Letter to Editor Open Access
A Traditional Medicine, Nigella Sativa Can Be Effective on Novel Coronavirus (Sars-Cov-2) and Pulmonary Diseases (Hypothesis)
This paper has been proposed as a result of the common thinking and work of the COVID19/STORM team
AFarmanli Orkhan*1, Bastug Samet2, Donmez Omer Faruk3, Gokdemir Cihan4, Uckun Ilknur5, Pamuk Ibrahim6, Jafarov Alemdar7
1Department of Pathology, Marmara University School of Medicine
2Faculty of Pharmacy, Istanbul University
3Faculty of Medicine, Istanbul Medeniyet University
4Faculty of Medicine, Marmara University
5Faculty of Medicine, Kırıkkale University
6Department of Eye diseases, Istanbul Education and Research Hospital
7Department of Hematology, Azerbaijan Medical University
*Corresponding author: Dr.Orkhan Farmanli, Department of Pathology, Marmara University School of Medicine, Turkey, E-mail: @
Received: 15 April 2020; Accepted: 20 April 2020; Published: 27 April 2020
Citation: Farmanli Orkhan, Bastug Samet, Donmez Omer Faruk, Gokdemir Cihan et al, (2020) A Traditional Medicine, Nigella Sativa Can Be Effective on Novel Coronavirus (Sars-Cov-2) and Pulmonary Diseases (Hypothesis). SOJ Pharm Sci 7(1):1-5. DOI: 10.15226/2374-6866/7/1/001100
Abstract
In late December 2019, a group of patients applied to hospitals with a diagnosis of pneumonia with an unknown etiology in Wuhan, China. The pathogen, novel coronavirus SARS-CoV-2 was detected by local hospitals using a monitoring mechanism for “pneumonia of unknown etiology”, which was established to identify new pathogens in a timely manner after the 2003 SARS outbreak. Nigella sativa is an annual herb. Nigella sativa has been considered for treatment of various diseases and is one of the most widely investigated herbs. In this review, we will especially focus on the antibacterial, antiviral effects of Nigella sativa. Most importantly, we aimed to review whether it is effective against the current SARS-CoV-2 (COVID19), and against bacterial and viral superinfection accompanying this virus, and whether it can be effective in the treatment of SARS-CoV-2 related lung diseases.

Keywords: Nigella sativa; SARS-Cov-2; COVID19; antiviral; antibacterial; pulmonary diseases; hypothesis
Introduction
Coronavirus (COVs) is a large single strand RNA virus family. Novel coronaviruses appear regularly, especially due to the high prevalence and wide distribution of coronaviruses, large genetic diversity and frequent recombination of their genomes [1]. Among the previous outbreaks of coronaviruses include severe Acute Respiratory Syndrome (SARS) -CoV and Middle East Respiratory Syndrome (MERS) -CoV, previously described as factors with a major public health threat. In late December 2019, a group of patients applied to hospitals with a diagnosis of pneumonia with an unknown etiology in Wuhan, China [2]. The pathogen, novel coronavirus SARS-CoV-2 was detected by local hospitals using a monitoring mechanism for “pneumonia of unknown etiology”, which was established to identify new pathogens in a timely manner after the 2003 SARS outbreak. On January 30, 2020, the World Health Organization (WHO) declared COVID-19 as a “public health emergency of international concern” [3].

Nigella sativa is an annual herb. Nigella sativa has been considered for treatment of various diseases and is one the most widely investigated herbs. This plant is known by different names, for example black cumin (English), black caraway seeds (USA), and corekotu (Turkish) [4].

Many active compounds of black seeds have been isolated, identified and reported so far. The ingredients of Nigella sativa (black cumin) seed includes: proteins, alkaloid, fixed oil, saponin and essential oil [5].

Some of these mixed oils contain unsaturated fatty acids which includes: arachidonic, linoleic, linolenic, eicosadienoic, palmitic, oleic, stearic acid and more [5, 6].

Nigella sativa contains essential oils such as thymoquinone (TQ), thymohydroquinone (THQ), nigellone, dithymoquinone, thymol and more. Quinine, where
TQ is mostly abundant, is responsible for most of the pharmacological effects. Moreover, Nigella sativa seeds also have different vitamins and minerals such as Fe, Ca, K, Zn, P, Cu [5].
Extensive studies were done to identify the biological activities and therapeutic potential of the Nigella sativa. As a result of the studies carried out so far, nigella sativa has been reported as having the following therapeutic effects; antioxidant, gastroprotective, anti-ulcer, antiasthmatic, anti-cancer, antiinflammatory, immunomodulatory and anti-tumor properties, hepatoprotective effect, antibacterial activity, antiviral activity and more [4].

