Critical Reviews in Food Science and Nutrition

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Nigella sativa: Reduces the Risk of Various

Maladies

Masood Sadiq Butt & Muhammad Tauseef Sultan

To cite this article: Masood Sadiq Butt & Muhammad Tauseef Sultan (2010) Nigella�sativa:
Reduces the Risk of Various Maladies, Critical Reviews in Food Science and Nutrition, 50:7,
654-665, DOI: 10.1080/10408390902768797

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Critical Reviews in Food Science and Nutrition, 50:654–665 (2010)
Copyright
C Taylor and Francis Group, LLC
ISSN: 1040-8398
DOI: 10.1080/10408390902768797

Nigella sativa : Reduces the Risk

of Various Maladies

MASOOD SADIQ BUTT and MUHAMMAD TAUSEEF SULTAN

National Institute of Food Science and Technology, University of Agriculture, Faisalabad

Coinage of terms like nutraceuticals, functional, and pharma foods has diverted the attention of human beings to where
they are seeking more natural cures. Though pharmaceutical drugs have been beneficial for human health and have cured
various diseases but they also impart some side effects. Numerous plants have been tested for their therapeutic potential;
Nigella sativa, commonly known as black cumin, is one of them. It possesses a nutritional dense profile as its fixed oil (lipid
fraction), is rich in unsaturated fatty acids while essential oil contains thymoquinone and carvacrol as antioxidants. N.
sativa seeds also contain proteins, alkaloids (nigellicines and nigelledine), and saponins (α-hederin) in substantial amounts.
Recent pharmacological investigations suggested its potential role, especially for the amelioration of oxidative stress through
free radical scavenging activity, the induction of apoptosis to cure various cancer lines, the reduction of blood glucose,
and the prevention of complications from diabetes. It regulates hematological and serological aspects and can be effective
in dyslipidemia and respiratory disorders. Moreover, its immunopotentiating and immunomodulating role brings balance
in the immune system. Evidence is available supporting the utilization of Nigella sativa and its bioactive components in a
daily diet for health improvement. This review is intended to focus on the composition of Nigella sativa and to elaborate its
possible therapeutic roles as a functional food to prevent an array of maladies.

Keywords black cumin, thymoquinone, oxidative stress, immunity, dyslipidemic effects hyperglycemia

