رویکردها و اثرات درمانی زعفران (Crocus sativus L.) و زرشک (Berberis vulgaris) در درمان و پیشگیری از بیماری ها: مروری

Subject Areas : Journal of Medicinal Herbs, "J. Med Herb" (Formerly known as Journal of Herbal Drugs or J. Herb Drug)

محمد  سعیدی ¹ (گروه علوم آزمایشگاهی، دانشکده پزشکی، دانشگاه علوم پزشکی سمنان، سمنان، ایران.)

Received: 2021-03-09 Accepted : 2021-07-11 Published : 2021-09-23

Keywords: Natural compounds, Traditional medicine, Therapeutic effects, Saffron (Crocus sativus L.), Barberry (Berberis vulgaris),

Abstract :

Background & Aim: Natural compounds as drugs have fewer and more cost-effective side effects that can be utilized as pharmacological and therapeutic approaches. Traditional medicine can be an efficacious resource in the development of research to treat diseases.Experimental: In this review article, keywords including Saffron (Crocus sativus L.), Barberry (Berberis vulgaris), and their medicinal attributes were searched in prominent databases (such as Scopus, and Web of Science, etc.) and professional websites to collect the medicinal properties of Saffron, and Barberry.Results: Saffron is one of the most important natural compounds that has a wide range of utilizations in traditional medicine and has effects such as anti-cancer, anti-depressant, antispasmodic, nerve sedative, appetizer and also barberry is another natural substance that has considerable influences such as anti-arrhythmia, sedative, reducing blood pressure (BP) and anti-cancer. Saffron and its bioactive components have been revealed to have anti-neurodegenerative influences.Recommended applications/industries: In the present review article, we have made an endeavor to explore approach and therapeutic effects of Saffron and Barberry in the treatment of diseases in clinical trials and animal model studies. Research in clinical trials promising findings that support the role of barberry and saffron in ameliorating disease and safety, although more research is needed to prove their role in treating the disease.

References:

Abdel-Rahman, R. F., S. A. El Awdan, R. R. Hegazy, D. F. Mansour, H. Ogaly and M. Abdelbaset. 2020. Neuroprotective effect of Crocus sativus against cerebral ischemia in rats. Metabolic Brain Disease, 35(3): 427-439.

Abe, K., M. Sugiura, Y. Shoyama and H. Saito. 1998. Crocin antagonizes ethanol inhibition of NMDA receptor-mediated responses in rat hippocampal neurons. Brain Research, 787(1): 132-138.

Abedimanesh, N., B. Motlagh, S. Abedimanesh, S. Z. Bathaie, A. Separham and A. Ostadrahimi. 2020. Effects of crocin and saffron aqueous extract on gene expression of SIRT1, AMPK, LOX1, NF‐κB, and MCP‐1 in patients with coronary artery disease: A randomized placebo‐controlled clinical trial. Phytotherapy Research, 34(5): 1114-1122.

Aggarwal, B., S. Prasad, B. Sung, S. Krishnan and S. Guha. 2013. Prevention and treatment of colorectal cancer by natural agents from mother nature. Current Colorectal Cancer Reports, 9(1): 37-56.

Ahmad, A. S., M. A. Ansari, M. Ahmad, S. Saleem, S. Yousuf, M. N. Hoda and F. Islam. 2005. Neuroprotection by crocetin in a hemi-parkinsonian rat model. Pharmacology Biochemistry and Behavior, 81(4): 805-813.

Akhondzadeh, S., M. S. Sabet, M. H. Harirchian, M. Togha, H. Cheraghmakani, S. Razeghi, S. S. Hejazi, M. H. Yousefi, R. Alimardani and A. Jamshidi. 2010. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology, 207(4): 637-643.

Amin, A., A. Farrukh, C. Murali, A. Soleimani, F. Praz, G. Graziani, H. Brim and H. Ashktorab. 2021. Saffron and Its Major Ingredients’ Effect on Colon Cancer Cells with Mismatch Repair Deficiency and Microsatellite Instability. Molecules, 26(13): 3855.

