Download PDF
Planta Med 2020; 86(07): 457-469
DOI: 10.1055/a-1143-8521
Biological and Pharmacological Activity
Reviews
Georg Thieme Verlag KG Stuttgart · New York

A Systematic Review of the Potential Effects of Nigella sativa on Rheumatoid Arthritis

Alireza Khabbazi
1   Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
,
Zeinab Javadivala
2   Department of Health Education & Promotion, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
,
Neda Seyedsadjadi
3   School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia
,
Aida Malek Mahdavi
1   Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
› Author Affiliations
Further Information

Publication History

received 08 November 2019
revised 20 March 2020

accepted 20 March 2020

Publication Date:
09 April 2020 (online)

Also available at
   Permissions and Reprints

Abstract

Considering the different untoward effects of the drugs prescribed for the treatment of rheumatoid arthritis (RA), there has been an increasing interest in adjuvant therapies devoid of such unfavorable reactions. Although the beneficial effects of Nigella sativa (N. sativa) on RA have been established, it seems that its mechanisms of action have not still been reviewed. The present review is designed to evaluate the effects of N. sativa on RA systematically. We searched these electronic databases until April 2019: PubMed, Scopus, ISI Web of Science, Cochrane Library, Embase, Ovid, ProQuest, and Google scholar. No restriction was conducted based on language or publication date. We selected all of the related clinical, animal, and in vitro studies. Review papers, abstracts in conferences, book chapters, and papers regarding the effects of N. sativa combined with other herbs, as well as articles regarding the effects of N. sativa on other diseases, were excluded. Each article was assessed critically for the possible risk of bias. Nineteen articles were reviewed. Animal and in vitro investigations supported the favorable effects of N. sativa on clinical, inflammatory, oxidative, and immunologic parameters on RA, whereas results of limited clinical studies did not illustrate any change or improvement of inflammatory and oxidative biomarkers in RA. N. sativa could control RA via multiple ways such as decreasing inflammation, inhibiting oxidative stress, and modulating the immune system. This paper provides persuasive clues to defend the efficacy of N. sativa in RA and justifies the significance of subsequent clinical trials.

