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
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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%) α-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. α-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, β-amyrin, butyro-spermol,
cycloartenol, 24-methylene-cycloartanol, taraxerol, tirucallol, 3-O-[β-D-xylopyranosyl(1→3)-α-L-rhamnopyranosyl(1→2)-α-L-arabino-pyranosyl]-28-O-[α-L-rhamnopyranosyl(1→4)-β-D-glucopyranosyl(1→6)-β-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, β-unsaturated hydroxy ketone,
hederagenin glycoside, melanthin, melanthigenin, bitter principle, tannin,
resin, protein, reducing sugar, glycosidal saponin, 3-O-[β-D-xylopyranosyl-(1→2)-α-L-rhamno-pyranosyl-(1→2)-β-D-glucopyranosyl]-11-methoxy-16,
23-dihydroxy-28-methy-lolean-12-enoate,stigma-5, 22-dien-3-β-D-gluco-pyranoside, cycloart-23-methyl-7, 20,
22-triene-3β, 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 ÒThe Canon of MedicineÓ, 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 ÔHabbatul barakahÕ, 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-1β, IL-6, TNF-α, IL-10, IFN-γ 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-1β, IL-6, TNF-α, IFN-γ 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 α-lipoic acid (α-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 α-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 α-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 β-cell integrity. The hypoglycemic
effect observed could be due to amelioration of β-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 β-cells against oxidative
stress[47].
The
protective effects of the volatile oil of N. sativa seeds on insulin
immunoreactivity and ultrastructural changes of pancreatic β-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 β-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 β-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 β-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-κB 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-κB 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-κB 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 µg/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-γ 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-γ 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-γ activity was prevented in the
presence of PPAR-γ specific inhibitor and PPAR-γ dominant negative plasmid, suggesting that TQ may act
as a ligand of PPAR-γ. 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-γ 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-γ 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 µL/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 κB. 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 β 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 µg/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-α, 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-γ (IFN-γ) 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-γ. 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 µg 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 µg/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 µmol/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 β-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, α-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, α-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 α-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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