Aryaeian, N., M. Hadidi, M. Mahmoudi, M. Asgari, Z. S. Hezaveh and S. K. Sadehi. 2021. The effect of black barberry hydroalcoholic extract on immune mediators in patients with active rheumatoid arthritis: A randomized, double–blind, controlled clinical trial. Phytotherapy Research, 35(2): 1062-1068.

Ashktorab, H., A. Soleimani, G. Singh, A. Amin, S. Tabtabaei, G. Latella, U. Stein, S. Akhondzadeh, N. Solanki and M. C. Gondré-Lewis. 2019. Saffron: the golden spice with therapeutic properties on digestive diseases. Nutrients, 11(5): 943.

Azimi, P., R. Ghiasvand, A. Feizi, M. Hariri and B. Abbasi. 2014. Effects of cinnamon, cardamom, saffron, and ginger consumption on markers of glycemic control, lipid profile, oxidative stress, and inflammation in type 2 diabetes patients. The Review of Diabetic Studies: RDS, 11(3): 258.

Babaei, A., J. Arshami, A. Haghparast and M. D. Mesgaran. 2014. Effects of saffron (Crocus sativus) petal ethanolic extract on hematology, antibody response, and spleen histology in rats. Avicenna Journal of Phytomedicine, 4(2): 103.

Bandegi, A. R., A. Rashidy-Pour, A. A. Vafaei and B. Ghadrdoost. 2014. Protective effects of Crocus sativus L. extract and crocin against chronic-stress induced oxidative damage of brain, liver and kidneys in rats. Advanced Pharmaceutical Bulletin 4, (Suppl 2): 493.

Bhargava, V. 2011. Medicinal uses and pharmacological properties of Crocus sativus Linn (Saffron). International Journal of Pharmacy and Pharmaceutical Sciences,  3(3).

Bhat, J. and R. Broker 1953). Riboflavine and thiamine contents of saffron, Crocus sativus linn. Nature 172(4377): 544-544.

Borghi, C., K. Tsioufis, E. Agabiti-Rosei, M. Burnier, A. F. Cicero, D. Clement, A. Coca, G. Desideri, G. Grassi and D. Lovic. 2020. Nutraceuticals and blood pressure control: a European Society of Hypertension position document. Journal of Hypertension, 38(5): 799-812.

Caliceti, C., P. Rizzo and A. F. G. Cicero. 2015. Potential benefits of berberine in the management of perimenopausal syndrome. Oxidative Medicine and Cellular longevity, 2015.

Christodoulou, E., N.P. Kadoglou, N. Kostomitsopoulos and G. Valsami. 2015. Saffron: a natural product with potential pharmaceutical applications. Journal of Pharmacy and Pharmacology, 67(12): 1634-1649.

Chun, Y., T. Yip, K. Lau, Y. Kong and U. Sankawa. 1979. A biochemical study on the hypotensive effect of berberine in rats. General Pharmacology: The Vascular System 10(3): 177-182.

Cicero, A. F. and S. Ertek. 2009. Berberine: metabolic and cardiovascular effects in preclinical and clinical trials. Nutrition and Dietary Supplements, 1(2): 1-10.

Cicero, A. F., F. Fogacci, G. Tocci, F. Ventura, V. Presta, E. Grandi, E. Rizzoli, S. D'Addato, C. Borghi and A. Cicero. 2020. Awareness of major cardiovascular risk factors and its relationship with markers of vascular aging: Data from the Brisighella Heart Study. Nutrition, Metabolism and Cardiovascular Diseases, 30(6): 907-914.

Der Marderosian, A. 2001. The Review of Natural Products: The Most Complete Source of Natural Product Information. 1. St. Louis, Missouri: Wolters Kluwer Health.

Duan, K., A. Vrieling, H. Kaveh and R. Darvishzadeh. 2021. Mapping saffron fields and their ages with Sentinel-2 time series in north-east Iran. International Journal of Applied Earth Observation and Geoinformation, 102: 102398.

Ebrahimi, F., A. Sahebkar, N. Aryaeian, N. Pahlavani, S. Fallah, N. Moradi, D. Abbasi and A. F. Hosseini. 2019. Effects of saffron supplementation on inflammation and metabolic responses in type 2 diabetic patients: A randomized, double-blind, placebo-controlled trial. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 12: 2107.