Key words

Nigella sativa - Ranunculaceae - thymoquinone - rheumatoid arthritis
 

  • References

  • 1 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205-2219
    CrossrefPubMedSearch in Google Scholar
  • 2 Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 2012; 18: S295-S302
    PubMedSearch in Google Scholar
  • 3 Lajas C, Abasolo L, Bellajdel B, Hernández-García C, Carmona L, Vargas E, Lázaro P, Jover JA. Costs and predictors of costs in rheumatoid arthritis: a prevalence-based study. Arthritis Care Res 2003; 49: 64-70
    CrossrefPubMedSearch in Google Scholar
  • 4 Kumar P, Banik S. Pharmacotherapy options in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord 2013; 6: 35-43
    PubMedSearch in Google Scholar
  • 5 World Health Organization. WHO Guidelines on Safety Monitoring of herbal Medicines in Pharmacovigilance Systems. Geneva: Switzerland; 2004
    Search in Google Scholar
  • 6 Kadhim MJ, Kaizal AF, Hameed IH. Medicinal plants used for treatment of rheumatoid arthritis: a review. Int J Pharm Clin Res 2016; 8: 1685-1694
    PubMedSearch in Google Scholar
  • 7 Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol 2005; 5: 1749-1770
    CrossrefPubMedSearch in Google Scholar
  • 8 Akram Khan M. Chemical composition and medicinal properties of Nigella sativa Linn. Inflammopharmacol 1999; 7: 15-35
    CrossrefPubMedSearch in Google Scholar
  • 9 Al-Bukhari MI. The Collection of authentic Sayings of Prophet Mohammad (Peace Be Upon Him), Division 71 on Medicine. 2nd edition. Ankara: Hilal Yayinlari; 1976
    Search in Google Scholar
  • 10 Ave-Sina AA. Law in Medicine. Tehran: Ministry of Guidance Publication; 1990: 314
    Search in Google Scholar
  • 11 Junemann M, Luetjohann S. Three great healing Herbs: Tea Tree, St. Johns Wort, and Black Cumin. 1st edition. Twin Lakes, WI: Lotus Light Publications; 1998: 91-116
    Search in Google Scholar
  • 12 Nergiz C, Ötleş S. Chemical composition of Nigella sativa L. seeds. Food Chem 1993; 48: 259-261
    CrossrefPubMedSearch in Google Scholar
  • 13 Cikman O, Ozkan A, Aras AB, Soylemez O, Alkis H, Taysi S, Karaayvaz M. Radioprotective effects of Nigella sativa oil against oxidative stress in liver tissue of rats exposed to total head irradiation. J Invest Surg 2014; 5: 262-266
    PubMedSearch in Google Scholar
  • 14 Burits M, Bucar F. Antioxidant activity of Nigella sativa essential oil. Phytother Res 2000; 14: 323-328
    CrossrefPubMedSearch in Google Scholar
  • 15 Mousavi S, Tayarani-Najaran Z, Asghari M, Sadeghnia H. Protective effect of Nigella sativa extract and thymoquinone on serum/glucose deprivation-induced PC12 cells death. Cell Mol Neurobiol 2010; 30: 591-598
    CrossrefPubMedSearch in Google Scholar
  • 16 Ghannadi A, Hajhashemi V, Jafarabadi H. An investigation of the analgesic and anti-inflammatory effects of Nigella sativa seed polyphenols. J Med Food 2005; 8: 488-493
    CrossrefPubMedSearch in Google Scholar
  • 17 Islam MH, Ahmad IZ, Salman MT. In vivo evaluation of anti-inflammatory and analgesic activies of Nigella sativa seed during germination. Int J Pharm Pharm Sci 2013; 5: 451-454
    PubMedSearch in Google Scholar
  • 18 Mahmoud SS, Torchilin VP. Hormetic/cytotoxic effects of Nigella sativa seed alcoholic and aqueous extracts on MCF-7 breast cancer cells alone or in combination with doxorubicin. Cell Biochem Biophys 2013; 66: 451-460
    CrossrefPubMedSearch in Google Scholar
  • 19 Al-Sheddi ES, Farshori NN, Al-Oqail MM, Musarrat J, Al-Khedhairy AA, Siddiqui MA. Cytotoxicity of Nigella sativa seed oil and extract against human lung cancer cell line. Asian Pac J Cancer Prev 2014; 15: 983-987
    CrossrefPubMedSearch in Google Scholar
  • 20 Hanafy MS, Hatem ME. Studies on the antimicrobial activity of Nigella sativa seed (black cumin). J Ethnopharmacol 1991; 34: 275-278
    CrossrefPubMedSearch in Google Scholar
