doi.org/10.1002/ptr.1498.
Mudnic, I., Modun, D., Rastija, V., Vukovic, J., Brizic, I., Katalinic, V., Kozina, B., Medic-
Saric, M., Boban, M., 2010. Antioxidative and vasodilatory effects of phenolic acids
in wine. Food Chem. 119, 1205–1210. https://doi.org/10.1016/j.
foodchem.2009.08.038.
Mustafa, B., Hajdari, A., Krasniqi, F., Hoxha, E., Ademi, H., Quave, C.L., Pieroni, A.,
2012a. Medical ethnobotany of the Albanian alps in Kosovo. J. Ethnobiol. Ethnomed.
8, 6. https://doi.org/10.1186/1746-4269-8-6.
Mustafa, B., Hajdari, A., Pajazita, Q., Syla, B., Quave, C.L., Pieroni, A., 2012b. An
ethnobotanical survey of the Gollak region, Kosovo. Genet. Resour. Crop Evol. 59,
739–754. https://doi.org/10.1007/s10722-011-9715-4.
Orch, H., Douira, A., Zidane, L., 2015. Étude ethnobotanique des plantes médicinales
utilisées dans le traitement du diabète, et des maladies cardiaques dans la région
d’Izarène (Nord du Maroc). J. App. Bioscience. 86, 7940. https://doi.org/10.4314/
jab.v86i1.3.
Orch, H., Douira, A., Zidane, L., 2015. Étude ethnobotanique des plantes médicinales
utilisées dans le traitement du diabète, et des maladies cardiaques dans la région
d’Izarène (Nord du Maroc). Journal of Applied Biosciences 86. https://doi.org/
10.4314/jab.v86i1, 7940–7956–7940–7956.
Orch, H., Zidane, L., Douira, A., 2020. Ethnobotanical study of plants used in the
treatment of respiratory diseases in a population bordering the forest of Izarène.
Journal of Pharmacy & Pharmacognosy Research 8, 18.
Orhan, I.E., Senol, F.S., Haznedaroglu, M.Z., Koyu, H., Erdem, S.A., Yılmaz, G., Cicek, M.,
Yaprak, A.E., Ari, E., Kucukboyaci, N., Toker, G., 2017. Neurobiological evaluation
of thirty-one medicinal plant extracts using microtiter enzyme assays. Clin Phytosci
2, 9. https://doi.org/10.1186/s40816-016-0023-6.
Paniagua-Zambrana, N.Y., Bussmann, R.W., 2020. <Emphasis
Type="Italic">Centaurium erythraea</Emphasis> Rafn G<Emphasis
Type="SmallCaps">entianaceae</Emphasis>. Ethnobotany of the Andes 477–480.
https://doi.org/10.1007/978-3-030-28933-1_60.
Pascual-Villalobos, M.J., Robledo, A., 1998. Screening for anti-insect activity in
Mediterranean plants. Ind. Crop. Prod. 8, 183–194. https://doi.org/10.1016/S0926-
6690(98)00002-8.
Pereira, E., Gomes, R., Freire, N., Aguiar, E., Brandão, M., Santos, V., 2011. In vitro
antimicrobial activity of Brazilian medicinal plant extracts against pathogenic
microorganisms of interest to dentistry. Planta Med. 77, 401–404. https://doi.org/
10.1055/s-0030-1250354.
Piatczak, E., Wielanek, M., Wysokinska, H., 2005. Liquid culture system for shoot
multiplication and secoiridoid production in micropropagated plants of Centaurium
erythraea Rafn. Plant Sci. 168, 431–437. https://doi.org/10.1016/j.
plantsci.2004.08.013.
Pieroni, A., Quave, C.L., 2005. Traditional pharmacopoeias and medicines among
Albanians and Italians in southern Italy: a comparison. J. Ethnopharmacol. 101,
258–270. https://doi.org/10.1016/j.jep.2005.04.028.
Rachid, A., Rabah, D., Farid, L., Zohra, S.F., Houcine, B., Nacera, B., 2012.
Ethnopharmacological survey of medicinal plants used in the traditional treatment
of diabetes mellitus in the North Western and South Western Algeria. JMPR 6,
2041–2050. https://doi.org/10.5897/JMPR11.1796.
Ragy, M., Elbassuoni, E., 2012. The role of nitric oxide and L-type calcium channel
blocker in the contractility of rabbit ileum in vitro. J. Physiol. Biochem. 68,
521–528. https://doi.org/10.1007/s13105-012-0167-x.
Rojas, A., Bah, M., Rojas, J.I., Gutiérrez, D.M., 2000. Smooth muscle relaxing activity of
gentiopicroside isolated from Gentiana spathacea. Planta Med. 66, 765–767. https://
doi.org/10.1055/s-2000-9774.