BACKGROUND Central, and South America (Phillipson, 2001; Eisenberg et al.,

1998). These herbal medicines are becoming an important com-
The concept of functional and nutraceuticals foods has ponent of the trend toward alternative medicines. They are of
opened newer horizons of research in the domain of nutri- significant importance in clinical prescriptions as part of the
tion (Schwager et al., 2008). In the recent era, the outcomes patient’s drug profile (Hart, 2005; Lozano, 1998).
of such interventions have been witnessed in the consumers Nigella sativa is among the intensively researched plants
who have begun to look at food not only for the basic nu- commonly known as black seed or black cumin. It is a dicotyle-
trition it provides but also for health improvement (Ramaa don of the Ranunculaceae family and has been employed since
et al., 2006; Liu–Stratton et al., 2004). The tenet, “Let food long as a spice and food preservative (Ali and Blunden, 2003).
be thy medicine and medicine be thy food” exposed by Hip- Seeds of black cumin have been used in herbal medicine by var-
pocrates nearly 2,500 years ago, has received reconsideration ious cultures and civilizations to treat and prevent a number of
and a worldwide acceptance of these facts formed a recog- diseases and as a supplement to maintain good health (Zargari,
nition link between nutrition and health (Ramaa et al., 2006; 1990; Salem, 2005). N. sativa is an annual flowering plant, na-
Hasler, 1998). tive to southwest Asia (Aqel and Shaheen, 1996; Mozzafari et
Plants are reservoirs of bioactive compounds as they synthe- al., 2003). It grows to 20–30 cm tall with finely divided and
size complex organic molecules for their structures and func- linear leaves. Its fruit is large and is in an inflated capsule that
tions (Haq et al., 1999). When plants or their crude extracts are is composed of 3–7 united follicles, each containing numerous
used for medicinal purposes they are called herbal medicines. seeds. The different parts of the plant are used for medicinal
Most herbal medicines of current interest have come from an- purposes (Prain, 1988; Salem, 2000).
cient civilizations of South and South East Asia and North, The historical tradition of black seed in medicine is sub-
stantial, identified as a curative black cumin in the Bible, and
is described as the Melanthion of Hippocrates and Dioscorides
Address correspondence to Masood Sadiq Butt, National Institute of Food
Science and Technology, University of Agriculture, Faisalabad, Pakistan.
and as the Gith of Pliny. The Prophet Muhammad (PBUH) also
E-mail: drmsbutt@yahoo.com advised his followers “Hold on to use the Black cumin, for it
654
 NIGELLA SATIVA
has a remedy for every illness except death” (Ata-ur-Rehman,
1985; Bukhari, 1985).
Classification
Kingdom Plantae—Plants
Subkingdom Tracheobionta—Vascular plants
Super division Spermatophyta—Seed plants
Division Magnoliophyta—Flowering plants
Class Magnoliopsida—Dicotyledons
Subclass Magnoliidae
Order Ranunculales
Family Ranunculaceae—Buttercup family
Genus Nigella L.—Nigella
Specie Nigella sativa L. (Black Cumin)
Main Constituents
In view of its wide range of medicinal applications, N. sativa
has been extensively researched. Scientific interventions led by
various scientists gave conclusive evidence about its composi-
tion. Moisture, fat, protein, fiber, ash, and the total carbohy-
drate content were found to be in the range of 3.8–7.0%, 22.0–
56.4%, 18.59–31.2%, 3.7–4.7%, 5.5–15.0, and 24.9–40.0% re-
spectively (Dandik and Aksoy, 1992; Abdel-Aal and Attia, 1993;
El-Dhaw and Abdel-Munaem, 1996; Takruri and Dameh, 1998;
Salem, 2001; Atta, 2003; Haq et al., 1999; Ashraf et al., 2006).
Proteins of black cumin seeds are of important consideration
for their possible dietary application as they are rich in lysine
and methionine, the two limiting amino acids in cereal proteins
(Babayan et al., 1978).
Minerals such as calcium, phosphorus, and iron are present
in higher amounts while zinc, calcium, magnesium, manganese,
and copper in lesser amounts in N. sativa seeds (Nergiz and
Ötles, 1993; Abu-Jadayil, 1999; Haq et al., 1999; Khan, 1999;
Ali and Blunden, 2003). Iron, copper, sodium, potassium, cal-
cium, zinc, phosphorus, and magnesium contents lie in the range
of 9.1–15.40, 1.5–3.75, 41.2–55.0, 442.3–675.0, 154.4–305.0,
3.36–6.6, 378.12–576.9, and 134.92–147.05 mg/100 g of seed,
respectively (Takruri and Dameh, 1998; Abu-Jadayil et al., 1999;
Ashraf et al., 2006; Cheikh-Rouhou et al., 2007). Polyphenols,
tocopherols, and selenium are also present in appreciable quan-
tities (Dandik and Aksoy, 1996; Ustun et al., 1998; Weinreb
et al., 2004).
655
Fat-soluble vitamins (FSV) have more than 0.2% of to-
tal oil content (Ramadan and Mörsel, 2003). Moreover, Al-
Saleh et al. (2006) determined concentrations of selenium,
DL-α-tocopherol, DL-γ -tocopherol, and all-trans-retinol in
N. sativa seeds as 0.177, 9.027, 5.427, 0.277 mg/kg fresh weight,
respectively. Water-soluble vitamins like B1, B6, Niacin, and
folic acid are also present in black cumin seed in a range of
13–18 mg Kg–1 , 4–15 mg Kg−1 , 33–97 mg Kg−1 , and 400–870
mg Kg−1 (Takruri and Dameh, 1998). These are nutritionally
essential components of diet and play an important role in the
proper health of humans (Goldhaber, 2003; Thomson, 2004).
According to the literature, the yield of Black cumin seed
fixed oil ranged from 26.6 to 38%; rich in unsaturated fatty
acids, mainly linoleic acid, oleic acid, eicosadienoic acid, di-
homolinoleic acid, palmitic, and stearic acid. Various scientific
interventions revealed its fatty acid composition (Sener et al.,
1985; Ali and Blunden, 2003).
Black cumin seed oil is a rich source of linoleic acids
(47.0–60.0%), oleic acid (18.9–25.69%), and palmitic acid (9.9–
18.4%). Additionally, it also contains some minor quantities
of linolenic acid, arachidic acid, eicosenoic acid, and dihomo-
lionolenic acid (Atta, 2003; Ramadan and Mörsel, 2004; Ashraf
et al., 2006). Polyunsaturated fatty acids constitute the bulk of
oil with quantities ranging from 48–70.0% while monounsatu-
rated and saturated fatty acids are in a lesser proportion (Ustun
et al., 1990; Nergiz and Otles, 1993; Nickavar et al., 2003;
Ramadan and Morsel, 2003; Atta, 2003). Additionally, the pres-
ence of dihomolionolenic acid (1.9–2.3%) is accredited for the
antioxidant and lipid-lowering potential of N. sativa fixed oil.
Recently, Cheikh-Rouhou et al. (2007) analyzed Tunisian and
Iranian black cumin seeds varieties for their oil characteristics.
656 M.S. BUTT AND M.T. SULTAN

Table 1 Chemical composition of black cumin seed

Proximate analysis (%) Fat soluble vitamin mg/Kg

Moisture (%) 3.87.0 DLαtocopherol, 0.177

Crude protein (%) 18.5931.2 DLβtocopherol 9.027
Crude fat (%) 22.053.4 DLγ tocopherol 5.427
Total ash (%) 3.74.7 Alltransretinol 0.277
Crude fiber (%) 5.5−15.0
Carbohydrates (%) 24.9−40.0

Fatty acid profiles Water soluble vitamin mg/Kg

Myristic acid 14:0 0.29−1.1 B1 13–18
Myristoleic acid 14:1 2.42−2.65 B6 4–15
Palimitic acid 16:0 9.9−18.4 Niacin 33–97
Stearic acid 18:0 1.51−3.70 Folic acid 400–870
Oleic acid 18:1 18.9−25.69
Linoleic acid 18:2 47.0−67.5 Minerals (mg/100 g)
Linolenic acid 18:3 0.19−2.70 Iron 9.1−15.40
Arachidic acid 20:0 0.14−0.90 Copper 1.5−3.75
Eicosenoic acid 20:1 0.32−1.0 Sodium 41.2−55.0
Dihomolionolenic acid 20:2 1.91−2.03 Potassium 442.3−675.0
Arachidonic acid20:6 0.19−0.25 Calcium 154.4−305.0
Behanic acid 22:0 1.80−2.60 Zinc 3.36−6.6
Saturated fatty acids 16.25−26.7 Phosphorus 378.12−576.9
Monounsaturated fatty acids 19.22−29.11 Magnesium 134.92−147.05
Figure 1 Important phytochemicals of black cumin seeds
Polyunsaturated fatty acids 49.1−72.42