In this review, we will especially focus on the antibacterial, antiviral effects of Nigella sativa. Most importantly, we aimed to review whether it is effective against the current SARSCoV- 2 (COVID19) and against bacterial, viral superinfection accompanying to this virus, and whether it can be effective in the treatment of SARS-CoV-2 related lung diseases.
Antibacterial Activity of Nigella Sativa
Nigella sativa has very well-known antibacterial effect which is shown in many in vitro and in vivo studies [6]. Hanafy et al. showed that dietyl ether extracted Nigella sativa is very effective against Gram positive and negative microorganisms. Also, the same study showed that Nigella sativa extracts are very useful as treatment of Staphylococcal infections in mice[7]. In another study, Hannan et al. used ethanolic extracts of Nigella sativa against Methicillin resistant Staphylacoccus aureus (MRSA) and study results showed that all tested strains of MRSA were sensitive to extract and the extract had an MIC range of 0.2-0.5 mg/ml [8]. Hasan et al. designed a study that compares the effectiveness of aqueous extract and methanol extract of Nigella sativa. Although aqueous extract of Nigella sativa is less effective compared to the methanol extract, aqueous extract of Nigella sativa at 100 mg/ml is effective against Pseudomonas aeruginosa in disc effusion method [9].

Hosseinzadeh et al. showed that the methanol and chloroform extracts of Nigella sativa seed total extract as well as the essential oil caused a dose dependent antibacterial activity on Gram-positive and Gram-negative organisms in vivo study [10]. According to Eida et al., a research designed to evaluate the therapeutic effect of the aqueous extract of Nigella sativa (NS) at different doses on B. hominis in vitro and in vivo in comparison to MTZ as a control drug and results of both in vivo and in vitro studies reveal potent lethal effect on B. Hominis without any cytopathic effects in infected mice [11]. These and other many studies prove that Nigella sativa has very strong and useful effect as an antibacterial agent.
Antiviral Activity of Nigella Sativa
We searched Nigella sativa for its antiviral activity and found 19 articles in PubMed. We have examined all of these publications and presented their results under this title. In a study that belongs to Oyero et al. Alpha-Zam(a Nigella sativa formulation) selectively inhibited HCV replication [12].This study leads us to consider Nigella sativa as a new antiviral agent against HCV infection. Furthermore, in another study belongs to Barakat et al. after 3 months of Nigella sativa treatment decreased viral load of HCV[13].

In one study belongs to Zaher et al. showed Nigella sativa’s antiviral activity against isolated Infectious Laryngotracheitis Virus [14]. Another study belongs to Umar et al. in infected with H9N2 turkeys, Nigella sativa’s immune-stimulant and immunomodulator activities decreased pathogenicity of H9N2 and inhibited viral replication [15].