Sandru, D., Niculescu, V., Lengyel, E., Tița, O., 2016. Identification and quantification of
total polyphenols in plants with bioactive potentially. IJPPE 4, 47–51. www.scipress.
com/IJPPE.4.47.
Saric-Kundalic, B., Mazic, M., Djerzic, S., Kerleta-Tuzovic, V., 2010. Ethnobotanical
Study on Medicinal Use of Wild and Cultivated Plants on Konjuh Mountain, North-
East Bosnia and Herzegovina. TTEM 11 208.
Schimmer, O., Mauthner, H., 1996. Polymethoxylated xanthones from the herb of
Centaurium erythraea with strong antimutagenic properties in Salmonella
typhimurium. Planta Med. 62, 561–564. https://doi.org/10.1055/s-2006-957973.
Sefi, M., Fetoui, H., Lachkar, N., Tahraoui, A., Lyoussi, B., Boudawara, T., Zeghal, N.,
2011. Centaurium erythrea (Gentianaceae) leaf extract alleviates streptozotocin-
induced oxidative stress and β-cell damage in rat pancreas. J. Ethnopharmacol. 135,
243–250. https://doi.org/10.1016/j.jep.2011.02.029.
Senouci, F., Ababou, A., Chouieb, M., Chouieb, M., 2019. Ethnobotanical survey of the
medicinal plants used in the southern mediterranean. Case study: the region of Bissa
27
Journal of Ethnopharmacology 276 (2021) 114171
(northeastern Dahra mountains, Algeria). Phcog. J. 11, 647–659. https://doi.org/
10.5530/pj.2019.11.103.
Shahat, A.A., Cos, P., Hermans, N., Apers, S., Bruyne, T.D., Pieters, L., Berghe, D.V.,
Vlietink, A.J., 2003. Anticomplement and antioxidant activities of new acetylated
flavonoid glycosides from Centaurium spicatum. Planta Med. 69, 1153–1156.
https://doi.org/10.1055/s-2003-818009.
Šiler, B., Avramov, S., Banjanac, T., Cvetković, J., Nestorović Živković, J., Patenković, A.,
Mišić, D., 2012. Secoiridoid glycosides as a marker system in chemical variability
estimation and chemotype assignment of Centaurium erythraea Rafn from the
Balkan Peninsula. Ind. Crop. Prod. 40, 336–344. https://doi.org/10.1016/j.
indcrop.2012.03.026.
Šiler, B., Živković, S., Banjanac, T., Cvetković, J., Nestorović Živković, J., Ćirić, A.,
Soković, M., Mišić, D., 2014. Centauries as underestimated food additives:
antioxidant and antimicrobial potential. Food Chem. 147, 367–376. https://doi.org/
10.1016/j.foodchem.2013.10.007.
Stefkov, G., Miova, B., Dinevska-Kjovkarovska, S., Stanoeva, J.P., Stefova, M.,
Petrusevska, G., Kulevanova, S., 2014. Chemical characterization of Centaurium
erythrea L. and its effects on carbohydrate and lipid metabolism in experimental
diabetes. J. Ethnopharmacol. 152, 71–77. https://doi.org/10.1016/j.
jep.2013.11.047.
Subotić, A., Jevremović, S., Grubisić, D., Janković, T., 2009. Spontaneous plant
regeneration and production of secondary metabolites from hairy root cultures of
Centaurium erythraea Rafn. Methods Mol. Biol. 547, 205–215. https://doi.org/
10.1007/978-1-60327-287-2_17.
Szelenyi, I., Brune, K., 1988. Possible role of oxygen free radicals in ethanol-induced
gastric mucosal damage in rats. Dig. Dis. Sci. 33, 865–871. https://doi.org/10.1007/
BF01550977.
Tahraoui, A., Israili, Z.H., Lyoussi, B., 2010. Acute and sub-chronic toxicity of a
lyophilised aqueous extract of Centaurium erythraea in rodents. J. Ethnopharmacol.
132, 48–55. https://doi.org/10.1016/j.jep.2010.07.038.
Tahraoui, A., Israili Z, H., Lyoussi, B., 2017. Hypoglycemic and hypolipidemic effects of
aqueous extracts of ajuga iva and Centaurium erythreae on a rodent model of
metabolic syndrome. Nat. Prod. J. 7, 47–57.
Takeuch, T., Sugimoto, K., Morimoto, H., Fujita, A., Hata, F., 2001. Mechanism of a nitric
oxide donor NOR 1-induced relaxation in longitudinal muscle of rat proximal colon.
Jpn. J. Pharmacol. 86, 390–398. https://doi.org/10.1254/jjp.86.390.
Tanaka, J., Yuda, Y., 1996. Lipid peroxidation in gastric mucosal lesions induced by
indomethacin in rat. Biol. Pharm. Bull. 19, 716–720. https://doi.org/10.1248/
bpb.19.716.
