J Endocrinol Invest (2014) 37:1031–1040 DOI 10.1007/s40618-014-0150-1
REVIEW
A review of the effects of Nigella sativa L. and its constituent, thymoquinone, in metabolic syndrome B. M. Razavi • H. Hosseinzadeh
Received: 29 June 2014 / Accepted: 29 July 2014 / Published online: 15 August 2014 Ó Italian Society of Endocrinology (SIE) 2014
Abstract Background Metabolic syndrome is an important risk factor for cardiovascular disease (CVD) occurrence and mortality. CVDs are leading cause of death worldwide. Recently, there has been an increasing interest in the use of herbal medicines with more efficiency and minimal undesirable effects than chemical drugs for a variety of disorders including CVD. Nigella sativa and its active constituent, thymoquinone, have been documented to exhibit antidiabetic, antiobesity, hypotensive and hypolipidemic properties. Aim In this review, we discussed the most relevant articles to find out the role of N. sativa in different components of metabolic syndrome and CVD risk factors including high blood pressure, obesity, dyslipidemia and high blood glucose. Conclusions This review suggests a potential role of N. sativa and TQ in the management of metabolic syndrome, however more studies should be conducted to evaluate their effectiveness. Keywords Nigella sativa Thymoquinone Metabolic syndrome Cardiovascular disease Hypertension Diabetes Dyslipidemia Obesity
B. M. Razavi Department of Pharmacodynamy and Toxicology, Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran H. Hosseinzadeh (&) Department of Pharmacodynamy and Toxicology, Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran e-mail: [email protected]
Introduction Metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism (high glucose level), overweight and abdominal fat distribution, dyslipidemia, and hypertension, is an important risk factor for cardiovascular disease incidence and mortality [1, 2]. People with at least three out of five risk factors, are considered to have metabolic syndrome based on the National Cholesterol Education Program (NCEP) definition (Table 1) [3]. Cardiovascular diseases (CVDs) are estimated to continue the distinct leading cause of death worldwide and by 2020 almost 23.6 million people are expected to die from CVD (WHO Death Estimated Report, 2011) [4]. Recently, there has been an increasing interest in the use of herbal medicines for the prevention and treatment of a variety of disorders including cardiovascular diseases because of their safety, efficacy, cultural acceptability and lesser side effects [5]. Nigella sativa, which belongs to the botanical family of Ranunculaceae, commonly grows in Eastern Europe, the Middle East, and Western Asia. N. sativa seeds, known as ‘‘Al-Habba Al-Sauda’’ and :Al-Habba Al-Barakah’’ in Arabic and black seed or black cumin in English [6]. For thousands of years, N. sativa seeds have been reported to be used as protective and therapeutic traditional medicine against a number of diseases in the Middle East and some Asian countries. A great importance has been given to this plant especially in Islamic countries, because of its various beneficial properties. Furthermore, N. sativa seed can reduce weakness and depression and enhance the body’s energy in the Avicenna’s famous book ‘‘Canon of Medicine’’. According to its traditional uses, this plant is also included in the list of natural drugs in different medicines including Tibb-e-Nabavi (The medicine of Prophet
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1032 Table 1 NCEP (National Cholesterol Education Program) definition of the metabolic syndrome in men [3] Fasting plasma glucose C130 mg/dl Abdominal obesity with waist girth [94 or 102 cm Serum Triglycerides C150 mg/dl Serum HDL cholesterol \40 mg/dl Blood pressure C130/85 mmHg or medication People with at least 3 of the above risk factors are considered to have metabolic syndrome
Mohammad), Unani Tebb and Indian system of medicine [7]. In traditional medicine, N. sativa seeds are widely used as a spice and carminative [6]. Moreover, it has been extensively used as liver tonics, diuretics, digestive, antidiarrheal, appetite stimulant, analgesics, anti-bacterial, in skin disorders and headache [6–8]. Its pharmacological activities include antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, antiinflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective and antioxidant properties [9–17]. N. sativa has got the place among the top ranked evidence based herbal medicines due to its marvelous power of therapeutic effects [18]. Medicinal benefits of N. sativa related to its wealthy and different chemical constituents including amino acids, proteins, carbohydrates, crude fiber, oils (fixed oil with 36–38 % composed of unsaturated fatty acids namely, linoleic (C18:2), oleic (C18:1), palmitic (C16:0), and stearic (C18:0) acids), minerals, alkaloids, saponin and others [19, 20]. Thymoquinone (TQ), (Fig. 1) is the main pharmacologically active constituents found abundantly (30–48 %) in the black seeds of N. sativa, together with its derivatives such as dithymoquinone, thymohydroquinone, and thymol [21]. TQ has been subjected to a variety of pharmacological investigations in recent years. It is known as a potent antioxidant [9, 22, 23]. Moreover, it has analgesic, antiinflammatory [24], antitussive [25], hepatoprotective [22], nephroprotective [26] neuroprotective [27–32], cardiovascular protective [33] and anticancer [34] properties. According to scientific based evidence, N. sativa and its active component (TQ) have a broad spectrum of
Fig. 1 Chemical structure of thymoquinone
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therapeutic potential especially in different components of metabolic syndrome. The prevention and treatment of metabolic syndrome should become an important approach for the reduction of the cardiovascular disease burden in the general population. In this review, we describe the most relevant animal and human studies to realize the role of N. sativa and its main active constituents (TQ) in different components of metabolic syndrome as metabolic CVD risk factors including dyslipidemia, high blood glucose, high blood pressure and obesity. Although the reported biological results showed that this plant is a highly promising cardiovascular protective agent, more studies are required to establish its bioavailability and in vivo cardioprotective effects, particularly in humans. Effects on lipid profile High triglyceride (TG) and low high-density cholesterol (HDL-C) levels are found to be CVD metabolic risk factors [35]. Most of human and animal studies on N. sativa and TQ demonstrated improvement in serum lipid levels including decrease in total lipids, TG and low-density lipoprotein (LDL) levels. However, increase in HDL level showed uncertain results [36]. The protective effects of N. sativa and TQ on dyslipidemia may be related to the significant decrease in hepatic HMG-CoA reductase activity, increase in arylesterase activity, regulatory effects on genes that influence cholesterol metabolism, as well as antioxidant mechanisms [37, 38]. Animal studies showed that oral feeding of 100 mg N. sativa methanolic extract or 20 mg volatile oil per rat/day effectively reduced the plasma TG to near normal level, while HDL-C and arylesterase activity levels were significantly increased. The effect of methanolic extract was more than volatile oil [31]. Similar findings were observed in administration of TQ (10 mg/ml, via gavage) for 30 days, in an atherogenic fed rats, or N. sativa oil for 4 weeks in rats [38, 39]. Another studies showed that TQ reduced total cholesterol, LDL-C, TG and thiobarbituric acid-reactive substances concentrations, while increased HDL-C concentration, as well as glutathione (GSH) content compared to cholesterol-enriched rabbit diet [40, 41]. In vitro study also revealed TQ is effective in regulating Apo A-1 and Apo B100 genes that influence cholesterol metabolism in HepG2 cells [37]. Several clinical studies also showed the beneficial effects of this plant on dyslipidemia in human beings. For examples dietary supplementation of N. Sativa seeds (400–600 mg/ kg) for 1, 2 or 4 weeks is useful in the prevention and treatment of the hyperlipidemia and hypercholesterolemia especially in patients suffering from diabetes [36]. N. sativa (500 mg, powder) significantly improved lipid profiles of menopausal women (decreased total cholesterol, LDL-C,
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Table 2 Summary of the effects of N. sativa and thymoquinone in metabolic syndrome Effect
Results
Study design
Constituents
Ref.
