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Essential oils from Dysphania
genus: Traditional uses, chemical
composition, toxicology, and
health benefits
Amal Dagni
1†
, Simona Codruta Hegheș
2†
,
Ramona Suharoschi
3
,
4
*
†
, Oana Lelia Pop
3
,
4
*, Adriana Fodor
5
,
Romana Vulturar
6
,
7
, Angela Cozma
8
, Oufaa Aniq filali
1
,
Dan Cristian Vodnar
3
,
9
, Abdelaziz Soukri
1
and
Bouchra El Khalfi
1
*
‡
1
Laboratory of Physiopathology, Molecular Genetics and Biotechnology, Faculty of Sciences Ain
Chock, Health and Biotechnology Research Centre, Hassan II University of Casablanca, Casablanca,
Morocco,
2
Department of Drug Analysis, “Iuliu Haţieganu”University of Medicine and Pharmacy, Cluj-
Napoca, Romania,
3
Department of Food Science, University of Agricultural Science and Veterinary
Medicine of Cluj-Napoca, Cluj-Napoca, Romania,
4
Molecular Nutrition and Proteomics Lab, CDS3,
Life Science Institute, University of Agricultural Science and Veterinary Medicine of Cluj-Napoca, Cluj-
Napoca, Romania,
5
Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “Iuliu Haţieganu”
University of Medicine and Pharmacy, Cluj-Napoca, Romania,
6
Department of Molecular Sciences,
“Iuliu Haţieganu”University of Medicine and Pharmacy, Cluj-Napoca, Romania,
7
Cognitive
Neuroscience Laboratory, Department of Psychology, Babeș-Bolyai University, Cluj-Napoca,
Romania,
8
Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu”University of Medicine
and Pharmacy, Cluj-Napoca, Romania,
9
Food Biotechnology and Molecular Gastronomy, CDS7, Life
Science Institute, University of Agricultural Science and Veterinary Medicine of Cluj-Napoca, Cluj-
Napoca, Romania
The genus Dysphania belongs to the Amaranthaceae family and is known for its
many health benefits. Therefore, it is commonly available worldwide and
includes more than 47 species, five species have been mainly reported, and
D. ambrosioides has been one of the most widely used plants for thousands of
years as a remedy for a wide range of ailments. In recent investigations, the
essential oils of the genus Dysphania have been examined for their antibacterial,
antioxidant, and antiviral properties related to specific components such as
terpenoid compounds that exhibit pharmacological activity. Moreover, some of
Dysphania’s compounds show a toxicological effect. Therefore, the objective of
the study was to provide EO chemical composition and pharmacological data
of the genus Dysphania.
KEYWORDS
Dysphania, ethnophamacology, essential oils, medicinal benefits, toxicology
OPEN ACCESS
EDITED BY
Daniela Rigano,
University of Naples Federico II, Italy
REVIEWED BY
Fatma Moharram,
Helwan University, Egypt
Amner Muñoz-Acevedo,
Universidad del Norte, Colombia
*CORRESPONDENCE
Oana Lelia Pop,
oana.pop@usamvcluj.ro
Ramona Suharoschi,
ramona.suharoschi@usamvcluj.ro
Bouchra El Khalfi,
bouchra.elkhalfi@gmail.com
†
These authors have contributed equally
to this work and share first authorship
†
These authors have contributed equally
to this work and share last authorship
SPECIALTY SECTION
This article was submitted to
Ethnopharmacology,
a section of the journal
Frontiers in Pharmacology
RECEIVED 21 August 2022
ACCEPTED 21 November 2022
PUBLISHED 08 December 2022
CITATION
Dagni A, HegheșSC, Suharoschi R,
Pop OL, Fodor A, Vulturar R, Cozma A,
Aniq filali O, Vodnar DC, Soukri A and
El KhalfiB (2022), Essential oils from
Dysphania genus: Traditional uses,
chemical composition, toxicology, and
health benefits.
Front. Pharmacol. 13:1024274.
doi: 10.3389/fphar.2022.1024274
COPYRIGHT
© 2022 Dagni, Hegheș, Suharoschi, Pop,
Fodor, Vulturar, Cozma, Aniq filali,
Vodnar, Soukri and El Khalfi. This is an
open-access article distributed under
the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the
original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution
or reproduction is permitted which does
not comply with these terms.
Abbreviations: A.P, Aerial parts; CarE, Carboxylesterase; CAT, catalase; DPPH, 2,2-diphenyl-1-
picrylhydrazyl; EO, essential oils; F, Fruits; GST, glutathione-S-transferase; IC50, 50% inhibitory
concentration; L, Leaves; MIC, Minimal Inhibition Concentration; POD, Peroxidase; S, Seeds; SOD,
superoxide dismutase; W.P, Whole plant; ZI, Zones of inhibition.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 08 December 2022
DOI 10.3389/fphar.2022.1024274
Introduction
Since antiquity, natural molecules from various sources have
been used to cure human ailments (Hassan et al., 2012;Murray
et al., 2013;Kola-Mustapha et al., 2020). Among the most
significant biomolecule sources are the derivatives of aromatic
medicinal plants. As a result, multiple studies have shown that
bioactive chemicals from plants have a promising benefic health
effect. Among these is the Amaranthaceae family, which is
distinguished by the diversity of produced secondary
metabolites. This family contains over 175 genera and
2,000 herb species (Mroczek, 2015). The genus Dysphania is
known for its many pharmacological and preclinical properties.
