Cichorium intybus: A bitter herb with remarkable therapeutic benefits

Introduction

The existence of plant-based medicines and their acceptance by people is as old as human civilization. Currently, researchers are paying much attention to the development of plantbased medicines due to their fewer side effects and a long history of use. Besides, ethnomedicinal plants have been reported to be a rich reservoir of many bioactive components with therapeutic potential. The plant Cichorium intybus L. or "chicory" belonging to the Asteraceae family is a typical Mediterranean therapeutic plant. C. intybus is a tiny (1m height) aromatic, biennial to a perennial herb with large leaves, a fleshy taproot, and bright flowers with blue petals [1,2] . C. intybus prefers to grow in open fields, waste places, roadsides, disturbed sites, and railroads [3] . C. intybus is widely cultivated in different parts of Europe, Asia, North America, and Egypt. The use of the herb in various food preparations dated back to the 16th century. The roots of C intybus var. sativum, has been used as a coffee additive in Europe. The roots of the Chicory plants have been reported to contain a significant amount of inulin (up to 40%). Inulin can be consumed as a sweetener, which has been reported to maintain the blood sugar level [3] . Flowers and roots of chicory contain various phytoconstituents such as different carbohydrates, methoxy coumarin cichorine, flavonoides, and essential oils [4] . The leaves of C. intybus are bitter due to the presence of sesquiterpene lactones [5] . The chicory herb can be added in the compost heap along with some other herbs to enhance bacterial activity [3] . The C. intybus herb has been reported to survive in extreme temperatures as well showed to have high adaptability to acidic and alkaline soil conditions, although the extremely high acidic condition is unfavourable for its growth [6] . Street et al. [7] reported four types of cultivated varieties of C. intybus based on their uses. The first one is "industrial" or root "chicory", the taproot of which is rich in inulin. The starch present in the roots of chicory can be used for the industrial production of alcohol. The second one is "forage" chicory which has the potential to be used as feed additives in animals. The third one is "Brussels" or "Witloof" chicory which is grown for commercial production of "Chicon". The fourth one is "leaf" chicory, which is used as leafy greens in a salad [8] . Different parts of C. intybus herb are used traditionally in various food preparations and treatment of common diseases in Europe, in some parts of Asia and Africa.

The chicory plant is rich in different phytoconstituents of medicinal importance. Chicory shows a long history of utilization as a tonic for liver diseases and digestive issues [9] . All imperative parts of this plant possess medicinal properties, mainly the root, seed, leaf, and flower extracts are used in different herbal remedies [10,11] . The root extracts are used in blood sugar and blood pressure regulation, jaundice, rheumatic, and gout disorders. The root extract is also used in folk medicines as an anti-tumorous agent [9] . There are numerous reports on pharmacological activities of chicory such as anti-cancer, anti-fungal, anti-malarial, antidiabetic, and free radical scavenging activity [3] . This review aims to investigate various traditional uses and scientific validation of C. intybus as well as the phytochemical composition of different parts and their pharmacological potential. The use of chicory in traditional medicine for curing liver and digestive problems has a long history [9] . The roots, leaves and flowers have been used as tonic and appetizers as well as for treatment of a variety of infectious ailments [10,11] .

Traditional uses

Most people of the world are dependent on the indigenous therapeutic plants for their primary health care needs [12] . In India, people living in rural areas mostly rely on herbal medicines for curing common diseases because of easy availability of plants and plant-based formulations in these areas. Herbal medicines are preferred over allopathic medicines by most people because of lesser toxicity and fewer side effects on human health. Ayurveda, Unani and Siddha are the best examples of traditional medicine systems with codified information. However, in folklore or ethno medicine, the therapeutic information is not well documented but are carried forward orally generation after generations. Due to the presence of therapeutically active compounds in medicinal plants, researchers are focusing on integrating folklore medicine with modern medicine system to develop desired therapeutic agents that can provide alternative remedies to infectious as well as non-infectious diseases. C. intybus is a multipurpose medicinal herb with antihepatotoxic, antidiabetic, anti-cancerous, antiulcerogenic, and anti-inflammatory properties [13,7] . In India and South Africa, formulations prepared by using various plant parts are used for plenty of herbal remedies. Mulabagal et al. [14] depicted the traditional use of chicory for the curing of various infectious as well as liver diseases. Some reports are available on the use of the roots of chicory plant as 'coffee additives' [5,15] and aerial parts in various diets in some countries of Western Europe and the United States [16] . In Eastern Anatolia, the powdered form of aerial parts and roots are used for the preparation of decoctions and infusions as a herbal remedy [17] . Tabata et al. [18] reported the use of root decoction of C. intybus in epilepsy. There is documented data available for use of chicory roots as well as roots/ leaves mixtures in the 'European traditional medication system' for healing some issues such as mild dyspeptic disorders, digestive disorders and as an appetizer [19] . Root decoctions are also used as a tonic and diuretic [20] . The herb is also reported to have shown cholesterol and blood sugar-lowering effects but with a high dose. Bischoff et al. [21] reported the remedial activity of aqueous extracts from roots of Cichorium intybus (L.) against malaria in Western Afghanistan. The isolated antimalarial compounds were reported to be lactucin and lactucopicrin (sesquiterpene lactones). There are reports on the use of the chicory flowers in the production of dye (Bremness 1998). Decoctions prepared from whorls of the herb are used as a depurative in Italy [22] . The use of chicory seeds as main constituent in "Jigrine", a commercial product for the treatment of liver diseases in India has been reported [23] . In Jordan cooked whole plant is used for the treatment of internal haemorrhage [23] . The prolific exploration of various plant parts in the healing of liver disorders is prevalent in many countries like Bosnia, Herzegovina [24] and Serbia [25] . The traditional uses of C. intybus in different regions of the world are represented in Table 1. Leaves [41, 42,43, 44] Triterpenoids and steroids 'Taraxerone' (23), 'bauerenyl acetate' (24), 'intybusoloid' ( 25) Roots [37] 'stigmasterol' (26), and 'campesterol' ( 27) Leaves [45] Sesquiterpenoids 'Jacquinelin' (28) 50), 'lactucopicrin-15-oxalate' (51), 'chicoralexin' (52), '1a,5aepoxy-4a-hydroxyl-4b', '10b-dimethyl-7aH', '10aH-guaia-l1( 13)-en-12-oic acid (138)', '3a-R-santamarine' ( 53)

Roots

Leaves seeds Whole plant [46] Nitrogen-contained compounds 'Caffeine' (54), 'theophylline' ( 55), '8-hydroxyquinoline' (56), 'zeatin' and 'riboside' ( 57) Roots [47, 48, 49, 50] Organic acids 'tartaric acid' (169), '4-hydroxycinnamic acid' (58), 'oxalic acid' (59), 'quinic acid' (60), 'ascorbic acid' (61), 'citric acid' (62), 'malic acid' ( 63), '4-Oferuloylquinicacid' (64), '5-O-feruloylquinic acid' (65), '3-caffeoylquinic acid' (66), '4-caffeoylquinic acid' (67), '5-caffeoylquinic acid' (68), 'cis-5caffeoylquinic acid' (69), 'ciscaftaricacid' ( 70 Aerial part/ roots [37, 7] Polysaccharides 'Inulin' (89) Roots/ seeds [7] Pharmacological activities of C. intybus Herein an attempt is made to review and provide information on the reported pharmacological activities of C. intybus.