Hypolipidemic effect
; TG, MDA, HMG-CoA reductase activity : HDL-C, arylesterase activity Prolongation the lag times of LDL, sd-LDL and lb-LDL ; HMG-CoA reductase activity, MDA. : Arylesterase activity Inhibition the shift in buoyancy from lb-LDL to sd-LDL Prolongation the lag times of LDL, sd-LDL and lb-LDL ; TC, LDL, TG : HDL ; TC, LDL-C : HDL-C,GSH ; Cholesterol, LDL-C, TG, MDA : HDL-C,GSH : HDL-C ; LDL-C, VLDL-C, TG and TC ; LDL-C : HDL-C ; TC, LDL-C, TG : HDL-C ; TC, LDL-C, TG : HDL-C
In vivo, Rats (atherogenic suspension)
NS methanolic extract (100 mg/ rat/day) or VO (20 mg/rat/day) orally for 30 days
[35]
In vivo, Rats (atherogenic suspension)
TQ (10 mg/day) orally for 30 days
[38]
In vivo Rats In vivo, Rabbit (cholesterol-enriched diet) In vivo, Rabbit (cholesterol-enriched diet)
NS oil (800 mg/kg/day) orally for 4 weeks
[39]
NS powder (1000 mg/kg) or oil (500 mg/kg) for 8 weeks
[40]
TQ
[41]
In vivo, Rats
NS seeds (400-600 mg/kg) for 1, 2 or 4 weeks
[36]
In vivo, Rats
NS (30 mg/kg) for 20 weeks
[80]
Human, Menopausal women Human, Patients with high cholesterol Human, Patients with hyperlipidemia Human, Patients with type 2 DM In vitro, HEPG2 cells
NS (500 mg, powder) for 2 month
[4]
NS (1000 mg, powder) for 2 month
[42]
NS ? Garlic ? SIM for 8 weeks
[43]
NS capsules (2 g/day) orally for 12 weeks.
[81]
TQ
[37]
NS capsules (1500 mg, twice a day) for 3 months
[44]
NS dichloromethane extract (0.6 mL/kg/day) orally for 15 days NS VO or TQ (IV) NS VO (DE-TQ), a-pinene and p-cymene (IV) NS (0.2 ml/kg/day, IP) for six weeks
[49]
[50] [52]
TQ (0.5 and 1 mg/kg/day) orally
[54]
Hypolipidemic effect
Hypolipidemic effect Hypolipidemic effect Hypolipidemic \effect
Hypolipidemic effect
Hypolipidemic effect Hypolipidemic effect Hypolipidemic effect
Hypolipidemic effect
Significant difference between all tested lipid profile
Hypolipidemic effect
; TC, TG, and LDL-C : HDL-C/LDL-C Regulation of apolipoprotein A-1 and apolipoprotein B100 genes ; BW, waist circumference, SBP
Hypolipidemic effects
Antiobesity effect Hypotensive effect
: Diuresis ;Arterial BP
Human, Obese central men In vivo, Spontaneously hypertensive rat
Hypotensive effect Hypotensive effect
; Arterial BP and HR ; Arterial BP and HR
In vivo, Rats In vivo, Rats
Hypotensive effect
; SBP, plasma CK, LDH, asymmetric DMA, MDA, : Tissue Na?K?ATPase activity and plasma No level ; SBP, serum creatinine :Kidney GSH
In vivo, Renovascular hypertensive rat
Hypotensive effect
In vivo, L-NAME-induced hypertensive rat
[53]
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Table 2 continued Effect
Results
Study design
Constituents
Ref.
Hypotensive effect
; Arterial BP
NS fixed oil (1 and 2 ml/kg/day, IP)
[56]
Hypotensive effect
; Arterial BP, SBP, DBP, and serum LDH : Serum No
NS seed extract (400 mg/kg) orally
[83]
Hypotensive and hypolipidemic effects
; TC, LDL-C, SBP, DBP
NS (100 and 200 mg) seed extract orally for 8 weeks
[57]
Hypotensive effect
; SBP and DBP ; HR and contractility via calcium channel inhibitory effect ; Glucose and MDA : GST and ceruloplasmin ; Glucose via extrapancreatic actions
NS oil (2.5 ml) twice a day for 8 weeks NS (aqueous and macerated extract)
[58]
Hypotensive effect
In vivo, Ph induced hypertensive rat In vivo, L-NAME-induced hypertensive rat Human, Patients with mild HT Human, Healthy volunteers In vitro, Isolated guinea-pig hearts
Antidiabetic effect Antidiabetic effect Antidiabetic effect
Antidiabetic effect Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
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; FBG,: hepatic glycogen content, number of islets, cells and islets diameter ; HR and glucose concentration : Insulin level, ; HR and glucose concentration and improved disturbances in pancreatic b-cells ; Morphological changes and preserving pancreatic betacell integrity ; MDA and glucose concentration : Insulin and SOD (preserving pancreatic beta-cell integrity) ; Serum glucose and : serum insulin Regeneration/proliferation of pancreatic beta-cells : GSH, GST and catalase, CKMB and ; 5-HT, NEP and DA A progressive normalization of glycaemia, : insulin and HDL-C ; OGTT and TG Simulated muscle and liver ACC phosphorylation :Muscle Glut4 Inhibition of sodium-dependent glucose transport across isolated rat jejunum and improved glucose tolerance like metformin in chronic exposure
[47]
In vivo, Alloxan diabetic rabbits In vivo, STZ diabetic rats In vivo, STZ diabetic rats
NS seed extract for 2 months
[61]
NS oil and TQ
[62]
NS hydroalcholic extract (5 mg/ kg, IP) for 32 days
[64]
In vivo, Alloxan-induced diabetic rabbits In vivo, Cadmium induced diabetic rats
NS orally for 2 months
[65]
NS (2 ml/kg) IP for one month
[66]
In vivo, STZ diabetic rats
NS VO (0.2 ml/kg) once a day orally for 4 weeks
[67]
In vivo, STZ diabetic rats
NS aq. extract (2 ml/kg, IP) and oil (0.2 ml/kg, IP) and TQ (3 mg/ ml, IP) for one month
[68]
In vivo, STZ diabetic rats
NS VO (0.20 ml/kg) for 30 days
[69]
In vivo, STZ diabetic rats
NS oil and TQ
[70]
In vivo, Meriones shawi after development diabetes
NS seed ethanol extract (2 g eq plant/kg/day) orally for 4 weeks
[71]
In vivo and in vitro, Rats
NS aq. extract (0.1 pg/ml to 100 ng/ml) and 2 g/kg/day for 6 weeks.
