NIGELLA SATIVA L.: A GOLDEN REMEDY: SIGNIFICANCE WORLDWIDE HIGHLIGHTING THEIR POSSIBLE USE FOR COVID-19 

Marwa A. A. Fayedimage 

Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt.

ABSTRACT 

Nigella sativa L. is a therapeutic natural herb that cures several serious ailments, so can be considered a Golden remedy. It has been used for centuries and has a long history in different cultures. This review article has surveyed nearly all the relevant literature on Nigella sativa L. from 1960-2020, offering a broad range of data including the origin, taxonomy, botany, history of traditional uses in different regions then passing through their phytochemistry, pharmacology, and consumed natural pharmaceutical preparations till recent findings and their possible use in COVID-19 therapy. The main aim of this review is to focus on the importance of Nigella sativa L. as a medicinal herb used widely in therapy and to correlate its phytochemical constituents with their pharmacological effects. The biological importance was attributed to Thymoquinone in the first-place present in the volatile oil of the seeds and other classes such as sterols, triterpenes, tannins, flavonoids, and cardiac glycosides, alkaloids, saponins, coumarins, volatile bases, glucosinolates, and anthraquinones. Moreover, several studies confirmed its benefits in Alzheimer’s disease, as a potent antioxidant, cytotoxic, antiallergic, antimicrobial, etc. In addition to other studies which documented the use of this plant mainly the seeds and the extracted essential oil, in the production of cosmeceutical preparations, and its role as a nutritive spice in the food industry due to its very low toxicity, besides their use as fodder for farm animals.

Keywords: Black cumin, essential oil, immuno-stimulant, Nigella sativa L., Ranunculaceae, Thymoquinone.

 

INTRODUCTION

 

Nigella sativa L. (known as Black cumin), one of the members of the Ranunculaceae family, is considered recently a “miraculous herb” for its broad pharmaco-logical significance1,2. Because N. sativa L. is extensively dispersed over the world, it has been given several names based on its geographical location and language. It's known as the black seed, black cumin, black coriander, and black caraway in English-speaking areas. It is known as Kalaunji or Kalonji in India, Melanthion or Melaspermm in Greece, Granonero in Italy, and Al-Habbeh As-Sudah, Habbat Al-baraka or Kamun-Aswad in Arabic3. The traditional importance of Nigella seeds and their essential oil returns to their ability to cure several ailments. Many herbal preparations are used clinically worldwide including black cumin as one of its constituents mainly in Africa, Arabia, South, and Southeast Asia besides Mediterranean regions1. In many instances, N. sativa L. plays an important role in preventing and healing intoxication. Several studies have shown that N. sativa L. can reduce or eliminate the harmful side effects of a variety of medications, including various chemothera-peutics, analgesics, and antibiotics, as well as other substances including pesticides, organic solvents, and hazardous metals4. A volatile oil found in the seeds has insect repelling effects. N. sativa L. is used in museums to protect textiles, particularly linen, woolen materials, and paper-related artifacts, from insects and bacteria. Seeds can be strewn between the folds of linen and woolen clothing, as well as in the manuscript storage area, to safeguard the manuscript5. N. sativa L. seeds, powder, and volatile oil have recently been touted as a viable natural therapy that is effective against the SARS-CoV-2 virus and COVID-19 illness via many pathways. It has antiviral, antioxidant, anti-inflammatory, anticoagulant, immune-modulatory, bro-nchodilatory, antihistaminic, antitussive, antipyre-tic, and analgesic properties, and is utilized in the treatment of patients with COVID-196.

History of medicinal use

Nigella (fennel flower) is a tiny genus belonging to the Ranunculaceae (buttercup) family, with just approximately 15 species7. Nigella species are all annual plants with a brief life cycle that require open areas to proliferate. As a result, many of them may be found in artificial habitats. N. sativa L. (Black cumin) is the genus' most extensively spread and arguably best-known species, utilized as a condiment in addition to its medical value. Since the ancient age, this condiment has been propagated and grown for thousands of years. It is now a popular condiment throughout North Africa, the Arabian Peninsula, and the Indian subcontinent, as well as the focus of extensive pharmacological research and a dependable phytomedicine business7. The evolutionary origins of this genus are most probably in the center of species diversity, which occurs in the Aegean7 and the adjacent Western-Irano-Turanian region8. N. sativa L. may thus have come into existence somewhere in this area, Also the great popularity that N. sativa L. has gained in pharmaceutical literature makes this review necessary due to the high amount of published literature generating the impression that the plant is of significant importance economically and medicinally or generally in the pharmaceutical industry.

Distribution and Taxonomic Consideration of N. sativa L.

