Cumin (Cuminum cyminum) and black cumin (Nigella sativa) seeds: traditional uses, chemical constituents, and nutraceutical effects

Cumin (Cuminum cyminum) and black cumin (Nigella sativa) seeds: traditional uses, chemical... Although the seeds of cumin (Cuminum cyminum L.) are widely used as a spice for their distinctive aroma, they are also commonly used in traditional medicine to treat a variety of diseases. The literature presents ample evidence for the biomedical activities of cumin, which have generally been ascribed to its bioactive constituents such as terpenes, phenols, and flavonoids. Those health effects of cumin seeds that are experimentally validated are discussed in this review. Black seeds (Nigella sativa), which are totally unrelated to C.  cyminum, have nevertheless taken the name ‘Black cumin’ and used in traditional systems of medicine for many disorders. Numerous pre- clinical and clinical trials have investigated its efficacy using the seed oil, essential oil, and its main constituent thymoquinone (TQ). These investigations support its use either independently or as an adjunct along with conventional drugs in respiratory problems, allergic rhinitis, dyspepsia, metabolic syndrome, diabetes mellitus, inflammatory diseases, and different types of human cancer. Multiple studies made in the last decades validate its health beneficial effects particularly in diabetes, dyslipidemia, hypertension, respiratory disorders, inflammatory diseases, and cancer. Nigella sativa seeds also possess immune stimulatory, gastroprotective, hepatoprotective, nephroprotective, and neuroprotective activities. TQ is the most abundant constituent of volatile oil of N. sativa seeds, and most of the medicinal properties of N. sativa are attributed mainly to TQ. All the available evidence suggests that TQ should be developed as a novel drug in clinical trials. Key words: Cuminum cyminum; Nigella sativa; digestive stimulant; antidiabetic; anti-inflammatory; cancer preventive; immune stimulatory; gastroprotective. traditional medicine. In the Ayurvedic system of medicine in India, Introduction cumin seeds have immense medicinal value, particularly for digestive Cumin seeds (Figure 1) are obtained from the herb Cuminum disorders. They are used in chronic diarrhoea and dyspepsia (Table 1). cyminum, native from East Mediterranean to South Asia belonging Black seed (also known as black cumin; Nigella sativa) (Figure 1) to the family Apiaceae—a member of the parsley family. Cumin seeds is an annual flowering plant belonging to the family Ranunculaceae are oblong and yellow–grey. Cumin seeds are liberally used in several and is a native of Southern Europe, North Africa, and Southwest Asia. cuisines of many different food cultures since ancient times, in both Black cumin is cultivated in the Middle Eastern Mediterranean region, whole and ground forms. In India, cumin seeds have been used for Southern Europe, Northern India, Pakistan, Syria, Turkey, Iran, and thousands of years as a traditional ingredient of innumerable dishes Saudi Arabia. Nigella sativa seeds and their oil have a long history of including kormas and soups and also form an ingredient of several folklore usage in Indian and Arabian civilization as food and medicine other spice blends. Besides food use, it has also many applications in © The Author(s) 2018. Published by Oxford University Press on behalf of Zhejiang University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact jour- nals.permissions@oup.com Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 2 K. Srinivasan, 2018, Vol. 2, No. 1 Figure 1 Different varieties of cumin. Figure 2. Major bioactive compounds of cumin and black seeds. Figure 3. Multiple medicinal properties of Cuminum cyminum (cumin seeds). (Yarnell and Abascal, 2011). The seeds of N. sativa have a pungent bit- Bunium persicum (occasionally referred to as Cuminum nigrum; ter taste and aroma and are used as a spice in Indian and extensively in also known as Shahi jeera), belonging to Apiaceae (parsley family), Middle Eastern cuisines. The dry-roasted nigella seeds flavour curries, is a smaller variety of cumin with a different flavour, popularly used vegetables, and pulses. Black seeds are used in food as a flavouring in North Indian, Pakistani, and Iranian foods (Figure 1). Until now, additive in breads and pickles. It is also used as an ingredient of the there is only very little scientific information on this spice. spice mixture (panch phoron) and also independently of many recipes in Bengali cuisine. Cumin was traditionally used as a preservative in Chemical constituents mummification in the ancient Egyptian civilization. Black cumin has a long history of use as medicine in the Indian traditional system of medi- Cumin seeds are nutritionally rich; they provide high amounts of fat cine like Unani and Ayurveda (Sharma et al., 2005). The black cumin (especially monounsaturated fat), protein, and dietary fibre. Vitamins seeds have traditionally been used in the Southeast Asian and Middle B and E and several dietary minerals, especially iron, are also con- East countries for the treatment of diseases such as asthma, bron- siderable in cumin seeds. Cuminaldehyde (Figure 2), cymene, and chitis, rheumatism, and other inflammatory diseases. Nigella sativa terpenoids are the major volatile components of cumin (Bettaieb has extensively been used because of its therapeutic potential and pos- et al., 2011). Cumin has a distinctive strong flavour. Its warm aroma sesses a wide spectrum of activities, namely, diuretic, antihypertensive, is due to its essential oil content. Its main constituent of aroma com- antidiabetic, anticancer, immune-modulatory, antimicrobial, anthel- pounds are cuminaldehyde and cuminic alcohol. Other important mintic, analgesic and anti-inflammatory, spasmolytic, bronchodilator, aroma compounds of roasted cumin are the substituted pyrazines, gastroprotective, hepatoprotective, and renal protective properties. 2-ethoxy-3-isopropylpyrazine, 2-methoxy-3-sec-butylpyrazine, and Traditionally, seeds of N. sativa are widely used for asthma, diabetes, 2-methoxy-3-methylpyrazine. Other components include γ-terpinene, hypertension, fever, inflammation, bronchitis, dizziness, rheumatism, safranal, p-cymene, and β-pinene (Li and Jiang, 2004). skin disorders, and gastrointestinal disturbances (Table 1). It is also Nigella sativa seeds contain protein (26.7%), fat (28.5%), carbohy- used as a liver tonic, digestive, antidiarrhoeal, emmenagogue, and to drates (24.9%), crude fibre (8.4%), and total ash (4.8%). Nigella sativa control parasitic infections and boost immune system (Goreja, 2003). seeds also contain a good amount of various vitamins and minerals Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 3 Figure 4. Multiple medicinal properties of Nigella sativa (black cumin seeds). like Cu, P, Zn, and Fe. Many active compounds have been identified in whether they have any stimulatory effect on the digestive enzymes. N. sativa. The most important active compounds of N. sativa are thy- The influence of cumin seeds on the digestive enzymes of the rat pan- moquinone (TQ) (30%–48%) (Figure 2), thymohydroquinone, dithy- creas and intestinal mucosa has particularly been investigated as a moquinone (nigellone), p-cymene (7%–15%), carvacrol (6%–12%), result of both continuous dietary intake and single oral administra- 4-terpineol (2%–7%), t-anethole (1%–4%), sesquiterpene longifolene tion (Platel and Srinivasan, 1996; 2000a) (Table 2). Dietary (1.25%) (1%–8%), α-pinene, and thymol. (Boskabady and Shirmohammadi, cumin lowered the activity of pancreatic lipase, whereas the activities 2002; Ali and Blunden, 2003). Nigella sativa also contains other com- of pancreatic trypsin, chymotrypsin, and amylase were significantly pounds such as carvone, limonene, citronellol in trace amounts, and enhanced by the same (Platel and Srinivasan, 2000a). When given as a two varieties of alkaloids, i.e. isoquinoline alkaloids (e.g. nigellicimine single oral dose, cumin exerted a lowering effect on pancreatic lipase, and nigellicimine-N-oxide) and pyrazole alkaloids (e.g. nigellidine amylase, trypsin, and chymotrypsin. Among the terminal digestive and nigellicine). Nigella sativa seeds also contain α-hederin, a water enzymes, a small intestinal maltase activity was significantly higher in soluble pentacyclic triterpene (Al-Jassir, 1992; Nickavar et al., 2003). animals fed with cumin, whereas lactase and sucrose were unaffected The pharmacological properties of N.  sativa are mainly attributable (Platel and Srinivasan, 1996). to its quinine constituents, TQ being the most abundant. The N. sativa Dietary cumin had a significant stimulatory effect on bile flow seeds contain fatty oil rich in unsaturated fatty acids, constituting lino- rate, the extent of increase in bile volume being 25 per cent, whereas leic acid (50%–60%), oleic acid (20%), eicosadienoic acid (3%), and its single oral dose did not have any effect on bile secretion rate dihomolinoleic acid (10%), and saturated fatty acids (palmitic and (Platel and Srinivasan, 2000b). Dietary intake of cumin had a pro- stearic acids) constitute up to 30 per cent. α-Sitosterol is the major found influence on bile acid output (quantity secreted per unit time), sterol, accounting for 44%–54% of the total sterols in N. sativa oils, bile acid secretion being as high as 70 per cent over the control. followed by stigmasterol (6.57%–20.9% of total sterols) (Cheikh- Similar significant increases in bile acid secretion were seen in the Rouhou et al., 2008; Mehta et al., 2008). case of cumin when administered as a single oral dose. Since bile Bitter cumin (Shahi jeera) seeds contain calcium, vitamin A, po- juice makes a significant contribution to the overall process of diges- tassium, sodium, iron, magnesium, and phosphorus. Bitter cumin tion and absorption, essentially by supplying bile acids required for (B.  persicum) has 0.5 to 1.6 per cent essential oil, mainly carvone micelle formation, it is expected that cumin, which has a digestive (45%–60%), limonene, and p-cymene. Oleoresin of bitter cumin is stimulant action, could do so by stimulating biliary secretion of brownish to yellowish green. As there is not enough scientific infor - bile acids. mation on the health effects of bitter cumin, this review is limited Another study has examined whether this digestive stimulant to C.  cyminum (cumin seeds) and N.  sativa (black seeds or black spice cumin also affects the duration of residence of food in the cumin) gastrointestinal tract of experimental rats (Platel and Srinivasan, 2001). Cumin produced a significant shortening of the food transit time by 25 per cent. The reduction in food transit time produced by Health effects of C. cyminum dietary cumin roughly correlates with their beneficial influence either on digestive enzymes or bile secretion. Although the seeds of cumin (C. cyminum L.) are widely used as the spice for their distinctive aroma, they are also commonly used in traditional medicine to treat a variety of diseases, including chronic Antidiabetic effects diarrhoea and dyspepsia, acute gastritis, diabetes, and cancer. The The antidiabetic effect of cumin seeds has been reported in human literature presents ample evidence for the biological and biomedical diabetics (Karnick, 1991) (Table 2). In this study, 80 patients with activities of cumin, which have generally been ascribed to its bio- non-insulin dependent diabetes mellitus were orally administered for active constituents such as terpenes, phenols, and flavonoids (Mnif 24 weeks with an Ayurvedic formulation containing C.  cyminum. and Aifa, 2015). Those health effects of cumin seeds that are experi- Fasting and post-prandial blood sugar at 6-week intervals was mentally validated (Figure 3) are discussed below. significantly reduced in all the patients. Dietary cumin seeds were observed to alleviate diabetes-related metabolic abnormalities in Digestive stimulant action STZ-diabetic rats (Willatgamuwa et  al., 1998). An 8-week dietary In the context of cumin seeds being claimed in home remedies and regimen containing cumin powder (1.25%) was found to be remark- traditional medicine, to aid digestion, an animal study has examined ably beneficial, as indicated by a reduction in hyperglycaemia and Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 4 K. Srinivasan, 2018, Vol. 2, No. 1 Table 1. Differences between seed spices closely related to cumin seeds. Common name of Cumin Black cumin (Nigella/kalonji) Bitter cumin (Kashmiri jeera/ Shahi jeera) the spice Scientific name Cuminum cyminum Nigella sativa Cuminum nigrum or Bunium persicum Genus/family Cuminum/Apiaceae (member of Nigella/Ranunculaceae Cuminum/Apiaceae Parsley family) Native of countries East Meditaranian to South Asia. South to Southwest Asia. Middle Eastern Central Asia to Northern India. growing Now mostly grown in Pakistan, India, Mediterranean region, South Europe, Mountainous regions of North India Uzbekistan Iran, Turkey, Morocco, Northern India, Pakistan, Syria, Turkey, Egypt, Syria, Chile, Mexico, and China Iran, and Saudi Arabia Traditional uses Both whole and ground seeds are used A spice in Indian and Middle Eastern A spice in Northern Indian cookery, often in the cuisines of many cultures for cuisines. In the ancient Egypt, it was the Moghul cooking ages. It has also many uses in trad- used as a preservative in mummification. itional medicine. They are used in Traditionally, it is used for asthma, dia- chronic diarrhoea and dyspepsia betes, hypertension, fever, inflammation, bronchitis, dizziness, eczema, and gastro- intestinal disturbances Main constituents Cuminaldehyde Thymoquinone Cuminaldehyde, p-mentha-1,3-dien-7-al and p-mentha-1,4-dien-7-al Table 2. Digestive stimulant and antidiabetic effects of Cumin seeds. Model/system Effect observed Researcher Digestive stimulant action Wistar rats Dietary 1.25% cumin for 8 weeks significantly enhanced the activities of Platel and Srinivasan, 2000a pancreatic trypsin, chymotrypsin, and amylase Wistar rats Dietary 1.25% cumin for 8 weeks significantly enhanced the small Platel and Srinivasan, 1996 intestinal maltase activity Wistar rats Dietary 1.25% cumin for 8 weeks had a significant stimulatory effect on Platel and Srinivasan, 2000b bile flow rate and bile acid secretion Wistar rats Dietary 1.25% cumin for 8 weeks reduced gastrointestinal food Platel and Srinivasan, 2001 transit time Antidiabetic action Human NIDDM subjects Fasting and post-prandial blood sugar was reduced when a formulation Karnick, 1991 consisting cumin was orally administered for 24 weeks STZ-diabetic rats Dietary cumin seeds for 8 weeks were observed to alleviate Willatgamuwa et al., 1998 diabetes-related metabolic abnormalities Alloxan-diabetic rats Hyperlipidemia associated with diabetes mellitus was also effectively Dandapani et al., 2002 countered by dietary cumin Alloxan-diabetic rabbits Cuminum nigrum seeds or their methanol/water extracts were found to be Akhtar and Ali, 1985 hypoglycemic Alloxan-diabetic rabbits The antihyperglycemic influence of Cuminum nigrum was produced by the Ahmad et al., 2000 fraction containing flavonoid compounds Normal rabbits Oral administration of C. cyminum decreased the area under the glucose Roman-Ramos et al., 1995 tolerance curve and the hyperglycemic peak. STZ-diabetic rats Methanolic extract of C. cyminum treated for 4 weeks mitigated oxidative Jagtap and Patil, 2010 stress and formation of AGEs Sprague-Dawley rats Cuminaldehyde isolated from C. cuminum inhibited lens aldose reductase Lee, 2005 and α-glucosidase of rats glucosuria. Hyperlipidemia associated with diabetes mellitus was glibenclamide (Jagtap and Patil, 2010). In vitro studies indicated that also effectively countered by dietary cumin in alloxan-diabetic rats cumin inhibited free radicals and AGE formation. The antidiabetic (Dandapani et al., 2002). effect of cumin (treated for 4 weeks) was comparable to glibencla- Cuminum nigrum seeds or their water or methanol extracts mide and even better in controlling oxidative stress and AGE forma- have been observed to be hypoglycemic in alloxan-diabetic rab- tion, which is implicated in pathogenesis of diabetic microvascular bits (Akhtar and Ali, 1985). The antihyperglycemic influence of complications. The inhibitory activity of C. cyminum seed–isolated C. nigrum has been attributed to the flavonoid compounds present component cuminaldehyde has been evaluated against lens aldose in these seeds (Roman-Ramos et  al., 1995; Ahmad et  al., 2000). reductase and α-glucosidase isolated from Sprague-Dawley rats and Methanolic extract of C.  cyminum has been investigated in strep- compared with that of quercetin as an aldose reductase inhibitor and tozotocin-diabetic rats on diabetes, oxidative stress, and forma- acarbose as an α-glucosidase inhibitor (Lee, 2005). Cuminaldehyde tion of advanced glycated end products (AGE) in comparison with was about 1.8 and 1.6 times less in inhibitory activity than acarbose Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 5 Table 3. Cardioprotective, anti-inflammatory, and chemopreventive effects of cumin seeds. Model/system Effect observed Researcher Cardioprotective influence Rat Orally administered aqueous cumin extract (200 mg/kg body for 9 weeks) Kalaivani et al., 2013 improved plasma nitric oxide and decreased the systolic blood pressure in hypertensive rats. Patients with Cumin extract significantly decreased the level of oxLDL while increasing the Samani and Farrokhi, 2014 hypercholesterolemia activities of paraoxonase, and arylesterase activities were increased in serum Anti-inflammatory effect LPS-stimulated RAW 264.7 cells Cumin