Crocus sativus L was used for the treatment of a wide range of disorders in traditional medicine. Due to the extensive protective and treatment properties of C. sativus and its constituents in various diseases, the purpose of this review is to collect a summary of its effects, on experimental studies, both in vitro and in vivo. Several investigations have indicated that the therapeutic properties of C. sativus may be due to its anti-oxidant and anti-inflammatory effects on the nervous, cardiovascular, immune, and respiratory systems. Further research has shown that its petals also have anticonvulsant properties. Pharmacological studies have shown that crocetin and safranal have anti-oxidant properties and through inhibiting the release of free radicals lead to the prevention of disorders. Therefore, in the present article, the effects of C. sativus and its constituents on the various system and the possible underlying mechanisms are reviewed. Our literature review showed that C. sativus and its components can be considered as promising agents in the treatment of various body system disorders.

• Medicinal plant
• Pharmacology
• Saffron
• Diseases
• Crocetin

Jadhav S, Momin M, Mohite N, Mohite V, Mudhale P, et al. (2024) Review on Pharmacognostic, Phytochemical and Pharmacological charac- teristics of Medicinal plants Crocus sativus L. Int J Plant Biol Res 12(1): 1141.

Crocus sativus L. (Iridaceae), commonly known as saffron, is a mythical aromatic medicinal plant whose stigmas provide saffron, also called “red gold” (Figure 1) [1],

Figure 1: Saffron ‘red gold’.

This plant belongs to the Iridaceae family [2-21] among the 85 species belonging to the Crocus genus, saffron is the most fascinating and intriguing spice 5.It is a perennial stemless herb that is widely cultivated in Iran and other countries such as India and Greece. Commercial saffron comprises the dried red stigma with a small portion of the yellowish style attached [2]. The history of saffron goes back 3000-4000 years and is associated with several continents and civilizations. Saffron is found in Greco-Roman, Egyptian and Persian cultures. It is from Persia that saffron would have spread to India and China. It is only at the beginning of the middle ages, around the 9th century, with the Arab-Muslim conquests, that saffron spread in North Africa. With the invasion of Europe by the Moors, the cultivation of saffron spread in Europe and more particularly in Spain. The introduction of saffron in France is associated with the crusades between the 11th and 13th centuries.

At that time, saffron was also cultivated in Germany, Switzerland and Italy. Currently, the main world producers of saffron are Iran, Greece, Morocco, Spain and India [1,3].The word saffron is derived from the Arabic word za‘fraan, which translates to yellow [4-6].

The term Saffron in:

• Ancient Greek Korikos,
• Romans → Crocum
• English → Saffron
• Italian → Zafferano
• French → safran
• Spanish → Azafran
• German → Saffran
• Russian → Shafran
• Turkish → Zaferen [7,8].

In Sanskrit → kumkuma and is described as charu (fair), vara (suitor), agnishikha (having a crest of fire), saurabh (fragrant) [9].

As a medicinal plant saffron has traditionally been considered as anodyne, antidepressant, respiratory decongestant, antispasmodic, aphrodisiac, diaphoretic, emmenagogue, expectorant, sedative. Used in scarlet fever, small pox, colds, asthma, heart diseases, tumour, cancer, flatulent colic and in menstrual disorders [10-13] and because of all these actions and uses saffron is included in various Unani and Ayurvedic polyherbal formulations.

• Kingdom : Plantae
• Division : Magnoliophyta
• Class : Liliopsida
• Order : Asparagales
• Family : Iridaceae
• Genus : Crocus
• Species : C. sativus

Synonyms

Hindi - kesar, zaffran; Sanskrit - avarakta, saurab, mangalya, agnishikha, kumkuma, mangal, kusrunam; English- saffron; Arab and Persian - zafrah, zipharana; Ben - jafran; Bom - safran, kessar; Mah - kecara; Guj - keshar; Tel - kunkuma-purva, kunkumma- purru; Tam. and Mal. - kunkumappu; Can. and Kon- kunkuma- kesara; Fr.and Ger. – safran [10-23].

Biological Source

Saffron is the dried stigma and styletops of Crocus sativus Linn., belonging to family Iridaceae [24].

Macroscopy

The macroscopic characteristics of saffron are in given in (Table 1) below- [11].

Microscopy

If the soaked drug is examined under a lens or microscope, the stigmas will be found either separate or united in three to the apex of yellowish styles. Each stigma is about 25-mm long and has the shape of a slender funnel, the rim of which is dentate or fmbricate (Figure 2) [4].