Hence, it is commonly available worldwide and includes more
than 47 species (Kim et al., 2019).
D. ambrosioides is known as one of the most important
species of the Dysphania genus, used in the food, cosmetic, and
pharmaceutical industries, and also used in traditional medicine
to treat several foods (Hallala et al., 2010;Kasali et al., 2021),
followed by Dysphania botrys (syn. Chenopodium botrys),which
represents the second species most studied in the literature
(Morteza-Semnani, 2015)Dysphania multifida, Dysphania
schraderiana,and Dysphania pumilio are still less studied. The
chemical composition of Dysphania essential oils (EOs) depends
on different environmental factors (Barra, 2009). However, the
composition of all the EO examined was different, with a
significant quantity of monoterpene compounds (Brahim
et al., 2015;Zefzoufiet al., 2020). Dysphania EO is also
antibacterial (Kandsi et al., 2022), antifungal (Chekem et al.,
2010), anti-oxidant (Villalobos-Delgado et al., 2020), and
antiviral (Arena et al., 2018).
To the best of our knowledge, there are no reports in the
literature that provide a comprehensive analysis of Dysphania
species. In an effort to better understand its current research
status and justify the further exploration and comprehensive
application of this genus, we review the botanical,
ethnopharmacological, chemical composition, and
pharmacological activities of Dysphania spp., in addition to its
distribution and its possible mechanisms of action and
toxicology.
Methodology
We searched for published articles and grey literature (e.g.,
unpublished studies, theses, reports, and conference abstracts)
that fit these two search criteria: 1. Original research articles with
hypothesis tested in the laboratory (e.g., in vitro,in vivo,
preclinical studies) assessing the essential oils’biological
activities and toxicology of the Dysphania genus, and 2.
studies published in English with full *pdf files available.
There were no restrictions on the publication dates of the
selected papers, which included both contemporary and older
works, to collect extensive data for the review. Using Science
GRAPHICAL ABSTRACT
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Dagni et al. 10.3389/fphar.2022.1024274
TABLE 1 Geographical distribution of some common Dysphania Spp.
Continent Species Regions
Africa D. ambrosioides (L.) Mosyakin and Clemants Southern Africa/North Africa
D. multifida (L.) Mosyakin and Clemants North Africa
D. botrys (L.) Mosyakin and Clemants Mountainous tropical Africa
D. schraderiana (Schult.) Mosyakin and Clemants East and Central Africa
D. pumilio (R.Br.) Mosyakin and Clemants Congo
D. procera (Hochst. ex Moq.) Mosyakin and Clemants East and Central Africa
D. congolana (Hauman) Mosyakin and Clemants East and Central Africa
D. pseudomultiflora (Murr) Verloove and Lambinon Southern Africa
Asia D. ambrosioides (L.) Mosyakin and Clemants India/China
D. multifida (L.) Mosyakin and Clemants India
D. botrys (L.) Mosyakin and Clemants China/India/pakistan
D. schraderiana (Schult.) Mosyakin and Clemants Southeast Asia
D. pumilio (R.Br.) Mosyakin and Clemants Southeast Asia/India
D. bhutanica Sukhorukov Southeast Asia
D. nepalensis (Link ex Colla) Mosyakin and Clemants Nepal
D. kitiae Uotila China
D. neglecta Sukhorukov Southeast Asia
D. geoffreyi Sukhor Himalayas and Tibet
D. himalaica Uotila Himalayas and Tibet
Australia D. congestiflora S.J.Dillon and A.S.Markey Western Australia
D sphaerosperma Paul G.Wilson Western Australia
D. plantaginella F.Muell. South Australia
D. carinata (R.Br.) Mosyakin and Clemants Eastern Australia
D. cristata (F.Muell.) Mosyakin and Clemants Australia
D. glandulosa Paul G.Wilson Western Australia
D. glomulifera (Nees) Paul G.Wilson Australia
D. kalpari Paul G.Wilson Central Australia
D. littoralis R.Br Eastern Australia
D. melanocarpa (J.M.Black) Mosyakin and Clemants Australia
D. platycarpa Paul G.Wilson Central Australia
D. rhadinostachya (F.Muell.) A.J.Scott Australia
D. pumilio (R.Br.) Mosyakin and Clemants Australia
D. saxatilis (Paul G.Wilson) Mosyakin and Clemants Western Australia
D. simulans F.Muell. and Tate Central Australia
D. sphaerosperma Paul G.Wilson Central and Western Australia
D. truncata (Paul G.Wilson) Mosyakin and Clemants Central Australia
D. valida Paul G.Wilson Eastern Australia
Europe D. ambrosioides (L.) Mosyakin and Clemants Italy/France
D. multifida (L.) Mosyakin and Clemants Bulgaria
D. botrys (L.) Mosyakin and Clemants Bulgaria/France
D. schraderiana (Schult.) Mosyakin and Clemants Poland
D. pumilio (R.Br.) Mosyakin and Clemants Italy/Romania
America D. ambrosioides (L.) Mosyakin and Clemants South America
D. multifida (L.) Mosyakin and Clemants South America
D. botrys (L.) Mosyakin and Clemants North America
D. cristata (F.Muell.) Mosyakin and Clemants North America
D. anthelmintica (L.) Mosyakin and Clemants Southern U.S.A., Mexico, and West Indies
D. atriplicifolia (Spreng.) G.Kadereit, Sukhor. and Uotila Mexico, and the U.S.A.
(Continued on following page)
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Dagni et al. 10.3389/fphar.2022.1024274
Direct, PubMed, ResearchGate, Google Scholar, and Web of
Science (WOS: 22 July 2022 with University Hassan II of
Casablanca institutional subscription), we found
1,000 publications (Figure 1) with this keyword search:
((Dysphania) AND (ethnopharmacology OR pharmacology*)
(activity* OR bio* activity) AND (toxicology*)).
