Sumber: Medicinus Edisi Desember 2021 Volume 34, Issue 3
Sitepu, Rimenda, Hartman, Kirsten Putriani, Utami, Yessy Adhi
Perkumpulan Disiplin Herbal Medik Indonesia
Abstract
Medicinal plants can be potential source to improve general health and perhaps for the treatment of various diseases. However, despite the fact that herbal medicine has been used among various civilizations worldwide, scientific research regarding many herbal medicines was still limited. Nigella sativa (N. sativa), commonly known as fennel flower, black caraway, black cumin, jintan hitam, or kalonji, is a widely used medicinal plant that has been used for the treatment of various health problems. N. sativa contains some compounds that are potentially beneficial for health and wellness, particularly thymoquinone (TQ). Studies have shown some therapeutic benefits of N. sativa, however most them require further investigations to evaluate its efficacy and safety profile. This paper provides summary of available studies and reviews of N. sativa, including findings and limitations of the studies.
Introduction
Medicinal plants can be potential source to improve general health and perhaps for the treatment of various diseases. The use of medicinal plants has increased tremendously in the past decades, with almost 80% of people worldwide relying on them for the treatment of various diseases.1 Many people choose medicinal plants since they are easy to access, affordable, and believed to have less side effects. There are more than 50,000 reported medicinal plants, one of them is Nigella sativa (N. sativa), or commonly known as fennel flower, black caraway, black cumin, jintan hitam, or kalonji. N. sativa is a dicotyledonous flowering plant that belongs to the botanical family of Ranunculaceae. It is about 20-90 cm in height and produces 5–10 petal-bearing flowers that are typically white, pale blue, pale purple, or dark blue. The black seed reproduces asexually, whereby the fruit forms with its encapsulated white seeds. Once ripen, the encapsulated white seeds break open, become exposed to the air, and turn black in color.1
N. sativa grows natively in South and Southwest Asia, but it also has been cultivated in other areas of the world, such as the Middle East, Northern Africa, and Southern Europe.2 Indonesia is a potential area for its’ growth due to the suitable tropical climate.3 N. sativa seeds are traditionally used as a food preservative, additive, or a spice in various cultures. Many populations also use the seeds or oil for various ailments.2 It is most commonly used to treat asthma, bronchitis, rheumatism and related inflammatory diseases, indigestion, loss of appetite, diarrhea, dropsy, amenorrhea, dysmenorrhea, worms and skin eruptions. Overall, it is used for various disorders of the respiratory system, digestive tract, cardiovascular, kidney, liver, and immune system. It is also used as antiseptic and local anesthetic.4 Although shown to have potential benefits, there are yet adequate studies to evaluate its’ therapeutic properties, mechanism of actions, as well as safety and toxicity profile.
Chemical composition of N. sativa
N. sativa contains protein (26.7%), fat (28.5%), carbohydrates (24.9%), crude fiber (8.4%), total ash (4.8%), volatile oil (0.5-1.6%), fatty oil (35.6-41.5%), cellulose (6.8-7.4%) and moisture (8.1-11.6%). The seeds are also rich in various vitamins (e.g. A, B1, B2, B3,C) and minerals (e.g. Ca, K, Se, Cu, P, Zn, Fe). Carotene and vanillic acid were also found in seeds, roots and shoots of the plant. The main unsaturated fatty acids are linoleic acid (50-60%), oleic acid (20%), dihomolinoleic acid (10%) and eicosadienoic acid (3%). The two main saturated fatty acids are palmitic acid and stearic acid, in which α-sitosterol (44-54%) and stigmasterol (6.57-20.92%) are the pioneers. Other fatty acids include myristic acid, palmitoleic acid, linoleic acid, linolenic acid, arachidonic acid, cholesterol, campesterol, β-sitosterol, ∆5-avenasterol, ∆7-stigmasterol, and ∆7- avenasterol.4
