Journal of Ethnopharmacology 257 (2020) 112853

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

Chemical profile, traditional uses, and biological activities of Piper chaba T

Vahl: A review
Muhammad Torequl Islama,b,∗∗, Jabed Hasanc, H. M. Shadid Hossain Snigdhad, Eunus S. Alie,
Javad Sharifi-Radf, Miquel Martorellg, Mohammad S. Mubarakh,∗
a
Laboratory of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City, 700000, Viet Nam
b
Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, 700000, Viet Nam
c
Department of Applied Chemistry and Chemical Engineering, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj,
8100, Bangladesh
d
Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh
e
College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
f
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
g
Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion, 4070386, Chile
h
Department of Chemistry, The University of Jordan, Amman, 11942, Jordan

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

Keywords: Ethnopharmacological relevance: Piper chaba Hunter, called Chui Jhal or Choi Jhal, is commonly used as a cu-
Piper chaba linary (spice) herb in India and Bangladesh. It exhibits numerous important biological activities and has been
Traditional medicine widely used in traditional medicine.
Chabamides Aim of the study: This review focuses on the chemical and pharmacological activities of a culinary ingredient P.
Cytotoxicity
chaba based on information extracted from the literature to highlight its use in traditional medicine.
Phytotherapy
Methods: A literature search in known databases was conducted (till September 2019) for published articles
Biological effects
using the relevant keywords.
Results: Findings suggest that, to date, a number of important phytoconstituents such as dimeric alkaloids, and
alkamides have been isolated from various parts of P. chaba. Extracts from P. chaba or derived compounds
exhibit diverse biological activities, such as anti-microbial, anti-leishmanial, anti-malarial, anti-parasitic, cyto-
toxic/anticancer, adipogenic, hepato- and gastro-protective, anti-diabetic, analgesic, anti-diarrheal, depressive,
anti-inflammatory, diuretic, anti-hypertensive, antipyretic, anti-ulcer, and immunomodulatory effect. Among
the isolated compounds, chabamides, piperine, piplartine, retrofractamides A/B, methylenedioxyphenyl)-nona-
2E,4E,8E-trienoic acid, n-butyl or n-pentyl amine, piperlonguminine, pipernonaline, dehydropipernonaline, N-
isobutyl-(2E,4E)-octadecadienamide, and N-isobutyl-(2E,4E,14Z)-eicosatrienamide have documented important
biological effects in various test systems.
Conclusions: Taken together, P. chaba may be a potential source of plant-based therapeutic lead compounds,
which justify its uses in traditional medicine.

1. Introduction their native habitat. Approximately ten (10) species of the genus Piper
have been used in traditional medicine to treat cancer or cancer-like
The word ‘Pepper’ is derived from the Sanskrit word for long pepper symptoms, and 35 extracts and 32 isolated compounds from more than
(pippali) (Kumar et al., 2011). The genus ‘Piper’ belonging to the family 24 Piper species have been reported for cytotoxic effects against dif-
‘Piperaceae’ is an economically and ecologically important genus. It ferent cancer cell lines (Wang et al., 2014). The species Piper longum L.
contains about 1,000–2,000 species of plants with dominant species in is commonly used to treat various diseases, including chronic

Abbreviations: p-Akt, Phospho-Akt; ERK1/2, Extracellular signal-regulated protein kinases 1 and 2; D-GalN, D-galactosamine; GLUT4, glucose transporter 4; IRS-1,
insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MIC, minimum inhibitory concentration; PARP-1, poly (ADP-ribose) polymerase
1; P-gp, P-glycoprotein; PPARγ2, peroxisome proliferator-activated receptor gamma2
∗
Corresponding author.
∗∗
Corresponding author. Laboratory of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City, 700000, Viet Nam.
E-mail addresses: [email protected] (M.T. Islam), [email protected] (M.S. Mubarak).

https://doi.org/10.1016/j.jep.2020.112853
Received 21 December 2019; Received in revised form 2 April 2020; Accepted 4 April 2020
Available online 10 April 2020
0378-8741/ © 2020 Elsevier B.V. All rights reserved.
M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

