Journal of Ethnopharmacology 277 (2021) 114244

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

Review

Codiaeum variegatum (L.) Rumph. ex A. Juss. (Euphorbiaceae): An

overview of its botanical diversity, traditional uses, phytochemistry,
pharmacological effects and perspectives towards developing its
plant-based products
Emmanuel Mfotie Njoya a, b, *, Paul Moundipa Fewou a, Timo H.J. Niedermeyer b
a
Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon
b
Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

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

Keywords: Ethnopharmacological relevance: Codiaeum variegatum also called miracle shrub, is a plant species constituted of more
Codiaeum variegatum than 300 cultivars which are mostly used as indoor plants for decoration. However, some of these varieties are used by
Traditional medicine indigenous populations for the treatment of diarrhoea, stomach ache, external wounds, intestinal worms and ulcers.
Efficacy
Aim of the study: This study describes an overview of the botanical diversity, medicinal uses, phytochemical
Toxicity
composition of C. variegatum. Then it critically discusses its pharmacological activities versus toxic potential and
Botanical diversity
Phytochemicals new perspectives are suggested for the development of its plant-based products.
Materials and methods: A bibliographic assessment of publications on C. variegatum indexed in Google Scholar,
PubMed, Science Direct, Scopus, Springer Link, and Web of Science online databases was conducted from 1970 to
2020, and 89 relevant articles related to the botanical diversity (17), traditional uses (22), phytochemical analysis
(11), pharmacological activity (31) and toxicity profile (18) of C. variegatum were selected for this review.
Results: Most commonly, it was found that aqueous leaf extracts or decoctions of C. variegatum are used in
traditional medicine to treat amoebic dysentery and stomach ache while a bath with root decoction or sap is
applied in small quantities on skin related infections. A total of 14 identified and 24 non-identified varieties of
C. variegatum were reported for pharmacological activity, and prominent research topics include the anti-
amoebic, antimicrobial, antiviral and cytotoxic activities. Alkaloids (3), terpenoids (5) and phenolics (15)
were the major compounds identified, and a new antiviral cyanoglucoside was isolated from the sap of
C. variegatum. Toxic substances (5-deoxyingenol and phorbol esters) were found in some varieties used as
ornamental plants, but the Mollucanum variety used in traditional medicine was found to be safe.
Conclusion: The present review revealed that the native variety of C. variegatum (cv. Mollucanum) can be used to
treat amoebic dysentery. Alkaloids, terpenoids and phenolic compounds have been characterized in this plant
species while other classes of phytochemicals are not yet investigated. The development of new cultivars rec­
ommends an in-depth toxicological study before any use. No clinical trial has been reported to date, and further
studies are needed to evaluate other claimed medicinal uses. Due to its efficacy and safety, the Mollucanum
variety is most likely suitable for the development of a medicine against amoebiasis, which will surely lay the
foundation for clinical studies.

and shrubs or trees found especially in the tropics (Mwine and Damme,
2011). This plant species is native to the Moluccan Islands (also called
1. Introduction
Maluku Islands) of Indonesia and tropical rainforests of Philippines,
Papua New Guinea and Australia (Brown, 1995; Deng et al., 2010a).
Codiaeum variegatum (L.) Rumph. ex A. Juss. belongs to the family of
Codiaeum variegatum has been introduced in many tropical and warm
Euphorbiaceae which is one of the largest family of flowering plants
regions where it grows easily (Govaerts et al., 2000). In Europe, it was
with more than 300 genera and 8000 species composed mostly of herbs,
* Corresponding author. Laboratory of Pharmacology and Toxicology, Department of Biochemistry, Faculty of Science, University of Yaoundé I, P.O. Box 812,
Yaoundé, Cameroon.
E-mail addresses: mfotiefr@yahoo.fr (E. Mfotie Njoya), pmoundipa@hotmail.com (P. Moundipa Fewou), timo.niedermeyer@pharmazie.uni-halle.de
(T.H.J. Niedermeyer).

https://doi.org/10.1016/j.jep.2021.114244
Received 6 January 2021; Received in revised form 5 May 2021; Accepted 24 May 2021
Available online 28 May 2021
0378-8741/© 2021 Elsevier B.V. All rights reserved.
E. Mfotie Njoya et al.
List of abbreviations
DW Dry weight
DMEM Dulbecco’s Modified Eagle’s Medium
DPPH 2,2-diphenyl-1-picrylhydrazyl
FRAP ferric-reducing antioxidant potential
EC50 50% efficient concentration
GC-MS Gas chromatography-mass spectrometry
HPLC-DAD High performance liquid chromatography with a diode-
array detector
LC50 50% lethal concentration
LC90 90% lethal concentration
MIC minimum inhibitory concentration
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
MS Mass spectrometry
1
H NMR Proton nuclear magnetic resonance
13
C NMR Carbon nuclear magnetic resonance
first introduced to England in 1804, but hybrids were developed mainly
in Belgium and France in the 1800s. The European hybrids were then
introduced in 1871 into the United States where several hybrids were
developed in South Florida during the 1920s and 1930s (Brown, 1995;
Deng et al., 2010a). The first native Codiaeum sp. (cultivar ‘Molluca­
num’) had all green leaves, and from it, a second cultivar ‘Aur­
eo-maculatum’ was developed with variegated leaves which was later
used to produce another cultivar, ‘Punctatum’ (Brown, 1995; Taylor,
1938). From these basic species, hybrids or mutants were developed
with the non-variegated cultivars being the more primitive relative to
the variegated cultivars (Babatunde et al., 2017; Taylor, 1938). The
most cultivated species is C. variegatum commonly known as ‘garden
croton’ from which many varieties were developed (Aguoru et al.,
2016). Currently, more than 300 cultivars of crotons are found around
the globe (Deng et al., 2010a), and these cultivars differ from each other
with the leaf sizes, shapes and color patterns (Magdalita et al., 2014;
Mollick et al., 2011; Ogunwenmo et al., 2007). The popular varieties of
C. variegatum include ‘Spirale’, ‘Andreanum’, ‘Majesticum’, and ‘Aur­
eo-maculatum’ (Huxley et al., 1992).
Plants have been used by populations of all continents for their
health benefits and their role to improve the quality of life. In fact, due to
the presence of bioactive ingredients, medicinal plants represent an
alternative solution to fight against various life-threatening diseases
(Cragg and Newman, 2005, 2013; Sofowora et al., 2013). The medicinal
uses of C. variegatum vary from one region of the world to another, and
with the part of plant being used. For instance, leaf decoction is mostly
used in the treatment of diarrhoea, stomachache, intestinal worms, and
bacterial infections (Labu et al., 2015; Moundipa et al., 2005; Norhanom
and Yadav, 1995; Ohigashi et al., 1985; Saffoon et al., 2014; WHO,
2009). On the other hand, root decoction is drunk against gastric ulcers
while the bark decoction and sap are applied on external ulcers or skin
infections (Ahmad and Holdsworth, 2003; Cambie and Ash, 1994;
Chand et al., 2018). Due to its genetic diversity, the phytochemical
composition of C. variegatum vary from one cultivar to another. To date,
alkaloids, terpenoids and phenolic compounds have been isolated from
this plant species (Hassan et al., 2014; Mona et al., 2019; Saffoon et al.,
2014). On the contrary, tannins, cardenolides, saponins, cardiac glyco­
sides and steroids identified by qualitative methods, are still not inves­
tigated (Ogunwenmo et al., 2007; Saffoon et al., 2010).
Furthermore, several published articles reported the pharmacolog­
ical activities of crude extracts and isolated compounds which confirm
the traditional use of this plant species against some diseases. However,
other claimed ethnomedicinal uses need to be evaluated. Reports on the
toxicity evaluation and quality control of C. variegatum are available for
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Journal of Ethnopharmacology 277 (2021) 114244
NO nitric oxide
IL interleukin
iNOS inducible nitric oxide synthase
COX-2 cyclooxygenase-2
NF-κB nuclear factor kappa B
MAPK mitogen activated protein kinase
STAT3 Signal transducer and activator of transcription 3
GABAA gamma-Aminobutyric acid activated
PTZ pentylenetetrazole
DSS dextran sulfate sodium
IR Infrared spectroscopy
i.p. intraperitoneal
i.c.v. intracerebroventricular
PGE2 prostaglandin E2
ZOI Zone of inhibition
matK maturase K
rbcL ribulose-1,5-biphosphate carboxylase oxygenase large
some cultivars. But, the high variability between cultivars requires to
establish a specific profile of each cultivar in terms of medicinal uses,
pharmacological activities, toxicity and phytochemical profiles. Thus, it
is imperative to proceed with an inventory of research that has been
carried out on this plant species, as it represents a good alternative
source for the discovery of novel compounds. This review will provide
an overview regarding the botanical diversity of C. variegatum, its eth­
nomedicinal uses, phytochemical composition and pharmacological
activities as to understand the importance of this plant species in pri­
mary healthcare systems of some local communities around the world.
2. Methodology
A bibliographic assessment by using online databases search was
carried out during the last 50 years (1970–2020) to gather all articles
containing relevant information about the ethnomedicinal uses, phyto­
chemicals, pharmacological and toxicological properties of cultivars of
C. variegatum. In our research strategy, we considered the fact that
C. variegatum is also known as garden croton or variegated croton,
however it should not be confused with Croton, a cosmopolitan genus
from the Euphorbiaceae family. A general search with the term
“Codiaeum variegatum” on Google scholar (https://scholar.google.com/)
resulted in 4310 documents comprising original research articles, re­
view articles, short communications, case reports or surveys, encyclo­
paedia, book chapters, conference abstracts and others. A similar search
with Web of Science (https://apps.webofknowledge.com/) yielded 84
documents including research articles, books and conference pro­
ceedings. Furthermore, the same seacrh on Pubmed (https://pubmed.
ncbi.nlm.nih.gov/), Springer Link (https://link.springer.com/), Scien­
ceDirect (https://www.sciencedirect.com/), Scopus (https://www.scop
us.com/) resulted in 21, 238, 138 and 113 articles, respectively from
these online databases. Additional materials such as books, theses and
ethnobotanical reports were also considered in this review.
As selection criteria, only literature available in English was
considered due to data accessibility, and conferences abstracts, non-peer
reviewed articles and duplicate data were excluded from the review
process. After consulting each of articles from the online databases with
more focus on the keywords such as “botanical diversity”; “medicinal
uses”; “phytochemicals”; “pharmacological activities”; “toxicity” and
“clinical studies” or their synonyms combined with “Codiaeum varie­
gatum”, 89 published articles were selected for this review. Of the
selected publications, 71.91% (64) appeared as original research arti­
cles, 12.35% (11) as ethnobotanical reports or surveys, 10.11% (9) as
books or theses and 5.61% (5) as review articles.
E. Mfotie Njoya et al.
3. Botanical and genetic diversity of Codiaeum variegatum
3.1. Cultivation of Codiaeum variegatum
Codiaeum variegatum can be cultivated by various methods such as
cuttings, grafting, by seeds and air layering (Nasib et al., 2008). The
most common propagation method of C. variegatum is via cuttings by
rooting a stem with at least three sets of leaves from a healthy mature
plant (Chen and Stamps, 2006). However, a more convenient and fast
method of propagation was developed in vitro by using freshly grown
shoot tips, and this technique is known to improve the yield of plants
(Nasib et al., 2008). Depending on the growth conditions and particu­
larly the light intensity, C. variegatum may develop different beautiful
foliage yielding several varieties which are selected and used as potted
ornamental plants popularly used for interior decoration (Mollick and
Yamasaki, 2012). In homes and gardens, C. variegatum is usually smaller
(1–2 m height) with a diversity of leaf shapes and colors, while in the
wild, it becomes an evergreen shrub or tree that can reach 3–6 m with
large, leathery and shiny leaves (Magdalita et al., 2014).
3.2. Botanical profile
Codiaeum variegatum belongs to the genus Codiaeum A. Juss. under
the Euphorbiaceae family. It is one of the most popular ornamental
plants which grows easily in tropical and warm regions (Govaerts et al.,
2000). Also known as garden croton or variegated croton, C. variegatum
is classified as a tree or shrub with different leaf shapes and variegation
patterns displayed as shades, blends or solid patches of red, pink, or­
ange, yellow, lavender, black, and green. (Deng et al., 2010a). Nasib
et al. (2008) reported that the young leaves of C. variegatum are usually
green, yellow, red or bronze, and the color change is observed later
during the maturation of the plant (Nasib et al., 2008). A systematic
classification of C. variegatum is not yet established, and the names given
to newly developed cultivars mostly rely on individual preference for
scientific or commercial purposes. However, several approaches have
been used by researchers to differentiate croton cultivars. For instance,
based on their leaf morphology, the Croton Society has classified culti­
vars of C. variegatum into nine types which are broad leaf; oak leaf;
semi-oak leaf; spiral leaf; narrow leaf; very narrow leaf; small leaf;
interrupted leaf; and recurved leaf (Brown, 1995; Deng et al., 2010b).
Mollick and coworkers have clustered 29 croton cultivars based on 12
quantitative leaf parameters by using the digital image-based procedure
coupled to Unweighted Pair-Group Method with Arithmetic average
(UPGMA) analysis which illustrated four major groups: Cluster I char­
acterized by large leaves; Cluster II characterized by spiral and appen­
diculate leaves; Cluster III having elliptic and semi-oak shaped leaves
and Cluster IV with narrow leaves (Mollick et al., 2011). Magdalita et al.
(2014) assessed the leaf morphological characteristics of 36 selected
cultivars and mutants of C. variegatum, and three major groups which are
red-leaf group, green-leaf group and yellow-leaf group were described
based on the predominant colors of the leaves (Magdalita et al., 2014).
Regarding the diversity in the classification of C. variegatum, the best
developed scientific basis to distinguish cultivars should include the
combination of several parameters. In fact, the leaf index obtained by
calculating the ratio of leaf length to leaf width, is a stable parameter to
characterize croton cultivars (Mollick et al., 2011). In addition, leaf
color and variegation patterns can be associated as they influence the
variation in chlorophyll and red pigment accumulation at the tissue
level. In this regards, anthocyanidin, a pigment found in red croton
cultivars, was not detected in green and yellow cultivars suggesting that
variation in leaf color between croton cultivars may affect their phyto­
chemical composition (Mollick et al., 2011). Furthermore, due to
spontaneous somatic mutation that can even occur within the same
variety of C. variegatum, it is highly recommended to associate genetic
factors or molecular markers for proper characterization of croton
cultivars.
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Journal of Ethnopharmacology 277 (2021) 114244
3.3. Genetic variation between cultivars of Codiaeum variegatum
The genetic basis of the leaf morphological variation of C. variegatum
is apparently related to a high frequency of somatic mutation and/or
cross pollination by ants, that usually lead to new phenotypes. In fact,
C. variegatum is predominantly polyploid as the chromosome numbers of
different varieties from Philippines, India, Nigeria and USA were highly
variable ranging from 2n = 24–120 (Chennaveeraiah and Wagley.,
1985; Deng et al., 2010b; Ogunwenmo et al., 2007; Pancho and Hilario.,
1963). The high polymorphism among the varieties of C. variegatum is
attributed to a significant gene loss or gain occurring through mutation
and/or chromosome variation during hybridization (Deng et al., 2010a).
Despite this high polymorphism, no correlation is established between
the chromosome number and the leaf morphology (Deng et al., 2010b;
Ogunwenmo et al., 2007). For instance, the investigation of the genetic
relationships between 44 cultivars of C. variegatum by using amplified
fragment length polymorphism (AFLP) markers indicated that all these
varieties had a narrow genetic distance from each other, and they
derived from a common progenitor which correlates with the history of
croton introduction, adaptation, geographical isolation, and breeding
activities (Deng et al., 2010a). Recently, it was reported that the hy­
bridization between two parent cultivars of C. variegatum having long
genetic distance produced new offsprings having different leaf shapes
and colors, but genetically closer to each other (Asniawati and Pur­
wantoro, 2019). The Random Amplified Polymorphic DNA (RAPD)
analysis revealed new molecular markers in the offsprings which do
exist neither in the male nor the female parent suggesting the occurrence
of genetic changes in the genome of the hybrids (Asniawati and Pur­
wantoro, 2019). Therefore, the determination of the genetic distance
and the analysis of RAPD markers can be used to differentiate croton
cultivars. Additionally, Nio et al. (2018) evaluated matK and rbcL genes
as markers in DNA barcoding for the differentiation of two cultivars of
C. variegatum (Gold star and Royal), and they found that rbcL gene was
more reliable to be used as DNA barcode for the identification of
C. variegatum (Nio et al., 2018). RAPD or DNA barcoding are therefore
recommended for the characterization of croton cultivars as they are
able to establish interspecific and intraspecific differences between
cultivars.
4. Ethnopharmacological uses of Codiaeum variegatum
Some varieties of C. variegatum are important due to their medicinal
properties, and they have been used in traditional medicine in different
regions of the world especially in Asian countries where this plant is
native. The indigenous C. variegatum (cv. Mollucanum) is the wild form
which originated from the Moluccan Islands of Indonesia, and other
cultivars derived from this species (Brown, 1995; Deng et al., 2010a;
Sangeetha et al., 2011). A total of 22 out of 89 selected publications (i.e.,
24.71%) discussed the ethnomedicinal use of C. variegatum. Overall,
different parts of this plant were used for the treatment of diarrhoea and
stomach ache, followed by skin related infections such as wounds, ul­
cers, psoriasis, fungal and bacterial infections (Fig. 1).
The most frequent medicinal use of C. variegatum was against diar­
rhoea and stomach ache reported in Philippines, India, Indonesia, and
Cameroon (Gertrudes, 2006; Moundipa et al., 2005; Raj et al., 2018;
Saffoon et al., 2010; Wiart, 2006). In most cases, fresh or dried leaves
were cooked, and the extract was administered to patients for the
treatment of stomach disorders including diarrhoea, gastroenteritis and
gastric ulcers. In addition, this plant species was also reported as being
used in Fiji Islands, India, Malaysia and Papua New Guinea against skin
related infections such as ulcers, psoriasis, fungal and bacterial in­
fections (Cambie and Brewis, 1997; Chand et al., 2018; Prescott et al,
2012, 2017; Sangeetha et al., 2011). For these infections, the leaf juice,
root decoction or latex was either applied as an ointment or massaged on
affected areas. Some side effects such as eczema and allergies have been
reported in Bangladesh where the latex of C. variegatum is massaged on
E. Mfotie Njoya et al.
Fig. 1. Frequency of medicinal usage of Codiaeum variegatum in the treatment of various diseases.
painful areas (Rahmatullah et al., 2009a). However, in this same
country, this latex continues to be used in small quantities in traditional
medicine to treat gastric ulcers (Rahman and Momota, 2013; Saffoon
et al., 2014) and leaf juice is used against fever, cough and cold (Rah­
matullah et al., 2009b).
The medicinal uses, modes of preparation of C. variegatum and
dosage are summarized in Table 1.
5. Phytochemistry
Most of the phytochemical studies on C. variegatum reported the
qualitative identification or quantification of classes of compounds
found in different varieties, and only very little is known about struc­
tural elucidation of specific compounds. The phytochemical content of
C. variegatum was related to the variety and the geographical origin of
the plant, and this could explain the diversity between cultivars and
different medicinal uses. However, the structural characterization of
compounds found in plant extracts is important to better understand the
use of some cultivars in folk medicine. Overall, it was observed that
some reports did not indicate the variety of C. variegatum used in the
phytochemical analysis. In addition, groups of compounds such as
coumarins, saponins, anthraquinones, cardenolides were only identified
by qualitative analysis (Bijekar and Gayatri, 2015; Ogunwenmo et al.,
2007), thus this review will encourage researchers in future studies to
investigate these groups of compounds in different cultivars of
C. variegatum, and selective polarity-guided fractionation may be
considered for the isolation of these compounds which structures should
be identified using appropriate spectroscopic techniques.
5.1. Alkaloids
Ogunwenmo et al. (2007) analyzed phytochemically fresh shoot
samples of six cultivars of C. variegatum (Spirale, Royal, Broad Spotted
Guinea, Punctatum, Sunray and Royal-like) collected from Babcock
University (Nigeria) by using standard qualitative phytochemical as­
says, and it was found that their ethanolic extracts contain higher
amounts of alkaloids compared to other detected phytochemicals
(Ogunwenmo et al., 2007). In contrast, using similar techniques, no
alkaloid was found in the methanolic leaf extracts of two varieties of
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Journal of Ethnopharmacology 277 (2021) 114244
C. variegatum (Curly boy and Spirale) collected in Stamford University
Bangladesh (Saffoon et al., 2010). Despite that, alkaloids (4.66–10.2%)
were detected in extracts from root, leaf, and stem of different varieties
of C. variegatum collected from Lal Bagh Botanical garden, Bangalore
(India) by using standard qualitative and quantitative phytochemical
assays (Anim et al., 2016; Bijekar and Gayatri, 2015; Mohamed et al.,
2019). Based on the above data, it can be concluded that the presence of
alkaloids in C. variegatum depends on the cultivar, the geographical
origin and the part of the plant used. To date, only three known alkaloids
(glaucine (1), oxoglaucine (2), and hemiargyrine (3)) were isolated from
a methanolic leaf extract of Codiaeum variegatum cv. ‘Petra’, collected at
the National Research Centre garden in Cairo (Egypt). Their structures
were elucidated using MS, 1H NMR and 13C NMR spectroscopy (Hassan
et al., 2014).
5.2. Terpenoids
Anim et al. (2016) analyzed the phytochemical composition of stem
bark and leaves of C. variegatum cv. ‘Gold dust’ collected in Accra
(Ghana), and triterpenoids were detected in the hydroethanolic (50:50,
v/v) leaf extract, but not in the stem bark (Anim et al., 2016). In addi­
tion, terpenoids were quantified in high amount (27–30%) in extracts
from root, leaf, and stem of different cultivars of C. variegatum collected
from Lal Bagh Botanical garden, Bangalore (India) (Bijekar and Gayatri,
2015). Four diterpenoids (α-amyrin (4), β-sitosterol (5),
ent-trachyloban-3-one (6), and ent-18-hydroxy-trachyloban-3-one (7))
have been identified in the methanolic leaf extract of C. variegatum cv.
‘Petra’, their structures have been elucidated with spectrometric and
spectroscopic techniques (MS and NMR) (Hassan et al., 2014). Silica gel
column chromatography of the chloroform fraction obtained from the
petroleum stem bark extract of C. variegatum yielded taraxerol (8) which
structure was elucidated using IR and NMR spectroscopy (Chauhan and
Singh, 2011).
5.3. Phenolic compounds
Naidu (1988) reported the presence of phenolic compounds
(chlorogenic acid (9), protocatechuic acid (10), p-hydroxy benzoic acid
(11), vanillic acid (12), trans and cis p-coumaric acid (13), trans and cis
E. Mfotie Njoya et al. Journal of Ethnopharmacology 277 (2021) 114244

