A review on
therapeutic potential of Nigella sativa: A miracle herb
Aftab Ahmad,1,* Asif Husain,2 Mohd Mujeeb,3 Shah Alam Khan,4 Abul Kalam Najmi,5 Nasir Ali Siddique,6 Zoheir A. Damanhouri,7 and Firoz Anwar8
1Health Information
Technology Department, Jeddah Community College, King Abdulaziz University,
Jeddah-21589, Kingdom of Saudi Arabia
2Department of
Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi,
India
3Department of
Pharmacognosy, Faculty of Pharmacy, Hamdard University, New Delhi, India
4Oman Medical College,
Muscat, Sultanate of Oman
5Department of
Pharmacology, Faculty of Pharmacy, Hamdard University, New Delhi-110062, India
6Department of
Pharmacognosy, College of Pharmacy, King Saud University, Riyadh-11451, Saudi
Arabia
7Department of
Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi
Arabia
8Siddhartha Institute of
Pharmacy, Dehradun, Uttarakhand, India
Reviewed by Dr. Kamal
Kishore
Head & Associate
Professor, Department of Pharmacy, MJP Rohilkhand University, Bareilly, U.P,
India-243006, E-mail: ni.oc.oohay@yllierablamak
Author information ? Article notes ? Copyright and License information ?
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Abstract
Nigella sativa (N. sativa) (Family Ranunculaceae)
is a widely used medicinal plant throughout the world. It is very popular in
various traditional systems of medicine like Unani and Tibb, Ayurveda and
Siddha. Seeds and oil have a long history of folklore usage in various systems
of medicines and food. The seeds of N. sativa have been widely used in
the treatment of different diseases and ailments. In Islamic literature, it is
considered as one of the greatest forms of healing medicine. It has been
recommended for using on regular basis in Tibb-e-Nabwi (Prophetic Medicine). It
has been widely used as antihypertensive, liver tonics, diuretics, digestive,
anti-diarrheal, appetite stimulant, analgesics, anti-bacterial and in skin
disorders. Extensive studies on N. sativa have been carried out by
various researchers and a wide spectrum of its pharmacological actions have
been explored which may include antidiabetic, anticancer, immunomodulator, analgesic,
antimicrobial, anti-inflammatory, spasmolytic, bronchodilator,
hepato-protective, renal protective, gastro-protective, antioxidant properties,
etc. Due to its miraculous power of healing, N. sativa has got the place
among the top ranked evidence based herbal medicines. This is also revealed
that most of the therapeutic properties of this plant are due to the presence
of thymoquinone which is major bioactive component of the essential oil. The
present review is an effort to provide a detailed survey of the literature on
scientific researches of pharmacognostical characteristics, chemical
composition and pharmacological activities of the seeds of this plant.
Keywords: Nigella sativa, Miracle herb,
Ranunculaceae, Habat-ul-Sauda, Thymoquinone, Tibb-e-Nabwi, Black seeds,
Anti-diabetic, Antioxidant
1.?Introduction
Medicinal plants have been used for
curing diseases for many centuries in different indigenous systems of medicine
as well as folk medicines. Moreover, medicinal plants are also used in the
preparation of herbal medicines as they are considered to be safe as compared
to modern allopathic medicines. Many researchers are focusing on medicinal
plants since only a few plant species have been thoroughly investigated for
their medicinal properties, potential, mechanism of action, safety evaluation
and toxicological studies.
Among various medicinal plants, Nigella
sativa (N. sativa) (Family Ranunculaceae) is emerging as a miracle
herb with a rich historical and religious background since many researches
revealed its wide spectrum of pharmacological potential. N. sativa is
commonly known as black seed. N. sativa is native to Southern Europe,
North Africa and Southwest Asia and it is cultivated in many countries in the
world like Middle Eastern Mediterranean region, South Europe, India, Pakistan,
Syria, Turkey, Saudi Arabia[1].
The seeds of N. sativa and
their oil have been widely used for centuries in the treatment of various
ailments throughout the world. And it is an important drug in the Indian
traditional system of medicine like Unani and Ayurveda[2],[9]. Among Muslims, it is
considered as one of the greatest forms of healing medicine available due to it
was mentioned that black seed is the remedy for all diseases except death in
one of the Prophetic hadith. It is also recommended for use on regular basis in
Tibb-e-Nabwi (Prophetic Medicine)[3].
N. sativa has been extensively studied for
its biological activities and therapeutic potential and shown to possess wide
spectrum of activities viz. as diuretic, antihypertensive, antidiabetic,
anticancer and immunomodulatory, analgesic, antimicrobial, anthelmintics,
analgesics and anti-inflammatory, spasmolytic, bronchodilator,
gastroprotective, hepatoprotective, renal protective and antioxidant
properties. The seeds of N. sativa are widely used in the treatment of
various diseases like bronchitis, asthma, diarrhea, rheumatism and skin
disorders. It is also used as liver tonic, digestive, anti-diarrheal, appetite
stimulant, emmenagogue, to increase milk production in nursing mothers to fight
parasitic infections, and to support immune system[4]?[9]. Most of the therapeutic properties
of this plant are due to the presence of thymoquinone (TQ) which is a major
active chemical component of the essential oil. Black seeds are also used in
food like flavoring additive in the breads and pickles because it has very low
level of toxicity[10].
2.?Pharmacognostical
characteristics
2.1. Morphology of the
plant
N. sativa is an annual flowering plant which
grows to 20-90 cm tall, with finely divided leaves, the leaf segments narrowly
linear to threadlike. The flowers are delicate, and usually colored white,
yellow, pink, pale blue or pale purple, with 5-10 petals. The fruit is a large
and inflated capsule composed of 3-7 united follicles, each containing numerous
seeds[9],[11].
N. sative (whole plant, flower and
seeds) adopted from internet.
2.2. Characteristics of
the seeds and powder
Macroscopically, seeds are small
dicotyledonous, trigonus, angular, regulose-tubercular, 2-3.5mm~1-2 mm, black
externally and white inside, odor slightly aromatic and taste bitter.
Microscopically, transverse section of seed shows single layered epidermis
consisting of elliptical, thick walled cells, covered externally by a papillose
cuticle and filled with dark brown contents. Epidermis is followed by 2-4
layers of thick walled tangentially elongated parenchymatous cells, followed by
a reddish brown pigmented layer composed of thick walled, rectangular elongated
cells. Inner to the pigment layer, is present a layer composed of thick walled
rectangular elongated or nearly columnar, elongated cells. Endosperm consists
of thin walled, rectangular or polygonal cells mostly filled with oil globules.
The powder microscopy of seed powder shows brownish black, parencymatous cells
and oil globules[1],[11].
3.?Chemical
composition of black seeds
Many active compounds have been
isolated, identified and reported so far in different varieties of black seeds.
The most important active compounds are thymoquinone (30%-48%),
thymohydroquinone, dithymoquinone, p-cymene (7%-15%), carvacrol (6%-12%), 4-terpineol
(2%-7%), t-anethol (1%-4%), sesquiterpene longifolene (1%-8%) Ώ-pinene and
thymol etc. Black seeds also contain some other compounds in trace
amounts. Seeds contain two different types of alkaloids; i.e.
isoquinoline alkaloids e.g. nigellicimine and nigellicimine-N-oxide, and
pyrazol alkaloids or indazole ring bearing alkaloids which include nigellidine
and nigellicine. Moreover, N. sativa seeds also contain alpha-hederin, a
water soluble pentacyclic triterpene and saponin, a potential anticancer agent[12],[13].
Some other compounds e.g.
carvone, limonene, citronellol were also found in trace amounts. Most of the
pharmacological properties of N. sativa are mainly attributed to quinine
constituents, of which TQ is the most abundant. On storage, TQ yields
dithymoquinone and higher oligocondensation products. The seeds of N. sativa
contain protein (26.7%), fat (28.5%), carbohydrates (24.9%), crude fibre (8.4%)
and total ash (4.8 %). The seeds are also containing good amount of various
vitamins and minerals like Cu, P, Zn and Fe etc. The seeds contain
carotene which is converted by the liver to vitamin A. Root and shoot are
reported to contain vanillic acid[12],[14].
The seeds reported to contain a
fatty oil rich in unsaturated fatty acids, mainly linoleic acid (50-60%), oleic
acid (20%), eicodadienoic acid (3%) and dihomolinoleic acid (10%). Saturated
fatty acids (palmitic, stearic acid) amount to about 30% or less. Ώ-sitosterol is
a major sterol, which accounts for 44% and 54% of the total sterols in Tunisian
and Iranian varieties of black seed oils respectively, followed by stigmasterol
(6.57-20.92% of total sterols)[15]?[17].
Examples of various other reported
chemical components includes nigellone,avenasterol-5-ene, avenasterol-7-ene,
campesterol, cholesterol, citrostadienol, cycloeucalenol,, gramisterol,
lophenol, obtusifoliol, stigmastanol, stigmasterol-7-ene, ΐ-amyrin,
butyro-spermol, cycloartenol, 24-methylene-cycloartanol, taraxerol, tirucallol,
3-O-[ΐ-D-xylopyranosyl(1¨3)-Ώ-L-rhamnopyranosyl(1¨2)-Ώ-L-arabino-pyranosyl]-28-O-[Ώ-L-rhamnopyranosyl(1¨4)-ΐ-D-glucopyranosyl(1¨6)-ΐ-D-gluco-pyranosyl]
hederagenin, volatile oil (0.5-1.6%), fatty oil (35.6-41.6%), oleic acid,
esters of unsaturated fatty acids with C15 and higher terpenoids, esters of
dehydrostearic and linoleic acid, aliphatic alcohol, ΐ-unsaturated hydroxy
ketone, hederagenin glycoside, melanthin, melanthigenin, bitter principle,
tannin, resin, protein, reducing sugar, glycosidal saponin,
3-O-[ΐ-D-xylopyranosyl-(1¨2)-Ώ-L-rhamno-pyranosyl-(1¨2)-ΐ-D-glucopyranosyl]-11-methoxy-16,
23-dihydroxy-28-methy-lolean-12-enoate,stigma-5,
22-dien-3-ΐ-D-gluco-pyranoside, cycloart-23-methyl-7, 20, 22-triene-3ΐ,
25-diol, nigellidine-4-O-sulfite, N. mines A3, A4, A5, C, N. mines A1, A2, B1,
and B2[18]?[22].
