Saffron against components of metabolic syndrome: current status and

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Saffron against components of metabolic syndrome: current status and prospective Mojtaba Shafiee, Nazanin Sadat Aghili Moghaddam, Mohammad Nosrati, Mahsa Tousi, Amir Avan, mikhail ryzhikov, Mohammad Reza Parizadeh, Hamid Fiuji, Majid Rajabian, Amirhosein bahreyni, Majid Khazaei, and Seyed Mahdi Hassanian J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b03762 • Publication Date (Web): 14 Nov 2017 Downloaded from http://pubs.acs.org on November 15, 2017

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Journal of Agricultural and Food Chemistry

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Saffron against components of metabolic syndrome: current status and prospective Mojtaba Shafiee1*, Nazanin Sadat Aghili Moghaddam1*, Mohammad Nosrati2*, Mahsa Tousi1*, Amir Avan3,4*, Mikhail Ryzhikov5, Mohammad Reza Parizadeh3,6, Hamid Fiuji7, Majid Rajabian7, Amirhossein Bahreyni8, Majid Khazaei9#, Seyed Mahdi Hassanian3,6,10#

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1) Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 2) Department of Nutrition, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3) Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. 4) Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 5) Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, USA. 6) Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 7) Department of Biochemistry, Payame-Noor University, Mashhad, Iran. 8) Department of Clinical Biochemistry and Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Mazandaran, Iran. 9) Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 10) Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

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Running title: Saffron against MetS

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The authors have no financial conflicts of interest. *Made equal contribution to this study. This study was supported by grants awarded by the Mashhad University of Medical Sciences (Grant No. 951824) and National Institute for Medical research Development (Grant No. 958349). # Corresponding Authors: Seyed Mahdi Hassanian, Ph.D. Department of Medical Biochemistry Faculty of Medicine, Mashhad University of Medical Sciences Mashhad, Iran. Phone: (+98) 5138002375, Fax: (+98) 5138002389 E-mail: [email protected] Majid Khazaei, MD, Ph.D. Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. Phone: (+98) 5138002227, Fax: (+98) 5138002389 E-mail: [email protected] 1 ACS Paragon Plus Environment


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Abstract

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Saffron, the dried stigmas of Crocus sativus L., is mainly used as a food coloring and

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flavoring agent. This agricultural product is used in traditional medicine for the treatment of

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several diseases including asthma, liver disease, menstruation disorders, and, of special

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interest in this review, in metabolic syndrome. Saffron and its active components including

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crocin, crocetin and safranal are potential therapeutic candidates for attenuating MetS

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complications including hypertension, hyperglycemia, obesity, and dyslipidemia. This review

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summarizes the protective role of saffron and its constituents in the pathogenesis of MetS for

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a better understanding and hence a better management of this disease.

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Keywords: Saffron, Natural food coloring, Phytomedicine, Metabolic syndrome

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Introduction

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Saffron, the world's most expensive spice, belongs to the large family of Iridaceae

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and to the genus Crocus, which are primarily distributed in the southwestern Asia and

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Mediterranean (1). Iran is the major supplier of this spice, producing more than 90% of the

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world’s total annual saffron, followed by India (5%) and countries of the Mediterranean basin

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(Spain, Morocco, Greece, Italy and Turkey) (2, 3). The optimal climatic conditions for better

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growth and development of this spice are rainy autumns, mild winters and warm summers

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(4, 5). A short flowering duration, the intensive hand labor for flower picking and stigma

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separation, the increasing labor costs, and the high number of flowers (i.e. 150,000 to

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200,000) required to produce 1 kg of pure dried saffron, all have made saffron production

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unprofitable (6, 7).

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Saffron has been used from ancient times as a spice in food and as a dye in

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perfumes and cosmetics preparation, due to the coloring, bitterness and aromatic power of

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its dried stigmas (8). It has also been used in traditional medicine for a wide range of

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ailments including cramps, asthma, depression, liver disease, menstruation disorders, pain

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and tumors (8). Saffron is comprised mainly of carbohydrates (63%) followed by protein

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(12%), moisture (10%), fat (5%), crude fiber (5%), minerals (5%) and vitamins (% w/w) (9).

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Moreover, a variety of biologically active ingredients has been isolated from saffron. It is now

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well-known that crocin (mono-glycosyl or di-glycosyl esters of crocetin), crocetin (a natural

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carotenoid dicarboxylic acid precursor of crocin), picrocrocin (monoterpene glycoside

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precursor of safranal), and safranal (the major organoleptic principle of the stigmas)

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comprise the four major bioactive compounds of saffron and are responsible not only for its

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sensory profile, but also for its health-promoting properties (9, 10). The structure of these

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active constituents is presented in Figure 1.

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Therapeutic potency of saffron (Crocus sativus L.) has been extensively investigated

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for the treatment of several diseases including metabolic syndrome (MetS) (11-14). MetS is

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a common pathophysiologic condition characterized by a cluster of metabolic and

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cardiovascular disorders such as hyperglycemia, hypertension, dyslipidemia and obesity 3 ACS Paragon Plus Environment


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(15). According to International Diabetes Federation (IDF), around 20-25 percent of the

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world’s adult population suffer from MetS (16). MetS confers a 2-fold increase in the risk of

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cardiovascular diseases (CVD) and a 5-fold risk of developing type 2 diabetes mellitus

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(T2DM) over the next 5 to 10 years (17). It is also reported that patients with MetS are at a 2-

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fold higher risk of dying from stroke or myocardial infarction (MI) compared with those

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without the syndrome (15). Thus, MetS constitutes a major challenge for public health and it

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is quite necessary to identify and manage patients with MetS (18). Since there is no

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recognized method to prevent or improve the whole syndrome, the clinical management of

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patients with MetS is difficult. For these reasons, there is a particular interest nowadays in

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the potential of functional foods to modify the components of MetS (19, 20). This review

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summarizes evidence that saffron and its active constitutes can be considered as a potential

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dietary agent for prevention and treatment of MetS.