essential oil exerted anti-inflammatory effects via inhibition of Wei et al., 2015 NF-κB and mitogen-activated protein kinases ERK and JNK Chemopreventive effect Mice Dietary 2.5 and 5.0% cumin alleviated benzo(α)pyrene-induced Gagandeep et al. 2003 forestomach tumourigenesis and 3-MCA-induced uterine cervix tumorigenesis, attributable to its ability to modulate carcinogen metabolism Rat Dietary cumin (1.25% for 32 weeks) suppressed DMH-induced colon Nalini et al., 2006 carcinogenesis. The excretion of fecal bile acids and neutral sterols was increased. HT29 colon cancer cells Spent cumin from Ayurvedic industry was effective in arresting the cell cycle Arun et al., 2016 and inducing apoptosis Miscellaneous nutraceutical effects PC12 cells C. cyminum essential oil inhibited the fibrillation of α-synuclein Morshedi et al., 2015 suggesting neuroprotective effects Rat Aqueous extract of cumin seeds showed anti-diarrhoeal effect when induced Sahoo et al., 2014 with castor oil and quercetin, respectively. Nonetheless, cuminaldehyde may be use- while increasing the activities of paraoxonase, and arylesterase activi- ful for antidiabetic therapeutics. ties were increased in serum (Samani and Farrokhi, 2014). The effect of cumin added to normal and hypercholesterolemia inducing diet on serum and liver cholesterol levels in rats has been studied (Sambaiah Anti-inflammatory effects and Srinivasan, 1991). Dietary cumin did not show any cholesterol Cumin essential oil was investigated for the anti-inflammatory effects lowering effect when included in the diet (1.25%) at about 5-fold the in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the normal consumption level. underlying mechanisms (Wei et al., 2015) (Table 3). Volatile constitu- ents were identified in essential oil using Gas Chromatography - Mass Spectrometry (GC-MS), the most abundant constituent being cumi- Chemopreventive effects naldehyde (48.8%). Cumin oil exerted anti-inflammatory effects in Cancer chemopreventive potentials of dietary 2.5 and 5.0 per cent LPS-stimulated RAW cells through inhibiting NF-κB and mitogen- cumin were evaluated against benzo(α)pyrene-induced tumorigenesis activated protein kinases suggesting its potential as an anti-inflam- in forestomach and 3-methylcholanthrene (MCA)-induced tumorigen- matory agent. esis in uterine cervix in mice (Gagandeep et al., 2003) (Table 3). Cumin produced a significant inhibition of stomach tumour. The effect on car - Cardio-protective influence through hypolipidemic cinogen/xenobiotic metabolizing phase I and phase II enzymes, antioxi- and hypotensive effects dant enzymes, and lipid peroxidation in the liver was also examined. Cuminum cyminum is traditionally used for the treatment of indigestion Cytochrome P and cytochrome b were significantly augmented by 450 5 and hypertension. The anti-hypertensive potential of aqueous extract dietary cumin. The phase II enzyme glutathione-S-transferase (GST) of cumin seed and its role in arterial–endothelial nitric oxide synthase was increased by cumin, whereas the specific activities of superoxide expression, inflammation, and oxidative stress have been evaluated in dismutase (SOD) and catalase were significantly elevated. Lipid peroxi- renal hypertensive rats (Kalaivani et al., 2013) (Table 3). Cumin admin- dation was inhibited by cumin, suggesting that the cancer chemopre- istered orally (200 mg/kg body) for 9 weeks improved plasma nitric ventive potential of cumin could be attributed to its ability to modulate oxide and reduced the systolic blood pressure in hypertensive rats. This carcinogen metabolism. was accompanied by the up-regulation of the expression of inducible The effect of cumin (C. cyminum; dietary 1.25% for 32 weeks) nitric oxide synthase (iNOS), Bcl-2, TRX1, and TRXR1 and down- was studied on colon cancer induced in rats by 1,2-dimethylhydrazine regulation of the expression of Bax, TNF-α, and IL-6. These data sug- (DMH) s.c. 20 mg/kg of body weight (15 doses, at weekly intervals) gest that cumin seeds augment endothelial functions and ameliorate (Nalini et al., 2006). Results showed that cumin suppresses colon car- inflammatory and oxidative stress in hypertensive rats. cinogenesis in the presence of the procarcinogen DMH. The excretion Paraoxanase-1 plays a protective role against the oxidative modi- of fecal bile acids and neutral sterols was significantly increased in fication of plasma lipoproteins and hydrolyzes lipid peroxides in cumin+DMH-administered rats. Cholesterol and 3-hydroxy-3-meth- human atherosclerotic lesions. Flavonoids present in cumin seeds ylglutaryl-CoA reductase activity were decreased in cumin+DMH- are recognized to have antioxidant activity and improve the antioxi- treated rats. Spent cumin generated from Ayurvedic industry was dant system. A study demonstrated that cumin extract significantly evaluated for its nutraceutical potential in terms of antioxidant (in decreased the level of oxidized Low-density lipoprotein (OxLDL) terms of scavenging 2,2-Diphenyl-1-picryl-hydrazyl-hydrate [DPPH] Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6 K. Srinivasan, 2018, Vol. 2, No. 1 Table 4. Antidiabetic effects of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher STZ-diabetic rats The oil of N. sativa significantly lowered blood glucose in STZ-diabetic El-Dakhakhny et al., 2002 rats after 2, 4, and 6 weeks Rat pancreatic islets Defatted extract of N. sativa seed increased glucose induced insulin re- Rchid et al., 2004 lease from isolated rat pancreatic islets in vitro STZ/NA-diabetic hamsters N. sativa oil treatment for 4 weeks decreased blood glucose and Fararh et al., 2002 increased serum insulin STZ-diabetic hamsters The hypoglycemic effect of N. sativa oil (400 mg/kg by p.o.) is partially Fararh et al., 2004 due to a decrease in hepatic gluconeogenesis Hepatocytes (HepG2) Defatted extract of N. sativa seeds increased glucose consumption by Yuan et al., 2014 hepatocytes (HepG2) in vitro through activation of AMPK Diabetic rabbits N. sativa extract (orally for 2 months) decreased lipid peroxidation and Meral et al., 2001 increased antioxidant defense system STZ-diabetic rats Daily oral administration of ethanol extract of N. sativa seeds Kaleem et al., 2006 (300 mg/kg for 30 days) reduced hyperglycemia and improved altered levels of lipid peroxidation products and antioxidant enzymes in liver and kidney STZ-diabetic rats N. sativa oil (0.2 ml/kg for 30 days) decreased hyperglycemia and Kanter et al., 2003 restored lowered serum insulin with partial regeneration of pancreatic β-cells STZ-diabetic rats N. sativa treatment exerts a protective effect on diabetes by decreasing Kanter et al., 2004 oxidative stress and preserving pancreatic β-cell integrity STZ-diabetic rats fed with Daily administration of N. sativa oil significantly induced the gene ex- Balbaa et al., 2016 high-fat diet pression of insulin receptor and upregulated the expression of insulin-like growth factor-1 STZ-diabetic rats N. sativa seed oil down-regulated the expression of apoptotic markers Cüce et al., 2015 in the aortic medial layer of diabetic rats, thus preventing apoptosis in vascular structures STZ-diabetic rats Protective effects of N. sativa oil on insulin sensitivity and ultrastructural Kanter et al., 2009 changes of pancreatic β-cells STZ-diabetic rats N. sativa extract, oil, and TQ decreased the diabetes-induced lipid Abdelmeguid et al., 2010 peroxides and hyperglycemia, and significantly increased serum insulin and SOD activity in tissues STZ-NA–induced diabetic rats Oral administration of TQ dose-dependently improved the glycemic Pari and Sankaranarayanan, 2009 status; levels of insulin and Hb increased; altered activities of carbohydrate metabolizing enzymes were restored Patients with diabetes N. sativa oil showed a beneficial effect on various clinical and Najmi et al., 2008 biochemical parameters of the insulin resistance syndrome Patients with type 2 diabetes N. sativa (2 g/day) brought reductions in fasting blood glucose, post- Bamosa et al., 2010 prandially, and glycosylated haemoglobin. radical), antidiabetic (in terms of better α-amylase inhibition and abundant natural compound, cuminaldehyde can modulate α-SN glucose uptake activity in L6 cells), and anticancer properties (in fibrillation, suggesting that such natural active aldehyde could have terms of arresting the cell cycle and inducing apoptosis in HT29 potential therapeutic applications (Morshedi et al., 2015). colon cancer cells) and compared with that of the raw cumin (Arun et al., 2016). The results suggested that nutraceutical food formula- Health effects of N. sativa tion made out of spent cumin could play a major role in the preven- tion or management of degenerative diseases. Black cumin (N.  sativa) has been in use in traditional systems of medicine for various medical disorders. Nigella sativa is used in Moroccan folk medicine for the treatment of diabetes mellitus. Miscellaneous nutraceutical effects Many pre-clinical and clinical trials have investigated its efficacy, Cumin seeds are traditionally used for the treatment of diarrhoea. using the seed oil, essential oil, and its isolated main constituent TQ The aqueous extract of cumin seeds (100, 250, and 500 mg/kg) has (Ali and Blunden, 2003). These investigations provide preliminary been examined against diarrhoea in albino rats induced with castor support for its use in asthma, allergic rhinitis, and atopic dermatitis oil (Sahoo et  al., 2014). The extract showed significant inhibition (Yarnell and Abascal, 2011). Black cumin might help in dyspepsia, in the frequency of diarrhoea, delaying the defecation time, secre- respiratory problems, diabetes mellitus, and metabolic syndrome tion of intestinal fluid, and intestinal propulsion in a dose-dependent (Yarnell and Abascal, 2011). A  meta-analysis of clinical trials sug- manner. Fibrillation of α-synuclein (α-SN) is a critical process in the gests that N. sativa has a short-term benefit in lowering systolic and pathophysiology of several neurodegenerative diseases, especially diastolic blood pressure, and its various extracts can reduce triglyc- Parkinson’s disease. A study on the inhibitory effects of C. cyminum erides, LDL, and total cholesterol (Sahebkar et al., 2016a; 2016b). essential oil on the fibrillation of α-SN indicated that the small Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 7 Table 5. Anti-cancer effects of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher Mice—B()P-induced forestomach cancer N. sativa extract ameliorated benz(a-)pyrene-induced carcinogenesis in Aruna and Sivarama-krishnan, the forestomach 1990 Rat—DMH-induced colon cancer Orally administered N.sativa oil (14 weeks) reduced the induction and Salim and Fukushima, 2003 development of 1,2-dimethylhydrazine-induced aberrant crypt foci (ACF), putative preneoplastic lesions for colon cancer Rats—gastric ulcer induced by necrotiz- N. sativa aqueous suspension significantly ameliorated the ulcer severity Al Mofleh et al., 2008 ing agents and basal gastric acid secretion. The anti-ulcer effect is possibly prosta- glandin- mediated and/or through its antioxidant and anti-secretory activities Wistar rats—colon cancer induced with 1000 or 4000 ppm N. sativa volatile oil in the diet for 30 weeks signifi- Salim, 2010 carcinogens cantly reduced malignant and benign colon tumour sizes, incidences and multiplicities Rats—colitis induced with TNBS Oral N. sativa oil, by preventing inflammatory status in the blood, partly Isik et al., 2011 protected colonic tissue against experimental ulcerative colitis Rat—DMBA-induced breast cancer Orally administered (1—10 mg/kg) N. sativa oil or thymoquinone thrice Linjawi et al., 2015 in a week for 4 months exerted a protective effect against DMBA-induced breast cancer Children with acute lymphoblastic Black cumin seeds (80 mg/kg/day for 1 week) decreased methotrexane Hagag et al., 2015 leukaemia hepatotoxicity and improved survival in children with leukaemia Cancer cells Thymoquinone suppressed tumour cell proliferation in colorectal Gali-Muhtasib et al., 2006 carcinoma, breast adenocarcinoma, osteosarcoma, ovarian carcinoma, myeloblastic leukaemia, and pancreatic carcinoma Cancer cells TQ suppressed tumor cell proliferation in the case of breast adenocar- Allahghadri et al., 2010 cinoma, pancreatic carcinoma, colorectal carcinoma, ovarian carcinoma, osteosarcoma, and myeloblastic leukaemia Prostate cancer (PC-3) cell TQ is shown to prevent tumour angiogenesis in a xenograft human Yi et al., 2008 cancer model MCF-7 cells N. sativa lipid extract and aqueous extract exhibited cytotoxicity to Mahmoud and Torchilin, 2012 MCF-7 cells with LC of 2.7 and 50 mg/ml Human cervical squamous carcinoma TQ was with IC values of 10.7 µg/ml; elimination of SiHa cells via Ng et al., 2011 cells (SiHa) apoptosis with down-regulation of the Bcl-2 protein Human osteosarcoma cell line SaOS-2 Anti-tumour and anti-angiogenic activity of TQ possibly mediated by an Peng et al., 2013 inhibition of NF-κB and downstream effector molecules Breast cancer MDA-MB-231 cells TQ exerted a strong anti-proliferative effect on breast cancer cells via its Woo et al. 2011 potential effect on the PPAR-γ activation pathway; migration and invasion were also reduced Pancreatic cancer cells Treatment with TQ down-regulated MUC4 expression and induced Torres et al., 2010 apoptosis; increased apoptosis, decreased motility, and decreased migration of pancreatic cancer cells Panc-1 cells TQ dose-dependently suppressed the migration and invasion of panc-1 Wu et al., 2011 cells by down-regulating NF-kB and MMP-9 PC-3 cells Administration of N. sativa reduced the carcinogenic effects of DMBA in Shafi et al., 2008 mammary carcinoma Gastric cancer cells Pre-treatment with TQ significantly increased the apoptotic effects Lei et al., 2012 induced by 5-FU in gastric cancer cell lines in vitro Several studies made in the last decades validate its health benefi- vitro in rat pancreatic islets in the presence of glucose (8.3 mmol/l). cial effects particularly in diabetes, dyslipidemia, hypertension, and Results showed that the antidiabetic properties of N.  sativa seeds obesity. A  systematic review of all human trials has revealed that may partially be mediated by the stimulation of insulin release, espe- N. sativa supplementation might be effective in glycemic control in cially by the basic subfraction of the seed. The possible insulinotropic humans (Mohtashami and Entezari, 2016). property of N.  sativa oil has also been studied in STZ plus nico- tinamide (NA) induced diabetes mellitus in hamsters. Nigella sativa oil treatment for four weeks decreased blood glucose and increased Antidiabetic effects serum insulin (Fararh et  al., 2002). Immunohistochemical staining Nigella sativa seeds are traditionally used in the management of dia- revealed the presence of insulin in the pancreas from N.  sativa oil- betes mellitus in indigenous systems of medicine and folk remedies. treated group, suggesting that the hypoglycemic effect results, at Defatted extract of N.  sativa seed is reported to increase glucose- least partly, from a stimulatory effect on β-cell function. induced insulin release from isolated rat pancreatic islets in vitro The oil of N. sativa significantly lowered blood glucose in STZ- (Rchid et al., 2004) (Table 4). The effect of N. sativa extracts (defatted diabetic rats after 2, 4, and 6 weeks (El-Dakhakhny et  al., 2002). fractions either containing acidic and neutral compounds or contain- A study of the effect of N.  sativa oil on insulin secretion from iso- ing basic compounds) have been investigated on insulin secretion in lated rat pancreatic islets in the presence of glucose indicated that its Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 8 K. Srinivasan, 2018, Vol. 2, No. 1 Table 6. Anti-inflammatory/analgesic effects and immunomodulatory property of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher Anti-inflammatory property and analgesic activity Rats N. sativa essential oil produced a significant analgesic effect on acetic Hajhashemi et al., 2004 acid-induced writhing, formalin, and light tail flick tests Rats Intraperitoneal injection of N. sativa oil from 100 to 400 µl/kg significantly Hajhashemi et al., 2004 inhibited carrageenan-induced paw oedema BV-2 murine microglia cells TQ showed an effective anti-inflammatory effect on LPS-stimulated Taka et al., 2015 microglial cells Human trials Anti-osteoporotic effects of N. sativa and TQ are evidenced by observing in- Shuid et al., 2012 hibition of inflammatory cytokines (interleukin-1 and 6) and the transcription factor (NFκB) Pancreatic ductal adenocar- TQ inhibited proliferation in these cells by inhibiting proinflammatory Chehl et al., 2009 cinoma (PDA) cells pathways; this anti-inflammatory potential involved modulation of the ex- pression of different pro-inflammatory cytokines and chemokines Rats Oral administration of TQ (5 mg/kg body/day for 21 days) showed Umar et al., 2012 anti-arthritic activity by significantly reducing pro-inflammatory mediators Immunomodulatory action BALB/c mice and C57/BL6 Aqueous extract of N. sativa significantly enhanced the total white blood Ghonime et al., 2011 primary cells cells count and increased spleen weight in BALB/c mice and enhanced splenocyte proliferation Long-Evans rat Treatment with N. sativa oil significantly decreased the antibody production Torres et al., 2010 in response to typhoid vaccination Pigeons Co-administration of N. sativa (2.5%) with oxytetracycline (OXT) Abel-Salam, 2012 completely blocked the decreasing effects on total leukocyte and lymphocyte counts elicited by OXT and produced immunostimulant effects