The botanical classification of the plant according to the International Code of Nomenclature (ICN) for Algae, Fungi, and Plants9 is documented to be as follows:

Kingdom: Plantae 

Subkingdom: Tracheobionta

Superdivision: Spermatophyta

Phylum: Magnoliophyta

Class: Magnoliopsida

Order: Ranunculales

Family: Ranunculaceae 

Genus: Nigella

Species: sativa9

Synonyms of N. sativa seeds L. includes Nigella cretica Mill., Nigella truncata Viv., Nigella indica  Roxb. ex Flem10, and common names includes  Kalonji, Habat-ul-Sauda, Black Cumin, Black caraway, Black onion seed, Fennel Flower, Nutmeg Flower, Roman Coriander, Black seed, Damascena, Devil in-the-bush, Wild Onion Seed1,11,12.

Genetic Issues

The genetic diversity of the N. sativa L. plant was investigated using random amplified polymorphic DNA (RAPD) markers, using samples taken from India, Pakistan, Saudi Arabia, Egypt, Oman, Syria, Tunisia, and Turkey. 

It was discovered that genetic diversity varies greatly depending on the geographical source. This was ascribed to N. sativa L.'s capacity to adapt to various environmental factors in these areas. Genetically, the strains acquired from India and Pakistan were determined to be quite similar. Those from Egypt and Oman, on the other hand, were very different from those from India, Pakistan, Saudi Arabia, Syria, and Tunisia13.

 

PHYTOCHEMICAL CHARACTERISTICS

 

Monoterpenes make up the majority of N. sativa L.'s volatile oil, but following seed maturation, Thymo-quinone becomes the most active element in the seeds and oil14. Only the seed coats contain volatile oil components as well as Nigellidine and Nigellicine alkaloids. Other compounds, such as dopamine, are located in the tissues of the inner seed, while other elements are scattered throughout the inner seed14. 

Volatile oil constituents

N. sativa L. volatile oil is a pale yellow liquid with a strong fragrant odor and flavor. Organic solvents such as ether, chloroform, and ethanol are readily soluble in the volatile oil, whereas water is sparsely soluble15. It is isolated by simple extraction with diethyl ether, then the organic solvent is evaporated under reduced pressure. The volatile oil content of N. sativa L. is about 0.4 %-0.5 % w/w15. Besides, the Soxhlet extraction method of the seeds with petroleum ether can be carried out to yield35% of the volatile oil which on steam distillation yielded a higher amount of 1.5%16. The chemical constituents of the (Figure 1) are mainly monoterpenes including: p-cymene (2.8 %), α-thujene (0.4 %), Thymoquinone (6.1 %), Carvacrol (traces), α-Longipinene (traces), Longifolene (0.6 %), Thymohydroquinone (1.6 %), Palmitic acid, ethyl ester (traces), Linoleic acid methyl ester (0.5 %), Linoleic acid, ethyl ester (traces), Oleic acid ethyl ester (traces), Oleic acid (traces), Linoleic acid (43 %), Linoleic acid, butyl ester (5.7 %), Oleic acid, butyl ester (4.5 %), Glyceryl palmitate (1.6 %), Glyceryl linoleate (21.9 %). Besides, sterols as β- sitosterol.

Alkaloids

- The seeds of N. sativa L. contain 2 classes of alkaloids (Table 1, Figure 2); Isoquinoline alkaloids, such as Nigellidine19, Nigellimine, and Indazole alkaloids as Nigellicine20, Nigellimine-N-oxide 21.

Flavonoids

- Some flavonoids22 were isolated and identified from the aerial parts of N. sativaL. as flaccidoside III, catechol, quercetin-3-gentiobioside, magnoflorine, nigelflavonoside B, nigelloside, quercetin sphorotri-oside, kaempferol-3,7- diglucoside, kaemp-ferol 3-O-rutinoside, rutin. Also,quercetin-3-O-α- L-rhamnopy-ranoside 1, quercetin-7-O-β-D-gluco- pyranoside were identified23.

Sterols

Sterols are listed in Table 1 are considered the main secondary metabolites of N. sativa L.18 as Cholesterol, Campesterol, Campestanol, Stigmasterol, Sitosterol, Stigmastanol, ∆5-avenasterol, ∆7-stigmasterol, ∆7-avenasterol, Lophenol, Obtusifoliol, 24-methyllophenol, Cycloeucalenol, Gramisterol, 24-ethyllophenol, Citrostadienol, Triucollol, Faraxerol, β-amyrin, Butyrospermol, Cycloartenol and 24- methylene cycloartanol

Triterpenoidal Saponins

Triterpenoidal saponins are the main class of saponins isolated from N. sativa L. (Table 1, Figure 3). Saponins isolated from the alcoholic extract of the seeds of N. sativa as Sativosides A and B 24, in addition to 3-O-[α-l-rhamnopyranosyl-(1→2)-α-l-arabino-pyranpsyl-hed-eragenin, 3β,23,28-trihydroxyolean-1-2-ene-3-O-α-l-arabinopyranoside(1→4)-α-rhamno-pyranosyl-(1→4)-β-d-glucopyranoside,3-O-α-l-rhamno-pyranosyl-(1→2) -α-l-arabino-pyranpsyl]-28-O-β-d-gluco-pyra-nosylhe deragenin22,25, 3-O-[β-d-xylo-pyranosyl-(1→3)-α-l-rhamno-pyranosyl-(1→2)-α-l-arabino-pyranosyl]-hed-eragenin26, Tauroside E, Sapindoside B23.