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Effect of saffron and its active constituents on components on MetS

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Insulin resistance

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The antidiabetic, hypoglycemic, and pancreas-protective effects of saffron and its

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active constituents have been investigated by several authors in chemically induced diabetic

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rats (21-25). Samarghandian et al. observed that saffron at 40 and 80 mg/kg significantly

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decreases blood glucose levels, glycosylated serum proteins, and serum advanced glycation

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end-products (AGEs) levels in streptozotocin (STZ)-induced type 2 diabetic rats (21).

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Similarly, Rajaei et al. found that crocin at a dose of 60 mg/kg significantly reduces the blood

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glucose level in STZ-induced diabetic animals (22). In another study, treatment of

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alloxanized mild diabetic (MD) and severely diabetic (SD) rats with saffron ethanolic extract

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at doses of 20, 40 and 80 mg/kg for 14 days significantly reduced fasting blood glucose

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(FBG) levels while increasing serum insulin level in these animals. The number of

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immunoreactive β-cells in the pancreas of extract-treated diabetic rats was also significantly

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increased (23). Elgazar et al. reported that oral administration of saffron extract induces

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significant increase in serum insulin levels and a decrease in blood glucose levels in all 4 ACS Paragon Plus Environment

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treated alloxan-induced diabetic groups, compared to the control group (24). In another

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animal model of alloxan-induced diabetes, saffron methanolic extract (80 and 240 mg/kg),

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crocin (50 and 150 mg/kg) and safranal (0.25 and 0.5 ml/kg) reduce the FBG and glycated

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hemoglobin, HbA1c, levels in diabetic rats (25). Consistent with these findings, intraperitoneal

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administration of 50 mg/kg saffron extract decreases serum glucose levels and increases

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serum insulin levels respectively, in healthy male rats (26).

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It has been shown that saffron and its constituents elicit antidiabetic and

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hypoglycemic effects by 1) regulating the expression of adiponectin, tumor necrosis factor

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(TNF)-α and leptin in white adipose tissue (27), 2) stimulating glucose uptake and increasing

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insulin

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[Phosphatidylinositol 3-kinase/AKT and mTOR] and insulin-independent [AMP-activated

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protein kinase(AMPK)/acetyl-CoA carboxylase (ACC) and mitogen-activated protein kinases

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(MAPKs)] pathways (14), 3) stimulating insulin release and increasing the expression of

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glucose transporter 4 (GLUT4) and AMPK (28), 4) increasing the number of immunoreactive

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β-cells in the pancreas (23), and 5) inhibiting protein tyrosine phosphatase 1B (PTP1B), a

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negative regulator of insulin signaling (29).

sensitivity

in

skeletal

muscle

cells

through

both

of

insulin-dependent

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There are several studies indicating that not only diabetes, but also diabetes-induced

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complications such as cardiovascular disease (30, 31), liver disease (32), neuropathy (33),

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and nephropathy (34) can be ameliorated by saffron and its constituents. For example, it

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was observed that saffron extract (5 and 25 mg/ml), crocin (10 and 50 µM) and ƴ-

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glutamylcysteinylglycine (GSH) (10 µM) decrease glucose-induced neurotoxicity and can be

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potentially useful in diabetic neuropathy treatment (33). Moreover, Altinoz et al. showed that

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treatment of diabetic rats with crocin decreases the high level of serum creatinine (Cr) and

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blood urea nitrogen (BUN) and markedly reduces the histopathological changes observed in

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the diabetes mellitus (DM) group (34). Therefore, saffron can be considered as a therapeutic

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agent in treating diabetes and diabetes-induced complications.

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Hypertension

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There are several studies, which confirm the antihypertensive effects of saffron and

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its constituents in chemically induced hypertensive rats (11, 35-38). Nasiri et al. investigated

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the effects of saffron stigma hydroalcoholic extract on blood pressure and histology of the

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aorta in normotensive and NG‐nitro‐L‐arginine methyl ester (L‐NAME) -induced hypertensive

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rats. Results clearly showed that saffron decreases blood pressure elevation in hypertensive

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rats. They also found that the media thickness and elastic lamellae number of the aorta are

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also reduced by saffron treatment (11). Moreover, Imenshahidi et al. evaluated the effects of

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three doses of saffron aqueous extract on blood pressure of normotensive and

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desoxycorticosterone acetate (DOCA) salt-induced hypertensive rats. The authors found that

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chronic administration of saffron aqueous extract can reduce the mean systolic blood

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pressure (MSBP) in DOCA salt treated rats in a dose dependent manner, but had no effect

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on the MSBP in normotensive rats (35). Consistent with the antihypertensive effects of

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saffron constituents, safranal and crocin also exhibited antihypertensive and normalizing

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effects on blood pressure (36, 38). Furthermore, the intravenous administration of three

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doses of aqueous extract (2.5, 5 and 10 mg/kg), crocin (50, 100 and 200 mg/kg), and

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safranal (0.25, 0.5 and 1 mg/kg) reduced the mean arterial blood pressure (MABP) in

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normotensive and DOCA-induced hypertensive rats in a dose-dependent manner. The

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authors concluded that the hypotensive properties of saffron can be attributable, in part, to

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the actions of two major constitutes of this spice, crocin and safranal. Further studies

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showed that safranal is more effective than crocin in lowering blood pressure in rats (37).

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The exact mechanisms of the hypotensive effect of these compounds are not yet known, but

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it can be partly attributed to the potent relaxant effect of saffron and safranal on smooth

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muscle cells (39). Moreover, Hoseinzadeh et al. showed that safranal regulates GABA(A)-

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benzodiazepine receptor complex (40). It has been shown that benzodiazepines, in pre-

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anesthetic doses, induces hypotension by decreasing peripheral resistance or cardiac output

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(41). Furthermore, Higashino et al. examined the effects of crocetin in stroke-prone

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spontaneously hypertensive rats (SHRSPs). Results showed that crocetin significantly 6 ACS Paragon Plus Environment

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inhibits the age-related increase in systolic blood pressures in SHRSPs at 25 and 50

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mg/kg/day (42).

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It has been shown that crocetin and crocin differentially affect vascular contractility

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and activate different mechanisms involved in the vasoconstriction pathway in hypertension.

