BIOLOGICAL ACTIVITIES AND THERAPEUTIC PROMISES OF NIGELLA SATIVA L

Nigella sativa L. (NS) is evident to have a number of important biological activities, such as antioxidant, anti-inflammatory, antibacterial, antifungal, anti-viral, anti-parasitic and anti-protozoal, cytotoxic, anticancer, neuro-, gastro-, cardio-, hetaptoand nephro-protective activities. In addition, the NS implies beneficiary effects on reproductive, pulmonary and immune systems as well as in diabetes mellitus (DM), fertility (male and female), breast cancer, dermatological complications, dehydration, dyspepsia, and osmotic balance and so on. Among the other isolated constituents, thymoquinone (TQ) is a vastly studied phytochemical in NS. A number of reports suggest that, the NS may be one of the potential herbs in health promotion. This paper will discuss the current scenario of NS activity in a mechanistic way. ISSN 2471-6782 237 List of abbreviations: 5-HIAA 5-HIAA: hydroxyindole acetic acid, 5-HT: serotonin, ACC: acetyl CoA carboxylase, AChE: acetylcholinesterase, ADA: adenosine deaminase, Akt: protein kinase B, ALT: alanine aminotransferase, AO: acid output, APAP: N-acetyl-p-aminophenol, AST: aspartate aminotransferase, bax/bcl-4: apoptosis regulator, bcl-1: cyclin b1, bcl-2: cyclin b2, bcl-xl: cyclin b xl, BUN: blood urea nitrogen, CAT: catalase, CDK-p16: cyclin-dependent kinase p16, CGD: conjugated diene, c-JUNK: c-Jun-amino-terminal kinase, CK: creatinine, COX-1: cyclooxygenase-1, COX-2: cyclooxygenase-2, CP: cisplatin, CVS: cardiovascular system, cyclin b1 (bcl-1), cyclin-dependent kinase p16 (CDK-p16), dcl-1: cyclin d1, DM: diabetes mellitus, FABPs: fatty acid binding proteins, FAS: fatty acid synthase, FGF: fibroblast growth factor, GPx: glutathione peroxidase, GSH: reduced glutathione, GSH-ST: glutathione-Stransferase, HbA1c: glycosylated hemoglobin, HDAC: histone deacetylase, HDL-C: high-density lipoprotein-cholesterol, HIV: human immunodeficiency virus, i.g.: intra-gastric, i.p.: intraperitoneal, IFN-γ: interferon-gamma, IL: interleukin, LDH: lactate dehydroginase, LDL-C: low-density lipoprotein-cholesterol, LPO: lipid peroxidase, LPO: lipid peroxidase, LT4: leukotriene-d4, MDA: malonilealdehyde, MPO: myloperoxidase, NF-κB: nuclear factor-kappa-B, NK: natural killer, NLRP3: NACHT, LRR, and pyrin domain-containing protein 3, NO: nitric oxide, OSI: oxidative stress index, OXT: oxytetracycline, p.o.: per oral, PET: pulmonary function test, PGD: prostaglandin, PGE2: prostaglandin, ROS: reactive oxygen species, SCC: squamous cell carcinoma, SOD: superoxide dismutase, SP-1: protein expression in papiloma, TAC: total antioxidant capacity, TBARS: thiobarbituric acid substances, TC: total cholesterol, TG: thyroglobulin, TGF-β: transforming growth factor beta, TNF-α: tumor necrosis factor-alpha, TNO: nitric oxide, TOS: total oxidative status, TQ: thymoquinone, TSH: thyroid stimulating hormone, UI: ulcer index


Introduction
Hindi/Nepali: Mangrail)1 contains all kinds of remedies except death. To date (March 2016) in the databases such as PubMed/ Medline, Science Direct, Web of Science, Scopus, and google, a total of 1290 published evidences were found on the following topics: morphology of the plant, isolated compounds and their derivatives, and pharmacological activities. One general revision of this plant was done by Ahmad et al 2 , following to a dermatological revision by Aljabre et al 3 , an immunomodulatory and anti-inflammatory revision by Majdalawieh and Fayyad 4 , an anti-inflammatory, antioxidant, an immunomodulatory revision by Gholamnezhad et al 5 , male fertility revision by Mahdavi et al 6 , metabolic parameters in diabetes mellitus revision by Heshmati and Namazi 7 , and thymoquinone and its therapeutic potentials by Darakhshan et al 8 .
This text summarizes the above mentioned seven revision articles. Additionally, data from 2014 to March 2016 were also included in this revision. More emphasize was given to the action mechanisms.