Nutritive value of N. sativa L. seeds

Proteins (26.7%), lipids (28.5%), carbs (24.9%), crude fibres (8.4%), and total ash (8.4%) are all present in significant concentrations in the seeds of N. sativa L. (4.8%). Furthermore, the liver converts vitamins and minerals such as Cu, P, Zn, and Fe, as well as carotenes, into vitamin A, C, thiamine, niacin, pyridoxine, and folate28,29. Vanillic acid is said to be present in the roots and shoots.28. The seeds are also said to have a good quantity of fixed oil, which is high in saturated and unsaturated fatty acids. Saturated fatty acids include palmitic and stearic acids, which are generally found in amounts of 30% or less, whereas unsaturated fatty acids include linoleic acid (50-60%), oleic acid (20%), eico-dadienoic acid (3%), and di-homo-linoleic acid (10 %).

Biological activities of extracts confirmed by scientific research

The applications of N. sativa L. confirmed by scientific experiments and the pharmacological action profile of this species highly recommended in modern phytotherapy are summarised in Table 2 with their suggested mechanism of action.

Natural preparations containing N. sativa L. and their uses

The combination of N. sativa L. ointment and the oral administration of the crude powder of the seeds exhibited effective anti-psoriatic activity 61.

Pharmaceutical Preparations including N. sativa L. and TQ

Thymoquinone is the main ingredient of N. sativa L. essential oil; it is of limited use in therapy due to its poor water solubility, high instability in aqueous solution, and pharmacokinetic drawbacks. TQ was combined with polymeric solubilizers for developing polymeric micelles which led to a bio-enhancement66. 

N. sativa L. seeds in veterinary medicine

Because N. sativa L. seeds and oil are included as a healthful and nutritious component in farm animal formulations, supplementation with N. sativa L. has a good effect on animal production metrics. Because of its therapeutic characteristics, N. sativa L. is used in animal feed. It is an excellent source of proteins, carbs, fatty acids, and a range of bioactive components. N. sativa L. is a versatile plant with many applications. Broiler chickens, laying hens, rabbits, ruminants, and pseudo-ruminants' feed consumption, mortality rate, digestibility, active and reproductive performances, milk yield and composition, egg compositional characteristics, blood chemistry parameters, health status, and carcass traits are all improved by N. sativa L67. Another study found that supplementing broiler diets with black cumin seeds (1%) increased body weight, feed conversion ratio, and carcass yield after a 6-week growing span, suggesting that N. sativa L. (1%) may be used as a natural growth promoter material in broiler diets68. N. sativa L. had a major impact on growing lambs as well, and growth efficiency parameters when fed to growing lambs69. N. sativa L. seeds in a study on 40-week-old White-Leghorn birds, significantly improved egg yield, egg mass, and eggshell thickness70.

Drug interactions and Toxicity 

Many human clinical studies stated that the simultaneous administration of N. sativa L. extracts and/or its essential oil with the conventional treating drug improved its activity and declined significantly its side effects. Many studies revealed the protective effect of N. sativa L. and intoxication activity against different chemical agents4,71. It possesses ameliorative effects against several drugs intoxication as71. Chemical war victims from mustard gas inhalation taking N. sativa L. extract required less salbutamol and corticosteroids72. Asthma patients using N. sativa L. decoction decreased the use of all the treating drugs as inhaled corticosteroids: beclomethasone or fluticasone inhalers and theophylline, and beta-agonists73. In another study, the use of N. sativa L. seeds helped in reducing acute opiate withdrawal symptoms, craving, and relapses through an open study including 50 persons addicted to opioids. This study continued for 12 weeks with a daily dose of N sativa L. seeds of 250-500 mg 3 times74. Some clinical studies were carried out one of which was on 40 females suffering from rheumatoid arthritis using anti-rheumatic drugs such as methotrexate, hydroxychloroquine, diclofenac.

It was revealed that when N. sativa L. seeds oil was administered as an adjuvant therapy a significant decrease in the disease score and less morning stiffness occurred75. In a 21 patients study with non-ulcer Helicobacter pylori, dyspepsia taking 2 grams of seed powder in combination with omeprazole daily for 4 weeks was significantly effective in eradicating the H. pylori in 66.7%76. On the contrary, N. sativa L. extract-phenobarbitone combination must be avoided as concomitant use of the herb during treatment with phenobarbitone showed undesirable drug interactions77.