Figure 2: Microscopic characteristics of saffron. A: Red contents of parenchyma cells (200 x). B: Terminal border of stigma with fingershaped papillae (400 x). C: Pollen grains with finely pitted exine (200 x).

Ultrasound Assisted Extraction (UAE)

Sample (1,00 g) was extracted with ethanol/water (50:50 v/v, 100 mL), the extractions were performed in a ultrasonic bath (Astrason the Heat System(Germany) with a working frequency of 33 KHz [25]. The samples after sonication at room temperature for 30 minutes, were centrifuged to 4000 rpm, at 4oC, filtered with filter paper and analyzed by mass spectrometry. The ultrasonic plant material extraction procedure was repeated three times.

Naviglio Extractor (NE)

Naviglio Extractor 500 mL model (Atlas Filtri Engineering, Padua, Italy), was used for the extractive process. The ethanol/ water (50:50 v/v) extracts were obtained with the following conditions [26-43].

Sample Weight

5,00 grams of saffron threads were extracted with 500 mL ethanol/water (50:50v/v) in the Naviglio extractor according to a method previously reported in the literature (.Ferrara, L.2002). Briefly static phase: 2 min.; dynamic phase: 5 cycles with 12 sec. of stop piston (2 min.); total cycles: 30 (2 hours). After evaporation of the solvent was obtained 2480 mg of a residue, which was dissolved in methanol and analyzed.

In view of its wide range of medical uses, the saffron has undergone extensive phytochemical and biochemical studies and variety of biologically active ingredients has been isolated. Characteristic components of saffron are crocin - (responsible for the color), picrocrocin- (responsible for the bitter taste), and safranal- (responsible for odor and aroma) (Tables1) (Figure 3) [44-74].

Figure 3: Structures of the chemical constituents.

Saffron contains more than 150 volatile and aroma-yielding compounds. It also has many non-volatile active components, many of which are carotenoids including zeaxanthin, lycopene, and various α- and β-carotenes [17]. The volatiles with a very strong odor are consistent of more than 34 components that are mainly terpenes, terpene alcohols, and their esters.

Non-volatiles include crocins 14 that are responsible for the red or reddish brown color of stigmas together with carotenes, crocetin, picrocrocin (a glycosidic precursor of safranal), the bitter substance and safranal the major organoleptic principle of stigmas [4]. However saffron’s golden yellow-orange color is primarily due to α-crocin. This crocin is trans-crocetin di-(β- Dgentiobiosyl) ester. Systematic (IUPAC) name: 8,8-diapo-8, 8carotenoic acid. This means that the crocin underlying saffron’s aroma is a digentiobiose ester of the carotenoid crocetin. Crocins themselves are a series of hydrophilic carotenoids that are either monoglycosyl or di-glycosyl polyene esters of crocetin [17]. Meanwhile crocetin is a conjugated polyene dicarboxylic acid that is hydrophobic and thus oil soluble. When crocetin is esterified with two water-soluble gentiobioses (which are sugars), a product results that is itself water soluble. The resultant α-crocin is a carotenoid pigment that may comprise more than 10% of dry saffron’s mass. The two esterified gentiobioses make α-crocin ideal for coloring waterbased (nonfatty) foods such as rice dishes [6].

A hypothetical protocrocin of the fresh plant is decomposed on drying into one molecule of crocin and two molecules of picrocrocin . Crocin on hydrolysis yields gentiobiose and crocetin, while picrocrocin yields glucose and safranal [4]. The bitter glucoside picrocrocin is responsible for saffron’s flavor. Picrocrocin (chemical formula: C16H26O7, systematic name: 4-(β-d glucopyranosyloxy)-2, 6.6trimethylcyclohex-1-ene-1- carboxaldehyde) is a union of an aldehyde subelement known as safranal (systematic name: 2,6,6-trimethylcyclohexa-1,3-dien- 1-carboxaldehyde) and a carbohydrate. It has insecticidal and pesticidal properties and may comprise upto 4% of dry saffron. Safranal is less bitter than picrocrocin and may comprise up to 70% of dry saffron’s volatile fraction in some samples. A second element underlying saffron’s aroma is 2-hydroxy-4,4,6-trimethyl- 2,5-cyclohexadien-1-one, the scent which has been described as -saffron, dried hay-like [18]. Callus cultures at ρH: 7.0-7.6 with added uridine-diphosphoglucose are able to transform all transcrocetin into its related glycosides. An antioxidant 3,8 dihydroxy-1-methylanthroquinone-2-carboxylic, claimed to be superior to vitamin E in its inhibition of oxidation of linoleic acid, has been isolated from callus stem tissue of saffron [4]. Dry saffron is highly sensitive to fluctuating pH levels and rapidly breaks down chemically in the presence of light and oxidizing agent. It must, therefore, be stored in air-tight containers in order to minimize contact with atmospheric oxygen. C. sativus has been shown to have anti-depressant effects, two active ingredients are crocin and safranal [19]. As preliminary phytochemical results indicated, it could be suggested that the antinociceptive and anti-inflammatory effects of the petal extracts may be due to their content of flavonoids, tannins, and anthocyanins. Other studies have demonstrated that various flavonoids such as rutin, quercetin, luteolin, hesperidin, and bioflavonoids are present [20-23].