The seed contains isoquinoline alkaloids (e.g. nigellicimine, nigellicimine-N-oxide) and pyrazole alkaloids or imidazole ring bearing alkaloids (e.g. nigellidine, nigellicine). It also contains terpenes (e.g. α-hederin) and saponins. Thymoquinone (30-48%), thymohydroquinone, dithymoquinone, p-cymene (7-15%), carvacrol (6-12%), 4-terpineol (2-7%), t-anethol (1-4%), sesquiterpene longifolene (1-8%), α-pinene and thymol are the most important active compounds of N. sativa. The other chemical compounds are carvone, nigellicine, nigellone, citrostradienol, cycloeucalenol, gramisterol, lophenol, ostusifoliol, stigmastanol, β-amyrin, butyrospermol, cycloartenol, 24-methylene-cycloartanol, taraxerol, tirucallol, 3-O-[β-D-xylopyranosyl(1 3)-α-L-arabino-pyranosyl]-28-O-[α-L-rhamnopyrano- syl(1 4)-β-D- glucopyranosyl(1 6)-β-D-glucopyranosyl] hederagenin, esters of unsaturated fatty acids with ≥C15 terpenoids, esters of dehydrostearic and linoleic acid, aliphatic alcohol, β-unsaturated hydroxyl ketone, hederagenin glycoside, melanthin, melanthigenin, bitter principle, tannin, resin, reducing sugars, glycosidal saponin, 3-O-[β-D-xylopyranosyl(1 2)-α-L-rhamnopyrasyl(1 2)-β-D-glucopyranosyl]-11-methoxy-16, 23-dihydroxy- 28-methylo-lean-12-enoate, stigma-5, 22-dien-3-β-D-glucopyranoside, cycloart-23-methyl-7, 20,22-triene-3β, 25-diol, nigellidine-4-O-sulfite, N. mines A3, a4, A5, C, N. mines A1, a2, B1, and B2.4
N. sativa contains chemical compounds that are potentially beneficial for health and wellness, particularly thymoquinone (TQ). TQ (2-isopropyl-5-methyl-1,4-benzoquinone), which chemical formula is C10H12O2 with molecular weight of 164.2 g/mol, is a major phytochemical bioactive ingredient in N. sativa oil and extracts. TQ makes about 30–48% of N. sativa seeds, and it has been extensively studied by many researchers worldwide.2
Pharmacological potentials of N. sativa
1. Anti-inflammation
Inflammation is a protective biological process carried out by endogenous mediators to eliminate harmful stimuli, such as infection, chemical, thermal and mechanical factors.1-2 The most common inflammatory mediators include eicosanoids, oxidants, cytokines, chemokines, and lytic enzymes. These are often secreted by macrophages and neutrophils. Moreover, cyclooxygenase (COX) and lipoxygenase (LO) enzymes are key factors in the biosynthesis of prostaglandins (PGs) and leukotrienes (LTs), which are critically involved in inflammatory responses. However, inflammation can have detrimental outcomes in the affected tissue leading to its damage, especially if the inflammatory reaction is accompanied by the production of reactive oxygen species (ROS). Furthermore, nitric oxide (NO) is a highly reactive free radical that could trigger toxic oxidative reactions leading to inflammation and tissue damage.2
In traditional medicine, fixed oil of N. sativa seed is widely used to treat skin rashes, back pain, rheumatism, and related inflammatory diseases. Studies have shown that fixed oil of black cumin seed and TQ exert their anti-inflammatory properties by inhibiting the production of these compounds. Eosinophils, oxidants, cytokines, and inflammatory macrophages and neutrophils are responsible for creating inflammation conditions in body. It is found that administration of aqueous extract of N. sativa or TQ in calcium ionophore-stimulated neutrophils inhibits production of 5-lipooxigenase. Anti-inflammatory effects of N. sativa oil (NSO) and TQ have been shown in several inflammatory models of experimental encephalomyelitis, colitis, peritonitis, arthritis and edema, which mediate inhibition of inflammatory mediators, prostaglandins, and leukotrienes. Also the anti-inflammatory effects of TQ and N. sativa extract on LPS-induced inflammation in the mix-glial cells and macrophages indicate a reduction in nitric oxide production by these cells, which is probably due to the inhibition of iNOS by TQ.5
Moreover, anti-inflammatory potential of TQ in PDA cells is compared with trichostatin A, a specific inhibitor of histone deacetylase (HDAC). TQ considerably reduces synthesis of MCP-1, TNF-α, interleukin (IL)-1β and Cox-2 in PDA cell dose- and time-dependently. TQ affects p21 WAF1 expression, inhibits HDAC activity and induces histone hyperacetylation, hence TQ suppresses inflammation associated with cancer, through HDAC inhibition. TQ affects adenosine receptors, which suggests that some of its anti-inflammatory effects may be mediated by these receptors. In another study, the antiasthmatic (bronchodilatory) effect of N. sativa extract in asthmatic patient airways was examined and the results showed that the extract caused significant increase in all pulmonary function tests.5