Rats N. sativa oil showed a promising radioprotective action against Assayed, 2010 immunosuppressive and oxidative effects of γ-radiation Mice N. sativa seed extract significantly improved symptoms and immune Duncker et al. 2012 parameters in murine OVA-induced allergic diarrhoea hypoglycemic effect might be mediated by extra-pancreatic actions Nigella sativa oil administration (daily) to STZ-induced diabetic rather than by stimulation of insulin release. The hypoglycemic rats maintained on a high-fat diet significantly induced the gene effect of N. sativa oil (400 mg/kg by p.o.) is partly due to decreased expression of insulin receptor (Balbaa et  al., 2016). Nigella sativa hepatic gluconeogenesis (Fararh et al., 2004). Indazole-type alkaloid oil upregulated the expression of IGF-1 and phosphoinositide-3 kin- 17-O-(β-D-glucopyranosyl)-4-O-methyl nigellidine present in the ase, whereas the expression of ADAM-17 was downregulated. Also, defatted extract of N.  sativa seeds increased glucose consumption the N.  sativa oil significantly reduced blood glucose level, individ- by hepatocytes (HepG2 cells) in vitro through activation of AMP- ual lipid profile, oxidative stress markers, serum insulin or insulin activated protein kinase (AMPK) (Yuan et al., 2014). receptor ratio, and the TNF-α, confirming that N.  sativa oil has an Nigella sativa extract given orally for 2 months decreased lipid antidiabetic activity. Thus, the daily N. sativa oil treatment improves peroxidation and increased antioxidant defence system and also insulin-induced signalling. prevented the lipid peroxidation-induced liver damage in diabetic Hyperglycaemia is an important risk factor for the development rabbits (Meral et  al., 2001). Daily oral administration of ethanol and progression of the macrovascular and microvascular complica- extract of N.  sativa seeds (300  mg/kg) to STZ-diabetic rats for tions that occur in diabetes. The expression of apoptotic markers in 30 days reduced the elevated levels of blood glucose, lipids, plasma the medial aortic layer of diabetic rats and the effects of N.  sativa insulin, and improved altered levels of lipid peroxidation products seed oil on the expression of these markers have been investigated and antioxidant enzymes in liver and kidney (Kaleem et al., 2006). (Cüce et al., 2015). It is understood that N. sativa seed oil is effective This suggested that in addition to antidiabetic activity, N.  sativa against diabetes and merits further treatment strategies for prevent- seeds may control diabetic complications through antioxidant ing apoptosis in vascular structures. effects. Treatment of N.  sativa oil (0.2  ml/kg, i.p.) for 30  days Treatment of streptozotocin-diabetic rats with N. sativa extract, decreased the elevation in serum glucose and restored lowered N.  sativa oil, and TQ, significantly decreased the diabetes-induced serum insulin with partial regeneration or proliferation of pancre- lipid peroxides and hyperglycemia, and significantly increased atic β-cells in STZ-diabetic rats (Kanter et al., 2003). The possible serum insulin and SOD activity in tissues. Nigella sativa oil and protective effects of N. sativa (0.2 ml/kg, i.p.) against β-cell damage TQ have therapeutic potential and are protective against STZ- from STZ-diabetes in rats have been evidenced by the observed diabetes by decreasing oxidative stress, thus preserving pancreatic decrease in lipid peroxidation and serum nitric oxide and increase β-cell integrity, leading to increased insulin levels (Abdelmeguid in the activities of antioxidant enzymes in the pancreas (Kanter et al., 2010). The protective effects of N. sativa oil on insulin sen- et  al., 2004). Increased staining for insulin and preservation of sitivity and ultrastructural changes of pancreatic β-cells in STZ- β-cell numbers were evident in N.  sativa–treated diabetic rats. induced diabetic rats are reported (Kanter et al., 2009). It is evident This suggests that N. sativa treatment exerts a protective effect on that N.  sativa treatment exerts a protective effect on diabetes by diabetes by decreasing oxidative stress and preserving pancreatic decreasing morphological changes and preserving the pancre- β-cell integrity. atic β-cell integrity (Kanter et  al., 2009). The anti-hyperglycemic Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 9 Table 7. Gastroprotectove, hepatoprotective, nephroprotective, and pulmonary-protective effects of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher Gastroprotective effect Rats N. sativa (2.5 and 5.0 ml/kg)/TQ administration (10, 20, 50, and El-Abhar et al., 2003 and 100 mg/kg) exerted gastro-protection when subjected to Magdy et al., 2012 ischemia/reperfusion insult Rats Anti-ulcer potential of N. sativa aqueous suspension on experimentally Al Mofleh et al., 2008 induced gastric ulcers (with various necrotizing chemicals) has been evidenced Hypothyroidal rats N. sativa and TQ protect gastric mucosa against the ulcerating effect of Khaled, 2009 alcohol Newborn Sprague-Dawley rats N. sativa oil (2 ml/kg daily; i.p.) showed beneficial effect in rats with Tayman et al., 2012 necrotizing enterocolitis Mice Treatment with TQ (5–25 mg/kg) ameliorated colonic inflammation in ex- Lei et al., 2012 perimental inflammatory bowel disease (C57BL/6 murine colitis induced with dextran sodium sulfate) Nephroprotective effect Rabbits Nephro-protective effect of N. sativa oil was observed against Saleem et al., 2012 gentamicin-associated nephrotoxicity Rats Protective effect of N. sativa oil against methotrexate-induced Yaman and Balikci, 2010 nephrotoxicity Rats Protective effects of N. sativa oil in the prevention of chronic cyclosporine Uz et al., 2008 A-induced nephrotoxicity by attenuation of the oxidative stress Rats TQ supplementation prevented the development of gentamycin-induced de- Sayed-Ahmed and Nagi, 2007 generative changes in kidney tissues Hepatoprotective effect Rats N. sativa (0.2 ml/kg) relieves the deleterious effects of ischemia-reperfusion Yildiz et al., 2008 injury on the liver Mice Pre-treatment with TQ (10 µmol/l) showed a significant protection on the Zafeer et al., 2012 hepatotoxicity of Cd++ particularly by relieving the depletion of non-enzymatic and enzymatic antioxidants Pulmonary protective effect Wistar rats N. sativa treatment showed beneficial effects on experimental lung injury; Kanter, 2009 inhibited the inflammatory pulmonary responses Rats N. sativa oil significantly reduced the severity of lung damage due to Tayman et al., 2012 hyperoxia Patients with asthma N. sativa (15 ml/kg of 0.1 g% boiled extract for 3 months) significantly Boskabady et al., 2007 alleviated symptoms and frequency of asthma symptoms, chest wheezing, and pulmonary function tests potential of TQ and the effect on the activities of key enzymes of useful adjuvant to oral hypoglycemic drugs in patients with type carbohydrate metabolism in STZ-NA–induced diabetic rats have 2 diabetes mellitus. been evaluated (Pari and Sankaranarayanan, 2009). Oral admin- istration of TQ (20, 40, and 80  mg/kg body weight for 45  days) Ameliorative effects of N. sativa on dyslipidemia dose-dependently improved the glycemic status in STZ/NA-induced Dyslipidemia is an established risk factor for ischemic heart disease. diabetic rats. The levels of insulin and haemoglobin increased along Nigella sativa has been used for the treatment and prevention of hyper- with a decrease in glucose and HbA1c levels. The altered activities lipidemia (Asgary et  al., 2015). Different preparations of N.  sativa of carbohydrate-metabolizing enzymes were also restored (Pari and including seed powder (100 mg–20  g daily), seed oil (20–800  mg Sankaranarayanan, 2009). daily), TQ (3.5–20 mg daily), and methanolic extract reduced plasma In a clinical study, the adjuvant effect of N. sativa oil on vari- levels of total cholesterol, low-density lipoprotein cholesterol, and tri- ous clinical and biochemical parameters of the insulin resistance glycerides. In clinical trials, N. sativa was found to be effective when syndrome in patients with diabetes and dyslipidemia has been evi- added as an adjunct to conventional hypolipidemic and antidiabetic denced (Najmi et  al., 2008). Nigella sativa accentuates glucose- medications. Inhibition of dietary cholesterol absorption, decreased induced secretion of insulin besides negatively affecting glucose hepatic cholesterol synthesis, and up-regulation of LDL receptors absorption. Hence, it is of immense therapeutic benefit in diabetic contribute to lipid-lowering effects of N. sativa. Overall, the evidence individuals (Kapoor, 2009). The effect of N. sativa seeds used as from an experimental and a clinical study suggests that N. sativa seeds an adjuvant therapy in addition to the anti-diabetic medications are promising natural therapy for patients with dyslipidemia. on the glycemic control of patients with type 2 diabetes melli- tus was investigated (Bamosa et  al., 2010). Nigella sativa at a Anti-inflammatory property and analgesic activity dose of 2 g/day caused significant reductions in fasting blood glu- cose, 2-hour post-prandially, and glycosylated haemoglobin. The The antinociceptive and anti-inflammatory effects of TQ ( Table 6), results indicate that a dose of 2 g/day of N. sativa could serve as a supporting the common perception of N. Sativa as a potent analgesic Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 10 K. Srinivasan, 2018, Vol. 2, No. 1 and anti-inflammatory agent, have been recently reviewed (Amin regulation of immune reactions in infectious and non-infectious con- and Hosseinzadeh, 2016). Many protective properties are attributed ditions such as allergy, autoimmunity, and cancer. to radical scavenging activity as well as an interaction with molecu- The potential immunomodulatory effects of aqueous extract of lar targets involved in inflammation (proinflammatory enzymes and N.  sativa investigated in BALB/c mice and C57/BL6 primary cells cytokines). Further investigations are needed to understand the pre- with respect to splenocyte proliferation, macrophage function, and cise mechanisms responsible for the antinociceptive and anti-inflam- anti-tumor activity demonstrated that N. sativa significantly enhances matory effects of its active constituents. splenocyte proliferation in a dose-responsive manner (Ghonime Development of solid tumour malignancies is closely associated et  al., 2011). Aqueous extract of N.  sativa significantly suppressed with inflammation. The steam-distilled essential oil of N.  sativa, the secretion of key proinflammatory mediators (IL-6, TNF-α, and which mainly contains p-cymene (37.3%) and TQ (13.7%), investi- NO) by primary macrophages indicating anti-inflammatory effects gated for its analgesic and antiinflammatory properties in rats was in vitro. Nigella sativa methanolic extract treatment (intraperito- found to produce a significant analgesic effect on acetic acid-induced neal) enhanced the total white blood cells count and increased spleen writhing, formalin, and light tail flick tests (Hajhashemi et  al., weight in BALB/c mice, suggesting the immunomodulatory activity 2004). Intraperitoneal injection of 100, 200, and 400 µl/kg signifi- of N. sativa seeds (Ghonime et al., 2011). Treatment with N. sativa cantly inhibited carrageenan-induced paw oedema. Mechanism(s) oil significantly decreased the antibody production in response to ty- other than opioid receptors are believed to be involved in this an- phoid vaccination (antigen typhoid TH) in a Long-Evans rat model. algesic effect of the Nigella essential oil. Its administration showed These results indicated that the N. sativa seeds could be considered anti-inflammatory activity probably attributable to TQ, one of the as a potential immunosuppressive cytotoxic agent (Torres et  al., major components of black cumin. The anti-inflammatory effect 2010). Co-administration of N.  sativa (2.5%) with oxytetracycline of TQ on LPS-stimulated BV-2 murine microglia cells has been completely blocked the leukocyte and lymphocyte decreasing effects reported, wherein TQ was effective in reducing nitrate with parallel elicited by oxytetracycline and produced immunostimulant effects decline of iNOS protein expression evidenced (Taka et al., 2015). TQ in pigeons indicating an immune-protective effect (Abel-Salam, also reduced LPS-mediated elevation in gene expression of Cxcl10 2012). Nigella sativa oil is also shown to have a promising radio- and some of other cytokines. The anti-inflammatory properties of protective action against immunosuppressive and oxidative effects TQ in LPS-activated microglial cells suggested the applicability of of γ-radiation in rats (Assayed, 2010). Nigella sativa seed extract TQ in delaying the onset of inflammation-mediated neurodegenera- significantly improved symptoms and immune parameters in murine tive disorders. ovalbumin-induced allergic diarrhoea in mice (Duncker et al., 2012). The aqueous extract of N.  sativa has been found to pos- sess anti-inflammatory and analgesic activities in animal models. Antioxidant and antimicrobial activity Although osteoporosis is linked to oxidative stress and inflamma- An evaluation of the essential oil of N.  sativa seeds, for antioxi- tion, the anti-osteoporotic effects of N. sativa and TQ are evidenced dants, showed that TQ and other components (carvacrol, t-anet- by observing the inhibition of inflammatory cytokines (interleukin hole, and 4-terpineol) have a radical scavenging property. These (IL)-1 and 6)  and the transcription factor (NFκB). Both N.  sativa constituents and the essential oil showed variable antioxidant ac- and TQ have shown potential as an anti-osteoporotic agent (Shuid tivity when tested in the diphenylpicrylhydrazyl assay; they also ef- et  al., 2012). TQ induced apoptosis and inhibited proliferation in fectively scavenged OH radical in the assay for non-enzymatic lipid pancreatic ductal adenocarcinoma (PDA) cells. This anti-inflam- peroxidation. matory potential involved an effect on the expression of different TQ has been shown to suppress the ferric nitrilotriacetate- proinflammatory cytokines and chemokines. TQ dose-dependently induced oxidative stress in Wistar rats (Khan and Sultana, 2005). reduced PDA cell synthesis of MCP-1, TNF-α, IL-1β, and Cox-2. Dietary N. sativa seeds inhibited the oxidative stress caused by oxi- TQ as an inhibitor of proinflammatory pathways provides an ef- dized corn oil in rats (Al-Othman et  al., 2006). Dietary N.  sativa fective strategy that combines anti-inflammatory and proapoptotic (10%) neutralized the oxidative stress induced by hepatocarcinogens modes of action (Chehl et al., 2009). A clinical trial was conducted such as dibutylamine and sodium nitrate in albino rats by normal- to investigate the anti-inflammatory effects of N.  sativa in patients izing glutathione and nitric oxide levels (Gendy et  al., 2007). The with allergic rhinitis symptoms. The anti-allergic effects of N. sativa N. sativa seed oil and TQ (intraperitoneal) are shown to have pro- components could be attributed to allergic rhinitis (Nikakhlagh tective effects on lipid peroxidation process during ischemia-reperfu- et  al., 2011). The anti-arthritic activity of orally administered TQ sion injury in rat hippocampus (Hosseinzadeh et al., 2007). Treating (5 mg/kg body once daily for 21 days) in collagen-induced arthritic broiler chicks with N.  sativa seed for 6 weeks reduced the oxida- Wistar rats was evidenced with significantly reduced proinflamma- tive stress in the liver by increasing the activities of myeloperoxi- tory mediators [IL-1β, IL-6, TNF-α, IFN-γ, and PGE ] and increased dase, glutathione-S-transferase, CAT, adenosine deaminase, and by IL-10 (Umar et al., 2012). decreasing hepatic lipid peroxidation (Sogut et  al., 2008). The TQ pre-treatment countered the increased level of lipid peroxidation and Immunomodulatory action augmented the antioxidant enzyme activities in the erythrocyte dur- The immunomodulatory properties of N. sativa and its major active ing 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar ingredient, TQ in terms of their experimentally documented abil- rats (Harzallah et al., 2012). ity to modulate cellular and humoral adaptive immune responses The bioactive compounds of N.  sativa essential oil identified (Table  6) have comprehensively been reviewed (Majdalawieh and using GC and GC-MS included p-cymene, TQ, α-thujene, longi- Fayyad, 2015). The molecular and cellular mechanisms underlying folene, β-pinene, α-pinene, and carvacrol. Nigella sativa essential such immunomodulatory effects of N. sativa and TQ are highlighted, oil exhibited different biological activities including antifungal, and the signal transduction pathways implicated in the immunoreg- antibacterial, and antioxidant potentials. Nigella sativa essential oil ulatory functions are suggested. Experimental evidence suggests that completely inhibited different Gram-negative and Gram-positive N.  sativa extracts and TQ can therapeutically be employed in the bacteria (Morsi, 2000). Nigella sativa oil also exhibited stronger Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 11 radical scavenging activity against DPPḢ radical in comparison with has been explained by its ability to modulate cell division in can- synthetic antioxidants. cer cells, involving downregulation of Bcl-xL, cyclin D1, and VEGF (Aggarwal et al., 2008). TQ is reported to be effective in inhibiting Anti-cancer properties human umbilical vein EC migration and invasion, suggesting its role The anti-cancer effect of N.  sativa has extensively been studied in in angiogenesis (Gali-Muhtasib et al., 2006). TQ is shown to prevent different in