Sulphuric Acid Test

The Carotenoid pigments like Crocin, Crocetin and Picocrocin reacts with the sulphuric acid to give bluish colour immediately, which finally changes to Violet to red, the reaction is due to the hydrolysis of the Carotenoid esters [73]. On reaction of sulphuric acid, the genuine saffron produces blue colour immediately, while as fake saffron yields yellow colour [74]. Results shown in (Figure 4).

Figure 4: Chemical test of saffron samples in Sulphuric acid.

Nitric Acid Test

Genuine saffron samples give light blue color with nitric acid result show in (Figure 5).

Figure 5: Chemical test of saffron samples with nitric acid.

Cytotoxic Activity

Cancer is a term used to describe malignancies in which abnormal cells multiply in an uncontrolled and continuous manner and can invade the surrounding healthy tissues [25,26]. Abnormal cells come from any tissue in the human body and can occur anywhere in the body [27,28].The malignancies caused by this uncontrolled multiplication are numerous and difficult to control therapeutically [29,30]. Antitumor effects of Crocus plant derivatives have been highlighted in a wide variety of isolated cell study models. The viability of healthy cells remained unaffected under treatment, while compared to malignant cells, including human cancer cells, saffron develops selective cytotoxic effects at micromolar doses. Aqueous extract of saffron used in different concentrations (100, 200, 400, and 800 μg/mL) exhibited cytotoxic and proapoptotic effects when investigated on lung cancer cell line A549. It was found that saffron reduced the proliferation of the A549 cells in a dose-dependent manner.

Antimicrobial Activity

Bacterial infections can trigger various diseases such as pneumonia, otitis, diarrhea, and skin infections and are the result of severe infections with germs difficult to treat such as bacteria in the category of Gram-negative germs Enterobacteriaceae, Streptococci, Escherichia coli, or Salmonella [31,32]. The main method of fighting bacterial infections is antibiotic treatment [33]. Although they are effective in most cases, their widespread use has led to antibiotic resistance. This phenomenon consists in the adaptation of bacteria and, consequently, to difficulties in treating infections. Due to the use of antibiotics, the saprophytic microbial flora is destroyed, the flora that facilitates digestion and supports the immune system. Thus, side effects such as gastrointestinal disorders, diarrhea, and allergic reactions occur. Therefore, alternative natural treatments with proven antibacterial effects are an important antimicrobial alternative.

Anti-Alzheimer Activity

The main carotenoid constituent, trans crocin 4, the digentibiosyl ester of crocetin, inhibited A beta fibrillogenesis in Alzheimers disease. The water: methanol (50:50, v/v) extract of Crocus sativus stigmas inhibited A beta fibrillogenesis in a concentration and time dependent manner at lower concentrations than it‘s another constituent dimethylcrocetin [34].

Antioxidant Activity

Oxidative stress is the term used for diseases caused by Reactive Oxygen Species (ROS) called free radicals [35,36]. and is defined as the imbalance between oxidants and antioxidants, in favor of oxidants, with destructive and pathogenetic potential [37,38]. Depending on the intensity, oxidative stress can occur intra- or extracellularly [39]. Intracellular oxidative stress can cause cell necrosis or more or less marked cell disorganization, with catastrophic effects in the case of a cell that cannot reproduce. Extracellular oxidative stress is also cytotoxic [40,41] (Figure 3). Among the saffron constituents, crocetin has stronger antioxidant activity (DPPH (2,2-diphenyl-1- picryl-hydrazyl-hydrate)) than safranal, and the potential of crocetin was equivalent to that of Trolox and Butyl Hydroxyl Toluene (BHT) [42].

