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Journal of HerbMed Pharmacology
Journal homepage: http://www.herbmedpharmacol.com
J HerbMed Pharmacol. 2016; 5(4): 125-130.
Haplophyllum tuberculatum: An overview
*Corresponding author: Abdolshakoor Raissi,
Email: Shakoorraissi@gmail.com
Introduction
Sistan and Baloochestan is extended in 187502 square ki-
lometer and has dedicated equally 11.5% of the country’s
area to itself. This province is located between 25 degree
and 3 minutes to 31 degree and 29 minutes of northern
width and 58 degree and 20 minutes of eastern length,
and 49 minutes to 36 degree. It is limited to Sothern Kho-
rasan from the north, to Afghanistan and Pakistan from
the east, to Oman sea from the south and to Kerman and
Hormozgan provinces from the west (1).
The genus Haplophyllum, belonging to the Rutaceae fam-
ily, comprises about 70 species distributed from the Medi-
terranean area to eastern Siberia (2). Haplophyllum is
distributed from Morocco and Spain in the west to China
in the east. It extends north to Romania and south to So-
malia and in the east it extends north to the Lake Baikal
region (3). Its range spans five different floristic regions:
Mediterranean, Saharo-Arabian, Irano-Turanian, and Su-
dano-Zambezian regions (4). The main center of diversity
is the Irano-Turanian region, Iran, Turkey, and Central
Asia which harbours 60% of the species diversity. Haplo-
phyllum tuberculatum is found in central and eastern areas
of Asia.
This genus consists of 22 species in the Asia to N. Africa.
Among the 18 species present in Iran, 9 species is endemic
(5). The Haplophyllum robustum is distributed in central
to south-eastern of Iran. The Persian name of this plant
is “Sodaby” and its Baluchi name is “Sadaap”. In Oman
trivially refer to the plant as “shagarat al baootha”, which
means “plant of the mosquito” (6). In Sudan it is called “a
plant of all disease”. It is used in most of Sudanese homes
as emergency medication and is mostly used by old Su-
danese in the rural areas. The purpose of this study was
to investigate and collect scientific reports such as mor-
Abdolshakoor Raissi1*, Mina Arbabi2, Javad Roustakhiz3, Masih Hosseini4
1Faculty of agriculture, Department of Horticulture, Velayat University, Iranshahr, Iran
2PhD Student of Medicinal Plant, Islamic Azad University, Science and Research Branch, Tehran, Iran
3Higher Educational Complex of Saravan, Saravan University, Saravan, Iran
4Medical Plants Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
Implication for health policy/practice/research/medical education:
The plant Haplophyllum tuberculatum in Sistan and Baluchistan province is an important medicinal plant that has many
medicinal properties. The bioactive molecules of this plant play an important role in human health. Hence, it might be used for
new drug preparation.
Please cite this paper as: Raissi A Arbabi M, Roustakhiz J. Hosseini M. Haplophyllum tuberculatum: An overview. J HerbMed
Pharmacol. 2016;5(4):125 -130 .
Introduction: Haplophyllum tuberculatum, belonging to the Rutaceae family, is distributed in
south-eastern regions of Iran, particularly in Baloochestan. This study was aimed to investigate
and collect scientific reports such as morphological characteristics, phytochemical compounds,
ecology, biotechnology and evaluation of the therapeutic properties of this valuable medicinal
plant.
Methods: In order to gather the information the keywords Haplophyllum tuberculatum, botany,
genetic, biotechnology, therapeutic, and pharmacology were searched until 2016 from journals
accessible in databases such as Scopus, EBSCO, Science Direct, Medline, PubMed, Embase, SID
and Iran Medex.
Results: The results in this study revealed various pharmacological properties including anti-
cancer, antioxidantant, uterus-relaxing, anti-bacterial and anti-HIV activities for this plant
which are probably due to the presence of aromatic compounds such as two alkaloids named
haplophytin-a and B, and essential oils.
Conclusion: Haplophyllum tuberculatum possesses various pharmacological properties and the
bioactive molecules of this plant play an important role in human health, hence, it might be used
for different drug productions.
