EFFECT OF NIGELLA SATIVA (BLACK CUMIN) ON HEALTH

Year 2024, , 83 - 98, 08.07.2024

Sultan Bilgesu Aygün , Ezgi Karataş

https://doi.org/10.58625/jfng-2477

Abstract

Oxidative stress is a condition resulting from the accumulation of reactive oxygen species (ROS) in the body. ROS can lead to negative effects such as lipid peroxidation, DNA damage and protein degradation in cells. This can lead to the formation of various diseases and aggravate the prognosis of existing diseases. Measures such as lifestyle, nutrition and the use of natural antioxidants can be important in reducing the effects of oxidative stress.

The Nigella Sativa plant has been used in various civilizations since ancient times and is believed to have positive health effects. Research on this plant provides evidence to support its health benefits. Nigella Sativa seeds and oil may have positive effects on many diseases such as oxidative stress, hypertension, epilepsy, fatty liver, asthma, arthritis. It is also thought to have anti-carcinogenic, anti-diabetic, antibacterial, anti-hepatotoxic, antifungal and other therapeutic effects. N. sativa is an annual flowering herb that grows mainly in Western Asia, the Mediterranean North Sea region and western-southern Europe. The flowers are white, pink, yellow or lavender in color and the fruits are capsules containing black seeds. The phytochemical composition of N. sativa varies depending on growing conditions, stage of maturity and processing methods. Components such as thymoquinone, flavonoids, alkaloids, tannins are the active phytochemical constituents of N. Sativa. N. Sativa may be effective in reducing oxidative stress through its thymoquinone and other phytochemical components. N. Sativa may be effective in reducing oxidative stress through its thymoquinone and other phytochemical components. Thymoquinone inhibits oxidative damage by interacting with free radicals and modulating multiple cellular signaling systems through its antioxidant effects. Moreover, the anti-inflammatory effects of Nigella Sativa and its regulation of cellular mechanisms may also play a role in reducing oxidative stress. The aim of this study was to review the literature on the effects of N. sativa on oxidative stress, diseases and health.

Keywords

Antioxidant, Black cumin, Oxidative stress, Nigella Sativa, Thymoquinone

NİGELLA SATİVA’NIN (ÇÖREK OTU) SAĞLIK ÜZERİNE ETKİSİ

Abstract

Oksidatif stres, vücutta reaktif oksijen türlerinin (ROS) birikmesi sonucunda ortaya çıkan bir durumdur. ROS, hücrelerde lipid peroksidasyonu, DNA hasarı ve protein bozulması gibi olumsuz etkilere yol açabilmektedir. Bu durum çeşitli hastalıkların oluşumuna, var olan hastalıkların prognozunda ağırlaşmaya sebep olabilmektedir. Yaşam tarzı, beslenme ve doğal antioksidanların kullanımı gibi önlemler, oksidatif stresin etkilerini azaltmada önemli olabilmektedir.

Nigella Sativa (Çörek otu) bitkisi, antik çağlardan beri çeşitli medeniyetlerde kullanılmaktadır ve sağlık üzerinde olumlu etkileri olduğuna inanılmaktadır. Bu bitkiyle ilgili yapılan araştırmalar, sağlık faydalarını destekleyebilecek kanıtlar sunmaktadır. N. Sativa tohumları ve yağı, oksidatif stres, hipertansiyon, epilepsi, yağlı karaciğer, astım, artrit gibi birçok hastalık üzerinde olumlu etkiler gösterebilir. Aynı zamanda anti-kanserojen, anti-diyabetik, antibakteriyel, anti-hepatotoksik, antifungal ve diğer terapötik etkilere sahip olduğu düşünülmektedir. N. Sativa, tek yıllık çiçekli bir bitki olup genellikle Batı Asya, Akdeniz Kuzey Denizi bölgesi ve batı-güney Avrupa'da yetişir. Çiçeklerinin renkleri beyaz, pembe, sarı veya lavantadır ve meyveleri siyah tohum içeren kapsüllerden oluşur. N. Sativanın fitokimyasal bileşimi yetiştirme koşullarına, olgunluk aşamasına ve işleme yöntemlerine bağlı olarak değişir. Timokinon, flavonoidler, alkaloidler, tanenler gibi bileşenler N. Sativanın aktif fitokimyasal bileşenleridir. N. Sativa, içerdiği timokinon ve diğer fitokimyasal bileşenler aracılığıyla oksidatif stresi azaltmada etkili olabilmektedir. Timokinon, antioksidan etkileriyle serbest radikallerle etkileşime girerek ve çoklu hücresel sinyal sistemlerini modüle ederek oksidatif hasarı engellemektedir. Ayrıca, N. Sativa'nın anti-inflamatuar etkileri ve hücresel mekanizmaları düzenlemesi de oksidatif stresi azaltmada rol oynayabilmektedir. Bu çalışmanın amacı N. Sativanın oksidatif stres, hastalıklar ve sağlık üzerine etkisi ile ilişkili literatürdeki çalışmaları incelemektir.