vitro and in vivo models (Table 5). Nigella sativa is able tumour angiogenesis in a xenograft human prostate cancer (PC-3) to exert antioxidant, anti-mutagenic, cytotoxic, pro-apoptotic, anti- model (Yi et  al., 2008). Nigella sativa, its oil, and TQ are effect- proliferative, and anti-metastatic effects in various primary cancer ive against cancer in the blood system, lung, kidney, liver, prostate, cells and cancer cell lines (Majdalawieh and Fayyad, 2016). The avail- breast, cervix, and skin. Some studies attribute the anti-cancer effect able studies strongly suggest that N. sativa could serve as an effective of TQ to its role as an antioxidant, ability to improve body’s immune agent to control tumour initiation, growth, and metastasis independ- system, and ability to induce apoptosis and control Akt pathway ently or in combination with conventional chemotherapeutic drugs. (Khan et al., 2011). Nigella sativa extract ameliorated the benz(α-)pyrene- The cytotoxic effects of N.  sativa seed extract as an adjuvant induced carcinogenesis in the forestomach in mice (Aruna and therapy to doxorubicin on human MCF-7 breast cancer cells are Sivaramakrishnan, 1990). This is partly attributed to the ability to reported. Nigella sativa lipid extract was found to be cytotoxic to influence phase II enzymes. Orally administered N.  sativa oil (14 MCF-7 cells with LC of 2.7  mg/ml, whereas its aqueous extract weeks) interfered with the induction of aberrant crypt foci (ACF) exhibited cytotoxicity at about 50 mg/ml (Mahmoud and Torchilin, by 1,2-dimethylhydrazine, putative preneoplastic lesions for colon 2012). TQ was found to be cytotoxic to human cervical squamous cancer in rats (Salim and Fukushima, 2003). This inhibition may be carcinoma cells (SiHa) with IC values of 10.7 µg/ml as determined associated, in part, with the suppression of cell proliferation in the by MTT assay, whereas it was less cytotoxic towards the normal cells. colonic mucosa. Nigella sativa aqueous suspension significantly pre- Cell cycle analysis indicated induction of apoptosis by the compound vented gastric ulcer formation experimentally induced by necrotiz- and elimination of SiHa cells via apoptosis with down-regulation ing agents and also significantly ameliorated the severity of ulcer of the Bcl-2 protein (Ng et  al., 2011). An investigation of the anti- and gastric acid secretion in pylorus-ligated Shay rats (Al Mofleh tumour and anti-angiogenic effects of TQ on osteosarcoma in vitro et al., 2008). and in vivo showed that TQ induced higher growth inhibition and The chemopreventive potential of N.  sativa oil on tumour for- apoptosis in the human osteosarcoma cell line SaOS-2. TQ signifi- mation has been revealed in a study using a rat multiorgan carcino- cantly blocked human umbilical vein endothelial cell tube formation genesis model induced by five different carcinogens (Salim, 2010). in a dose-dependent manner. The anti-tumour and anti-angiogenic Post-initiation administration of 1000 or 4000 ppm N. sativa vola- activity of TQ in osteosarcoma is possibly mediated by inhibition of tile oil in the diet for 30 weeks significantly reduced colon tumour NF-κB and downstream effector molecules (Peng et al., 2013). sizes, incidences, and multiplicities. Nigella sativa volatile oil also TQ exerted a strong anti-proliferative effect in breast cancer cells significantly decreased the incidences and multiplicities of tumours via its potential effect on the PPAR-γ activation pathway, and in in the lungs and alimentary canal (particularly the oesophagus and combination with doxorubicin and 5-fluorouracil, TQ’s cytotoxicity forestomach). Thus, N.  sativa exerts potential inhibitory effects on was found to be increased. Migration and invasion of MDA-MB-231 tumour development in multiple organ sites (Salim, 2010). Nigella cells were also reduced by TQ, which was found to increase PPAR-γ sativa oil (orally administered for 3 days) decreased the proinflam- activity and down-regulate the expression of Bcl-2, Bcl-xL, and sur- matory cytokines (TNF-α, IL-1β, and IL-6) in the blood of rats with vivin in breast cancer cells (Woo et  al., 2011). An investigation of experimental colitis induced with trinitrobenzene sulfonic acid (Isik the effect of TQ on pancreatic cancer cells and on MUC4 expres- et  al., 2011). Nigella sativa oil, by preventing inflammatory status sion revealed down-regulated MUC4 expression and induced apop- in the blood, partly protected colonic tissue against experimental tosis in pancreatic cancer cells. The decrease in MUC4 expression ulcerative colitis. Oral TQ (1–10  mg/kg) or N.  sativa oil (thrice was accompanied by increased apoptosis, decreased motility, and in a week for 4  months) exerted a protective effect against breast decreased migration of pancreatic cancer cells (Torres et al., 2010). cancer in female rats induced by 7,12-dimethylbenz[α-]anthracene The administration of N. sativa reduced the carcinogenic effects as revealed by tumour markers, histopathological alterations, and of DMBA in mammary carcinoma which indicated its protective the regulation of several genes (Brca1, Brca2, Id-1, and P53 muta- role in mammary carcinoma (Shafi et  al., 2008). TQ dose-depend- tion) related to breast cancer (Linjawi et al., 2015). ently suppressed the migration and invasion of Panc-1 cells. TQ Acute lymphoblastic leukaemia (ALL) is a common childhood also significantly down-regulated NF-kB and MMP-9 in Panc-1 malignancy and is conventionally treated with methotrexate which cells. Administration of TQ significantly reduced tumour metasta- also produces hepatotoxicity. The therapeutic value of N. sativa oil sis. Furthermore, the expression of NF-kB and MMP-9 protein in in methotrexate-induced hepatotoxicity has been assessed in 40 tumour tissues was down-regulated after treatment with TQ, thus Egyptian children with ALL under methotrexate therapy (Hagag exerting anti-metastatic activity on pancreatic cancer both in vitro et al., 2015). Nigella sativa oil (80 mg/kg/day for 1 week) produced and in vivo (Wu et al., 2011). The chemo-sensitizing effect of TQ and significant differences in remission, relapse, death, and disease-free 5-fluorouracil (5-FU) on gastric cancer cells both in vitro and in vivo survival. Nigella sativa seeds decreased methotrexate hepatotoxicity is reported (Lei et  al., 2012). Pre-treatment with TQ significantly and improved survival. This report is suggestive of its application as increased the apoptotic effects induced by 5-FU in gastric cancer cell an adjuvant drug in patients under methotrexate therapy. lines in vitro. The combined treatment of TQ with 5-FU was more Nigella sativa seed oil and TQ have been understood to exert effective in anti-tumour action than either of them individually in a antioxidant and chemopreventive properties (Allahghadri et  al., xeno-graft tumour mouse model. The TQ/5-FU-combined treatment 2010). TQ could suppress tumour cell proliferation in the case of induces apoptosis by enhancing the activation of both caspase-3 and breast adenocarcinoma, pancreatic carcinoma, colorectal carcin- caspase-9 in gastric cancer cells (Lei et al., 2012). oma, osteosarcoma, ovarian carcinoma, and myeloblastic leukaemia In summary, N. sativa oil and TQ are found to inhibit experimen- (Allahghadri et al., 2010). The cancer chemopreventive ability of TQ tal carcinogenesis in different animal models. It has been shown to Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 12 K. Srinivasan, 2018, Vol. 2, No. 1 arrest the growth of various cancer cells in culture as well as xeno- and reduced the occurrence of diarrhoea and body weight loss, graft tumours in vivo. The mode of anticancer effects of TQ includes associated with amelioration of colitis-related damage. Also, there inhibition of carcinogen-metabolizing enzyme activity and oxidative was a significant reduction in colonic myeloperoxidase activity and damage to cellular macromolecules, amelioration of inflammation, malondialdehyde levels and an increase in glutathione levels (Lei inhibition of cell cycle and apoptosis in tumour cells, inhibition of et al., 2012). tumour angiogenesis, and suppression of migration, invasion, and metastasis of cancer cells. TQ improves anti-cancer effects when Nephroprotective effect combined with conventionally used chemotherapeutic agents. At the The nephroprotective effect of N.  sativa oil is observed in gen- molecular level, TQ targets intracellular signalling pathways, par- tamicin-induced nephrotoxicity in rabbits (Saleem et  al., 2012) ticularly a variety of kinases and transcription factors, which are (Table 7). Vitamin C and N.  sativa oil when given as combination activated during tumourigenesis. showed a synergistic nephroprotective effect (Saleem et  al., 2012). Oral treatment of N.  sativa oil (0.5, 1.0, or 2.0  ml/kg/day for Gastroprotective effect 10  days) produced a dose-dependent amelioration of gentamycin- Nigella sativa oil and its constituents are proved to exert gastro- induced nephrotoxicity in rats as assessed by the biochemical and protective effect (Table 7); some of the potential mechanisms exhib- histological indices of nephrotoxicity (Ali, 2004). The protective ited by N. sativa in preventing or curing gastric ulcers are reviewed effect of N.  sativa oil on methotrexate-induced nephrotoxicity has recently (Khan et  al., 2016). The mechanism of gastroprotective been reported in albino rats which is medicated through restoring effect of TQ has been assessed in rats injected with TQ (10 and the antioxidant status (Abul-Nasr et  al., 2001; Yaman and Balikci, 20  mg/kg) and subsequently subjected to ischemia or reperfusion 2010). The protective effects of N.  sativa oil in the prevention of insult. TQ restored the altered acid secretion, gastric mucosal con- chronic cyclosporine A-induced nephrotoxicity in rats were evi- tent, lipid peroxide, and the activity of myeloperoxidase, reduced denced by attenuation of the oxidative stress (Uz et  al., 2008). TQ glutathione, and total nitric oxide along with ulcer index, the effi- supplementation prevented the development of gentamycin-induced cacy being comparable with that of the reference drug omeprazole. degenerative changes in kidney tissues and cisplatin-induced renal TQ exerted gastroprotection via inhibiting proton pump, acid secre- injury in rats as indicated by lipid peroxides and renal organic anion tion and neutrophil infiltration, while enhancing mucin secretion, and cation transporters (Sayed-Ahmed and Nagi, 2007; Ulu et  al., and nitric oxide production, in addition to the antioxidant influences 2012). Nigella sativa significantly prevented renal ischemia- or rep- (Magdy et al., 2012). erfusion-induced functional and histological injuries in Wistar rats The anti-ulcer potential of N. sativa aqueous suspension on gas- (Mousavi, 2015). Nigella sativa showed protective effects against tric ulcers experimentally induced with various noxious chemicals ischemia-perfusion damage on kidney tissue based on the total anti- (indomethacin, 80% ethanol, and 0.2 M NaOH) in Wistar rats oxidant capacity, oxidative status index, and activities of catalase was examined (Al Mofleh et  al., 2008). Nigella sativa significantly and myeloperoxidase in the kidney tissue (Yildiz et al., 2010). prevented gastric ulcer formation induced by necrotizing agents by significantly replenishing the depleted gastric wall mucus content Hepatoprotective effect and gastric mucosal non-protein sulfhydryl concentration. The anti- It is reported that N.  sativa (i.p.  0.2  ml/kg) relieves the deleterious ulcer effect of N.  sativa was exerted through its antioxidant and effects of ischemia-reperfusion injury on liver in rats, as indicated by anti-secretory activities (Al Mofleh et al., 2008). Both N. sativa (2.5 titers of marker enzymes, total antioxidant capacity, total oxidative and 5.0 ml/kg, p.o.) and TQ (5, 20, 50, and 100 mg/kg, p.o.) were status, and myeloperoxidase in the liver tissue (Yildiz et  al., 2008) ++ found to possess gastro-protective activity against gastric mucosal (Table 7). The protective effect of TQ on the Cd -induced hepato- injury induced by ischemia or reperfusion in Wistar rats (El-Abhar toxicity in mice, particularly the perturbation of non-enzymatic and et al., 2003). Lipid peroxidation and lactate dehydrogenase, elevated enzymatic antioxidants, has been reported (Zafeer et al., 2012). Pre- by the ischemia or reperfusion insult and decreased glutathione and treatment with TQ (10  µmol/l) showed a significant protection as activity of SOD accompanied by an increased formation of gastric indicated by an attenuation of protein oxidation and recovery of the lesions, were countered by N.  sativa or TQ treatment, indicating depleted antioxidants, suggesting that TQ exerts modulatory influence their gastroprotective effect, probably by conservation of the gastric on the antioxidant defence system when subjected to toxic insult. mucosal redox state. Pulmonary-protective activity and anti-asthmatic Nigella sativa and TQ are reported to protect gastric mucosa against the ulcerating effect of alcohol on hypothyroidal rats and effects mitigate most of the biochemical adverse effects on gastric mucosa, Nigella sativa has been investigated for the possible beneficial viz., increase in lipid peroxidation and reduced gastric glutathione effects on experimental lung injury in rats after pulmonary aspir- content, and enzyme activities of gastric SOD and GST (Khaled, ation (Kanter, 2009) (Table 7) and found that N.  sativa treatment 2009). The beneficial effect of N.  sativa oil (2  ml/kg daily, i.p.) inhibits the inflammatory pulmonary responses. Nigella sativa ther - in rats with necrotizing enterocolitis (NEC) was studied in new- apy resulted in a significant reduction in the activity of iNOS and born Sprague-Dawley rats (Tayman et al., 2012). Histopathologic an increase in surfactant protein D in the lung tissue of different and apoptosis evaluation indicated that the bowel damage was less pulmonary aspiration models. It is concluded that N.  sativa treat- severe in the N.  sativa oil–treated group. Nigella sativa oil had a ment might be beneficial in lung injury that merits potential clinical beneficial preserving effect on tissue antioxidant enzymes, whereas use. The ameliorative effect of N. sativa oil in rats with hyperoxia- lipid peroxide levels were significantly lower than those in the NEC induced lung injury has also been reported (Tayman et al., 2012). control group. In a mouse model of inflammatory bowel disease The prophylactic effect of an extract of N.  sativa (15  ml/kg of (C57BL/6 murine colitis induced with dextran sodium sulfate), 0.1 g% boiled extract for 3 months) has been examined in asthmatic treatment with TQ (5, 10, or 25 mg/kg) ameliorated colonic inflam- adults. All asthma symptoms, the frequency of symptoms, chest wheez- mation (Lei et al., 2012). The treatment of mice with TQ prevented ing, and pulmonary function tests (PFT values) were significantly Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 13 improved as a result of N.  sativa treatment, generally suggesting a constituents like TQ could be used in suitable combinations with prophylactic effect on asthma disease (Boskabady et  al., 2007). TQ conventional therapeutic agents for maximizing the effectiveness in potently and dose-dependently inhibited the formation of leukot- the treatment of many infectious diseases and also to circumvent the rienes—supposedly important mediators in asthma and inflammatory drug resistance problem. Further investigations are recommended to processes, in human blood cells (Mansour and Tornhamre, 2004). explore the specific cellular and molecular targets of various con- stituents of N. sativa, particularly TQ. Miscellaneous nutraceutical effects During the last three decades, several in vitro and in vivo animal References studies have ascertained the pharmacological properties of N. sativa, Abdelmeguid, N. E., Fakhoury, R., Kamal, S. M., Al Wafai, R. J. (2010). including its antioxidant, antibacterial, anti-proliferative, proa- Effects of Nigella sativa and thymoquinone on biochemical and subcel- poptotic, anti-inflammatory, and antiepileptic properties, and its lular changes in pancreatic β-cells of streptozotocin-induced diabetic rats. beneficial effect in conditions of atherogenesis, endothelial dys- Journal of Diabetes, 2: 256–266. Abel-Salam, B. K. (2012). 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Chemico- induced hepatotoxicity and its abrogation by thymoquinone. Journal of Biological Interactions, 197: 40–46. Biochemical and Molecular Toxicology, 26: 199–205. Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Food Quality and Safety Oxford University Press

Cumin (Cuminum cyminum) and black cumin (Nigella sativa) seeds: traditional uses, chemical constituents, and nutraceutical effects

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Abstract

