J Endocrinol Invest DOI 10.1007/s40618-015-0337-0

REVIEW

Ameliorative effects of Nigella sativa on dyslipidemia S. Asgary1 · A. Sahebkar2 · N. Goli‑malekabadi3 

Received: 15 March 2015 / Accepted: 9 June 2015 © Italian Society of Endocrinology (SIE) 2015

Abstract  Introduction  Dyslipidemia is an established risk factor for ischemic heart disease. Nigella sativa (NS) is a medicinal plant that has been used for the treatment and prevention of a variety of diseases, in particular hyperlipidemia. Methods  We reviewed the existing literature published until 2014 by using the following keywords: ‘‘Nigella sativa’’, ‘‘black cumin’’, ‘‘black seeds’’, ‘‘thymoquinone’’, and ‘‘lipid’’. Results  In the conducted studies, different preparations of NS including seed powder (100 mg–20 g daily), seed oil (20–800 mg daily), thymoquinone (3.5–20 mg daily), and seed extract (methanolic extract especially), were shown to reduce plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, but the effect on high-density lipoprotein cholesterol (HDL-C) was not significant. NS and thymoquinone have been reported to be safe and well tolerated with no severe adverse effect. In clinical trials, NS was found to be effective when added as adjunct to standard antihyperlipidemic and antidiabetic

* N. Goli‑malekabadi [email protected] S. Asgary [email protected] A. Sahebkar [email protected] 1

Isfahan Cardiovascular Research Institute, Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2

Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3

Isfahan Cardiovascular Research Institute, Isfahan Cardiovascular Research Center, Isfahan University of Medical Sciences, Khorram st., Isfahan, Iran





medications. Lipid-modifying effects of NS could be attributed to the inhibition of intestinal cholesterol absorption, decreased hepatic cholesterol synthesis, and up-regulation of LDL receptors. Conclusions  Overall, the evidence from experimental and a clinical studies suggests that NS seeds are a promising natural therapy for dyslipidemic patients. Keywords  Nigella sativa · Black cumin · Dyslipidemia · Thymoquinone · Hypercholesterolemia

Introduction Dyslipidemia is a broad term covering different lipid and/ or lipoprotein abnormalities [1]. The main manifestations of this disorder include elevated plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and low concentrations of high-density lipoprotein cholesterol (HDL-C). Dyslipidemia is one of the major but modifiable risk factors for atherosclerosis and ischemic heart disease (IHD), and its treatment has a significant effect in blunting or reversing the progression of IHD [2]. The prevalence of dyslipidemia is high and increasing in both developed and developing world [3]. Several lines of evidence have shown that effective prevention and treatment of dyslipidemia can significantly reduce the rate of morbidity and mortality due to IHD [4]. Although statins have been the mainstay of treating dyslipidemia, there is a huge interest in developing and/or discovering novel lipid-lowering agents to be used either as alternative or adjunct to statin therapy. The reason for such an interest is the significant residual cardiovascular risk that is present in statin-treated subjects, as well as limitation of statins in achieving optimal LDL-C target

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been quoted by Prophet Muhammad (PBUH) that NS seeds are a remedy for all diseases except death [20]. Ibn Sina (Avicenna) has referred to NS in his book “the Canon of Medicine” as an energizer agent and a cure for fatigue [21]. In the Iranian folk medicine, NS seeds have been used for the treatment of bronchial asthma, cough, headache, rheumatic disorders, fever, influenza, hypertension, obesity, back pain, and gastrointestinal problems [22]. The major bioactive constituent of NS, thymoquinone, has also been demonstrated to possess a variety of biological activities including antioxidant and antiinflammatory properties [23] as well as lipid-lowering effects [24]. The present study aimed to review available evidence from experimental and clinical studies investigating the impact of supplementation with NS preparations, including purified thymoquinone, on plasma lipids and other features of dyslipidemia and IHD. We reviewed the existing literature published until 2014 by using the following key words: ‘‘Nigella sativa’’, ‘‘black cumin’’, ‘‘black seeds’’, ‘‘thymoquinone’’, and ‘‘lipid’’.