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Liorens et al. reported that crocetin exerts pro-relaxing actions through endothelial cells

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which are partially dependent on nitric oxide (NO), while crocin has pro-contractile effects on

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smooth muscle cells (43). However, the contractile effects of crocin observed in this study

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are in contrast to vasodilatory effects observed in other studies (39, 44). The precise

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mechanisms of antihypertensive and vasomodulatory effects of saffron and its constituents

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are not yet clear. For instance, it has been shown that saffron and its constituents increase

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the levels of antioxidant NO by enhancing endothelial NO synthase (eNOS) activity (42, 45-

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47). Moreover, these molecules elicit vasorelaxing functions on smooth muscle cells via

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blocking of calcium channels (48) or inhibiting sarcoplasmic reticulum Ca2+ release into the

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cytosol (49). Understanding these mechanisms can lead to the development of new

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strategies to advance therapeutic procedures for hypertension-related complications

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including MetS.

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Obesity

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The anti-obesity and weight-loss promoting effects of saffron and its constituents

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have been reported in several studies (12, 50, 51). In a study by Mashmoul et al., the 8-

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week treatment with crocin (80 mg/kg) significantly decreases rate of body weight gain, total

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fat pad and weight ratio of epididymal fat to body in obese rats that were on a high fat diet

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(HFD) for 12 weeks. Moreover, treatment with saffron extracts (40 and 80 mg/kg)

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significantly reduces food consumption in rats (50). In another study, treatment of high-fat-

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fed obese rats with different concentrations of saffron stigma, petal, and their mixture for 3

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weeks significantly decreased body weight and leptin levels in all experimental groups (51).

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Moreover, Kianbakht et al. reported that daily gavage of saffron methanolic extract (25, 50,

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100, 200 mg/kg) and its active constituent crocin (5, 15, 30, 50 mg/kg) to obese rats for 2 7 ACS Paragon Plus Environment


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months reduces body weight, food intake and leptin levels (12). Decrease in leptin levels is

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at least partially due to the reduction of fat mass, since leptin is a hormone secreted by

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adipose tissue and adipocytes (52). In a randomized, placebo-controlled study on sixty

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healthy, mildly overweight women, supplementation with Satiereal (176.5 mg per day), a

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novel extract of saffron stigma, potentiated body weight reduction after 8 weeks of treatment

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(53). Moreover, Gout et al. reported a significant decrease in mean snacking frequency

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among Satiereal group as compared with the placebo group (53). Consistently, examining

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the antidepressant effects of saffron on major depressive disorder, a meta-analysis of five

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randomized clinical trials (two placebo-controlled trials and three antidepressant-controlled

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trials)showed that appetite reduction is one of the most frequent reported adverse effects of

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saffron supplementation (54).

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In an in-vivo study using a rat model, crocin showed several anti-obesity mechanisms

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similar to those of orlistat (13). The results of the in situ loop method as well as enzyme

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essay showed that crocin could selectively inhibit the activity of pancreatic and gastric

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lipases as a competitive inhibitor. However, there are some differences between the

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inhibitory functions of crocin with orlistat. For instance, 1) orlistat reduces the dietary fat

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absorption more effectively than crocin. Orlistat reduces the dietary fat absorption by

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approximately 30% at a dose of 40 µmol/kg (55) but crocin reduces the dietary fat absorption

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by 12% at a dose of 102 µmol/kg. 2) The inhibitory effect of orlistat on lipase is irreversible,

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whereas crocin inhibits the lipase reversibly, since no covalent modification of lipase by

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crocin occurs (13). 3) Orlistat strongly inhibits both pancreatic and gastric lipases, but crocin

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has a more potent inhibitory effect on pancreatic lipase. 4) The other difference is that

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although crocin is not absorbable, orlistat can be minimally absorbed and consequently

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leads to hepatotoxicity (56) and 5) finally, orlistat has some adverse gastrointestinal effects

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including fatty/oily stool, fecal urgency, diarrhea, system flatulence and abdominal pain (57),

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whereas these side effects are not observed following crocin treatment. In agreement with

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this result, a 1-month randomized double-blind placebo-controlled trial evaluating the short-

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term safety and tolerability of crocin tablets (20 mg/day) in 44 healthy volunteers reported no 8 ACS Paragon Plus Environment

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major adverse events during one month of crocin treatment (58). Taken together, it can be

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suggested that saffron and its constituents exert anti-obesity effects through at least three

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mechanisms: 1) inhibiting the pancreatic and gastric lipases and reducing dietary fat

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absorption, 2) decreasing appetite and creating a satiating effect (53, 54) and 3) increasing

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the total antioxidant capacity which has been suggested to be inversely related to central

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adiposity (59). Therefore, saffron can be considered as a promising natural medicine in the

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treatment of obesity.

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Dyslipidemia

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There are studies supporting the role of saffron and its active constituents in

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modulating serum total cholesterol (TC), total triglyceride, low density lipoprotein cholesterol

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(LDL-C) and high density lipoprotein cholesterol (HDL-C) (21, 26, 51, 60). For instance, in a

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study investigating the protective activities of saffron in streptozotocin (STZ)-induced type 2

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diabetic rats, saffron at 40 and 80 mg/kg significantly increases HDL-C, whereas it

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decreases cholesterol, triglyceride, and LDL-C after 28 days of treatment (21). Similar to

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these findings, Arasteh et al. reported that intraperitoneal administration of 50 mg/kg saffron

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extract significantly decreases levels of cholesterol in healthy male rats (26). To further

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support the protective functions of saffron on dyslipidemia, Hoshyar et al. investigated the

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effects of extracts from saffron stigma, petal, and their mixture on dyslipidemia. Results

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showed that saffron extracts markedly decrease the serum total cholesterol, triglyceride, and

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LDL-C in obese rats, while HDL-C is increased (51). Furthermore, in another study by

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Mashmoul et al., the saffron extracts and crocin were fed to rats by mixing with a high fat diet

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for 8 weeks. The authors reported that crocin (80 mg/kg) significantly reduces plasma levels

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of triglyceride and TC while the saffron extract (40 mg/kg) showed major improvement in

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LDL/HDL level (50). Consistent with these results, Shirali et al. showed that intraperitoneal

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injection of crocin at doses of 50 or 100 mg/kg significantly decreases the levels of serum

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triglyceride, TC, and LDL-C and increases the HDL-C in the STZ-induced diabetic rats (60).

