Nigella sativa and Non-Alcoholic Fatty Liver Disease: A Review of the Current Evidence


avatar Mina Darand 1 , avatar Seyed Moayed Alavian 2 , avatar Azita Hekmatdoost 3 , *

Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

how to cite: Darand M, Alavian S M, Hekmatdoost A. Nigella sativa and Non-Alcoholic Fatty Liver Disease: A Review of the Current Evidence. Hepat Mon. 2018;18(10):e68046.



Nigella sativa (NS) has been used as an herbal remedy for the treatment and prevention of a variety of diseases. In this review, we aimed to summarize the current evidence on the effects of NS consumption on non-alcoholic fatty liver disease (NAFLD) characteristics.

Evidence Acquisition:

We reviewed the existing literature published by the end of 2017 using the following key words: “Nigella sativa”, “black seeds”, “black cumin”, “thymoquinone”, “NAFLD”, “NASH”, and “diabetes”. Papers used in this study were collected by searching the PubMed, Google Scholar, Science Direct and Scopus databases. Our search was limited to English-language articles. All the articles published between 2000 and 2017 meeting the inclusion criteria were included in the study.


The results of current studies indicate that NS has many biological effects such as anti-inflammatory, anti-hyperlipidemic, anti-microbial, anti-cancer, anti-oxidative, anti-diabetic, anti-hypertensive and wound healing activities. In summary, it can be used as a valuable plant for designing therapeutic strategies in NAFLD.


Results from available studies indicate that NS can ameliorate the main metabolic disturbances related to NAFLD including hyperglycemia, hyperlipidemia, and overweight. These effects are mainly attributed to the anti-oxidative and anti-inflammatory properties of thymoquinone. Clinical trials on human subjects are highly essential to confirm the results found in in vivo and in vitro studies.

1. Context

Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of liver disorders worldwide (1-5), which may progress to nonalcoholic steatohepatitis (NASH) and hepatic cirrhosis (6-11). NAFLD usually develops due to the accumulation of fatty acids in hepatocytes, which can progress to steatohepatitis through rise in oxidative stress in the body (6, 12, 13). Due to the rising prevalence of obesity and sedentary life, NAFLD has become the most common cause of chronic liver disease (14-16).

Nigella sativa (NS), also known as black seed, is from Ranunculaceae family that is cultivated in Asia (17-20). The main components of NS are thymoquinone (TQ), unsaturated fatty acids, flavonoids, nigellone, p-cymene and carvone (19, 21-27).

It has been shown that nutrition and dietary supplements play a pivotal role in the treatment of NAFLD (28-40). Recently, some studies have evaluated the effects of medicinal herbs such as NS on some risk factors for NAFLD such as insulin resistance, hyperlipidemia, oxidative stress and inflammation in experimental models (41-44). In this study, we sought to review the results of these studies and find the future direction in this field of science.

2. Evidence Acquisition

We searched the literature published until 2017 using the following key words: “Nigella sativa”, “thymoquinone”, “black seeds”, “NAFLD”, NASH, and “diabetes”. Papers used in this study were collected by searching the PubMed, Google Scholar, Science Direct and Scopus databases and journals. To avoid the use of duplicate studies, titles and abstracts were screened. Then, compatibility of the selected articles was assessed according to our inclusion criteria. All the articles published between 2000 and 2017 meeting the inclusion criteria were included in the study. Review articles, case reports, conference abstracts and symposium publications were excluded.

3. Results

3.1. In Vitro and In Vivo Studies

In vitro and in vivo studies have shown some mechanisms for hepato-protective effects of TQ as the main effective component of NS. Bai et al. demonstrated the antifibrotic effects of TQ in their in vitro study. They found that these anti-fibrotic effects are attributed to the inhibition of apoptosis through attenuation in the expression of CD14, Toll-like receptor 4 (TLR4), α-SMA, collagen-I, X-linked inhibitor of apoptosis protein (XIAP), and expression of cellular FLIP (c-FLIPL) and other genes related to the regulation of apoptosis. Furthermore, these properties of TQ have been shown in in vivo studies (45). It has been proposed that TQ improves survival against LPS challenge in D-galactosamine (D-GlaN)-sensitized mice through the inhibition of TLR4 expression and PI3K phosphorylation. Therefore, it seems that TQ may be a potential candidate for hepatic fibrosis treatment (45).