Ustun et al., 1990; Dandik and Aksoy, 1992; Abdel-Aal and Attia, 1993; Nergiz
and Otles, 1993; Dandik and Aksoy, 1996; El-Dhaw and Abdel-Munaem,
1996; Takruri and Damed, 1998; Ustun et al., 1998; Abu Jadayil, 1999; Ali
and Blunden, 2003; Atta, 2003; Nickavar et al., 2003; Ramadan and Mörsel,
2003; Ramadan and Mörsel, 2004; Al-Saleh et al., 2006; Ashraf et al., 2006;
Cheikh-Rouhou et al., 2007.
Their finding also suggests that it contains 49.8–50.7% of PUFA,
25.0–26.6% of MUFA while saturated fatty acids only account
for 22.7–25.5% of the total oil contents. According to their
findings, linoleic, oleic, and palmitic acids were found to be in
higher quantities (Nickavar et al., 2003; Ashraf et al., 2006).
Moreover, it contains sterols (ST) which ranged from 0.33–
0.36% and β-sitosterol (32.2–34.1% of total ST content)
represents the main component followed by 5-avenasterol
(27.8–27.9%), and 7-avenasterol (18.5–22.0%). Stigmasterol,
campesterol, and lanosterol are in lesser amounts but together
account for 17.6–19.5% of the ST contents (Menounos et al.,
1986; Ramadan and Mörsel, 2003).
N. sativa is naturally bestowed with antioxidant rich volatile
oil (0.40–1.50%) that contains 18.4–24% thymoquinone and
46% monoterpenes such as p-cymene and α-pinene (Al-Jassir
1992; El-Tahir et al., 1993; Ashraf et al., 2006). Burits and Bucar
(2000) analyzed essential oil using GC–MS and characterized
many components. The major ones were thymoquinone (27.8%–
57.0%), ρ-cymene (7.1%–15.5%), carvacrol (5.8%–11.6%), t-
anethole (0.25%–2.3%), 4-terpineol (2.0%–6.6%), and 1.0%–
8.0% of longifoline (Nickavar et al., 2003; Mozaffari et al.,
2000). More recently, Ashraf et al. (2006) and Wajs et al. (2008)
determined p-cymene as a major component of black cumin seed
essential oil.
Furthermore, traces of alkaloids are found which belong to
two different types— isochinoline alkaloids are represented by
nigellimin and nigellimin-N-oxide, and pyrazol alkaloids in-
clude nigellidine and nigellicine (Nickavar et al., 2003; Mozaf-
fari et al., 2000; Ali et al., 2008). Morikawa et al. (2004) isolated
new dolabellane-type diterpene alkaloids, nigellamines A(3),
A(4), A(5), and C, from the methanolic extract of black cumin.
Singh et al. (2005) separated two new aliphatic compounds from
the hexane extract of Nigella saliva. The compounds were char-
acterized as 16-triecosen-7-ol-1 and 6-nonadecanone-2. These
components have different pharmacological applications. Its
component, α-henderin, has been identified as a possible anti-
cancer agent (Swamy and Huat, 2003).
Interventions are in process to identify and separate com-
ponents which have not been determined and some of them
provided some more evidence about the rich phytochemistry of
this plant that in turn can produce some extra health benefits
(Singh et al., 2005)
N. Sativa and Oxidative Stress
Oxidation is essential to nearly all cells in the body to
provide energy for vital functions. Uncontrolled oxidation
results in the production of free radicals like reactive oxygen
species (ROS) and reactive nitrogen species (NOS) that
override the antioxidant capability of the target cells resulting
in oxidative stress (Opara, 2004; Vina et al., 2006). It results
in damage to macromolecules, especially DNA, the production
of mutated tumor-suppressor genes, and induction of cell
death (Kang et al., 1997; Farah, 2005). Free radicals have
been implicated in mediating various pathological processes
such as cancer, ischemia, inflammatory diseases, diabetes, and
atherosclerosis (Vina et al., 2006; Wilson and Demmig-Adams,
2007). These pathological events are involved in cardiovascular,
 NIGELLA SATIVA
neurodegenerative, and carcinogenic processes (Molbey and
Brueggemeirers, 2004; Ferrari, 2004; Hussein et al., 2005).
Intake of antioxidant vitamins and trace elements is essential in
protecting the human body against these physiological threats
(Blomhoff, 2004; Ji et al., 2004; Berger, 2005).
Lipid peroxidation is an autocatalytic mechanism leading to
the oxidative destruction of cellular membranes that could lead
to cell death and degenerative disorders. It is an important con-
sequence of free radicals being produced in the body (Casini et
al., 1997; Paradis et al., 1997; El–Missiry and El–Gindy, 2000;
Türkdoğan et al., 2001). Houghton et al. (1995) provided some
evidence that the oil of N. sativa inhibits the lipid peroxidation
of biological membranes and prevents the lipid peroxidation in-
duced liver damage (Clarkson, 1995; Meral et al., 2001). Burits
and Bucar (2000) observed OH-radical scavenging property of
N. sativa in the assay for non-enzymatic lipid peroxidation in
liposomes and in the deoxy-ribose degredation assay.
N. sativa and thymoquinone both inhibit nonenzymatic lipid
peroxidation in liposomes and prevent the CCl4 -induced dis-
turbances of anemia and the body’s defense mechanism in
rats (Al-Ghamdi., 2003). CCl-4 induced hepatotoxicity and the
protective effects of N. sativa or its active ingredient thymo-
quionone may be due to its ability to inhibit lipid peroxidation
(Al-Gharably et al., 1997). Kanter et al. (2008) augments that
N. sativa seed oil improves the antioxidant defense system in
CCL-4 treated rats. Turkdogan et al. (2001) also observed the
significant hepatoprotective effect of N. sativa in CCl4 - admin-
istrated rabbits. In another study, N. sativa produced a protective
effect against oxidative damage in isolated rat hepatocytes (Daba
and Abdel-Rahmen, 1998).
Lipid peroxidation and H2 O2 results in degradation, loss of
deformability, and an increased osmotic fragility in erythro-
cytes. Preincubation of erythrocytes with N. sativa protects them
