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Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 47603

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Prof. Dr. Nikolaos Pitsikas

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Department of Pharmacology, School of Medicine, School of Health Sciences, University of Thessaly, Larisa, Greece
Interests: behavioral pharmacology; neuroscience; psychopharmacology
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Prof. Dr. Konstantinos Dimas

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Department of Pharmacology, School of Medicine, School of Health Sciences, University of Thessaly, Larisa, Greece
Interests: cancer; natural products; small molecules; drug discovery and development
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Dear Colleagues,

The search for beneficial effects of plant extracts in therapy is a hot issue. Crocus sativus L. and its constituents are being studied intensively as potential candidates for the treatment of a wide range of diseases, including cancer, diabetes, cardiovascular diseases, neuropsychiatric disorders, and neurodegenerative diseases.

This Special Issue of Molecules aims to assess new advances in understanding of the therapeutic action of saffron and its constituents in targeting different pathologies. In this context, we intend to highlight and emphasize their pharmacological activity.

We cordially invite researchers working in the field to contribute original research articles as well as critical review articles, that unravel the therapeutic potential of Crocus sativus L. and its bioactive constituents.

Prof. Nikolaos Pitsikas
Prof. Konstantinos Dimas
Guest Editors

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Keywords

Crocus sativus L.
Biological targets
Pharmacology
Therapeutic approaches

Related Special Issue

Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential, 2nd Edition in Molecules

Published Papers (13 papers)

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Editorial

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3 pages, 172 KiB

Open AccessEditorial

Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential

by Nikolaos Pitsikas and Konstantinos Dimas

Molecules 2021, 26(14), 4226; https://doi.org/10.3390/molecules26144226 - 12 Jul 2021

Cited by 2 | Viewed by 1648

Abstract

Natural products or organic compounds isolated from natural sources as primary or secondary metabolites have inspired numerous drugs [...] Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

Research

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18 pages, 2743 KiB

Open AccessArticle

Saffron and Its Major Ingredients’ Effect on Colon Cancer Cells with Mismatch Repair Deficiency and Microsatellite Instability

by Amr Amin, Aaminah Farrukh, Chandraprabha Murali, Akbar Soleimani, Françoise Praz, Grazia Graziani, Hassan Brim and Hassan Ashktorab

Molecules 2021, 26(13), 3855; https://doi.org/10.3390/molecules26133855 - 24 Jun 2021

Cited by 64 | Viewed by 4706

Abstract

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide. One of its subtypes is associated with defective mismatch repair (dMMR) genes. Saffron has many potentially protective roles against colon malignancy. However, these roles in the context of dMMR tumors have not been explored. In this study, we aimed to investigate the effects of saffron and its constituents in CRC cell lines with dMMR. Methods: Saffron crude extracts and specific compounds (safranal and crocin) were used in the human colorectal cancer cell lines HCT116, HCT116+3 (inserted MLH1), HCT116+5 (inserted MSH3), and HCT116+3+5 (inserted MLH1 and MSH3). CDC25b, p-H2AX, TPDP1, and GAPDH were analyzed by Western blot. Proliferation and cytotoxicity were analyzed by MTT. The scratch wound assay was also performed. Results: Saffron crude extracts restricted (up to 70%) the proliferation in colon cells with deficient MMR (HCT116) compared to proficient MMR. The wound healing assay indicates that deficient MMR cells are doing better (up to 90%) than proficient MMR cells when treated with saffron. CDC25b and TDP1 downregulated (up to 20-fold) in proficient MMR cells compared to deficient MMR cells, while p.H2AX was significantly upregulated in both cell types, particularly at >10 mg/mL saffron in a concentration-dependent manner. The reduction in cellular proliferation was accompanied with upregulation of caspase 3 and 7. The major active saffron compounds, safranal and crocin reproduced most of the saffron crude extracts’ effects. Conclusions: Saffron’s anti-proliferative effect is significant in cells with deficient MMR. This novel effect may have therapeutic implications and benefits for MSI CRC patients who are generally not recommended for the 5-fluorouracil-based treatment. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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10 pages, 1872 KiB

Open AccessArticle

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice

by Suhrid Banskota, Hassan Brim, Yun Han Kwon, Gulshan Singh, Sidhartha R. Sinha, Huaqing Wang, Waliul I. Khan and Hassan Ashktorab

Molecules 2021, 26(11), 3351; https://doi.org/10.3390/molecules26113351 - 2 Jun 2021

Cited by 15 | Viewed by 3335

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray–Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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16 pages, 6677 KiB

Open AccessArticle

Phytochemical Differentiation of Saffron (Crocus sativus L.) by High Resolution Mass Spectrometry Metabolomic Studies

by Evangelos Gikas, Nikolaos Stavros Koulakiotis and Anthony Tsarbopoulos

Molecules 2021, 26(8), 2180; https://doi.org/10.3390/molecules26082180 - 10 Apr 2021

