The Common Cichory (Cichorium intybus L.) as a Source of Extracts with Health-Promoting Properties—A Review

Natural products are gaining more interest recently, much of which focuses on those derived from medicinal plants. The common chicory (Cichorium intybus L.), of the Astraceae family, is a prime example of this trend. It has been proven to be a feasible source of biologically relevant elements (K, Fe, Ca), vitamins (A, B1, B2, C) as well as bioactive compounds (inulin, sesquiterpene lactones, coumarin derivatives, cichoric acid, phenolic acids), which exert potent pro-health effects on the human organism. It displays choleretic and digestion-promoting, as well as appetite-increasing, anti-inflammatory and antibacterial action, all owing to its varied phytochemical composition. Hence, chicory is used most often to treat gastrointestinal disorders. Chicory was among the plants with potential against SARS-CoV-2, too. To this and other ends, roots, herb, flowers and leaves are used. Apart from its phytochemical applications, chicory is also used in gastronomy as a coffee substitute, food or drink additive. The aim of this paper is to present, in the light of the recent literature, the chemical composition and properties of chicory.


Introduction
The name of the common chicory plant (Cichorium intybus L.) most probably derives from several Greek and Latin words. Cichorium is Latin for "field", while intybus finds a counterpart in both languages. The Greek counterpart means "to cut", and pertains to the morphology of the leaves. In turn, the Latin tubus-meaning "(a) tube"-describes the structure of the stem [1]. The name of the genus is representative of its habitat, while the species name describes the plant itself [1]. The name Cichorium was in fact created by latinization of the Greek kichorion, oftentimes encountered in works by ancient medics. It is an archeophyte of Mediterraneo-irano-turan origin. The plant boasts a long history of almost universal application, though its medical use is particularly interesting, as it dates back to prehistorical times. In ancient Rome, Greece and Egypt it was used for boosting metabolism and digestion. The plant was used as a vegetable as well as a pasture plant [1,2]. Many accounts exist of its medical properties, i.a. from Theophrastus of Eresos, Pedanios Dioscorides, Pliny the Elder or Avicenna, who used chicory preparations for treatment of digestive or visual disorders. Avicenna also applied chicory root decoctions for alleviation of gout pain. (Cichorium intybus) has been extensively used for a long period in the Unani system of medicine, too [3]. Apart from the abovementioned, medieval Europeans would use chicory to treat jaundice, or even malaria [4][5][6]. Cultivated chicory can be sorted into groups, according to their use: (1) "Industrial" or "root" chicory, grown mostly in northwestern Europe, India, South Africa and Chile; it is mostly used for extraction of inulin or production of a coffee substitute from the plant's taproot; (2) "Brussels" or "witloof" chicory, the most common industrial European variety; its buds are bleached by storing

Chemical Composition
All morphological parts of chicory (roots, herb, flowers and leaves) contain a large number of various chemical compounds. Cichoric acid was found to be the main component of the methanolic extract from C. intybus L. Aliphatic compounds and their derivatives are the main fraction, with terpenoids slightly less abundant in the plant. Roots of chicory contain, amongst others, sap, sesquiterpene lactones, such as e.g., germacranolides (lactucin, lactucopicrin and 8-deoxylactucin) as well as guajanolides (cycriozides B and C, sonchuzide C), which gives a bitter taste. Also, taraxane-type triterpenes can be found here, such as taraxasterol, phenolic acids (e.g., chlorogenic, isochlorogenic, neochlorogenic, caffeic and cichoric acids) The root contains 0.01-0.02% of the bitter intybin glycoside (whereby the herb contains between 0.1-2.0% of this chemical), 9-15% reducing sugars, and between 40-60% of inulin (as the plant energy store); however, no starch is present in chicory roots. Also worth mentioning are: intybinene, a common component of the coffee substitutes, pectins, vitamins B and C [2,11]. Chicory leaves contain inulin, A, B 1 , B 2 and C vitamins, Ca, K, Mg, Na, Fe, Cu, Mn, Zn, phenolic compounds, amongst others [11].