[72]
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Table 2 continued Effect
Results
Study design
Constituents
Ref.
Antidiabetic effect
Insulin-sensitizing action by enhancing the activity of the two major intracellular signal transduction pathways (MAPK and PKB) Modifying weight gain, improving lipid profile and blood glucose as well as hormonal level ; Glucose, TC
In vivo, Rats
NS petroleum ether seed extract, orally
[73]
In vivo, Ovariectomized rat model
NS (300, 600, 1200 mg/kg/day) for 21 days
[74]
Human, Healthy subjects Human, Patients with type 2 DM
NS capsules (2 g/day) orally for 2 weeks.
[82]
NS (2 g/day, powder) for 3 months
[78]
NS oil 2.5 ml twice a day plus statin, metformin, amlodipine and atenolol for 6 weeks
[63]
NS seed extracts (0.01, 0.1, 1 and 5 mg/mL).
[75]
NS ethanol extract
[76]
TQ (2.5 lM) and NS oil
[77]
Antidiabetic effect
Antidiabetic and hypolipidemic effecs Antidiabetic effect
Antidiabetic and hypolipidemic effects
; FBG, 2hPG, HbA1c, insulin resistance : b-cell function without change in body weight. ; LDL and FBG :HDL
Antidiabetic effect
Increase glucose-induced insulin release from the islets
Antidiabetic effect
Increase activity of Akt and AMPK in C2C12 and H4IIE NS behaves as an agonist of PPARc in adipocytes
Antidiabetic effect
Increase glucose stimulated insulin secretion and improve oxidative damages induced by PIs (nelfinavir, saquinavir and atazanavir)
Human, Patients with DM and dyslipidemia In vitro, Isolated rat pancreatic islets In vitro, C2C12: SMCells, H4IIE: Hepatocytes 3T3-L1 : Adipocytes In vitro, Rat pancreatic beta-cells
Abbreviations: : : Increase; ; : decrease; NS Nigella sativa, VO volatile oil, DE- TQ dethymoquinonated, TG triglyceride, MDA malondealdehyde, HMG-CoA reductase hydroxyl methyl glutaryl reductase, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, VLDL-C very low-density lipoprotein cholesterol, sd-LDL small, dense low-density lipoprotein, Ib LDL large buoyant low-density lipoprotein, TQ thymoquinone; GSH: reduced glutathione; FBG fast blood glucose, 2 h PG 2-h plasma glucose, HBA1C hemoglobin A1c, CK creatine kinase, No nitric oxide, HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, OGTT oral glucose tolerance test, ACC acetyl-CoA carboxylase, MAPK mitogen-activated protein kinase, PKB protein kinase B, DA dopamine, NEP norepinephrine, 5-HT 5-hydroxytryptamine, GST glutathion-S-transferase, PPAR peroxisome proliferator-activated receptor; PI protease inhibitor, DM diabetes mellitus, SMC skeletal muscle cells, STZ streptozotocin, HT hypertension, Ph phenylephrine, SIM simvastatin
cholesterol and TG, and increased HDL-C) more than the placebo treatment over 2 months of intervention [4]. Also, oral administration of powdered black seeds (1 g/day) to hypercholesterolemic patients for 2 months significantly decreased the total cholesterol, TG, and LDL-C levels and increased the HDL-C level [42]. Furthermore in a randomized, double-blind, placebo controlled, two arms parallel study showed that patients who received simvastatin plus black seed and garlic for 8 weeks have significant differences between baseline and after treatment for all tested lipid profiles [43]. Based on document, N. sativa and its different preparations can be used as an adjuvant with lipid lowering drugs (Table 2).
Effects on obesity Obesity or especially excess fat in abdominal is a great risk factor for heart disease [44]. N. sativa and TQ exhibit suitable anti- obesity effects because of their cardiovascular protection, anticancer, insulin sensitivity and immunomodulatory effects [45]. The findings of a study showed that the consumption of N. sativa (3 g/day) in central obesity in men can significantly reduce body weight, waist circumference and systolic blood pressure (SBP). It is suggested that larger dose and longer duration of N. sativa consumption will give better results [41]. Although there was no report of side effect, however, the safety of this
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Fig. 2 Schematic description for protective effects of N. sativa and thymoquinone in different components of metabolic syndrome
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plant still remains to be elucidated by further long-term studies [46] (Table 1; Fig. 2). Effects on high blood pressure Hypertension is another metabolic risk factor for CVD. Hypertension increases the risk for a variety of cardiovascular diseases, including stroke, coronary artery disease, heart failure and peripheral vascular disease [47]. The potential role of N. sativa and its active constituent have been documented both in animal and human studies in the management of hypertension via several mechanisms including antioxidant [47], calcium channel blockade [48], diuretic [49] and cardiac depressant properties [50–52]. The therapeutic potential of N. sativa oil (0.2 ml/kg/day, intraperitoneally) for 6 weeks in renovascular hypertension using a renal artery clip (2-kidney-1-clip, 2K1C) in Wistar albino rats has been shown through reduction in SBP, plasma creatine kinase (CK), lactate dehydrogenase (LDH), asymmetric dimethylarginine, attenuation of oxidative injury (decrease in malondealdehyde), increase in tissue Na?K?ATPase activity and plasma No level [53]. Furthermore, N. sativa seed oil was found to have a modulator of Na?K?ATPase activity. It is suggested that oleic acid, active principle in N. sativa would be a specific chaperon which modulates interaction of cardiac glycosides with the sodium pump [54]. In another animal study concurrent treatment with TQ (0.5 and 1 mg/kg/day, orally) reduced the increase in rat SBP induced by L-NAME in a dose-dependent manner via antioxidant effects through reduction in the elevated creatinine, increase in kidney GSH and inhibition of in vitro production of superoxide radical [55]. Moreover, N. sativa fixed oil (1 and 2 ml/kg/day, IP) significantly suppressed aadrenoceptor-mediated phenylephrine-induced rise in the arterial BP in normal rats [56]. Clinical investigations also showed that the daily consumption of N. sativa seed extract (100 and 200 mg/twice a day) for 2 months may exhibit a BP-lowering effect in patients with mild hypertension [57]. In addition, oral daily administration of N. sativa oil to healthy volunteers for two months reduced SBP and diastolic blood pressure (DBP) without any adverse effects [58]. Further studies should be carried out on human to confirm its efficacy (Table 1, Fig. 2). Effects on high glucose level Diabetes is a chronic metabolic problem strictly related to CVD leading to premature death [59]. The hypoglycemic and antidiabetic effects of N. sativa and TQ have been reported by numerous in vivo and in vitro scientific studies [60–63]. N. sativa and TQ are found to exhibit antidiabetic