bronchitis, asthma, constipation, gonorrhea, paralysis of the tongue,

diarrhea, cholera, chronic malaria, viral hepatitis, respiratory infec-
tions, stomachache, bronchitis, diseases of the spleen, cough, and tu-
mors (Kumar et al., 2011). Other important species of this genus are P.
nigrum, P. betle, and P. auritum. Many plants of this genus have been
used to treat several diseases Worldwide and could be used as natural
antioxidants and antimicrobial agents in food preservation (Salehi
et al., 2019). In a recent comprehensive review, Salehi et al. (2019)
concluded that Piper species may be a potential source of secondary
metabolites that could be used to maintain human health.
Research findings indicated that Piper chaba Hunter (syn. of Piper
retrofractum Vahl and Piper officinarum (Miq.) C. DC.) (The Plant List,
2020) exhibits diverse biological activities (Sawangjaroen et al., 2005;
Romero-Benavides et al., 2017) including, anticancer (Ruangnoo et al.,
2012; Rattarom et al., 2014) and immunomodulatory effect (Panthong
and Itharat, 2014). Moreover, chabamide (1), a dimeric alkaloid iso-
lated from P. chaba, exhibited antimalarial, antituberculosis, and cy-
totoxic activities (Ren et al., 2015). Piperine (2), a pungent alkaloid and
is the main compound present in black pepper and some other Piper
species, including P. chaba, has numerous important pharmacological
activities, including antimicrobial, immunomodulatory, hepatoprotec-
tive, antioxidant, antimetastatic, and antitumor, among others
(Stojanovíc-Radíc et al., 2019). In addition, this compound can be one
of the potential phytotherapeutic tools in the treatment of oxidative
stress, gastrointestinal tract complications, oxidative stress-related dis-
eases and disorders, and cancer (Srinivasan, 2007; Manayi et al., 2018).
Similarly, piplartine (3, 4), an amide alkaloid of this plant, is an ex- Fig. 1. Different parts of Piper chaba Hunter.
ample of another important anticancer lead compound (Wang et al.,
2014; Piska et al., 2018). Other important pharmacological effects of Fruits are elongated in shape (up to 3 inches long), red when ripe, turns
piplartine (3, 4) include cytotoxic, genotoxic, antitumor, anti- dark brown to black when dry (Ruangnoo et al., 2012).
angiogenic, antimetastatic, antiplatelet aggregation, antinociceptive,
anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, anti-
2.3. Geographical distribution
bacterial, antifungal, leishmanicidal, trypanocidal, and schistosomi-
cidal activities (Bezerra et al., 2013). Another important P. chaba
Piper chaba (Fig. 1), a flowering vine, native to South and Southeast
compound is sesamin (5) that can be considered an effective adjuvant
Asia, is called Chui Jhal or Choi Jhal in Bangladesh and India. P. chaba
therapeutic agent in ameliorating tumor development and progression,
is found throughout India and other warmer regions of Asia, including
and hence, could be used in the prevention and/or treatment of various
Malaysia, Indonesia, Singapore, and Sri Lanka (Ruangnoo et al., 2012).
types of cancer (Majdalawieh et al., 2017). Accordingly, this review
focuses on the current knowledge about the therapeutic ability, tradi-
tional uses, and pharmacological activities of P. chaba and/or its ex- 3. Chemical profile, traditional uses and biological activities of P.
tracts and derived compounds. For this purpose, recent relevant refer- chaba
ences, dealing with these topics, have been obtained from different
databases such as PubMed, ScienceDirect, and Google Scholar. We hope To date, a number of important phytoconstituents have been iso-
this work will be a useful addition and a good help to researchers in the lated from various parts of P. chaba. Compounds isolated from the stem
field. included β-sitosterol, piperine (2), piplartine (3, 4) (Mishra and Tewari,
1964), [SR,S’R]-9-hydroxy,3,4-dimethoxy,3’,4’-methylene dioxy-9,9’
2. Plant profile epoxy lignan (Bhandari et al., 1998), and chabamide (1)
(Rukachaisrikul et al., 2002). On the other hand, research findings in-
2.1. Taxonomy dicated that roots of P. chaba contain alkamides, sitosterol (Patra and
Ghosh, 1974), piperlonguminine (6), pipercallosine, dihydropipercide,
Kingdom: Plantae piperine (2), sylvatine (Strunz, 2000), cis & trans-piplartine (3, 4)
Phylum: Magnoliophyta (Jyothi et al., 2009), dimeric alkaloids (e.g., chabamide F and G), pi-
Class: Eudicots perine (2), guineesine (7), brachystamide B (8) (Rao et al., 2009),
Order: Piperales chabamide F and K, pellitorine (9), trichostachine (10) (Rao et al.,
Family: Piperaceae 2011), bornyl piperate, piperlonguminine (6) and piperine (2) (Naz
Genus: Piper et al., 2012). Similarly, published work revealed that fruits of P. chaba
Species: Piper chaba Hunter are rich in phytochemicals such as amide constituents (e.g., piperine
(2), piperchabamides A-E (11–16), and piperanine (17)) (Matsuda
Plant taxonomy has been confirmed in the "The Plant List" database et al., 2008), amide constituents (e.g., piperlonguminine (6) and ret-
(www.theplantlist.org). rofractamides A, B, and C (18–20); methyl piperate (21), piperanine
(17), piperine (2), piperoleine B (22), pipernonaline (23), dehy-
2.2. Morphology dropipernonaline (24), piperundecalidiene (25), piperlonguminine (6),
piperchabamide D (14), guineesine (7), brachystamide B (8), N-iso-
Piper chaba is a creeper plant that spreads on the ground and may butyl-(2E,4E)-decadienamide (26), N-isobutyl-(2E,4E)-dodecadiena-
also grow around large trees. Leaves are oval-shaped (about 2 to 3 in- mide (27), N-isobutyl-(2E,4E)-octadecadienamide (28), N-isobutyl-
ches long), flowers are monoceous and blossom during the monsoon. (2E,4E,14Z)-eicosatrienamide (29), troglitazone) (Zhang et al., 2008),

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M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

Table 1
Phytochemical profile of Piper chaba Hunter.
Secondary metabolites/Isolated compoundsa Chemical class Plant part References
(s)

Piperine (2), piplartine (3, 4) Alkaloids Stem Mishra and Tewari (1964)
β-sitosterol Phytosterol Stem Mishra and Tewari (1964)
[SR,S’R]-9-hydroxy,3,4-dimethoxy,3’,4’-methylene dioxy-9,9’ epoxy lignan Epoxylignane Stem Bhandari et al. (1998)
Chabamide (1) Piperine dimer alkaloid Stem Rukachaisrikul et al. (2002)
Alkamides, sitosterol Root Patra and Ghosh (1974)
Piperlonguminine (6), pipercallosine, dihydropipercide, piperine (2), sylvatine Alkaloids Root Strunz (2000)
cis & trans-piplartine (3, 4) Root Jyothi et al. (2009)
Dimeric alkaloids (e.g., chabamide F and G), piperine (2), guineesine (7), brachystamide B (8) Dimeric alkaloids Root Rao et al. (2009)
Chabamide F and K, piperine (2), pellitorine (9), trichostachine (10) Root Rao et al. (2011)
Bornyl piperate, piperlonguminine (6), piperine (2) Root Naz et al. (2012)
Amide constituents (e.g., piperine (2), piperchabamides A-E (11 to 15), and piperanine (17)) Alkaloid amide Fruit Matsuda et al. (2008)
Amide constituents (e.g., piperlonguminine (6) and retrofractamides A, B, and C (18, 19, 20); methyl Alkaloids containing amide Fruit Zhang et al. (2008)
piperate (21), piperanine (17), piperine (2), piperoleine B (22), pipernonaline (23), constituents
dehydropipernoline, piperundecalidiene, piperchabamide D (14), guineesine (7), brachystamide
B (8) , N-isobutyl-(2E,4E)-decadienamide (26), N-isobutyl-(2E,4E)-dodecadienamide (27), N-
isobutyl-(2E,4E)-octadecadienamide (28), N-isobutyl-(2E,4E,14Z)-eicosatrienamide (29),
troglitazone)
Piperchabamide F (15), piperchabaosides A and B (30, 31) Fruit Morikawa et al. (2009)
Piperine (2) Alkaloid Fruit Plengsuriyakarn et al. (2012)
Retrofractamide A (18) Alkaloid Fruit Matsuda et al., 2014
9-(3’,4’-methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid and an n-butyl or n-pentyl amine Fruit Mourad et al. (2013)
Piperlonguminine (6) Alkaloid amide Fruit Yamaguchi et al., 2014
2,4-decadienoylpiperidine, (2E,4E)-N-isobutyldecadienamide, piperlonguminine (6), sylvetin – Parmar et al. (1997)
Piplartine (3, 4) – Rao et al. (2012)
Sesamin (5) – Mgbeahuruike et al. (2017)

a
Number of the compounds (from Fig. 2) are shown here in parenthesis.