Antispasmodic and Digestive Tonic

Virtues have been attributed to saffron concerning the gastrointestinal and genital system, in particular, those of stimulating the stomach, reducing appetite, treating hemorrhoids, treating anus prolapse, limiting intestinal fermentations, helping with the treatment of amenorrhea, or to stimulate menstruation—and not to mention its abortifacient power [43]. Safranal normalized gastric volume and pH, reduced the surface of gastric ulcer and produced gastric protection. In addition, it was able to improve the histological changes induced by indomethacin and the biochemical alterations of tissues [44].

Anti-Inflammatory and Analgesic Effect

There is great interest in natural compounds such as dietary supplements and herbal remedies used for centuries to reduce pain and inflammation [45]. Extracts and tinctures of saffron have been used to treat fever, wounds, lower back pain, abscesses, and gingivitis as well as pain related to the eruption of the first teeth in infants [43]. Aqueous and alcoholic extracts of stigmas and saffron petals have an antinociceptive and anti-inflammatory activity for both acute and chronic pain [46].

Effects on the Eyes

Saffron has been used traditionally by different nations for various eye diseases such as corneal disease, sore eyes, cataracts and purulent eye infection [47,48] .The kohl pencil was used in Egyptian antiquity. It is still used today to make eyes black. In fact, oriental women used it to protect themselves from attacks related to the sun, the wind, the sand and possibly ocular infections as well. Kohl was, in fact, a very fine powder obtained by grinding cloves, rosewood, saffron, and antimony (Figure 6) [53].

Figure 6: Effect on eye.

Current investigations show that saffron extract can reduce eye diseases such as cataracts [49], retinal degeneration [50], light-mediated photoreceptor cell death [51], and improves blood circulation and retinal function [52].

Cosmetology and Perfume Uses of Saffron

More recently, saffron has attracted a renewed interest for its use in cosmetics. Since ancient times, saffron is used for cosmetic purposes, absorbed in infusion or even in the cutaneous application, mixed with fat or macerated in donkey milk, for its eternal youthful properties. Cleopatra used it in her beauty products (Figure 7).

Figure 7: Cosmetology and Perfume Uses of Saffron

In traditional Iranian medicine, saffron can improve the complexion and can be used to treat erysipelas. In traditional Greek medicine, it can refresh the skin of the face and is used to relieve the liver of the domination of bile and to treat acne, skin diseases and wounds. In addition, the body may look younger and brighter [54,55]. In another category, Hindu women used saffron to make the bindi, the yellow dot on the forehead. It is, in a way, a third eye symbolizing good fortune conscience [56,57]. Nowadays, saffron tepals have been studied in several studies as being rich in crocin and kaempferol, thus representing an important source of bioactive compounds for potential cosmetic formulations [57,59].Beside the antioxidant properties, saffron presents multiple interests for cosmetic applications. The most promising activities are listed hereafter.

Anti-UV Agent

Prolonged exposure to the sun is extremely harmful because it puts the skin in contact with UV rays, known to cause serious lesions. Saffron is known to have anti-sun effects that can protect the skin from harmful UV rays. Studies show that saffron lotion may be a better sunscreen than homosalate (an organic compound used in some sunscreens). Thus, saffron can be used as a natural UV absorbing agent [60,61]. In addition to the antisolar and moisturizing properties of saffron, the prevention of skin cancers by saffron because of its antioxidant properties is important as well (Figure 8) [62,63].

Figure 8: Anti UV agent effect

Redness of Dark Spots

Saffron is known to reduce the pigment called melanin. Thus, it is very effective as a lightening agent for the skin. The formulation containing C. sativus extract caused significant depigmentation and anti-rhythmic effect on human skin [64]. Melanocytes produce melanin in skin as a mixture of two pigments eumelanin and phaeomelanin, which are (brown black) and (red yellow) respectively (Figure 9) [65].

Figure 9: Redness or Rash.

Melanogenesis is accomplished by a series of oxidative reactions controlled by various enzymes. Tyrosinase is the main catalyst for this phenomenon [66]. Antioxidant activity is mainly exhibited by monoterpenoids, crocin, quercetin, kaempferol, and by other phenolic components of C. sativus. The mode of action of these compounds to reduce skin melanin is by inhibiting the activity of tyrosinase [67].