Table 1
Local names, distribution, and medicinal uses of Codiaeum variegatum.
Country Variety/local names Mode of preparation/Medicinal uses Dosage References

Bangladesh Pata-bahar • Leaf juice is boiled with olive oil and Each mixture is applied to the affected part (Rahman and Momota, 2013;
massaged on painful areas. of the body once per day till the relieve of Rahmatullah et al., 2009a)
• Sap is toxic, though it is used in small pain or the disappearance of disease
quantities to treat gastric ulcers. symptoms.
• Sap mixed with coconut milk is spread on
affected areas of syphilis.
Boangkhela-paingda • Leaf juice is taken against fever, cough and 3 leaves are chewed and juice is swallowed. Rahmatullah et al. (2009b)
cold
Cameroon Mollucanum • Root decoction used for gastric ulcers. About 10 leaves boiled in water per day for Moundipa et al. (2005)
• Leaves’s decoction for bloody diarrhoea and three consecutive days.
stomachache.
China bian ye mu • Leaf decoction is massaged to disperse – FOC (2015)
extravasated blood and drunk as an anti-
inflammatory agent.
Fiji Islands Sacasaca • Crushed leaves are used to treat fish For gonorrhoea, eight leaves are crushed, (Cambie and Ash, 1994;
poisoning and gonorrhoea. then mixed with coconut milk and drunk. Sangeetha et al., 2011)
• Bark decoction is used against eczema,
psoriasis, and allergies.
Vasa damu • Young leaves are crushed and juice is drunk – (Cambie and Ash, 1994;
against gonorrhoea. Chand et al., 2018)
• Root is used to treat toothache.
• Bathing in boiled leaves can treat fever.
• The sap of the stem is applied on affected
areas to treat sores.
• Leaf decoction is drunk against cancer.
India Pattabahargach • Alcoholic root decoction is mixed with an Ointment formulation made of 4 g of Sangeetha et al. (2011)
ointment to fomenting, sealing of secondary alcoholic root extract mixed 100 g of simple
infection, healing of wounds and skin ointment base.
eruptions.
• Crushed root is applied to tooth cavities for
temporary relief of pain.
• Gastroenteritis, ulcers. Leaf is cooked and its extract is consumed Raj et al. (2018)
on empty stomach (2 spoons for 2–3 days)
to cure gastroenteritis and other stomach
problems.
Indonesia Tarimas, Silastom, Nasalou, • Leaf decoction is used relieve the bowels of – Wiart (2006)
Pudieng, Katomas, Daun garida, costiveness.
Uhung, Dahengora, Abam • Leaf juice is applied on affected areas for the
treatment of eczema.
Malaysia Bunga mas • Hot water extract from the leaves is drunk – (Ahmad and Holdsworth,
for parturition. 2003; Ahmad and Ismail,
• Root decoction is drunk to treat gastric 2003; Cambie and Brewis,
ulcers. 1997)
• Leaf juice used as antibacterial agent
• Pounded root and juice is rubbed into
syphilitic sores.
• Leaves are heated and applied on the
abdomen of children with urinary
problems.
Panama – • Leaf decoction used as a bath for body aches – Cambie and Brewis (1997)
and eye diseases.
Papua New Dokodoko, • Sap applied to mouth ulcers. – Prescott et al. (2012)
Guinea Marakeh • Sap applied to ulcers.
Prumen, • The leaves are squeezed and the resulting – (Koch et al., 2015; Prescott
Diripmi exudate is applied to ulcers. et al., 2017);
• The stem sap is applied to ulcers.
Kai; Tubuloko; Marmara; • Root is chewed with betel nut to treat – WHO (2009)
Baba’a; Simpika; stomachache and crushed root is applied for
Babaka pain relief from toothache.
• Leaf juice or bark sap is applied on sores and
fungal infections.
• Drink prepared from sap is given for snake
bites and applied to the affected bite area.
• Decoction of entire plant is drunk to
facilitate parturition.
Philippines cv. Gold Sun; • Dried leaf decoction is taken as tea against Three bags with 14.5 g per tea bag in 24 h Gertrudes (2006)
Sagilala, Kila, Kilala-puti, coughs. administered every 8 h.
Kalipayang • Crushed leaf juice used against diarrhoea. LD50 to mice (34.2 g/kg)
Tanzania – • Leaf decoction or alcoholic extract used for – Moshi and Kagashe (2004)
the treatment of epilepsy.
Thailand – • Leaves are used against bacterial infections. – Phumthum and Balslev
(2020)
Vanuatu Inloptahow, Tangalao • Chewing of leaves is used against 3 leaves are used per day against Bourdy and Walter (1992)
amenorrhea. amenorrhea.
• Whole plant decoction is used to facilitate
parturition.

-: information not available.

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E. Mfotie Njoya et al. Journal of Ethnopharmacology 277 (2021) 114244

ferulic acid (14)) in 80% ethanolic leaf extracts of C. variegatum using 5.4. Other phytochemicals
paper chromatography, and it was observed that the content of each
phenolic acid varied between young and mature leaves (Naidu, 1988). Forero et al. (2008) reported the isolation from fresh latex of
Additionally, Saffon and co-workers (2014) investigated phenolic C. variegatum of a cyanoglucoside identified as 2-(3,4,5)-trihydrox­
compounds in ethanolic leaf extract of C. variegatum collected in y-6-hydroxymethyltetrahydropyran-2-yloxymethyl acrylonitrile and
Bangladesh, and they found that out of eleven different phenolic stan­ named codiacyanoglucoside (24). Its structure was determined through
dards, only four of them ((− )-epicatechin (16), p-coumaric acid (13), NMR, MS and X-ray diffraction analysis (Forero et al., 2008). The
rutin (17), and ellagic acid (18)) were detected by HPLC-DAD. Quan­ compounds identified so far from C. variegatum are shown in Fig. 2.
tification of the detected compounds indicated that ellagic acid was
present in high concentration (around 200 mg per 100 g of dry weight)
5.5. Essential oil composition
compared to other compounds (Saffoon et al., 2014). Moreover, from
the 80% methanolic leaf extract of C. variegatum cv. ‘Spirale’ collected in
The phytochemical composition of leaves of C. variegatum (L.)
Cairo (Egypt), two phenolic acids (caffeic acid (15) and p-coumaric acid
Rumph. Ex A. Juss collected in Bogor (West Java, Indonesia) was
(13)) and five flavonoids (apigenin (19), orientin (20), vitexin (21),
analyzed using GC-MS, and 12 volatile compounds were identified
isovitexin (22), and vicenin-2 (23)) were isolated by Sephadex LH-20
among which (6Z,9Z)-6,9-pentadecadiene-1-ol (35%), hexadecanoic
column chromatography, and their structures were elucidated using
acid (21%), and 2,3-dihydro-3,5-dihydroxy-6-methyl-4pyran-4-one
MS as well as 1H and 13C NMR spectroscopy (Hassan et al., 2014; Mona
(11%) were the major compounds (Nurwanti et al., 2018). In addition,
et al., 2019).
Lawal et al. (2018) reported compounds of essential oil obtained by

Fig. 2. Compounds isolated from Codiaeum

variegatum cultivars. Alkaloids: glaucine (1),
oxoglaucine (2) and hemiargyrine (3); Terpe­
noids: α-amyrin (4), β-sitosterol (5), ent-
trachyloban-3-one (6), ent-18-hydroxy-
trachyloban-3-one (7) and taraxerol (8);
Phenolic compounds: chlorogenic acid (9),
protocatechuic acid (10), p-hydroxy benzoic
acid (11), vanillic acid (12), trans and cis p-
coumaric acid (13), trans and cis ferulic acid
(14), caffeic acid (15), (− )-epicatechin (16),
rutin (17), ellagic acid (18), apigenin (19),
orientin (20), vitexin (21), isovitexin (22) and
vicenin-2 (23); other compound: codiacyano­
glucoside (24).

6
E. Mfotie Njoya et al.
hydrodistillation from leaves of four varieties of C. variegatum, namely
Blume f. Lobatum cv. Disraeli (Cv1), var. Pictum ‘Congo’ (Cv2), Blume
F. Taeniosum cv. Gold Sun (Cv3), and ‘Dreadlocks’ (Cv4) grown in
Nigeria, and 33 compounds of the essential oil were identified by
GC-MS. The main constituents of Cv1 were oxygenated sesquiterpenes, i.
e., caryophyllene oxide (58%), and sesquiterpene hydrocarbons (33%),
dominantly (Z)-β-farnesene (20%). Four major compounds namely
linalool (39%), 1,2,4-trimethylbenzene (21%), β-pinene (22%), and
α-pinene (18%) were present in significant amounts within Cv2, while
phytol (18%), β-bisabolene (10%), and linalool (9%) were the major
components of Cv3. The dominant constituents of Cv4 were β-ionone
epoxide (30%), γ-muurolene (21%), naphthalene (16%) and
(E)-α-ionone (15%) (Lawal et al., 2018).
6. Pharmacological properties
A total of 31 out of 89 selected articles (i.e., 34.83%) reported in vitro
(28) and in vivo (3) biological activities of 38 varieties of C. variegatum.
So far, no clinical study was found with C. variegatum-based products.
The most important biological properties of C. variegatum were the
antimicrobial, cytotoxic, anti-amoebic and antiviral activities which
correlated with the medicinal use of their respective varieties in tradi­
tional medicine (Fig. 3). Fourteen identified varieties (Curly boy,
Dreadlocks, Gold dust, Royal like, Spirale, Nordwood beauty, Lobatum
Disraeli, Mollucanum, Ovalifolium, Petra, Pictum ‘Congo’, Punctatum
aureum, Taeniosum ‘Gold sun’ and Undulatum) were used for the
evaluation of the pharmacological properties, and the varieties Mollu­
canum and Spirale were the most studied among these cultivars. In
contrast, 24 varieties of C. variegatum were not identified in 18 out of 31
publications which makes it difficult to follow up further research done
on these varieties. The most interesting biological effects of varieties of
C. variegatum are summarized in Table 2.
6.1. Anti-amoebic activity
Moundipa et al. (2005) investigated the in vitro anti-amoebic activity
of 55 Cameroonian medicinal plants by using a polyxenic culture of
Entamoeba histolytica, and the aqueous leaf extract of C. variegatum (cv.
Mollucanum) was found to exhibit significant anti-amoebic activity
Fig. 3. In vitro and in vivo biological activities and their frequency among different varieties of Codiaeum variegatum.
7
Journal of Ethnopharmacology 277 (2021) 114244
(EC50 of 10.74 μg/mL, 48 h of incubation) compared to the reference
drug metronidazole (Moundipa et al., 2005). Further investigations on
the aqueous extract via bioassay-guided fractionation on an axenic
culture of E. histolytica resulted in the isolation of a sub-fraction SF9B
with significantly higher efficacy (EC50 of 2.75 μg/mL, 48 h of incuba­
tion) compared to the unfractionated extract (Mfotie Njoya et al.,
2014b). The qualitative analysis of this active sub-fraction showed the
presence of alkaloids, flavonoids and terpenoids (Mfotie Njoya et al.,
2014a). (− )-epicatechin (16) ellagic acid (18) and apigenin (19) found
in the leaf extract of C. variegatum were reported as a potent antiamoebic
compounds with an IC50 values of 1.9, 56.5 and 12.7 μg/mL respectively
(Alanis et al., 2003; Cimanga et al., 2006). The presence of these fla­
vonoids in C. variegatum may justify its antiamoebic activity, but can be
also attributed to other bioactive compounds that have not yet been
identified. Accordingly, the isolation of compounds within the most
active sub-fraction SF9B is highly recommended.
The study of the mode of action indicated that the sub-fraction SF9B
caused significant morphological changes on trophozoites of
E. histolytica, leading to parasite death through the destabilization of
Gal/GalNAc lectin, an abundant protein on the parasite surface. Besides,
transcriptomic analysis using RNA sequencing showed that treatment
with the active sub-fraction induces the upregulation of the gene
responsible for the synthesis of ceramide synthase which plays an
important role in cell differentiation and apoptosis (Mfotie Njoya et al.,
2014b). In addition, other signaling pathways such as cell division,
virulence, energy production, stress and oxydoreduction were signifi­
cantly affected. These findings provided scientific evidence on the effi­
cacy of the cultivar Mollucanum used by the local population in
Cameroon for the treatment of amoebic dysentery.
6.2. Anticonvulsant activity
The aqueous and methanolic leaf extracts of C. variegatum were
tested at 100 and 200 mg/kg for their ability to inhibit picrotoxin-
induced convulsions in adult white Wistar albino mice using both the
intraperitoneal and oral routes. The methanolic extract showed a sig­
nificant anticonvulsant activity via both routes, while the aqueous
extract was active when administered via the intraperitoneal but not the
oral route which suggested an inactivation of active compounds during
 E. Mfotie Njoya et al.
Table 2
Biological properties of Codiaeum variegatum cultivars used in folk medicine.
Activity Variety (plant part) Study type Experimental models Tested materials (active compounds) Dose range Controls Results References