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Moreover, Sheng et al. reported that a 10-day treatment of diet-induced hyperlipidemic rats 9 ACS Paragon Plus Environment


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with crocin in a daily dose range of 25 to 100 mg/kg can significantly reduce serum

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triglyceride, TC, LDL-C and very low density lipoprotein cholesterol (VLDL-C) levels (13). To

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further support the protective role of saffron on dyslipidemia, He et al. also reported that

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crocin has a potent hypotriglyceridemic and hypocholesterolemic activity in atherosclerotic

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quails (31). Moreover, Asdaq et al. showed that antihyperlipidemic and antioxidant function

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of saffron is more effective than crocin, suggesting the presence of other constituents other

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than crocin in saffron extracts with antioxidant and hypolipidemic properties (61).

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Several mechanisms have been proposed to explain the hypolipidemic effects of

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saffron extract and its constituents including 1) inhibitory effect on pancreatic and gastric

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lipases as a competitive inhibitor (13), 2) stimulating effects on serum adiponectin levels (51,

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62) and 3) modulatory effects on the oxidant-antioxidant system (63). Therefore, considering

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these potent antihyperlipidemic and antioxidant effects, saffron can be considered as a

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promising agent in treating dyslipidemia.

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Conclusion

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Recently, saffron attracted attention in the management of MetS complications and

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provides a new research area for therapy purposes. There are studies showing that saffron

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and its major bioactive components including crocin, crocetin, and safranal could ameliorate

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MetS symptoms in both animal and clinical studies. In line with above-mentioned findings, 66

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patients diagnosed with schizophrenia who were on olanzapine treatment were randomly

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allocated to receive a capsule of saffron aqueous extract (30 mg/day), crocin (30 mg/day) or

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placebo in a 12-week triple-blind trial. The results showed that saffron aqueous extract and,

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to some extent, crocin could effectively prevent reaching the criteria of MetS in schizophrenic

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patients who were treated with olanzapine (64). Furthermore, saffron and its active

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constituents have also shown anti-inflammatory effects in subjects with MetS (65, 66). In a

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study conducted by Kermani et al., forty-four adults diagnosed with MetS were randomly

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divided into 2 groups, to receive 100 mg/day saffron for 12 weeks. The authors reported that

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saffron is able to modulate the serum concentrations of several pro-inflammatory and anti10 ACS Paragon Plus Environment

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inflammatory cytokines such as vascular endothelial growth factor (VEGF), interleukin-6 (IL-

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6) and epidermal growth factor (EGF) (65). In another study, 8-week supplementation with

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crocin reduced serum anti-hsp27 titers by 13% in patients with MetS (66). This review

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summarizes the recent findings on the protective roles of saffron in the pathogenesis of

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MetS (Figure 2).

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The precise mechanisms of the protective functions of saffron and its constituents on

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MetS constituents are not yet clear. Better understanding of these regulatory mechanisms

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can lead to the development of new strategies to advance therapeutic procedures for this

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disease. It is well known that signaling functions of herbal extracts are complex and

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paradoxical in some cases. It is recommended that further investigation be performed in this

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regard in order to determine the exact mechanism of saffron and its components in

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combination with other standard therapeutic approaches on MetS patients. Furthermore, it is

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not yet clearly understood whether these beneficial effects are attributable to crocin,

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crocetin, picrocrocin, safranal or a combination of these active ingredients. Understanding of

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the molecular mechanisms involved in saffron protective properties as well as identifying the

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active components responsible for these protective effects could therefore help to design

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novel active molecules and potentially new drugs to regulate pathological responses and

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have a great clinical significance in terms of the treatment of MetS complications.

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References

330

1.

331

sustainable agricultural systems. A review. Agronomy for sustainable development 2008, 28,

332

95-112.

333

2.

334

Recent research developments in plant science. Vol. 2 2004, 127-159.

335

3.

336

1999; pp 1-17.

337

4.

338

Research Developments in Plant Science 2004, 127-159.

339

5.

340

of saffron (Crocus sativus L.), I International Symposium on Saffron Biology and

341

Biotechnology 650, 2003; 2003; pp 195-200.

342

6.

343

uses. WMW Wiener Medizinische Wochenschrift 2007, 157, 315-319.

344

7.

345

storage of corms extends the flowering season of saffron (Crocus sativus L.). The Journal of

346

Horticultural Science and Biotechnology 2005, 80, 319-326.

347

8.

Basker, D.; Negbi, M., Uses of saffron. Economic Botany 1983, 37, 228-236.

348

9.

Rios, J.; Recio, M.; Giner, R.; Manez, S., An update review of saffron and its active

349

constituents. Phytotherapy Research 1996, 10, 189-193.

350

10.

351

spice. Food Reviews International 2000, 16, 39-59.

352

11.

353

reduced the blood pressure and prevented remodeling of the aorta in L-NAME-induced

354

hypertensive rats. Iran J Basic Med Sci 2015, 18, 1143-6.

355

12.

356

and its constituent crocin in obese Wistar rat. Journal of Medicinal Plants 2015, 1, 25-33.

Gresta, F.; Lombardo, G.; Siracusa, L.; Ruberto, G., Saffron, an alternative crop for

Fernández, J.-A.; Pandalai, S., Biology, biotechnology and biomedicine of saffron.

Negbi, M.; Negbi, M., Saffron cultivation. In Saffron: Crocus sativus L., CRC Press:

Fernández, J.-A., Biology, biotechnology and biomedicine of saffron. Recent

Mollafilabi, A. In Experimental findings of production and echo physiological aspects

Schmidt, M.; Betti, G.; Hensel, A., Saffron in phytotherapy: pharmacology and clinical

Molina, R.; Valero, M.; Navarro, Y.; Garcia-Luis, A.; Guardiola, J., Low temperature

WINTERHALTER, P.; STRAUBINGER, M., Saffron—renewed interest in an ancient

Nasiri, Z.; Sameni, H. R.; Vakili, A.; Jarrahi, M.; Khorasani, M. Z., Dietary saffron

Kianbakht, S.; Hashem Dabaghian, F., Anti-obesity and anorectic effects of saffron

12 ACS Paragon Plus Environment

Page 12 of 28

Page 13 of 28


357

13.

