Effect of Nigella sativa supplementation on human lipids : systematic review

1 Faculty of Medicine, Universiti Teknologi MARA (UiTM), Selangor, Malaysia, 2 Faculty of Medicine and Defence Health, National Defence University of Malaysia. (UPNM), Kuala Lumpur, Malaysia, 3 Faculty of Medicine, Universiti Kebangsaan Malaysia (The National University of Malaysia), Malaysia, 4 Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Malaysia, 5 College of Pharmacy, Qassim University, Saudi Arabia.


INTRODUCTION
Hyperlipidemia is a common risk factor for the development of cardiovascular illness (Graham et al., 2007).Increased serum total cholesterol concentrations are directly associated with an increased risk for coronary heart disease (Navar-Boggan et al., 2015).Pharmacologic treatment used for treating high-risk persons with lipid-lowering drugs include3hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, fibrates, and nicotinates (Last AR et al., 2011).None of the above pharmacologic options are free of adverse effects (Maron et al. 2000), and some have been associated with potential carcinogenicity (Newman and Hulley, .1996).Effective treatment with a harmless for lowering cholesterol levels would therefore be of considerable interest.For the past decade non-pharmacologic treatment has been by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program has recommended as initial therapy in most patients with hyperlipidemia (Expert Panel, 2011).Nigella sativa among the best rated evidence based herbal medicines (Ahmad et al., 2013).Nigella sativa (NS) (Family Ranunculaceae) is a widely used medicinal plant around the world.It is very popular in various traditional systems of medicine like Unani, Ayurveda, Siddha and Chinese.
Seeds and oil have a long history of folklore usage in various systems of medicines and food.The seeds of NS have been widely used in the treatment of different diseases and illnesses.In Islamic literature, it is considered as one of the greatest forms of healing medicine.It has been recommended for using on regular basis in Tibb-e-Nabwi (Prophetic Medicine).
It has been widely used as antihypertensive, liver tonics, diuretics, digestive, anti-diarrheal, appetite stimulant, analgesics, anti-bacterial and in skin disorders.Extensive studies on NS have been carried out by various groups of researcher and a wide spectrum of its pharmacological actions have been explored which may include antidiabetic, anticancer, immunomodulator (Hmza et al., 2013), analgesic, antimicrobial, anti-inflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective, antioxidant properties (Ahmad et al., 2013).The seeds of NS are widely used in the treatment of numerous diseases like bronchitis, asthma, diarrhea, rheumatism and skin disorders.It is also has been reported that used as liver tonic, digestive, antidiarrheal, appetite stimulant, emmenagogue, to increase milk production in nursing mothers to fight parasitic infections, and to support immune system (Goreja, 2003;Khaled, 2009;Assayed, 2010;Boskabady et al., 2010;Abdel-Zaher et al., 2011;Abdel-Salam, 2012).Most of the therapeutic properties of this plant are due to the presence of thymoquinone (TQ) which is a major active chemical component of the essential oil.Black seeds are also used in food like flavoring additive in the breads and pickles because it has very low level of toxicity (Al-Ali et al., 2008).There are a few review articles that have surveyed the effect of N. sativa on some diseases.However, we are going to conduct a systematic review of the literatures to identify relevant studies about the effect of N. sativa supplementation on human lipids.

METHODOLOGY
The protocol that was used in this study is the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.A search of published studies was performed by using computer databases including Scopus, PubMed, Google Scholar, Thomas Reuters Web of Science, and CINAHIL.

Literature Review:
A systematic review of the literature was conducted to identify relevant studies about Nigella sativa and human lipids/cholestrol.To conduct a comprehensive search of health science journals, we used Medline via Ovid Medline (published between 1946and March 2015) and CINAHL via Ebscohost (published between 1946and 2015).The search strategy involved a combination of the following two sets of key words; (1) Nigella sativa OR black seeds OR Habutulsuda, Black cumin OR thymoquinone; (2) Lipids OR cholesterol OR triglyceride OR hyperlipidemia.

Inclusion criteria 1.
The effect of Nigella sativa on human lipids changes.2.
Clinical trial.
Review studies.

3.
The effect of Nigella sativa on unrelated blood or clinical parameters.

4.
The effect of Nigella sativa in combination with other plants or exercise.5.

Selection of Research Articles
The results were limited to studies that were published in English language that included abstracts.To be included, studies had to (1) report the association or effect of Nigella sativa and human lipid changes.Papers were excluded if the studies were related to reviews, news, letter, editorials, or case studies.