Moreover, several in- vitro and in-silico studies were carried out on the effect of N. sativa L. and volatile oil constituents in the presence of certain drugs. An in vitro study on the anticancer effect of Oxaliplatin and/or Gemcitabine against pancreatic cancer which increased significantly after adding 3 mg thymoquinone reducing local invasion and nodal metastasis reduced pancreatic cancer cell growth78. The use of Gentamicin with 50 mg/L thymoquinone in drinking water for 8 days completely reversed its kidney toxicity and the increase in serum creatinine, BUN, TBARs, and total nitrate/nitrate and decreases in kidney glutathione, glutathione peroxidase, catalase, and ATP levels in rats79. Doxorubicin-induced cardiotoxicity was indicated by the increase in serum lactate dehydrogenase and creatine phosphokinase levels phosphokinase was prevented with 5 days of pretreatment and 2 days of parallel treatment with 10 mg/kg daily of thymoquinone in rats. This protection is due to the in vitro superoxide radical scavenger potency and inhibition of lipid peroxidation possessed by thymoquinone80. The hepatotoxicity caused by acetaminophen was prevented by 5 days of 2 mg/kg/day of thymoquinone in mice. This in vitro study was carried out by measuring the level of certain liver enzymes which returned to the normal levels upon the addition of Thymoquinone in therapy81. When the seed oil was given at 880 mg/kg for 2 weeks before a 1 ml dose of ethanol, it significantly reduced the formation of stomach ulcers by increasing mucosal glutathione levels and mucin and decreasing mucosal histamine in rats82. Thymoquinone given at 20 mg/kg reduced ethanol-induced stomach ulcers and the associated lipid peroxidation and glutathione depletion in rats83.

Furthermore, N. sativa L. and its main constituent Thymoquinone could protect some tissues against most drug overdoses including analgesics, anti-cancer, immune-suppressive, antibiotics, antiretrovirals, and anti-seizures 71. Several mechanisms are involved in N. sativa L. antidotal effects including antioxidant, anti-inflammatory, free radical scavenging, improvement in the disturbing levels of biochemical markers, modulation of antioxidant defense systems, inhibition of apoptosis, and regulatory effects on genes expression, and different signaling pathways71.

N. sativa L. and COVID-19

N. sativa L. was reported to have antiviral activity either separately or in combination with other herbs. A herbal preparation that consists of Extracts of (Anthemis hyaline DC., N. sativa L., and Citrus sinensis (L.) Osbeck) was found to decrease the replication of CoV virus, as it increased  IL-8  level, expression of the genes TRPA1,  TRPC4,  TRPM6,  TRPM7,  TRPM8, and TRPV4 changed significantly84.  

Several studies recommended N. sativa L. as an adjuvant therapy with repurposed drugs including Chloroquine, Hydroxychloroquine, Remdesivir, and Favipiravir used to manage patients with COVID-1946.Various randomized controlled trials, case reports, pilot studies, and in vitro and in vivo investigations confirmed that N. sativa L. possesses antiviral, antioxidant, anti-inflammatory, immunomodulatory, broncho-dilatory, anti-histaminic, anti-tussive activities related to Coronavirus and signs of COVID-1946.

The main active constituents revealed in silico affinity with SARS-CoV-2 enzymes and proteins. They possess high to moderate affinities where they potentially inhibit SARS-CoV-2 replication and attachment to host cell receptors. These constituents include nigelledine, α-hederin, hederagenin, thymo-hydroquinone, and thymoquinone85. Besides, Nigellidine and α-hederin have been identified as a potential inhibitors of SARS CoV-26. 

Finally, N. sativa L. may be used as an adjuvant treatment alongside repurposed chemical drugs for the treatment of COVID-19, which nearly diminishes the side effects of other medications by lowering their doses. However, further randomized controlled trials are required to validate the potential and benefits of N. sativa L. seeds and essential oil as an alternative herbal therapy for SARS CoV-2.

 

CONFLICT OF INTEREST

 

The author declares that there is no conflict of interest.

 

REFERENCES 

 

