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Thymoquinone, Inflammation, and King Tut

Flashback to February 16th, 1923 – Egypt, Valley of the Kings. 

A seasoned British archaeologist is searching for the discovery of a lifetime – the mysterious and lost tomb of King Tutankhamun, or as we know him, King Tut. This will be his last search for history’s hidden treasures as he nears the end of his funding and ultimately his career. Little did Howard Carter know that today he would make history. [1]

Following a year of searching – Carter and his crew had finally discovered a sealed door with Egyptian hieroglyphics. Could this be the very chamber they had been searching for?

Once carefully through the door, the explorers were astonished. After over 3,000 years of undisturbed peace, King Tut now had visitors. 

The tomb of King Tut was and still is considered to be the most intact pharaoh’s tomb ever discovered. H.V. Mortan, a reporter forthe Times magazine was given permission to view the tomb and the sarcophagus of King Tut. In his report for the Daily Express, Mortan describes the tomb as containing “priceless treasures”, a “solid gold sarchouoghous”, and even a dagger that was later analyzed as having a blade made from a meteorite rock [2]. Only the best treasures were reserved for and later buried with ancient Egypt’s pharaohs.  

Among these priceless treasures was something small and almost unnoticed – black seeds[3].

Black seeds, also known as black cumin, are seeds that stem from theNigella Sativa plant – which originates from Southeast Asia. Surprisingly, this is not the first time black seeds have made a celebrity appearance in history. Black seeds have been referenced in multiple distinguished ancient texts includingDe Materia Medica,the predecessor of modern pharmacopoeia authored by Hippocrates and Dioscorides in 70 A.D., the Bible – Isiah 28:25-27, and in the Hadith – a collection of quotes from the Prophet Muhammad [4]. History has been treating black seeds quite kindly. 

So why are black seeds appearing in ancient Greek medical texts, spanning both Islamic and Chrisitan sacred histories, as well as occupying the same tomb as the ancient King Tut? 

Well, to answer that question, we’ll have to dive into the composition of black seeds with the help of modern scientific research.

Black seeds come from theNigella Sativaplant as described before and have been used in the past for quite a few ailments – however, their most concentrated form is as black seed oil. Black seed oil is extracted from black seeds through a series of highly-controlled extraction methods – with the goal of isolating only the oil which contains the bioactive phytochemicals within black seeds [5]. So what does modern research say about these small, and once mysteriously powerful seeds?

Well according to institutions such as the Wayne State University School of Medicine located in Detroit, the JSS College of Pharmacy located in India, the Faculty of Medicine at Tanta University in Egypt, and many more institutions – the science supports its usefulness. 

Black seed oil has been observed in multiple studies to possess possible anti-carcinoma characteristics[6], psoriasis relief[7][8], antimicrobial effects[9], and most importantly – anti-inflammatory effects [10].  

Black seed oil is commonly used to combat inflammation, specifically skin inflammation – also known as dermatitis. Inflammation is a broad term in the medical field – but plays an important role in all biological functions. Psoriasis, eczema, general skin irritation, and acne are all forms of dermatitis that fall under the umbrella of inflammation.  In a previous post, researchers from various institutions have found a clear connection between black seed oil and antipsoriatic activity (reducing psoriasis inflammation). 

From the JSS College of Pharmacy, researchers found that the ethanolic extract from black seed oil significantly improved the degree of healthy skin proliferation – also known as the degree of orthokeratosis – for mice suffering from psoriasis on their tails. Specifically, the researchers found that black seed oil had approximately 80% of the effectiveness as a commercial product, Tazarotene gel – but also helped improve the epidermal thickness of the mice. Comparing black seed oil to commercial products is the first step to understanding if black seed oil can be used as an alternative or even a complementary solution to much more expensive products[7].

A second study from the Faculty of Medicine form Tanta University and Suez University also found antipsoriatic effects of black seed oil. The researchers induced psoriasis via a psoriasis-inducing cream to shaved mice and allowed one group to receive no treatment while a second group was given black seed oil topically. The mice were treated with black seed oil for ten days and the inflammatory response for both groups was closely monitored. The researchers discovered that the group that received the topical black seed oil had a 94.8% reduction in inflammatory cell proliferation compared to the group that only received the psoriasis-inducing cream [8]. 

Even more interestingly, the control group, which was not given the psoriasis-inducing cream nor black seed oil, had a similar inflammatory cell value (5.8±0.43) as the group of mice that received both the psoriasis-inducing cream as well as topical black seed oil treatment (7.2±1.23) – the inflammatory cell value for the group that only received the psoriasis-inducing cream was 143.25±6.76 for reference [8].

 

The skeptical individual may ask, how is black seed oil doing these things? What is the active component? Well, as mentioned in the previous posts, there is more to black seed oil than what meets the eye.

Upon further analysis of black seeds, and more specifically black seed oil – researchers have discovered a series of phytochemical bioactive components that they believe account for black seed oil’s beneficial effects. These phytochemicals include Diithymoquninone, Thymol, Thymohydroquinone, and last but certainly not least – Thymoquninone [4]. Of the various phytochemicals within black seed oil – the component that has been dominating the scientific landscape is Thymoquinone. 