4.?Traditional
uses of folk remedies
N. sativa has been traditionally used for the
treatment of a variety of disorders, diseases and conditions pertaining to
respiratory system, digestive tract, kidney and liver function, cardio vascular
system and immune system support, as well as for general well-being[2],[9].
Avicenna refers to black seeds in
the gThe Canon of Medicineh, as seeds stimulate the body's energy and helps
recovery from fatigue and dispiritedness. Black seeds and their oil have a long
history of folklore usage in Indian and Arabian civilization as food and
medicine[11],[23]. The seeds have been
traditionally used in Southeast Asian and the Middle East countries for the
treatment of several diseases and ailments including asthma, bronchitis,
rheumatism and related inflammatory diseases. Its many uses have earned Nigella
the Arabic approbation eHabbatul barakahf, meaning the seed of blessing. A
tincture prepared from the seeds is useful in indigestion, loss of appetite,
diarrhoea, dropsy, amenorrhoea and dysmenorrhoea and in the treatment of worms
and skin eruptions. Externally the oil is used as an antiseptic and local
anesthetic. Roasted black seeds are given internally to stop the vomiting[2],[11],[23],[24].
5.?Scientific
researches and pharmacological potentials
The extensive researches using
modern scientific techniques were carried out by various researchers on N.
sativa since it is believed to be a miraculous herb that can cure multiple
ailments and disorders. A number of pharmacological actions of N. sativa
have been investigated in the past few decades.
5.1. Antibacterial
activity
The antibacterial effect of ground
black seeds was studied in a modified paper disc diffusion method. A clear
inhibition of the growth of Staphylococcus aureus was observed by
concentration of 300 mg/mL with distilled water as control, this inhibition was
confirmed by using the positive control Azithromycin. The inhibition obtained
was higher with N. sativa ground seeds from Hadramout than with N.
sativa ground seeds from Ethiopia. The positive inhibition may be
attributed to the two important active ingredients of N. sativa, TQ and
melanin[25].
Different crude extracts of N. sativa were tested for antimicrobial
effectiveness against different bacterial isolates which comprised of 16 gram
negative and 6 gram positive representatives. These isolates showed multiple
resistances against antibiotics, specially the gram negative ones. Crude
extracts of N. sativa showed a promising effect against some of the test
organisms. The most effective extracts were the crude alkaloid and water
extracts. Gram negative isolates were affected more than the gram positive ones[26].
Antibacterial activity of N. sativa against clinical isolates of
methicillin resistant Staphylococcus aureus was investigated in 2008 by
Hannan et al. All tested strains of methicillin resistant Staphylococcus
aureus were sensitive to ethanolic extract of N. sativa at a
concentration of 4 mg/disc with an MIC range of 0.2-0.5 mg/mL[27].
Antibacterial activity of N. sativa against and triple therapy in
eradication of Helicobacter Pylori in patients with non-ulcer dyspepsia was
carried out. It was showed that N. sativa seeds possess clinically
useful anti H. pylori activity, comparable to triple therapy[28]. The
antibacterial activity of TQ and its biofilm inhibition potencies were
investigated on 11 human pathogenic bacteria. TQ exhibited a significant
bactericidal activity against various human pathogenic bacteria especially Gram
positive cocci (Staphylococcus aureus ATCC 25923 and Staphylococcus
epidermidis CIP 106510). TQ prevented cell adhesion to glassslides surface[29].
5.2. Antifungal activity
Methanolic extracts of N. sativa
have the strongest antifungal effect followed by the chloroform extracts
against different strains of Candida albicans. Aqueous extracts showed
no antifungal activity. An intravenous inoculum of Candida albicans
produced colonies of the organism in the liver, spleen and kidneys. Treatment
of mice with the plant extract 24 h after the inoculation caused a considerable
inhibitory effect on the growth of the organism in all organs studied. Khan et
al. in 2003 reported that the aqueous extract of N. sativa seeds
exhibits inhibitory effect against candidiasis in mice. A 5-fold decrease in
Candida in kidneys, 8-fold in liver and 11-fold in spleen was observed in the
groups of animals post-treated with the plant extract. These findings were also
confirmed by Histopathological examination of the respective organs[30].
Antidermatophyte activity of ether extract of N. sativa and TQ was
tested against eight species of dermatophytes: four species of Trichophyton
rubrum and one each of Trichophyton interdigitale, Trichophyton
mentagrophytes, Epidermophyton floccosum and Microsporum canis
using Agar diffusion method with serial dilutions of ether extract of N.
sativa, TQ and griseofulvin. The MICs of the ether extract of N. sativa
and TQ were between 10-40 and 0.125-0.250 mg/mL, respectively, while those of
griseofulvin ranged from 0.00095 to 0.01550 mg/mL. These results denote the
potentiality of N. sativa as a source for antidermatophyte drugs and
support its use in folk medicine for the treatment of fungal skin infections[31]. The
antiyeast activity of the black cumin seed quinines, dithymoquinone,
thymohydroquinone, and TQ were evaluated in vitro with a broth
microdilution method against six dairy spoilage yeast species. It was found
that Antifungal effects of the quinones were compared with those of
preservatives commonly used in milk products (calcium propionate, natamycin,
and potassium sorbate) at two pH levels (4.0 and 5.5), while thymohydroquinone
and TQ possessed significant antiyeast activity[32]. Two novel antifungal defensins
named Ns-D1 and Ns-D2, were isolated from seeds of N. sativa and
sequenced. The Ns-D1 and Ns-D2 defensins displayed strong divergent antifungal
activity towards a number of phytopathogenic fungi[33].
5.3. Anti-schistosomiasis
activity
The effect of NSO against the liver
damage induced by Schistosoma mansoni (S. mansoni) infection in
mice was studied by Mahmoud et al. When the NSO was given alone, it
reduced the number of S. mansoni worms in the liver and decreased the total
number of ova deposited in both the liver and the intestine. When NSO was
administered in combination with PZQ, the most prominent effect was a further
lowering in the dead ova number over that produced by PZQ alone. Infection of
mice with S. mansoni produced a pronounced elevation in the serum
activity of ALT, GGT, with a slight increase in AP level, while reduce serum
albumin level. Administration of NSO succeeded partially to correct the
previous changes in ALT, GGT, AP activity, as well as the Alb content in serum.
These results suggest that NSO may play a role against the alterations caused
by S. mansoni infection[34].
Results of in vitro testing of N. sativa seeds against Schistosoma
mansoni, miracidia, cercariae, and adult worms indicate its
strong biocidal effects against all stages of the parasite and an inhibitory
effect on egg-laying of adult female worms. N. sativa seeds also induced
an oxidative stress against adult worms which indicated by a decrease in the
activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione
peroxidase, and glutathione reductase and enzymes of glucose metabolism,
hexokinase and glucose-6-phosphate dehydrogenase. Disturbing of such enzymes of
adult worms using N. sativa seeds could in turn render the parasite
vulnerable to damage by the host and may play a role in the anti-schistosomal
potency of the N. sativa seed[35]. The
antioxidant and anti-schistosomal activities of the garlic extract (AGE) and
NSO on normal and Schistosoma mansoni-infected mice was investigated. Result
showed that, protection with AGE and NSO prevented most of the hematological
and biochemical changes and markedly improved the antioxidant capacity of
schistosomiasis mice compared to the infected-untreated ones. These results
suggested that AGE and NSO may be promising agents to complement schistosomiasis
specific treatment[36].
5.4. Antioxidant activity
The antioxidant and antiarthritic
activity of TQ in Wistar rat by collagen induced arthritis was evaluated. TQ
was administered at a dose of 5 mg/kg body weight once daily for 21 d. The
effects of treatment in the rats were assessed by biochemical (articular
elastase, myeloperoxdase (MPO), LPO, glutathione (GSH), catalase (CAT), SOD and
NO), inflammatory mediators [IL-1ΐ, IL-6, TNF-Ώ, IL-10, IFN-Α and PGE(2)] and
histological studies in joints. TQ was effective in bringing significant
changes on all the parameters (articular elastase, MPO, LPO, GSH, CAT, SOD and
NO) studied. Oral administration of TQ resulted in significantly reduced the
levels of pro-inflammatory mediators [IL-1ΐ, IL-6, TNF-Ώ, IFN-Α and PGE (2)]
and increased level of IL-10[37]. The antioxidant,
anti-inflammatory, anticancer and antibacterial activities of the shoots, roots
and seeds methanol extracts from N. sativa were studied. The three
organs exhibited strong antioxidant activity using the oxygen radical
absorbance capacity method and a cell-based assay[38]. TQ
has been shown to suppress the Fe-NTA-induced oxidative stress,
hyperproliferative response and renal carcinogenesis in Wistar rats[39]. It
was suggested that dietary supplementation of black seeds powder inhibits the
oxidative stress caused by oxidized corn oil in rats[40]. It
was also reported that oral feeding of the diet containing black seed powder at
10% level antagonized the oxidative stress effects induced by
hepato-carcinogens like dibutylamine and Sodium Nitrate (NaNO3) in Swiss
albino rats by normalizing GSH and NO levels[41]. The
black seed oil and TQ by intraperitonial injection were found to shown
protective effects on lipid peroxidation process during ischemia-reperfusion
injury (IRI) in rat hippocampus[42].
Treating broiler chicks with black seed for 6 weeks prevented the liver from
oxidative stress by increasing the activities of enzymes such as
myeloperoxidase, glutathione-S-transferase, CAT, adenosine deaminase,
myeloperoxidaseand bydecreasing hepatic lipid peroxidation[43]. The
crude methanolic extract of black cumin seed cake was found to shown with
significant antioxidant properties under in vitro systems[44].The modulatory effect of
TQ on erythrocyte lipid peroxidation and antioxidant status during
1,2-dimethylhydrazine- (DMH-) induced colon carcinogenesis after initiation in
male Wistar rats was investigated and The TQ pre-treatment restored the
increased level of malondialdehyde and conjugated diene levels, and an
augmentation of enzyme activities like CAT, glutathione peroxidase, and SOD
activities due to exposure to DMH. TQ was a useful compound preventing
DMH-induced erythrocyte damages[45].