Keywords

Antioksidan, Çörek otu, Oksidatif stres, Nigella Sativa, Timokinon

References

• Referans1. Ahmad, A., Husain, A., Mujeeb, M., Khan, S. A., Najmi, A. K., Siddique, N. A., Damanhouri, Z. A., & Anwar, F. (2013). A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pacific journal of tropical biomedicine, 3(5), 337–352. https://doi.org/10.1016/S2221-1691(13)60075-1
• Referans2. Gali-Muhtasib, H., El-Najjar, N., & Schneider-Stock, R. (2006). The medicinal potential of black seed (Nigella sativa) and its components. Advances in Phytomedicine, 2, 133-153. https://doi.org/10.1016/s1572-557x(05)02008-8
• Referans3. Mohsen, Z. A., Gheni, S. W., & Hussein, J. M. (2009). Study of the effect of black seed extract in some bacteria that cause urinary tract infection. J. Kerbala Univ, 7, 156-160.
• Referans4. Hannan, M. A., Rahman, M. A., Sohag, A. A. M., Uddin, M. J., Dash, R., Sikder, M. H., ... & Kim, B. (2021). Black cumin (Nigella sativa L.): A comprehensive review on phytochemistry, health benefits, molecular pharmacology, andsafety. Nutrients, 13(6), 1784 . https://doi.org/10.3390/nu13061784
• Referans5. Montazeri, R. S., Fatahi, S., Sohouli, M. H., Abu‐Zaid, A., Santos, H. O., Găman, M. A., & Shidfar, F. (2021). The effect of nigella sativa on biomarkers of inflammation and oxidative stress: A systematic review and meta‐analysis of randomized controlled trials. Journal of Food Biochemistry, 45(4), e13625. https://doi.org/10.1111/jfbc.13625
• Referans6. Malekian, S., Ghassab-Abdollahi, N., Mirghafourvand, M., & Farshbaf-Khalili, A. (2021). The effect of Nigella sativa on oxidative stress and inflammatory biomarkers: A systematic review and meta-analysis. Journal of Complementary and Integrative Medicine, 18(2), 235-259. https://doi.org/10.1515/jcim-2019-0198
• Referans7. Hallajzadeh, J., Milajerdi, A., Mobini, M., Amirani, E., Azizi, S., Nikkhah, E., ... & Mirhashemi, S. M. (2020). Effects of Nigella sativa on glycemic control, lipid profiles, and biomarkers of inflammatory and oxidative stress: A systematic review and meta‐analysis of randomized controlled clinical trials. Phytotherapy Research, 34(10), 2586-2608. https://doi.org/10.1002/ptr.6708
• Referans8. Betul, A. Y., & Semin, G. (2019). Wound healing effects of Nigella sativa L. essential oil in streptozotocin induced in diabetic rats. GSC Biological and Pharmaceutical Sciences, 7(3). https://doi.org/10.30574/gscbps.2019.7.3.0095
• Referans9. Kaatabi, H., Bamosa, A. O., Badar, A., Al-Elq, A., Abou-Hozaifa, B., Lebda, F., ... & Al-Almaie, S. (2015). Nigella sativa improves glycemic control and ameliorates oxidative stress in patients with type 2 diabetes mellitus: placebo controlled participant blinded clinical trial. PloS one, 10(2), e0113486. https://doi.org/10.1371/journal.pone.0113486
• Referans10. Ahmad, S. H. A. H. Z. A. D., Chughtai, A., Hussain, R. I. Z. W. A. N. A., & Iqbal, S. H. A. Z. I. A. (2017). Physiological and biochemical role of nigella sativa in hyperlipidemic albino rats a comparative study. Pak. J. Med. Health Sci, 11, 195-196.
• Referans11. Tasawar, Z., Siraj, Z., Ahmad, N., & Lashari, M. H. (2011). The effects of Nigella sativa (Kalonji) on lipid profile in patients with stable coronary artery disease in Multan, Pakistan. Pakistan journal of nutrition, 10(2), 162-167. https://doi.org/10.3923/pjn.2011.162.167
