Sesquiterpene Lactones in Cynara: Biological Activities, Agriculture Applications, Extraction Techniques, and Production Enhancement Strategies
by
, , , and
Habiba Nechchadi
1,*
,
Youssef Nadir
2,
Hicham Berrougui
1,
Samira Boulbaroud
1 and
Mhamed Ramchoun
1 1
Biochemistry and Integrative Neuroscience for Health and the Environment Unit, Polydisciplinary Faculty, Sultan Moulay Slimane University, Beni Mellal 23000, Morocco
2
Biological Engineering Laboratory, Faculty of Sciences and Technology, University Sultan Moulay Slimane, Beni Mellal 23000, Morocco
*
Author to whom correspondence should be addressed.
Compounds 2026, 6(3), 39; https://doi.org/10.3390/compounds6030039
Submission received: 9 May 2026
/
Revised: 15 June 2026
/
Accepted: 22 June 2026
/
Published: 30 June 2026
(This article belongs to the Special Issue Compounds–Derived from Nature)
Abstract
The genus Cynara is native to the Mediterranean region and is widely used in food and traditional medicine worldwide. Cynara is characterized by its diverse phytochemical composition, with sesquiterpene lactones, a subclass of terpenoids, being particularly distinctive. These compounds are naturally synthesized as defense mechanisms against herbivores and pathogens while acting as allelochemicals. The sesquiterpene lactones found in Cynara exhibit potential anticancer, anti-inflammatory, and antimicrobial activities. They also possess significant phytotoxic activity, making them promising natural bioherbicides for agricultural applications. The effective exploitation of these compounds requires the use of appropriate extraction solvents and techniques. Compared with conventional solvents and extraction methods, green solvents, including ionic liquids and deep eutectic solvents, together with modern extraction techniques, particularly ultrasound-assisted extraction, supercritical fluid extraction, and Naviglio extraction, have proven highly effective for their recovery. In addition, the application of elicitation strategies, such as salt stress, shading, hormones, and microbial biostimulants, has emerged as a promising approach for enhancing the production of these compounds during cultivation. Therefore, this review highlights Cynara as a valuable source of sesquiterpene lactones with broad applications in medicine and agriculture and provides guidance on technical approaches relevant to their extraction and the enhancement of their production.
1. Introduction
Natural products are defined as compounds derived from diverse natural sources, including animals, plants, and microorganisms [1]. Plant-derived natural products have played a significant role in improving human health since ancient times. In traditional medicine, herbal remedies containing natural compounds are consumed in various forms of preparation, such as macerations, decoctions, infusions, and poultices. Advances in extraction, isolation, and identification techniques have enabled the isolation of numerous compounds, such as morphine, paclitaxel, silymarin, artemisinin, and codeine, which are currently used as drugs to treat human diseases [2].
Plants produce a variety of natural products known as secondary metabolites. These compounds are not directly involved in primary metabolic processes, such as growth, cell division, respiration, photosynthesis, and reproduction, but play important roles in plant adaptation to biotic and abiotic stress conditions [3]. They protect plants against herbivores and pathogens, including bacteria, fungi, and viruses, and contribute to plant communication and pollinator attraction [4]. Secondary metabolites are derived from primary metabolic intermediates, such as acetyl-CoA, shikimic acid, and mevalonic acid. Through various biosynthetic pathways, these intermediates undergo modifications, such as hydroxylation and acylation, generating a wide variety of structurally diverse compounds [1]. To date, more than 200,000 secondary metabolite structures have been identified. Based on their biosynthetic pathways and chemical structures, they are classified into terpenoids, polyphenols, and nitrogen-containing compounds. The concentrations of these compounds vary according to genetic and environmental factors, including the intensity of UV radiation, temperature, salinity, drought, and ozone stress [5].
Terpenoids are one of the most widespread and structurally diverse classes of compounds in plants, with more than 55,000 molecules identified to date [6]. These compounds originate from the mevalonate pathway in the cytosol and the methylerythritol phosphate pathway in the chloroplast, generating isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The head-to-tail condensation of IPP and DMAPP produces geranyl diphosphate (GPP), whereas the addition of a second IPP unit generates the 15-carbon compound farnesyl pyrophosphate (FPP). Subsequent addition of another IPP unit to FPP generates the geranylgeranyl diphosphate (GGPP) [7].
Sesquiterpene lactones (STLs) are synthesized through the cyclization of FPP by germacrene A synthase (GAS) to form germacrene A, which is subsequently oxidized by germacrene A oxidase (GAO) to produce germacrene A acid. Subsequent modifications, including hydroxylation, lactonization, and desaturation, generate a 15-carbon structure containing the α-methylene-γ-lactone moiety characteristic of sesquiterpene lactones. Additional structural modifications, such as hydroxylation, epoxidation, and esterification, generate the structural diversity of STLs, with more than 5000 structures identified to date [8]. STLs are classified into eudesmanolides (6/6 bicyclic structures), guaianolides and pseudoguaianolides (5/7 bicyclic compounds), germacranolides (10-membered rings), and xanthanolides (a non-cyclic carbon chain and a 7-membered ring) [9,10]. Among these classes, germacranolides, guaianolides, pseudoguaianolides, and eudesmanolides are the most common in plants [11].
The use of STLs in medicine dates back to ancient times and involved the use of specific plants whose effects are now attributed to the presence of these compounds [12]. It is now well established that STLs are beneficial to human health due to their diverse biological activities. STLs have demonstrated significant antiviral activity against hepatitis A, B, and C viruses, SARS-CoV-2, herpes simplex virus (HSV-1), and influenza virus (A/H1N1) by inhibiting viral entry, replication, and protein assembly [13]. In addition, STLs have shown strong anti-leishmanial activity against Leishmania donovani and Leishmania mexicana, as well as potent trypanocidal activity against Trypanosoma cruzi and Trypanosoma brucei, through increased reactive oxygen species (ROS) production within parasites and the induction of apoptosis in infected cells [14]. Extensive research has demonstrated the effectiveness of STLs in inhibiting several types of cancer by suppressing proliferation, differentiation, and angiogenesis [15]. They inhibit cancer cell proliferation by inducing apoptosis through increased ROS production, causing cell cycle arrest in the G2/M phase, increasing endoplasmic reticulum stress, and modulating the expression of transcription factors such as nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription (STAT) [16]. They also exert immunoregulatory effects by reducing the proliferation of T and B cells, and anti-inflammatory effects by inhibiting pathways involved in inflammatory responses, notably NF-κB, mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)/STAT pathways [12]. The biological activities of STLs are linked to the α-methylene-γ-lactone moiety, which contains an α, β-unsaturated carbonyl group. This highly reactive group acts as a Michael acceptor, reacting with nucleophiles such as cysteine residues in proteins, enzymes, and glutathione, and catalyzes the alkylation of thiol groups of cysteine residues, thereby altering their structure and thus explaining the cytotoxic, anti-inflammatory, and anticancer activities of these compounds [11,15].
The Mediterranean basin, characterized by its unique climate, harbors a rich botanical diversity used in both food and pharmaceutical applications. The Asteraceae family, also known as the Compositae family, is one of the most widespread and diverse plant families, comprising approximately 1600 genera and 25,000 species [17]. STLs are found in several plant families, such as Lauraceae, Apiaceae, and Euphorbiaceae [9], but the Asteraceae family contains the highest abundance and the greatest structural diversity [11,18]. This diversification is attributed to speciation within the Asteraceae family. Therefore, STLs have been used as chemotaxonomic markers for taxonomic classification [19]. These compounds are localized in Asteraceae, primarily in the leaves, within specialized structures such as capitate glandular trichomes and laticifers. This specific localization confers anti-herbivore activity and highlights their role in the evolutionary adaptation of this plant family [11].
The genus Cynara, belonging to the Asteraceae family, comprises eight species, including Cynara cardunculus L., from which three varieties, Cynara scolymus, Cynara altilis, and Cynara sylvestris, are recognized [20]. C. cardunculus L. has been used in food and medicine since ancient times by Egyptian, Greek, and Roman civilizations [21]. In medicine, it has been used to manage metabolic disorders such as hypertension, hypercholesterolemia, diabetes, and non-alcoholic fatty liver disease [22], as well as neuroinflammation and microbial infections [23]. This plant species is widely exploited in the food industry for the preparation of functional foods due to its antioxidant, anti-inflammatory, and prebiotic properties. In this regard, stem, bract, and leaf extracts are used in the formulation of food products such as bakery and pastry items, meat and fish products, and dairy products [24]. In addition, Cynara species are used for the production of bioethanol and biomethane, as well as bioherbicides for weed control and paper pulp [25].
Although C. cardunculus L. is a rich source of phenolic acids and flavonoids, sesquiterpene lactones, particularly cynaropicrin, are considered chemotaxonomic markers of this species [26,27]. The sesquiterpene lactones found in Cynara are of the guaianolide type and occur in varying concentrations in the roots, stems, flower heads, and leaves. In particular, the leaves contain the highest levels of sesquiterpene lactones and the greatest diversity of compounds [28]. Among these compounds, cynaropicrin is the most abundant, followed by grosheimin and dehydrocynaropicrin [29]. Metabolomics techniques have demonstrated that STLs in Cynara can serve as fingerprinting markers, enabling effective differentiation among varieties [30]. Using NMR-based metabolomics, aguerin B has been identified as a marker to distinguish wild artichokes from cultivated forms, the latter being characterized by high levels of O-caffeoylquinic acid and luteolin [31]. In addition, STLs isolated from Cynara exhibit antitumor, anti-inflammatory, hypolipidemic, and antimicrobial activities [28]. Moreover, these compounds are of significant agricultural interest because they inhibit weeds such as Echinochloa crus-galli L. and Brachiaria spp., which are among the most harmful to crops [32].
Given the promising applications of STLs, the scientific community’s interest in their isolation and evaluation of biological properties has increased considerably in recent years [10]. Therefore, considerable attention has been paid to their extraction, which is a key factor affecting the biological activities of these compounds [33]. To this end, research is being conducted to replace organic solvents, which have harmful effects on human health and the environment, with effective, sustainable, and bio-based alternatives. In addition, conventional extraction techniques are considered unsuitable for large-scale applications due to their high energy consumption and the use of highly toxic solvents. Recently, green extraction techniques have been effectively applied for STL extraction from plant materials [33]. These sustainable extraction techniques are considered highly effective for extracting sesquiterpene lactones due to their high yields and the high quality of the extracted compounds [12,33]. On the other hand, different approaches, including in vitro plant cell culture, metabolic and genetic engineering, and biotic, physical, and hormonal elicitors, are effective for enhancing the production of these metabolites [34].
Taking into account the richness of Cynara in STLs, this review aims to report on the different STLs isolated from Cynara, their biological activities, and their potential applications in agriculture. In addition, this review highlights the solvents and extraction techniques used for the recovery of STLs from Cynara, with a focus on the advantages of newly developed methods. Furthermore, different approaches and types of elicitors used to improve the production of sesquiterpene lactones in Cynara are also discussed in this review.