Phytochemistry of NS Fig. 1  Nigella sativa whole plant, flower, and seeds

levels and producing muscle-related adverse events in some patients [5–9]. Complementary and alternative medicine has a long reputation in Asian countries. In the last few decades, a variety of natural remedies have been reported in the form of single herbs, extracts, purified phytochemicals, or optimized formulations for the prevention and treatment of dyslipidemia and mitigation of IHD risk [10]. Nigella sativa (NS) is one of the famous medicinal plants that has been investigated for its lipid-modifying effects in several experimental and clinical studies [11, 12]. NS is an annual medicinal plant belonging to the Ranunculaceae family, and is popularly known as black seed (‘‘Siah Daneh’’ in Persian) or “black cumin” [13]. It is a grassy plant with larger leaves above and blue or white flowers which bear small black seeds [14] (Fig. 1). These seeds can be used as an additive with high nutritional value in several food products such as tea, coffee, and bread. In the Persian cuisine, NS seeds are usually consumed by mixing with honey or sprinkling on salads, cheese, and bread. NS seeds are used in the preparation of a traditional sweet dish, composed of black seed paste which is sweetened with honey or syrup, and in the preparation of black seed pastry [15–17]. Besides many nutritional uses, NS is widely used as a medicine in the Middle Eastern region and in Asian countries including India, Pakistan, and Iran [18, 19]. NS has also been cited as an Islamic traditional medicine. It has

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Nigella sativa seeds contain a multitude of components including essential oil, proteins, sugars, sterols, alkaloids, saponins, thymoquinone and dithymoquinone, and nigellin [13]. The seeds also contain relatively high amounts of crude fiber and minerals such as calcium, iron, sodium, and potassium [18]. Fixed and volatile oil constitute 30–33 % and 0.43–0.72 % w/w of NS seeds, respectively. The main volatile constituents of NS have been reported to be estragole, apiol, myristicin, and myrcene [25], but the composition is subject to change as a function of environmental variations and herbivorous pressure [26]. Another major ingredient of NS volatile oil is the terpenoid derivative thymoquinone (18.4–24 %), which is the main biologically active ingredient of the plant [27]. Phytochemical analysis of NS fixed oil has revealed a rich content of unsaturated fatty acids including linoleic, oleic, linolenic, arachidic, palmitoleic, eicosadienoic, palmitic, stearic, and myristic acid [20].

Biological activities Pharmacological studies have shown numerous pharmacological effects from NS or its active ingredient thymoquinone. These pharmacological effects include hypoglycemic [28–31], antihypertensive [32], antiinflammatory [33, 34], and antioxidant [35, 36] actions. Besides, there has been a surge of interest in studying the beneficial effects of NS in the treatment of cardiovascular diseases [20], cancer [37],

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epilepsy [38] and gastrointestinal disorders [39]. There is also evidence showing that NS, both in the raw powdered and extract forms, has antimicrobial and antifungal actions [40, 41]. NS seed supplementation resulted in a potent hepatoprotective effect, in particular in the powdered form against liver damage in experimental models [31, 42].

Lipid‑modifying effects Modification of plasma lipids is one of the well-documented properties of NS and thymoquinone. Different preparations of NS including seed powder, extracts, oil, and thymoquinone have so far been investigated for their therapeutic potential against dyslipidemia and other closely associated cardiometabolic diseases including type 2 diabetes, obesity, metabolic syndrome, and fatty liver disease. The findings of these studies are reviewed in the following sections (Fig. 2).

Animal studies Several studies have shown hypolipidemic effects of NS in experimental diabetic models. Eight weeks supplementation with NS seed fixed oil (4.0 %) and essential oil (0.30 %) has been reported to improve serum TC, TG, and LDL-C, but not HDL-C concentrations in streptozotocin-induced rats [43]. Significant results in streptozotocin-induced diabetic rats have been reported with ethanol extract of NS after 30 days of supplementation at a dose of 300 mg/kg bw [44]. Ethanolic extract of NS also has hypolipidemic effect at lower dose, 100 mg/kg