Nigella sativa (NS) in short
The NS is a small shrub (20 to 90 cm in tall) under the family, Ranunculaceae. It is native to Southern Europe, North Africa and Southeast Asia; cultivated in many countries in the world like Middle Eastern, Mediterranean region, South Europe, India, Pakistan, Syria, Turkey, Saudi Arabia 2 . It has tapering green leaves and rosaceous white, yellow, pink, pale blue or purplish flowers with 5-10 petals. The ripe fruit (capsule: 3-7 united follicles) contains numerous tiny seeds, dark black in color. The seed and oil of NS was frequently used in ancient remedies (Unani, Ayurveda, Chinese and Arabic) in Asian countries and in the Middle-East. The use of black seeds (seeds of NS) had been mentioned by Ibne-Sina (980-1037) in his famous book Al-Qanoon fitt-Tibb 3 .
Traditionally NS is used as a medicament of a variety of disorders, including the respiratory system, digestive tract, cardiovascular system (CVS), kidney, liver, and immune system. The use of NS in fatigue and dispiritedness is antique. The most common traditional uses belong to the ailments, including asthma, bronchitis, rheumatism and related inflammatory diseases, indigestion, loss of appetite, diarrhea, dropsy, amenorrhea, dysmenorrhea, worms and skin eruptions. It is also used as an antiseptic and local anesthetic 2 .

NS against bacteria
The NS is found to act against gram positive (Staphylococcus aureus) and gram negative (Pseudomonas aeruginosa and Escherichia coli) species. It showed synergistic effects with streptomycin and gentamycin, while additive with spectinomycin, erythromycin, tobramycin, doxycycline, chloramphenicol, nalidixic acid, ampicillin, lincomycin and co-trimoxazole and similar to topical mupirocin. Moreover, the NS has potent inhibitory activity against antibiotic resistant microorganisms, including many multi-drug-resistant (MDR) gram positive and gram negative bacteria 3 . According to Manju et al 10 the EO from NS is able to protect Artemia spp. from Vibrio parahaemolyticus Dahv2 infection. According to Hariharan et al 11 , thymoquinone (TQ) the well known NS compound has shown antimethicillinresistant activity in S. aureus. TQ is also evident to act against a number of gram positive and gram negative pathogenic bacteria 8 .

NS against fungi
The NS is found to inhibit the growth of Candida albicans and Madurella mycetomatis, while TQ by Aspergillus niger, Fusarium solani and Scopulariopsis brevicaulis more effectively than the amphotericin-B and griseofulvin. The TQ also acted against Trichophyton spp., Epidermophyton spp., and Microsporum spp. In addition TQ, thymohydroquinone and thymol are also demonstrated to have an antifungal effect against many clinical isolates, including dermatophytes, molds and yeasts3. Furthermore, the NS seed oil (10-200 μg/mL) was found to act against Saccharomyces cerevisiae and C. utilis 12 .

NS against viruses
In a study, the NS enhanced helper-T-cell (T4) and suppressor-T-cell (T8) ratio and increased the natural killer (NK) cell activity in human. Furthermore, it significantly inhibited the human immunodeficiency virus (HIV) protease and murine cytomegalovirus. In the latter case, it was found to increase in number and function of the M-phi and CD4+ve T cells with the production of interferon-gamma (INF-γ) 3 .

NS against parasites
The NS is evident to have anti-leishmaniasis, anti-miracidia, anticercariae and anti-Schistosoma mansoni potentials. In the latter case the oil of the black seed showed a strong activity as compared to the anti-schistosomal and anthelmintic drug for domestic animals, prazequantel; where it produced a potentiating effect with the co-treatment 3 . Moreover, Simalango and Utami 13 suggested that the ethanol extract of NS (0.5-8%) has significant anti-Ascaris suum activity.

NS in wound infection
The wound healing capacity of NS was evaluated in farm animals, mice and human gingival fibroblast. The accumulated result suggests that there is a reduction in absolute differential leukocytes (WBC) counts, local infection and inflammation, bacterial expansion and tissue impairment, and free radical production. An elevation of basic fibroblast growth factor (FGF) and transforming growth factor beta (TGF-β) were also reported (Aljabre et al.