Teixeira, J., Gaspar, A., Garrido, E.M., Garrido, J., Borges, F., 2013. Hydroxycinnamic
acid antioxidants: an electrochemical overview. BioMed Res. Int. 1–11. https://doi.
org/10.1155/2013/251754, 2013.
Tene, V., Malagón, O., Finzi, P.V., Vidari, G., Armijos, C., Zaragoza, T., 2007. An
ethnobotanical survey of medicinal plants used in Loja and Zamora-Chinchipe,
Ecuador. J. Ethnopharmacol. 111, 63–81. https://doi.org/10.1016/j.
jep.2006.10.032.
Toda, N., Baba, H., Okamura, T., 1990. Role of nitric oxide in non-adrenergic, non-
cholinergic nerve-mediated relaxation in dog duodenal longitudinal muscle strips.
Jpn. J. Pharmacol. 53, 281–284. https://doi.org/10.1254/jjp.53.281.
Trifunović-Momčilov, M., Krstić Milošević, D., Trifunović, S., Podolski-Renić, A.,
Pešić, M., Subotić, A., 2016. Secondary metabolite profile of transgenic centaury
(Centaurium erythraea Rafn.) plants, potential producers of anticancer compounds.
Transgenesis and Secondary Metabolism 1–26. https://doi.org/10.1007/978-3-319-
27490-4_5-2.
Trombetta, D., Castelli, F., Sarpietro, M.G., Venuti, V., Cristani, M., Daniele, C., Saija, A.,
Mazzanti, G., Bisignano, G., 2005. Mechanisms of antibacterial action of three
monoterpenes. Antimicrob. Agents Chemother. 49, 2474–2478. https://doi.org/
10.1128/AAC.49.6.2474-2478.2005.
Tuluce, Y., Ozkol, H., Koyuncu, I., Ine, H., 2011. Gastroprotective effect of small centaury
(Centaurium erythraea L) on aspirin-induced gastric damage in rats. Toxicol. Ind.
Health 27, 760–768. https://doi.org/10.1177/0748233710397421.
Tuttolomondo, T., Licata, M., Leto, C., Bonsangue, G., Letizia Gargano, M.,
Venturella, G., La Bella, S., 2014. Popular uses of wild plant species for medicinal
purposes in the Nebrodi Regional Park (North-Eastern Sicily, Italy).
J. Ethnopharmacol. 157, 21–37. https://doi.org/10.1016/j.jep.2014.08.039.
Tuğlu, M.İ., Aydemi˙r, İ., Sönmez, P.K., Buran, T., Mete, M., 2018. The effects of
medicinal plants on cancer cell lines and efficacy of experimental animal model.
International Journal of Secondary Metabolite 5, 49–59. https://doi.org/10.21448/
ijsm.365065.
Ultee, A., Kets, E.P.W., Smid, E.J., 1999. Mechanisms of action of carvacrol on the food-
borne pathogen Bacillus cereus. Appl. Environ. Microbiol. 65, 4606–4610.
Valentão, P., Areias, F., Amaral, J., Andrade, P., Seabra, R., 2000. Tetraoxygenated
xanthones from Centaurium erythraea. Nat. Prod. Lett. 14, 319–323. https://doi.
org/10.1080/10575630008043763.
Valentão, P., Fernandes, E., Carvalho, F., Andrade, P.B., Seabra, R.M., Bastos, M.L., 2001.
Antioxidant activity of Centaurium erythraea infusion evidenced by its superoxide
radical scavenging and xanthine oxidase inhibitory activity. J. Agric. Food Chem. 49,
3476–3479. https://doi.org/10.1021/jf001145s.
Valentão, P., Andrade, P.B., Silva, E., Vicente, A., Santos, H., Bastos, M.L., Seabra, R.M.,
2002. Methoxylated xanthones in the quality control of small centaury (Centaurium
erythraea) flowering tops. J. Agric. Food Chem. 50, 460–463. https://doi.org/
10.1021/jf0109571.
Valentão, P., Fernandes, E., Carvalho, F., Andrade, P.B., Seabra, R.M., Bastos, M.L., 2003.
Hydroxyl radical and hypochlorous acid scavenging activity of small Centaury
(Centaurium erythraea) infusion. A comparative study with green tea (Camellia
N. El Menyiy et al.
sinensis). Phytomedicine 10, 517–522. https://doi.org/10.1078/
094471103322331485.
van der Sluis, W.G., Labadie, R.P., 1981. Secoiridoids and xanthones in the genus
Centaurium. Planta Med. 41, 221–231. https://doi.org/10.1055/s-2007-971707.
Van Rossum, F., 2009. Succession stage variation in population size in an early-
successional herb in a peri-urban forest. Acta Oecol. 35, 261–268. https://doi.org/
10.1016/j.actao.2008.11.005.