Health-Promoting Properties
Fresh and dried material is the most commonly used for medicinal purposes [1,30]. It is one most important therapeutic plant which belongs to family Asteraceae [15]. Various C. intybus extracts have demonstrated a wide range of biological and pharmacological properties viz., anti-hyperuricemia, antiinflammatory, and antidiabetic, antinematodal, antioxidant and antiproliferative, hepatoprotective antibacterial antiprotozoal effects [1,8,10,[31][32][33][34]. The plant also shows laxative, detoxifying, invigorating, blood-cleansing and anti-oxidative properties. Also observed is the diuretic effect, attributed to phenolic acids. In the Unani and Ayurvedic medicine systems the seeds of Cichorium intybus have been used efficaciously [15]. High levels of inulin facilitate the development and maintenance of proper gut microbiota, thus giving the plant a "probiotic" label [2,35,36].

Antiviral Properties
The extracts of Cichorium intybus L. showed great anti viral activity against HSV-1 and partial activity against adenovirus at higher concentrations [37]. In the study Zhang et al., the anti-hepatitis B property of cichoric acid was evaluated by the D-galactosamine (D-GalN)-induced normal human HL-7702 hepatocyte injury model, the duck hepatitis B virus (DHBV)-infected duck fetal hepatocytes and the HBV-transfected cell line HepG2.2.15 cells, respectively. This study verifies the anti-hepatitis B effect of cichoric acid from C. intybus leaves, therefore cichoric acid could be used to design the antiviral agents [38].
Since the outbreak of the coronavirus disease (COVID-19) caused by SARS-CoV-2 in December 2019, there has been no vaccine or specific antiviral medication for treatment of the infection where supportive care and prevention of complications is the current management strategy. Shawky et al. [39] using a molecular docking method investigated the potential of using medicinal plants in alleviating the novel SARS-CoV-2 infection. A database comprising more than 16,000 compounds was compiled and docked against the crucial viral proteins; 3-chymotypsin protease (3CLpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp) to find potential inhibitors for these enzymes.
Furthermore, network pharmacology analysis of all the compounds in the database was attempted to speculate those that can target the inflammatory and immunity-related pathways at the molecular level and revealing those plants with potential multi-components and multi-targets that may help regulate the body functions and possibly will play a therapeutic role in the mitigation of the disease. C. intybus was found, along with Glycyrrhiza glabra and Hibiscus sabdariffa among plants with high antiviral potential. Chicory is a rich source of caffeic acid with antiviral properties. The authors suggest that further in vitro and in vivo analyses are needed to confirm the findings. Nevertheless, chicory was among the plants with potential against SARS-CoV-2 [39][40][41]

Antibacterial and Antifungal Properties
Chicory plant was active against gram positive and negative bacteria and yeast. C. intybus extracts inhibits Agrobacterium radiobacter sp. tumefaciens, Erwinia carotovora, Pseudomonas fluorescens, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Bacillus thuringiensis, Bacillus subtilis, Salmonella typhi, Micrococcus luteus, Candida albicans, Klebsiella pneumoniae, Enterobacter cloacae and Streptococcus pyogenes [14][15][16]21,[42][43][44]. Rahimullah et al. examined ethanol, chloroform, aqueous and hexane extracts from C. intybus seeds againts Escherichia coli and Staphylococcus aureus. All extracts showed activity against both organisms but aqueous extracts were more active and show a larger inhibition zone against S. aureus. Hexane, ethanol and chloroform extracts show significant zones of inhibition against both organisms. The authors of this study suggested that the medicinal plant has significant antibacterial activity and can utilize for the treatment and control of bacterial infections [15]. Methanolic and aqueous extracts of aerial parts of chicory were also investigated against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Erwinia carotovora, Proteus vulgaris, Enterobacter cloacae, Streptococcus pyogenes, and Candida albicans. The methanol extract exhibited broader antimicrobial spectrum than the aqueous extract compared with the standard antibiotics gentamicin and tobramycin. The water extract showed stronger activity against Staphylococcus epidermidis, Streptococcus pyogenes and Staphylococcus aureus, even more than that of the standard antibiotics [16]. Antibacterial activity of the water, ethanol and ethyl acetate extracts of C. intybus was investigated by Petrovic et al. All the tested extracts showed antibacterial activity, the ethyl acetate extract being the most active. A water extract inhibits Agrobacterium radiobacter sp. tumefaciens, Erwinia carotovora, Pseudomonas fluorescens and P. aeruginosa [14]. On the other hand, Shaikh et al. studied the antimicrobial properties of seed extracts using ethanol and ethyl acetate againts S. aureus, P. aeruginosa, E. coli and C. albicans. All the extracts showed significant antimicrobial activity against the tested microorganism, but S. aureus was found to be most sensitive and had the widest zone of inhibition. Aqueous extract showed maximum activity against S. aureus while did not show any significant activity against C. albicans. Ethyl acetate extract activity against P. aeruginosa and S. aureus was found to be significant [44].