5.5. Antidiabetic
activity
The therapeutic potentials of
Ώ-lipoic acid (Ώ-LA), L-carnitine, and N. sativa or combination of them
in carbohydrate and lipid metabolism was evaluated in a Rat model of diabetes
which was induced by single i.p. injection of streptozocin (STZ) 65
mg/kg. For evaluation of glucose metabolism, fasting blood glucose, insulin,
insulin sensitivity, HOMA, C-peptide, and pyruvate dehydrogenase activity were
determined. Either Ώ-LA or N. sativa significantly reduced the elevated
blood glucose level. The combination of 3 compounds significantly increased the
level of insulin and C-peptide. Combination of Ώ-LA, L-carnitine and N.
sativa will contribute significantly in improvement of the carbohydrate
metabolism in diabetic rats, thus increasing the rate of success in management
of DM[46].
The effects of N. sativa aqueous extract and oil, as well as TQ, on
serum insulin and glucose concentrations in streptozotocin diabetic rats were
studied. Serum insulin and glucose concentrations, SOD levels, and pancreatic
tissue malondialdehyde (MDA) were determined. Electron microscopy was used to
identify any subcellular changes. Diabetes increased tissue MDA and serum
glucose levels and decreased insulin and SOD levels. Treatment of rats with N.
sativa extract and oil, as well as TQ, significantly decreased the
diabetes-induced increases in tissue MDA and serum glucose and significantly
increased serum insulin and tissue SOD. Ultrastructurally, TQ ameliorated most
of the toxic effects of streptozotocine(STZ), including segregated nucleoli,
heterochromatin aggregates (indicating DNA damage), and mitochondrial
vacuolization and fragmentation. The aqueous extract of N. sativa also
reversed these effects of STZ, but to a lesser extent. The N. sativa oil
restored normal insulin levels, but failed to decrease serum glucose
concentrations to normal. The biochemical and ultrastructural findings suggest
that N. sativa extract and TQ have therapeutic and protect against
STZ-diabetes by decreasing oxidative stress, thus preserving pancreatic ΐ-cell
integrity. The hypoglycemic effect observed could be due to amelioration of
ΐ-cell ultrastructure, thus leading to increased insulin levels. N. sativa
and TQ may prove clinically useful in the treatment of diabetics and in the
protection of ΐ-cells against oxidative stress[47]. The
protective effects of the volatile oil of N. sativa seeds on insulin
immunoreactivity and ultrastructural changes of pancreatic ΐ-cells in
STZ-induced diabetic rats was reported by Kanter et al. 2009. STZ was
injected intraperitoneally at a single dose of 50 mg/kg to induce diabetes.
Increased intensity of staining for insulin, and preservation of ΐ-cell numbers
were apparent in the N. sativa-treated diabetic rats. The protective
effect of N. sativa on STZ-diabetic rats was evident by a moderate increase
in the lowered secretory vesicles with granules and also slight destruction
with loss of cristae within the mitochondria of ΐ-cell when compared to control
rats. It is evident that N. sativa treatment exerts a therapeutic
protective effect in diabetes by decreasing morphological changes and
preserving pancreatic ΐ-cell integrity[48]. The
antihyperglycemic potential of TQ on the activities of key enzymes of
carbohydrate metabolism in streptozotocin (STZ)-nicotinamide (NA)-induced
diabetic rats was evaluated. Oral administration of TQ at 20, 40, 80 mg/kg body
weight for 45 d, dose dependently improved the glycemic status in STZ-NA
induced diabetic rats. The levels of insulin, Hb increased with significant
decrease in glucose and HbA (1C) levels. The altered activities of carbohydrate
metabolic enzymes were restored to near normal. These results proved that TQ at
80 mg/kg body weight is associated with beneficial changes in hepatic enzyme
activities and thereby exerts potential anti-hyperglycemic effects[49]. The N.
sativa showed the synergistic effect with human parathyroid hormone in
improving bone mass, connectivity, biomechanical behavior and strength in
insulin-dependent diabetic rats and found to be more effective as compared to
the treatment with N. sativa or human parathyroid hormone alone[50]. In a clinical study,
the adjuvant effect of N. sativa oil on various clinical and biochemical
parameters of the insulin resistance syndrome were investigated. N. sativa
oil was found to be effective as an add-on therapy in patients of insulin
resistance syndrome. N. sativa oil has a significant activity in
diabetic and dyslipidemic patients[51]. N.
sativa is of immense therapeutic benefit in diabetic individuals and those
with glucose intolerance as it accentuates glucose-induced secretion of insulin
besides having a negative impact on glucose absorption from the intestinal
mucosa[52].
The effects of the TQ in STZ-induced diabetes in rats were investigated. The
Effect of N. sativa seeds on the glycemic control of patients with type
2 diabetes mellitus was investigated in 2010. N. sativa seeds were used
as an adjuvant therapy in patients with diabetes mellitus type 2 added to their
anti-diabetic medications. N. sativa at a dose of 2 gm/day caused
significant reductions in fasting blood glucose, 2 h postprandially (2 hPG),
and glycosylated hemoglobin (HbA1c) without significant change in body weight.
The results indicate that a dose of 2 gm/day of black seed might be a
beneficial adjuvant to oral hypoglycemic agents in type 2 diabetic patients[53]. The in
vivo antidiabetic activity of N. sativa seed ethanol extract (NSE)
was evaluated in diabetic Meriones shawi. Plasma lipid profile, insulin,
leptin, and adiponectin levels were assessed. ACC phosphorylation and Glut4
protein content were determined in liver and skeletal muscle. NSE animals
showed a progressive normalization of glycaemia. It was also demonstrate that in
vivo treatment with NSE exerts an insulin-sensitizing action by enhancing
ACC phosphorylation, a major component of the insulin-independent AMPK
signaling pathway, and by enhancing muscle Glut4 content[54].
5.6. Anticancer activity
In vitro study of TQ to determine whether or
not TQ can increase survival and sustain the expression of the homing receptor
CD62L in antigen-specific T cells. The results showed that stimulation of OT-1
(transgenic CD+) T cells with OVA antigen resulted in activation, as shown by a
decrease in the surface expression of CD62L which coincided with significant
apoptosis measured three and five days after antigen stimulation. Addition of
low concentrations of TQ during CD85+ T-cell activation resulted in enhanced
survival of the activated T cells and sustained expression of CD62L. These
effects coincided with enhancement in the capability of CD8+ T cells to produce
the effector cytokine interferon-gamma (IFNgamma). This is concluded that TQ
has a beneficial effect in conditioning T cells in vitro for adoptive
T-cell therapy against cancer and infectious disease[55]. The
cytotoxic effects of different N. sativa seed extracts as an adjuvant
therapy to doxorubicin on human MCF-7 breast cancer cells was reported. The
study showed N. sativa lipid extract is cytotoxic to MCF-7 cells with LC50
of 2.720 } 0.232 mg/mL, while its aqueous extract cytotoxicity exhibited when
the applied concentration is high as about 50 mg/mL[56].
The antitumor and anti-angiogenic
effects of TQ on osteosarcoma in vitro and in vivo were
investigated. Results showed that TQ induced a higher percentage of growth
inhibition and apoptosis in the human osteosarcoma cell line SaOS-2 compared to
that of control, and TQ significantly blocked human umbilical vein endothelial
cell tube formation in a dose-dependent manner. It was found that TQ
significantly downregulated NF-ΘB DNA-binding activity, XIAP, survivin and VEGF
in SaOS-2 cells. Moreover, the expression of cleaved caspase-3 and Smac were upregulated
in SaOS-2 cells after treatment with TQ. It was also found that TQ inhibits
tumor angiogenesis and tumor growth through suppressing NF-ΘB and its regulated
molecules. It was concluded that TQ effectively inhibits tumor growth and
angiogenesis both in vitro and in vivo. Therefore, inhibition of
NF-ΘB and downstream effector molecules is a possible underlying mechanism of
the antitumor and anti-angiogenic activity of TQ in osteosarcoma[57].
The cytotoxicity of TQ in human
cervical squamous carcinoma cells (SiHa) was investigated. TQ was cytotoxic
towards SiHa cells with IC50 values of 10.67}0.12 and 9.33}0.19
Κg/mL as determined by MTT assay and trypan blue dye exclusion test,
respectively, after 72 h of incubation. TQ was found to be more cytotoxic
towards SiHa cells compared to cisplatin. Interestingly, TQ was less cytotoxic
towards the normal cells (3T3-L1 and Vero). Cell cycle analysis performed by
flowcytometer showed a significant increase in the accumulation of TQ-treated
cells at sub-G1 phase, indicating induction of apoptosis by the compound. TQ
was more potent than cisplatin in elimination of SiHa cells via apoptosis with
down-regulation of Bcl-2 protein[58].