Cited by 14 | Viewed by 2587

Abstract

The metabolite profiling of saffron (Crocus sativus L.) from several countries was measured by using ultra-performance liquid chromatography combined with high resolution mass spectrometry (UPLC-HR MS). Multivariate statistical analysis was employed to distinguish among the several samples of C. sativus L. from Greece, Italy, Morocco, Iran, India, Afghanistan and Kashmir. The results of this study showed that the phytochemical content in the samples of C. sativus L. were obviously diverse in the different countries of origin. The metabolomics approach was deemed to be the most suitable in order to evaluate the enormous array of putative metabolites among the saffron samples studied, and was able to provide a comparative phytochemical screening of these samples. Several markers have been identified that aided the differentiation of a group from its counterparts. This can be important for the selection of the appropriate saffron sample, in view of its health-promoting effect which occurs through the modulation of various biological and physiological processes. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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19 pages, 1965 KiB

Open AccessArticle

Bioanalytical Method Development and Validation Study of Neuroprotective Extract of Kashmiri Saffron Using Ultra-Fast Liquid Chromatography-Tandem Mass Spectrometry (UFLC-MS/MS): In Vivo Pharmacokinetics of Apocarotenoids and Carotenoids

by Aboli Girme, Sandeep Pawar, Chetana Ghule, Sushant Shengule, Ganesh Saste, Arun Kumar Balasubramaniam, Amol Deshmukh and Lal Hingorani

Molecules 2021, 26(6), 1815; https://doi.org/10.3390/molecules26061815 - 23 Mar 2021

Cited by 14 | Viewed by 3715

Abstract

Kashmir saffron (Crocus sativus L.), also known as Indian saffron, is an important Asian medicinal plant with protective therapeutic applications in brain health. The main bioactive in Kashmir or Indian Saffron (KCS) and its extract (CSE) are apocarotenoids picrocrocin (PIC) and safranal (SAF) with carotenoids, crocetin esters (crocins), and crocetins. The ultra-fast liquid chromatography(UFLC)- photodiode array standardization confirmed the presence of biomarkers PIC, trans-4-GG-crocin (T4C), trans-3-Gg-crocin (T3C), cis-4-GG-crocin (C4C), trans-2-gg-crocin (T2C), trans-crocetin (TCT), and SAF in CSE. This study’s objectives were to develop and validate a sensitive and rapid UFLC-tandem mass spectrometry method for PIC and SAF along T4C and TCT in rat plasma with internal standards (IS). The calibration curves were linear (R² > 0.990), with the lower limit of quantification (LLOQ) as 10 ng/mL. The UFLC-MS/MS assay-based precision (RSD, <15%) and accuracy (RE, −11.03–9.96) on analytical quality control (QC) levels were well within the acceptance criteria with excellent recoveries (91.18–106.86%) in plasma samples. The method was applied to investigate the in vivo pharmacokinetic parameters after oral administration of 40 mg/kg CSE in the rats (n = 6). The active metabolite TCT and T4C, PIC, SAF were quantified for the first time with T3C, C4C, T2C by this validated bioanalytical method, which will be useful for preclinical/clinical trials of CSE as a potential neuroprotective dietary supplement. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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13 pages, 1923 KiB

Open AccessArticle

Crocetin Mitigates Irradiation Injury in an In Vitro Model of the Pubertal Testis: Focus on Biological Effects and Molecular Mechanisms

by Giulia Rossi, Martina Placidi, Chiara Castellini, Francesco Rea, Settimio D'Andrea, Gonzalo Luis Alonso, Giovanni Luca Gravina, Carla Tatone, Giovanna Di Emidio and Anna Maria D’Alessandro

Molecules 2021, 26(6), 1676; https://doi.org/10.3390/molecules26061676 - 17 Mar 2021

Cited by 7 | Viewed by 2953

Abstract

Infertility is a potential side effect of radiotherapy and significantly affects the quality of life for adolescent cancer survivors. Very few studies have addressed in pubertal models the mechanistic events that could be targeted to provide protection from gonadotoxicity and data on potential radioprotective treatments in this peculiar period of life are elusive. In this study, we utilized an in vitro model of the mouse pubertal testis to investigate the efficacy of crocetin to counteract ionizing radiation (IR)-induced injury and potential underlying mechanisms. Present experiments provide evidence that exposure of testis fragments from pubertal mice to 2 Gy X-rays induced extensive structural and cellular damage associated with overexpression of PARP1, PCNA, SOD2 and HuR and decreased levels of SIRT1 and catalase. A twenty-four hr exposure to 50 μM crocetin pre- and post-IR significantly reduced testis injury and modulated the response to DNA damage and oxidative stress. Nevertheless, crocetin treatment did not counteract the radiation-induced changes in the expression of SIRT1, p62 and LC3II. These results increase the knowledge of mechanisms underlying radiation damage in pubertal testis and establish the use of crocetin as a fertoprotective agent against IR deleterious effects in pubertal period. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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14 pages, 1237 KiB