piperchabamide F (16), piperchabaosides A and B (30, 31) (Morikawa In general, the stem, roots, and peel of P. chaba are chopped into small
et al., 2009), piperine (2) (Plengsuriyakarn et al., 2012), retro- pieces and added to meat and fish, especially the mutton, in Bangla-
fractamide A (18) (Matsuda et al., 2014), 9-(3’,4’-methylenediox- desh, India, and Thailand. Fruits of the plant are evident to possess
yphenyl)-nona-2E,4E,8E-trienoic acid and an n-butyl or n-pentyl amine antidiarrhetic, carminative (Atjanasuppat et al., 2009; Plengsuriyakarn
(Mourad et al., 2013), piperlonguminine (6) (Yamaguchi et al., 2014). et al., 2012), digestive tonic, antidinic, and expectorant activity
Other constituents isolated from this plant are: 2,4-decadienoylpiper- (Atjanasuppat et al., 2009) (Table 2).
idine, (2E,4E)-N-isobutyldecadienamide, piperlonguminine (6), syl-
vetin (Parmar et al., 1997), piplartine (3, 4) (Rao et al., 2012), sesamin
3.2. Pharmacological activities
(5) (Mgbeahuruike et al., 2017). Summarized in Table 1 are the dif-
ferent phytoconstituents isolated from P. chaba, whereas shown in
3.2.1. Anti-bacterial effect
Fig. 2 are the chemical structures of these compounds.
Research conducted by Rukachaisrikul and coworkers revealed that
chabamide (1), isolated from the stem of P. chaba exhibits activity
against Mycobacterium tuberculosis (strain: H37Ra) with the minimum
3.1. Ethnobotanical uses
inhibitory concentration (MIC) of 12.5 μg/mL (Rukachaisrikul et al.,
2002). Bornyl piperate and piperlonguminine (6) (200 μg/disc) isolated
Ethnomedical uses contribute to a higher rate of activity in drug
from the root of the plant showed antibacterial activity against Bacillus
discovery and development worldwide (Gyllenhaal et al., 2012). Piper
subtilis, Bacillus megaterium, Staphylococcus aureus, Staphylococcus β-
species are commonly used to treat numerous diseases, including ur-
haemolyticus, Escherichia coli, Salmonella typhi, Shigella dysenteriae, Shi-
ological problems, skin, liver and stomach ailments, wound healing,
gella shiga, and Shigella boydii (zones of inhibition between 9 to 14 mm)
fever, and inflammation (Salehi et al., 2019). Furthermore, P. chaba is
(Naz et al., 2012). On the other hand, petroleum ether and chloroform
used in asthma, bronchitis, piles, colic pain, dyspepsia and gastralgia
extracts of the root at 200 μg/disc also show anti-bacterial effects
(Chopra, 1958; Krishnan, 1986). The aerial part of the plant exerts
against the same bacterial species (13 to 19 mm zones of inhibition).
carminative, diuretic, stimulant, expectorant, analgesic, and smooth
Similarly, an ethanol extract of the plant exhibited activity against
muscle relaxant properties (Yusuf et al., 1994; Ghani, 2003; Haque
Streptococcus pyogenes (MIC: 1000 μg/mL) (Limsuwan and
et al., 2004). On the other hand, the fruits exhibit gastro-protective,
Voravuthikunchai, 2013). In a most recent study, Panphut et al. (2020)
anti-flatulent, appetizing, expectorant, erythropoietic and anti-tussive
examined the antimicrobial activity of the fruit extracts of P. retro-
properties (Chojnowska et al., 1979; Sireeratawong et al., 2012),
fractum (syn. P. chaba) and showed that the methanol extract inhibits
whereas the stem is used in rheumatic pains and diarrhea and also to
nine of ten of human and animal pathogens tested.
reduce post-delivery pain in mothers (Yusuf et al., 1994). P. longum,
another species of the Genus Piper, is also used in traditional medicine,
including the Ayurvedic system of medicine (Kumar et al., 2011). 3.2.2. Anti-fungal effect
P. chaba is considered one of the expensive spices in Bangladesh, Research findings by Naz and colleagues indicated that bornyl pi-
and its taste is similar to horseradish. Benjakul preparation, an inter- perate and piperlonguminine (6) (200 μg/disc), isolated from the roots
esting Thai traditional medicine, is composed of five plants: P. chaba of P. chaba showed potent anti-fungal activity against Aspergillus fumi-
fruit, Piper sarmentosum Roxb. root, Piper interruptum Opiz stem, gatus, Aspergillus niger, Aspergillus flavus, and Candida albicans (zones of
Plumbago indica L. root, and Zingiber officinale Roscoe rhizome. This inhibition between 10 to 20 mm) when compared with standard drug
preparation has been used to treat cancer on the basis of selective in- nystatin. In addition, petroleum ether and chloroform extracts of the
terviews of folk doctors in Southern Thailand (Ruangnoo et al., 2012). root at 200 μg/disc exhibited anti-fungal effects against the same fungi

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M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

Fig. 2. Chemical structures of some important phytoconstituents isolated from Piper chaba.