Anti-Aging Effect and Diseases of the Skin

In traditional herbal cosmetics uses, saffron can be soaked with a few basil leaves to treat blemishes such as acne. A mixture of soaked saffron strands and virgin coconut oil, or olive oil, and a bit of raw milk is an effective way to exfoliate and improve blood circulation face skin. Saffron is known to reduce a skin condition called erythema, characterized by inflammation, redness or rash. Saffron is rich in antioxidants expected to inhibit the expression of markers of inflammation such as Tumor Necrosis Factor (TNF) and interleukin. An application of the formulation containing 3% C. sativus extract to human skin may be useful in the management of melanoma. Similar effects have been reported by Moshiri et al. who found that clinical trials on the anti-pruritic and skin- promoting effects on saffron’s effects on skin care both confirmed that saffron was more effective than placebo [68].

Perfumery

Once dried, the spice releases a pleasant aroma described by Aristophanes as a -sensual smell? (Clouds 51) admired by the Greeks [37]. It is from safranal, which is the main odoriferous compound of saffron that we obtain the note-saffron. In ancient Greece (around 2000 to 146 BC), saffron was a royal dye and was used as a perfume in salons, courts, theaters and bathrooms. Later, its use spread among ordinary people (Figure 10,11) [69,70].

Figure 10: Use as Perfume.

Figure 11: As food colour of saffron.

Additionally, during the Parthian Dynasty, they used saffron among the ingredients of a royal scent, which included a refreshing oil facial for kings and ritual leaders [71]. Today, we find this woody, sweet note and harmonious in the composition of different perfumes both feminine and masculine, with an original and exotic potential.

Saffron as Natural Pigments in Cosmetics

Historically, plant pigments such as curcumin, beet anthocyanins, carotenoids from peppers, chlorophyll from green leaves and saffron, have been used to color food and cosmetics, for centuries. Nowadays, many commercially used cosmetics are made with the synthetic colorants, which can cause side effects due to prolonged use. However, the current trend matches towards healthy natural ingredients incorporated within these cosmetic products. In cosmetics, saffron has been used at low levels due to its high cost. It has been used as a substitute for turmeric where light exposure would cause fading of turmeric. It also used as a substitute for tartrazine [72].