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Crocins, the Bioactive Components of Crocus sativus L., Counteract the Disrupting Effects of Anesthetic Ketamine on Memory in Rats

by Nikolaos Pitsikas and Petros A. Tarantilis

Molecules 2021, 26(3), 528; https://doi.org/10.3390/molecules26030528 - 20 Jan 2021

Cited by 4 | Viewed by 1710

Abstract

Consistent experimental evidence suggests that anesthetic doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine cause severe memory impairments in rodents. Crocins are among the various bioactive ingredients of the plant Crocus sativus L., and their implication in memory is well-documented. It has not yet been elucidated if crocins are able to attenuate the memory deficits produced by anesthetic ketamine. The present study was undertaken aiming to clarify this issue in the rat. For this aim, the object recognition, the object location and the habituation tests, reflecting non-spatial recognition memory, spatial recognition memory and associative memory, respectively, were utilized. A post-training challenge with crocins (15–30 mg/kg, intraperitoneally (i.p.), acutely) counteracted anesthetic ketamine (100 mg/kg, i.p.)-induced performance impairments in all the above-mentioned behavioral memory paradigms. The current findings suggest that crocins modulate anesthetic ketamine’s amnestic effects. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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9 pages, 469 KiB

Open AccessFeature PaperArticle

The GABA_A-Benzodiazepine Receptor Antagonist Flumazenil Abolishes the Anxiolytic Effects of the Active Constituents of Crocus sativus L. Crocins in Rats

by Nikolaos Pitsikas and Petros A. Tarantilis

Molecules 2020, 25(23), 5647; https://doi.org/10.3390/molecules25235647 - 30 Nov 2020

Cited by 6 | Viewed by 2826

Abstract

Anxiety is a chronic severe psychiatric disorder. Crocins are among the various bioactive components of the plant Crocus sativus L. (Iridaceae) and their implication in anxiety is well-documented. However, which is the mechanism of action underlying the anti-anxiety effects of crocins remains unknown. In this context, it has been suggested that these beneficial effects might be ascribed to the agonistic properties of these bioactive ingredients of saffron on the GABA type A receptor. The current experimentation was undertaken to clarify this issue in the rat. For this research project, the light/dark and the open field tests were used. A single injection of crocins (50 mg/kg, i.p., 60 min before testing) induces an anti-anxiety-like effect revealed either in the light-dark or open field tests. Acute administration of the GABA_A-benzodiazepine receptor antagonist flumazenil (10 mg/kg, i.p., 30 min before testing) abolished the above mentioned anxiolytic effects of crocins. The current findings suggest a functional interaction between crocins and the GABA_A receptor allosteric modulator flumazenil on anxiety. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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15 pages, 2443 KiB

Open AccessArticle

Saffron: Chemical Composition and Neuroprotective Activity

by Maria Anna Maggi, Silvia Bisti and Cristiana Picco

Molecules 2020, 25(23), 5618; https://doi.org/10.3390/molecules25235618 - 29 Nov 2020

Cited by 32 | Viewed by 3317

Abstract

Crocus sativus L. belongs to the Iridaceae family and it is commonly known as saffron. The different cultures together with the geoclimatic characteristics of the territory determine a different chemical composition that characterizes the final product. This is why a complete knowledge of this product is fundamental, from which more than 150 chemical compounds have been extracted from, but only about one third of them have been identified. The chemical composition of saffron has been studied in relation to its efficacy in coping with neurodegenerative retinal diseases. Accordingly, experimental results provide evidence of a strict correlation between chemical composition and neuroprotective capacity. We found that saffron’s ability to cope with retinal neurodegeneration is related to: (1) the presence of specific crocins and (2) the contribution of other saffron components. We summarize previous evidence and provide original data showing that results obtained both “in vivo” and “in vitro” lead to the same conclusion. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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13 pages, 1295 KiB

Open AccessArticle

Crocins from Crocus sativus L. in the Management of Hyperglycemia. In Vivo Evidence from Zebrafish

by Eleni Kakouri, Adamantia Agalou, Charalabos Kanakis, Dimitris Beis and Petros A. Tarantilis

Molecules 2020, 25(22), 5223; https://doi.org/10.3390/molecules25225223 - 10 Nov 2020