Furthermore, N. sativa also has the potential to be combined with other medicinal plants, as shown by Tjandrawinata et al. (2015), where N. sativa and Phaleria macrocarpa (P. macrocarpa) were combined to form DLBS0533. Carrageenan-induced paw edema in mice was used as the inflammation model for the study. Mice were randomly divided into negative control, positive control, and dose groups; then each group was treated with distilled water, diclofenac potassium and treatment dose of 39, 78 and 156 mg/kg b. w. DLBS0533, respectively. The result of this study shows that DLBS0533 has an anti-inflammatory effect. This is due to the combination of P. macrocarpa and N. sativa, which contains TQ, flavonoids and phenolic. Once more, this research showed that TQ works by inhibiting 5-LO and LT synthesis in a dose- dependent manner. N. sativa also contains phenolic, which is believed to have diverse physiological properties, including anti-inflammatory and analgesic activities.3
We have included and further compiled the findings of Majdalawieh et al. (2015) on the signaling pathways underlying the anti-inflammatory effects of N. sativa. This table includes the effects on TQ that have been researched separately from other N. sativa components.2
2. Immunomodulatory effects
The authors have included and further compiled the findings of Majdalawieh et al. (2015) on the signaling pathways underlying the immunomodulatory effects of N. sativa. This table includes the effects on TQ that have been researched separately from other N.sativa components.2
3. Antioxidant
Studies have been conducted using N. sativa extracts, seed oil and TQ itself, with findings suggesting there were potential radical scavenging and inhibitory effects of oxidative stress. TQ effectively changed the parameters of adenosine deaminase (ADA), catalase (CAT), myeloperoxidase (MPO), lipid peroxidase (LPO), reduced glutathione (GSH), glutathione-S-transferase (GSH-ST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO). It also reduced malondialdehyde (MDA), conjugated diene (CGD), proinflammatory mediators interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and prostaglandin (PGE2) levels.4
4. Antimicrobial
The antibacterial property of N. sativa has shown effectiveness against Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherischia coli) bacteria. Moreover, it has inhibitory effects on the growth of Yersinia enterocolitica, Listeria monocytogenes, Corynebacterium pseudotuberculosis and Staphylococcus aureus. These antimicrobial effects are mainly due to TQ and melanin. It also shows synergistic effects with streptomycin and gentamicin, as well as an additive effect with spectinomycin, erythromycin, tobramycin, doxycycline, chloramphenicol, nalidixic acid, ampicillin, lincomycin and cotrimoxazole and similar to topical mupirocin. Most importantly, it shows potential against resistant microorganisms. N. sativa is also reported to be able to protect Artemia spp. from Vibrio parahaemolyticus Dahv2 infection. In addition, TQ has shown anti methicillin-resistant activity in Staphylococcus aureus.4,5
On the other hand, the antifungal property of N. sativa, along with isolated TQ on its own, has shown effectiveness against Candida albicans, Aspergillus niger, Madurella mycetomatis, Fusarium solani, Scopulariopsis brevicaulis, Saccharomyces cerevisiae, C. utilis, Trichophyton spp., Epidermophyton spp., and Microsporum spp. N. sativa was shown to be more effective than amphotericin B and griseofulvin. In addition to TQ, its’ other active components, thymohydroquinone and thymol, are also effective against many clinical isolates, including dermatophytes, molds and yeasts.4
The antiparasitic property of N. sativa has shown antileishmanial, antimiracidia, anticercariae and anti-Schistosoma mansoni potentials. Its’ oil showed strong activity as compared to a well-known antischistosomal and anthelmintic drug, praziquantel. A study also suggested that ethanol extract of N. sativa (0.5-8%) produced significant anti-Ascaris suum activity.4 Another study found when combined with garlic extract, the NSO was proven to be effective in eradicating schistostomal infections.
