Centratherum anthelminticum (L.) Kuntze a Potential Medicinal Plant
with Pleiotropic Pharmacological and Biological Activities
Bushra Abdulkarim Moharam,
Yi Li Wong,
Chung Yeng Looi,
Won Fen Wong,
Centratherum anthelminticum is an ethnomedicinal plant
in India and a common ingredient in Ayurvedic medicine. To date, many scientific
studies have been carried out, but a comprehensive review on this plant is lacking.
This review aims to cover the biological activities and the active compounds
derived from C. anthelminticum. Exploration of more than 40 papers available
in literature (up to 20th of April 2013) revealed that the pharmacological effects
of C. anthelminticum range from anti-oxidant, anti-diabetic, anti-microbial
to recently found anti-cancer property. Over 120 compounds consisting of fatty
acid, sterols, sesquiterpene lactones, flavonoids and carbohydrates have been
identified from different parts of the plant. Many of these active compounds
were derived from the seeds and have been evaluated for a variety of biological
activities. Despite the encouraging results demonstrated by these studies and
the traditional use as nutraceutical agent, clinical trials of C. anthelminticum
extracts or derivatives are absent. Thus, a systematic documenting review would
provide more insights and spur further research that would lead to production
of safer and economical alternative medicine from C. anthelminthicum.
to cite this article:
Mohammadjavad Paydar, Bushra Abdulkarim Moharam, Yi Li Wong, Chung Yeng Looi, Won Fen Wong, Shaik Nyamathulla, Vijayapandi Pandy, Behnam Kamalidehghan and Aditya Arya, 2013. Centratherum anthelminticum (L.) Kuntze a Potential Medicinal Plant
with Pleiotropic Pharmacological and Biological Activities. International Journal of Pharmacology, 9: 211-226.
Received: April 21, 2013;
Accepted: May 15, 2013;
Published: August 03, 2013
Centratherum anthelminticum (L.) Kuntze is an ethnomedicinal plant commonly
grown in India and Southeast Asia. It is a member of Asteraceae family of the
flowering plants. Vernonia anthelmintica and Conyza anthelmintica
are scientific synonyms of this plant. Locally, the plant is known as black/bitter
cumin, or kalijiri in India. The plant is an erect, pubescent, annual herb which
can grow up to 90 cm in height. The leaves of the plant are elliptic-lanceolate,
5 to 9 cm long and 2.5 to 3.2 cm wide. The apex of the leaves is acute, base
tapering into the petiole, margins coarsely serrate and pubescent on both surfaces.
It has homogamous purple florets, which can be found as solitary, axillary or
terminal heads. The seeds are brownish in color, with a hot sharp taste and
astringent properties (Rastogi et al., 1995; Mehta
et al., 2004; Bhatia et al., 2008a;
Ani and Naidu, 2011). It is widely used as folk medicine
for diabetes in Rayalaseema, India and a popular ingredient in Ayurvedic medicine.
In other places, C anthelminticum has been traditionally applied as anthelmintic,
stomachic, digestive, diuretic, tonic, alterative, anti-phlegmatic, anti-asthmatic,
anti-phlegmatic treatment, as well as a therapeutic agent for cough, diarrhea,
helmint, skin diseases, ulcers, leucoderma and fevers (Nadkarni
and Nadkarni, 1955; Chopra et al., 1956; Kirtikar
and Basu, 1987; Nagaraju and Rao, 1989; Amir
and Chin, 2011; Arya et al., 2012a).
To the best of our knowledge, experimental investigations on the extracts or
pure compounds isolated from the plant indicated a vast variety of pharmacological
effects, including anti-inflammation/anti-pyretic (Purnima
et al., 2009; Ashok et al., 2010),
anti-helminthic (Iqbal et al., 2006), anti-viral
(Bhakuni et al., 1969), insecticidal (Verma
et al., 1982), anti-microbial (Sharma and Mehta,
1991), anti-filarial (Singhal et al., 1992;
Nisha et al., 2007), anti-cancer (Arya
et al., 2012a), anti-diabetic (Ani and Naidu,
2008; Fatima et al., 2010; Arya
et al., 2012b), diuretic (Koti and Purnima, 2008),
melanogenesis (Zhou et al., 2012) and wound
healing activities (Sahoo et al., 2012). These
properties will be discussed in details in the following sections to unravel
the mystery and magical usage of C. anthelminticum.
CHEMICAL CONSTITUENTS OF Centratherum anthelminticum
C. anthelminticum has been investigated for its bioactive compounds
since the early 1960. To date, more than 120 compounds were identified, ranging
from fatty acid, sterols, sesquiterpene lactones, carbohydrates and flavonoids
(Table 1). The chemical components were mostly identified
from the seeds of C. anthelminticum, followed by leaves and aerial parts.
Some of these identified compounds were isolated using chromatographic techniques
and the structures were elucidated through spectroscopic techniques. A number
of these compounds exhibited significant biological activities, which serve
as the scientific evidence for the traditional usage of C. anthelminticum.