Sheng, L.; Qian, Z.; Zheng, S.; Xi, L., Mechanism of hypolipidemic effect of crocin in

358

rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 2006, 543, 116-22.

359

14.

360

Saffron (Crocus sativus L.) increases glucose uptake and insulin sensitivity in muscle cells

361

via multipathway mechanisms. Food Chem 2012, 135, 2350-8.

362

15.

363

definition. Lancet 2005, 366, 1059-62.

364

16.

365

definition of the metabolic syndrome. Brussels: International Diabetes Federation 2006, 1-

366

23.

367

17.

368

A.; Fruchart, J. C.; James, W. P.; Loria, C. M.; Smith, S. C., Jr., Harmonizing the metabolic

369

syndrome: a joint interim statement of the International Diabetes Federation Task Force on

370

Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart

371

Association; World Heart Federation; International Atherosclerosis Society; and International

372

Association for the Study of Obesity. Circulation 2009, 120, 1640-5.

373

18.

374

cardiovascular risk reduction. Preventive cardiology 2005, 8, 47-52; quiz 53-4.

375

19.

376

hypertension and dyslipidemia) and cardiovasular disease. Trends in Food Science &

377

Technology 2014, 35, 114-128.

378

20.

379

to pharmacotherapy for treating disorders of metabolic syndrome. Annals of medicine 2010,

380

42, 317-33.

381

21.

382

aqueous extract on hyperglycemia, hyperlipidemia, and oxidative stress on diabetic

383

encephalopathy in streptozotocin induced experimental diabetes mellitus. Biomed Res Int

384

2014, 2014, 920857.

Kang, C.; Lee, H.; Jung, E. S.; Seyedian, R.; Jo, M.; Kim, J.; Kim, J. S.; Kim, E.,

Alberti, K. G.; Zimmet, P.; Shaw, J., The metabolic syndrome--a new worldwide

Alberti, G.; Zimmet, P.; Shaw, J.; Grundy, S. M., The IDF consensus worldwide

Alberti, K. G.; Eckel, R. H.; Grundy, S. M.; Zimmet, P. Z.; Cleeman, J. I.; Donato, K.

Wong, N. D., Intensified screening and treatment of the metabolic syndrome for

Mohamed, S., Functional foods against metabolic syndrome (obesity, diabetes,

Marinangeli, C. P.; Jones, P. J., Functional food ingredients as adjunctive therapies

Samarghandian, S.; Azimi-Nezhad, M.; Samini, F., Ameliorative effect of saffron



385

22.

Rajaei, Z.; Hadjzadeh, M. A.; Nemati, H.; Hosseini, M.; Ahmadi, M.; Shafiee, S.,

386

Antihyperglycemic and antioxidant activity of crocin in streptozotocin-induced diabetic rats.

387

Journal of medicinal food 2013, 16, 206-10.

388

23.

389

effects of Crocus sativus L.(Saffron) stigma ethanolic extract on rats with alloxan-induced

390

diabetes. Journal of Biological Sciences 2009, 9, 302-310.

391

24.

392

extract in alloxan-induced diabetic rats. Eur J Biol Sci 2013, 5, 14-22.

393

25.

394

constituents, crocin and safranal, in alloxan-induced diabetic rats. Journal of Medicinal

395

Plants 2011, 3, 82-89.

396

26.

397

Crocus sativus on serum glucose, insulin and cholesterol levels in healthy male rats. Journal

398

of Medicinal Plants Research 2010, 4, 397-402.

399

27.

400

Beneficial impact of crocetin, a carotenoid from saffron, on insulin sensitivity in fructose-fed

401

rats. J Nutr Biochem 2007, 18, 64-72.

402

28.

403

S.; Salim, L. Z.; Azarbayjani, M. A., Saffron with resistance exercise improves diabetic

404

parameters through the GLUT4/AMPK pathway in-vitro and in-vivo. Sci Rep 2016, 6, 25139.

405

29.

406

phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves

407

glucose tolerance in diabetic KK-Ay mice. Mol Nutr Food Res 2014, 58, 1177-89.

408

30.

409

active constituent, crocin) on the cardiovascular complication and dyslipidemia in

410

streptozotocin induced diabetic rats. African Journal of Traditional, Complementary and

411

Alternative Medicines 2015, 12, 1-7.

Mohajeri, D.; Mousavi, G.; Doustar, Y., Antihyperglycemic and pancreas-protective

Elgazar, A. F.; Rezq, A. A.; Bukhari, H. M., Anti-hyperglycemic effect of saffron

Kianbakht, S.; Hajiaghaee, R., Anti-hyperglycemic effects of saffron and its active

Arasteh, A.; Aliyev, A.; Khamnei, S.; Delazar, A.; Mesgari, M.; Mehmannavaz, Y.,

Xi, L.; Qian, Z.; Xu, G.; Zheng, S.; Sun, S.; Wen, N.; Sheng, L.; Shi, Y.; Zhang, Y.,

Dehghan, F.; Hajiaghaalipour, F.; Yusof, A.; Muniandy, S.; Hosseini, S. A.; Heydari,

Maeda, A.; Kai, K.; Ishii, M.; Ishii, T.; Akagawa, M., Safranal, a novel protein tyrosine

Altinoz, E.; Taskin, E.; Oner, Z.; Elbe, H.; Arslan, B. A., The effect of saffron (its


Page 14 of 28

Page 15 of 28


412

31.

He, S. Y.; Qian, Z. Y.; Tang, F. T.; Wen, N.; Xu, G. L.; Sheng, L., Effect of crocin on

413

experimental atherosclerosis in quails and its mechanisms. Life Sci 2005, 77, 907-21.

414

32.

415

active constituent, crocin) on oxidative stress and hepatic injury in streptozotocin induced

416

diabetic rats. Gene Therapy and Molecular Biology 2014, 16, 160-171.

417

33.

418

crocin on reactive oxygen species-mediated high glucose-induced toxicity in PC12 cells.