Table 2
Traditional uses of Piper chaba.
Plant part(s)/Preparation Effects References

Fruits Antidiarrhetic, carminative Atjanasuppat et al. (2009); Plengsuriyakarn et al. (2012)

Digestive tonic, antidinic, expectorant Atjanasuppat et al. (2009)

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M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

species (10 to 14 mm zones of inhibition) (Naz et al., 2012). compounds induced cell cycle arrest at the G1 phase, suppressed the
diferuloylmethane-induced G2/M arrest in combination, and inhibited
3.2.3. Anti-leishmanial effect the cell cycle progression by inactivating cdk2 and destabilizing cyclin
Along with their antibacterial and anti-fungal activity, bornyl pi- D1. In contrast, a combination with diferuloylmethane inhibited the
perate and piperlonguminine (6) exerted activity against Leishmania extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and
donovani (IC50 values 16 and 30 μg/mL, respectively). Furthermore, Raf-1 signaling in addition to the inhibition of cell cycle progression
petroleum ether and chloroform extracts of the root also showed anti- (Jyothi et al., 2009). Research findings by Mahavorasirikul et al. (2010)
leishmanial effects, where IC50 values were 32 and 34 μg/mL, re- revealed that the ethanol fruit extract of P. chaba exhibits cytotoxic
spectively (Naz et al., 2012). effect against a number of cancer cell lines (e.g., CL-6, HepG2, Hep-2,
HRE) (IC50 values: 50.62 ± 3.10, 72.25 ± 1.15, 12.42 ± 7.99, and
3.2.4. Anti-malarial effect 119.14 ± 9.94 μg/mL, respectively) (Mahavorasirikul et al., 2010). In
Malaria is considered one of the world's leading killer infectious a similar fashion, chabamide (1) and chabamide G exhibited cytotoxic
diseases with high incidence and morbidity, and the problem of mul- effects against human cervical (HELA), breast (MCF-7), liver (HEPG2),
tidrug-resistant Plasmodium falciparum has been alarming in several colon (HT-29), and colon (COLO-205) cancer cell lines (Rao et al.,
parts of the globe, particularly in Southeast Asia. Hence, the search for 2011). In addition, both of these compounds exhibited potent cytotoxic
new effective and potent antimalarial drugs is becoming a necessity. In effect against COLO-205 cell line (IC50 value of 3.10 and 0.018 μg/mL,
this context, a team of researchers examined the antimalarial activity of respectively).
27 medicinal plants and 5 herbal formulations used in Thai traditional Researchers studied the molecular mechanism underlying the cy-
medicine against chloroquine-resistant (K1) and chloroquine-sensitive totoxicity and down-regulation of P-gp expression by chabamide (1) in
(3D7) P. falciparum clones. These researchers found that the ethanol adriamycin-resistant human leukemia cells (K562/ADR). These re-
extract of P. chaba, among others, exhibit significant and promising searchers showed that chabamide (1) inhibits the growth of K562/ADR
activity against P. falciparum (strains: K 1 and 3D7) with IC50 values of cells in a dose- and time-dependent manner, and substantially sup-
5.3 and 4.1 μg/mL, respectively (Thiengsusuk et al., 2013). Previously, presses cell proliferation by cell cycle arrest in the G0/G1 phase, which
chabamide (1) displayed activity against P. falciparum (strain: KI) with was linked to an increase in p21 and a decrease in cyclin D1 and CDK2/
an IC50 value 2.7 μg/mL (Rukachaisrikul et al., 2002). Recently, find- 4/6 protein expression. Moreover, chabamide (1) regulated the changes
ings by Thiengsusuk et al. (2018) demonstrated that piperine (2), the in the mitochondrial membrane potential, increased the expression of
major isolated constituent of P. chaba fruits showed activity against 3D7 apoptosis-related proteins, such as Bax and cytochrome c, and de-
(chloroquine-sensitive) and K1 (chloroquine-resistant) P. falciparum creased the protein expression levels of Bcl-2, caspase-9, caspase-3, poly
clones with IC50 values of 111.5 and 59 μM, respectively. These re- (ADP-ribose) polymerase 1 (PARP-1), and phospho-Akt (p-Akt). It also
searchers suggested that piperine (2) could be a promising candidate regulated the c-Jun N-terminal kinase (JNK), ERK1/2, and p38 (Ren
for the development of an antimalarial drug on the basis of its anti- et al., 2015; Hu et al., 2016). It also induced autophagy through au-
malarial potency and low risk of resistance development (Thiengsusuk tophagic vacuole and active autophagosome formation. Listed in
et al., 2018). On the other hand, the ethanol fruit extract of P. chaba and Table 3 are the biological effects of P. chaba.
other medicinal plants exhibited inhibitory activities against cyto-
chrome P450-mediated hepatic metabolism (CYP1A2, CYP2C19, 3.2.7. Adipogenesis effect
CYP2D6 and CYP3A4) (IC50 values within 0.04 ± 0.01 and Research by Zhang and coworkers indicated that several amide
29.39 ± 1.82 μg/mL) in malaria and cholangiocarcinoma using constituents from the fruit of P. chaba, including piperlonguminine (6)
human liver microsomes (in vitro) (Sumsakul et al., 2015). and retrofractamides A, B, and C (18–20) promoted adipogenesis of
3T3-L1 cells. These researchers also found that retrofractamide A (18)
3.2.5. Anti-parasitic effect was the most active and significantly increased the amount of adipo-
Methylene chloride extract of fruits exerted a strongest effect on nectin released into the medium and the uptake of 2-deoxyglucose into
Schistosome cercariae (Atjanasuppat et al., 2009). This extract exhibited the cells. It additionally increased mRNA levels of adiponectin, per-
higher SI (> 100) than the positive control used towards S. cercariae. oxisome proliferator-activated receptor gamma 2 (PPARγ2), glucose
transporter 4 (GLUT4), and insulin receptor substrate 1 (IRS-1) (Zhang
3.2.6. Cytotoxicity and potential anti-cancer activity et al., 2008). A similar effect was observed for an amide composed of 9-
Cancer continues to be a global concern, despite the technological (3’,4’-methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid and an n-
and pharmaceutical improvements over the years (Seyed et al., 2016). butyl or a n-pentyl amine. The amide with the n-pentyl amine con-
It is the second leading cause of death worldwide, and results in siderably increased the uptake of 2-deoxyglucose into the cells. It ad-
thousands of deaths each year. Chemotherapy continues to be an im- ditionally increased the mRNA levels of adiponectin, PPARγ2, GLUT4,
portant treatment option for different cancers, although resistance, fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein
toxicity, and mutation of targets remain the major causes of che- (C/EBP) α and β in a similar manner as the PPARγ agonist troglitazone
motherapy failure (Tiwari et al., 2011). Thus, more research is required (Mourad et al., 2013). Moreover, piperlonguminine (6) (3–30 μM)
in the area of discovery and development of novel anticancer agents showed an adipogenesis effect, through an increase in mRNA levels of
that can deal with these causes of chemotherapeutic failure. Along this adiponectin, GLUT4, aP2, and PPARγ2 in 3T3-L1 cells (Yamaguchi
line, numerous medicinal plants and related compounds have been et al., 2014).
found promising in the chemoprevention and treatment of cancer. In
this context, petroleum ether and chloroform root extracts of P. chaba 3.2.8. Hepatoprotective effect
along with the isolated compounds bornyl piperate and piperlongumi- Research findings demonstrated that the aqueous acetone extract
nine (6) displayed cytotoxic effects against Artemia salina (LC50 values from the fruit of P. chaba (80%) at 25, 50, and 100 mg/kg (p.o.), and
within 0.76 to 1.53 μg/mL) (Naz et al., 2012). On the other hand, the piperine (2) (5 and 10 mg/kg (p.o.)) exhibit hepatoprotective effects
chloroform fruit extract of the plant exerted a cytotoxic effect against against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced
Entamoeba histolytica (HM1: IMSS) (IC50: 71.4 μg/mL) (Sawangjaroen liver injury in mice (n = 8) (Matsuda et al., 2009). On the other hand,
et al., 2006). Similarly, cis & trans-piplartine (3, 4) (2–25 μM) induced piperine (2) (2.5–10 mg/kg (p.o.)), a component of P. chaba, exerted a
dose-dependent cytotoxic effects on rat histiocytoma (BC-8), mouse dose-dependent hepatoprotective effect in D-GalN/LPS-induced liver
embryonal carcinoma (PCC4), mouse macrophages (P388D1 and J774), injury in mice (n = 4) (Matsuda et al., 2008). Moreover, piperine (2)
and human neuroblastoma (IMR32) tumor cells. In addition these (10–100 μM) inhibited the increase in serum GPT and GOT levels, and