Edamula, R., M. Deecaraman, D. Kumar, H. Krishnamurthy and M. Latha. 2014. Prenatal developmental toxicity of crocus sativus (saffron) in wistar rats. International Journal of Pharmacology and Toxicology, 2(2): 46-49.

EL-Maraghy, S. A., S. M. Rizk and M. M. El-Sawalhi. 2009. Hepatoprotective potential of crocin and curcumin against iron overload-induced biochemical alterations in rat. African Journal of Biochemistry Research, 3(5): 215-221.

Emamat, H., S. Asadian, A. Zahedmehr, M. Ghanavati and J. Nasrollahzadeh. 2021. The effect of barberry (Berberis vulgaris) consumption on flow‐mediated dilation and inflammatory biomarkers in patients with hypertension: A randomized controlled trial. Phytotherapy Research, 35(5): 2607-2615.

Fatehi, M., T.M. Saleh, Z. Fatehi-Hassanabad, K. Farrokhfal, M. Jafarzadeh and S. Davodi. 2005. A pharmacological study on Berberis vulgaris fruit extract. Journal of Ethnopharmacology, 102(1): 46-52.

Fukuda, K., Y. Hibiya, M. Mutoh, M. Koshiji, S. Akao and H. Fujiwara. 1999. Inhibition of activator protein 1 activity by berberine in human hepatoma cells. Planta Medica, 65(04): 381-383.

Ghaderi, A., M. Rasouli‐Azad, N. Vahed, H. R. Banafshe, A. Soleimani, A. Omidi, F. S. Ghoreishi and Z. Asemi. 2019. Clinical and metabolic responses to crocin in patients under methadone maintenance treatment: A randomized clinical trial. Phytotherapy Research, 33(10): 2714-2725.

Ghadrdoost, B., A.A. Vafaei, A. Rashidy-Pour, R. Hajisoltani, A.R. Bandegi, F. Motamedi, S. Haghighi, H.R. Sameni and S. Pahlvan. 2011. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. European Journal of Pharmacology, 667(1-3): 222-229.

Ghaffari, S. and N. Roshanravan. 2019. Saffron; An updated review on biological properties with special focus on cardiovascular effects. Biomedicine & Pharmacotherapy, 109: 21-27.

Ghiasian, M., F. Khamisabadi, N. Kheiripour, M. Karami, R. Haddadi, A. Ghaleiha, B. Taghvaei, S. S. Oliaie, M. Salehi and P. Samadi. 2019. Effects of crocin in reducing DNA damage, inflammation, and oxidative stress in multiple sclerosis patients: A double‐blind, randomized, and placebo‐controlled trial. Journal of Biochemical and Molecular Toxicology, 33(12): e22410.

Giaccio, M. 2004. Crocetin from saffron: an active component of an ancient spice. Critical Reviews in Food Science and Nutrition 44(3): 155-172.

Gohari, A. R., S. Saeidnia and M. K. Mahmoodabadi. 2013. An overview on saffron, phytochemicals, and medicinal properties. Pharmacognosy Reviews, 7(13): 61.

Gundogdu, M. 2013. Determination of antioxidant capacities and biochemical compounds of Berberis vulgaris L. fruits. Advances in Environmental Biology, 7(2): 344-348.

Hadi, A., A. Arab, E. Ghaedi, N. Rafie, M. Miraghajani and M. Kafeshani. 2019. Barberry (Berberis vulgaris L.) is a safe approach for management of lipid parameters: A systematic review and meta‐analysis of randomized controlled trials. Complementary Therapies in Medicine, 43: 117-124.

Hamidi, Z., N. Aryaeian, J. Abolghasemi, F. Shirani, M. Hadidi, S. Fallah and N. Moradi. 2020. The effect of saffron supplement on clinical outcomes and metabolic profiles in patients with active rheumatoid arthritis: A randomized, double‐blind, placebo‐controlled clinical trial. Phytotherapy Research, 34(7): 1650-1658.

Hasani, H., A. Arab, A. Hadi, M. Pourmasoumi, A. Ghavami and M. Miraghajani. 2019. Does ginger supplementation lower blood pressure? A systematic review and meta‐analysis of clinical trials. Phytotherapy Research, 33(6): 1639-1647.