• Referans12. Darand, M., Darabi, Z., Yari, Z., Hedayati, M., Shahrbaf, M. A., Khoncheh, A., ... & Hekmatdoost, A. (2019). The effects of black seed supplementation on cardiovascular risk factors in patients with nonalcoholic fatty liver disease: A randomized, double‐blind, placebo‐controlled clinical trial. Phytotherapy Research, 33(9), 2369-2377. https://doi.org/10.1002/ptr.6424
• Referans13. Kheirouri, S., Hadi, V., & Alizadeh, M. (2016). Immunomodulatory effect of Nigella sativa oil on T lymphocytes in patients with rheumatoid arthritis. Immunological investigations, 45(4), 271-283. https://doi.org/10.3109/08820139.2016.1153649
• Referans14. Hadi, V., Kheirouri, S., Alizadeh, M., Khabbazi, A., & Hosseini, H. (2016). Effects of Nigella sativa oil extract on inflammatory cytokine response and oxidative stress status in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial. Avicenna journal of phytomedicine, 6(1), 34
• Referans15. Mahmoud, Y. K., & Abdelrazek, H. M. (2019). Cancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy. Biomedicine & Pharmacotherapy, 115, 108783. https://doi.org/10.1016/j.biopha.2019.108783
• Referans16. Takruri, H. R., & Dameh, M. A. (1998). Study of the nutritional value of black cumin seeds (Nigella sativaL). Journal of the Science of Food and Agriculture, 76(3), 404-410. https://doi.org/10.1002/(sici)1097-0010(199803)76:3%3C404::aid-jsfa964%3E3.0.co;2-l
• Referans17. Hajhashemi, V., Ghannadi, A., & Jafarabadi, H. (2004). Black cumin seed essential oil, as a potent analgesic and antiinflammatory drug. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives, 18(3), 195-199. https://doi.org/10.1002/ptr.1390
• Referans18. Rastogi, R. P., Mehrotra, B. N., Pastogi, R. P. (1993). Compendium of Indian Medicinal plants. Central Drug Research Institute. Lucknow and Publications & Information Directorate, New Delhi, India, 2,10.
• Referans19. Goreja, W. G. (2003). Black seed. Nature’s Miracle, Remedy. Amazing Herbs Press.
• Referans20. Warrier, P. K. (1993). Indian medicinal plants: a compendium of 500 species (5). Orient Blackswan.
• Referans21. Al-Kalaf, M. I., Ramadan, K. S. (2013). Antimicrobial and anticancer activity of Nigella sativa oil a review Australian. J Basic Appl Sci Res, 7, 505-514.
• Referans22. AL-Mousawi, A. H., Jassim, A. N., & Al-Zendi, S. K. J. (2009). The effect of hot water and ethanol extract of Nigella sativa in immune system of Albino Mice. Baghdad Science Journal, 6(2). https://doi.org/10.21123/bsj.2009.6.2.235-243
• Referans23. Salem, M. L. (2005). Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. International immunopharmacology, 5(13-14), 1749-1770. https://doi.org/10.1016/j.intimp.2005.06.008
• Referans24. Nautiyal, O. H. (2019). Black seed (Nigella sativa) oil. Fruit Oils: Chemistry and Functionality, 839-857. https://doi.org/10.1007/978-3-030-12473-1_46
• Referans25. Ojueromi, O. O., Oboh, G., & Ademosun, A. O. (2022). Effect of black seeds (Nigella sativa) on inflammatory and immunomodulatory markers in Plasmodium berghei‐infected mice. Journal of food biochemistry, 46(11), e14300. https://doi.org/10.1111/jfbc.14300
• Referans26. Janfaza, S., & Janfaza, E. (2012). The study of pharmacologic and medicinal valuation of thymoquinone of oil of Nigella sativa in the treatment of diseases. Annals of Biological Research, 3(4), 1953-1957.