Data Extraction and Management
We selected papers to be included in the review in three phases.First, we excluded any paper that did not match the inclusion criteria based solely on the title.Second, we screened all the abstracts of the remaining papers and then excluded a second group of papers that did not meet our inclusion criteria.Lastly, we read the remaining papers from the second phase to exclude any paper that did not meet our inclusion criteria.After the initial screening of the titles and abstracts, duplicates were removed and the remaining papers were again screened by at least two reviewers.The inclusion of the full papers into the review had to be agreed by at least two reviewers before the data extraction phase.Any discrepancies were resolved through discussion between the reviewers.Initially, 432 articles were extracted.After reviewing their titles and abstracts and removing unrelated, animal, and review studies, 312 articles (Medline; 206, Scopus; 90, EBSCO; 16) were retrieved for further evaluation.After excluding the animal studies, reviews, removal of abstracts due to duplicates and unrelated studies.Finally, 14 studies were considered eligible for our review [Table 1].

RESULTS
Data extraction was performed independently from 14 studies and in a standardized manner with the use of a data collection form.We recorded the following data from the studies: (1) the type of study, (2) a brief description of the sample/population of the study; (3) a brief description of the methods used in the study; (4) the brief description of the results of the study; (5) comments and conclusion of the study (6) complications if any.All studies were clinical trials and have been conducted on different patients and subjects (Heshmati et al., 2015;Ibrahim et al., 2014;Qibi et al., 2006;Najmi et al., 2012;Tasawar et al., 2011;Kaatabi et al., 2012;Najmi et al., 2008;Bhatii et al., 2009;Sabzghabaee et al., 2012;Datau et al., 2010;Qidwai et al., 2009;Dehkordi et al., 2008;Bamosa et al., 1997;Ahmed et al., 2012).Information of these studies is summarized in the table 2.
The total number of subjects in these trials was 738 from different conditions and diseases as hyperlipidemia in diabetic patients (Heshmati et al., 2015;Kaatabi et al., 2012;Ahmed et al., 2012), menopausal women (Ibrahim et al., 2014), metabolic syndrome (Najmi et al., 2012;Najmi et al., 2008) and coronary heart disease (Tasawar et al., 2011).The duration of the trials was between 2 weeks-3 months.The dose of NS supplements was between 500 mg and 2 g per day and was administered orally in all studies.The age range of the participants in trials was 18-yea0rs old.Supplementation with NS oil can significantly improve lipid profile in hyperlipidemic patients with T2DM (Heshmati et al., 2015;Kaatabi et al., 2012;Ahmed et al., 2012), with menopausal women (Ibrahim et al., 2014), with metabolic syndrome (Najmi et al., 2012;Najmi et al., 2008), and with coronary heart disease (Tasawar et al., 2011).However, no complications caused by NS were observed in all studies (Table 2).