When we searched for the effect of Nigella sativa on HIV in PubMed, we found 7 publications. We have examined all of these publications and presented some of their results under this title. In a study that belongs to Mandana Behbahani, honey obtained from Petro selinum sativum, Nigella sativa, Citrus sinensis, Zataria multiflora, Citrus aurantium and Zizyphus mauritiana flowers have a strong anti-HIV1 activity [16]. Onifade et al. established that Nigella Sativa reduced the viral load in 6 months in a study on an HIV positive patient [17]. Gurmu et al. have interviewed 300 patients used Nigella sativa and similar traditional medicine methods. As a result, they suggested that Nigella sativa can be used additionally in HIV / AIDS patients [18]. In another study by Onifade et al. A 27-year-old HIV-positive woman is diagnosed in the antenatal period. This patient received Nigella sativa treatment instead of antiretroviral treatment. In repeated serology tests, the patient’s HIV test results were negative[19].
The Effect 0f Nigella Sativa 0n Pulmonary DisordersTop
In Vitro and in Vivo Effects of Thymoquinone on Pulmonary Disorders in Different Experimental Studies
Pulmonary diseases such as Chronic Obstructive Pulmonary Disease (COPD), asthma, lung fibrosis and lung cancer are known as causes of morbidity and death all over the world and could occur following abnormal inflammatory process. It has been showed that Thymoquinone(TQ) which is the major component of the volatile oil of Nigella sativa (54%) has beneficial protective effects against various diseases through anti-inflammatory, antioxidant and anti- apoptotic activities in various experimental studies [20]. Ahmet Feridun Isik et al, designed one of these studies and revealed that thymoquinone improved oxygenation while both thymoquinone and steroids protect lung tissue from Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) histopathologically[21]. Mohamed El Gazzar et al showed that TQ attenuates allergic airway inflammation by inhibiting Th2 cytokines and eosinophil infiltration into the airways; thus demonstrating its potential anti-inflammatory role during the allergic response in the lung in his in vivo experimental model[22]. In another in vivo experiment, completed on guinea pigs showed that thymoquinone has a preventive effect on model of asthma, according to Keyhanmanesh et al [23]. Ulasli et al studied an in vitro experimental model of lung cancer cells and revealed the molecular basis and utility of the anti-tumor activity of TQ [24]. These and other many studies suggest that TQ has very beneficial effect on various pulmonary disorders and show its likely favorable effects in other pulmonary diseases such as pneumonia. In this way, further in vivo and in vitro experiments are needed to see TQ’s likely effects and for its clinical usage.
The Use of Nigella Sativa on Coronavirus
As explained in the previous sections, which has been demonstrated by its antibacterial and antiviral effects, many researches and experimental models, there are only two studies in the literature on the effect of Nigella sativa on Coronavirus. One of these studies was done by Mustafa Ulasli et al. , published in 2014. In the study; Nigella sativa, Anthemis hyalina, Citrus sinensis plant extracts were used and their effect on Coronavirus and TRP gene family was examined. After the treatment with the extract, IL 8 levels and extracellular release of the virus in CoV infected cells were examined. As a result of the study, no virus was detected in the cells receiving Anthemis hyalina extract. After treatment with Nigella sativa extract, it was found that there was a great decrease in the number of viruses, but there were no changes in the cells treated with Citrus sinensis extract[25]. Another study was done by Christie Chen et al., published in 2014. Chen et al. investigated the effect of Rhodiola rosea (goldenroot), Nigella sativa (black cumin) and Sambucus nigra (common elderberry) extracts on avian IBV (Infectious Bronchitis Virus) replication. Unlike Nigella sativa and Rhodiola, they have found that Rosea sambucus nigra inhibited early viral replication [26]. Although Nigella sativa has two different effects in these two studies, we suggest that further studies should be established to make sure that this estimation can be effective against SARS-CoV-2 , which is molecularly similar to SARS-CoV
Nigella Sativa L. Dosage and Part Used
During PubMed searchwe made, we found that Nigella sativa was used in different ways. In particular, different doses and usage patterns have been reported according to the disease [27]. Although its use in the form of oil obtained from seeds is common it has also been shown to be used as an extract in some studies [25, 27-29, 30,31]. For its use as medicinal tea, a teaspoon of crushed seeds is added to a glass of boiling water and can be taken twice a day as a tonic [32]. In addition, intravenous, intramuscular, intraperitoneal use have been reported in animals in some studies [28,31]. Especially in the literature on antiviral uses, 10 ml of oral intake has been reported 3 times a day [27]. Nigella sativa has also been reported to have a hypotensive effect in studies [28]. Therefore, we recommend that hypotensive patients to be under doctor’s control. It has been reported to be safe for use in pregnant women [33]. As a result of the compilation we have made regarding the way of use, we anticipate that Nigella sativa can be used in the form of 10 ml 3 times a day in the treatment and especially in the prevention of SARS-CoV-2 (COVID19). Although it can be used differently, oral use can be envisaged especially for its preventive effect, but it requires further clinical studies that the use of im and / or iv may be more effective during pulmonary disease due to SARS-CoV-2 (COVID19).

As a result, when we examine the article titled “A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)” published by Jin et al., [34]we see that traditional treatment methods have a very important role in the treatment and especially in the prevention of the disease. Interestingly, when we search for articles, we also encountered studies that some traditional medicines are effective on coronavirus. We summarized the traditional medicine used in these studies and the results of which type of coronavirus was studied in Table 1. As a result of the literature review, in studies related to Nigella sativa, we found that there are positive results regarding the use of this traditional medicine in antibacterial, anti-viral, pulmonary diseases.Further laboratory and clinical studies are required to prove the effect of Nigella sativa on SARSCoV- 2 (COVID19).