Traditional healers in India used seeds of Centratherum anthelminticum as
a medication capable of causing the evacuation of parasitic intestinal worms
and showed successful results in deworming small children and adults.
|| Bioactive compounds extracted from C. anthelminticum
The anthelmintic property, as displayed by the name of the plant itself, demonstrates
its great potential in expelling different types of house worms. This activity
of the plant is evident through some scientific evaluations by the previous
Singh et al. (1985) demonstrated in vitro
anthelmintic activity on the alcoholic extract of C. anthelminticum seeds
against Fasciolopsis buski, Ascaris lumbricoides and Hymenolepis nana
worms. Next, Iqbal et al. (2006) demonstrated
in vitro and in vivo anthelmintic activity of C. anthelminticum
seeds in sheep naturally infected with gastrointestinal nematodes. Crude
Methanolic Extract (CME) and Crude Aqueous Extract (CAE) of C. anthelminticum
seeds were applied in vitro and CME indicated higher activity compared
to CAE. However, CME exhibited no anthelmintic activity in the in vivo
studies and maximum reduction in fecal egg counts per gram (EPG) was observed
in the animals treated with CAE (73.9% at 3 g kg-1 body weight on
day 5 post-treatment) followed by Crude Powder (CP), which indicated 55.6% reduction
at 3 g kg-1 body weight on day 3 post-treatment.
Lymphatic Filariasis (LF), commonly known as elephantiasis, is a tropical disease
caused by the nematode parasites Brugia malayi, Brugia timori
and Wuchereria bancrofti. Recent surveys show that more than 1.3 billion
people in 72 countries, mostly in South-East Asia, Africa and other tropical
areas are at high risk of LF (WHO, 2012).
There are claims of antifilarial activity of this plant seeds, thus study by
Singhal et al. (1992) demonstrated antifilarial
activities of the aqueous and alcoholic extract of C. anthelminticum
seeds on Setaria cervi. Nisha et al. (2007)
showed in vitro macrofilaricidal activity of C. anthelminticum
seeds against adult S. digitata, the cattle filarial worm.
Mehta et al. (2010) investigated the antifilarial
activity of the aqueous and methanolic extracts of C. anthelminticum. Both
extracts inhibited spontaneous motility of the whole worm and the nerve-muscle
preparation of S. cervi. Only the methanolic extract was able to block
the stimulatory response of acetylcholine. The two extracts caused significant
death of microfilariae in vitro, with LC50 and LC90
values of 75 and 32.5 mg mL-1, respectively. The isolated glycosides,
acid and 3-O-[β-D-glucopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]-28-O-[β-D-glucopyranosyl-(1→3)-β-D-
glucopyranosyl]-hederagenin from the methanol extract were also active in
vitro against the S. cervi. However, the antifilarial activity of
the two compounds was not efficient.
Oxidative stress and anti-oxidants: Reactive oxygen species (ROS) are
oxygen containing molecules, which are highly disruptive to cellular function.
They constitute most of the important free radicals with indispensable roles
in homeostasis and cell signaling (Halliwell, 2006).
These chemically reactive molecules are natural byproducts of aerobic metabolic
processes like respiration. Drastic increase in ROS by environmental stress
like heat or UV exposure, could damage proteins, DNA, lipids and cause oxidative
stress. Some disorders have been shown to associate with oxidative stress, including
diabetes, inflammation, cancer, neural degenerative disease, atherosclerosis,
ageing and chronic airway inflammation in asthma (Smith
et al., 1996; Finkel and Holbrook, 2000; Rosen
et al., 2001; Neumann et al., 2003;
Zhang et al., 2009).
Anti-oxidants are compounds that prevent damage to cell structures caused by
chemical reactions involving free radicals. 1940s marked the beginning
of using synthetic anti-oxidant, butylated hydroxyanisole (BHA) in food. Other
synthetic anti-oxidants, like butylated hydroxytoluene (BHT) and tertiary butyl
hydroquinone (TBHQ), were used to inhibit or reduce oxidative rancidity of foods
(Fasseas et al., 2008). However, serious side
effects of synthetic anti-oxidants, including their carcinogenic potential,
led to a general desire to replace them with natural anti-oxidants (Grice,
1988; Namiki, 1990; Altmann
et al., 1986; Van Esch, 1986; Jayaprakasha
and Rao, 2000; Miller et al., 2000a, b;
Paydar et al., 2013b).
C. anthelminticum, a potential source of natural anti-oxidants:
The anti-oxidant property of C. anthelminticum was first reported by
Ani and Naidu (2011). The anti-oxidant activity of different
extracts (aqueous-methanol-acetone, aqueous-methanol and aqueous extracts) of
C. anthelminticum seeds was determined by 1,1-Diphenyl-2-picrylhydrazyl
(DPPH●), ABTS●+ radical scavenging and phosphomolybdenum
reducing assays. The extracts showed significant anti-oxidant activity against
DPPH and ABTS radicals. Aqueous methanol acetone extract indicated the highest
DPPH● (IC50 20.8±0.18 μg), ABTS●+
(IC50 8.3 μg) scavenging activity and phosphomolybdenum
reducing power (IC50 0.31 μg). They found a remarkable correlation
between anti-oxidant activity and the total phenol content of C. anthelminticum,
indicating the phenolic compounds might be responsible for the anti-oxidant
activity of the seeds.