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effects in animal models of diabetes type 1 including streptozotocin (STZ), cadmium and alloxan-induced hyperglycemia [64–66]. In these models, the mechanisms of their antidiabetic effects could be related in part due to the increase in insulin secretion by acting on the pancreas and b-cells proliferation [67–69]. It was shown that N. sativa and TQ corrected STZ induced alterations in CKMB and brain monoamines due to their antioxidant properties [70]. Hypoglycemic effect of hydroalcoholic extract of N. sativa at low doses has been shown in another study through regeneration of pancreatic islets. Therefore it may be used as a therapeutic agent in the management of diabetes mellitus [64]. Besides the effect of this plant in type I diabetes, it is documented that N. sativa and its constituent, TQ, possess hypoglycemic effect in type II diabetes both in animal and human studies [71–74]. In animal studies, N. sativa stimulated the adenosine monophosphate-activated protein kinase (AMPK) in the liver and muscles. It also increased the sensitivity to insulin by reduction in the acteyl-CoA carboxylase, an enzymatic pathway involved in increasing fatty acid production by the liver. The activation of AMPK could inhibit gluconeogenesis in the liver. In the muscle, N. sativa activated AMPK and caused the increase in synthesis and translocation of Glut4 and accordingly the increase in glucose transport in muscles [71]. Another animal studies have been reported that N. sativa inhibited intestinal glucose absorption and improved glucose tolerance in rats [72] and also N. sativa seed extracts could increase glucose-induced insulin release from rat isolated Langerhans islets [75]. The effect of N. sativa extract in adipocytes has been shown in another in vitro study [76]. It is indicated that N. sativa behaves as an agonist of PPAR gamma (peroxisome proliferator-activated receptor gamma) [76]. It is wellknown that dyslipidemia is an important risk factor responsible for CVD in patients with diabetes [36]. Majority of human and animal studies showed that dietary supplementation of black seed caused reduction in weight and improvement in serum lipid levels including decrease total lipids, TG and LDL levels in diabetic population [36]. Moreover, study on ovariectomized rat model suggested that treatment with N. sativa (300, 600, and 1200 mg/kg/ day) exhibits therapeutic and protective effects through modulating weight gain, improving lipid profile and blood glucose as well as hormonal level which is supposed to play an important role in the pathogenesis of metabolic syndrome during menopause [74]. Furthermore another study showed that TQ may be used as a probable therapeutic agent to adjust the dysregulated insulin production observed in HIV-1 protease inhibitors treated patients [64, 77]. In summary, although antidiabetic activity of this plant was evaluated in human volunteers [78, 79], however,
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more studies are needed to perform on human to confirm its efficacy (Table 1, Fig. 2).
14.
Conclusion This review article summarized a variety of in vitro and in vivo studies in order to find out the role of N. sativa and its active constituent, TQ, in metabolic syndrome. The results of several important studies have been shown that this plant exhibits beneficial effects in different components of metabolic syndrome including diabetes, dyslipidemia, hypertension and obesity. In addition, based on the current review, it has been concluded that N. sativa has an extensive spectrum of therapeutic potential particularly in CVD. To establish the therapeutic utility of N. sativa and TQ, more human trials should be carried out. Conflict of interest of interest.
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The authors declare that there are no conflicts
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1039 50. El-Tahir KEH, Ashour MM, AlHarbi MM (1993) The cardiovascular actions of the volatile oil of the black seed (Nigella sativa) in rats: elucidation of the mechanism of action. Gen Pharmacol 24:1123–1131 51. El-Tahir KEH, Ageel AM (1994) Effect of volatile oilof Nigella sativa on the arterial blood pressure and heart rate of the guineapig. Saudi Pharm J 2:163–168 52. El-Tahir KEH, Al-Ajmi MF, Al-Bekairi AM (2003) Some cardiovascular effects of the dethymoquinonated Nigella sativa volatile oil and its major components. Saudi Pharm J 11:104–110 53. Tasar N, Sehirli O, Yigner O et al (2012) Protective effects of Nigella sativa against hypertension-induced oxidative stress and cardiovascular dysfunction in rats. Marmara Pharm J 16:141–149 54. Mahmmouda YM, Christensen S (2011) Oleic and linoleic acids are active principles in Nigella sativa and stabilize an E 2P conformation of the Na, K-ATPase. Fatty acids differentially regulate cardiac glycoside interaction with the pump. Biochim Biophys Acta 1808:2413–2420 55. Khattab MM, Nagi MN (2007) Thymoquinone supplementation attenuates hypertension and renal damage in nitric oxide deficient hypertensive rats. Phytother Res 21:410–414 56. ElTahir KEH, Al-Tahir AY, Ageel AM (1999) Pharmacological studies on sesame and Nigella sativa fixed oils: Effects on the sensitivities of the adrenoceptors, baroreceptors, platelets and the uterus of the rat. Saudi Pharm J 7:205–215 57. Dehkordi F, Kamkhah A (2008) Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension. Fundam Clin Pharmacol 22:447–452 58. Fallah Huseini H, Amini M, Mohtashami R, Ghamarchehre ME, Sadeqhi Z, Kianbakht S et al (2013) Blood pressure lowering effect of Nigella sativa l. seed oil in healthy Volunteers: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res 27:1849–1853 59. Qidwai W, Ashfaq T (2014) Effect of dietary supplementation of black seed (N. Sativa L.) on lipid profile of patients suffering from diabetes. Anti Inflam Anti Allergy Agents Med Chem 13:3–8 60. Ghorbani A (2013) Best herbs for managing diabetes: A review of clinical studies. Braz J Pharm Sci 49:413–422 61. Meral I, Yener Z, Kahraman T, Mert N (2001) Effect of Nigella sativa on glucose concentration, lipid peroxidation, antioxidant defence system and liver damage in experimentally induced diabetic rabbits. J Vet Med Ser 48:593–599 62. El-Dakhakhny M, Mady N, Lembert N, Ammon HPT (2002) The hypoglycemic effect of Nigella sativa oil is mediated by extrapancreatic actions. Planta Med 48:465–466 63. Najmi A, Haque S, Khan RA, Nasiruddin M (2008) Therapeutic effect Of Nigella sativa oil on different clinical and biochemical parameters in metabolic syndrome. Inter J Pharmacol 5:8 64. Alimohammadi S, Hobbenaghi R, Javanbakht J, Kheradmand D, Mortezaee R, Tavakoli M et al (2013) Protective and antidiabetic effects of extract from Nigella sativa on blood glucose concentrations against streptozotocin (STZ)-induced diabetic in rats: An experimental study with histopathological evaluation. Diagn Pathol 8:137 65. Meral I, Donmez N, Baydas B, Belge F, Kanter M (2004) Effect of Nigella sativa L. on heart rate and some haematological values of alloxan-induced diabetic rabbits. Scandinavian J Lab Animal Sci 31:49–53 66. Demir H, Kanter M, Coskun O et al (2006) Effect of black cumin (Nigella sativa) on heart rate, some hematological values, and pancreatic beta-cell damage in cadmium-treated rats. Trace Elem Res 110:151–162 67. Kanter M, Akpolat M, Aktas C (2009) Protective effects of the volatile oil of Nigella sativa seeds on beta-cell damage in