Anti-Protozoal and Antiparasitic Properties
C. intybus is a plant with great potential against parasites, both in the context of livestock and humans [5]. This plant synthesizes several bioactive compounds with potential antiparasitic activity, but most studies have been devoted to the role of sesquiterpene lactones (SL). Woolsey et al. demonstrated the efficacy of chicory leaf and root extracts against Cryptosporidium parvum, with the lower SL extract (leaf) showing greater inhibition. Based on the results, the authors suggest that the antiparasitic activity does not appear to be related only to the SL content [45]. Marley et al. conducted a study on lambs that acquired parasites by natural transmission. The effects of chicory on total helminth parasites showed that this forage reduced the number of adult abomasal helminth parasites in lambs [46].

Hepatoprotective Properties
The hepatoprotective properties of extracts from various morphological parts of C. intybus have been confirmed in recent years by many authors [47][48][49][50][51]. One study, which used mice with liver previously damaged with acetaminophen and carbon tetrachloride, demonstrated, that application of a aqueous-and methanolic chicory seed extract to the animals lowered their mortality, as well as serum levels of alkaline phosphatase (AP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Analogous results were obtained for alcoholic extracts of seeds and aqueous extracts of root and root callusbiochemical parameters, as e.g., elevated bilirubin levels, of treated animal health improved, and histological procedures confirmed significant alleviation of liver damage [1]. A number of liver damage markers, including low levels of superoxide dismutase, glutathione peroxidase, catalase and high levels of liver enzymes, were alleviated with a chicory-containing diet. Asadi et al. induced oxidative stress in rat liver with methotrexate [52]. This resulted in dramatic reduction in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) and a significant increase in the levels of total bilirubin (TB) and malondialdehyde (MDA). The groups pretreated with C. intybus extratcs showed a significant increase in the levels of AST, ALT, ALP, GSH, CAT, SOD, and GPx and a significant decrease in the levels of TB and MDA. The extract of C. intybus seeds showed similar protective properties in a study, whereby rats were exposed to 4-tert-octophenol. In contrast, Ghaffari et al. studied the effects of turmeric and chicory seed supplementation (in a 1:3 ratio) on obesity markers and lipid profile in non-alcoholic fatty liver disease (NAFLD) in 92 patients. Turmeric supplementation alone and plus chicory seed led to significant reductions in serum levels of TG/HDL-C and LDL-C/HDL-C. In conclusion, turmeric and chicory seed supplementation can be significantly useful in management of NAFLD risk factors [53]. Most studies indicated that the positive effect of the extracts was related to their antioxidant activity [31,51,52].