A R T I C L E I N F O
Keywords:
Haplophyllum tuberculatum
Medicinal plant
Sistan and Baloochestan
Article History:
Received: 20 June 2016
Accepted: 3 September 2016
Article Type:
Review
A B S T R A C T
Raissi A et al
Journal of HerbMed Pharmacology, Volume 5, Number 4, October 2016 http://www.herbmedpharmacol.com
126
phological characteristics, phytochemical compounds,
ecology, biotechnology and evaluation of the therapeutic
properties of this valuable medicinal plant.
Methods
In order to gather the information the keywords Haplo-
phyllum tuberculatum, botany, genetic, biotechnology,
therapeutic, and pharmacology have been searched until
2016 from journals accessible in databases such as Scopus,
EBSCO, Science Direct, Medline, PubMed, Embase, SID
and Iran Medex.
Results
Genetic evaluations
The phylogenies established from DNA sequences and
morphological as well as cytogenetic analyses support the
separation of Haplophyllum species. The change in the
number of chromosomes might be the main mechanism
of speciation of the genus Haplophyllum (7). Phylogenetic
analysis of the internal transcribed sequences of the ribo-
somal DNA was performed using neighbour-joining (NJ)
and maximum-parsimony methods. Results showed that
the Haplophyllum bastetanumis a diploid species (2n = 18)
distinguished primarily for its non-trifoliate glabrous
leaves, dark-green petals with a dorsal band of hairs, and a
highly hairy ovary with round-apex locules. Another two
Iberian species (H. linifolium and H. rosmarinifolium) are
tetraploid (2n = 36) and have yellow petals. The species
diversity in Haplophyllum in a phylogenetic and biogeo-
graphic context was evaluated. It was generated gene trees
from DNA sequences of four regions of the chloroplast
genome for 118 accessions, representing 66% of the spe-
cies diversity. Additionally, Haplophyllum was examined
morphologically. The phylogenetic analyses revealed that
a number of species do not form reciprocally monophy-
letic groups. Optimization of morphological characters on
the chloroplast DNA revealed that most of the species, in
particular those with a widespread geographic distribu-
tion, might only be diagnosed by homoplasious charac-
ter states. Homoplasy notwithstanding, the predominant
characters used to classify the genus are consistent with
the molecular phylogeny of Haplophyllum. The Mediter-
ranean representatives of Haplophyllum were found to be
embedded within a clade that include primarily Irano-
Turanian species, suggesting multiple invasions of the
Mediterranean basin from the east (8).
Botany
Synonyms: Haplophyllum villosulum
The mode of propagation: by seed or root suckers.
Life form: Hemicryptophyte
Floristic categories (Chorotype): IR-TR + SA-SI
Habit: Shrub
Habitat: Sandy soils and resistant to Swamp and Saline
Habitats
Chromosome number: 2n = 18
Haplophyllum (5-locular ovary and dehiscent fruit).
Perennial herb, up to 40 cm tall, glabrous to short-hairy;
stem usually much branched from the base, yellowish
green to almost white; glands numerous on all parts; and
very variable. Leaves alternate, strong smelling, variable
in shape, from narrowly linear to short in size. Flowers
are yellow and variable in size. Petiole short below, absent
above; blade very variable, shortly obovate, elliptical, lan-
ceolate or linear, sometimes deeply cut into 3 lobes. In-
florescence a lax corymbose cyme, upper leaf axils, 2–10
(–15) cm in diameter, many-flowered, but flowers well-
separated; bracts small, green. The flowers are in loose
corymbose terminal panicles, with five free ovate sepals.
The stamens 10 are filamentous and hairy. The petals
are five and bright yellow in color (9). Flowers bisexual,
5-merous, regular; sepals deltoid-ovate to broadly lanceo-
late, c. 1 mm long, free; petals elliptical-oblong, 3–5.5 mm
long, boat-shaped, narrowed into a claw, bright yellow,
glabrous; anthers twice as many as the petals; ovary almost
round, 5-lobed, style 1.5–2.5 mm long. Fruit a 3–5-lobed
capsule, 2.5–4.5 mm × 1.5–2 mm, hairy, with a lot of in-
conspicuous to warty glands, segments apically opening,
5–10-seeded. Seeds are kidney-shaped, dark brown or
brownish-black, densely ridged.