• Referans27. El-Dakhakhny, M., Barakat, M., Abd El-Halim, M., & Aly, S. M. (2000). Effects of Nigella sativa oil on gastric secretion and ethanol induced ulcer in rats. Journal of ethnopharmacology, 72(1-2), 299-304. https://doi.org/10.1016/s0378-8741(00)00235-x
• Referans28. Hosseinzadeh1ABCDEG, H., Parvardeh2ABCDEF, S., Nassiri-Asl2A, M., & Mansouri2A, M. T. (2005). Intracerebroventricular administration of thymoquinone, the major constituent of Nigella sativa seeds, suppresses epileptic seizures in rats. Med Sci Monit, 11(4), 110.
• Referans29. Khonche A, Gholamian M, Kianbakht S, Husseini H, Mohtashami R, Bayatpoor ME, Mirzadeh M, Mashayekh A, Hosseini MA (2018). Effectiveness of Nigella sativa oil on patients with non-alcoholic fatty liver: A randomized double-blind placebo-controlled trial. Acad. J. Med. Plants. 6(10): 307-312.
• Referans30. Azizi, F., Ghorat, F., Rakhshani, M. H., & Rad, M. (2019). Comparison of the effect of topical use of Nigella Sativa oil and diclofenac gel on osteoarthritis pain in older people: A randomized, double-blind, clinical trial. Journal of Herbal Medicine, 16, 100259. http://dx.doi.org/10.1016/j.hermed.2019.100259
• Referans31. Koshak, A., Wei, L., Koshak, E., Wali, S., Alamoudi, O., Demerdash, A., ... & Heinrich, M. (2017). Nigella sativa supplementation improves asthma control and biomarkers: A randomized, double‐blind, placebo‐controlled trial. Phytotherapy Research, 31(3), 403-409. https://doi.org/10.1002/ptr.5761
• Referans32. Mabrouk, A. (2017). Protective effect of thymoquinone against lead-induced antioxidant defense system alteration in rat liver. Acta Biologica Hungarica, 68(3), 248-254. https://doi.org/10.1556/018.68.2017.3.2
• Referans33. Liu, H., Liu, H. Y., Jiang, Y. N., & Li, N. (2016). Protective effect of thymoquinone improves cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by mediating the PI3K/Akt pathway in diabetic rats. Molecular medicine reports, 13(3), 2836-2842. https://doi.org/10.3892/mmr.2016.4823
• Referans34. Mohit, M., Farrokhzad, A., Faraji, S. N., Heidarzadeh-Esfahani, N., & Kafeshani, M. (2020). Effect of Nigella sativa L. supplementation on inflammatory and oxidative stress indicators: A systematic review and meta-analysis of controlled clinical trials. Complementary Therapies in Medicine, 54, 102535. https://doi.org/10.1016/j.ctim.2020.102535
• Referans35. Baltgalvis, K. A., Greising, S. M., Warren, G. L., & Lowe, D. A. (2010). Estrogen regulates estrogen receptors and antioxidant gene expression in mouse skeletal muscle. PloS one, 5(4), e10164. https://doi.org/10.1371/journal.pone.0010164
• Referans36. Sanhez-Rodriguez; M. A., Zacarias-Flores, M., Arronte-Rosales, A., Correa-Munoz, E., & Mendoz-Nunez, V. M. (2012). Menopause as a risk factor for oxidative stress. Menopause, 19(3), 361-367. https://doi.org/10.1097/gme.0b013e318229977d
• Referans37. Ibrahim, R. M., Hamdan, N. S., Ismail, M., Saini, S. M., Abd Rashid, S. N., Abd Latiff, L., & Mahmud, R. (2014). Protective effects of Nigella sativa on metabolic syndrome in menopausal women. Advanced pharmaceutical bulletin, 4(1), 29. https://doi.org/10.5681/apb.2014.005
• Referans38. Mostafa R M, Moustafa Y M, Mirghani Z, AlKusayer G M, Moustafa K M. Antioxidant effect of garlic (Allium sativum) and black seeds (Nigella sativa) in healthy postmenopausal women. SAGE Open Med. 2013;1. https://doi.org/10.1177/2050312113517501