Anti-amoebic Mollucanum (leaf) in vitro Polyxenic and axenic Aqueous leaf extract and fractions 31.25–500 μg/ Metronidazole Aqueous leaf extract (EC50 = 10.74/120 μg/ (Mfotie Njoya
culture of Entamoeba (alkaloids, flavonoids, terpenoids) mL for extract; mL). Isolation of a sub-fraction with higher et al., 2014b;
histolytica 1.56–50 μg/mL efficacy (EC50 = 2.75 μg/mL). Moundipa et al.,
for fractions 2005)
Antibacterial Norwood beauty, in vitro Well diffusion and disc (acetone, benzene, chloroform, 100 mg/mL Distilled water as Punctatum leaf callus extract (ZOI = 24.3 mm) Bhot et al. (2010)
Punctatum and diffusion method ethanol, methanol, petroleum ether negative control against Arthrobacter.
Undulatum (leaf, and water) fresh and dried leaf
callus) extracts; fresh leaf callus
Ovalifolium (leaf) Agar well diffusion Ethanolic, methanolic and aqueous 100 mg/mL Distilled water or Ethanolic leaf extract exhibited (ZOI = 30 mm) Anyasor et al.
method leaf extracts ethanol as negative against Streptococcus pneumoniae Te2. (2010)
controls
Not identified (leaf) Modified Kirby-Bauer Ethanolic fresh leaf extracts 100 mg/mL Gentamicin None of the extracts was as active as Gastador and
disc diffusion method gentamicin. Oling (2011)
Ethanolic and aqueous leaf extracts 15–120 mg/mL Tetracycline Both extracts strongly inhibited the growth of Mohamed et al.
(flavonoids, alkaloids, phenolics) B. subtilis and Serratia marcescens. (2019)
Activity Variety (plant part) Study type Experimental Models Tested materials (active compounds) Dose range Controls Results References
Antibacterial Not identified (leaf) in vitro Microplate Alamar Blue Dichloromethane/methanolic leaf ≤100 μg/mL Rifampicin MIC of 55.8 μg/mL against Mycobacterium Case et al. (2006)
Assay extract tuberculosis (H37Rv)
Anticonvulsant Not identified (leaf) in vivo (oral and Picrotoxin-induced Aqueous and methanolic leaf extracts 100–200 mg/ Distilled water The aqueous extract inhibited picrotoxin- Moshi and
intraperitoneal convulsions in adult kg induced convulsions after intraperitoneal but Kagashe (2004)
routes) white Swiss albino mice not the oral route.
Anti-diarrhoeal Not identified (leaf) in vivo (oral route) Castor oil-induced Ethanolic leaf extract (tannins, steroids 250 and 500 Loperamide 50 The extract reduced defecations, intestinal Labu et al.
diarrhoea in Swiss albino and alkaloids) mg/kg mg/kg inflammation and fluid accumulation. (2015)
mice
Antifungal Not identified (leaf) in vitro Agar diffusion method Ethanolic young and old leaf extracts 10, 25, 50 mg/ Young leaf extract was active against Alternaria Naidu (1988)
8

–
(chlorogenic, ferulic, p-coumaric, mL alternata while old leaf extract was active
vanillic, protocatechuic acids) against Fusarium oxysporum.
Anti-inflammatory Not identified (leaf) in vitro Nitric oxide (NO) Methanolic leaf extract (flavonoids) 50 μg/mL Untreated LPS- Moderate NO production inhibition (41–54%) Bijekar et al.
inhibitory assay in stimulated cells (2015)
macrophage RAW
264.7 cell line
Antiviral Not identified (leaf) in vitro Herpes simplex type-1 Ethanolic leaf extract 1–100 μg/mL – The ethanolic leaf extract possessed selective Ali et al. (1996)
(DNA type) and antiviral activity against VSV.
vesicular stomatitis
(RNA type) viruses.
Antiviral Not identified in vitro Influenza A virus (A/ Fresh latex (codiacyanoglucoside) 7.81–250 μg/ – Codiacyanoglucoside had an IC50 of 17 μg/mL Forero et al.
(latex) PR/8/34.H1N1) mL and a selectivity index (SI) greater than 14.9. (2008)
Cytotoxic Gold dust Petra in vitro MTT assay (HeLa, Crude hydroethanolic and methanolic 0–1000 μg/mL Curcumin, Stem bark extract had stronger inhibitory effect (Anim et al.,
(leaf, stem bark) Jurkat, MCF7, PC3, leaf and stem bark extract (glaucine, for extracts; doxorubicin on all cell lines compared to the leaf extract. 2016; Hassan

Journal of Ethnopharmacology 277 (2021) 114244

HepG2, HCT116, A549 oxoglaucine, hemiargyrine) 100 μg/mL for Hemiargyrine was the most active (with 90% et al., 2013)
cells) compounds. growth inhibition) against HepG2 cells.
Curly boy Spirale Brine shrimp lethality Methanolic leaf extracts (saponins, 2–200 μg/mL Vincristine sulfate The spirale extract was more cytotoxic than the Saffoon et al.
(leaf) bioassay tannins and gums) Curly boy extract, but less active than the (2010)
positive control.
Wound healing Not identified in vivo (dermal Excision, incision and Methanol root extract (flavonoids and 2–4 g of extract Nitrofurazone Remarkable pro-healing activity by affecting Sangeetha et al.
(roots) route) burn wound models on tannins) per 100 g various stages of healing process. (2011)
Wistar albino rats ointment