from damage caused by lipid peroxidation (Suboh et al., 2004).
Houghton et al. (1995) reported that fixed oil of N. sativa inhib-
ited eicosanoid generation in leukocytes. They also attributed
this antioxidant effect to thymoquinone and unusual fatty acid
(dihomolinolenic acid, C20:2). N. sativa seeds at a dose of
0.2 g/rat/rat protect against methylnitrosourea (MNU)-induced
oxidative stress by 80% (Mabrouk et al., 2002).
Thymoquinone, carvacrol, t-anethol, and 4-terpineol are im-
portant components found in N. sativa and the antioxidant ef-
fects are mainly attributed to them (Burits and Bucar, 2000).
Thymoquinone and tert-butylhydroquinone (TBHQ) exhibits
strong antioxidant potential and can suppress the expression of
the inducible isoform of nitric oxide synthase enzyme. They can
even suppress nitric oxide (NO) production from lipopolysac-
charide (LPS)-induced peritoneal macrophages in normal rats
(El-Mahmoudy et al., 2002). Badary et al. (2003) further inves-
tigated that thymoquinone is more active than TBHQ as a su-
peroxide anion scavenger with inhibitory concentration (IC50)
of 3.35 microM compared to 18.1 microM for TBHQ.
The roles of enzymes and electrolytes in the amelioration
of oxidative stress are indispensable. Free radicals production if
unchecked can decrease the activities of enzymes that are indeed
657
risk factors in the pathogenesis of various diseases. N. sativa oil
tends to normalize the level of lipid peroxide (LPX), lactate
dehydrogenase (LDH), glutathione (GSH), and superoxide dis-
mutase (SOD). N. sativa could decrease the elevated serum K
and Ca levels and tends to increase RBC, WBC, Hb levels, and
packed cell volume (Suboh et al., 2004). Improvement can also
be seen with enhanced activities of antioxidant enzymes like su-
peroxide dismutase (SOD), glutathione peroxidase (GSH-Px),
and catalase (CAT) enzyme, and a decreased level of lipid per-
oxides and protein carbonyl levels in induced spinal cord injury
in rat (Kanter et al., 2008). The antioxidizing and free radi-
cal scavenging properties exhibited by thymoquinone may add
positively to its cytoprotective action (Beckman et al., 1990;
Ohkuwa et al., 1997). Kanter (2008 observed the neuroprotec-
tive effects of N. sativa and thymoquinone at doses of 400 mg/kg
and 50 mg/kg body weight, respectively. N. sativa supplemen-
tations potentially improve the overall antioxidant protection
capacity of the body (Abdulaziz et al., 2006).
The pharmacological actions of the crude extracts of the
seeds (and some of its active constituents, e.g. volatile oil
and thymoquinone) that have been reported include protec-
tion against nephrotoxicity and hepatotoxicity induced by either
disease or chemicals (Ali and Blunden, 2003; Ali, 2004; Uz
et al., 2008). It produced a hepatoprotective effect in some mod-
els of liver toxicity. Administration of N. sativa oil succeeded
partially in correcting the previous changes in L-alanine amino-
transferase (ALT), gamma-glutamyl transferase (GGT), alkaline
phosphatase (ALP), and albumin contents in serum (Mahmoud
et al., 2002). N. sativa may suppress KBrO3 (potent nephro-
toxic agent) mediated renal oxidative stress, toxicity, and tumor
promotion response in rats (Khan et al., 2003).
Various research interventions indicated the importance of
N. sativa as an antioxidant, anti-protein-oxidant activity which
could be useful in pathological conditions related to free radi-
cals.
N. SATIVA: IMMUNITY AND INFLAMMATION
Many investigations have been carried out in recent years
on the pharmacological effects of N. sativa seeds unveiling its
anti-inflammatory and immunological effects (Tekeoglu et al.,
2007). Inflammation is an integral part of the immune system
but sometimes becomes a causative agent for the occurrence and
progression of some diseases (Bystrianyk, 2005).
El-Kadi and Kandil (1986) investigating the effects of N.
sativa on immune system. Their findings suggest that the ad-
ministration of 1 g of black cumin seeds in human volunteers
twice a day enhanced immune functions as manifested by the
improved helper T-cell (T4) to suppressor T-cell (T8) ratio and
an improved natural killer cell activity. Leukotrienes are impor-
tant mediators in asthma and inflammatory processes. Cytokines
can enhance immunogenicity and promote tumor regression and
in the last few decades, various immune-modulating nutrients
658 M.S. BUTT AND M.T. SULTAN
have been identified (Dijsselbloem et al., 2004). N. sativa en-
hances the production of interleukin-3 by human lymphocytes
and increase in interleukin-1 beta (IL-1β) suggesting that it has
a stimulatory effect on macrophages (Haq et al., 1995). Studies
have proved that N. sativa has a cytoprotective effect on hu-
man T-cell and an antioxidant effect on cardiovascular tissue
(El-Kadi et al., 1995; El-Tahir et al., 1993).
Nitric oxide (NO) is an important effector molecule in both
physiological conditions and in disease states characterized by
inflammation. N. sativa extract caused a decrease NO produc-
tion by murine macrophages that also validate the traditional
use of the N. sativa seeds for the treatment of rheumatism
(Mahmood et al., 2003). Thymoquinone at a dosage of 2.5 to
5.0 mg/kg suppresses adjuvant-induced arthritis in rats, inhibits
the formation of leukotrienes (LTs) in human blood cells,
and exerts an inhibitory effect on 5-lipoxygenase and LTC4
synthase activity (Mansour amd Tornhamre, 2004; Tekeoglu et
al., 2006). Thymoquinone challenges inhibited 5–lipoxygenase,
and significantly reduces the levels of LTB4 and LTC4 owing to
its antioxidative action (El-Dakhakhny et al., 2002; El-Gazzar et
al., 2006). Inhibition of lipoxygenase and cyclooxygenases by