The anticancer effects of TQ on
breast cancer cells, and its potential effect on the PPAR-Α activation pathway
was investigated and it was found that TQ exerted strong anti-proliferative
effect in breast cancer cells and when TQ combined with doxorubicin and
5-fluorouracil, cytotoxicity was found to be increased. TQ was found to
increase sub-G1 accumulation and annexin-V positive staining, indicating
apoptotic induction. In addition, TQ activated caspases 8, 9 and 7 in a
dose-dependent manner. Migration and invasive properties of MDA-MB-231 cells
were also reduced in the presence of TQ. Interestingly, TQ was found to
increase PPAR-Α activity and down-regulate the expression of the genes for
Bcl-2, Bcl-xL and survivin in breast cancer cells. More importantly, the
increase in PPAR-Α activity was prevented in the presence of PPAR-Α specific
inhibitor and PPAR-Α dominant negative plasmid, suggesting that TQ may act as a
ligand of PPAR-Α. It was observed by using molecular docking analysis that TQ
indeed formed interactions with 7 polar residues and 6 non-polar residues
within the ligand-binding pocket of PPAR-Α that are reported to be critical for
its activity. Thus, it was concluded that TQ may have potential implication in
breast cancer prevention and treatment and anti-tumor effect of TQ may also be
mediated through modulation of the PPAR-Α activation pathway[59]. It
was also revealed in a study of the assessment of the chemo-preventive
potential of crude oils in N. sativa on tumor formation using a
well-established rat multi-organ carcinogenesis model featuring initial
treatment with five different carcinogens that post-initiation administration
of 1?000 or 4?000 mg/L N. sativa volatile oil in the diet of male Wister
rats for 30 weeks significantly reduced malignant and benign colon tumor sizes,
incidences and multiplicities. The treatment also significantly decreased the
incidences and multiplicities of tumors in the lungs and in different parts of
the alimentary canal, particularly the esophagus and fore stomach. It was shown
that N. sativa administration exerts potent inhibitory effects on rat
tumor development and on cellular proliferation in multiple organ sites like
colon, lung, esophageal and fore stomach tumors in the post-initiation phase
with no evidence of clinical side effects[60]. The
potential immuno-modulatory effects of N. sativa are investigated in
light of splenocyte proliferation, macrophage function, and NK anti-tumor
activity using BLAB/c and C57/BL6 primary cells. NK cytotoxic activity against
YAC-1 tumor cells was examined by JAM assay. The study demonstrated that the
aqueous extract of N. sativa significantly enhances splenocyte
proliferation in a dose-responsive manner. It was also evident that the aqueous
extract of N. sativa significantly enhances NK cytotoxic activity
against YAC-1 tumor cells[61]. The
effect of TQ on pancreatic cancer cells and its effect on MUC4 expression were
investigated. The MUC4-expressing pancreatic cancer cells FG/COLO357 and
CD18/HPAF were incubated with TQ, and in vitro functional assays were
also done. The results indicated that treatment with TQ down regulated MUC4
expression through the proteasomal pathway and induced apoptosis in pancreatic
cancer cells by the activation of c-Jun NH(2)-terminal kinase and p38 mitogen-activated
protein kinase pathways. The decrease in MUC4 expression correlated with an
increase in apoptosis, decreased motility, and decreased migration of
pancreatic cancer cells. Therefore, it was concluded that TQ has potential for
the development of novel therapies against pancreatic cancer[62]. TQ
alone was found to possess a weak anticancer constituent of black seeds oil. TQ
Derivatives bearing terpene-terminated 6-alkyl residues were tested in cells of
human HL-60 leukemia, 518A2 melanoma, multidrug-resistant KB-V1/Vbl cervix, and
MCF-7/Topo breast carcinomas, as well as in non-malignant human foreskin
fibroblasts. Derivatives with a short four-atom spacer between quinone and
cyclic monoterpene moieties were more anti-proliferative than analogues with
longer spacers. 6-(Menthoxybutyryl) TQ (3a) exhibited single-digit micromolar
IC50 (72 h) values in all four cell lines. It was seven times more
active than TQ (1) in 518A2 melanoma cells and four times in KB-V1/Vbl cervix
carcinoma cells, while only half as toxic in the fibroblasts. Compound 3a was
also not a substrate for the P-gp and BCRP drug transporters of the resistant
cancer cells. The caryophyllyl and germacryl conjugates 3e and 3f specifically
inhibited the growth of the resistant MCF-7 breast carcinoma cells. Conjugation
of TQ with the triterpene betulinic acid via the OH group as in 3g led to a
loss in activity, while conjugation via the carboxylic acid afforded compound 4
with nanomolar IC50 (72 h) activity against HL-60 cells. All
anticancer-active derivatives of TQ (1) induced apoptosis associated with DNA
laddering, a decrease in mitochondrial membrane potential and a slight increase
in reactive oxygen species[63]. In
another study, 4-Acylhydrazones and 6-alkyl derivatives of TQ were tested for
growth inhibition of human HL-60 leukemia, 518A2 melanoma, KB-V1/Vbl cervix,
and MCF-7/Topo breast carcinoma cells. It was revealed that unsaturated side
chains conferred greater activities than equally long saturated chains. The
number of C==C bonds was less decisive than chain length. The 6-hencosahexaenyl
conjugate 3 e was most active in all resistant tumor cells, with IC50
(72 h) values as low as 30 nmol/L in MCF-7/Topo cells. The conjugates are
likely to operate by mechanisms different from that of TQ. For instance, 3 e
induced distinct caspase-independent apoptosis in HL-60 and 518A2 cells concomitant
with a loss of mitochondrial membrane potential and a subsequent rise in the
levels of reactive oxygen species[64]. The
administration of N. sativa was found to reduce the carcinogenic effects
of DMBA carcinogen in mammary carcinoma which indicated the protective role of N.
sativa in mammary carcinoma[65]. TQ
suppressed the migration and invasion of Panc-1 cells in a dose-dependent
manner. It was also found that TQ significantly down-regulates NF-kappa B and
MMP-9 in Panc-1 cells. In addition, metastatic model simulating human
pancreatic cancer was established by orthotropic implantation of histologically
intact pancreatic tumor tissue into the pancreatic wall of nude mice. And
administration of TQ significantly reduced tumor metastasis compared to
untreated control. Furthermore, the expression of NF-kappa B and MMP-9 in tumor
tissues was also suppressed after treatment with TQ. TQ exerts anti-metastatic
activity on pancreatic cancer both in vitro and in vivo, which
may be related to down-regulation of NF-kappa B and its regulated molecules
such as MMP-9 protein. Consequently, these results provide important insights
into TQ as an anti-metastatic agent for the treatment of human pancreatic
cancer[66].
The chemo-sensitizing effect of TQ and 5-fluorouracil (5-FU) on gastric cancer
cells both in vitro and in vivo is reported by Lei et al.
Pre-treatment with TQ significantly increased the apoptotic effects induced by
5-FU in gastric cancer cell lines in vitro. TQ also enhanced the
5-FU-induced killing of gastric cancer cells by mediating the down-regulation
of the anti-apoptotic protein bcl-2, the up-regulation of the pro-apoptotic
protein bax, and the activation of both caspase-3 and caspase-9. And further,
the combined treatment of TQ with 5-FU represents a significantly more
effective antitumor agent than either agent alone in a xeno-graft tumor mouse
model. This study suggested that the TQ/5-FU combined treatment induces
apoptosis by enhancing the activation of both caspase-3 and caspase-9 in
gastric cancer cells[67].
5.7. Anti-inflammatory
and analgesic activity
The aqueous extract of N. sativa
was found to possess anti-inflammatory and analgesic but not antipyretic
activities in animal models while anti-inflammatory effect of the alcoholic
extracts of N. sativa seeds and its callus on mix glial cells of rat
with regard to their TQ content was investigated. The mix glial cells, inflamed
by lipopolysaccharide, were subjected to anti-inflammatory studies in the
presence of various amounts of TQ and the alcoholic extracts. Results confirmed
that TQ content of the callus of leaf was 12 times higher than that measured in
the seeds extract. Studies on the inflamed rat mix glial cells revealed
significant reduction in the nitric oxide production in the presence of 0.2 to
1.6 mg/mL of callus extract and 1.25 to 20 ΚL/mL of the seed extracts[68].
Osteoporosis has been linked to oxidative stress and inflammation. The studies
on the anti-osteoporotic effects of N. sativa and TQ were carried out.
It was revealed that N. sativa and TQ were shown to inhibit inflammatory
cytokines such as interleukin-1 and 6 and the transcription factor, nuclear
factor ΘB. Both NS and TQ have shown potential as anti-osteoporotic agent[69].
Inflammation has been identified as a significant factor in the development of
solid tumour malignancies. Studies show that TQ, induced apoptosis and
inhibited proliferation in pancreatic ductal adenocarcinoma (PDA) cells. The
anti-inflammatory potential of TQ in PDA cells was evaluated in comparison with
that of a specific histone deacetylase (HDAC) inhibitor, trichostatin A. The
effect of TQ on the expression of different pro-inflammatory cytokines and
chemokines was analyzed by real-time polymerase chain reaction. TQ dose and
time-dependently significantly reduced PDA cell synthesis of MCP-1, TNF-alpha,
interleukin (IL)-1 ΐ and Cox-2. At 24 h, Tq almost completely abolished the
expression of these cytokines. TQ also increased p21 WAF1 expression, inhibited
HDAC activity, and induced histone hyperacetylation. HDAC inhibitors have been
shown to ameliorate inflammation-associated cancer. TQ as a novel inhibitor of
proinflammatory pathways provides a promising strategy that combines
anti-inflammatory and proapoptotic modes of action[70]. TQ
exhibit a slight inhibitory effect on COX-1 expression and PGE2 production in a
mouse model of allergic airway inflammation. This finding suggests that TQ has
an anti-inflammatory effect during the allergic response in the lung through
the inhibition of PGD2 synthesis and Th2-driven immune response[71]. The
antioxidant, anti-inflammatory, anticancer and antibacterial activities of the
shoots, roots and seeds methanol extracts from N. sativa were studied.
The seeds hexane fraction of the methanol extract showed significant
anti-inflammatory activity, inhibiting nitric oxide release with an IC50
value of 6.20 Κg/mL in lipopolysaccharide-stimulated RAW 264.7 macrophages[72]. A
clinical trial study was conducted as prospective and double blind with
descriptive analytic to investigate the anti-inflammatory effects of N.
sativa in patients with allergic rhinitis symptoms. The sample included 66
patients (case and placebo) with allergic rhinitis exposed to N. sativa
oil. Individual characteristics, including age and sex, and characteristics of
the disease, including nasal congestion, runny nose, itchy nose, and sneezing
attacks, were evaluated for a period of 30 d The results show that N. sativa
could reduce the presence of the nasal mucosal congestion, nasal itching, runny
nose, sneezing attacks, turbinate hypertrophy, and mucosal pallor during the
first 2 weeks (day 15). The anti-allergic effects of N. sativa
components could be attributed to allergic rhinitis. Moreover, N. sativa
should be considered for treating allergic rhinitis when the effects of other
anti-allergic drugs need to be avoided[73].