  1. Ahmad A, Husain A, Mujeeb M. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed 2013; 3 (5): 337-352.https://doi.org/10.1016/S2221-1691(13)60075-1
  1. EI-Dakhakhny M. Egyptian Nigella sativa. Arzneimittel-Forsch 1965; 15:1227-1229.
  2. Elnour SA, Abdelsalam EB. Some biological and pharmacological effects of the Black Cumin (Nigella sativa): A concise review. American J Res Comm 2018; 6 (3).
  3. Elshama SS. The preventive and curative role of Nigella sativa in poisoning cases. J Clin Exp Tox 2018;2 (2): 18-24.
  4. Soumoni De. Controlling biological infestations in museums by medicinal plants. Medicinal Plants: Biodiversity, sustainable utilization and conservation, Khasim, SM; Long, C.;  Thammasiri, K.; Lutken, H., Eds. Springer Singapore: Singapore 2020; 271-283.https://doi.org/10.1007/978-981-15-1636-8_16
  1. Maideen PMN. Prophetic Medicine- Nigella sativa (Black Cumin Seeds)-Potential Herb for COVID-19? J Pharmacopunct 2020; 23(2):62-70.
  2. Heiss AG, Stika H, De Zorzi N, Jursa M. Nigella in the mirror of time a brief attempt to draw a genus’ ethnohistorical portrait. Offa 2012/13; 69(70): 147-169.
  3. Zohary M. The Genus Nigella (Ranunculaceae), A Taxonomic Revision. Plant Systematics and Evolution 1983; 142: 71-107.
  4. Sharma NK, AAhirwar D., Jhade D, Gupta S. Medicinal and pharmacological potential of Nigella sativa: A review. Ethnobotanical leaflets 2009; 11.
  5. Reference taxon from World Plants in Species & ITIS Catalogue of Life. In Encyclopedia of Life, 2000.
  6. Singh BR, Sinha DK, Bhardwaj M et al. Antimicrobial activity of kalonji oil and its comparison with methanolic and aqueous extracts of Nigella sativa (Kalonji) Seeds. Nat Prod Ind J 2017; 13(2):107.
  7. Chevallier A. Encyclopedia of medicinal plants. DK Publishing: New York, NY, 1996; 237.
  8. Sudhir SP, KKumarappan A, Malakar J, Verma HN. Genetic diversity of Nigella sativa from Different geographies using RAPD markers. American J Life Sci 2016; 4(6): 175-180.https://doi.org/10.11648/j.ajls.20160406.15
  1. Botnick I, Xue W, Bar E, et al. Distribution of primary and specialized metabolites in Nigella sativa seeds, a spice with vast traditional and historical uses. Molecules 2012;17 (9): 10159-10177. https://doi.org/10.3390/molecules170910159
  2. El-Fatatry HM. Isolation and structure assignment of an antimicrobial principle from the volatile oil of Nigella sativa seeds. Pharmazie 1975; 30:109-111. PMID: 238225
  3. Rathee PS, Mishra SH, Kaushal R. Antimicrobial activity of essential oil, fixed oil and unsaponified matter of Nigella sativa Indian J Pharmac 1982; 44: 8-10.
  4. Singh S, Das SS,  Singh G,  et al. Composition in vitro antioxidant and antimicrobial activities of essential oil and oleoresins obtained from black cumin seeds Nigella sativa. Bio Med Res Int 2014; 918209.https://doi.org/10.1155/2014/918209
  1. Gad AM, El–Dakhakhny M, Hassan MM. studies on the chemical constitution of Egyptian Nigella sativa Oil. Planta Med 1963; 11(2):134-138. https://doi.org/10.1055/s-0028-1100226
  1. Ur-Rahman A, Sohail M, Hasan SS, et al. Nigellidine- A new indazole alkaloid from the seeds of Nigella sativa. Tetrahedron Lett 1995;36 (12): 1993-1996.https://doi.org/10.1016/0040-4039(95)00210-4
  1. Ur-Rahman A, Malik S, Cunheng H, Clardy J. Isolation and structure of determination of nigellicine, a novel alkaloid from the seeds of Nigella sativa. Tetrahedron Lett 1985,26, 2759-62. https://doi.org/10.1016/S0040-4039(00)94904-9
  2. Ur-Rahman A, Malik S, Ahmad S, et al. Nigellimine N-oxide-A new isoquinoline alkaloid from the seeds of Nigella sativa. J Nat Prod 1992; 55(5): 676–678.https://doi.org/10.1021/np50083a020
  1. Parveen A, Farooq MA, Kyunn WW. A New oleanane type saponin from the aerial parts of Nigella sativa with anti-oxidant and anti-diabetic potential. Molecules 2020;25 (2171). https://doi.org/10.3390/molecules25092171
  2. Elkhayat ES, Alorainy MS, El-Ashmawy IM, Fat'hi S. Potential antidepressant constituents of Nigella sativa Pharmacogn Mag 2016;12 (Suppl 1): S27-31.https://doi.org/10.4103/0973-1296.176118
  1. Elbandy M, Kang O, Kwon DY, Jung-Rae Rho. Two new antiinflammatory triterpene saponins from the Egyptian medicinal food Black Cumin (Seeds of Nigella sativa). Bull Korean Chem Soc 2009;30(8).https://doi.org/10.5012/bkcs.2009.30.8.1811