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M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

Table 3
Pharmacological effects of crude extracts or fractions of Piper chaba.
Extract/Fractions Conc./Dose/Admin. route & Test system Activity (Possible mechanism) References

Methanol stem bark extract 125, 250, and 500 mg/kg (p.o.) in mice (n = 6) for Significant dose-dependent analgesic, Taufiq-Ur-Rahman et al.
analgesic, antidiarrheal, sleeping, and antiinflammatory, antidiarrheal, gastrointestinal (2005)
gastrointestinal motility test motility, and depressant effects, with moderate diuretic
In Wistar rats (n = 6) for diuretic and anti- activity only at highest dose.
inflammatory activity test
Chloroform fruit extract Entamoeba histolytica (strains: HTH-56:MUTM and Cytotoxic effect against HM1: IMSS strain (IC50 = 71.4 Sawangjaroen et al.
HM1:IMSS) μg/mL). (2006)
Methylene chloride fruit extract Schistosome cercariae Strongest effect. Atjanasuppat et al. (2009)
80% aqueous acetone extract of 25, 50, and 100 mg/kg (p.o.) in D-galactosamine/ Hepatoprotective effect. Matsuda et al. (2009);
fruit lipopolysaccharides- induced liver injury in mice Morikawa (2010)
(n = 8)
Ethanol fruit extract Cancer cell lines (CL-6, HepG2, Hep-2, HRE) Cytotoxic effect (IC50 values: 50.62 ± 3.10, Mahavorasirikul et al.
72.25 ± 1.15, 12.42 ± 7.99, and (2010)
119.14 ± 9.94 μg/mL, respectively).
Ethanol fruit extract 100, 500, and 1000 mg/kg (p.o.) in mice (n = 6) Antihypertensive, analgesic, anti-inflammatory, Plengsuriyakarn et al.
antipyretic, and anti-ulcer activities. (2012)
Petroleum ether and chloroform Bacillus subtilis, Bacillus megaterium, Staphylococcus Anti-bacterial, anti-fungal effect (zones of inhibition Naz et al. (2012)
root extracts aureus, Streptococcus. β-haemolyticus, Escherichia coli, between 9 to 20 mm)
Salmonella typhi, Shigella dysenteriae, Shigella shiga, Antileishmanial activity (IC50 values 16 and 30 μg/mL,
Shigella boydii, Aspergillus fumigatus, Aspergillus niger, respectively)
Aspergillus flavus, Candida albicans, Leishmania Cytotoxicity in Artenia salina (LC50 values 0.76 and
donovani, Artemia salina 0.83 μg/mL, respectively)
Ethanol fruit extract 300, 600, and 1200 mg/kg (p.o.) in ethyl Dose-dependent inhibition of ear edema, hind paw Sireeratawong et al.
phenylpropiolate-induced ear edema, carrageenan- edema inflammation, and pyrexia in rats, while (2012)
induced hind paw edema, cotton pellet-induced analgesic effect in mice.
granuloma formation, and yeast-induced
hyperthermia in rats (n = 6); formalin test in mice
(n = 6)
Ethanol extract Streptococcus pyogenes Antibacterial effect (MIC: 1000 μg/mL) Limsuwan and
Voravuthikunchai (2013)
Ethanol extract Plasmodium falciparum (strains: KI and 3D7) Antimalarial effect (IC50 values 5.3 and 4.1 μg/mL, Thiengsusuk et al. (2013)
respectively)
Ethanol fruit extract Malaria and cholangiocarcinoma using human liver Exhibited inhibitory activities against cytochrome Sumsakul et al. (2015)
microsomes (in vitro) P450-mediated hepatic metabolism (CYP1A2,
CYP2C19, CYP2D6 and CYP3A4) (IC50 values within
0.04 ± 0.01 and 29.39 ± 1.82 μg/mL)
Clinical reports
Panchakola Siddha 70 g dose in 47 patients in 10–30 days Agnidipana effect: Complete cure (17.24%) moderate to More and Dwivedi (2011)
Yavagu comprises with Piper markedly improved (34.48%) and mild improvement
longum, Piper longum root, Piper (13.80%) patients
chaba, Plumbago zeylanic and
Zingiber officinale