thymoquinone attenuates the production of leukotrienes; potent
pro-inflammatory mediators (Marsik et al., 2005) that explain
partially the mechanisms of its anti-inflammatory activities.
The volatile oil of black cumin produces a significant anal-
gesic effect in acetic acid-induced writhing, formalin, and light
tail flick tests. Its oral administration (Dosage; 10 and 20 µL)
significantly inhibits carrageenan-induced paw edema and re-
duces croton oil-induced edema (Hajhashemi et al., 2004).
Ghannadi et al. (2005) reported similar anti-inflammatory ef-
fects for extracted N. sativa polyphenols. Ozugurlu et al. (2005)
reported that N. sativa protects brain and medulla spinalis tis-
sues against autoimmune encephalomyelitis (EAE)-induced ox-
idative stress. They also suggested that N. sativa displayed its
antioxidant and regulatory effects via inflammatory cells rather
than the host tissue (brain and medulla spinalis) against EAE in
rats.
El-Obeid et al. (2006) indicated that herbal melanin obtained
from N. sativa enhanced the expression for tumor necrosis factor
alpha (TNF-alpha), interleukin 6 (IL-6) and vascular endothelial
growth factor (VEGF), mRNA expression by the monocytes, pe-
ripheral blood mononuclear cells (PBMC), and THP-1 cell line.
Their findings include herbal melanin which also mimics the
action of LPS in the induction of IL-8 by PBMC. These ob-
servations raise the prospects of using herbal melanin for the
treatment of diseases associated with imbalanced cytokine pro-
duction and for enhancing cancer and other immunotherapies.
Further studies are urgently required to explore the by-
stander effects of N. sativa and its active ingredients on the
antigen producing cells, including macrophages and dendritic
cells, as well as its modulatory effects upon cytokines and Th1-
and Th2-mediated inflammatory immune diseases. Dithymo-
quinone, thymohydroquinone, thymol, and thymoquinone are
the main participants in the general anti-inflammatory activ-
ity of N. sativa and they should be further studied separately
for their possible use as anti-inflammatory drugs (Marsik et al.,
2005). Ultimately, the results emerging from such studies would
substantially improve the immunotherapeutic application of N.
sativa and thymoquinone in clinical settings.
N. SATIVA AGAINST CANCER
Cancer has been reported to be the second common cause
of death in the United States after cardiovascular disorders. The
immune system plays a crucial role in cancer insurgence and
inflammation and eventually causes aggregation of cells due
to disturbances in signaling pathways (Noonan et al., 2007).
It has been estimated that 30–40% of all kinds of cancer can
be prevented with a healthy lifestyle and dietary measures. The
relevance of nutrition on the cancer process is evident—some di-
etary components result in cancer progression and some act as
chemopreventive agents (Divisi et al., 2006). Harmlessly dis-
posing of cancer cells is one of the main considerations in
chemotherapy. Cell death can occur by either of two distinct
mechanisms—necrosis (“accidental” cell death) and apoptosis
(“programmed” cell death). A variety of pharmacological and
physiological agents can trigger the cascade of events that leads
to apoptosis (Bursch et al., 1992; Chan et al., 2003). Multi-drug
resistance is a serious limitation in chemotherapy and in some
cases leads to failure of cancer treatment (Murray, 2000; Setzer
and Setzer, 2003; Thabrew et al., 2005).
Many naturally occurring compounds have been reported to
have cancer-preventive effects (Yamagishi et al., 2001; de Ste-
fani et al., 2004; Vuorelaa et al., 2004; Halder et al., 2005; Tapsell
et al., 2006). Generally, chemopreventive agents can be divided
into two groups (antimutagenic and antiproliferative) on the ba-
sis of the mechanism through which they exert anticancer effects
(Steele, 2003). Antimutagens reduce the formation of mutagens
or carcinogens thereby preventing DNA damage. Chemopreven-
tive agents may also exert antiproliferative effects via induction
of cell cycle arrest or apoptosis, inhibition of angiogenesis, in-
duction of terminal differentiation, and inhibition of oncogene
activity or DNA synthesis (Manson, 2003).
N. sativa have been shown in a number of studies to pos-
sess chemo-preventive potential. Its components are effective
in mediating inflammation and cancerous cell growth side by
side. Induction of apoptosis by the tumor necrosis factor and
chemotherapeutic agents can lead to reduced quantities of the
nuclear factor kappaB (NF-kappaB). Sayed (2008) observed that
thymoquinone (TQ) decreased NF-kappaB activation in a dose-
dependent manner with a maximum inhibitory effect at a con-
centration of 500 nM. Production of ROS during cancerous in-
vasion can result in tumor reduction in number and sizes. Some
of its components, especially α-Hederin, have shown some sig-
nificant effects in mitigating the cancerous cell growth (Salem,
2005; Ramadan, 2007).
The effectiveness of N. sativa or its components have been
recorded against colon, breast cancer, etc. but yet concluding
 NIGELLA SATIVA
its anti-cancer prospects require thorough research in order to
recommend N. sativa and its components as chemopreventive
agents. Colon cancer is one of the leading causes of cancer
morbidity and mortality worldwide (Parkin et al., 1999) and the
surgical success rate is less than 40% (Bond, 2005; Seven et al.,
1999). Colon cancer incidence is inversely correlated with serum
α-tocopherol level (Stone and Papas 1997; Nair et al., 1991).
The delivery of the natural agents may offer a safe alterna-
tive treatment for colon cancer and thymoquinone is significant