Cited by 12 | Viewed by 3464

Abstract

Diabetes mellitus is a disease characterized by persistent high blood glucose levels and accompanied by impaired metabolic pathways. In this study, we used zebrafish to investigate the effect of crocins isolated from Crocus sativus L., on the control of glucose levels and pancreatic β-cells. Embryos were exposed to an aqueous solution of crocins and whole embryo glucose levels were measured at 48 h post-treatment. We showed that the application of crocins reduces zebrafish embryo glucose levels and enhances insulin expression. We also examined whether crocins are implicated in the metabolic pathway of gluconeogenesis. We showed that following a single application of crocins and glucose level reduction, the expression of phosphoenolpyruvate carboxykinase1 (pck1), a key gene involved in glucose metabolism, is increased. We propose a putative role for the crocins in glucose metabolism and insulin management. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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14 pages, 1134 KiB

Open AccessArticle

Antianhedonic and Antidepressant Effects of Affron^®, a Standardized Saffron (Crocus Sativus L.) Extract

by Laura Orio, Francisco Alen, Antonio Ballesta, Raquel Martin and Raquel Gomez de Heras

Molecules 2020, 25(14), 3207; https://doi.org/10.3390/molecules25143207 - 15 Jul 2020

Cited by 16 | Viewed by 6260

Abstract

Anxiety and depression have high prevalence in the general population, affecting millions of people worldwide, but there is still a need for effective and safe treatments. Nutritional supplements have recently received a lot of attention, particularly saffron. Thus, several pre-clinical studies support a beneficial role for bioactive compounds, such as saffron, in anxiety and depression. Here we used an animal model of depression based on social isolation to assess the effects of affron^®, a standardized saffron extract containing ≥3.5% of total bioactive compounds safranal and crocin isomers. Affron^® was administered both through the oral and the intraperitoneal routes, and several tasks related to anxiety and depression, such as the elevated plus maze, the forced swimming test or the sucrose preference test, were assessed. These tasks model key features of depressive states and anxious states relating to fear, behavioral despair or anhedonia, the lack of motivation and/or pleasure from everyday activities, respectively. Animals receiving oral affron^® displayed behaviors congruent with improvements in their anxious/depressive state, showing the enhanced consumption of a sweet solution, as well as an increase in certain escape responses in the forced swimming test. Our data support a beneficial role for oral saffron in anxious/depressive states. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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Review

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11 pages, 420 KiB

Open AccessReview

Crocus sativus L. Extracts and Its Constituents Crocins and Safranal; Potential Candidates for Schizophrenia Treatment?

by Nikolaos Pitsikas

Molecules 2021, 26(5), 1237; https://doi.org/10.3390/molecules26051237 - 25 Feb 2021

Cited by 10 | Viewed by 2773

Abstract

Schizophrenia is a chronic mental devastating disease. Current therapy suffers from various limitations including low efficacy and serious side effects. Thus, there is an urgent necessity to develop new antipsychotics with higher efficacy and safety. The dried stigma of the plant Crocus sativus L., (CS) commonly known as saffron, are used in traditional medicine for various purposes. It has been demonstrated that saffron and its bioactive components crocins and safranal exert a beneficial action in different pathologies of the central nervous system such as anxiety, depression, epilepsy and memory problems. Recently, their role as potential antipsychotic agents is under investigation. In the present review, I intended to critically assess advances in research of these molecules for the treatment of schizophrenia, comment on their advantages over currently used neuroleptics as well-remaining challenges. Up to our days, few preclinical studies have been conducted to this end. In spite of it, results are encouraging and strongly corroborate that additional research is mandatory aiming to definitively establish a role for saffron and its bioactive components for the treatment of schizophrenia. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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16 pages, 507 KiB

Open AccessFeature PaperReview

Recent Advances on the Anticancer Properties of Saffron (Crocus sativus L.) and Its Major Constituents

by Andromachi Lambrianidou, Fani Koutsougianni, Irida Papapostolou and Konstantinos Dimas

Molecules 2021, 26(1), 86; https://doi.org/10.3390/molecules26010086 - 27 Dec 2020

Cited by 43 | Viewed by 6842

Abstract

Cancer is the second leading cause of death globally with an estimated 9.6 million deaths in 2018 and a sustained rise in its incidence in both developing and developed countries. According to the WHO, about 1 in 6 deaths is due to cancer. Despite the emergence of many pioneer therapeutic options for patients with cancer, their efficacy is still time-limited and noncurative. Thus, continuous intensive screening for superior and safer drugs is still ongoing and has resulted in the detection of the anticancer properties of several phytochemicals. Among the spices, Crocus sativus L. (saffron) and its main constituents, crocin, crocetin, and safranal, have attracted the interest of the scientific community. Pharmacological experiments have established numerous beneficial properties for this brilliant reddish-orange dye derived from the flowers of a humble crocus family species. Studies in cultured human malignant cell lines and animal models have demonstrated the cancer prevention and antitumor activities of saffron and its main ingredients. This review provides an insight into the advances in research on the anticancer properties of saffron and its components, discussing preclinical data, clinical trials, and patents aiming to improve the pharmacological properties of saffron and its major ingredients. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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