Antioxidant activity

The role of polyphenols such as flavonoids as antioxidants have been well documented [52, 53, and 54]. Phytochemical analysis showed the presence of more than 20 flavonoids in C. intybus (Table 2). There are various reports on the antioxidant activity of polyphenolic components isolated from C. intybus [7] . Abbas et al, (2015) determined that the hydroalcoholic extract of leaves of C. intybus exhibited a significant level of antioxidant activity. Similar results were obtained by Mathur et al, [55] for the hydroalcoholic extract of C. intybus showing the restoration of the toxicity effects induced by hydrogen peroxide in HepG2 cell lines. The 'DPPH) assay' showed the IC50 value of the leaf extract was very low (67.2 µg/ mL). The investigation carried out by Jancic et. al. [56], for antioxidant activity of chicory leaf extracts, showed that the wild type varieties exhibited more antioxidant activity than that of the cultivated varieties. They used 'DPPH', 'FRAP' and 'TEAC' assays to evaluate the trait of antioxidant. Phytochemical based evaluation showed that the level of phenolic content was more in wild varieties of chicory than that of the cultivated ones with lower antioxidant activity. The experimental study exhibited that the leaf extract of chicory is rich in organic acids, which could be the possible reason for a high level of antioxidant and enzyme inhibitory properties on α-glucosidase [17] . Zeb et al. [57] showed that preheating of C. intybus with microwave treatment resulted in increased antioxidant activity due to the enhancement of bioactive components.

Hepatoprotective Activity

The indigenous use of C. intybus in curing liver disorders in different parts of the world has been well documented. "Liv52" is an Ayurvedic tonic used for liver protection in India and C. intybus is one of the major herbal ingredients in it. "Jigrine", another herbal medicine, used in Ayurveda for liver protection is known to contain C. intybus leaves. Aqueous-methanolic extract of seeds of C. intybus tested against induced liver damage in rats by acetaminophen and carbon tetrachloride (CCL4) showed a considerable level of decrease in the amount of various elevated liver enzymes such as alkaline phosphatase, glutamyl oxaloacetate transaminase, alanine aminotransferase, hexadecenoic acid and glutamyl pyruvate transaminase in serum [58,59] . Saggu et al. [60] analyzed the ability of C. intybus fruit extract to improve biochemical and antioxidant activities in male rates with 4-tert-OP induced oxidative stress. Elgengaihi et al. [61] experimented to study the hepatoprotective potential of C. intybus extracts against CCl4 induced toxicity in male albino rats. For their experiments, one control group, one CCl4 treated group, one C. intybus extract-treated group and one both CCl4 and C. intybus extract-treated group of mice were taken. The fifth group of mice taken was treated with a standard hepatic drug (silymarin). Their results showed significant levels of restoration of the liver damage caused in CCl4 induced mice when treated with C. intybus extracts. Esculetin and cichotyboside isolated from C. intybus have been reported to possess a considerable level of hepatoprotective activity [62] .

Antimicrobial activity

There have been a few reports on the antimicrobial potential of C. intybus extracts against both 'Gram-positive' and 'Gram-negative' bacteria. The methanol extract of C. intybus exhibited a higher level of antimicrobial activity than aqueous extract against a wide variety of pathogenic bacterial strains such as 'E. coli', 'S. aureus', 'S. epidermidis', 'Bacillus subtilis', 'P. aeruginosa', 'K. pneumoniae', 'Erwinia carotovora', 'P. vulgaris', 'Enterobacter cloacae' and 'S. pyogenes' as well as a fungal strain, 'Candida albicans' [63] . Liu et al. [64] revealed that the root extract exerted antibacterial trait against both types of bacterial strains ('Gram-positive' and 'Gram-negative'). Fusarium solani, appeared to be the most sensitive against chloroform, aqueous, and ethyl acetate extracts of chicory [65] . Seed extracts were reported to possess antibacterial potenlity towards two bacterial strains ('P. aeruginosa' and 'S. aureus') [66] , while on the contrary, leaf extract showed activity towards Saccharomyces sp. and Lactobacillus sp. [67] .

Antidiabetic and hypolipidemic activity

The traditional use of chicory in diabetes leads the researchers to investigate the antidiabetic activity of the whole plant [27,68] . Chandra et al. [69] demonstrated the antidiabetic activity of seed aqueous extract of C. intybus. Oral administration of the extract to diabetic rats showed a decreased pattern in the level of blood glucose and triglyceride (TG) levels. C. intybus leaf administration to diabetic rats resulted in a considerable decline in the serum glucose level [70] . Phytochemical analysis of chicory showed the presence of large quantities of inulin, especially in its root extracts. Lin et al. [71] examined the efficiency of inulin isolated from C. intybus in the high fatty diet-induced quail model. They reported a considerable level of increase in lipid metabolism after in the obese quails.

Gastroprotective activity

The traditional use of 'chicory' as an antiulcerogenic agent is prevalent in many European countries. The scientific investigation demonstrated that prior to ulcerogenesis induction, oral administration of C. intybus aqueous root extract (decoction) to Sprague-Dawley rats resulted in 95% of ulcer inhibition as compared to the untreated ulcer induced rats [72] . Wu [73] showed that C. intybus root powder administration resulted in improved regulation of imbalances of gut microbiota in cyclophosphamide-induced immunosuppressive mice. The leaf extract of C. intybus has been also reported to show antidiabetic activity, probably due to its high content of anthocyanins [74] .

Antimalarial activity

In Western Afghanistan, C. intybus aqueous root extracts are used as indigenous medicine for malaria treatment. Bischoff et al. [21] validated the traditional belief by reporting an exhibition of antimalarial effectiveess of 'lactucin' and 'lactucopicrin' isolated from roots. In addition to these, 'guaianolide', reported exhibiting antimalarial activity has been derived from the chicory root [7].