Fig. 2  The mechanism of lipid-modifying by Nigella sativa

bw; however its methanolic extract acts better to improve lipid profile levels than the one in diabetic rabbits [45]. In another study, a polyherbal mixture comprising Allium sativum, Cinnamomum zeylanicum, Citrullus colocynthis, Juglan sregia, Oleaeur opaea, Punicagra natum, Salvia officinalis, Teucrium polium, Trigonella foenum, Urtica dioica, and Vaccinium arctostaphylos plus NS seed powder showed a reducing effect on TC and TG concentrations in streptozotocin-induced diabetic rats that were supplemented for 4 weeks [46]. Another polyherbal mixture comprising NS powder, Allium sativum, Cinnamomum zeylanicum, Punica granatum, Salvia officinalis, and Teucrium polium also showed a hypolipidemic effect in streptozotocin-induced diabetic rats. In this study, the levels of TG and TC were significantly decreased after 4 weeks of supplementation with the above-mentioned mixture. However, there was no significant change in HDL-C concentrations following 4 weeks of treatment with this polyherbal preparation [30]. Aside from diabetes, lipid-lowering effects of NS have also been shown in high-fat-induced dyslipidemic models. In a 4-week study, methanolic seed extract and volatile oil of NS were both shown to attenuate dyslipidemia induced in rats by a lipogenic diet. The results showed that serum HDL-C levels were increased following NS treatment and TG levels returned to normal [19]. In another study, 7-day administration of an NS-containing polyherbal preparation in high-fat-fed rats resulted in improvement of lipid profile, reduction of hepatic enzymes, and attenuation of insulin resistance, parameters that are crucial to the pathogenesis of NAFLD [47]. Thymoquinone supplementation has also been reported to have a protective effect in rabbits fed a cholesterol-enriched diet. These protective effects included improvement of lipid profile parameters (TC, LDL-C, TG, and HDL-C), counterbalancing cholesterol-induced endothelial damage, and formation of foam cells and atherosclerotic lesions [48]. Thymoquinone administration twice daily has also been effective on lipid profile modifying in hyperlipidemic rats [49]. In a similar study on hypercholesterolemic rabbits, thymoquinone significantly reduced TC and LDL-C concentrations at two different doses of 10 mg/ kg/day and 20 mg/kg/day following 8 weeks of treatment [50]. Asgary et al. conducted a study on hypercholesterolemic rabbits that were treated with NS seed powder. The results showed a positive effect of NS treatment on serum Apo-A and Apo-B concentrations [51]. In another study, hypercholesterolemic rabbits were treated with NS powder and atorvastatin, the most frequently used chemical drug for dyslipidemia, in two separate groups for 16 weeks. Although the NS powder could modify the lipid profile in dyslipidemic animals, atorvastatin was more effective [52]. NS powder had a similar effect in a smaller period, also at 8 weeks [53]. In another study, supplementation with NS seed powder resulted in a significant reduction in plasma

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LDL-C as early as 2 weeks and additional reductions in VLDL-C and triglycerides after 4 weeks of treatment [11]. Pre-treatment with NS oil (800 mg/kg orally for 4 weeks) was reported to protect against D-galactosamine- and carbon tetrachloride-induced hepatotoxicity and improve lipid indices by reducing serum concentrations of TC, LDL-C, and TG, and elevating those of HDL-C [54] (Table 1). Dyslipidemia is one of the diagnosis criteria in metabolic syndrome. Studies have shown a declining effect of NS supplementation on serum LDL-C and TG concentration, and an elevating effect on serum HDL-C concentrations in rats with metabolic syndrome [55]. NS seed powder supplementation at doses 300–600 and 1200 mg/kg/bw could not change the lipid profile in metabolic syndrome rats after 21 days of treatment. However, this treatment increased HDL-C level at 300 mg/kg/bw and 600 mg/kg/ bw doses [56]. Hexane and methanolic extracts of NS have also shown improved effect on lipid profile in metabolic syndrome rats [57]. NS seed powder has also an ameliorative effect on lipid profile in healthy rats [58].

Clinical studies Dyslipidemia is a common feature of several cardiometabolic diseases and is usually present in overweight and obese individuals [59]. In a randomized double-blind trial, overweight and hypertriglyceridemic Iranian women were treated with NS capsules (containing crushed NS seeds) plus an aerobic training program. Subjects were administrated daily 2 g of NS for a period of 2 months. The results showed that a combination of NS supplementation with aerobic training significantly improves lipid profile by decreasing plasma TC, LDL-C, and TG, and increasing HDL-C concentrations [60]. Results of a similar study that was performed on hyperglycemic subjects showed hypolipidemic effects of NS seed powder following 4 weeks of treatment [61]. In another study, NS seed powder and Allium Sativum were administrated as adjunct to simvastatin and could significantly improve lipid profile after 8 weeks of treatment in a randomized, double-blind, placebo-controlled trial [62]. Hormonal changes in menopausal women often contribute to lipid profile deregulation. Daily treatment with NS seed powder for 2 months has been reported to modulate lipid levels in menopausal women with metabolic syndrome [63]. Also, in a trial among subjects with metabolic syndrome, administration of NS oil (2.5 mL/day) as adjunct to atorvastatin (10 mg/day) and metformin (1000 mg/day) for a period of 6 weeks resulted in a significant reduction of plasma TC and LDL-C [64]. NS powder at 500 mg/kg bw also decreased LDL-C level in metabolic syndrome patients significantly [65] (Table 1).