Yang et al. ascribed that TQ has hepato-protective effects via AMP- activated protein kinase (AMPK) signaling in hepatic stellate cells (HSCs). They reported that TQ inhibits fibrogenic agents such as collagen-I and TGF-β, while inducing peroxisome proliferator activated receptor-γ (PPAR-γ) expression. Moreover, TQ (20 or 40 mg/kg) attenuated the rise in hepatic enzymes and triglycerides in an experimental model of alcoholic fatty liver disease (46). Moreover, there are some reports that supplementation with NS oil in experimental models of diabetes ameliorated serum sugar, oxidative stress, and hyperlipidemia after eight weeks and that essential oils were more effective than fixed oils (47, 48). Moreover, Awad et al. showed that TQ improves hepatic steatosis, oxidative stress, inflammatory and apoptotic status (49). Oguz et al. demonstrated that two weeks of supplementation with TQ (50 mg/kg) improved antioxidant enzyme activity in hepatic tissues (50). Furthermore, Kong et al. evaluated the effects of two dosages of TQ, low-dose (25 mg/kg) and high-dose (50 mg/kg); they observed that TQ reduced hepatic hydroxyproline (HP) and malondialdehyde (MDA) levels and increased antioxidant enzyme activity. Thus, TQ reduced oxidative stress injury and fibrosis in the liver (51).

3.2. Human Studies

Although there are some studies that have shown that NS consumption ameliorates some NAFLD risk factors such as fasting blood glucose and lipid profile (52), we could find only one study that evaluated the effects of NS on human subjects with NAFLD (53). This study evaluated the effects of 12 weeks of supplementation with 2 g/day of NS on body weight and liver enzymes. Although the study suffered from several limitations, it showed promising effects. Further well-designed studies are required in this regard to draw any conclusions.

3.3. Possible Mechanism of Action

It seems that NS improves lipid profile and glycemic indices through its anti-oxidative and insulin sensitizer properties. The main antioxidant components of NS are TQ and dithymoquinone (54). TQ can scavenge free radicals in different body tissues such as the liver (55). Moreover, NS contains other antioxidant agents such as tocopherols, phytosterols, and polyunsaturated fatty acids, which can protect cholesterol molecules from oxidation and inhibit the process of atherosclerosis (1). Anti-oxidative action of NS induces pancreatic beta cell regeneration and rise in their integrity, which result in more insulin secretion and less insulin resistance (56, 57).

Moreover, NS reduces glucose absorption by the inhibition of sodium–glucose co-transporter (58). All of these lead to reduction in insulin resistance and its related metabolic disturbances. Furthermore, it has been shown that NS can decline gluconeogenesis through reduction in gluconeogenic enzymes gene expression by TQ (59). Moreover, it has been shown that TQ up-regulates LDL-C receptors on hepatocytes to reduce the uptake of LDL-C; it also reduces the production of cholesterol by the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CO-A) reductase (60).

Another proposed mechanism for the beneficial effects of NS on NAFLD risk factors is through its effects on weight management. One-month supplementation of NS extract caused a significant reduction in food consumption and body weight in experimental models and human studies (61).

4. Conclusions

Results from available studies indicate that NS can ameliorate the main metabolic disturbances related to NAFLD including hyperglycemia, hyperlipidemia and overweight. These effects are mainly attributed to anti-oxidative and anti-inflammatory properties of TQ. Clinical trials on human subjects are highly essential to confirm the results found in in vivo and in vitro studies.


  • 1.

    Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009;13(1):9-19. [PubMed ID: 19240815]. [PubMed Central ID: PMC2633261].

  • 2.

    Bagheri Lankarani K, Ghaffarpasand F, Mahmoodi M, Lotfi M, Zamiria N, Heydari ST, et al. Non alcoholic fatty liver disease in southern Iran: a population based study. Hepat Mon. 2013;13(5).

  • 3.

    Feridouni F, Geramizadeh B, Sepehrimanesh M, Safarpour AR, Fattahi MR. Histologically proved cytomegalovirus as a terrible and neglect disease: a 13-year report of gastrointestinal and hepatobiliary manifestations from single referral center. Comparat Clin Pathol. 2017;26(6):1253-7.

  • 4.

    Shamsdin SA, Sepehrimanesh M, Pezeshki B, Nejabat M. [Seroprevalence of hepatitis B and C in patients with hemophilia: a single-centre descriptive study]. Shiraz E-Med J. 2015;16(7). Persian.

  • 5.

    Sima H, Hekmatdoost A, Ghaziani T, Alavian SM, Mashayekh A, Zali MR. The prevalence of celiac autoantibodies in hepatitis patients. Iran J Allergy Asthma Immunol. 2010;9(3):157-62. [PubMed ID: 20952805].

  • 6.