Furthermore, liposome oxidation and oxidative DNA damage assays were performed
using egg lecithin and bacterial genomic DNA, respectively, to determine the
protective effects of the extracts from free radicals. The highest inhibitory
effect on phospholipid peroxidation and comprehensive protection activity against
DNA damage was obtained from aqueous methanol acetone extract. In particular,
the phospholipid peroxidation activity was 41 times higher than the standard
anti-oxidant α-tocopherol (Ani and Naidu, 2011).
Therefore they conclude that aqueous methanol acetone extract is a potent anti-oxidant
agent in preventing serious damages to DNA and other biomolecules of living
cells (Halliwell, 1991).
Arya et al. (2012a) tested the anti-oxidant activity
of the chloroform fraction of C. anthelminticum seeds using DPPH radical
scavenging, oxygen radical absorbance capacity (ORAC) and ferric reducing/anti-oxidant
power (FRAP) assays (Arya et al., 2012a). The
fraction exhibited a high dose-dependent inhibition of DPPH activity (IC50
22.56±1.4 μg mL-1) and FRAP value (1048.3 μM), compared
to the positive controls, ascorbic acid and BHT. The ORAC value of the fraction
(992.34±45.12 μM) was comparable to quercetin (1018.00±34.82
μM) (Arya et al., 2012a).
Overall, these in vitro studies have clearly demonstrated the worthiness of C. anthelminticum seeds as an alternative natural source to substitute the synthetic anti-oxidants. However, in vivo study using animal model is lacking to confirm the anti-oxidant potential of the seeds for clinical application.
Inflammation is a common condition seen in many diseases of high prevalence
worldwide, such as rheumatoid arthritis, type 2 diabetes mellitus and cardiovascular
diseases (Mueller et al., 2010). Different cultures
of population practiced the use of plants or plant-derived compounds to treat
inflammatory related diseases or disorders (Mueller
et al., 2010; Paydar et al., 2013a).
Some species under the family of Asteraceae, for instance, Vernonia cinerea,
had been reported by a few studies to possess anti-inflammatory activity (Iwalewa
et al., 2003; Mazumder et al., 2003).
There are several components in C. anthelminticum found to be similar
in the species of Vernonia cinerea such as flavanoid, steroid and alkaloid,
which prompted the investigation of anti-inflammation activity in C. anthelminticum.
Ashok et al. (2010) examined the anti-inflammatory
activity of C. anthelminticum seed using acute and subacute animal models
C. anthelminticum in acute phase of inflammation: The process
of inflammation is mediated by various components in different phases. Early
stage of inflammation is mainly mediated by the release of histamine, serotonin
and bradykinin, while prostaglandin level will increase in later stage (Chaudhari
et al., 2012; De Melo et al., 2006).
Ashok et al. (2010) showed that both petroleum
ether and alcohol extracts were effective on oedema reduction after 3 hours,
with percentage inhibition of 46.15 and 41.54%, respectively, in carrageenan-induced
oedema rats. The finding was comparable to the standard drug, sodium diclofenac
(50.77%). The standard sodium diclofenac has been reported to inhibit prostaglandin
synthethase (Ku et al., 1975), indicating that
the extracts could have similar prostaglandin release inhibition activity. This
hypothesis was also supported by Purnima et al.
(2009), as they reported the anti-pyretic property of C. anthelminticum
petroleum ether and alcohol extracts using brewer's yeast-induced fever
model in rat. The effects of C. anthelminticum were similar to paracetamol
in reducing fever induction caused by prostaglandin production in central nervous
system (Moltz, 1993; Purnima et
al., 2009). In the same study, the authors showed that both extracts
demonstrated analgesic effect using Eddy's hot plate methods in mice compared
to the standard drug, ibuprofen (Purnima et al.,
Another possibility of anti-inflammatory activity of C. anthelminticum
could be mediated by inhibiting myeloperoxide (MPO). MPO activity marks the
accumulation of polymorphonuclear cells (PMNs) such as neutrophils, monocytes
and macrophages in subplantar areas. The level of MPO correlates to the degree
of inflammation (Krawisz et al., 1984). In Ashoks
study, the petroleum ether and alcohol extracts of C. anthelminticum exhibited
anti-inflammatory activity by MPO inhibition and reducing the infiltration of
inflammatory cells (Ashok et al., 2010).
C. anthelminticum in subacute phase of inflammation: Ashok
et al. (2010) used the cotton pellet-induced granuloma test, a method
employed to access the transudative, exudative and proliferative components
of subacute inflammation (Swingle and Shiderman, 1972).