1. Palomares C, Le Safran. Précieuse Épice Ou Précieux Médicament. 2022.
2. Gadd CJ. The dynasty of Agade and the Guitan invasion. In: Edwards, I.E.S., C.J. Gadd, and N.G.L. Hammand, ed Cambridge, Cambridge University Press Cambridge, Cambridge University Press1971; 417- 463.
3. Dubois A. Analyse de la Filière Safran du MAROC: Quelles, Perspectives Pour la Miseen PlaceD‘Une Indication Géographique? 2010.
4. Evans WC. Trease and Evans-Pharmacognosy. China: Saunders© Elsevier Limited. 1996; 438.
5. Farhan S, Shamsi S , Alam MT ,Perveen A. Saffron (Crocus sativus L.): A Review of its Ethnopharmacological value. Am J PharmTech Res. 2020; 10: 1-18.
6. Wallis TE. Textbook of Pharmacognosy. New Delhi: CBS Publishers and Distributors. 2005; 163-165.
7. Caiola MG, Canini A. Looking for Saffron‘s (Crocus sativus L.) Parents: FunctionalBioscience and Biotechnology. 2010; 4(2): 1-14.
8. Indian Spices.
9. Dymock W, Warden CJH, Hooper D. Pharmacographia Indica: A History of the Principal Drug.
10. Nadkarni KM. Indian Materia Medica. Vol 1. Bombay: Popular Prakashan. 2000; 390-391.
11. S Farhan. Drugs of Vegetable Origin (Vol. 1); Srishti Book Distributors, New Delhi. 2005; 453-461
12. Kokate CK, Purohit AP, Gokhale SB. Pharmacognosy. Pune: Nirali Prakashan. 2006; 390.
13. Abdullaev FI, Espinosa-Aguirre JJ. Biomedical properties of saffron and its potential use in cancer therapy and chemoprevention trials. Cancer Detect Prev. 2004; 28(6): 426-432.
14. Al-Mofleh LA, Alhaider AA, Mossa JS, Al-Sohaibani MO, Qureshi S, Rafatullah S. Antigastric Ulcer Studies on ‘Saffron’ Crocus sativus L. in Rats: Pakistan Journal of Biological Sciences., 2006; 9(6):1009-1013.
15. Bentley R, Trimen H. Medicinal Plants. Asiatic Publishing House, Delhi.2004; 4.
16. Kokate CK, Purohit PA, Gokhale BS. Pharmacognosy; Nirali Prakashan, Pune. 2009; 11: 98-11.
17. Mohajeri D, Mousavi G, Doustar Y. Antihyperglycemic and Pancreas Protective Effects of Crocus sativus L. (Saffron) Stigma Ethanolic Extract on rats with Alloxan Induced Diabetes: Journal of Biological Sciences. 2009; 9(4): 302-310.
18. Liakopulou-Kyriakides M, Kyriakides DA. Crocus sativusBiological active Constituents. Stud Nat Prod Chem. 2002; 26: 293-312.
19. Bittar M, de Souza MM, Yunes RA, Lento R, Delle Monache F, Cechinel Filho V. Antinociceptive activity of I3,II8-binaringenin, a biflavonoid present in plants of the guttiferae. Planta Med. 2000; 66: 84-86.
20. Calixto JB, Beirith A, Ferreira J, Santos AR, Filho VC, Yunes RA. Naturally occurring antinociceptive substances from plants. Phytother Res. 2000; 14(6): 401-418.
21. Ali M. Textbook of Pharmacognosy; 2nd Ed., CBS Publishers and Distributors, New Delhi. 2008; 190-192.
22. Antidepressant effect of Crocus sativus L. stigma extracts and their constituents,crocin and safranal, in mice. 2008.
23. Fatehi M, Rashidabady T, Fatehi-Hassanabad Z. Effects of Crocus sativus petals’ extract on rat blood pressure and on responses induced by electrical field stimulation in the rat isolated vas deferens and guinea-pig ileum. J Ethnopharmacol. 2003; 84: 199-203.
24. Kokate CK, Purohit AP, Gokhale SB. Pharmacognosy. Pune: Nirali Prakashan; 2006.
25. Abderrahim Benkhaled, Abderrahmane Senator, Amel Boudjelal, Abdelhakim Kheniche, Amine Belbahi, Yassine Réggami, et al. Oral acute toxicity and red blood cytotoxicity of the medicinal halophyte Limoniastrum guyonianum leaf extract. ? Farmácia. 2020; 68: 1136-1146.
26. Das SS, Alkahtani S, Bharadwaj P, Ansari MT, ALKahtani MDF, Pang Z, et al. Molecular insights and novel approaches for targeting tumor metastasis. Int J Pharm. 2020; 585: 119556.
27. Jain D, Chaudhary P, Varshney N, Bin Razzak KS, Verma D, Khan Zahra TR, et al. Tobacco Smoking and Liver Cancer Risk: Potential Avenues for Carcinogenesis. J Oncol. 2021; 2021: 5905357.
28. Sharifi-Rad J, Quispe C, Butnariu M, Rotariu LS, Sytar O, Sestito S, et al. Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment. Cancer Cell Int. 2021; 21: 318.