• Referans39. Hadi, S., Mirmiran, P., Daryabeygikhotbehsara, R., & Hadi, V. (2018). Effect of Nigella sativa oil extract on inflammatory cytokine response and oxidative stress among people with type 2 diabetes mellitus: a randomized, double-blind, placebo controlled trial. https://doi.org/10.1002/ptr.6990
• Referans40. Heshmati, J., Namazi, N., Memarzadeh, M. R., Taghizadeh, M., & Kolahdooz, F. (2015). Nigella sativa oil affects glucose metabolism and lipid concentrations in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Food Research International, 70, 87-93. http://dx.doi.org/10.1016/j.foodres.2015.01.030
• Referans41. Rahmani, A., Niknafs, B., Naseri, M., Nouri, M., & Tarighat-Esfanjani, A. (2022). Effect of Nigella Sativa Oil on Oxidative Stress, Inflammatory, and Glycemic Control Indices in Diabetic Hemodialysis Patients: A Randomized Double-Blind, Controlled Trial. Evidence-based complementary and alternative medicine : eCAM, 2022, 2753294. https://doi.org/10.1155/2022/2753294
• Referans42. Ansari Z M, Nasiruddin M, Khan RA, Haque S F. (2017). Protective role of Nigella sativa in diabetic nephropathy: A randomized clinical trial. Saudi J. Kidney Dis. Transplant, 28(1), 9–14 https://doi.org/10.4103/1319-2442.198093
• Referans43. Kattoor, A. J., Pothineni, N., Palagiri, D., & Mehta, J. L. (2017). Oxidative stress in atherosclerosis. Current Atherosclerosis Reports, 19, 1-11. https://doi.org/10.1007/s11883-017-0678-6
• Referans44. Ghoreyshi, M., Mahmoudabady, M., Bafadam, S., & Niazmand, S. (2020). The protective effects of pharmacologic postconditioning of hydroalcoholic extract of Nigella sativa on functional activities and oxidative stress injury during ischemia–reperfusion in isolated rat heart. Cardiovascular Toxicology, 20, 130-138. https://doi.org/10.1007/s12012-019-09540-x
• Referans45. Rizka A, Setiati S, Lydia A, Dewiasty E. (2017). Effect of Nigella sativa Seed Extract for Hypertension in Elderly: A Double-blind, Randomized Controlled Trial. Acta Med. Indones. 49(4), 307–313.
• Referans46. Hussain, N., Majid, S. A., Abbasi, M. S., Hussain, M. A., Rehman, K., Khan, M. Q., ... & Habib, T. (2017). Use of black seed (Nigella sativa L.) oil in the management of hypertensive and hyperlipidemic individuals of district Muzaffarabad, Azad Kashmir, Pakistan. Applied Ecology & Environmental Research, 15(4). http://dx.doi.org/10.15666/aeer/1504_031048
• Referans47. Badar, A., Kaatabi, H., Bamosa, A., Al-Elq, A., Abou-Hozaifa, B., Lebda, F., ... & Al-Almaie, S. (2017). Effect of Nigella sativa supplementation over a one-year period on lipid levels, blood pressure and heart rate in type-2 diabetic patients receiving oral hypoglycemic agents: nonrandomized clinical trial. Annals of Saudi medicine, 37(1), 56-63. https://doi.org/10.5144/0256-4947.2017.56
• Referans48. Mohtashami, A., Mahaki, B., Azadbakht, L., & Entezari, M. H. (2016). Effects of bread with Nigella sativa on lipid profiles, apolipoproteins and inflammatory factor in metabolic syndrome patients. Clinical nutrition research, 5(2), 89-95. https://doi.org/10.7762/cnr.2016.5.2.89
• Referans49. Elfouly, A. E., Ismail, M. A., Kamal, H. M., Ahmed, S. A., & Fiala, L. E. (2019). A randomized controlled trial measuring the effect of Nigella sativa extract on lipid profile in adult patients with dyslipidemia attending family practice clinic.”. Ismailia, Egypt: Suez Canal University Hospital. https://doi.org/10.1016/s0378-8741(00)00235-x