Heitmar, R., J. Brown and I. Kyrou. 2019. Saffron (Crocus sativus L.) in ocular diseases: A narrative review of the existing evidence from clinical studies. Nutrients, 11(3): 649.

Hensel, A., M. Niehues, M. Lechtenberg, B. Quandt, D. Schepmann and B. Wünsch. 2006. Analytical and functional aspects on Saffron from Crocus sativus L.: development of quality control methods, species assortment and affinity to sigma-1 and NMDA receptors. Planta Medica, 72(11): P_074.

Hosseinzadeh, H., H. R. Sadeghnia, F. A. Ghaeni, V. S. Motamedshariaty and S. A. Mohajeri. 2012. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytotherapy Research, 26(3): 381-386.

Husaini, A. M., K. N. Jan and G. A. Wani. 2021. Saffron: A potential drug-supplement for severe acute respiratory syndrome coronavirus (COVID) management. Heliyon: e07068.

Inoue, E., Y. Shimizu, M. Shoji, H. Tsuchida, Y. Sano and C. Ito. 2005. Pharmacological properties of N-095, a drug containing red ginseng, polygala root, saffron, antelope horn and aloe wood. The American Journal of Chinese Medicine, 33(01): 49-60.

José Bagur, M., G. L. Alonso Salinas, A. M. Jiménez-Monreal, S. Chaouqi, S. Llorens, M. Martínez-Tomé and G. L. Alonso. 2018. Saffron: An old medicinal plant and a potential novel functional food. Molecules, 23(1): 30.

Kalmarzi, R. N., S. N. Naleini, D. Ashtary-Larky, I. Peluso, L. Jouybari, A. Rafi, F. Ghorat, N. Heidari, F. Sharifian and J. Mardaneh. 2019. Anti-inflammatory and immunomodulatory effects of barberry (Berberis vulgaris) and its main compounds. Oxidative Medicine and Cellular longevity, 2019.

Kanakis, C., P. Tarantilis, C. Pappas, J. Bariyanga, H. Tajmir-Riahi and M. Polissiou. 2009. An overview of structural features of DNA and RNA complexes with saffron compounds: Models and antioxidant activity. Journal of Photochemistry and Photobiology B: Biology, 95(3): 204-212.

Kanakis, C. D., D. J. Daferera, P. A. Tarantilis and M. G. Polissiou. 2004. Qualitative determination of volatile compounds and quantitative evaluation of safranal and 4-hydroxy-2, 6, 6-trimethyl-1-cyclohexene-1-carboxaldehyde (HTCC) in Greek saffron. Journal of Agricultural and Food Chemistry, 52(14): 4515-4521.

Karami, M., M. Sepehrimanesh, O. Koohi-Hosseinabadi, M. Fattahi, I. R. Jahromi, M. Mokhtari and M. V. Farahani. 2016. Therapeutic effects of hydroalcoholic and aqueous extracts of Berberis vulgaris fruits in streptozotocin induced type 1 diabetes mellitus rats. Romanian Journal of Diabetes Nutrition and Metabolic Diseases, 23(3): 239-245.

Karimi, G., N. Taiebi, H. Hosseinzadeh and F. Shirzad. 2004. Evaluation of subacute toxicity of aqueous extract of Crocus sativus L. stigma and petal in rats. Journal of Medicinal Plants, 3(12): 29-35.

Kario, K., J. A. Chirinos, R. R. Townsend, M. A. Weber, A. Scuteri, A. Avolio, S. Hoshide, T. Kabutoya, H. Tomiyama and K. Node. 2020. Systemic hemodynamic atherothrombotic syndrome (SHATS)–coupling vascular disease and blood pressure variability: proposed concept from Pulse of Asia. Progress in Cardiovascular Diseases, 63(1): 22-32.

Kashani, L., F. Raisi, S. Saroukhani, H. Sohrabi, A. Modabbernia, A. A. Nasehi, A. Jamshidi, M. Ashrafi, P. Mansouri and P. Ghaeli. 2013. Saffron for treatment of fluoxetine‐induced sexual dysfunction in women: randomized double‐blind placebo‐controlled study. Human Psychopharmacology: Clinical and Experimental, 28(1): 54-60.