NS in inflammation
Findings from different animal models suggest that, the NS extracts, seed oil and TQ have strong anti-inflammatory activities.
In some studies, they were found to reduce the synthesis of NO, IL-1, cyclooxygenase (COX)-1, COX-2, histone deacetylase (HDAC) along with other pro-inflammatory mediators such as -IL-1β, IL-6, TNF-α, IFN-γ, and PGE 2 2 . The topical application of TQ was found to induce an expression of hemeoxygenase (HO)-1, NAD(P)H-quinoneoxidoreductase-1, GSH-ST and glutamate cysteine ligase in mice; while the seed oil inhibited COXs, 5-LPO in the pathways of arachidonate metabolism in rats 3 . TQ is also evident to down-regulate the nuclear translocation and the DNA binding of nuclear factor-kappa-B (NF-κB) via the blockade of phosphorylation and subsequent degradation of IκBα in mice. Moreover, the TQ was also attenuated the phosphorylation of Akt (protein kinase B), c-Jun-amino-terminal kinase (c-JUNK) and p38 mitogen-activated protein kinase (MAPK-p38). In another study, a decrease in expression of the NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) in B16F10 mouse resulted in inactivation of caspase-1 followed by the inhibition of IL-1β and IL-18. In addition, the inhibitory effect of TQ to NF-κB and reactive oxygen species (ROS) resulted in the partial inactivation of NLRP3 inflammasome 3,4,14 . Figure 3 tells the basic antiinflammatory activity pathways of NS.

NS in cancer
The black seed oil can stimulate the NK cells, which is a potential applicability in immune therapy. Otherwise, the oil components may induce pro-oxidative effects thus the carcinogeneticity. The TQ tested in a number cancer cells derived from mice, suggesting its ability to arrest G 0 /G 1 phases of cell-cycle, which correlated with sharp increases in the expression of the cyclindependent kinase p16 (CDK-p16) and a decrease in cyclin d1 (dcl-1) protein expression in papiloma (SP-1) cell line and G 2 /M arrest associated with an increase in the expression of the tumor suppressor protein p53 with a decreased level of cyclin b1 (bcl-1) protein. The chemopreventive potential of TQ may be due to its ability to increase the ratio of apoptosis regulator (bcl-4)/cyclin-2 (bax/bcl-2) expression and decreasing cyclin-xl (bcl-xl) protein.
The antitumor activity of TQ was also reported in squamous cell carcinoma (SCC VII), FsaR and murine tumor models of fibrosarcoma and SCC. TQ showed potent anticancer activity in A431 and Hep2 cells via apoptosis by increasing the sub-G1 population, live/dead cytotoxicity, chromatin condensation, DNA laddering and Tunel-positive cells. Along with an increase in bax/ bcl-2 ratio activation of cell proliferation of caspases and cleavage of poly ADP ribose polymerase was also observed 3 .  15 suggesting that TQ induced apoptosis through p53-independent pathway with an expression of p21 and cell-cycle S phase arresting in human colon cancer cells. TQ also exerted an anticancer effect in a number of cancer cell lines, including MCF-7/Topo breast carcinoma cells. It was found to down-regulate the NF-κB and MMP-9 in Panc-1 cells and bcl-2 in gastric cancer cells, while up-regulator of caspase-3 and caspase-9 in the later one. A number of derivatives of TQ namely 6-menthoxybutyryl, 6-hencosahexanyl conjugate, 4-acylhydrazones and 6-alkyl derivatives are also evident to produce anticancer activity in cancer cell lines 2 .
Recent evidence suggests that the nanoemulsion of NS oil at a concentration of 20-80 µL/mL caused cell membrane blebbing, cytoplasmic vacuolation, marginalization of chromatin, and fragmentation of the nucleus in MCF-7 cells 16 . A recent evidence suggests that topical use of black seed oil (600 mg) reduced cyclic mastalgia in woman (n = 52), where the activity was found significant when compared to the painkiller, diclofenac 17 . A basic NS-anticancer traits has been sketched in Figure 4.