  1. Ansari AA, Hassan S, Kenne L. Ur-Rahman A, Thomas W. Structural Studies On a Saponin Isolated from Nigella sativa  Phytochem 1988;21 (12): 3971-3919.
  2. Taskin MK, CÇaliskan OA, Abou-Gazar AH, Khan IA, Bedir E. Triterpene Saponins from Nigella sativa Turk J Chem 2005;29: 561-569.
  3. Salama RB. Sterols in the seed oil of Nigella sativa. Planta Med 1973;24 (4):375-7.https://doi.org/10.1055/s-0028-1099512
  1. Al-Jassir MS. Chemical composition and microflora of black cumin (Nigella sativa) seeds growing in Saudi Arabia Food Chem 1992;45: 239-242.https://doi.org/10.1016/0308-8146(92)90153-S
  1. Majid A. The Chemical constituents and pharmacological effects of Nigella sativa- A review. J Biosci App Res 2018;4 (4): 389-400. https://doi.org/10.21608/jbaar.2018.151793
  2. Duncker SC, Phillipe D, Martin-Paschoud C, Moser M, Mercenier A, Nutten S. Nigella sativa (Black Cumin) seed extract alleviates symptoms of allergic diarrhea in mice, involving opioid receptors. Plosone 2012; 7(6): e39841.https://doi.org/10.1371/journal.pone.0039841
  1. Alsamarai AM, Satar MA, Alobaidi AHA. Evaluation of therapeutic efficacy of Nigella sativa (Black Seed) for treatment of allergic rhinitis. In: Kowalski, M. L. Allergic Rhinitis. London: Intech Open; 2012.https://doi.org/10.5772/26946
  1. Sharaf R, Mansour R, El-Sayed N, Mahran L. Neuroprotective effect of thymoquinone against lipopolysaccharide-induced Alzheimer’s disease in an animal model. European Geriatric Medicine 2014; 5(1): S83-S158.https://doi.org/10.1016/S1878-7649(14)70253-0
  1. Ibrahim T, AL-Rashidi B. Evaluation of the analgesic effects of Nigella sativa ethanolic extracts on experimentally induced pain in albino mice. British J Pharm Res 2016;10(5): 1-7. https://doi.org/10.9734/BJPR/2016/24041
  2. Bano F, Wajeeh M, Baig N. Antiobesity, antihyperlipidemic and hypoglycemic effects of the aqueous extract of Nigella sativa seeds (Kalongi). Pak J Biochem Mol Biol 2009;42(4): 136-140.
  3. Badary OA, Taha R, Gamal El-Din AM. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol 2003; 26(2): 87-98. https://doi.org/10.1081/dct-120020404
  4. Gali-Muhtasib H, RRoessner A, Schneider-Stock R.  Thymoquinone: A promising anti-cancer drug from natural sources. Int J Biochem Cell Biol 2006; 38(8): 1249-1253.https://doi.org/10.1016/j.biocel.2005.10.009
  1. Adamska A, Hajduk JS, Ochocka JR. Alpha-Hederin, the active saponin of Nigella sativa, as an anticancer agent inducing apoptosis in the SKOV-3 Cell Line. Molecules 2019; 24: 2958. https://doi.org/10.3390/molecules24162958
  2. Toma CC, Olah N, Vlase L, Mogoșan C, Mocan A. Comparative studies on polyphenolic composition, antioxidant and diuretic effects of Nigella sativa (Black Cumin) and Nigella damascena L. (Lady-in-a-Mist) seeds molecules 2015; 20: 9460-9574.https://doi.org/10.3390/molecules20069560
  1. Khan MA, Afzal M. Chemical composition of Nigella sativa Linn: Part 2 Recent advances. Inflammopharmacology 2016; 24: 67-79. https://doi.org/10.1007/s10787-016-0262-7
  2. Umar S, Zargan J, Umar K. Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. J Chem Biol Interact 2012; 197(1): 40-46.https://doi.org/10.1016/j.cbi.2012.03.003
  1. Swamy S, Tan BK. Cytotoxic and immunopotentiating effects of ethanolic extract of Nigella sativa seeds. J Ethnopharmacol 2000; 70(1): 1-7.https://doi.org/10.1016/s0378-8741(98)00241-4
  1. Yehuda S, Carasso RL. Modulation of learning, pain thresholds, and thermoregulation in the rat by preparations of free purified alpha-linolenic and linoleic acids: determination of the optimal omega 3-to-omega 6 ratio. Proc Natl Acad Sci USA 1993; 90(21):10345-10349.https://doi.org/10.1073/pnas.90.21.10345
  1. Boskabady MH, Mohsenpoor N, Takaloo L. Antiasthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomed 2010; 17(10): 707-713.https://doi.org/10.1016/j.phymed.2010.01.002
  1. Ibrahim RM, Hamdan N, Mahmud R. A randomised controlled trial on hypolipidemic effects of Nigella sativa seeds powder in menopausal women. J Transl Med 2014;12: 82. https://doi.org/10.1186/1479-5876-12-82