Antidiabetes Properties
A study utilizing rats with streptozotocin-induced diabetes, found reduced serum levels of glucose, cholesterol and triglycerides upon application of whole-plant ethanolic extract at a dose of 125 mg/kg body mass. It was also determined that the chicory extract brought about a decrease in glucose-6-phosphatase levels, as compared with the control group. Similar hypoglycemic effects were observed using the aqueous seed extract, applied during either early or late phase of diabetes; it was observed that the extract prevents loss of body mass in the treated animals [1]. Pushparaj et al. investigated the effects of alcoholic extracts of whole chicory plants on rats with streptozotocin-induced diabetes (STZ, 50 mg/kg). Feeding chicory extract (125 mg/kg body weight) once daily for 14 days reduced serum glucose by 20%, triglycerides by 91%, and total cholesterol by 16%. The absence of changes in serum insulin levels ruled out the possibility that chicory induces insulin secretion by pancreatic β-cells. In addition, hepatic glucose-6phosphatase (Glc-6-Pase) activity was significantly reduced. Decreased hepatic Glc-6-Pase activity may reduce hepatic glucose production, which in turn results in lower blood glucose levels in rats taking chicory extracts [31]. The aim of the study of Sharma et al. was to investigate the effects of C. intybus on lipid peroxidation activities of both enzymatic and non-enzymatic antioxidants, inflammatory mediators, myocardial enzymes and the histopathology of cardiac tissues in experimental diabetic cardiomyopathy (DCM). DCM was induced by single intraperitoneal injection of streptozotocin (40 mg/kg) combined with high energy intake in rats. Seed extract of C. intybus (250 and 500 mg/kg) was administered orally once a day for 3 weeks. Seed extract of C. intybus confirmed a significant potency towards restoring the blood glucose, an elevation of the levels of aspartate aminotransferase, lactate dehydrogenase, superoxide dismutase, thiobarbituric acid reactive substances, blood glutathione, TNF-α and IL-6 and a reduction in the levels of catalase was observed following the streptozotocin treatment. The extensive necrotic changes of cardiac tissue by streptozotocin was minimized to normal morphology upon C. intybus extract administration. The study demonstrates the cardioprotective effect of C. intybus extract via inhibition of oxidative stress and pro-inflammatory cytokines [54]. The caffeic and chlorogenic acids, found throughout the chicory plant, have been described as able antidiabetics, due to their effect on glucose reuptake in muscles. Both compounds are also potent inductors of insulin secretion. Another formerly mentioned compound of analogous properties is the cichoric acid, which also displays insulin-sensitizing and dose-dependent glucose tolerance-induction properties. Other data suggests that the whole-plant methanolic extract positively influences glucose transport, while not inducing adipogenesis at the same time [55]. Chadra et al. in a rat study showed that administration of an aqueous chicory seed extract significantly reduced serum glucose and triglyceride levels [56]. A later study by this author on 150 type 2 diabetes mellitus patients confirmed that ingestion of C. intybus water seed has significantly decreased inflammation, oxidative stress, and hypertriglyceridemia [33].

Effect on the Immune System
C. intybus is a medicinal plant commonly used in traditional medicine for its benefits in immune-madiated disorders. There are several evidences showing that C. intybus can modulate immune responses. Karimi et al. [57] studied the effect of ethanolic extract of chicory root on the immune system by targeting mouse dendritic cells. C. intybus at higher concentrations inhibited proliferation of allogenic T cells and in lower concentrations changed the level of cytokines such that IL-4 decreased and IFN-γ increased.

Analgesic Properties
The analgesic properties of three particular active substances of chicory-lactucin, lactucopicrin and 11β,13-dihydrolactucin-were proven in mice subjected to the hot plate (proving lactucopicrin the most potent) and the tail-flick test. It is noteworthy that a 30 mg/kg dose of any of these compounds used in the tail-flick test produced an effect comparable to that of a 60 mg/kg dose of ibuprofen. Furthermore, lactucin and lactucopicrin provided some extent of tranquilization as observed by reduction in spontaneous motor activity of the animals [1].

Anti-Cancer Properties
In recent years, cytotoxicity studies of C. intybus extracts have shown its antitumor potential [58,59]. The studies also identified metabolite constituents including guaianolides, 6-methoxyflavone, eudesmanolides, germacranolides, polyacetylene, sterol, anthocyanin, delphinidin, 3,4-dihydroxyphenethyl and other novel compounds. Many of these phytometabolites have shown positive cytotoxic activities in vitro, and antitumor action in vivo and in clinical trials, demonstrating the potential of C. intybus metabolites as antitumor drugs. Structural activity relationship studies have further confirmed these bioactivities [58]. C. intybus extracts have a cytotoxic effect among others on breast cancer (MCF-7), amelanotic melanoma (C32), prostate cancer (LNCaP), renal adenocarcinoma (ACHN), leukemia cells [59]. A study using Ehrlich ascites carcinoma mice proved a significant reduction in tumor progression upon application of raw ethanolic extract of the root. As high as 70% increase in average lifespan was observed upon intraperitoneal administration of 700 mg/kg body mass per day In turn, the aqueous-ethanolic macerate of the leaves suppressed proliferation of the C32 amelanotic melanoma cells [1].