The petroleum ether and alcohol extracts of C. anthelminticum at the
dose of 100 mg kg-1 indicated significant inhibition of wet weight
granuloma at 42.62 and 36.13%, respectively. To further prove the anti-inflammatory
effect, they measured the alkaline phosphatase (ALP) level in the blood, as
it acts as a marker for acute inflammation (Krotzsch et
al., 2005). The petroleum ether and alcohol extracts showed 60.79 and
44.30% ALP inhibitory activity, respectively, at 200 mg kg-1 compared
to standard drug, diclofenac (66.23%). Interestingly, this study showed that
both extracts of C. anthelminticum and diclofenac exhibited similar anti-inflammatory
effects. However, the animal models developed significant gastric lesion when
they were administered with diclofenac, suggesting C. anthelminticum
extracts can be a safer alternative for acute and subacute inflammation treatment
(Ashok et al., 2010).
Vitiligo, or commonly regarded as leucoderma, is a depigmentation disorder
characterized by white patches on the skin. This condition is caused by default
function of melanocytes (Kaur et al., 2012).
Treating leucoderma with C. anthelminticums fruit extract is a
popular practice among uygur ethnic minority in China. However, the mechanism
of the extract on melanogenesis was unknown. Zhou et
al. (2012) demonstrated that the ethanol extract of C. anthelminticum
fruit was able to enhance the tyrosinase activity and melanin synthesis in cell-lines
B16F10 (murine B16 melanoma cell line) and NHMC (normal human primary melanocytes)
after 48 h treatment, indicating that C. anthelminticum fruit extract
could treat leucoderma by enhancing melanogenesis. Tian
et al. (2004) separated and identified three effective flavonoids
from C. anthelminticum seeds for vitiligo, including 2',3,4,4',-tetrahydroxychalcone,
5,6,7,4',-tetrahydroxyflavone and Butin.
The microphthalmia-associated transcription factor (MITF) is crucial in expressing
pigmentation-related genes and proliferating melanoma cells (Vachtenheim
and Borovansky, 2012), whereas tyrosinase protein is needed to synthesise
melanin pigment (Hara et al., 1994). The protein
level of MITF and tyrosinase were up-regulated after the skin cells were treated
with C. anthelminticum extract (Zhou et al.,
2012). This effect is reported to be induced via the activation of p38 mitogen
activated protein kinase (MAPK) and cyclic adenosine monophosphate response
element-binding (CREB) (Saha et al., 2006;
Singh et al., 2005). Addition of p38 MAPK and
protein kinase A (PKA) inhibitors abrogated the up-regulation of MITF and tyrosinase.
Of note, melanin synthesis was suppressed by p38 MAPK inhibitor but not by PKA
inhibitor (CREB activation mediator). This result indicated that C. anthelminticum-induced
melanogenesis was primarily mediated through p38 MAPK activation and secondarily
by CREB activation (Zhou et al., 2012).
Diabetes mellitus is a metabolic disorder characterized by chronically high
blood glucose level. It can be classified into two major categories: Type 1
(caused by destruction of beta cells of islet of Langerhans, resulting in insulin
deficiency) and Type 2 (caused by disorder in insulin secretion or action, resulting
in predominantly insulin resistance) (Alberti and Zimmet,
1998). Based on a study by King et al. (1998),
there will be an increase prevalence of diabetes in world population, in which
developing countries such as India shows the highest rise estimated at 59%.
Thus, there is a need for cheaper and more effective treatment. Due to the limitation
on available resources and reported side effects of modern drugs, many researchers
have turned their attention to medicinal plants in hope to find a possible cure
(Grover et al., 2002; Modak
et al., 2007).
Activity of C. anthelminticum on α-glucosidase, α-amylase
and PTP-1B: In a report by Ani and Naidu (2008),
the anti-hyperglycemic effect of C. anthelminticum was evaluated against
key enzymes important for glucogenesis. Different concentrations of aqueous
methanol-acetone extract were tested on the activity of α-glucosidase (PNP-G
hydrolysis, sucrose and maltase). The IC50 values for the C. anthelminticum
extract on disaccharide substrates PNP-G, sucrose and maltose were 500.5, 34.1
and 62.2 μg, respectively. This results show that C. anthelminticum
extract is a potent sucrase and maltase inhibition agent compared to PNP-G hydrolysis.
In contrast, the synthetic drug, acarbose showed high affinity towards sucrase
only. This data indicates that C. anthelminticum will be a better alternative
for diabetic treatment because it reduces hydrolysis of the disaccharides via
sucrase and maltase inhibition, resulting in lower blood glucose level. They
further validated the findings by administrating maltose and different dosages
of extract orally into rats. These investigations proved the potentiality of
C. anthelminticum in suppressing maltose digestion and absorption (Ani
and Naidu, 2008).