Ecology
This common perennial herb is found wild even growing
as a common weed among summer crops. Haplophyllum
tuberculatum occurs in sandy desert, on a variety of soils,
often on silt deposits, and also in dried watercourses, cul-
tivated and ruderal localities, from sea-level up to 1330
m altitude. The psammophytic community inhabits the
sand dunes of Haplophyllum tuberculatum on the upper
positive part of axis 1 are correlated with species concen-
tration of dominance. These combinations are typical
of grass communities inhabiting the wadi bed and sand
dunes (10). This genus distributed throughout temperate
and subtropical zones of Eurasia and the northern tropi-
cal zone of eastern Africa (Somalia). The plant’s chemical
composition has been shown to vary as a function of geo-
graphic location and time of collection. It includes alka-
loids, lignans, flavonoids and essential oils (11-13).
Traditional use
It is used in traditional medicine as a remedy for head-
aches and arthritis, skin discoloration, the juice is applied
as a wart removal, and against parasitic diseases and other
infections (12). It is also used to treat nervous system, in-
fertility and fever (14). Decoctions of the plant are rec-
ommended by herbalists for preparations used as carmi-
natives for children. In the north of Oman, the juice ex-
pressed from the leaves is used as a remedy for headaches
and arthritis (15). In Saudi Arabia, Haplophyllum tuber-
culatum is used to treat malaria, rheumatoid arthritis and
gynecological disorders (16). While, in Sudan the herb
is used as an antispasmodic, to treat allergic rhinitis and
gynecological disorders, asthma and breathing difficulties
(17) and so on, indicating a large degree of variability in its
traditional uses as a function of geographic and ecological
location.
Haplophyllum tuberculatum: An overview
Journal of HerbMed Pharmacology, Volume 5, Number 4, October 2016
http://www.herbmedpharmacol.com 127
Phytochemical studies
Many studies have evaluated the medicinal properties and
phytochemistry of some of these species, analyzing their
contents for alkaloids, lignanes, glycosides and flavonoids,
etc. During the phytochemical investigation of Haplo-
phyllum acutifolium, two alkaloids named haplophytin-
A and B have been obtained. In addition, some known
constituents: flindersine, kusunokinin, β-sitosterol, cho-
lesterol, oleanolic acid, and hexadecanoic acid, have also
been obtained. Two new alkaloids, haplotubinone and
haplotubine, were isolated from the aerial parts of Hap-
lophyllum tuberculatum together with the known Lignan
Diphyllin (18).
The chemical components of the Haplophyllum tubercu-
latum essential oil was analyzed by gas chromatography–
mass spectral (GC–MS) as well as 13C NMR spectroscopy.
More than 30 compounds, constituting about 99.7% of the
total oil, were identified. The most abundant oil compo-
nents were β-phellandrene (23.3%), limonene (12.6%),
(Z)-β-ocimene (12.3%), β-caryophyllene (11.6%), myr-
cene (11.3%), and α-phellandrene (10.9%) (9).
The GC-MS analyses on the essential oils from the aer-
ial parts of H. tuberculatum led to the identification of
39 compounds, representing 91.3% of the whole oil. H.
tuberculatum essentials oils were mainly composed by
oxygenated monoterpenes (71.0 % of the whole oil). The
major compounds of H. tuberculatum in essential oil of
the plant were cis-p-menth-2-en-1-ol as well as trans-p-
menth-2-en-1-ol (22.9 and 16.1 %, respectively) (19). In
an investigation in Larestan, Iran, main components of
Haplophyllum tuberculatum was borneol (25.73%). Other
major compounds were α-Pinene (14%), Bornyl acetate
(18.07%) and β-caryophyllene (7.43%) (20).
The main constituents were terpinene-4-ol (3.2.%)
hexadec-1-ene (3.2%), -phellandrene (2.1%), -phellan-
drene (3.0%), p-cymene-8-ol (2.9%), piperitone (17.8),
2,4-bis(1,1-dimethylethyl)-phenol (28.3%), (1E,4E)-ger-
macrene B (2.1%) and octadec-1-ene (2.1%), (63). The oil
of this species from Oman revealed that the most abun-
dant components were limonene (12.6%), α-phellandrene
(23.3%), (Z)-β-ocimene (12.3%), β-caryophyllene (11.6%),
myrcene (11.3%) and β-phellandrene (10.9%) (4). In other
sample the major components were cis-p-menth-2-en-1-
ol (13.2%), trans-p-menth-2-en-1-ol (19.2%), myrcene
(10.1%), δ-3-carene (8.8%), β-phellandrene (6.9%), limo-
nene (6.6%) and cis-piperitol (6.4%) (21).