Hypotensive Effect
According to Sedighi et al. ethanol leaves extract of C. intybus plays a protective role against hypertension. In this study, 32 male Wistar rats were divided into four groups of eight each. Animals in the control group were administered with normal saline and in the C. intybus groups with extract at 25, 50, and 100 mg/kg for two weeks. Median (MAP), systolic (SAP) and diastolic arterial pressure (DAP) significantly decreased in the 50 mg/kg extract-treated group compared to the control and 200 mg/kg extract treated groups [60].

Anti-Inflammatory Properties
Chicory is used externally in compresses useful for treatment of skin disorders, incl. dermatitis, inflammatory diseases of mucous membranes, ulcers, wounds and trauma. Flower infusion is excellent for treatment of inflammation-irritated skin and eyes, thanks to its antiseptic, anti-inflammatory, moisturizing and nutritious properties [61]. It also aids treatment of eczema and poorly healing wounds, improves periocular circulation, alleviates periorbital puffiness and symptoms of eye tiredness; it's also excellent for dry skin care [61]. The medicinal materials of C. intybus are usually prepared as mixes with other herbs. Rizvi et al. evaluated the anti-inflammatory effects of root extracts by study rats. Chicory roots demonstrated significant dose-dependent decrease in paw edema in carrageenan-induced paw edema method. Chicory roots diminished the serum TNF-α, IL-6, and IL-1 levels. They also significantly attenuated the malonylaldehyde levels and increased the activities of CAT and GPx in paw tissue [62]. A placebo-controlled, double-blind, dose-escalating trial, was conducted to determine the safety and tolerability of a proprietary bioactive extract of chicory root in patients with osteoarthritis (OA). The results of the pilot study suggested that a proprietary bioactive extract of chicory root has a potential role in the management of OA. Only one patient treated with the highest dose of chicory discontinued treatment due to an adverse effects [63].

Anti-Neurotoxic Properties
Cichorium intybus contains glycosides and triterpenoids, which inhibit glutamatergic transmission and enhance GABAergic transmission. The present study was aimed at studying the effect of chicory extract on the pyridoxine-induced peripheral neuropathy with a particular focus on glutamatergic and GABAergic systems. In experimental study, a high dose of pyridoxine (800 mg/kg, i.p.) was injected for 14 days to induce neuropathy in male rats. Results showed beneficial effects of chicory extract on pyridoxine-induced peripheral neuropathy. Modulating of the GABAergic system mediated by TNF-α may be involved in the of chicory extract [64].The most important actions of chicory extracts are presented in the Table 3.