5.8. Immunomodulatory
activity
The potential immunomodulatory
effects of N. sativa were investigated in light of splenocyte
proliferation, macrophage function, and NK anti-tumor activity using BLAB/c and
C57/BL6 primary cells. Results demonstrated that the aqueous extract of N.
sativa significantly enhances splenocyte proliferation in a dose-responsive
manner. In addition, the aqueous extract of N. sativa favors the
secretion of Th2, versus Th1, cytokines by splenocytes. The secretion of IL-6,
TNF-Ώ, and NO; key pro-inflammatory mediators, by primary macrophages is
significantly suppressed by the aqueous extract of N. sativa, indicating
that N. sativa exerts anti-inflammatory effects in vitro.
Finally, experimental evidence indicates that the aqueous extract of N.
sativa significantly enhances NK cytotoxic activity against YAC-1 tumor
cells, suggesting that the documented anti-tumor effects of N. sativa
may be, at least in part, attributed to its ability to serve as a stimulant of
NK anti-tumor activity. It was anticipated that N. sativa ingredients
may be employed as effective therapeutic agents in the regulation of diverse
immune reactions implicated in various conditions and diseases such as cancer[74]. A
group of medicinal plants including black seed were examined for their
immuno-modulatory effect in BALB/c mice. Treatment (intraperitoneal injection)
with five doses of methanolic extract for Black seed was found to enhance the
total white blood cells count [up to 1.2~104 cells/mm3].
Bone marrow cellularity also increased significantly (P<0.01) after
the administration of the Black seed extract. Spleen weight of the black seed
treated groups was significantly increased (P<0.01). Two groups of
mice were immunosuppressed with cyclophosphamide, the one which pretreated with
the black seed extracts significantly (P<0.01) restored their
resistance against lethal infection with the predominately
granulocyte-dependant Candida albicans. These results confirmed the
immunomodulatory activity of black seed, and may have therapeutical
implications in prophylactic treatment of opportunistic infections and as
supportive treatment in oncogenic cases[75]. The
immunomodulating and cytotoxic properties of volatile oil of N. sativa
seeds was investigated in a Long-Evans rat model designed to examine the effect
of N. sativa seeds on selected immune components. Long-Evans rats were
challenged with a specific antigen (typhoid TH) and treated with N. sativa
seeds; Treatment with N. sativa oil induced about 2-fold decrease in the
antibody production in response to typhoid vaccination as compared to the
control rats but there was a significant decrease in splenocytes and
neutrophils counts, but a rise in peripheral lymphocytes and monocytes in the
these animals. These results indicated that the N. sativa seeds could be
considered as a potential immunosuppressive cytotoxic agent[62].
Chronic administration of oxytetracycline (OXT) (incorporated at a level of
0.05 g/kg of feed for 50 d) to pigeons, significantly decreased total leukocyte
and lymphocyte counts, increased heterophil: lymphocyte ratio and lysosomal
enzyme activity, and decreased reticuloendothelial system function compared
with controls. Coadministration of black seed at a level of 2.5% with OXT
completely blocked the effects elicited by OXT and produced immunostimulant
effects in pigeons. The addition of black seed to feed of pigeons could act as
an immunoprotective agent when chronic administrations of antibiotics are
considered[4].
The effect of TQ was tested on experimental autoimmune encephalomyelitis (EAE)
animal model that mimic human multiple sclerosis. Myelin oligodendrocyte
glycoprotein subcutaneously was used to induce chronic relapsing EAE. TQ
intraperiotoneally was found to be almost 90% preventive and 50% curative in
chronic relapsing EAE due to its antioxidant effect[76]. N.
sativa oil is a promising natural radioprotective agent against
immunosuppressive and oxidative effects of ionizing radiation[6]. Daily
oral administration of N. sativa oil to rats before whole body gamma
irradiation resulted in significant reversal of reduction of hemolysin
antibodies titers.Potential immunomodulation effect of the extract of N.
sativa on ovalbumin sensitized guinea pigs was evaluated. The effect of the
extract of N. sativa on lung pathology and blood interleukin-4 (IL-4)
and interferon-Α (IFN-Α) of sensitized guinea pigs was examined. Treatment of
sensitized animals with the extract of N. sativa led to a significant
decrease in pathological changes of the lung, except for the oedema in the
sensitized group treated with low concentration of the extract, but an
increased IFN-Α. These results confirm a preventive effect of N. sativa
extract on lung inflammation of sensitized guinea pigs[77]. To
determine the possible alleviating effect of N. sativa and TQ on food
allergy, ovalbumin (OVA) -sensitized BALB/c-mice were pre-treated either with a
hexanic N. sativa seed extract TQ and subsequently challenged
intra-gastrically with OVA. All 4 treatments significantly decreased clinical
scores of OVA-induced diarrhea. N. sativa seed extract, TQ decreased
intestinal mast cell numbers and plasma mouse mast cell protease-1. It was
demonstrated that N. sativa seed extract significantly improves symptoms
and immune parameters in murine OVA-induced allergic diarrhea; this effect is
at least partially mediated by TQ[78].
5.9. Cardiovascular
activity
The acute (at 4 and 18 h) effects of
diesel exhaust particles (DEP) on cardiopulmonary parameters in mice and the
protective effect of TQ were investigated. Mice were given, intratracheally,
either saline (control) or DEP (30 Κg per mouse). At 18 h (but not 4 h) after
giving DEP, there was lung inflammation and loss of lung function. At both 4
and 18 h, DEP caused systemic inflammation characterized by leucocytosis,
increased IL-6 concentrations and reduced systolic blood pressure. SOD activity
was decreased only at 18 h. DEP reduced platelet numbers and aggravated in
vivo thrombosis in pial arterioles. In vitro, addition of DEP (0.1-1
Κg/mL) to untreated blood-induced platelet aggregation. Pretreatment of mice
with TQ prevented DEP-induced decrease of systolic blood pressure and
leucocytosis, increased IL-6 concentration and decreased plasma SOD activity.
TQ also prevented the decrease in platelet numbers and the prothrombotic events
but not platelet aggregation in vitro[79].
5.10. Gastro-protective
activity
The mechanism of gastroprotective
effect of TQ was assessed. Animals were injected with vehicle, TQ (10, 20
mg/kg), omeprazole (10, 20 mg/kg) or their combination (10 mg/kg). Thirty
minutes later, pyloric ligation was carried out and followed consequently with
ischemia for another 30 min, abided by reperfusion for 120 min. The
ischemia/reperfusion insult increased the gastric acid secretion, acid output,
and pepsin, as well as the gastric mucosal content/activity of lipid peroxide,
proton pump and myeloperoxidase, along with ulcer index. However,
content/activity of gastric mucin, reduced glutathione, total nitric oxide, and
SOD were decreased. TQ, especially the high dose level, corrected the altered
parameters in a comparable manner to that of the reference drug used,
omeprazole. In addition, when the low doses were combined they add to each
other to reach the effect of the high dose of either drug. Besides the
antioxidant property, TQ has novel gastroprotective mechanisms via inhibiting
proton pump, acid secretion and neutrophil infiltration, while enhancing mucin
secretion, and nitric oxide production[80]. The
anti-ulcer potential of N. sativa aqueous suspension on experimentally
induced gastric ulcers and basal gastric secretion in rats was examined to
rationalize its use by herbal and Unani medicine practitioners. Acute gastric
ulceration was produced by various noxious chemicals (80% ethanol, 0.2 mol/L
NaOH, 25% NaCl and indomethacin) in Wistar albino rats. Anti-secretory studies
were undertaken in a separate group of rats. Gastric wall mucus contents and
non-protein sulfhydryl concentration were estimated, and gastric tissue was
examined histopathologically. An aqueous suspension of black seeds
significantly prevented gastric ulcer formation induced by necrotizing agents.
It also significantly ameliorated the ulcer severity and basal gastric acid
secretion in pylorus-ligated Shay rats. Moreover, the suspension significantly
replenished the ethanol-induced depleted gastric wall mucus content levels and
gastric mucosal non-protein sulfhydryl concentration. The anti-ulcer effect was
further confirmed histopathologically. The anti-ulcer effect of N. sativa
is possibly prostaglandin-mediated and/or through its antioxidant and
anti-secretory activities[81]. Both
and its constituent, TQ was found to possess Gastro protective activity against
gastric mucosal injury induced by ischaemia/reperfusion in rats.
Ischaemia/reperfusion (I/R) induced gastric lesion is known to be linked with
free radical formation. Male Wistar rats were subjected to I/R and were
injected with either NO (2.5 and 5.0 mL/kg, p.o.) or TQ (5, 20, 50 and
100 mg/kg, p.o.). The results showed that I/R elevated the levels of
lipid peroxide and lactate dehydrogenase, while decreased those of reduced GSH
and SOD. These biochemical changes were accompanied by an increase in the
formation of gastric lesions, which was reduced by either treatment. This
indicates that both NSO and TQ possess gastroprotective effect against gastric
lesions which may be related to the conservation of the gastric mucosal redox
state[82].
N. sativa prevents alcohol induced increase in lipid peroxidation (i.e.
thiobarbituric acid reactive substances) and reduced gastric GSH content,
enzyme activities of gastric SOD, GSH-S-Transferase[83]. TQ
was found to protect gastric mucosa against the ulcerating effect of alcohol
and mitigated most of the biochemical adverse effects induced by alcohol in
gastric mucosa, but the effect of TQ was found to be a lesser than black seed
whole. Both N. sativa and TQ did not affect the CAT activity in gastric
tissue[5].
The beneficial effects of NSO on rats with necrotizing enterocolitis (NEC) were
studied in newborn Sprague-Dawley rats. NEC was induced by enteral formula
feeding, exposure to hypoxia-hyperoxia and cold stress. Pups in the NEC+NSO
group were administered NOS at a dose of 2 mL/kg daily by intraperitoneal (i.p.)
route from the first day until the end of the study. Proximal colon and ileum
were excised for histopathologic, apoptosis (TUNEL) and biochemical evaluation,
including xanthine oxidase, SOD, GSH peroxidase (GSH-Px), MDA, and MPO
activities. Pups in the NEC+NOS group had better clinical sickness scores and
weight gain compared to the NEC group (P<0.05). In the macroscopic
assessment, histopathologic and apoptosis evaluation (TUNEL), severity of bowel
damage was significantly lower in the NEC+NOS group compared to the NEC group (P<0.05).