    Mohamed WS, Mostafa AM, Mohamed KM, Serwah AH. Effects of fenugreek, Nigella, and termis seeds in nonalcoholic fatty liver in obese diabetic albino rats. Arab J Gastroenterol. 2015;16(1):1-9. [PubMed ID: 25670619].

  • 7.

    Jegatheesan P, De Bandt JP. Fructose and NAFLD: the multifaceted aspects of fructose metabolism. Nutrients. 2017;9(3). [PubMed ID: 28273805]. [PubMed Central ID: PMC5372893].

  • 8.

    Xiao J, Ching YP, Liong EC, Nanji AA, Fung ML, Tipoe GL. Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model. Eur J Nutr. 2013;52(1):179-91. [PubMed ID: 22278044]. [PubMed Central ID: PMC3549410].

  • 9.

    Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol. 2005;16(4):421-7. [PubMed ID: 15990591].

  • 10.

    Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013;10(6):330-44. [PubMed ID: 23507799].

  • 11.

    Serfaty L, Lemoine M. Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. Diabetes Metabol. 2008;34(6):634-7.

  • 12.

    Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM. 2010;103(2):71-83. [PubMed ID: 19914930]. [PubMed Central ID: PMC2810391].

  • 13.

    Abbas AS, Abbasi MH, Malik IA, Sheikh N. Non-alcoholic fatty liver disease and associated changes in serum hepcidin, iron, ferritin-r levels and total iron binding capacity in weaning wistar rats (rattus norvegicus). J Anim Plant Sci. 2014;24(2):418-24.

  • 14.

    Fan JG, Kim SU, Wong VWS. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67(4):862-73.

  • 15.

    Fattahi MR, Niknam R, Safarpour A, Sepehrimanesh M, Lotfi M. The prevalence of metabolic syndrome in non-alcoholic fatty liver disease; a population-based study. Middle East J Dig Dis. 2016;8(2):131-7. [PubMed ID: 27252820]. [PubMed Central ID: PMC4885612].

  • 16.

    Rojhani-Shirazi Z, Amini M, Meftahi N, Sepehrimanesh M, Poorbaghi SL, Vafa L. Comparison of anthropometric measures in people with and without short- and long-term complications after laparoscopic sleeve gastrectomy. Comparat Clin Pathol. 2017;26(6):1375-9.

  • 17.

    Heshmati J, Namazi N. Effects of black seed (Nigella sativa) on metabolic parameters in diabetes mellitus: a systematic review. Complement Ther Med. 2015;23(2):275-82. [PubMed ID: 25847566].

  • 18.

    Mahdavi R, Heshmati J, Namazi N. Effects of black seeds (Nigella sativa) on male infertility: a systematic review. J Herb Med. 2015;5(3):133-9.

  • 19.

    Golparvar AR, Hadipanah A, Gheisari MM. Chemical analysis and identification of the components of two ecotypes of (Mentha Longifolia L.) in Iran province. Int J Agricult Crop Sci. 2013;5(17):1946.

  • 20.

    Shuid AN, Mohamed N, Mohamed IN, Othman F, Suhaimi F, Mohd Ramli ES, et al. Nigella sativa: a potential antiosteoporotic agent. Evidence-Based Complementary and Altern Med. 2012;2012.

  • 21.

    Toma CC, Olah NK, Vlase L, Mogosan C, Mocan A. Comparative studies on polyphenolic composition, antioxidant and diuretic effects of Nigella sativa L. (black cumin) and nigella damascena l. (lady-in-a-mist) seeds. Molecules. 2015;20(6):9560-74. [PubMed ID: 26016547].

  • 22.

    Mohammed NK, Manap A, Yazid M, Tan CP, Muhialdin BJ, Alhelli AM, et al. The effects of different extraction methods on antioxidant properties, chemical composition, and thermal behavior of black seed (Nigella sativa L.) oil. Evidence-Based Complementary and Altern Med. 2016;2016.

  • 23.

    Asgary S, Sahebkar A, Goli-Malekabadi N. Ameliorative effects of Nigella sativa on dyslipidemia. J Endocrinol Invest. 2015;38(10):1039-46. [PubMed ID: 26134064].

  • 24.

    Samir Bashandy AE. Effect of fixed oil of Nigella sativa on male fertility in normal and hyperlipidemic rats. Int J Pharmacol. 2007;3(1):27-33.

  • 25.

    Kooti W, Hasanzadeh-Noohi Z, Sharafi-Ahvazi N, Asadi-Samani M, Ashtary-Larky D. Phytochemistry, pharmacology, and therapeutic uses of black seed ( Nigella sativa ). Chinese J Natur Med. 2016;14(10):732-45.