NS in diabetes
The NS was found to reduce blood glucose level with an augmenting insulin level and C-peptide in rats. Whereas, TQ reduces the tissue MDA levels, DNA damage, mitochondrial vacuolization and fragmentation, and preserves pancreatic β-cell integrity via antioxidant capacity. In a study TQ increased the levels of insulin, Hb with a significant decrease in glucose and glycosylated hemoglobin (HbA1c) levels. The NS showed a synergistic activity with parathyroid hormone in improving bone mass, connectivity, biomechanical behavior and strength in T2D rats. The NS is also evident to show some advantages in insulin resistance syndrome and dislipidemic patients. Furthermore, an insulin-sensitization action via enhancing ACC phosphorylation (mainly MAPK signaling pathway) and muscle GLUT4 content as well as progressive normalization of glycaemia are also seen in NA-treated diabetic Meriones shawi 2,7 . In a study, the lipid (4%) and volatile oil fractions (3%) of NS in streptozotocin-induced diabetes mellitus (DM) rats reduced toxicological and adverse consequences significantly 18 . In addition, an improved glycemic status and lipid profile with NS oil treatment at 3 g/3-times/day in DM patients (n = 72) were also reported by Heshmati et al 19 .
TQ when tested in clonal β-cells and rodent islets it caused a protective effect with normalization of chronic accumulation of malonyl CoA, and elevation of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS) and fatty acid binding proteins (FABPs) following a chronic glucose overload, suggesting the modulation in β-cell redox circuitry and enhancing sensitivity of β-cell metabolic pathways to glucose and glucose-stimulated insulin secretion (GSIS) under both normal conditions and hyperglycemia 20 . Generally, the MAPK regulates a number of transcriptional factors, altering of which interferes in cell-cycle. Thus, NS and TQ may be a good remedy for both type 1 and 2 DM patients, as in this consequence maintenance of beta-cell integrity and secretion of insulin sufficient for glycogenesis and phosphorylation of raised glucose in the blood are crucial. Otherwise, along with ingested food, oxidative stress, infection and trauma are the factors that increase in blood sugar levels. Thus, the antidiabetic activity of NS and TQ may connect with their antioxidant, antimicrobial, cytotoxic and anti-inflammatory activities. Otherwise, the decreasing level of HbA1c is one of the remedy for cardiovascular disease, nephropathy, neuropathy, and retinopathy. Figure 5 tells the possible anti-diabetic action pathways of NS.

NS effects on immune system
Along with NK antitumor activity, the NS is a demodulator of the secretion of a number of pro-inflammatory mediators with upmodulation of secretion of Th2/Th1, cytokines in splenocytes. The NS is also evident to restore the resistance against granulocytedependent C. albicans. A study performed by the NS oil suggests decreasing antibody production in typhoid vaccination, which may be due to its immunosuppressive cytotoxic effect. It is also evident to correct the imbalance situation caused by oxytetracycline (OXT) in leukocyte, lymphocyte counts, heterophil:lymphocyte ratio, lysosomal enzyme activity and reticuloendothelial system function. Moreover, the NS produced an immunoprotective effect in chronic antibiotic loaded pigeons. The NS oil was also exerted radioprotectivity, immune-stimulatory, reducing the effects of ionizing radiation-induced situations. In addition, an increased level of IFN-γ with a significant decreased in pathological changes of the guinea pigs' lung was reported by NS oil treatment. It is also effective in allergic diarrhea 3,4,14 . A recent evidence suggests that, the seed oil is protective against γ-radiation-induced damage in jejunal mucosa 21 . Moreover, EO from NS at 5-20 g/kg (oral feed for 6 weeks) in chickens improved FCR and plasma lipid profile and antibody-mediated immunity 22 . In a study, the NS oil also reduced thyroid stimulating hormone (TSH) and anti-thyroid peroxidase antibodies in patients with Hashimoto's thyroiditis 23 .

NS on nervous system
Methanolic extract of NS is reported as a potent analgesic and antidepressant. In addition, an anxiolytic activity via increasing serotonin (5-HT) and decreasing hydroxyindole acetic acid (5-HIAA) levels were also reported in rat brain. In another study, an increased 5-HT secretion along with improving learning and memory capacity in rats were detected with NS treatment. As NS may augment in tryptophan levels, it may be helpful in anxiety treatment. Otherwise, TQ produced GABA-mediated anxiolyticlike effect in mice with a decline of NO and MDA production 2 .
The possible neuroprotective activity may be due to its antioxidant, free radical scavenging and anti-inflammatory capacities.
Along with these, anti-acetylcholinesterase (anti-AChE) and anticonvulsant activities were also evident with NA and TQ treatments, respectively. There is a suggestion for GABAA-ergic anticonvulsant effect of TQ 2 .
NS EO at 1 g/kg (i.g.)/day and TQ 30 at mg/kg/day (i.p.) in Wistar albino rats produced anti-nitrosative effects after a 10 days treatment 24 . The NS EO is also evident to prevent cerebral edema in the hippocampus tissue of the rat brain 25

Effects on cardiovascular system (CVS)
TQ is evident to decrease motor fuel (diesel particle)-induced systolic blood pressure, leukocytes, IL-6 and plasma SOD activity. It is also prevented to decrease platelet counts and the prothrombin events rather than platelet aggregation 2 . The black seed oil reduced the total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and thyroglobulin (TG) with an increased high-density lipoprotein-cholesterol (HDL-C) level 29 .