reduced the sensitivity of hepatocytes to TNF-α in a dose-dependent 3.2.11. Immunomodulatory effect

manner. Morikawa (2010) also reported that piperine (2) showed a Findings by Panthong and Itharat demonstrated that aqueous ex-
significant hepatoprotective effect in 2.5, 5, and 10 mg/kg (p.o.) in tracts of P. chaba at concentrations of l ng/mL to 100 μg/mL sig-
experimental animals. In addition, piperine (2) mediated hepatopro- nificantly increase lymphocyte proliferation, suggesting an im-
tective effects were reported by other researchers (Arcaro et al., 2014; munomodulatory effect, especially through activation of both
Ochiai et al., 2015). Similarly, Ochiai et al. (2015) showed that piperine lymphocyte proliferation and NK cell activity (Panthong and Itharat,
(2) stimulates LDL receptor gene expression and uptake of LDL in cul- 2014).
tured hepatocytes.

3.2.12. Other biological activities

3.2.9. Gastro-protective effect Researchers showed that the methanol stem bark extract of P. chaba
Piperine (2), pipernonaline (23), dehydropipernonaline (24), ret- at 125, 250, and 500 mg/kg (p.o.) in mice exhibits significant dose-
rofractamide B (19), N-isobutyl-(2E,4E)-octadecadienamide (28), and dependent analgesic, antidiarrheal, anti-gastrointestinal motility, and
N-isobutyl-(2E,4E,14Z)-eicosatrienamide (29) at 25 mg/kg (p.o.) anti-depressant effects, while in Wistar rats a significant anti-in-
showed significant gastro-protective effects in ethanol and in- flammatory and moderate diuretic effects were observed only at the
domethacin-induced gastric lesions in rats (n = 5–9) (Morikawa et al., highest dose (Taufiq-Ur-Rahman et al., 2005). Similarly, the ethanol
2004). fruit extract exerted antihypertensive, analgesic, anti-inflammatory,
antipyretic, and anti-ulcer activities at 100, 500 and 1000 mg/kg (p.o.)
in mice (n = 6) (Plengsuriyakarn et al., 2012). In another study, the
3.2.10. Antidiabetic effect ethanol fruit extract (300, 600 and 1200 mg/kg (p.o.)) dose-depen-
Piplartine (3, 4), isolated from P. chaba was found to inhibit re- dently inhibited the ear edema, hind paw edema inflammation, and
combinant human aldose reductase (ALR2) with an IC50 value of pyrexia in rats, while exerting an analgesic effect in mice
160 μM, suggesting an antidiabetic effect (Rao et al., 2012). In addition (Sireeratawong et al., 2012). Recently, chabamide (1) exerted an anti-
to the hepatoprotective effect, Arcaro et al. (2014) demonstrated that inflammatory effect via activation of the Nrf2/heme-oxygenase-1
piperine (2) at a dose of 20 mg/kg exhibits antidiabetic and antioxidant pathway in RAW264.7 cells (Ngo et al., 2017). Shown in Table 4 are the
activities in streptozotocin-diabetic rats. biological effects of isolated compounds of P. chaba.

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M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

Table 4
Pharmacological effects of isolated compounds of Piper chaba Hunter.
Isolated compoundsa Conc./Dose/Admin. route & Test system Activity (Possible mechanism) References