Anthelmintic Activity

C. intybus petroleum ether extract has been reported to show anthelmintic activity [75] . Forage chicory extracts showed antilarval activity against Ostartagia ostertagi [76] and Cooperia. oncophora [77] .

Antitumour effects

Root ethanolic extract of C. intybus depicted considerable high antitumour efficacy [78] . Aqueous-alcoholic leaf extracts of chicory showed antiproliferative activity on malignant C32 cell lines [79] . 'Magnolialide' (1끫뷺hydroxyeudesmanolide), derived from root portion of chicory, showed significant antitumour activity [80] . Chicory polysaccharide (CPS) isolated from the herb inhibited the growth of sarcoma in mice when CPS was orally administered prior to receiving tumour cells [81] .

Immunomodulatory effects

Crude C intybus extracts were reported to show effective immunomodulatory effects [82] . Oral administration of CPS to mice resulted in a significant increase in antibodyforming cells, activity of macrophages and size of the thymus gland and spleen [83] . CPS was also shown to have immunity-boosting effects on human [84] .

Anti-inflammatory effects

Rizvi et. al. [85] attempted to validate the traditional use of C. intybus as an effective anti-inflammatory remedy. In their experiment, carrageenan-induced paw edema Albino Wistar rats were administered with root ethanolic and aqueous extracts of C. intybus to observe anti-inflammatory potential of the extracts. Both extracts (aqueous and ethanolic extracts) depicted a significant decline in paw edema. There was a decrease in the level of cytokines such as 'TNF-α' (tumour necrosis factor alpha)', 'interleukin 6 (IL-6)', and 'IL-1' in the serum whereas there was an enhanced action of 'antioxidant enzymes' (especially glutathione peroxidase and catalase) indicating reduced inflammatory effects. The inflammatory effects of C. intybus could be due to various phytochemicals such as Sesquiterpene lactones, flavonoids, glycosides and tannins [86,7] . Flavonoids isolated from Chicory showed inhibitory effects on prostaglandin synthesis which are responsible for acute inflammation [87] .

Other pharmacological activities

In addition to the above-mentioned bioactivities C. intybus also showed neuritogenesis and neurotrophic effects [88,89,90] , Antihyperuricemia activity [91,92,93,94,95,96,97] and antiosteoporotic effects [98] .

Sesquiterpene lactones: a bitter constituent in C. intybus

Sesquiterpene lactones, one of the major bioactive constituents found in C. intybus is considered to be the reason for the slightly bitter taste of the plant [99,100] . Schenck and Graf [101] determined that lactucin and lactucopicrin are two sesquiterpene lactones that could confer bitterness at a considerably low concentration. Five sesquiterpene lactones namely lactucin, lactucopicrin, 8deoxylactucin, 11(S), 1 3-dihydrolactucin and 11 (S), 13dihydro-8-deoxylactucin were isolated from C. intybus and assessed for their detection thresholds for the bitter tastes [100] . Out of these five sesquiterpene lactones, 11(S), 13dihydrolactucopicrin was proven to be most bitter. Price et al. [102] measured the sensory threshold for the bitterness of sesquiterpene lactones, lactucin, 8-deoxylactucin and lactucopicrin and their glycosides isolated from red chicory and lettuce. When they compared the quantities of these bioactive compounds with the bitterness level, they found that there was a relation between the increase in bitterness and a higher level of one of these sesquiterpene lactones, lactucin glycoside. Similar data by Peters et al. [103] showed a strong correlation between the level of lactucin glycoside and bitterness. The plants belonging to the Asteraceae family were reported to be a rich source of sesquiterpene lactones [104] . There are various documented as well as undocumented information on the indigenous use of medicinal plants, rich in sesquiterpene lactones, for the treatment of bacterial infections, stomach ulcers, neurotoxicity, contact dermatitis as well as migraine [105,106,107,108] . Comparative analysis of sesquiterpene lactone, isolated from Artemisia douglasiana Besser suggested that the α-methylene-γlactone group (αMγL) play a key role in reducing gastric ulcer in mice induced with ethanol. The sesquiterpene lactones are known for their ability to influence αMγL unit by alkylation of thiol groups mostly found in proteins [109] . Lactucin and lactucopicrinare are the two most effective sesquiterpene lactones commonly found in chicory and lettuce that have sedative effects [110] (Wesolowska et al. 2006). Although the study on the antitumour activity of sesquiterpene lactones is limited, Sweeney et al. [111] reported that oral administration of parthenolide, a sesquiterpene lactone to mouse showed significant antitumour activity. The bitter sesquiterpene lactones presumably protect against herbivores and pathogens [112] . Although sesquiterpene lactones are known to have medicinal properties, due to the bitter taste, their consumption is limited. The level of sesquiterpene lactones in chicory can be lowered by altering the cultivation conditions [113] . However, shortfall of sesquiterpene lactones levels may engender a decrease in resistance patterns of the herb towards biotic stress, thus, affecting the crop yield.