Although the seeds of cumin (Cuminum cyminum L.) are widely used as a spice for their distinctive aroma, they are also commonly used in traditional medicine to treat a variety of diseases. The literature presents ample evidence for the biomedical activities of cumin, which have generally been ascribed to its bioactive constituents such as terpenes, phenols, and flavonoids. Those health effects of cumin seeds that are experimentally validated are discussed in this review. Black seeds (Nigella sativa), which are totally unrelated to C.  cyminum, have nevertheless taken the name ‘Black cumin’ and used in traditional systems of medicine for many disorders. Numerous pre- clinical and clinical trials have investigated its efficacy using the seed oil, essential oil, and its main constituent thymoquinone (TQ). These investigations support its use either independently or as an adjunct along with conventional drugs in respiratory problems, allergic rhinitis, dyspepsia, metabolic syndrome, diabetes mellitus, inflammatory diseases, and different types of human cancer. Multiple studies made in the last decades validate its health beneficial effects particularly in diabetes, dyslipidemia, hypertension, respiratory disorders, inflammatory diseases, and cancer. Nigella sativa seeds also possess immune stimulatory, gastroprotective, hepatoprotective, nephroprotective, and neuroprotective activities. TQ is the most abundant constituent of volatile oil of N. sativa seeds, and most of the medicinal properties of N. sativa are attributed mainly to TQ. All the available evidence suggests that TQ should be developed as a novel drug in clinical trials. Key words: Cuminum cyminum; Nigella sativa; digestive stimulant; antidiabetic; anti-inflammatory; cancer preventive; immune stimulatory; gastroprotective. traditional medicine. In the Ayurvedic system of medicine in India, Introduction cumin seeds have immense medicinal value, particularly for digestive Cumin seeds (Figure 1) are obtained from the herb Cuminum disorders. They are used in chronic diarrhoea and dyspepsia (Table 1). cyminum, native from East Mediterranean to South Asia belonging Black seed (also known as black cumin; Nigella sativa) (Figure 1) to the family Apiaceae—a member of the parsley family. Cumin seeds is an annual flowering plant belonging to the family Ranunculaceae are oblong and yellow–grey. Cumin seeds are liberally used in several and is a native of Southern Europe, North Africa, and Southwest Asia. cuisines of many different food cultures since ancient times, in both Black cumin is cultivated in the Middle Eastern Mediterranean region, whole and ground forms. In India, cumin seeds have been used for Southern Europe, Northern India, Pakistan, Syria, Turkey, Iran, and thousands of years as a traditional ingredient of innumerable dishes Saudi Arabia. Nigella sativa seeds and their oil have a long history of including kormas and soups and also form an ingredient of several folklore usage in Indian and Arabian civilization as food and medicine other spice blends. Besides food use, it has also many applications in © The Author(s) 2018. Published by Oxford University Press on behalf of Zhejiang University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact jour- nals.permissions@oup.com Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 2 K. Srinivasan, 2018, Vol. 2, No. 1 Figure 1 Different varieties of cumin. Figure 2. Major bioactive compounds of cumin and black seeds. Figure 3. Multiple medicinal properties of Cuminum cyminum (cumin seeds). (Yarnell and Abascal, 2011). The seeds of N. sativa have a pungent bit- Bunium persicum (occasionally referred to as Cuminum nigrum; ter taste and aroma and are used as a spice in Indian and extensively in also known as Shahi jeera), belonging to Apiaceae (parsley family), Middle Eastern cuisines. The dry-roasted nigella seeds flavour curries, is a smaller variety of cumin with a different flavour, popularly used vegetables, and pulses. Black seeds are used in food as a flavouring in North Indian, Pakistani, and Iranian foods (Figure 1). Until now, additive in breads and pickles. It is also used as an ingredient of the there is only very little scientific information on this spice. spice mixture (panch phoron) and also independently of many recipes in Bengali cuisine. Cumin was traditionally used as a preservative in Chemical constituents mummification in the ancient Egyptian civilization. Black cumin has a long history of use as medicine in the Indian traditional system of medi- Cumin seeds are nutritionally rich; they provide high amounts of fat cine like Unani and Ayurveda (Sharma et al., 2005). The black cumin (especially monounsaturated fat), protein, and dietary fibre. Vitamins seeds have traditionally been used in the Southeast Asian and Middle B and E and several dietary minerals, especially iron, are also con- East countries for the treatment of diseases such as asthma, bron- siderable in cumin seeds. Cuminaldehyde (Figure 2), cymene, and chitis, rheumatism, and other inflammatory diseases. Nigella sativa terpenoids are the major volatile components of cumin (Bettaieb has extensively been used because of its therapeutic potential and pos- et al., 2011). Cumin has a distinctive strong flavour. Its warm aroma sesses a wide spectrum of activities, namely, diuretic, antihypertensive, is due to its essential oil content. Its main constituent of aroma com- antidiabetic, anticancer, immune-modulatory, antimicrobial, anthel- pounds are cuminaldehyde and cuminic alcohol. Other important mintic, analgesic and anti-inflammatory, spasmolytic, bronchodilator, aroma compounds of roasted cumin are the substituted pyrazines, gastroprotective, hepatoprotective, and renal protective properties. 2-ethoxy-3-isopropylpyrazine, 2-methoxy-3-sec-butylpyrazine, and Traditionally, seeds of N. sativa are widely used for asthma, diabetes, 2-methoxy-3-methylpyrazine. Other components include γ-terpinene, hypertension, fever, inflammation, bronchitis, dizziness, rheumatism, safranal, p-cymene, and β-pinene (Li and Jiang, 2004). skin disorders, and gastrointestinal disturbances (Table 1). It is also Nigella sativa seeds contain protein (26.7%), fat (28.5%), carbohy- used as a liver tonic, digestive, antidiarrhoeal, emmenagogue, and to drates (24.9%), crude fibre (8.4%), and total ash (4.8%). Nigella sativa control parasitic infections and boost immune system (Goreja, 2003). seeds also contain a good amount of various vitamins and minerals Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 3 Figure 4. Multiple medicinal properties of Nigella sativa (black cumin seeds). like Cu, P, Zn, and Fe. Many active compounds have been identified in whether they have any stimulatory effect on the digestive enzymes. N. sativa. The most important active compounds of N. sativa are thy- The influence of cumin seeds on the digestive enzymes of the rat pan- moquinone (TQ) (30%–48%) (Figure 2), thymohydroquinone, dithy- creas and intestinal mucosa has particularly been investigated as a moquinone (nigellone), p-cymene (7%–15%), carvacrol (6%–12%), result of both continuous dietary intake and single oral administra- 4-terpineol (2%–7%), t-anethole (1%–4%), sesquiterpene longifolene tion (Platel and Srinivasan, 1996; 2000a) (Table 2). Dietary (1.25%) (1%–8%), α-pinene, and thymol. (Boskabady and Shirmohammadi, cumin lowered the activity of pancreatic lipase, whereas the activities 2002; Ali and Blunden, 2003). Nigella sativa also contains other com- of pancreatic trypsin, chymotrypsin, and amylase were significantly pounds such as carvone, limonene, citronellol in trace amounts, and enhanced by the same (Platel and Srinivasan, 2000a). When given as a two varieties of alkaloids, i.e. isoquinoline alkaloids (e.g. nigellicimine single oral dose, cumin exerted a lowering effect on pancreatic lipase, and nigellicimine-N-oxide) and pyrazole alkaloids (e.g. nigellidine amylase, trypsin, and chymotrypsin. Among the terminal digestive and nigellicine). Nigella sativa seeds also contain α-hederin, a water enzymes, a small intestinal maltase activity was significantly higher in soluble pentacyclic triterpene (Al-Jassir, 1992; Nickavar et al., 2003). animals fed with cumin, whereas lactase and sucrose were unaffected The pharmacological properties of N.  sativa are mainly attributable (Platel and Srinivasan, 1996). to its quinine constituents, TQ being the most abundant. The N. sativa Dietary cumin had a significant stimulatory effect on bile flow seeds contain fatty oil rich in unsaturated fatty acids, constituting lino- rate, the extent of increase in bile volume being 25 per cent, whereas leic acid (50%–60%), oleic acid (20%), eicosadienoic acid (3%), and its single oral dose did not have any effect on bile secretion rate dihomolinoleic acid (10%), and saturated fatty acids (palmitic and (Platel and Srinivasan, 2000b). Dietary intake of cumin had a pro- stearic acids) constitute up to 30 per cent. α-Sitosterol is the major found influence on bile acid output (quantity secreted per unit time), sterol, accounting for 44%–54% of the total sterols in N. sativa oils, bile acid secretion being as high as 70 per cent over the control. followed by stigmasterol (6.57%–20.9% of total sterols) (Cheikh- Similar significant increases in bile acid secretion were seen in the Rouhou et al., 2008; Mehta et al., 2008). case of cumin when administered as a single oral dose. Since bile Bitter cumin (Shahi jeera) seeds contain calcium, vitamin A, po- juice makes a significant contribution to the overall process of diges- tassium, sodium, iron, magnesium, and phosphorus. Bitter cumin tion and absorption, essentially by supplying bile acids required for (B.  persicum) has 0.5 to 1.6 per cent essential oil, mainly carvone micelle formation, it is expected that cumin, which has a digestive (45%–60%), limonene, and p-cymene. Oleoresin of bitter cumin is stimulant action, could do so by stimulating biliary secretion of brownish to yellowish green. As there is not enough scientific infor - bile acids. mation on the health effects of bitter cumin, this review is limited Another study has examined whether this digestive stimulant to C.  cyminum (cumin seeds) and N.  sativa (black seeds or black spice cumin also affects the duration of residence of food in the cumin) gastrointestinal tract of experimental rats (Platel and Srinivasan, 2001). Cumin produced a significant shortening of the food transit time by 25 per cent. The reduction in food transit time produced by Health effects of C. cyminum dietary cumin roughly correlates with their beneficial influence either on digestive enzymes or bile secretion. Although the seeds of cumin (C. cyminum L.) are widely used as the spice for their distinctive aroma, they are also commonly used in traditional medicine to treat a variety of diseases, including chronic Antidiabetic effects diarrhoea and dyspepsia, acute gastritis, diabetes, and cancer. The The antidiabetic effect of cumin seeds has been reported in human literature presents ample evidence for the biological and biomedical diabetics (Karnick, 1991) (Table 2). In this study, 80 patients with activities of cumin, which have generally been ascribed to its bio- non-insulin dependent diabetes mellitus were orally administered for active constituents such as terpenes, phenols, and flavonoids (Mnif 24 weeks with an Ayurvedic formulation containing C.  cyminum. and Aifa, 2015). Those health effects of cumin seeds that are experi- Fasting and post-prandial blood sugar at 6-week intervals was mentally validated (Figure 3) are discussed below. significantly reduced in all the patients. Dietary cumin seeds were observed to alleviate diabetes-related metabolic abnormalities in Digestive stimulant action STZ-diabetic rats (Willatgamuwa et  al., 1998). An 8-week dietary In the context of cumin seeds being claimed in home remedies and regimen containing cumin powder (1.25%) was found to be remark- traditional medicine, to aid digestion, an animal study has examined ably beneficial, as indicated by a reduction in hyperglycaemia and Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 4 K. Srinivasan, 2018, Vol. 2, No. 1 Table 1. Differences between seed spices closely related to cumin seeds. Common name of Cumin Black cumin (Nigella/kalonji) Bitter cumin (Kashmiri jeera/ Shahi jeera) the spice Scientific name Cuminum cyminum Nigella sativa Cuminum nigrum or Bunium persicum Genus/family Cuminum/Apiaceae (member of Nigella/Ranunculaceae Cuminum/Apiaceae Parsley family) Native of countries East Meditaranian to South Asia. South to Southwest Asia. Middle Eastern Central Asia to Northern India. growing Now mostly grown in Pakistan, India, Mediterranean region, South Europe, Mountainous regions of North India Uzbekistan Iran, Turkey, Morocco, Northern India, Pakistan, Syria, Turkey, Egypt, Syria, Chile, Mexico, and China Iran, and Saudi Arabia Traditional uses Both whole and ground seeds are used A spice in Indian and Middle Eastern A spice in Northern Indian cookery, often in the cuisines of many cultures for cuisines. In the ancient Egypt, it was the Moghul cooking ages. It has also many uses in trad- used as a preservative in mummification. itional medicine. They are used in Traditionally, it is used for asthma, dia- chronic diarrhoea and dyspepsia betes, hypertension, fever, inflammation, bronchitis, dizziness, eczema, and gastro- intestinal disturbances Main constituents Cuminaldehyde Thymoquinone Cuminaldehyde, p-mentha-1,3-dien-7-al and p-mentha-1,4-dien-7-al Table 2. Digestive stimulant and antidiabetic effects of Cumin seeds. Model/system Effect observed Researcher Digestive stimulant action Wistar rats Dietary 1.25% cumin for 8 weeks significantly enhanced the activities of Platel and Srinivasan, 2000a pancreatic trypsin, chymotrypsin, and amylase Wistar rats Dietary 1.25% cumin for 8 weeks significantly enhanced the small Platel and Srinivasan, 1996 intestinal maltase activity Wistar rats Dietary 1.25% cumin for 8 weeks had a significant stimulatory effect on Platel and Srinivasan, 2000b bile flow rate and bile acid secretion Wistar rats Dietary 1.25% cumin for 8 weeks reduced gastrointestinal food Platel and Srinivasan, 2001 transit time Antidiabetic action Human NIDDM subjects Fasting and post-prandial blood sugar was reduced when a formulation Karnick, 1991 consisting cumin was orally administered for 24 weeks STZ-diabetic rats Dietary cumin seeds for 8 weeks were observed to alleviate Willatgamuwa et al., 1998 diabetes-related metabolic abnormalities Alloxan-diabetic rats Hyperlipidemia associated with diabetes mellitus was also effectively Dandapani et al., 2002 countered by dietary cumin Alloxan-diabetic rabbits Cuminum nigrum seeds or their methanol/water extracts were found to be Akhtar and Ali, 1985 hypoglycemic Alloxan-diabetic rabbits The antihyperglycemic influence of Cuminum nigrum was produced by the Ahmad et al., 2000 fraction containing flavonoid compounds Normal rabbits Oral administration of C. cyminum decreased the area under the glucose Roman-Ramos et al., 1995 tolerance curve and the hyperglycemic peak. STZ-diabetic rats Methanolic extract of C. cyminum treated for 4 weeks mitigated oxidative Jagtap and Patil, 2010 stress and formation of AGEs Sprague-Dawley rats Cuminaldehyde isolated from C. cuminum inhibited lens aldose reductase Lee, 2005 and α-glucosidase of rats glucosuria. Hyperlipidemia associated with diabetes mellitus was glibenclamide (Jagtap and Patil, 2010). In vitro studies indicated that also effectively countered by dietary cumin in alloxan-diabetic rats cumin inhibited free radicals and AGE formation. The antidiabetic (Dandapani et al., 2002). effect of cumin (treated for 4 weeks) was comparable to glibencla- Cuminum nigrum seeds or their water or methanol extracts mide and even better in controlling oxidative stress and AGE forma- have been observed to be hypoglycemic in alloxan-diabetic rab- tion, which is implicated in pathogenesis of diabetic microvascular bits (Akhtar and Ali, 1985). The antihyperglycemic influence of complications. The inhibitory activity of C. cyminum seed–isolated C. nigrum has been attributed to the flavonoid compounds present component cuminaldehyde has been evaluated against lens aldose in these seeds (Roman-Ramos et  al., 1995; Ahmad et  al., 2000). reductase and α-glucosidase isolated from Sprague-Dawley rats and Methanolic extract of C.  cyminum has been investigated in strep- compared with that of quercetin as an aldose reductase inhibitor and tozotocin-diabetic rats on diabetes, oxidative stress, and forma- acarbose as an α-glucosidase inhibitor (Lee, 2005). Cuminaldehyde tion of advanced glycated end products (AGE) in comparison with was about 1.8 and 1.6 times less in inhibitory activity than acarbose Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 5 Table 3. Cardioprotective, anti-inflammatory, and chemopreventive effects of cumin seeds. Model/system Effect observed Researcher Cardioprotective influence Rat Orally administered aqueous cumin extract (200 mg/kg body for 9 weeks) Kalaivani et al., 2013 improved plasma nitric oxide and decreased the systolic blood pressure in hypertensive rats. Patients with Cumin extract significantly decreased the level of oxLDL while increasing the Samani and Farrokhi, 2014 hypercholesterolemia activities of paraoxonase, and arylesterase activities were increased in serum Anti-inflammatory effect LPS-stimulated RAW 264.7 cells Cumin essential oil exerted anti-inflammatory effects via inhibition of Wei et al., 2015 NF-κB and mitogen-activated protein kinases ERK and JNK Chemopreventive effect Mice Dietary 2.5 and 5.0% cumin alleviated benzo(α)pyrene-induced Gagandeep et al. 2003 forestomach tumourigenesis and 3-MCA-induced uterine cervix tumorigenesis, attributable to its ability to modulate carcinogen metabolism Rat Dietary cumin (1.25% for 32 weeks) suppressed DMH-induced colon Nalini et al., 2006 carcinogenesis. The excretion of fecal bile acids and neutral sterols was increased. HT29 colon cancer cells Spent cumin from Ayurvedic industry was effective in arresting the cell cycle Arun et al., 2016 and inducing apoptosis Miscellaneous nutraceutical effects PC12 cells C. cyminum essential oil inhibited the fibrillation of α-synuclein Morshedi et al., 2015 suggesting neuroprotective effects Rat Aqueous extract of cumin seeds showed anti-diarrhoeal effect when induced Sahoo et al., 2014 with castor