Previous investigations on the essential oil of this species
showed variable chemical compositions. Sample from Iran
was found to contain limonene (27, 3%) and α-pinene (21,
9 %) as major constituents (22). The air-dried aerial parts
of Haplophyllum robustum growing in Iran and analyzed
by gas chromatography (GC) and gas chromatography-
mass spectrometry (GCMS) was poor in essential oil
(yield = 0.5%). However, thirty constituents represent-
ing 99.23% of total essential oil were identified in it. The
main constituents of the oil were found to be 1,8-cineole
(38.1%), myrcene (10.69 %), α-pinene (8.46%), 4-terpin-
eol (6.96%) and sabinene (6.15%). Other representative
compounds were identified as methyl geranate (4.69%),
γ-terpinen (4.3%) and α-terpinene (3.43%) (23). An ear-
lier report shows the major components of C. copticum
fruits essential oil as 1,8-cineole. But there is not any trace
of sesquiterpenes in all samples of this work (24). These
differences might have been derived both from harvest
time and local, climatic and seasonal factors or we may
hypothesize that this sample belongs to a different chemo-
type. However, further investigations are needed to eluci-
date this hypothesis.
Pharmacological aspects
Effect on skin diseases remedy
Natural products are considered as important source for
new drug preparation. Many natural products, semi-
synthetic or NP derived candidates are now in clinic or
in clinical trials (25). This plant is a member of Rutaceae
family, a family reported to be rich in furocoumarin (pso-
ralen). These compounds are considered as one of the im-
portant class of natural compounds, widely used to treat
dermatological conditions for different skin diseases. The
available imported preparations of these compounds are
very expensive. They have been prominent in the United
States for phytochemotherapy of vitiligo, psoriasis, para-
psoriasis, mycosis fungoides (26). Recently some other
biological activities of Psoralens and related compounds
have been reported, including anti-inflammatory, anal-
gesic, antitumor, and calcium antagonist activities. Also
these compounds show encouraging levels of phytochem-
icals against Fusarium culmorum and may have a potential
use as phytoactive pesticides.
Anticancer effect
The extracts from Haplophyllum tuberculatum was toxic
against the seven solid cancer cell lines studied with the
highest IC50 values of 31.64 μg/mL (against Hep-G2 cells).
Haplophyllum tuberculatum induced cell cycle arrest in
G0/G1 and S phases. Haplophyllum tuberculatum extract
caused apoptosis in CCRF-CEM cells by the alteration of
the mitochondrial membrane potential (9).
Uterus-relaxing activity
The pharmacological profile of 6-MKG (6-Methoxykaemp-
ferol-3-O-glucoside) isolated from Haplophyllum tubercu-
latum was determined basis on its uterus-relaxing proper-
ty, employing β2-adrenoceptors as main target. It was test-
ed on isolated pregnant or none-pregnant rats uteri, whilst
docking studies were carried out modeling of the bind-
ing of 6-MKG to the rat β2-adrenoceptorin. Studies have
shown that 6-MKG was able to relax both the late-preg-
nant and the none-pregnant uterine contractility equalto
50% of the Emax of terbutaline, whilst the EC50 for 6-MKG
was at least half of terbutaline result. A β2-adrenoceptor
antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)
oxy]butan-2-ol (ICI118,551) antagonized competitively
the relaxing effect of 6-MKG. Radioligand binding and
cAMP studies confirmed the β2-adrenoceptors agonis-
tic activity of this compound. In a study, 6-MKG bound
Raissi A et al
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128
to rat β2-adrenoceptors with low ΔGbind value interacted
with four residues of the active site (Asp113, Asn312, Cys191
an d Ty r316). It is concluded that 6-MKG exerts weak β2-
adrenoceptor agonistic activity and might be considered
as a natural compound with therapeutic effect in the field
of premature pregnant uterine contractions and asthmatic
problems (27). β2-Adrenoceptor agonists have therapeutic
potential due to their use for asthma (28) and to inhibit
pre-term labour (19), which is still a medical challenge
(29). A few β2-adrenoceptor drugs are of a natural origin.