The current transgenic approach in improving medicinal trait Because of its high medicinal and nutritional value C. intybus is predominantly grown in continental Europe, Northern and Southern Africa, southwestern Asia and in some areas of Australia and North America. In order to improve production, as well as the quality of the plant, researchers have paid their attention to developing various breeding techniques [114] . But there is a little investigation on the genetic engineering approach of improving the productivity of C. intybus [115,116] . This review focuses on providing information on various attempts made for the production of improved varieties of C. intybus by using different genetic transformation approaches. Sun et al. [117] first reported the genetic transformation of C. intybus using Agrobaterium rhizogenes. The transformed plants were able to flower annually without the need for vernalization. Vermeulen et al. [118] inserted acetolactate synthase gene isolated from Arabidopsis thaliana to produce herbicides resistant C. intybus. Although in vitro culture techniques have been attempted for achieving the taget of the better production of especillay 'bioactive compounds' in C. intybus, the outcome was not as effective as expected [119] . Nowadays, a technique involving either Agrobacterium rhizogenes or A. tumefaciens-mediated genetic transformation to produce hairy root cultures is gaining considerable interest because of the high level of secondary metabolite yield through this approach [120,121,122] . Hanafy et al. [119] reported that the genetic transformation of chicory hairy root cultures resulted in increased growth rates as well as more synthesis of inulin as compared to the non-transformed chicory. C. intybus growth is adversely affected by various abiotic stresses such as salinity, drought and low temperature. Li. et al. [123] in his experimental study, inserted a novel betaine aldehyde dehydrogenase (HvBADH1) gene isolated from Tibetan hulless barley into C. intybus by A. tumefaciensmediated genetic transformation. Various physiological factors associated with stress tolerance were analysed to study the stress resistance traits of the transgenic chicory plants. They observed that there was better retention of K + , a significantly higher amount of glycine betaine (GB) accumulation, reduced oxidative stress and enhanced growth rate in transformed C. intybus as compared to nontransformed wild type plants. The results indicated enhanced salinity resistance of transgenic C. intybus due to overexpression of HvBADH1gene in transgenic tissues. Inulin, a type of fructan in plants is acknowledged for depicting a noteworthy function in providing resistance to abiotic stresses [124] . The inulin isolated from C. intybus herb is used in a variety of food items such as in fat-free yoghurt and bread to get a better taste [125,126] . Inulin is also known to increase gut health [127] . The quality of inulin produced in industrial scale is affected by its polymer length [128] . '1-SST' (Sucrose-sucrose 1-fructosyltransferase) enzyme commences an imperative job in the production of inulin (particularly 'long-chain inulin') in C. intybus [129] . In chicory, 1-SST activity was suggested to decline at harvest time, therefore, affecting the polymer length of inulin [130] . Vijn et al. [131] attempted to produce transgenic chicory, overexpressing fructan 6-fructosyltransferase (SST) enzyme. The transformed plants were known to synthesise a new type of long-chain fructan in addition to the endogenous inulin. Maroufi et. al. [132] produced C. intybus plants overexpressing '1-SST enzyme' under the regulation of the 'CaMV 35S promoter'. Their study revealed that overexpression of 1-SST resulted in accumulation of longchain inulin in the roots of transgenic C. intybus. There have been a few reports on the enhancement of sesquiterpene lactone through biotechnological approach in chicory. Malarz et al. [133] could successfully enhance the production of '8-deoxylactucin' in the roots of chicory by the use of elicitors and growth condition optimization. Costunolide is an instantaneous precursor of parthenolide and costunolide synthase gene producing enzyme for the conversion of germacrenoic acid to costunolide was derived and derived from chicory [134,135] . There are also reports on the application of metabolic engineering method to improved accumulation of 'sesquiterpene lactone' in chicory roots by inhibition of its modification into another compound [136] . Transient co-expression of a 'germacrene A synthase' from feverfew [137] , a 'germacrene A oxidase' from chicory [138] , and 'costunolide synthase' from chicory [134] in N. benthamiana leaves resulted in the synthesis of two costunolide conjugates, 'costunolide-cysteine' and 'costunolide-glutathione'. Germacrene A synthase from 'chicory' [139] and a germacrene A synthase from 'feverfew' (GenBank JF819848.1) [137] in S. cerevisiae exhibited a noteworthy disparity in the production of 'germacrene A'. From feverfew, the Germacrene A synthase, was found to be more efficient in germacrene synthesis. So, overexpression of germacrene A synthase from feverfew in 'hairy roots' of chicory would be a prolific tactic to acquire huge scale yield of parthenolide for commercialization

Conclusion and future prospects

A comprehensive analysis of the published literature for C. intybus supported its various ethnomedicinal uses as well as its popularity as a coffee substitute. This versatile plant is a rich source of many nutritive elements and bioactive components [140] . The inulin isolated from the roots of this plant has been proven to possess many health benefits [141] . The traditional uses of this plant as therapeutic agents have been validated by scientific investigation of the bioactive potentials of the isolated phytoconstituents. But there is scope for more research to understand the biological activity against diseases of various unexplored phytochemicals isolated from chicory [140] . In recent years, various research strategies have been implemented for the generation of transgenic chicory with improved phenotypes. Through genetic engineering technique, researchers have successfully attempted to enhance the accumulation of secondary metabolites in in -vitro hairy roots [122] and also to produce stress-resistant varieties [123] . There are ongoing researches on producing chicory with newer bioactive potentials through genetic manipulation of various pathways of phytochemical synthesis. In future, crop improvement through genetic engineering approach will increase the economic benefit potentials of C. intybus.