2. Methodology
Published articles were collected from multiple databases, including PubMed, Scopus, and Google Scholar, using the keywords “sesquiterpene lactones,” “Cynara,” “extraction,” “bioactivity,” and “improvement,” in various combinations using the “AND” and “OR” operators to ensure the retrieval of the maximum number of results. The literature search was conducted without time restrictions, covering all publications up to December 2026. After collection, the articles were screened based on their abstracts and categorized, and the full texts were then analyzed for synthesis into four sections, including sesquiterpene compounds in Cynara, biological activities (antioxidant, anti-inflammatory, anticancer, etc.), extraction techniques, and approaches for improving their production.
3. Cynara as a Source of Sesquiterpenes Lactones
Cynara is a promising source of terpenoids, including monoterpenes, diterpenes, triterpenoids, and sesquiterpene lactones (Table 1). The content of sesquiterpene lactones is approximately 10 times higher in Cynara leaves than in stalks [29]. Guaianolides are the most common class, in particular cynaropicrin, grosheimin, and cynaratriol (Figure 1) [28]. Additional minor STL compounds, including 8-deoxy-11,13-dihydroxygrosheimin, 11β,13-dihydrocynaropicrin, isoamberboin, dodecylcynaropicrin 8-O-β-D-glucopyranoside, cynarinin B, and sesquiterpene glycosides named cynarascoloside A, B, and C, have been isolated from artichoke and cardoon leaves [35,36,37,38,39]. In addition, aguerin B, 8α-acetoxyzaluzanin C, and dehydromelitensin have been isolated from cardoon leaves [40].
Cynaropicrin was first isolated in 1960 from artichoke [10]. The concentration of cynaropicrin in Cynara varies according to genotypes and tissues [41]. Cynaropicrin constitutes the major compound in artichoke leaves, accounting for approximately 60% of the total STLs content [29,37], but it is present in smaller quantities in stalks, receptacles, bracts, and roots [28]. Most importantly, the stem contains a concentration of cynaropicrin approximately two times higher than that of the flower head [41]. This compound is particularly responsible for about 80% of the total bitter taste of artichoke leaves [28].
In Cynara leaves, cynaropicrin is synthesized and stored in trichomes [42]. The first step in the biosynthesis of cynaropicrin begins with the cyclization of FPP to (+)-germacrene A by GAS located in the cytoplasm, thereby forming germacrene A. The latter is then oxidized in the endoplasmic reticulum to germacra-1(10), 4, 11(13)-trien-12-oic acid by CYP71AV9, which acts as a GAO. Germacrene A acid subsequently undergoes hydroxylation to form hydroxygermacrene A acid under the action of CYP71BL5, which acts as costunolide synthase. The latter undergoes spontaneous lactonization, leading to the formation of costunolide, which is the common precursor of germacranolides, eudesmanolides, and guaianolides. Subsequent steps involving hydroxylation, cyclization, oxidation, and acylation lead to the biosynthesis of cynaropicrin from costunolide [42,43,44].
Table 1.
The sesquiterpenes lactone compounds in different parts of the Cynara species.
| Cynara Species | Plant Part | Terpenoids Classes | Compounds | Extraction Method | Technique of Isolation and Identification | Reference |
|---|---|---|---|---|---|---|
| Cynara cornigera | Aerial part | STLs | Grosheimin | Maceration in aqueous methanol (80%) | Fractionation by silica gel chromatography and purification by Sephadex LH-20 column chromatography. | [45] |
| Solstitalin A | ||||||
| STLs | Cornigeraline A | Maceration in aqueous methanol (80%) | Spectroscopic methods coupled with single-crystal X-ray crystallography | [46] | ||
| Sibthorpine | ||||||
| 3-hydroxy-grosheimin | ||||||
| Grosheimin | ||||||
| Solstitalin A | ||||||
| 13-chlorosolstitialine | ||||||
| Cyanaropicrin | ||||||
| Cynara Humulis | Aerial part | STLs | Cynaropicrin | Maceration in MeOH-Et2-O + petrol (1:1:1) for 18 h at room temperature | Fractionation by CC and isolation by H1 and C13 NMR spectroscopy | [47] |
| Aguerin B | ||||||
| Solstitialin | ||||||
| 13-acetylsolstitialin | ||||||
| 13-chlorosolstitialin | ||||||
| 3-actyl-13-chlorosolstitiain | ||||||
| ll,13-epoxysolstitialin | ||||||
| Cynara syriaca | Leaf | STLs | 11,13-dihydrodeacylcynaropicrin | Percolation with petroleum ether: ether: methanol (1:1:1) mixture | Isolation by vacuum liquid chromatography and identification by 13C NMR | [48] |
| 11,13-dihydroxy-8-desoxygrosheimin | ||||||
| Solstitialin | ||||||
| C. scolymus | Leaf | STLs | Cynaropicrin | Bligh–Dyer extraction | Identification by 1H- and 13C NMR | [29] |
| Dehydrocynaropicrin | ||||||
| Grosheimin | ||||||
| Cynaratriol | ||||||
| 8-deoxy-11,13-dihydroxygrosheimin | ||||||
| Chlorophylls | Pheophytin a | |||||
| Pheophytin b | ||||||
| Leaf and stem | Triterpenoids | Squalene | ||||
| C. scolymus | Leaf | Monoterpene | Salvene | Dynamic headspace system using diethyl ether as solvent | Gas chromatography–mass spectrometry (GC-MS) | [49] |
| Myrtenal | ||||||
| Verbanol | ||||||
| Carveol | ||||||
| Thymol | ||||||
| Eugenol | ||||||
| Sesquiterpene | Bourbonene | |||||
| Myristicin | ||||||
| Selinene | ||||||
| Xanthorrhizol | ||||||
| Dihydrofarensol | ||||||
| Bisabolen-12-ol | ||||||
| Catalponol | ||||||
| Canellal | ||||||
| Santonine | ||||||
| Dihydrofarensol | ||||||
| Caryophyllene oxide | ||||||
| Thujaplicinol | ||||||
| C. scolymus | Leaf | Sesquiterpenoids | Mintsulfide | A homogenization-assisted-extraction with 80% methanol acidified with 0.1% formic acid | High-pressure liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer (UHPLC-ESI/QTOF-MS) | [50] |
| Epi-Antheindurolide A | ||||||
| Tataroside | ||||||
| Antheindurolide A | ||||||
| Lactucain B | ||||||
| Diterpenoids | Armillane | |||||
| (R)-3,4-Dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2H-1-benzopyran-6-ol | ||||||
| Monoterpenoids | Tsugaric acid B | |||||
| Triterpenoids | Ganoderic acid H | |||||
| C. scolymus | Leaf | Diterpenes | Rosmanol | Two consecutive reflux extractions with 50% ethanol | Ultra-High Performance Liquid Chromatography coupled with High Resolution Mass Spectrometry (UHPLC–HRMS/MS) | [51] |
| Epirosmanol | ||||||
| rosmanol methyl ether | ||||||
| Rosmadial | ||||||
| Carnosol | ||||||
| Sesquiterpenes | Cichorin | |||||
| Cynaropicrin | ||||||
| Leaf | Sesquiterpene lactone | Cynaratriol | Agitation for 4 h at 40 °C using 50% ethanol | Ultra-High Performance Liquid Chromatography coupled with Electrospray Ionization-Mass Spectrometry (UHPLC-ISI-MS) | [52] | |
| Triterpenoids | Ursolic acid | |||||
| Leaf | STLs | 3β,8α,11α,13-tetrahydroxy-10(14)-guaien1α,4β,5α,6βH-6α,12-olide | SLDE Naviglio extractor with 75% ethanol | LC-ESI/LTQ Orbitrap/MS/MS | [53] | |
| Cynaratriol | ||||||
| Diidrodesacylcynaropicrin 8-O-β-glucopyranoside | ||||||
| Deacylcynaropicrin | ||||||
| Cynarinin A | ||||||
| Cynarinin B | ||||||
| Kotschyol B | ||||||
| Aguerin B | ||||||
| Pertosin A | ||||||
| Cynaropicrin | ||||||
| Cynaropicrin methoxylate | ||||||
| C. scolymus | Leaf | STLs | Cynaropicrin | Maceration in water | HPLC | [39] |
| Deacylcynaropicrin | ||||||
| C. scolymus | Leaf | STLs | 3β, 8α, 11α, 13-tetrahydroxy-10 (14)-guaien-1α, 4β, 5α, 6βH-6α, 12-olide | Maceration in ethanol | LC-ESI/HRMS | [35] |
| Cynarascoloside A/B | ||||||
| dodesacylcynaropicrin 8-O-β-D-glucopyranoside | ||||||
| Cynaratriol | ||||||
| Cynarinin B | ||||||
| C. scolymus | Leaf | STLs | Cynaropicrin | Ethyl acetate fraction of water decoction | 1HNMR and 13C and 2D NMR | [37] |
| 11,13-dihydro-8-desoxigrosheimin | ||||||
| 11,13-dihidrodesacylcynaropicrin | ||||||
| Cynaratriol | ||||||
| Grosheimin | ||||||
| Grosheimin | Extraction with 75% (v/v) methanol acidified with formic acid using a pestle and mortar | UHPLC/Q-TOF-MS | [54] | |||
| Cynaratriol | ||||||
| 8-deoxy-11,13-dihydroxygrosheimin | ||||||
| Dihydrocynaropicrin | ||||||
| Cynaropicrin | ||||||
| C. scolymus | Leaf and stalk | Pentacyclic triterpenes | Lupeol | Supercritical extraction | GC-MS | [55] |
| Lup-20(29)-en-3-one | ||||||
| Olean-12-en-3-one | ||||||
| β-amyrin | ||||||
| Ψ-taraxasterol | ||||||
| Taraxasterol | ||||||
| Ψ-taraxasteryl acetate | ||||||
| Taraxasteryl acetate | ||||||
| C. scolymus | Head | STLs | Dehydrocynaropicrin | Homogenization in 80% methanol | UHPLC/QTOF | [56] |
| Grosheimin | ||||||
| Cynaratriol | ||||||
| C. scolymus | Leaf | STLs | Cynaropicrin | Supercritical CO2 extraction | LC-ESI-QTOF MS/MS | [27] |
| Cynaroscoloside A/B | ||||||
| Cynaroscoloside C | ||||||
| C. scolymus | Leaf | STLs | Cynaropicrin | Methanolic extract and fractionation with Ethyl-acetate | Reversed-phase column chromatography and HPLC | [38] |
| Grosheimin | ||||||
| 11β,13-dihydrocynaropicrin | ||||||
| 3β-hydroxy-8α-[(S)-3-hydroxy-2-methylpropionyloxy] guaia-4(15),10(14),11(13)-trien-1α,5α,6βH-12,6-olide | ||||||
| 3β-hydroxy-8α-[2-methoxymethyl-2-propenoyloxy] guaia-4(15),10(14),11(13)-trien-1α,5α,6βH-12,6-olide | ||||||
| Deacylcynaropicrin | ||||||
| Isoamberboin | ||||||
| C. scolymus | Receptacle | Monoterpene hydrocarbons | Camphor | Solid phase micro-extraction | Gas Chromatography-Chemical Ionization Mass Spectrometry (GC-CIMS) | [57] |
| Oxygenated monoterpenes | α-longipinene | |||||
| Cyclosativene | ||||||
| Longicyclene | ||||||
| α-copaene | ||||||
| β-elemene | ||||||
| Longifolene | ||||||
| β-caryophyllene | ||||||
| α-himachalene | ||||||
| α-humulene | ||||||
| α-acoradiene | ||||||