Kermani, T., T. Kazemi, S. Molki, K. Ilkhani and G. Sharifzadeh. 2020. The Effect of Berberis vulgaris (Barberry Fruit) on a Component of Metabolic Syndrome: A Randomized Clinical Trial. Modern Care Journal, 17(2).

Kermani, T., T. Kazemi, S. Molki, K. Ilkhani, G. Sharifzadeh and O. Rajabi. 2017. The efficacy of crocin of saffron (Crocus sativus L.) on the components of metabolic syndrome: A randomized controlled clinical trial. Journal of Research in Pharmacy Practice, 6(4): 228.

Kiashemshaki, B., H.-A. Safakhah, A. Ghanbari, A. Khaleghian and H. Miladi-Gorji. 2021. Saffron (Crocus sativus L.) stigma reduces symptoms of morphine-induced dependence and spontaneous withdrawal in rats. The American Journal of Drug and Alcohol Abuse, 47(2): 170-181.

Končić, M. Z., D. Kremer, K. Karlović and I. Kosalec. 2010. Evaluation of antioxidant activities and phenolic content of Berberis vulgaris L. and Berberis croatica Horvat. Food and Chemical Toxicology, 48(8-9): 2176-2180.

Kumar, V., Z. Bhat, D. Kumar, N. Khan, I. Chashoo and M. Shah. 2011. Pharmacological profile of crocus sativus-a comprehe sive review. Pharmacologyonline, 3: 799-811.

Lautenschläger, M., J. Sendker, S. Hüwel, H. Galla, S. Brandt, M. Düfer, K. Riehemann and A. Hensel. 2015. Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier. Phytomedicine, 22(1): 36-44.

lazavi, f., p. mirmiran, G. Sohrab, N. Eshkevari, M. Hedayati and s. S. Akbarpour. 2016. Effect of barberry juice consumption on blood pressure in patients with type 2 diabetes. Pejouhesh dar Pezeshki (Research in Medicine), 39(4): 183-188.

Lazavi, F., P. Mirmiran, G. Sohrab, O. Nikpayam, P. Angoorani and M. Hedayati. 2018. The barberry juice effects on metabolic factors and oxidative stress in patients with type 2 diabetes: a randomized clinical trial. Complementary Therapies in Clinical Practice, 31: 170-174.

Lee, I.-A., J. H. Lee, N.-I. Baek and D.-H. Kim 2005). Antihyperlipidemic effect of crocin isolated from the fructus of Gardenia jasminoides and its metabolite crocetin. Biological and Pharmaceutical Bulletin, 28(11): 2106-2110.

Liu, C.-S., Y.-R. Zheng, Y.-F. Zhang and X.-Y. Long. 2016. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia, 109: 274-282.

Lopresti, A. L. and P. D. Drummond. 2017. Efficacy of curcumin, and a saffron/curcumin combination for the treatment of major depression: A randomised, double-blind, placebo-controlled study. Journal of Affective Disorders, 207: 188-196.

Lopresti, A. L. and S. J. Smith. 2021. The Effects of a Saffron Extract (affron®) on Menopausal Symptoms in Women during Perimenopause: A Randomised, Double-Blind, Placebo-Controlled Study. Journal of Menopausal Medicine, 27.

Luqman, S., S. I. Rizvi, A.-M. Beer, S. K. Khare and P. Atukeren. 2014. Efficacy of herbal drugs in human diseases and disorders, Hindawi.

Mahdavi, N., S. Joukar, H. Najafipour and M. Asadi-Shekaari. 2016. The promising effect of barberry (Zereshk) extract against experimental pulmonary microvascular remodeling and hypertension: A comparison with sildenafil. Pharmaceutical Biology, 54(3): 509-515.

Marin‐Neto, J., B. Maciel, A. Secches and L. Gallo 1988). Cardiovascular effects of berberine in patients with severe congestive heart failure. Clinical Cardiology, 11(4): 253-260.

Mazidi, M., M. Shemshian, S. H. Mousavi, A. Norouzy, T. Kermani, T. Moghiman, A. Sadeghi, N. Mokhber, M. Ghayour-Mobarhan and G. A. Ferns. 2016. A double-blind, randomized and placebo-controlled trial of Saffron (Crocus sativus L.) in the treatment of anxiety and depression. Journal of Complementary and Integrative Medicine, 13(2): 195-199.