ZOI: Zone of inhibition, EC50: Half maximal effective concentration; IC50: Half maximal inhibitory concentration; MIC: minimum inhibitory concentration.
E. Mfotie Njoya et al.
metabolism (Moshi and Kagashe, 2004). On the other hand, Finbarrs-­
Bello et al. (2016) administered orally the ethanolic fresh leaf extract of
C. variegatum (Punctatum) at doses of 200, 400 and 600 mg/kg to adult
Wistar albino rats, and adverse effects on the cerebrum such as sparse
cellular population, microglial infiltration, focal and liquefactive ne­
crosis were reported as compared to the control group (Finbarrs-Bello
et al., 2016). Knowing that the cerebral cortex is the major part of the
brain affected by epilepsy, these adverse effects of C. variegatum on the
cerebrum may compromise its anticonvulsant activity. But, as the doses
used in both studies were very different, and two different cultivars were
used, this controversy cannot be solved with the data available to date.
Otherwise, the ethanolic leaf extract of the Punctatum variety may
contain toxins which cannot be found in the leaf aqueous concoction
used in Tanzanian folk medicine.
Several compounds found in leaf extract of C. variegatum have been
reported with antiepileptic or anticonvulsant properties. For example,
caffeic acid (15) and its ester derivative (chlorogenic acid (9)) signifi­
cantly decreased pilocarpine-induced seizures either by modulating
hippocampal oxidative stress or by inhibiting inflammation and
acetylcholinesterase activity (Dos Santos et al., 2006; Dos Santos Sales
et al., 2011; Kim and Oh, 2012; Kwon et al., 2010). Additionally, three
flavonoids (rutin (17), apigenin (19) and vitexin (21)) exerted their
anticonvulsant effect on picrotoxin-induced convulsions or
pentylenetetrazole-induced seizures via potential binding to
gamma-aminobutyric acid-activated (GABAA)-benzodiazepine receptor
complex (Abbasi et al., 2012; Avallone et al., 2000; de Oliveira et al.,
2020; Nassiri-Asl et al, 2008, 2010). These results confirmed the pres­
ence of active ingredients in the leaf concoction of C. variegatum used in
traditional medicine by people of Kagera and Coast regions (Tanzania)
for the treatment of epilepsy, but it raised questions about its potential
toxicity. Therefore, further studies on this cultivar are needed to support
its safe usage as an anticonvulsant medicine.
6.3. Antidiarrhoeal activity
The antidiarrhoeal activity of the ethanolic leaf extract of
C. variegatum was evaluated in vivo on castor oil-induced diarrhoea in
Swiss albino mice, and the extract improved the conditions of treated
animals at doses of 250 and 500 mg/kg compared to untreated group by
reducing the number of defecations and by inhibiting castor oil-induced
inflammation of the intestinal mucosa and the accumulation of fluid
(Labu et al., 2015). Apigenin (19), a flavonoid constituent of C. varie­
gatum, at doses of 2 and 10 mg/kg, was reported to inhibit castor
oil-induced diarrhoea in mice by 36% and 63% respectively in com­
parison with the untreated group (Sadraei et al., 2016). Besides, the
castor oil-induced diarrhoea is mostly associated with intestinal hyper­
secretion of fluid caused by an inflammatory response and gross damage
to the intestinal mucosa. Therefore, chlorogenic acid (9), a known
anti-inflammatory compound identified in 80% ethanolic leaf extract of
C. variegatum, was reported to exert its antidiarrheal activity by reducing
the accumulation of intestinal fluid (Tenório et al., 2016). The above
reports provide scientific proof for the traditional use of this plant as
antidiarrhoeal remedy. However, it is also recommended to evaluate the
effect of this plant extract on infectious diarrhoea models since some
varieties of C. variegatum had promising antimicrobial property (dis­
cussed below).
6.4. Anti-inflammatory activity
The anti-inflammatory activity of the flavonoid fractions of
C. variegatum was evaluated on mouse leukemic monocyte macrophage
RAW 264.7 cells, and it was reported that these fractions at 50 μg/mL
significantly inhibit the nitric oxide (NO) production by 41–54% as
compared to lipopolysaccharide (LPS)-stimulated RAW 264.7 cells
(negative control) (Bijekar et al., 2015). Additionally, these flavonoid
fractions were not significantly cytotoxic to the RAW 264.7 cells as
9
Journal of Ethnopharmacology 277 (2021) 114244
measured by the 3- (4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium
bromide (MTT) assay, which confirms their NO production inhibitory
activity. Flavonoids such as (− )-epicatechin (16), rutin (17), ellagic acid
(18), apigenin (19), orientin (20), vitexin (21), isovitexin (22) and
vicenin-2 (23) were found in methanolic leaf extract of C. variegatum,
and the anti-inflammatory activity of flavonoids is mediated through
various mechanisms. A flavonoid enriched extract containing (20), (21)
and (22) has been shown to exert its anti-inflammatory activity by
inhibiting the production of pro-inflammatory mediators such as NO,
tumor necrosis factor-α (TNF- α), interleukin- (IL-) 6, and IL-12 in
LPS-stimulated RAW 264.7 macrophages (Nam et al., 2017). Similar
pharmacological effect was observed with (16) which also inhibited
these pro-inflammatory mediators (Wang and Cao, 2014). Moreover,
(21) induced in vitro (25–100 μg/mL) and in vivo (5–30 mg/kg)
anti-inflammatory effect by reducing the production prostaglandin E2
(PGE2), pro-inflammatory cytokines such as IL-1β, IL-33, and by
increasing IL-10 production in LPS-activated RAW 264.7 cells (Borghi
et al., 2013; Iara et al., 2016). Vitexin (21) was also involved in the
down-regulation of transcriptional factors such as mitogen-activated
protein kinase (p-p38, p-ERK1/2 and p-JNK) (Iara et al., 2016). Taken
together, these data supported the anti-inflammatory effect of flavonoid
fractions of C. variegatum.
In another above-mentioned study, Labu et al. (2015) reported that
C. variegatum reduced castor oil-induced intestinal inflammation and
accumulation of fluid in the mucosa which imply its potential
anti-inflammatory property (Labu et al., 2015). Perhaps, compounds
such as (17), (18), (19) and (23) are involved in this pharmacological
property since they have previously shown their anti-inflammatory ef­
fect on dextran sulfate sodium-induced murine experimental colitis by
either inhibiting NOD-, LRR- and pyrin domain-containing protein 3
(NLRP3) inflammasome or by blocking transcriptional factors (p38
MAPK, NF-κB, STAT3) and down-regulating mediators such as inducible
nitric oxide synthase (iNOS), cyclooxygenase (COX-2) (Hassan et al.,
2018; Kwon et al., 2005; Marín et al., 2013; Márquez-Flores et al., 2016).
Moreover, it has also been reported that caffeic acid (15) exerts its
anti-inflammatory activity via suppression of eicosanoids synthesis, in­
hibition of the activation of NF-κB and downregulation of COX-2 gene
expression (Okutan et al., 2005; Rossi et al., 2002). Chlorogenic acid (9),
an ester of caffeic acid (15) and quinic acid, was found to inhibit the
production of NO and pro-inflammatory mediators such as TNF-α, IL-6
and IL-1β by down-regulating the expression of iNOS, COX-2 and
NF-κB (Hwang et al., 2014). According to the above observations, the
efficacy of C. variegatum leaf extract should be evaluated in animal
inflammation models in order to confirm its in vivo anti-inflammatory
potential.
6.5. Antimicrobial activity
Naidu (1988) reported the antifungal activity of ethanolic young and
mature leaf extracts of C. variegatum against Alternaria alternata and
Fusarium oxysporum (Naidu, 1988). Both extracts inhibited the growth of
the two fungi with young leaves being more active against A. alternata
and old leaves more active against F. oxysporum. Moreover, the anti­
mycobacterial activity of the dichloromethane/methanol leaf extract of
C. variegatum was evaluated in vitro using a microplate alamar blue assay
against a virulent strain of Mycobacterium tuberculosis (H37Rv), and this
extract was active with a minimal inhibitory concentration (MIC) of
55.8 μg/mL (Case et al., 2006). In addition, the antibacterial activity of
ethanolic fresh leaf extract of C. variegatum cv. (L.) Blume was evaluated
against four microorganisms (Escherichia coli, Pseudomonas aeruginosa,
Bacillus subtilis and Staphylococcus aureus) using the Kirby-Bauer disc
diffusion method. It was then found that this extract exhibited clear
zones of inhibition supporting its antibacterial activity, though it was
not as active as gentamicin used as positive control (Gastador and Oling,
2011). Then again, several solvent (acetone, benzene, chloroform,
ethanol, methanol, petroleum ether and water) extracts of fresh leaves,
E. Mfotie Njoya et al.
dried leaves and fresh callus from three varieties of C. variegatum (L.)
Blume (Norwood beauty, Punctatum and Undulatum) were tested
against six different bacterial strains including the Gram-positive bac­
teria Arthrobacter, B. subtilis, Corynebacterium diphtheria, and the
Gram-negative bacteria E. coli, Klebsiella pneumoniae, P. aeruginosa using
the well diffusion and disc diffusion method. It was found that the
antimicrobial activity varied according to the cultivar, solvents used for
extraction and the organisms tested. The largest zone of inhibition (ZOI
= 24.3 mm) was observed with the variety Punctatum methanolic leaf
callus extract against Arthrobacter (Bhot et al., 2010). Besides, the
ethanolic leaf extract of C. variegatum cv. Ovalifolium was reported to
inhibit the growth of Streptococcus pneumoniae Te2 (ZOI = 30 mm), S.
pyrogeneae Td2 (ZOI = 14 mm), Salmonella typhi Tc2 (ZOI = 7 mm),
S. typhi Tc19 (ZOI = 13 mm), S. typhi Sat7 (ZOI = 10 mm) and E. coli Ecl7
(ZOI = 17 mm), suggesting that this plant extract contains antimicrobial
agents (Anyasor et al., 2010). Recently, Mohamed et al. (2019) reported
the antibacterial activity of ethanolic and aqueous leaf extracts of
C. variegatum using the modified Kirby-Bauer disc diffusion technique to
determine the zone of inhibition, and it was found that both crude ex­
tracts strongly inhibited the growth of Gram-positive bacteria
(B. subtilis) and Gram-negative bacteria (Serratia marcescens) with ZOI of
12 and 20 mm respectively (Mohamed et al., 2019). Based on the above
reports, it is obvious that some varieties of C. variegatum contains anti­
microbial agents that are effective against a wide range of
micro-organisms.
Phenolic acids such as chlorogenic acid (9), protocatechuic acid
(10), p-hydroxy benzoic acid (11), vanillic acid (12), p-coumaric acid
(13) and ferulic acid (14) were identified from the leaf extract of
C. variegatum which exhibit antimicrobial activity against Gram-positive
bacteria, Gram-negative bacteria as well as fungi (Cueva et al., 2010;
Kozyra et al., 2017; Liu et al., 2020; Puupponen-Pimia et al., 2001). The
antimicrobial mechanism of action of phenolic acids includes changing
the bacterial physicochemical properties on gram-positive (increased
acceptor components) and gram-negative (decreased acceptor compo­
nents) strains (Campos et al., 2008). Additionally, phenolic acids are
able either to modify the permeability of bacteria cytoplasmic mem­
brane causing leakage of cytoplasmic content or to inhibit extracellular
microbial enzymes (Borges et al., 2013; Lou et al., 2011). Similar effects
of phenolic acids are suggested against fungi, but it needs to be further
investigated. From these observations, it is obvious that the organic and
aqueous extracts from different varieties of C. variegatum contain anti­
microbial compounds. However, the method (Kirby-Bauer disc diffu­
sion) used in most cases, is limited to determine the ability of plant
extracts to inhibit or kill micro-organisms. In this regard, further in­
vestigations are requested with the most interesting cultivars Ovalifo­
lium and Punctatum to determine the effect of these plant extracts and
isolated compounds on bacterial quorum sensing or biofilm formation
which are new approaches to manage microbial infections (Zhao et al.,
2020).
6.6. Antioxidant activity
Saffoon et al. (2014) determined the antioxidant activity of three
cultivars (Spirale, Gold dust and Royal like) of C. variegatum by evalu­
ating the DPPH free radical scavenging, nitric oxide scavenging,
hydrogen peroxide, reducing power, total antioxidant, protection of
lipid peroxidation and red blood cell (RBC) membrane stabilization
activities (Saffoon et al., 2014). The authors found that the ethanolic leaf
extracts from two varieties (Spirale and Royal like) showed antioxidant
activity, which was less effective compared to the standard (ascorbic
acid). The antioxidant activity of these ethanolic leaf extracts was
attributed to the presence of phenolic compounds such as (− )-epi­
catechin (16), p-coumaric acid (13), rutin hydrate (17) and ellagic acid
(18) which are well-known antioxidants (Saffoon et al., 2014). Besides
that, flavonoids such as apigenin (19), orientin (20), vitexin (21), iso­
vitexin (22) and vicenin-2 (23) along with phenolic acids such as caffeic
10
Journal of Ethnopharmacology 277 (2021) 114244
(15) and p-coumaric acids (13) were isolated from the methanolic
extract of C. variegatum cv. Spirale, and their antioxidant potential was
determined by evaluating the DPPH scavenging, total reduction capa­
bility and inhibition of lipid peroxidation activities. Depending on the
assay, some isolated compounds exhibited significant activity compared
to the standard controls (ascorbic acid and butylated hydroxytoluene).
Vitexin (21) exhibited the highest DPPH radical scavenging activity
(IC50 = 8.95 μg/mL), and it also had a significant reducing power (RP50
= 8.65), followed by isovitexin (22) (RP50 = 9.27 μg/mL). Oppositely,
none of the tested compounds was found to be significantly active
against the lipid peroxidation process (Hassan et al., 2014). The DPPH
radical scavenging activity of another variety of Codiaeum variegatum cv.
“Gold dust” indicated an antioxidant potential of the hydroethanolic
stem bark extract with EC50 value of 53 μg/mL compared to the control
butylated hydroxytoluene (EC50 = 45.4 μg/mL) (Anim et al., 2016).
Phenolic compounds are considered to be major contributors to the
antioxidant capacity of plants which resulted from their protective role
against excessive oxidative damage induced by reactive oxygen species
(ROS) (Hasanuzzaman et al., 2020). Almost all plants elaborate anti­
oxidant mechanism by producing phytochemicals for their protection
against environmental oxidative agents which may justify the fact that
some varieties of C. variegatum (Gold dust and spirale) exhibited anti­
oxidant activity under in vitro conditions. On the other hand, phenolic
compounds can display pro-oxidant activity under certain conditions,
leading to oxidative damage of cellular components (Eghbaliferiz and
Iranshahi, 2016). Therefore, the determination of the
antioxidant/pro-oxidant ratio may be used as a better approach to
evaluate the net antioxidant capacity of the extracts (Ling et al., 2010). It
will be most relevant to evaluate the antioxidant/pro-oxidant ratio of
C. variegatum extracts and isolated compounds. Additionally, the anti­
oxidant activity of C. variegatum (Gold dust and spirale) need to be
studied in vivo since phenolic compounds identified as being responsible
for their activity may be influenced under in vivo conditions by several
physiopharmacological factors such as absorption, metabolism,
bioavailability.
6.7. Antiviral activity
Ali et al. (1996) carried out an ethnopharmacological survey where
61 Malaysian plants were collected and screened for antiviral activities
against both herpes simplex type-1 (DNA type) and vesicular stomatitis
(RNA type) viruses using Vero cells, and they found that the ethanolic
leaf extract of C. variegatum possessed selective antiviral activity to­
wards vesicular stomatitis virus with a MIC of 10 μg/mL (Ali et al.,
1996). This observed activity may be attributed to the presence of
compounds such as chlorogenic acid (9) and caffeic acid (15) identified
in C. variegatum, which are known to selectively inhibit viral replication
without reducing the growth of target cells (Chiang et al., 2002).
However, the phytochemical exploration of the ethanolic extract of
C. variegatum may reveal other antiviral constituents which are not yet
identified.
Forero et al. reported the antiviral activity of the latex of
C. variegatum and the isolation of a bioactive codiacyanoglucoside (24)
against the influenza A virus (A/PR/8/34. H1N1) with an IC50 of 91 and
17 μg/mL respectively (Forero et al., 2008). The latex of C. variegatum is
known to be potentially toxic and is recommended to be used only in
small quantity in traditional medicine which is demonstrated in the
current study by the fact that the initial fraction of the latex and its
purified compound (24) inhibited influenza A viral replication in a
dose-dependent manner with selectivity index (SI) of 2.7 and 14.9 to­
wards Madin-Darby Canine Kidney (MDCK) cells respectively. There­
fore, the usage of the latex of C. variegatum for medicinal purpose
required the chemical characterization and isolation of active in­
gredients which may be less toxic when used alone. Considering its
structural characteristics, (24) was found not to be associated with toxic
effects due to the presence of an exocyclic methylene within its structure
E. Mfotie Njoya et al.
which prevents the production of toxic cyanide during its chemical or
enzymatic hydrolysis (Forero et al., 2008). The mechanism of action of
antiviral compounds involves either to block viral attachment, pene­
tration, replication or to reduce the virus susceptibility (Li et al., 2018).
It is then important to study the effect of (24) on these processes as it
might help to avoid the development of resistance.
6.8. Cytotoxic activity
Four cultivars (Gold dust, Petra, Curly boy, and Spirale) and a non-
identified variety were reported for their cytotoxic potential. In a
screening of 61 Malaysian medicinal plants against HeLa cells, the
ethanolic leaf extract of C. variegatum was among the 18 cytotoxic plants
with a cytotoxic dose (CD50) of 100 μg/mL (Ali et al., 1996). Recently,
Anim et al. (2016) evaluated the cytotoxic activity of hydroethanolic
(50:50; v/v) C. variegatum stem bark and leaf extracts with isolated
fractions against human leukemic (Jurkat), breast (MCF7), prostate
(PC3) and liver (HepG2) cancer cell lines using the MTT assay. It was
found that the stem bark extract had stronger inhibitory effect on all the
cell lines compared to the leaf extract, however both extracts had poor
selectivity towards the normal human liver cells (WRL 68) (Anim et al.,
2016). In another report, the methanolic C. variegatum cv. Petra leaf
extract as well as three isolated alkaloids (glaucine (1), oxoglaucine (2),
and hemiargyrine (3)) were tested at 100 μg/mL for their cytotoxic
activity on human hepatocellular (HepG2), breast (MCF7), colon
(HCT116) and lung (A549) cancer cell lines, and it was found that the
methanolic extract was more cytotoxic against all cancer cells than the
isolated compounds, except that (2) and (3) were more potent against
HepG2 cells with growth inhibition of 66.1% and 90.9% respectively
(Hassan et al., 2013). In this report, neither the methanolic extract nor
the isolated compounds were found to be more cytotoxic than doxoru­
bicin used as positive control. Saffoon et al. (2010) reported the cyto­
toxic potential of the methanolic leaf extracts of two cultivars of
C. variegatum (Spirale, Curly boy) by using the brine shrimp lethality
bioassay, and they found that the Spirale extract was more cytotoxic
than the Curly boy extract, although both extracts were less effective
than vincristine sulfate used as positive control (Saffoon et al., 2010).
Furthermore, an enriched phenolic fraction of C. variegatum (cv. Spirale)
was administered to male Swiss albino mice (125–500 mg/kg) and it was
observed that this fraction (containing p-coumaric acid (13), caffeic acid
(15), apigenin (19), orientin (20), vitexin (21), isovitexin (22) and
vicenin-2 (23)) had an ameliorative effect in dose-dependent manner
against mitomycin-induced cytotoxicity and genotoxicity in mouse so­
matic and germ cells of treated groups as compared to untreated group
(Mona et al., 2019). Therefore, it can be concluded that the cytotoxicity
of C. variegatum depends on the variety of the plant which differ from
each other by the phytochemical composition, and synergistic action
may explain the high cytotoxicity of crude plant extracts compared to
isolated compounds.
6.9. Wound healing activity
Sangeetha and collaborators (2011) evaluated the wound healing
activity of the methanolic root extract of C. variegatum incorporated in a
simple ointment at concentrations of 2% (w/w) and 4% (w/w) in the
excision, incision and burn wound models on Wistar albino rats. These
authors observed that compared to the standard drug (nitrofurazone),
the two formulations exhibited remarkable pro-healing activity by
affecting various stages of healing process, i.e. wound contracting abil­
ity, wound closure time, and tensile strength (Sangeetha et al., 2011). By
using three wound models, the formulation made with C. variegatum is
efficient which supported the use of C. variegatum roots for its wound
healing potential. As a matter of fact, antioxidant, antimicrobial and
anti-inflammatory agents found in plant extracts may interact syner­
gistically to exert their wound healing property via the enhancement of
re-epithelialization and collagen formation (Sivamani et al., 2012).
11
Journal of Ethnopharmacology 277 (2021) 114244
Tannins and flavonoids were the major phytochemicals in the meth­
anolic root extract used for wound healing activity (Sangeetha et al.,
2011). These phytochemicals have antiseptic and antibacterial activ­
ities, and they are easily absorbed on superficial layers of the skin
enabling them to enhance the rate of wound closure and recovery
(Ibrahim et al., 2018). Oppositely, some varieties of C. variegatum con­
tains toxic substances that induce side effects including irritation and
allergy, it is therefore recommended to consider these potential adverse
effects before applying this plant in wound healing process.
6.10. Other biological applications
Codiaeum variegatum may find use in environmental protection and
disease vector control which do not concern direct application in
humans. For instance, the biological properties against mosquitoes are
relevant in the prevention of several infectious diseases. Monzon et al.
(1994) evaluated the larvicidal activity of five Filipinos plants against
Aedes aegypti (Linnaeus) and Culex quinquefasciatus (Say) by exposing
3rd- 4th instar larvae, and they found that the aqueous fresh leaf extract
of C. variegatum exhibited time-dependent larvicidal activity with
highest activity against C. quinquefasciatus (LC50 = 9.42% and LC90 =
34.92%) after 48 h of exposure (Monzon et al., 1994). Moreover, it has
been reported that the ethanolic leaf extract of C. variegatum was more
toxic to A. aegypti eggs and larvae after 24 h exposure (Monzon et al.,
1994). A. aegypti is the mosquito spreading Zika, Chikungunya and
Dengue viruses, and thus this plant might be a powerful weapon in
fighting these life-threatening diseases. In addition, Awosolu and co­
workers demonstrated that the aqueous fresh leaf extract of
C. variegatum induced the highest mortality rate (100%) on 4th instar
Culex mosquito larvae at 6.25% (w/v) after 30 h of exposure with the
LC50 of 0.71% (0.15–1.27%) (Awosolu et al., 2018). The good larvicidal
property of the fresh leaf aqueous extract of C. variegatum suggested that
it may serve as an alternative bio-insecticide in the control of Culex
mosquito.
In an investigation carried out on 200 Puerto Rican plant species,
Medina and Woodbury (1978) found that the aqueous fresh leaf extract
of C. variegatum (at 1000 ppm) was active against snails such as Lymnaea
cubensis and L. columella (Medina and Woodbury, 1978). Moreover, it
was shown that the aqueous fresh leaf extract of C. variegatum collected
in the Philippines has molluscicidal property against Oncomelania
hypensis quadrasi, the snail host of Schistosoma japonicum (Garcia, 1990;
Monzon et al., 1994). In India, Yadav and Singh demonstrated that the
exposure of the snail L. acuminate to the latex of C. variegatum at
sub-lethal doses (0.15 DW, mg/L and 0.30 DW, mg/L for 24 h) and (0.06
DW, mg/L and 0.12 DW, mg/L for 96 h) caused significant reduction in
the activity of enzymes such as acetylcholinesterase or acid and alkaline
phosphatase in the nervous, hepatopancreas, and ovotestis tissues.
Within similar conditions of exposure, the non-target fish Channa
punctatus, which shares the habitat with L. acuminate, was also affected
with significant reduction in the activity of acetylcholinesterase, acid
and alkaline phosphatase in muscle, liver and gonadal tissues (Yadav
and Singh, 2003). Knowing that C. variegatum is non-sensitive to pests
and resistant to fungal infections (Naidu, 1988), it can therefore be
suggested that this plant is able to synthesize diverse metabolites for its
protection. Taraxerol (8) is a plant metabolite isolated from the petro­
leum stem bark of C. variegatum with potent molluscicidal activity
against the harmful disease-causing snails Indoplanorbis exustus and
L. acuminata (Chauhan and Singh, 2011, 2016). Taraxerol had negative
effect on fecundity, hatchability and survivability against the snail
I. exustus, but was safe for non-target organisms such as fishes which
supported its use in the control of schistosomiasis in domestic animals
(Chauhan and Singh, 2016).
Four varieties of C. variegatum (Lobatum cv. Disraeli; var. Pictum
‘Congo’; Taeniosum cv. ‘Gold Sun’ and ‘Dreadlocks’) were found to have
insecticidal activity against adult insects Sitophilus zeamais of both sexes
after 96 h of exposure, and the cultivars ‘Dreadlocks’ and Taeniosum cv.
E. Mfotie Njoya et al.
‘Gold Sun’ were the most toxic with LC50 values of 44.04 and 47.43 μg/
mL respectively (Lawal et al., 2018). The variation of the bioactivity
between these cultivars was attributed to the difference in their essential
oils composition which may be explained by the presence of a major
bioactive compound or a synergy between the major and minor con­
stituents to induce the observed activity. The use of plant crude extracts
or isolated ingredients and essential oils in vector control is an important
method of preventing vector-borne diseases, and the above reports
indicated the efficacy of some cultivars of C. variegatum against
mosquitoes therefore reducing the transmission of pathogens to humans
and animals.
6.11. Structure-activity relationships of compounds isolated from
C. variegatum
The mode of action of compounds is directly related to their chemical
structures as the pharmacological effect may result from a direct or in­
direct interaction with the cells or its molecular targets. It was observed
that some compounds isolated from C. variegatum were structurally
related, and they were either not active at the same doses or they
exhibited different biological activities. For example, the presence of
two hydroxyl groups in protocatechuic acid (10) may justify its
enhanced antioxidant properties compared to p-hydroxy benzoic (11)
and vanillic acids (12) which on the contrast had strong antimicrobial
activity (Liu et al., 2020; Min et al., 2010; Varì et al., 2011). In fact,
hydroxyl groups within compounds are involved in their antioxidant
effect via the free radical scavenging activity.
Furthermore, it was observed that flavonoids isolated from
C. variegatum were the most compounds involved in various biological
activities. Regardless to the experimental model used, all these flavo­
noids had anti-inflammatory activity, but the doses and routes of
administration differ. Flavonoids exert their anti-inflammatory activity
by inhibiting the production of a plethora of inflammatory molecules
such as NO, TNF-α, IL-6, IL-12, IL-1β, IL-33, IL-12, and PGE2, which are
secreted through the induction of protein expression or the activation of
NF-κB and MAPK signaling pathways (Hassan et al., 2018; Lv et al.,
2016; Márquez-Flores et al., 2016; Xiao et al., 2017). The
anti-inflammatory effect requires for the flavonoids to cross the plasma
membrane to induce its activity. Therefore, the O-glycosylation of fla­
vonoids increase their hydrophobicity resulting to a decrease membrane
permeability which influence the anti-inflammatory activity. In this
regard, apigenin (19) which is the only flavonoid without glycosidic
residue will be the most potential anti-inflammatory compound isolated
in C. variegatum. However, by comparing apigenin (19) versus glyco­
sylated flavonoids (rutin (17), orientin (20), vitexin (21), isovitexin (22)
and Vicenin-2 (23)), it is possible that the in vitro bioactivity of flavo­
noids may differ from their in vivo biological effect. This may be illus­
trated by the fact that rutin and apigenin were both used at 0.1% of diet
to induce similar anti-inflammatory effect (Kwon et al., 2005;
Márquez-Flores et al., 2016). On the other hand, glycosylation of fla­
vonoids is considered as an efficient approach to increase their solubility
in water, which increases their bioavailability and sometimes decreases
their toxicity or harmful effects (Plaza et al., 2014). This aspect may be
beneficial for the safety of C. variegatum-based products, but further
investigations are required to clarify the effect of glycosylation of all
these flavonoids on the ant-inflammatory activity by using same
experimental models.
The anticonvulsant activity was influenced by the O-glycosylation of
flavonoids. Rutin (17) with two glycosides was used via intra-
cerebroventricular route at low concentrations (25–150 nM) while
vitexin (21) with one glycoside was used at 100–200 μM via the same
route of administration to induce similar biological effect (Abbasi et al.,
2012; Nassiri-Asl et al., 2008). Most interesting, both compounds had
similar mode of action through positive allosteric modulation of the
GABAA receptor complex via interaction at the benzodiazepine site
which suggested that the bulkiness of an additional glycosidic residue on
12
Journal of Ethnopharmacology 277 (2021) 114244
rutin did not interfere with its binding to the active site. Table 3 sum­
marizes the chemical structures of compounds and their mode of action.
7. Toxic potential and safety analysis of Codiaeum variegatum
Some varieties of C. variegatum (Aureo-maculatum, Pictum, Puncta­
tum) were reported for their toxic potential (Finbarrs-Bello et al., 2016;
Hausen and Shulz, 1977; Olumuyiwa et al., 2010) while Mollucanum,
Spirale varieties were found to be safe (Mfotie Njoya et al, 2014a, 2018;
Mona et al., 2019) as summarized in Table 3. The toxic potential of
C. variegatum is related to the presence of toxic substances in the sap
which is released during mechanical injury of the aerial parts of the
plant. On the contrary, the safety of other varieties may be attributed
either to the less extraction of toxic substances by decoction which is the
common mode of preparation of medicinal recipes or to the phyto­
chemical variation between different cultivars. Therefore, it is important
to detect the presence of toxic substances before making decision on the
medicinal use of each cultivar of C. variegatum.
7.1. Safety evaluation of cultivars of Codiaeum variegatum
Till date, the safety profile of two cultivars was found to be exten­
sively studied therefore supporting either their promotion or prohibition
for medicinal use. Olumuyiwa and coworkers reported that feeding male
adult albino rats with feed supplemented with finely ground leaves of
C. variegatum (cv. Aureo-maculatum) at dose of 10 mg/kg for 12 weeks
induced toxic effects on animals characterized by a significant reduction
of weight gain, testicular and epididymal sperm reserves counts with an
increase of leukocyte and neutrophil counts. This study revealed that the
leaf powder of C. variegatum (cv. Aureo-maculatum) have immunosti­
mulant and spermatotoxic properties even when administered in small
quantities (2.5 mg/kg) over a long period of time (Olumuyiwa et al.,
2010). As these authors reported the Aureo-maculatum variety as being
used as ornamental plant, and regarding the potential presence of toxic
substances in some Euphorbiaceae plants, it is recommended that the
determination of the toxicity of cultivars of C. variegatum should be
mandatory for quality control and safety definition before their usage for
medicinal purposes.
On the other hand, the toxicological profile of C. variegatum (cv.
Mollucanum), the indigenous variety from which all varieties were
developed, was studied as recommended by institutional regulatory
organizations. As this plant is used for the treatment of intestinal
amoebiasis, the aqueous leaf extract of C. variegatum (AECV) was found
to be non-cytotoxic up to 500 μg/mL on intestinal Caco-2 cells and he­
patocellular HepG2 cells, while the EC50 of this extract against the
parasite Entamoeba histolytica was about 120 μg/mL (Mfotie Njoya et al.,
2014b). Additionally, the in vitro genotoxicity and mutagenicity of the
AECV and its enriched fraction (SF9B) were evaluated by quantifying
DNA damage and chromosomal aberrations through comet, micronu­
cleus and mouse lymphoma mutation assays, and results showed that
both tested samples (up to 1000 μg/mL for AECV and 500 μg/mL for
SF9B) were neither genotoxic on non-competent (L5178Y) and meta­
bolic competent (HepG2) cell lines nor mutagenic in mouse lymphoma
L5178Y cells after short and long term exposure (Mfotie Njoya et al.,
2014a). The median lethal dose (LD50) of the aqueous extract of
C. variegatum (cv. Mollucanum) was higher than 16 g/kg on male and
female Wistar albino mice, and its administration at 50–200 mg/kg on
Wistar albino rats of both sexes for 28 consecutive days caused neither
significant visible sign of toxicity nor mortality in treated animals
(Mfotie Njoya et al., 2018). Besides that, no significant changes were
observed concerning body weight, relative organ weight and biochem­
ical parameters of hepatic and renal toxicity (transaminases, total pro­
tein and creatinine) in treated groups compared to the control groups
(Mfotie Njoya et al., 2018). These reports demonstrated that the aqueous
extract of C. variegatum (cv. Mollucanum) is safe at therapeutic doses. It
is therefore expected that the leaves of this variety can be used according
E. Mfotie Njoya et al. Journal of Ethnopharmacology 277 (2021) 114244

Table 3
Compounds isolated from Codiaeum variegatum, their pharmacological activities and mode of action.
Compound/Chemical structure Family Part Method of isolation Testing models Biological activity Mode of action References
group of the (Active
plant concentrations)

Glaucine (1) Alkaloid Leaf - Extraction with 80% MCF-7, MDA-MB- Cytotoxic - Inhibited MMP-9 (Kang et al.,
Oxoglaucine (2) methanol, 231, (15–30 μM for (1) gene expression 2015; Liu et al.,
- Paper chromatography BEL-7404, and 20 μM for (2)) - Suppressed NF-κB 2014)
- Sephadex LH-20 column SGC7901, and activation
separation. A549 cell lines - Lanthanide
complexes of (2)
exhibited enhanced
cytotoxicity.