  • 26.

    Al-Jassir MS. Chemical composition and microflora of black cumin (Nigella sativa L.) seeds growing in Saudi Arabia. Food Chem. 1992;45(4):239-42.

  • 27.

    Khan MA. Chemical composition and medicinal properties of Nigella sativa Linn. Inflammopharmacology. 1999;7(1):15-35. [PubMed ID: 17657444].

  • 28.

    Askari F, Rashidkhani B, Hekmatdoost A. Cinnamon may have therapeutic benefits on lipid profile, liver enzymes, insulin resistance, and high-sensitivity C-reactive protein in nonalcoholic fatty liver disease patients. Nutr Res. 2014;34(2):143-8. [PubMed ID: 24461315].

  • 29.

    Emamat H, Foroughi F, Eini-Zinab H, Hekmatdoost A. The effects of onion consumption on prevention of nonalcoholic fatty liver disease. India J Clin Biochem. 2018;33(1):75-80.

  • 30.

    Emamat H, Foroughi F, Eini-Zinab H, Taghizadeh M, Rismanchi M, Hekmatdoost A. The effects of onion consumption on treatment of metabolic, histologic, and inflammatory features of nonalcoholic fatty liver disease. J Diabetes Metab Disord. 2015;15:25. [PubMed ID: 27453880]. [PubMed Central ID: PMC4957858].

  • 31.

    Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr. 2014;99(3):535-42. [PubMed ID: 24401715].

  • 32.

    Faghihzadeh F, Adibi P, Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Br J Nutr. 2015;114(5):796-803. [PubMed ID: 26234526].

  • 33.

    Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res. 2014;34(10):837-43. [PubMed ID: 25311610].

  • 34.

    Ghaemi A, Taleban FA, Hekmatdoost A, Rafiei A, Hosseini V, Amiri Z, et al. How much weight loss is effective on nonalcoholic fatty liver disease? Hepat Mon. 2013;13(12). e15227. [PubMed ID: 24358045]. [PubMed Central ID: PMC3867211].

  • 35.

    Hekmatdoost A, Shamsipour A, Meibodi M, Gheibizadeh N, Eslamparast T, Poustchi H. Adherence to the dietary approaches to stop hypertension (dash) and risk of nonalcoholic fatty liver disease. Int J Food Sci Nutr. 2016;67(8):1024-9. [PubMed ID: 27436528].

  • 36.

    Mofidi F, Poustchi H, Yari Z, Nourinayyer B, Merat S, Sharafkhah M, et al. Synbiotic supplementation in lean patients with non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-controlled, clinical trial. Brit J Nutrit. 2017;117(5):662-8.

  • 37.

    Mokhtari Z, Gibson DL, Hekmatdoost A. Nonalcoholic fatty liver disease, the gut microbiome, and diet. Adv Nutr. 2017;8(2):240-52. [PubMed ID: 28298269]. [PubMed Central ID: PMC5347097].

  • 38.

    Mokhtari Z, Poustchi H, Eslamparast T, Hekmatdoost A. Egg consumption and risk of non-alcoholic fatty liver disease. World J Hepatol. 2017;9(10):503-9. [PubMed ID: 28443155]. [PubMed Central ID: PMC5387362].

  • 39.

    Noori M, Jafari B, Hekmatdoost A. Pomegranate juice prevents development of non-alcoholic fatty liver disease in rats by attenuating oxidative stress and inflammation. J Sci Food Agric. 2017;97(8):2327-32. [PubMed ID: 27717115].

  • 40.

    Yari Z, Rahimlou M, Eslamparast T, Ebrahimi-Daryani N, Poustchi H, Hekmatdoost A. Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study. Int J Food Sci Nutr. 2016;67(4):461-9. [PubMed ID: 26983396].

  • 41.

    Kanter M, Akpolat M, Aktas C. Protective effects of the volatile oil of Nigella sativa seeds on beta-cell damage in streptozotocin-induced diabetic rats: a light and electron microscopic study. J Mol Histol. 2009;40(5-6):379-85. [PubMed ID: 20049514].

  • 42.

    Mansi KMS. Effects of oral administration of water extract of Nigella sativa on serum concentrations of insulin and testosterone in alloxan-induced diabetic rats. Pakistan J Biolog Sci. 2005;8(8):1152-6.

  • 43.

    Tembhurne SV, Feroz S, More BH, Sakarkar DM. A review on therapeutic potential of Nigella sativa (kalonji) seeds. J Med Plants Res. 2014;8(3):167-77.