Mentis, A.-F. A.. 2021. What neurological and psychiatric effects does COVID-19 have on its survivors? BMC Medicine, 19(1): 1-3.

Mentis, A.-F. A., E. Dardiotis, E. Katsouni and G. P. Chrousos. 2021. From warrior genes to translational solutions: novel insights into monoamine oxidases (MAOs) and aggression. Translational Psychiatry, 11(1): 1-11.

Mirenayat, M. S., S. Moradi, H. Mohammadi and M. H. Rouhani. 2018. Effect of L-Citrulline supplementation on blood pressure: a systematic review and meta-analysis of clinical trials. Current Hypertension Reports, 20(11): 1-8.

Moallem, S. A., M. Afshar, L. Etemad, B. M. Razavi and H. Hosseinzadeh. 2016. Evaluation of teratogenic effects of crocin and safranal, active ingredients of saffron, in mice. Toxicology and Industrial Health, 32(2): 285-291.

Moallem, S. A., A. T. Hariri, M. Mahmoudi and H. Hosseinzadeh. 2014. Effect of aqueous extract of Crocus sativus L. (saffron) stigma against subacute effect of diazinon on specific biomarkers in rats. Toxicology and Industrial Health, 30(2): 141-146.

Mobasseri, M., A. Ostadrahimi, A. Tajaddini, S. Asghari, M. Barati, M. Akbarzadeh, O. Nikpayam, J. Houshyar, N. Roshanravan and N. M. Alamdari. 2020. Effects of saffron supplementation on glycemia and inflammation in patients with type 2 diabetes mellitus: A randomized double-blind, placebo-controlled clinical trial study. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 14(4): 527-534.

Modabbernia, A., H. Sohrabi, A.-A. Nasehi, F. Raisi, S. Saroukhani, A. Jamshidi, M. Tabrizi, M. Ashrafi and S. Akhondzadeh. 2012. Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology, 223(4): 381-388.

Moghadam, B. H., R. Bagheri, B. Roozbeh, D. Ashtary-Larky, A. A. Gaeini, F. Dutheil and A. Wong. 2021. Impact of saffron (Crocus Sativus Linn) supplementation and resistance training on markers implicated in depression and happiness levels in untrained young males. Physiology & Behavior, 233: 113352.

Mohamadpour, A. H., Z. Ayati, M. R. Parizadeh, O. Rajbai and H. Hosseinzadeh. 2013. Safety evaluation of crocin (a constituent of saffron) tablets in healthy volunteers. Iranian Journal of Basic Medical Sciences, 16(1): 39.

Mohebbati, R., Y. Kamkar-Del, M. N. Shafei, H. Rakhshandeh and A. Aghaei. 2021. Effects of hydroalcoholic extract of saffron petal on blood pressure and heart rate in hypertension induced by angiotensin II and L-NAME in anesthetized rats. Veterinary Research Forum, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Moradzadeh, M., M. R. Kalani and A. Avan (2019). The antileukemic effects of saffron (Crocus sativus L.) and its related molecular targets: A mini review. Journal of Cellular Biochemistry, 120(4): 4732-4738.

Mousavi, B., S. Z. Bathaie, F. Fadai and Z. Ashtari. 2015. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna Journal of Phytomedicine, 5(5): 413.

Mzabri, I., M. Addi and A. Berrichi. 2019. Traditional and modern uses of saffron (Crocus sativus). Cosmetics, 6(4): 63.

Organization, W. H.. 2015. World Health Statistics 2015, World Health Organization.

Pachikian, B. D., S. Copine, M. Suchareau and L. Deldicque. 2021. Effects of Saffron Extract on Sleep Quality: A Randomized Double-Blind Controlled Clinical Trial. Nutrients, 13(5): 1473.

Pirouzpanah, S., S. Asemani, A. Shayanfar, B. Baradaran and V. Montazeri. 2019. The effects of Berberis vulgaris consumption on plasma levels of IGF-1, IGFBPs, PPAR-γ and the expression of angiogenic genes in women with benign breast disease: a randomized controlled clinical trial. BMC Complementary and Alternative Medicine, 19(1): 1-14.