oil and quercetin, respectively. Nonetheless, cuminaldehyde may be use- while increasing the activities of paraoxonase, and arylesterase activi- ful for antidiabetic therapeutics. ties were increased in serum (Samani and Farrokhi, 2014). The effect of cumin added to normal and hypercholesterolemia inducing diet on serum and liver cholesterol levels in rats has been studied (Sambaiah Anti-inflammatory effects and Srinivasan, 1991). Dietary cumin did not show any cholesterol Cumin essential oil was investigated for the anti-inflammatory effects lowering effect when included in the diet (1.25%) at about 5-fold the in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the normal consumption level. underlying mechanisms (Wei et al., 2015) (Table 3). Volatile constitu- ents were identified in essential oil using Gas Chromatography - Mass Spectrometry (GC-MS), the most abundant constituent being cumi- Chemopreventive effects naldehyde (48.8%). Cumin oil exerted anti-inflammatory effects in Cancer chemopreventive potentials of dietary 2.5 and 5.0 per cent LPS-stimulated RAW cells through inhibiting NF-κB and mitogen- cumin were evaluated against benzo(α)pyrene-induced tumorigenesis activated protein kinases suggesting its potential as an anti-inflam- in forestomach and 3-methylcholanthrene (MCA)-induced tumorigen- matory agent. esis in uterine cervix in mice (Gagandeep et al., 2003) (Table 3). Cumin produced a significant inhibition of stomach tumour. The effect on car - Cardio-protective influence through hypolipidemic cinogen/xenobiotic metabolizing phase I and phase II enzymes, antioxi- and hypotensive effects dant enzymes, and lipid peroxidation in the liver was also examined. Cuminum cyminum is traditionally used for the treatment of indigestion Cytochrome P and cytochrome b were significantly augmented by 450 5 and hypertension. The anti-hypertensive potential of aqueous extract dietary cumin. The phase II enzyme glutathione-S-transferase (GST) of cumin seed and its role in arterial–endothelial nitric oxide synthase was increased by cumin, whereas the specific activities of superoxide expression, inflammation, and oxidative stress have been evaluated in dismutase (SOD) and catalase were significantly elevated. Lipid peroxi- renal hypertensive rats (Kalaivani et al., 2013) (Table 3). Cumin admin- dation was inhibited by cumin, suggesting that the cancer chemopre- istered orally (200 mg/kg body) for 9 weeks improved plasma nitric ventive potential of cumin could be attributed to its ability to modulate oxide and reduced the systolic blood pressure in hypertensive rats. This carcinogen metabolism. was accompanied by the up-regulation of the expression of inducible The effect of cumin (C. cyminum; dietary 1.25% for 32 weeks) nitric oxide synthase (iNOS), Bcl-2, TRX1, and TRXR1 and down- was studied on colon cancer induced in rats by 1,2-dimethylhydrazine regulation of the expression of Bax, TNF-α, and IL-6. These data sug- (DMH) s.c. 20 mg/kg of body weight (15 doses, at weekly intervals) gest that cumin seeds augment endothelial functions and ameliorate (Nalini et al., 2006). Results showed that cumin suppresses colon car- inflammatory and oxidative stress in hypertensive rats. cinogenesis in the presence of the procarcinogen DMH. The excretion Paraoxanase-1 plays a protective role against the oxidative modi- of fecal bile acids and neutral sterols was significantly increased in fication of plasma lipoproteins and hydrolyzes lipid peroxides in cumin+DMH-administered rats. Cholesterol and 3-hydroxy-3-meth- human atherosclerotic lesions. Flavonoids present in cumin seeds ylglutaryl-CoA reductase activity were decreased in cumin+DMH- are recognized to have antioxidant activity and improve the antioxi- treated rats. Spent cumin generated from Ayurvedic industry was dant system. A study demonstrated that cumin extract significantly evaluated for its nutraceutical potential in terms of antioxidant (in decreased the level of oxidized Low-density lipoprotein (OxLDL) terms of scavenging 2,2-Diphenyl-1-picryl-hydrazyl-hydrate [DPPH] Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6 K. Srinivasan, 2018, Vol. 2, No. 1 Table 4. Antidiabetic effects of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher STZ-diabetic rats The oil of N. sativa significantly lowered blood glucose in STZ-diabetic El-Dakhakhny et al., 2002 rats after 2, 4, and 6 weeks Rat pancreatic islets Defatted extract of N. sativa seed increased glucose induced insulin re- Rchid et al., 2004 lease from isolated rat pancreatic islets in vitro STZ/NA-diabetic hamsters N. sativa oil treatment for 4 weeks decreased blood glucose and Fararh et al., 2002 increased serum insulin STZ-diabetic hamsters The hypoglycemic effect of N. sativa oil (400 mg/kg by p.o.) is partially Fararh et al., 2004 due to a decrease in hepatic gluconeogenesis Hepatocytes (HepG2) Defatted extract of N. sativa seeds increased glucose consumption by Yuan et al., 2014 hepatocytes (HepG2) in vitro through activation of AMPK Diabetic rabbits N. sativa extract (orally for 2 months) decreased lipid peroxidation and Meral et al., 2001 increased antioxidant defense system STZ-diabetic rats Daily oral administration of ethanol extract of N. sativa seeds Kaleem et al., 2006 (300 mg/kg for 30 days) reduced hyperglycemia and improved altered levels of lipid peroxidation products and antioxidant enzymes in liver and kidney STZ-diabetic rats N. sativa oil (0.2 ml/kg for 30 days) decreased hyperglycemia and Kanter et al., 2003 restored lowered serum insulin with partial regeneration of pancreatic β-cells STZ-diabetic rats N. sativa treatment exerts a protective effect on diabetes by decreasing Kanter et al., 2004 oxidative stress and preserving pancreatic β-cell integrity STZ-diabetic rats fed with Daily administration of N. sativa oil significantly induced the gene ex- Balbaa et al., 2016 high-fat diet pression of insulin receptor and upregulated the expression of insulin-like growth factor-1 STZ-diabetic rats N. sativa seed oil down-regulated the expression of apoptotic markers Cüce et al., 2015 in the aortic medial layer of diabetic rats, thus preventing apoptosis in vascular structures STZ-diabetic rats Protective effects of N. sativa oil on insulin sensitivity and ultrastructural Kanter et al., 2009 changes of pancreatic β-cells STZ-diabetic rats N. sativa extract, oil, and TQ decreased the diabetes-induced lipid Abdelmeguid et al., 2010 peroxides and hyperglycemia, and significantly increased serum insulin and SOD activity in tissues STZ-NA–induced diabetic rats Oral administration of TQ dose-dependently improved the glycemic Pari and Sankaranarayanan, 2009 status; levels of insulin and Hb increased; altered activities of carbohydrate metabolizing enzymes were restored Patients with diabetes N. sativa oil showed a beneficial effect on various clinical and Najmi et al., 2008 biochemical parameters of the insulin resistance syndrome Patients with type 2 diabetes N. sativa (2 g/day) brought reductions in fasting blood glucose, post- Bamosa et al., 2010 prandially, and glycosylated haemoglobin. radical), antidiabetic (in terms of better α-amylase inhibition and abundant natural compound, cuminaldehyde can modulate α-SN glucose uptake activity in L6 cells), and anticancer properties (in fibrillation, suggesting that such natural active aldehyde could have terms of arresting the cell cycle and inducing apoptosis in HT29 potential therapeutic applications (Morshedi et al., 2015). colon cancer cells) and compared with that of the raw cumin (Arun et al., 2016). The results suggested that nutraceutical food formula- Health effects of N. sativa tion made out of spent cumin could play a major role in the preven- tion or management of degenerative diseases. Black cumin (N.  sativa) has been in use in traditional systems of medicine for various medical disorders. Nigella sativa is used in Moroccan folk medicine for the treatment of diabetes mellitus. Miscellaneous nutraceutical effects Many pre-clinical and clinical trials have investigated its efficacy, Cumin seeds are traditionally used for the treatment of diarrhoea. using the seed oil, essential oil, and its isolated main constituent TQ The aqueous extract of cumin seeds (100, 250, and 500 mg/kg) has (Ali and Blunden, 2003). These investigations provide preliminary been examined against diarrhoea in albino rats induced with castor support for its use in asthma, allergic rhinitis, and atopic dermatitis oil (Sahoo et  al., 2014). The extract showed significant inhibition (Yarnell and Abascal, 2011). Black cumin might help in dyspepsia, in the frequency of diarrhoea, delaying the defecation time, secre- respiratory problems, diabetes mellitus, and metabolic syndrome tion of intestinal fluid, and intestinal propulsion in a dose-dependent (Yarnell and Abascal, 2011). A  meta-analysis of clinical trials sug- manner. Fibrillation of α-synuclein (α-SN) is a critical process in the gests that N. sativa has a short-term benefit in lowering systolic and pathophysiology of several neurodegenerative diseases, especially diastolic blood pressure, and its various extracts can reduce triglyc- Parkinson’s disease. A study on the inhibitory effects of C. cyminum erides, LDL, and total cholesterol (Sahebkar et al., 2016a; 2016b). essential oil on the fibrillation of α-SN indicated that the small Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 7 Table 5. Anti-cancer effects of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher Mice—B()P-induced forestomach cancer N. sativa extract ameliorated benz(a-)pyrene-induced carcinogenesis in Aruna and Sivarama-krishnan, the forestomach 1990 Rat—DMH-induced colon cancer Orally administered N.sativa oil (14 weeks) reduced the induction and Salim and Fukushima, 2003 development of 1,2-dimethylhydrazine-induced aberrant crypt foci (ACF), putative preneoplastic lesions for colon cancer Rats—gastric ulcer induced by necrotiz- N. sativa aqueous suspension significantly ameliorated the ulcer severity Al Mofleh et al., 2008 ing agents and basal gastric acid secretion. The anti-ulcer effect is possibly prosta- glandin- mediated and/or through its antioxidant and anti-secretory activities Wistar rats—colon cancer induced with 1000 or 4000 ppm N. sativa volatile oil in the diet for 30 weeks signifi- Salim, 2010 carcinogens cantly reduced malignant and benign colon tumour sizes, incidences and multiplicities Rats—colitis induced with TNBS Oral N. sativa oil, by preventing inflammatory status in the blood, partly Isik et al., 2011 protected colonic tissue against experimental ulcerative colitis Rat—DMBA-induced breast cancer Orally administered (1—10 mg/kg) N. sativa oil or thymoquinone thrice Linjawi et al., 2015 in a week for 4 months exerted a protective effect against DMBA-induced breast cancer Children with acute lymphoblastic Black cumin seeds (80 mg/kg/day for 1 week) decreased methotrexane Hagag et al., 2015 leukaemia hepatotoxicity and improved survival in children with leukaemia Cancer cells Thymoquinone suppressed tumour cell proliferation in colorectal Gali-Muhtasib et al., 2006 carcinoma, breast adenocarcinoma, osteosarcoma, ovarian carcinoma, myeloblastic leukaemia, and pancreatic carcinoma Cancer cells TQ suppressed tumor cell proliferation in the case of breast adenocar- Allahghadri et al., 2010 cinoma, pancreatic carcinoma, colorectal carcinoma, ovarian carcinoma, osteosarcoma, and myeloblastic leukaemia Prostate cancer (PC-3) cell TQ is shown to prevent tumour angiogenesis in a xenograft human Yi et al., 2008 cancer model MCF-7 cells N. sativa lipid extract and aqueous extract exhibited cytotoxicity to Mahmoud and Torchilin, 2012 MCF-7 cells with LC of 2.7 and 50 mg/ml Human cervical squamous carcinoma TQ was with IC values of 10.7 µg/ml; elimination of SiHa cells via Ng et al., 2011 cells (SiHa) apoptosis with down-regulation of the Bcl-2 protein Human osteosarcoma cell line SaOS-2 Anti-tumour and anti-angiogenic activity of TQ possibly mediated by an Peng et al., 2013 inhibition of NF-κB and downstream effector molecules Breast cancer MDA-MB-231 cells TQ exerted a strong anti-proliferative effect on breast cancer cells via its Woo et al. 2011 potential effect on the PPAR-γ activation pathway; migration and invasion were also reduced Pancreatic cancer cells Treatment with TQ down-regulated MUC4 expression and induced Torres et al., 2010 apoptosis; increased apoptosis, decreased motility, and decreased migration of pancreatic cancer cells Panc-1 cells TQ dose-dependently suppressed the migration and invasion of panc-1 Wu et al., 2011 cells by down-regulating NF-kB and MMP-9 PC-3 cells Administration of N. sativa reduced the carcinogenic effects of DMBA in Shafi et al., 2008 mammary carcinoma Gastric cancer cells Pre-treatment with TQ significantly increased the apoptotic effects Lei et al., 2012 induced by 5-FU in gastric cancer cell lines in vitro Several studies made in the last decades validate its health benefi- vitro in rat pancreatic islets in the presence of glucose (8.3 mmol/l). cial effects particularly in diabetes, dyslipidemia, hypertension, and Results showed that the antidiabetic properties of N.  sativa seeds obesity. A  systematic review of all human trials has revealed that may partially be mediated by the stimulation of insulin release, espe- N. sativa supplementation might be effective in glycemic control in cially by the basic subfraction of the seed. The possible insulinotropic humans (Mohtashami and Entezari, 2016). property of N.  sativa oil has also been studied in STZ plus nico- tinamide (NA) induced diabetes mellitus in hamsters. Nigella sativa oil treatment for four weeks decreased blood glucose and increased Antidiabetic effects serum insulin (Fararh et  al., 2002). Immunohistochemical staining Nigella sativa seeds are traditionally used in the management of dia- revealed the presence of insulin in the pancreas from N.  sativa oil- betes mellitus in indigenous systems of medicine and folk remedies. treated group, suggesting that the hypoglycemic effect results, at Defatted extract of N.  sativa seed is reported to increase glucose- least partly, from a stimulatory effect on β-cell function. induced insulin release from isolated rat pancreatic islets in vitro The oil of N. sativa significantly lowered blood glucose in STZ- (Rchid et al., 2004) (Table 4). The effect of N. sativa extracts (defatted diabetic rats after 2, 4, and 6 weeks (El-Dakhakhny et  al., 2002). fractions either containing acidic and neutral compounds or contain- A study of the effect of N.  sativa oil on insulin secretion from iso- ing basic compounds) have been investigated on insulin secretion in lated rat pancreatic islets in the presence of glucose indicated that its Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 8 K. Srinivasan, 2018, Vol. 2, No. 1 Table 6. Anti-inflammatory/analgesic effects and immunomodulatory property of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher Anti-inflammatory property and analgesic activity Rats N. sativa essential oil produced a significant analgesic effect on acetic Hajhashemi et al., 2004 acid-induced writhing, formalin, and light tail flick tests Rats Intraperitoneal injection of N. sativa oil from 100 to 400 µl/kg significantly Hajhashemi et al., 2004 inhibited carrageenan-induced paw oedema BV-2 murine microglia cells TQ showed an effective anti-inflammatory effect on LPS-stimulated Taka et al., 2015 microglial cells Human trials Anti-osteoporotic effects of N. sativa and TQ are evidenced by observing in- Shuid et al., 2012 hibition of inflammatory cytokines (interleukin-1 and 6) and the transcription factor (NFκB) Pancreatic ductal adenocar- TQ inhibited proliferation in these cells by inhibiting proinflammatory Chehl et al., 2009 cinoma (PDA) cells pathways; this anti-inflammatory potential involved modulation of the ex- pression of different pro-inflammatory cytokines and chemokines Rats Oral administration of TQ (5 mg/kg body/day for 21 days) showed Umar et al., 2012 anti-arthritic activity by significantly reducing pro-inflammatory mediators Immunomodulatory action BALB/c mice and C57/BL6 Aqueous extract of N. sativa significantly enhanced the total white blood Ghonime et al., 2011 primary cells cells count and increased spleen weight in BALB/c mice and enhanced splenocyte proliferation Long-Evans rat Treatment with N. sativa oil significantly decreased the antibody production Torres et al., 2010 in response to typhoid vaccination Pigeons Co-administration of N. sativa (2.5%) with oxytetracycline (OXT) Abel-Salam, 2012 completely blocked the decreasing effects on total leukocyte and lymphocyte counts elicited by OXT and produced immunostimulant effects Rats N. sativa oil showed a promising radioprotective action against Assayed, 2010 immunosuppressive and oxidative effects of γ-radiation Mice N. sativa seed extract significantly improved symptoms and immune Duncker et al. 2012 parameters in murine OVA-induced allergic diarrhoea hypoglycemic effect might be mediated by extra-pancreatic actions Nigella sativa oil administration (daily) to STZ-induced diabetic rather than by stimulation of insulin release. The hypoglycemic rats maintained on a high-fat diet significantly induced the gene effect of N. sativa oil (400 mg/kg by p.o.) is partly due to decreased expression of insulin receptor (Balbaa et  al., 2016). Nigella sativa hepatic gluconeogenesis (Fararh et al., 2004). Indazole-type alkaloid oil upregulated the expression of IGF-1 and phosphoinositide-3 kin- 17-O-(β-D-glucopyranosyl)-4-O-methyl nigellidine present in the ase, whereas the expression of ADAM-17 was downregulated. Also, defatted extract of N.  sativa