In contrast, the results of human salivary α-amylase test showed less
inhibition by the extract compared to standard, acarbose, with IC50
values of 185.5 and 17.4 μg, respectively (Ani and
Naidu, 2008). Although C. anthelminticum showed lower inhibitory
effect on α-amylase, a report by Krentz and Bailey
(2005) indicates that lower inhibitory effect on α-amylase and higher
inhibitory effect on α-glucosidase will be a better formulation for management
of type 2 diabetes condition. This is important as α-amylase catalyzes
the digestion of dietary starch to disaccharides and trisaccharides, which act
as a source of glucose to the human body.
Protein Tyrosine Phosphatase-1B (PTP-1B) is an intracellular phosphatase, which
negatively regulates the insulin signaling pathway. PTP-1B-deficient mice have
significantly reduced body weight and lower adiposity despite being given high
fat diet compared to the wild-type control (Tsou et
al., 2012). In view of these protective effects, PTP-1B has emerged
as a new target in tackling diabetes and other associated metabolic syndromes.
Recently, we found that the methanolic fraction of C. anthelminticum
seeds inhibited PTP-1B enzyme at IC50 38±5.8 μM, compared
to standard drug, RK-682 (4.1±0.6 μM). In contrast, C. anthelminticum
leaves were less effective (64±5.8 μM), possibly due to lower total
flavanoid, phenolic, tannin content in the leaves (Arya
et al., 2013).
Activity of C. anthelminticum in pancreatic cell-line and diabetic
animal model: Bhatia et al. (2008a) showed
that water extract of C. anthelminticum seeds at dosages of 200 and 500
mg kg-1 markedly reduced blood glucose level after 7-day treatment,
at 35.61 and 40.1%, respectively. Meanwhile, the standard drug, glibenclamide,
showed a decrease at 48.63%. Diabetic rats treated with C. anthelminticum
extracts exhibited less complications such as thirst, tiredness and irritation,
compared to rats treated with glibenclamide. Shah et
al. (2008) reported similar observations using methanol extract of
C. anthelminticum. These studies indicated that treatment with C. anthelminticum
is beneficial with less side effects, compared to the standard drug glibenclamide
(Bhatia et al., 2008b; Shah
et al., 2008).
In 2012, our group reported the anti-diabetic potential of the crude methanolic
fraction of C. anthelminticum seeds (CAMFs) using β-TC6 mouse pancreatic
cell-line and type 2 diabetic rat model. CAMFs showed non-cytotoxic effect on
β-TC6 cell proliferation at 50 mg mL-1, compared to untreated
control cells. Glucose uptake was increased via up-regulation of glucose transporter
proteins, Glut-2 and Glut-4 expression level in CAMFs treated cells. In vivo
studies on streptozotocin induced diabetic rat models revealed that CAMFs significantly
reduced hyperglycemia by augmenting insulin secretion in type 2 diabetic rats
(Arya et al., 2012b). Thus, we hypothesize that
CAMFs carried out anti-diabetic actions by increasing glucose uptake and insulin
secretion (Fig. 1).
In addition, further studies result indicated the power of CAMFs by decreasing
type 2 diabetes and its associated complications by increasing serum insulin,
C-peptide, total protein and albumin levels, significantly, whereas, elevated
blood glucose, glycated hemoglobin, lipids and enzyme activities were restored
to near normal.
||Graphical image depicting the anti-diabetic mechanism of crude
methanolic fraction of C. anthelminticum (modified from Arya
et al., 2012b, c)
CAMFs confirmed antioxidant potential by elevating glutathione (GSH) and reducing
malondialdehyde (MDA) levels in diabetic rats. Interestingly, CAMFs down-regulated
elevated tumor necrosis factor α (TNF-α), interleukin (IL)-1β
and IL-6 in the tissues and serum of the diabetic rats. This study postulated
that CAMFs may be a valuable candidate nutraceutical for insulin-resistant type
2 diabetes and its associated complications such as dyslipidemia, oxidative
stress and inflammation (Fig. 1) (Arya
et al., 2012c).
WOUND HEALING ACTIVITY
Wound healing is a dynamic and intricate process of skin (or any organ-tissue)
self-repairing by restoring cellular structures and tissue layers (Nguyen
et al., 2009). A vital component in wound healing is angiogenesis,
which is the formation of new blood vessels from the pro-existing vessels. Various
medicinal plants have been used in treating wounds and promoting angiogenesis
(Nagori and Solanki, 2011; Majewska
and Gendaszewska-Darmach, 2011). Sahoo et al.
(2012) studied the wound healing property of C. anthelminticum seeds
on excision and incision wounds in Wistar albino rats. The aqueous methanol
extract of C. anthelminticum seeds was prepared in ointment form with
two concentrations, 5% w/w and 10% w/w. The results showed that 10% (w/w) C.
anthelminticum ointment and standard drug, nitrofurazone ointment exhibited
complete healing of the wound on the 18th day, with wound area of 00±0.4
mm2 and 00±0.0 mm2, respectively. Whereas lower
healing activity was observed with 5% (w/w) C. anthelminticum ointment
Histological study on the skin specimens collected from the healed wounds showed
that the wounds either treated with the C. anthelminticum extract and
the standard drug exhibited less scar formation and more healing characteristics
(e.g., angiogenesis, formation of epithelial and keratin tissues). The results
obtained from this study revealed the potential of C. anthelminticum
as a wound healing therapeutic agent. However, the chemical components of C.
anthelminticum which contribute to this wound healing mechanisms are yet
to be investigated (Sahoo et al., 2012).