In terms of its antiviral properties, N. sativa is effective in enhancing helper-T-cell (T4) and suppressor-T-cell (T8) ratio and increasing natural killer (NK) cell activity in humans. As such, it was shown to be a good inhibitor to the human immunodeficiency virus (HIV) protease and murine cytomegalovirus. In the latter case, it was shown to increase in number and improve the function of M-phi and CD4+ T cells with the production of interferon-gamma (INF-γ).4
5. Nervous system
Methanolic extract of N. sativa is a potent analgesic and antidepressant. In addition, an anxiolytic activity via increasing serotonin (5-HT) and decreasing hydroxyindole acetic acid (5-HIAA) levels were noticed in rat brains. Improved learning and memory capacity were also found. N. sativa is believed to be helpful in anxiety treatment, as it can augment tryptophan levels, along with TQ being able to produce GABA-mediated anxiolytic-like effect in mice. The neuroprotective activity may be due to its antioxidant, free radical scavenging and anti- inflammatory capacities. Furthermore, anticholinesterase (anti-AChE) suggests N. sativa and TQ have anticonvulsant activity. N. sativa is also shown to prevent cerebral edema in the hippocampus tissue of the rat brain. Study found reduced oxidative stress parameters in the cortex and hippocampus as well as enhanced remyelination in the hippocampus. Along with the protection of cortical neurons and myelinated axons.4
6. Cardiovascular system
According to Islam et al. (2017), TQ is evident to decrease motor fuel (diesel particle)-induced systolic blood pressure, leukocytes, IL-6 and plasma SOD activity.3 The proposed mechanism was through nitric oxide production and vasodilatory effect of TQ, presence of linoleic acid thus affecting ionic fluxes across the vascular endothelial cells, and calcium channel blocking. Another mechanism is through the inhibition of angiotensin converting enzyme by flavonoids. However, although it seems promising, due to low numbers of research, the effect of N. sativa in decreasing blood pressure was not significant.5
On the other hand, there was a study reported that N. sativa had prevented a decrease in platelet counts and the prothrombin events rather than platelet aggregation. Along with studies that reported a reduction in the total cholesterol (TC), low-density lipoprotein-C (LDL-C), and thyroglobulin (TG) with an increased high-density lipoprotein-C (HDL-C) level.3 Several mechanisms are proposed in explaining the hypolipidemic effect of N. sativa. Some of which are the increase in cholesterol metabolism due to polyunsaturated fatty acids, reduction of insulin resistance, reduction of serum TG due to the presence of nigellamin that acts like clofibrate and the increase of secretion of cholesterol in the bile - thus, excretion in the feces. However, bigger studies are needed to confirm these findings.6
7. Pulmonary system
Nigellone and TQ have been reported to inhibit leukotriene-d4 (LT4) in the trachea, in which the activity of nigellone was concluded via mucociliary clearance. N. sativa significantly reduced peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudates, alveolar macrophages, intestinal fibrosis, granuloma, necrosis formation and NOS. An increase in surfactant protein D was also reported. Furthermore, N. sativa has been reported to have beneficial effects against lung injury and hypoxia-induced lung damage. N. sativa puffs has been found to relieve asthma symptoms, frequency of asthma symptoms/weakness, and chest wheezing, as well as improving pulmonary function test (PFT) values with a bronchodilatory effect.4
8. Gastrointestinal system
TQ has been reported to have gastroprotective properties as it was found to decrease gastric acid secretion, acid output (AO), pepsin, the mucosal content/activity of lipid peroxidase (LPO), proton (H+) pump, MPO and ulcer index (UI), while also increasing the content and activity of gastric mucin, GSH, total nitric oxide (TNO) and SOD. The pathways to decreased ulcer severity are hypothesized to be via prostaglandin (PGD)-mediated and/or through antioxidant and antisecretory pathways. Furthermore, a decrease in LPO and lactate dehydroginase (LDH), MPO, MDA and increased GSH, SOD, GPx, GSH-ST without altering of gastric CAT was also reported. In this same study, TQ was reported to have significant effects in diarrhea, colitis, inflammatory bowel diseases, anti-Helicobacter pylori and body weight loss.4
9. Hepatic system