important. It causes cellular destruction and interference of cel-
lular metabolic functions of SW-626 human colon cancer cells.
It has chemotherapeutic effects comparable with 5-fluorouracil
(5–FU) as explored by a reduced number of cancerous cells
(Norwood et al., 2006). Moreover, Gali-Muhtasib et al. (2004)
also supported the use of thymoquinone for the treatment of
colon cancer. Volatile oil of N. sativa inhibits colon carcino-
genesis of rats in the post-initiation stage and inhibition may
be associated, in part, with the suppression of cell proliferation
in the colonic mucosa (Salim and Fukushima, 2003). Thymo-
quinone and α-Hederin, important constituents of black cumin
seeds, possess both cytotoxic and apoptotic/necrotic effects in
the HT-29 (colon adenocarcinoma) cancer cell line (Rooney and
Ryan, 2005).
Supplementation of N. sativa seeds to the diet of
methylnitrosourea-induced mammary cancer rats was reported
to protect against oxidative stress, inflammatory response, and
carcinogenesis (Mabrouk et al., 2002). N. sativa was found to be
effective (in vitro) in influencing the survival of MCF–7 breast
cancer cells, unveiling promising opportunities in the field of
cancer chemoprevention (Farah, 2005). The administration of
N. sativa and its component melatonin could reduce the car-
cinogenic effects of 7, 12 di-methylbenz(a)anthracene (DMBA),
suggesting a protective role against breast cancer (El-Aziz et al.,
2005). Effects of melatonin and N. sativa may be due to their
ability to act as an antioxidant (Tan et al. 2002; Mahmood et al.
2003; Hussein et al. 2005).
Thymoquinone protected mice against benzo(a)pyrene
(B(a)P)-induced forestomach carcinogenesis. Daily intake of
thymoquinone significantly reduced the frequencies of chro-
mosomal aberrations and damaged cells (Badary et al., 2007).
Recent in vivo studies have shown that tumor development in
mice skin could be inhibited by thymoquinone (Salomi et al.,
1992; Kumara and Huat, 2001). Angiogenesis is an important
step in the growth of cancerous cells and more recently, thy-
moquinone reportedly blocked angiogenesis in vitro and in vivo
and prevented tumor angiogenesis in a xenograft human prostate
cancer (PC3) model in mice (Yi et al., 2008). Furthermore, they
also provided evidence that treatment with thymoquinone did
not produce side-effects.
Like thymoquinone, another active ingredient of N. sativa
is α-hederin that possesses anti-tumor activity against cultured
B16 melanoma cells (Danloy et al., 1994). In vivo anti-tumor
activity of α-hederin against LL/2 (Lewis lung carcinoma) in
BDF1 mice (Kumara and Huat, 2001) increased apoptosis in
murine leukemia P388 cells were also observed (Swamy and
659
Tan, 2000). α-hederin rapidly increased the production of reac-
tive oxygen species (ROS) and inhibited DNA, RNA, and protein
synthesis (Baker and Hagner, 1990; Swamy and Huat, 2003).
Mba Gachou et al. (1999) reported that α-hederin exerted a pro-
tective effect against human hepatocellular carcinoma (HepG2)
cells.
Islam et al. (2004) reported the LC(50) values for N. sativa
volatile oil and they were in the range of 155.02 +/– 10.4, 185.77
+/– 2.9, 120.40 +/– 20.5, 384.53 +/– 12.1, and 286.83 +/–
23.3 micro g/ml respectively against the SCL, SCL–6, SCL–
37 6, NUGC–4 cancer lines and 3T6 fibroblast line. Shoieb
et al. (2003) conducted in vitro trial to check the inhibitory
effect of thymoquinone on growth and induction of apoptosis
in cancer cell lines. He suggested antiproliferative mode of ac-
tion for thymoquinone as it produces cell cycle arrest. Likewise,
α–hederin has an antiproliferative mode of action but with dif-
ferent mechanisms as it produces some cytotoxic effects and
brings apoptosis to combat cancerous cell growth. It has also
the ability to produce ROS species to inhibit DNA and RNA
synthesis.
Overall, anticancer and antiinflammatory activities of N.
sativa and thymoquinone may be mediated in part through the
suppression of the NF-kappa B activation pathway (Sethi et al.,
2008). N. sativa volatile oil containing thymoquinone and other
antioxidants could also be considered as a potential immunosup-
pressive cytotoxic agent agent (Swamy and Huat, 2003; Salim
and Fukushima, 2003; Ramadan, 2007). Black cumin or its ac-
tive bioactive components in the form of its volatile oil, thymo-
quinone and α-hederin, require further research to be considered
as chemopreventive.
N. SATIVA IN RELATION TO HYPERGLYCEMIA
Diabetes mellitus is now the seventh leading cause of mor-
tality in the United States and one of the most common non-
communicable diseases and if uncontrolled, targets multi-organ
systems. Drug therapy led to much complication and even the
effectiveness of manufactured drugs decrease after the third
month (Zakir et al., 2008).
Many researchers designed studies to elucidate the role
of medicinal plants; N. sativa is one of them for the man-
agement of diabetes (Mansi, 2005). Various hypotheses have
been presented by different research groups for its mode of
actions to cure hyperglycaemia. Recently, Kanter (2008) ob-
served that N. sativa and thymoquionone at a dose of 400
and 50 mg/kg body weight/day respectively, caused a sharp
decrease in the elevated serum glucose and increased the serum
insulin concentrations in streptozotocin-induced diabetic rats
(Kanter, 2008).
Kanter et al. (2004) suggested that N. sativa at a dose of
0.2 ml/kg/day, i.p. exerts a therapeutic protective effect in dia-
betes by decreasing oxidative stress and preserving pancreatic
beta-cell integrity. At the molecular level, pancreatic β cell loss
660 M.S. BUTT AND M.T. SULTAN
by apoptosis appears to play an important role in the develop-
