Journal of Ethnopharmacology 232 (2019) 90–102

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

Review

The chemistry and biological activities of Peperomia pellucida (Piperaceae): A T

critical review
⁎
Nayara Sabrina F. Alvesa, William N. Setzerb,c, Joyce Kelly R. da Silvaa,
a
Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Pará, 66075-900 Belém, Brazil
b
Department of Chemistry, University of Alabama in Huntsville, Huntsville, AL 35899, USA
c
Aromatic Plant Research Center, 230 N 1200 E, Suite 102, Lehi, UT 84043, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Ethnopharmacological relevance: Peperomia pellucida (L.) Kunth is an annual weed with a preference to humid
Peperomia pellucida places with reduced solar radiation. This plant is mainly distributed in the Neotropics, Africa, Southeast Asia,
Ethnomedicinal practices and Australia. It is popularly employed in the treatment of a variety of health conditions such as abscesses,
Phytochemistry abdominal pain, skin sores, conjunctivitis, measles, and kidney troubles. Several studies have also described its
Pharmacological applications
antimicrobial, cytotoxic, antidiabetic and a variety of other bioactivities.
The aim of the review: The aim of this work is to evaluate, using a critical review, the present ethnomedicinal
applications, phytochemistry and pharmacological studies of P. pellucida essential oils (EOs) and extracts from
different locations around the world.
Materials and methods: This review was performed through an online survey of the ethnomedicinal practices,
chemical compositions and pharmacological applications of P. pellucida EOs and extracts. The data were mainly
obtained from online journals and books published in English, Portuguese and Spanish. The information was
collected from websites such as Google, Google Scholar, PubMed, Science Direct, ResearchGate and other online
databases that provided more information about this herb.
Results: Peperomia pellucida bioactivities such as antimicrobial, cytotoxic, antioxidant, fracture healing, anti-
diabetic and anti-hypercholesterolemia have been described in several literature sources. Nonetheless, most
reports only provide the phytochemical screening of extracts, which does not allow the identification of the
active compounds. From these studies, some reported constituents are not included in the Dictionary of Natural
Products (DNP), which raises questions toward their identification. In addition, some biological assays were even
performed without standard controls for comparison which also makes these results questionable.
Conclusion: This review evaluates data regarding the phytopharmaceutical potential of P. pellucida. In general,
several important aspects were questionable or missing in these manuscripts, which points out the need of more
investigation on the pharmacological properties and phytochemical compositions of this herb.

1. Introduction Neotropics followed by Southern Asia (about 100 species), Madagascar

The Piperaceae is a large family of angiosperms composed of around
3700 species (Christenhusz and Byng, 2016). It is among the oldest of
the pan-tropical plants and its species are mainly distributed in two
genera: Piper with around 2000 species (Quijano-Abril et al., 2006) and
Peperomia with approximately 1600 (Frenzke et al., 2015). The group
Peperomia is one of the largest genera of basal angiosperms (Wanke
et al., 2006) and is composed of herbs usually perennial (Shu, 1999).
Several Peperomia species are cultivated as ornamentals because of the
beauty of their foliage (Guimarães and Carvalho-Silva, 2012). Its spe-
cies are dispersed pantropically, having the greatest biodiversity in the
(about 40 species), Africa (about 20 species), Australia and New
Zealand (less than 20 species) (Wanke et al., 2006).
Peperomia pellucida (L.) Kunth (Fig. 1) is known for its variety of
pharmacological properties. This plant is an herbaceous herb with
succulent, alternate oval leaves and inflorescences in terminal spikes,
axillary and opposite to the leaves. The species grows well in humid and
loose soils in places with reduced solar radiation with preference to
rainy periods (Arrigoni-Blank et al., 2004). Stems are succulent,
translucent green, erect or ascending, and internodes are usually
3–8 cm long, glabrous and hairless (Majumder, 2011). It is an annual,
fasciculate short-rooted herb usually having a height of 15–45 cm

⁎
Corresponding author.
E-mail addresses: nayara.alves@icb.ufpa.br (N.S.F. Alves), setzerw@uah.edu (W.N. Setzer), joycekellys@ufpa.br (J.K.R. da Silva).

https://doi.org/10.1016/j.jep.2018.12.021
Received 4 July 2018; Received in revised form 13 December 2018; Accepted 14 December 2018
Available online 15 December 2018
0378-8741/ © 2018 Elsevier B.V. All rights reserved.
N.S.F. Alves et al. Journal of Ethnopharmacology 232 (2019) 90–102

pharmacological properties have been reported for its EO and extracts,

Fig. 1. Peperomia pellucida L. inflorescences (A) and leaves (B) (Photographed
by NAYARA ALVES).
(Majumder and Kumar, 2011). The plant is a weed with heart-shaped
leaves and tiny seeds attaching to the cord-like spikes (Mosango, 2008;
Ooi et al., 2012).
Its scientific name is usually written in books and publications in
South America as P. pellucida (L.) H.B.K. However, P. pellucida (L.)
Kunth should be applied since Kunth was responsible for the present
classification of this species (previously named by Linnaeus – 1753 – as
Piper pellucidum L.) in the genus Peperomia (Mathieu and Posada, 2006).
The abbreviation H.B.K. is possibly used because of its taxonomic in-
formation published in the book “Nova Genera et Species Plantarum”
which was written by Humboldt et al. (1815) – H.B.K.
Traditionally, Peperomia pellucida has been utilized in the folk
medicine of several pantropical countries to treat a wide spectrum of
ailments and diseases such as skin sores (Arrigoni-Blank et al., 2002),
gastrointestinal disorders (Mollik et al., 2010), dysentery, diarrhea,
indigestion (Mollik et al., 2010), abscesses and injuries (Bojo et al.,
1994). In the literature, numerous studies on chemical and
which include cytotoxic (Xu et al., 2006), analgesic (Aziba et al., 2001),
antibacterial (Khan and Omoloso, 2002), and anti-inflammatory po-
tential (Arrigoni-Blank et al., 2004). Peperomia pellucida essential oils
(EOs) and extracts are typically composed of phenylpropanoids fol-
lowed by sesquiterpenes (De Diaz et al., 1988). However, the chemical
composition can vary significantly depending on its place of origin.
The aim of this review is to evaluate the present ethnomedicinal
applications, phytochemical and pharmacological studies of P. pellucida
EOs and extracts from different locations around the world under a
critical view. A similar review on P. pellucida was published by
Raghavendra and Prashith Kekuda (2018). However, a more detailed
survey with a critical analysis of the available data is still needed to
understand the state of the research on this species. In the present work,
there is a more extensive coverage of this plant's ethnopharmacological
and phytochemical characteristics. The biological activities and eth-
nopharmacological aspects reported also include new references. Fur-
thermore, a critical selection of the material included was also done
since several studies have described pharmacological properties with
high concentrations of extracts and/or essential oils of P. pellucida. In
general, the literature previously published failed to report several
scientific details, which emphasizes the importance of conducting more
complete studies focused on P. pellucida ethnomedicinal, pharmacolo-
gical potential and phytochemical composition.
2. Distribution and local names
Peperomia pellucida is mainly distributed in countries of Central and
South America, Africa, Southeast Asia, and Australia (Loc et al., 2010).
The plant is commonly known as ‘erva-de-jaboti’ and ‘língua de sapo’ in
Brazil (Arrigoni-Blank et al., 2004), ‘lochi pata’ and ‘mashitandu chedi’
in India (Flowers of India, 2005), but it also receives a variety of dif-
ferent popular names in countries such as Puerto Rico, Suriname, Ma-
laysia, Thailand and many others as shown on Table 1.