  • 21 Dey D, Ray R, Hazra B. Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates. Phytother Res 2014; 28: 1014-1021
    CrossrefPubMedSearch in Google Scholar
  • 22 Awad E, Austin D, Lyndon AR. Effect of black cumin seed oil (Nigella sativa) and nettle extract (quercetin) on enhancement of immunity in rainbow trout, Oncorhynchus mykiss (Walbaum). Aquaculture 2013; 388 – 391: 193-197
    PubMedSearch in Google Scholar
  • 23 Assayed ME. Radioprotective effects of black seed (Nigella sativa) oil against hemopoietic damage and immunosuppression in gamma-irradiated rats. Immunopharmacol Immunotoxicol 2010; 32: 284-296
    CrossrefPubMedSearch in Google Scholar
  • 24 Meddah B, Ducroc R, El Abbes Faouzi M, Eto B, Mahraoui L, Benhaddou-Andaloussi A, Martineau LC, Cherrah Y, Haddad PS. Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. J Ethnopharmacol 2009; 121: 419-424
    CrossrefPubMedSearch in Google Scholar
  • 25 Zaoui A, Cherrah Y, Lacaille-Dubois MA, Settaf A, Amarouch H, Hassar M. Diuretic and hypotensive effects of Nigella sativa in the spontaneously hypertensive rat. Therapie 2000; 55: 379-382
    PubMedSearch in Google Scholar
  • 26 Ibrahim RM, Hamdan NS, Mahmud R, Imam MU, Saini SM, Rashid SN, Abd Ghafar SA, Latiff LA, Ismail M. A randomized controlled trial on hypolipidemic effects of Nigella sativa seeds powder in menopausal women. J Transl Med 2014; 12: 82
    CrossrefPubMedSearch in Google Scholar
  • 27 Ebru U, Burak U, Yusuf S, Reyhan B, Arif K, Faruk TH, Emin M, Aydin K, Atilla II, Semsettin S, Kemal E. Cardioprotective effects of Nigella sativa oil on cyclosporine A-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxicol 2008; 103: 574-580
    CrossrefPubMedSearch in Google Scholar
  • 28 Nagi MN, Mansour MA. Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity in rats: a possible mechanism of protection. Pharmacol Res 2000; 41: 283-289
    CrossrefPubMedSearch in Google Scholar
  • 29 Abdel-Sater KA. Gastroprotective effects of Nigella sativa oil on the formation of stress gastritis in hypothyroidal rats. Int J Physiol Pathophysiol Pharmacol 2009; 1: 143-149
    PubMedSearch in Google Scholar
  • 30 Mahmoud MR, El-Abhar HS, Saleh S. The effect of Nigella sativa oil against the liver damage induced by Schistosoma mansoni infection in mice. J Ethnopharmacol 2002; 79: 1-11
    CrossrefPubMedSearch in Google Scholar
  • 31 Dollah MA, Parhizkar S, Izwan M. Effect of Nigella sativa on the kidney function in rats. Avicenna J Phytomed 2013; 3: 152-158
    PubMedSearch in Google Scholar
  • 32 Hadjzadeh MA, Rad AK, Rajaei Z, Tehranipour M, Monavar N. The preventive effect of N-butanol fraction of Nigella sativa on ethylene glycol-induced kidney calculi in rats. Pharmacogn Mag 2011; 7: 338-343
    CrossrefPubMedSearch in Google Scholar
  • 33 Gilani AH, Aziz N, Khurram IM, Chaudhary KS, Iqbal A. Bronchodilator, spasmolytic and calcium antagonist activities of Nigella sativa seeds (Kalonji): a traditional herbal product with multiple medicinal uses. J Pak Med Assoc 2001; 51: 115-120
    PubMedSearch in Google Scholar
  • 34 Boskabady MH, Farhadi F. The possible prophylactic effect of Nigella sativa seed extract on respiratory symptoms, pulmonary function tests on chemical war victims. J Altern Complement Med 2008; 14: 1137-1144
    CrossrefPubMedSearch in Google Scholar
  • 35 Boskabady MH, Mohsenpoor N, Takaloo L. Antiasthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomedicine 2010; 17: 707-713
    CrossrefPubMedSearch in Google Scholar
  • 36 Hosseinzadeh H, Tafaghodi M, Mosavi MJ, Taghiabadi E. Effect of aqueous and ethanolic extracts of Nigella sativa seeds on milk production in rats. J Acupunct Meridian Stud 2013; 6: 18-23
    CrossrefPubMedSearch in Google Scholar