References

1. Bais HP, Ravishankar GA. Cichorium intybus Lcultivation, processing, utility, value addition, and biotechnology, with an emphasis on current status and future prospects. J Sci Food Agric. 2001;81:467-484.
2. Judzentiene A, Budiene J. Volatile constituents from aerial parts and roots of Cichorium intybus L. (chicory) grown in Lithuania. Chemija. 2008;19:25-28.
3. Peters AM, Amerongen AV. Sesquiterpene lactones in chicory (Cichorium intybus L.): Distribution in chicons and effect of storage. Food Res Int. 1996;29:439-444.
4. Wang Q, Xie B, Wu C, et al. Models analyses for allelopathic effects of chicory at equivalent coupling of nitrogen supply and pH level on F. arundinacea, T. repens and M. sativa. PLoS One. 2012;7:e31670. https://DOI.org/10.1371/journal.pone.0031670.
5. Street RA, Sidana J, Prinsloo G. Cichorium intybus: Traditional uses, phytochemistry, pharmacology, and toxicology. Evid Based Complement Alternat Med. 2013;1:1-13. http://dx.DOI.org/10.1155/2013/579319.
6. Lucchin M, Varotto S, Barcaccia G, Parrini P. Chicory and endive. In: Prohens J, Nuez F, editors. Vegetables I. Handbook of Plant Breeding. New York: Springer; 2008. p. 3-48.
7. Doughari JH, El-Mahmood AM, Tyoyina I. Antimicrobial activity of leaf extracts of Senna obstusifolia. Afr J Pharm Pharmacol. 2008;2:344-346.
8. Nandagopal S, Kumari RBD. Phytochemical and antibacterial studies of chicory (Cichorium intybus L.)-a multipurpose medicinal plant. Adv Biol Res. 2007;1:17-21.
9. Mulabagal V, Wang HB, Ngouajio M, Nair MG. Characterization and quantification of health beneficial anthocyanins in leaf chicory (Cichorium intybus) varieties. Eur Food Res Technol. 2009;230:47-53.
10. Poli F, Sacchetti G, Tosi B, et al. Variation in the content of the main guaianolides and sugars in Cichorium intybus var. "Rosso di Chioggia" selections during cultivation. Food Chem. 2002;76:139-147.
11. Vanzani P, Rossetto M, De Marco V, et al. Efficiency and capacity of antioxidant-rich foods in trapping peroxyl radicals: A full evaluation of radical scavenging activity. Food Res Int. 2011;44:269-275.
12. Dalar A, Konczak I. Cichorium intybus from Eastern Anatolia: Phenolic composition, antioxidant, and enzyme inhibitory activities. Ind Crops Prod. 2014;60:79-85.
13. Tabata M, Sezik E, Honda G, et al. Traditional medicine in Turkey III. Folk medicine in East Anatolia Van and Bitlis provinces. Pharm Biol. 1994;32:3-12.
14. European Medicines Agency. Community herbal monograph on Cichorium intybus L., radix. EMA/HMPC/121816/2010; c2012.
15. Poletti A, Schilcher H, Muller A. In: Heilkraftige Pflanzen. Switzerland: Walter Hadecke Verlag; 1989.
16. Bischoff TA, Kelley CJ, Karchesy Y, et al. Antimalarial activity of lactucin and lactucopicrin: Sesquiterpene lactones isolated from Cichorium intybus L.. J Ethnopharmacol. 2004;95:455-457.
17. Pieroni A. Medicinal plants and food medicines in the folk traditions of the upper Lucca Province, Italy. J Ethnopharmacol. 2000;70:235-273.
18. Ahmed B, Al-Howiriny TA, Siddiqui AB. Antihepatotoxic activity of seeds of Cichorium intybus. J Ethnopharmacol. 2003;87:237-240.
19. Hanlidou E, Karousou R, Kleftoyanni V, Kokkini S. The herbal market of Thessaloniki (N Greece) and its relation to the ethnobotanical tradition. J Ethnopharmacol. 2004;91:281-299.
20. Jaric S, Popovic Z, Macukanovic-Jocic M, et al. An ethnobotanical study on the usage of wild medicinal International Journal of Advanced Biochemistry Research https://www.biochemjournal.com herbs from Kopaonik Mountain (Central Serbia). J Ethnopharmacol. 2007;111:160-175.
21. Pushparaj PN, Low HK, Manikandan J, Tan H, Tan CH. Anti-diabetic effects of Cichorium intybus in streptozotocin-induced diabetic rats. J Ethnopharmacol. 2007;111:430-434.
22. Siddhan P, Kumari R. Phytochemical and antibacterial studies of chicory (Cichorium intybus L.)-a multipurpose medicinal plant. Adv Biol Res. 2007;1:17-21.
23. Altundaga E, Ozturk M. Ethnomedicinal studies on the plant resources of East Anatolia, Turkey. Procedia Soc Behav Sci. 2011;19:756-777.
24. Gumus I. Agrı yoresinde yetisen bazı faydalı bitkilerin yerel adları ve kullanılısları. Turk J Bot. 1994;18:107112.
25. Gencay A. Cizre (Sırnak)'nin etnobotanik ozellikleri. Yuzuncu Yıl Universitesi, Fen Bilimleri Enstitusu, Yuksek Lisans Tezi. Van, Turkey; 2007. p. 1-267.
26. Mukemre M. Konalga, Sırmalı, Dokuzdam (Catak-Van) ve Cevrelerinin etnobotanik ozellikleri. Yuzuncu Yıl Universitesi, Fen Bilimleri Enstitusu, Yuksek Lisans Tezi. Van, Turkey; 2013. p. 1-400.
27. Aisa HA, Xin X, Tang D. Chemical constituents and their pharmacological activities of plants from Cichorium genus. Chin Herb Med. 2020;12:224-236.
28. Kisiel W, Michalska K, Szneler E. Norisoprenoids from aerial parts of Cichorium pumilum. Biochem Syst Ecol. 2004;32:343-346.
29. Hussain H, Hussain J, Saleem M, Miana GA, et al. Cichorin A: A new benzo-isochromene from Cichorium intybus. J Asian Nat Prod Res. 2011;13:566-569.
30. Liang C, Ju W, Pei S, Tang Y, Xiao Y. Pharmacological activities and synthesis of esculetin and its derivatives: A mini-review. Molecules. 2017;22:387. https://DOI.org/10.3390/molecules22030387.
31. Frezza C, Venditti A, Serafini M, Bianco A. Phytochemistry, chemotaxonomy, ethnopharmacology, and nutraceutics of Lamiaceae. In: Rahman A, editor. Studies in Natural Products Chemistry. 1st ed. Elsevier; 2019. p. 125-178.
32. Yordanova ZP, Zhiponova MK, Iakimova ET, et al. Revealing the reviving secret of the white dead nettle (Lamium album L.). Phytochem Rev. 2014;13:375-389. https://DOI.org/10.1007/s11101-014-9356-2.
33. Cai W, Chen Y, Xie L, et al. Characterization and density functional theory study of the antioxidant activity of quercetin and its sugar-containing analogues. Eur Food Res Technol. 2014;238:121-128. https://DOI.org/10.1007/s00217-013-2091-x.
34. Dar RA, Naikoo GA, Hassan IU, Shaikh AMH. Electrochemical behavior of kaempferol and its determination in the presence of quercetin employing multi-walled carbon nanotube modified carbon paste electrode. Anal Chem Res. 2016;7:1-8.