Culinary Applications of the Common Cichory
Roots, leaves and flowers are the most popular chicory parts for culinary and industrial applications [2,11,79,80]. The usage of chicory root as coffee substitute dates back to the XVIth century and continued through XVIIIth century, the discovery being attributed to the royal gardener Timme of Thuringen. Inulin, a polysaccharide present in roots, is converted during roasting into fructose and caramel, hence contributing to the dried roots' dark hue and a pleasant taste with a bitter tinge, hence making it handy as a beer coloring. It is also useful for the preparation of syrup or sugar, subsequently used in the confectionery or alcohol production [7,11]. However, young roots can be boiled as is the case with similar root vegetables and served with sour cream or herbal sauce. Alternatively, they may be butter-fried, or cut into cubes and served to enhance the flavoring of various soups. Mature roots, after removal of the bitter core part, serve as a valuable addition to soups and meat dishes. Young leaves of the wild chicory variety may be prepared for salads, alone or with other leafy plants. Alternatively, they may be fried like spinach, and served with meat. Beforehand, they are often subject to bleaching to eliminate the bitterness, which is accomplished by burying the plant in soil at the beginning of spring, or by storing it in a dark cellar. Another, more facile, method to achieve this is to soak the leaves in boiling hot water before serving. Young leaves can also be ground, mixed with salt and stored for several months, for use in soups and sauces. They can also be boiled and served with tomato sauce, or added as spice to ham or cheese casseroles [2]. Chicory roots are also used to prepare drinks. The most popular are coffee surrogate. An interesting example is koumiss-a drink prepared traditionally by nomadic populations of Central Asia through fermenting mare milk. Nowadays, scientists used chicory root in order to reinvent this drink in a functional product with a positive impact on a cardiovascular and digestive level [81]. Another very interesting example is a functional drink obtained mainly from burdock root with added ginger juice and 10% chicory root. Such a functional drink has a unique organoleptic profile and diabetic patients can consume it as an aid to their therapy [82]. Thanks to their vivid color, fresh flowers are a perfect addition to salads, fish or as decoration for meat dishes [80]. Anthodia can be preserved in vinegar, and the buds can be marinated and served quite as the capparis are. Several other varieties of the chicory are cultivated. Apart from the Cichorium intybus L., there is also the so-called "salad chicory" (Cichorium endivia), or "root chicory" (Cichorium intybus var. radicorum and Cichorium intybus var. sativum). The last two are a common material for coffee substitutes, while leaves of the Cichorium intybus var. foliosum are fit for salads. Chicory is most commonly served in salads, since its bitterness is well complemented by other popular salad components, e.g., nuts, varieties of blue cheese, apples or balsamic vinegar. It is also excellent served hot, e.g., under Béchamel sauce, although the British are known to prepare a soup of it. Insurmountable are the ever-coming propositions for chicory-containing meals, such as: chicory root salad with vinaigrette sauce, asparagus style-served roots, marinated buds, crepe cake, spinach-chicory or tomato-chicory mixes, chicory rolls with ham and parmesan cheese, braised chicory with blackberries, young leaf salad with vinaigrette sauce, salad of chicory root, pickled flower buds.

Allergies to the Common Cichory
A rare allergy to the chicory plant has been documented in~20 cases over the last 100 years. Most of these cases occurred in adults who were in contact with chicory due to their occupation, and only a single case involved a child reacting to inulin. Depending on the individual, allergic symptoms can be systemic and/or local, ranging from rhinoconjunctivitis, to asthma and anaphylactic reactions, to contact dermatitis. As individual as the allergic reactions are, the chicory preparations and routes of exposure are also unique and varied. There are only two reported cases where fresh chicory roots induced an allergic reaction topically. The majority of reactions occurred in response to leaves (raw and cooked) after skin contact or inhalation. Sometimes, reactions were also caused by the inhalation of dried chicory roots and inulin, consumption of inulin-containing products, and once by intravenous inulin administration during a standard renal function test. It is not yet clear exactly how allergic reactions to chicory are triggered. Proteins from chicory or newly formed inulin-protein compounds (arising during production), as well as sesquiterpene lactones could be potential allergens. Sensitization might arise from repeated exposures or from cross-sensitization with birch pollen or lettuce. Due to all this ambiguity, the general advice is that people with allergies or occupational exposure to Asteraceae family members, people with birch-pollen allergies, and people with atopic dermatitis should be cautious when coming into contact or consuming chicory-and inulin-containing foods [2,83].

Conclusions
In conclusion, Cichorium intybus L. is a common plant with great potential. It certainly does deserve a wider use in medical prophylaxis and phytotherapy. Individual parts, e.g., leaves or flowers, both in fresh and dried form, can be a valuable addition to daily diet. The multipurpose effects of C. intybus extracts may be a promising alternative source for the pharmaceutical industry. It is interesting to note that chicory was among the plants with potential against SARS-CoV-2. However, further studies, including in vitro and in vivo studies, are needed to confirm this antiviral property of chicory.