The antimicrobial potential of different extracts of C. anthelminticum seeds
was first investigated by Sharma and Mehta (1991),
using filter paper disc method. They reported significant inhibitory effects
of the extracts against several bacteria and fungi. Later, other studies on
the antimicrobial activity of various extracts of C. anthelminticum indicated
that it could serve as a potential antimicrobial agent against a number of pathogenic
bacterial and fungal strains.
Anti-bacillus spp., Activity: Bacillus subtilis and Bacillus
cereus of Bacillaceae family are Gram-positive heterotrophic rod-shaped
bacteria with the ability to produce protective endospores. B. subtilis
is usually found in water, soil, air and decomposing matter (Alexander,
1977). It produces an extracellular toxin known as subtilisin, which is
capable of causing allergic reactions (Edberg, 1991),
despite its low toxigenic property (Gill, 1982). B.
cereus is the cause of fried rice syndrome (Glenn et
al., 2005) that may lead to severe nausea, vomiting and diarrhea (Kotiranta
et al., 2000). Ani (2008) reported that aqueous
methanol acetone extract of C. anthelminticum showed high inhibitory
activity against B. subtilis and B. cereus. The extract has minimum
inhibitory concentration (MIC) at 50±7 μg mL-1 against
B. cereus (Ani, 2008). However, Patel
et al. (2012) reported that ethanol extract of C. anthelminticum
showed low inhibitory activity against B. cereus and B. pumilus,
with MIC at 10 mg mL-1. Hua et al. (2012a)
isolated and identified 24 μ-hydroperoxy-24-vinyllathosterol, from the
seed of C. anthelminticum. The compound showed high activity on B.
cereus and B. subtilis with MIC values of 7.25 and 15.5 μg
Anti-Enterobacteriaceae activity: The Enterobacteriaceae is a large
family of gram-negative rod-shaped bacteria that comprises of many harmless
symbionts and familiar pathogens. Mehta et al.
(2005) reported two new steroidal compounds, (24α/R)-Stigmasta-7-en-3-one
and (24α/R)-Stigmasta-7, 9(11)-dien-3-one, from benzene:acetone extract
of C. anthelminticum seeds. These compounds possessed moderate activity
(inhibition zone of 9-16 mm) against some bacterial species of Enterobacteriaceae
family, including Salmonella typhimurium, Escherichia coli and
Proteus vulgaris. Patel et al. (2012)
also reported anti-microbial activity against Enterobacteriaceae family. The
ethanol extract of C. anthelminticum seeds showed moderate activity against
Klebsiella pneumonia (inhibition zone of 10-15 mm) and low activity
against P. vulgaris, E. coli and S. typhi (inhibition zone
of 1-9 mm).
Anti-Staphylococcus aureus activity: Staphylococcus aureus,
a Gram-positive spherical bacterium of Staphylococcaceae family, is frequently
found in the human respiratory tract and skin surface. S. aureus is one
of the main pathogenic causes of skin and tissue infections, pneumonia, septicemia
and device-associated infections (Harmsen et al.,
2003). Ani reported high antibacterial activity of aqueous methanol acetone
extract of C. anthelminticum against S. aureus with MIC of 260±18
μg mL-1 (Ani, 2008).
Another study has also reported the antimicrobial activity of methanolic and
acetone extracts of C. anthelminticum seeds on S. aureus using
agar diffusion technique (Mehta et al., 2010).
The methanol and acetone extracts possessed very good (12.0-14.0 mm) and moderate
(9.0-11.0 mm) activity, respectively, against S. aureus. Two novel triterpenoid
acid and 3-O-[β-D-glucopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]-28-O-[β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl]-hederagenin
have been isolated from the seeds. Both compounds showed high to moderate activity
against S. aureus. Recently, 24ξ-hydroperoxy-24-vinyllathosterol,
a steroidal compound, has been isolated from C. anthelminticum seeds.
The compound exhibited high activity on S. aureus with MIC value of 3.15
μg mL-1 (Hua et al., 2012b).
Anti-Pseudomonas aeruginosa activity: Pseudomonas aeruginosa
is a genus of gram-negative rod-shaped bacteria that belongs to the family Pseudomonadaceae
(Rossolini and Mantengoli, 2005). It is reported as
one of the most common causes of nosocomial infections and a typical opportunistic
pathogen. The intrinsic resistance of P. aeruginosa to various antimicrobial
agents has made it difficult to be eliminated (Rossolini
and Mantengoli, 2005). Patel et al. (2012)
showed that ethanol extract of C. anthelminticum seeds is effective
against P. aeruginosa, with MIC of 2 mg mL-1.