| β-selinene | ||||||
| α-selinene | ||||||
| δ-cadinene | ||||||
| Sesquiterpene hydrocarbons | Caryophyllene oxide | |||||
| Oxygenated sesquiterpenes | Safranal | |||||
| 2,3-butandiol | ||||||
| Hexanal | ||||||
| 2-methylbutanoic acid | ||||||
| 1-hexanol | ||||||
| 3-methyl-1-hexanol | ||||||
| Methyl hexanoate | ||||||
| 1-octen-3-ol | ||||||
| 2-pentylfuran | ||||||
| 3-ethyl-1-hexanol | ||||||
| 3-octen-2-one | ||||||
| (E)-2-octenal | ||||||
| (E)-2-octen-1-ol | ||||||
| (E, Z)-3,5-octadien-2-one | ||||||
| (E, E)-3,5-octadien-2-one | ||||||
| n-undecane | ||||||
| (Z)-2-nonenal | ||||||
| 2-butyl-2-octenal | ||||||
| (Z)-jasmone | ||||||
| C. scolymus | Roots | Triterpenoids | Taraxasterol | Chloroform fraction obtained by percolation | 1HNMR and 13CNMR spectroscopy | [58] |
| Lupeol | ||||||
| Flowers | Triterpene alcohols | α-Amyrin | Maceration with methanol | HPLC coupled with spectroscopy NMR | [59] | |
| α-Amyrin acetate | ||||||
| β-Amyrin | ||||||
| β-Amyrin acetate | ||||||
| Taraxasterol | ||||||
| Taraxasterol acetate | ||||||
| Ψ-Taraxasterol | ||||||
| Ψ-Taraxasterol acetate | ||||||
| C. altilis | Leaf | STLs | Cynaropicrin | Pulsed ultrasound-assisted extraction | UPLC-QTOF | [60] |
| Grosheimin | ||||||
| Aguerin B | ||||||
| Deacylcynaropicrin | ||||||
| C. altilis | Leaf | STLs | Cynaropicrin | Pulsed ultrasound-assisted extraction | UHPLC-MS/MS | [61] |
| Aguerin B | ||||||
| Grosheimin | ||||||
| 11,13-dihydroxy-8-deoxygrosheimin | ||||||
| Cynaratriol | ||||||
| Deacylcynaropicrin | ||||||
| 11,13-dihydro-deacylcynaropicrin | ||||||
| C. altilis | Leaf | STLs | Aguerin B | Ultrasounds assisted extraction | Chromatography coupled with spectroscopy | [40] |
| Grosheimin | ||||||
| 8α-acetoxyzaluzanin C | ||||||
| Dehydromelitensin | ||||||
| Cynaropicrin | ||||||
| 11,13-dihydroxy-8-desoxygrosheimin, | ||||||
| Stalk and leaf | STLs | Grosheimin | Soxhlet extraction with dichloromethane | GC−MS | [62] | |
| Cynaropicrin | ||||||
| Deacylcynaropicrin | ||||||
| Pentacyclic triterpenes | β-amyrin | |||||
| α-amyrin | ||||||
| Lupeol | ||||||
| β-amyrin acetate | ||||||
| α-amyrin acetate | ||||||
| Lupenyl acetate | ||||||
| ψ-taraxasterol | ||||||
| Taraxasterol | ||||||
| Ψ-taraxasteryl acetate | ||||||
| Taraxasteryl acetate | ||||||
| C. altilis | Aerial parts (leaves and floral stems) | STLs | Grosheimin | Cold maceration at room temperature using 80% ethanol | Column chromatographic separation coupled with 1H- and 13C- NMR | [63] |
| Cynaropicrin | ||||||
| C. altilis | Leaf | STLs | Cynaratriol | Maceration in water | HPLC | [39] |
| Cynaropicrin | ||||||
| Deacylcynaropicrin | ||||||
| 11,13-dihydro-deacylcynaropicrin | ||||||
| 11,13-dihydroxi-8-deoxygrosheimin | ||||||
| C. altilis | Leaf | STLs | Cynaropicrin | Maceration in water and fractionation in ethyl acetate | HPLC coupled with spectroscopy NMR | [64] |
| Cynaratiol | ||||||
| Desacylcynaropicrin | ||||||
| (11R)-11,13-dihydroxydesacylcynaropicrin | ||||||
| (11S)-11,13-dihydroxy-desacylcynaropicrin | ||||||
| C. sylvestris | Leaf | STLs | Cynaratriol | Maceration in water | HPLC | [39] |
| Cynaropicrin | ||||||
| Deacylcynaropicrin |
4. The Biological Activities of Sesquiterpenes Lactones from Cynara
The STLs from the genus Cynara have a wide range of biological activities demonstrated in several studies by acting on different targets and pathways (Figure 2).
4.1. Anticancer Activity
Sesquiterpene lactones have emerged as promising candidates for cancer treatment. The Asteraceae family is a source of sesquiterpene lactones endowed with notable anticancer potential. The costunolide and dihydrocortisone lactone isolated from the root of the Asteraceae family have potent anticancer activity against breast, prostate, bladder, colon, liver, and leukemia by inducing cell cycle arrest and apoptosis and inhibiting tumor proliferation, migration, and invasion by acting on different targets and pathways [65,66].
Cynara STLs exhibit promising anticancer activity against multiple types of cancer. Evidence from in vitro studies suggests that the treatment of human colon cancer cells (HCT-116) with cynaropicrin for 24 h at a concentration of 25 µM induces apoptosis and reduces cell proliferation. Apoptosis is mediated through increased ROS production, which decreases matrix metalloproteinase (MMP) levels, while increasing the expression of caspase-9, caspase-3, and Bcl-2-associated X protein (Bax) and decreasing the expression of B-cell lymphoma 2 (Bcl-2) [67]. Furthermore, cynaropicrin inhibits the growth, proliferation, and migration of human colorectal cancer cells (RKO, HCT116, and DLD-1) while inducing apoptosis. These effects are mediated through the inhibition of leukemia inhibitory factor receptor protein (LIFR), leading to the suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation and nuclear translocation, as well as the inhibition of heterodimer formation between STAT3 and signal transducer and activator of transcription 4 (STAT4) within the nucleus [68]. In addition, ethanolic artichoke leaf extract containing cynaropicrin decreases the viability of HT-29 and RKO colorectal cancer cells, induces G1-phase cell cycle arrest, enhances DNA damage-induced genotoxicity, and promotes both early and late apoptosis in these cell lines [69].
Additionally, sesquiterpene lactones present in the lipophilic fractions of C. altilis delay the progression of hepatocellular carcinoma in both in vitro and in vivo models induced by diethylnitrosamine (DEN). The administration of 150 mg/kg of the extract to DEN-treated Wistar rats reduces liver lesions, transaminase levels, and alpha-fetoprotein levels. In addition, the extract contains cynaropicrin and grosheimin, which exhibit high cytotoxicity against HepG2 cells, with IC50 values of 7.49 µg/mL and 13.9 µg/mL, respectively. The anticancer effects of these compounds are mediated through the induction of apoptosis via hydrogen bonding interactions with caspase-3 [63]. In addition, cynaropicrin inhibits hepatocellular carcinoma by inducing paraptosis. In vitro treatment of Hep3B cells with cynaropicrin (2 μg/mL) induces mitochondrial dysfunction, thereby increasing ROS production. The elevated ROS levels activate p38 MAPK signaling, which suppresses the expression of ALG-2-interacting protein X (Alix), acting as a paraptosis suppressor protein, and enhances endoplasmic stress, thereby triggering paraptosis in hepatocellular carcinoma cells [70].
The dichloromethane extract of C. altilis leaves, which is rich in cynaropicrin, exerts antiproliferative and anti-metastatic effects in in vitro models of triple-negative breast cancer. This extract exhibited a cytotoxic effect against the MDA-MB-231 triple-negative breast cancer cell line, with an IC50 value of 10.39 µg/mL after 48 h of treatment, accompanied by a reduction in the number and size of colonies. The underlying mechanism involves the induction of apoptotic cell death through increased caspase-3 expression and G2-phase cell cycle arrest [71]. In addition, treatment of the MDA-MB-231 and MDA-MB-468 cell lines with cynaropicrin at concentrations of 6 μM and 30 μM inhibited cancer cell proliferation after 72 h, with IC50 values of 7.96 μM and 9.95 μM, respectively, while effectively inhibiting cancer cell migration and invasion at 10 μM. The anti-metastatic effect of cynaropicrin was mediated by increased E-cadherin expression and decreased expression of N-cadherin, vimentin, fibronectin 1, and vascular endothelial growth factor (VEGF) [72].
On the other hand, the lipophilic fraction of C. cardunculus, which is rich in cynaropicrin, can be effectively used as an adjuvant treatment for chronic myeloid leukemia resistant to imatinib. An in vitro study conducted using K562 leukemia cells and imatinib-resistant K562/IMAR cells demonstrated that this extract inhibits the viability and proliferation of both K562 and K562/IMAR cells through the suppression of p210 BCR-ABL oncoprotein expression at a concentration of 240 µg/mL [73].
Moreover, in vitro treatment of human neuroblastoma cell lines (SK-N-BE and SH-SY5Y) with cynaropicrin inhibits cell proliferation, with IC50 values of 9.731 and 5.738 µM, respectively. The antiproliferative effect of cynaropicrin is mediated through G2-phase cell cycle arrest and the induction of apoptosis by increasing the expression of poly (ADP-ribose) polymerase (PARP), caspase-3, and Bax, while decreasing Bcl-2 expression [74]. Cynaropicrin has also demonstrated significant potential in inhibiting lung carcinoma. In vitro treatment of lung carcinoma cells with cynaropicrin at 30 μM inhibits the expression and activity of pyruvate kinase M2 (PKM2), which induces DNA damage through the reduction in PARP and promotes G2/M-phase cell cycle arrest by increasing tumor protein p53 expression. The reduction in PKM2 is associated with a decline in nuclear factor erythroid 2-related factor 2 (NRF2) protein levels, thereby diminishing antioxidant capacity and increasing mitochondrial damage. In addition, cynaropicrin induces apoptosis in these cells by decreasing Bcl-2 expression and increasing the expression of Bax and caspase-3 [75].
Similar to cynaropicrin, aguerin B also has anticancer potential. Aguerin B showed high cytotoxic activity in the human pancreatic adenocarcinoma cell line MIA PaCa-2. Aguerin B has demonstrated potent anti-proliferative activity with an IC50 of 7.5 ± 1.2, superior to 5-fluorouracil (IC50 of 14 ± 1.2), by inducing apoptosis mediated by the α-methylene-γ-lactone ring in its structure [76].