Hemiargyrine (3) Alkaloid Leaf - Extraction with 80% HepG2 cells Cytotoxic Not found. Hassan et al.
methanol, (growth (2013)
- Paper chromatography inhibition of
- Sephadex LH-20 column 90.9% at 100 μg/
separation. mL)

α-amyrin (4) Terpenoid Leaf - Extraction with 80% PTZ-induced Anticonvulsant - Binding to the Aragão et al.
methanol, seizures (5–25 mg/kg, p.o. GABA complex (2015)
- Paper chromatography and i.p.) - Inhibition of the
Sephadex LH-20 column signaling cascade of
separation. PKC.

β-sitosterol (5) Terpenoid/ Leaf - Extraction with 80% Human skin Wound healing - Enhanced wound Abbas et al.
phytosterol methanol, fibroblast cells (50–100 μM) closure (2019)
- Paper chromatography - Increased
Sephadex LH-20 column antioxidant defense
separation. mechanism
- Decreased IL-1β
production.

Ent-trachyloban-3-one (6) Terpenoid Leaf - Extraction with 80% HeLa, Cytotoxic (IC50 Not found. Block et al.
Ent-18-hydroxy-trachyloban- methanol, HL-60 cells = 9.6 and 12.2 (2004)
3-one (7) - Paper chromatography μg/mL)
Sephadex LH-20 column
separation.

Taraxerol (8) Terpenoid Stem - Soxhlet apparatus with Lymnaea acuminata Molluscicidal - Reduced the Chauhan and
bark petrol solvent snails (LC50 = 1.44 mg/ fecundity, Singh (2011)
Silica gel column L and LC90 = 3.59 hatchability and
chromatography. mg/L, 24 h) survivability of the
snail.

Chlorogenic acid (9) Phenolic Leaf - Extraction with 80% Influenza A virus Antiviral (EC50 - Down-regulation of Ding et al.
Caffeic acid (15) ethanol (H1N1/H3N2) = 44.87–62.33 nucleoprotein (2017)
- Paper chromatography. μM for (9)) expression
- Neuraminidase
blocker.
Pentylenetetrazole- Anticonvulsant - Inhibition of (Kim and Oh,
induced models in (10–20 mg/kg for reactive oxygen 2012; Nugroho
mice. (15)) species (ROS) et al., 2012)
production.
LPS-stimulated Anti- - Inhibition of NO, (Dos Santos
RAW 264.7 cells (in inflammatory TNF-α, IL-6 and IL- et al., 2006;
vitro). (2–20 μM and 1β Hwang et al.,
Carrageenan- 50–100 mg/kg for - Down-regulation of 2014)
induced paw edema (9)) iNOS, COX-2 and
(in vivo) NF-κB.
(continued on next page)

13
E. Mfotie Njoya et al. Journal of Ethnopharmacology 277 (2021) 114244

Table 3 (continued )
Compound/Chemical structure Family Part Method of isolation Testing models Biological activity Mode of action References
group of the (Active
plant concentrations)

S. aureus, Antimicrobial - Increase of the (Andrade et al.,

S. pneumoniae, (MIC = 20–80 μg/ permeability of the 2015; Lou et al.,
B. subtilis, mL for (15)) plasma membrane 2011)
E. coli - Intracellular
potassium leakage.
Scavenging Antioxidant Not found. Sato et al.
superoxide anion (IC50 = 41.0 μM (2011)
activity for (9) and 10.1
Total antioxidant μM for (15))
performance
Protocatechuic acid (10) p- Phenolic Leaf - Extraction with 80% E. coli, Antimicrobial Increase of the cell Liu et al. (2020)
hydroxy benzoic acid (11) ethanol S. epidermidis, (based on IC50 membrane
Vanillic acid (12) - Paper chromatography. S. aureus values, (11) > permeability and
(12) > (10)) synergistic effects
with antibiotics.
LPS-induced RAW Anti- - Suppression of TNF- Min et al. (2010)
264.7 cells (in vitro) inflammatory α, IL-1β, iNOS and
Carrageenan- (1–5 μM; 5 and 25 COX-2 expression
induced mg/kg for (10)) - Down-regulation of
inflammation in NF-kB and MAPKs.
mice (in vivo)
J774 A.1 Antioxidant (25 - Reduction of ROS Varì et al.
macrophages μM for (10)) production (2011)
- Inhibition of
superoxide and
H2O2 production
- Restoration of
glutathione related
enzymes
- Activation of Nrf2.
p-coumaric acid (13) Phenolic Leaf - Extraction with 80% H2O2 scavenging Antioxidant (1 Not found. Liu et al. (2020)
Ferulic acid (14) ethanol activity mg/mL)
Paper chromatography.

(− )-epicatechin (16) Flavonoid Leaf - Extraction with ethanol LPS-induced RAW Anti- - Inhibition of NO, Wang and Cao
- HPLC-DAD. 264.7 cells inflammatory TNF-α, IL-6, and (2014)
(5–25 μM) PGE2.
Entamoeba Antiamoebic - Down-regulation of (Bolaños et al.,
histolytica (IC50 = 1.9 μg/ cytoskeleton 2014; Calzada
mL) proteins (α-actinin, et al., 2003;
myosin II heavy Soto et al.,
chain and actin). 2010)
- Induction of nuclear
and cytoplasmic
changes
Ellagic acid (18) Flavonoid Leaf - Extraction with ethanol Entamoeba Antiamoebic Not found. Alanis et al.
- HPLC-DAD. histolytica (IC50 = 56.5 μg/ (2003)
mL)
DSS-induced acute Anti- - Down-regulation of Marín et al.
and chronic mice inflammatory iNOS, COX-2, p38 (2013)
colitis (25 mg of (18) MAPK, NF-κB,
daily per mouse) STAT3 gene
expression.

Codiacyanoglucoside (24) Glucoside Fresh - Extraction with Influenza A virus Antiviral (IC50 = - No impairment of Forero et al.
latex hexane–CH2Cl2–MeOH (A/PR/8/34.H1N1) 17 μg/mL, SI > the influenza (2008)
(2:1:1, v/v) 14.9) haemagglutination
- Sephadex LH-20 column activity.
chromatography

Rutin (17) Flavonoid Leaf - Extraction with ethanol PTZ-induced Anticonvulsant - Binding to GABAA- (Abbasi et al.,
Apigenin (19) and HPLC-DAD for (17) seizures (100–200 μM, i.c. benzodiazepine 2012; Avallone
Orientin (20) - Extraction with 80% v. or (1.25–5 mg/ receptor complex. et al., 2000; de
Vitexin (21) methanol, paper kg; i.p. for (21)); Oliveira et al.,
Isovitexin (22) chromatography and (50 and 100 mg/ 2020;
Vicenin-2 (23) Sephadex LH-20 column kg, i.p. or 25–150 Nassiri-Asl et al.,
chromatography for nM, i.c.v. for (17)) 2008)
(19–23) DSS-induced colitis Anti- - Inhibition of NLRP3 (Hassan et al.,
(in vivo). inflammatory inflammasome 2018; Lv et al.,
(continued on next page)

14
E. Mfotie Njoya et al. Journal of Ethnopharmacology 277 (2021) 114244

Table 3 (continued )
Compound/Chemical structure Family Part Method of isolation Testing models Biological activity Mode of action References
group of the (Active
plant concentrations)

LPS-induced RAW ((17) at 0.1% of - Inhibition of NO, 2016;

264.7, THP-1 cells diet); ((19) at TNF-α, IL-6, IL-12, Márquez-Flores
(in vitro) 0.1% of diet); IL-1β, IL-33, IL-12, et al., 2016;
(25–100 μg/mL in and PGE2 Xiao et al.,
vitro and 10 mg/ - Down-regulation of 2017)
kg i.p. for (20)); iNOS, COX-2, p38
(10–40 μg/mL in MAPK, NF-κB,
vitro and 5–30 STAT3.
mg/kg i.p. for
(21)); (50–100
mg/kg i.p for
(22)); (1.6–160
nM for (23)).
Entamoeba Antiamoebic Not found Cimanga et al.
histolytica (IC50 = 12.7 μg/ (2006)
mL for (19))
Castor oil-induced Antidiarrhoeal - Reduction of Sadraei et al.
diarrhoea (2–10 mg/kg p.o. number of wet (2016)
for (19)). defecations.

LPS: lipopolysaccharide.
DSS: dextran sulfate sodium, LPS: lipopolysaccharide.
PTZ: pentylenetetrazole, DSS: dextran sulfate sodium, LPS: lipopolysaccharide.

to traditional advice to formulate a medicine against intestinal amoe­ Tanzania (Ito, 1986; Mizuno et al., 1986). Ohigashi et al. (1985)
biasis which will be tested in a clinical setting for its valorization in the demonstrated the Epstein-Barr virus (EBV)-activating potency of meth­
traditional health-care system. anolic extracts of 11 out of 12 Cameroonian plants of the Euphorbiaceae
family including C. variegatum (Ohigashi et al., 1985). This study sug­
gested the possibility that Burkitt lymphoma (BL) incidence reported in
7.2. The effect of solvent extraction on toxic substances
Cameroon may be caused either by the contact to these plants or the
unconscious inhalation of EBV-activating principles such as 5-deoxyin­
Decoction or extraction with a mixture of water/ethanol is often
genol (25) or phorbol esters. Moreover, during an in vitro screening of
recommended for the preparation of medicinal recipes in folk medicine.
48 Malaysian plants of the Euphorbiaceae family using a human lym­
The decoction extracted mainly polar components, but some less polar
phoblastoid cell line harbouring the EBV genome, 13 ether extracts,
components may also be extracted. Mfotie Njoya and coworkers re­
including C. variegatum, exhibited EBV-inducing activity at lower con­
ported that the aqueous leaf extract of C. variegatum (cv. Mollucanum)
centrations of 1.2–40 μg/mL, suggesting that caution is needed with
was non-toxic in both in vitro and in vivo studies (Mfotie Njoya et al,
regular use of this plant because of its tumor-promoting activity
2014a, 2018). On the contrary, a daily application of a methanolic leaf
(Norhanom and Yadav, 1995).
extract of C. variegatum (L.) A. Juss (cv. Pictum) on shaved skin of five
In contrast, tumor-promoting activity of some varieties of
guinea pigs for 3 weeks induced a slight erythema on the fourth day.
C. variegatum is attributed to phorbol esters which also possess some
Similar sensitization of animals was observed after 24 and 48 h with the
beneficial effects such as anticancer activity and inhibition of human
milky sap exuding from a fresh cut leaf (Hausen and Shulz, 1977). In
immunodeficiency virus (HIV) replication (Bond et al., 2007; Chen et al.,
addition, these authors reported skin eruption on the hands of a nursery
2007; El-mekkawy et al., 2000; Falodun et al., 2012; Handa et al., 1983).
gardener 6 months after being in contact with C. variegatum hybrids.
Vogg et al. (1999) examined 22 commercial cultivars of Euphorbiaceae
Most importantly, this condition was cleared after changing his job. It
indoor plants for tumor-promoting diterpenoids by high-performance
was then concluded that the sap of C. variegatum produces no primary
liquid chromatography (HPLC), and they found that the sap and meth­
irritant reaction, but induces contact allergy after long term exposure
anolic leaf extracts of C. variegatum (cv. Batic Red, Batic Green, Iceton,
(Hausen and Shulz, 1977). The compounds responsible for this irritation
Mara, Pinocchio, Scarletta, Tamara, Yellow Tip) were deficient in three
were identified as di- and triesters of phorbol (26) isolated from the sap
toxic diterpenes (ingenol, phorbol and 12-deoxyphorbol). In addition,
of various Euphorbiaceae species (Fig. 4) (Hergenhahn et al., 1974).
these cultivars were devoid of EBV-inducing activity, and thus without
Phorbol esters are lipophilic compounds which are mostly extracted in
tumor promoting potential (Vogg et al., 1999). Table 4 summarizes the
organic solvents and poorly soluble in aqueous solutions (Goel et al.,
toxicity profile of some cultivars of C. variegatum.
2007; Wang et al., 2000). Therefore, these toxic substances can only be
found in organic solvent extracts which are not commonly used as me­
dicinal recipes in folk medicine. It may then justify the fact that me­
dicinal preparations with water are deficient of these toxic substances
and are safe to be used without significant adverse effects.

7.3. Tumor-promoting activity versus beneficial effects of phorbol esters

The diversity of cultivars of C. variegatum and their inappropriate

identification have been the main reasons for the warning or prohibition
of their medicinal uses in some countries. The fact is that an incidence
between the occurrence of some malignant diseases and the distribution
of Euphorbiaceae has been reported in different countries around the Fig. 4. Toxic 5-deoxyingenol (25) and phorbol (26) found in latex/sap of
world including Southern China, Cameroon, Kenya, Uganda and Codiaeum variegatum.

15
E. Mfotie Njoya et al. Journal of Ethnopharmacology 277 (2021) 114244

The controversy about the variability in the tumor promoting ac­
tivity of C. variegatum is mainly due to the diversity observed within the
varieties of this plant, and it clearly emphasizes the need for the selec­
tion of less toxic cultivars for their medicinal use. The development of
new cultivars from the native plant implies the change in the phyto­
chemical composition which may explain the presence of toxic sub­
stances in newly developed cultivars mostly used as ornamental plants.
In fact, throughout our search in different databases, the ethnomedicinal
use of C. variegatum was mainly recorded in countries where it is native
while toxic effects were mostly reported on new cultivars developed for
ornamental use. It can therefore be suggested that the parent variety
(Mollucanum) may be safely used for medicinal purposes, and the
detection of toxic substances in newly developed varieties should be
required before any use.
CYP2D6 and CYP3A4 (Larson et al., 2014). This inhibitory effect may be
attributed to caffeic acid (15), a phenolic acid found in C. variegatum
which is known as a potent inhibitor of CYP2D6 and a weak inhibitor of
CYP3A4 (Rastogi and Jana, 2014). Nevertheless, caffeic acid (15) pre­
sent in plants, is most often esterified with quinic acid yielding chloro­
genic acid (9) which has very little or no inhibitory effect on CYP2D6,
CYP1A2 and CYP3A4 (Fliszar-Nyúl et al., 2020; Obach, 2000; Pang
et al., 2015). Based on these observations, and knowing that CYPs are
very essential for the metabolism of many medications, it is advised to
avoid co-administration of pharmaceutical drugs with
C. variegatum-based products as it might result in potential herb-drug
interactions.
8. Future perspectives

7.4. Herb-drug interactions
Documented clinical trials with C. variegatum-based products are not
reported so far. However, C. variegatum is regularly used by populations
either as tea in Philippines (Gertrudes, 2006), or as vegetables and
ingredient of curry in northern Thailand (Suphiratwanich et al., 2021).
In Papua New Guinea, potential herb-drug interaction was suggested
between antiretroviral therapy and some commonly-used medicinal
plants via the modulation of cytochrome P450s (CYPs) enzymatic ac­
tivity in Human hepatoma cells and liver microsomes. Among the
investigated plants, the methanolic leaf extract of C. variegatum was
found to induce CYP1A2 enzymatic activity, but was inhibitory towards
Less or no toxic effects were reported for the cultivars of
C. variegatum used in folk medicine because traditional healers are
usually aware of potential toxicity of some plants. In this regard, it was
found in a report that the sap of C. variegatum can only be used in small
quantities when applied on external infections in order to reduce the
adverse effects (Saffoon et al., 2014). Moreover, the mode of preparation
of traditional medicines is mostly aqueous extraction or decoction which
may explain why no relevant toxic effects have been observed in the
populations using C. variegatum as medicine – the lipophilic toxins such
as phorbol esters are present in these aqueous extracts in very low
amounts. In addition, leaves, which contain fewer toxic substances than
the sap, are the parts of C. variegatum mostly used in traditional