This paper has chosen, evaluated, and discussed a few
selected publications. After duplicate removal, excluded
studies that were not in our specific aim, and excluded reports
resulted in 333 studies.
We established the requirements for the studies’selection;
articles with extensive studies on the Dysphania essential oils
(EOs) composition, therapeutic uses, biological, and
pharmacological activities, as well as toxicity, were eligible for
inclusion. The exclusion criteria were as follows: if the topic field
is not our aim, not the entire research has been published, and
studies that were not published in English. We found the
essential data/results/papers on the subject, which resulted in
129 publications included in the screening, from which 57 have
only an abstract or the title, with no available *pdf files. We
conducted the selection procedure for the most relevant articles
for this research based on this selected article.
Dysphania genus
Currently, Dysphania genus belongs to the new classification,
which aggregates the Chenopodiaceae-Amaranthaceae in a
single-family known as Amaranthaceae according to the APG
III system (Group, 2009), this genus comprises more than
47 species. The representatives of the genus are mainly
ruderal and weed plants, more common in the tropics,
subtropics, and warm-temperate zones (Judd and Ferguson,
1999;Sukhorukov et al., 2016). Five species have been
reported in the literature; D. ambrosioides,D. botrys,D.
multifida,D. schraderiana,and D. pumilio (Mosyakin and
Clemants, 2002;The Plant List, 2020). The Dysphania species
are known to generate glandular white hairs and yellow or orange
subsessile glands. These glands contain essential oils that give off
a distinctive aromatic odor that frequently remains in herbarium
specimens for years (Uotila et al., 2021).
Distribution
Dysphania Spp., are pervasively distributed throughout both
temperate and tropical parts of the world. This genus became
more widespread due to its ability to adapt to a variety of
ecological conditions. There are two majors domesticated
Dysphania,D. ambrosioides, and D. botrys. These two species
have been cultivated over vast areas of the old world (Sukhorukov
et al., 2016). Table 1 provides a list of the common Dysphania
species distribution.
TABLE 1 (Continued) Geographical distribution of some common Dysphania Spp.
Continent Species Regions
D. chilensis (Schrad.) Mosyakin and Clemants South America
D. graveolens (Willd.) Mosyakin and Clemants Mexico and the southern U.S.A
FIGURE 1
Flowchart of the study design and the bibliographic sources
selection process. The search protocol using keywords selection
(EO of Dysphania chemical composition, bioactivity, and toxicity)
resulted in 1,000 publications; 20 duplicates were removed;
426 studies were excluded due to the presence of abstract,
citations, and thesis; 221 full-text excluded not fitting eligibility
criteria with the topic field out of our study aim, 204 were excluded
when not the entire research published, studies not in English, and
57 studies were excluded because the data reported have been not
founded. The figure was done using R metagear package.
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Dagni et al. 10.3389/fphar.2022.1024274
FIGURE 2
Dysphania species. (A) D. ambrosioides,(B) D. botrys,(C) D. mutifida,(D) D. schraderiana,(E) D. pumilio.
TABLE 2 Traditional uses of Dysphania Spp.
Species Ethnomedical uses Used
parts
Method of
preparation
References
D.
ambrosioides
Gastrointestinal disorders, typhoid, dysentery, galactogen, oral abscesses, ulcers,
purulent wounds, and diabetes.
W.P Infusion (Hallala et al., 2010;Brahim
et al., 2015).
Decoction
Poultice
D. multifida Digestive and antiparasitic L Infusion Yossen et al. (2019).
Condiment
D. botrys Asthma, cough, wounds, fever, pain, liver, respiratory, urinary, and gastric
complaints, as an antiseptic and for wound healing
S Infusion Khan and Jan, (2019).
Decoction
D.
schraderiana
Reducing wheezing, inflammation, cramping, and migraines L Infusion Łuczaj et al. (2022).
D. pumilio Nr* Nr* Nr* —
Legend: *Nr, not reported.
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Botanical description
D. ambrosioides (L.) Mosyakin and Clemants, is the most
well-known species from this genus, represents an annual or
short-lived perennial herbaceous plant, with a strong odor, which
reaches up to 1 m high, with erect stems, very branched, alternate
leaves elongated with acute apex, edges serrated, hairy, of
different sizes sessile; racemose inflorescence presenting small
white flowers with 3–5 free or united sepals and 3 to 5 free or
rarely adnate stamens, compressed spherical ovary and many
black seeds (with a length less than 0.08 mm) (Sá et al., 2016;
Paniagua-Zambrana et al., 2020).