• Referans50. Rashidmayvan, M., Mohammadshahi, M., Seyedian, S. S., & Haghighizadeh, M. H. (2019). The effect of Nigella sativa oil on serum levels of inflammatory markers, liver enzymes, lipid profile, insulin and fasting blood sugar in patients with non-alcoholic fatty liver. Journal of diabetes & metabolic disorders, 18, 453-459. https://doi.org/10.1007/s40200-019-00439-6
• Referans51. Doğan, P., Tanrikulu, G., Soyuer, Ü., & Köse, K. (1994). Oxidative enzymes of polymorphonuclear leucocytes and plasma fibrinogen, ceruloplasmin, and copper levels in Behcet's disease. Clinical biochemistry, 27(5), 413-418. https://doi.org/10.1016/0009-9120(94)90046-9
• Referans52. Sharifian, A., Farahani, S., Pasalar, P., Gharavi, M., & Aminian, O. (2005). Shift work as an oxidative stressor. Journal of circadian rhythms, 3(1), 1-3. https://doi.org/10.1186/1740-3391-3-15
• Referans53. Mantas, C. (1999). Serum levels of Th2 cytokines IL-4 and IL-10 in Behcet's disease. J Rheumatol, 26, 510-512.
• Referans54. Köse, K., Doğan, P., Asçıoğlu, M., Erkılıç, K., & Asçıoğlu, Ö. (1995). Oxidative stress and antioxidant defenses in plasma of patients with Behcet's disease. The Tohoku journal of experimental medicine, 176(4), 239-248. https://doi.org/10.1620/tjem.176.239
• Referans55. Takeno, M., Kariyone, A. I., Yamashita, N., Takiguchi, M., Mizushima, Y., Kaneoka, H., & Sakane, T. (1995). Excessive function of peripheral blood neutrophils from patients with behcet's disease and from hla‐b51 transgenic mice. Arthritis & Rheumatism, 38(3), 426-433. https://doi.org/10.1002/art.1780380321
• Referans56. Nielsen, F., Mikkelsen, B. B., Nielsen, J. B., Andersen, H. R., & Grandjean, P. (1997). Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clinical chemistry, 43(7), 1209-1214. https://doi.org/10.1093/clinchem/43.7.1209
• Referans57. Amizadeh, S., Rashtchizadeh, N., Khabbazi, A., Ghorbanihaghjo, A., Ebrahimi, A. A., Vatankhah, A. Mahdavi A.M., & Taghizadeh, M. (2020). Effect of Nigella sativa oil extracts on inflammatory and oxidative stress markers in Behcet’s disease: A randomized, double-blind, placebo-controlled clinical trial. Avicenna journal of phytomedicine, 10(2), 181.
• Referans58. Shahba, A., Esheba, N. E., Fooda, A. A., El-Dardiry, S., Wagih, A., & el-Deeb, O. (2015). Effect of nigella sativa and vitamin E on some oxidative/nitrosative biomarkers in systemic lupus erythematosus patients. Life Sci J, 12, 157-62.
• Referans59. Khaldi, T., Chekchaki, N., Boumendjel, M., Taibi, F., Abdellaoui, M., Messarah, M., & Boumendjel, A. (2018). Ameliorating effects of Nigella sativa oil on aggravation of inflammation, oxidative stress and cytotoxicity induced by smokeless tobacco extract in an allergic asthma model in Wistar rats. Allergologia et Immunopathologia, 46(5), 472-481. https://doi.org/10.1016/j.aller.2018.02.005
• Referans60. Alhibshi, A. H., Odawara, A., & Suzuki, I. (2019). Neuroprotective efficacy of thymoquinone against amyloid beta-induced neurotoxicity in human induced pluripotent stem cell-derived cholinergic neurons. Biochemistry and biophysics reports, 17, 122-126. https://doi.org/10.1016/j.bbrep.2018.12.005
• Referans61. Ismail, N., Ismail, M., Azmi, N. H., Bakar, M. F. A., Yida, Z., Abdullah, M. A., & Basri, H. (2017). Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. Biomedicine & Pharmacotherapy, 95, 780-788. https://doi.org/10.1016/j.biopha.2017.08.074