ment of insulin deficiency and the onset and/or progression
of the disease. Using immunohistochemical staining, Fararh
et al. (2002) observed big areas with positive immuno–reactivity
for the presence of insulin in the pancreas from the N. sativa
oiltreated group that indicates N. sativa oil has insulinotropic
properties in type 2 like model. Similarly, research interventions
led by Kanter et al. (2003), Al Haider et al. (1993), and Meral
et al. (2003 also support the insulinotropic mode of action. The
hypoglycemic effect of N. sativa oil may be mediated by extra-
pancreatic actions rather than by stimulated insulin release and
partial regeneration/ proliferation of pancreatic beta-cells (El-
Dakhakhny, 2002; Kanter et al., 2003). Mansi (2006) suggested
that increased glucose metabolism in turn produces increased
insulin release in serum. These researchers also indicated that
the insulinotropic properties of N. sativa results in increased
production of insulin that may also affect gluconeogenesis in
liver.
Hepatic glucose production contributes significantly to hy-
perglycemia in diabetic patients (Nordlie and Foster, 1999).
Farah et al. (2004) attributed the hypoglycemic effect of N.
sativa oil to decreased hepatic glucose production. Gluconeoge-
nesis is highly responsive to insulin. Insulin decreases gluconeo-
genesis by decreasing intracellular cyclic adenosine monophos-
phate (cAMP) levels, which inhibits the phosphorylation of en-
zymes (Sun et al., 1986; DeFronzo, 1988). An elevated level
of different enzymes results in lower permeability of glucose
precursors to liver resulting in lower gluconeogenesis (Meral
et al., 2001). A lower supply of gluconeogenic precursors (ala-
nine, glycerol, and lactate) to liver results in decreased hepatic
gluconeogenesis as observed by Farah et al. (2004) in N. sativa
treated diabetic hamsters.
Enzymes play an important role in the regulation of proper
blood glucose metabolism (Vats et al., 2003). The long-term
hyperglycemia results in decreased activities of liver enzymes
26% in glutathione peroxidase (GSHPx), 34% in catalase, 27%
in glucose-6-phosphate dehydrogenase (G6PDH), and 38% in
glutathione S-transferase (GST) activity (Lapshina et al., 2006;
Ugochukwu and Figgers, 2007). Decreased activities of en-
zymes results in oxidative stress (Lipid peroxidation) that may
damage liver and even disturb the integrity of pancreatic beta-
cells (Kaleem et al., 2006). Hyperketonemia is another com-
plication arising due to diabetes (Jain et al., 2006). N. sativa
treatments resulted in marked elevation in the activities of liver
enzymes (El-Dakhakhny et al., 2002; Meral et al., 2003; Kanter
et al., 2004; Kaleem et al., 2006).
N. sativa possesses blood glucose lowering effects, but the
mechanism involved is not yet established. Extrapancreatic ac-
tions resulting in stimulated insulin release and the protection of
pancreatic beta-cells, reducing oxidative stress, and decreased
gluconeogenesis could be possible reasons for its anti-diabetic
action (Kanter et al., 2004). N. sativa, because of its antioxidant
properties may be useful in controlling the diabetic complica-
tions in experimental diabetic rats (Kaleem et al., 2006; Kanter
et al., 2006).
Furthermore, clinical studies and community based trails are
urgently needed to comprehend the hypoglycemic potential of
black cumin seed and its components.
N. SATIVA AND DYSLIPIDEMIC EFFECTS
Dyslipidemia is a common risk factor for cardiovascular dis-
ease, the leading cause of morbidity and mortality among such
patients. N. sativa constitute a good alternative source of essen-
tial fatty acids compared with that of common vegetable oils
and could contribute to the overall dietary intake of the min-
eral elements. Cheikh-Rouhou et al. (2007) and Atta (2003)
reported that linoleic acid is the dominating fatty acid in N.
sativa oil. Aurand et al. (1987) highlighted the nutritional value
of linoleic acid. It is highly valuable due to its imperative role in
metabolism at tissue levels with the ability to produce hormone-
like prostaglandins. Their activities include lowering of blood
pressure and constriction of smooth muscle. N. sativa fixed oil
could produce a favorable effect on serum lipid profile, decreas-
ing its total cholesterol, low density lipoprotein, triglycerides,
and elevating the high density lipoprotein level (El-Dakhakhny
et al., 2000).
Animal modeling studies conducted in various parts of the
world explain the administration of herbal extracts and N. sativa
seed oil in decreasing cholesterol and total lipids in rats. Supple-
mentation of black cumin seeds in diets of rats decreased their
serum triglyceride level (Bashandy,1996; Zaoui et al., 2002). Le
et al. (2004) also reported that N. sativa has a slight anorexic
effect, and it holds the dyslipidemic activity. Grundy (1986)
reported that N. sativa caused activation of LDL receptor that
caused a rapid clearance of LDL-cholestrol from circulating
lipids thus reducing the chances of potential atherogenecity.
Akhtar et al. (2003) supplemented the commercial layer-ration
with N. sativa seeds and observed reduced yolk cholesterol con-
tents. Their findings also elucidate that serum triglycerides, low-
density lipoprotein, cholesterol, and total cholesterol contents
were reduced, while serum high density lipoprotein cholesterol
levels were increased.
Badary et al. (2000) and Hussain and Hussan (1996), while
studying the effect of thymoquinone on serum triglycerides in
rats, arrived at the same conclusions. The dyslipidemic effects
may be caused either by reducing the synthesis of cholesterol by