Traditional Medicine Agent

Affected Coronavirus Type

References

Sambucus Formosana Nakai, also known by Sambucus chinensis

Human coronavirus NL63 (HCoV-NL63)

Jing-Ru Wenga et al., Antiviral activity of Sambucus Formosana Nakai ethanol extract and related phenolic acid constituents against human coronavirus NL63, Virus Research, Volume 273, November 2019, 197767

Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine)

2019-nCoV

Zhenwei Wang et al., Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment, BioScience Trends. 2020; 14(1):64-68

Strobilanthes cusia

Human coronavirus NL63 (HCoV-NL63)

Yu-Chi Tsai et al., Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63, Biomolecules 2020, 10, 366

Shuanghuanglian oral liquid (SHL), a Chinese traditional patent medicine containing extracts of three Chinese herbs, namely, honeysuckle, forsythia, and Scutellaria baicalensis

SARS-CoV2

Li Ni et al., Combination of western medicine and Chinese traditional patent medicine in treating a family case of COVID-19 in Wuhan, Front. Med.

Lianhuaqingwen

SARS-CoV2

Li Runfeng et al., Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2), Pharmacological Research (2020)

Cimcifuga racemose, Melia azedarach, Coptis chinensis, Phellodendron amurense, Sophora subprostrata

SARS CoV

In vitro inhibition of coronavirus replications by the traditionally used medicinal herbal extracts, Cimicifuga rhizoma, Meliae cortex, Coptidis rhizoma, and Phellodendron cortex. Journal of Clinical Virology 41 (2008) 122-128

Morus alba+ Chrysanthemum vulgare+ Prunus armeniaca+  Forsythia koreana+ mentha piperita X+ Platycodon grandiflorum+ Glycyrrhiza glabra+ Phragmites communis+ Scutellaria pekinensis+ Isatisindigotica+ Astragalus membranaceus+ Saposhnikovia divaricata

SARS-CoV

Immunomodulatory activities of the herbal formula Kwan Du Bu Fei Dang in healthy subjects: a randomised, double-blind, placebo-controlled study. Hong Kong Med J 2011;17(Suppl 2):S41-3