419

Cellular and molecular neurobiology 2010, 30, 185-91.

420

34.

421

(its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Human

422

& experimental toxicology 2015, 34, 127-34.

423

35.

424

Hosseinzadeh, H., The Effect of Chronic Administration of Saffron (Crocus sativus) Stigma

425

Aqueous Extract on Systolic Blood Pressure in Rats. Jundishapur journal of natural

426

pharmaceutical products 2013, 8, 175-9.

427

36.

428

Hosseinzadeh, H., The effect of chronic administration of safranal on systolic blood pressure

429

in rats. Iranian journal of pharmaceutical research : IJPR 2015, 14, 585-90.

430

37.

431

saffron extract (Crocus sativus L.) and its constituents, safranal and crocin, in normotensive

432

and hypertensive rats. Phytotherapy research : PTR 2010, 24, 990-4.

433

38.

434

Hosseinzadeh, H., Effects of chronic crocin treatment on desoxycorticosterone acetate

435

(doca)-salt hypertensive rats. Iran J Basic Med Sci 2014, 17, 9-13.

436

39.

437

guinea-pig tracheal chains and its possible mechanisms. The Journal of pharmacy and

438

pharmacology 2006, 58, 1385-90.

Altinoz, E.; Oner, Z.; Elbe, H.; Turkoz, Y.; Cigremis, Y., Protective effect of saffron (its

Mousavi, S. H.; Tayarani, N. Z.; Parsaee, H., Protective effect of saffron extract and

Altinoz, E.; Oner, Z.; Elbe, H.; Cigremis, Y.; Turkoz, Y., Protective effects of saffron

Imenshahidi, M.; Razavi, B. M.; Faal, A.; Gholampoor, A.; Mousavi, S. M.;


Imenshahidi, M.; Hosseinzadeh, H.; Javadpour, Y., Hypotensive effect of aqueous


Boskabady, M. H.; Aslani, M. R., Relaxant effect of Crocus sativus (saffron) on



Hosseinzadeh,

H.;

Sadeghnia,

H.

R.,

Protective

Page 16 of 28

439

40.

effect

of

safranal

on

440

pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids

441

systems. Phytomedicine 2007, 14, 256-62.

442

41.

443

protective effects of midazolam maleate: comparison to diazepam. Anesthesiology 1982, 56,

444

172-6.

445

42.

446

Horikawa, Y.; Yamamoto, J., Crocetin, a carotenoid from Gardenia jasminoides Ellis,

447

protects against hypertension and cerebral thrombogenesis in stroke-prone spontaneously

448

hypertensive rats. Phytotherapy research : PTR 2014, 28, 1315-9.

449

43.

450

L.; Carmona, M., Effects of Crocetin Esters and Crocetin from Crocus sativus L. on Aortic

451

Contractility in Rat Genetic Hypertension. Molecules 2015, 20, 17570-84.

452

44.

453

extract on rat blood pressure and on responses induced by electrical field stimulation in the

454

rat isolated vas deferens and guinea-pig ileum. Journal of ethnopharmacology 2003, 84,

455

199-203.

456

45.

457

Crocetin

458

hypercholesterolemic rabbit by increasing eNOS activity. Biochem Pharmacol 2006, 72, 558-

459

65.

460

46.

461

Carmona, M.; Llorens, S., Crocetin, a carotenoid derived from saffron (Crocus sativus L.),

462

improves acetylcholine-induced vascular relaxation in hypertension. Journal of vascular

463

research 2014, 51, 393-404.

464

47.

465

induced reactive oxygen species in the stroke-prone spontaneously hypertensive rats

466

(SHRSPs) brain. Journal of clinical biochemistry and nutrition 2011, 49, 182-187.

Nugent, M.; Artru, A. A.; Michenfelder, J. D., Cerebral metabolic, vascular and

Higashino, S.; Sasaki, Y.; Giddings, J. C.; Hyodo, K.; Sakata, S. F.; Matsuda, K.;

Llorens, S.; Mancini, A.; Serrano-Diaz, J.; D'Alessandro, A. M.; Nava, E.; Alonso, G.

Fatehi, M.; Rashidabady, T.; Fatehi-Hassanabad, Z., Effects of Crocus sativus petals'

Tang, F. T.; Qian, Z. Y.; Liu, P. Q.; Zheng, S. G.; He, S. Y.; Bao, L. P.; Huang, H. Q., improves

endothelium-dependent

relaxation

of

thoracic

aorta

in

Mancini, A.; Serrano-Diaz, J.; Nava, E.; D'Alessandro, A. M.; Alonso, G. L.;

Yoshino, F.; Yoshida, A.; Umigai, N.; Kubo, K., Crocetin reduces the oxidative stress


Page 17 of 28


467

48.

Boskabady, M. H.; Shafei, M. N.; Shakiba, A.; Sefidi, H. S., Effect of aqueous-ethanol

468

extract from Crocus sativus (saffron) on guinea-pig isolated heart. Phytotherapy research :

469

PTR 2008, 22, 330-4.

470

49.

471

concentration in cultured bovine aortic smooth muscle cells. Yao xue xue bao = Acta

472

pharmaceutica Sinica 2004, 39, 778-81.

473

50.

474

M. T., Effects of saffron extract and crocin on anthropometrical, nutritional and lipid profile

475

parameters of rats fed a high fat diet. Journal of Functional Foods 2014, 8, 180-187.

476

51.

477

Valavi, M.; Beyki, M. Z.; Mehrpour, O., Anti-Dyslipidemic Properties of Saffron: Reduction in

478

the Associated Risks of Atherosclerosis and Insulin Resistance. Iranian Red Crescent

479

medical journal 2016, 18.

480

52.

481

Nature 1998, 395, 763-70.

482

53.

483

reduces snacking and increases satiety in a randomized placebo-controlled study of mildly

484

overweight, healthy women. Nutrition research (New York, N.Y.) 2010, 30, 305-13.

485

54.

486

and major depressive disorder: a meta-analysis of randomized clinical trials. Journal of

487

integrative medicine 2013, 11, 377-83.

488

55.

489

S., A gastrointestinal lipase inhibitor reduces progression of atherosclerosis in mice fed a

490

western-type diet. Eur J Pharmacol 2004, 501, 137-42.