D. botrys (L.) Mosyakin and Clemants, is a naturally growing
wild plant, traditionally used by rural and endemic inhabitants,
has a characteristic odor due to the presence of sesquiterpenes
and monoterpenes, and is an annual plant of 20–50 cm, stem
erect, angular, branching often from the base, with erect-
spreading branches, lower leaves long petiolate, pinnately
lobed, racemose inflorescence of a yellowish green (Khan and
January 2019).
D. multifida (L.) Mosyakin and Clemants, commonly known
as “paico”, is an aromatic plant widely used for medicinal
purposes, perennial plant of 30–80 cm, pubescent, with a
penetrating and pleasant smell, stems numerous, very
branchy, leaves small, puberulous-glandulosa, shortly petiolate,
with lanceolate or linear lobes, greenish (Yossen et al., 2019).
D. schraderiana (Schult.) Mosyakin and Clemants, this plant
is used in a variety of applications such as medicine. Pubescent
annual (height: 20–60 cm), oblong leaves (long: 2–6 cm, wide:
1.5–3.5 cm), attenuated base, obtuse to acuminate apex,
pinnately lobed margins, glabrescent petiole (2–10 mm long).
Flowers with 5 oval sepals (long: 1 mm), and 5 stamens, are
grouped in inflorescence (Łuczaj et al., 2022).
D. pumilio (R.Br.) Mosyakin and Clemants, is one of the
popular invasive species, pubescent annual (height: 5–45 cm).
Leaves ovate to elliptical (length: 0.5–2.5 cm, width: 0.5–1.5 cm),
wedge-shaped base, obtuse apex, entire margins, glabrescent
petiole (3–15 mm) (see Figure 2). Flowers with 5 elliptical to
oblong sepals (long: 1 mm), and 1 stamen sometimes absent,
grouped in inflorescence (diameter: 2–3 mm) assembled in
axillary cymes (length: 3–7 cm) (Bogosavljevićand Zlatković,
2017).
Ethnopharmacology
Since ancient times, Dysphania species have been used
around the world to cure various ailments (Table 2),
specifically circulatory diseases, digestive, musculoskeletal,
reproductive, respiratory, and sexual health systems
(Bussmann et al., 2018). Aside from being utilized as an
herbal remedy, some plants of this genus may be consumed
due to their nutritional components. The leaves, fruits, and
flowers can also be made into different food products. For
example, they are used as spices in different countries
(Barragán and Carpio, 2009;Barros et al., 2013). Traditional
uses of Dyphania Spp., are represented in Table 2.
Chemical composition
Several studies have revealed that Dysphania is an important
genus with various compounds, especially essential oils. The
most prevalent were monoterpenes, and sesquiterpenes
(Kokanova-Nedialkova et al., 2009;Barros et al., 2013).
Currently, approximately 45 terpenoid compounds have been
reported and isolated from the fruits, seeds, leaves, and flowers of
Dysphania species EO. The main chemical compounds occurring
in the essential oils obtained from the Dysphania genus are
represented in Table 3.
Approximately 44 papers covered the Dysphania EO
assessment. The majority of the paper identified the
components of D. ambrosioides EO are oxygenated
monoterpenes. In several studies (Gupta et al., 2002;
Boutkhil et al., 2009;Brahim et al., 2015;Bisht and Kumar,
2019), α-terpinene (5) was quantified as the main constituent
TABLE 3 Chemical composition of Dysphania Spp., plant essential oils.
Species Chemical compounds References
D. ambrosioides α-terpinene: 23.77% Brahim et al. (2015)
Ascaridole: 14.48% p-cymene: 12.22%
D. multifida α-terpinene: 18.5% Yossen et al. (2019)
Ascaridole: 61.1% p-cymene: 12.7%
D. botrys α-terpineol: 52.8% Morteza-Semnani, (2015)
Iso-ascaridole: 7% p-cymene: 19%
D. schraderiana Nr* —
D. pumilio Nr* —
Legend: *Nr, not reported.
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Dagni et al. 10.3389/fphar.2022.1024274
in D. ambrosioides EO, while ascaridole (29) was reported as
the most abundant components in D. multifida EO (Yossen
et al., 2019). Less frequently, δ-3-carene (10),limonene(4),
thymol (20),carvacrol(19),γ-terpinene (6),α-terpinolene
(7), piperitone oxide (31),geraniol(15),α-pinene (12),β-
pinene (26),iso-ascaridole(20),β-myrcene (1),α-ocimene
(2),β-ocimene (3), citronellyl acetate (21),β-phellandrene
(8),dihydroascaridole(32),trans-pinocarveol (17),carvone
(24), piperitone (23) were reported in D. multifida and D.
ambrosioides EO (Arena et al., 2018), while p-cymene (9),and
4-carene (11) were reported as main components of D.
ambrosioides EO in another study (Zefzoufiet al., 2020).
Other compounds, camphor (22),δ-3-carene (23),
fenchone (25), linalool (16),menthone(26),nerol(14),β-
pinene (13),pulegone(27), terpineol-4-ol (18),thujone(28),
and iso-ascaridole (30) are represented in D. botrys EO. The
structures of monoterpenes from 1to 32 are shown in
Figure 3.
Major sesquiterpenes in D. ambrosioides included β-
caryophyllene (33),γ-curcumene (34),and caryophyllene
oxide (35) (Kokanova-Nedialkova et al., 2009). While, D.
botrys included elemol (39), elemol acetate (41),α-
FIGURE 3
Monoterpenes of Dysphania spp essential oils.