35. Krebsky EO, Geunsb JMC, Proft MD. Polyamines and sterols in Cichorium heads. Phytochemistry. 1999;550:549-553.
36. Long T, Gao Y, Niu YJ, Wang H. Research progress in chemical constituents and pharmacological activities of plants in Cichorium genus. Strait Pharm J. 2014;26:1-6.
37. Bui-Dang-Ha D, Nitsch JP. Isolation of zeatin riboside from chicory root. Planta. 1970;95:119-126.
38. He T, Guo YJ, Gao YN. The study of chemical constituents on the root of Cichorium intybus L.. Chin J Chin Mater Med. 2002;27:209-210.
39. Rahman A, Zareen S, Choudhary MI, Akhtar MN, Khan SN. Alpha-glucosidase inhibitory activity of triterpenoids from Cichorium intybus. J Nat Prod. 2008;71:910-913. DOI:10.1021/np800001v.
40. Liu H, Wang Q, Liu Y, Chen G, Cui J. Antimicrobial and antioxidant activities of Cichorium intybus root extract using orthogonal matrix design. J Food Sci. 2013;78:258-263. DOI:10.1111/1750-3841.12040.
41. Tsai KL, Kao CL, Hung CH, et al. Chicoric acid is a potent anti-atherosclerotic ingredient by antioxidant action and anti-inflammation capacity. Oncotarget. 2017;8:29600-12. DOI:10.18632/oncotarget.16768.
42. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: An overview. Sci World J. 2013;2013:162750. https://DOI.org/10.1155/2013/162750.
43. Mamadalieva NZ, Herrmann F, El-Readi MZ, et al. Flavonoids in Scutellaria immaculata and ramosissima (Lamiaceae) and their biological activity. J Pharm Pharmacol. 2011;63:1346-1357.
44. Panche AN, Diwan AD, Chandra SR. Flavonoids: An overview. J Nutr Sci. 2016;5:e47. DOI:10.1017/jns.2016.41.
45. Mathur N, Katare DP, Vidhu A, Amitesh K, Joshi V, Madaan A, et al. Determination of antioxidant and hepatoprotective ability of flavonoids of Cichorium intybus. Int J Toxicol. 2014;6:107-112.
46. Jancic D, Todorovic V, Šircelj H, et al. Biologically active compounds and antioxidant capacity of Cichorium intybus L. leaves from Montenegro. Ital J Food Sci. 2017;29:2017-27. DOI:10.14674/IJFS-789.
47. Zeb A, Haq A, Murkovic M. Effects of microwave cooking on carotenoids, phenolic compounds and antioxidant activity of Cichorium intybus L. (chicory) leaves. Eur Food Res Technol. 2019;245:365-74. DOI:10.1007/s00217-018-3168-3.
48. Gilani AH, Janbaz KH. Evaluation of the liver protective potential of Cichorium intybus seed extract on acetaminophen and CC14-induced damage. Phytomedicine. 1994;1:193-197.
49. Nallamilli BR, Kumar CSP, Reddy KV, et al. Hepatoprotective activity of Cichorium intybus (Linn.) root extract against carbon tetrachloride-induced hepatotoxicity in albino Wistar rats. Drug Invent Today. 2013;5:311-314.
50. Saggu S, Sakeran MI, Zidan N, Tousson E, Mohan A, Rehman H. Ameliorating effect of chicory (Cichorium intybus L.) fruit extract against 4-tert-octylphenolinduced liver injury and oxidative stress in male rats. Food Chem Toxicol. 2014;72:138-146.
51. Elgengaihi S, Refaie AA, Aboubaker D. Hepatoprotective efficacy of Cichorium intybus extract against carbon tetrachloride-induced liver damage in rats. J Diet Suppl. 2016;13:570-584. DOI:10.3109/19390211.2016.1144230.
52. Ahmed B, Khan S, Masood MH, Siddique AH. Antihepatotoxic activity of cichotyboside, a sesquiterpene glycoside from the seeds of Cichorium intybus. J Asian Nat Prod Res. 2008;10:223-231.
53. Jasim RS. Antioxidant, antimicrobial activities and phytochemical constituents of Cichorium intybus aerial parts. Int J Bot. 2018;14:24-29.
54. Liu H, Wang Q, Liu Y, Chen G, Cui J. Antimicrobial and antioxidant activities of Cichorium intybus root extract using orthogonal matrix design. J Food Sci. 2013;78:258-63. DOI:10.1111/1750-3841.12040.
55. Rehman A, Ullah N, Ullah H, Ahmad I. Antibacterial and antifungal study of Cichorium intybus. Asian Pac J Trop Dis. 2014;4:943-945.
56. Shaikh T, Rub RA, Sasikumar S. Antimicrobial screening of Cichorium intybus seed extracts. Arab J Chem. 2016;9:1569-1573.
57. Kagkli DM, Corich V, Bovo B, Lante A, Giacomini A. Antiradical and antimicrobial properties of fermented red chicory (Cichorium intybus L.) byproducts. Ann Microbiol. 2016;66:1377-1386.
58. Hardeep FM, Pandey DK. Anti-diabetic activity of methanolic extract of chicory roots in streptozocininduced diabetic rats. Int J Pharm. 2013;3:211-216.
59. Chandra K, Khan W, Jetley S, Ahmed S, Jain SK. Antidiabetic, toxicological, and metabolomic profiling of aqueous extract of Cichorium intybus seeds. Phcog Mag. 2018;14:377-383.
60. Abdel-Rahim EA, Rashed MM, ElHawary ZM, Abdelkader MM, Kassem SS, Mohamed RS. Antidiabetic effect of Cichorium intybus leaves and Plantago ovata seeds in high-fat diet-streptozotocininduced diabetic rats. J Food Nutr Res. 2016;4:276-281.
61. Lin ZJ, Zhang B, Li LY, Wang HP, Zhu CS. Experimental study on protective and anti-obesity effects of inulin from chicory (Cichorium intybus L.) on quail model. Integr Med Res. 2015;4:1. DOI:10.1016/j.imr.2015.04.285.
62. Gürbüz I, Ustün O, Yeşilada E, Sezik E, Akyürek N. In vivo gastroprotective effects of five Turkish folk remedies against ethanol-induced lesions. J Ethnopharmacol. 2002;83:241-244.
63. Wu W. Effect of superfine powder of Cichorium intybus L. root on intestinal microflora in immunosuppressive mice. Nat Prod Res Dev. 2016;28:429-432.
64. Devoli L, Morroni F, Lombardi-Boccia G, et al. Red chicory (Cichorium intybus L. cultivar) as a potential source of antioxidant anthocyanins for intestinal health. Oxid Med Cell Longev. 2013;2013:e704310. https://DOI.org/10.1155/2013/704310.
65. Mansour SA, Ibrahi RM, El-Gengaihi SE. Insecticidal activity of chicory (Cichorium intybus L.) extracts against two dipterous insect-disease vectors: Mosquito and housefly. Ind Crops Prod. 2014;54:192-202.
66. Peña-Espinoza M, Boas U, Williams AR, Thamsborg SM, Simonsen HT, Enemark HL. Sesquiterpene lactone-containing extracts from two cultivars of forage chicory (Cichorium intybus) show distinctive chemical profiles and in vitro activity against Ostertagia ostertagi. Int J Parasitol Drugs Drug Resist. 2015;5:191-200.