The effects of a methanolic extract of H. tuberculatum and
teflubenzuron on several reproductive variables and ec-
dysteroid titers were investigated. The test products were
administered orally to newly emerged females at doses
of 1500 and 10 µg/female of Haplophyllum tuberculatum
and teflubenzuron, respectively. Both were able to de-
lay the first oviposition and reduce fecundity and fertil-
it y. Haplophyllum tuberculatum and teflubenzuron also
showed similar properties on ovarian growth, ecdysteroid
titers and vitellogenesis. Both treatments induced a drop
in hemolymph protein and reduced vitellogenin uptake
by oocytes. This delay in oogenesis was accompanied
by a resorption of terminal oocytes. However, whereas
teflubenzuron completely blocked egg hatch, Haplophyl-
lum tuberculatum had a modest preventive effect on this
factor. Hemolymph and ovarian ecdysteroid titers, as
measured by radioimmunoassay, were similarly low in
control and treated females, except for a peak observed
only in control females at the end of vitellogenesis. As-
sayed against various organisms, H. tuberculatum extracts
have been observed to display insecticidal (5), nematicidal
(30), antifungal and antibacterial (12,31) properties. The
plant is used to cure scorpion stings. It is usually used to
strengthen the children back muscles, chest pains, flatu-
lence, stomach problems and has sedative effects (32).
Effect on nervous system
Four amides (veskamide, enferamide, becatamide, and
oretamide) were investigated for their protective effects on
H2O2-induced apoptosis in PC-12 cells. These compounds
are Nphenylethylbenzoylamide-type phenolic amides,
found in plants such as Aniba riparia Begonia nantoensis,
Haplophyllum tuberculatum, and Houttuynia cordata. The
decreasing order of the protective effects on H2O2-induced
apoptosis was becatamide > enferamide ≥ oretamide >
veskamide. Becatamide suppressed H2O2-induced mito-
chondrial membrane depolarization in a dose-dependent
manner. At the concentration of 10 µM, becatamide main-
tained mitochondrial membrane depolarization at 16%
compared to 51% in H2O2-treated PC-12 cells (33). Cer-
tain neurodegenerative diseases progressively deteriorate
the structure and/or the function of neurons in the central
nervous system, eventually leading to cell death (34,35).
Neurodegenerative processes are very much responsible
for several neuronal diseases such as Alzheimer’s, Parkin-
son’s, and Huntington’s diseases (7,36). Although there
are several mechanisms involved in neuronal cell death, a
most common mechanism is through the well-known in-
trinsic mitochondrial apoptotic pathway (38). Depolariza-
tion of mitochondria membrane potential caused damage
to outer membrane resulted in the loss of its dye from the
mitochondria decreasing the intracellular fluorescence
(39).
Anti-HIV effect
Anti-HIV agents from natural resources are belonged to
various classes including terpenoids, coumarins, alkaloids,
polyphenols, tannins and flavonoids (40). The buchapine,
quinolone alkaloid, was isolated from methanolic extract
of the epigeal part of Haplophyllum bucharicum (41), Hap-
lophyllum tuberculatum (42). The natural products of this
plant exhibit anti-HIV activity against HIV-1 in cultured
human lymphoblastoid CEM-SS cells (EC50 0.94 µM, IC50
29.0 µM and EC50 1.64 µM, IC50 26.9 µM), respectively
(43). Naturally occurring quinolone alkaloid buchapine
was evaluated for anti-HIV activity on CEM-GFP (human
CD4+ T cell line), infected with HIV-1NL4.3 virus by p24
antigen capture ELISA assay. The compounds1and 2 re-
vealed inhibitory activity with IC50 value of 2.99 and 3.80
µM, respectively (44). Further, 45 alkylated derivatives of a
base compound, quinoline 2,4-diol were then synthesized
and tested for anti-HIV potential in human CD4
+ T cell
line CEM-GFP. Among these, 13 derivatives have shown
more than 60% inhibition. All active compounds showed
higher CC50 values which indicate that they have better
therapeutic indices. Bevirimat, a semi-synthetic deriva-
tive of betulinic acid, is in phase IIb trials in HIV-infected
patients (25). Bevirimat blocks HIV maturation by in-
hibiting the final step of the HIV Gag protein processing.