Chabamide (1) Plasmodium falciparum (strain: KI) Antimalarial (IC50 = 2.7 μg/mL) and Rukachaisrikul et al.
Mycobacterium tuberculosis (strain: H37Ra) antituberculosis effect (MIC = 12.5 μg/mL) (2002)
Piperine (2), pipernonaline (23), 25 mg/kg (p.o.) in ethanol and indomethacin- Significant ethanol and indomethacin- induced Morikawa et al.
dehydropipernonaline (24), retrofractamide B indued gastric lesions in rats (n = 5–9) gastric lesions in experimental animals. (2004)
(19), N-isobutyl-(2E,4E)-octadecadienamide (28),
N-isobutyl-(2E,4E,14Z)-eicosatrienamide (29)
Piperine (2) 3D7 (chloroquine-sensitive) and K1 Antimalarial effect (IC50 values: 111.5 and Thiengsusuk et al.
(chloroquine-resistant) Plasmodium 59 μM, respectively). (2018)
falciparum clones
2.5–10 mg/kg (p.o.) in D-galactosamine Dose-dependently inhibited increase in serum Matsuda et al. (2008)
(D-GalN)/lipopolysaccharide-induced liver GPT and GOT levels; reduced sensitivity of
injury in mice (n = 4); hepatocytes to TNF-α.
10–100 μM in hepatocytes and L929 cells
5 and 10 mg/kg (p.o.) in D-GalN/ Hepatoprotective effect. Matsuda et al. (2009);
lipopolysaccharide-induced liver injury in Morikawa (2010)
mice (n = 8)
Amide constituents (e.g., piperlonguminine (6) and 1–30 μM in 3T3-L1 cells; agonstic effects of Adipogenesis effect of retrofractamide A Zhang et al. (2008)
retrofractamides A, B, and C (18, 19, 20); troglitazone and retrofractamides A/B (increased mRNA levels of adiponectin,
troglitazone) peroxisome proliferator-activated receptor γ2
(PPARγ2), glucose transporter 4 (GLUT4), and
insulin receptor substrate 1 (IRS-1)).
cis & trans-piplartine (3, 4) 2–25 μM in rat histiocytoma (BC-8), mouse Piplartine induced a dose-dependent Jyothi et al. (2009)
embryonal carcinoma (PCC4), mouse cytotoxicity (2–24 μM) (cell cycle arrest at G1
macrophages (P388D1 and J774), and human phase, surpassed diferuloylmethane-induced
neuroblastoma (IMR32) tumor cells G2/M arrest in combination, inhibited the cell
cycle progression by inactivating cdk2 and
destabilizing cyclin D1, with diferuloylmethane,
inhibited the ERK1/2 and Raf-1 signaling in
addition to the inhibition of cell cycle
progression.)
Chabamide (1), chabamide G Human cervical (HELA), breast (MCF-7), liver Exhibited potent cytotoxic effect against COLO- Rao et al. (2011)
(HEPG2), colon 205 cell line with IC50 values of 3.10 and
(HT-29), and colon (COLO-205) cancer cell 0.018 μg/mL, respectively.
lines
Bornyl piperate, Bacillus subtilis, Bacillus megaterium, Anti-bacterial, anti-fungal effect (zones of Naz et al. (2012)
Piperlonguminine (6) Staphylococcus aureus, Streptococcus β- inhibition between 9 to 20 mm)
haemolyticus, Escherichia coli, Salmonella typhi, Antileishmanial activity (IC50 values of 16 and
Shigella dysenteriae, Shigella shiga, Shigella 30 μg/mL, respectively)
boydii, Aspergillus fumigatus, Aspergillus niger, Cytotoxicity in Artenia. salina (LC50 values 0.76
Aspergillus flavus, Candida albicans, Leishmania and 0.83 μg/mL, respectively)
donovani, Artemia salina
Piplartine (3, 4) Human red blood cells Antidiabetic effect (Aldose reductase inhibitory Rao et al. (2012)
capacity with an IC50 value of 160 μM)
9-(3’,4’-methylenedioxyphenyl)-nona-2E,4E,8E- 3T3-L1 cells Adipogenesis effect (increased mRNA levels of Mourad et al. (2013)
trienoic acid and an n-butyl or n-pentyl amine adiponectin, peroxisome proliferator-activated
receptor γ2 (PPARγ2), glucose transporter 4
(GLUT4), fatty acid-binding protein
(aP2), and CCAAT/enhancer-binding protein
(C/EBP) α and β).
Piperlonguminine (6) 3–30 μM in 3T3-L1 cells Adipogenesis effect (increased mRNA levels of Yamaguchi et al.
adiponectin, glucose transporter 4, fatty acid (2014)
binding protein (aP2), and PPARγ2).

a
Number of the compounds (from Fig. 2) are shown here in parenthesis.

3.2.13. Clinical reports natural products. On the other hand, the use of synthetic drugs often
More and Dwivedi (2011) examined the Agnidipana effect (a state produces side effects (Calixto, 2019; Ravi and Bharadvaja, 2019). Ac-
quite disturbing to routine life) of Panchakola Siddha Yavagu which cording to WHO reports, around 80 % of the global population still rely
consists of P. longum, P. longum root, P. chaba, Plumbago zeylanica L., on plant-based drugs (Sen and Samanta, 2015).
and Z. officinale at a dose of 70 g dose in 47 patients of Agnimandya Chronic diseases are major social challenges worldwide. Cumulative
(irregular life style, such as very fast and stressful life style with sup- reports suggest that consumption of plant foods can reduce the risk of
pression of natural urges). Results were based on food consumption and these kinds of diseases (Martin et al., 2013). In this context, crude ex-
digestive capacity, and showed a complete Agnidipana cure in 17.24% tracts and some isolated compounds from different parts of P. chaba
of the patients, whereas 34.48% of patients improved moderately as have been reported to exhibit hepatoprotective (Matsuda et al., 2008,
well as markedly (More and Dwivedi, 2011). 2009; Morikawa, 2010), gastroprotective (Morikawa et al., 2004; More
and Dwivedi, 2011), antidiabetic (Rao et al., 2012), and im-
munomodulatory effects (Panthong and Itharat, 2014), among others.
4. Discussion Traditionally, Piper species have been used due to their important
health benefits to human beings, including anti-inflammatory effect and
The last few decades have witnessed an increase in the use of herbal can be used to treat liver diseases (Salehi et al., 2019). Traditional re-
drugs around the world, and the global medical market is about 1.1 ports also suggest that P. chaba exhibits gastro-protective effects
trillion US dollars. Approximately, 35% of medicines have come from