491

56.

492

medicale (Paris, France : 1983) 2001, 30, 673-6.

He, S. Y.; Qian, Z. Y.; Tang, F. T., Effect of crocin on intracellular calcium

Mashmoul, M.; Azlan, A.; Yusof, B. N. M.; Khaza'ai, H.; Mohtarrudin, N.; Boroushaki,

Hoshyar, R.; Hosseinian, M.; Naghandar, M. R.; Hemmati, M.; Zarban, A.; Amini, Z.;

Friedman, J. M.; Halaas, J. L., Leptin and the regulation of body weight in mammals.

Gout, B.; Bourges, C.; Paineau-Dubreuil, S., Satiereal, a Crocus sativus L extract,

Hausenblas, H. A.; Saha, D.; Dubyak, P. J.; Anton, S. D., Saffron (Crocus sativus L.)

Ueshima, K.; Akihisa-Umeno, H.; Nagayoshi, A.; Takakura, S.; Matsuo, M.; Mutoh,

Barbare, J. C.; Imbert, A.; Benkirane, A., [Hepatotoxicity of medications]. Presse



493

57.

Filippatos, T. D.; Derdemezis, C. S.; Gazi, I. F.; Nakou, E. S.; Mikhailidis, D. P.;

494

Elisaf, M. S., Orlistat-associated adverse effects and drug interactions: a critical review. Drug

495

safety 2008, 31, 53-65.

496

58.

497

Safety Evaluation of Crocin (a constituent of saffron) Tablets in Healthy Volunteers. Iran J

498

Basic Med Sci 2013, 16, 39-46.

499

59.

500

Martinez, J. A., Dietary total antioxidant capacity is inversely related to central adiposity as

501

well as to metabolic and oxidative stress markers in healthy young adults. Nutrition &

502

metabolism 2011, 8, 59.

503

60.

504

resistance and lipid profile of streptozotocin-induced diabetic rats. Phytotherapy research :

505

PTR 2013, 27, 1042-7.

506

61.

507

constituent, crocin, as hypolipidemic and antioxidant in rats. Applied biochemistry and

508

biotechnology 2010, 162, 358-72.

509

62.

510

Barberry, Jujube and Saffron petals on serum level of adiponectin and lipid profile in diabetic

511

rats. Iranian Journal of Endocrinology and Metabolism 2015, 16, 329-337.

512

63.

513

Moghiman, T.; Ghayour-Mobarhan, M.; G, A. F., Saffron supplements modulate serum pro-

514

oxidant-antioxidant balance in patients with metabolic syndrome: A randomized, placebo-

515

controlled clinical trial. Avicenna J Phytomed 2015, 5, 427-33.

516

64.

517

Shahhamzei, N.; Bathaie, S. Z., Saffron aqueous extract prevents metabolic syndrome in

518

patients with schizophrenia on olanzapine treatment: a randomized triple blind placebo

519

controlled study. Pharmacopsychiatry 2014, 47, 156-61.

Mohamadpour, A. H.; Ayati, Z.; Parizadeh, M. R.; Rajbai, O.; Hosseinzadeh, H.,

Hermsdorff, H. H.; Puchau, B.; Volp, A. C.; Barbosa, K. B.; Bressan, J.; Zulet, M. A.;

Shirali, S.; Zahra Bathaie, S.; Nakhjavani, M., Effect of crocin on the insulin

Asdaq, S. M.; Inamdar, M. N., Potential of Crocus sativus (saffron) and its

Hemmati, M.; Asghari, S.; Zohoori, E., Effects of alcoholic and aqueous extract of

Kermani, T.; Mousavi, S. H.; Shemshian, M.; Norouzy, A.; Mazidi, M.; Moezzi, A.;

Fadai, F.; Mousavi, B.; Ashtari, Z.; Ali beigi, N.; Farhang, S.; Hashempour, S.;


Page 18 of 28

Page 19 of 28


520

65.

Kermani, T.; Zebarjadi, M.; Mehrad-Majd, H.; Mirhafez, S. R.; Shemshian, M.;

521

Ghasemi, F.; Mohammadzadeh, E.; Mousavi, S. H.; Norouzy, A.; Moghiman, T.; Sadeghi, A.;

522

Ferns, G.; Avan, A.; Mahdipour, E.; Ghayour-Mobarhan, M., Anti-inflammatory effect of

523

Crocus sativus on the serum cytokines levels in subjects with Metabolic Syndrome: A

524

Randomized, Double-blind, Placebo - controlled trial. Current clinical pharmacology 2017.

525

66.

526

Hadizadeh, F.; Hosein Sahebkar, A.; Tavallaie, S.; Taherzadeh, Z.; Ghayour-Mobarhan, M.;

527

G, A. A. F., Effect of crocin on antibody titers to heat-shock protein 27 in subjects with

528

metabolic syndrome. Current clinical pharmacology 2017.

Nosrati, M.; Nikbakht-Jam, I.; Eslami, S.; Khademi, M.; Foroutan-Tanha, M.;

529 530



Figure legends Table 1. STZ: Streptozotocin; L‐NAME: NG‐nitro‐L‐arginine methyl ester; DOCA: Desoxycorticosterone acetate; HbA1c: Hemoglobin A1c; TG: Triglyceride; TC: Total cholesterol; LDL-C: Low-density lipoprotein-cholesterol; HDL-C: High-density lipoproteincholesterol; VLDL-C: Very low-density lipoprotein-cholesterol; IP: Intraperitoneal; IV: intravenous.

Figure 1. The chemical structures of main secondary metabolites of saffron.

Figure 2. Schematic representation of saffron-mediated protective responses in MetS pathology. Saffron attenuates MetS complications including hypertension, hyperglycemia, obesity, and dyslipidemia.


Page 20 of 28

Page 21 of 28


Table 1. Regulatory effects of saffron and its active constituents on MetS. Authors

MetS

Impairment

component

cause

Samarghandian Insulin et al. (21)

STZ

Agent

Dose

Saffron extract

40-80 mg/kg

Route

IP

Species

Rat

Effects

Saffron extract reduced hyperglycemia and

resistance,

hyperlipidemia risk and also reduced the

dyslipidemia

oxidative stress in diabetic encephalopathy rats.