4.2. Antimicrobial Activity
Sesquiterpene lactones are potent antimicrobial compounds acting on bacteria, viruses, parasites, and fungi [77]. The Cynara species is a source of sesquiterpene lactones with antimicrobial activity. Hydroalcoholic extracts of C. altilis leaves have demonstrated antibacterial effects against Gram-positive and Gram-negative bacteria, mediated by synergism between phenolic compounds and cynaropicrin. This extract has inhibited the growth of Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Listeria innocua, Pseudomonas fluorescens, and Pseudomonas syringae pv. tomato, Rhodococcus fascians, Staphylococcus aureus, and Xanthomonas perforans [78]. The sesquiterpene lactones of Cynara are also effective against several parasites. In particular, cynaropicrin has demonstrated high efficacy in inhibiting the promastigote form of Leishmania infantum (IC50 = 23 ± 1 µmol/L) and its amastigote form (IC50 = 10 µmol/L), L. donovani (IC50 = 1.56 µmol/L), the blood form of T. brucei rhodesiense (IC50 = 0.28 ± 0.001 µmol/L), and Plasmodium falciparum (IC50 = 2.99 ± 1.2 µmol/L). The antileishmanial activity of cynaropicrin is greater than that of deacylcynaropicrin due to the presence of the ester side chain, which plays a crucial role in this activity. Furthermore, 13-hydroxy-11β,13-dihydro-deacylcynaropicrin has no antileishmanial activity but exerts greater activity than deacylcynaropicrin in inhibiting P. falciparum, with an IC50 of 29 ± 2 µmol/L [79]. Cynaropicrin inhibits T. brucei by targeting pteridine/folate metabolism, a vital process for parasite survival, via the combined inhibition of two key enzymes: pteridine reductase-1 (PTR1) and bifunctional dihydrofolate reductase–thymidylate synthase (DHFR-TS). Cynaropicrin is able to inhibit 92.1% of PTR1 at a concentration of 100 µM, with an IC50 of 12.4 µM, and 95.8% of DHFR at a concentration of 50 µM, with an IC50 of 7.3 µM [80].
Furthermore, the sesquiterpene lactones grosheimol and cynaropicrin, isolated from the aqueous leaf extract of the wild Egyptian artichoke, were demonstrated to have potent antiviral activity in in vitro assays using a highly permissive human hepatoma cell line (Huh7/Scr). Grosheimol, cynaropicrin, and the total extract exerted their antiviral effects against HCV during the early stages of viral entry through direct inhibition of the virus and by preventing its binding to host cells. These compounds were also able to inhibit cell-to-cell transmission of the virus [81]. The effect of this extract in the treatment of hepatitis C virus infection was evaluated in a clinical trial involving 15 patients infected with the hepatitis C virus who received the aqueous extract three times daily for 3 months. As a result, 12 of the 15 patients included in the study showed complete viral clearance, accompanied by normalization of aspartate aminotransferase and alanine aminotransferase levels, as well as resolution of infection-associated signs and symptoms, including muscle pain, fatigue, nausea, and weight loss [30].
4.3. Antioxidant Activity
Sesquiterpene lactones suppress oxidative stress in cells by inducing endogenous antioxidant enzymes through activation of the NRF2–antioxidant response element (ARE) pathway [10]. The methanolic extract of C. cornigera aerial parts containing sesquiterpene lactone has promising antioxidant activity based on different in vitro assays. Cornigeralin A is a strong metal chelator in comparison with butylhydroxytoluene (BHT). This compound, together with 3-hydroxy-grosheimin, exerts strong antioxidant activity by scavenging 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals. 13-chlorosolstitialin is a strong scavenger of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, possessing high reducing capacity and high superoxide radical scavenging capacity, with 100% inhibition at a concentration of 20 µg/mL. In addition, grosheimin possesses high antioxidant activity through DPPH radical scavenging and reducing capacity [46]. Moreover, the ethyl acetate fraction of C. scolymus leaves, rich in cynaropicrin, has demonstrated high antioxidant activity in in vitro assays. Using the DPPH assay, this extract scavenges DPPH radicals with an IC50 of 16.45 ± 4.32 μg/mL. In addition, this fraction at a concentration of 25 μg/mL exerts promising antioxidant activity by effectively protecting Saccharomyces cerevisiae from oxidative stress, compared with the aqueous fraction [37]. Similarly, the powerful antioxidant activity of cynaropicrin isolated from artichoke has been demonstrated in an in vitro assay using normal human epidermal keratinocytes exposed to ultraviolet-B radiation. Cynaropicrin reduces the ROS generation by activating the AhR–NRF2–NQO1 axis. It binds to the activated aryl hydrocarbon receptor (AhR) and promotes its nuclear translocation, thereby activating NRF2 mRNA transcription and its subsequent nuclear translocation. NRF2 activates NAD(P)H: quinone oxidoreductase 1 (NQO1) mRNA, a powerful antioxidant enzyme that effectively reduces ROS production in keratinocytes [82].
4.4. Anti-Inflammatory Activity
Sesquiterpene lactones are effective in treating inflammation by inhibiting the transcription of genes encoding interleukin-1 beta (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the inflammatory enzymes inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [83]. The sesquiterpene lactones in Cynara exert promising anti-inflammatory activity by regulating inflammatory mediators and pathways. Cynaropicrin inhibits human periodontal tissue inflammation induced by lipopolysaccharides (LPS) produced by Porphyromonas gingivalis. Cynaropicrin at a concentration of 10 μM inhibits the in vitro production of pro-inflammatory cytokines IL-6 and IL-8 induced by LPS in periodontal fibroblast cells. LPS promotes cytokine production through the activation of NF-κB, whereas cynaropicrin at 10 μM inhibits NF-κB activation by reducing the phosphorylation of its p65 subunit in the nucleus [84]. In addition, cynaropicrin, 3β-hydroxy-8α-[2-methoxymethyl-2-propenoyloxy]guaia-4(15),10(14),11(13)-trien-1α,5α,6βH-12,6-olide, and grosheimin inhibit NO production in murine macrophage RAW264.7 cells stimulated by LPS, with IC50 values of 1.2, 2.4, and 3.5 μM, respectively, while 11β,13-dihydrocynaropicrin and 3β-hydroxy-8α-[(S)-3-hydroxy-2-methylpropionyloxy]guaia-4(15),10(14),11(13)-trien-1α,5α,6βH-12,6-olide show moderate inhibitory activities with IC50 values of 8.7 and 10.5 μM, respectively. These compounds inhibit NO production by downregulating iNOS via the negative regulation of NF-κB and JAK/STAT pathways [38].
Furthermore, grosheimin is capable of inhibiting T-cell-mediated inflammatory responses by blocking the initial stages of T-cell receptor (TCR) activation through inhibition of extracellular signal-regulated kinase (ERK1)/2 phosphorylation, calcium mobilization, and depletion of intracellular glutathione (GSH). Treatment of Jurkat T cells with 10 μM grosheimin demonstrated an inhibitory effect on ERK1/2 phosphorylation, with an IC50 of 15.4 ± 4.3 μM; inhibited calcium mobilization with an IC50 of 43.0 ± 7.5 μM; and depleted GSH with an IC50 of 16.6 ± 4.8 μM [85].
4.5. Other Biological Activities
The sesquiterpene lactones in Cynara exert neuroprotective, hepatoprotective, anti-spasmodic, and anti-arthritic activities. In effect, sesquiterpene lactones contained in the methanolic extract of C. cornigera exert a promising neuroprotective effect by inhibiting acetylcholinesterase activity through the action of cornigeraline A, sibthorpine, 3-hydroxy-grosheimin, grosheimin, solstitalin A, 13-chlorosolstitialin, and cynaropicrin. All these compounds inhibit acetylcholinesterase in vitro with very high activity for cornigeraline A (IC50 = 6.1 µg/mL), followed by sibthorpine (IC50 = 7.2 µg/mL), 3-hydroxy-grosheimin (IC50 = 8.1 µg/mL), grosheimin and solstitalin A (IC50 = 10 µg/mL), and then cynaropicrin (IC50 = 18.5 µg/mL) [46]. In addition, C. cardunculus leaf extract containing 10% cynaropicrin protects rats fed a high-fat diet (HFD) against hepatic steatosis. Administration of the extract to Sprague-Dawley rats at doses of 10 mg/kg and 20 mg/kg for 4 weeks via daily gastric gavage decreased body weight, cholesterol, triglycerides, and malondialdehyde (MDA) levels compared with HFD rats, while reducing lipid accumulation in the liver. On the other hand, the high-fat diet reduced the expression of both organic cation transporter 2 (OCTN2) and organic cation transporter 1 (OCTN1) at the hepatic level, leading to a carnitine deficit that favors fat accumulation in the liver. In contrast, the extract increases the expression of both OCTN2 and OCTN1 transporters, which explains its preventive effect against hepatic steatosis [86].
On the other hand, the sesquiterpene lactones from the leaves of C. scolymus, in particular cynaropicrin, inhibit ultraviolet-induced skin aging. Ultraviolet radiation induces skin aging via activation of NF-κB, which promotes the expression of MMP-1 and basic fibroblast growth factor (bFGF) genes, thereby inducing hyperproliferation of keratinocytes and melanocytes. In contrast, cynaropicrin protects against skin aging through inhibition of NF-κB translocation into the nucleus, thereby suppressing MMP-1 and bFGF production. The effect of cynaropicrin was confirmed in mice, where a significant reduction in keratinocyte and melanocyte proliferation was observed [87]. In addition, cynaropicrin isolated from artichoke has been shown to prevent photoaging by inhibiting IL-6 and TNF-α production in keratinocytes exposed to UV-B radiation [30]. Recently, a new chlorinated sesquiterpene lactone of the guaiane type, named pertosine A, was isolated from the ethanolic extract of the leaves of the Carciofo Bianco di Pertosa cultivar of C. scolymus. Therefore, pertosine A has been identified as a promising compound for preventing skin photoaging by effectively inhibiting tyrosinase with an IC50 of 139 μM [53].
Furthermore, artichoke leaves are effective in managing intestinal disorders. The dichloromethane fraction of artichoke leaves exerts an antispasmodic effect by inhibiting acetylcholine-induced ileal contractility, with an IC50 of 0.93 mg/mL. Cynaropicrin isolated from this fraction exhibits promising inhibitory activity (IC50 = 0.065 mg/mL), comparable to that of papaverine, a well-known antispasmodic agent [88]. Furthermore, the ethanolic extract of artichoke leaves containing 1% cynaropicrin and 0.8% chlorogenic acid protects against acute mucosal gastritis induced by ethanol and water-immersion stress in rats. Cynaropicrin exerts superior efficacy at low concentrations compared with the antiulcer agent sofalcone, inhibiting 98% of gastric lesions at a dose of 5 mg/kg when mixed with dextrin (495 mg/kg). The gastroprotective effects of cynaropicrin are mediated by the inhibition of gastric muscular depletion, thereby protecting against gastric lesions [89].