Vinagre, C., Vinagre, S., Carrilho, E., 2019. The use of medicinal plants by the population
from the Protected Landscape of “Serra de Montejunto”, Portugal. J. Ethnobiol.
Ethnomed. 15, 30. https://doi.org/10.1186/s13002-019-0309-0.
Vokou, D., Katradi, K., Kokkini, S., 1993. Ethnobotanical survey of Zagori (Epirus,
Greece), a renowned centre of folk medicine in the past. J. Ethnopharmacol. 39,
187–196. https://doi.org/10.1016/0378-8741(93)90035-4.
Wallace, J.L., Keenan, C.M., Granger, D.N., 1990. Gastric ulceration induced by
nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am. J.
Physiol. Gastrointest. Liver Physiol. 259, G462–G467. https://doi.org/10.1152/
ajpgi.1990.259.3.G462.
Xiao, H.-B., Jun-Fang, Lu, X.-Y., Chen, X., Chao-Tan, Sun, Z.-L., 2009. Protective effects
of kaempferol against endothelial damage by an improvement in nitric oxide
production and a decrease in asymmetric dimethylarginine level. Eur. J. Pharmacol.
616, 213–222. https://doi.org/10.1016/j.ejphar.2009.06.022.
Xu, J., Zhou, F., Ji, B.-P., Pei, R.-S., Xu, N., 2008. The antibacterial mechanism of
carvacrol and thymol against Escherichia coli. Lett. Appl. Microbiol. 47, 174–179.
https://doi.org/10.1111/j.1472-765X.2008.02407.x.
Yoshikawa, T., Naito, Y., Kishi, A., Tomii, T., Kaneko, T., Iinuma, S., Ichikawa, H.,
Yasuda, M., Takahashi, S., Kondo, M., 1993. Role of active oxygen, lipid
peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced
by indomethacin in rats. Gut 34, 732–737.
28
Journal of Ethnopharmacology 276 (2021) 114171
Zahrae Redouan, F., Benitez, G., Aboubakr, B., Bassma, E.B., Picone, R.M., Crisafulli, A.,
Ben Driss, A., Kadiri, M., Molero Messa, J., Merzouki, A., 2020. The status and
perception of medicinal plants by local population of Talassemtane National Park
(Northern Morocco). Caspian Journal of Environmental Sciences 18, 131–147.
https://doi.org/10.22124/cjes.2020.4069.
Zeltner, L., 1970. Recherches de biosystematique sur les genres Blackstonia Huds. et
Centaurium Hill. Bull Soc Neuch1i.tel Sci Nat 93, 1–164.
Zlatković, B.K., Bogosavljević, S.S., Radivojević, A.R., Pavlović, M.A., 2014. Traditional
use of the native medicinal plant resource of Mt. Rtanj (Eastern Serbia):
ethnobotanical evaluation and comparison. J. Ethnopharmacol. 151 (1), 704–713.
Zyromski, N.J., Duenes, J.A., Kendrick, M.L., Balsiger, B.M., Farrugia, G., Sarr, M.G.,
2001. Mechanism mediating nitric oxide-induced inhibition in human jejunal
longitudinal smooth muscle. Surgery 130, 489–496. https://doi.org/10.1067/
msy.2001.116414.
Đorđević, M., Mihailović, M., Arambašić Jovanović, J., Grdović, N., Uskoković, A.,
Tolić, A., Sinadinović, M., Rajić, J., Mišić, D., Šiler, B., Poznanović, G.,
Vidaković, M., Dinić, S., 2017. Centaurium erythraea methanol extract protects red
blood cells from oxidative damage in streptozotocin-induced diabetic rats.
J. Ethnopharmacol. 202, 172–183. https://doi.org/10.1016/j.jep.2017.03.016.
Đorđević, M., Grdović, N., Mihailović, M., Arambašić Jovanović, J., Uskoković, A.,
Rajić, J., Sinadinović, M., Tolić, A., Mišić, D., Šiler, B., Poznanović, G.,
Vidaković, M., Dinić, S., 2019. Centaurium erythraea extract improves survival and
functionality of pancreatic beta-cells in diabetes through multiple routes of action.
J. Ethnopharmacol. 242, 112043. https://doi.org/10.1016/j.jep.2019.112043.
Đorđević, Miloš, Grdović, N., Mihailović, M., Arambašić-Jovanović, J., Uskoković, A.,
Rajić, J., Đorđević, Marija, Tolić, A., Mišić, D., Šiler, B., Poznanović, G.,
Vidaković, M., Dinić, S., 2020. Centaurium erythraea extract reduces redox
imbalance and improves insulin expression and secretion in pancreatic β-cells
exposed to oxidative and nitrosative stress. Arch. Biol. Sci. 72, 117–128.