• Referans62. Ebrahimi, S. S., Oryan, S., Izadpanah, E., & Hassanzadeh, K. (2017). Thymoquinone exerts neuroprotective effect in animal model of Parkinson’s disease. Toxicology letters, 276, 108-114. https://doi.org/10.1016/j.toxlet.2017.05.018
• Referans63. Sandhu, K. S., & Rana, A. C. (2013). Evaluation of anti parkinson’s activity of Nigella sativa (kalonji) seeds in chlorpromazine induced experimental animal model. mortality, 22(5), 23.
• Referans64. Shawki, M., El Wakeel, L., Shatla, R., El-Saeed, G., Ibrahim, S., & Badary, O. (2013). The clinical outcome of adjuvant therapy with black seed oil on intractable paediatric seizures: a pilot study. Epileptic disorders, 15, 295-301. https://doi.org/10.1684/epd.2013.0602
• Referans65. Ansary, J., Giampieri, F., Forbes-Hernandez, T. Y., Regolo, L., Quinzi, D., Gracia Villar, S., Garcia Villena, E., Tutusaus Pifarre, K., Alvarez-Suarez, JM., Battino, M., & Cianciosi, D. (2021). Nutritional value and preventive role of Nigella sativa L. and its main component thymoquinone in cancer: an evidenced-based review of preclinical and clinical studies. Molecules, 26(8), 2108. https://doi.org/10.3390/molecules26082108
• Referans66. Khan, M. A., Tania, M., Wei, C., Mei, Z., Fu, S., Cheng, J., ... & Fu, J. (2015). Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition. Oncotarget, 6(23), 19580. https://doi.org/10.18632/oncotarget.3973
• Referans67. Rooney, S., & Ryan, M. F. (2005). Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer research, 25(3B), 2199-2204.
• Referans68. Raghunandhakumar, S., Paramasivam, A., Senthilraja, S., Naveenkumar, C., Asokkumar, S., Binuclara, J., ... & Devaki, T. (2013). Thymoquinone inhibits cell proliferation through regulation of G1/S phase cell cycle transition in N-nitrosodiethylamine-induced experimental rat hepatocellular carcinoma. Toxicology letters, 223(1), 60-72. https://doi.org/10.1016/j.toxlet.2013.08.018
• Referans69. Zhu, N., Zhao, X., Xiang, Y., Ye, S., Huang, J., Hu, W., ... & Zeng, C. (2016). Thymoquinone attenuates monocrotaline-induced pulmonary artery hypertension via inhibiting pulmonary arterial remodeling in rats. International Journal of Cardiology, 221, 587-596. https://doi.org/10.1016/j.ijcard.2016.06.192
• Referans70. El Daly, E. S. (1998). Protective effect of cysteine and vitamine E, Crocus sativus and Nigella sativa extracts on cisplatine-induced toxicity in rats. Journal de pharmacie de Belgique, 53, 87-95.
• Referans71. Khanna, T., Zaidi, F. A., & Dandiya, P. C. (1993). CNS and analgesic studies on Nigella sativa. Fitoterapia-milano, 64, 407-407.
• Referans72. Zaoui, A., Cherrah, Y., Mahassini, N., Alaoui, K., Amarouch, H., & Hassar, M. (2002). Acute and chronic toxicity of Nigella sativa fixed oil. Phytomedicine, 9(1), 69-74. https://doi.org/10.1078/0944-7113-00084
• Referans73. Dollah, M. A., Parhizkar, S., Latiff, L. A., & Hassan, M. H. B. (2013). Toxicity effect of Nigella sativa on the liver function of rats. Advanced pharmaceutical bulletin, 3(1), 97. https://doi.org/10.5681/apb.2013.016
• Referans74. Badary, O. A., Al‐Shabanah, O. A., Nagi, M. N., Al‐Bekairi, A. M., & Elmazar, M. (1998). Acute and subchronic toxicity of thymoquinone in mice. Drug Development Research, 44(2‐3), 56-61. https://doi.org/10.1002/(SICI)1098-2299(199806/07)44:2/3%3C56::AID-DDR2%3E3.0.CO;2-9