Table 1
Peperomia pellucida traditional names in different countries.
Local name Country/region Continent Reference

Rinrin, Renren Nigeria Africa Soladoye et al. (2010), Sonibare et al. (2009)
丁草 (Ding Cao) Singapore Asia Siew et al. (2014)
Diya Thippili, Wathura Gas Sri Lanka Asia Barberyn Ayurveda Resorts and the University of Ruhuna
(2017), Ediriweera (2007)
Sirih cina, ketumpangan air, tumpang angin or căo hú jīao Malaysia Asia Mosango (2008), De Padua et al. (1999)
Ketumpangan air, sasaladaan, suruh-suruhan Indonesia Asia De Padua et al. (1999)
Pak-krasang, chaa kruut, phak krasang, phak haak kluai Thailand Asia Mosango (2008), De Padua et al. (1999)
Càng cua Vietnam Asia Mosango (2008)
Usuba sunakosho Japan Asia Mosango (2008)
Lochi pata, mashitandu chedi, pononoa, toyakandha, varshabhoo, India Asia Ghani (1998), Flowers of India (2005), Panghal et al.
latapate, panpatta, charkouma, ponownowa (2010), Shil et al. (2014), Buragohain (2011)
Luchi pata, paneri Bangladesh Asia Mosango (2008), Uddin (2014)
Olasiman-bato, Pansit-pansitan or ulasimang bato, Sinaw-sinaw, Philippines Asia Manalo et al. (1983), Mosango (2008), Morilla et al. (2014),
ulasimang bato, olasiman-ihalas, tangon-tangon Batugal et al. (2004)
Kaca-kaca, surukan and sasaladaan Indonesia Asia Oceania Mosango (2008), Susilawati et al. (2017)
Corazón de hombre Cuba Caribbean, Latin Cano and Volpato (2004)
America
Prenetaria Puerto Rico Caribbean, Latin Bosque (2014)
America
Zèb kourès Martinique Caribbean, Latin Longuefosse and Nossin (1996)
America
Sumu mairen, Hierba de sapo, sumu yal Nicaragua Central America Coe et al. (1997), Coe and Anderson (2005), Coe and
Anderson (1999)
Alumbre or erva-de-vidro Spain Europe Mosango (2008)
Pépéromie or herbe à couleuvre France Europe Mosango (2008)
Pepper elder, silverbush, rat-ear, man-to-man, clearweed North America North America Mosango (2008)
Coraçãozinho, erva-de-jaboti, língua de sapo, erva-de-vidro, Brazil South America Arrigoni-Blank et al. (2004), De Albuquerque et al. (2007)
favaquinha
Konsaka wiwiri, eagoe ragoe, kosaka wi, sapoe rakei Suriname South America Ruysschaert et al. (2009), Flora of the Guianas (2018)