Rajaei et al.

Insulin

(22)

resistance

STZ

Crocin

15, 30, and 60 mg/kg

IP

Rat

Crocin at a dose of 60 mg/kg significantly reduced the blood glucose level in diabetic animals.

Mohajeri et al.

Insulin

(23)

resistance

Alloxan

Saffron ethanolic

20, 40, and 80 mg/kg

Oral, IP

Rat

extract

Saffron

ethanolic

extract

produced

antihyperglycemic effects in experimental diabetes.

Elgazar et al.

Insulin

(24)

resistance

Alloxan

Saffron extract

200, 400, 600 mg/kg

Oral

Rat

Saffron extract reduced blood glucose level and the incidence of different complications as results of hyperglycemia.

Kianbakht et al.

Insulin

(25)

resistance

Alloxan

1) Saffron

1) 80 and 240 mg/kg

IP

methanolic extract 2) 50 and 150 mg/kg 21

ACS Paragon Plus Environment

Rat

Saffron

methanolic

extract,

crocin

and

safranal significantly reduced the fasting


2) Crocin

Page 22 of 28

3) 0.25 and 0.5 ml/kg

blood

3) Safranal

glucose

significantly

and

HbA1c

increased

the

levels

blood

but

insulin

levels. Arasteh et al.

Insulin

None

Saffron extract

50 mg/kg

IP

Rat

Hydromethanolic

(26)

resistance,

significantly decreased serum glucose and

dyslipidemia

cholesterol

levels

extract

and

of

increased

saffron

serum

insulin. Nasiri et al. (11) Hypertension

L‐NAME

Saffron extract

200 mg/kg

Oral

Rat

Dietary saffron prevented blood pressure increases and remodeling of the aorta in hypertensive rats.

Imenshahidi et

Hypertension

DOCA-salt

al. (35)

Saffron aqueous

10, 20 and 40 mg/kg

IP

Rat

extract

Chronic administration of saffron aqueous extract reduced the mean systolic blood pressure in DOCA salt treated rats in a dose dependent manner.

Imenshahidi et

Hypertension

DOCA-salt

Safranal

1, 2 and 4 mg/kg

IP

al. (36)

Rat

Chronic administration of safranal reduced the mean systolic blood pressure in DOCA salt treated rats in a dose dependent manner.

22


Page 23 of 28

Imenshahidi et


Hypertension

DOCA-salt

al. (37)

1) Crocin

1) 50, 100 and 200 IV

Rat

The aqueous extract of saffron stigma,

2) Safranal

mg/kg

safranal and crocin reduced the mean

3) Saffron

2) 0.25, 0.5 and 1 mg/kg

systolic blood pressure in normotensive and

aqueous extract

3) 2.5, 5 and 10 mg/kg

hypertensive anaesthetized rats in a dosedependent manner.

Boskabady et

Hypertension

DOCA-salt

Crocin

50, 100 and 200 mg/kg

IP

Rat

al. (38)

Chronic administration of crocin reduced the mean systolic blood pressure in DOCA salt treated rats in a dose dependent manner.

Higashino et al.

Hypertension

None

Crocetin

25 and 50 mg/kg

Oral

Rat

(42)

Crocetin

exert

antihypertensive

and

antithrombotic effects via an increase in bioavailable nitric oxide.

Mashmoul et al. Obesity,

High-fat

1) Saffron extract

1) 40 and 80 mg/kg

(50)

diet

2) Crocin

2) 40 and 80 mg/kg

dyslipidemia

Oral

Rat

Crocin showed a higher anti-obesity activity compared with ethanolic extract of saffron but overall lower in comparison to orlistat. Moreover, crocin significantly reduced plasma levels of TG and TC while saffron extract showed major improvement in LDL/HDL

23



Page 24 of 28

level. Hoshyar et al.

Obesity,

High-fat

1) Saffron stigma

1) 40 mg/kg

Oral

Rat

Saffron stigma, petal, and their mixture

(51)

dyslipidemia

diet

2) Saffron petal

2) 80 mg/kg

markedly decreased body weight and leptin

3) Mixture

3) 80 mg/kg

levels as well as TC, TG, and LDL-C, and increased HDL-C in all experimental groups.

Kianbakht et al.

Obesity

None

(12)

Gout et al. (53)

Obesity

None

1) Saffron

1) 25, 50, 100, 200 Gavage

Rat

Saffron extract and crocin at all doses

methanolic extract mg/kg

significantly reduced body weight, food intake

2) Crocin

2) 5, 15, 30, 50 mg/kg

and leptin levels.

Satiereal

176.5 mg/day

Oral

Women

Satiereal consumption produced a reduction of snacking and created a satiating effect.

Shirali et al.

Insulin

STZ

Crocin

50 or 100 mg/kg

IP

Rat

Administration

of

crocin

significantly

(60)

resistance,

decreased the levels of serum glucose,

dyslipidemia

advanced glycation end products, TG, TC, and LDL-C and increased the HDL-C in the diabetic rats.

Sheng et al.

Dyslipidemia

Diet

Crocin

25, 50 and 100 mg/kg

Oral

(13)

Rat

Crocin inhibited the absorption of fat and Cholesterol and reduced serum TG, TC, LDL-

24


Page 25 of 28


C and VLDL-C levels Asdaq et al. (61)

Dyslipidemia

Diet

Oral

Rat

Both saffron and crocin were effective in

1) Saffron

1) 25, 50 and 100 mg/kg

2) Crocin

2) 4.84, 9,69 and 19.38

decreasing the elevated levels of TG, TC and

mg/kg

LDL-C.

25



TOC graphic:


Page 26 of 28

Page 27 of 28


The chemical structures of main secondary metabolites of saffron. 254x190mm (96 x 96 DPI)



Schematic representation of saffron-mediated protective responses in MetS pathology. Saffron attenuates MetS complications including hypertension, hyperglycemia, obesity, and dyslipidemia. 254x190mm (96 x 96 DPI)


Page 28 of 28

Saffron against components of metabolic syndrome: current status and

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