First isolated in 1963 by M. El-Dakhakhny of the Faculty of Medicine at Alexandria University, thymoquinone has proven itself to be a clinically active molecule and considered to be a superoxide free radical scavenger [11]. Thymoqunione is specifically being researched for its effects against various carcinoma strands, preventing neurological degenerative disease, and its anti-oxidative and anti-inflammatory abilities. developing. 

Since its discovery in the 1960s, the quantities of research publications investigating this compound follow an exponential curve. The scientific consensus to why black seed oil is so effective at reducing inflammation is most likely due to Thymoquinone. 

Staying within the realm of inflammation, Thymoquinone is currently being put to the test. The physiological phenomenon of inflammation is complex. Inflammation can occur at micro and macro scales, from light acne to the swelling observed from an ankle sprain. Inflammation is everywhere. The science behind inflammation involves several biological pathways and mediators that signal to the body whether it’s time to have an immune response or to relax and let things be. This signalling is facilitated by compounds within the body called leukotrienes [12]. 

Leukotrienes are a group of compounds produced by the human body, specifically within leukocytes blood cells – which are found in blood and lymph tissue. Leukotrienes serve as immune response communicators between leukocytes and neighboring cells in the vicinity. 

Simply put, leukotrienes deliver the inflammation signal to the necessary cells that need to produce an immune response. Without leukotrienes, cells would struggle to receive signals that would lead to inflammation, and would less likely produce an immune response. 

On the other hand, overproduction of leukotrienes can lead to excessive inflammatory responses, such as the overproduction of inflammatory cytokines, which can lead to various forms of inflammation. A possible avenue to reducing inflammation is through the reduction of leukotriene production, specifically LTC4 (a leukotriene associated with inducing bronchoconstriction and asthma through inflammatory processes) as well as LTB4 (another leukotriene associated with free radical generation, activating inflammatory cells, and prolonging tissue inflammation) [10]. By targeting these inflammatory mediators, inflammation begins to become a more manageable phenomenon. 

So what does black seed oil, and more specifically Thymoquinone do to levels of inflammatory mediators such as LTC4 and LTB4? 

Well, researchers from the Department of Medical Biochemistry and Biophysics from the Karolinska Institute in Stockholm, Sweden as well as researchers from the Faculty of Pharmacy of Al-Azhar University in Cairo, Egypt collaborated to test the effects of various concentrations of Thymoquinone on leukotriene concentrations produced by human platelet blood cells [10]. 

The researchers incubated human granulocyte platelet cells, a form of white blood cell, with and without 1,3,10 and 100 μM of our good friend Thymoquinone. The researchers allowed the cells to incubate for 15 minutes, then using high performance liquid chromatography or HPLC (a chemical characterization technique), the researchers then compared the LTC4 and LTB4 concentrations of the control, untreated human platelet cells to that of the Thymoquinone treated human platelet cells [10]. 

If Thymoquinone reduces inflammatory mediators, and therefore inflammation – the hypothesis would then be that the cells treated with Thymoquinone should have lower levels of  leukotrienes LTC4 and LTB4 then that of the untreated, control platelet cells. And ideally, as the concentration of Thymoquinone increases, then the leukotriene concentration should also decrease. This would highlight Thymoquinone’s direct affinity to LTC4 and LTB4 production. 

The hypothesis was proven correct. The platelet cells treated with Thymoqunine had a significantly lower concentration of leukotriene LTC4 and LTB4 than that of the control. Furthermore, and most excitingly, this effect was dose-dependent – meaning that as Thymoquione concentration was increased (from 1 μM to 100 μM) the concentration of LTC4 and LTB4 decreased. The researchers found that even the lowest concentration of Thymoquinone, specifically 1.3 – 2.8 μM, was enough to reduce leukotriene LTC4 and LTB4 production by greater than 50% in the human platelet cells, compared to that of the control cells which did not receive any Thymoquinone treatment [10]. 

So wait a minute, Thymoquinone inhibits the production of inflammation mediators – why? Well, lets keep going down the rabbithole further.

Leukotrienes are produced by an enzyme within leukocytes called 5-lipoxygenase. 5-lipoxygenase produces leukotrienes via a free radical generation mechanism from fatty acids within the body – meaning the enzyme takes fatty acids, breaks them apart to from an unstable reactive compound called a free radical, then this free radical can further react with another compound until LTC4 and LTB4 leukotrienes are produced [13].

Remember how Thymoquninone was characterized as a superoxide free radical scavenger? Well, according to the researchers, Thymoquninone inhibits the production of leukotrienes because of this very characteristic. 

Thymoquinone’s molecular structure allows it to behave as a free radical scavenger, and is able to swoop into the 5-lipoxygenase biochemical pathway and steal the generated free radicals – denying the production of leukotriene LTC4 and LTB4 [10].

Basically, Thymoqunione stops the production of inflammatory mediators in their tracks.