91
N.S.F. Alves et al.
3. Local and traditional uses
The traditional use of plants has been associated with medical ap-
plication for millennia (Lowe et al., 2001). In folk medicine, P. pellucida
is widely reported as a medicinal species in many cultures (Telban,
1988). The plant is distributed in several countries in South America,
including Argentina, Bolivia, Brazil, Colombia, Ecuador, French
Guiana, Guyana, Paraguay, Peru, Suriname, Uruguay, and Venezuela
(Tropicos, 2018). In the Northeast region of Brazil, for example, this
species is usually used to treat abscesses, furuncles, skin sores and
conjunctivitis (Bojo et al., 1994; Arrigoni-Blank et al., 2002). In the
Caatinga, a Brazilian semi-arid biome, P. pellucida leaves are used to
treat inflammation in general and hypertension (De Albuquerque et al.,
2007). In addition, it is applied as an emollient, taken orally as a
diuretic agent as well as for the treatment of cough and cardiac ar-
rhythmia (Van Den Berg, 1993; Pimentel, 1994). In Suriname, the plant
is applied topically to treat inflammations and skin bruises and taken
orally as a diuretic agent (Flora of the Guianas, 2018). The extract,
mixed with oil of Cocos nucifera, is rubbed on the body of babies to treat
pain (Ruysschaert et al., 2009). In this country, an infusion is employed
as both an eye bath to improve the sight and as eye drops to aid with
sore eyes (Heyde, no date; Morton, 1981). In Bolivia, this herb is ap-
plied to stop hemorrhages and to treat fever and wounds (Muñoz et al.,
2000). Besides this, in both South and Central America, it is widely used
in food preparation by the local community because it stimulates ap-
petite and digestion (De Padua et al., 1999).
Aerial parts are also applied to treat inflammation, dermatological
and various kidney diseases in Central America and Mexico (Heinrich
et al., 1998). A decoction of the whole plant is orally administered in
Garífuna and Miskitu of eastern Nicaragua against animal bites and
stings (snakes, scorpions and insects), infections, venereal diseases and
menstrual disorders associated with hemorrhage (Coe and Anderson,
1996; Coe et al., 1997). Furthermore, a decoction of the whole plant is
taken orally to treat the side effects caused by snakebites in eastern
Nicaragua (Coe and Anderson, 2005). In addition, Rama midwives in
eastern Nicaragua indicated that a decoction of the whole plant is orally
taken to treat vaginal infections and alleviate menstrual pain (Coe,
2008). The same uses and mode of application were reported in Sumu
(Ulwa) of Southeastern Nicaragua (Coe and Anderson, 1999).
In the Caribbean region, which is part of the Neotropics, P. pellucida
is applied against several health problems. For instance, the plant is
employed as diuretic, hypotensive, coolant, depurative, anti-poisonous
as well as antibiotic and fungicide in Puerto Rico (Bosque, 2014). In
Cuba, a plant decoction is administrated orally against calculus and as a
diuretic agent (Cano and Volpato, 2004). An infusion is also taken or-
ally to relieve constipation and rectal inflammation (Roig y Mesa, 1945;
Morton, 1981). Besides this, aerial parts of P. pellucida are used in the
village Bwa Mawego of Dominica to treat inflammation and skin
eruptions (Quinlan and Quinlan, 2007). In the Grenadines, a tea is used
as a treatment for undernourished children (Howard, 1952; Asprey and
Thornton, 1953a)
In addition, a decoction of the plant is used as a cold remedy in
Jamaica, Caribbean (Asprey and Thornton, 1953a, 1953b, 1955a,
1955b; Morton, 1981). In this island it is also seen as a valuable chil-
dren's remedy. An informant who had lived in Cuba mentioned it as an
excellent blood cooler and sleeping herb (Dalziel, 1937; Beckwith,
1927). In Martinique, a decoction or juice made from the herb is in-
stilled to treat ocular infection (Longuefosse and Nossin, 1996). The
plant is used as a condiment to help with appetite and digestion in
Puerto Rico. A decoction is also employed as a diuretic and to expel
kidney stones (Nuñez-Melendez, 1964; Morton, 1981). In Barbados it is
applied to treat children with marasmus, a serious malnutrition. Besides
this, the herb is taken to treat kidney complaints in adults and is used
externally on sores and skin eruptions in children in Barbados
(Gooding, 1940; Morton, 1981).
Furthermore, in Trinidad and Tobago, Caribbean, P. pellucida is
92
Journal of Ethnopharmacology 232 (2019) 90–102
applied as a blood cleanser and is used to treat common cold symptoms
and general health conditions (Clement et al., 2007). An infusion or a
decoction of the whole plant is also employed to treat coughs, colds,
influenza, fever, diarrhea, and for cooling, stoppage of water, and as a
cleanser (Lans, 2006; Clement et al., 2015). The fresh plant is also in-
gested for sore throat (Williams and Williams, 1951; Wong, 1976;
Morton, 1981).
The herb also plays an important role in the popular medicine of
several Asian countries. In Sri Lanka, its use is usually associated with
the Ayurvedic medicine for the treatment of diarrhea, dysentery, naso-
pharyngeal infections, paralysis, epilepsy, convulsions, skin and mu-
cosae tumors and, cancers (Barberyn Ayurveda Resorts and the
University of Ruhuna, 2017). In addition, in Western and Sabar-
agamuwa provinces in Sri Lanka, the plant is applied against bites of
different types of snakes such as cobras, vipers, kraits, hump-nosed
vipers and scant venomous snakes. The two main treatment types em-
ployed are paththu (for bandaging) and peyawa (for drinking)
(Dharmadasa et al., 2016). In Ayurveda, P. pellucida is also used in the
treatment of several other health problems such as constipation, kidney
diseases, urinary infections, emaciation, edema and general weakness.
Furthermore, the Karens of Middle Andaman Islands use the complete
herb to treat cuts and wounds (Sharief et al., 2005). Additionally, the
whole plant is crushed and rubbed on burned areas to minimize burning
sensation and prevent blisters (Ediriweera, 2007).
In Bangladesh, Asia, the plant is commonly consumed to treat gas-
trointestinal disorders such as dysentery, diarrhea, indigestion, colic,
acidity, constipation, bloating, lack of appetite and stomachache
(Mollik et al., 2010). Furthermore, a paste is prepared from P. pellucida
leaves and is popularly applied against boils in the country (Faruque
and Uddin, 2011). In the Kanda tribe, one of the lesser known small
tribes of Bangladesh, the whole plant is cleaned, macerated and turned
into a paste to be applied adjacent to the site of poisonous snakes, in-
sects or reptiles bites. This alternative treatment seems unique to the
Kanda healers. The interesting fact is that the paste cannot be applied
on the top of bitten areas (Rahmatullah et al., 2013). In the Katakhali
Pouroshova of Rajshahi district, the whole plant is used as a treatment
for eczema, abdominal pains, headache and fever (Rahman and Kumar,
2015). The whole plant in Vietnam is employed as a warm poultice
against malaria, headache, injuries and burns (Vo, 2012). Besides this,
the juice from its leaves is used to treat colic (Vo, 2012) and as an
antihypertensive agent (Pham, 2002).
In addition, Asian peoples also employ P. pellucida against various
respiratory tract disorders and skin diseases (Mollik et al., 2010). Leaf
extracts are also applied by local people to treat mental disorders (Khan
et al., 2008). A decoction of the plant is used to treat bone aches and
pains in the Malay community (Ong and Nordiana, 1999). The plant is
used in Philippines to treat several diseases and disorders. Peperomia
pellucida is boiled and then used to reduce uric acid levels and in the
treatment of renal disease while a topical solution is applied against
acne and boils (Egwuche et al., 2011). In the Philippines, the whole
herb is applied as a warm poultice to treat abscesses, boils and pimples.
Furthermore, a decoction is employed against gout, kidney troubles and
rheumatic pain (De Padua et al., 1999). An infusion of the whole plant
is also used to treat kidney stones in Subanens in the municipality of
Dumingag, province of Zamboanga del Sur (Morilla et al., 2014).
Furthermore, in Peninsular Malaysia, Asia, P. pellucida is boiled and
the decoction is drunk to treat rheumatism and fatigue. In addition, the
leaf juice is applied against colic and abdominal pains while crushed
leaves are used to cure headache in Java (De Padua et al., 1999). It is
also popularly applied against several dermatological diseases in Tig-
bauan, Iloilo (Tantiado, 2012). Besides this, a decoction of the whole
plant is employed to treat joint pain in Singapore (Siew et al., 2014).
In Asia, specifically among the Nicobarese of Car Nicobar Island,
India, the plant juice is administered orally against diarrhea, dysentery
and to stop frequent urination (Verma et al., 2010). The Karens of
Middle Adaman, India, use the plant as a treatment for cuts, wounds,
N.S.F. Alves et al.
Table 2
Essential oil compositions of Peperomia pellucida collected from different sites around the world.
Plant part extracted Compounds
a
Leaf trans-3-Pinanone (32.6%), 1-methylethylidene propane dinitrile (18.6%) and 3-octyl
acetate (13.1%)
Leaf Germacrene D (10.3%), myristicin (11.3%) and dillapiole (37.8%)
Leaf Linalool (17.1%), limonene (14.2%) and β-caryophyllene (12.5%)
Stem Linalool (12.6%), β-caryophyllene (11.5%) and limonene (10.7%).
Whole plant Carotol (26.6–32.0%), dillapiole (25.1–30.2%), pygmaein (5.5–10.5%), and β-
caryophyllene (5.6–8.3%)
Leaf Carotol (32.1%), dillapiole (20.7%), and β-caryophyllene (7.6%)
Roots Dillapiole (63.9%), apiole (9.2%), and β-caryophyllene (4.4%)
Leaf Dillapiole (39.7%), β-caryophyllene (10.7%), and bicyclogermacrene (4.9%)
Leaf Dillapiole (36.9%), carotol (13.4%) and 5-hydroxy-3,4-methylenedioxy allylbenzenea
(10.6%)
Whole plant Dillapiole (55.3%), β-caryophyllene (14.3%) and carotol (8.1%)
a
The identification of this compound is in doubt.
headache, fever and weakness. In this process, a paste of the whole
plant is applied as poultice, and bruised leaves are added to the head at
the temporal region (Sharief et al., 2005). In the North-Kamrup district
of Assam, India, a plant paste is employed externally to reduce little
pimples and white spots of the body (Das et al., 2006). In the Saperas
community of Khetawas, Jhajjar District, Haryana, India, the herb is
used to treat fistula (Panghal et al., 2010). In the Reang tribe of Tripura
State of India, a paste of P. pellucida leaves is applied externally to heal
wounds (Shil et al., 2014). The whole plant paste from Jalpaiguri dis-
trict, West Bengal, India, is applied against boils (Bose et al., 2015). A
paste of the complete plant is even applied on burns for quick relief in
Tinsukia District of Assam, India (Buragohain, 2011).
Traditional healers in African countries have also reported the uses
of P. pellucida as a medicinal herb. In Western Africa, it is locally used
by local medicine to treat convulsions (De Padua et al., 1999). The plant
is employed in the treatment of measles, small pox, male impotence,
mental disorders, and breast cancer in Nigeria (Aziba et al., 2001).
Infusion associated with milk is further applied to boost the immune
system of sick people (Idris et al., 2016). In Cameroon, the aqueous
extract is commonly applied for fracture healing (Florence et al., 2017).
The plant is locally applied in Gabon for the treatment of fever and
hypertension (Mengome et al., 2010). The whole plant is used in the
treatment of hemorrhoids in southwestern, Nigeria (Soladoye et al.,
2010). A recipe combination of leaves of P. pellucida, Ocimum gra-
tissimum and Vernonia amygdalina are squeezed with water, filtered and
taken with glass cup thrice daily to treat diabetes in Lagos State, Nigeria
(Gbolade, 2009). In Okaakoko, Nigeria, the herb is used as a treatment
against eczema and skin diseases. The plant is ground to a paste and
applied to the affected parts to soften boils and treat skin bumps (Obata
and Aigbokhan, 2012).
Besides this, it is employed in Papua New Guinea, Oceania, against
many health problems, which include wounds, boils, pimples, ab-
scesses, abdominal pain, colic, gout, kidney troubles, rheumatic pain,
fatigue, headache, measles, small-pox, male impotence and mental
disorders (Khan and Omoloso, 2002). Peperomia pellucida leaves are also
applied as a postpartum remedy after heating (not in water) or
pounding by healers in Sukajadi, Indonesia (Roosita et al., 2008). Ad-
ditionally, leaves and stems can be used as food in many cultures
(Philippine Medicinal Plant, 2018; Ade-Ademilua et al., 2017; De Padua
et al., 1999). In salads, the plant has the crispness of carrot sticks and
celery (Philippine Medicinal Plant, 2018).
4. Phytochemistry
4.1. Volatile compounds
The essential oils of P. pellucida are typically composed of phenyl-
propanoids as major compounds followed by sesquiterpenes (De Diaz
93
Journal of Ethnopharmacology 232 (2019) 90–102
Country Continent Ref.
Nigeria Africa Oloyede (2010)
Western Cameroon Africa François et al. (2013)
Southwest Nigeria Africa Okoh et al. (2017)
Southwest Nigeria Africa Okoh et al. (2017)
Northern India Asia Verma et al. (2014)
Northern India Asia Verma et al. (2014)
Northern India Asia Verma et al. (2014)
Northern Brazil South America Da Silva et al. (1999)
Southeast Brazil South America Moreira et al. (1999)
Northern Brazil South America De Lira et al. (2009)
et al., 1988). The most predominant chemotype is characterized by the
presence of dillapiole with amounts ranging of 20.7–55.3% (Verma
et al., 2014; De Lira et al., 2009). The chemical composition of speci-
mens collected in the Brazilian Amazon is marked by dillapiole
(39.7–55.3%), β-caryophyllene (10.7–14.3%) and carotol (0–8.1%) (Da
Silva et al., 1999; De Lira et al., 2009). Likewise, a specimen collected
near to Rio de Janeiro (Brazil) had as major constituents dillapiole
(36.9%) and carotol (13.4%). In addition, the authors reported the
presence of 5-hydroxy-3,4-methylenedioxyallylbenzene (10.6%), but
this compound is not found in the Dictionary of Natural Products (DNP)
(Moreira et al., 1999).
Dillapiole (37.8%) was also detected in the EO of P. pellucida from
Bamboutos Mountain (Cameroon), followed by myristicin (11.3%) and
germacrene D (10.3%) (François et al., 2013). However, the major
compounds of the EO of the whole plant from Uttarakhand (India) were
carotol (26.6–32.0%), dillapiole (25.1–30.2%), pygmaein (5.5–10.5%)
and β-caryophyllene (5.6–8.3%). The root and aerial parts oils con-
tained dillapiole and apiole in the proportions of 63.9% and 9.2%, and
20.7% and 1.1%, respectively (Verma et al., 2014). Atypically, a spe-
cimen collected in Nigeria displayed trans-3-pinanone (32.6%), 1-me-
thylethylidenepropane dinitrile (18.6%), which is also not found in the
DNP, and 3-octyl acetate (13.1%) as the main constituents (Oloyede,
2010).
The EO from southwest Nigeria had linalool (17.1%), limonene
(14.3%) and β-caryophyllene (12.5%) in the leaves, while the stem EO
was mainly composed of linalool (12.6%) and β-caryophyllene (11.5%)
and limonene (10.7%) (Okoh et al., 2017). Some of the GC-MS results
are not correct. The compound phenylethyl alcohol is listed in the
manuscript with RI of 856 and coumarin with 879. However, according
to the Adams library, they should have RI values of 1107 and 1434,
respectively. The RI value attributed to 3-phenylpropanoic acid was
897, which is considered very low. According to molecular weight it
should be between 1329 and 1356 (Peng et al., 1998; Yuceer et al.,
2001; NIST, 2007). EO compositions of P. pellucida from different lo-
cations in the world are summarized in Table 2.
4.2. Non - volatile compounds
The chemical composition of extracts of P. pellucida is dominated by
phenylpropanoid pathway derivatives with a large diversity of lignans
with different skeletons (C6C3 dimers) (see Fig. 2) (Parmar et al.,
1997). Methylenedioxy lignans such as sesamin (1) were isolated from
leaves of P. pellucida and some members of a specific compound class
called peperomins (2−9) and the norlignan 7-oxopachypostaudin A
(10) (Xu et al., 2006). In addition, cyclobutane dimers such as pellu-
cidin A (11) (Bayma et al., 2000) and tetrahydrofuran lignans (12–15)
have been reported (Fig. 2).
The structural diversity of flavonoids produced by Peperomia species
N.S.F. Alves et al. Journal of Ethnopharmacology 232 (2019) 90–102