  • 37 Hosseinzadeh H, Parvardeh S, Nassiri-Asl M, Mansouri MT. Intracerebroventricular administration of thymoquinone, the major constituent of Nigella sativa seeds, suppresses epileptic seizures in rats. Med Sci Monit 2005; 11: BR106-BR110
    PubMedSearch in Google Scholar
  • 38 Damião PD, Franklin FFN, Camila CMPS, Rubens BB, Ygor WV, Marciana PU, Timothy JB, Reinaldo ND. Anti-convulsant activity of thymoquinone and its structural analogues. Rev Bras Farmacogn 2011; 21: 427-433
    PubMedSearch in Google Scholar
  • 39 Perveen T, Haider S, Zuberi NA, Saleem S, Sadaf S, Batool Z. Increased 5-HT levels following repeated administration of Nigella sativa L. (black seed) oil produce antidepressant effects in rats. Sci Pharm 2014; 82: 161-170
    CrossrefPubMedSearch in Google Scholar
  • 40 Kolahdooz M, Nasri S, Modarres SZ, Kianbakht S, Huseini HF. Effects of Nigella sativa L. seed oil on abnormal semen quality in infertile men: a randomized, double-blind, placebo-controlled clinical trial. Phytomedicine 2014; 21: 901-905
    CrossrefPubMedSearch in Google Scholar
  • 41 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. Chin J Integr Med 2015; 21: 438-444
    CrossrefPubMedSearch in Google Scholar
  • 42 Al-Ali A, Alkhawajah AA, Randhawa MA, Shaikh NA. Oral and intra-peritoneal LD50 of thymoquinone, an active principle of Nigella sativa, in mice and rats. J Ayub Med Coll Abbottabad 2008; 20: 25-27
    PubMedSearch in Google Scholar
  • 43 Gali-Muhtasib H, El-Najjar N, Schneider-Stock R. The medicinal potential of black seed (Nigella sativa) and its components. Adv Phytomed 2006; 2: 133-153
    PubMedSearch in Google Scholar
  • 44 Paarakh PM. Nigella sativa Linn. A comprehensive review. Indian J Nat Prod Resour 2010; 1: 409-429
    PubMedSearch in Google Scholar
  • 45 Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddique NA, Damanhouri ZA, Anwar F. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed 2013; 3: 337-352
    PubMedSearch in Google Scholar
  • 46 Vaillancourt F, Silva P, Shi Q, Fahmi H, Fernandes JC, Benderdour M. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. J Cell Biochem 2011; 112: 107-117
    CrossrefPubMedSearch in Google Scholar
  • 47 Umar S, Hedaya O, Singh AK, Ahmed S. Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation. Toxicol Appl Pharmacol 2015; 287: 299-305
    CrossrefPubMedSearch in Google Scholar
  • 48 Arjumand S, Shahzad M, Shabbir A, Yousaf M. Thymoquinone attenuates rheumatoid arthritis by downregulating TLR2, TLR4, TNF-α, IL-1, and NF-κB expression levels. Biomed Pharmacother 2019; 111: 958-963
    CrossrefPubMedSearch in Google Scholar
  • 49 Faisal R, Imran U. Comparative evaluation of thymoquinone and methotrexate in lung inflammation in murine model of rheumatiod arthritis. J Postgrad Med Inst 2015; 29: 88-92
    PubMedSearch in Google Scholar
  • 50 Tekeoglu I, Dogan A, Ediz L, Budancamanak M, Demirel A. Effects of thymoquinone (volatile oil of black cumin) on rheumatoid arthritis in rat models. Phytother Res 2007; 21: 895-897
    CrossrefPubMedSearch in Google Scholar
  • 51 Umar S, Zargan J, Umar K, Ahmad S, Katiyar CK, Khan HA. Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. Chem Biol Interact 2012; 197: 40-46
    CrossrefPubMedSearch in Google Scholar
  • 52 Kheirouri S, Hadi V, Alizadeh M. Immunomodulatory effect of Nigella sativa oil on T lymphocytes in patients with rheumatoid arthritis. Immunol Invest 2016; 45: 271-283
    CrossrefPubMedSearch in Google Scholar
  • 53 Al-Okbi SY, Ammar NM, Soroor KHA, Mohammed DA. Impact of natural oils supplements on disease activity and antioxidant state of Egyptian patients with rheumatoid arthritis. Med J Islamic World Acad Sci 2000; 13: 161-171
    PubMedSearch in Google Scholar
  • 54 Gheita TA, Kenawy SA. Effectiveness of Nigella sativa oil in the management of rheumatoid arthritis patients: a placebo controlled study. Phytother Res 2011; 26: 1246-1248