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chenopodiol (36),β-chenopodiol (37), botrydiol (38), and
eudesmol (40) are shown in Figure 4. These main
sesquiterpenes were identical across different Dysphania
populations based on GC-MS data, although relative quantity
varied (Pino et al., 2003;Singh et al., 2008).
In addition, many intrinsic and extrinsic factors, such as
environmental factors, affect the D. ambrosioides essential oils
yield and constituents. Plants may be stressed due to high or
low salinity, causing a change in the content of EO (Verma
and Shukla, 2015). According to several authors (de Carvalho
et al., 2018b), the amount of four main volatile constituents
(α-terpinene, p-cymene, E-ascaridole, and Z-ascaridole) is
affected by salt concentrations. Salts are essential to plant
growth and metabolism. High concentrations may be toxic
(Mosa et al., 2017). The blue LED was also shown to block the
production of ascaridole (29) (53.21%), whereas fluorescent
light increased the conversion of α-terpinene (5) to ascaridole
(29) (de Carvalho et al., 2020). In general, these results agree
with the observation that many enzymes of the secondary
pathways are light-dependent (Yabuta et al., 2007;Alvarenga
et al., 2015). Another study (Yousefiet al., 2011)showedthat
the development stages of D. botrys are affected by heavy
metals. Treatments without CaCl
2
and MgSO
4
had an
antagonistic connection with p-cymene (9), and treatments
with MgSO
4
at 1,480 mg L
−1
gave higher levels of ascaridole
(19).KH
2
PO
4
at a concentration of 680 mg L
−1
caused an
excess of ascaridole (29) to be found in the treatment. α-
terpinene (5) represents a significant amount in treatment by
CaCl
2
at a concentration of 880 mg L
−1
(de Carvalho et al.,
2018a) ascaridole (29) content in the leaves increased when
quail manure was used, whereas it increased in the
inflorescences when chicken manure was used (Bibiano
et al., 2019). However, the greatest α-terpinene (5) content
was reported without using chitosan. According to the
biosynthetic pathway, chitosan and salicylic acid favoured
the conversion of α-terpinene (5) to ascaridole (29)
(Dembitsky et al., 2008;de Carvalho et al., 2020). This
paper mainly focused on C
10
monoterpenes, and C
15
sesquiterpenes for their importance. All these terpenoids
are derived from two distinct biochemical pathways; the
(MEP) 2C-methyl-D-erythritol-4-phosphate pathway, which
is active in the plastids, begins from pyruvate and
glyceraldehyde-3-phosphate, whereas the (MVA) mevalonic
acid pathway active in the cytosol and starts from acetyl CoA
(Bergman et al., 2019).
Health benefits
Antimicrobial effects
Bacteria have evolved several mechanisms to withstand
antibiotic action. Several investigations have indicated that D.
ambrosioides L. has inhibitory action against a wide spectrum of
pathogenic bacteria.Brahim et al., 2015 (Brahim et al., 2015)
reported that EO isolated from D. ambrosioides are more active
against Bacillus cereus and Micrococcus luteus than Klebsiella
pneumoniae and Pseudomonas aeruginosa with zones of
inhibition ranging from 15.33 to 21.5 mm and from 7.17 to
19.17 mm, for Gram-positive and Gram-negative bacteria,
respectively. The cell envelope structure explains this, since
Gram-negative bacteria have an additional membrane,
limiting hydrophobic compound diffusion. D. ambrosioides
EO has also been shown to have antibacterial activity against
Helicobacter pylori (Ye et al., 2015), also, against Escherichia coli,
staphylococcus aureus, and Enterococcus faecalis(Kandsi et al.,
2022) with ZI ranging from 9 to 24 mm. D. botrys EO also
showed strong antimicrobial activity against a variety of bacteria
(Staphylococcus aureus,Bacillus cereus, Staphylococcus
saprophyticus,Klebsiella pneumoniae,Staphylococcus
FIGURE 4
The Structure of the main sesquiterpenes in Dysphania spp essential oils.
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TABLE 4 Biological effects of Dysphania Spp.
Activity Species Plant
part
Source Dosage/
Duration
Model Positive
controls
Mechanisms References
Antibacterial D.
ambrosioides
Whole
plant
EO 500 μgml
−1
in vitro Norfloxacin
Tetracycline
Lansoprazole
Metronidazole
Clarithromycin
Alteration of bacterial
cellular integrity and
permeability;
de Morais Oliveira-Tintino,
Tintino, Limaverde,
Figueredo, Campina, da
Cunha, da Costa, Pereira,
Lima, and de Matos (2018)
Leaves 49.32 mg kg
1
in vivo
Aerial
parts
2 weeks Inhibition of respiration. Limaverde et al. (2017)
D. botrys Aerial
parts
EO 98.6 μgml
−1
in vitro Kanamycin
Cephalexin
Reduction of efflux pump in
Staphylococcus aureus
Foroughi et al. (2016)
Antifungal D.
ambrosioides
Leaves EO 0.25–2mgml
−1
in vitro Ciprofloxacin Increase the membrane
permeability
(Brahim et al., 2015;P.