29. Panigrahi BK, Nayak AK. Carbon Nanotubes: An Emerging Drug Delivery Carrier in Cancer Therapeutics. Curr Drug Deliv. 2020; 17: 558-576.
30. Sharifi-Rad J, Quispe C, Patra JK, Singh YD, Panda MK, Das G, et al. Paclitaxel: Application in Modern Oncology and Nanomedicine-Based Cancer Therapy. Oxid Med Cell Longev. 2021; 2021: 3687700.
31. Zlatian O, Balasoiu AT, Balasoiu M, Cristea O, Docea AO, Mitrut R, et al. Antimicrobial resistance in bacterial pathogens among hospitalised patients with severe invasive infections. Exp Ther Med. 2018; 16: 4499-4510.
32. Ungureanu A, Zlatian O, Mitroi G, Droca? A, ?îrc? T, C?lina D, et al. Staphylococcus aureus colonisation in patients from a primary regional hospital. Mol Med Rep. 2017; 16: 8771-8780.
33. Taheri Y, Jokovi? N, Vitorovi? J, Grundmann O, Maroyi A, Calina D. The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol. Front Pharmacol. 2021; 11: 578823.
34. Vijaya BK. Medicinal Uses and Pharmacological Properties of Crocus Sativus Linn (Saffron): International Journal of Pharmacy and Pharmaceutical Sciences. 2011; 3: 22-26.
35. Mititelu RR, P?dureanu R, B?c?noiu M, P?dureanu V, Docea AO, Calina D, et al. Inflammatory and Oxidative Stress Markers-Mirror Tools in Rheumatoid Arthritis. Biomedicines. 2020; 8: 125.
36. Docea AO, Calina D, Buga AM, Zlatian O, Paoliello MMB, Mogosanu GD, et al. The Effect of Silver Nanoparticles on Antioxidant/Pro-Oxidant Balance in a Murine Model. Int J Mol Sci. 2020; 21: 1233.
37. Tsatsakis A, Docea AO, Calina D, Tsarouhas K, Zamfira LM, Mitrut R, et al. A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse. J Clin Med. 2019; 8: 1295.
38. Tsatsakis A, Docea AO, Calina D, Tsarouhas K, Zamfira LM, Mitrut R, et al. A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse. J Clin Med. 2019; 8: 1295.
39. Salehi B, Rescigno A, Dettori T, Calina D, Docea AO, Singh L, et al. Avocado-Soybean Unsaponifiables: A Panoply of Potentialities to Be Exploited. Biomolecules. 2020; 10: 130.
40. Salehi B, Shivaprasad Shetty M, V Anil Kumar N, Živkovi? J, Calina D, Oana Docea A, et al. Veronica Plants-Drifting from Farm to Traditional Healing, Food Application, and Phytopharmacology. Molecules. 2019; 24: 2454.
41. Sharifi-Rad M, Anil Kumar NV, Zucca P, Varoni EM, Dini L, Panzarini E, Rajkovic J, et al. Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases. Front Physiol. 2020; 11: 694.
42. Kanakis CD, Tarantilis PA, Tajmir-Riahi HA, Polissiou MG. Crocetin, dimethylcrocetin, and safranal bind human serum albumin: stability and antioxidative properties. J Agric Food Chem. 2007; 55: 970-977.
43. Premkumar K, Abraham SK, Santhiya ST, Ramesh A. Protective effects of saffron (Crocus sativus Linn.) on genotoxins-induced oxidative stress in Swiss albino mice. Phytother Res. 2003; 17: 614-617.
44. Hosseinzadeh H, Nassiri-Asl M. Avicenna’s (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): a review. Phytother Res. 2013; 27: 475-483.
45. Tamaddonfard E, Erfanparast A, Farshid AA, Imani M, Mirzakhani N, Salighedar R, Tamaddonfard S. Safranal, a constituent of saffron, exerts gastro-protective effects against indomethacin-induced gastric ulcer. Life Sci. 2019; 224: 88-94.
46. Tamaddonfard E, Farshid AA, Eghdami K, Samadi F, Erfanparast A. Comparison of the effects of crocin, safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats. Pharmacol Rep. 2013; 65: 1272-1280.
47. Khorasani G, Hosseinimehr SJ, Zamani P, Ghasemi M, Ahmadi A. The effect of saffron (Crocus sativus) extract for healing of second-degree burn wounds in rats. Keio J Med. 2008; 57:190-195.
48. McGee H. On Food and Cooking: The Science and Lore of the Kitchen; Scribner: New York, NY, USA. 2004; 422: ISBN 0-68480001-2.
49. Makri OE, Ferlemi AV, Lamari FN, Georgakopoulos CD. Saffron administration prevents selenite-induced cataractogenesis. Mol Vis. 2013; 19: 1188-1197.
50. Fernández-Sánchez L, Lax P, Esquiva G, Martín-Nieto J, Pinilla I, Cuenca N. Safranal, a saffron constituent, attenuates retinal degeneration in P23H rats. PLoS One. 2012; 7: e43074.