  • 44.

    Ali BH, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 2003;17(4):299-305. [PubMed ID: 12722128].

  • 45.

    Bai T, Lian LH, Wu YL, Wan Y, Nan JX. Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells. Int Immunopharmacol. 2013;15(2):275-81. [PubMed ID: 23318601].

  • 46.

    Yang Y, Bai T, Yao YL, Zhang DQ, Wu YL, Lian LH, et al. Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicol Lett. 2016;262:80-91. [PubMed ID: 27688165].

  • 47.

    Sultan MT, Butt MS, Karim R, Iqbal SZ, Ahmad S, Zia-Ul-Haq M, et al. Effect of Nigella sativa fixed and essential oils on antioxidant status, hepatic enzymes, and immunity in streptozotocin induced diabetes mellitus. BMC Complement Altern Med. 2014;14:193. [PubMed ID: 24939518]. [PubMed Central ID: PMC4077235].

  • 48.

    Meral I, Yener Z, Kahraman T, Mert N. Effect of Nigella sativa on glucose concentration, lipid peroxidation, anti-oxidant defence system and liver damage in experimentally-induced diabetic rabbits. J Vet Med A Physiol Pathol Clin Med. 2001;48(10):593-9. [PubMed ID: 11848252].

  • 49.

    Awad AS, Abd Al Haleem EN, El-Bakly WM, Sherief MA. Thymoquinone alleviates nonalcoholic fatty liver disease in rats via suppression of oxidative stress, inflammation, apoptosis. Naunyn Schmiedebergs Arch Pharmacol. 2016;389(4):381-91. [PubMed ID: 26753695].

  • 50.

    Oguz S, Kanter M, Erboga M, Erenoglu C. Protective effects of thymoquinone against cholestatic oxidative stress and hepatic damage after biliary obstruction in rats. J Mol Histol. 2012;43(2):151-9. [PubMed ID: 22270828].

  • 51.

    Kong LY, Li GP, Yang P, Xi Z. Protective effect of thymoquinone on cholestatic rats with liver injury. Genet Mol Res. 2015;14(4):12247-53. [PubMed ID: 26505373].

  • 52.

    Najmi A, Nasiruddin M, Khan RA, Haque SF. Effect of Nigella sativa oil on various clinical and biochemical parameters of insulin resistance syndrome. Int J Diabetes Dev Ctries. 2008;28(1):11-4. [PubMed ID: 19902033]. [PubMed Central ID: PMC2772004].

  • 53.

    Hussain M, Tunio AG, Akhtar L, Shaikh GS. Effects of nigella sativa on various parameters in Patients of non-alcoholic fatty liver disease. J Ayub Med Coll Abbottabad. 2017;29(3):403-7. [PubMed ID: 29076670].

  • 54.

    Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol. 2005;5(13-14):1749-70. [PubMed ID: 16275613].

  • 55.

    Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol. 2003;26(2):87-98. [PubMed ID: 12816394].

  • 56.

    Kaleem M, Kirmani D, Asif M, Ahmed Q, Bano B. Biochemical effects of Nigella sativa L seeds in diabetic rats. CSIR. 2006.

  • 57.

    Alimohammadi S, Hobbenaghi R, Javanbakht J, Kheradmand D, Mortezaee R, Tavakoli M, et al. 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. 2013;8:137. [PubMed ID: 23947821]. [PubMed Central ID: PMC3849825].

  • 58.

    Meddah B, Ducroc R, El Abbes Faouzi M, Eto B, Mahraoui L, Benhaddou-Andaloussi A, et al. Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. J Ethnopharmacol. 2009;121(3):419-24. [PubMed ID: 19061948].

  • 59.

    Houcher Z, Boudiaf K, Benboubetra M, Houcher B. Effects of methanolic extract and commercial oil of Nigella sativa l. on blood glucose and antioxidant capacity in alloxan-induced diabetic rats. Pteridines. 2007;18(1).

  • 60.

    Fararh KM, Ibrahim AK, Elsonosy YA. Thymoquinone enhances the activities of enzymes related to energy metabolism in peripheral leukocytes of diabetic rats. Res Vet Sci. 2010;88(3):400-4. [PubMed ID: 19931880].

  • 61.

    Mohtashami A, Entezari MH. Effects of Nigella sativa supplementation on blood parameters and anthropometric indices in adults: a systematic review on clinical trials. J Res Med Sci. 2016;21:3. [PubMed ID: 27904549]. [PubMed Central ID: PMC5122217].

Copyright © 2018, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.