    PubMedSearch in Google Scholar
  • 55 Hadi V, Kheirouri S, Alizadeh M, Khabbazi A, Hosseini H. 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 J Phytomed 2016; 6: 34-43
    PubMedSearch in Google Scholar
  • 56 Mahdy A, Gheita T. Beneficial effects of Nigella sativa seed oil as adjunct therapy in rheumatoid arthritis. J Egypt Soc Toxicol 2009; 41: 31-37
    PubMedSearch in Google Scholar
  • 57 Mahboubi M, Taghizadeh Kashani ML, Mahboubi M. Nigella sativa fixed oil as alternative treatment in management of pain in arthritis rheumatoid. Phytomedicine 2018; 46: 69-77
    CrossrefPubMedSearch in Google Scholar
  • 58 Gholamnezhad Z, Havakhah S, Boskabady MH. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: a review. J Ethnopharmacol 2016; 190: 372-386
    CrossrefPubMedSearch in Google Scholar
  • 59 Tavakkoli A, Mahdian V, Razavi BM, Hosseinzadeh H. Review on clinical trials of black seed (Nigella sativa) and its active constituent, thymoquinone. J Pharmacopuncture 2017; 20: 179-193
    CrossrefPubMedSearch in Google Scholar
  • 60 Yimer EM, Tuem KB, Karim A, Ur-Rehman N, Anwar F. Nigella sativa L. (black cumin): a promising natural remedy for wide range of illnesses. Evid Based Complement Alternat Med 2019; 2019: 1-16
    CrossrefPubMedSearch in Google Scholar
  • 61 Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA. PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 62 Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L. Sterne JA; Cochrane Bias Methods Group, Cochrane Statistical Methods Group. The Cochrane collaborationʼs tool for assessing risk of bias in randomised trials. BMJ 2011; 343: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 63 Krithikadatta J, Gopikrishna V, Datta M. CRIS Guidelines (Checklist for Reporting In vitro Studies): A concept note on the need for standardized guidelines for improving quality and transparency in reporting in-vitro studies in experimental dental research. J Conserv Dent 2014; 17: 301-304
    CrossrefPubMedSearch in Google Scholar
  • 64 Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLEʼs risk of bias tool for animal studies. BMC Med Res Methodol 2014; 14: 1-9
    CrossrefPubMedSearch in Google Scholar
  • 65 Nasuti C, Fedeli D, Bordoni L, Piangerelli M, Servili M, Selvaggini R, Gabbianelli R. Anti-inflammatory, anti-arthritic and anti-nociceptive activities of Nigella sativa oil in a rat model of arthritis. Antioxidants (Basel) 2019; 8: 342-358
    CrossrefPubMedSearch in Google Scholar
  • 66 Faisal R, Ahmad N, Fahad YS, Chiragh S. Anti-arthritic effect of thymoquinone in comparison with methotrexate on pristane induced arthritis in female sprague dawley rats. J Ayub Med Coll Abbottabad 2018; 30: 3-7
    PubMedSearch in Google Scholar
  • 67 Faisal R, Chiragh S, Popalzai AJ, Rehman KU. Anti-inflammatory effect of thymoquinone in comparison with methotrexate on pristane induced arthritis in rats. J Pak Med Assoc 2015; 65: 519-525
    PubMedSearch in Google Scholar
  • 68 Faisal R, Shinwari L, Jehangir T. Comparison of the therapeutic effects of thymoquinone and methotrexate on renal injury in pristane induced arthritis in rats. J Coll Physicians Surg Pak 2015; 25: 597-601
    PubMedSearch in Google Scholar
  • 69 Hou W, Meng L, Zheng F, Wen Y, Zhu W, Jiang C, He X, Zhou Y, Lu S. Methotrexate ameliorates pristane-induced arthritis by decreasing IFN-γ and IL-17A expressions. J Zhejiang Univ Sci B 2011; 12: 40-46
    CrossrefPubMedSearch in Google Scholar
  • 70 Sajad M, Asif M, Umar S, Zargan J, Rizwan M, Ansari SH, Ahmad M, Khan HA. Amelioration of inflammation induced oxidative stress and tissue damage by aqueous methanolic extract of Nigella sativa Linn. in arthritic rats. J Altern Complement Med 2010; 7: 1-21
    CrossrefPubMedSearch in Google Scholar