On the other hand, the ethanolic extract of artichoke leaves containing 1% cynaropicrin exerts an anti-arthritic effect. Arthrosis is characterized by increased collagen and proteoglycan degradation resulting from an imbalance between degradation mediated by elevated aggrecanases (ADAMTS) and hypoxia-inducible factor-2α (HIF-2α) and cartilage synthesis caused by decreased expression of SRY-box transcription factor 9 (SOX9). This imbalance is most often associated with increased levels of TNF-α and NF-κB. Cynaropicrin restores this balance, as demonstrated in human chondrogenic OUMS-27 and SW1353 cells treated with TNF-α and NF-κB. Indeed, cynaropicrin inhibits HIF-2α expression by preventing the nuclear translocation of p65 (RelA), thereby suppressing MMP3 expression. In addition, cynaropicrin increases SOX9 expression through the inhibition of IκB-α phosphorylation, which reduces aggrecanase expression [90]. Deacylcynaropicrin prevents bone disease through the inhibition of osteoclastogenesis and bone inflammation. Treatment of bone marrow-derived macrophages with 10 μM deacylcynaropicrin inhibited osteoclastogenesis by decreasing the expression of NFATC1 and c-Fos through inhibition of NF-κB activation via suppression of IκBα phosphorylation and the JNK/ERK signaling pathway. Deacylcynaropicrin has also demonstrated anti-inflammatory properties by inhibiting the secretion of pro-inflammatory cytokines produced by bone marrow macrophages, notably TNF-α, IL-1β, and IL-6, and by promoting the polarization of M1 macrophages toward the anti-inflammatory M2 phenotype through iNOS inhibition. Administration of deacylcynaropicrin at 20 mg/kg/day by intraperitoneal injection for seven days effectively inhibited bone destruction induced by inflammatory osteolysis in an LPS-induced mouse calvarial osteolysis model [91].
Furthermore, grosheimin regulated the biogenesis of primary cilia, organelles essential for cell signaling and tissue development. In vitro treatment of human fibroblasts with grosheimin (10 μM) significantly increased the formation and stability of primary cilia in these cells by increasing the expression of the PLK1, AURKA, WDR62, and CENPF genes involved in microtubule-organizing center function, while preserving Hedgehog signaling in cilia [92].
5. Bioavailability of Sesquiterpene Lactones in Cynara
Bioavailability refers to the fraction of bioactive compounds that remains available after gastrointestinal digestion and reaches the systemic circulation following absorption and distribution [93]. Sesquiterpene lactones are characterized by low bioavailability due to their poor water solubility [10]. The bioavailability of sesquiterpene lactones is influenced by several factors, including chemical structure, gastrointestinal stability, interactions with the food matrix, and microbial metabolism. The sesquiterpene lactones in Cynara are characterized by low oral bioaccessibility. Only 1.6% of the sesquiterpene lactones present in the artichoke head are bioavailable after oral digestion, unlike the anthocyanins, flavones, and lignans present in artichoke extract, which exhibit high oral bioaccessibility [56]. This limited bioaccessibility is attributed to the binding of sesquiterpene lactones to the food matrix, which protects them from salivary degradation. The effect of the food matrix on the bioavailability of sesquiterpene lactones has been demonstrated. Thus, incorporating 9% artichoke stem powder rich in cynaropicrin into bread increases the bioaccessibility of cynaropicrin in the duodenum to 74%, which is associated with promising antioxidant and antidiabetic effects [94]. After intestinal digestion, cynaropicrin undergoes microbial fermentation in the colon, releasing this compound. Finally, 82% of cynaropicrin is bioavailable, as demonstrated in Caco-2 cells, suggesting efficient epithelial transport once the compound becomes bioaccessible [56].
Currently, encapsulation techniques have emerged as promising strategies for ensuring the stability of bioactive compounds in the gastrointestinal tract. Several encapsulation approaches have been developed to improve the bioavailability of bioactive compounds derived from Cynara [95]. Solid lipid nanoparticles loaded with artichoke flower head extract rich in polyphenols and flavonoids, prepared using poloxamer 407 as the aqueous phase and coated with chitosan, demonstrated high encapsulation efficiency (79.20%). These nanoparticles possess the unique ability to slow the release of the encapsulated compounds while enhancing intestinal permeation owing to the high mucoadhesive properties of chitosan. Administration of these nanoparticles loaded with artichoke extract to mice was effective in treating Alzheimer’s disease by reducing the levels of TNF-α, β-amyloid, and tau protein [96]. In addition, polymeric nanoparticles prepared using a green method involving the expansion of a supercritical fluid into an aqueous solution demonstrated high encapsulation efficiency (87%) for artichoke leaf extract, ensuring the stability of cynarin and saponins F and E, which exhibit potent antioxidant activity [97].
These nanoencapsulation techniques are costly and have a limited ability to protect both hydrophobic and hydrophilic compounds. Given these limitations, liposome-based nanoencapsulation offers several advantages. Liposomes are characterized by high biocompatibility owing to the presence of phospholipid bilayers that resemble biological cell membranes, thereby facilitating the transport of compounds across biological barriers. The phospholipid bilayer forms a vesicular structure capable of encapsulating both hydrophobic and hydrophilic compounds, thereby ensuring their targeted delivery [95]. These characteristics make liposomes a promising strategy for the encapsulation of lipophilic compounds such as sesquiterpene lactones. Wild cardoon leaf extract containing 45 mg/g DM of cynaropicrin was encapsulated in nanosized enteric polymer-coated liposomes prepared by coating the liposomes with a pH-responsive polymer (Eudragit® L100). Cynaropicrin encapsulation efficiency exceeding 63% has been demonstrated using this technique, as well as high stability in the gastric and intestinal fluids of rats, thereby providing effective protection against gastric acid and digestive enzymes [98]. In addition to increasing the stability of cynaropicrin during digestion, liposomes improve its organoleptic qualities by masking the bitterness of cynaropicrin, making them suitable for inclusion in foods and oral formulations [95,98].
6. The Application of Cynara Sesquiterpene Lactones in Agriculture
Plants belonging to the Asteraceae family are characterized by their potent allelopathic potential. In particular, C. cardunculus exhibits the most pronounced phytotoxic effect by completely inhibiting the root development of Portulaca oleracea, compared with other thistle species such as Silybum marianum (L.) Gaertn. and Galactites tomentosus Moench [99]. The sesquiterpene lactones produced by Cynara species play important allelopathic roles. The aqueous extracts of globe artichoke and wild cardoon leaves exert allelopathic effects on the seedling growth of Amaranthus retroflexus L. and P. oleracea, with wild cardoon exhibiting the highest activity. The aqueous extract of wild cardoon significantly inhibits P. oleracea by reducing root length through the action of the sesquiterpene lactones cynaratriol, cynaropicrin, and deacylcynaropicrin [39]. In addition, wild cardoon leaf extract significantly inhibits wheat coleoptile elongation, followed by cultivated cardoon and then artichoke, and the allelopathic activity of wild cardoon correlates with its high concentration of sesquiterpene lactones, particularly cynaropicrin [100]. Furthermore, cultivating wild cardoon for three consecutive years significantly reduces the soil weed seed bank through the secretion of allelochemicals, particularly sesquiterpene lactones, thereby depleting the seed reservoir. At the same time, wild cardoon inhibits the growth of B. subtilis while promoting the growth of nitrogen-fixing bacteria, particularly Pseudomonas putida and Azospirillum brasilense [101].
The harvest time affects the allelopathic activity of the leaves. Leaves harvested in April significantly inhibit wheat coleoptile elongation compared with those harvested in November and January, and this correlates with the high content of sesquiterpene lactones during this period. In addition, the ethanolic extract of C. altilis leaves containing a high cynaropicrin content (107 mg/kg DW) completely inhibits the germination of four weed species (Amaranthus retroflexus L., Portulaca oleracea L., Stellaria media (L.) Vill., and Anagallis arvensis L.), particularly by reducing shoot length. The methanolic and aqueous extracts also exert inhibitory activity, but to a lesser extent than the ethanolic extract [102]. In a further study, ethanolic extract of cultivated cardoon leaves containing high concentrations of sesquiterpene lactones, particularly cynaropicrin and cynartriol, inhibited shoot length of the weed A. retroflexus L. by 93% at 800 ppm [103]. Ethyl acetate extracts of cardoon leaves exhibit more potent phytotoxic activity than ethanolic extracts. It has been demonstrated that the ethanolic extract at a concentration of 400 ppm inhibits 80% of etiolated wheat coleoptile growth, in contrast to the ethyl acetate extract, which inhibits growth by 100%. Both extracts effectively inhibited germination of six weed species (A. retroflexus L., P. oleracea L., S. media L., A. arvensis (L.) Vill., E. crus-galli L., and Lolium perenne L.) by reducing root length by up to 90% at 800 ppm, and this activity was associated with the presence of sesquiterpene lactones, including cynaropicrin and desacylcynaropicrin [64]. In another study, it has been demonstrated that the ethyl acetate extract of cardoon leaves inhibits 87% of etiolated wheat coleoptiles at a concentration of 0.4 mg/mL. In particular, three sesquiterpene lactones, aguerin B, grosheimin, and cynaropicrin, isolated from the extract, inhibited 90% of etiolated wheat coleoptile growth at a concentration of 10−3 M. These compounds are as active as Logran in inhibiting root growth in watercress, tomato, onion, and weeds (barnyardgrass and brachiaria) [40]. Although these compounds have a high phytotoxic effect when used alone, their effect is more pronounced when administered in binary combinations [104].
Furthermore, the use of dia-ultrafiltration with the Suez™ GH separation membrane made it possible to enrich the C. cardunculus leaf extract with sesquiterpene lactones, increasing their content from 31% to 71% through improved separation of cynaropicrin from chlorophylls. The filtrate was particularly rich in cynaropicrin and 11,13-dihydroxy-8-deoxygrosheimin that exhibited strong phytotoxic activity by inhibiting the shoot growth of P. oleracea at 800 ppm [61].
In addition, an advanced delivery system was developed to enhance the phytotoxic activity of Cynara sesquiterpene lactones. In this regard, an oil-in-water nanoemulsion enriched with C. cardunculus leaf extract rich in sesquiterpene lactones contained high concentrations of cynaropicrin (299.35 ± 6.70 mg/g of extract) and aguerin B (89.36 ± 3.75 mg/g of extract), as well as small amounts of grosheimin and deacylcynaropicrin. This formulation enhanced the phytotoxic activity of the extract by increasing the stability, bioavailability, and bioactivity of these compounds. Moreover, the nanoformulation, containing 0.5% w/w of sesquiterpene lactone-rich extract, 5% w/w of grape seed extract (GSO), 4% Tween® 80, and 1% pectin, exhibited strong phytotoxic activity against P. oleracea by inhibiting germination by 40% and reducing root and shoot growth by 91% and 92%, respectively, at 800 ppm, exceeding the activity of the free extract [60].
In addition, encapsulating molecules in organic nanotubes enhances their phytotoxic effects by increasing their recognition by plant cells and ensuring the targeted release of the compounds using minimal quantities. Importantly, the encapsulation of aguerin B, cynaropicrin, and grosheimin, isolated from the leaves of C. scolymus, in nanotubes based on the natural steroid lithocholic acid effectively inhibits germination, root growth, and shoot growth of Phalaris arundinacea L., L. perenne L., and P. oleracea L., compared with the free compounds, thereby demonstrating the effectiveness of encapsulation in enhancing the bioherbicidal activity of sesquiterpene lactones [105].