Table 4
Toxicity profile of varieties of Codiaeum variegatum.
Variety (plant Type of extract Dosage/Route of Experimental models Compounds Results References
part) administration

Mollucanum Aqueous extract - ≤ 500 μg/mL (in - Cytotoxicity Not identified - No cytotoxic, genotoxic and (Mfotie Njoya et al,
(leaf) vitro) - Genotoxicity mutagenic effect. 2014a, 2018,
- ≤ 16 g/kg - Mutagenicity - LD50 > 16 g/kg 2014a)
(orally, single - Acute toxicity (male and - No mortality in mice and rats
dose in one day) female mice) - No significant adverse effects
- 50–200 mg/kg - Subchronic toxicity (male
(orally, and female rats)
repetitive dose,
28 days)
Aureo- Animal feed 2.5–10 mg/kg Long-term toxicity (male Not identified Spermatotoxic and Olumuyiwa et al.
maculatum supplemented (orally, repetitive rats) immunostimulant effects on male (2010)
(leaf) with leaf powder dose, 12 weeks) rats
Pictum (leaf, Methanolic - 10% solution - Dermal application on di- and triesters of - Skin erythrema and irritation Hausen and Shulz
milky sap, extract (daily, 3 weeks) guinea pigs phorbol - Allergy (1977)
whole plant) - Contact with a - Occupational exposure
nursery gardener
(daily, 6 months)
Non-identified Ether and 0.2–40 μg/mL Epstein-Barr virus (EBV)- 5-deoxyingenol EBV-induced activity observed at (Norhanom and
Malaysian methanolic induced activity in Raji cells 1.2–40 μg/mL. Yadav, 1995;
variety (leaf) extracts Ohigashi et al.,
1985)
Punctatum Ethanolic extract 200–600 mg/kg Histological analysis of saponins, phenols, The extract at all doses induced an Finbarrs-Bello
(leaf) (orally, 2 weeks) cerebrum (male and female flavonoids, tannins, adverse effect on the cerebrum et al. (2016)
rats) and glycosides (inflammation, sparse cellular
population, hypertrophy, and
liquefactive neurosis)
Spirale (leaf) 80% methanolic 1–500 mg/kg - Cytotoxicity caffeic and Phenolic compounds prevented Mona et al. (2019)
extract (orally, single - Anti-genotoxic assay on ρ-coumaric acids, the cytotoxic and genotoxic
dose, 24 h) mitomycin C (MMC)- apigenin, orientin, effects that were induced by the
induced chromosome vitexin, isovitexin mutagenic agent MMC in mice
aberrations (male mice) and vicenin-2 bone-marrow cells.
- Batic Red, Methanol/water 1–20 μL of extract - (EBV)-induced activity in Ingenol, phorbol and - Sap and leaf extract failed to Vogg et al. (1999)
- Batic Green, (17:3, v/v) extract (added to cells for Raji cells 12-deoxyphorbol activate the EBV promoter.
- Iceton, 2 days) - High- performance liquid - Absence of the three toxic
- Mara, chromatography (HPLC). diterpenes in sap and leaf
- Pinocchio, extracts
- Scarletta,
- Tamara,
- Yellow Tip
(leaf, sap)