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streptozotocin-induced diabetic rats: a light and electron microscopic study. J Mol Histol 40:379–385 Abdelmeguid N, Fakhoury R, Kamal S, Al Wafai R (2010) Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic b-cells of streptozotocininduced diabetic rats. J Diabetes 2:256–266 Kanter M, Meral I, Yener Z et al (2003) Partial regeneration/ proliferation of the beta-cells in the islets of Langerhans by Nigella sativa L. in streptozotocin-induced diabetic rats. Tohoku J Exp Med 201:213–219 Hamdy N, Taha R (2009) Effects of N. sativa oil and thymoquinone on oxidative stress and neuropathy in streptozotocininduced diabetic rats. Pharmacology 84:127–134 Benhaddou-Andaloussi A, Martineau L, Vuong T et al (2011) The in vivo antidiabetic activity of Nigella sativa is mediated through activation of the AMPK pathway and increased muscle Glut4 content. Evid Based Complement Alter Med. doi:10.1155/ 2011/538671 Meddah B, Ducroc R, El Abbes Faouzi M, et al (2009) Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. J Ethnopharmacol 121:419–24 Le P, Benhaddou-Andaloussi A, Elimadi A et al (2004) The petroleum ether extract of Nigella sativa exerts lipid-lowering and insulin-sensitizing actions in the rat. J Ethnopharmacol 94:251–259 Saadat P, Latiffa AL, Sabariah AR, Mohammad AD (2011) Preventive effect of nigella sativa on metabolic syndrome in menopause induced rats. J Med Plants Res 5:1478–1484 Rchid H, Chevassus H, Nmila R et al (2004) Nigella sativa seed extracts enhance glucose-induced insulin release from rat-isolated Langerhans islets. Fund Clin Pharmacol 18:525–529
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REVIEW
A review of the effects of Nigella sativa L. and its constituent, thymoquinone, in metabolic syndrome B. M. Razavi • H. Hosseinzadeh
Received: 29 June 2014 / Accepted: 29 July 2014 / Published online: 15 August 2014 Ó Italian Society of Endocrinology (SIE) 2014
Abstract Background Metabolic syndrome is an important risk factor for cardiovascular disease (CVD) occurrence and mortality. CVDs are leading cause of death worldwide. Recently, there has been an increasing interest in the use of herbal medicines with more efficiency and minimal undesirable effects than chemical drugs for a variety of disorders including CVD. Nigella sativa and its active constituent, thymoquinone, have been documented to exhibit antidiabetic, antiobesity, hypotensive and hypolipidemic properties. Aim In this review, we discussed the most relevant articles to find out the role of N. sativa in different components of metabolic syndrome and CVD risk factors including high blood pressure, obesity, dyslipidemia and high blood glucose. Conclusions This review suggests a potential role of N. sativa and TQ in the management of metabolic syndrome, however more studies should be conducted to evaluate their effectiveness. Keywords Nigella sativa Thymoquinone Metabolic syndrome Cardiovascular disease Hypertension Diabetes Dyslipidemia Obesity
B. M. Razavi Department of Pharmacodynamy and Toxicology, Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran H. Hosseinzadeh (&) Department of Pharmacodynamy and Toxicology, Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran e-mail: [email protected]
Introduction Metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism (high glucose level), overweight and abdominal fat distribution, dyslipidemia, and hypertension, is an important risk factor for cardiovascular disease incidence and mortality [1, 2]. People with at least three out of five risk factors, are considered to have metabolic syndrome based on the National Cholesterol Education Program (NCEP) definition (Table 1) [3]. Cardiovascular diseases (CVDs) are estimated to continue the distinct leading cause of death worldwide and by 2020 almost 23.6 million people are expected to die from CVD (WHO Death Estimated Report, 2011) [4]. Recently, there has been an increasing interest in the use of herbal medicines for the prevention and treatment of a variety of disorders including cardiovascular diseases because of their safety, efficacy, cultural acceptability and lesser side effects [5]. Nigella sativa, which belongs to the botanical family of Ranunculaceae, commonly grows in Eastern Europe, the Middle East, and Western Asia. N. sativa seeds, known as ‘‘Al-Habba Al-Sauda’’ and :Al-Habba Al-Barakah’’ in Arabic and black seed or black cumin in English [6]. For thousands of years, N. sativa seeds have been reported to be used as protective and therapeutic traditional medicine against a number of diseases in the Middle East and some Asian countries. A great importance has been given to this plant especially in Islamic countries, because of its various beneficial properties. Furthermore, N. sativa seed can reduce weakness and depression and enhance the body’s energy in the Avicenna’s famous book ‘‘Canon of Medicine’’. According to its traditional uses, this plant is also included in the list of natural drugs in different medicines including Tibb-e-Nabavi (The medicine of Prophet
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1032 Table 1 NCEP (National Cholesterol Education Program) definition of the metabolic syndrome in men [3] Fasting plasma glucose C130 mg/dl Abdominal obesity with waist girth [94 or 102 cm Serum Triglycerides C150 mg/dl Serum HDL cholesterol \40 mg/dl Blood pressure C130/85 mmHg or medication People with at least 3 of the above risk factors are considered to have metabolic syndrome