67. Peña-Espinoza M, Williams AR, Thamsborg SM, Simonsen HT, Enemark HL. Anthelmintic effects of forage chicory (Cichorium intybus) against free-living and parasitic stages of Cooperia oncophora. Vet Parasitol. 2017;243:204-220.
68. Hazra B, Sarkar R, Bhattacharyya S, Roy P. Tumour inhibitory activity of chicory root extract against Ehrlich ascites carcinoma in mice. Fitoterapia. 2002;73:730-733.
69. Conforti F, Ioele G, Statti GA, et al. Antiproliferative activity against human tumor cell lines and toxicity test on Mediterranean dietary plants. Food Chem Toxicol. 2008;46:3325-3332.
70. Lee KT, Kim JI, Park HJ, et al. Differentiationinducing effect of magnolialide, a1끫뷺hydroxyeudesmanolide isolated from Cichorium intybus, on human leukemia cells. Biol Pharm Bull. 2000;23:1005-1007.
71. Chen LG, Chang YQ, Zheng HY, Ma JR, Chang XT. The experimental study of CPS antitumor. Food Sci. 2004;25:276-280.
72. Amirghofran Z, Azadbakht M, Karimi MH. Evaluation of the immunomodulatory effects of five herbal plants. J Ethnopharmacol. 2000;72:167-172.
73. Ni XZ, Zheng HY, Chang YQ. Immunological regulation of chicory polysaccharides. Food Sci. 2005;26:534-536.
74. Ren BG, Chang YQ, Zheng HY, Cao BY, Qi YX. Study on the effect of chicory polysaccharides on humans. Food Sci. 2008;29:579-581.
75. Rizvi W, Fayazuddin M, Shariq S, et al. Antiinflammatory activity of roots of Cichorium intybus due to its inhibitory effect on various cytokines and antioxidant activity. Anc Sci Life. 2014;34:44-9. DOI:10.4103/0257-7941.150780.
76. Mehmood N, Zubair M, Rizwan K, et al. Antioxidant, antimicrobial and phytochemical analysis of Cichorium intybus seed extract and various organic fractions. Iran J Pharm Res. 2012;11:1145-51.
77. Narayana KR, Reddy KS, Chaluvadi MR, Krishna DR. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J Pharmacol. 2001;33:2-16.
78. Dem'yanenko VG, Dranik LI. Coumarins of the racemes of Cichorium intybus. Chem Nat Compd. 1971;7:104.
79. Vardanyan S. Pharmacology in ancient Armenia. Hist Philol J. 1979;2:179-194.
80. Rollinger JM, Mocka P, Zidorn C, Ellmerer EP, Langer T, Stuppner H. Application of the in-combo screening approach for the discovery of nonalkaloid acetylcholinesterase inhibitors from Cichorium intybus. Curr Drug Discov Technol. 2005;2:185-93.
81. Zhang B, Liu XQ, Hu J, Jiao YF, Jia XD, He T, et al. The influence of Cichorium capsule on blood glucose, serum uric acid and blood lipid in alloxan-induced diabetic rabbit models. Tradit Chin Drugs Res Clin Pharmacol. 1998;9:221-223.
82. Hyun MK, Hyw WK, Yeoung SL, et al. Inhibitory effect of mast cell-mediated immediate-type allergic reactions by Cichorium intybus. Pharmacol Res. 1999;40:61-65.
83. Zheng HM, Wang DG, Gao YY, Zhang B. The influence of n-hexane extraction of Cichorium on blood glucose and lipid. Chin J Inf Tradit Chin Med. 2000;7:38-39.
84. Kong Y, Zhang B, Liu XQ, Sa Y, Ye GH. Effect and mechanism study of Cichorium extracts on hyperuricemic model quail. Mod J Integr Tradit Chin West Med. 2003;12:1138-1139.
85. Liu XQ, Zhang B, Hu J, et al. Study on establishing hyperuricemia quail model and effect of Cichorium extracts. Chin J Integr Tradit West Med. 2003;23:4547.
86. Sa Y, Zhang B, Liu XQ, Ye GH. Effect of herba Cichorium extracts in reducing serum uric acid and blood lipid. Tradit Chin Drug Res Clin Pharmacol. 2004;15:227-229.
87. Hozayen WG, El-Desouky MA, Soliman HA, Ahmed RR, Khaliefa AK. Antiosteoporotic effect of Petroselinum crispum, Ocimum basilicum and Cichorium intybus L. in glucocorticoid-induced osteoporosis in rats. BMC Complement Altern Med. 2016;16:165. DOI:10.1186/s12906-016-1140-y.
88. Ungnade HE, Hendley EC. The bitter principle of Helenium tenuifolium. J Am Chem Soc. 1948;70:39214. DOI:10.1021/ja01191a118.
89. Van Beek TA, Maas P, King BM, et al. Bitter sesquiterpene lactones from chicory roots. J Agric Food Chem. 1990;38:1035-1038.
90. Schenck G, Graf H. Die Bitterstoffgeschmacksbestimmung der Bitterstoffe des Milchsaftes von Lactuca virosa. Arch Pharm. 1939;277:257-261.
91. Price KR, Dupont MS, Shepherd R, Chan HW, Fenwick GR. Relationship between the chemical and sensory properties of exotic salad crops: Coloured lettuce (Lactuca sativa) and chicory (Cichorium intybus). J Sci Food Agric. 1990;53:185-192.
92. Peters AM, Haagsma N, Gensch KH, van Amerongen A. Production and characterization of polyclonal antibodies against the bitter sesquiterpene lactones of chicory (Cichorium intybus L.). J Agric Food Chem. 1996;44:3611-3615.
93. Chadwick M, Trewin H, Gawthrop F, Wagstaff C. Sesquiterpenoids lactones: Benefits to plants and people. Int J Mol Sci. 2013;14:12780-805. DOI:10.3390/ijms140612780.
94. Giordano OS, Guerreiro E, Pestchanker MJ, et al. The gastric cytoprotective effect of several sesquiterpene lactones. J Nat Prod. 1990;53:803-809.
95. Tournier H, Schinella G, de Balsa EM, et al. Effect of the chloroform extract of Tanacetum vulgare and one of its active principles, parthenolide, on experimental gastric ulcer in rats. J Pharm Pharmacol. 1999;51:215219.
96. Canales M, Hernández T, Caballero J, et al. Informant consensus factor and antibacterial activity of the medicinal plants used by the people of San Rafael Coxcatlán, Puebla, México. J Ethnopharmacol. 2005;97:429-439.
97. Ivie GW, Witzel DA, Rushing DD. Toxicity and milk bittering properties of tenulin, the major sesquiterpene lactone constituent of Helenium amarum (bitter sneezeweed). J Agric Food Chem. 1975;23:845-849.
98. Kupchan SM, Eakin MA, Thomas AM. Tumor inhibitors. 69. Structure-cytotoxicity relationships among the sesquiterpene lactones. J Med Chem. 1971;14:1147-1152.
99. Wesołowska A, Nikiforuk A, Michalska K, Kisiel W, Chojnacka-Wójcik E. Analgesic and sedative activities of lactucin and some lactucin-like guaianolides in mice. J Ethnopharmacol. 2006;107:254-258.
100. Sweeney CJ, Mehrotra S, Sadaria MR, Kumar S, et al. The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol Cancer Ther. 2005;4:1004-1012.