16
E. Mfotie Njoya et al.
medicine, and this may also support the observation of little or no
adverse effect recorded during their usage. Mostly in vitro models were
used for the evaluation of the bioactivity; however, in vivo models are
much more meaningful for the bioactivity determination, as it takes into
account the metabolism of the animals. Another aspect that needs
further investigation is the fact that many reports only described the
ethnomedicinal use of the variety of C. variegatum used in a particular
region of the world, without any further studies regarding the scientific
evidence of the claimed medicinal property. It is therefore mandatory to
carry out experimental work to confirm such claims.
The genetic variation between cultivars of C. variegatum explains the
high variability of their phytochemical composition, which may also
justify the medicinal use of some cultivars and not others. For example, a
specific cultivar (Mollucanum) out of several cultivars of C. variegatum
found in Cameroon, is used as a decoction by the Bamun population for
the treatment of intestinal amoebiasis. This may result from the fact that
active metabolites found in the Mollucanum variety are absent in others
cultivars. So, further work is needed to understand the interest of the
local population in using this specific cultivar instead of others. To
promote the rational and safe use of this variety for the management of
diseases, the identification and comparison of active substances from
several cultivars of C. variegatum is necessary for quality control pur­
poses. In addition, more attention should be given to the toxicological
analysis of each cultivar in order to enable local communities to make
the best use of traditional knowledge and promote its inclusion into the
local health-care system.
Overall, the aqueous extract from the wild variety of C. variegatum
(cv. Mollucanum) used by the Bamun people in the West region of
Cameroon was pharmacologically active against the intestinal parasite
E. histolytica, and no adverse effect was observed even at high dosage.
The mode of action of an extract fraction on E. histolytica was deter­
mined, and signaling pathways such as cell division, virulence, energy
production, stress and oxydoreduction were down-regulated by active
substances of the most active fraction (Mfotie Njoya et al., 2014b). Some
major groups of compounds such as alkaloids, terpenoids and phenolics
have been characterized in C. variegatum, but less is known about sa­
ponins, tannins, coumarins, anthraquinones, and cardenolides.
Recently, new antiviral compounds such as daphnane-type diterpenoid
orthoesters (codiapeltines A and B), actephilols B and C, and four known
1,4-dioxane-fused phenanthrene dimers (actephilol A, epi-actephilol A,
fimbricalyx C and D) were isolated from Codiaeum peltatum, a species
endemic from New Caledonia (Olivon et al., 2019). Based on the fact
that plants of the same genus would tend to produce similar metabolites
and regarding the low availability of data on the chemical composition
of C. variegatum, it can be expected that either novel compounds might
be discovered in this plant species or other bioactive factors such as
endophytes might synthesize active secondary metabolites that
contribute to the efficacy of this plant species against amoebiasis. To
date, (− )-epicatechin (16) and apigenin (19) found in C. variegatum
were the most active compounds against Entamoeba histolytica. These
compounds also had antidiarrhoeal and anti-inflammatory properties
which are relevant for the management of symptoms associated to
amoebiasis. It is therefore possible to use these two compounds for the
development of antiamoebic drugs.
9. Conclusions
In this review, it was found that most often leaf decoction and
aqueous extracts of C. variegatum are used in folk medicine for the
treatment of amoebiasis, and the absence of adverse effects is explained
by the lipophilicity of Codiaeum toxic substances which cannot be
extracted by water. As a matter of fact, traditional methods of medicinal
preparations should be encouraged as it may selectively extract the
bioactive compounds while excluding the toxic substances. Addition­
ally, the quality control can be established based on the analysis of the
identified toxic substances (5-deoxyingenol and phorbol esters) in
17
Journal of Ethnopharmacology 277 (2021) 114244
cultivars of C. variegatum used in traditional medicine. Moreover,
different medicinal uses of C. variegatum was dependent to the presence
of groups of phytochemicals which vary with the cultivar, the
geographical origin and the part of the plant used. The results collected
so far have proven the presence of alkaloids, terpenoids and phenolic
compounds in some cultivars of C. variegatum supporting their phar­
macological activities. Structure-activity relationship of some of these
compounds indicated that O-glycosylation and/or hydroxylation may
either modulate the biological efficacy of compounds or lead to a
different bioactivity. Most interestingly, based on the reports available
to date, the structural modifications of all these compounds did not
turned into toxic effects which suggested that the potential adverse ef­
fects of C. variegatum can only result from the presence of phorbol esters
which cannot be extracted in aqueous extracts used in the preparation of
traditional medicines. Furthermore, a few studies did not use updated
methods for the bioactivity determination and in vivo experiments were
rarely used. In addition, the plant varieties were not specified in many
reports which makes it difficult to follow-up other studies carried out on
them. Therefore, it is recommended in future scientific studies to
properly identify the variety of the plant used and determine its toxicity
and phytochemical profiles. Actually, sufficient evidences discussed in
this review are supporting the efficacy and the safety of C. variegatum
(cv. Mollucanum) against amoebiasis, and compounds such as (− )-epi­
catechin (16) and apigenin (19) can serve as active ingredients for the
development of plant-based products from this variety.
Author contribution
EMN conceptualized the idea and conducted the literature survey,
wrote and submitted the manuscript. PFM and THJN provided input
during preparation and edited the manuscript.
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgement
EMN wishes to acknowledge the Alexander von Humboldt Founda­
tion for awarding a Georg-Forster postdoctoral fellowship (CMR-
1204519-GF-P).
References
Abbas, M.M., Al-rawi, N., Abbas, M.A., Al-khateeb, I., 2019. Naringenin potentiated β
-sitosterol healing effect on the scratch wound assay. Res. Pharm. Sci. 14, 566–573.
https://doi.org/10.4103/1735-5362.272565.
Abbasi, E., Nassiri-Asl, M., Shafeei, M., Sheikhi, M., 2012. Neuroprotective effects of
vitexin, a flavonoid, on pentylenetetrazole-induced seizure in rats. Chem. Biol. Drug
Des. 80, 274–278. https://doi.org/10.1111/j.1747-0285.2012.01400.x.
Aguoru, C.U., Ujor, C.J., Olasan, J.O., 2016. Gross macro and micro-morphologic studies
on four species of Codiaeum in North Central Nigeria. J. Glob. Biosci. 5, 4258–4266.
Ahmad, F.B., Holdsworth, D.K., 2003. Medicinal plants of Sabah, East Malaysia - Part I.
Pharm. Biol. 41, 340–346. https://doi.org/10.1076/phbi.41.5.340.15940.
Ahmad, F.B., Ismail, G., 2003. Medicinal plants used by Kadazandusun. ASEAN Rev.
Biodivers. Environ. Convers. 1–10.
Alanis, A.D., Calzada, F., Cedillo-Rivera, R., Meckes, M., 2003. Antiprotozoal activity of
the constituents of Rubus coriifolius. Phyther. Res. 17, 681–682. https://doi.org/
10.1002/ptr.1150.
Ali, A.M., Mackeen, M.M., Ei-sharkawy, S.H., Nor, H.I., Ahmad, F.B.H., Lajisi, N.H.,
1996. Antiviral and cytotoxic activities of some plants used in Malaysian indigenous
medicine. Pertanika J. Trop. Agric. Sci. 19, 129–136.
Andrade, M., Benfeito, S., Soares, P., Magalhães e Silva, D., Loureiro, J., Borges, A.,
Borges, F., Simões, M., 2015. Fine-tuning of the hydrophobicity of caffeic acid:
studies on the antimicrobial activity against Staphylococcus aureus and Escherichia
coli. RSC Adv. 5, 53915–53925. https://doi.org/10.1039/c5ra05840f.
Anim, M.T., Larbie, C., Appiah-Opong, R., Tuffour, I., Owusu, K.B.A., Aning, A., 2016.
Extracts of codiaeum variegatum (L.) A. Juss is cytotoxic on human leukemic, breast
and prostate cancer cell lines. J. Appl. Pharmaceut. Sci. 6 https://doi.org/10.7324/
JAPS.2016.601114, 087–093.
Anyasor, G.N., Esiaba, I.O., Ogunwenmo, K.O., Esan, E.B., Olajuyigbe, O.O., Ikpeoha, N.
S., Onyishi, C.C., Bright, O.C., 2010. Biochemical and antimicrobial effects of
E. Mfotie Njoya et al.
aqueous and alcoholic extracts of codiaeum variegatum (Euphorbiaceae). In: 3rd
International E-Conference Agricultural Biosciences. Lagos, Nigeria, pp. 35–36.
Aragão, G.F., Maria, L., Carneiro, V., Paulino, A., Bandeira, P.N., Leda, T., Lemos, G. De,
Frota-junior, P., Bandeira, P.N., 2015. Alterations in brain amino acid metabolism
and inhibitory effects on PKC are possibly correlated with anticonvulsant effects of
the isomeric mixture of α - and β -amyrin from Protium heptaphyllum Alterations in
brain amino acid metabolism and inhibitory e. Pharm. Biol. 53, 407–413. https://
doi.org/10.3109/13880209.2014.923001.
Asniawati, M.D., Purwantoro, A., 2019. Genetic diversity of Croton (codiaeum
variegatum (L .) rumph . ex A . Juss) and its offspring based on RAPD markers. Ilmu
Pertan. (Agric. Sci.) 4, 52–58. https://doi.org/10.22146/ipas.40899.
Avallone, R., Zanoli, P., Puia, G., Kleinschnitz, M., Schreier, P., Baraldi, M., 2000.
Pharmacological profile of apigenin, a flavonoid isolated from Matricaria
chamomilla. Biochem. Pharmacol. 59, 1387–1394. https://doi.org/10.1016/S0006-
2952(00)00264-1.
Awosolu, O., Adesina, F., Iweagu, M., 2018. Larvicidal effects of croton (Codiaeum
variegatum) and Neem (Azadirachta indica) aqueous extract against Culex mosquito.
Int. J. Mosq. Res. 5, 15–18.
Babatunde, E.E., Banji, A.F., Foluke, O., Ayandiran, A.D., Fatima, K., 2017. Comparative
study of leaf morphology, phytochemical, mineral and proximate analysis of
Codiaeum variegatum (L.) A. Juss. (Malpighiales: Euphorbiaceae) and its stable
mutant. Braz. J. Biol. Sci. 4, 25–34. https://doi.org/10.21472/bjbs.040704.
Bhot, M., Saha, M., Phatak, A., Chandra, N., 2010. Antimicrobial activity of leaf extracts
of Codiaeum variegatum (l.) Blume. Int. J. Pharm. Biol. Sci. 4, 17–24.
Bijekar, S., Gayatri, M.C., Rajanna, L., 2015. Evaluation of antiinflammatory activity of
flavonoid fractions from Euphorbiaceae members on RAW 264.7 cell lines. J. Cytol.
Genet. 16, 39–46.
Bijekar, S.R., Gayatri, M.C., 2015. Phytochemical profile of Codiaeum variegatum (L.) Bl.
Int. J. Pharm. Pharmaceut. Sci. 2, 22–31.
Block, S., Baccelli, C., Tinant, B., Meervelt, L. Van, Rozenberg, R., Jiwan, J.H., Llabre, G.,
Pauw-gillet, M. De, Quetin-leclercq, J., 2004. Diterpenes from the leaves of Croton
zambesicus. Phytochemistry 65, 1165–1171. https://doi.org/10.1016/j.
phytochem.2004.02.023.
Bolaños, V., Díaz-martínez, A., Soto, J., Rodríguez, M.A., López-camarillo, C., Marchat, L.
A., Ramírez-moreno, E., 2014. The flavonoid (− )-epicatechin affects cytoskeleton
proteins and functions in Entamoeba histolytica. J. Proteomics 111, 74–85. https://
doi.org/10.1016/j.jprot.2014.05.017.
Bond, J.A., Gescher, A.J., Verschoyle, R.D., Lemoine, N.R., Errington, R., Wiltshire, M.,
Smith, P.J., Wynford-thomas, D., 2007. Cytotoxic action of phorbol esters on human
pancreatic cancer cells. Int. J. Canc. 121, 1445–1454. https://doi.org/10.1002/
ijc.22869.
Borges, A., Ferreira, C., Saavedra, M.J., Simoes, M., 2013. Antibacterial activity and
mode of action of ferulic and gallic acids against pathogenic bacteria. Microb. Drug
Resist. 19 (6), 256–265. https://doi.org/10.1089/mdr.2012.0244.
Borghi, S.M., Carvalho, T.T., Staurengo-ferrari, L., Hohmann, M.S.N., Pinge-filho, P.,
Casagrande, R., Verri, W.A., 2013. Vitexin inhibits inflammatory pain in mice by
targeting TRPV1, oxidative stress, and cytokines. J. Nat. Prod. 76, 1141–1149.
https://doi.org/10.1021/np400222v.
Bourdy, G., Walter, A., 1992. Maternity and medicinal plants in Vanuatu I. The cycle of
reproduction. J. Ethnopharmacol. 37, 179–196. https://doi.org/10.1016/0378-8741
(92)90033-n.
Brown, B.F., 1995. A Codiaeum Encyclopedia: Crotons of the World. Valkaria Trop. Gard.
Valkaria, FL.
Calzada, F., Velázquez, C., Cedillo-Rivera, R., Esquivel, B., 2003. Antiprotozoal activity
of the constituents of Teloxys graveolens. Phyther. Res. 17, 731–732. https://doi.
org/10.1002/ptr.1192.
Cambie, R., Brewis, A., 1997. Anti-fertility Plants of the Pacific. National Library of
Australia. CSIRO Publishing. https://doi.org/10.1071/9780643100626.
Cambie, R.C., Ash, J., 1994. Fijian Medicinal Plants. CSIRO Publishing, Australia.
Campos, F.M., Couto, J.A., Figueiredo, A.R., Tóth, I.V., Rangel, A.O.S.S., Hogg, T.A.,
2008. Cell membrane damage induced by phenolic acids on wine lactic acid bacteria.
Int. J. Food Microbiol. 135, 144–151. https://doi.org/10.1016/j.
ijfoodmicro.2009.07.031.
Case, R.J., Franzblau, S.G., Wang, Y., Cho, S.H., Soejarto, D.D., Pauli, G.F., 2006.
Ethnopharmacological evaluation of the informant consensus model on anti-
tuberculosis claims among the Manus. J. Ethnopharmacol. 106, 82–89. https://doi.
org/10.1016/j.jep.2005.12.005.
Chand, R.R., Devi, S.S., Kumari, S.S., Kumar, S.S., Goundar, N., Naranyan, N.,
Chandra, P., 2018. Traditional use of medicinal plants among selected villages in Fiji
Islands: a review perspective. Pac. Med. Student J. 3–13.
Chauhan, S., Singh, A., 2016. Toxicological investigation and anti-reproductive effect of
phyto-molluscicide against harmful aquatic snail. Eur. J. Biol. Res. 6, 260–266.
https://doi.org/10.5281/zenodo.163655.
Chauhan, S., Singh, A., 2011. Impact of Taraxerol in combination with extract of
Euphorbia tirucalli plant on biological parameters of Lymnaea acuminata. Rev. Inst.
Med. Trop. Sao Paulo 53, 265–270. https://doi.org/10.1590/S0036-
46652011000500005.
Chen, H., Zhang, R., Luo, R.H., Yang, L.M., Wang, R.R., Hao, X.J., Zheng, Y.T., 2007.
Anti-HIV activities and mechanism of 12- O -Tricosanoylphorbol-20-acetate, a novel
phorbol ester from Ostodes katharinae. Molecules 22. https://doi.org/10.3390/
molecules22091498.
Chen, J., Stamps, R.H., 2006. Cutting propagation of foliage plants. In: Dole, J.M.,
Gibson, J.L. (Eds.), Cutting Propagation: A Guide to Propagating and Producing
Floriculture Crops. Ball Publishing, Batavia, IL., pp. 203–228
Chennaveeraiah, M.S., Wagley, S.K., 1985. Chromosome mosaicism in cultivars of
garden crotons (Codiaeum variegatum). Nucleus 28, 8–13.
18
Journal of Ethnopharmacology 277 (2021) 114244
Chiang, L.C., Chiang, W., Chang, M.Y., Ng, L.T., Lin, C.C., 2002. Antiviral activity of
Plantago major extracts and related compounds in vitro. Antivir. Res. 55, 53–62.
Cimanga, R.K., Kambu, K., Tona, L., Hermans, N., Apers, S., Totté, J., Pieters, L.,
Vlietinck, A.J., 2006. Cytotoxicity and in vitro susceptibility of Entamoeba
histolytica to Morinda morindoides leaf extracts and its isolated constituents.
J. Ethnopharmacol. 107, 83–90. https://doi.org/10.1016/j.jep.2006.02.010.
Cragg, G.M., Newman, D.J., 2013. Natural products: a continuing source of novel drug
leads. Biochim. Biophys. Acta Gen. Subj. 1830 (6), 3670–3695. https://doi.org/
10.1016/j.bbagen.2013.02.008.
Cragg, G.M., Newman, D.J., 2005. Plants as a source of anti-cancer agents.
J. Ethnopharmacol. 100, 72–79. https://doi.org/10.1016/j.jep.2005.05.011.
Cueva, C., Moreno-Arribas, M.V., Martın-Alvarez, P.J., Bills, G., Vicente, M.F., Basilio, A.,
Lopez Rivas, C., Requena, T., Rodriguez, J.M., Bartolome, B., 2010. Antimicrobial
activity of phenolic acids against commensal , probiotic and pathogenic bacteria.
Res. Microbiol. 161, 372–382. https://doi.org/10.1016/j.resmic.2010.04.006.
de Oliveira, D.D., da Silva, C.P., Iglesias, B.B., Beleboni, R.O., 2020. Vitexin possesses
anticonvulsant and anxiolytic-like effects in murine animal models. Front.
Pharmacol. 11, 1–9. https://doi.org/10.3389/fphar.2020.01181.
Deng, M., Chen, J., Henny, R.J., Li, Q., 2010a. Genetic relationships of Codiaeum
variegatum cultivars analyzed by amplified fragment length polymorphism markers.
Hortscience 45, 868–874. https://doi.org/10.21273/hortsci.45.6.868.
Deng, M., Chen, J., Henny, R.J., Li, Q., 2010b. Chromosome number and karyotype
variation in codiaeum variegatum cultivars. Hortscience 45, 538–540. https://doi.
org/10.21273/hortsci.45.4.538.
Ding, Y., Cao, Z., Cao, L., Ding, G., Wang, Z., Xiao, W., 2017. Antiviral activity of
chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of
neuraminidase. Sci. Rep. 7, 1–11. https://doi.org/10.1038/srep45723.
Dos Santos, M.D., Almeida, M.C., Lopes, N.P., De Souza, G.E.P., 2006. Evaluation of the
anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol
chlorogenic acid. Biol. Pharm. Bull. 29, 2236–2240. https://doi.org/10.1248/
bpb.29.2236.
Dos Santos Sales, Í.M., Do Nascimento, K.G., Feitosa, C.M., Saldanha, G.B., Feng, D., De
Freitas, R.M., 2011. Caffeic acid effects on oxidative stress in rat hippocampus after
pilocarpine-induced seizures. Neurol. Sci. 32, 375–380. https://doi.org/10.1007/
s10072-010-0420-4.
Eghbaliferiz, S., Iranshahi, M., 2016. Prooxidant activity of polyphenols , flavonoids ,
anthocyanins and Carotenoids : updated review of mechanisms and catalyzing
metals. Phyther. Res. 30, 1379–1391. https://doi.org/10.1002/ptr.5643.
El-mekkawy, S., Meselhy, M.R., Nakamura, N., Hattori, M., Kawahata, T., Otake, T.,
2000. Anti-HIV-1 phorbol esters from the seeds of Croton tiglium. Phytochemistry
53, 457–464. https://doi.org/10.1016/S0031-9422(99)00556-7.
Falodun, A., Kragl, U., Touem, S.M., Villinger, A., Fahrenwaldt, T., Langer, P., 2012.
A novel anticancer diterpenoid from Jatropha gossypifolia. Nat. Prod. Commun. 7,
151–152. https://doi.org/10.1177/1934578X1200700204.
Finbarrs-Bello, E., Egwu, O., Atuadu, V., Egwu, E., 2016. Histological effects of ethanolic
leaf extract of Codiaeum variegatum on the cerebrum of adult Wistar rats. J. Exp.
Clin. Anat. 15, 1. https://doi.org/10.4103/1596-2393.190823.
Fliszar-Nyúl, E., Mohos, V., Csepregi, R., Mladenka, P., Poor, M., 2020. Inhibitory effects
of polyphenols and their colonic metabolites on CYP2D6 enzyme using two different
substrates. Biomed. Pharmacother. 131 https://doi.org/10.1016/j.
biopha.2020.110732.
FOC, 2015. Codiaeum variegatum (linnaeus) Rumphius ex A. Jussieu. In: Flora of China.
Guangzhou, Guangdong Province, China, p. 268.
Forero, J.E., Avila, L., Taborda, N., Tabares, P., López, A., Torres, F., Quiñones, W.,
Bucio, M.A., Mora-Pérez, Y., Rugeles, M.T., Joseph-Nathan, P., Echeverri, F., 2008.
In vitro anti-influenza screening of several Euphorbiaceae species: structure of a
bioactive Cyanoglucoside from Codiaeum variegatum. Phytochemistry 69 (16),
2815–2819. https://doi.org/10.1016/j.phytochem.2008.09.003.
Garcia, R.G., 1990. Molluscicidal effect of Codiaeum variegatum (L.) Blumeon
Oncomelania hupensisquadrasi, the snail host of Schistosoma japonicum in the
Philippines. In: Philippine Society of Parasitology Annual Convention.
Gastador, F.T., Oling, I.O., 2011. Antibacterial Activity of the Extracts of the Fresh Leaves
of Codiaeum variegatum cv. (L.) BI. (croton). family Euphorbiaceae. University of
San Carlos - Josef Baumgartner Learning Resource Center.
Gertrudes, Q.B., 2006. Phytochemical analysis and toxicity test of functional foods. In:
24th Annual Meeting: Philippine-American Academy of Science and Technology.
August 13-14, 2004. University of Maryland, College Park, MD.
Goel, G., Makkar, H.P.S., Francis, G., Becker, K., 2007. Phorbol Esters : structure ,
biological activity , and toxicity in animals phorbol Esters : structure , biological
activity , and toxicity in animals. Int. J. Toxicol. 26, 279–288. https://doi.org/
10.1080/10915810701464641.
Govaerts, R., Frodin, D.G., Radcliffe-Smith, A., 2000. World Checklist and Bibliography
of Euphorbiaceae (With Pandaceae): Croton -Excoecariopsis, World Checklists and
Bibliographies. https://doi.org/10.2307/2666560.
Handa, S.S., Kinghorn, A.D., Cordell, G.A., Farnsworth, N.R., 1983. Plant anticancer
agents. XXII. Isolation of a phorbol diester and its delta 5,6-7 beta-hydroperoxide
derivative from Ostodes paniculata. J. Nat. Prod. 46, 123–126. https://doi.org/
10.1021/np50025a013.
Hasanuzzaman, M., Bhuyan, M.H.M.B., Zulfiqar, F., Raza, A., Mohsin, S.M., Mahmud, J.
A., Fujita, M., Fotopoulos, V., 2020. Reactive oxygen species and antioxidant defense
in plants under abiotic Stress : revisiting the crucial role of a universal defense
regulator. Antioxidants 9, 52. https://doi.org/10.3390/antiox9080681.
Hassan, E.M., Hassan, R.A., El-Toumy, S.A., Mohamed, S.M., Omer, E.A., 2014. Phenolic
metaboloites and antioxidant activity of codiaeum variegatum cv. spirale. J. Pharm.
Res. 8, 619–623. https://doi.org/10.13140/2.1.3450.1761.
E. Mfotie Njoya et al.
Hassan, E.M., Hassan, R.A., Salib, J.Z., Mohamed, S.M., ElßToumz, S.A., 2013. Chemical
constituents and cytotoxic activity of codiaeum variegatum cv. petra. J. Appl. Sci.