Tissue GSH-Px and SOD levels were significantly preserved in the NEC+NSO group
(P<0.05), whereas, tissue MDA, MPO levels of the NEC+NSO group were
significantly lower than those in the NEC group (P<0.05). It is
concluded that NSO significantly reduced the severity of intestinal damage in
NEC[84].
A study was designed to determine whether treatment with TQ prevents and
ameliorates colonic inflammation in a mouse model of inflammatory bowel
disease. C57BL/6 murine colitis was induced by the administration of dextran
sodium sulfate (DSS) (3% W/V) in the drinking water supplied to the mice for 7
consecutive d. The mice with colitis were treated with 5, 10, or 25 mg/kg TQ
orally, and changes in body weight and macroscopic and microscopic colitis
scores were examined. In addition, biochemical analyses were conducted. The
treatment of mice with TQ prevented and significantly reduced the appearance of
diarrhea and body weight loss. These results were associated with amelioration
of colitis-related damage, as measured by macroscopic and microscopic colitis
scores. In addition, there was a significant reduction in colonic
myeloperoxidase activity and malondialdehyde levels and an increase in
glutathione levels. These results indicate that TQ administration can prevent
and improve murine DSS-induced colitis. These findings suggest that TQ could
serve as a potential therapeutic agent for the treatment of patients with
inflammatory bowel disease[85].
5.11. Hepato-protective
activity
It is reported that N. sativa
(0.2 mL/kg) intraperitoneally relieves the deleterious effects of ischemia
reperfusion injury on liver. Biochemical parameters like the serum aspartate
aminotransferase, alanine aminotransferase lactate dehydrogenase levels and
total antioxidant capacity (TAC), CAT, total oxidative status (TOS), oxidative
stress index (OSI) and MPO were determined in hepatic tissue in rats with
hepatic ischemia. Results suggested that N. sativa treatment protects
the rat liver against hepatic ischemia reperfusion injury[86]. N.
sativa administration protects hepatic tissue from deleterious effects of
toxic metals such as lead, and attenuates hepatic lipid peroxidation following
exposure to chemicals such as carbon tetrachloride[52].
Cadmium (Cd++) causes alteration of the cellular homeostasis and
oxidative damage. The protective role of TQ on the hepatotoxicity of Cd++
with special reference to its protection against perturbation of nonenzymatic
and enzymatic antioxidants was investigated. The effect of TQ pretreatment was
examined in post-nuclear supernatant prepared from liver of Swiss albino mice
under in vitro conditions. CdCl2 treatment (5 mmol/L)
resulted in a significant increase in antioxidant enzymatic activities. It also
caused a significant (P<0.001) increase in protein carbonyl and
reduced glutathione content. Pretreatment with TQ (10 Κmol/L) showed a
significant protection as manifested by noticed attenuation of protein
oxidation and rejuvenation of the depleted antioxidants of cellular fraction.
These results strengthen the hypothesis that TQ exerts modulatory influence on
the antioxidant defense system on being subjected to toxic insult[87].
5.12. Nephroprotective
activity
The nephro-protective effect of
vitamin C and N. sativa oil was observed against gentamicin (GM)
associated nephrotoxicity in rabbits. Serum creatinine, blood urea nitrogen,
and antioxidant activity were measured as indicators of nephrotoxicity for all
the groups of rabbits. It was revealed that vitamin C and N. sativa oil
both had nephroprotective effect as they lowered the values of serum
creatinine, blood urea nitrogen, and antioxidant activity as compared to GM
control group values. When these two antioxidants were given as combination,
they proved to have synergistic nephroprotective effect[88].
Recenty, it was observed that there is an inherent lack in regulation of renal
organic anion and cation transporters in cisplatin-induced nephrotoxicity. The
effect of TQ on alterations in the renal expression of organic anion
transporters and organic cation transporters, as well as multidrug
resistance-associated proteins in rats treated with cisplatin was reported.
Cisplatin-induced MDA and 8-isoprostane increase was found to be markedly
reduced in rats treated with TQ. In cisplatin only treated rats, the induced
renal injury increased protein levels of the efflux transporters MRP2 and MRP4
while expression of OAT1, OAT3, OCT1 and OCT2 was reduced. In combination TQ-
and cisplatin-treated rats, expression of MRP2 and MRP4 proteins was decreased
in the kidneys. Conversely, TQ treatment increased levels of OCT1, OCT2, OAT1
and OAT3 and decreased levels of 8-isoprostane and MDA levels in cisplatin-treated
rats. This is concluded that TQ synergizes with its nephroprotective effect
against cisplatin-induced acute kidney injury in rats[89]. The
protective effects of N. sativa oil on methotrexate-induced
nephrotoxicity were also studied in albino rats and this study revealed the
protective effect of Black cumin in the methotrexate-induced nephrotoxcity[90]. The
protective effects of N. sativa against ischemia-perfusion damage on
kidney tissue were examined. TAC, CAT, TOS, OSI, and MPO in kidney tissue and
blood were measured. Serum urea and creatinine levels were also determined.
Kidney tissue histopathology was also evaluated. N. sativa was effective
in reducing serum urea and creatinine levels as well as decreasing the tubular
necrosis score. N. sativa treatment significantly reduced OSI and TOS
levels and increased TAC levels in both kidney tissue and blood. Results
revealed the protective effect of N. sativa against renal I/R injury in
rat kidneys[91].
GM induced nephrotoxicity has been shown to involve the generation of oxygen
free radicals. Nephrotoxicity was evaluated histopathologically and by
measuring concentrations of urea, creatinine and total antioxidant status (TAS)
in plasma and reduced GSH and TAS in kidney cortex. The effect of oral
treatment of N. sativa oil (0.5, 1.0 or 2.0 mL/kg/day for 10 d) on GM
(80 mg/kg/day given intramuscularly) induced nephrotoxicity in rats produced a
dose-dependent amelioration of the biochemical and histological indices of GM
nephrotoxicity that was statistically significant at the two higher doses used.
Treatments of rats with N. sativa increased TAS in plasma and reduced
GSH concentrations in renal cortex and enhanced growth while it did not cause
any over toxicity. The results suggest that N. sativa may be useful in
ameliorating signs of GM nephrotoxicity in rats[92]. TQ
supplementation prevents the development of GM-induced acute renal toxicity in
rats. TQ was found to prevent the degenerative changes in kidney tissues
against GM induced nephrotoxicity. TQ supplementation resulted in a complete
reversal of the GM-induced increase in serum creatinine, blood urea nitrogen,
thibarbituric acid reactive substances, total nitrate/nitrite and decrease in
GSH, glutathione peroxidase (GPx), CAT and ATP to control values suggesting
that TQ prevents GM-induced degenerative changes in kidney tissues[93].The protective effects
of NSO in the prevention of chronic cyclosporine A (CsA) -induced
nephrotoxicity in rats were investigated. NSO significantly improved the
functional and histological parameters and attenuated the oxidative stress
induced by CsA. NSO protects kidney tissue against oxygen free radicals,
preventing renaldysfunction and morphological abnormalities associated with
chronic CsA administration[94].
Administration of N. sativa with GM intra-peritonealinjection resulted
in significantly decreased creatinine, urea, MDA, NO generation and increased
SOD and GSH-Px activities when compared with GM group suggesting
nephro-protective activity. N. sativa acts in the kidney as a potent
scavenger of free radicals to prevent the toxic effects of GM both in the
biochemical and histopathological parameters[95]. N.
sativa seeds had non-significant effects on biochemical parameters in
Cisplatin-induced nephrotoxicity, although the histo-pathologic properties of
the kidneys relatively recovered after N. sativa use[96].
5.13.
Pulmonary-protective activity and anti-asthmatic effects
Wienkotter et al., reported
the effect of nigellone and TQ on trachea (antispasmodic effect) and their
influence on respiratory clearance. The effects on Ba++ carbachol-
and leukotriene-induced trachea contractions and the transport of the
fluorescence dye rhodamin B concerning ciliary action in the tracheal area were
investigated using a micro dialysis technique. Nigellone and high
concentrations of TQ had a concentration-dependent inhibitory effect on the
trachea when being contracted by the depolarizing effect of Ba2+.