Batzelladines (45), harmine (46), michellamine B (47),
calanolide A and B, calceolarioside B (48), mallotojaponin
(49); and macrocarpals (50) are a few other examples of
anti-HIV natural products.
Antimicrobial effect
Ten microlitres (25 mg) of pure oil of Haplophyllum tuber-
culatum partially inhibited the growth of Escherichia coli,
Salmonella choleraesuis, and Bacillus subtilis to the same
extent as 0.10 µg of gentamycin sulfate. The oil also affect-
ed the mycelial growth of Curvularia lunata and Fusar-
ium oxysporum in a dose-dependent manner, however,it
had not any effect on the germination of their spores (9).
Antimicrobial testing of polyphenolic and alkaloid com-
pounds, on solid medium, showed the presence of anti-
bacterial properties of some tested strains including Ba-
cillus subtilis ATCC 6633, Staphylococcus aureus ATCC
25923 and Pseudomonas aeruginosa ATCC 27953. Their
MICs ranged from 0.625 mg/mL to 10 mg/mL for alka-
loids and 5 mg/mL to 20 mg/mL for polyphenols (51).
Insecticidal effect
Haplophyllum tuberculatum is used to protect livestock
from biting insects and flies (6). The ethanol extract of the
aerial parts of Haplophyllum tuberculatum possess good
insecticidal activity against Culex quinquefasciatus (52).
The nematicidal properties of Haplophyllum tuberculatum
Haplophyllum tuberculatum: An overview
Journal of HerbMed Pharmacology, Volume 5, Number 4, October 2016
http://www.herbmedpharmacol.com 129
against root-knot nematode were reported, which is due
to the presence in the plant of three known alkaloids: faga-
rine, skimmianine and evoxine. The effects of Plectranthus
cylindraceus and Haplophyllum tuberculatum oils to con-
trol Meloidogyne javanica were investigated. A mixture of
plectranthus and haplophyllum oils (1:1) was highly toxic
to M. javanica in vitro, as it killed all nematode juveniles
and inhibited hatching of eggs at 12.5 mg/mL concentra-
tion after 24 hours exposure time. In the green-house, to-
matoes grown in soil treated with a combination of the two
essential oils caused fewer root galls than those grown in
soil treated with higher doses of either oil. The oil mixture,
at 2.5 and 5.0 mg/mL of soil, was not phytotoxic to tomato
plant after 12 weeks exposure time, compared to treat-
ment over the same period at lower effective doses (53).
Nematicidal activities of the combined essential oils were
suggested by the presence of C10 dienes, C10 trienes and C10
phenol (54). Meloidogyne javanica (Treub) Chitwood is
one of the most common and widespread species of root-
knot nematodes in world. This Meloidogyne species can
cause severe yield losses on tomato, okra, eggplant, melon,
onion, carrot, cabbage, pepper, sweet potato and lettuce
in greenhouse (53). The major chemical components with
nematicidal activities have been previously identified as
thymol, carvacrol, pulegone, limonene, anethole, geranial
and artemisia ketone (54).
Conclusion
Sistan and Baloochestan province is a rich center of me-
dicinal plants. One of the important medicinal plants in
this region, distributed in three locations of this province,
is Haplophyllum tuberculatum. It is used in traditional
medicine as a remedy for headaches and arthritis, the
juice is applied as a wart removal, infections skin discolor-
ation, and parasitic diseases. In Baloochestan, it is use by
women for healing after childbirth ailments. It has many
other medicinal properties and the bioactive molecules of
this plant play an important role in human health, hence,
it might be used for different drug productions. Because of
importance of this plant, cultivation of it is very necessary.
Authors’ contributions
All the authors wrote the manuscript equally.
Conflict of interests
The authors declared no competing interests.
Ethical considerations
Ethical issues (including plagiarism, misconduct, data
fabrication, falsification, double publication or submis-
sion, redundancy) have been completely observed by the
authors.
Funding/Support
None.
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