Pour, F. K., N. Aryaeian, M. Mokhtare, R. S. Mirnasrollahi Parsa, L. Jannani, S. Agah, S. Fallah and N. Moradi. 2020. The effect of saffron supplementation on some inflammatory and oxidative markers, leptin, adiponectin, and body composition in patients with nonalcoholic fatty liver disease: A double‐blind randomized clinical trial. Phytotherapy Research, 34(12): 3367-3378.

Rahimi-Madiseh, M., Z. Lorigoini, H. Zamani-Gharaghoshi and M. Rafieian-Kopaei. 2017. Berberis vulgaris: specifications and traditional uses. Iranian Journal of Basic Medical Sciences, 20(5): 569.

Ramezani, F., S. P. H. Shekarabi, M. S. Mehrgan, F. Foroudi and H. R. Islami. 2021. Supplementation of Siberian sturgeon (Acipenser baerii) diet with barberry (Berberis vulgaris) fruit extract: Growth performance, hemato-biochemical parameters, digestive enzyme activity, and growth-related gene expression. Aquaculture, 540: 736750.

Rashidi, H., F. Namjoyan, Z. Mehraban, M. Zakerkish, S. B. Ghaderian and S. M. Latifi. 2018. The effects of active ingredients of barberry root (Berberine) on Glycemic control and insulin resistance in type 2 diabetic patients. Jundishapur Journal of Natural Pharmaceutical Products, 13(1).

Razavi, B. M., H. Hosseinzadeh, K. Abnous and M. Imenshahidi. 2014. Protective effect of crocin on diazinon induced vascular toxicity in subchronic exposure in rat aorta ex-vivo. Drug and Chemical Toxicology, 37(4): 378-383.

Rios, J., M. Recio, R. Giner and S. Manez 1996). An update review of saffron and its active constituents. Phytotherapy Research, 10(3): 189-193.

Roustazade, R., M. Radahmadi and Y. Yazdani. 2021. Therapeutic effects of saffron extract on different memory types, anxiety, and hippocampal BDNF and TNF-α gene expressions in sub-chronically stressed rats. Nutritional Neuroscience, 1-15.

Saeedi, M. and A. Rashidy-Pour. 2021. Association between chronic stress and Alzheimer’s disease: Therapeutic effects of Saffron. Biomedicine & Pharmacotherapy, 133: 110995.

Salehi, B., Z. Selamoglu, B. Sener, M. Kilic, A. Kumar Jugran, N. de Tommasi, C. Sinisgalli, L. Milella, J. Rajkovic and F. B. Morais-Braga. 2019. Berberis plants—drifting from farm to food applications, phytotherapy, and phytopharmacology. Foods, 8(10): 522.

Samarghandian, S., M. E. Shoshtari, J. Sargolzaei, H. Hossinimoghadam and J. A. Farahzad. 2014. Anti-tumor activity of safranal against neuroblastoma cells. Pharmacognosy Magazine 10(Suppl 2): S419.

Shahbazian, H., A. M. Aleali, R. Amani, F. Namjooyan, B. Cheraghian, S. M. Latifi, S. Bahrainian and A. Ghadiri. 2019. Effects of saffron on homocysteine, and antioxidant and inflammatory biomarkers levels in patients with type 2 diabetes mellitus: a randomized double-blind clinical trial. Avicenna Journal of Phytomedicine, 9(5): 436.

Siedlinski, M., E. Jozefczuk, X. Xu, A. Teumer, E. Evangelou, R. B. Schnabel, P. Welsh, P. Maffia, J. Erdmann and M. Tomaszewski. 2020. White blood cells and blood pressure: a Mendelian randomization study. Circulation, 141(16): 1307-1317.

Sohaei, S., R. Amani, M. J. Tarrahi and H. Ghasemi-Tehrani. 2019. The effects of curcumin supplementation on glycemic status, lipid profile and hs-CRP levels in overweight/obese women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled clinical trial. Complementary Therapies in Medicine 47: 102201.

Soheilipur, K., M. R. Khazdair, S. A. Moezi and G. Mahmoudirad. 2021. Comparing the effects of saffron, lippia, and saffron-lippia combination on anxiety among candidates for coronary angiography. Avicenna Journal of Phytomedicine.