The trachea contractions induced by leukotriene-d (4) LT4 were inhibited by
nigellone and by TQ. It was concluded that nigellone possesses an antispasmodic
effect and an increase in mucociliary clearance but TQ do not have such
effects. Therefore, it is suggested that nigellone but not TQ may be useful in
treatment of different respiratory diseases[97]. The
relaxant effects of four cumulative concentrations of n-hexane,
dichloromethane, methanol and aqueous fractions of N. sativa (0.8, 1.2,
1.6 and 2.0 g%) in comparison with saline as negative control and four
cumulative concentrations of theophylline (0.2, 0.4, 0.6 and 0.8 mmol/L) were
examined by their relaxant effects on precontracted tracheal chains of guinea
pig by 60 mmol/L KCl (group 1) and 10 microM methacholine (group 2). The
results showed relaxant effect of most fractions from N. sativa on
tracheal chains of guinea pigs which was more potent for methanol and
dichloromethane fractions[98]. The
protective effect of N. sativa on tracheal responsiveness (TR) and lung
inflammation of sulfur mustard gas exposed guinea pigs was examined. Guinea
pigs were exposed to diluent's solution (ethanol, control group), 100 mg/m3
inhaled sulfur mustard (SME group), and SME treated with N. sativa, 0.08
g daily (SME+N), n=6 for each group. TR to methacholine, total white
blood cell count of lung lavage, and differential white blood cell were done 14
d post exposure. The results showed a preventive effect of N. sativa on
TR of sulfur mustard gas-exposed guinea pigs[99]. The
possible beneficial effects of the seeds of N. sativa L. on experimental
lung injury in male Wistar rats after pulmonary aspiration of different
materials was investigated. Results showed that N. sativa treatment
inhibits the inflammatory pulmonary responses, reducing significantly (P<0.05)
peribronchial inflammatory cell infiltration, alveolar septal infiltration,
alveolar edema, alveolar exudate, alveolar macrophages, interstitial fibrosis,
granuloma and necrosis formation in different pulmonary aspiration models. Data
indicated a significant reduction in the activity of inducible nitric oxide
synthase and a rise in surfactant protein D in lung tissue of different
pulmonary aspiration models after N. sativa therapy. It was concluded
that N. sativa treatment might be beneficial in lung injury and have
potential clinical use[100]. The
beneficial effects of NSO on rats with hyperoxia-induced lung injury were
evaluated since oxygen-induced lung injury is believed to lead to the
development of broncho-pulmonary dysplasia in premature infants. NSO
significantly reduced the severity of lung damage due to hyperoxia[101]. The
prophylactic effect of boiled extract of N. sativa on asthmatic disease
was examined. Twenty-nine asthmatic adults were randomly divided into control
group (14 patients) and study group (15 patients), and they were studied for 3
months. In the study group 15 mL/kg of 0.1 g% boiled extract and in the control
group a placebo solution was administrated daily throughout the study. Asthma
symptom score, asthma severity, frequency of symptoms/week and wheezing were
recorded in the beginning (first visit), 45 d after treatment (second visit),
and at the end of the study (third visit). Pulmonary function tests (PFTs) were
also measured, and the drug regimen of the patients was evaluated at three
different visits. All asthma symptoms, frequency of asthma symptoms/week, chest
wheezing, and PFT values in the study group significantly improved in the
second and third visits compared with the first visit (P<0.05 to P<0.001).
In addition, further improvement of chest wheezing and severity of disease on
the third visit were observed compared with the second visit in this group (P<0.05
for both cases). In the third visit all symptoms in the study group were
significantly different from those of the control group (P<0.01 to P<0.001).
However, in the control group, there were only small improvements in some
parameters in just the second visit. The usage of inhaler and oral ΐ-agonists,
oral corticosteroid, oral theophylline and even inhaler corticosteroid in the
study group decreased at the end of the study while there were no obvious
changes in usage of the drugs in control subjects. The results of phase I study
generally suggested a prophylactic effect of N. sativa on asthma disease[102]. The
anti-asthmatic (bronchodilatory) effect of the boiled extract of N. sativa
in the airways of asthmatic patients was examined. The bronchodilatory effects
of 50 and 100 mg/kg of boiled extract in comparison with 6 mg/kg theophylline
were studied on 15 asthmatic patients. PFTs including forced expiratory volume
in one second, peak expiratory flow, maximal mid expiratory flow (MMEF),
maximal expiratory flow at 75%, 50% and 25% of the FVC [MEF(75), MEF(50), and
MEF(25,) respectively] and specific airway conductance (sGaw) were measured
before administration and repeated 30, 60, 90, 120, 150 and 180 min after
administration of the oral extract and theophylline. The results showed that
the extract caused significant increase in all measured PFTs, in most time
intervals, (P<0.05 to P<0.001). However, the increase in
forced expiratory volume in one second, MMEF and MEF (50) due to both doses of
boiled extract and increase in MEF (75) and MEF (25) due to its lower doses
were significantly lower than those of theophylline (P<0.05 to P<0.001).
The onset of brochodilatory effect of extract was similar to that of
theophylline beginning 30 min, and the effect of extract decline after 150 min
following administration similar to the effect of theophylline. The effect of
both doses of the extract was also significantly less than that of salbutamol
at 30 minutes post administration (P<0.001 for all cases). The
results of the this study showed that N. sativa has a relatively potent
antiasthmatic effect on asthmatic airways. However, the effects of boiled
extract of this plant on most measured PFTs were less than those of
theophylline at concentrations used[8].
5.14.
Testicular-protective activity
The protective role of TQ on
testicular toxicity of methotrexate on male C57BL/6 mice (6 weeks old, 20}2 g)
was investigated. TQ treatment decreased TAC and prevented the increasein the
myeloperoxidase activity. Light microscopy showed in mice that receiving
methotrexate resulted in interstitial space dilatation, edema, severe
disruption of the seminiferous epithelium and reduced diameter of the
seminiferous tubules. Administration of TQ reversed histological changes of
methotrexate significantly. It was suggested that TQ use may decrease the
destructive effects of methotrexate on testicular tissue of patients using this
agent[103].
5.15.
Neuro-pharmacolgical activities
The aqueous and methanol extracts of
defatted N. sativa L. seeds were shown to possess a potent central
nervous system and analgesic activities, especially depressant action in the
case of the methanolic extract[104]. An
anxiolytic drug acts by increasing the 5-HT and decreasing the 5-HIAA
(hydroxyindole acetic acid) levels in brain. A long term administration of N.
sativa increases 5-HT levels in brain and improves learning and memory in rats[105].
Repeated administration of N. sativa decreases 5-HT turnover and
produces anxiolytic effects in rats. The aqueous and methanol extracts of N.
sativa L. seeds were evaluated for their effects on the central nervous
system and NSO was used to study its effect on anxiety in rats. Open field and
elevated plus maze models were selected for the evaluation of anxiolytic effect
of drug. After four weeks of daily administration of drug, the rats exhibited
an increase in open field activity. The drug also produced anti-anxiety effect
in rats when tested in elevated plus maze. The oral administration of NSO
increased brain levels of 5-HT (Serotonin), but the levels of brain 5-HIAA
(hydroxyindole acetic acid) decreased significantly. Brain and plasma levels of
tryptophan also increased significantly following oral repeated administration
of NSO. Therefore, it may be suggested that NSO is a useful choice for the
treatment of anxiety[106]. TQ
produced antianxiety-like effects in mice through modulation of GABA and NO
levels. The role of GABAergic and nitriergic modulation in the antianxiety
effect of TQ was investigated in mice under unstressed and stressed conditions.
TQ (10 and 20 mg/kg), methylene blue (1 mg/kg) and diazepam (2 mg/kg) were
administered followed by behavioral testing using an elevated plus maze, the
light/dark test and the social interaction test in both unstressed and stressed
mice (mice subjected to 6 h immobilization). The effects of the above-mentioned
drugs on plasma nitrite, a stable metabolite of nitric oxide and brain GABA
content were also studied. TQ (10 and 20 mg/kg) produced significant
antianxiety effects in unstressed mice without altering nitrite levels, but
only the higher dose (20 mg/kg) of TQ increased the GABA content in unstressed
mice. In stressed mice, TQ (20 mg/kg) showed anxiolytic effects, with a
significant decrease in plasma nitrite and reversal of the decreased brain GABA
content. Pre-treatment with methylene blue enhanced the antianxiety effect of
TQ in both unstressed and stressed mice. Therefore, this is indicated an
involvement of NO-cGMP and GABAergic pathways in the anxiolytic-like activity
of TQ[107].
In 2011, Abdel-Zaher et al. reported that NSO can protect against
tramadol-induced tolerance and dependence in mice. They found that repeated
administration of NSO (4 mL/kg, p.o.) along with tramadol (50 mg/kg, s.c.)
inhibited the development of tramadol tolerance and dependence as measured by
the hot plate test and naloxone (5 mg/kg, i.p.)-precipitated withdrawal
manifestations respectively. Concomitantly, nitric oxide overproduction and
increase in brain malondialdehyde level induced by repeated administration of
tramadol to mice or by administration of naloxone to tramadol-dependent mice
were inhibited by co-administration of the black seed oil. Also, the decrease
in brain intracellular reduced glutathione level and glutathione peroxidase
activity induced by both treatments was inhibited by co-administration of the
oil. The increase in brain glutamate level induced by both treatments was not
inhibited by concurrent administration of the oil. The inhibitory effect of N.
sativa oil on tramadol-induced tolerance and dependence was enhanced by
concurrent intraperitonial (i.p.) administration of the NMDA receptor
antagonist, dizocilpine (0.25mg/kg). Also, the inhibitory effect of the oil on
naloxone-induced biochemical alterations in tramadol-dependent mice was
enhanced by concurrent administration of dizocilpine. Similarly, concurrent
i.p. administration of the NO synthase inhibitor, L-N (G)-nitroarginine methyl
ester (10mg/kg) or the antioxidant, N-acetylcysteine (50mg/kg) enhanced these
inhibitory effects of N. sativa oil. On the other hand, these effects
were antagonized by concurrent i.p. administration of the NO precursor,
L-arginine (300 mg/kg). These results provide evidence that N. sativa
oil appears to have a therapeutic potential in tramadol tolerance and
dependence through blockade of NO overproduction and oxidative stress induced
by the drug[7].
Neuroprotective effects of Aqueous and hydroalcoholic extracts of N. sativa
(400 mg/kg, orally) were evaluated for their neuroprotective effects on middle
cerebral artery occluded (MCAO) rats. Locomotor activity and grip strength of
animals were improved in both aqueous and hydroalcoholic extracts pretreated
rats. Infarct volume was also reduced in both extracts pretreated rats as
compared with MCAO rats. An elevation of thiobarbituric acid reactive substance
and a reduction in glutathione and antioxidant enzymes, viz., SOD and
CAT levels were observed following MCAO. Pretreatment of N. sativa
extracts showed the reduction in TBARS, elevation in glutathione, SOD and CAT
levels as compared with MCAO rats. The neuroprotective effects of both the
extracts of N. sativa in cerebral ischemia were observed. The
neuroprotective effects could be due to its antioxidant, free radical
scavenging, and anti-inflammatory properties[108].