7. The Green Extraction of Sesquiterpene Lactone from Cynara Species
The recovery of sesquiterpene lactones from Cynara is a crucial step that significantly impacts their biological activity. Therefore, the extraction techniques and solvents used are considered the main factors influencing the recovery of sesquiterpene lactones from different parts of this plant.
7.1. Extraction Solvents
The chemical nature of the solvent influences the solubility and therefore the selectivity of the molecules to be extracted [106]. In particular, the solvent is a key factor in the extraction of sesquiterpene lactones from Cynara [107]. Ethanol is the most effective solvent for cynaropicrin extraction from C. cardunculus leaves. Indeed, high yields of cynaropicrin were obtained using ethanol as a solvent in both batch extraction (56.90 ± 1.47 mg/g DW) and ultrasound-assisted extraction (UAE) (55.00 ± 2.92 mg/g DW), followed by ethyl acetate in batch extraction (37.48 ± 2.19 mg/g DW) and UAE (52.57 ± 1.73 mg/g DW). Water is not suitable for cynaropicrin extraction, as demonstrated by the low yields obtained using batch extraction (13.60 ± 1.13 mg/g DW), UAE (23.76 ± 1.56 mg/g DW), and microwave-assisted extraction (1.47 ± 0.16 mg/g DW) [108]. In addition, pure ethanol is more effective than 70% ethanol and water for extracting cynaropicrin from C. scolymus leaves [37].
Although solvents such as ethanol and ethyl acetate are effective for extracting sesquiterpene lactones from Cynara, they remain highly toxic and non-recyclable. Recently, ionic liquids have attracted increasing interest. They are characterized by low volatility, non-flammability, high thermal stability, viscosity, and recyclability. Ionic liquids are organic salts composed of combinations of anions and cations [109]. Various types of cations and anions can be combined to design ionic liquids. Acyclic cations (phosphonium, ammonium, sulfonium, cholinium) and cyclic cations (imidazolium, pyridinium, pyrrolidinium, and piperidinium) can be paired with inorganic anions (halides, cyanate, phosphate, sulfate, nitrate, and borate) or organic anions (phenolate, benzoate, malonate, and amines). The properties of these ionic liquids can be further tuned by incorporating functional groups such as long-chain hydrocarbons, ethers, hydroxyl, phenyl, and nitrile groups [110]. Recently, extraction via centrifugation–decantation using mixtures of ionic liquids and organic solvents has proven efficient and safe for recovering cynaropicrin from artichokes. The ionic liquids 1-ethyl-3-methylimidazolium methylphosphonate ([C2mim][MeO(H)PO2]) and N, N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium 2-methoxyacetate ([DEME][MOAc]) have been used in combination with organic solvents to enhance cynaropicrin extraction from artichoke. Indeed, the [C2mim] [MeO(H)PO2]/ethanol (1:1 w/w) system improves cynaropicrin yield by 0.59% compared with ethanol alone, which yields 0.35% cynaropicrin. Similarly, the same ionic liquid combined with ethyl acetate yields 0.67% cynaropicrin compared with 0.43% using ethyl acetate alone. The [C2mim][MeO(H)PO2]/acetone (1:1 w/w) system is the most effective solvent system, enabling a cynaropicrin recovery of 0.74%, which is 1.4 times higher than acetone alone. This yield further increases to 0.92% when the extraction time is extended to 120 min. The ionic liquid N, N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium 2-methoxyacetate ([DEME][MOAc]) also enhances cynaropicrin extraction when combined with organic solvents. Using [DEME][MOAc]/ethanol (1:1 w/w), a cynaropicrin yield of 0.62% was obtained, compared with 0.60% for both [DEME][MOAc]/acetone (1:1 w/w) and [DEME][MOAc]/ethyl acetate (1:1 w/w) [111].
The effectiveness and efficiency of pure ionic liquids can be further improved by adding an aqueous solution, which enhances mass transfer and reduces ionic liquid consumption. Surface-active ionic liquids increase cynaropicrin yield by 1.19% to 3.18% compared with hydrotropic ionic liquids. Aqueous solutions of cationic surface-active ionic liquids, such as [C8–14mim] Cl with alkyl side chains, are more effective than anionic surface-active ionic liquids for cynaropicrin extraction. Extraction of C. cardunculus leaves by agitation using [Cnmim]Cl ionic liquids (n = 8–14) at a concentration of 500 mM, at 25 °C for 60 min, and a solid-to-solvent ratio of 1:20 resulted in a cynaropicrin yield of 3.73%, which increased to 6.47% (w/w) after three extraction cycles. These solvents can be recycled by adding water as an anti-solvent, which precipitates cynaropicrin, after which the solvent is recovered by evaporating the water [112].
Moreover, deep eutectic solvents (DESs) have emerged as promising green solvents for the extraction of phytochemicals for food and pharmaceutical applications [113]. DESs are mixtures of two or more organic or inorganic compounds linked by hydrogen bonds and van der Waals interactions that form a liquid phase under appropriate temperature conditions. They are composed of a hydrogen bond donor (HBD), commonly urea, sugars, organic acids, and polyalcohols, and a hydrogen bond acceptor (HBA), most frequently cholinium chloride ([Ch]Cl) [114]. DESs are non-toxic, easy to prepare, recyclable, and cost-effective, making them a suitable alternative to conventional organic solvents [113]. DESs also offer several advantages over ionic liquids, particularly in terms of ease of preparation and lower cost [110]. The type of DES, the HBD/HBA molar ratio, and viscosity are the main factors influencing the extraction efficiency of bioactive molecules [113]. Deep eutectic solvents are effective for extracting cynaropicrin from Cynara leaves compared with organic solvents such as hexane, acetone, and dichloromethane. The type of DES used is an important factor in cynaropicrin extraction; in particular, a mixture of decanoic acid and [N4444] Cl at a molar ratio of 2:1 is the most optimal. Extraction of cynaropicrin from C. cardunculus leaves by stirring using a decanoic acid: [N4444] Cl (2:1 molar ratio) system, under a solid-to-liquid ratio of 1:30 at 25 °C for 60 min and with the addition of 70% (w/w) water, resulted in an extraction yield of 6.20 wt% cynaropicrin. A higher yield (8.96 wt%) was obtained after three extraction cycles using fresh solvent, which is comparable to that obtained by Soxhlet extraction using dichloromethane (8.65 wt%), with the advantage of lower temperature operation and reduced energy consumption. The main advantage of this solvent system is its recyclability: the addition of water as an anti-solvent induces precipitation of cynaropicrin, after which the deep eutectic solvent can be recovered by evaporating the water [115]. Furthermore, a more efficient extraction of sesquiterpene lactones from artichoke leaves using a mixture of choline chloride and levulinic acid (1:2 ratio) enabled the extraction of a high concentration of cynaropicrin (3.19 ± 0.26 mg/g dry matter), along with traces of cynaroscoloside A/B [27].
7.2. Extraction Methods
7.2.1. Conventional Extraction Methods
The extraction technique significantly impacts the recovery of STLs from Cynara. Conventional extraction techniques are widely used for the recovery of these compounds, notably Soxhlet extraction and maceration (Table 2).
- Soxhlet extraction
The Soxhlet extraction technique is based on repeated contact between the solid material contained in an extraction cartridge and the solvent under reflux conditions [116]. Despite the advantage of continuous solvent–solid interaction, this technique involves high temperatures that may degrade the target compounds, in addition to long extraction times due to multiple extraction cycles required to maximize yield [117]. Soxhlet extraction using ethanol has been shown to be more effective than maceration and infusion for recovering sesquiterpene lactones from artichoke leaves [107]. Dichloromethane is also widely used as a solvent. A cynaropicrin concentration of 40.32 ± 1.13 mg/g DW was obtained from artichoke leaves using dichloromethane after 7 h of Soxhlet extraction [108]. Under similar Soxhlet conditions, a total of 484 ± 15.8 mg/g extract of sesquiterpene lactones was obtained from cultivated cardoon leaves, with cynaropicrin present at high concentrations (455.2 ± 14.7 mg/g extract) [71]. In addition, 841 mg/kg DW of deacylcynaropicrin and 87,482 mg/kg DW of cynaropicrin were extracted from cardoon leaves, while 230 mg/kg DW of cynaropicrin was obtained from the outer parts of the stalks using this method [62].
- Maceration
The maceration technique is a simple method consisting of bringing the plant material, placed in a closed container, into contact with the extraction solvent for a defined period [117]. This technique is more effective for cynaropicrin extraction from Cynara compared with decoction and infusion [37]. The main disadvantage of this technique is the long extraction time, typically up to 3 days. In this context, maceration using 70% methanol for 72 h at room temperature yielded a cynaropicrin concentration of 158 mg·kg−1 dry matter from cultivated cardoon leaves [102]. On the other hand, some authors have applied hot maceration, which can degrade STLs results in lower extraction yields. Accordingly, the extraction of artichoke bracts using 70% ethanol overnight under agitation at 70 °C allowed the isolation of cynaropicrin only at a low concentration (405.2 ± 1.3 µg/g) [118]. Additionally, the solvent used in maceration influences the selectivity of the extracted compounds. Maceration of artichoke leaves using 50:50 ethanol at room temperature for 3 h enabled the extraction of eight sesquiterpene lactones (3β,8α,11α,13-tetrahydroxy-10(14)-guaien-1α,4β,5α,6βH-6α,12-olide, cynarascoloside A/B, cynaratriol, cynarinin B, and deacylcynaropicrin 8-O-β-D-glucopyranoside) [35], whereas maceration in water led to the isolation of only cynaropicrin and deacylcynaropicrin [39].
Another maceration process consists of soaking the plant material in acetone at room temperature for 3 h, followed by chlorophyll removal using lead diacetate, and subsequent enrichment of the extract through re-extraction with ethyl acetate, followed by drying with anhydrous Na2SO4. The use of this technique allowed the recovery of 3.6 g (41.9%) of cynaropicrin and 0.2 g (2.3%) of grosheimin from artichoke leaves [119]. This maceration process demonstrated high extraction efficiency within a short time; however, its main drawback is the need for successive filtration and centrifugation steps, making the protocol difficult to apply, particularly on a large scale.
- The Bligh–Dyer extraction technique
The Bligh–Dyer extraction technique is a classical method that uses a chloroform/methanol mixture for lipid extraction from animal and plant tissues [120]. This technique has also been applied to extract lipophilic compounds from artichoke leaves and stalks. The protocol consists of mixing the plant material with a methanol/chloroform mixture at a 2:1 ratio, followed by the addition of distilled water. After extraction, chloroform and then water are added, allowing phase separation into two fractions: a hydroalcoholic fraction and a chloroform fraction. Using this technique, a cynaropicrin concentration of 27.5 ± 2.7 µmol/g DW was obtained in leaves, while 2.47 ± 0.21 µmol/g DW was reported in stalks. Moreover, the concentrations of dehydrocynaropicrin and grosheimin were 7.22 ± 0.92 and 10.8 ± 1.7 µmol/g DW, respectively [29].