Activity on other bacterial species: Mehta et
al. (2005) isolated and identified four steroidal compounds (Table
1) from the seeds of C. anthelminticum. The compounds were tested
for their antibacterial activity against various bacterial species using agar
diffusion technique. Among the compounds (24α/R)-Stigmasta-7-en-3-one exhibited
moderate antibacterial activity (disc diameter, 9.0-16.0 mm) on Salmonella
typhimurium and Escherichia coli, while (24α/R)-Stigmasta-7,
9(11)-dien-3-one showed moderate activity on Proteus vulgaris. Further
more, six steroidal compounds have been isolated from the seeds of C. anthelminticum
(Table 1) and tested for their antibacterial activity against
E. coli (Hua et al., 2012b). Only 24
μ-hydroperoxy-24-vinyllathosterol showed high activity on E. coli with
MIC value of 7.25 μg mL-1.
Mehta et al. (2010) also reported the antimicrobial
activity of methanolic and acetone extracts of the seeds of C. anthelminticum
against various bacteria using agar diffusion technique. The methanol extract
possessed a significant activity against Arthrobacter (16.0-20.0 mm),
a very good activity against Micrococcus luteus (12.0-14.0 mm) and moderate
activity against Klebsiella pneumonia (9.0-11.0 mm). The acetone extract
showed strong activity against Arthrobacter (12.0-14.0 mm) and moderate
activity against M. luteus. However, it showed poor activity against
E. coli and K. pneumonia (6.8-8.0 mm).
Anti-fungal activity: Singh et al. (2012)
reported the antifungal activity of C. anthelminticum seed extracts on
Aspergillus flavus, Candida albicans and Penicillium citrinum.
This activity was demonstrated by methanolic extract of the seeds of C. anthelminticum
and two of the isolated compounds, centratherumnaphthyl pentol and centratherumnaphthyl
hexol. The extract and the compounds exhibited inhibitory effect on all fungal
strains tested. Poor antifungal activity was also reported from (24α/R)-stigmasta-7-en-3-one
and (24α/R)-stigmasta-7, 9(11)-dien-3-one, steroidal compounds isolated
from the seeds of C. anthelminticum, against Aspergillus niger, A.
alternate and A. flavus (Mehta et al.,
The methanol and acetone extracts of C. anthelminticum seeds have been
also investigated for their antifungal activity against various fungi. The methanol
extract showed very good to moderate activity against Trichothecium roseum
(12.0-14.0 mm), Candida albicans (9.0-11.0 mm) and Fusarium solani
(12.0-14.0 mm), while no activity was observed against Penicillium notatum.
Meanwhile, the acetone extract showed lower activity against the fungi than
the methanol. Two new triterpenoid saponin compounds, 3-O-[β-D-glucopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]-28-O-[α-D-xylopyranosyl-(1→4)-α-L-rhamnopyranosyl-(1→3)-β-D-glucopyranosyl]-23-hydroxyolean-12-en-28-oic
acid and 3-O-[β-D-glucopyranosyl-(1→2)-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl]-28-O-[β-D-glucopyranosyl-(1→3)-β-D-
glucopyranosyl]-hederagenin, were isolated from the methanol extract of C.
anthelminticum seeds. The compounds showed very good to moderate activity
against T. roseum, C. albicans, F. solani and P. notatum
(Mehta et al., 2010).
Overall, these studies imply the potential of C. anthelminticum seed extracts worth to be further developed as an alternative anti-microbial agent.
Srivastava et al. (2008) investigated the
larvicidal activity of the petroleum ether extracts of C. anthelminticum
against Anopheles stephensi, the primary mosquito vector of malaria.
They reported significant larvicidal activity of both leaf and fruit extracts
against instar larvae. The lethal concentration that caused 50% death of the
larvae (LC50) was 522.94 ppm and 162.60 ppm, respectively after 24
hours. The fruit extract exhibited higher toxicity compared with the leaf extract
at both LC90 and LC50 levels. The findings indicated that
the petroleum ether extract of C. anthelminticum fruits can serve as
an active agent to control Anopheles larvae.
Two novel elemanolide dimers, vernodalidimers A and B, were isolated from the
seeds of C. anthelminticum and examined for their cytotoxic activity
against Human promyelocytic leukemia cells (HL-60). Both compounds exhibited
potent cell growth inhibitory effect on HL-60 cells with IC50 values
of 0.72 and 0.47 μM, respectively (Liu et al.,
In 2012, our group demonstrated that the chloroform fraction of C. anthelminticum
(CACF) possessed higher anti-cancer activity compared to methanolic and hexane
fractions (Arya et al., 2012a). CACF effectively
inhibited growth of A549 (lung), PC-3 (prostate), MCF-7 (breast) cancer cells
with IC50 values of 31.42±5.4, 22.61±1.7 and 8.1±0.9
μg mL-1, respectively. In addition, we showed that CACF was
less toxic to normal hepatic cells WRL-68 (54.93±8.3 μg mL-1).
We found that CACF dose-dependently inhibited the activation and nuclear translocation
of NF-κB in TNF-stimulated MCF-7 cells (Arya et al.,
2012a). This study revealed the potential of CACF in the treatment of breast
cancer associated with oxidative stress conditions and inflammatory responses.