seeds increased glucose consumption the N.  sativa oil significantly reduced blood glucose level, individ- by hepatocytes (HepG2 cells) in vitro through activation of AMP- ual lipid profile, oxidative stress markers, serum insulin or insulin activated protein kinase (AMPK) (Yuan et al., 2014). receptor ratio, and the TNF-α, confirming that N.  sativa oil has an Nigella sativa extract given orally for 2 months decreased lipid antidiabetic activity. Thus, the daily N. sativa oil treatment improves peroxidation and increased antioxidant defence system and also insulin-induced signalling. prevented the lipid peroxidation-induced liver damage in diabetic Hyperglycaemia is an important risk factor for the development rabbits (Meral et  al., 2001). Daily oral administration of ethanol and progression of the macrovascular and microvascular complica- extract of N.  sativa seeds (300  mg/kg) to STZ-diabetic rats for tions that occur in diabetes. The expression of apoptotic markers in 30 days reduced the elevated levels of blood glucose, lipids, plasma the medial aortic layer of diabetic rats and the effects of N.  sativa insulin, and improved altered levels of lipid peroxidation products seed oil on the expression of these markers have been investigated and antioxidant enzymes in liver and kidney (Kaleem et al., 2006). (Cüce et al., 2015). It is understood that N. sativa seed oil is effective This suggested that in addition to antidiabetic activity, N.  sativa against diabetes and merits further treatment strategies for prevent- seeds may control diabetic complications through antioxidant ing apoptosis in vascular structures. effects. Treatment of N.  sativa oil (0.2  ml/kg, i.p.) for 30  days Treatment of streptozotocin-diabetic rats with N. sativa extract, decreased the elevation in serum glucose and restored lowered N.  sativa oil, and TQ, significantly decreased the diabetes-induced serum insulin with partial regeneration or proliferation of pancre- lipid peroxides and hyperglycemia, and significantly increased atic β-cells in STZ-diabetic rats (Kanter et al., 2003). The possible serum insulin and SOD activity in tissues. Nigella sativa oil and protective effects of N. sativa (0.2 ml/kg, i.p.) against β-cell damage TQ have therapeutic potential and are protective against STZ- from STZ-diabetes in rats have been evidenced by the observed diabetes by decreasing oxidative stress, thus preserving pancreatic decrease in lipid peroxidation and serum nitric oxide and increase β-cell integrity, leading to increased insulin levels (Abdelmeguid in the activities of antioxidant enzymes in the pancreas (Kanter et al., 2010). The protective effects of N. sativa oil on insulin sen- et  al., 2004). Increased staining for insulin and preservation of sitivity and ultrastructural changes of pancreatic β-cells in STZ- β-cell numbers were evident in N.  sativa–treated diabetic rats. induced diabetic rats are reported (Kanter et al., 2009). It is evident This suggests that N. sativa treatment exerts a protective effect on that N.  sativa treatment exerts a protective effect on diabetes by diabetes by decreasing oxidative stress and preserving pancreatic decreasing morphological changes and preserving the pancre- β-cell integrity. atic β-cell integrity (Kanter et  al., 2009). The anti-hyperglycemic Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 9 Table 7. Gastroprotectove, hepatoprotective, nephroprotective, and pulmonary-protective effects of black cumin (Nigella sativa) seeds. Model/system Effect observed Researcher Gastroprotective effect Rats N. sativa (2.5 and 5.0 ml/kg)/TQ administration (10, 20, 50, and El-Abhar et al., 2003 and 100 mg/kg) exerted gastro-protection when subjected to Magdy et al., 2012 ischemia/reperfusion insult Rats Anti-ulcer potential of N. sativa aqueous suspension on experimentally Al Mofleh et al., 2008 induced gastric ulcers (with various necrotizing chemicals) has been evidenced Hypothyroidal rats N. sativa and TQ protect gastric mucosa against the ulcerating effect of Khaled, 2009 alcohol Newborn Sprague-Dawley rats N. sativa oil (2 ml/kg daily; i.p.) showed beneficial effect in rats with Tayman et al., 2012 necrotizing enterocolitis Mice Treatment with TQ (5–25 mg/kg) ameliorated colonic inflammation in ex- Lei et al., 2012 perimental inflammatory bowel disease (C57BL/6 murine colitis induced with dextran sodium sulfate) Nephroprotective effect Rabbits Nephro-protective effect of N. sativa oil was observed against Saleem et al., 2012 gentamicin-associated nephrotoxicity Rats Protective effect of N. sativa oil against methotrexate-induced Yaman and Balikci, 2010 nephrotoxicity Rats Protective effects of N. sativa oil in the prevention of chronic cyclosporine Uz et al., 2008 A-induced nephrotoxicity by attenuation of the oxidative stress Rats TQ supplementation prevented the development of gentamycin-induced de- Sayed-Ahmed and Nagi, 2007 generative changes in kidney tissues Hepatoprotective effect Rats N. sativa (0.2 ml/kg) relieves the deleterious effects of ischemia-reperfusion Yildiz et al., 2008 injury on the liver Mice Pre-treatment with TQ (10 µmol/l) showed a significant protection on the Zafeer et al., 2012 hepatotoxicity of Cd++ particularly by relieving the depletion of non-enzymatic and enzymatic antioxidants Pulmonary protective effect Wistar rats N. sativa treatment showed beneficial effects on experimental lung injury; Kanter, 2009 inhibited the inflammatory pulmonary responses Rats N. sativa oil significantly reduced the severity of lung damage due to Tayman et al., 2012 hyperoxia Patients with asthma N. sativa (15 ml/kg of 0.1 g% boiled extract for 3 months) significantly Boskabady et al., 2007 alleviated symptoms and frequency of asthma symptoms, chest wheezing, and pulmonary function tests potential of TQ and the effect on the activities of key enzymes of useful adjuvant to oral hypoglycemic drugs in patients with type carbohydrate metabolism in STZ-NA–induced diabetic rats have 2 diabetes mellitus. been evaluated (Pari and Sankaranarayanan, 2009). Oral admin- istration of TQ (20, 40, and 80  mg/kg body weight for 45  days) Ameliorative effects of N. sativa on dyslipidemia dose-dependently improved the glycemic status in STZ/NA-induced Dyslipidemia is an established risk factor for ischemic heart disease. diabetic rats. The levels of insulin and haemoglobin increased along Nigella sativa has been used for the treatment and prevention of hyper- with a decrease in glucose and HbA1c levels. The altered activities lipidemia (Asgary et  al., 2015). Different preparations of N.  sativa of carbohydrate-metabolizing enzymes were also restored (Pari and including seed powder (100 mg–20  g daily), seed oil (20–800  mg Sankaranarayanan, 2009). daily), TQ (3.5–20 mg daily), and methanolic extract reduced plasma In a clinical study, the adjuvant effect of N. sativa oil on vari- levels of total cholesterol, low-density lipoprotein cholesterol, and tri- ous clinical and biochemical parameters of the insulin resistance glycerides. In clinical trials, N. sativa was found to be effective when syndrome in patients with diabetes and dyslipidemia has been evi- added as an adjunct to conventional hypolipidemic and antidiabetic denced (Najmi et  al., 2008). Nigella sativa accentuates glucose- medications. Inhibition of dietary cholesterol absorption, decreased induced secretion of insulin besides negatively affecting glucose hepatic cholesterol synthesis, and up-regulation of LDL receptors absorption. Hence, it is of immense therapeutic benefit in diabetic contribute to lipid-lowering effects of N. sativa. Overall, the evidence individuals (Kapoor, 2009). The effect of N. sativa seeds used as from an experimental and a clinical study suggests that N. sativa seeds an adjuvant therapy in addition to the anti-diabetic medications are promising natural therapy for patients with dyslipidemia. on the glycemic control of patients with type 2 diabetes melli- tus was investigated (Bamosa et  al., 2010). Nigella sativa at a Anti-inflammatory property and analgesic activity dose of 2 g/day caused significant reductions in fasting blood glu- cose, 2-hour post-prandially, and glycosylated haemoglobin. The The antinociceptive and anti-inflammatory effects of TQ ( Table 6), results indicate that a dose of 2 g/day of N. sativa could serve as a supporting the common perception of N. Sativa as a potent analgesic Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 10 K. Srinivasan, 2018, Vol. 2, No. 1 and anti-inflammatory agent, have been recently reviewed (Amin regulation of immune reactions in infectious and non-infectious con- and Hosseinzadeh, 2016). Many protective properties are attributed ditions such as allergy, autoimmunity, and cancer. to radical scavenging activity as well as an interaction with molecu- The potential immunomodulatory effects of aqueous extract of lar targets involved in inflammation (proinflammatory enzymes and N.  sativa investigated in BALB/c mice and C57/BL6 primary cells cytokines). Further investigations are needed to understand the pre- with respect to splenocyte proliferation, macrophage function, and cise mechanisms responsible for the antinociceptive and anti-inflam- anti-tumor activity demonstrated that N. sativa significantly enhances matory effects of its active constituents. splenocyte proliferation in a dose-responsive manner (Ghonime Development of solid tumour malignancies is closely associated et  al., 2011). Aqueous extract of N.  sativa significantly suppressed with inflammation. The steam-distilled essential oil of N.  sativa, the secretion of key proinflammatory mediators (IL-6, TNF-α, and which mainly contains p-cymene (37.3%) and TQ (13.7%), investi- NO) by primary macrophages indicating anti-inflammatory effects gated for its analgesic and antiinflammatory properties in rats was in vitro. Nigella sativa methanolic extract treatment (intraperito- found to produce a significant analgesic effect on acetic acid-induced neal) enhanced the total white blood cells count and increased spleen writhing, formalin, and light tail flick tests (Hajhashemi et  al., weight in BALB/c mice, suggesting the immunomodulatory activity 2004). Intraperitoneal injection of 100, 200, and 400 µl/kg signifi- of N. sativa seeds (Ghonime et al., 2011). Treatment with N. sativa cantly inhibited carrageenan-induced paw oedema. Mechanism(s) oil significantly decreased the antibody production in response to ty- other than opioid receptors are believed to be involved in this an- phoid vaccination (antigen typhoid TH) in a Long-Evans rat model. algesic effect of the Nigella essential oil. Its administration showed These results indicated that the N. sativa seeds could be considered anti-inflammatory activity probably attributable to TQ, one of the as a potential immunosuppressive cytotoxic agent (Torres et  al., major components of black cumin. The anti-inflammatory effect 2010). Co-administration of N.  sativa (2.5%) with oxytetracycline of TQ on LPS-stimulated BV-2 murine microglia cells has been completely blocked the leukocyte and lymphocyte decreasing effects reported, wherein TQ was effective in reducing nitrate with parallel elicited by oxytetracycline and produced immunostimulant effects decline of iNOS protein expression evidenced (Taka et al., 2015). TQ in pigeons indicating an immune-protective effect (Abel-Salam, also reduced LPS-mediated elevation in gene expression of Cxcl10 2012). Nigella sativa oil is also shown to have a promising radio- and some of other cytokines. The anti-inflammatory properties of protective action against immunosuppressive and oxidative effects TQ in LPS-activated microglial cells suggested the applicability of of γ-radiation in rats (Assayed, 2010). Nigella sativa seed extract TQ in delaying the onset of inflammation-mediated neurodegenera- significantly improved symptoms and immune parameters in murine tive disorders. ovalbumin-induced allergic diarrhoea in mice (Duncker et al., 2012). The aqueous extract of N.  sativa has been found to pos- sess anti-inflammatory and analgesic activities in animal models. Antioxidant and antimicrobial activity Although osteoporosis is linked to oxidative stress and inflamma- An evaluation of the essential oil of N.  sativa seeds, for antioxi- tion, the anti-osteoporotic effects of N. sativa and TQ are evidenced dants, showed that TQ and other components (carvacrol, t-anet- by observing the inhibition of inflammatory cytokines (interleukin hole, and 4-terpineol) have a radical scavenging property. These (IL)-1 and 6)  and the transcription factor (NFκB). Both N.  sativa constituents and the essential oil showed variable antioxidant ac- and TQ have shown potential as an anti-osteoporotic agent (Shuid tivity when tested in the diphenylpicrylhydrazyl assay; they also ef- et  al., 2012). TQ induced apoptosis and inhibited proliferation in fectively scavenged OH radical in the assay for non-enzymatic lipid pancreatic ductal adenocarcinoma (PDA) cells. This anti-inflam- peroxidation. matory potential involved an effect on the expression of different TQ has been shown to suppress the ferric nitrilotriacetate- proinflammatory cytokines and chemokines. TQ dose-dependently induced oxidative stress in Wistar rats (Khan and Sultana, 2005). reduced PDA cell synthesis of MCP-1, TNF-α, IL-1β, and Cox-2. Dietary N. sativa seeds inhibited the oxidative stress caused by oxi- TQ as an inhibitor of proinflammatory pathways provides an ef- dized corn oil in rats (Al-Othman et  al., 2006). Dietary N.  sativa fective strategy that combines anti-inflammatory and proapoptotic (10%) neutralized the oxidative stress induced by hepatocarcinogens modes of action (Chehl et al., 2009). A clinical trial was conducted such as dibutylamine and sodium nitrate in albino rats by normal- to investigate the anti-inflammatory effects of N.  sativa in patients izing glutathione and nitric oxide levels (Gendy et  al., 2007). The with allergic rhinitis symptoms. The anti-allergic effects of N. sativa N. sativa seed oil and TQ (intraperitoneal) are shown to have pro- components could be attributed to allergic rhinitis (Nikakhlagh tective effects on lipid peroxidation process during ischemia-reperfu- et  al., 2011). The anti-arthritic activity of orally administered TQ sion injury in rat hippocampus (Hosseinzadeh et al., 2007). Treating (5 mg/kg body once daily for 21 days) in collagen-induced arthritic broiler chicks with N.  sativa seed for 6 weeks reduced the oxida- Wistar rats was evidenced with significantly reduced proinflamma- tive stress in the liver by increasing the activities of myeloperoxi- tory mediators [IL-1β, IL-6, TNF-α, IFN-γ, and PGE ] and increased dase, glutathione-S-transferase, CAT, adenosine deaminase, and by IL-10 (Umar et al., 2012). decreasing hepatic lipid peroxidation (Sogut et  al., 2008). The TQ pre-treatment countered the increased level of lipid peroxidation and Immunomodulatory action augmented the antioxidant enzyme activities in the erythrocyte dur- The immunomodulatory properties of N. sativa and its major active ing 1,2-dimethylhydrazine-induced colon carcinogenesis in Wistar ingredient, TQ in terms of their experimentally documented abil- rats (Harzallah et al., 2012). ity to modulate cellular and humoral adaptive immune responses The bioactive compounds of N.  sativa essential oil identified (Table  6) have comprehensively been reviewed (Majdalawieh and using GC and GC-MS included p-cymene, TQ, α-thujene, longi- Fayyad, 2015). The molecular and cellular mechanisms underlying folene, β-pinene, α-pinene, and carvacrol. Nigella sativa essential such immunomodulatory effects of N. sativa and TQ are highlighted, oil exhibited different biological activities including antifungal, and the signal transduction pathways implicated in the immunoreg- antibacterial, and antioxidant potentials. Nigella sativa essential oil ulatory functions are suggested. Experimental evidence suggests that completely inhibited different Gram-negative and Gram-positive N.  sativa extracts and TQ can therapeutically be employed in the bacteria (Morsi, 2000). Nigella sativa oil also exhibited stronger Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 11 radical scavenging activity against DPPḢ radical in comparison with has been explained by its ability to modulate cell division in can- synthetic antioxidants. cer cells, involving downregulation of Bcl-xL, cyclin D1, and VEGF (Aggarwal et al., 2008). TQ is reported to be effective in inhibiting Anti-cancer properties human umbilical vein EC migration and invasion, suggesting its role The anti-cancer effect of N.  sativa has extensively been studied in in angiogenesis (Gali-Muhtasib et al., 2006). TQ is shown to prevent different in vitro and in vivo models (Table 5). Nigella sativa is able tumour angiogenesis in a xenograft human prostate cancer (PC-3) to exert antioxidant, anti-mutagenic, cytotoxic, pro-apoptotic, anti- model (Yi et  al., 2008). Nigella sativa, its oil, and TQ are effect- proliferative, and anti-metastatic effects in various primary cancer ive against cancer in the blood system, lung, kidney, liver, prostate, cells and cancer cell lines (Majdalawieh and Fayyad, 2016). The avail- breast, cervix, and skin. Some studies attribute the anti-cancer effect able studies strongly suggest that N. sativa could serve as an effective of TQ to its role as an antioxidant, ability to improve body’s immune agent to control tumour initiation, growth, and metastasis independ- system, and ability to induce apoptosis and control Akt pathway ently or in combination with conventional chemotherapeutic drugs. (Khan et al., 2011). Nigella sativa extract ameliorated the benz(α-)pyrene- The