Fig. 2. Lignans identified in P. pellucida.

Fig. 3. Flavonoids present in P. pellucida.

is limited to flavones and C-glycosylated flavones (exclusively on the A-
ring) (16, 17) (Aqil et al., 1993; Xu et al., 2006). A methylated flavan-3-
ol called pellucidatin (18) has been reported only in P. pellucida (Aqil
et al., 1993). A flavonoid inhibitor of angiotensin-converting-enzyme
(ACE) was isolated from aerial parts using chromatography. Its struc-
ture was determined as caryatin-7-O-β-rhamnoside (19) (Kurniawan
et al., 2016). In addition, the isolation of a xanthone glycoside from P.
pellucida called patuloside A (20) has been reported in the literature
(Fig. 3) (Khan et al., 2010).
The occurrence of steroids as another compound class has been
reported for P. pellucida collected in Asia. The ether-soluble neutral
fraction of the whole plant from the Philippines had apiole, 2,4,5-tri-
methoxystyrene, and three phytosterols: campesterol, stigmasterol and
β-sitosterol (Manalo et al., 1983). The isolation compounds from the
hexane and ethyl acetate fractions of P. pellucida, collected in Indonesia
and obtained by maceration with methanol, resulted in the identifica-
tion of stigmasterol, an analogue of pheophytin and β-sitosterol-D-
glucopyranoside (Hartati et al., 2015).

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The extract of P. pellucida from Malaysia was obtained by extraction
with 70% methanol, and the authors reported GC-MS analysis of the
extract to show phytol (37.88%), decahydro-2-naphthalenol, (26.20%),
which is not in the Dictionary of Natural Products and therefore raises
questions regarding its identification, methyl palmitate (18.31%), and
methyl linoleate (17.61%) as the only compounds in the extract (Wei
et al., 2011). Unfortunately, GC-MS analysis of a polar extract will
likely miss many non-polar volatiles as well as the higher molecular
weight non-volatile components. The other problem with this work is
that retention indices (RI) and retention times (RTs) values were not
reported, so there is nothing to compare with. The fact that four com-
pounds made up 100% of the extract is also improbable.
Ethanolic leaf extract of P. pellucida from Nigeria was rich in apiole
(15.0%), methyl 10-octadecenoate (15.3%) and phytol (16.6%) (Igwe
and Mgbemena, 2014). As above, GC-MS was used to analyze the
ethanol extract, so the non-polar EO components as well as the non-
volatiles were likely missed. In addition, several reported components
are doubtful. The identification of 10,12-octadecadiynoic acid (eluting
between β-caryophyllene and bicyclogermacrene) is dubious. The bu-
tylated hydroxytoluene (BHT) is most likely a contaminant and not a
natural product, 1,2-dimethoxy-4-(2-methoxyethenyl)benzene might be
2,4,5-trimethoxystyrene, which had been previously reported in P.
pellucida (Da Silva et al., 1999), and the MS shown in the manuscript for
methyl 10-octadecenoate is more consistent with methyl oleate (methyl
9-octadecenoate).
Phytochemical screening of crude extracts from different tissues of
P. pellucida has been described in the literature. The extracts and frac-
tions were mainly composed of: alkaloids, flavonoids (Ibibia, 2012),
sterols, tannins, reducing sugars (Mengome et al., 2010), saponins,
triterpenoids (Bialangi et al., 2016), carbohydrates, phenols (Oloyede
et al., 2011), azulenes, carotenoids, depsides (Mendes et al., 2011), and
quinones (Mazroatul et al., 2016).
5. Biological activities
5.1. Antibacterial and antifungal activity
Bioprospecting effective compounds against antibiotic- and anti-
fungal-resistant microorganisms has become a major priority in the last
few years (Arunachalam and Gayathri, 2010; Chandra et al., 2017). The
potential of P. pellucida EOs and extracts against a large spectrum of
Gram-positive, Gram-negative and acid-fast microorganisms has been
reported in several works (Table 3). Antimicrobial assays have also
been performed against human pathogenic fungi (Candida albicans,
Penicillium notatum) and phytopathogenic organisms, which include
Rhizopus stolonifera (also known as Rhizopus stolon), Fusarium mon-
iliforme, Aspergillus niger and Aspergillus flavus (Table 3).
The antimicrobial activity of P. pellucida EO from Nigeria was
evaluated against Gram-negative bacteria, which include Escherichia
coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella typhi,
Gram-positive microorganisms such as Staphylococcus aureus and
Bacillus subtilis, and against the fungi Candida albicans, Rhizopus stolon,
Aspergillus niger and Penicillium notatum. A complete list with the names
and morphological characteristics of the bacteria inhibited by P. pellu-
cida can be found in Table 4. Minimum inhibitory concentrations (MIC)
ranged from 25,000 to 200,000 µg/mL in comparison to standards
gentamicin and tioconazole for bacteria and fungi, respectively
(Oloyede, 2010). Usually, the antimicrobial activity of extracts is clas-
sified according to MIC values as good (MIC < 100 µg/mL), moderate
(MIC from 100 to 500 µg/mL) and weak (MIC from 500 to 1000 µg/mL)
(Holetz et al., 2002). Extracts with MIC values over 1000 µg/mL are
considered inactive.
EO from southwest Nigeria has been reported as effective to combat
pathogenic bacteria by microdilution method. Escherichia coli,
Enterobacter cloacae, Mycobacterium smegmatis, Listeria ivanovii,
Staphylococcus aureus, Streptococcus uberis, and Vibrio paraheamolyticus
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Journal of Ethnopharmacology 232 (2019) 90–102
had MIC values ranging from 150 to 200 µg/mL considering cipro-
floxacin (MIC 25–500 µg/mL) as the standard (Okoh et al., 2017).
The methanol leaf extract from Malaysia, which contained phytol,
decahydro-2-naphthalenol and methyl palmitate, was screened for an-
timicrobial activity. Edwardsiella tarda, Escherichia coli, Flavobacterium
sp., Pseudomonas aeruginosa and Vibrio cholerae were inhibited with a
MIC of 31.2 μg/mL; Klebsiella sp., Aeromonas hydrophila and Vibrio al-
ginolyticus at 62.5 μg/mL; and Salmonella sp. as well as V. para-
haemolyticus were inhibited at 125 μg/mL (Wei et al., 2011). Phytol was
previously described as active against eight bacterial (MIC 3–38 μg/mL)
and eight fungal strains (MIC 8–16 μg/mL) (Pejin et al., 2014). How-
ever, methyl palmitate is not described as antimicrobial agent. The
identification of MeOH extract was carried out by GC-MS, so these
substances do not necessarily represent its composition. Furthermore,
the compound decahydro-2-naphthalenol is not found in the DNP.
The ethanolic leaf extract of P. pellucida from Avodim Ubakala
(Nigeria) was evaluated against S. aureus, Enterococcus faecalis, B.
cereus, S. typhi, Proteus mirabilis and E. coli by disc diffusion technique.
The MIC values were very high, ≥ 25%, indicating the extract to be
inactive. Additionally, no positive control was reported. The major
components reported for this extract were apiole (15.0%), methyl 10-
octadecenoate (15.3%) and phytol (16.6%) (Igwe and Mgbemena,
2014). Note, however, that these compounds are the major volatile
compounds in the EtOH extract and not necessarily the main compo-
nents of the extract. The antifungal potential of apiole is well-known
(Meepagala et al., 2005; Razzaghi-Abyaneh et al., 2007), but there are
no reports on its antibacterial activity. Fatty acids (as their conjugate
bases) tend to be antimicrobial because they are surfactants, but methyl
esters tend not to be active (Thormar, 2011).
Methanolic extract of different tissues of P. pellucida collected in
Papua New Guinea was fractionated into petroleum ether (P), di-
chloromethane (DCM), ethyl acetate (EtOAc) (E) and butanol (BuOH).
The fractions were mainly composed of alkaloids, flavonoids, saponins,
sterols, tannins, triterpenoids. Butanol fractions (4 mg/disc) were the
most effective against Bacillus coagulans, Micrococcus roseus, E. faecalis,
E. coli and P. aeruginosa. Chloramphenicol was used as the positive
control (Khan and Omoloso, 2002). The xanthone glycoside patuloside
A (3-β-D-glucopyranosyloxy-1,5,6-trihydroxy-9H-xanthene-9-one) iso-
lated from P. pellucida displayed a high effect against four Gram-posi-
tive bacteria (B. subtilis, Bacillus megaterium, S. aureus, Staphylococcus
haemolyticus) and six Gram-negative bacteria (E. coli, Shigella dysen-
teriae, Shigella sonnei, Shigella flexneri, P. aeruginosa, S. typhi) with MIC
values ranging from 8 to 64 μg/mL where kanamycin (2–16 μg/mL) was
used as the standard antibiotic (Khan et al., 2010).
Phytochemical screening of ethanolic leaf extract of plants from the
Brazilian Amazon revealed the presence of phenols and tannins, fla-
vonoids, steroids and triterpenoids, azulenes, carotenoids, depsides and
depsidones. The extract exhibited antimicrobial potential against S.
aureus and P. aeruginosa with MIC of 625,000 µg/mL, but no reference
standard was described (Mendes et al., 2011). This assay was performed
by disc diffusion technique and the MIC value was greater than
1000 µg/mL, which can be considered inactive.
Phytochemical screening of aerial parts of individuals from
Ogbomoso, Nigeria revealed the presence of alkaloids and flavonoids in
the methanol extract. Antimicrobial assays were performed by the disc
diffusion test. The extract showed activity against S. typhi, P. aeruginosa,
and S. dysenteriae with MIC values varying from 1200 to 2500 µg/mL in
comparison to the standard ciprofloxacin (Ibibia, 2012). Furthermore,
ethanol leaf extract diluted in water at 70% was active against C. al-
bicans using agar diffusion method and Nystatin as the positive control
(Hastuti et al., 2017). Antimicrobial assays were also performed by
applying the agar well diffusion method. Proteus mirabilis, P. aeruginosa
and E. coli showed the highest susceptibility to the aqueous extract of
leaf of P. pellucida (17.4–21.2 mm) while P. aeruginosa (13.4–19.6 mm)
displayed the highest vulnerability to the ethanolic extract
(Akinnibosun et al., 2008). Nonetheless, this method does not allow
 Table 3
Peperomia pellucida essential oil, extract composition and antimicrobial activity.
N.S.F. Alves et al.