Mohammad), Unani Tebb and Indian system of medicine [7]. In traditional medicine, N. sativa seeds are widely used as a spice and carminative [6]. Moreover, it has been extensively used as liver tonics, diuretics, digestive, antidiarrheal, appetite stimulant, analgesics, anti-bacterial, in skin disorders and headache [6–8]. Its pharmacological activities include antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, antiinflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective and antioxidant properties [9–17]. N. sativa has got the place among the top ranked evidence based herbal medicines due to its marvelous power of therapeutic effects [18]. Medicinal benefits of N. sativa related to its wealthy and different chemical constituents including amino acids, proteins, carbohydrates, crude fiber, oils (fixed oil with 36–38 % composed of unsaturated fatty acids namely, linoleic (C18:2), oleic (C18:1), palmitic (C16:0), and stearic (C18:0) acids), minerals, alkaloids, saponin and others [19, 20]. Thymoquinone (TQ), (Fig. 1) is the main pharmacologically active constituents found abundantly (30–48 %) in the black seeds of N. sativa, together with its derivatives such as dithymoquinone, thymohydroquinone, and thymol [21]. TQ has been subjected to a variety of pharmacological investigations in recent years. It is known as a potent antioxidant [9, 22, 23]. Moreover, it has analgesic, antiinflammatory [24], antitussive [25], hepatoprotective [22], nephroprotective [26] neuroprotective [27–32], cardiovascular protective [33] and anticancer [34] properties. According to scientific based evidence, N. sativa and its active component (TQ) have a broad spectrum of
Fig. 1 Chemical structure of thymoquinone
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therapeutic potential especially in different components of metabolic syndrome. The prevention and treatment of metabolic syndrome should become an important approach for the reduction of the cardiovascular disease burden in the general population. In this review, we describe the most relevant animal and human studies to realize the role of N. sativa and its main active constituents (TQ) in different components of metabolic syndrome as metabolic CVD risk factors including dyslipidemia, high blood glucose, high blood pressure and obesity. Although the reported biological results showed that this plant is a highly promising cardiovascular protective agent, more studies are required to establish its bioavailability and in vivo cardioprotective effects, particularly in humans. Effects on lipid profile High triglyceride (TG) and low high-density cholesterol (HDL-C) levels are found to be CVD metabolic risk factors [35]. Most of human and animal studies on N. sativa and TQ demonstrated improvement in serum lipid levels including decrease in total lipids, TG and low-density lipoprotein (LDL) levels. However, increase in HDL level showed uncertain results [36]. The protective effects of N. sativa and TQ on dyslipidemia may be related to the significant decrease in hepatic HMG-CoA reductase activity, increase in arylesterase activity, regulatory effects on genes that influence cholesterol metabolism, as well as antioxidant mechanisms [37, 38]. Animal studies showed that oral feeding of 100 mg N. sativa methanolic extract or 20 mg volatile oil per rat/day effectively reduced the plasma TG to near normal level, while HDL-C and arylesterase activity levels were significantly increased. The effect of methanolic extract was more than volatile oil [31]. Similar findings were observed in administration of TQ (10 mg/ml, via gavage) for 30 days, in an atherogenic fed rats, or N. sativa oil for 4 weeks in rats [38, 39]. Another studies showed that TQ reduced total cholesterol, LDL-C, TG and thiobarbituric acid-reactive substances concentrations, while increased HDL-C concentration, as well as glutathione (GSH) content compared to cholesterol-enriched rabbit diet [40, 41]. In vitro study also revealed TQ is effective in regulating Apo A-1 and Apo B100 genes that influence cholesterol metabolism in HepG2 cells [37]. Several clinical studies also showed the beneficial effects of this plant on dyslipidemia in human beings. For examples dietary supplementation of N. Sativa seeds (400–600 mg/ kg) for 1, 2 or 4 weeks is useful in the prevention and treatment of the hyperlipidemia and hypercholesterolemia especially in patients suffering from diabetes [36]. N. sativa (500 mg, powder) significantly improved lipid profiles of menopausal women (decreased total cholesterol, LDL-C,
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1033
Table 2 Summary of the effects of N. sativa and thymoquinone in metabolic syndrome Effect
Results
Study design
Constituents
Ref.
Hypolipidemic effect
; TG, MDA, HMG-CoA reductase activity : HDL-C, arylesterase activity Prolongation the lag times of LDL, sd-LDL and lb-LDL ; HMG-CoA reductase activity, MDA. : Arylesterase activity Inhibition the shift in buoyancy from lb-LDL to sd-LDL Prolongation the lag times of LDL, sd-LDL and lb-LDL ; TC, LDL, TG : HDL ; TC, LDL-C : HDL-C,GSH ; Cholesterol, LDL-C, TG, MDA : HDL-C,GSH : HDL-C ; LDL-C, VLDL-C, TG and TC ; LDL-C : HDL-C ; TC, LDL-C, TG : HDL-C ; TC, LDL-C, TG : HDL-C
In vivo, Rats (atherogenic suspension)
NS methanolic extract (100 mg/ rat/day) or VO (20 mg/rat/day) orally for 30 days
[35]
In vivo, Rats (atherogenic suspension)
TQ (10 mg/day) orally for 30 days
[38]
In vivo Rats In vivo, Rabbit (cholesterol-enriched diet) In vivo, Rabbit (cholesterol-enriched diet)
NS oil (800 mg/kg/day) orally for 4 weeks
[39]
NS powder (1000 mg/kg) or oil (500 mg/kg) for 8 weeks
[40]
TQ
[41]
In vivo, Rats
NS seeds (400-600 mg/kg) for 1, 2 or 4 weeks
[36]
In vivo, Rats
NS (30 mg/kg) for 20 weeks
[80]
Human, Menopausal women Human, Patients with high cholesterol Human, Patients with hyperlipidemia Human, Patients with type 2 DM In vitro, HEPG2 cells
NS (500 mg, powder) for 2 month
[4]
NS (1000 mg, powder) for 2 month
[42]
NS ? Garlic ? SIM for 8 weeks
[43]
NS capsules (2 g/day) orally for 12 weeks.
[81]
TQ
[37]
NS capsules (1500 mg, twice a day) for 3 months
[44]
NS dichloromethane extract (0.6 mL/kg/day) orally for 15 days NS VO or TQ (IV) NS VO (DE-TQ), a-pinene and p-cymene (IV) NS (0.2 ml/kg/day, IP) for six weeks
[49]
[50] [52]
TQ (0.5 and 1 mg/kg/day) orally
[54]
Hypolipidemic effect
Hypolipidemic effect Hypolipidemic effect Hypolipidemic \effect
Hypolipidemic effect
Hypolipidemic effect Hypolipidemic effect Hypolipidemic effect
Hypolipidemic effect
Significant difference between all tested lipid profile
Hypolipidemic effect
; TC, TG, and LDL-C : HDL-C/LDL-C Regulation of apolipoprotein A-1 and apolipoprotein B100 genes ; BW, waist circumference, SBP
Hypolipidemic effects
Antiobesity effect Hypotensive effect
: Diuresis ;Arterial BP
Human, Obese central men In vivo, Spontaneously hypertensive rat
Hypotensive effect Hypotensive effect
; Arterial BP and HR ; Arterial BP and HR
In vivo, Rats In vivo, Rats
Hypotensive effect
; SBP, plasma CK, LDH, asymmetric DMA, MDA, : Tissue Na?K?ATPase activity and plasma No level ; SBP, serum creatinine :Kidney GSH
In vivo, Renovascular hypertensive rat
Hypotensive effect
In vivo, L-NAME-induced hypertensive rat
[53]
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Table 2 continued Effect
Results
Study design
Constituents
Ref.