Although inflammation is a complex process of various physiological events, preventing the inflammation message from being sent appears to be a novel approach to various forms of inflammation that may have resulted from overproduction of leukotrienes. 

In respect to the ketogenic diet specifically – fatty acids are in no short supply. The ketogenic diet favors breaking down fat as fuel to mimic a fasted state – this breakdown of fat produces fatty acids. With abundant raw material (the fatty acids) to produce excessive leukotrienes – the keto rash may be the result of excessive inflammatory mediator production. 

By silencing those mediators, you may be able to silence the keto rash after all. However, this is only speculation – but promising nonetheless. As the research surrounding black seed oil and Thymoqunione continues to develop, we at SciZenna promise to continue investigating all aspects of this ever-changing landscape. 

One thing is for certain – King Tut probably had great skin.

 

 

Citations:

  1. Luca, Araldo De. “How Howard Carter Almost Missed Finding King Tut’s Tomb.” Finding King Tut’s Tomb, National Geographic, 31 Oct. 2019, www.nationalgeographic.com/history/magazine/2018/03-04/findingkingtutstomb/.

  2. Comelli, D., D’orazio, M., Folco, L., El‐Halwagy, M., Frizzi, T., Alberti, R., Capogrosso, V., Elnaggar, A., Hassan, H., Nevin, A., Porcelli, F., Rashed, M.G. and Valentini, G. (2016), The meteoritic origin of Tutankhamun’s iron dagger blade. Meteorit Planet Sci, 51: 1301-1309. doi:10.1111/maps.12664
  3. Padhye, S., Banerjee, S., Ahmad, A., Mohammad, R., & Sarkar, F. H. (2008). From here to eternity – the secret of Pharaohs: Therapeutic potential of black cumin seeds and beyond. Cancer therapy6(b), 495–510.
  4. Faiza, M., Abdullah, T., Wang, P. (2017). Dithymoquinone as a Novel Inhibitor for 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) to Prevent Renal Failure. Quantitative Methods: q-bio.QM, 2017, arxiv: 1709.03813.
  5. Mohammed, N. K., Abd Manap, M. Y., Tan, C. P., Muhialdin, B. J., Alhelli, A. M., & Meor Hussin, A. S. (2016). The Effects of Different Extraction Methods on Antioxidant Properties, Chemical Composition, and Thermal Behavior of Black Seed (Nigella sativa L.) Oil. Evidence-based complementary and alternative medicine : eCAM2016, 6273817. https://doi.org/10.1155/2016/6273817
  6. Agbaria, R., Gabarin, A., Dahan, A., & Ben-Shabat, S. (2015). Anticancer activity of Nigella sativa (black seed) and its relationship with the thermal processing and quinone composition of the seed. Drug design, development and therapy9, 3119–3124. doi:10.2147/DDDT.S82938
  7. Dwarampudi, L. P., Palaniswamy, D., Nithyanantham, M., & Raghu, P. S. (2012). Antipsoriatic activity and cytotoxicity of ethanolic extract of Nigella sativa seeds. Pharmacognosy magazine8(32), 268–272. doi:10.4103/0973-1296.103650
  8. Okasha, E. F., Bayomy, N. A., & Abdelaziz, E. Z. (2017). Effect of Topical Application of Black Seed Oil on Imiquimod-Induced Psoriasis-like Lesions in the Thin Skin of Adult Male Albino Rats. The Anatomical Record, 301(1), 166–174. doi: 10.1002/ar.23690
  9. Mohammed, S. J., Amin, H., Aziz, S. B., Sha, A. M., Hassan, S., Abdul Aziz, J. M., & Rahman, H. S. (2019). Structural Characterization, Antimicrobial Activity, and In Vitro Cytotoxicity Effect of Black Seed Oil. Evidence-based complementary and alternative medicine : eCAM, 2019, 6515671. doi:10.1155/2019/6515671
  10. Mahmoud Mansour & Susanne Tornhamre (2004) Inhibition of 5-lipoxygenase
    and Leukotriene C4 Synthase in Human Blood Cells by Thymoquinone, Journal of Enzyme
    Inhibition and Medicinal Chemistry, 19:5, 431-436, DOI:10.1080/14756360400002072
  11. El–Dakhakhny, M. (1963). Studies on the Chemical Constitution of Egyptian Nigella SativaL. Seeds. The Essential Oil. Planta Med 1963; 11(4): 465-470.DOI: 10.1055/s-0028-1100266
  12. Spanbroek, R., Grabner, R., Lotzer, K., Hildner, M., Urbach, A., Ruhling, K., … Habenicht, A. J. (2003). Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proceedings of the National Academy of Sciences of the United States of America100(3), 1238–1243. doi:10.1073/pnas.242716099
  13. Shaterzadeh-Yazdi, H., Noorbakhsh, M.F., Hayati, F., Samarghandian, S., Farkhondeh, T. (2018).

    Immunomodulatory and Anti-inflammatory Effects of Thymoquinone. Cardiovascular & Hematological Disorders-Drug Targets. doi: 10.2174/1871529X18666180212114816