Material Plant part Compounds Microorganisms MIC Ref.

EO Leaf trans-3-pinanone (32.6%), 1-methylethylidene propane dinitrilea Bacteria: E. coli, S. aereus, B. subtilis, P. aeruginosa, K. pneumoniae and S. typhi. 100,000 to 200,000 µg/mL Oloyede (2010)
(18.6%) and 3-octyl acetate (13.1%) Fungi: C. albicans, R. stolon, A. niger and P. notatum
EO Leaf Germacrene D (10.3%), myristicin (11.3%) and dillapiole (37.8%) R. stolonifera and F. moniliforme 1250 to 5000 µg/mL François et al. (2013)
EO Stem and Leaf Stem: linalool (12.6%), β caryophyllene (11.5%) and limonene E. coli, E. cloacae, M. smegmatis, L. ivanovii, S. aureus, S. uberis, and V. 150–200 µg/mL Okoh et al. (2017)
(10.7%). paraheamolyticus
Leaves: linalool (17.1%), limonene (14.2%) and β-caryophyllene
(12.5%)
Extract Leaf EE: Alkaloids, tannins, saponins, terpenoids, flavonoids and cardaic EE: Klebsiella spp., Enterobacter, P. aeruginosa, E. coli 12.5 × 106 and 200 × 106 µg/ Ojo et al. (2012)
glycosides mL
Extract – – DE, EAE and ME: P. aeruginosa – Mohamad et al. (2015)
Extract Leaf HF: steroid, alkaloids, tannins, flavonoids; CF and EF: carbohydrates, EAF (S. aureus, B. subtilis, E. coli, P. mirabilis, P. fluorescens, P. aeruginosa, S. 1000 to 5,000 µg/mL Zubair et al. (2015)
alkaloids, tannins, flavonoids typhi); EF (E. coli, P. mirabilis, P. fluorescens, P. aeruginosa, S. typhi) and HF (S.
aureus, B. subtilis, B. cereus, E. coli, P. mirabilis, P. fluroescens, P. aeruginosa, S.
typhi); aqueous (no activity); CF (E. coli, P. fluorescens, P. aeruginosa And S.
typhi)
Extract Leaf HE: alkaloids, tannins, flavonoids, antraquinones, glycosides. ME: HE, ME and EAE: S. aureus, S. typhi, E. coli, K. pneumoniae, P. aeruginosa 25,000 to 200,000 µg/mL Idris et al. (2016)
alkaloids, saponins, tannins, flavonoids, glycosides. EAE: tannins,
flavonoids, antraquinones.
Extract Whole plant CE: steroids. CE: B. Subtilis and E. coli. – Kalaiarasi et al. (2016)
AE and ME: alkaloids and phenolics. AE and ME: B. subtilis, E. coli and P. aeruginosa
Extract Leaf alkaloids, tannins and flavonoids (type of extract not indicated) ME: S. aureus, E. coli, P. aeruginosa, K. pneumoniae, B. subtilis and C. albicans 25–50 μg/mL Abere et al. (2012)
Extract Leaf ME: flavonoids and alkaloids. ME and EAE: P. aeruginosa, S. typhii, S. dysenteriae 1250 to 2500 µg/mL Ibibia (2012)

96
EAE: flavonoids
Extract Leaf alkaloids, saponins, tannins, flavonoids and cardiac glycosides (type of Alcohol: S. aureus, S. mutans, E. coli, K. pneumoniae – Mensah et al. (2013)
extract not indicated)
Extract Leaf – EE: S. dysenteriae – Uddin (2014)
Extract Leaves, stems, alkaloids, saponin, tannins, flavanoids, steroids, and glycosides (type of ME: A. hydrophila, S. agalactiae 6200 to 12,500 µg/mL Manaf and Daud
flowers extract not indicated) (2016)
Extract Whole plant – EAE: S. aureus, B. subtilis, P. aeruginosa, and E. coli 200 µg/mL Bojo et al. (1994)
Extract Leaf Pachypophyllin (isolated from CE) E. coli – Ragasa et al. (1998)
Extract Leaf ME: Phytol (37.9%), decahydro-2-naphthalenola (26.2%) and methyl ME: E. tarda, E. coli, Flavobacterium sp., P. aeruginosa, V. cholerae, Klebsiella 31.2–125 μg/mL Wei et al. (2011)
palmitate (18.3%) sp., A. hydrophila, V. alginolyticus, Salmonella sp.
Extract Leaf EE: Apiole (15%), methyl 10-octadecenoatea (15.3%) and phytol EE: S. aureus, E. faecalis, B. cereus, S. typhi, P. mirabilis and E. coli – Igwe and Mgbemena
(16.6%) (2014)
Extract – BF: flavonoids, saponins and tannins BF: B. coagulans, M. roseus, S. faecalis, E. coli and P. aeruginosa – Khan and Omoloso
(2002)
Extract – Patuloside A (3-β-D-glucopyranosyloxy-1,5,6-trihydroxy-9H-xanthene- B. subtilis, B. megaterium, S. aureus, S. haemolyticus, E. coli, S. dysenteriae, S. 8–64 µg/mL Khan et al. (2010)
9-one) –isolated from EE sonnei, S. flexneri, P. aeruginosa, S. typhi
Extract Leaf EE: proteins, aminoacids, phenols and tannins, flavonoids, steroids and EE: S. aureus and P. aeruginosa 62,500 µg/mL Mendes et al. (2011)
triterpenoids, azulenes, carotenoids, depsides and depsidones
Extract Leaf – EE: C. albicans – Hastuti et al. (2017)
Extract Leaf – EE and AE: E. coli, P. mirabilis, P. aeruginosa and E. coli – Akinnibosun et al.
(2008)
Extract Leaf ME: alkaloids, tannins, resins, steroids, phenols and carbohydrates MF, HF, EAF, BE, AE: E. coli, S. aereus, B. subtilis, P. aeruginosa, K. pneumonae, 50,000–200,000 µg/mL Oloyede et al. (2011)
S. typhi, C. albicans, R. stolon, A. niger and P. notatum