Soltani, R., S. M. Ghanadian, B. Iraj, A. Homayouni, T. S. Esfahani and M. Akbari. 2021. The Effects of Berberis integerrima Fruit Extract on Glycemic Control Parameters in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Clinical Trial. Evidence-Based Complementary and Alternative Medicine, 2021.

Sun, W., M. H. Shahrajabian and Q. Cheng. 2021. Barberry (Berberis vulgaris), a medicinal fruit and food with traditional and modern pharmaceutical uses. Israel Journal of Plant Sciences, 1(aop): 1-11.

Tahvilian, N., M. Masoodi, A. Faghihi Kashani, M. Vafa, N. Aryaeian, A. Heydarian, A. Hosseini, N. Moradi and F. Farsi. 2021. Effects of saffron supplementation on oxidative/antioxidant status and severity of disease in ulcerative colitis patients: A randomized, double‐blind, placebo‐controlled study. Phytotherapy Research, 35(2): 946-953.

Tajaddini, A., N. Roshanravan, M. Mobasseri, A. Aeinehchi, P. Sefid‐Mooye Azar, A. Hadi and A. Ostadrahimi. 2021. Saffron improves life and sleep quality, glycaemic status, lipid profile and liver function in diabetic patients: A double‐blind, placebo‐controlled, randomised clinical trial. International Journal of Clinical Practice, e14334.

Tarride, J.-E., M. Lim, M. DesMeules, W. Luo, N. Burke, D. O’Reilly, J. Bowen and R. Goeree (2009). A review of the cost of cardiovascular disease. Canadian Journal of Cardiology, 25(6): e195-e202.

Whelton, P. K., R. M. Carey, W. S. Aronow, D. E. Casey, K. J. Collins, C. Dennison Himmelfarb, S. M. DePalma, S. Gidding, K. A. Jamerson and D. W. Jones. 2018. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 71(19): e127-e248.

Xu, G., S. Yu, Z. Gong and S. Zhang 2005). Study of the effect of crocin on rat experimental hyperlipemia and the underlying mechanisms. Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China Journal of Chinese Materia Medica, 30(5): 369-372.

Xu, Z., S. Lin, J. Gong, P. Feng, Y. Cao, Q. Li, Y. Jiang, Y. You, Y. Tong and P. Wang. 2021. Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation. Frontiers in Medicine, 8: 862.

Zahra, W., S. N. Rai, H. Birla, S. S. Singh, A. S. Rathore, H. Dilnashin, C. Keswani and S. P. Singh 2020. Economic Importance of Medicinal Plants in Asian Countries. Bioeconomy for Sustainable Development, Springer: 359-377.

Zeynali, F., M. Dashti, M. Anvari, S. Hosseini and S. M. Miresmaeili. 2009. Studing Teratogenic and Abortificant Effects of Different Doses of Saffron (Crocus Sativus) Decoction in Whole Gestational Period and the 3RD Trimester of Gestational Period in Mice.

Zhang, Y., F. Fei, L. Zhen, X. Zhu, J. Wang, S. Li, J. Geng, R. Sun, X. Yu and T. Chen. 2017. Sensitive analysis and simultaneous assessment of pharmacokinetic properties of crocin and crocetin after oral administration in rats. Journal of Chromatography B, 1044: 1-7.

Zheng, S., Z. Qian, L. Sheng and N. Wen 2006. Crocetin attenuates atherosclerosis in hyperlipidemic rabbits through inhibition of LDL oxidation. Journal of Cardiovascular Pharmacology, 47(1): 70-76.

Zilaee, M., T. Kermany, S. Tavalaee, M. Salehi, M. Ghayour‐Mobarhan and G. A. Ferns. 2014. Barberry treatment reduces serum anti‐heat shock protein 27 and 60 antibody titres and high‐sensitivity C‐reactive protein in patients with metabolic syndrome: A double‐blind, randomized placebo‐controlled trial. Phytotherapy Research, 28(8): 1211-1215.

Zilaee, M., M. Safarian, T. Kermany, M. Emamian, M. Mobarhan and G. Ferns. 2015. Effect of barberry treatment on blood pressure in patients with metabolic syndrome. Journal of Natural Products, 8: 59-63.