Hypotensive effect
; Arterial BP
NS fixed oil (1 and 2 ml/kg/day, IP)
[56]
Hypotensive effect
; Arterial BP, SBP, DBP, and serum LDH : Serum No
NS seed extract (400 mg/kg) orally
[83]
Hypotensive and hypolipidemic effects
; TC, LDL-C, SBP, DBP
NS (100 and 200 mg) seed extract orally for 8 weeks
[57]
Hypotensive effect
; SBP and DBP ; HR and contractility via calcium channel inhibitory effect ; Glucose and MDA : GST and ceruloplasmin ; Glucose via extrapancreatic actions
NS oil (2.5 ml) twice a day for 8 weeks NS (aqueous and macerated extract)
[58]
Hypotensive effect
In vivo, Ph induced hypertensive rat In vivo, L-NAME-induced hypertensive rat Human, Patients with mild HT Human, Healthy volunteers In vitro, Isolated guinea-pig hearts
Antidiabetic effect Antidiabetic effect Antidiabetic effect
Antidiabetic effect Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
Antidiabetic effect
123
; FBG,: hepatic glycogen content, number of islets, cells and islets diameter ; HR and glucose concentration : Insulin level, ; HR and glucose concentration and improved disturbances in pancreatic b-cells ; Morphological changes and preserving pancreatic betacell integrity ; MDA and glucose concentration : Insulin and SOD (preserving pancreatic beta-cell integrity) ; Serum glucose and : serum insulin Regeneration/proliferation of pancreatic beta-cells : GSH, GST and catalase, CKMB and ; 5-HT, NEP and DA A progressive normalization of glycaemia, : insulin and HDL-C ; OGTT and TG Simulated muscle and liver ACC phosphorylation :Muscle Glut4 Inhibition of sodium-dependent glucose transport across isolated rat jejunum and improved glucose tolerance like metformin in chronic exposure
[47]
In vivo, Alloxan diabetic rabbits In vivo, STZ diabetic rats In vivo, STZ diabetic rats
NS seed extract for 2 months
[61]
NS oil and TQ
[62]
NS hydroalcholic extract (5 mg/ kg, IP) for 32 days
[64]
In vivo, Alloxan-induced diabetic rabbits In vivo, Cadmium induced diabetic rats
NS orally for 2 months
[65]
NS (2 ml/kg) IP for one month
[66]
In vivo, STZ diabetic rats
NS VO (0.2 ml/kg) once a day orally for 4 weeks
[67]
In vivo, STZ diabetic rats
NS aq. extract (2 ml/kg, IP) and oil (0.2 ml/kg, IP) and TQ (3 mg/ ml, IP) for one month
[68]
In vivo, STZ diabetic rats
NS VO (0.20 ml/kg) for 30 days
[69]
In vivo, STZ diabetic rats
NS oil and TQ
[70]
In vivo, Meriones shawi after development diabetes
NS seed ethanol extract (2 g eq plant/kg/day) orally for 4 weeks
[71]
In vivo and in vitro, Rats
NS aq. extract (0.1 pg/ml to 100 ng/ml) and 2 g/kg/day for 6 weeks.
[72]
J Endocrinol Invest (2014) 37:1031–1040
1035
Table 2 continued Effect
Results
Study design
Constituents
Ref.
Antidiabetic effect
Insulin-sensitizing action by enhancing the activity of the two major intracellular signal transduction pathways (MAPK and PKB) Modifying weight gain, improving lipid profile and blood glucose as well as hormonal level ; Glucose, TC
In vivo, Rats
NS petroleum ether seed extract, orally
[73]
In vivo, Ovariectomized rat model
NS (300, 600, 1200 mg/kg/day) for 21 days
[74]
Human, Healthy subjects Human, Patients with type 2 DM
NS capsules (2 g/day) orally for 2 weeks.
[82]
NS (2 g/day, powder) for 3 months
[78]
NS oil 2.5 ml twice a day plus statin, metformin, amlodipine and atenolol for 6 weeks
[63]
NS seed extracts (0.01, 0.1, 1 and 5 mg/mL).
[75]
NS ethanol extract
[76]
TQ (2.5 lM) and NS oil
[77]
Antidiabetic effect
Antidiabetic and hypolipidemic effecs Antidiabetic effect
Antidiabetic and hypolipidemic effects
; FBG, 2hPG, HbA1c, insulin resistance : b-cell function without change in body weight. ; LDL and FBG :HDL
Antidiabetic effect
Increase glucose-induced insulin release from the islets
Antidiabetic effect
Increase activity of Akt and AMPK in C2C12 and H4IIE NS behaves as an agonist of PPARc in adipocytes
Antidiabetic effect
Increase glucose stimulated insulin secretion and improve oxidative damages induced by PIs (nelfinavir, saquinavir and atazanavir)
Human, Patients with DM and dyslipidemia In vitro, Isolated rat pancreatic islets In vitro, C2C12: SMCells, H4IIE: Hepatocytes 3T3-L1 : Adipocytes In vitro, Rat pancreatic beta-cells
Abbreviations: : : Increase; ; : decrease; NS Nigella sativa, VO volatile oil, DE- TQ dethymoquinonated, TG triglyceride, MDA malondealdehyde, HMG-CoA reductase hydroxyl methyl glutaryl reductase, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, VLDL-C very low-density lipoprotein cholesterol, sd-LDL small, dense low-density lipoprotein, Ib LDL large buoyant low-density lipoprotein, TQ thymoquinone; GSH: reduced glutathione; FBG fast blood glucose, 2 h PG 2-h plasma glucose, HBA1C hemoglobin A1c, CK creatine kinase, No nitric oxide, HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, OGTT oral glucose tolerance test, ACC acetyl-CoA carboxylase, MAPK mitogen-activated protein kinase, PKB protein kinase B, DA dopamine, NEP norepinephrine, 5-HT 5-hydroxytryptamine, GST glutathion-S-transferase, PPAR peroxisome proliferator-activated receptor; PI protease inhibitor, DM diabetes mellitus, SMC skeletal muscle cells, STZ streptozotocin, HT hypertension, Ph phenylephrine, SIM simvastatin
cholesterol and TG, and increased HDL-C) more than the placebo treatment over 2 months of intervention [4]. Also, oral administration of powdered black seeds (1 g/day) to hypercholesterolemic patients for 2 months significantly decreased the total cholesterol, TG, and LDL-C levels and increased the HDL-C level [42]. Furthermore in a randomized, double-blind, placebo controlled, two arms parallel study showed that patients who received simvastatin plus black seed and garlic for 8 weeks have significant differences between baseline and after treatment for all tested lipid profiles [43]. Based on document, N. sativa and its different preparations can be used as an adjuvant with lipid lowering drugs (Table 2).