  2. Kaatabi H, Bamosa A, Lebda FM. Favorable impact of Nigella sativa seeds on lipid profile in type 2 diabetic patients. J Family Community Med 2012; 19(3): 155-161.https://doi.org/10.4103/2230-8229.102311
  1. Maideen PMN. Prophetic medicine-Nigella sativa (Black cumin seeds)- Potential herb for COVID-19. J Pharmaco-puncture 2020; 23(2): 62-70.https://doi.org/10.3831/KPI.2020.23.010
  1. Khabbazi A, Javadivala Z,  Seyedsadjadi N, Malek Mahdavi A. A systematic review of the potential effects of Nigella sativa on rheumatoid arthritis. Planta Med 2020; 86(07): 457-469. https://doi.org/10.1055/a-1143-8521
  2. Houghton PJ, Zarka R, de las Heras B, Hoult JR. Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation. Planta Medica 1995; 61: 33-36.https://doi.org/10.1055/s-2006-957994
  1. Mansour M, Tornhamre S, Inhibition of 5-lipoxygenase and leukotriene C4 synthase in human blood cells by thymoquinone. J Enzyme Inhib Med Chem 2004; 19:431-436. https://doi.org/10.1080/14756360400002072
  2. Al-Sa'aidi JAA, Al-Khuzai ALD, Al-Zobaydi NFH. Effect of alcoholic extract of Nigella sativa on fertility in male rats. Iraqi J Vet Sci 2009; 23:123-128.
  3. Ping NC, Hashim N, Hasan Adli DS. Effects of Nigella sativa (Habbatus sauda) oil and nicotine chronic treatments on sperm parameters and testis histological features of rats. Evid Based Complement Alt Med 2014; 2014 (18293).https://doi.org/10.1155/2014/218293
  1. Abu-Zinadah O.A., Using Nigella sativa oil to treat and heal chemical induced wound of rabbit skin JKAU: Sci 2009;21 (2): 335-346. https://doi.org/10.4197/Sci.21-2.11
  2. Pari L, Sankaranarayanan C. Beneficial effects of thymoquinone on hepatic key enzymes in streptozotocin– nicotinamide induced diabetic rats. Life Sci 2009; 85(23-26): 830-834. https://doi.org/10.1016/j.lfs.2009.10.021
  3. Wienkötter N, Hopner D, Schütte U. The effect of nigellone and thymoquinone on inhibiting trachea contraction and mucociliary clearance. Planta Med 2008; 74(2):105-108.https://doi.org/10.1055/s-2008-1034280
  1. Al-Hader A, Aqel M, Hasan Z. Hypoglycemic effects of the volatile oil of Nigella sativa Pharm Biol 1993; 31:96-100. https://doi.org/10.3109/13880209309082925
  2. Abdel-Fattah AM, Matsumoto K, Watanabe H. Antinoci-ceptive effects of Nigella sativa oil and its major component, thymoquinone in mice. Eur J Pharmacol 2000; 400 (1): 89-97. https://doi.org/10.1016/s0014-2999(00)00340-x
  3. Ullah R, Rehman A, Zafeer MF, Rehman L, Khan YA, Khan MA, Khan SN, Khan AU, Abidi SM. Anthelmintic potential of thymoquinone and curcumin on Fasciola gigantica. PLoS One 2017; 12(2): e0171267.https://doi.org/10.1371/journal.pone.0171267
  1. Kamil ZH. Spectacular black seeds (Nigella sativa): Medical importance review. Med J Babylon 2013; 10(4): 1-9.
  2. Toama MA, El-Alfy T.S., El-Fatatry HM. Antimicrobial activity of the volatile oil of Nigella sativa Linneaus seeds. Antimicrob Agents Chemother 1974; 6(2): 225-226.https://doi.org/10.1128/aac.6.2.225
  1. Hosseini M, Mohammadpour T, Karami R, Rajaei Z, Sadeghnia HR, Soukhtanloo M. Effects of the hydro-alcoholic extract of Nigella sativa on scopolamine-induced spatial memory impairment in rats and its possible mechanism. Chinese J Integ Med 2015; 21(6):438-444.https://doi.org/10.1007/s11655-014-1742-5
  1. Jawad HA, Azhar YI, Khalil A. Evaluation of efficacy, safety and antioxidant effect of Nigella sativa in patients with psoriasis: A randomized clinical trial. J Clin Exp Invest 2014; 5(2): 186-193.https://doi.org/10.5799/ahinjs.01.2014.02.0387
  1. Pop RM, Bocsan L, Buzoianu AD, Chedea VS, Ancut S, Socaci A, Pecoraro M, Popolo A. Evaluation of the antioxidant activity of Nigella sativa and Allium ursinum extracts in a cellular model of doxorubicin-induced cardiotoxicity. Molecules 2020; 25(5259).https://doi.org/10.3390/molecules25225259
  1. Agarwal R, Kharya M, Shrivastava R. Antimicrobial & anthelmintic activities of the essential oil of Nigella sativa Indian J Exp Biol 1979; 17(11):1264-5. PMID: 549848.
  2. Khurshid Y, Syed B, Simjee SU, Beg O, Ahmed A. Antiproliferative and apoptotic effects of proteins from black seeds (Nigella sativa) on human breast MCF-7 cancer cell line. BMC Comp Med Therapies 2020; 20(1):5. https://doi.org/10.1186/s12906-019-2804-1