Res. 9, 4884–4888.
Hassan, N., Ali, A., Withycombe, C., Ahluwalia, M., Al-nasseri, R.H., Tonks, A.,
Morris, K., 2018. Cytokine TET-2 up-regulation is associated with the anti-
inflammatory action of Vicenin-2. Cytokine 108, 37–42. https://doi.org/10.1016/j.
cyto.2018.03.016.
Hausen, B.M., Shulz, K.H., 1977. Occupational contact dermatitis due to Croton
(Codiaeum variegatum (L.) A. Juss var. pictum (Lodd) Muell. Arg.). Contact
Dermatitis 3, 289–292.
Hergenhahn, M., Kusumoto, S., Hecker, E., 1974. Diterpene esters from “Euphorbium”
and their irritant and cocarcinogenic activity. Experientia 30, 1438–1440. https://
doi.org/10.1007/BF01919683.
Huxley, A., Griffiths, M., Levy, M., 1992. The New Royal Horticultural Society Dictionary
of Gardening, vol. 1. A-C. Macmillan, London.
Hwang, S.J., Yong-Wan, K., Park, Y., Hyo-jong, L., Kyu-Won, K., 2014. Anti-
inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264
. 7 cells. Inflamm. Res. 63, 81–90. https://doi.org/10.1007/s00011-013-0674-4.
Iara, S., Rosa, G., Rios-santos, F., Olaitan, S., Tabajara, D., Martins, D.O., 2016. Vitexin
reduces neutrophil migration to inflammatory focus by down-regulating pro-
inflammatory mediators via inhibition of p38, ERK1/2 and JNK pathway.
Phytomedicine 23, 9–17. https://doi.org/10.1016/j.phymed.2015.11.003.
Ibrahim, N.I., Wong, S.K., Mohamed, I.N., Mohamed, N., Kok-Yong, C., Soelaiman, I.-N.,
Shuid, A.N., 2018. Wound healing properties of selected natural products. Int. J.
Environ. Res. Publ. Health 15, 1–23. https://doi.org/10.3390/ijerph15112360.
Ito, Y., 1986. Vegetable activators of the viral genome and the causation of Burkitt’s
lymphoma and Nasopharyngeal Carcinoma. In: Epstein, M.A., Achong, B. (Eds.), The
Epstein-Barr Virus: Recent Advances, pp. 207–236. London.
Kang, H., Sung-wuk, J., Jhang Ho, P., Sungbo, S., 2015. Glaucine inhibits breast cancer
cell migration and invasion by inhibiting MMP-9 gene expression through the
suppression of NF- kB activation. Mol. Cell. Biochem. 403, 85–94. https://doi.org/
10.1007/s11010-015-2339-9.
Kim, H.G., Oh, M.S., 2012. Natural products as potential anticonvulsants: caffeoylquinic
acids. Arch Pharm. Res. (Seoul) 35, 389–392. https://doi.org/10.1007/s12272-012-
0300-y.
Koch, M., Kehop, D.A., Kinminja, B., Sabak, M., Wavimbukie, G., Barrows, K.M.,
Matainaho, T.K., Barrows, L.R., Rai, P.P., 2015. An ethnobotanical survey of
medicinal plants used in the East Sepik province of Papua New Guinea. J. Ethnobiol.
Ethnomed. 11 https://doi.org/10.1186/s13002-015-0065-8.
Kozyra, M., Biernasiuk, A., Malm, A., 2017. Analysis of phenolic acids and antibacterial
activity of extracts obtained from the flowering herbs of Carduus acanthoides L. Acta
Pol. Pharm. Drug Res. 74, 161–172.
Kwon, H.K., Murakami, A., Tanaka, T., Ohigashi, H., 2005. Dietary rutin , but not its
aglycone quercetin , ameliorates dextran sulfate sodium-induced experimental colitis
in mice : attenuation of pro-inflammatory gene expression. Biochem. Pharmacol. 69,
395–406. https://doi.org/10.1016/j.bcp.2004.10.015.
Kwon, S.H., Lee, H.K., Kim, J.A., Hong, S.I., Kim, H.C., Jo, T.H., Park, Y.I., Lee, C.K.,
Kim, Y. Bin, Lee, S.Y., Jang, C.G., 2010. Neuroprotective effects of chlorogenic acid
on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative
activities in mice. Eur. J. Pharmacol. 649, 210–217. https://doi.org/10.1016/j.
ejphar.2010.09.001.
Labu, Z.K., Laboni, F.R., Mamun, M.M.A. Al, Howlader, M.S.I., 2015. Antidiarrhoeal
activity and total tannin content of ethanolic leaf extract of codiaeum variegatum.
Dhaka Univ. J. Pharm. Sci. 14, 87–90. https://doi.org/10.3329/dujps.v14i1.23740.
Larson, E.C., Hathaway, L.B., Lamb, J.G., Pond, C.D., Rai, P.P., Matainaho, T.K.,
Piskaut, P., Barrows, L.R., Franklin, M.R., 2014. Interactions of Papua New Guinea
medicinal plant extracts with antiretroviral therapy. J. Ethnopharmacol. 155,
1433–1440. https://doi.org/10.1016/j.jep.2014.07.023.
Lawal, O.A., Ogunwande, I.A., Gbetoyon, F.S., Kasali, A.A., Opoku, A.R., 2018. Chemical
composition and insecticidal activity of essential oils of four varieties of codiaeum
variegatum (L.) from Nigeria. J. Essent. Oil-Bearing Plants 21, 840–847. https://doi.
org/10.1080/0972060X.2017.1422440.
Li, W., Wang, X., Luo, Z., Liu, L., Yan, Chang, Yan, Chang-yu, Guo-Dong, C., Gao, H.,
Wen-Jun, D., Hiroshi, K., Yi-Fang, L., Rong-Rong, H., 2018. Traditional Chinese
medicine as a potential source for HSV-1 therapy by acting on virus or the
susceptibility of host. Int. J. Mol. Sci. 19, 1–23. https://doi.org/10.3390/
ijms19103266.
Ling, L.T., Palanisamy, U.D., Cheng, H.M., 2010. Prooxidant/antioxidant ratio
(ProAntidex) as a better index of net free radical scavenging potential. Molecules 15,
7884–7892. https://doi.org/10.3390/molecules15117884.
Liu, J., Du, C., Beaman, H.T., Monroe, M.B.B., 2020. Characterization of phenolic acid
antimicrobial and antioxidant structure – property relationships. Pharmaceutics 12,
17. https://doi.org/10.3390/pharmaceutics12050419.
Liu, Y., Chen, Z., Shi, Y., Huang, K., Geng, B., Liang, H., 2014. Oxoglaucine-lanthanide
Complexes : synthesis , crystal structure and cytotoxicity. Anticancer Res. 34,
531–536.
Lou, Z., Wang, H., Zhu, S., Ma, C., Wang, Z., 2011. Antibacterial activity and mechanism
of action of chlorogenic acid. J. Food Sci. 76 https://doi.org/10.1111/j.1750-
3841.2011.02213.x.
Lv, H., Yu, Z., Zheng, Y., Wang, L., Qin, X., Cheng, G., Ci, X.X., 2016. Isovitexin exerts
anti-inflammatory and anti-oxidant activities on lipopolysaccharide-induced acute
lung injury by inhibiting MAPK and NF-κB and activating HO-1/Nrf2 pathways. Int.
J. Biol. Sci. 12, 72–86. https://doi.org/10.7150/ijbs.13188.
Magdalita, Torreta, N.K., Sotto, R.C., 2014. Characterization of phenotypic variation in
selected Croton [codiaeum variegatum (L.) Rhumph. ex A. Juss.] varieties and
natural mutants. J. Nat. Stud. 13, 41–55.
19
Journal of Ethnopharmacology 277 (2021) 114244
Marín, M., Giner, R.M., Ríos, J., Recio, C.M., 2013. Intestinal anti-inflammatory activity
of ellagic acid in the acute and chronic dextrane sulfate sodium models of mice
colitis. J. Ethnopharmacol. 150, 925–934. https://doi.org/10.1016/j.
jep.2013.09.030.
Márquez-Flores, Y.K., Villegas, I., Cárdeno, A., Rosillo, M.Á., Alarcón-de-la-Lastra, C.,
2016. Apigenin supplementation protects the development of dextran sulfate
sodium- induced murine experimental colitis by inhibiting canonical and non-
canonical inflammasome signaling pathways. J. Nutr. Biochem. 30, 143–152.
https://doi.org/10.1016/j.jnutbio.2015.12.002.
Medina, F.R., Woodbury, R., 1978. Terrestrial plants molluscicidal to lymnaeid hosts of
Fascioliasis hepatica in Puerto Rico. J. Agric. Univ. Puert. Rico 366–376.
Mfotie Njoya, E., Flore, M., Kamini, G., Abia, W.A., Pechangou, S.N., Njayou, F.N.,
Tchana, A.N., Moundipa, P.F., 2018. Acute and sub-chronic toxicity evaluation of the
aqueous extract of Codiaeum variegatum leaves on Wistar albino rodents of both
sexes. J. Complement. Med. Res. 7, 108–114. https://doi.org/10.5455/
jcmr.20170412114130.
Mfotie Njoya, E., Moundipa, P.F., Stopper, H., 2014a. In vitro genotoxic and mutagenic
evaluation of the aqueous extract of Codiaeum variegatum and its amoebicidal sub-
fraction. J. Ethnopharmacol. 155, 823–829. https://doi.org/10.1016/j.
jep.2014.06.038.
Mfotie Njoya, E., Weber, C., Hernandez-Cuevas, N.A., Hon, C.-C., Janin, Y., Kamini, M.F.
G., Moundipa, P.F., Guillén, N., 2014b. Bioassay-guided fractionation of extracts
from codiaeum variegatum against Entamoeba histolytica discovers compounds that
modify expression of ceramide biosynthesis related genes. PLoS Negl. Trop. Dis. 8
https://doi.org/10.1371/journal.pntd.0002607.
Min, S., Ryu, S., Kim, D., 2010. Anti-inflammatory effects of black rice , cyanidin-3-O-
β-D-glycoside , and its metabolites , cyanidin and protocatechuic acid. Int.
Immunopharmacol. 10, 959–966. https://doi.org/10.1016/j.intimp.2010.05.009.
Mizuno, F., Osato, T., Imai, S., Koizumi, S., Aya, T., Kinoshita, T., Hirai, N., Hirota, M.,
Ohigashi, H., Koshimizu, K., 1986. Epstein-Barr virus-enhancing plant promoters in
East Africa. AIDS Res. 2, S151–S155.
Mohamed, N., El-Masry, R., Awad, A., Badr, H., 2019. Chemical composition and
antibacterial activity of Codiaeum variegatum leaves. Zagazig J. Agric. Res. 46,
1133–1140. https://doi.org/10.21608/zjar.2019.47093.
Mollick, A.S., Shimoji, H., Denda, T., Yokota, M., Yamasaki, H., 2011. Croton Codiaeum
variegatum (L.) Blume cultivars characterized by leaf phenotypic parameters. Sci.
Hortic. (Amsterdam) 132, 71–79. https://doi.org/10.1016/j.scienta.2011.09.038.
Mollick, A.S., Yamasaki, H., 2012. Phenotypic variations in Croton codiaeum variegatum
(L .) Blume characterized by digital image-based procedure. ISHS Acta Hortic.
393–400. https://doi.org/10.17660/actahortic.2012.937.48.
Mona, A.M.A.Z., Farghaly, A.A., Hassan, E.M., Abdel-Samie, N.S., 2019. Phenolic
compounds of codiaeum variegatum spirale lessened cytotoxic and genotoxic effects
of mitomycin C in mice somatic and germ cells. Cytol. Genet. 53, 494–501. https://
doi.org/10.3103/S0095452719060057.
Monzon, R.B., Alvior, J.P., Luczon, L.L., Morales, A.S., Mutuc, F.E., 1994. Larvicidal
potential of five philippine plants against Aedes aegypti (linnaeus) and Culex
quinquefasciatus (Say). Southeast Asian J. Trop. Med. Publ. Health 25, 755–759.
Moshi, M.J., Kagashe, G.A., 2004. A study of the effect of extracts of Codiaeum
variegatum (L.) A. Juss on Picrotoxin-induced convulsions in mice. Tanzania Med. J.
19 https://doi.org/10.4314/tmj.v19i1.39192.
Moundipa, P.F., Kamini, F.G.M., Bilong, C.F.B., Bruchhaus, I., 2005. In vitro amoebicidal
activity of some medicinal plants of the Bamun region (Cameroon). Afr. J. Tradit.,
Complementary Altern. Med. 2, 113–121. https://doi.org/10.4314/ajtcam.
v2i2.31109.
Mwine, J.T., Damme, P. Van, 2011. Why do Euphorbiaceae tick as medicinal plants? A
review of Euphorbiaceae family and its medicinal features. J. Med. Plants Res. 5,
652–662.
Naidu, P.G., 1988. Antifungal activity in Codiaeum variegatum leaf extract. Curr. Sci. 57,
502–504.
Nam, T.G., Lim, T., Lee, B.H., Lim, S., Kang, H., Eom, S.H., Yoo, M., Jang, H.W., Kim, D.,
2017. Comparison of anti-inflammatory effects of flavonoid-rich common and
tartary buckwheat sprout extracts in lipopolysaccharide-stimulated RAW 264 . 7 and
peritoneal macrophages. Oxid. Med. Cell. Longev. 12. https://doi.org/10.1155/
2017/9658030. Article ID.
Nasib, A., Ali, K., Khan, S., 2008. In vitro propagation of Croton (Codiaeum variegatum).
Pakistan J. Bot. 40, 99–104.
Nassiri-Asl, M., Mortazavi, S.R., Samiee-Rad, F., Zangivand, A.A., Safdari, F.,
Saroukhani, S., Abbasi, E., 2010. The effects of rutin on the development of
pentylenetetrazole kindling and memory retrieval in rats. Epilepsy Behav. 18, 50–53.
https://doi.org/10.1016/j.yebeh.2010.03.005.
Nassiri-Asl, M., Shariati-Rad, S., Zamansoltani, F., 2008. Anticonvulsive effects of
intracerebroventricular administration of rutin in rats. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 32, 989–993. https://doi.org/10.1016/j.
pnpbp.2008.01.011.
Nio, S.A., Kolondam, B., Tallei, T., 2018. Evaluation of matK and rbcL genes as markers
in DNA barcoding of Codiaeum variegatum (L.) Blume. Biosci. Res. 15, 192–198.
Norhanom, a W., Yadav, M., 1995. Tumour promoter activity in Malaysian
Euphorbiaceae. Br. J. Cancer 71, 776–779. https://doi.org/10.1038/bjc.1995.150.
Nugroho, A., Kim, M., Choi, J., Choi, J.S., Jung, W.T., Lee, K., Park, H., 2012.
Phytochemical studies of the phenolic substances in aster glehni extract and its
sedative and anticonvulsant activity. Arch Pharm. Res. (Seoul) 35, 423–430. https://
doi.org/10.1007/s12272-012-0304-7.
Nurwanti, S.W., Aritonang, R.E., Warnetty, H., Puspayani, R.S., 2018. In vitro
antioxidant activity of garden Croton (Codiaeum variegatum (L .) rumph . Ex A . Juss
.) and phytochemical analysis using gas chromatography – mass spectrometry. Drug
Invent. Today 10.
E. Mfotie Njoya et al.
Obach, R.S., 2000. Inhibition of human cytochrome P450 enzymes by constituents of St.
John’s Wort, an herbal preparation used in the treatment of depression.
J. Pharmacol. Exp. Therapeut. 294, 88–95.
Ogunwenmo, Idowu, O.A., Chukwudi, I., Esan, E.B., Oyelana, O.A., 2007. Cultivars of
Codiaeum variegatum (L.) Blume(Euphorbiaceae) show variability in phytochemical
and cytological characteristics. Afr. J. Biotechnol. 6, 2400–2405. https://doi.org/
10.5897/AJB2007.000-2376.
Ohigashi, H., Koshimizu, K., Tokuda, H., Hiramatsu, S., Jato, J., Ito, Y., 1985. Epstein-
Barr virus-inducing activity of Euphorbiaceae plants commonly grown in Cameroon.
Cancer Lett. 28, 135–141. https://doi.org/10.1016/0304-3835(85)90068-0.
Okutan, H., Ozcelik, N., Ramazan Yilmaz, H., Uz, E., 2005. Effects of caffeic acid
phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart.
Clin. Biochem. 38, 191–196. https://doi.org/10.1016/j.clinbiochem.2004.10.003.
Olivon, F., Remy, S., Grelier, G., Apel, C., Eydoux, C., Guillemot, J.C., Neyts, J.,
Delang, L., Touboul, D., Roussi, F., Litaudon, M., 2019. Antiviral compounds from
codiaeum peltatum targeted by a multi-informative molecular networks approach.
J. Nat. Prod. 82, 330–340. https://doi.org/10.1021/acs.jnatprod.8b00800.
Olumuyiwa, S.S.V., Obidike, I.R., Ocheni, S.O., 2010. Effect of experimental feeding of
Codiaeum variegatum leaves on growth, hematology, gonadal, and extra-gonadal
sperm reserves of adult albino rats. Comp. Clin. Pathol. 19, 21–27. https://doi.org/
10.1007/s00580-009-0894-8.
Pancho, J.V., Hilario, F., 1963. Chromosome numbers and intraspecific hybridization in
croton (Codiaeum variegatum Blume). Philipp. Agric. 47, 104–112.
Pang, C., Sheng, Y., Jiang, P., Wei, H., Ji, L., 2015. Chlorogenic acid prevents
acetaminophen-induced liver injury : the involvement of CYP450 metabolic enzymes
and some antioxidant signals. J Zhejiang Univ.-Sci. B (Biomed.. Biotechnol.) 16,
602–610. https://doi.org/10.1631/jzus.B1400346, 2015.
Phumthum, M., Balslev, H., 2020. Anti-infectious plants of the thai karen: a meta-
analysis. Antibiotics 9, 1–15. https://doi.org/10.3390/antibiotics9060298.
Plaza, M., Pozzo, T., Liu, J., Gulshan Ara, K.Z., Turner, C., Nordberg Karlsson, E., 2014.
Substituent effects on in vitro antioxidizing properties, stability, and solubility in
flavonoids. J. Agric. Food Chem. 62, 3321–3333. https://doi.org/10.1021/
jf405570u.
Prescott, T.A.K., Homot, P., Lundy, F.T., Fang, R., Patrick, S., Cámara-Leret, R.,
Kiapranis, R., 2017. Tropical ulcer plant treatments used by Papua New Guinea’s
Apsokok nomads. J. Ethnopharmacol. 205, 240–245. https://doi.org/10.1016/j.
jep.2017.05.001.
Prescott, T.A.K., Kiapranis, R., MacIver, S.K., 2012. Comparative ethnobotany and in-the-
field antibacterial testing of medicinal plants used by the Bulu and inland Kaulong of
Papua New Guinea. J. Ethnopharmacol. 139, 497–503. https://doi.org/10.1016/j.
jep.2011.09.058.
Puupponen-Pimia, R., Nohynek, L., Meier, C., Kahkonen, M., Heinonen, M., Hopia, A.,
Oksman-Caldentey, K.-M., 2001. Antimicrobial properties of phenolic compounds
from berries. J. Appl. Microbiol. 90, 494–507. https://doi.org/10.1046/j.1365-
2672.2001.01271.x.
Rahman, M., Momota, A., 2013. Taxonomy and medicinal uses of Euphorbiaceae
(spurge) family of Rajshahi. Res. Plant Sci. 1, 74–80. https://doi.org/10.12691/aees-
2-2-3.
Rahmatullah, M., Ferdausi, D., Mollik, A.Q., Azam, N.K., Taufiq-Ur-Rahman, M.,
Jahan, R., 2009a. Ethnomedicinal survey of bheramara area in Kushtia district,
Bangladesh. Am. J. Sustain. Agric. 3, 534–541.
Rahmatullah, M., Hossan, S., Hanif, A., Roy, P., Jahan, R., Khan, M., Chowdhury, M.H.,
Rahman, T., 2009b. Ethnomedicinal applications of plants by the traditional healers
of the marma tribe of Naikhongchhari, Bandarban district, Bangladesh. Adv. Nat.
Appl. Sci. 3, 392–401.
Raj, A.J., Biswakarma, S., Pala, N.A., Shukla, G., Kumar, M., Chakravarty, S.,
Bussmann, R.W., 2018. Indigenous uses of ethnomedicinal plants among forest-
dependent communities of Northern Bengal, India. J. Ethnobiol. Ethnomed. 14,
1–28. https://doi.org/10.1186/s13002-018-0208-9.
Rastogi, H., Jana, S., 2014. Evaluation of inhibitory effects of caffeic acid and quercetin
on human liver cytochrome P450 activities. Phyther. Res. 28, 1873–1878. https://
doi.org/10.1002/ptr.5220.
Rossi, A., Ligresti, A., Longo, R., Russo, A., Borrelli, F., Sautebin, L., 2002. The inhibitory
effect of propolis and caffeic acid phenethyl ester on cyclooxygenase activity in J774
macrophages. Phytomedicine 9, 530–535. https://doi.org/10.1078/
09447110260573164.
20
Journal of Ethnopharmacology 277 (2021) 114244
Sadraei, H., Asghari, G., Shahverdi, F., 2016. Antidiarrhoeal assessment of
hydroalcoholic and hexane extracts of Dracocephalum kotschyi Boiss. and apigenin
in mice. Res. Pharm. Sci. 11, 200–209.
Saffoon, N., Alam Ashraful, M.D., Uddin, G.M., 2010. Phytochemical and cytotoxicity
investigation of Codiaeum variegatum Linn. Leaf. Stamford J. Pharm. Sci. 3, 51–53.
https://doi.org/10.3329/sjps.v3i2.8039.
Saffoon, N., Uddin, R., Subhan, N., Hossain, H., Reza, H.M., Alam, M.A., 2014. In vitro
anti-oxidant activity and HPLC-DAD system based phenolic content analysis of
Codiaeum variegatum found in Bangladesh. Adv. Pharmaceut. Bull. 4, 533–541.
https://doi.org/10.5681/apb.2014.079.
Sangeetha, G., Mohan, K.G., Aruna, G., Sekar, M.B., Balammal, G., 2011. Study on wound
healing activity of root of codiaeum variegatum. Int. J. Innovat. Drug Discov. 1,
19–23.
Sato, Y., Itagaki, S., Kurokawa, T., Ogura, J., Kobayashi, M., Hirano, T., Sugawara, M.,
Iseki, K., 2011. In vitro and in vivo antioxidant properties of chlorogenic acid and
caffeic acid. Int. J. Pharm. 403, 136–138. https://doi.org/10.1016/j.
ijpharm.2010.09.035.
Sivamani, R.K., Ma, Brian R., Wehrli, Lisa N., Maverakis, Emanual, 2012. Phytochemicals
and naturally derived substances for wound healing. Adv. Wound Care 1, 213–217.
https://doi.org/10.1089/wound.2011.0330.
Sofowora, A., Ogunbodede, E., Onayade, A., 2013. The role and place of medicinal plants
in the strategies for disease prevention. Afr. J. Tradit. Complement. Altern. Med. 10,
210–229. https://doi.org/10.4314/ajtcam.v10i5.2.
Soto, J., Gómez, C., Calzada, F., Ramírez, M.E., 2010. Ultrastructural changes on
Entamoeba histolytica HM1-IMSS caused by the flavan-3-ol, (-)-epicatechin. Planta
Med. 76, 611–612. https://doi.org/10.1055/s-0029-1240599.
Suphiratwanich, P., Lomarat, P., Julsrigival, J., 2021. Assessment of total phenolic and
flavonoid contents , antioxidant activity , and anti-acetylcholinesterase activity from
Codiaeum variegatum (L .) Blume leaves found in Thailand. Khon Kaen Agric. J. 49,
517–523. https://doi.org/10.14456/kaj.2021.45.518.
Taylor, N., 1938. The Garden Dictionary : an Encyclopedia of Practical Horticulture,
Garden Management and Landscape Design. Cambridge: Houghton Mifflin
Company, Boston, New York.
Tenório, J.A.B., Dulciana, S., Thelma, M.G., Teresinha, G., Ramos, C.S., 2016. Solanum
paniculatum root extract reduces diarrhea in rats. Rev. Bras. Farmacogn. 26,
375–378. https://doi.org/10.1016/j.bjp.2016.02.003.
Varì, R., Archivio, M.D., Filesi, C., Carotenuto, S., Scazzocchio, B., Santangelo, C.,
Giovannini, C., Masella, R., 2011. Protocatechuic acid induces antioxidant/
detoxifying enzyme expression through JNK-mediated Nrf2 activation in murine
macrophages. J. Nutr. Biochem. 22, 409–417. https://doi.org/10.1016/j.
jnutbio.2010.03.008.
Vogg, G., Mattes, E., Polack, a, Sandermann, H., 1999. Tumor promoters in commercial
indoor-plant cultivars of the Euphorbiaceae. Environ. Health Perspect. 107,
753–756.
Wang, H., Cao, Z., 2014. Anti-inflammatory effects of (-) -epicatechin in
lipopolysaccharide-stimulated raw 264.7 macrophages. Trop. J. Pharmaceut. Res.
13, 1415–1419.
Wang, Q.J., Fang, T., Fenick, D., Garfield, S., Bienfait, B., Marquez, V.E., Blumberg, P.M.,
2000. The lipophilicity of phorbol esters as a critical factor in determining the
pattern of translocation of protein kinase C fused to green fluorescent protein.
J. Biol. Chem. 275, 12136–12146. https://doi.org/10.1074/jbc.275.16.12136.
WHO, 2009. Medicinal Plants in Papua New Guinea : Information on 126 Commonly
Used Medicinal Plants in Papua New Guinea. WHO Regional Office for the Western
Pacific.
Wiart, C., 2006. Medicinal Plants of the Asia-Pacific: Drugs for the Future? World
Scientific Publishing Co. Pte. Ltd. Singapore, World Scientific Publishing Co. Pte.
Ltd. Singapore, ISBN 981-256-341-5, p. 345.
Xiao, Q., Qu, Z., Zhao, Y., Yang, L., Gao, P., 2017. Orientin ameliorates LPS-induced
inflammatory responses through the inhibitory of the NF- B pathway and NLRP3
inflammasome. Evidence-Based Complement. Altern. Med. 8. https://doi.org/
10.1155/2017/2495496, 2017.
Yadav, R.P., Singh, A., 2003. Effect of sub-lethal concentrations of codiaeum variegatum
latex on freshwater target snail Lymnaea acuminata and non-target fish Channa
punctatus. Niger. J. Nat. Prod. Med. 7, 20–24. https://doi.org/10.4314/njnpm.
v7i1.11699.
Zhao, X., Yu, Z., Ding, T., 2020. Quorum-sensing regulation of antimicrobial resistance in
bacteria. Microorganisms 8, 1–21. https://doi.org/10.3390/
microorganisms8030425.