Hexane extract (HE); Chloroform extract (CE); Dichloromethane extract (DE); Ethyl acetate extract (EAE); Ethanolic extract (EE); Methanol extract (ME); Aqueous extract (AE); Hexane fraction (HF); Butanol fraction (BF);
Chloroform fraction (CF); Ethyl acetate fraction (EAF).
a
The positive identification of this compound is in doubt.
Journal of Ethnopharmacology 232 (2019) 90–102
N.S.F. Alves et al. Journal of Ethnopharmacology 232 (2019) 90–102

Table 4
General characterization of the bacteria strains inhibited by Peperomia pellucida essential oils and extracts.
Bacteria Staining Shape Bacteria Staining Shape

Bacillus cereus Gram + Rod Enterobacter aerogenes Gram - Rod

Bacillus coagulans Gram + Rod Enterobacter cloacae Gram - Rod
Bacillus megaterium Gram + Rod Escherichia coli Gram - Rod
Bacillus subtilis Gram + Rod Flavobacterium sp. Gram - Rod
Enterococcus faecalis Gram + Spherical Klebsiella sp. Gram - Rod
Listeria ivanovii Gram + Rod Proteus mirabilis Gram - Rod
Micrococcus roseus Gram + Spherical Pseudomonas aeruginosa Gram - Rod
Mycobacterium smegmatis AF Rod Salmonella sp. Gram - Rod
Staphylococcus aereus Gram + Spherical Salmonella typhi Gram - Rod
Streptococcus agalactiae Gram + Spherical Shigella flexneri Gram - Rod
Streptococcus haemolyticus Gram + Spherical Shigella sonnei Gram - Rod
Streptococcus uberis Gram + Spherical Vibrio alginolyticus Gram - Curved-rod
Aeromonas hydrophila Gram - Rod Vibrio cholera Gram - Curved-rod
Edwardsiella tarda Gram - Rod Vibrio paraheamolyticus Gram - Curved-rod

Gram-positive (Gram +); Gram negative (Gram -); Acid-fast (AF).

comparison since MIC values are not provided in the manuscript. Ad-
ditional information regarding the antimicrobial potential of P. pellu-
cida EOs and extracts can be found in Table 3.
5.2. Cytotoxic activity
The use of anticancer drugs requires a balance between medical
safety and efficacy in patients (Hait, 2010). For this reason, the scien-
tific community's major goal has been to search for new efficient and
safe natural compounds against the variety of cancers present nowa-
days (Poonam and Chandana, 2015; Seca and Pinto, 2018). Wei and co-
workers (2011) have screened the methanol extract of P. pellucida
against the human breast adenocarcinoma (MCF-7) cell line and re-
ported an IC50 of 10.4 μg/mL. However, the data shown in their paper
reveals an IC50 > 30 μg/mL. Furthermore, the analysis of the extract by
GC-MS showed phytol, methyl palmitate, and decahydro-2-naphtha-
lenol (which is not found in the Dictionary of Natural Products). Phytol
had previously shown in-vitro cytotoxic activity against MCF-7 cells
(Satyal et al., 2012; Pejin et al., 2014).
A MeOH extract of P. pellucida exhibited a significant cytotoxic ac-
tivity against human cervical cancer cell line (HeLa) and the human
hepatic carcinoma cell line (Hep G2) and showed no toxicity against
normal human kidney cells (HEK 293) (Pappachen and Chacko, 2013).
The α-methylene lactones, 2-methylene-3-[(3′,4′,5′-trimethoxyphenyl)
(5″-methoxy-3″,4″-methylenedioxyphenyl)methyl] butyrolactone (ent-
7,8-didehydropaperomin B), and peperomin E, isolated from the EtOAc
extract of the whole plant, inhibited growth of human promyelocytic
leukemia (HL 60, IC50 1.4 and 1.8 µM), breast cancer (MCF-7, IC50 of
3.8 and 3.9 µM) and cervical cancer (HeLa, IC50 9.1 and 11.1 µM) cells
having etoposide (IC50 0.21, 0.19 and 3.6 µM) as the reference standard
(Xu et al., 2006).
5.3. Antioxidant activity
Antioxidants are molecules capable of neutralizing free radicals,
which are molecules characterized by the presence of an unpaired
electron. These radicals act by attacking important macromolecules
causing damage to the cell. Due to their instability and reactive char-
acteristic, they are usually associated with diseases such as cancer,
atherosclerosis, neurodegenerative syndromes and aging (Lobo et al.,
2010; Pisoschi and Negulescu, 2011). Several studies have reported the
potential of P. pellucida against free radicals. The EO from Nigeria at
concetrations of 0.1 mg/mL and 0.2 mg/mL showed 97.9% and 98.6%
of inhibition of free radical 2,2-diphenyl-1-picryhydrazyl radical
(DPPH) being more active than the standards ascorbic acid (90.9% and
68.7%), butylated hydroxyl anisole-BHA (95.4% and 94.3%) and α-
tocopherol (15.4% and 12.4%) (Oloyede, 2010); the antioxidant
activity the essential oil better than ascorbic acid, BHA and α-toco-
pherol is very surprising. The authors did not determine IC50 values for
the DPPH assay; the concentrations used were relatively high (100 and
200 μg/mL), so that the percent inhibitions were above 90%. In general,
BHA, ascorbic acid, and α-tocopherol are much better antioxidants and
free-radical scavengers than essential oils or essential oil components
(Ruberto and Baratta, 2000; Agnaniet et al., 2005; Wang et al., 2010;
Tsai et al., 2011; Amorati et al., 2013; Sharopov et al., 2015a, 2015b).
Note that reported IC50 values for DPPH activity are BHA, 3.09 μg/mL
(Mimica-Dukić et al., 2010); ascorbic acid, 7 μg/mL (Sharopov et al.,
2015a); and α-tocopherol, 0.041 μg/mL (Tsai et al., 2011).
Peperomia pellucida raw samples were exposed to γ-irradiation at
doses of 0, 2.5, 5, 7.5 and 10 kilogray (kGy). The results indicated that
ethanol crude extract of 7.5 kGy significantly increased activity, pro-
moting a decrease of IC50 value from IC50 244.9 μg/mL to 166.2 μg/mL
using the DPPH method. Quercetin was applied as the reference drug,
but no chemical composition was indicated (Mun'im et al., 2017).
The effect of extraction methods (maceration and reflux) with dif-
ferent solvents (methanol, butanol and ethylacetate) on DPPH sca-
vening was investigated. The extract obtained by refluxing EtOAc
showed the best IC50 value (74.0 µg/mL) in comparison to the methanol
extract (150.0 µg/mL). However, the chemical composition was not
idenfied, and the standard drug was not reported (Phongtongpasuk and
Poadang, 2014). The plant methanol extract from Malaysia had the
strongest free radical scavenging (IC50 83.0 µg/mL) in comparison to
the reference stantard BHT (IC50 27.0 µg/mL). However, the chemical
composition was not described (Mutee et al., 2010). Wei and co-
workers had reported that the methanol leaf extract of P. pellucida from
Malaysia showed significant DPPH radical inhibitory activity of 30%
inhibition at a concentration of 625 μg/mL (Wei et al., 2011). However,
a 30% inhibition of DPPH radical at 625 μg/mL cannot be considered
“significant” for a methanol extract. Free-radical scavenging activities
of IC50 < 100 μg/mL should be considered good activity in a DPPH
assay (Kukić et al., 2006; Jeong et al., 2008; Atmani et al., 2009).
Furthermore, it is not clear what the inhibitory components in the ex-
tract may be; these workers used only GC-MS to analyze the methanol
extract.
5.4. Fracture healing
Fractures are the most common large-organ injury in humans. Their
healing represents a postnatal regenerative process that resembles
embryonic bone development (Einhorn and Gerstenfeld, 2015). The
effect of the whole P. pellucida aqueous extract on fracture healing was
evaluated in female Wistar rats at doses of 100, 200, and 400 mg/kg.
The negative control received distilled water, and a second control
group of rats with no fractures was administered with 400 mg/kg of