Recently, we successfully isolated and identified two compounds from CACF through
bioassay guided isolation, vernodalin and 12,13-dihydroxyoleic acid (Looi
et al., 2013). Vernodalin, a sesquiterpene lactone, exhibited potent
growth inhibition on MCF-7 and MDA-MB-231, human breast cancer cells, with IC50
values of 2.5±0.3 and 3.4±0.6 μg mL-1, respectively.
Meanwhile, 12,13-dihydroxyoleic acid indicated no activity on the tested cell
lines. Morphological studies of vernodalin-treated samples suggested cell death
by apoptosis, as evidenced by cell shrinkage, nuclear condensation and formation
of apoptotic bodies (Looi et al., 2013). In
vivo studies (toxicology and mouse xenograft model) are undergoing to further
understand the mechanism of vernodalin isolated from C. anthelminticum.
Diuretics are therapeutic agents that can adjust the composition and volume
of body fluids by increasing the rate of urine flow and sodium excretion. They
are used in treating a number of diseases including nephritic syndrome, cirrhosis,
congestive heart failure, renal failure, pregnancy toxaemia and hypertension
(Agunu et al., 2005). Most of the diuretic drugs
indicate high efficiency in sodium excretion. However, they cause a drop in
blood potassium levels which eventually leads to high blood pressure and may
induce the risk of developing type 2 diabetes (Shafi et
al., 2008; Grossman et al., 2011). Thus,
investigators are hoping to find new efficient diuretic drugs with less side
effects (Rang et al., 1994).
Koti and Purnima (2008) tested petroleum ether, chloroform
and alcohol extracts of C. anthelminticum seeds on Albino Wistar rats,
at dosage of 200 mg kg-1 body weight. The alcohol and chloroform
extracts exhibited significant diuretic activity, compared to the standard drug,
spiranolactone. Both extracts significantly increased Na+ excretion
and surprisingly, decreased K+ excretion, drastically. This finding
indicated the potential of C. anthelminticum as a new source of potassium-sparing
So far, only one report on the anti-viral activity of C. anthelminticum
is available in the literature. Bhakuni et al. (1969)
reported the anti-viral effect of C. anthelminticum extracts against
Ranikhet (Newcastle) disease virus and Vaccinia virus. Hence, further investigations
are required to confirm and clarify the possible mechanisms of antiviral activities
of the plant.
INHIBITION OF AROMATASE
Aromatase is an enzyme responsible for the conversion of the adrenal androgen
substrate androstenedione, to estrogen in peripheral tissues (Evans
et al., 1986). Estrogen participates also in pathological processes
such as breast, endometrial and ovarian cancers (Stocco,
2008). Thus, aromatase inhibitors are important in inhibiting the peripheral
production of estrogen, eliminating the external supply of estrogen to the tumour
cell (Bhatnagar et al., 2001). In searching
for novel compounds that can promote estrogen biosynthesis, Hua
et al. (2012b) isolated six steroidal compounds from C. anthelminticum
seeds and tested them for their effects on estrogen biosynthesis in human
ovarian granulosa-like KGN cells. Among the compounds (Table 1),
only 24μ-hydroperoxy-24-vinyllathosterol was effective as it increased
the 17β-estradiol biosynthesis with EC50 value of 56.95 μg
Several investigators reported significant medicinal potential of different extracts of C. anthelminticum and their wide therapeutic activities against numerous illnesses. These evidential properties indicate the importance of this plant for further studies directed to drug development. However, most of the studies were conducted with extracts and there is a lack in isolation of bioactive compounds as well as mechanistic studies. Recent studies unraveled the anti-cancer activity of C. anthelminticum extract, which revealed another aspect of its potential to be investigated in future studies. Likewise, anti-viral, larvicidal and wound healing activities could be further explored. Advanced molecular approaches, such as molecular docking studies can contribute towards plant-based drug development in the future.
Numerous scientific investigations have indicated high medicinal potential of C. anthelminticum in many diseases (Fig. 2). Despite these facts, clinical trials using extracts or bioactive compounds are absent, possibly due to mass production issues or lack of mechanistic studies to understand its pharmacological effects. Thus, there is a definite requirement for further studies, both clinical and on the bench for further development of extracts or bioactive compounds isolated from C. anthelminticum. Improvement of medicinal chemistry methods could provide the opportunity to further evaluate the natural compounds and to investigate their biosynthetic pathways.
||Overview of various biological effects and the involvement
of multiple signaling pathways targeted by C. anthelminticum
This study was supported by University Malaya Research grants (RG434-12HTM, PG015-2012B, BK020-2012 and BK008-2012). The funding sources were not involved in the study design, collection, analysis, interpretation o f data, writing of the report or the decision to submit the article for publication. The authors sincerely thank Nitika Rai (Amritum Bio-Botanica Herbs Research Laboratory) for providing insightful information on C. anthelminticum for this review.
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