DISCUSSION
In this systematic review we have tried to evaluate the effects of Nigella sativa supplementation on lipid profile in hyperlipidemia accompanied with many conditions.Lipid profiles constitute one of the most important factors that can be changed in many diseases and are used to evaluate conditions of the patients and subjects (Mohtashami and Entezari, 2016).In our review, Nigella sativa supplement can change lipid profiles significantly in different conditions (Heshmati et al., 2015;Ibrahim et al., 2014;Qibi et al., 2006;Najmi et al., 2012;Tasawar et al., 2011;Kaatabi et al., 2012;Najmi et al., 2008;Bhatii et al., 2009;Sabzghabaee et al., 2012;Datau et al., 2010;Qidwai W et al., 2009;Dehkordi FR et al., 2008;Bamosa et al., 1997;Ahmed et al., 2012).
In one trial study (Heshmati et al., 2015) reported that NS oil decreased LDL-C and TG levels after 3months while other previous studies reported different effects of NS on lipid The first group included 41 patients with T2DM.DM was diagnosed according to the ADA, 2012.The patients were chosen to be free of diabetic complications.
All subjects received oral N. sativa tea (5gm/day) daily for 6 months.This was added to their oral antidiabetic drugs in the patients group.
N. sativa tea improved the glycemic control and the lipid profile and increased PON-1 activity in T2DM.
No complications caused by NS were observed.
parameters.Kaatabi et al. (2012) evaluated different dosages of powdered NS (1, 2 and 3 g/day) in patients with type 2 diabetes.They indicated that 1 g/ day NS increased HDL-C levels after 12 weeks.Two and 3 g/day of black seed decreased TC, TG and LDL-C levels and increased HDL-C concentration.However another study used supplementation with NS powder concurrent with aerobic training program decreased TC, LDL-C, TG and increased HDL-C in overweight females after 8 weeks (Heshmati et al., 2015;Farzaneh et al., 2014).Najmi et al., 2008 reported that 2.5 ml NS oil decreased TC and LDL-C levels with no changes in HDL and TG concentrations (Farzaneh et al., 2014).These mentioned studies indicated positive effects of NS on lipid profile, but differences in dose and type of NS, dietary intake, physical activity level, baseline lipid profile, duration of intervention, type of disease, ethnicity and genotype may lead to different results.
In another trial the hypolipidemic effects of N. sativa was studied in menopausal women as part of the increasing drive to provide better insights into the effects of plant bioresources on health, and their potential use for therapy of chronic diseases (Ibrahim et al., 2014).Also, increasing numbers of women are thought to use complementary medicines for disorders associated with their menopause, and studies like these could provide evidence-based rationale for their choice of plant bioresources (Ibrahim et al., 2014).Specifically, about 75% of women were reported to be using herbal and complementary medicines in their menopausal period in place of hormone replacement therapy due to considerations on its side effects (Ibrahim et al., 2014;Tong IL, 2013).
Current study showed highly significant results noted on the lipids on healthy subjects (Qibi et al., 2006).These results support the benefit of a simple dietary element in improving lipid profile in normal people.Nigella sativa was shown to reduce TC, LDL-C and TG, while increasing HDL-C.All these effects are in favor of reducing the risks of atherosclerosis (Qibi et al., 2006;Nickavar et al., 2003).
The fatty acid composition of the black seed, including a predominance of linoleic acid (n6 polyunsaturated fatty acid) (Qibi et al., 2006;Hassanien, 2004), may explain its lipid lowering activity.Epidemiological and clinical studies have established that n6 fatty acids protect against CHD (Morikawa, 2004).These favorable results on normal people should stimulate a further work on large number of persons and in studying the effect of N. sativa as a lipid lowering remedy in dyslipidaemic patients on a wider scale (Qibi et al., 2006).Current study revealed the effect of Nigella sativa on FBG, PPBG, HbA1C & lipid profile of metabolic syndrome patients with poor glycemic control (HbA1C > 7 %) (Najmi et al., 2012).Reduction in FBG, PPBG, HbA1C were more ( P value < 0.001) in Nigella sativa group as compared to standard group Significant improvement in HbA1C indicates that Nigella sativa can be used as add on therapy to those patients whose glycemic control cannot be achieved by conventional drugs.Reduction in LDL cholesterol was more (P value < 0.001) in Nigella sativa group (NS) as compared to standard group (Najmi et al., 2012).These results were the same as reported previously in various studies.Insulin resistance leads to the overproduction of very low density lipoproteins (VLDLs) and to reduced lipoprotein lipase activity, thereby resulting in dyslipidemia.Therefore, attainment of better glycemic control may improve the lipid profile (Najmi et al., 2012).The presence of various unsaturated fatty acids like Arachidonic, eicosadienoic, linoleic, linolenic, oleic and almitoleic acid (Najmi et al., 2012;El. D. M et al., 2000), may be responsible for the improvement of lipid profile.The various mechanisms were proposed for the lowering of cholesterol.The seeds may either inhibit de novo cholesterol synthesis or stimulate bile acid excretion.It is well-known that both effects would lead to a decrease in serum cholesterol (Najmi et al., 2012;Beynen et al., 1987).These results confirmed that Nigella sativa can be used as add on drug therapy in patients of metabolic syndrome with poor glycemic control (Najmi et al., 2012).
The cholesterol lowering effect of N. sativa may be attributed to the presence of phytosterols like Beta-sitosterol, polyunsaturated fatty acids and its antioxidant activity.N. sativa may be able to reduce synthesis of cholesterol by hepatocytes and lower its absorption from the small intestine (Sabzghabaee et al., 2012, De Jong et al., 2003); it may also activate LDL-receptor by decreasing intracellular cholesterol, which leads to rapid clearance of LDL-cholesterol from blood circulation (Bamosa et al., 1997).The effect of N. sativa on increasing cholesterol secretion in the bile is another probable mechanisms witch can enhance its cholesterol lowering properties (Ibraheim Z, 2002).
Although Bamosa et al., 1997, worked on effects of daily oral ingestion of 2 g N. sativa on some blood parameters for 2 weeks and reported a pattern of decreased levels of FBS and cholesterol on 16 second year medical students but there was no significant decrease in triglyceride level (Bamosa et al., 1997).

CONCLUSION
This systematic review on 14 studies demonstrated that Nigella sativa supplement in different doses and durations can improve lipid profiles in humans either with hyperlipidemia alone or associated with other conditions as diabetes mellitus and metabolic syndrome.However, the effect of this supplement is more pronounced on levels of TC, LDL, than on TG, HDL.Therefore, it is suggested that consumption of Nigella sativa supplementation be considered as a complementary treatment protocol for many diseases, especially hyperlipidemia and metabolic disorders.Although, NS can be used as a complementary therapies in cases related to hyperlipidemia, but due to differences in models, chemical compositions of difference sources of NS, dosage, and duration of intervention, it is difficult to determine effective type and dosage of NS.More studies are suggested to clarify effective type and dosage of NS in patients with hyperlipidemia.

Table 1 :
Process of study selection.

Table 2 :
Characteristics of human studies that eligible to the study.