Singh and Pandey 2021;
Prasad et al., 2010)
Whole
plant
0.1%, 1%
and 10%
in vivo
Aerial
parts
7–21 days
D. botrys Aerial
parts
EO 4 μLml
−1
in vitro Vancomycin
Gentamicin
Amphotericin B
Antioxidant D.
ambrosioides
Leaves EO 500 μgml
−1
in vitro Quercetin Upregulation or protection
of antioxidant defenses,
scavenging of reactive
oxygen species, and
suppressing their formation
through both enzyme
inhibition and chelation of
trace elements involved in a
free radical generation
(Bezerra et al., 2019;Kandsi
et al., 2022)
BHT
Antiviral D.
ambrosioides
Leaves EO 21.75 μgml
−1
in vitro Human Coxsackie
virus-B
NR* Mokni et al. (2019)
in silico
Antileishmanial D.
ambrosioides
Leaves EO 30 mg kg
−1
in vivo Chloroquine Inhibition of
NADH
−
Reduction of
succinate-dependent
cytochrome C
(Monzote et al., 2014;
Machín, Tamargo, Piñón,
et al., 2019)
Benznidazol
14 days Suramine Generation of oxygen
radicals, mitochondrial
dysfunction, and a
modification of redox
indexes
Miltefosine
Amoebicidal D.
ambrosioides
Leaves EO 0.75 mg ml
−1
in vitro Metronidazole Endoperoxide that it can
deliver reactive oxygen
species and damage the
trophozoites in a similar
way that oxygen peroxide
induces toxicity to amoeba
free radical-triggered DNA
or protein alterations
Ávila-Blanco et al. (2014)
8 mg kg-
1
80 mg kg
−1
in vivo
7 days
Insecticidal D.
ambrosioides
Whole
plant
EO 8.80 μgL
−1
in vitro Acetone Inhibition of GSTs and
CarE activity;
Wei et al. (2015)
Disrupted the activities of
some endogenous
protective enzymes (SOD,
POD, CAT);
Aerial
parts
2.437 mg L
−1
in vivo Interfere with the
neuromodulator
octopamine;
24h/48 h Modulate GABA-gated
chloride channels.
(Continued on following page)
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Dagni et al. 10.3389/fphar.2022.1024274
epidermidis,Streptococcus mutans,Listeria monocytogenes, and
Salmonella typhimurium) with ZI ranging from (9–22 mm)
(Foroughi et al., 2016). Numerous studies evaluated the
antifungal activity of D. ambrosioides EO against fungal.
Brahim et al., 2015 (Brahim et al., 2015) also reported high
anticandidal activity, where Candida albicans was the most
susceptible yeast, having the lowest minimum inhibitory
concentration. Likewise, Mokni et al., 2019 (Mokni et al.,
2019) observed that D. ambrosioides EO exhibited
considerable antifungal activity against Candida albicans.
Similarly, good activity was recorded for D. botrys EO on C.
albicans and showed an inhibitory effect on Aspergillus species
and Bacillus subtilis (Mahboubi et al., 2011), while for
Trichophyton mentagrophytes, Epidermophyton floccosum,
Candida albicans, Aspergillus niger, and Microsporum canis.
D. botrys EO showed ZI ranging from (14–20 mm) (Tzakou
et al., 2007). Available scientific data have shown consistent
findings from several authors. The following main points have
evolved as a result of this: These plants EO have good
antimicrobial activity against a wide range of pathogens,
including Gram-negative and Gram-positive bacteria and
fungi, this high activity has been linked to the presence of
monoterpene hydrocarbons (limonene (4),p-cymene (9), and
ascaridole (29), thymol (20), carvacrol (19), and α-terpinene (5)).
All mechanisms described in the literature show that Dysphania
EO affects the cellular integrity of bacteria, a decrease in
respiration, and an alteration in permeability. Few studies
have described the antimicrobial activities from other
Dysphania species (Table 4). The inhibitory effectiveness of
Dysphania EO against microbial growth is stronger than
reference antimicrobials even in experiments with the positive
control, hence, EO from this species can be advised as a
replacement for conventional antimicrobial agents. It should
be noted that most research on the antibacterial properties of
Dysphania spp. has been conducted in vitro, which does not
ensure that the results would be the same in vivo. Furthermore,
the susceptibility testing in the aforementioned research solely
employed traditional techniques. However, additional
techniques may be modified to determine the antimicrobial
susceptibility of EO, including bioautography, flow cytometry,
and bioluminescence experiments.
Antiviral effects
One of the common viruses is enteroviruses, specifically the
Coxsackie B4 virus (CVB4) enteroviruses that belong to the
Picornaviridae family, which is associated with serious
illnesses, including myocarditis and meningoencephalitis (Sin
et al., 2015). In this context, the EO obtained from D.
ambrosioides L., growing wildly in Tunisia, demonstrated a
significant antiviral effect against the CV-B4 virus. This
activity could be attributed to ascaridole (29) (Mokni et al.,
2019). However, more research in vitro and in vivo is needed to
TABLE 4 (Continued) Biological effects of Dysphania Spp.