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Safety and toxicity Nigella sativa is a useful remedy for many diseases with no adverse effects in patients on administration of different plant parts. The longtime use of NS as a routine traditional medicine is a strong proof for the safety of this plant [65]. Further proofs of evidence for the safety of NS have been provided by modern toxicological studies. In an experimental study on rabbits, oral administration of NS seed powder at a high dose of 28 mg/kg did not produce any harmful effect. Likewise, NS oil and thymoquinone were found to be safe with LD50 values of 28.8 mL/kg and 2.4 g/kg, respectively [66]. In an animal study, acute toxicity of aqueous methanol and chloroform extracts of the seeds were investigated. These extracts were administered orally at 6, 9, 14, and 21 g/kg doses for 7 days. All NS extracts were non-toxic in the acute toxicity test. However, when the aqueous extract was administered at a dose of 6 g/kg/ day for 14 days, some hepatic adverse effects including histopathological changes and elevations in plasma alkalinephosphatase, aspartate-aminotransferase (AST) and alanine-aminotransferase (ALT) activities were observed [67]. In another study, no histopathological changes and elevation of liver enzymes (including AST, ALT, and gammaglutamyl transferase) was observed in rats treated with NSfixed oil orally at a daily dose of 2 ml/kg bw for 12 weeks [68]. The safety of NS has also been documented in clinical practice. In a phase I clinical study, adults with solid tumors tolerated a thymoquinone dose range of 75–2600 mg/day [69].

Conclusions This review has summarized experimental and clinical findings with respect to hypolipidemic actions of NS seed powder, seed oil, seed extract, and the main NS phytochemical, thymoquinone. Conducted studies have shown that consumption of NS is safe and has no toxic effect. In the reviewed studies, NS seed powder was used in a wide dose range of 100–600 mg/kg bw, seed oil in the range of 20–800 mg/kg bw, and thymoquinone in the range of 3.5– 20 mg/kg bw. NS seed extracts that were used in the investigations were hydroalcoholic and ethanolic. Overall, the majority of studies have shown that supplementation with NS preparations reduces plasma concentrations of TC, LDL-C, and TG in normolipidemic, hyperlipidemic, metabolic syndrome, and diabetic animal models, and also in humans, whereas HDL-C is generally not affected by NS consumption. Nigella sativa and its main bioactive component, thymoquinone, have also strong antioxidant properties that

J Endocrinol Invest Table 1  Effect of Nigella sativa administration on lipid profile in dyslipidemic animal models and humans Sample examined

Dose administration

Animal model/subject

Treatment duration Effects of NS on lipid profile

References

LDL HDL TG TC VLDL Fixed oil of seed Essential oil of seed Methanolic extract of NS seed oil

4.0 % daily 0.3 % daily 100 mg daily

Diabetic rats Diabetic rats Hyperlipidemic rats

8 weeks 8 weeks 30 days

↓ ↓ ↓

ND ND ↑

↓ ↓ ↓

↓ ↓ ↓

– – ↓

[12] [12] [19]

Volatile oil extract of seed

20 mg daily

Hyperlipidemic rats

30 days











[19]

Seed oil

800 mg daily

Carbon tetrachloride hepatotoxicity rats

4 weeks











[54]

2.5 ml (twice daily)

Insulin resistance syndrome patient

6 weeks



ND

ND ↓



[64]

5 % daily

Hypercholesterolemic rabbits

8 weeks



ND

ND ↓



[51]

100 mg daily Healthy rats 200 mg daily 400 mg daily 600 mg daily 500 ± 10 mg (2 g daily)  Hypertriglyceridemic women

4 weeks

↓ ↓ ↓ ↓ ↓

ND ND ↑ ND ↑

↓ ↓ ↓ ↓ ↓

↓ ↓ ↓ ↓ ↓

ND ↓ ↓ ↓ –

[11]

[60]

500 ± 10 mg (2 g daily) Hyperglycemic subjects 4 weeks 500 mg (1 g daily) Menopausal women with 8 weeks metabolic syndrome

↓ ↓

ND ↑

↓ ↓

↓ ↓

– –

[61] [63]

200 mg daily 5 g daily

Metabolic syndrome rats 8 weeks Hypercholesterolemic 16 weeks rabbits

↓ ↓

↑ ND

↓ ↓

↓ ↓

– –

[55] [52]

300 mg daily

Metabolic syndrome and 21 day menopausal rats

ND



ND ND –

[56]

600 mg daily

Metabolic syndrome and 21 day menopausal rats

ND



ND ND –

[56]

1200 mg daily

Metabolic syndrome and 21 day menopausal rats

ND



ND ND –

[56]