101. Rees SB, Harborne JB. Role of sesquiterpene lactones and phenolics in the chemical defence of the chicory plant. Phytochemistry. 1985;24:2225-2231.
102. Peters AM, Haagsma N, van Amerongen AV. A pilot study on the effects of cultivation conditions of chicory (Cichorium intybus L.) roots on the levels of sesquiterpene lactones in chicons. Z Lebensm Unters Forsch A. 1997;205:143-147.
103. Mathieu AS, Lutts S, Vandoorne B, et al. High temperatures limit plant growth but hasten flowering in root chicory (Cichorium intybus) independently of vernalisation. J Plant Physiol. 2014;171:109-118.
104. Matveeva NA, Kishchenko EM, Shakhovskii AM, Potrokhov AA, Kuchuk NV. Regeneration of transgenic plants from Cichorium intybus L. var. foliosum Hegi hairy roots. Tsitol Genet. 2011;45:11-16.
105. Matveeva NA, Vasilenko M, Shakhovskii AM. Effective Agrobacterium-mediated transformation of chicory (Cichorium intybus L.) using vector with gene of tuberculosis antigen ESAT6. Tsitol Genet. 2011;45:11-17.
106. Sun LY, Touraud G, Charbonnier C, Tepfer D. Modification of phenotype in Belgian endive (Cichorium intybus) through genetic transformation by Agrobacterium rhizogenes: Conversion from biennial to annual flowering. Transgenic Res. 1991;1:14-22.
107. Vermeulen A, Vaucheret H, Pautot V, Chupeau Y. Agrobacterium-mediated transfer of a mutant Arabidopsis acetolactate synthase gene confers resistance to chlorsulfuron in chicory (Cichorium intybus L.). Plant Cell Rep. 1992;11:243-247.
108. Hanafy MS, Asker MS, El-Shabrawi H, Matter MA. Agrobacterium rhizogenes-mediated genetic transformation in Cichorium spp.: Hairy root production, inulin and total phenolic compounds analysis. J Hortic Sci Biotechnol. 2018;93:1-9. DOI:10.1080/14620316.2017.1420429.
109. Chandra S, Chandra R. Engineering secondary metabolite production in hairy roots. Phytochem Rev. 2011;10:371-95. DOI:10.1007/s11101-011-9210-9218.
110. Bais H, George J, Ravishankar G. Influence of polyamines on growth of hairy root cultures of witloof International Journal of Advanced Biochemistry Research https://www.biochemjournal.com chicory (Cichorium intybus L. cv. Lucknow Local) and formation of coumarins. J Plant Growth Regul. 1999;18:33-37. DOI:10.1007/PL00007043.
111. Bais H, Sudha G, George J, Ravishankar G. Influence of exogenous hormones on growth and secondary metabolite production in hairy root cultures of Cichorium intybus L. cv. Lucknow Local. In vitro Cell Dev Biol. 2000;37:293-9. DOI:10.1007/s11627-0010052-8.
112. Li X, Lai P, Li P, Zhao Y. Transformation of Cichorium intybus with the HvBADH1 gene enhanced the salinity tolerance of the transformants. S Afr J Bot. 2016;102:110-119.
113. Livingston DP, Hincha DK, Heyer AG. Fructan and its relationship to abiotic stress tolerance in plants. Cell Mol Life Sci. 2009;66:2007-23. DOI:10.1007/s00018009-0002-x.
114. Kip P, Meyer D, Jellema RH. Inulins improve sensory and textural properties of low-fat yoghurts. Int Dairy J. 2006;16:1098-103. DOI:10.1016/j.idairyj.2005.10.011.
115. Morris C, Morris GA. The effect of inulin and fructooligosaccharide supplementation on the textural, rheological and sensory properties of bread and their role in weight management: A review. Food Chem. 2012;133:237-48. DOI:10.1016/j.foodchem.2012.01.027.
116. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology. 1995;108:975-82. DOI:10.1016/0016-5085(95)901922.
117. Van Arkel J, Vergauwen R, Sévenier R. Sink filling, inulin metabolizing enzymes and carbohydrate status in field-grown chicory (Cichorium intybus L.). J Plant Physiol. 2012;169:1520-1529.
118. Van den Ende W, Wonterghem D, Van Dewil E, et al. Purification and characterization of 1-SST, the key enzyme initiating fructan biosynthesis in young chicory roots (Cichorium intybus). Physiol Plant. 1996;98:455466. DOI:10.1111/j.1399-3054.1996.tb05699.x.
119. Vijn I, van Dijken A, Sprenger N, et al. Fructan of the inulin neoseries is synthesized in transgenic chicory plants (Cichorium intybus L.) harboring onion (Allium cepa L.) fructan: fructan 6G-fructosyltransferase. Plant J. 1997;11:387-398.
120. Maroufi A, Karimi M, Mansour M, Mehdikhanlou K, Loose M. Inulin chain length modification using a transgenic approach opening new perspectives for chicory. 3 Biotech. 2018;8:349. DOI:10.1007/s13205018-1377-x.
121. Malarz J, Stojakowska A, Kisiel W. Effect of methyl jasmonate and salicylic acid on sesquiterpene lactone accumulation in hairy roots of Cichorium intybus. Acta Physiol Plant. 2007;29:127-132.
122. Liu Q, Majdi M, Cankar K, et al. Reconstitution of the costunolide biosynthetic pathway in yeast and Nicotiana benthamiana. PLoS One. 2011;6:e23255.
123. Ikezawa N, Goepfert JC, Nguyen DT, et al. Lettuce costunolide synthase (CYP71BL2) and its homolog (CYP71BL1) from sunflower catalyze distinct regioand stereo-selective hydroxylations in sesquiterpene lactone metabolism. J Biol Chem. 2011;286:21601-11.
124. Frey U, Claude J, Crelier S, Juillert M. UV degradation of sesquiterpene lactones in chicory extract: Kinetics and identification of reaction products by HPLC-MS. Chimia. 2002;56:292-293.
125. Majdi M, Liu Q, Karimzadeh G, et al. Biosynthesis and localization of parthenolide in glandular trichomes of feverfew (Tanacetum parthenium L. Schulz Bip.). Phytochemistry. 2011;72:1739-1750.
126. Cankar K, Houwelingen A, Bosch D, Sonke T, Bouwmeester H, Beekwilder J. A chicory cytochrome P450 mono-oxygenase CYP71AV8 for the oxidation of (+)-valencene. FEBS Lett. 2011;585:178-182.
127. Bouwmeester HJ, Kodde J, Verstappen FWA, et al. Isolation and characterization of two germacrene A synthase cDNA clones from chicory. Plant Physiol. 2002;129:134-144.
128. Wang Q, Cui J. Perspectives and utilization technologies of chicory (Cichorium intybus L.): A review. Afr J Biotechnol. 2011;10:1966-1977.
129. Kaur N, Gupta AK. Applications of inulin and oligofructose in health and nutrition. J Biosci. 2002;27:703-714.