Activity Species Plant
part
Source Dosage/
Duration
Model Positive
controls
Mechanisms References
Nematicidal D.
ambrosioides
Fruits EO 500 μgml
−1
in vitro Carbofuran Reduction in hatching of a
nematode
(A.F. Barros et al., 2019)
Seeds 7 days in vivo
Anticancer D.
ambrosioides
Whole
plant
EO 50 μgml
−1
in vitro DMSO Affects antioxidant system
of cancer cells
Ya-Nan et al. (2015)
125 μgml
−1
31.25 μgml
−1
in vivo
24 h
Wound healing D. botrys Leaves EO 1 ml in vivo Tetracycline NR* Sayyedrostami et al. (2018)
10 days
Molluscicidal D.
ambrosioides
Leaves EO 2.40 and
8.75 ppm
in vivo NR* Alteration in mitochondrial
membrane potential,
causing oxidative
phosphorylation
breakdown and
modification of redox
indexes
Ignacchiti et al. (2022)
D.
ambrosioides
Leaves EO 49.32 mg kg
1
in vivo Lansoprazole NR* Ye et al. (2015)
Metronidazole,
2 weeks Clarithromycin
Relaxant D.
ambrosioides
Leaves EO 1,000 μg/ml in vivo Nifedipine Block the KCl-induced
contractile response
Pereira-de-Morais et al.
(2020)
5–15 min
Legend: *Nr, Not reported.
Frontiers in Pharmacology frontiersin.org10
Dagni et al. 10.3389/fphar.2022.1024274
evaluate the antiviral activity of EO and their active compounds
isolated from all Dysphania spp.
Anti-leishmanial effects
The hunt for effective therapeutics to treat Leishmaniasis
has become an urgent requirement due to the absence of
effective medicines and the limits of present treatments
(Machín et al., 2019). The anti-leishmanial activity of D.
ambrosioides was demonstrated by Monzote et al., 2014 and
2018 (Monzote et al., 2014;Monzote et al., 2018)
against amastigotes and promastigotes of Leishmania
amazonensis. Results show a more significant inhibitory
effect of ascaridole (29). This effect is by reducing
succinate-dependent cytochrome C due to the inhibition
of NADH. To more understand the effects of D.
ambrosioides EO and resolve the stability and solubility
problems of EO, some studies (Machín et al., 2019) aim to
explore the encapsulation of D. ambrosioides L. EO in
nanocochleates (lipid-based delivery system) and
investigated in vitro and in vivo against L. amazonensis.
The results showed that D. ambrosioides L. EO-
nanocochleates (NC) did not affect the EOs’in vitro
inhibitory efficacy. The formulation caused no mortality
or weight loss higher than 10% in the animal model
(Table 4). Mice treated with D. ambrosioides EO-NC had
more extensive lesions than those treated with EO. This
activity may be related to the presence of some terpenoid
compounds. Hence, the results showing a potent anti-
leishmanial activity from in vitro and in vivo indicating a
safe application as drug.
Antioxidant effects
Several studies showed that D. ambrosioides L. EO had an
essential antioxidant activity. Santiago et al., 2016 (Santiago
et al., 2016) reported this activity by different methods DPPH
and β-carotene/linoleic acid, showed higher activity of EO in
the β-carotene/linoleic acid test. Also, Brahim et al., 2015
(Brahim et al., 2015)demonstratedthatD. ambrosioides L.
EO exhibits free radical scavenging activity by using the
DPPH test. Indeed, they found the highest antioxidant
capacity by inhibiting lipid peroxidation via aβ-Carotene/
linoleic acid bleaching test. Also, Brahim et al., 2015 (Brahim
et al., 2015) marked the high activity by reducing potency
(Table 4). The potent antioxidant activity of Dysphania EO
can be due to its high content of α-terpinene (5),whichis
characterized by its powerful antioxidant capacity that is
probably attributed to the presence of strongly activated
methylene groups (Table 4). However, the in vitro assays
for measuring antioxidant activity have little
pharmacological significance and only partially validate
the biological impact, more studies in vivo about oxidative
stress are needed.
FIGURE 5
Toxicity mechanisms of ascaridole (29), carvacrol (19), and caryophyllene oxide (35) in mitochondria. Both oxidative stress and mitochondrial
dysfunction are employed in the mechanism of toxicity by the Dysphania’s EO. The EO have inhibitory effects on mitochondria’s ETC (electron
transport chain) complex I-III. Caryophyllene oxide (35) carries out inhibition on complex III (CIII). Ascardiole (29) following activation by iron (Fe
2+
)
threatens mitochondrial uncoupling and triggers superoxide radical formation (O
2
.-
). Carvacrol (19) has no direct inhibiting effects, but a
synergistic effect with ascaridole. *complex I: NADH ubiquinone oxidoreductase; complex II: succinate ubiquinone oxidoreductase; complex III:
ubiquinol cytochrome c oxidoreductase; complex IV: cytochrome C oxidase; complex V: F
1
F
0
ATP synthase. NADH, nicotinamide adenine
dinucleotide hydrogen; NAD
+
, nicotinamide adenine dinucleotide; FADH
2
,flavin adenine dinucleotide (hydroquinone form); FAD, flavin adenine
dinucleotide; H
+
, protons; H
2
O, water; H, hydrogen; O, oxygen; Fe, iron. The figure was produced using Servier Medical Art.