7
M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

(Chopra, 1958; Chojnowska et al., 1979; Krishnan, 1986; Atjanasuppat et al., 2009; Plengsuriyakarn et al., 2012).
Plengsuriyakarn et al., 2012; Sireeratawong et al., 2012) and can be At present, some other major global health threats are tuberculosis,
used as a carminative and digestive tonic (Atjanasuppat et al., 2009; malaria, HIV, enteric/diarrheal diseases (Waldman and Balskus, 2018),
Plengsuriyakarn et al., 2012). Accordingly, these scientific reports are leishmaniasis, and schistosomiasis. Findings from this review showed
in line with the traditional information about this herb. that bornyl piperate and piperlonguminine (6) isolated from P. chaba
A. salina (also called brine shrimp lethality bioassy/test) is ex- exhibit anti-Leishmania donovani effects (Naz et al., 2012). In addition,
tensively used in toxicity analysis of a wide variety of substances, in- crude extracts of P. chaba showed anti-malarial activity (Thiengsusuk
cluding crude extracts, drugs and chemicals, and ecotoxicants, and is et al., 2013; Sumsakul et al., 2015). Moreover, chabamide (1)
commonly employed to evaluate anti-cancer drugs (Islam et al., 2017). (Rukachaisrikul et al., 2002) and piperine (2) (Thiengsusuk et al.,
In general, substances that display moderate to strong cytotoxic effects 2018) exerted activity against P. falciparum, and piperine (2) against
on a test system can be considered as potential anticancer drugs. In this chloroquine sensitive and resistant P. falciparum clones. Similarly, fruit
respect, two root extracts of P. chaba, along with the isolated com- extracts of the plant exhibited strong effects on S. cercariae
pounds bornyl piperate and piperlonguminine (6) exhibited strong cy- (Atjanasuppat et al., 2009). Furthermore, findings suggest that the herb
totoxic effects against A. salina (Naz et al., 2012). has anti-diarrheal effects in experimental animals (Taufiq-Ur-Rahman
Cancer is considered one of the major causes of death worldwide. To et al., 2005; Plengsuriyakarn et al., 2012; Sireeratawong et al., 2012).
date, a number of chemotherapeutic drugs have been discovered and Taken all together, our findings have highlighted the medicinal uses of
developed from natural sources to combat this dreadful disease. this important edible plant and its role in the traditional system of
Research findings suggest that numerous important clinically relevant medicine.
herbs can be used to treat cancers, including Triticum aestivum L.,
Viscum album L., Z. officinale, Ephedra foeminea Forssk, and Viscum
5. Conclusions
cruciatum Sieber ex Boiss., among others (Ben-Arye et al., 2017). Si-
milarly, P. chaba extracts and some isolated compounds have been
At the present time, people are paying more attention towards the
found to act against a number of human or other animal cancer cell
consumption of natural food products in the fight against diseases such
lines (Jyothi et al., 2009; Mahavorasirikul et al., 2010; Rao et al.,
as cardiovascular disorders, cancer insurgence, and immune dysfunc-
2011). On the other hand, P-glycoprotein (P-gp) is a drug transporter
tion. In addition, consumers resort to compounds obtained from med-
that effluxes chemotherapeutic drugs and is involved in the develop-
icinal plants to treat numerous diseases, including cancer; this is due to
ment of resistance of cancer cells to chemotherapeutic drugs. Un-
their lesser side effects and cost. In this context, traditional therapies
fortunately, no drug has been approved to inhibit P-gp and restore
have attracted the attention of the scientific and medical communities
chemotherapy efficacy (Syed et al., 2017). In this context, chabamide
in the search for potent drugs to cure diseases that affect people.
(1) has been found to down-regulate P-gp expression in adriamycin-
Findings from this review, demonstrated that P. chaba, the culinary
resistant human leukemia cells (K562/ADR) (Ren et al., 2015).
plant, not only is used as foodstuff in many parts of the world, but also
Adipocytes play an important role in energy homeostasis and pro-
has its place in traditional medicine because it contains many important
cesses, where it stores triglycerol when there is an excess of nutritional
therapeutically active lead compounds. Scientific reports suggest that P.
caloric intake and mobilizes this reserve when caloric expenditure
chaba and/or its derived extracts/preparations or compounds may act
surpasses intake (Cornelius et al., 1994). In this process, pre-adipocytes
against infectious agents (e.g., bacteria, fungi, virus), parasites, cancer,
become adipocytes by cellular differentiation. In 3T3-L1 cells, retro-
vertigo, liver and gastrointestinal complications, diabetes, pain, diar-
fractamides A (18) (Zhang et al., 2008), an amide that is composed of 9-
rhea, anxiety, inflammation, metabolic syndromes (e.g., diabetes, hy-
(3’,4’-methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid and n-butyl
pertension), fever, ulcer, and immune-suppression. Chabamides, pi-
or n-pentyl amine (Mourad et al., 2013), and piperlonguminine (6)
perine (2), piplartine (3, 4), among others, are examples of some
(Yamaguchi et al., 2014) isolated from P. cahba exhibited adipogenesis
important pharmacologically active lead compounds of P. chaba. In this
effects. There is evidences that suggests mRNAs' dysregulation with
review, we have established that P. chaba and its phyto-constituents,
adipogenesis and obesity, where an alteration in miRNAs expression
whether alone or in combination with other drugs, offer a wide range of
may change in the pattern of genes controlling a range of biological
therapeutic options against different diseases, including cancer.
processes including inflammation, lipid metabolism, insulin resistance
In summary, this review has demonstrated that compounds ex-
and adipogenesis. Thus, the role of circulating miRNAs may be new
tracted from P. chaba can be a useful complementary medicine to treat
promising therapeutic and attractive tools for the treatment of obesity
many ailments, and can be potential sources of phytotherapeutic lead
and associated diseases (Zaiou et al., 2018). Compounds derived from
compounds. However, published research indicated that the tox-
P. chaba showed differential expression of mRNA levels in 3T3-L1 cells.
icological evidence of this promising edible medicinal plant and its
Moreover, P. chaba exhibits significant anti-inflammatory effects in
derivatives are not adequate. Therefore, more research is highly re-
experimental animals (Taufiq-Ur-Rahman et al., 2005; Plengsuriyakarn
quired on these natural compounds, especially on their toxicogenetical
et al., 2012; Sireeratawong et al., 2012).
profile.
Although we have a number of antimicrobial drugs to treat in-
fectious diseases, however, the morbidity and mortality associated with
microbial infection remain a challenge worldwide. At present, combi- Authors’ contribution
nation of vaccines, drugs, maintaining hygiene standards, and disease-
specific interventions are the potential strategies to combat microbial All authors participated in the formation and design of this study.
infections (Waldman and Balskus, 2018). In this context, a number of All authors have read and approved the final manuscript. MTI and MSM
isolated P. chaba extracts (Naz et al., 2012; Limsuwan and proposed the subject, designed the study, and drafted the manuscript
Voravuthikunchai, 2013), and some isolated compounds such as cha- synthesis of the new compounds. JH and HMSHS gathered the material
bamide (1), (Rukachaisrikul et al., 2002), bornyl piperate, and pi- and wrote the first draft of the manuscript. MTI, ESA, JS-R, MM, and
perlonguminine (6) (Naz et al., 2012) have been found exhibit re- MSM edited, corrected, and wrote the manuscript in its final form.
markable activity against a number of pathogenic bacteria and fungi.
These compounds can be used to develop potent drugs in the fight
against infectious diseases. Along this line, Piper species have been Declaration of competing interest
traditionally used against infections, and in wound healing (Salehi
et al., 2019), and are used to treat diarrhea (Yusuf et al., 1994; Authors declare no conflict of interest.

8
M.T. Islam, et al. Journal of Ethnopharmacology 257 (2020) 112853

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