  1. Cascella M, Bimonte S, Barbieri A. Dissecting the potential roles of Nigella sativa and its constituent thymoquinone on the prevention and on the progression of Alzheimer's disease. Front Aging Neurosci 2018; 10: 16.https://doi.org/10.3389/fnagi.2018.00016
  1. Bergonzi MC, Marroncini MV, Barletta E, Degl D. Innocenti Thymoquinone-Loaded Soluplus®-Solutol® HS15 Mixed Micelles: Preparation, in vitro characterization, and effect on the SH-SY5Y cell migration. Molecules 2020; 25: 4707. https://doi.org/10.3390/molecules25204707
  2. Longato E, Meineri G, Peiretti PG. Nutritional and zootechnical aspects of Nigella sativa: A review. The J Animal Plant Sci 2015; 25(4): 921-934.http://thejaps.org.pk/docs/v-25-04/03.pdf
  1. Singh PK, Anil K. The effect of dietary black cumin seeds (Nigella sativa) on the performance of broilers Asian-Aust. J Anim Sci 2006; 19(3): 425-430.https://doi.org/10.5958/0974-181X.2018.00038.0
  1. Obeidat BS. the inclusion of black cumin meal improves growth performance of growing awassi lambs. Vet Sci 2020; 7(40).https://doi.org/10.3390/vetsci7020040
  1. Akhtar MS, Zahid N, Abdurehman A. Effect of feeding powdered Nigella sativa seeds on poultry egg production and their suitability for human consumption. Vetrinariski Arhiv 2003; 73(3):181-190.
  2. Tavakkoli A, Ahmadi A, Razavi BM, Hosseinzadeh H. Black seed (Nigella sativa) and its constituent thymoquinone as an antidote or a protective agent against natural or chemical toxicities. Iranian J Pharm Res 2017; 16 (Supp;.): 2-23. PMID: 29844772
  3. Francis Brinker ND. Updates and Additions for Herbal Contraindications & Drug Interactions plus Herbal Adjuncts with Medicines. 4th; 2016.
  4. Boskabady MH, Javan H, Sajady M. The possible prophylactic effect of Nigella sativa seed extract in asthmatic patients. Fund Clin Pharmacol 2007; 21:559-566.https://doi.org/10.1111/j.1472-8206.2007.00509.x
  1. Yarnell E, Abascal K., Nigella sativa holy herb of the Middle East. Altern Compl Ther 2011; 17(2): 99-105.
  2. Haghighi M, Khalvat A, Toliat T. Comparing the effects of ginger (Zingiber officinale) extract and ibuprofen on patients with osteoarthritis. Arch Iran Med 2005; 8 (4): 267-271.
  3. Salem EM, Yar T, Bamosa AO. Comparative study of Nigella sativa and triple therapy in eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Saudi J Gastroent 2010; 16(3):207-214.https://doi.org/10.4103/1319-3767.65201
  1. Joseph L, Puthillath R, Rao S. Drug interaction analysis-Nigella sativa seed (Black Cumin) ethanolice xtract on antiseizure activity of Phenobarbitone sodium. Asian J Med Sci 2020; 11(2):18-20.https://doi.org/10.3126/ajms.v11i2.27308
  1. Psaltopoulou TKR, Haidopoulos D. Olive oil intake is inversely related to cancer prevalence: A systematic review and a meta-analysis of 13800 patients and 23340 controls in 19 observational studies. Lipids Health Dis 2011; 10: 127.
  2. Sayed-Ahmed MM, Nagi M. Thymoquinone supplemen-tation prevents the development of gentamicin-induced acute renal toxicity in rats. Clin Exp Pharm Physiol 2007; 34: 399-405. https://doi.org/10.1111/j.1440-1681.2007.04560.x
  3. Banerjee S, Kasseb AWZ. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res 2009; 69(13):5575-5583.https://doi.org/10.1158/0008-5472
  1. Nagi MN, Almakki HA,  Sayed-Ahmed MM, Al-Bekairi A M. Thymoquinone supplementation reverses acetaminophen-induced oxidative stress, nitric oxide production and energy decline in mice liver. Food Chemical Toxicol 2010; 48(8-9): 2361-5. https://doi.org/10.1016/j.fct.2010.05.072
  2. El-Dakkakhny M, Barakat M, El-Halim MA. Effects of Nigella sativa oil on gastric secretion and ethanol induced ulcer in rats. J Ethnopharm 2000; 72: 299-304.https://doi.org/10.1016/s0378-8741(00)00235-x
  1. Arslan SO, Gelir E, Armutcu F. The protective effect of thymoquinone on ethanol-induced acute gastric damage in the rat. Nutrit Res 2005; 25: 673-680.
  2. Refaey MS, Fayed MA. Traditional to recent approaches in herbal medicine therapy of COVID-19. Universal J Pharm Res 2020; 5(5): 71-84. https://doi.org/10.22270/ujpr.v5i5.49
  3. Koshak DAE, Koshak PEA. Nigella sativa L as a potential phytotherapy for coronavirus disease 2019: A mini review of in silico Curr Therap Res 2020; 93: 10060.https://doi.org/10.1016/j.curtheres.2020.100602