hepatocytes or by decreasing its fractional re-absorption from
the small intestine and thus lowering serum cholesterol level.
Bamosa et al. (2002) observed a significant effect of six dif-
ferent doses of thymoquinone on blood lipids in rats. The oil
also contains appreciable quantities of sterols, especially β-
sitosterol, that are reported to inhibit the absorption of dietary
cholesterol (Moghadasian and Frohlich, 1999; Atta, 2003). De
Jong et al. (2003) while studying the metabolic effects of plant
sterols reached similar conclusions that those serum lipids lev-
els reduced significantly with supplementation of diets with
sterols. Morikawa et al. (2004) reported another component,
 NIGELLA SATIVA
nigellamines A–(5), that has the potential to lower triglyceride
levels in primary cultured mouse hepatocytes and its activity
was equivalent to dyslipidemic agent clofibrate.
Furthermore, Kalus et al. (2003) observed a slight decrease in
plasma triglycerides and a discrete increase in HDL cholesterol,
while they also observed no change in lymphocyte subpopula-
tions, endogenous cortisol levels, and adrenocortocitropic hor-
mone (ACTH) release. The oil could decrease blood pressure,
increase respiration, increase PCV, Hb, and decrease plasma
concentrations of cholesterol, triglycerides, and glucose (Ali
and Blunden, 2003).
In Pakistan, the University of Karachi is conducting commu-
nity based trails sponsored by the Higher Education Commis-
sion of Pakistan to evaluate the hypercholesterolemic potential
of black cumin seed and its components. Some research tri-
als are also in progress at the National Institute of Food Science
and Technology, Faisalabad that involve rat modeling in induced
hypercholesterolemic rats/hamsters. Results from such studies
would further facilitate in finding appropriateness of use for
humans.
The aforementioned results support the traditional use of N.
sativa seeds as a treatment of hyperlipidemia and related ab-
normalities thereby reducing the risk of coronary heart diseases
(CHD). Acute and chronic toxicity and the mode of action of
the N. sativa fixed oil must be studied. Furthermore, without
results from clinical studies at community based trials, it is not
possible to advise the use of black cumin seed or its components
to the patients with abnormal lipids profile.
N. SATIVA AGAINST RESPIRATORY DISORDERS
Anticholinergic, histamine H1 inhibitory, β-adroceptor stim-
ulatory, and potassium channel opening effects of N. sativa may
contribute to the bronchodilatory effect (Boskabady and Shir-
mohammadi, 2001; Boskabady et al., 2004). The other possi-
ble mechanisms responsible for the bronchodilatory effect of
N. sativa are stimulation of inhibitory non-adrenergic, non-
cholinergic nervous system (NANC) or the inhibition of stimula-
tory NANC (Linden et al., 1993), methylxanthine activity of the
plant (Meini et al., 1993), and inhibition of phosphodiesterase
(Van Amsterdam et al., 1989).
Kacem and Meraihi (2006) reported the effects of ma-
jor components of essential oil on human neutrophil elastase
(HNE) activity and found that the inhibitory effects of essen-
tial oil on HNE activity are due to the presence of the bioac-
tive molecule carvacrol that could be considered as a possible
candidate for phytotherapy in tructive pulmonary disease and
emphysema.
Isik (2005) reported that the treatment of injuries that appear
in some pathologic cases such as chronic obsmoquinone also
affect acute respiratory distress syndrome (ARDS) and acute
lung injury (ALI) in a rat model study. They found that thy-
moquinone improved oxygenation while both thymoquinone
and steroids protect lung tissue from hazardous effects of hu-
661
man gastric juice histopathologically. ALI/ARDS are important
clinical problems in thoracic surgery and critical care medicine
and even in allergic asthma N. sativa significantly reduced pe-
ripheral blood eosinophil count, IgG1 and IgG2a levels, cy-
tokine profiles, and inflammatory cells in lung tissue in mouse
model study. N. sativa exhibits anti-airway inflammation and
immunoregulatory effect which may be useful for the treatment
of allergic asthma and other respiratory disorders (Abbas et al.,
2005).
CONCLUSIONS
Medicinal plants are proven health pills encouraging hu-
man beings to seek natural cures. Nigella sativa is a good
source of nutritionally essential components and its oil is rich
in PUFA, phyto-sterols, antioxidants, and anti-tumor agents.
Nigella sativa supplementation may improve the overall antiox-
idant status of the body. Immunopotentiating and immunomodu-
lating effects could be due to its ability to interfere with immune
modulators. By means of apoptosis, it is effective against vari-
ous cancer cell lines. Extrapancreatic actions resulting in stim-
ulated insulin release and protection of pancreatic beta-cells,
reducing oxidative stress, and decreased gluconeogenesis could
be possible reasons for its anti-diabetic action. Nigella sativa
possesses dyslipidemic effects by inhibiting cholesterol absorp-
tion and activating LDL receptors. Anticholinergic, histamine
H1 inhibitory, β-adroceptor stimulatory, and potassium channel
opening effects of Nigella sativa may contribute towards bron-
chodilatory effects. The nutritional quality of Nigella sativa
seeds enhances its chance of inclusion in diet-based strategies
that may play a role in improving human health. Conclusively,
there is a dire need to conduct community based trials to vali-
date its nutraceutical worth. Results gathered from such studies
would open new avenues in the field of alternative medicines
for preventing various maladies.
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