Table 2.
Conventional extraction techniques used for the recovery of cynaropicrin from Cynara.
| Extraction Technique | Extraction Conditions | Cynara Variety | Plant Part | Concentration | Quantification Method | Reference | Advantages and Limitations |
|---|---|---|---|---|---|---|---|
| Maceration | Solvent: EtOH-H2O 70/30 (v/v) with agitation overnight at 70 °C | Artichoke (Tema cultivar) | Bract | 405.2 ± 1.3 µg/g | HPLC-DAD | [118] | Simple and low- cost process Long extraction time Organic solvents used are harmful to humans and the environment High solvent consumption Requires additional filtration and concentration steps |
| Extraction with acetone with agitation at room temperature | Artichoke (Carciofo di Malegno cultivar) | Leaf | 2.36 ± 0.39 mg/g DW | HPLC | [26] | ||
| Solvent: 70% methanol at a solid/liquid ratio of 1/10 for 72 h at room temperature | Cultivated cardoon | Leaf | 15.8 ± 0.1 mg/L | HPLC-UV | [78] | ||
| Solvent: 70% methanol at a solid/liquid ratio of 1/10 for 72 h at room temperature | Cultivated cardoon | Leaf | 158 ± 2 mg/Kg DM | HPLC-UV | [102] | ||
| Soxhlet | Solvent: dichloromethane for 7 h | Cultivated cardon | Leaf | 40.32 ± 1.13 mg/g DW | HPLC-UV | [108] | Simple and lowcost process High yield due to the continuous extraction cycles Long extraction time Usage of organic solvents Application of high temperatures that degrade the compounds High energy consumption |
| Solvent: dichloromethane for 7 h | Cultivated cardon | Leaf | 455.2 ± 14.7 mg/g | GC-MS | [71] | ||
| Solvent: dichloromethane for 7 h | Cultivated cardoon | Leaf | 87,482 mg/kg DW | GC-MS | [62] | ||
| Stalk | 230 mg/kg DW |
7.2.2. Modern Extraction Techniques
Recently, there has been growing interest in unconventional extraction techniques for isolating sesquiterpene lactones from Cynara. Various modern extraction techniques have been evaluated for their efficacy, including ultrasonic extraction, pressurized liquid extraction, and supercritical fluid extraction (Table 3). These techniques have enabled the extraction of high yields of these compounds in a shorter time frame while reducing energy consumption [121].
- The ultrasound-assisted extraction
The ultrasound-assisted extraction technique is based on the phenomenon of acoustic cavitation generated by ultrasound, creating cycles of compression and decompression and thereby facilitating solvent penetration into the plant material [122]. This simple extraction process offers several advantages over conventional techniques, in particular low temperature operation, low solvent consumption, and short extraction time [123]. Ultrasound-assisted extraction is an efficient technique for extracting cynaropicrin from C. cardunculus leaves. Ultrasonic extraction using ethanol as a solvent, with a liquid-to-solid ratio of 16:1 mL/g, at 20 kHz for 5 min, an amplitude of 15%, and a temperature of 40 °C, was more efficient for cynaropicrin extraction than Soxhlet extraction using dichloromethane. Using this technique, the yield of cynaropicrin was 55.00 ± 2.92 mg/g DW versus 40.32 ± 1.13 mg/g DW obtained by Soxhlet, with a reduction in extraction time of 99% (from 7 h to 5 min) and energy consumption of 97% [108]. Ultrasound-assisted extraction was further optimized for recovering high concentrations of cynaropicrin from C. cardunculus leaves. Using pulsed mode with a duty cycle of 25%, higher extraction yields were obtained with lower energy consumption compared with continuous mode, which requires more energy. A cynaropicrin yield of 23.99 mg/g DW and a concentration of 192.23 mg/g extract were obtained using a solid-to-liquid ratio of 1:27, ethanol as solvent, an amplitude of 67%, and a temperature of 44 °C [121].
- Pressurized liquid extraction
Pressurized liquid extraction is performed at high temperature and pressure by placing the sample in a closed system in contact with the extraction solvent. The high temperature and pressure conditions increase the diffusion rate, thereby enhancing the solubility of the analytes while using a small amount of solvent over a short time [117]. Cynaropicrin recovery using pressurized liquid extraction in a single static cycle for 5 min at a pressure of 10.77 kPa is highly efficient for extracting cynaropicrin from C. cardunculus leaves compared with batch extraction. Using ethyl acetate as a solvent, a yield of 56.96 ± 4.52 mg/g DW was obtained, which is higher than that obtained using a batch extractor with the same solvent (37.48 ± 2.19 mg/g DW) and comparable to ethanol extraction (56.90 ± 1.47 mg/g DW), with a reduced extraction time from 1 h to 5 min and a reduction in energy consumption from 1.160 to 0.176 kWh/g of cynaropicrin [108].
- The supercritical fluid extraction
Supercritical fluid extraction is based on the use of a supercritical fluid as a solvent, which, upon reaching its critical point, acquires the physical properties of a liquid, thereby combining properties of a solvent and gas, thus facilitating the diffusion of extractable compounds. Supercritical carbon dioxide (CO2) is the most widely used solvent in this process due to its low toxicity, low cost, and the ability to modify its density by changing temperature and pressure [117]. In addition, this solvent is highly selective for nonpolar compounds. Compared with polluting organic solvents, supercritical fluids reduce the time and cost associated with solvent removal [106].
The supercritical fluid extraction technique has proven to be highly effective for extracting STLs from Cynara leaves, ensuring high selectivity for these compounds. In terms of selectivity, two sesquiterpene lactones, cynaropicrin and cynaroscolosides A and B, were isolated from artichoke leaves using supercritical CO2 extraction, whereas ultrasound-assisted extraction was only able to extract cynaropicrin. In fact, supercritical CO2 extraction yielded a high recovery of cynaropicrin (48.33 ± 2.42 mg/g DW) and cynaroscolosides (8.22 ± 0.74 mg/g DW) using a temperature of 40 °C, a pressure of 300 bar, and a CO2 flow rate of 1.4 kg CO2/h for 60 min. In contrast, a lower concentration of cynaropicrin (3.02 ± 0.29 mg/g DW) was obtained using ultrasound-assisted extraction with 96% ethanol at an amplitude of 60%, a power of 400 W, and a frequency of 24 kHz. In addition, supercritical fluid extraction is highly effective compared with deep eutectic solvent extraction using choline chloride and levulinic acid in a 1:2 ratio, which allowed the extraction of only cynaropicrin at a concentration of 3.19 ± 0.26 mg/g DW [27].
- The ultra-turrax assisted extraction technique
Homogenization-assisted extraction is a physical intensification method that applies high mechanical shear forces to rupture cell membranes and release intracellular compounds [124]. Ultra-Turrax homogenization is widely used for the extraction of bioactive compounds from plant materials; it offers the advantages of reducing extraction time, minimizing solvent consumption, and preserving compound integrity through the use of low temperatures [125]. This technique is more efficient for the extraction of lipophilic compounds than conventional extraction techniques [126]. The application of this technique, involving blending wild cardoon leaves with 80% ethanol at a 2:5 (w/v) ratio using an immersion blender, followed by homogenization with an Ultra-Turrax, resulted in the recovery of cynaropicrin concentration of 45 ± 0.02 mg/g DW from this variety [98]. In addition, extraction of artichoke capitula using this technique with 80% methanol at a solid-to-solvent ratio of 1:10 for 5 min at 20,000 rpm allowed the extraction of 1199.87 mg/100 g DW of sesquiterpene lactones, with identification of five compounds, among which dehydrocynaropicrin, grosheimin, and cynaratriol were the major compounds [56].
- Naviglio
The Naviglio extraction technique, also known as rapid solid–liquid extraction, is based on alternating cycles of compression and decompression to facilitate the transfer of target compounds from plant material. The static phase involves applying high pressure (10 bar) while the solvent is in contact with the plant material for 1 to 3 min in order to allow its penetration into the plant tissues. This phase is followed by a dynamic decompression phase, which consists of a rapid pressure drop that expels intracellular compounds from the solid material. This technique, considered an efficient method for solid–liquid extraction, offers several advantages, including simplicity, low cost, low energy consumption, and high extraction yield compared with conventional and modern techniques such as ultrasound-assisted extraction and supercritical fluid extraction [127]. This technique was more effective for the recovery of cynaropicrin from cardoon leaves compared with supercritical fluid extraction. Using Naviglio with ethanol as solvent at 25 °C, a high yield of cynaropicrin (0.23 w/w) was obtained, in contrast to the lower yield of 0.020 w/w obtained by supercritical fluid extraction [128]. Moreover, the application of the Naviglio extraction technique using 75% ethanol for 20 cycles of 12 min allowed the extraction of eight sesquiterpene lactones from artichoke leaves, including 3β,8α,11α,13-tetrahydroxy-10(14)-guaien-1α,4β,5α,6βH-6α,12-olide, cynarinin A, cynaratriol, deacylcynaropicrin, and cynaropicrin, in addition to the isolation of dihydrodesacylcynaropicrin 8-O-β-glucopyranoside, aguerin B, and cynaropicrin methoxylate for the first time in this genus [53].
Table 3.
The modern extraction techniques of cynaropcrin from the different parts of Cynara.