97
N.S.F. Alves et al.
extract. The dry extract revealed the presence of some minerals such as
potassium (K), phosphorus (P), magnesium (Mg), calcium (Ca) and
sodium (Na). The effects on body weight, the relative weights of organs
(femurs, uteri and ovaries) and on hematology were evaluated. Peper-
omia pellucida extract increased body weight at 400 mg/kg, the amounts
of white blood cells (WBCs) by 60% at 200 mg/kg, and the amounts of
calcium, phosphorus and bone alkaline phosphatase (Florence et al.,
2017).
Ethanol extract was administered at doses of 100 and 200 mg/kg in
adult females Sprague-Dawley rats having a drill hole injury (0.80 mm)
in the femur diaphysis. Control groups received gum-acacia in distilled
water. The extract stimulated bone regeneration at the injury site and
increased mineral deposition to 9.4% at 100 mg/kg dose and to 84.8%
at 200 mg/kg. Furthermore, micro-computed tomography (mCT) was
performed to assess the internal microstructure of the mineralized
tissue. The results indicated that both doses increased bone volume,
trabecular thickness, trabecular number and decreased trabecular se-
paration and structure model index. The extract also induced the ex-
pression of osteogenic genes and increased mineralized nodule forma-
tion of bone marrow stromal cells (BMCs) over control, but the
chemical composition was not reported (Ngueguim et al., 2013).
5.5. Anti-inflammatory and analgesic activity
Pathogenic microrganisms, temperature changes and chemicals can
cause a series of damages to body tissues. Thus, the first step is to ac-
tivate the defense mechanism. In the initial stage, immune cells are
released into the affected area, causing inflammation which creates a
hostile environment against invading microorganisms. However, if in-
flammation is not controlled, it can become a chronic problem, causing
a series of damages to health (DeWit et al., 2017). Petroleum ether,
chloroform and methanol extracts of P. pellucida were evaluated in re-
gards to their effect on paw edema inhibition. The petroleum ether
extract significantly reduced inflammation at a dose of 1000 mg/kg in
comparison to the positive control indomethacin (10 mg/kg) (Mutee
et al., 2010). Similarly, 200 and 400 mg/kg of aqueous leaf extract
showed anti-inflammatory activity of 49.1% and 51.1% on edema in-
hibition in rats (Arrigoni-Blank et al., 2004). The anti-inflammatory
potential was assessed by using the carrageenan-induced rat hind paw
edema method.
Additionally, variations on the anti-inflammatory potential of P.
pellucida were evaluated during the four seasons of the year in east-
central Brazil, considering the vegetative (phenophase 1), beginning of
bloom (phenophase 2), complete bloom (phenophase 3), and seed set
(phenophase 4) phases. In the winter, the extract exhibited anti-in-
flammatory activity of 41.60% (phenophase 1), 36.70% (phenophase
2), and 36.90% (phenophase 4). In the summer, plants displayed po-
tential mainly on phenophases 1 and 2 with inhibition of 43% and 42%,
applying indomethacin (10 mg/kg) as the reference standard (Arrigoni-
Blank et al., 2002).
The analgesic potential of P. pellucida has also been assayed. This
activity refers to the property of relieving pain (Shipton, 1997). Aqu-
eous extract of aerial parts was evaluated by the abdominal writhing
test (induced by acetic acid) and the hot-plate method in mice. The
results showed that in the first test 400 mg/kg inhibited pain by 50.1%
while in the hot-plate test 100 mg/kg was enough to inhibit pain by
53.4% (Arrigoni-Blank et al., 2004). Likewise, the methanol extract of
aerial parts of plants from Nigeria was also reported as an analgesic
agent. MeOH extract exhibited a significant effect on acetic acid-in-
duced writhing in mice at doses of 70, 140 and 210 mg/kg with in-
hibition values of 37.7%, 66.4% and 78.3%, correspondingly (Aziba
et al., 2001).
5.6. Antidiabetic and anti-hypercholesterolemia activities
The plant antidiabetic activity was evaluated in alloxan-induced
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Journal of Ethnopharmacology 232 (2019) 90–102
diabetic rats. The blood glucose level had a 62%, 64% and 68% re-
duction in rats fed with glibenclamide (600 µg/kg body weight), P.
pellucida at 10% and 20% diet supplementation, in comparison to the
normal control group, which were fed with water. Treatment with
glibenclamide and the plant at 10% and 20% also led to increased ac-
tivities of superoxide dismutase (SOD), catalase (CAT) and glutathione
(GSH). The levels of aspartate transaminase (AST), alanine transami-
nase (ALT) and alkaline phosphate (ALP) were reduced in rats fed with
the plant compared to the diabetic control group (Hamzah et al., 2012).
The Oral Glucose Tolerance Test (OGTT) of the whole plant extract
in alloxan-induced diabetic mice indicated that animals fed with
500 mg/kg of extract significantly decreased blood glucose concentra-
tion at 90 and 120 min compared to diabetic control groups.
Phytochemical screening of leaf and stem extracts showed the presence
of flavonoids, glycosides, saponins and carbohydrates but was negative
for tannins (Sheikh et al., 2013). A new antidiabetic compound, 8,9-
dimethoxy ellagic acid, was isolated from the ethyl acetate fraction of P.
pellucida leaves from Indonesia by chromatographic separations on si-
lica gel 60 (Merck). The compound exhibited 33.7% of blood glucose
reduction in a normoglycemic model at 100 mg/kg body weight in al-
loxan-induced hyperglycemic Swiss Webster mice in comparison to the
diabetic control group (Susilawati et al., 2017).
The anti-hypercholesterolemia potential of an ethanol extract was
also tested with respect to total cholesterol, HDL, LDL, and triglycerides
present in the serum of Wistar rats. The ethanol extract at a dose of
300 mg/kg of body weight reduced total cholesterol and LDL, increased
HDL levels, but had no significant effect on triglycerides. The phyto-
chemical screening showed flavonoids, tannins, alkaloids, steroids and
quinones as major constituents of the extract (Mazroatul et al., 2016).
The anti-cholesterol activity was further evaluated in alloxan-induced
diabetic rats fed with P. pellucida 10% and 20% (w/w) diet supple-
mentation as well as mouse chow. The levels of total serum cholesterol,
triglycerides and LDL-cholesterol were reduced compared to untreated
diabetic rats. In addition, HDL-cholesterol was increased in these
groups having the diabetic control group as a reference (Hamzah et al.,
2012).
5.7. Toxicological studies
Peperomia pellucida (L.) Kunth toxicity has been evaluated in several
studies. Its aqueous extract at a dose of 5000 mg/kg in Swiss mice for 14
days indicated low toxicity because there were no changes in their
behavior or weight (Arrigoni-Blank et al., 2004). The plant ethanol
extract had mild toxicity with LD50 of 15.13 g/kg for male and 11.87 g/
kg for female mice (Dewijanti et al., 2014). The methanol (LC50
260.89 μg/mL), hexane (LC50 333.91 μg/mL), and ethyl acetate (LC50
45.85 μg/mL) fractions of the plant leaves were toxic, but the most
polar fractions (butanol and aqueous fractions) with lethal doses
greater than 1000 μg/mL were non-toxic using the brine shrimp leth-
ality assay (Oloyede et al., 2011).
The plant methanol extract had LD50 values higher than 4000 mg/
kg of body weight with no sign of toxicity on the skin and hair, re-
spiration system, defecation, feed intake and behavior using the acute
toxicity tests in Deutschland, Denken, and Yoken mice – DDY mice
(Waty et al., 2017). The acute toxicity of petroleum ether at 1200 mg/
kg and ethyl acetate fractions at 1000 mg/kg were found to be safe and
no mortality was observed for albino mice (Khan et al., 2008). Peper-
omia pellucida methanol extract showed LC50 of 2.4 ± 0.5 μg/mL while
the oil indicated LC50 of 8.3 ± 0.2 μg/mL employing the brine shrimp
bioassay (De Lira et al., 2009). When applying this method, crude ex-
tracts and isolated substances are classified as toxic with values of
LC50 < 1000 μg/mL and non-toxic with LC50 > 1000 μg/mL (Meyer
et al., 1982). The compound Patuloside A, isolated from the plant
leaves, had its toxicity determined by the same method, and the results
showed a LC50 value of 18.24 µg/mL which can be considered toxic
(Khan et al., 2010).
N.S.F. Alves et al.
5.8. Other activities
Angiotensin-converting enzyme (ACE) is a component of the renin-
angiotensin system (RAS). This system controls the blood pressure and
sodium homeostasis (Sparks et al., 2014). The enzyme increases blood
pressure by causing the constriction of blood vessels. For this reason,
ACE inhibitors have an important role in the treatment of hypertension,
heart failure as well as other hypertension-related end-organ damage
(Miller et al., 2006). ACE inhibition activity was evaluated after P.