Effects on hepatic system
The NS effect on alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, total antioxidant capacity (TAC), CAT, MPO, total oxidative status (TOS) and oxidative stress index (OSI) tells that it has hepatoprotective activity. In addition GSH, TQ increased protein carbonyl content, thus the attenuation of protein oxidation and upgrading of the depleted antioxidant cellular fraction 2 . Moreover, the NS oil at a dose of 25-100 μg/ mL protected hepatocytes from N-acetyl-p-aminophenol (APAP)induced hepatotoxicity and metabolic disturbances in TIB-73 cells of mice 30 . A similar activity was also observed by Hamza and Al-Harbi 31 with aqueous extract of NS, where the activity was thought to be linked with an improved antioxidant potential and suppressed in lipid peroxidation and ROS generation 30 . In addition, the black seed oil at a dose of 2 mg/kg (p.o.) with cisplatin (CP)treated rats are also evident for its hepatoprotective activity via improving energy metabolism and strengthening antioxidant defense pathways 32 .

Effects on urinary system
The NS along with ascorbic acid (Vitamin C) produced a nephroprotective effect by lowering serum creatinine (CK), blood urea nitrogen (BUN) and antioxidant activity in rabbits. On the other hand, the TQ showed an effect on renal expression of organic ion transporters and multidrug resistance-associated proteins in rats. TQ-mediated increased in protein levels of the efflux transporters MRP2 and MRP4, and decreased expression of OAT1, OAT3, OCT1 and OCT2 was also observed in rats. Along with decreasing tubular necrosis score, NS significantly reduced the CK, urea, MDA, NO, ROS, OSI and TOS levels and augmenter of TAC, SOD, GPx in kidney tissue and blood. Furthermore, the TQ is also evident to antagonize the gentamicin (GM)-induced alteration of serum CK, BUN, thiobarbituric acid substances (TBARS), total nitrite/nitrate content, GSH, GPx, CAT and ATP values in rats 2 . Moreover, the ethanol extract of NS at 250-100 mg/kg (p.o.) in female Wistar Albino rats showed a significant nephroprotective activity against paracetamol-induced nephrotoxicity 33 . In another study, the NS exhibited a significant nephroprotective effect in Cdinduced nephrotoxicity in rats 34 .

Effects on respiratory system
Both nigellone and TQ are evident to inhibit leukotriene-d4 (LT4) in the trachea, where the activity of the first one was suggested via mucociliary clearance. However, NS is evident to reduce the peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudates, alveolar macrophages, intestinal fibrosis, granuloma, necrosis formation, NOS and surfactant protein D in the pulmonary system. The NS is also evident to have beneficial effects against lung injury and hypoxia-induced lung damage. In a study, the NS puffs were proven to relieve asthma symptoms, frequency of asthma symptoms/weakness, chest wheezing and pulmonary function test (PFT) values with a bronchodilatory effect 2 . Effects on reproductive system TQ decreased TAC and MPO levels in C57BL/6 male mice. In addition, TQ alerted the events produced by methotrexate such as intestinal space dilatation, edema, disruption in the somniferous epithelium and reduced diameter of the semniferous tubules. Moreover, infertile men (n = 34) when treated with 2.5 mL NS oil for 2 months, significantly improved abnormal semen quality without producing any adverse effect was observed 35 . According to Mahdavi et al 36 the NS oil is a good candidate for treating male infertility. Hexane and methanol extracts of NS produced significant anti-fertility in Sprague-Dawley male and female rats, respectively. Otherwise, NS is evident to inhibit the uterine smooth muscle contraction in rats and guinea pigs 2,36 . TQ when treated with olive oil caused a reduction in polycystic overy in rats possibly, via NF-κB signaling pathway 37

NS in dyspepsia
Patients (n = 70) with functional dyspepsia when treated with NS oil of 5 mL (p.o.) for 8 weeks, a significant lowering of dyspepsia was observed 38 .

NS in osmotic balance
The geriatric patients (n = 42) when treated with NS oil (22.6 µg/25 µL) for 2 weeks, it was demonstrated that NS may be an alternative therapy of the isotonic sodium chloride (0.9% NaCl) solution 39 .