  • 71 Budancamanak M, Kanter M, Demirel A, Ocakci A, Uysal H, Karakaya C. Protective effects of thymoquinone and methotrexate on the renal injury in collagen-induced arthritis. Arch Toxicol 2006; 80: 768-776
    CrossrefPubMedSearch in Google Scholar
  • 72 May M. The Role of Antioxidants (Gag S & Tq) on the Viability and Proliferation of an Htb-93 rheumatoid Arthritis Cell Model [dissertation]. Jackson: Mississippi Medical Center University; 2007
    PubMedSearch in Google Scholar
  • 73 Bauer R. Quality criteria and standardization of phytopharmaceuticals: can acceptable drug standard can be achieved. Drug Info J 1998; 32: 101-110
    CrossrefPubMedSearch in Google Scholar
  • 74 Sachan A, Vishnoi G, Kumar R. Need of standardization of herbal medicines in modern era. Int J Phytomedicine 2016; 8: 300-307
    PubMedSearch in Google Scholar
  • 75 Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S. Thymoquinone and its therapeutic potentials. Pharmacol Res 2015; 95 – 96: 138-158
    PubMedSearch in Google Scholar
  • 76 Salmani JM, Asghar S, Lv H, Zhou J. Aqueous solubility and degradation kinetics of the phytochemical anticancer thymoquinone; probing the effects of solvents, pH and light. Molecules 2014; 19: 5925-5939
    CrossrefPubMedSearch in Google Scholar
  • 77 Schneider-Stock R, Fakhoury IH, Zaki AM. Thymoquinone: fifty years of success in the battle against cancer models. Drug Discov Today 2014; 19: 18-30
    CrossrefPubMedSearch in Google Scholar
  • 78 Alkharfy KM, Ahmad A, Khan RM, Al-Shagha WM. Pharmacokinetic plasma behaviors of intravenous and oral bioavailability of thymoquinone in a rabbit model. Eur J Drug Metab Pharmacokinet 2015; 40: 319-323
    CrossrefPubMedSearch in Google Scholar
  • 79 Kowshik Aravilli R, Laveen Vikram S, Kohila V. Phytochemicals as potential antidotes for targeting NF-κB in rheumatoid arthritis. 3 Biotech 2017; 7: 253-263
    CrossrefPubMedSearch in Google Scholar
  • 80 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 Med 1995; 61: 33-36
    Thieme ConnectPubMedSearch in Google Scholar
  • 81 Mansour M. Tornhamre S. Inhibition of 5-lipoxygenase and leukotriene C4synthase in human blood cells by thymoquinone. J Enzyme Inhib Med Chem 2004; 19: 431-436
    CrossrefPubMedSearch in Google Scholar
  • 82 El-Dakhakhny M, Madi NJ, Lembert N, Ammon HP. Nigella sativa oil, nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in polymorphonuclear leukocytes from rats. J Ethnopharmacol 2002; 81: 161-164
    CrossrefPubMedSearch in Google Scholar
  • 83 Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol 2012; 83: 443-451
    CrossrefPubMedSearch in Google Scholar
  • 84 Mor A, Abramson SB, Pillinger MH. The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol 2005; 115: 118-128
    CrossrefPubMedSearch in Google Scholar
  • 85 Roman-Blas JA, Jimenez SA. NF-κB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthr Cartilage 2006; 14: 839-848
    CrossrefPubMedSearch in Google Scholar
  • 86 Sayed AA, Morcos M. Thymoquinone decreases AGE-induced NF-kappaB activation in proximal tubular epithelial cells. Phytother Res 2007; 21: 898-899
    CrossrefPubMedSearch in Google Scholar
  • 87 Keyhanmanesh R, Boskabady MH, Eslamizadeh MJ, Khamneh S, Ebrahimi MA. The effect of thymoquinone, the main constituent of Nigella sativa on tracheal responsiveness and white blood cell count in lung lavage of sensitized guinea pigs. Planta Med 2010; 76: 218-222
    Thieme ConnectPubMedSearch in Google Scholar
  • 88 Bordoni L, Fedeli D, Nasuti C, Maggi F, Papa F, Wabitsch M, De Caterina R, Gabbianelli R. Antioxidant and anti-inflammatory properties of Nigella sativa oil in human pre-adipocytes. Antioxidants (Basel) 2019; 8: 51-62
    CrossrefPubMedSearch in Google Scholar
  • 89 Seo WG, Pae HO, Oh GS, Chai KY, Kwon TO, Yun YG, Kim NY, Chung HT. Inhibitory effects of methanol extract of Cyperus rotundus rhizomes on nitric oxide and superoxide productions by murine macrophage cell line, RAW 264.7 cells. J Ethnopharmacol 2001; 76: 59-64