N. sativa has been reported to have hepatoprotective activity as it has significant effects on alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, total antioxidant capacity (TAC), CAT, MPO, total oxidative status (TOS) and oxidative stress index (OSI). TQ increases GSH and protein carbonyl content, as such it attenuates protein oxidation and upgrades the depleted antioxidant cellular fraction. N. sativa has been reported to protect hepatocytes from N-acetyl-p-aminophenol (APAP)-induced hepatotoxicity and metabolic disturbances in TIB-73 cells of mice. A similar activity was also observed by another study, in which the activity was hypothesized to be linked with improving antioxidant potential and suppressing both lipid peroxidation and ROS generation. N.sativa has also been reported for its hepatoprotective activity via improving energy metabolism and strengthening antioxidant defence pathways.4
10. Urinary system
In a study, N. sativa along with ascorbic acid (vitamin C) have been reported to produce a nephroprotective effect by lowering serum creatinine (CK), blood urea nitrogen (BUN) and antioxidant activity in rabbits. Furthermore, TQ showed an effect on renal expression of organic ion transporters and multidrug resistance-associated proteins in rats. An increased protein levels of the efflux transporters MRP2 and MRP4 and decreased expression of OAT1, OAT3, OCT1 and OCT2 was also reported. Along with decreasing tubular necrosis score, N. sativa reduces CK, urea, MDA, NO, ROS, OSI and TOS levels and augments TAC, SOD, GPx in kidney tissue and blood. TQ has been reported to completely reverse the gentamicin (GM)-induced alteration of serum CK, BUN, thiobarbituric acid substances (TBARS), total nitrite/ nitrate content, GSH, GPx, CAT and ATP values in rats. N. sativa also shows a significant nephroprotective activity on paracetamol-induced nephrotoxicity. Furthermore, Cd-induced nephroprotectivity has also been reported in rats.4
11. Reproductive system
In terms of N.sativa’s effects on the reproductive system, TQ has been reported to decrease TAC and MPO levels in male mice and alerted the events produced by methotrexate such as intestinal space dilatation, edema, disruption in the somniferous epithelium and reduced diameter of the semniferous tubules. Infertile men treated with N. sativa for 2 months were reported to have improved abnormal semen quality without producing any adverse effect. According to another study, N. sativa is a good candidate for treating male infertility as they found hexane and methanol extracts of N. sativa produced significant antifertility in rats. Moreover, N. sativa inhibited uterine smooth muscle contraction in rats and guinea pigs. A combination of TQ and olive oil has also shown a reduction of polycystic ovary cysts in rats via NF-κB signaling pathway.4
12. Glycemic control
N. sativa also showed a robust effect in terms of glycemic control, monitored by fasting blood glucose and HbA1c. Some of the mechanisms are reduction of oxidative stress to pancreatic beta cells leading to increased blood insulin, activation of insulin receptors and improvement of tissue sensitivity to insulin, decreasing gluconeogenesis, and reduction in glucose absorption.6
13. Asthma
Asthma is one of the most common long-term pulmonary conditions affecting children and adults. It affects approximately 460,000 people worldwide annually, and may cause death by half. The main characteristic is airway hyper-responsiveness due to inflammatory disorder in the airway and spasm of airway smooth muscle due to reactive oxygen species. Various studies previously showed N. sativa’s promising anti-inflammatory activities towards asthma. TQ works mainly affects H1 (histamine) receptors, thus contributing to the anti-inflammatory and antitussive effects. Moreover, the antispasmodic effect also increases mucociliary response. However, relaxant effect of N. sativa could not be proven. 7
Conclusion
N.sativa has been studied quite extensively for its anti-inflammation and immunomodulatory potential. So far, it shows promising results and further studies would definitely be valuable. It also has promising results regarding glycemic control and asthma treatment. All these promising effects appeared to be dose- and duration- dependent. Furthermore, it is important to note that, as with any existing studies, we need to take these small studies and turn them into large studies to get stronger scientific evidence as well as dose standardization of N. sativa.
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