Topical applications
A TQ-induced skin darkening via chlonergic mechanisms of muscarinic receptor in the melanin dispersion is evident, whereas, NS oil for decreasing vitiligo area scoring index without seeing adverse effects. Moreover, TQ and nigellone inhibited histamine release, protected histamine-induced bronchospasm in guinea pigs, decreased lung ensiphilia, elevated Th2 cytokines and raised IgE and IgG1 antibodies in mice. To be mentioned that, the NS has a good recommendation in hand eczema. Linoleic acid from this plant is known for its percutaneous adsorption enhancing capability of drugs, while the oil emulsion for reducing skin irritation and improving moisturizing and epidermal barrier function. It has also anti-aging, mitigating, and protective effects 3 . Both NS and TQ can be used in oral health and hygiene 40 .    Table 2 suggests NS interaction profiles with drugs/chemicals/biochemicals.

Authors' view-points
At low levels and temporary spikes of ROS are beneficial for health 55 rather than high production and chronic effects as they may up-regulate pro-inflammatory cytokines, chemokines and pro-inflammatory transcription factors 56 and induces cell death by damaging macromolecules such as lipids, DNA, RNA, and other proteins. In extrinsic pathway, excessive ROS are generated by Fas ligand which in association with death domain and caspase-8 cause apoptosis 56 . Otherwise, in the caspase cascade pathway (intrinsic) ROS facilitate to release cytochrome C by activating bcl-2 and bcl-xl and bcl-2-associated X protein as well as bcl-2 homologous antagonist/killer 57 . ROS implicates a variety of detrimental responses, including CVS diseases (e.g. -stroke and heart attack), hearing impairment via cochlear damage, decline memory capability (degenerative diseases, e.g. -AD), ischaemic injury, and so on. Unlike apoptosis and necrosis, autophagy cell death occurs by self-digest of the damaging portion to take an attempt to minimize the damage and can no longer survive. However, it is possible to make available ROS to the other normal cells by this process as cellular programming is enough for a programmed cell death. Radiations form radiotherapy induces ROS-mediated cell death and mitotic failure 56 . However, an ideal ROS neutralizer (antioxidant/cytoprotective agent) is not enough in the cancer therapy, even if it has antioxidant-mediated prooxidant effect, as it may act like dual nature of ROS! Therefore, cell targeting, self-redox balancing; genotoxic, but non-mutagenic, exact concentrations of ROS at the targeted site along with action period are the major concerns in the chemo-/radio-therapeutic cancer treatments.
In the above discussion, TQ, the well-known NS-derived quinone and other NS constitutions are evident to have targeted effects in a range of cellular proteins. It is doubtless, that TQ is ready to go for a clinical trial, due to its numerous promising biological effects and therapeutic potentials 8 . Having strong antioxidant capacity through antiradical including ROS, direct reduction of oxidizable substrates and induction of cellular antioxidant molecules, they may be good sources as cytoprotective agents, especially, the TQ, although' its mutagenic effect is yet to be found out. The carcinogenic and immunosuppressive cytotoxic effects of NS oil can be overcome by the co-treatment with antibiotics or radiotherapy.
Being a spacious habitual world-wide and having good number already isolated chemical moieties, NS is a weapon to the drug scientists. A number of researches have been done on this plant and its isolated compounds, especially on TQ and its derivatives and nigellone telling that chemical modification may bring a fruitful outcome to the drug library. In addition, some clinical uses suggest that NS is a safe and health promoter, especially observed in antifertility test. Although, the exact mechanism of actions of the investigated pharmacological potentials is yet to be found out, but the toxicological and its interaction profiles suggesting beneficial rather than detrimental effects. Generally, substances having antioxidant, antimicrobial or cytotoxic other than genotoxic and mutagenic potentials are good for healthy consumption. NS falls in this category. Finally, for its wide variety of activities, NS may be called the 'marvelous shrub'.

CONCLUSION
Drugs from the shrubs are one of the potential plant derived sources. Interestingly, now a day herbal medicaments are in a great attention to the consumers world-wide. Doubtless, the traditional medicines are still occupying potential sources of phyto-based remedies. A potential and diverse activity of a scrupulous source is the stimulation to the drug researchers. The NS and few of its isolated compounds such as TQ (including its derivatives), nigellone, α-hederin and linoleic acid have been demonstrated for a number of important pharmacological activities. In addition, the clinical usages of NS, making the herb and its constituents potential phytotherapeutic tools. The NS is a health promoting herb.