cytotoxic effects of N.  sativa seed extract as an adjuvant induced carcinogenesis in the forestomach in mice (Aruna and therapy to doxorubicin on human MCF-7 breast cancer cells are Sivaramakrishnan, 1990). This is partly attributed to the ability to reported. Nigella sativa lipid extract was found to be cytotoxic to influence phase II enzymes. Orally administered N.  sativa oil (14 MCF-7 cells with LC of 2.7  mg/ml, whereas its aqueous extract weeks) interfered with the induction of aberrant crypt foci (ACF) exhibited cytotoxicity at about 50 mg/ml (Mahmoud and Torchilin, by 1,2-dimethylhydrazine, putative preneoplastic lesions for colon 2012). TQ was found to be cytotoxic to human cervical squamous cancer in rats (Salim and Fukushima, 2003). This inhibition may be carcinoma cells (SiHa) with IC values of 10.7 µg/ml as determined associated, in part, with the suppression of cell proliferation in the by MTT assay, whereas it was less cytotoxic towards the normal cells. colonic mucosa. Nigella sativa aqueous suspension significantly pre- Cell cycle analysis indicated induction of apoptosis by the compound vented gastric ulcer formation experimentally induced by necrotiz- and elimination of SiHa cells via apoptosis with down-regulation ing agents and also significantly ameliorated the severity of ulcer of the Bcl-2 protein (Ng et  al., 2011). An investigation of the anti- and gastric acid secretion in pylorus-ligated Shay rats (Al Mofleh tumour and anti-angiogenic effects of TQ on osteosarcoma in vitro et al., 2008). and in vivo showed that TQ induced higher growth inhibition and The chemopreventive potential of N.  sativa oil on tumour for- apoptosis in the human osteosarcoma cell line SaOS-2. TQ signifi- mation has been revealed in a study using a rat multiorgan carcino- cantly blocked human umbilical vein endothelial cell tube formation genesis model induced by five different carcinogens (Salim, 2010). in a dose-dependent manner. The anti-tumour and anti-angiogenic Post-initiation administration of 1000 or 4000 ppm N. sativa vola- activity of TQ in osteosarcoma is possibly mediated by inhibition of tile oil in the diet for 30 weeks significantly reduced colon tumour NF-κB and downstream effector molecules (Peng et al., 2013). sizes, incidences, and multiplicities. Nigella sativa volatile oil also TQ exerted a strong anti-proliferative effect in breast cancer cells significantly decreased the incidences and multiplicities of tumours via its potential effect on the PPAR-γ activation pathway, and in in the lungs and alimentary canal (particularly the oesophagus and combination with doxorubicin and 5-fluorouracil, TQ’s cytotoxicity forestomach). Thus, N.  sativa exerts potential inhibitory effects on was found to be increased. Migration and invasion of MDA-MB-231 tumour development in multiple organ sites (Salim, 2010). Nigella cells were also reduced by TQ, which was found to increase PPAR-γ sativa oil (orally administered for 3 days) decreased the proinflam- activity and down-regulate the expression of Bcl-2, Bcl-xL, and sur- matory cytokines (TNF-α, IL-1β, and IL-6) in the blood of rats with vivin in breast cancer cells (Woo et  al., 2011). An investigation of experimental colitis induced with trinitrobenzene sulfonic acid (Isik the effect of TQ on pancreatic cancer cells and on MUC4 expres- et  al., 2011). Nigella sativa oil, by preventing inflammatory status sion revealed down-regulated MUC4 expression and induced apop- in the blood, partly protected colonic tissue against experimental tosis in pancreatic cancer cells. The decrease in MUC4 expression ulcerative colitis. Oral TQ (1–10  mg/kg) or N.  sativa oil (thrice was accompanied by increased apoptosis, decreased motility, and in a week for 4  months) exerted a protective effect against breast decreased migration of pancreatic cancer cells (Torres et al., 2010). cancer in female rats induced by 7,12-dimethylbenz[α-]anthracene The administration of N. sativa reduced the carcinogenic effects as revealed by tumour markers, histopathological alterations, and of DMBA in mammary carcinoma which indicated its protective the regulation of several genes (Brca1, Brca2, Id-1, and P53 muta- role in mammary carcinoma (Shafi et  al., 2008). TQ dose-depend- tion) related to breast cancer (Linjawi et al., 2015). ently suppressed the migration and invasion of Panc-1 cells. TQ Acute lymphoblastic leukaemia (ALL) is a common childhood also significantly down-regulated NF-kB and MMP-9 in Panc-1 malignancy and is conventionally treated with methotrexate which cells. Administration of TQ significantly reduced tumour metasta- also produces hepatotoxicity. The therapeutic value of N. sativa oil sis. Furthermore, the expression of NF-kB and MMP-9 protein in in methotrexate-induced hepatotoxicity has been assessed in 40 tumour tissues was down-regulated after treatment with TQ, thus Egyptian children with ALL under methotrexate therapy (Hagag exerting anti-metastatic activity on pancreatic cancer both in vitro et al., 2015). Nigella sativa oil (80 mg/kg/day for 1 week) produced and in vivo (Wu et al., 2011). The chemo-sensitizing effect of TQ and significant differences in remission, relapse, death, and disease-free 5-fluorouracil (5-FU) on gastric cancer cells both in vitro and in vivo survival. Nigella sativa seeds decreased methotrexate hepatotoxicity is reported (Lei et  al., 2012). Pre-treatment with TQ significantly and improved survival. This report is suggestive of its application as increased the apoptotic effects induced by 5-FU in gastric cancer cell an adjuvant drug in patients under methotrexate therapy. lines in vitro. The combined treatment of TQ with 5-FU was more Nigella sativa seed oil and TQ have been understood to exert effective in anti-tumour action than either of them individually in a antioxidant and chemopreventive properties (Allahghadri et  al., xeno-graft tumour mouse model. The TQ/5-FU-combined treatment 2010). TQ could suppress tumour cell proliferation in the case of induces apoptosis by enhancing the activation of both caspase-3 and breast adenocarcinoma, pancreatic carcinoma, colorectal carcin- caspase-9 in gastric cancer cells (Lei et al., 2012). oma, osteosarcoma, ovarian carcinoma, and myeloblastic leukaemia In summary, N. sativa oil and TQ are found to inhibit experimen- (Allahghadri et al., 2010). The cancer chemopreventive ability of TQ tal carcinogenesis in different animal models. It has been shown to Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 12 K. Srinivasan, 2018, Vol. 2, No. 1 arrest the growth of various cancer cells in culture as well as xeno- and reduced the occurrence of diarrhoea and body weight loss, graft tumours in vivo. The mode of anticancer effects of TQ includes associated with amelioration of colitis-related damage. Also, there inhibition of carcinogen-metabolizing enzyme activity and oxidative was a significant reduction in colonic myeloperoxidase activity and damage to cellular macromolecules, amelioration of inflammation, malondialdehyde levels and an increase in glutathione levels (Lei inhibition of cell cycle and apoptosis in tumour cells, inhibition of et al., 2012). tumour angiogenesis, and suppression of migration, invasion, and metastasis of cancer cells. TQ improves anti-cancer effects when Nephroprotective effect combined with conventionally used chemotherapeutic agents. At the The nephroprotective effect of N.  sativa oil is observed in gen- molecular level, TQ targets intracellular signalling pathways, par- tamicin-induced nephrotoxicity in rabbits (Saleem et  al., 2012) ticularly a variety of kinases and transcription factors, which are (Table 7). Vitamin C and N.  sativa oil when given as combination activated during tumourigenesis. showed a synergistic nephroprotective effect (Saleem et  al., 2012). Oral treatment of N.  sativa oil (0.5, 1.0, or 2.0  ml/kg/day for Gastroprotective effect 10  days) produced a dose-dependent amelioration of gentamycin- Nigella sativa oil and its constituents are proved to exert gastro- induced nephrotoxicity in rats as assessed by the biochemical and protective effect (Table 7); some of the potential mechanisms exhib- histological indices of nephrotoxicity (Ali, 2004). The protective ited by N. sativa in preventing or curing gastric ulcers are reviewed effect of N.  sativa oil on methotrexate-induced nephrotoxicity has recently (Khan et  al., 2016). The mechanism of gastroprotective been reported in albino rats which is medicated through restoring effect of TQ has been assessed in rats injected with TQ (10 and the antioxidant status (Abul-Nasr et  al., 2001; Yaman and Balikci, 20  mg/kg) and subsequently subjected to ischemia or reperfusion 2010). The protective effects of N.  sativa oil in the prevention of insult. TQ restored the altered acid secretion, gastric mucosal con- chronic cyclosporine A-induced nephrotoxicity in rats were evi- tent, lipid peroxide, and the activity of myeloperoxidase, reduced denced by attenuation of the oxidative stress (Uz et  al., 2008). TQ glutathione, and total nitric oxide along with ulcer index, the effi- supplementation prevented the development of gentamycin-induced cacy being comparable with that of the reference drug omeprazole. degenerative changes in kidney tissues and cisplatin-induced renal TQ exerted gastroprotection via inhibiting proton pump, acid secre- injury in rats as indicated by lipid peroxides and renal organic anion tion and neutrophil infiltration, while enhancing mucin secretion, and cation transporters (Sayed-Ahmed and Nagi, 2007; Ulu et  al., and nitric oxide production, in addition to the antioxidant influences 2012). Nigella sativa significantly prevented renal ischemia- or rep- (Magdy et al., 2012). erfusion-induced functional and histological injuries in Wistar rats The anti-ulcer potential of N. sativa aqueous suspension on gas- (Mousavi, 2015). Nigella sativa showed protective effects against tric ulcers experimentally induced with various noxious chemicals ischemia-perfusion damage on kidney tissue based on the total anti- (indomethacin, 80% ethanol, and 0.2 M NaOH) in Wistar rats oxidant capacity, oxidative status index, and activities of catalase was examined (Al Mofleh et  al., 2008). Nigella sativa significantly and myeloperoxidase in the kidney tissue (Yildiz et al., 2010). prevented gastric ulcer formation induced by necrotizing agents by significantly replenishing the depleted gastric wall mucus content Hepatoprotective effect and gastric mucosal non-protein sulfhydryl concentration. The anti- It is reported that N.  sativa (i.p.  0.2  ml/kg) relieves the deleterious ulcer effect of N.  sativa was exerted through its antioxidant and effects of ischemia-reperfusion injury on liver in rats, as indicated by anti-secretory activities (Al Mofleh et al., 2008). Both N. sativa (2.5 titers of marker enzymes, total antioxidant capacity, total oxidative and 5.0 ml/kg, p.o.) and TQ (5, 20, 50, and 100 mg/kg, p.o.) were status, and myeloperoxidase in the liver tissue (Yildiz et  al., 2008) ++ found to possess gastro-protective activity against gastric mucosal (Table 7). The protective effect of TQ on the Cd -induced hepato- injury induced by ischemia or reperfusion in Wistar rats (El-Abhar toxicity in mice, particularly the perturbation of non-enzymatic and et al., 2003). Lipid peroxidation and lactate dehydrogenase, elevated enzymatic antioxidants, has been reported (Zafeer et al., 2012). Pre- by the ischemia or reperfusion insult and decreased glutathione and treatment with TQ (10  µmol/l) showed a significant protection as activity of SOD accompanied by an increased formation of gastric indicated by an attenuation of protein oxidation and recovery of the lesions, were countered by N.  sativa or TQ treatment, indicating depleted antioxidants, suggesting that TQ exerts modulatory influence their gastroprotective effect, probably by conservation of the gastric on the antioxidant defence system when subjected to toxic insult. mucosal redox state. Pulmonary-protective activity and anti-asthmatic Nigella sativa and TQ are reported to protect gastric mucosa against the ulcerating effect of alcohol on hypothyroidal rats and effects mitigate most of the biochemical adverse effects on gastric mucosa, Nigella sativa has been investigated for the possible beneficial viz., increase in lipid peroxidation and reduced gastric glutathione effects on experimental lung injury in rats after pulmonary aspir- content, and enzyme activities of gastric SOD and GST (Khaled, ation (Kanter, 2009) (Table 7) and found that N.  sativa treatment 2009). The beneficial effect of N.  sativa oil (2  ml/kg daily, i.p.) inhibits the inflammatory pulmonary responses. Nigella sativa ther - in rats with necrotizing enterocolitis (NEC) was studied in new- apy resulted in a significant reduction in the activity of iNOS and born Sprague-Dawley rats (Tayman et al., 2012). Histopathologic an increase in surfactant protein D in the lung tissue of different and apoptosis evaluation indicated that the bowel damage was less pulmonary aspiration models. It is concluded that N.  sativa treat- severe in the N.  sativa oil–treated group. Nigella sativa oil had a ment might be beneficial in lung injury that merits potential clinical beneficial preserving effect on tissue antioxidant enzymes, whereas use. The ameliorative effect of N. sativa oil in rats with hyperoxia- lipid peroxide levels were significantly lower than those in the NEC induced lung injury has also been reported (Tayman et al., 2012). control group. In a mouse model of inflammatory bowel disease The prophylactic effect of an extract of N.  sativa (15  ml/kg of (C57BL/6 murine colitis induced with dextran sodium sulfate), 0.1 g% boiled extract for 3 months) has been examined in asthmatic treatment with TQ (5, 10, or 25 mg/kg) ameliorated colonic inflam- adults. All asthma symptoms, the frequency of symptoms, chest wheez- mation (Lei et al., 2012). The treatment of mice with TQ prevented ing, and pulmonary function tests (PFT values) were significantly Downloaded from https://academic.oup.com/fqs/article-abstract/2/1/1/4823052 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Nutraceutical effects of cumin and black cumin seeds, 2018, Vol. 2, No. 1 13 improved as a result of N.  sativa treatment, generally suggesting a constituents like TQ could be used in suitable combinations with prophylactic effect on asthma disease (Boskabady et  al., 2007). TQ conventional therapeutic agents for maximizing the effectiveness in potently and dose-dependently inhibited the formation of leukot- the treatment of many infectious diseases and also to circumvent the rienes—supposedly important mediators in asthma and inflammatory drug resistance problem. Further investigations are recommended to processes, in human blood cells (Mansour and Tornhamre, 2004). explore the specific cellular and molecular targets of various con- stituents of N. sativa, particularly TQ. Miscellaneous nutraceutical effects During the last three decades, several in vitro and in vivo animal References studies have ascertained the pharmacological properties of N. sativa, Abdelmeguid, N. E., Fakhoury, R., Kamal, S. M., Al Wafai, R. J. (2010). including its antioxidant, antibacterial, anti-proliferative, proa- Effects of Nigella sativa and thymoquinone on biochemical and subcel- poptotic, anti-inflammatory, and antiepileptic properties, and its lular changes in pancreatic β-cells of streptozotocin-induced diabetic rats. beneficial effect in conditions of atherogenesis, endothelial dys- Journal of Diabetes, 2: 256–266. Abel-Salam, B. K. (2012). 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Standard clinical trials are however needed for Sung, B., Anand, P. (2008). Potential of spice-derived phytochemicals for N. sativa supplementation for its promotion as an adjuvant therapy. cancer prevention. Planta Medica, 74: 1560–1569. Long-term administration of N. sativa increased brain serotonin Ahmad, M., Akhtar, M. S., Malik, T., Gilani, A. H. (2000). Hypoglycaemic action of the flavonoid fraction of Cuminum nigrum seeds. Phytotherapy levels and improved learning ability and memory in rats (Perveen Research: PTR, 14: 103–106. et al., 2008). Chronic administration of N. sativa decreased sero- Akhtar, M. S., Ali, M. R. (1985). Study of hypogiycaemic activity of Cuminum tonin turnover and produced anxiolytic effects in rats. Tryptophan nigrum seeds in normal and alloxan diabetic rabbits. Planta Medica, 2: concentration in brain and plasma also increased significantly fol- 81–85. lowing repeated oral administration of N. sativa oil, suggesting that Akhtar, M., Maikiyo, A. M., Khanam, R., Mujeeb, M., Aqil, M., Najmi, A. K. this oil is useful for the treatment of anxiety (Perveen et al., 2009). (2012). Ameliorating effects of two extracts of Nigella sativa in middle Anti-anxiety-like effects of TQ (20 mg/kg) was observed in mice, cerebral artery occluded rat. Journal of Pharmacy & Bioallied Sciences, which involved modulation of GABA and NO levels. The anxiolytic 4: 70–75. effect was accompanied by a significant decrease in plasma nitrite Al Mofleh, I. A., et al. (2008). Gastroprotective effect of an aqueous suspen- and countering of decreased γ-aminobutyric acid content in the sion of black cumin Nigella sativa on necrotizing agents-induced gas- tric injury in experimental animals. Saudi Journal of Gastroenterology: brain (Gilhotra and Dhingra, 2011). The neuroprotective effects of Official Journal of the Saudi Gastroenterology Association, 14: 128–134. the aqueous extract of N. sativa have been recorded during cere- Ali, B. H. (2004). 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