500 mg daily

Metabolic syndrome subject

8 weeks



ND

ND ND –

[83]

20 g daily 7/5 g daily

6 weeks 8 weeks

↓ ↓

ND ↑

↓ ↓

↓ ↓

ND –

[58] [53]

300 mg daily

Healthy rats Hypercholesterolemic rabbits Diabetic rats

30 days



ND







[44]

100 mg daily 100 mg daily

Diabetic rabbits Diabetic rabbits

2 weeks 2 weeks

↓ ↓

ND ND

ND ND – ↓ ↓ –

[45] [45]

300 mg daily 300 mg daily

Metabolic syndrome rats 21 days Metabolic syndrome rats 21 days

↓ ↓

↑ ↑

↓ ↓

– –

[57] [57]

Seed powder

Ethanol extract of NS seeds Methanol extract of NS seeds Hexan extract of NS seeds

Polyherbal including NS 250 mg daily seed powder 5 %w/w of daily 250, 500, and 750 mg Polyherbal including daily ethanolic extract of seeds

8 weeks

↓ ↓

Hyperlipidemic subject

8 weeks



[62]

Diabetic rats Nonalcoholic fatty liver rats

4 weeks 7 days

– ↓

– ↑

↓ ↓

↓ ↓

– –

[46] [47]

4 weeks



ND







[30]

Polyherbal including NS 4 % (w/w) of polyherbal Diabetic rats daily hydroalcoholic extract









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Table 1  continued Sample examined

Dose administration

Animal model/subject

Treatment duration Effects of NS on lipid profile

References

LDL HDL TG TC VLDL Thymoquinone

3.5 mg daily

Hypercholesterolemic rabbits

4 weeks











[48]

10 mg daily 20 mg daily

Hypercholesterolemic rabbits

8 weeks

ND ND

[50]

Hyperlipidemic rats

30 days

ND ↓ ↓ ↓

– –

10 mg twice daily

↓ ↓



[49]









The sign (↓) means significant decrease, (↑) means significant increase, and (ND) means no significant difference

may explain part of their antiatherosclerotic and cardioprotective actions [70, 71]. Thymoquinone has a potent protective effect against oxidative organ damage through scavenging different types of free radicals [36, 72]. Dietary intake of antioxidants can inhibit oxidation of LDL-C and thereby prevent formation of foam cells and fatty streaks [73, 74]. Besides thymoquinone, NS also contains other antioxidants such as tocopherols, phytosterols, and polyunsaturated fatty acids that can contribute to cholesterol reduction and prevention of cholesterol oxidation [75, 76]. Several lines of evidence have shown that phytosterols, including β-sitosterol, can effectively lower plasma lipid levels [77, 78]. Lipid-modifying effects of phytosterols result from suppression of both intestinal cholesterol absorption and cholesterol biosynthesis [79]. NS consumption can also up-regulate LDL receptors by decreasing intracellular cholesterol, an effect that leads to rapid clearance of LDL particles from circulation [76]. In addition, thymoquinone supplementation has been shown to enhance the expression of LDL receptor gene [80]. The choleretic activity of NS and increased biliary excretion of cholesterol are other possible causes of the observed hypolipidemic, in particular hypotriglyceridemic, effects of this plant [18, 81]. Although a considerable number of previous studies have shown the hypolipidemic effects of NS and thymoquinone, most of them have focused on measurement of TC, TG, LDL-C, and HDL-C. Further evidence is required as to the impact of NS on VLDL metabolism and also plasma levels of apolipoproteins such as apo AI, apo AII, ApoB48, and apo B100. Another important subject that needs to be addressed by future studies is the impact of NS supplementation on lipoprotein-associated enzymes such as phospholipase and paraoxonase that are both important determinants of cardiovascular risk [82]. To conclude, NS and thymoquinone appear as effective and safe natural treatments for patients with dyslipidemia and could be considered for the management and prevention of dyslipidemia and IHD, in those who are resistant to statins or those who are intolerant of statins. The clinical

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usefulness of adding NS preparations to statins is yet to be determined; however, there is evidence on the incremental lipid-lowering effects of adjunctive therapy with NS seed powder [62] and oil [64] in subjects on simvastatin [62] and atorvastatin [64]. Compliance with ethical standard  Conflict of interest  The authors declare that they have no conflict of interest. Ethical approval  This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent  For this type of study formal consent is not required.

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Ameliorative effects of Nigella sativa on dyslipidemia.

Dyslipidemia is an established risk factor for ischemic heart disease. Nigella sativa (NS) is a medicinal plant that has been used for the treatment a...
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