Frontiers in Pharmacology frontiersin.org11
Dagni et al. 10.3389/fphar.2022.1024274
Anticancer effects
Some studies demonstrate the cytotoxic activity of D.
ambrosioides L. EO against tumours; the authors have
demonstrated that the EO reduced cell growth and were
cytotoxic to human breast cancer cell lines MCF-7 in a
dose and time-dependent manner, via an apoptosis-related
mechanism. D. botrys EO showed maximum growth
inhibitions against the A549 cell line and inhibited the
growth of the MCF-7 cell line (Table 4)(Shameem et al.,
2019). The reported research has shown the precise anti-
tumor mechanisms of D. ambrosioides EO, which are
related to apoptosis induction (Table 4). Therefore, these
results could offer an actual overview on the effects of
Dysphania EO on tumoural cells. However, in these
investigations, the cytotoxic effects of Dysphania EO were
only assessed in tumour cell lines. There have not been any
human clinical trials to look at the pharmacokinetics and
therapeutic effects of EO and their compounds on cancer
patients. Clinical investigations involving humans and
animal models should be the main topics of future study.
Moreover, further studies to elucidate the antitumoral effect
are required.
The benefic effect of Dysphania EO (antimicrobial, antiviral,
antifungal, antileishmanial, insecticidal, nematocidal,
antioxidant, antitumoral, anti-ulcer, and relaxant) are sown in
Table 4.
Toxicology
The centuries-old use of medicinal plants has shown that
some of these plants contain potentially dangerous substances
(Ndhlala et al., 2013). D. ambrosioides L. is one of the plants
described as having a toxicological risk, specially indicated for
essential oils (GUYTON, 1946).
Several species, including D. botrys, and D. ambrosioides
possess compounds that have been demonstrated to interfere
with mitochondrial function (Nagle et al., 2011). The toxicity of
EO obtained from Dysphania can be associated with the presence
of some major components, carvacrol (19), caryophyllene oxide
(35), and ascaridole (29), which induce suppression of the
respiratory function in the mitochondria, or in the complex I
of the mitochondrial electron transport chains (Figure 5)
(Monzote et al., 2018), this toxic effect emerging on the
kidneys, liver, and intestine (Derraji et al., 2014). Nevertheless,
in a recent study by Li et al., 2020 (Li et al., 2020), dose-dependent
toxicity was demonstrated in mice, providing some support for
using the EO in a safe way in traditional medicine. However, their
utilization is contraindicated during pregnancy and
breastfeeding for infants under three, and adult patients who
are distressed or suffer from liver or renal illnesses (Potawale
et al., 2008).
The toxicity of ascaridole (29) was observed by activation
in the presence of iron, which allows it to be more toxic,
resulting in carbon-centred radicals, which are very reactive
and can initiate lipid peroxidation and reduce respiration.
Caryophyllene oxide (35) is the principal generator
of superoxide radicals and directly influences complex III.
Carvacrol (19) reacts as a protonophore and does not have
a direct physiological effect. All these actions induce a
decrease in ATP production and an increase in superoxide
radicals.
Conclusions and further perspectives
The present review offers the first insights of selected
literature regarding the chemical composition of Dysphania
EOs, their pharmacological properties, and their applications
in traditional medicine. Plants of this genus have been used
since ancient times to treat many diseases, and these
properties have been confirmed by numerous
pharmacological studies.
Distinctive chemical constituents have been isolated and
identified as belonging to different species. Indeed, the
literature has shown that the main components of these
essential oils are α-terpinene, ascaridole, iso-ascaridole, α-
terpineol, and p-cymene. Overall, these compounds can
change due to abiotic and biotic factors that affect essential
oil content and yield. Most chemical studies have focused on
the EO content of D. ambrosioides,D. multifida,andD. botrys,
while further research on the chemical composition of the EO
of other species is needed in order to determine their chemical
composition. Determining the bioactivity of other volatile
compounds from all species of Dysphania would be critical
for future investigation and its impact on health. Previous
research has revealed the extensive medicinal applications of
volatile compounds from different botanical parts of
Dysphania spp. (seeds, fruits, and leaves) in a range of
in vitro and in vivo test models. Dysphania spp. EOs have
been demonstrated to possess antibacterial, antifungal,
antioxidant, anti-cancer, antiviral, antileishmanial,
amoebicidal, and anti-inflammatory properties, and lastly,
nematocidal, and insecticidal activities at different doses/
concentrations. The chemical composition and
pharmacological results validate and support some
ethnopharmacological uses of Dysphania spp. in traditional
medicine.
As this review shown, the Dysphania genus EOs, rich in
secondary metabolites and various biological activities, can
constitute an alternative to certain synthetic drugs to bring
health benefits to human diseases in the future. However,
according to the literature, current knowledge of Dysphania
species contains several gaps that require further investigation
in preclinical and clinical studies.
Frontiers in Pharmacology frontiersin.org12
Dagni et al. 10.3389/fphar.2022.1024274
Author contributions
Conceptualization, AD, SCH, and RS; Funding acquisition,
DV and OP; Writing—Original Draft Preparation, AD and SCH;
Visualization, RV and RS; Writing—Review and Editing, AF, AC,
RV, and OA; Supervision, BEK, RS, and AS. All authors have read
and agreed to the published version of the manuscript.
Funding
This work was supported by grants from the Romanian
Ministry of Education and Research, CCCDI—UEFISCDI,
project number PN-III-P4-ID-PCE-2020-2126, within
PNCDI III.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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