    CrossrefPubMedSearch in Google Scholar
  • 90 Savnik A, Malmskov H, Thomsen HS, Graff LB, Nielsen H, Danneskiold-Samsoe B, Boesen J, Bliddal H. Magnetic resonance imaging of the wrist and finger joints in patients with inflammatory joint diseases. J Rheumatol 2001; 28: 2193-2200
    PubMedSearch in Google Scholar
  • 91 Romas E, Sims NA, Hards DK, Lindsay M, Quinn JWM, Ryan PFJ, Dunstan CR, Martin TJ, Gillespie MT. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 2002; 161: 1419-1427
    CrossrefPubMedSearch in Google Scholar
  • 92 Blanco FJ, Ochs RL, Schwarz H, Lotz M. Chondrocyte apoptosis induced by nitric oxide. Am J Patholo 1995; 146: 75-85
    PubMedSearch in Google Scholar
  • 93 Shukla M, Gupta K, Rasheed Z, Khan KA, Haqqi TM. Bioavailable constituents/metabolites of pomegranate (Punica granatum L) preferentially inhibit COX2 activity ex vivo and IL-1beta-induced PGE2 production in human chondrocytes in vitro . J Inflamm 2008; 5: 9-18
    CrossrefPubMedSearch in Google Scholar
  • 94 Mansour MA, Nagi MN, El-Khatib AS, Al-Bekairi AM. Effects of thymoquinone on antioxidant enzyme activities, lipid peroxidation and DT-diaphorase in different tissues of mice: a possible mechanism of action. Cell Biochem Funct 2002; 20: 143-151
    CrossrefPubMedSearch in Google Scholar
  • 95 Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol 2003; 26: 87-98
    CrossrefPubMedSearch in Google Scholar
  • 96 Daba MH, Abdel-Rahman MS. Hepatoprotective activity of thymoquinone in isolated rat hepatocytes. Toxicol Lett 1998; 95: 23-29
    PubMedSearch in Google Scholar
  • 97 Khalife KH, Lupidi G. Nonenzymatic reduction of thymoquinone in physiological conditions. Free Radic Res 2007; 41: 153-161
    CrossrefPubMedSearch in Google Scholar
  • 98 Kundu J, Kim DH, Kundu JK, Chun KS. Thymoquinone induces hemeoxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPK as upstream targets. Food Chem Toxicol 2014; 65: 18-26
    CrossrefPubMedSearch in Google Scholar
  • 99 Swamy S, Tan B. Cytotoxic and immunopotentiating effects of ethanolic extract of Nigella sativa L. seeds. J Ethnopharmacol 2000; 70: 1-7
    CrossrefPubMedSearch in Google Scholar
  • 100 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 U S A 1993; 90: 10345-10349
    CrossrefPubMedSearch in Google Scholar
  • 101 Abdel-Zaher AO, Abdel-Rahman MS, Elwasei FM. Protective effect of Nigella sativa oil against tramadol-induced tolerance and dependence in mice: role of nitric oxide and oxidative stress. Neurotoxicol 2011; 32: 725-733
    CrossrefPubMedSearch in Google Scholar
  • 102 Işık H, Çevikbaş A, Gürer ÜS, Kiran B, Uresin Y, Rayaman P, Gürbüz B, Büyüköztürk S. Potential adjuvant effects of Nigella sativa seeds to improve specific immunotherapy in allergic rhinitis patients. Med Princ Pract 2010; 19: 206-211
    CrossrefPubMedSearch in Google Scholar
  • 103 Haq A, Abdullatif M, Lobo PI, Khabar KS, Sheth KV, al-Sedairy ST. Nigella sativa: effect on human lymphocytes and polymorphonuclear leukocyte phagocytic activity. Immunopharmacol 1995; 30: 147-155
    CrossrefPubMedSearch in Google Scholar
  • 104 Haq A, Lobo PI, Al-Tufail M, Rama NR, Al-Sedairy ST. Immunomodulatory effect of Nigella sativa proteins fractionated by ion exchange chromatography. Int J Immunopharmacol 1999; 21: 283-295
    CrossrefPubMedSearch in Google Scholar
  • 105 Wu D, Meydani M, Leka LS, Nightingale Z, Handelman GJ, Blumberg JB, Meydani SN. Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects. Am J Clin Nutr 1999; 70: 536-543
    CrossrefPubMedSearch in Google Scholar
  • 106 Hirst JA, Howick J, Aronson JK, Roberts N, Perera R, Koshiaris C, Heneghan C. The need for randomization in animal trials: An overview of systematic reviews. PLoS One 2014; 9: 1-11
    PubMedSearch in Google Scholar