| Cynara Variety | Geographical Origin | Plant Parts | Concentration | Technique of Extraction | Extraction Conditions | Technique of Quantification | Reference |
|---|---|---|---|---|---|---|---|
| Artichoke (Carciofo Ortano cultivar) | Italy | Secondary flower head | 976.85 ± 10.46 mg/kg DW | Ultrasound-assisted extraction | Solvent: 100% methanol Amplitude: 200 W Three cycles of 30 min, at room temperature | HPLC-DAD | [41] |
| Artichoke (Carciofo Ortano cultivar) | Italy | Stem | 2254.58 ± 61.95 mg/kg DW | Ultrasound-assisted extraction | Solvent: 100% methanol Amplitude: 200 W, three cycles of 30 min, at room temperature | HPLC-DAD | [41] |
| Artichoke (Carciofo Ortano cultivar) | Italy | Leaf | 8143.3 ± 2845.4 mg/kg DW | Ultrasound-assisted extraction | Solvent: 100% methanol Amplitude: 200 W Three cycles of 30 min, at room temperature. | HPLC-DAD | [129] |
| Artichoke (Imperial star cultivar) | Italy | Leaf | 3.02 ± 0.29 mg/g DW | Ultrasound-assisted extraction | Solvent: 96%, ethanol Amplitude: 60 Pulsion: 100 Power: 400 W Frequency: 24 kHz | HPLC-DAD | [27] |
| Artichoke (Imperial star cultivar) | Italy | Leaf | 48.33 ± 2.42 mg/g DW | Supercritical CO2 extraction | Temperature: 40 °C Time: 60 min Pressure: 300 bar, CO2 mass flow rate: 1.4 kg CO2/h. | HPLC-PDA | [27] |
| Artichoke (Imperial star cultivar) | Italy | Leaf | 3.19 ± 0.26 mg/g DW | Deep Eutectic Solvent Extraction | Binary mixture of choline chloride and levulinic acid in a 1:2 ratio | HPLC-DAD | [27] |
| Cultivated cardoon | ND | Leaf | 119.34 ± 5.97 mg/g of extract | Pulsed ultrasound-assisted extraction | Solvent: ethanol Duty cycle: 25 % Solid/liquid ratio: 1/27 (g/mL) Extraction temperature: 44 °C Amplitude: 67 % (54.3 µm) Time: 30 min | HPLC-DAD | [61] |
| Cultivated cardoon | ND | Leaf | 299.35 ± 6.70 mg/g extract | Ultrasound-assisted extraction with ethanol | Liquid/solid ratio: 16/1 mL/g, 20 kHz, for 5 min with an amplitude of 15% at 40 °C | UPLC-QTOF | [60] |
| Cultivated cardoon | Spain | Leaf | 55.00 ± 2.92 mg/g DW | Ultrasound-assisted extraction with ethanol | Liquid/solid ratio: 16/1 mL/g, 20 kHz, for 5 min with an amplitude of 15% at 40 °C | HPLC-UV | [108] |
| 56.96 ± 4.52 mg/g DW | Pressurized liquid extraction | Solvent: Ethyl acetate Single static cycle during 5 min, with pressure of 10.77 kPa and temperature of 40 °C | HPLC-UV | [108] | |||
| 38.41 ± 1.61 mg/g DW | Microwave-assisted extraction | Solvent: ethyl acetate Microwave power of 1000 W for 15 min at 80 °C | HPLC-UV | [108] | |||
| Cultivated cardoon | Italy | Leaf | 0.230 mg/mg extract | Naviglio extractor | Solvent: 25 °C ethanol Pression: 9 bars Cycle: static phase 2 min; dynamic phase 2 min, with 12 s stop piston Time: 24 h | GC-MS | [128] |
| Wild cardoon | Italy | Leaf | 45 ± 0.02 mg/g of DW | Ultra-turrax assisted extraction | Solvent: 80% ethanol Solid liquid ratio: 2:5 (w/v) | HPLC-PDA | [98] |
8. The Approaches for Improving Production of Sesquiterpenes Lactones from Cynara
Various biotechnological approaches have been devised to improve the production of plant secondary metabolites. Callus culture, organ culture, and micropropagation are attractive approaches; however, due to the difficulty of applying them on a large scale, different, more scalable strategies have emerged [130]. Elicitation is one of the most effective approaches for inducing or enhancing the biosynthesis of secondary metabolites in the Asteraceae family [131]. This approach is based on stimulating the production of secondary metabolites through the activation of regulatory transcription factors and enzymes following exposure to elicitors. Elicitors can be biotic (microorganisms, polysaccharides, pectin, chitosan) or abiotic, including physical, chemical, or hormonal factors [130]. Physical elicitors include light, temperature, water stress, and salinity. Salinity has been shown to be an effective approach for stimulating the production of secondary metabolites (hydroxycinnamic acids, flavonoids, sugars, and volatiles) in the Asteraceae family [131]. The effectiveness of salt stress in improving the accumulation of sesquiterpene lactones in Cynara has been demonstrated. Under salt stress conditions induced by treatment of C. altilis with 100 mM NaCl for 21 days, cynaropicrin concentration increased slightly, particularly in the Spagnolo genotype, compared with untreated plants. The increase in cynaropicrin synthesis is mediated by upregulated expression of the GAO and COS sesquiterpene lactone biosynthesis genes under salt stress [132]. In addition, shading is an abiotic stress that induces the accumulation of sesquiterpene lactones in cardoon leaves. Exposure of cardoon to 60% shade increases the concentration of total sesquiterpenes in the leaves, in particular cynaropicrin and cynartriol, compared with the control, and is associated with higher phytotoxic potential [103].
In addition, the use of hormonal elicitors such as methyl jasmonate (MeJA) has proven effective in promoting the production of sesquiterpene lactones in the Asteraceae family [131]. Gibberellic acid (GA3) is a growth regulator widely used to enhance artichoke yield. The effect of gibberellic acid treatment on three genotypes of C. scolymus was evaluated under field cultivation conditions. GA3 treatment induced a significant accumulation of cynaropicrin in the leaves. Treatment of the “Violet de Provence” and “Tema 2000” genotypes with an aqueous solution of GA3 acidified with urea phosphate at a concentration of 0.01 g/L, and of the “Apollo” genotype at concentrations of 0.03, 0.06, and 0.1 g/L, significantly increased cynaropicrin accumulation in the leaves compared with the untreated controls [133].
Moreover, microbial biostimulants are powerful biotic elicitors, among which arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) are widely used. Inoculation of the roots of C. scolymus with a commercial AMF preparation (a mixture of Rhizophagus intraradices and Funneliformis mosseae), either alone or in combination with PGPR (a mixture of A. brasilense, Azotobacter chroococcum, B. megaterium, and P. fluorescens), at a dose of 2 kg ha−1, affected the content of sesquiterpene lactones in both the leaves and edible parts. The combined application of AMF and PGPR increased the contents of cynartriol and cynaropicrin in the edible parts and enhanced the content of grosheimin in the leaves compared with untreated plants [134].
On the other hand, several factors affect the content and profile of sesquiterpene lactones in Cynara species. Understanding the optimal factors that promote the accumulation of sesquiterpene lactones facilitates the development of strategies to enhance their production. The Cynara variety is an important factor influencing both the amount and composition of sesquiterpene lactones. In effect, wild cardoon contains the highest concentration of sesquiterpene lactones, followed by cultivated cardoon, whereas artichoke contains the lowest concentration. Wild cardoon is particularly rich in cynaropicrin, 11,13-dihydro-deacylcynaropicrin, and 11,13-dihydroxy-8-deoxygrosheimin. Cultivated cardoon constitutes an important source of cynaratriol and aguerin B, in contrast to artichoke, which contains significant amounts of grosheimin [82]. In addition, the genotype of Cynara is an important factor influencing the qualitative and quantitative profiles of sesquiterpene lactones. Comparison of the STL profiles of the Marsala and Valparaiso cultivars of wild cardoon revealed that the Marsala cultivar is rich in cynaropicrin, grosheimin, 11,13-dihydro-deacylcynaropicrin, 11,13-dihydroxy-8-deoxygrosheimin, and deacylcynaropicrin, whereas the Valparaiso cultivar contains higher levels of cynaratriol and aguerin B [100]. Additionally, the choice of harvest time is of great importance for obtaining significant concentrations of sesquiterpene lactones from Cynara. Regardless of genotype and variety, the concentration of sesquiterpene lactones is highest in April, followed by November, whereas winter harvests contain the lowest amounts [135]. This finding is explained by the climatic conditions prevailing in April, particularly higher temperatures and lower precipitation, which stimulate their synthesis. In addition, the maturation stage of the leaves affects STL concentrations; young leaves constitute an important source of cynaropicrin, whereas adult leaves contain lower concentrations [135].
9. Conclusions and Future Perspectives
Cynara species are important sources of sesquiterpene lactones, which are particularly concentrated in the leaves. These compounds exhibit promising biological activities, and various approaches have been developed to enhance their production. Improvement of sesquiterpene lactone production at the crop level through the use of biotic and abiotic elicitors has proven effective in increasing their accumulation. In addition, novel methods characterized by high efficiency and low cost have emerged to improve the production of plant-derived bioactive compounds. Nanotechnology has recently gained attention as a potential elicitation strategy that promotes the accumulation of secondary metabolites, and the use of nanoparticles may effectively enhance the production of sesquiterpene lactones in Cynara. Moreover, certain elicitors, such as NaCl, microorganisms, and hormones, have been shown to stimulate the accumulation of sesquiterpene lactones in Cynara, and greater attention should be directed toward the use of nanotechnology for the targeted delivery of these elicitors. On the other hand, extraction represents a crucial approach for recovering high quantities and ensuring the quality of sesquiterpene lactones from Cynara. The use of green solvents and modern extraction techniques has proven more effective than conventional solvents and extraction methods. To date, only ultrasound-assisted extraction has been optimized for the recovery of STLs from Cynara. Recently, enzyme-assisted extraction techniques have emerged, and their application for the extraction of sesquiterpene lactones deserves further investigation. In addition, the combination of green solvents with modern extraction techniques should be explored to achieve optimal extraction efficiency.
Author Contributions
Conceptualization, H.N., Y.N., H.B., S.B. and M.R.; methodology, S.B., H.B. and M.R.; software, H.N. and Y.N.; validation, S.B., H.B. and M.R.; formal analysis, H.N. and Y.N.; investigation, H.N., Y.N. and M.R.; resources, H.N.; data curation, H.N. and Y.N.; writing—original draft preparation, H.N.; writing—review and editing, H.N. and M.R.; visualization, H.N. and Y.N.; supervision, S.B., H.B. and M.R.; project administration, M.R. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Data Availability Statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflicts of interest.
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Figure 1.
Structure of the main sesquiterpene lactones in Cynara.
Figure 2.
The biological activities of sesquiterpene lactones from the genus Cynara and their regulatory mechanisms demonstrated by in vitro studies. Red arrows indicate activation. Red upward and downward arrows indicate increased and decreased expression or activity. Red T-bars and green or blue (X) marks indicate inhibition or suppression of targets and molecular pathway.
Figure 2.
The biological activities of sesquiterpene lactones from the genus Cynara and their regulatory mechanisms demonstrated by in vitro studies. Red arrows indicate activation. Red upward and downward arrows indicate increased and decreased expression or activity. Red T-bars and green or blue (X) marks indicate inhibition or suppression of targets and molecular pathway.
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Nechchadi, H.; Nadir, Y.; Berrougui, H.; Boulbaroud, S.; Ramchoun, M. Sesquiterpene Lactones in Cynara: Biological Activities, Agriculture Applications, Extraction Techniques, and Production Enhancement Strategies. Compounds 2026, 6, 39. https://doi.org/10.3390/compounds6030039
AMA Style
Nechchadi H, Nadir Y, Berrougui H, Boulbaroud S, Ramchoun M. Sesquiterpene Lactones in Cynara: Biological Activities, Agriculture Applications, Extraction Techniques, and Production Enhancement Strategies. Compounds. 2026; 6(3):39. https://doi.org/10.3390/compounds6030039
Chicago/Turabian StyleNechchadi, Habiba, Youssef Nadir, Hicham Berrougui, Samira Boulbaroud, and Mhamed Ramchoun. 2026. "Sesquiterpene Lactones in Cynara: Biological Activities, Agriculture Applications, Extraction Techniques, and Production Enhancement Strategies" Compounds 6, no. 3: 39. https://doi.org/10.3390/compounds6030039
APA StyleNechchadi, H., Nadir, Y., Berrougui, H., Boulbaroud, S., & Ramchoun, M. (2026). Sesquiterpene Lactones in Cynara: Biological Activities, Agriculture Applications, Extraction Techniques, and Production Enhancement Strategies. Compounds, 6(3), 39. https://doi.org/10.3390/compounds6030039