5.16. Anticonvulsant
activity
The antioxidant effects of curcumin,
NSO and valproate on the levels of malondialdehyde, nitric oxide, reduced
glutathione and the activities of CAT, Na+, K+-ATPase and
acetylcholinesterase in the hippocampus of pilocarpine-induced animal model of
epilepsy was evaluated and left for 22 d to establish the chronic phase of
epilepsy. The animals were then treated with curcumin, NSO or valproate for 21
d. Treatment with curcumin, NSO or valproate ameliorated most of the changes
induced by pilocarpine and restored Na+, K+-ATPase
activity in the hippocampus to control levels. Results indicated the anticonvulsant
and potent antioxidant effects of curcumin and NSO in reducing oxidative
stress, excitability and the induction of seizures in epileptic animals and
improving some of the adverse effects of antiepileptic drugs[109]. The
antiepileptic effects of aqueous extract, fixed oil, volatile oil of N.
sativa seeds and its major constituents i.e. TQ, Ώ-pinene and
p-cymene against PTZ and maximal electroshock (MES)-induced convulsions were
investigated. The potential of these constituents to induce minimal
neurological deficit (MND) was also evaluated by using chimney test. All of the
N. sativa seed constituents protected mice effectively against
PTZ-induced convulsions except fixed oil. The antiepileptic activity of the
volatile oil in this model maybe attributed mainly to its content of TQ and
p-cymene and to a lesser extent, Ώ-pinene. Volatile oil and its component
p-cymene effectively suppressed convulsions induced by MES. All of the N.
sativa seed constituents induced varying degrees of MND in the chimney
test. MND induced by volatile oil may pertain to its contents of TQ (63%),
p-cymene (23%) and Ώ-pinene (<14%). Exploration on the role of receptors
suggests that picrotoxin and bicuculline-sensitive GABA receptors, most
probably GABAA receptors, mediate an increase in GABAergic response. In the
part dealing with the interaction of valproate with TQ, it can be mentioned
that TQ increased the potency of valproate in both PTZ and MES models[110]. The
antiepileptic effect of curcumin and N. sativa oil in the pilocarpine
model of epilepsy in comparison with valproate was evaluated by Noor et al.
Epilepsy was induced by i.p. injection of pilocarpine, and the animals
were left for 22 d to establish spontaneous recurrent seizures. They were then
treated with curcumin, NSO or valproate for 21 d. Pilocarpine induced a
significant increase in hippocampal aspartate and a significant decrease in
glycine and taurine levels. In the cortex, a significant increase in aspartate,
glutamate, GABA, glycine, and taurine levels was obtained after pilocarpine
injection. Treatment of pilocarpinized rats with curcumin and valproate
ameliorated most of the changes in amino acid concentrations and reduced the
histopathological abnormalities induced by pilocarpine, while N. sativa
oil failed to improve the pilocarpine-induced abnormalities[111].
5.17. Contraceptive and
anti-fertility activity
Oral administration of Hexane
extract of N. sativa seeds L. prevented pregnancy in Sprague-Dawley rats
at a dose of 2 g/kg daily on day's 1-10 postcoitum. While column fractions and
sub-fractions of Hexane extract of N. sativa seeds also showed
significant anti-fertility activity. At contraceptive dose, the active hexane
extract exhibited only mild uterotrophic activity comparable almost to 0.002
mg/kg dose of 17 varies; is directly proportional to-Ethinylestradiol, but was
devoid of any estrogenicity in the immature rat bioassay[112]. The
ethanolic extract of N. sativa seeds was found to possess an
anti-fertility activity in male rats which might be due to inherent estrogenic
activity of N. sativa[113].
5.18. Antioxytocic
activity
The antioxytocic properties of N.
sativa were reported in some preliminary studies. N. sativa seeds
inhibit the uterine smooth muscle contraction induced by oxytocin
stimulation.The volatile oil of N. sativa seeds inhibited the
spontaneous movements of rat and guinea piguterine smooth muscle and also the
contractions induced by oxytocin stimulation which suggest the anti-oxytocic
potential of N. sativa seeds oil[114].
5.19. Toxicological
studies
Many toxicological studies have been
carried out on N. sativa seeds. It has been shown that no toxic effects
were reported when N. sativa fixed oil was given to mice via the stomach
in an acute study. In a chronic toxicity study rats treated daily with an oral
dose for 3 months caused no changes in key hepatic enzyme levels particularly
aspartate-aminotransferase, alanine-aminotranferase, and
gammaglutamyl-transferase. Moreover, the histopathological results also showed
to be normal for the tissues of heart, liver, kidneys and pancreas LD50
values of fixed oil of N. sativa obtained by single doses orally and
intraperitoneally in mice, were reported to be 26.2-31.6 and 1.86-2.26,
respectively. The low toxicity of N. sativa fixed oil, evidenced by high
LD50 values, key hepatic enzyme stability and organ integrity,
suggests a wide margin of safety for therapeutic doses of N. sativa
fixed oil[115]. In another study, the
LD50 of TQ was found to be 104.7 mg/kg (89.7-119.7) and 870.9 mg/kg
(647.1-1?094.8) after intra-peritoneal injection and oral ingestion
respectively. Whereas, LD50 in rats was found to be 57.5 mg/kg
(45.6-69.4) and 794.3 mg/kg (469.8-1?118.8) after intra-peritoneal injection
and oral ingestion respectively. The LD50 values presented here
after intra-peritoneal injection and oral gavages are 10-15 times and 100-150
times greater than doses of TQ reported for its anti-inflammatory, anti-oxidant
and anti-cancer effects. These observations revealed that TQ is a relatively
safe compound, particularly when given orally to experimental animals[10],[116].
5.20. Drugs-nigella
interaction
There is a possibility that N.
sativa may interact with co-administered drugs and affect their intestinal
availability and pharmacological effect. In vitro studies have shown
that N. sativa extracts inhibit cDNA-expressed human cytochrome P-450
3A4, 2C9, 3A5 and 3A7-mediated metabolism of marker substrates therefore may
affect and/or inhibit the metabolism of a wide range of drugs (117). Further,
the effect of N. sativa on bioavailability of amoxicillin was
investigated in everted rat intestinal sacs. The in vitro studies both
with methanol and hexane extracts of Nigella increased the permeation of
amoxicillin significantly (P<0.001) as compared to control.
Permeation was also found to be significantly higher for the hexane extract (P<0.001)
in comparison to methanol extract at the same dose levels. in vivo
experiments revealed that Cmax of amoxicillin in rat plasma when administered
orally alone and in combination with hexane extract increased correspondingly
from 4?138.251}156.930 to 5?995.045}196.280 ng/mL while as AUC 0¨t increased
from 8?890.40}143.33 to 13?483.46}152.45 ng/mL/h. Nigella enhanced
amoxicillin availability in both in vivo and in vitro studies[117].
6.?Conclusion
The use of herbal drugs as
complementary medicine is prevalent and gaining world wide popularity. Many
drugs are derived directly from plants; while the others are chemically
modified natural products. The original research articles published so far have
confirmed the pharmacological potential of N. sativa seeds, its oil and
extracts and some of its active principles, particularly TQ and alpha-hederin,
possess remarkable in vitro and in vivo pharmacological
activities against a large variety of diseases and found to be relatively safe.
7.?Future
perspectives
Further investigations are required
to study the mechanism of actions of N. sativa seeds and its
constituents by which they exert their therapeutic effects. Chemical
modifications in the molecular structure of TQ, alpha-hederin and other
constituents of N. sativa seeds could lead to more effective and safer
drugs for the treatment of wide variety of diseases in the future. N. sativa
seeds, its oil, constituents of N. sativa seeds like TQ, alpha-hederin
or others could be used in suitable combinations with existing chemotherapeutic
agents for an effective treatment of many infectious diseases and to overcome
the resistance problem. Moreover, further researches should focus and explore
the specific cellular and molecular targets of various constituents of N.
sativa, particularly TQ. This review article is dedicated to all those
researchers who are interested in focussing their research on this miracle herb
and hope, this review article would help them in investigating and conducting
further preclinical and clinical studies on the use of N. sativa for the
treatment of variety of diseases.
Acknowledgments
This research is supported by
Deanship of Scientific Research, King Abdulaziz University, Jeddah, Saudi
Arabia (Grant No. 431-044).
Notes
Comments
Background
The seeds of N. sativa Linn
are used in various traditional systems of medicines and folk medicine all over
the world for the treatment and prevention of a variety of diseases. This
article contains wide spectrum researches and authors well done to collect and
compile current research data. The article is well written which includes
current researches from all over the world. The scientific data in this article
will help the researchers to get updated information about N. sativa.
Research frontiers
A detailed literature survey on N.
sativa has been collected, nicely compiled and presented by the authors and
Many researches indicated the mechanism of action, chemicals responsible for
the medicinal uses of N. sativa TQ, some of its analogues and alpha
hedrine are the major chemical constituents are responsible for the therapeutic
potential actions of black seeds.
Related reports
Many researchers focus on Nigella
due to its miraculous power of healing. There are tremendous researches on N.
sativa are being carried out all over the world & continuously
published. One can found many research articles in different peer reviewed
journals. This review article is a good attempt to compilation researches in
the recent past.
Innovations and
breakthroughs
A review on therapeutic potential of
N. sativa: A miracle herb included a wide range of therapeutic potential
of this medicinal plant and well supported by scientific documents Data
regarding the medicinal uses, chemical constituents and pharmacological actions.
This article is well organized and presented in scientific manner. Most
importantly, this article included recent advances on the topic.
Applications
It is highly recommended to publish
this article since it explains various new discoveries on mechanism of action,
therapeutic potential about this miracle herb and let the world community knows
about the scientific facts of this medicinal plant.
Peer review
The current review on Nigella
provide the detailed scientific information of this medicinal plant. Due to its
miraculous power of healing N. sativa, It has been widely used as
antihypertensive, liver tonics, diuretics, digestive, anti-diarrheal, appetite
stimulant, analgesics, anti-bacterial and in skin disorders. Extensive research
studies on N. sativa have been carried out by various researchers and a
wide spectrum of its pharmacological actions have been explored which include
antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial,
anti-inflammatory, spasmolytic, bronchodilator, hepatoprotective, renal
protective, gastroprotective and antioxidant properties.
Footnotes
Foundation Project: Supported by
Deanship of Scientific Research, King Abdulaziz University, Jeddah, Saudi
Arabia (Grant No. 431-044).
Conflict of interest statement: We declare that we have
no conflict of interest.
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