Effects on obesity Obesity or especially excess fat in abdominal is a great risk factor for heart disease [44]. N. sativa and TQ exhibit suitable anti- obesity effects because of their cardiovascular protection, anticancer, insulin sensitivity and immunomodulatory effects [45]. The findings of a study showed that the consumption of N. sativa (3 g/day) in central obesity in men can significantly reduce body weight, waist circumference and systolic blood pressure (SBP). It is suggested that larger dose and longer duration of N. sativa consumption will give better results [41]. Although there was no report of side effect, however, the safety of this
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Fig. 2 Schematic description for protective effects of N. sativa and thymoquinone in different components of metabolic syndrome
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plant still remains to be elucidated by further long-term studies [46] (Table 1; Fig. 2). Effects on high blood pressure Hypertension is another metabolic risk factor for CVD. Hypertension increases the risk for a variety of cardiovascular diseases, including stroke, coronary artery disease, heart failure and peripheral vascular disease [47]. The potential role of N. sativa and its active constituent have been documented both in animal and human studies in the management of hypertension via several mechanisms including antioxidant [47], calcium channel blockade [48], diuretic [49] and cardiac depressant properties [50–52]. The therapeutic potential of N. sativa oil (0.2 ml/kg/day, intraperitoneally) for 6 weeks in renovascular hypertension using a renal artery clip (2-kidney-1-clip, 2K1C) in Wistar albino rats has been shown through reduction in SBP, plasma creatine kinase (CK), lactate dehydrogenase (LDH), asymmetric dimethylarginine, attenuation of oxidative injury (decrease in malondealdehyde), increase in tissue Na?K?ATPase activity and plasma No level [53]. Furthermore, N. sativa seed oil was found to have a modulator of Na?K?ATPase activity. It is suggested that oleic acid, active principle in N. sativa would be a specific chaperon which modulates interaction of cardiac glycosides with the sodium pump [54]. In another animal study concurrent treatment with TQ (0.5 and 1 mg/kg/day, orally) reduced the increase in rat SBP induced by L-NAME in a dose-dependent manner via antioxidant effects through reduction in the elevated creatinine, increase in kidney GSH and inhibition of in vitro production of superoxide radical [55]. Moreover, N. sativa fixed oil (1 and 2 ml/kg/day, IP) significantly suppressed aadrenoceptor-mediated phenylephrine-induced rise in the arterial BP in normal rats [56]. Clinical investigations also showed that the daily consumption of N. sativa seed extract (100 and 200 mg/twice a day) for 2 months may exhibit a BP-lowering effect in patients with mild hypertension [57]. In addition, oral daily administration of N. sativa oil to healthy volunteers for two months reduced SBP and diastolic blood pressure (DBP) without any adverse effects [58]. Further studies should be carried out on human to confirm its efficacy (Table 1, Fig. 2). Effects on high glucose level Diabetes is a chronic metabolic problem strictly related to CVD leading to premature death [59]. The hypoglycemic and antidiabetic effects of N. sativa and TQ have been reported by numerous in vivo and in vitro scientific studies [60–63]. N. sativa and TQ are found to exhibit antidiabetic
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effects in animal models of diabetes type 1 including streptozotocin (STZ), cadmium and alloxan-induced hyperglycemia [64–66]. In these models, the mechanisms of their antidiabetic effects could be related in part due to the increase in insulin secretion by acting on the pancreas and b-cells proliferation [67–69]. It was shown that N. sativa and TQ corrected STZ induced alterations in CKMB and brain monoamines due to their antioxidant properties [70]. Hypoglycemic effect of hydroalcoholic extract of N. sativa at low doses has been shown in another study through regeneration of pancreatic islets. Therefore it may be used as a therapeutic agent in the management of diabetes mellitus [64]. Besides the effect of this plant in type I diabetes, it is documented that N. sativa and its constituent, TQ, possess hypoglycemic effect in type II diabetes both in animal and human studies [71–74]. In animal studies, N. sativa stimulated the adenosine monophosphate-activated protein kinase (AMPK) in the liver and muscles. It also increased the sensitivity to insulin by reduction in the acteyl-CoA carboxylase, an enzymatic pathway involved in increasing fatty acid production by the liver. The activation of AMPK could inhibit gluconeogenesis in the liver. In the muscle, N. sativa activated AMPK and caused the increase in synthesis and translocation of Glut4 and accordingly the increase in glucose transport in muscles [71]. Another animal studies have been reported that N. sativa inhibited intestinal glucose absorption and improved glucose tolerance in rats [72] and also N. sativa seed extracts could increase glucose-induced insulin release from rat isolated Langerhans islets [75]. The effect of N. sativa extract in adipocytes has been shown in another in vitro study [76]. It is indicated that N. sativa behaves as an agonist of PPAR gamma (peroxisome proliferator-activated receptor gamma) [76]. It is wellknown that dyslipidemia is an important risk factor responsible for CVD in patients with diabetes [36]. Majority of human and animal studies showed that dietary supplementation of black seed caused reduction in weight and improvement in serum lipid levels including decrease total lipids, TG and LDL levels in diabetic population [36]. Moreover, study on ovariectomized rat model suggested that treatment with N. sativa (300, 600, and 1200 mg/kg/ day) exhibits therapeutic and protective effects through modulating weight gain, improving lipid profile and blood glucose as well as hormonal level which is supposed to play an important role in the pathogenesis of metabolic syndrome during menopause [74]. Furthermore another study showed that TQ may be used as a probable therapeutic agent to adjust the dysregulated insulin production observed in HIV-1 protease inhibitors treated patients [64, 77]. In summary, although antidiabetic activity of this plant was evaluated in human volunteers [78, 79], however,
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more studies are needed to perform on human to confirm its efficacy (Table 1, Fig. 2).
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Conclusion This review article summarized a variety of in vitro and in vivo studies in order to find out the role of N. sativa and its active constituent, TQ, in metabolic syndrome. The results of several important studies have been shown that this plant exhibits beneficial effects in different components of metabolic syndrome including diabetes, dyslipidemia, hypertension and obesity. In addition, based on the current review, it has been concluded that N. sativa has an extensive spectrum of therapeutic potential particularly in CVD. To establish the therapeutic utility of N. sativa and TQ, more human trials should be carried out. Conflict of interest of interest.
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The authors declare that there are no conflicts
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