pellucida samples were treated with gamma irradiation at doses of 0,
2.5, 5, 7.5 and 10 kGy. The data indicated that doses of 10 kGy in-
creased ACE inhibitory effect from 50.1% to 57.6% (Mun'im et al.,
2017). Moreover, a flavonoid inhibitor of ACE was isolated from the
aerial parts using chromatography. Its structure was determined as
3′,4′-dihydroxy-3–5-dimethoxyflavone-7-O-β-rhamnose. Later, its in-
hibitory activity was evaluated by using the in vitro hippuryl-L-histidyl-
L-leucine (HHL) substrate degradation method and showed IC50 of
7.7 μg/mL (Kurniawan et al., 2016).
The thrombolytic activity of P. pellucida has also been reported.
Thrombosis is an arterial disease associated with myocardial infarction
and stroke. It occurs when pathologic processes disregulate hemostasis
and excessive quantities of thrombin form in the site (Furie and Furie,
2008). Thrombolytic activity was evaluated by the Daginawala method
and streptokinase (SK) was used as the standard drug. The crude
ethanolic extract of leaves was partioned into solvents of different po-
larities. Phytochemical screening of the hexane-soluble fraction (HXSF)
showed steroid, alkaloids, tannins and flavonoids as the main compo-
nents while the chloroform extract (CSF) and ethanol-soluble fraction
(ESF) had carbohydrates, alkaloids, tannins and flavonoids. ESF ex-
hibited the highest activity (50.6%) against thrombosis when compared
to SK 62.7% (Zubair et al., 2015).
This plant species has also been popularly used to treat gastric ul-
cers. Scientifically, its gastroprotective activity has been identified by
applying the ethanol-induced gastric ulcer experimental in a rat model.
The highest activity was reported to be the dichloromethane extract
(82.3%) at 100 mg/kg, with dillapiole being the most active compound
present in the extract. Rats treated with dillapiole at 3, 10, 30 and
100 mg/kg indicated gastroprotective activity of 23.1%, 56.1%, 73.2%
and 85.5% in comparison to the negative control Tween 80 0.5%
(Rojas-Martínez et al., 2013).
Besides this, P. pellucida extract has also been described as an an-
tipyretic agent. This means that this herb has the potential to reduce
fever, which is a physiologic response triggered by infectious or aseptic
stimuli (Aronoff and Neilson, 2001). Petroleum ether and ethyl acetate-
soluble fractions of the ethanol leaf extract significantly reduced body
temperature in rabbits by 90% and 70% at 80 mg/kg body weight, re-
spectively. Pyrexia or fever had been previously induced in albino
rabbits by intraperitoneal administration of boiled milk at 0.5 mL/kg
body weight. These results were compared to the potential of aspirin
(positive control) which reduced fever by 92.5% (Khan et al., 2008).
The antisickling activity of aqueous methanol extract of P. pellucida
leaves from Benin City, Nigeria was evaluated in the HbSS (homo-
zygous form) red blood cells collected from sickle cell patients who
were not in crises (Abere and Okpalaonyagu, 2015). Sickle-cell disease
(SCD) is an inherited condition that causes abnormalities in ery-
throcytes, by not allowing an appropriate oxygen circulation (Rees
et al., 2010). The maximum inhibition was 57.5% at 90 min of in-
cubation with 500 mg/mL of the extract. The presence of alkaloids,
tannins, flavonoids, saponins and cardiac glycosides was reported in the
extract (Abere and Okpalaonyagu, 2015). The problem with most of
these reports is that phytochemical screening was performed, but not
phytochemical analysis. For this reason, it is not possible to know what
the active compounds are.
Furthermore, antidiarrheal activity of leaves extract was assayed by
using the castor oil-induced method. Diarrhea was caused by oral ad-
ministration of castor oil in mice (1.0 mL/mice). The positive control
99
Journal of Ethnopharmacology 232 (2019) 90–102
group received Loperamide (50 mg/kg), the negative control group
received distilled water (2 mL/mice) and the test groups were treated
with 250 mg and 500 mg/kg body weight of the ethanol leaf extract.
Phytochemical screening indicated that the ethanolic soluble fraction
(ESF) had carbohydrates, alkaloids, tannins and flavonoids as major
components. The ESF reduced the number of excretions by 41.8% at
250 mg/kg and 60.2% at 500 mg/kg body weight (Zubair et al., 2015).
Hair-growth-promoting activity of ethanolic extract of plants from
Indonesia has also been investigated. Rabbits were shaved and treated
with extracts at 25% (S1), 50% (S2), 75% (S3) and 100% (S4) (v/v).
Carboxymethyl cellulose (CMC) gel without the plant and 2% minoxidil
were used as negative and positive control, respectively. The results
indicated that topical CMC gel containing the ethanolic extracts in-
creased hair growth by approximately 8.68 mm (S1), 9.42 mm (S2),
10.50 mm (S3) and 11.02 mm (S4). Although these data were not sta-
tistically significant when compared to the positive control (11.3 mm),
this herb can still be a potent alternative for hair growth promotion
(Kanedi et al., 2017).
The effectiveness of the plant has been investigated against malaria,
a mosquito-borne infectious illness caused by the protozoan Plasmodium
falciparum. Malaria has been a major health problem because it has
caused illness and death in many children and adults around the world
(WHO, 2015). Antimalarial activity of P. pellucida extracts from Gor-
ontalo, Indonesia, indicated that fractions of n-hexane, ethyl acetate
and water had IC50 values of 12.8, 2.9 and 10.7 mg/mL against P. fal-
ciparum, respectively. Phytochemical screening of the methanol extract
indicated the presence of alkaloids, flavonoids, steroids, saponins and
triterpenoids (Bialangi et al., 2016).
The plant has also been popularly applied as an antihypertensive
remedy. Intravenous administration of aqueous extract (30 mg/kg)
from Jamaica caused a dose-dependent reduction in systolic blood
pressure (SBP) by 63.3% (40 ± 10 mmHg), diastolic blood pressure
(DBP) by 81.7% (15 ± 7 mmHg), heart rate (HR) by 91.6% (20 ± 7
beats/min) and mean arterial pressure (MAP) by 67.7%
(23.3 ± 5 mmHg) (Nwokocha et al., 2012). The phytochemical
screening of the methanol extract from Nigeria was positive for cardiac
glycosides and alkaloids and showed hypotensive activity on arterial
blood pressure. Intravenous administration of the extract reduced Mean
Arterial Blood Pressure—MABP (-75 ± 4.1%) and HR (-200 ± 20.4%)
compared to control (108 ± 2.1 mmHg and 420 ± 10 beats /min)
(Fasola and Adeboye, 2015).
6. Conclusion
Peperomia pellucida has been shown to be an important species in
traditional herbal medicine, which can be confirmed by its biological
potential presented in the literature surveyed. Nevertheless, some stu-
dies reporting biological assays were performed using sample at very
high concentrations or lacking in comparison with standard samples
and even without determining MIC values, potentially leading to false
positive results. Several reports on the essential oil composition have
appeared in the literature as well as studies with only phytochemical
screening which does not allow the identification of the components.
However, some of these reports identified compounds that are not
present in the Dictionary of Natural Products, which raises questions
regarding their identification since there may be new substances
without their chemical structure elucidated.
The next steps on studying P. pellucida should be to carry out a
comprehensive phytochemical analysis of the plant and to more accu-
rately define its biological activities so that bioactivities can be corre-
lated to phytochemical components. Furthermore, antimicrobial and
anticancer essays, for example, need to be further explored in order to
comprehend the species potential as a whole. Additionally, new bio-
logical tests are still needed to scientifically validate some of its eth-
nopharmacological applications so that the plant can be used as a future
resource for disease treatment.
N.S.F. Alves et al.
CRediT authorship contribution statement
Nayara Sabrina F. Alves: Conceptualization, Investigation,
Resources, Writing - original draft, Writing - review & editing.
William N. Setzer: Conceptualization, Investigation, Resources,
Writing - original draft, Writing - review & editing. Joyce Kelly
R. da Silva: Supervision.
Acknowledgements
The authors are grateful to the Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES - Coordination for the Improvement
of Higher Education Personnel) for providing a scholarship to N.S.F.
Alves. They also thank Prof. Huy Hùng Nguyễn for providing in-
formation on traditional medicinal uses of Peperomia pellucida in
Southeast Asia.
Conflict of interest statement
The authors have no conflict of interest.
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