Houttuynia cordata (HC), Ganoderma lucidum

SARS-CoV

Immunomodulatory activities of the herbal formula Kwan Du Bu Fei Dang in healthy subjects: a randomised, double-blind, placebo-controlled study. Hong Kong Med J 2011;17(Suppl 2):S41-3
ReferencesTop
  1. Wu D, Wu T, Liu Q, Yang Z. The SARS-CoV-2 outbreak: what we know. Int J Infect Dis. 2020;pii: S1201-9712(20)30123-5. doi: 10.1016/j.ijid.2020.03.004
  2. Hussin A Rothanet al. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity. 2020;109:102433.
  3. Sohrabi, Alsafi Z, O'Neill N, Khan M, Kerwan A, Al-Jabir A, Iosifidis C. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19). Int J Surg. 2020;76:71-76. doi: 10.1016/j.ijsu.2020.02.034
  4. Fatemeh Forouzanfar, et al. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Iran J Basic Med Sci. 2014;17:929-938.
  5. Ahmad et al. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed. 2013;3(5):337-352. doi: 10.1016/S2221-1691(13)60075-1
  6. Tembhurneet al. A review on therapeutic potential of Nigella sativa (kalonji) seeds. J Med Plants Res. 2014;8(3):166-167. DOI: 10.5897/JMPR10.737
  7. Hanafy et al. Studies on the antimicrobial activity of Nigella sativa seed (black cumin). J Ethnopharmacol. 1991;34(2-3):275–278.
  8. Hannan et al. Anti-bacterial activity of Nigella sativa against clinical isolates of methicillin resistant Staphylococcus aureus. J Ayub Med Coll Abbottabad. 2008;20(3):72–74.
  9. Hasan et al.Anti microbial activity of Nigella sativa seed extract. SainsMalaysiana. 2013;42:143–147.
  10. Hosseinzadeh H et al. Antibacterial activity of total extracts and essential oil of Nigella sativa L. seeds in mice. Pharmacolgyonline. 2007;2:429–435.
  11. Eida OM et al. In vivo and in vitro efficacy of nigella sativa aqueous extract on blastocystis hominis. J Egypt Soc Parasitol. 2016;46(1):27–34.
  12. Oyero OG et al. Selective inhibition of hepatitis C virus replication by Alpha-zam, a Nigella Sativa seed formulation. African journal of traditional, complementary, and alternative medicines. AJTCAM. 2016;13(6):144-148.
  13. Barakat et al. Effects of Nigella sativa on outcome of hepatitis C in Egypt. World J Gastroenterol. 2013;19(16):2529-2536.
  14. Zaher et al. Observations on the Biological Effects of Black Cumin Seed (Nigella sativa) and Green Tea (Camellia sinensis). Global Veterinaria.
  15. Umar et al. Synergistic effects of thymoquinone and curcumin on immune response and anti-viral activity against avian influenza virus (H9N2) in turkeys. Poult Sci. 2016;95(7):1513-1520.doi: 10.3382/ps/pew069
  16. Behbahaniet al. Anti-HIV-1 Activity of Eight Monofloral Iranian Honey Types. PLoS ONE. 9(10): e108195.doi:10.1371/journal.pone.0108195
  17. Onifadeet al. Nigella sativa concoction induced sustained seroreversion in HIV patient Afr J Tradit Complement Altern Med. 2013;10(5):332-335.
  18. Gurmuet al. Pattern of Traditional Medicine Utilization among HIV/AIDS Patients on Antiretroviral Therapy at a University Hospital in Northwestern Ethiopia: A Cross-Sectional Study, Evidence-Based Complementary and Alternative Medicine Volume 2017, Article ID 1724581, 6 pages
  19. Onifadeet al.Seronegative conversion of an HIV positive subject treated with Nigella sativa and honey. AfrJ Infect Dis. 2015;9(2):47-50.
  20. Noorbakhshet al. Protective Effects of Thymoquinon on Pulmonary Disorders in Experimental Studies. Tanaffos. 2018;17(4):211–222.
  21. Isiket al. A new agent for treatment of acute respiratory distress syndrome: thymoquinone. An experimental study in a rat model. Eur J Cardiothorac Surg. 2005;28(2):301–305.
  22. El Gazzaret al.Anti-inflammatory effect of thymoquinone in a mouse model of allergic lung inflammation. Int Immunopharmacol. 2006;6(7):1135–1142.
  23. Keyhanmaneshet al. The effect of single dose of thymoquinone, the main constituents of Nigella sativa, in guinea pig model of asthma. Bioimpacts. 2014;4(2):75–81. doi: 10.5681/bi.2014.006
  24. Ulasliet al. Anticancer effects of thymoquinone, caffeic acid phenethyl ester and resveratrol on A549 non-small cell lung cancer cells exposed to benzo(a)pyrene. Asian Pac J Cancer Prev. 2013;14(10):6159–6164.
  25. Ulasliet al., The effects of Nigella sativa (Ns), Anthemishyalina (Ah) and Citrus sinensis (Cs) extracts on the replication of coronavirus and the expression of TRP genes family. Mol Biol Rep. 2014;41:1703–1711. doi: 10.1007/s11033-014-3019-7
  26. Chen et al. Sambucus nigra extracts inhibit infectious bronchitis virus at an early point during replication. BMC Vet Res. 10, 24 2014).
  27. Ebrahim et al.Nigella sativa L. (Black Cumin): A Promising Natural Remedy for Wide Range of Illnesses Based Complementary and Alternative Medicine Volume 2019, Article ID 1528635, 16 pages.
  28. Leong et al.Nigella Sativa and Its Protective Role in Oxidative Stress and Hypertension. Complementary and Alternative Medicine Volume 2013, Article ID 120732, 9 pages.
  29. Shanmugam et al. Modulation of Diverse Oncogenic Transcription Factors by Thymoquinone, an Essential Oil Compound Isolated From the Seeds of Nigella Sativa Linn. Pharmacol Res. 2018;129:357-364. doi: 10.1016/j.phrs.2017.11.023
  30. Tavakkoliet al.Review on Clinical Trials of Black Seed (Nigella sativa ) and Its Active Constituent, Thymoquinone. Journal of Pharmacopuncture. 2017;20[3]:179-193. doi: 10.3831/KPI.2017.20.021
    31. Razin
  31. etal.Immun responses to killed reassorted Influenza Virus supplemented with natural adjuvants. Acta Microbiol Immunol Hung. 2017;64(3):313–330. doi: 10.1556/030.64.2017.011
  32. Wyk van B.E. & Wink M. Medicinal Plants of the World. Timber Press. 2004;1:216.
  33. https://www.webmd.com/vitamins/ai/ingredientmono-901/black-seed
  34. Jin et al., A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version), Military Medical Research (2020) 7:4. Clinical Medicine 2020 Vol 20, No 2: 124–7
 
Listing : ICMJE   

Creative Commons License Open Access by Symbiosis is licensed under a Creative Commons Attribution 4.0 Unported License