51. Laabich A, Vissvesvaran GP, Lieu KL, Murata K, McGinn TE, Manmoto CC, Sinclair JR, Karliga I, Leung DW, Fawzi A, Kubota R. Protective effect of crocin against blue light- and white light-mediated photoreceptor cell death in bovine and primate retinal primary cell culture. Invest Ophthalmol Vis Sci. 2006; 47: 3156-3163.
52. Xuan B, Zhou YH, Li N, Min ZD, Chiou GC. Effects of crocin analogs on ocular blood flow and retinal function. J Ocul Pharmacol Ther. 1999; 15: 143-152.
53. John P Melnyk, Sunan Wang, Massimo F Marcone. Chemical and biological properties of the world‘s most expensive spice: Saffron. Food Res Int. 2010; 43: 1981-1989.
54. Zargari A. Medicinal Plants. 1st ed. Tehran University Publication,Tehran. 1997.
55. Mir H. Herbal Knowledge: Usage of Herbs in Prevention and Treatment of Diseases, with Latest Research around the World, 2nd ed. Daftare Nashre Farhange Eslami, Tehran. 2004.
56. Li CY, Lee EJ, Wu TS. Antityrosinase principles and constituents of the petals of Crocus sativus. J Nat Prod. 2004; 67(3): 437-440.
57. Zeka K, Ruparelia KC, Continenza MA, Stagos D, Vegliò F, Arroo RRJ. Petals of Crocus sativus L. as a potential source of the antioxidants crocin and kaempferol. Fitoterapia. 2015; 107: 128-134.
58. Ahrazem O, Argandoña J, Fiore A, Aguado C, Luján R, Rubio-Moraga Á, et al. Transcriptome analysis in tissue sectors with contrasting crocins accumulation provides novel insights into apocarotenoid biosynthesis and regulation during chromoplast biogenesis. Sci Rep. 2018; 8(1): 2843.
59. Golmohammadzadeh S, Jaafari MR, Hosseinzadeh H. Does saffron have antisolar and moisturizing effects? Iran J Pharm Res. 2010; 9(2): 133- 140.
60. Tabrizi H, Mortazavi SA, Kamalinejad M. An in vitro evaluation of various Rosa damascena flower extracts as a natural antisolar agent. Int J Cosmet Sci. 2003; 25: 259-265.
61. Carmona M, Sanchez AM, Ferreres F, Zalacain A, TomasBarberan,F, Alonso GL. Identification of the flavonoid fraction in saffron spice by LC/DAD/ MS/MS: Comparative study of samples from different geographical origins. Food Chem. 2007; 100: 445-450.
62. Das I, Chakrabarty RN, Das S. Saffron can prevent chemically induced skin carcinogenesis in Swiss albino mice. Asian Pac J Cancer Prev. 2004; 5: 70-76.
63. Das I, Das S, Saha T. Saffron suppresses oxidative stress in DMBA- induced skin carcinoma: A histopathological study. Acta Histochem. 2010; 112: 317-327.
64. Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical Applications of Saffron (Crocus sativus) and its Constituents: A Review. Drug Res (Stuttg). 2015; 65: 287-295.
65. Ferrence SC, Bendersky G. Therapy with saffron and the goddess at Thera. Perspect Biol Med. 2004; 47: 199-226.
66. De Leeuw SM, Smit NP, Van Veldhoven M, Pennings EM, Pavel S, Simons JW, et al. Melanin content of cultured human melanocytes and UV-induced cytotoxicity. J Photochem Photobiol B. 2001; 61: 106-113.
67. Gao XH, Zhang L, Wei H, Chen HD. Efficacy and safety of innovative cosmeceuticals. Clin Dermatol. 2008; 26: 367-374.
68. Li CY, Wu TS. Constituents of the pollen of Crocus sativus L. and their tyrosinase inhibitory activity. Chem Pharm Bull (Tokyo). 2002; 50: 1305-1309.
69. Giaccio M. Crocetin from saffron: an active component of an ancient spice. Crit Rev Food Sci Nutr. 2004; 44: 155-172.
70. MH Abrishami. Understanding of Iranian Saffron. 1st ed. Tous, Tehran.1987.
71. Dadkhah M, Ehtesham M, Fekrat H. ëIranian Saffron an Unknown Jewelí. 1st ed. Shahr Ashub Publication, Tehran. 2003.
72. Colledge MAR. Parthians,Translated to Persian by M Rajabnia, Hirmand. Tehran. 2005; 1-86.
73. Tarantilis PA, Tsoupras G, Polissiou M. Determination of saffron (Crocus sativus L.) components in crude plant extract using high- performance liquid chromatography-UV-visible photodiode-array detection-mass spectrometry. J Chromatogr A. 1995; 699(1-2): 107-118.
74. Orfanou O, Tsimidou M. Evaluation of the coloring strength of saffron spice by UV-Vis spectrometry. Food Chemistry. 1996; 57(3): 463-469.